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Choudhury, Abrar, Martha Cady, Calixto Lucas, Brisa Palikuqi, Ophir Klein, Shawn Hervey-Jumper, Joanna Phillips, et al. "STEM-27. A PERIVASCULAR STEM CELL UNDERLIES VERTEBRATE MENINGEAL TUMORIGENESIS." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi26—vi27. http://dx.doi.org/10.1093/neuonc/noab196.101.
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Abstract BACKGROUND Meningiomas are the most common primary intracranial tumors in humans and dogs, but biologic drivers and cell types underlying meningeal tumorigenesis are incompletely understood. Here we integrate meningioma single-cell RNA sequencing with stem cell approaches to define a perivascular stem cell underlying vertebrate meningeal tumorigenesis. METHODS Single-cell RNA sequencing was performed on 57,114 cells from 8 human meningiomas, 54,607 cells from 3 dog meningiomas, and human meningioma xenografts in mice. Results were validated using immunofluorescence (IF), immunohistochemistry (IHC), and deconvolution of bulk RNA sequencing of 200 human meningiomas. Mechanistic and functional studies were performed using clonogenic and limiting dilution assays, xenografts, and genetically engineered mouse models. RESULTS Copy number variant identification from human meningioma single cells distinguished tumor cells with loss of chr22q from non-tumor cells with intact chr22q. A single cluster distinguished by expression of Notch3 and other cancer stem cell genes had an intermediate level of loss of chr22q, suggesting this cluster may represent meningioma stem cells. In support of this hypothesis, pseudotime trajectory analysis demonstrated transcriptomic progression starting from Notch3+ cells and encompassing all other meningioma cell types. Notch3+ meningioma cells had transcriptomic concordance to mural pericytes, and IF/IHC of prenatal and adult human meninges, as well as lineage tracing using a Notch3-CreERT2 allele in mice, confirmed Notch3+ cells were restricted to the perivascular stem cell niche in mammalian meningeal development and homeostasis. Integrating human and dog meningioma single cells revealed Notch3+ cells in tumor and non-tumor clusters in dog meningiomas. Notch3 IF/IHC and cell-type deconvolution of bulk RNA sequencing showed Notch3+ cells were enriched in high-grade human meningiomas. Notch3 overexpression in human meningioma cells increased clonogenic growth in vitro, and increased tumorigenesis and tumor growth in vivo, decreasing overall survival. CONCLUSIONS Notch3+ stem cells in the perivascular niche underlie vertebrate meningeal tumorigenesis.
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Cady, Martha, Abrar Choudhury, Calixto-Hope Lucas, Joanna J. Phillips, Brisa Palikuqi, Nancy Ann Oberheim Bush, Ophir Klein, et al. "CSIG-36. NOTCH3 DRIVES MENINGIOMA TUMORIGENESIS AND RESISTANCE TO RADIOTHERAPY." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii47. http://dx.doi.org/10.1093/neuonc/noac209.185.
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Abstract There are no approved targeted therapies for meningiomas and the cell types underlying meningeal tumorigenesis are incompletely understood. To address these limitations, we performed single-cell RNA sequencing of 57,114 cells from 8 human meningiomas and 54,607 cells from 3 canine meningiomas. Pseudotime, gene ontology, and copy number variant analyses revealed a population of pericyte-like meningioma cells that were conserved across human and canine tumors and were enriched in expression of Notch3 and other cancer stem cell genes. Deconvolution of cell types from bulk RNA sequencing and DNA methylation profiling of 200 human meningiomas integrated with immunohistochemistry (IHC), immunofluorescence (IF), and RNAScope demonstrated Notch3+ pericytes and Notch3 expression were enriched in high grade or Immune-enriched meningiomas, which were distinguished from other meningioma DNA methylation groups by genes driving vasculature development. IHC and IF of human meninges integrated with lineage tracing approaches using Notch3-CreERT2 ROSAmT/mG alleles in mice demonstrated Notch3 expression was restricted to the perivascular stem cell niche during meningeal development and homeostasis. Mice harboring Notch3-CreERT2 Nf2fl/fl alleles developed meningeal hyperproliferation. Overexpression of constitutively activated Notch3 (Notch3AICD) in Immune-enriched human meningioma cells increased the expression of cancer stem cell genes, driving clonogenic growth in vitro, limiting dilution tumor-initiating capacity in vivo, and resistance to radiotherapy in vivo. A selective Notch3 neutralizing antibody (αNRR3) blocked meningioma cell proliferation and expression of Notch3 target genes, inhibiting meningioma xenograft growth and prolonging overall survival. Single-cell RNA sequencing of 187,366 cells from meningioma xenografts after αNRR3 or radiotherapy treatment ± Notch3AICD overexpression revealed distinct meningioma cell-intrinsic or cell-extrinsic mechanisms driving responses to radiotherapy or αNRR3, respectively. Combined treatment with αNRR3 and radiotherapy additively blocked meningioma xenograft growth and extended survival benefit. In sum, these data shed light on a novel cell type, molecular mechanism, and therapeutic vulnerability in the most common primary intracranial tumor.
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Ochiai, Naoya, Chihiro Shimazaki, Akira Okano, Mayumi Hatsuse, Ryouichi Takahashi, Hideyo Hirai, Eishi Ashihara, Tohru Inaba, Naohisa Fujita, and Masao Nakagawa. "Meningeal Relapse after Double Peripheral Blood Stem Cell Transplantation in IgD Myeloma." Leukemia & Lymphoma 43, no. 3 (January 2002): 641–43. http://dx.doi.org/10.1080/10428190290012191.
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Sakai, Miwa, Kazuteru Ohashi, Takeshi Kobayashi, Takuya Yamashita, Hideki Akiyama, Tetuo Nemoto, Shuji Kishida, Noriko Kamata, and Hisashi Sakamaki. "Meningeal hematopoiesis following radiation myelitis in a hematopoietic stem-cell transplant recipient." American Journal of Hematology 79, no. 4 (2005): 291–93. http://dx.doi.org/10.1002/ajh.20341.
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Rua, Rejane, Kory Johnson, and Dorian B. McGavern. "Discovery of two meningeal macrophage populations with differential roles during homeostasis and inflammation." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 68.6. http://dx.doi.org/10.4049/jimmunol.198.supp.68.6.
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Abstract The meningeal and perivascular spaces of the central nervous system (CNS) are inhabited by specialized macrophages. Under steady state conditions, we discovered two populations: immature macrophages (MHC-II−) and mature macrophages (MHC-II+). Microarray analyses revealed that IL-10 and TGFb were upstream regulators of the immature macrophage transcriptome, which included stem cell-specific genes. These data suggest that immature macrophages represent local progenitors maintained by anti-inflammatory cytokines within the meninges. Interestingly, in naïve mice MHC-II+ macrophages were enriched upon aging and upregulated inflammatory genes, suggesting age-based maturation. To better understand the dynamics of these macrophages, we triggered CNS inflammation by inoculating mice with lymphocytic choriomeningitis virus (LCMV). Both myeloid populations were infected by the virus, and intravital imaging studies revealed that they were targeted by infiltrating virus-specific CD8+ T cells, which promoted their depletion. Following viral clearance, myeloid repopulation of the meninges was derived largely from infiltrating monocytes that engrafted this CNS niche and adopted a transcriptomic signature of mature resident meningeal macrophages. In stark contrast, sterile depletion of meningeal macrophages without infection induced massive local proliferation of immature macrophages that transformed into mature macrophages and repopulated the meninges. This occurred in the absence of peripheral monocyte engraftment. Collectively, these data indicate that the CNS meninges are inhabited by two macrophage populations with a differential ability to repopulate the niche based on the inflammatory milieu.
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Pechey, Victoria, John Parratt, Linh Vo, and William Stevenson. "Successful treatment of meningeal graft-versus-host disease in a haematopoietic stem cell transplant recipient." International Journal of Hematology 101, no. 2 (November 22, 2014): 203–6. http://dx.doi.org/10.1007/s12185-014-1704-x.
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Koeniger, Tobias, Luisa Bell, Anika Mifka, Michael Enders, Valentin Hautmann, Subba Rao Mekala, Philipp Kirchner, et al. "Bone marrow-derived myeloid progenitors in the leptomeninges of adult mice." Stem Cells 39, no. 2 (December 11, 2020): 227–39. http://dx.doi.org/10.1002/stem.3311.
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Abstract Although the bone marrow contains most hematopoietic activity during adulthood, hematopoietic stem and progenitor cells can be recovered from various extramedullary sites. Cells with hematopoietic progenitor properties have even been reported in the adult brain under steady-state conditions, but their nature and localization remain insufficiently defined. Here, we describe a heterogeneous population of myeloid progenitors in the leptomeninges of adult C57BL/6 mice. This cell pool included common myeloid, granulocyte/macrophage, and megakaryocyte/erythrocyte progenitors. Accordingly, it gave rise to all major myelo-erythroid lineages in clonogenic culture assays. Brain-associated progenitors persisted after tissue perfusion and were partially inaccessible to intravenous antibodies, suggesting their localization behind continuous blood vessel endothelium such as the blood-arachnoid barrier. Flt3Cre lineage tracing and bone marrow transplantation showed that the precursors were derived from adult hematopoietic stem cells and were most likely continuously replaced via cell trafficking. Importantly, their occurrence was tied to the immunologic state of the central nervous system (CNS) and was diminished in the context of neuroinflammation and ischemic stroke. Our findings confirm the presence of myeloid progenitors at the meningeal border of the brain and lay the foundation to unravel their possible functions in CNS surveillance and local immune cell production.
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Sternberg, Hal, Jianjie Jiang, Pamela Sim, Jennifer Kidd, Jeffrey Janus, Ariel Rinon, Ron Edgar, et al. "Human embryonic stem cell-derived neural crest cells capable of expressing markers of osteochondral or meningeal–choroid plexus differentiation." Regenerative Medicine 9, no. 1 (January 2014): 53–66. http://dx.doi.org/10.2217/rme.13.86.
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Petersen, S�ren L., Aase Wagner, and Peter Gimsing. "Cerebral and meningeal multiple myeloma after autologous stem cell transplantation. A case report and review of the literature." American Journal of Hematology 62, no. 4 (December 1999): 228–33. http://dx.doi.org/10.1002/(sici)1096-8652(199912)62:4<228::aid-ajh5>3.0.co;2-3.
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Damaj, Gandhi, Sarah Ivanoff, Diane Coso, Loic Ysebaert, Sylvain Choquet, Caroline Houillier, Wajed Abarah, et al. "Concomitant Systemic and Neuro-Meningeal Non-Hodgkin’s Lymphoma: The Role of Consolidation with Intensive Chemotherapy and Autologous Stem Cell Transplantation. a Retrospective Study of 65 Cases." Blood 124, no. 21 (December 6, 2014): 3102. http://dx.doi.org/10.1182/blood.v124.21.3102.3102.
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Abstract Purpose To determine the characteristics of Non-Hodgkin’s lymphoma (NHL) patients with concomitant systemic and central nervous system localization at diagnosis, as well as the impact of consolidation with high dose chemotherapy followed by hematopoietic stem cell rescue on outcome Patients and Methods Newly diagnosed NHL patients with concomitant systemic and cerebral or meningeal involvement at diagnosis have been included in this study. Patients were retrieved from the database of the participating centers of the LYSA and LOC study groups Results Sixty-five patients (37 males; 28 females) were included. Median age was 60 years (23-85). Histological subtype was mainly diffuse large B-cell lymphoma (n=54; 83%). The IPI was >2 in 43 (66%) patients. LDH level was elevated in 27 (55%) patients. Median number of extranodal positive sites was 2 (1-5) and bone marrow involvement was documented in 30 (46%) patients. CNS involvement was documented in 51 patients. Paravertebral and epidural compressive mass with (n=5) or without (n=2) CSF involvement were present. Five patients had both CNS and peripheral nervous system involvement. Anthracycline-based chemotherapy with high dose metothrexate with or without cytarabine was the most chemotherapy used. Autologous stem cell transplantation was performed in 21 patients in response. BEAM (n=9) or thiotepa-based (n=9) conditioning regimen was the most intensive chemotherapy used before autologous SCT Post-chemotherapy ORR was 77%(CR69%;PR8%). 3-year overall survival (OS) and progression free survival (PFS) were 48±7% and 46±7% respectively. The consolidation strategy using high dose chemotherapy and autologous stem cell transplant positively impacted patient’s outcome. For the whole group as well as for patients ≤65 years, the 3-year OS and PFS were (77%vs29%;p=0.002) and (77%vs25%;p=0.001) and (75% vs 37%;p=0.002) and (75%vs32%;p=0.007) respectively. In multivariate analysis and for the whole group of patients, the absence high dose therapy had a negative impact on 3-year OS and PFS [p=0.003;HR=5.05[1.76-14.49]) and PFS by [p=0.002;HR=5.46(1.91-15.26)] respectively. This is remained true for younger patients 65 years or less who had poorer 3-year OS [p=0.036;HR=3.41 (1.08-10.75)]. Conclusion First line consolidative high dose therapy followed by autologous SCT in patients with systemic and neuro-meningeal NHL improve patient’s outcome Disclosures No relevant conflicts of interest to declare.
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Reiss, K., R. Mentlein, J. Sievers, and D. Hartmann. "Stromal cell-derived factor 1 is secreted by meningeal cells and acts as chemotactic factor on neuronal stem cells of the cerebellar external granular layer." Neuroscience 115, no. 1 (November 2002): 295–305. http://dx.doi.org/10.1016/s0306-4522(02)00307-x.
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Cascavilla, Nicola, Carlo Bodenizza, Angelo Michele Carella, Matteo Dell’Olio, Antonietta Falcone, Michele Mario Greco, Antonio La Sala, et al. "Use of Intrathecal Liposomal Cytarabine (DepoCyte) as Treatment of Lymphomatous Meningitis." Blood 108, no. 11 (November 16, 2006): 4677. http://dx.doi.org/10.1182/blood.v108.11.4677.4677.
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Abstract The Lymphomatous Meningitis (LM) is an uncommon event, either as an initial diagnosis and in the course (or as an outcome) of a front line treatment. In the latter cases the LM has a poor prognosis and a median survival of few months in untreated patients. Its occurrence is tightly related to the histology, the response to the therapy and the introduction of a proper prophylaxis. Currently, high doses of Methotrexate (HD-MTX) (3 g/sqm) followed by radiotherapy (WBRT: 50 Gy) represents the elective treatment. The role of the intrathecal therapy (IT-T) isn’t well defined: as a matter of facts, it doesn’t seem more effective than the systemic treatment with HD-MTX and it is burdened by a higher neurotoxicity. Furthermore, more frequent intrathecal administrations, a proper concentration and a prolonged exposition to the drugs are required. Recently, an important role both in the prophylaxis and in the therapy of LM is played by the IT-T of Cytarabine in liposomal formulation (DepoCyte): the slow release from the multivescicular lipidic particles improves the distribution in the liquor, allows a lesser number of IT-T, reduces the undesired effects due to the treatment and increases the compliance of patients. Randomized studies have shown a significant better effectiveness and a reduced toxicity of liposomal formulation treatment with respect to the traditional one. In the present work 9 cases of LM treated with systemic chemotherapy and with DepoCyte (50 mg IT every 15 days x 6 times) are shown. Male/Female ratio is 6/3; average age is 46 years (range 24–78). In all patients neurological symptoms were present; lymphomatous cells were identified in the CSF of 5 patients and Central Nervous System (CNS) localizations were detected by NMR in 7 patients. The 5 CSF-positive cases were heterogeneous, as follows: B-lineage CD10+ ALL meningeal relapse (after two marrow relapses), already undertaken to allogeneic stem cells transplantation, treated only with DepoCyte; Lymphoblastic T-Cell Lymphoma meningeal localization, with mediastinic mass, treated with DepoCyte associated to LSA2L2 Protocol and autologous stem cells tranplantation; DLBCL meningeal localization treated with DepoCyte associated to R-CHOP Protocol; LM at diagnosis in a 78 years old patient with inadequate compliance to systemic therapy, treated with DepoCyte; Mantle Cell Lymphoma meningeal (and systemic) relapse treated with DepoCyte associated to Codox-M Protocol. In patients 1) to 4) the CR was obtained and they are still alive; only the latter patient, namely, case 5), died for disease progression. The remaining 4 CSF-negative cases had been diagnosed as DLBCL (3 at diagnosis and 1 at relapse) CNS solitary localizations. In all cases L-VAMP Protocol (modified with HD-MTX) was associated to IT-T with DepoCyte. With the only exception of the relapsed patient, the remaining 3 patients had a good response to therapy and they are still alive and in CR.Overall, DepoCyte was shown to be mostly effective, well tolerated by all patients and devoid of undesired side effects. The association with various systemic chemotherapy protocols had been demonstrated to be suitable and endowed with synergic effects. Studies with higher number of patients might validate the effectiveness of DepoCyte also in those CSF-negative cases with solitary CNS localization.
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Thiel, Eckhard, Igor W. Blau, Martin Neumann, Carola Tietze-Buerger, Armin Gerbitz, and Lutz Uharek. "Treatment of Leukemic Meningeosis by CD 14 Depleted Adoptive Intrathecal Cell Therapy." Blood 112, no. 11 (November 16, 2008): 3261. http://dx.doi.org/10.1182/blood.v112.11.3261.3261.
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Abstract Background: Leukemic relapse within the central nervous system (CNS) is generally difficult to treat and results in poor outcome. Limiting factors for effective treatment are mainly extended neurotoxicity and availability of only few agents that will effectively act across the blood brain barrier (BBB). Although graft versus leukemia effects after allogeneic stem cell transplantation are well documented, its application is not recommended in patients with CNS disease. Since the CNS represents an immunologically privileged organ, conventional donor lymphocyte infusion (DLI) has not proven to be effective in CNS relapse situation after stem cell transplantation. Here we present results from three patients suffering from isolated CNS relapse of CML or AML after allogeneic stem cell transplantation receiving for the first time intrathecal cell therapy using CD14 depleted peripheral blood mononuclear cells from their allogeneic donor. Besides leukemic blast cell counts of the CSF molecular genetic analyses for chimerism as well as for translocations were applied for monitoring in addition to MRI and to neuroclinical symptoms. Results: Up to eight consecutive CD14 depleted intrathecal infusions were applied in escalating doses starting at 1x106 CD3+ cells. In all cases we did not observe any immediate or delayed side effects post application. In the case of the CML patient we observed disappearance of the leukemic blasts and of bcr-abl translocations and reversal to full donor chimerism of the CSF. In one AML patient we observed a transient disappearance of leukemic blasts, followed by a delayed increase. No clear and sustained response was recorded in the other AML patient. All patients are still under observation (9–14 months) and remained full chimeras in peripheral blood and bone marrow; however, the AML patients meanwhile developed chloroma lesions. Conclusion: Intrathecal DLI for CNS relapse of leukemia after allogeneic stem cell transplantation is a new still experimental approach. The first applications indicate no side effects e.g. cerebral or meningeal GVHD and a possible efficacy in CNS relapse of CML. This new approach merits further investigation in the setting of a clinical trial.
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Sousa, Aida B., Joana Veiga, Gilda Ferreira, Antonio S. Rodrigues, Madalena Silva, and Joaquim Gouveia. "Leukemic Meningitis as the Presenting Manifestation of Chronic Lymphocytic Leukemia (CLL) in a Young Man." Blood 110, no. 11 (November 16, 2007): 4681. http://dx.doi.org/10.1182/blood.v110.11.4681.4681.
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Abstract Meningeal infiltration is extremely rare in CLL. Moreover, part of the cases found in the literature occurred in fact in patients with prolymphocytic leukemia. In the few CLL cases, this complication was reported at late stages of the disease, in elderly patients. A previously healthy 30-year-old man was referred to the emergency department for evaluation of blurred vision and headache that developed 2 weeks earlier. Bilateral papilledema was observed, with no other neurological abnormality. CT and MRI of the head and orbits disclosed thickening of both optic nerves. Hemoglobin and platelet count were within normal limits. The WBC count was 41800/μl with 83% small lymphocytes, which were SmIg+ λ(weak) CD19+, CD5+, CD23+, CD20+, CD79b+, CD11c+, bcl2+, CD38+, ZAP70+ and CD10 negative. Moderately enlarged cervical lymph nodes were present. A diagnosis of Binet stage A, Rai stage I B-CLL was made. Bone marrow aspiration and biopsy showed 95% lymphocytes, with a diffuse pattern of infiltration. No metaphases were obtained for karyotyping. FISH disclosed a rearranged IgH, and was negative for trisomy 12 and for deletions of 11q, 13q and 17q. Abdominal CT showed retroperitoneal lymphadenopathy. Serology for HIV and EBV was negative. The cerebrospinal fluid (CSF) revealed >1000 lymphocytes/μl which were immunophenotypically identical to the peripheral blood cells. Systemic corticosteroids and intrathecal chemotherapy (methotrexate and dexamethasone) followed by cranial irradiation led to resolution of headache, but blurred vision persisted. Clearance of leukemic cells from the CSF was slow, a normal CSF being achieved only after 6 alternate day intrathecal injections. Systemic chemotherapy and stem cell transplantation are planned. To our knowledge this is the first reported case of CLL presenting as meningeal infiltration. Two possible reasons for the apparent rarity of CLL meningitis can be put forward: meningeal invasion would frequently be clinically silent, a hypothesis that is strengthened by autopsy findings; and it would usually occur in very advanced stages of CLL (with misinterpretation of neurological symptoms in erderly patients) making underdiagnosis easy.
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Penna, Vanessa, Niamh Moriarty, Yi Wang, Kevin C. L. Law, Carlos W. Gantner, Richard J. Williams, David R. Nisbet, and Clare L. Parish. "Extracellular Matrix Biomimetic Hydrogels, Encapsulated with Stromal Cell-Derived Factor 1, Improve the Composition of Foetal Tissue Grafts in a Rodent Model of Parkinson’s Disease." International Journal of Molecular Sciences 23, no. 9 (April 22, 2022): 4646. http://dx.doi.org/10.3390/ijms23094646.
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Clinical studies have provided evidence for dopamine (DA) cell replacement therapy in Parkinson’s Disease. However, grafts derived from foetal tissue or pluripotent stem cells (PSCs) remain heterogeneous, with a high proportion of non-dopaminergic cells, and display subthreshold reinnervation of target tissues, thereby highlighting the need to identify new strategies to improve graft outcomes. In recent work, Stromal Cell-Derived Factor-1 (SDF1), secreted from meninges, has been shown to exert many roles during ventral midbrain DA development and DA-directed differentiation of PSCs. Related, co-implantation of meningeal cells has been shown to improve neural graft outcomes, however, no direct evidence for the role of SDF1 in neural grafting has been shown. Due to the rapid degradation of SDF1 protein, here, we utilised a hydrogel to entrap the protein and sustain its delivery at the transplant site to assess the impact on DA progenitor differentiation, survival and plasticity. Hydrogels were fabricated from self-assembling peptides (SAP), presenting an epitope for laminin, the brain’s main extracellular matrix protein, thereby providing cell adhesive support for the grafts and additional laminin–integrin signalling to influence cell fate. We show that SDF1 functionalised SAP hydrogels resulted in larger grafts, containing more DA neurons, increased A9 DA specification (the subpopulation of DA neurons responsible for motor function) and enhanced innervation. These findings demonstrate the capacity for functionalised, tissue-specific hydrogels to improve the composition of grafts targeted for neural repair.
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Kondo, Toshinori, Taizo Tasaka, Kana Matsumoto, Rui Matsumoto, Lisa Koresawa, Fuminori Sano, Hirotoshi Tokunaga, et al. "Philadelphia chromosome-positive acute lymphoblastic leukemia with extramedullary and meningeal relapse after allogeneic hematopoietic stem cell transplantation that was successfully treated with dasatinib." SpringerPlus 3, no. 1 (2014): 177. http://dx.doi.org/10.1186/2193-1801-3-177.
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Ferreri, Andrés J. M., Giovanni Donadoni, Maria Giuseppina Cabras, Caterina Patti, Michael Mian, Renato Zambello, Corrado Tarella, et al. "High Doses of Antimetabolites Followed by High-Dose Sequential Chemoimmunotherapy and Autologous Stem-Cell Transplantation in Patients With Systemic B-Cell Lymphoma and Secondary CNS Involvement: Final Results of a Multicenter Phase II Trial." Journal of Clinical Oncology 33, no. 33 (November 20, 2015): 3903–10. http://dx.doi.org/10.1200/jco.2015.61.1236.
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Purpose Treatment of secondary CNS dissemination in patients with aggressive lymphomas remains an important, unmet clinical need. Herein, we report the final results of a multicenter phase II trial addressing a new treatment for secondary CNS lymphoma based on encouraging experiences with high doses of antimetabolites in primary CNS lymphoma and with rituximab plus high-dose sequential chemoimmunotherapy (R-HDS) in relapsed aggressive lymphoma. Patients and Methods HIV-negative patients with aggressive B-cell lymphoma and secondary CNS involvement at diagnosis or relapse, age 18 to 70 years, and Eastern Cooperative Oncology Group performance status ≤ 3 were enrolled and treated with high-doses of methotrexate and cytarabine, followed by R-HDS (cyclophosphamide, cytarabine, and etoposide) supported by autologous stem-cell transplantation (ASCT). Treatment included eight doses of rituximab and four doses of intrathecal liposomal cytarabine. The primary end point was 2-year event-free survival; the planned accrual was 38 patients. Results Thirty-eight patients were enrolled; CNS disease was detected at presentation in 16 patients. Toxicity was usually hematologic and manageable, with grade 4 febrile neutropenia in 3% of delivered courses and grade 4 nonhematologic toxicity in 2% of delivered courses. Four patients died because of toxicity. Autologous stem cells were successfully collected in 24 (89%) of 27 patients (median, 10 × 106/kg); 20 patients underwent ASCT. Complete response was achieved in 24 patients (complete response rate, 63%; 95% CI, 48% to 78%). At a median follow-up of 48 months, 17 patients remained relapse free, with a 2-year event-free survival rate of 50% ± 8%. At 5 years, 16 patients were alive, with a 5-year overall survival rate of 41% ± 8% for the whole series and 68% ± 11% for patients who received transplantation. Systemic (extra-CNS) and/or meningeal disease did not affect outcome. Conclusion The combination of high doses of antimetabolites, R-HDS, and ASCT is feasible and effective in patients age 18 to 70 years old with secondary CNS lymphoma, and we propose it as a new standard therapeutic option.
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Ferreri, Andrés J. M., Giovanni Donadoni, Maria Giuseppina Cabras, Caterina Patti, Michael Mian, Renato Zambello, Corrado Tarella, et al. "High Doses of Antimetabolites Followed By High-Dose Sequential Chemoimmunotherapy and Autologous Stem Cell Transplant in Patients with Systemic B-Cell Lymphoma and Secondary Central Nervous System Involvement: Final Results of a Multicenter Phase II Trial." Blood 124, no. 21 (December 6, 2014): 1724. http://dx.doi.org/10.1182/blood.v124.21.1724.1724.
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Abstract INTRODUCTION: Secondary central nervous system (CNS) dissemination is a lethal event in patients (pts) with aggressive lymphomas. A few studies focused on the treatment of this condition are available, confirming the dismal prognosis and the high rate of severe neurotoxicity in pts managed with radiotherapy-based induction. Thus, the most effective treatment for secondary CNS lymphoma remains an important, unmet clinical need. Herein, we report the final results of a multicenter phase II trial addressing a new treatment in pts with aggressive B-cell lymphoma and CNS involvement (NCT00801216). Experimental treatment is based on the encouraging experiences with high doses of antimetabolites in pts with primary CNS lymphoma (Ferreri et al. Lancet 2009), and with high-dose sequential chemotherapy combined with rituximab (R-HDS) and supported by autologous stem cell transplant (ASCT) in pts with relapsed aggressive B-cell lymphoma (Tarella et al. JCO 2008). METHODS: Selection criteria were: 1) histological diagnosis of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma blastoid variant (MCLb) or grade-3 follicular lymphoma (FL); 2) secondary CNS involvement at diagnosis or relapse; 3) age 18-70 years; 4) ECOG PS ≤3; 5) absence of HIV infection; 6) adequate organ functions. Pts with primary CNS lymphoma (exclusive CNS disease at diagnosis) were excluded. Experimental treatment consisted of an induction phase with 2 courses of methotrexate 3.5 g/m2 d1 + cytarabine 2 g/m2 x2/d d2-3, followed by an intensification phase with R-HDS (cyclophosphamide 7 g/m2 d1; cytarabine 2 g/m2 x2/d d22-25; pts with residual extra-CNS disease received also etoposide 2 g/m2 d43) and a consolidation phase with BCNU-thiotepa conditioning + ASCT (figure). Treatment included 8 doses of rituximab and 4 of intrathecal liposomal cytarabine. The primary endpoint was 2-year PFS; the planned accrual was 38 pts. RESULTS: 39 pts were registered (age 32-70 ys, median 59; M/F ratio 1.5): 33 had DLBCL, 3 MCLb, 3 FL. CNS disease (brain 21, meninges 5, spinal cord 2, multiple 11) was detected at diagnosis in 16 pts (all with extra-CNS disease) and at relapse in 23 (8 with extra-CNS disease). The median TTP from the previous treatment line was 3 months (range 0-77 months). Thirty-four pts completed the induction phase; 73 (93%) of 78 planned courses were actually delivered; G4 neutropenia, thrombocytopenia and anemia were recorded in 77%, 63% and 5% of courses, G3-4 febrile neutropenia in 16%, CMV reactivation in 3 pts. Transient G4 transaminases increase (3% of courses) was the only G4 non-hematological toxicity. Drugs dose reduction was indicated in 3 pts. Response after induction phase was complete in 11 pts and partial in 19 (ORR= 77%; 95%CI=64-90%). Thirty pts were referred to intensification phase (figure); 58 (97%) of 60 planned courses were actually delivered; G4 neutropenia, thrombocytopenia and anemia were recorded in 67%, 60% and 7% of courses, G3-4 febrile neutropenia in 22%, G4 sepsis in 8%. CMV reactivation was diagnosed in 4 pts, pulmonary aspergillosis in 1. No cases of G4 extra-hematological toxicity were recorded. Response after intensification phase (before conditioning) was complete in 22 pts and partial in 2 (ORR= 62%; 95%CI=47-77%). ASCs were collected in 21/22 (95%) pts (median 9.5 x 106/kg; range 6-19); 20 pts underwent ASCT. Response at the end of the whole program was complete in 23 pts and partial in 1 (ORR= 62%, 95%CI= 47-77%), 1 pt had SD, 10 experienced PD (all in the CNS), and 4 died of toxicity (sepsis 2, stroke, acute tracheal obstruction). Importantly, no pt was irradiated to the brain to achieve lymphoma remission, and no evidence of neurotoxicity was recorded in pts with a survival longer than 3 years. One pt was referred to sibling-donor transplant due to sMDS, and is alive and NED at 91 months of follow-up. At a median follow-up of 42 months, 16 pts remain relapse-free, with a 2-yr PFS of 42±8%. Sixteen pts are alive, with a 2-yr OS of 42±8%; 2-yr OS of transplanted pts was 72±11%. Extra-CNS and/or meningeal disease did not affect outcome, and survival was similar in both pts treated at presentation or at relapse. CONCLUSION: This radiotherapy-free combination of high doses of antimetabolites, R-HDS and ASCT is feasible and effective in pts ≤70 ys with secondary CNS lymphoma. Toxicity is usually haematological and manageable. Survival benefit is attainable also in pts with meningeal and/or concomitant extra-CNS disease. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Reinwald, Mark, Eberhard Schleyer, Philipp Kiewe, Igor Wolfgang Blau, Thomas Burmeister, Stefan Pursche, Martin Neumann, et al. "Efficacy and Pharmacologic Data of Second-Generation Tyrosine Kinase Inhibitor Nilotinib in BCR-ABL-Positive Leukemia Patients with Central Nervous System Relapse after Allogeneic Stem Cell Transplantation." BioMed Research International 2014 (2014): 1–7. http://dx.doi.org/10.1155/2014/637059.
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Central nervous system (CNS) involvement is a severe complication of BCR-ABL-positive leukemia after allogenic stem cell transplantation (alloSCT) associated with fatal outcome. Although second-generation tyrosine-kinase inhibitors (TKI) such as nilotinib have shown activity in systemic BCR-ABL+disease, little data exists on their penetration and efficacy within the CNS. Four patients (3 male, 1 female; age 15–49) with meningeal relapse after alloSCT and subsequent treatment with nilotinib were identified. A total of 17 cerebrospinal fluid (csf) and serum samples were assessed for nilotinib concentration and patient outcome was recorded. Nilotinib concentrations showed a low median csf/plasma ratio of 0.53% (range 0.23–1.5%), yet pronounced clinical efficacy was observed with long-lasting responses (>1 year) in three patients. Comparison with historical data showed a trend towards superior efficacy of nilotinib versus imatinib. Despite poor csf penetration, nilotinib showed significant clinical activity in CNS relapse of BCR-ABL+leukemias. As nilotinib has a high protein-binding affinity, the low-protein concentration in csf could translate into a relatively higher amount of free and therefore active nilotinib in csf as compared to blood, possibly explaining the observed efficacy. Thus, treatment with a 2nd generation TKI warrants further investigation and should be considered in cases of CNS relapse of BCR-ABL-positive leukemia after alloSCT.
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Stachel, Daniel, Nora Naumann-Bartsch, Patrick Morhart, Markus Metzler, Thorsten Langer, Klaus Schwarz, and Wolfgang Holter. "TBI Based Conditioning Regimen and Intra Osseous Application of PBSC to Overcome Graft Resistance In a Patient with Autoimmune Lymphoproliferative Syndrome (ALPS)." Blood 116, no. 21 (November 19, 2010): 4696. http://dx.doi.org/10.1182/blood.v116.21.4696.4696.
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Abstract Abstract 4696 Autoimmune lymphoproliferative syndrome (ALPS) is a rare immunologic disorder caused by defects in the Fas-induced programmed cell death pathway. Impaired lymphocyte apoptosis results in gradual lymphocyte accumulation and dysregulation of lymphocyte homeostasis. ALPS patients usually suffer from persistent generalized lymphadenopathy, hepato-splenomegaly, immune-mediated cytopenias, and other autoimmune phenomena. A 15-month-old boy was diagnosed with ALPS when he presented with typical symptoms. Lab exams showed a pancytopenia, elevated serum immunoglobulin levels, a peripheral expansion of double-negative T lymphocytes of up to 40% of TCRab+ T cells and impaired lymphocyte apoptosis. Molecular analysis confirmed the diagnosis of a type Ia ALPS by identifying a heterozygous Fas gene mutation (D260H). Despite treatment with repeated pulses of high-dose methylprednisolone, intravenous immunoglobulins, and mycophenolate mofetil (MMF) to control lymphoproliferation and recurrent pancytopenia his disease progressed. At three years of age he developed numerous arterial aneurysms of the iliac, mesenterial, renal, hepatic, right middle meningeal, brachial and femoral arteries up to 2.6 cm in diameter and lymphoproliferation resulting in paraplegia and right arm paresis. Stem cell transplantation was considered, and BMT from a 9/10 matched unrelated donor (MUD) after a reduced intensity conditioning regimen (CR) with Fludarabin (150 mg/m2), Melphalan (140 mg/m2/d) and ATG (60mg/kg) was performed using 5.22 × 106 CD34+ cells/kg body weight. However, graft failure had to be diagnosed on day +27. 53 days after the first BMT a PBSCT from the same donor after myeloablative CR using Busulfan (19.2 mg/kg/d i.v.), Etoposid (30 mg/kg/d), Cyclophosphamid (120 mg/kg/d) and ATG (60mg/kg) was performed (24.5 × 106 CD34+ cells/kg bw). Again, graft failure was seen. At day +55 a third HSCT using PBSCT from another 9/10 MUD after CR with Fludarabin i.v. (160 mg/m2), Thiotepa (5 mg/kg/d), 4 Gy total body irradiation (TBI) and campath (1 mg/kg) was performed. 10.8 × 106 CD34+ cells/kg bw were given intra osseous, 9.8 × 106 CD34+ cells/kg bw were given i.v. Engraftment was slow (Leukos 980 day +35), but chimerism showed 99 % donor cells. Two years later the patient is alive and well, with persistent engraftment and good hematological and immunological function. Arterial aneurysms stopped growing and some have thrombosed. This case illustrates some interesting points. Atypical and unusually severe manifestations of ALPS forced us to perform a HSCT in this patient. In severe ALPS stem cell engraftment is difficult to achieve as previously reported in the Fas deficient lpr mouse model. One reason might be the reduced ability of cytotoxic drugs to induce apoptosis in the Fas deficient recipient T cells. Thus, recipient T cells could persist and kill donor cells resulting in graft failure or rejection. Additionally, increased FasL expression on recipient cells could induce apoptosis in Fas bearing donor stem cells as shown in lpr mice. Also, trapping of infused stem cells in the extremely enlarged liver and spleen could have played a role. A 3rd attempt was therefore designed to overcome graft resistance and proved finally successful. The use of TBI together with campath possibly induced more T cell apoptosis than chemotherapy alone. The intra osseous application probably increased engraftment efficiency by avoiding trapping of stem cells in liver and spleen and possibly by induction of tolerance by intra osseous application as described before. Disclosures: No relevant conflicts of interest to declare.
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McClune, Brian, Francis Buadi, Naveed Aslam, and Donna Przepiorka. "Intrathecal Liposomal Cytarabine (Depocyt) Is Safe and Effective for Prevention of Meningeal Disease in Patients with Acute Lymphoblastic Leukemia and High-Grade Lymphoma Treated with the HyperCVAD Regimen." Blood 106, no. 11 (November 16, 2005): 4594. http://dx.doi.org/10.1182/blood.v106.11.4594.4594.
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Patients with acute lymphoblastic leukemia (ALL) and high-grade lymphoma have a 10–20% risk of meningeal disease during induction and in remission when given standard-dose chemotherapy. This risk has been reduced to about 1% using intrathecal prophylaxis with cytarabine and methotrexate in addition to the systemic regimen of hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone (hyperCVAD) alternating with high-dose methotrexate-cytarabine (MA). The discomfort and potential adverse events with frequent lumbar punctures may impair patient compliance. Liposomal cytarabine (Depocyt) is an intrathecal preparation of cytarabine with a prolonged half-life. Use of Depocyt could potentially reduce the number of lumbar punctures needed for routine neuroprophylaxis. We reviewed the tolerability and activity of Depocyt for neuroprophylaxis in 15 patients treated with the hyperCVAD regimen. The cohort included 12 males and 3 females of median age 48 years (range, 23–72 years) with precursor B-cell ALL (8), T-cell ALL (3), Burkitt lymphoma and HIV (2), Ph-positive ALL (1), and lymphoblastic lymphoma (1). The patients received a total of 65 cycles of systemic chemotherapy, 36 with hyperCVAD and 29 with MA. Depocyt was given IT or IO in 33 cycles, methotrexate IT in 5, and no intrathecal therapy in 27. When treated with Depocyt, patients also received dexamethasone pre- and postmedication.. The planned dose of Depocyt was 50 mg for all patients, but after one serious adverse event, the dose was reduced to 25 mg when administered by Omaya. Depocyt was instilled on a median of day 8 of the cycle (range, −4 to 13). To date, a meningeal relapse has not occurred in any of the patients. Although minor neurological events (transient headache or neckache) were not uncommon, there were two serious adverse events. One patient developed a severe but transient headache during the fourth cycle and was readmitted for pain control. A second patient received Depocyt four days prior to MA. Shortly after completing chemotherapy, this patient developed hyponatremia and somnolence. The neurological status normalized after several days with supportive care alone. Since leakage of Depocyt into the peripheral blood might cause myelosuppression, hematologic recovery was also assessed. There was a significant difference in time to ANC>500 (p=0.02) and platelets >20,000 (p=0.005) between hyperCVAD and MA cycles, so hematologic recovery was assessed separately for these regimens, as shown in the Table. Median Day of Hematopoietic Recovery Cycle Outcome All Cycles Depocyt No IT PX MTX IT “1” indicates the platelet count did not fall below 20,000 during that cycle. HyperCVAD ANC>500 15 15 14 16.5 Plts>20,000 1 1 1 1 MA ANC>500 16 16 16 15 Plts>20,000 13 13 14 15 There were no significant differences in time to neutrophil or platelet recovery between neuroprophylaxis regimens. Three patients received cranial or craniospinal radiation to compete neuroprophylaxis prior to allogeneic stem cell transplantation without notable neurotoxicity after transplantation. We conclude that it is safe to use a single dose of Depocyt (50 mg IT or 25 mg IO) following completion of administration of chemotherapy (around Days 6 – 8) during each cycle of the hyperCVAD regimen. This approach should be studied in a randomized trial to further assess its efficacy in comparison to more frequent instillations of methotrexate/cytarabine.
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Muller, Daniel, Harvey Chim, Augustinus Bader, Matthew Whiteman, and Jan-Thorsten Schantz. "Vascular Guidance: Microstructural Scaffold Patterning for Inductive Neovascularization." Stem Cells International 2011 (2011): 1–6. http://dx.doi.org/10.4061/2011/547247.
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Current tissue engineering techniques are limited by inadequate vascularisation and perfusion of cell-scaffold constructs. Microstructural patterning through biomimetic vascular channels within a polymer scaffold might induce neovascularization, allowing fabrication of large engineered constructs. The network of vascular channels within a frontal-parietal defect in a patient, originating from the anterior branch of the middle meningeal artery, was modeled using computer-aided design (CAD) techniques and subsequently incorporated into polycaprolactone (PCL) scaffolds fabricated using fused deposition modeling (FDM). Bone marrow-derived mesenchymal stem cells (MSCs) were seeded onto the scaffolds and implanted into a rat model, with an arteriovenous bundle inserted at the proximal extent of the vascular network. After 3 weeks, scaffolds were elevated as a prefabricated composite tissue-polymer flap and transferred using microsurgical technique. Histological examination of explanted scaffolds revealed vascular ingrowth along patterned channels, with abundant capillary and connective tissue formation throughout experimental scaffolds, while control scaffolds showed only granulation tissue. All prefabricated constructs transferred as free flaps survived and were viable. We term this concept “vascular guidance,” whereby neovascularization is guided through customized channels in a scaffold. Our technique might potentially allow fabrication of much larger tissue-engineered constructs than current technologies allow, as well as allowing tailored construct fabrication with a patient-specific vessel network based on CT scan data and CAD technology.
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Korfel, Agnieszka, Gerald Illerhaus, Mathias Haenel, Robert Moehle, Roland Schroers, Thomas Elter, Marcel Reiser, et al. "CNS-directed chemotherapy including high-dose chemotherapy with autologous stem cell transplantation (HD-ASCT) for CNS relapse of aggressive lymphomas: Final analysis of a phase II study." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 8031. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.8031.
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8031 Background: The outcome of patients with CNS relapse of aggressive lymphoma (secondary CNS lymphoma, SCNSL) is poor with no standard therapy established thus far. Here we present the final analysis of a prospective multicenter phase II study using an intensive induction regimen followed by high-dose chemotherapy and autologous stem-cell transplantation. Methods: Adult immunocompetent patients ≤65 years with SCNSL were eligible. Induction chemotherapy consisted of two cycles MTX/IFO (methotrexate 4g/m2 iv. d1, ifosfamide 2g/m2 iv. d3-5 and i.th. liposomal cytarabine 50mg d6) and one cycle AraC/TT (cytarabine 3g/m2 d1-2, thiotepa 40mg/m2 iv. d2 and i.th. liposomal cytarabine 50mg d3). Then, patients without progression received high-dose chemotherapy with carmustine 400mg/m2 iv. d -5, thiotepa 2x5mg/kg iv. d -4 to -3 and etoposide 150mg/m2 iv. d -5 to -3 followed by ASCT d0. Results: Thirty eligible patients (median age 58 years) were enrolled. Three patients had T-cell and 27 aggressive B-cell lymphoma. Pre-treatment was CHOP-like in 29 patients, including rituximab in 26. CNS relapse occurred after a median of 8.5 (3-80) months and was intracerebral in 23 and meningeal in13 patients (combined in 7); 6 had concomitant systemic lymphoma. After induction therapy CNS response was found in 22 (73%) patients (8xCR, 14xPR), 3 patients had SD, 4 patients PD and 1 patient no response evaluation. HD-ASCT was performed in 24 patients; resulting in 15 CR (63%), 2 PR (8%) and 7 PD (29%). Myelotoxicity was the most frequent WHO grade 3-4 adverse event with infections in 8/30 pts on MTX/IFO (27%), 5/23 (22%) on AraC/TT and 11/20(55%) on HD-ASCT. One patient died due to septic diverticulitis and one developed persisting fecal incontinence. The median follow up was 21 months. The median PFS was 12.1 months (95% CI 6.4-17.7) in all patients and 30.4 (95%CI 2.5-58.3) months after HD-ASCT, the median overall survival was 27.4 months and not reached, respectively. Conclusions: This first prospective study on SCNSL demonstrates that lasting remissions can be achieved with CNS-directed HD-ASCT in a large proportion of patients and probably cure in some.
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Hayashi, Hideki, Asuka Morizane, Masaomi Koyanagi, Yuichi Ono, Yoshiki Sasai, Nobuo Hashimoto, and Jun Takahashi. "Meningeal cells induce dopaminergic neurons from embryonic stem cells." European Journal of Neuroscience 27, no. 2 (January 18, 2008): 261–68. http://dx.doi.org/10.1111/j.1460-9568.2008.06027.x.
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Ferreri, Andres JM, Jeanette K. Doorduijn, Chiara Cattaneo, Maria Giuseppina Cabras, Jeffery Smith, Fiorella Ilariucci, Franco Narni, et al. "Sequential Matrix-RICE Therapy Followed By Autologous Stem Cell Transplant in Patients with Diffuse Large B-Cell Lymphoma and Secondary Central Nervous System Involvement: The International Extranodal Lymphoma Study Group-42 Phase II (MARIETTA) Trial." Blood 134, Supplement_1 (November 13, 2019): 353. http://dx.doi.org/10.1182/blood-2019-129835.
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Introduction: Secondary CNS dissemination (SCNSL) is a rare but lethal event in pts with diffuse large B-cell lymphoma (DLBCL). It can occur both at presentation, in pts with systemic disease, or at relapse, during or after primary therapy. Following the experience from primary CNS lymphoma, pts with SCNSL are currently treated with high-dose-methotrexate-based chemo and autologous transplant (ASCT). However, this strategy is associated with poor control of extra-CNS disease, and only 1/3 of pts proceed to ASCT and recover from this event. Thus, we designed a multicenter phase II trial addressing an intensified chemoimmunotherapy consolidated by ASCT in HIV-neg pts with SCNSL (NCT02329080). Methods: Inclusion criteria were: histologically confirmed DLBCL; CNS involvement at presentation (concomitant to systemic disease) or relapse (isolated or concomitant to systemic lymphoma); age 18-70 ys; ECOG-PS ≤3; no prior treatment with high-dose methotrexate. Registered pts received 3 courses of MATRIX followed by 3 courses of RICE combined with intrathecal chemo and consolidated by BCNU-thiotepa/ASCT. The primary endpoint was 1-yr PFS. The Fleming design was used; to detect a difference in 1-yr PFS from 50% (P0) to 65% (P1), 69 pts were required (one-sided, type I error 5%, power 80%), with a dropout of 10%, 76 pts were needed. If ≥41 pts were progression-free at 1 yr, the strategy would be considered effective. Results: Between 3/2015 and 8/2018, 79 pts were enrolled at 24 centers in 4 countries; 75 pts (median age 58, range 23-70; 38 males) were assessable. CNS involvement was recorded at presentation in 32 (43%) pts and at relapse in 43 (isolated site in 15, concomitant to systemic relapse in 28). CNS sites were brain parenchyma in 34 (45%) pts, brain + eyes in 10 (13%), brain + CSF in 13 (17%), brain + CSF + eyes in 6 (8%), CSF/meninges in 8 (11%), spinal cord in 2 (3%), and eyes in 2 (3%). Median time to CNS involvement was 5 months (range 1-61) in the 43 pts registered at relapse; 20 (47%) of them had refractory disease. 320 (71%) of the 450 planned chemo courses were delivered; 64 (85%) pts received intrathecal chemo. 78 SAEs were recorded in 42 pts, mostly due to FN and infections (64) or bleeding (5); 74 (95%) SAEs were followed by recovery. The 4 lethal SAEs (TRM= 5%) and the 5 transient interruptions occurred during MATRIX. Dose reductions were indicated in 33 (10%) courses. Most common g4 toxicities were thrombocytopenia in 118 (37%) courses, neutropenia in 113 (35%) and infections in 9 (3%). Stem cells collection was successful (median of 6.75M/kg; range: 2.4 - 45) in 42 (88%) of the 48 pts referred for leukapheresis. 55 (73%; 95%CI 63-83%) pts achieved a response after 2 courses of MATRIX; 19 (95%) of the 20 pts who had a CR after 2 MATRIX maintained the response after RICE; 9 (26%) of the 35 pts who had a PR after 2 MATRIX achieved a CR after RICE. Conversely, only 3 of 16 pts with PD/SD after 2 MATRIX achieved a response from RICE. 49 pts (65%; 95%CI 54-76%) achieved a response after MATRIX-RICE induction, and 36 responders received ASCT; 13 responders did not receive ASCT due to insufficient mobilization (n=4), PD due to treatment delay (5), frailty (2), neurological decline (1), and consent withdrawal (1). 45 pts (60%; 95%CI 50-70%) had responsive disease after the whole treatment. At 1 year from registration, 41 pts were progression free (efficacy threshold ≥41). At a median follow-up of 25 (12-47) months, 31 pts are progression free, with a 2-yr PFS of 42 ± 6% for the whole series and 75 ± 7% for the 36 transplanted pts (Fig. A & B). Sites of relapse/progression were CNS in 10 pts, extra-CNS organs in 9 and both in 18. Overall, 33 pts are alive, with a 2-yr OS of 42 ± 6% for the whole series and 82 ± 7% for transplanted pts. Causes of death were lymphoma (35) and toxicity (4); 3 pts died without evidence of disease due to neurological decline, PTE and sudden death. Pts with CNS disease at presentation had the best outcome (Fig. C), whereas CSF/meningeal disease (Fig. D) and age >60 ys were independently associated with poor outcome. Conclusions: MATRIX-RICE followed by ASCT achieved the primary endpoint in this very-poor-prognosis population, without major safety concerns. Survival figures of transplanted pts seem a little better than reported in prior trials, whereas pts with MATRIX-refractory disease had no benefit from crossing to RICE. The best survival figures were recorded in chemo-naïve pts treated at presentation and in pts without CSF/meningeal disease. Figure Disclosures Ferreri: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding. Doorduijn:Roche: Honoraria, Research Funding. Nassi:Merck: Consultancy; Takeda: Consultancy; Janssen: Consultancy. McKay:Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Davies:ADCT Therapeutics: Honoraria, Research Funding; Karyopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; MorphoSys AG: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Janssen: Honoraria, Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioInvent: Research Funding. Fox:Celgene: Consultancy; Gilead: Consultancy; AbbVie: Consultancy; Janssen: Consultancy; Sunesis: Consultancy; Takeda Pharmaceuticals: Consultancy; Atara Biotherapeutics: Consultancy; Adienne: Other: Travel Support. Osborne:Gilead: Membership on an entity's Board of Directors or advisory committees; NIL: Employment; NIL: Other: leadership; NIL: Other: Stock & other ownership interests; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees. Liberati:Incyte: Consultancy; Novartis: Other: Clinical trial support; Janssen: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Roche: Other: Clinical trial support; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Celgene: Honoraria, Other: Clinical trial support; Bristol-Myers Squibb: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zambello:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Zucca:Celltrion Helathcare: Membership on an entity's Board of Directors or advisory committees; AstraZenaca: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Merck: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Research Funding; Kite, A Gilead Company: Membership on an entity's Board of Directors or advisory committees; Abbvie: Other: Travel Grant. Cwynarski:Adienne: Consultancy; Takeda: Consultancy, Other: conference and travel support , Speakers Bureau; Roche,: Consultancy, Other: conference and travel support, Speakers Bureau; Autolus: Consultancy; KITE: Consultancy; Gilead: Consultancy, Other: conference and travel support, Speakers Bureau; Celgene: Consultancy; Atara: Consultancy; Janssen: Other: conference and travel support, Speakers Bureau.
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Reimann, Maurice, Sven Masswig, Kolja Schleich, Andrea Herrmann, Philipp Lohneis, Jens Schrezenmeier, Bernd Dörken, and Clemens Schmitt. "Modeling the CNS Tropism of Diffuse Large B-Cell Lymphomas in Vivo." Blood 126, no. 23 (December 3, 2015): 576. http://dx.doi.org/10.1182/blood.v126.23.576.576.
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Abstract Introduction: Central nervous system (CNS) manifestation accounts for dismal prognosis in patients diagnosed with systemic diffuse large B-cell lymphoma (DLBCL). Myc rearrangement, deletions encompassing the CDKN2A (a.k.a. INK4a/ARF) or ATM gene loci as well as NF-kB-hyperactivating mutations are frequently detected in primary and secondary CNS-tropic lymphoma, however, investigations that functionally link these lesions to CNS involvement in adequate in vivo model systems are missing. Methods: We generated primary Eµ-myc transgenic mouse lymphomas with and without distinct naturally occurring NF-kB mutations (within genes encoding for MyD88, CD79B, A20, IkBζ, IkBε or BIRC3) or deletions at the INK4a/ARF and ATM loci by retroviral gene transfer and crossbreeding to the respective knockout strains. A subset of the lymphomas was subjected to gene expression profiling and whole-exome sequencing (WES). Wild-type recipient mice propagated with lymphoma cells via tail vein injection were monitored for systemic lymphoma development, the time at which the brain was isolated and examined regarding lymphoma infiltration. Results: Underlining Myc's role as a putative co-driver of CNS involvement, we found in about 40% of primary Eµ-myc lymphomas (with no additional exogenous lesions) meningeal lymphoma manifestations, and transplantation of the same individual lymphomas into numerous recipients reproduced the CNS lymphoma status. Gene set enrichment analysis of genome-wide transcriptome profiles indicated NF-kB hyperactivation in the CNS-tropic lymphoma group, suggesting that constitutive NF-kB signaling may promote CNS-prone pathogenesis in vivo. Transplantation of Eµ-myc transgenic hematopoietic stem cells expressing a variety of NF-kB-activating mutants in myeloablated recipient mice resulted in a significant acceleration of Eµ-myc -driven lymphomagenesis, with some, but not all of these mutants conferring a CNS-tropic lymphoma phenotype. Global NF-kB suppression in CNS-tropic Eµ-myc lymphomas via the NF-kB-antagonizing IkBΔN super-repressor did not fully abrogate lymphoma infiltration of the brain, suggesting that additional factor(s) must contribute. Accordingly, targeted ablation of the INK4a/ARF and ATM loci robustly enhanced CNS tropism of Eµ-myc lymphomas. Conclusions: The Eµ-myc mouse lymphoma model is well-suited to genetically dissect and rebuild components of DLBCL-like CNS tropism. We identified CDKN2A or ATM deletions as critical determinants of CNS tropism in vivo. Our systematic analyses of different NF-kB mutants - so far rather recognized as functionally interchangeable - indicated that only distinct NF-kB mutants contribute to CNS tropism in B-cell lymphomas. WES data, results from compound genotypes (e.g. combining ATM deletions with an NF-kB-activating mutation), and the impact of the host's cellular immune status will be reported at the meeting. Our findings underscore the need for functional analyses of oncogenic network contexts, and provide important insights into candidate target lesions for personalized CNS-directed therapies in DLBCL patients in the future. Disclosures No relevant conflicts of interest to declare.
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Bernard, Sophie, Lauriane Goldwirt, Sandy Amorim, Pauline Brice, Josette Briere, Helene Sauvageon, and Catherine Thieblemont. "Promising Results of Ibrutinib in Three Patients with Secondary Central Nervous System Mantle Cell Lymphoma." Blood 124, no. 21 (December 6, 2014): 3105. http://dx.doi.org/10.1182/blood.v124.21.3105.3105.
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Abstract Introduction. Risk of CNS dissemination in mantle cell lymphoma (MCL) is a rare and secondary event that occurs during the course of the disease. Prognosis from time of CNS involvement diagnosis is poor despite high-dose metabolite chemotherapy. New drugs are emerging in MCL treatment. The oral inhibitor of Bruton's tyrosine kinase (BTK), Ibrutinib (Pharmacylics, Sunnyvale, CA), has demonstrated unprecedented single agent overall response rate in relapsed or refractory MCL. Efficacy of Ibrutinib in CNS relapse is not known. Patients and methods. In 2014, three patients with MCL presented with a refractory secondary CNS dissemination at our institution. Patient 1, a 61 years old man, was first diagnosed in November 2009 with MCL, stage IV with a nodal, bone marrow and colon dissemination. MIPI score was evaluated as 5.5 (low risk). Patient received R-DHAX (rituximab, dexamethasone, aracytine, oxaliplatine) x 4 cycles followed by a high-dose R-BEAM therapy plus autologous stem cell transplantation (ASCT) (LYMA trial). First CNS relapse occurred in November 2012 as a right retro-ocular nodule and optic nerve infiltration. Patient was treated with R-IVAM, (rituximab, aracytine, ifosfamide, vepeside, high-dose methotrexate) x 6 cycles, with a complete response. He relapsed in December 2013 during rituximab maintenance, and was treated with CHOP-procarbazine x 3 cycles with a progression of the retro-ocular nodule and a peripheral nodal dissemination. Ibrutinib single agent was started in April 2014 at standard dose (560 mg/day). Patient 2, a 77 years old woman, was first diagnosed in February 2013 with MCL, stage IV disease with a nodal, splenic, blood, and bone marrow dissemination. MIPI score was 7.67 (high risk). Six cycles of R-CHOP followed by Rituximab maintenance was given. Relapse occurred during the Rituximab maintenance as an isolated meningeal dissemination. Patient received 6 cycles of R-DHA with a complete response. One month later, she presented an early relapse with meningeal dissemination and a left retro-orbital nodule. Ibrutinib single agent was started in May 2014 at standard dose. Patient 3, a 62 years old man, was first diagnosed in January 2011 with MCL stage IV with a splenic, blood and nodal dissemination. MIPI score was evaluated at 5.8 (intermediate risk). The patient had a splenectomy in March 2011. He relapsed in July 2013 with a blood, liver and nodal infiltration. The patient was treated with R-DHAX x 4 cycles followed by a high-dose R-BEAM therapy plus ASCT. He relapsed in July 2014 with a transverse myelitis. Ibrutinib single agent was started at standard dose. In parallel we studied plasmatic and CSF pharmacokinetic of Ibrutinib in one patient. Results. All patients were alive, respectively at 4 and 3 months and two weeks. CNS response of patient 1 by CT showed a tumor reduction of 81% with a complete CNS response on TEP at 4 months (Fig 2A and 2B). A complete response of peripheral nodal involvement was also observed. Patient 2 was evaluated with CSF study and CNS MRI. We observed an important decrease of CSF involvement (from 900 cells/mL to 100 cells/mL) as early as day 15 (Fig 1), and a response of the retro-orbital lesion (-23%). However an increase of lymphoma cells in CSF was observed at day 64 and was associated with 88 % decrease in Ibrutinib plasma exposure. At the same time, Ibrutinib CSF concentration measured at Tmax remained stable from day 8 to day 36, ranging from 1 to 3 ng/mL, with a CSF concentration/plasmatic concentration ratio of 0,019. Patient 3 rapidly improve his clinical exam with a recuperation of motor deficit and sensitive level at day 8. MRI was evaluated at day 8 of Ibrutinib and showed a spectacular response with a 69% decrease of myelitis trasverse and a regression of contrast enhancement (Fig 2C). Conclusion. This is the first report of efficacy of Ibrutinib in CNS lymphoma dissemination. We observed in these 3 cases an objective response and a pharmacodynamy proof of Ibrutinb CSF diffusion. Hypotheses for progression in patient 2 are 1/ a variability of Ibrutinib exposure; or 2/ the apparition of a C481S mutation of BTK. This observation is pivotal as CNS dissemination of other lymphoma subtypes, such as diffuse large B-cell lymphoma, or indolent lymphomas (follicular or marginal zone lymphoma) are all associated with poor prognosis. Given Ibrutinib upfront may eradicate this risk of dissemination and has to be prospectively evaluated. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Amorim: Oncoethix SA: Research Funding. Brice:Seattle Genetics, Inc.: Research Funding; Takeda Pharmaceuticals International Co.: Honoraria, Research Funding; Roche: Honoraria. Thieblemont:Oncoethix SA: Research Funding.
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Royer, Bruno, Florence Magrangeas, Bruno Lioure, Jean-Paul Fermand, Cyrille Hulin, Lionel Karlin, Sylvie Cailleres, et al. "First Large Prospective Study For Patients With Primary Plasma Cell Leukemia: Bortezomib-Doxorubicine-Dexamethasone/Bortezomib-Cyclophosphamide-Dexamethasone Regimens As Induction Before Stem Cell Transplantation Followed By Consolidation With Lenalidomide-Bortezomib-Dex Or Allograft. (a study of the IFM group)." Blood 122, no. 21 (November 15, 2013): 761. http://dx.doi.org/10.1182/blood.v122.21.761.761.
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Abstract Introduction Primary plasma cell leukemia (pPCL) is a rare form of plasma cell malignancy with poor prognosis (usually less than 12 months survival with conventional chemotherapy). Only one prospective study with Lenalidomide-Dex before high dose therapy has been recently reported1. Bortezomib-based regimens and high dose Melphalan/ autologous stem cell transplantation (HDM/ASCT) have shown promising results in small retrospective studies. We report here the first prospective multicenter phase II trial for pPCL patients (pts) treated with Bortezomib-Doxorubicine-Dexamethasone (PAD) / Bortezomib-Cyclosphosphamide-Dexamethasone (VCD) as induction before HDM/ASCT. With the aim to improve response and survival, allograft or second ASCT plus consolidation/maintenance with Lenalidomide-Bortezomib-Dex (VRD) were proposed. Patients and method Non-previously treated pts with a diagnosis of pPCL were enrolled in this phase II study of the IFM group from April 2010 to July 2013. PAD (dexa 40 mg + bortezomib 1,3 mg/m2 on day 1, 4, 8, 11 + doxorubicine 30 mg/m2 day 4) and VCD (dexa + bortezomib + cyclophosphamide 300 mg/m2 day 1, 8) were administrated alternatively each 21 days for 4 cycles. For responding patients with circulating plasma cell < 1%, peripheral stem cells were collected after Cyclophosphamide + G-CSF. Either (i) double HDM/ASCT was performed followed by consolidation/maintenance íVDR (dexa 40mg + bortezomib 1,3 mg/m2 on day 1, 4, 8, 11 + lenalidomide 15 mg day 1-15) each 3 months and Lenalidomide 15 mg 21/28 days on others months, for 1 yearý or (ii) tandem HDM/ASCT-reduced intensity conditioning-allograft if there were < 66 years-old. Primary end-point was progression free survival (PFS); secondary end-points were responses rates, overall survival (OS), feasibility, and toxicity. We evaluated the disease response to therapy with the IMWG criteria and the percentage of circulating plasma cells; minimal residual disease (MRD) was evaluated during follow-up. Peripheral circulating plasma cells and bone marrow plasmocytes were collected at diagnosis for centralized FISH and SNP array analysis. Results 40 pts were enrolled with a median age of 55y (27-71). Median follow-up was 12.6 months (7.6-24.8). At diagnosis, the median number of circulating plasma cell was 5.2 G/L (1.3-66). Twenty-two percent had creatinine clearance < 50 ml/min, and 11% < 30 ml/min, 44% had an ISS score of 2 and 37% ISS 3. After induction 35 pts are evaluable. In the intent to treat analysis, 25 (72%) responded (VGPR+CR 37%, PR 28%, SD 5%) and 10/35 (28%) were refractory (pts having circulating plasma cell ≥ 1%) and did not continue the study. Twenty-three of the 25 responding pts underwent HDM/auto and 20 pts are evaluable at 3 months: CR+VGPR 14/20 (70%), PR 4/20 (20%), 1/20 (5%) and PD 1/20 (5%). Second HDM/auto was performed in 6 pts and allograft in 12. Ten of the 14 (72%) evaluable pts achieved VGPR or better and 4/14 (28%) PR. Six pts are currently on consolidation/maintenance phase with VRD. Median PFS was 17.8 months. Median OS was not reached. Genomic data are shown in Table I. MDR evaluation will be presented later. Major toxicities were hematological and infections. Eight pts died: 5 during induction, 1 at HDM/ASCT and 2 post allograft while in relapse. Of note, 2 pts had meningeal involvement at relapse. Conclusion This first large study for pPCL patients with PAD/VCD as induction and HDM/ASCT is effective and induce high responses rates. Consolidation with Allograft or bortezomib-lenalidomide-dex is currently investigated. 1Musto P et al. Blood (ASH Annual Meeting Abstracts) 2011; 118 Abstract2925Table I: genomic Disclosures: Leleu: CELGENE: Honoraria; JANSSEN: Honoraria. Moreau:Celgene: Honoraria, Speakers Bureau. Avet-Loiseau:CELGENE: Honoraria, Speakers Bureau; JANSSEN: Honoraria, Speakers Bureau.
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Doorduyn, Jeanette K., Gustaaf W. van Imhoff, Kees CAGM van Montfort, Harry C. Schouten, Martyn Ronald Schaafsma, Johanna W. Baars, Marie Jose Kersten, et al. "Treatment of Secondary Central Nervous System Lymphoma with Intrathecal Rituximab, High Dose Methotrexate and R-DHAP, Followed by Autologous Stem Cell Transplantation. A Phase II HOVON Study." Blood 120, no. 21 (November 16, 2012): 306. http://dx.doi.org/10.1182/blood.v120.21.306.306.
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Abstract Abstract 306 Introduction. The prognosis of patients with relapsed diffuse large B-cell lymphoma (DLBCL) and central nervous system (CNS) involvement is poor, with a median survival of 2–4 months, and less than 10% 1-year survival. Generally, CNS recurrence is concurrent with or followed soon by systemic relapse or progression. The CNS localization is often meningeal. Therefore, we decided to study the feasibility and efficacy of a new treatment regimen consisting of the standard treatment of relapsed DLBCL (R-DHAP and autologous stem cell transplantation (ASCT)) combined with intrathecal rituximab and high dose methotrexate (MTX) intravenously. Methods. Patients aged 18–65 years with a CNS relapse of DLBCL, based on positive cerebrospinal fluid (CSF) or biopsy proven parenchymal brain localization, with or without systemic progression or relapse, were eligible for our study. Patients with CNS localization based on a typical MRI and concurrent systemic progression or relapse could be included as well. Treatment consisted of 3 cycles of R-DHAP-MTX (dexamethason 40 mg d1-4, cisplatin 100 mg/m2 d1, cytarabine 2 × 2 g/m2 d2, rituximab 375 mg/m2, d5, methotrexate 3 g/m2 d15). Intrathecal rituximab 10 mg was scheduled on d0, followed by 25 mg on day 4, 8, 11 and 21 during cycle 1, and 4 and 3 administrations during cycle 2 and 3, respectively. Patients failing to clear the CSF at the start of cycle 2 could switch to intrathecal methotrexate/cytarabine/dexamethason. In patients with at least a PR and no evidence of lymphoma in bone marrow and CSF after cycle 2, stem cells were harvested after the third R-DHAP cycle. This was followed by MTX cycle 3 and consolidation with busulfan/cyclophosphamide and ASCT. Patients with stable disease or progression, or evidence of lymphoma in the bone marrow or CSF after 2 cycles, went off protocol. Results. 36 patients, aged 23–65 year (median age 57) entered the study between May 2007 and April 2011. The CNS relapse was diagnosed 63–3174 days (median 352) after the primary diagnosis. 23 patients had a parenchymal localization on MRI, 16 patients had a positive CSF. At the time of CNS relapse 18 patients had no evidence of systemic relapse. After inclusion of 13 patients, 3 patients had experienced a temporary severe painful radiculopathy after the first intrathecal injection with 25 mg rituximab. Therefore, the study was amended and the dose of all intrathecal rituximab administrations was reduced to 10 mg. After this amendment no more side effects of intrathecal rituximab were observed. 34 patients started the intrathecal rituximab. 14 patients received the planned amount of 12 intrathecal rituximab injections. 8/16 patients with positive CSF cleared the CSF from lymphoma before the start of the second R-DHAP. 6/16 failed to clear the CSF from lymphoma, and had to switch to MTX/ARA-C/dexa. 4 of these 6 obtained a negative CSF following this treatment change. 1/16 experienced side effects from rituximab and had to switch to MTX/ARA-C/dexa. In 1/16 patients the CSF response could not be evaluated. After 2 cycles of systemic and intrathecal therapy the CNS response (based on CSF and MRI) was CR or PR in 10 and 13 patients respectively. The overall response rate (including CT and bone marrow) was 53% (19/36), CR rate 28% (10/36). 15 patients (42%) completed treatment according to protocol. The median response duration is 6 months. With a median follow-up of the patients still alive of 20.5 months, the median PFS and OS is 6 and 7 months respectively. PFS at 1 year is 21%, and OS 22%. 20/36 patients died due to NHL, other causes of death were excessive toxicity (n=3), late infection (>3 months after ASCT)(n=2) and unknown (n=2). Conclusion. The combination of R-DHAP-MTX with intrathecal rituximab at a dose of 10 mg is feasible. 25 mg intrathecal rituximab resulted in unacceptable side effects. The outcome of secondary CNS lymphoma following high dose chemotherapy however remains poor, with a median OS of 7 months and a 1-year overall survival of 22%. Disclosures: Off Label Use: intrathecal rituximab.
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Reilly, Eileen, and Justin Hwang. "Listeria Cerebritis with Tumor Necrosis Factor Inhibition." Case Reports in Infectious Diseases 2020 (April 25, 2020): 1–5. http://dx.doi.org/10.1155/2020/4901562.
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Background. Listeria monocytogenes is historically a central nervous system pathogen of consideration in the very young, very old, and immune suppressed. Diagnosis of Listeria is based on positive bodily fluid culture or PCR testing. Cerebral edema is nonspecific and can be a manifestation of vasculitis, trauma, anoxia, ischemia, infarction, malignancy, or an infectious process. A main mechanism of immune protection against Listeria is tumor necrosis factor (TNF). Lenalidomide, an immunosuppressant, inhibits TNF. Case Presentation. A 61-year-old female with diabetes mellitus 2 and multiple myeloma treated with stem cell transplant and immunosuppressant (lenalidomide) was found to have cerebral edema after presenting with headache for 3 weeks and new focal neurologic deficits. Vitals signs were stable, with no meningeal exam findings and unremarkable initial serum testing. Blood cultures on days 0 and 2 of hospitalization as well as cerebral spinal fluid cultures were negative for infectious organisms. PCR testing of CSF was also negative for microorganisms. Brain biopsy was scheduled but postponed due to outstanding prion testing. The patient’s focal neurologic deficits worsened prompting administration of dexamethasone after extensive negative infectious disease workup. By day 6, gross neurologic function deteriorated prompting transfer to higher level of care where the patient spiked a fever and one set of blood cultures revealed Gram-positive bacillus. Aggressive antimicrobial therapy was initiated, excluding ampicillin; however, this was later added. Blood culture further identified Listeria monocytogenes. By day 17, the patient suffered demise. Autopsy revealed brain microabscess lesions consistent with Listeria. Conclusion. Clinicians should employ prophylactic antimicrobial treatment for Listeria when caring for those patients presenting with cerebral edema who are immune suppressed with TNF inhibition no matter the initial exam findings, serum testing, and/or radiologic interpretation. If initial workup is negative and brain biopsy is needed to determine the next course of action in the patient with cerebral edema, transfer the patient to a higher level of care if unable to complete biopsy at your facility in an expedient fashion.
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Fischer, L., A. Korfel, K. Jahnke, P. Kiewe, and E. Thiel. "High-dose methotrexate and ifosfamide for CNS relapse of aggressive lymphoma." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 12524. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.12524.
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12524 Background: CNS involvement is a grave complication of malignant lymphoma. Therapy traditionally includes intrathecal chemotherapy, radiotherapy and systemic chemotherapy for concomitant systemic lymphoma. However, optimal therapy has not been established thus far for CNS lymphoma. In this pilot study a combination of systemic high-dose (HD) methotrexate (MTX) and ifosfamide (IFO) was evaluated for toxicity and response rate. Methods: 10 patients (pts.) with CNS relapses of aggressive lymphoma (5 nodal DLBCL, 4 PCNSL/PIOL and 1 T-NHL) were treated. Nine pts. had intracerebral lesions, the meningeal compartment was involved in three. Three pts. had systemic manifestations. Median age was 63 years (32 - 83). Therapy consisted of 4g/m2 MTX (4h infusion on day 1) with dose adjustment for creatinine clearance (CC) < 100ml/min (CC/100 * 4g/m2) and 1.5 to 2g/m2/day IFO (3h infusion day 3 to 5). Supportive therapy included mesna and a leucovorin rescue beginning at 24h after start of MTX. Two pts. were treated with intrathecal chemotherapy before MTX/IFO. Results: A median of 4 cycles chemotherapy was administered. Treatment response was documented in 9 pts. (3 CR, 6 PR), and one patient had stable disease. The toxicity was mainly hematologic with grade 3/4 neutropenia in 6 pts., grade 3/4 thrombocytopenia in 4 pts. and grade 3 anemia in 2 pts. One pat. died from sepsis in neutropenia and one pat. with long-term corticosteroid therapy developed an aspergillus pneumonia grade 3. Nephrotoxicity grade 1/2 was observed in 6 pts.. Four pts. were further treated with HD chemotherapy followed by autologous stem cell transplantation or salvage radio-/chemotherapy. A median progression free survival of 6.5+ months (range 1–41+) for all pts. has been reached with persisting remission after 4 to 41 months in 5 pts.. Conclusions: Systemic combination therapy with MTX and IFO is feasible and exhibits a promising activity in CNS relapses of aggressive lymphoma. No significant financial relationships to disclose.
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Baron, Marine, Emmanuel Gyan, Hélène Merle-Beral, Veronique Leblond, Nathalie Cassoux, Valerie Touitou, Bahram Bodaghi, Adil Darugar, and Sylvain Choquet. "High Efficiency and Tolerance of Temozolomide in Relapse/Refractory Primary Intra-Ocular Lymphoma (R/R PIOL). a Retrospective Multicentric Study from the LOC Network." Blood 124, no. 21 (December 6, 2014): 3080. http://dx.doi.org/10.1182/blood.v124.21.3080.3080.
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Abstract Background: PIOL, now named “primary vitreo-retinal lymphoma”, is a very rare subset of non Hodgkin lymphoma, usually arising in elderly patients and characterized by a high level of relapse, mainly in the first year, with more than 20% of cases relapsing in brain, and a short survival. There is no consensus on treatment procedures, even in first line, and prospective comparative studies do not exist. Classical attitudes are systemic chemotherapy (SC), often high dose methotrexate, radiotherapy or intraocular injection of methotrexate but publication on R/R PIOL are exceptional. New treatments are necessary, especially with a good tolerance profile. As Temozolomide (Te) hassome efficiency on primary-central-nervous-system lymphoma (PCNSL) we used this drug in R/R PIOL in our center. Methods: Inclusion criteria were R/R PIOL and/or PIOL not eligible for IV chemotherapy. Diagnosis was established on cytological and molecular analysis after vitrectomy, and the absence of brain or meningeal localization verified by MRI and lumbar puncture. Treatment consisted in Te at 150mg/m2 orally 5 days per month, without corticosteroid use, in absence of any response, dosage was increased to 200mg/m². A complete response was defined as a normalization of eye exam and intraocular interleukins 10 and 6 levels. Results: Sixteen patients were analyzed, 3 males and 13 females, mean age 75 years [35-90]. All but two received systemic chemotherapy with at least high dose methotrexate and high dose cytarabin before Te, 8 were in second line, 4 in third, with 1 patient who relapsed after autologous stem-cell transplantation (ASCT) conditioned by thiotepa, cyclophosphamide and busulfan, and 2 in forth. The 2 patients treated in first line where more than 80 years old. Median duration of treatment was 5 months. The median follow-up (fu) is 16 months. Overall response rate is 75%, with 10 CR (63%) and 2 PR (13%). At the last fu, 7 patients are still in CR, with a median DFS of 13 months. The patient treated after ASCT relapse is still in CR at 62 months. The two old patients treated in first line are in CR at last fu. Two patients where treated a second time by Te after relapse, obtaining 2 new CR, one of 4 months, one persistent at 14 months. Median OS is not reached. Only 3 patients experienced hematological grade 3/4 toxicity. Conclusion: This work represents the biggest study with an homogeneous treatment in R/R PIOL. Temozolomide appears as a safe and efficient treatment of R/R PIOL or in first line in patients in bad condition, even after high dose chemotherapy and/or in elderly patients. Longer follow-up, prospective and larger studies are necessary to confirm these data Disclosures Leblond: Roche: Honoraria, Speakers Bureau.
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Mesmoudi, Mohamed, Nathalie Cassoux, Veronique Leblond, Helene Merle-Beral, Sylvie Baudet, and Sylvain Choquet. "First Use of Temozolomide in Primary Intra-Ocular Lymphoma (PIOL): a Very Well Tolerated and Potentially Effective Treatment." Blood 114, no. 22 (November 20, 2009): 4760. http://dx.doi.org/10.1182/blood.v114.22.4760.4760.
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Abstract Abstract 4760 Background PIOL is a rare subset of primary central nervous system lymphoma (PCNL), representing 5 to 20% of PCNL. It is usually an aggressive diffuse large B-cell lymphoma. There is no consensus on treatment procedures, classical attitudes are systemic chemotherapy (SC), radiotherapy or intraocular injection of methotrexate (IM). Relapse rate is high, with more than 10% of cases relapsing in brain. New treatments are necessary, especially with a good tolerance profile. Temozolomide (Te) has some efficiency on PCNL and seems to be a potential candidate. Methods we retrospectively analyzed PIOL treated by Te in our unit. Inclusion criteria were a diagnosis established on cytological and molecular analysis after vitrectomy or anterior chamber puncture, and the absence of brain or meningeal localization. Interleukin 10 (IL10) and 6 (IL6) dosages were made by enzyme-linked immunosorbent assay on ocular material. IL10/6 ratio >1 is a specific and sensitive test for PIOL diagnosis and IL10 kinetic a good marker of response in parallel with clinical examination. Treatment consisted in Te at 150mg/m2 orally 5 days per month, in monotherapy, without corticosteroid use. Results four patients were analyzed, 3 males and one female. All received systemic chemotherapy with at least high dose methotrexate in first line, two with addition of high dose cytarabin. First patient, aged 84 at diagnosis, relapsed 15 month after CR and received Te for three months until here death, probably by CNS lymphoma. Second patient, aged 65, progressed under SC and subsequently received IM without any success; Te was used in third line but no effect was seen. Third patient, aged 48, had a partial response after first line treatment and received SC with high dose cytarabin and stem cell transplantation; after CR he relapsed 33 months later and then received Te, partial response was clinically confirmed at 3 months and is stable at 6 months. Last patient, age 71, had a localized PIOL 3 years after the treatment of a follicular lymphoma; PIOL relapsed 6 month after the first line and Te began; clinical response was spectacular, with a vision normalization in less than one month, a clinical CR confirmed at two months, IL10 dosages were at more than 1500 pg/ml in both eyes before Te, at 22 pg/ml (left eye) after one month and 202 pg/ml (right eye) after two months, response is stable at 5 months. No toxicity appeared during treatment except for hematological grade I or II. Conclusion Temodal is a safe and effective treatment of PIOL after classical chemotherapy. Longer follow-up and larger studies are necessary to confirm these data Disclosures: No relevant conflicts of interest to declare.
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Decimo, Ilaria, Francesco Bifari, Francisco Javier Rodriguez, Giorgio Malpeli, Sissi Dolci, Valentina Lavarini, Silvia Pretto, et al. "Nestin- and Doublecortin-Positive Cells Reside in Adult Spinal Cord Meninges and Participate in Injury-Induced Parenchymal Reaction." STEM CELLS 29, no. 12 (November 16, 2011): 2062–76. http://dx.doi.org/10.1002/stem.766.
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Castagnola, Carlo, M. Lunghi, S. Calatroni, and M. Lazzarino. "Liposomal Cytarabine for Central Nervous System (CNS) Relapse in Acute Promyelocytic Leukemia (APL)." Blood 108, no. 11 (November 16, 2006): 4588. http://dx.doi.org/10.1182/blood.v108.11.4588.4588.
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Abstract CNS relapse occurs in ~5% of cases of APL. Conventional treatment includes intrathecal (IT) chemotherapy with methotrexate (MTX) and/or cytarabine, systemic salvage chemotherapy, and sometimes cranial irradiation: survival is poor, ranging from weeks to a few months. Liposomal cytarabine (DepoCyte®) is a novel sustained-release formulation with a terminal half-life ~40 × longer than free cytarabine (Bleyer et al. Clin Cancer Res 99;5:3349) and is approved for the treatment of adults with lymphomatous meningitis (LM): liposomal cytarabinbe has been shown to be more effective than free cytarabine in patients with LM (Glantz et al. JCO1999;17:3110). Intrathecal (IT) injections of this agent are given once every 2 weeks during treatment, as opposed to 2–3 × per week for free cytarabine or MTX, and an Ommaya reservoir is not required. In this report we present the case of a patient with CNS relapse of APL, refractory to conventional treatment including chemotherapy with high-dose (HD) cytarabine plus idarubicin, IT MTX, and cranial irradiation, who has been treated successfully with liposomal cytarabine.In July 2003, a 33-year-old woman was admitted with low-risk APL (hypergranular leukemic promyelocytes). Blood counts showed: Hb 5.3 g/dL, leukocytes 9.3 ×109/L, platelets 53 ×109/L. Cytogenetics showed t(15;17) and RT-PCR was positive for PML/RARα (bcr1 isoform). The patient achieved a hematological remission after induction and a molecular remission after consolidation using the AIDA protocol (Mandelli et al. Blood1997;90:1014). Molecular relapse during maintenance was treated with idarubicin plus ATRA resulting in a second molecular remission. In June 05, autologous peripheral blood stem cell transplant (PML/RARα-negative) was performed during molecular remission. Following a third molecular relapse in September 2005, with headache, APL cells and PML/RARα transcript were identified in the cerebrospinal fluid (CSF). Prolonged cytopenia characterized by fever and possible fungal pneumonia followed IT MTX, HD cytarabine plus idarubicin and cranial radiation, which induced a bone marrow molecular remission, but CSF showed persistence of APL cells, confirmed by PML/RARα. In November, the patient was treated with IT liposomal cytarabine 50 mg every 2 weeks with concomitant dexamethasone. CSF was obtained before each IT treatment: 14 days after the first treatment, no APL cells or PML/RARα transcript were found in CSF. Unfortunately, despite the use of dexamethasone, after the third IT injection, arachnoiditis developed, with headache, pain, confusion, somnolence and agitation. Arachnoiditis can be caused by meningeal infiltration by tumor cells, cranial irradiation and IT administration of drugs: it is difficult to distinguish between these causes. HD steroid was started, and the patient recovered after a few days. The patient remains in CNS remission, but suffered a bone marrow relapse in May 2006, which was treated with chemotherapy. In this patient, IT liposomal cytarabine resulted in a prolonged remission of CNS disease. Unfortunately, treatment of her systemic disease proved less successful.
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Choquet, Sylvain, Nathalie Cassoux, Hlne Merle-Beral, and Veronique Leblond. "Exceptional Efficiency and Tolerance of Temozolomide in Relapse/Refractory Primary Intra-Ocular Lymphoma (R/R PIOL)." Blood 118, no. 21 (November 18, 2011): 4939. http://dx.doi.org/10.1182/blood.v118.21.4939.4939.
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Abstract Abstract 4939 Background: PIOL is a very rare subset of non Hodgkin lymphoma, usually arising in elderly patients and characterized by a high level of relapse, mainly in the first year, with more than 10 of cases relapsing in brain, and a short survival. There is no consensus on treatment procedures, even in first line, and prospective comparative studies do not exist. Classical attitudes are systemic chemotherapy (SC), often high dose methotrexate, radiotherapy or intraocular injection of methotrexate (IM) but publication on R/R PIOL are exceptional. New treatments are necessary, especially with a good tolerance profile. As Temozolomide (Te) hassome efficiency on primary-central-nervous-system lymphoma (PCNSL) we used this drug in R/R PIOL in our center. Methods: Inclusion criteria were a diagnosis established on cytological and molecular analysis after vitrectomy or anterior chamber puncture, and the absence of brain or meningeal localization. Treatment consisted in Te at 150mg/m2orally 5 days per month, without corticosteroid use, in absence of any response, dosage was increased to 200mg/m2. A complete response was defined as a normalization of eye exam and intraocular interleukins 10 and 6. Results: Six patients were analyzed, 2 males and 4females, mean age 70 years \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\frac{49}{82}.\) \end{document}. All received systemic chemotherapy with at least high dose methotrexate and high dose cytarabin before Te, five were in second line and one in third, after autologous hemopoietic stem cells transplantation (ASCT) conditioned by thiotepa, cyclophosphamide and busulfan. Mean response duration before Te was 241 days \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\frac{23}{524}.\) \end{document}. All but one received Te in monotherapy, one having an association with ifosfamid followed by ASCT. CR has been obtained in 3 patients, PR in one, progressive disease in two. One of the 3 patients in CR stopped Te by himself after three months, relapsed two months later and is again in CR after reintroduction of Te. CR patients are still disease free at 42, 190 and 878 days; two of these patents described a clear improvement of their vision as soon as one or two weeks after Te introduction. Overall survival for the six patients, from day 1 of Te is 313 days \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\frac{101}{1001}.\) \end{document} No grade 3/4 toxicity has been described. Conclusion: This study describe for the first time use of Te in PIOL, and in this very rare disease, it represents significant series. Te appears as a safe and efficient treatment of R/R PIOL, even after high dose chemotherapy and/or in elderly patients. Longer follow-up and larger studies are necessary to confirm these data. Disclosures: No relevant conflicts of interest to declare.
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Sockanathan, Shanthini, and Nicholas Gaiano. "Meninges Play a RAdical Role in Embryonic Neural Stem Cell Regulation." Cell Stem Cell 5, no. 5 (November 2009): 455–56. http://dx.doi.org/10.1016/j.stem.2009.10.010.
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Labar, Boris, Stefan Suciu, Petra Muus, Roelof Willemze, Jean-Pierre Marie, Georges Fillet, Zwi Berneman, et al. "Dexamethasone Versus Methyl-Prednisolone in Induction Therapy for Adult Acute Lymphoblastic (ALL) and Non-Hodgkin Lymphoma (NHL) Patients ≤ 60 Yrs Old: Final Results of the Eortc All-4 Phase III Trial." Blood 106, no. 11 (November 16, 2005): 1834. http://dx.doi.org/10.1182/blood.v106.11.1834.1834.
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Abstract In some recent trials high dose of Dexamethasone (Dexa) combined with chemotherapy has been used for induction therapy in adults with ALL because it may exert higher antileukemic activity. Increased level of drug in the cerebrospinal fluid might also prevent meningeal leukemic infiltration. However, high dose of Dexa may be associated with an increased risk of sepsis and fungal infections. By using a lower dose of dexamethasone these serious infections may be circumvented without jeopardize the antileukemic activity. The main aim of the EORTC ALL-4 study was to determine the efficacy and toxicity of a lower dose of Dexa administered during the induction therapy, as vs the ones of conventional dose of prednisone (Pred). In the ALL-4 study, patients (pts) ≤ 60 years had to receive either dexamethasone (10 mg/m2/day) or 6-methyl-prednisolone (60 mg/m2/day) on days 1–8 and 15–22 with standard induction chemotherapy (cyclophosphamide i.v. 750 mg/m2 on day 1 and 8; daunorubicine 30 mg/m2 on day 1–3 and 15–16; vincristine 1.4 mg/m2 (maximum 2 mg) and methotrexate /MTX/ i.t. 15 mg on days 1, 8, 15 and 22). All pts than receive the HAM consolidation course (HD-AraC 3 g/m2 every 12 hours on days 1–4; mitoxantrone 10 mg/m2 on days 5–7 and MTX 15 mg i.t. on day 1). Pts in CR received two courses of MA consolidation (MTX 1.5 g/m2 i.v on day 1 and L-asparaginase 104 IU/m2 on day 2). All pts with a family donor were assigned to undergo allo-SCT. Pts without the donor were randomized either to receive autologous stem cells from peripheral blood or continuous standard high maintenance chemotherapy. After a median follow-up of 4.9 years, 198 pts died. Between 1996 and 2003 a total of 325 pts were randomized in the ALL-4 study: 163 in the Dexa arm and 162 in the Pred arm. CR after induction/HAM was achieved in 128 (78.5%) pts receiving Dexa and in 120 (74.1%) pts treated with Pred. Among them, in Dexa group 61 pts relapsed, 19 died in CR and 48 are still in CCR, whereas in the Pred group, 58 pts relapsed, 8 died in CR and 54 are in CCR. The 5-year DFS rates was 32.7% in the Dexa group vs. 34% in the Pred group, the HR=1.15, 95% CI 0.83–1.59, p=0.40. The relapse rates were extremely similar (HR=0.99, p=0.96), whereas the death in CR rate was higher in the Dexa group compared to Pred group: HR=2.33, 95% CI 1.02–5.33, p=0.04. The overall 5-year survival rate in Dexa vs Pred group was 30.7% and 32.5% respectively (HR=1.11, 95% CI 0.84–1.43, p=0.46). The incidence of infection was similar during induction (Dexa: 55% vs Pred: 59%) and during HAM consolidation (Dexa: 85% vs Pred: 78%). More pts were allografted in CR1 in the Dexa than in the Pred arm (45 vs 33), and the mortality post allo-SCT was higher in the Dexa group (12/45=26.7%) than in the Pred group (5/33=15.2%). The results of ALL-4 trial indicate that there is no benefit of dexamethasone compared to 6-methyl prednisone during induction therapy in adult ALL-NHL pts.
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Lesueur, P., G. Damaj, K. Hoang-Xuan, V. Rolland, A. Schmitt, O. Chinot, M. Fabbro, et al. "P14.73 Toxicity and outcomes of reduced-dose whole brain radiotherapy as consolidation treatment for patients with CNS lymphoma in real life setting." Neuro-Oncology 21, Supplement_3 (August 2019): iii84—iii85. http://dx.doi.org/10.1093/neuonc/noz126.308.
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Abstract BACKGROUND Optimal treatment strategy for newly diagnosed primary PCNSL remains controversial. The high risk of radio-induced late-delayed neurotoxicity in patients who achieve long-term disease control constrains the use of classical consolidation WBRT. So as to reduce side cognitive effects, Morris et al, reported a phase II study, to assess the efficacy and toxicity of consolidation reduced-dose (23.4Gy) WBRT (rdWBRT) for patients with complete response after high dose methotrexate based chemotherapy. The study reported a 2-year PFS rate for these patients of 77%, with no evidence of significant cognitive decline during the follow-up (FU) period. The aim of this retrospective study was to report toxicity and outcomes of rdWBRT, in patients < 60 years old with complete response (CR) after HD-MTX based chemotherapy, in real life setting, without selection bias. MATERIAL AND METHODS Patients were selected from the French LOC network database, a nationwide database centralizing since 2011 information from 28 different centers in France, representing the main centers involved in PCNSL management. Patients were retrospectively selected according to the following criteria: 1) Pathological diagnosis of diffuse large B cell PCNSL; 2) age>18 and <60 years; 3) immunocompetent status; 4) First line induction treatment based on high dose MTX (At least MTX>1.5 g/m2); 5) CR according to the IPCG criteria after first-line induction treatment. Patients should have received a rdWBRT (23.4Gy in 13 fractions of 1.8Gy). RESULTS Twenty seven patients, were included. The median FU from initial diagnosis was 28.5 months [9.6–50.7]. Median age was 50.2 years [25–60]. Median Karnofsky Performans Status (KPS) was 90% [40–100%]. Seventeen patients had a multi focal disease at diagnosis (meningeal involvement n=6, in ophthalmic involvement n=4). PFS rates were 85% IC95[76–100 %], 65% IC95 [45–85%] and 65% IC95 [45–85%] at 1, 2, and 3 years respectively. The OS rates were 100%, 90,5% IC95 [77–100%] and 85%IC95 [69–100%]. 8 patients relapsed, with a median time from radiotherapy to recurrence of 6.5months [2.4–17]. All recurrences were outside the initially involved site(s), and 62.5% of tumors recurred as multifocal disease. All patients received salvage treatment, including intensive chemotherapy with autologous stem cell transplantation in 4 cases. No acute grade III-IV toxicity related to rdWBRT was reported. Neuropsychological follow up was available for 14 patients with no cognitive impairment at last follow up. CONCLUSION This is the largest retrospective study evaluating outcomes of rdWBRT for PCNSL young patients with CR after HD-MTX chemotherapy. Real life setting data from this study are quite reassuring, and rdWBRT could be considered as an efficient and safe consolidation strategy in this population. We need a longer FU to confirm the absence of cognitive deterioration.
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Simon, Laurence, Xavier Leleu, Jehan Dupuis, Therese Aurran, Lauris Gastaud, Carole Soussain, Beatrice Mahe, et al. "Bing Neel Syndrome: The French Experience." Blood 124, no. 21 (December 6, 2014): 3068. http://dx.doi.org/10.1182/blood.v124.21.3068.3068.
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Abstract Background: Bing-Neel syndrome (BNS) is a rare complication of Waldenström Macroglobulinemia (WM) defined as the direct involvement of central nervous system (CNS) by neoplastic cells. Because of its rarity, few data are currently available in the literature, which is mostly based on case-reports descriptions. The management of these patients is challenging with no consensus about the best treatment strategies to use. Patients and Methods: We retrospectively analyzed 37 patients out of 15 French centers databases, treated for a BNS between 1995 and 2014. Results: At the time of BNS diagnosis, the median age was 64 years. In 13 cases (35%), BNS was the first manifestation of WM. In others cases, median time between WM diagnosis and BNS was 96 months (range 2-300).BNS occurrence was correlated with a systemic progression of WM in 30% of cases. For the others patients with no systemic progression of WM, median time between the end of the last treatment of WM and BNS diagnosis was 30 months (range 10-72). The median IgM level was 11.25 g/L (range 0.35-60.8) at the time of BNS onset. Clinical manifestations: the most frequent symptoms at the time of BNS diagnosis were cognitive impairment (32%), motor or sensory deficits (30% and 16% respectively), pain (16%), cranial nerves involvement (30%), headache (21%), poor performance status (32%) and cauda equina syndrome (18%). The median interval between appearance of neurological symptoms and diagnosis of BNS was 4 months. Cerebrospinal fluid (CSF) analysis showed a lymphocytic meningitis in 81% of cases with a median of 33 cells/mm3 (range 7-3900), all with monoclonal B-cell population when phenotyping was available (except one case). Protein level was elevated in 94% (1,77 g/L in median, range 0,52-7,23). Magnetic resonance imaging (MRI) showed abnormalities in 83% (n=29/35) of cases. Meningeal enhancement was present in 52% of cases with conus medullaris infiltration in half of these patients. Cerebral enhancement was present in 45 % of cases and a normal pressure hydrocephalus in 3 cases. In 17% of cases, MRI was normal. Based on MRI results and CSF analysis, the majority of patients (81%, n=30/37) had an infiltrative form with only 7 patients presenting with a pseudotumoral involvement of brain parenchyma. The diagnosis was made on CSF analysis in the majority of cases (82%, n= 28/34). In four cases the diagnosis required a brain biopsy. First-line treatment comprised systemic chemotherapy in 89% (n=33/37) of cases. Treatment of CNS involvement was based on high-dose chemotherapy in 17 cases (methotrexate and/or aracytine). Intra-thecal chemotherapy was used in 70% of cases, and rituximab in 58% of cases. Autologous stem-cell transplantation (ASCT) in first-line was performed in 4 cases. 4 patients were treated up-front by whole-brain radiotherapy (in combination with systemic chemotherapy by fludarabine, cyclophosphamide and rituximab in 1 case). Outcome: 31 patients were assessable for first-line treatment response: overall response rate (ORR) was 68% (n=21/31) including 7 complete remissions; 7 patients had a progressive disease. 9 patients died. Median follow-up of alive patients was 23 months. At 5 years after BNS diagnosis, 79% of the patients were alive. Conclusion: Up to now, this is the most important retrospective cohort of patients presenting with Bing-Neel syndrome. In more than one third of the cases, BNS was the first manifestation of WM disease. Noteworthy is the late occurrence of some cases, up to 25 years. No correlation was observed between systemic progression of WM and BNS occurrence. BNS should be considered even in the context of a stable WM disease. In order to define the best treatment strategies, collection of additional cases is currently ongoing, and data will be up-dated at time of the meeting. Disclosures No relevant conflicts of interest to declare.
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Kasamon, Yvette L., Robert A. Brodsky, Michael J. Borowitz, Pamela A. Crilley, Richard F. Ambinder, Richard J. Jones, and Lode J. Swinnen. "Efficacy of a Brief, Cyclophosphamide-Intensive Regimen for Older Patients with Newly Diagnosed Burkitt's or Atypical Burkitt's Lymphoma/Leukemia." Blood 114, no. 22 (November 20, 2009): 2685. http://dx.doi.org/10.1182/blood.v114.22.2685.2685.
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Abstract Abstract 2685 Poster Board II-661 Background: Although standard therapies cure most adolescents and young adults with Burkitt's lymphoma/leukemia (BL), older patients (pts) have an inferior prognosis with an estimated 1-year survival of 50%. The inferior outcome is attributable to both insufficient efficacy and excess toxicity. Cyclophosphamide (Cy) has long been recognized to be arguably the most active agent in BL. Prior work at our institution showed that high-dose Cy, equivalent to transplantation doses, could be given without stem cell rescue with minimal toxicity even in older pts. Patients and Methods: A phase II trial for pts age ≥ 30, based on intensive Cy and incorporating rituximab but no anthracycline, was developed with a primary endpoint of 1-year overall survival. Entry requirements included newly diagnosed BL or atypical BL; any performance status (PS); HIV negative; and no significant cardiac dysfunction. Renal failure, even if necessitating dialysis, was permitted if it was acute. Treatment consisted of 3 cycles, with successive cycles beginning on day 15 or when ANC was ≥ 500/μL. Cycles 1 and 2 consisted of Cy 1500 mg/m2 IV day 1; vincristine 1.4 mg/m2 (2 mg cap) day 1; prednisone 100 mg days 1-5; rituximab 375 mg/m2 IV days 1 and 8; methotrexate 3 g/m2 IV day 8 with leucovorin rescue; cytarabine 100 mg intrathecally days 1, 4, and 11; and filgrastim. Cycle 3 consisted of rituximab 375 mg/m2 IV day 1; high-dose Cy (50 mg/kg IV days 2, 3, 4, and 5) with uroprotection; filgrastim; and rituximab 375 mg/m2 IV weekly for 4 weeks once ANC was ≥ 1000/μL. Eligibility for cycle 3 included ECOG PS < 4; no disease progression or uncontrolled meningeal disease; not on dialysis; and transaminases ' 5X upper limit of normal. Results: A prespecified interim analysis of the first 12 of a planned 20 evaluable pts is presented. Diagnosis was BL in 8 and atypical BL/unclassifiable high-grade lymphoma with features intermediate between BL and diffuse large B-cell lymphoma in 4. Median age was 56 (range 34 – 75), 8/12 (67%) had Ann Arbor stage III/IV disease, and all were high-risk by Magrath's criteria. PS ranged from 0 to 4. Two pts received hemodialysis on presentation. For all pts, actuarial event-free survival and overall survival (Figure) are 66% and 75%, respectively, at both 1 year and 2 years after treatment initiation. Three pts died during cycle 1: tumor lysis syndrome on day 1, neutropenic sepsis on day 8, multiorgan failure on day 46 after respiratory arrest on day 20. All of the other 9 pts completed protocol therapy: 8 (89%) achieved anatomic CR/CRu as well as a complete metabolic response by PET, and are event-free at a median of 29 months (range < 1 – 44 months) after therapy completion. The remaining pt had residual marrow disease followed by progression and is in remission 1 year after myeloablative allogeneic BMT. Adverse events in these 9 pts included 7 neutropenic fevers; 1 non-neutropenic bacteremia; and 1 self-limited episode of pericarditis with rapid atrial fibrillation. Grade 3 peripheral neuropathy was limited to 2 pts. The planned dose intensity was achievable: median time to cycle 2 was 15 days (14 – 21), and median time from start of cycle 1 to start of cycle 3 was 31 days (28 – 35). Median time to neutrophil recovery after the last dose of Cy was 16 days (10 – 21); median time to platelets ≥ 20,000/μL, without transfusion in the preceding week, was 22 days (0 – 30). Early stopping criteria for response or all-cause mortality have not been met. Conclusion: A very short regimen based on intensive Cy without anthracycline produces a high rate of durable CR's in older, poorer-risk pts with BL or atypical BL. Disclosures: Kasamon: Genentech: Research Funding. Swinnen:Genentech: Consultancy, Research Funding; Enzon: Consultancy; Abbot: Consultancy, Research Funding.
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Paludo, Jonas, Utkarsh Painuly, Shaji Kumar, Francis Buadi, Suzanne R. Hayman, Martha Q. Lacy, Angela Dispenzieri, et al. "Myelomatous Involvement Of The Central Nervous System: Mayo Clinic Experience." Blood 122, no. 21 (November 15, 2013): 3119. http://dx.doi.org/10.1182/blood.v122.21.3119.3119.
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Abstract Background Limited data exist with respect to outcome and optimal therapeutic strategies in patients with central nervous system (CNS) involvement in multiple myeloma (MM). We present a single center experience of patients with myelomatous CNS involvement in newly diagnosed and relapsed / refractory MM. Methods Of 4060 patients with MM seen at Mayo Clinic, Rochester, MN between January, 1st 1998 and December, 31st 2012, 26 patients had identifiable CNS involvement confirmed by biopsy / presence of plasma cells in the cerebrospinal fluid (CSF) and/or identification of intraparenchymal or meningeal involvement by imaging (MRI/CT). Patients were risk stratified by mSMART (Mayo Stratification for Myeloma And Risk-adapted Therapy) criteria. Overall survival (OS) from diagnosis and the time of CNS involvement was calculated using the Kaplan-Meier method. Results Myelomatous CNS involvement occurred in 26 (0.6%) patients with MM of whom 3 were newly diagnosed. The median time to detection of CNS involvement was 24 months (range: 0-125) from diagnosis of MM. Median age at CNS myeloma diagnosis was 58 years (range 37-80) and 73% were male. Abnormally high LDH was observed in 11 out of 22 patients at the time of CNS involvement. Lumbar puncture was performed on 16 patients, 13 (81%) of whom had plasma cells in the CSF detected by cytology/flow-cytometry. Two patients, without evidence of plasma cells, had abnormally high CSF protein and 1 had normal CSF analysis. Of the 25 patients who underwent MRI, 16 (64%) had at least one of the following significant abnormalities; intraparenchymal disease (37%), leptomeningeal enhancement (68%) or direct extension of MM (31%). The neurological symptoms at or after diagnosis of CNS myeloma included headache (38%), cranial nerve palsy (38%), visual disturbance (38%), gait disturbance (35%), paresthesias (35%), limb weakness (31%), confusion (30%), nausea/vomiting (15%), dysarthria (12%), seizures (8%) and urinary incontinence (4%). Fluorescent in-situ hybridization (FISH n=7), cytogenetics (n=8) and/or plasma cell labeling index (PCLI n=12) were available in 18 patients prior to the diagnosis of CNS disease. Ten (56%) out of those 18 patients had high-risk features at least by one criterion. At the time of CNS involvement, six additional patients demonstrated high risk features [5 by PCLI (≥ 3%) and 1 by FISH]. Overall, 16 out of 26 (62%) patients were classified as high risk by mSMART criteria prior to or at the time of CNS involvement. Four (27%) out of 15 had a deletion p53 or monosomy 17 chromosomal abnormality. Median OS was 42 (95% CI, 19-55) months from the diagnosis of MM and 3 months (95% CI: 1-7.9) from the time of CNS involvement (Figure). OS of patients with high risk features was significantly worse (27 months) compared to standard risk disease (67 months, p=0.02) from diagnosis of MM. Eighteen patients received radiation therapy for CNS myeloma. Five of those patients also received intrathecal (MTX and ARA-C) therapy. One patient received intrathecal and systemic chemotherapy. Four patients did not receive any treatment. Novel agents, including bortezomib (23%), thalidomide (15%), and pomalidomide (4%) were administered to the patients post diagnosis of CNS disease. Six (23%) patients underwent autologous stem cell transplant post diagnosis of CNS disease with a median OS of 19 months (95% CI: 10-122 months) from the time of CNS involvement. Conclusion CNS involvement is a rare complication of MM that portends a poor survival outcome. It is likely that the rates in this study are an underestimate of the true incidence due the perceived futility of CNS directed therapy in this disease. Among those recognized, high-risk genetic and markers of increased proliferative activity, including deletion p53 / monosomy 17 and elevated PCLI (≥ 3%) appear to cluster in this cohort. Current therapeutic approaches are largely ineffective in managing this aggressive subset of myeloma patients. Disclosures: No relevant conflicts of interest to declare.
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Chevallier, Patrice, Caroline bodet-Milin, Nelly Robillard, Thomas Eugene, Audrey Ménard, Claire Le Houerou, Thierry Guillaume, et al. "BCR-ABL1 Molecular Remission After 90y-Epratuzumab Tetraxetan Radioimmunotherapy In CD22+ Ph+ B-ALL: A Potential New Treatment Paradigm." Blood 122, no. 21 (November 15, 2013): 3910. http://dx.doi.org/10.1182/blood.v122.21.3910.3910.
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Abstract Introduction Targeted therapies are increasingly becoming treatment options for many hematological diseases. While immuno/chemoimmunotherapy is a recent area of research in acute lymphoblastic leukemia (ALL) (Raetz, JCO, 2008; Advani, Blood, ASH Meeting 2012, abstract 2603), we are unaware of any published studies in ALL using radioimmunotherapy (RAIT), where a potent radionuclide conjugated to an antibody can deliver radiation selectively to the tumor. CD22 is highly expressed in B-ALL. As such, the anti-CD22 humanized antibody, epratuzumab (Immunomedics, Inc., Morris Plains, NJ), which has been studied extensively in non-Hodgkin lymphoma, is also under active investigation in adult and pediatric ALL (see references above). Here we report a patient with Ph+ B-ALL who presented in third relapse and who received RAIT with 90yttrium (90Y)-labeled anti-CD22 epratuzumab tetraxetan, resulting in an outstanding response. Patient and Methods A 57-year-old woman was diagnosed in July 2004 with Ph+ B-ALL. She was documented with a first (meningeal) relapse in September 2009, then a second (bone marrow) relapse in July 2012. Because of no suitable stem-cell donor, the patient was never allografted when achieving first, second, or third complete remission (CR). Previous treatments included various chemotherapy regimens as well all the three available generations of targeted BCR-ABL1 protein fusion tyrosine kinase inhibitors. A third (bone marrow) relapse occurred in December 2012. The peripheral blood showed normal levels of hemoglobin, leukocytes and platelets, with no circulating leukemic blasts, the bone marrow showed 60% blast infiltration, and BCR-ABL1/ABL1 ratios in blood and bone marrow were 22.4% and 13%, respectively. Taking advantage of the patient’s good performance status (ECOG 1) and the high CD22 expression (100%) in the blast population, we decided to treat this patient by RAIT alone. We reduced the treatment dose to be conservative, since we had no prior experience in ALL and the bone marrow showed 60% blast infiltration, which is above the 25% cutoff for standard RAIT dosing in lymphoma. Accordingly, the patient received 2 cycles of 2 doses of 185 MBq/m290Y-epratuzumab tetraxetan administered intravenously one week apart. The Nantes ethics committee approved the treatment plan, and signed informed consent was obtained from the patient. Results Cycle 1: The patient completed both doses of 185 MBq/m290Y-epratuzumab tetraxetan without infusion reactions. Two weeks after starting treatment, she developed Grade 4 neutropenia and thrombocytopenia that subsequently recovered to Grade 1 levels at weeks 7 and 8, respectively. Grade 3 anemia developed 4 weeks after starting treatment and recovered to Grade 1 at week 7. Phenotypic minimal residual disease (MRD) was negative at 4 and 7 weeks. At 4 weeks, BCR-ABL1 transcript was detectable but not quantifiable (<0.01%) in blood sample and positive at 0.017% in bone marrow. Finally, at 7 weeks, BCR-ABL1 transcript was no longer detectable in both samples. No renal or liver toxicities were observed. Cycle 2: Eight weeks after starting the initial treatment, the same treatment was repeated. The patient again completed both doses of 185 MBq/m290Y-epratuzumab tetraxetan with no infusion reactions. No Grade 3-4 hematologic toxicity was observed. Contrary to cycle 1, no transfusions or cytokine support was given. Again, no renal or liver toxicities occurred. Most importantly, evaluations 7 weeks after retreatment and now 6 months (June 2013) from the beginning of RAIT confirmed the persistence of complete phenotypic and molecular responses. Conclusion We report here, for the first time, the feasibility as well as the unexpected efficacy of 90Y-labeled anti-CD22 RAIT in a CD22+, Ph+, B-ALL patient in third relapse. This novel targeted-radiation approach may be a promising therapeutic option for other CD22+ B-ALL patients. We are now conducting a phase I/II study testing this strategy (clinicaltrials no. NCT01354457). Disclosures: Wegener: Immunomedics: Employment, stock options, stock options Patents & Royalties. Goldenberg:Immunomedics: Employment, stock options, stock options Patents & Royalties.
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Ferreri, Andrés J. M., Kate Cwynarski, Elisa Jacobsen Pulczynski, Christopher P. Fox, Elisabeth Schorb, Paul La Rosée, Mascha Binder, et al. "Effects on Survival and Neurocognitive Functions of Whole-Brain Radiotherapy (WBRT) and Autologous Stem Cell Transplantation (ASCT) as Consolidation Options after High-Dose Methotrexate-Based Chemoimmunotherapy in Patients with Newly Diagnosed Primary CNS Lymphoma (PCNSL): Results of the Second Randomization of the IELSG32 Trial." Blood 128, no. 22 (December 2, 2016): 511. http://dx.doi.org/10.1182/blood.v128.22.511.511.
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Abstract Introduction: IELSG32 is an international randomized phase II trial with 2 key clinical questions in pts with PCNSL. The first question focused on optimal induction therapy, and results of the 1st randomization have demonstrated that MATRix combination (methotrexate (MTX), cytarabine (ARAC), thiotepa, rituximab (R)) is associated with significantly better outcome [Ferreri AJ, et al. Lancet Haematol 2016]. The second question addresses the efficacy and neurotolerability of ASCT, as an alternative to WBRT as consolidation. Herein, we report the results of the 2nd randomization (NCT01011920). Methods: HIV-neg pts 18-70 ys and ECOG PS ≤3 with new histology-proven PCNSL and measurable disease were randomly assigned to receive 4 courses of MTX-ARAC (arm A); or R-MTX-ARAC (arm B); or MATRix (arm C). ASC were collected after 2nd c. Pts with responsive or stable disease were further randomized between WBRT 36 ± 9 Gy (arm D) and BCNU-thiotepa conditioned/ASCT (arm E). Stratification parameters were induction arm and response . Primary endpoint of the 2ndrandomization was 2-year PFS. To demonstrate a 2-yr PFS improvement from 65% (P0) to 85% (P1), 52 pts/arm (one-sided; α 5%; β 95%) were required. Consolidation arm would be considered effective if ≥40 pts were progression-free survivors at 2 ys. Analyses were performed on an intention-to-treat (ITT) basis. Effects of consolidation treatments on neurocognitive functions and quality of life (QoL) were assessed with the IPCG tests panel and EORTC-QLQ at baseline, after treatment and every 6 months afterwards. Results: 227 pts were enrolled in 52 centers of 5 countries; 219 assessable pts were referred to 1st randomization (arm A 75; B 69; C 75). 167 pts had responsive or stable disease after induction: 49 pts were excluded from 2nd randomization (poor mobilization, poor condition or patients' refusal); 118 pts were thus randomized (59 pts/arm) and constitute the study population (median age 58 ys; range 18-70). 15 (13%) pts had high IELSG risk, 3 pts had ocular disease and 20 pts had meningeal disease; with the exception of a higher male prevalence in arm D, there were no differences in clinical presentation between two arms; There were 6 protocol violations: 4 pts randomly allocated to arm D were treated with ASCT and 2 pts randomly allocated to arm E were treated with WBRT; 5 pts (D 2; E 3) refused consolidation. Therefore, per-protocol (PP) groups consisted of 55 pts treated with WBRT and 58 with ASCT. Both consolidation therapies were well tolerated. Grade 4 toxicity was uncommon (≤5% of pts); as expected, hematological toxicity was more common in arm E (neutropenia 5% vs. 71%; p=0.00001 - thrombocytopenia 2% vs. 72%; p=0.00001). There were 2 toxic deaths (infections), both in arm E. Neuropsychological tests showed a significant impairment of attention/executive functions and a non-significant trend to impaired memory among pts treated with WBRT, whereas pts treated with ASCT exhibited improved functions. Both consolidation therapies were associated with significant improvement in language and QoL. Both WBRT and ASCT were active and resulted in significant improvement in CR rate: from 54% after induction to 95% (95%CI: 90-100) after consolidation in arm D, and from 53% to 93% (95%CI: 87-99) in arm E. After a median follow-up of 40 months (range 24-76), there were 20 events (16 relapses, 2 PDs, 2 off-therapy deaths) in arm D, and 25 events (18 relapses, 2 PDs, 2 toxic deaths, 3 off-therapy deaths) in arm E. Importantly, WBRT and ASCT were both effective, with a number of progression-free survivors at 2 ys equal to the pre-determined efficacy threshold: 40 among both the first 52 arm-D and 52 arm-E pts. There were no significant differences in PFS between WBRT and ASCT; on ITT basis, the 2-yr PFS was 80 ± 5% after WBRT and 70 ± 6% after ASCT; per protocol, the 2-yr PFS was 76 ± 6% and 75 ± 6%, respectively. In multivariate analysis, IELSG risk group, number of lesions and induction arm were independently associated with PFS; gender, CSF cytology status and consolidation arm were not. Forty-two pts randomized to arm D and 37 randomized to arm E are alive, with 2-year OS of 85 ± 5% and 71 ± 6% (p=0.12), respectively. Conclusions: WBRT and ASCT are both feasible, active and effective as consolidation therapies after high-dose-MTX-based chemoimmunotherapy in pts ≤70 ys with PCNSL. Potential impairment of specific neurocognitive functions after WBRT should be considered at the time of therapeutic decision. Disclosures Ferreri: Sandoz: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Research Funding, Speakers Bureau; Italfarmaco: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adienne: Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees. Fox:Adienne: Honoraria, Research Funding; Takeda: Honoraria, Other: travel funding; Gilead: Honoraria, Other: travel funding; Janssen: Honoraria, Other: travel funding; AbbVie: Consultancy. Röth:Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria. Johnson:Celldex Therapeutics: Research Funding. Linton:Takeda: Research Funding. Hess:Roche: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Roche, CTI, Pfizer, Celgene: Research Funding; Celgene: Honoraria; Pfizer: Honoraria. Stilgenbauer:Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Genentech: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau. Rummel:Roche Pharma AG: Other: Personal fees, Research Funding; Mundipharma GmbH: Other: Personal fees, Research Funding. Illerhaus:Riemser: Honoraria; Amgen: Honoraria.
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Choquet, Sylvain, Caroline Houillier, Fontanet Bijou, Roch Houot, Eileen Boyle, Remy Gressin, Emmanuelle Nicolas-Virelizier, et al. "Ibrutinib Monotherapy in Relapse or Refractory Primary CNS Lymphoma (PCNSL) and Primary Vitreo-Retinal Lymphoma (PVRL). Result of the Interim Analysis of the iLOC Phase II Study from the Lysa and the French LOC Network." Blood 128, no. 22 (December 2, 2016): 784. http://dx.doi.org/10.1182/blood.v128.22.784.784.
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Abstract RATIONAL Primary CNS lymphoma (PCNSL) is a diffuse large B-cell lymphoma (DLBCL), predominantly of non-germinal center (non-GC) subtype, carrying a pejorative prognosis. Constitutive activation of the NF-kB pathway via mutations in B cell receptor (BCR) pathway (CD79B) and mutation of MYD 88 and TBL1XR1 plays an important role in PCNSL. Ibrutinib, an inhibitor of BCR signaling, has been found to have significant therapeutic activity in relapsed or refractory non-CNS non-GC DLBCL. METHODS In this prospective, multicenter, open-label phase II, we enrolled immuno-competent patients over 18 with a refractory or relapse of PCNSL or primary vitreo-retinal lymphoma (PVRL) of DLBCL type. The treatment consisted in ibrutinib monotherapy given orally at 560 mg daily until disease progression or unacceptable toxicity. Additional corticosteroids treatment was allowed during the first 4 weeks of treatment in case of a threatening or symptomatic edema. Therapeutic responses were assessed according to the international primary CNS lymphoma collaborative group (IPCG) criteria. The primary objective of the study was the disease control (DC) rate (CR + CRu + PR + SD) after two months of treatment. This study is a two-stage Simon's design. Patients were evaluable for response if they received > 90 % of the expected dose during the first month of treatment. An interim analysis for futility was planned when 18 patients were evaluable for response. P0 and P1 hypotheses were < 10 % and > 30 % respectively. A total of 35 evaluable patients are required for the final analysis. Exploratory ancillary studies are planned and consist in dosage of ibrutinib in the cerebrospinal fluid after one cycle of treatment, and correlation of therapeutic response with mutational status of the disease. This study is registered with ClinicalTrials.gov, number NCT02542514. RESULTS BetweenSeptember 25, 2015 and June 30, 2016, 52 patients were recruited in 10 French centers of the French LOC network for PCNSL. The interim analysis was done on the first 18 patients evaluable for response (median age: 70 y, range 49-80). At initial diagnosis, diagnoses were PCNSL (n = 12) and PVRL (n = 6). Patients were included in the study for a relapse (n = 13) or a progressive disease (n = 5). At time of inclusion in the study, disease status was PCNSL (n = 11) and PVRL or isolated intra-ocular relapse of a PCNSL (n = 7). ECOG performance status was 0, 1 and 2 in 4, 10 and 4 patients respectively. All the patients had previously received high-dose methotrexate-based chemotherapy. Four patients had previously received high-dose chemotherapy followed by autologous stem cell transplantation. Patients had received 1, 2 or 3 prior treatments in 12, 5 and 1 cases respectively. Three patients had a concomitant meningeal involvement. Five patients received concomitant corticosteroids during the first month of treatment. At the time of analysis (median follow-up = 6.6 months), nine patients discontinued ibrutinib after a median duration of 3 months (range, 0.9 -6.4) because of a disease progressive(n = 8) or a concurrent illness (n=1). Median number of treatment cycles was 5 (range, 1-9). One patient experienced a pulmonary aspergillosis with a favorable outcome. No hemorrhagic complication was reported. Five patients died due to disease progression (n = 4), and concurrent illness (n = 1). After two months of treatment, a DC was achieved in 15/18 patients (83 %, IC 95 %, [59-96%]) (complete and unconfirmed complete response: n =3; partial response: n = 7; stable disease: n =5). CONCLUSION In this interim analysis, Ibrutinib monotherapy demonstrated a high DC rate of 83%, including 56% objective responses in patients with relapse/refractory PCNSL or PVRL. Regarding safety, Ibrutinib might be a risk factor for aspergillosis in this population of PCNSL patients, otherwise not exposed to fungal infection. A security warning was sent to all the investigators for a close monitoring of infections. The second cohort of patients has been recruited. Thirty-three patients are currently on study treatment. The final analysis of the iLOC study is awaited to confirm these encouraging results and better define the positioning of ibrutinib in the therapeutic strategy of PCNSL and PVR patients. Disclosures Choquet: Janssen: Consultancy; Celgene: Consultancy. Ghesquieres:Mundipharma: Consultancy; Roche France: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Soussain:Celgene: Research Funding; Roche: Research Funding; Pharmacyclics: Research Funding.
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Schmitz, Norbert, Samira Zeynalova, Bertram Glass, Ulrich Kaiser, Eva Cavallin-Stahl, Max Wolf, Mathias Haenel, Markus Loeffler, Lorenz Trümper, and M. Pfreundschuh. "CNS Disease In Younger Patients (<=60 years) with Aggressive Lymphoma Treated In Trials of the German High Grade Non Hodgkin Lymphoma Study Group (DSHNHL) and the MabThera International Trial (MInT)." Blood 116, no. 21 (November 19, 2010): 112. http://dx.doi.org/10.1182/blood.v116.21.112.112.
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Abstract Abstract 112 Background: CNS involvement by aggressive lymphoma carries a poor prognosis. Little is known about the frequencies of CNS relapse or progression, risk factors, and the efficacy of prophylaxis in younger patients (pts) undergoing modern chemoimmunotherapy (R-CHOP). Methods: 2.797 younger pts (<= 60 years) with aggressive lymphoma were treated on trials of the DSHNHL and the Mabthera International Trial. Pts with B-cell lymphoma (n=2.196) received 6 or 8 courses of CHO(Etoposid)P ± Rituximab (R) or were treated on the MegaCHOEP + R protocols featuring high doses of C, H, E, and P necessitating repetitive transplantation of autologous stem cells (Schmitz et al., BLOOD 2009, 404 a). Pts with lymphoma in testes, bone marrow, upper cervical nodes, sinuses, or other sites in the cranial region were to receive four i. th. injections of 15 mg MTX for prophylaxis of meningeosis during treatment courses 1 and 2 except for pts on the NHL-A and -B1 trials. In the latter studies, CNS prophylaxis was recommended for pts with lymphoblastic lymphoma only. Results: Overall, sixty-five of 2.797 pts (2.3%) developed meningeal and/or parenchymal CNS relapse (43.1 %) or progressed during therapy (56.9%). Relapse/ progression in the CNS was combined with systemic disease in 20 pts (32.3%) but represented the only site of disease in the majority of cases (67.7 %). Median time to relapse/ progression was 7.2 months (range: 0.2– 85.2 months); median survival after relapse or progression was 4.2 months (0 - 54.0 months). The incidence of CNS relapse/ progression was low in pts with age-adjusted International Prognostic Index (aaIPI) 0 or 1 (High-CHOEP phase III study with 385 pts: CNS events 0.3%; MInT trial with 818 pts: CNS events 1.6 %) but was significantly higher in the 463 pts on the MegaCHOEP phase II/III trials which included pts with aaIPI 2 or 3 only (CNS events: 6.4 % and 7.5 %, respectively). Focusing on 663 pts treated with state-of-the-art chemoimmunotherapy including rituximab, multivariate Cox regression analysis identified LDH>N (relative risk [RR]=4.5, p=0.046) and stage III/IV (RR=6.2, p= 0.016) as significant risk factors for CNS disease. Using this model, 32.7 % of all pts would have been considered “high-risk”; 82.4 % of those pts who developed CNS disease carried both risk factors. However, only 14/217 (6.5%) of the “high-risk” pts defined by elevated LDH and advanced stage actually experienced CNS relapse or progression. Rituximab significantly reduced the risk for CNS disease when all 1.570 pts treated with CHO(E)P- 14/21 were considered (RR= 0.3, p=0.03). In contrast, the addition of R did not reduce the RR in 309 pts treated with MegaCHOEP ± R (RR=0.8, p= 0.54). There was no indication that the addition of etoposide to CHOP (CHOEP) reduced the risk of CNS disease in any patient cohort treated with chemotherapy and R. Conclusions: Pts with aggressive lymphoma and aaIPI 0 or 1 show low frequencies of CNS relapse or progression. Omitting CNS prophylaxis in such pts seems reasonable also because – similar to our recent findings in the elderly (Boehme et al., BLOOD 2009; 113: 3896) – this analysis in younger pts failed to show benefit of prophylaxis with i.th. MTX in any of the risk groups analyzed. CNS disease remains a serious problem in younger pts with aaIPI 2 or 3. We failed to discover clinical or laboratory features to precisely define a “high-risk” group of patients all of whom might benefit from CNS-directed prophylaxis. Unfortunately, neither high-dose therapy including high-doses of etoposide (MegaCHOEP), standard dose etoposide (CHOEP), nor i. th. MTX reduced the incidence of CNS disease. Rituximab reduced the RR of CNS disease in pts with B-cell lymphoma treated with CHO(E)P- 14/21 but failed to do so in pts treated with R-MegaCHOEP. Disclosures: Schmitz: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Glass:Roche: Honoraria, Research Funding. Pfreundschuh:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
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Orvain, Corentin, Sylvain Chantepie, Xavier Thomas, Martine Escoffre-Barbe, Francoise Huguet, Yohan Desbrosses, Gaelle Guillerm, et al. "Impact of Central Nervous System Involvement in Adult Patients with Acute Lymphoblastic Leukemia Treated in a Pediatrics-Inspired Protocol - a Graall Study." Blood 138, Supplement 1 (November 5, 2021): 215. http://dx.doi.org/10.1182/blood-2021-150705.
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Abstract Background: The prognosis of central nervous system (CNS) involvement in adult patients with acute lymphoblastic leukemia (ALL) has been historically associated with a dismal outcome. Whereas the prognosis of adult patients with ALL has greatly improved since the advent of pediatrics-inspired regimens, the prognostic impact of CNS involvement has not been formerly reevaluated. We report herein the impact of CNS involvement in patients included in the pediatric-inspired prospective GRAALL-2005 study. Methods: All patients received a 5-drug induction therapy with native E. Coli-ASP intravenous injections. Patients in complete remission (CR) received two consolidation courses with alternating cycles including high dose cytarabine (2g/m2/12h on days 1 and 2), high dose methotrexate (3 g/m2 on day 1), and cyclophosphamide. All patients in persistent CR and with no indication for allogeneic stem cell transplantation (SCT) received late intensification, followed by one last consolidation course. Patients with initial CNS involvement, clinically and/or cytologically (cerebrospinal fluid), were recommended to receive an increased number of triple intrathecal therapy, CNS irradiation, and were eligible for allogeneic SCT in first CR. They received less Asp injections during induction therapy to avoid CNS adverse events. CNS irradiation included two lateral fields encompassing the skull, facial, the base of the skull, and the first two cervical vertebrae at a dose of 24 grays for those not receiving allogeneic SCT and 15 grays for those receiving allogeneic SCT. Results: Between 2006 and 2014, 784 adult patients with newly diagnosed Philadelphia-negative ALL were included with 55 (7%) having initial CNS involvement. These patients were more likely to be of T-phenotype (51 versus 32%, p=.004) and had more white blood cells at diagnosis (median 23 G/l versus 11 G/l, p=.02). Most patients (36 pts, 66%) were classified as CNS-3 (> 5 white blood cells/µl and a positive cytospin and/or clinical signs) whereas 5 patients (9%) were CNS-2 (< 5 white blood cells/µl and a positive cytospin), and 14 (25%) have data pending. Among patients with details regarding CNS involvement, 25/41 (61%) had clinical signs including trigeminal anesthesia (9 pts, 36%), facial paralysis (4 pts, 16%), extremities paresthesia (4 pts, 16%), visual signs (2 pts, 8%), meningeal syndrome (2 pts, 8%), and motor deficit (2 pts, 8%), and 4/18 (22%) had radiological signs. Induction death, CR1 rate, and negative minimal residual disease after induction were similar whether patients had CNS involvement or not (6 vs 6%, 89 vs 89%, 73 vs 62%, 26 vs 22%, respectively). Patients with CNS involvement had a worse outcome than those without with a median event-free survival (EFS) of 391 days (versus not reached for patients without CNS involvement, HR: 1.7, 95% CI: 1.2 - 2.5, p=.002) and a median overall survival (OS) of 608 days (versus not reached for patients without CNS involvement, HR: 1.8, 95% CI: 1.3 - 2.6, p=.001) (figure). Similar results were observed when patients who received allogeneic SCT in CR1 were censored at the time of graft. As recommended, patients with CNS involvement were more likely to receive allogeneic SCT than those without (53 versus 34%, p=.01), with a median time of 169 days. A 150-day landmark analysis, excluding 12 patients with an EFS event before 150 days, was performed to study the impact of allogeneic SCT on the outcome of patients with CNS involvement. Allogeneic SCT had no impact on either EFS (HR: .5, 95% CI: .2 - 1.2, p=.15) or OS (HR: .8, 95% CI: .3 - 1.8, p=.53). Conclusion: Despite improved outcome in young adult ALL patients with pediatrics-inspired protocols, CNS involvement remains a poor-risk feature. The historical use of allogeneic SCT does not improve outcome. Specific regimens should be developed for adult ALL patients with CNS involvement. Figure 1 Figure 1. Disclosures Huguet: Amgen: Other: Advisor; BMS: Other: Advisor; Celgene: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Novartis: Other: Advisor; Pfizer: Other: Advisor. Barbieux: ASTRA-ZENECCA: Consultancy. Vey: Amgen: Honoraria; BMS: Honoraria; BIOKINESIS: Consultancy, Research Funding; NOVARTIS: Consultancy, Honoraria, Research Funding; SERVIER: Consultancy; JAZZ PHARMACEUTICALS: Honoraria; JANSSEN: Consultancy. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. Boissel: Bristol-Myers Squibb: Honoraria, Research Funding; Servier: Consultancy, Honoraria; Incyte: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; JAZZ Pharma: Honoraria, Research Funding; CELGENE: Honoraria; SANOFI: Honoraria; PFIZER: Consultancy, Honoraria. Mathilde: ABBVIE: Consultancy; SERVIER: Consultancy.
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Gilpin, Trey E., Fruzsina R. Walter, Melinda Herbath, Matyas Sandor, and Zsuzsanna Fabry. "Dendritic Cell-Induced Dissemination of Mycobacterium tuberculosis into the Central Nervous System." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 51.8. http://dx.doi.org/10.4049/jimmunol.202.supp.51.8.
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Abstract Central nervous system tuberculosis (CNSTB) is the most serious manifestation of extrapulmonary tuberculosis infections representing 5–10% of all cases. Knowledge of CNSTB stems from observations made in 1933 by pathologists Rich and McCordock, who found caseating foci in the brain parenchyma or meninges that rupture into the subarachnoid space leading to diffuse meningeal infection. However, the mechanism of how immobile Mycobacterium tuberculosis, the causative agent of TB crosses the highly regulated blood-brain barrier (BBB) and enters the CNS forming these foci and infection is unknown. We have developed a novel in vitro BBB model that combines Mycobacteria-infected DCs, PBMCs, and primary mouse brain endothelial cells to observe early cellular interaction and aggregate formation at the BBB similar to previous observations by Rich and McCordock. With this model we observed Mycobacteria impedes migration of DCs but increases DC initiation of aggregation on a primary mouse endothelial BBB with a cellular composition similar to pulmonary granulomas. Aggregates induce an inflammatory response by increasing ICAM-1 and VCAM-1 expression and dysregulation of tight junction proteins and mitochondria suggesting barrier damage possibly due to increased iNOS expression observed during within aggregates. Mycobacteria-infected DC transmigration is increased in the presence of aggregation. Previous research from our lab and others have shown DC transmigration across an in vitro BBB rely on MMP-9 secretion while TNF-alpha is necessary for pulmonary granuloma formation and Mtb infection control. Here we will show the role iNOS, MMP-9 and TNF-alpha play in DC-mediated dissemination of Mycobacterium across the BBB.
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Friedman, Judah, Hun Ju Lee, Linda Ho, and Ian W. Flinn. "Brentuximab Vedotin in Combination with Nivolumab, Doxorubucin, and Dacarbazine in Newly Diagnosed Patients with Advanced Stage Hodgkin Lymphoma." Blood 134, Supplement_1 (November 13, 2019): 2836. http://dx.doi.org/10.1182/blood-2019-122969.
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Background For patients with advanced classical Hodgkin lymphoma (cHL), the most common frontline regimen has historically consisted of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), which originated in 1975 (Connors 2018). However, up to 30% of patients treated with ABVD as frontline therapy will relapse or are refractory to treatment (Canellos 1992; Carde 2016; Gordon 2013). Additionally, bleomycin is associated with potentially fatal pulmonary toxicity (Canellos 2004; Martin 2004), and vinblastine is associated with neutropenia and peripheral neuropathy. Brentuximab vedotin (BV, ADCETRIS®) has been approved for the treatment of adult patients with previously untreated Stage III or IV cHL in combination with doxorubicin, vinblastine, and dacarbazine based on the results of the ECHELON-1 study (Connors 2017). Data reported from ECHELON-1 showed patients randomized to the BV + doxorubicin, vinblastine, and dacarbazine (A + AVD) treatment arm had a statistically significant 23% risk reduction in modified PFS events vs patients randomized to the ABVD arm of the study. The combination of BV plus nivolumab was reported as showing potential for the treatment of cHL. The combination was evaluated as a potential frontline treatment option for patients with cHL who are over 60 years of age and ineligible for or declining conventional combination chemotherapy (Friedberg, 2018). The ongoing study reported an ORR of 82% in 11 patients and the regimen appears well tolerated in this population. In another trial in 62 patients in the first salvage setting, the combination produced a 61% CR rate (Herrera 2018) and the patients were able to undergo subsequent stem cell transplant. BV and nivolumab have been combined separately with doxorubicin, vinblastine, and dacarbazine and shown to be active and well tolerated. Furthermore, BV has been evaluated in combination with just doxorubicin and dacarbazine, omitting vinblastine, in 34 patients with previously untreated non-bulky stage I/II cHL and showed 100% complete response rate at end of treatment (EOT) and PFS and OS rates of 100% at last follow up (median=15 months; Abramson 2018). This combination resulted in a low incidence of neutropenia and alopecia, and moderate (Grade 1 or 2) peripheral neuropathy. It is therefore reasonable to expect that the combination of BV, nivolumab, doxorubicin, and dacarbazine (AN + AD) will result in high response rates and be well tolerated, with potentially less toxicity. Study Design SGN35-027 (NCT03646123) is a phase 2 study designed to evaluate growth factor prophylaxis plus BV in combination with AVD in patients with stage III and IV cHL (Part A). A second cohort has been added to the study (Part B), which will evaluate the combination of AN + AD in this patient population. The primary objective of Part B is to estimate the CR rate at EOT with AN + AD in patients with previously untreated advanced cHL. All enrolled patients will be 12 years or older, with an ECOG performance status of ≤2. Patients in Part B will be treatment-naïve with Ann Arbor Stage IIB/III/IV cHL or Stage IIA cHL with bulky disease. Patients must have bidimensional measurable disease, as documented by radiographic technique, and qualifying baseline laboratory data. Patients will be excluded if they have nodular lymphocyte predominant HL or have symptomatic neurologic disease that compromises normal activities of daily living or requires medication. Patients with known cerebral or meningeal disease, including signs or symptoms of progressive multifocal leukoencephalopathy, will also be excluded. Approximately 50 patients will be enrolled in Part B. All patients will be treated with BV 1.2 mg/kg, nivolumab 240 mg, doxorubicin 25 mg/m2, and dacarbazine 375 mg/m2. All study drugs will each be administered separately by IV infusion on Days 1 and 15 of each 28-day cycle for up to 6 cycles of treatment. Efficacy will be assessed by PET and CT scans at Cycle 2 and EOT. Disease assessments will be performed during follow-up every 3 months for the first year, every 6 months for 2 additional years, and then per institutional standard of care. Disease response and progression will be assessed by investigators using the Lymphoma Response to Immunomodulatory Therapy Criteria modification of Lugano Classification Revised Staging System for nodal non-Hodgkin and Hodgkin lymphomas (Cheson 2016). Disclosures Friedman: Amgen: Speakers Bureau; Celgene: Speakers Bureau; Seattle Genetics, Inc.: Research Funding. Lee:Seattle Genetics, Inc.: Research Funding. Ho:Seattle Genetics, Inc.: Employment, Equity Ownership. Flinn:AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding.
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Niu, Chunxiao, Jijun Yu, Tao Zou, Yuchen Lu, Lijiao Deng, Hongfang Yun, Chuan-Yimu Si, et al. "Identification of hematopoietic stem cells residing in the meninges of adult mice at steady state." Cell Reports 41, no. 6 (November 2022): 111592. http://dx.doi.org/10.1016/j.celrep.2022.111592.
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