Journal articles on the topic 'Lytic induction therapy'
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1
Yiu, Stephanie Pei Tung, Mike Dorothea, Kwai Fung Hui, and Alan Kwok Shing Chiang. "Lytic Induction Therapy against Epstein–Barr Virus-Associated Malignancies: Past, Present, and Future." Cancers 12, no. 8 (August 2, 2020): 2142. http://dx.doi.org/10.3390/cancers12082142.
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Epstein–Barr virus (EBV) lytic induction therapy is an emerging virus-targeted therapeutic approach that exploits the presence of EBV in tumor cells to confer specific killing effects against EBV-associated malignancies. Efforts have been made in the past years to uncover the mechanisms of EBV latent-lytic switch and discover different classes of chemical compounds that can reactivate the EBV lytic cycle. Despite the growing list of compounds showing potential to be used in the lytic induction therapy, only a few are being tested in clinical trials, with varying degrees of success. This review will summarize the current knowledge on EBV lytic reactivation, the major hurdles of translating the lytic induction therapy into clinical settings, and highlight some potential strategies in the future development of this therapy for EBV-related lymphoid and epithelial malignancies.
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Feng, Wen-hai, Gregory Hong, Henri-Jacques Delecluse, and Shannon C. Kenney. "Lytic Induction Therapy for Epstein-Barr Virus-Positive B-Cell Lymphomas." Journal of Virology 78, no. 4 (February 15, 2004): 1893–902. http://dx.doi.org/10.1128/jvi.78.4.1893-1902.2004.
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ABSTRACT A novel therapy for Epstein-Barr virus (EBV)-positive tumors involves the intentional induction of the lytic form of EBV infection combined with ganciclovir (GCV) treatment. Virally encoded kinases (thymidine kinase and BGLF4) which are expressed only during the lytic form of infection convert GCV (a nucleoside analogue) into its active, cytotoxic form. However, tightly latent EBV infection in B cells has made it difficult to identify drugs that can be used clinically to induce lytic viral infection in B-cell lymphomas. Here we demonstrate that gemcitabine and doxorubicin (but not 5-azacytidine, cis-platinum, or 5-fluorouracil) induce lytic EBV infection in EBV-transformed B cells in vitro and in vivo. Gemcitabine and doxorubicin both activated transcription from the promoters of the two viral immediate-early genes, BZLF1 and BRLF1, in EBV-negative B cells. This effect required the EGR-1 motif in the BRLF1 promoter and the CRE (ZII) and MEF-2D (ZI) binding sites in the BZLF1 promoter. GCV enhanced cell killing by gemcitabine or doxorubicin in lymphoblastoid cells transformed with wild-type EBV, but not in lymphoblastoid cells transformed by a mutant virus (with a deletion in the BZLF1 immediate-early gene) that is unable to enter the lytic form of infection. Most importantly, the combination of gemcitabine or doxorubicin and GCV was significantly more effective for the inhibition of EBV-driven lymphoproliferative disease in SCID mice than chemotherapy alone. In contrast, the combination of zidovudine and gemcitabine was no more effective than gemcitabine alone. These results suggest that the addition of GCV to either gemcitabine- or doxorubicin-containing chemotherapy regimens may enhance the therapeutic efficacy of these drugs for EBV-driven lymphoproliferative disease in patients.
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Daibata, Masanori, Kentaro Bandobashi, Masayuki Kuroda, Shosuke Imai, Isao Miyoshi, and Hirokuni Taguchi. "Induction of Lytic Epstein-Barr Virus (EBV) Infection by Synergistic Action of Rituximab and Dexamethasone Renders EBV-Positive Lymphoma Cells More Susceptible to Ganciclovir Cytotoxicity In Vitro and In Vivo." Journal of Virology 79, no. 9 (May 1, 2005): 5875–79. http://dx.doi.org/10.1128/jvi.79.9.5875-5879.2005.
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ABSTRACT The purposeful induction of the lytic form of Epstein-Barr virus (EBV) infection combined with ganciclovir (GCV) treatment has been advocated as a novel strategy for EBV-positive B-cell lymphoma. We demonstrated that rituximab had a synergistic effect with dexamethasone on induction of the lytic EBV infection in CD20-positive lymphoma cells. Addition of GCV to the dexamethasone/rituximab-treated cells was more effective than dexamethasone/rituximab alone in killing EBV-positive lymphoma cells in vitro and in lymphoma-bearing nude mice but not in EBV-negative cells. These data suggest that induction of the lytic EBV infection with dexamethasone/rituximab in combination with GCV could be a potential virally targeted therapy for EBV-associated B-cell lymphoma.
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Korsak, Dorota, Sylvia Liebscher, and Waldemar Vollmer. "Susceptibility to Antibiotics and β-Lactamase Induction in Murein Hydrolase Mutants of Escherichia coli." Antimicrobial Agents and Chemotherapy 49, no. 4 (April 2005): 1404–9. http://dx.doi.org/10.1128/aac.49.4.1404-1409.2005.
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ABSTRACT The antibiotic susceptibilities and capabilities to induce β-lactamases were studied in multiple Escherichia coli murein (peptidoglycan) hydrolase mutants. E. coli mutants lacking either three amidases, three amidases and one lytic transglycosylase, or six lytic transglycosylases showed higher levels of susceptibility to bacitracin, erythromycin, gallidermin, and vancomycin than the wild type. Mutant cells without three amidases lost viability in the presence of vancomycin and gallidermin, whereas the wild type was resistant to both antibiotics. β-Lactamase induction was studied after introduction of a plasmid carrying the ampC and ampR genes. Upon addition of cefoxitin to the growth medium, the wild type as well as a mutant lacking all known amidases and dd-endopeptidases induced β-lactamase, whereas a mutant lacking all known lytic transglycosylases was unable to induce β-lactamase, showing that lytic transglycosylase activity is essential for β-lactamase induction. Consequently, cells lacking lytic transglycosylase activity lysed in the presence of penicillin, despite the presence of the inducible β-lactamase system. We discuss the potential of murein hydrolase inhibitors for antibiotic therapy.
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Yiu, Stephanie Pei Tung, Kwai Fung Hui, Christian Münz, Kwok-Wai Lo, Sai Wah Tsao, Richard Yi Tsun Kao, Dan Yang, and Alan Kwok Shing Chiang. "Autophagy-Dependent Reactivation of Epstein-Barr Virus Lytic Cycle and Combinatorial Effects of Autophagy-Dependent and Independent Lytic Inducers in Nasopharyngeal Carcinoma." Cancers 11, no. 12 (November 26, 2019): 1871. http://dx.doi.org/10.3390/cancers11121871.
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Autophagy, a conserved cellular mechanism, is manipulated by a number of viruses for different purposes. We previously demonstrated that an iron-chelator-like small compound, C7, reactivates Epstein-Barr virus (EBV) lytic cycle by activating the ERK1/2-autophagy axis in epithelial cancers. Here, we aim to identify the specific stage of autophagy required for EBV lytic reactivation, determine the autophagy dependency of EBV lytic inducers including histone deacetylase inhibitor (HDACi) and C7/iron chelators, for EBV lytic reactivation and measure the combinatorial effects of these types of lytic inducers in nasopharyngeal carcinoma (NPC). Inhibition of autophagy initiation by 3-MA and autolysosome formation by chloroquine demonstrated that only autophagy initiation is required for EBV lytic reactivation. Gene knockdown of various autophagic proteins such as beclin-1, ATG5, ATG12, ATG7, LC3B, ATG10, ATG3 and Rab9, revealed the importance of ATG5 in EBV lytic reactivation. 3-MA could only abrogate lytic cycle induction by C7/iron chelators but not by HDACi, providing evidence for autophagy-dependent and independent mechanisms in EBV lytic reactivation. Finally, the combination of C7 and SAHA at their corresponding reactivation kinetics enhanced EBV lytic reactivation. These findings render new insights in the mechanisms of EBV lytic cycle reactivation and stimulate a rational design of combination drug therapy against EBV-associated cancers.
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Tanner, JE, and J. Menezes. "Interleukin-6 and Epstein-Barr virus induction by cyclosporine A: potential role in lymphoproliferative disease." Blood 84, no. 11 (December 1, 1994): 3956–64. http://dx.doi.org/10.1182/blood.v84.11.3956.bloodjournal84113956.
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Posttransplant patients undergoing prolonged cyclosporine A (CsA) immunosuppressive therapy have been reported to have increased incidence of Epstein-Barr virus (EBV)-associated lymphoproliferative disorders. We undertook experiments to analyze the possible actions of CsA during EBV-infection of human peripheral blood mononuclear cells (PBMC). EBV-infected B cells cultured with CsA demonstrated increased EBV B-cell outgrowth as compared with those cultured without CsA. PBMC, after infection with EBV and CsA treatment, demonstrated increased interleukin-6 (IL-6) activity in the culture supernatant. The induction of IL-6 appears to differ within the various lymphocyte populations. In monocytes, IL-6 expression appears preferentially induced by EBV and is initiated by the binding of the two major virion glycoproteins, gp350 and gp220. Expression of IL-6 in T cells appears to be due mainly to CsA. B cells also express IL-6 after EBV exposure, but not after CsA treatment. EBV-immortalized B-cell lines cultured with CsA exhibited both an increased number of cells expressing viral lytic-cycle antigens and increased amounts of lytic-cycle proteins. IL-6, which is induced by CsA in PBMC, was also capable of inducing the lytic viral cycle in several EBV-immortalized cells. CsA, in promoting both increased numbers of lytic EBV B cells and an EBV paracrine factor, IL-6, within the microenvironment of EBV B cell:T cell and EBV B cell:monocyte interactions, may result in increased EBV B-cell immortalization and ultimately lead to the promotion of B-cell lymphomas in immunosuppressed patients.
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Lechowicz, Mary Jo, Jeannette Lee, Dirk Dittmer, Susan Krown, Jonathan Said, and Richard F. Ambinder. "A Pilot Trial of Valproic Acid in Patients with Kaposi’s Sarcoma: A Multi-Center Trial of the AIDS Malignancy Consortium." Blood 110, no. 11 (November 16, 2007): 2279. http://dx.doi.org/10.1182/blood.v110.11.2279.2279.
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Abstract PURPOSE: Although the use of highly active antiretroviral therapy (HAART) has led to improvements in the management of AIDS-associated Kaposi’s sarcoma (KS), KS may persist or progress despite HAART. It has been hypothesized that activation of KS-associated herpesvirus (KSHV, HHV8) lytic expression might render tumor cells susceptible to immune surveillance by cytotoxic T cells. Alternatively, it has been suggested that lytic induction could lead to tumor progression. In vitro, valproic acid (VA) and other histone deacetylase inhibitors induce KSHV lytic gene expression in primary effusion lymphoma cell lines. We investigated VA in AIDS/KS patients to assess its safety and its impact on lytic viral gene expression in tumor and viral copy number in blood. PATIENTS AND METHODS: VA was given orally to patients with AIDS and cutaneous KS on stable antiviral regimens; the dose was titrated to maintain trough concentrations between 50 and 100 mcg/mL. VA was given daily for 28 days followed by a rapid taper and patients were then followed for 6 months. Quantitative real time PCR was used to assess viral DNA in plasma and PBMC, and viral RNA in tumor specimens. Immunohistochemistry was used to assess viral antigen expression in tumor specimens. RESULTS: 18 patients were treated. 15/18 patients completed therapy; 3 patients discontinued therapy early, one secondary to grade 2 toxicity and 2 to patient preference. One patient showed a partial response and 17 showed stable disease at the completion of therapy. No patients progressed during treatment. There were no differences between KSHV copy number in plasma or PBMC before, during, or after therapy. Similarly, although serial biopsies in some patients showed an increase in lytic gene expression, these changes did not achieve statistical significance. However, in multivariate analyses, viral lytic RNA increased in tumor biopsies on day 8 as a function of VA level. There was no change in HIV viral load with VA treatment. CONCLUSION : VA was well tolerated in AIDS patients, was not associated with accelerated disease progression, but rarely induced tumor regression after short-term treatment. In patients who achieved the highest serum VA levels there was increased lytic viral RNA expression. These findings support investigation of more potent HDAC inhibitors over longer treatment courses in patients with AIDS-associated KS.
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Coileoni, Marco, Anna Maria Bochicchio, Franco Nolè, and Emilio Bajetta. "Disodium Pamidronate in the Treatment of Bone Metastases from Breast Cancer." Tumori Journal 79, no. 5 (October 1993): 340–42. http://dx.doi.org/10.1177/030089169307900511.
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Aims and Background Symptomatic relief of bone metastases with biphosphonates has been previously reported, but limited data are available on the possibility of the induction of sclerosis in osteolytic lesions. Methods We therefore initiated an open study with disodium pamidronate (45 mg infused over 1 h and repeated every 21 days) in patients with bone metastases from breast cancer pretreated with chemotherapy and/or hormonetherapy. Fourteen patients wiht measurable lytic or mixed bone disease entereted the study. No other systemic therapy for breast cancer was allowed after their Inclusion in the study. Results No radiologic evidence of bone sclerosis of lytic disease was seen. After 2 months of therapy, 9 patients had progressed and 5 had stable disease. The median time to progression of bone disease was 1.6 months (range, 1-9). No significant improvement in terms of symptomatic status or analgesic consumption was recorded. The treatment was well tolerated, and no significant local or systemic toxicity was observed. Conclusions Disodium pamidronate at a dose of 45 mg every 3 weeks is not capable of inducing sclerosis of lytic lesions from pretreated breast cancer. Further trials concentrating on higher dosages of disodium pamidronate are warranted.
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Howard-Varona, Cristina, Dean Vik, Natalie Solonenko, Yueh-Fen Li, M. Gazitua, Lauren Chittick, Jennifer Samiec, et al. "Fighting Fire with Fire: Phage Potential for the Treatment of E. coli O157 Infection." Antibiotics 7, no. 4 (November 16, 2018): 101. http://dx.doi.org/10.3390/antibiotics7040101.
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Hemolytic–uremic syndrome is a life-threating disease most often associated with Shiga toxin-producing microorganisms like Escherichia coli (STEC), including E. coli O157:H7. Shiga toxin is encoded by resident prophages present within this bacterium, and both its production and release depend on the induction of Shiga toxin-encoding prophages. Consequently, treatment of STEC infections tend to be largely supportive rather than antibacterial, in part due to concerns about exacerbating such prophage induction. Here we explore STEC O157:H7 prophage induction in vitro as it pertains to phage therapy—the application of bacteriophages as antibacterial agents to treat bacterial infections—to curtail prophage induction events, while also reducing STEC O157:H7 presence. We observed that cultures treated with strictly lytic phages, despite being lysed, produce substantially fewer Shiga toxin-encoding temperate-phage virions than untreated STEC controls. We therefore suggest that phage therapy could have utility as a prophylactic treatment of individuals suspected of having been recently exposed to STEC, especially if prophage induction and by extension Shiga toxin production is not exacerbated.
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Scott, Emma, and Donna Reece. "What is the Benefit of Maintenance Therapy with Lenalidomide or Bortezomib after Autologous Stem Cell Transplantation in Multiple Myeloma and What is the Risk of Developing a Secondary Primary Malignancy?" Hematology 2011, no. 1 (December 10, 2011): 205–7. http://dx.doi.org/10.1182/asheducation-2011.1.205.
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Abstract An otherwise healthy 60-year-old male was diagnosed with stage II multiple myeloma by the International Staging System characterized by anemia, diffuse lytic bone lesions, IgG kappa paraproteinemia, 45% bone marrow plasmacytosis and the t(4;14) by FISH and conventional cytogenetics. The patient had a very good partial remission with initial induction therapy consisting of four 3-week cycles of bortezomib 1.3 mg/m2 IV on days 1, 4, 8, and 11 plus dexamethasone 40 mg days 1-4 (all cycles), followed by a cyclophosphamide and G-CSF mobilized melphalan 200 mg/m2 autologous stem cell transplantation (ASCT) and experienced minimal side effects. He is doing well 60 days post-ASCT and is in a near complete remission. His oncologist recommends maintenance therapy with lenalidomide or bortezomib, but the patient is concerned about the increased risk of developing a secondary malignancy (SM), and because he has had such an encouraging response to induction therapy, he wonders if he could remain off therapy.
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Lakshminarasimhan, Anirudha. "Prophage induction therapy: Activation of the lytic phase in prophages for the elimination of pathogenic bacteria." Medical Hypotheses 169 (December 2022): 110980. http://dx.doi.org/10.1016/j.mehy.2022.110980.
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Ghobrial, Irene M., and A. Keith Stewart. "ASH evidence-based guidelines: what is the role of maintenance therapy in the treatment of multiple myeloma?" Hematology 2009, no. 1 (January 1, 2009): 587–89. http://dx.doi.org/10.1182/asheducation-2009.1.587.
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Abstract A 51-year-old male was diagnosed with an IgA multiple myeloma (MM) after having back pain for several months. His bone marrow showed 30% involvement with plasma cells and his cytogenetics showed t(4:14). His β2-microglobulin was 6.5 mg/dL at diagnosis and he had multiple lytic lesions, along with a creatinine of 2.3 mg/dL and significant anemia. Induction therapy with lenalidomide, bortezomib and dexamethasone was used, and he was able to achieve complete remission after 4 cycles of therapy. He then went on to receive high-dose chemotherapy with a single autologous stem cell transplant. He tolerated it well and now comes to discuss follow-up treatment plans. He wants to discuss maintenance therapy.
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Clayman, Gary L., Howard E. Savage, Gregory Young, Pierre Lavedan, Dorothy L. Taylor, and Stimson P. Schantz. "Detection of Regulatory Factors of Lymphokine-Activated Killer Cell Activity in Head and Neck Cancer Patients Treated with Interleukin-2 and Interferon Alpha." Annals of Otology, Rhinology & Laryngology 101, no. 11 (November 1992): 909–15. http://dx.doi.org/10.1177/000348949210101105.
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Interleukin-2 (IL-2) and interferon-α (INF-α) are biologic modifiers that have met with limited clinical success in the treatment of human malignancies. We conducted a phase 2 trial of IL-2-IFN-α in patients with advanced or unresectable squamous cell carcinoma of the upper aerodigestive tract. Two patients were analyzed sequentially for serum induction phase–blocking factors of lymphokine-activated killer (LAK) cell activity in their therapy. Serum also modulated LAK activity independent of autologous or allogeneic effector cells. Significantly inhibitory serum samples were stable in multiple freezings and thawings. Heat-treating the inhibitory serum, at 56°C for 30 minutes, only partially removed the serum inhibitory capacity. Sequential analysis of p55 and p75, subunits of IL-2 receptors, showed that absence of effector cell lytic activity was associated with markedly decreased fluorescence of the IL-2Rp75 subunit only. No significant alteration of the IL-2Rp55 subunit occurred with therapy. These studies support the theory that lymphocyte and multiple serum factors, developing during IL-2-IFN-α therapy, regulate the induction of in vitro LAK activity. Further understanding of these factors may lead to improvements in biologic modifier therapy.
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Cleeland, Charles S., Xin Shelley Wang, Sheeba K. Thomas, Ping Liu, Mary H. Sailors, Tito R. Mendoza, James M. Reuben, et al. "Predictive value of baseline serum MIP-1α and CRP on symptom burden and tumor response to induction therapy in patients with multiple myeloma." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 8091. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.8091.
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8091 Background: Macrophage inflammatory protein-1α(MIP-1α) is a growth factor for human multiple myeloma (MM) cells. As an osteoclastic factor, its presence provides pathophysiological evidence of the development of lytic bone lesions in MM. C-reactive protein (CRP) indicates systemic inflammation. The relationship between disease-driven inflammatory markers and both patient-experienced symptoms and tumor response to induction therapy is unknown. Methods: MM patients (N=39) who were either newly diagnosed or had received fewer than 2 cycles of chemotherapy, and who also were to receive induction therapy, were enrolled. To test concentrations of MIP-1α and CRP, serum samples were collected before and after induction and assayed by Luminex. Multiple symptoms were measured twice a week via the M. D. Anderson Symptom Inventory MM module (MDASI-MM) from -8 to +112 days of induction. The MM-specific items of the MDASI-MM are bone aches, constipation, muscle weakness, diarrhea, sore mouth or throat, rash, and difficulty paying attention. Correlation between symptom severity and inflammatory markers at baseline was examined by linear regression modeling. Kruskal-Wallis significance test and Wilcoxon test were used to examine association between MIP-1α and tumor response. Results: Patients received either bortezomib-based (89%) or lenalidomide-based induction therapy. Baseline MIP-1α and CRP were significantly inversely related to the mean severity component score of the 5 most-severe symptoms (fatigue, pain, bone aches, poor sleep, drowsiness) (p=.03; p=.02), and significantly inversely related to the severity of a component score of the module-specific symptoms (p=0.04; p=.002). Change over time in MIP-1α differed significantly by tumor response category (p=.04), with the partial response group having a higher median score than the complete response group (1.483 vs. 0.016, p=.01). Conclusions: Our data suggest that higher baseline levels of serum MIP-1α and CRP predict effective chemotherapy-induced reduction of disease-related symptoms in MM patients. Higher serum MIP-1α expression after induction therapy was related to less-ideal tumor response.
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Faller, Douglas V., Sajal K. Ghosh, Susan P. Perrine, Robert M. Williams, and Ronald J. Berenson. "Histone Deacetylase Inhibitors: Potent Inducers of Tumor Latent EBV Thymidine Kinase Induction." Blood 116, no. 21 (November 19, 2010): 1831. http://dx.doi.org/10.1182/blood.v116.21.1831.1831.
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Abstract Abstract 1831 Strong epidemiological association of Epstein-Barr Virus (EBV) with various human lymphoid malignancies and in vitro studies demonstrating tumorigenic activity of many EBV latent gene products suggest a causal relationship between EBV and these diseases. However, as EBV maintains a latent state of infection in these lymphomas, typical anti-herpesviral drugs, such as the nucleoside analogs ganciclovir (GCV) or acyclovir, are ineffective as these pro-drugs require expression of a lytic phase EBV protein, thymidine kinase (TK), for their activity. Therefore, selective induction of EBV lytic-phase gene expression in lymphoma cells that harbor latent EBV, coupled with simultaneous exposure to anti-herpesviral drugs, has been advanced as promising targeted therapy, because of resulting targeting of cytotoxicity to the EBV-infected tumor cells. A variety of agents including short-chain fatty acids and chemotherapeutic drugs, have been used to induce EBV lytic-phase infection in cultured cells, but these in vitro studies have generally not translated into clinical application. We have successfully used arginine butyrate and GCV to treat EBV-positive lymphoid malignancies in a recent Phase I/II clinical trial. In this study of 15 patients with relapsed or refractory EBV-positive lymphoid tumors, 4 patients achieved complete tumor remissions and 6 patients partial tumor remissions. However, the rapid metabolism of butyrate requires continuous IV administration of high doses. Butyrate has pan-HDAC inhibitory activity, and we have established that this activity is responsible for the induction of the EBV-TK protein. In recent years, several potent HDAC inhibitors (HDACi) have been tested in the clinic as anti-cancer agents. In the current study, we have investigated a number of HDACi, including some new, highly-potent compounds, for their potential to induce EBV lytic phase gene expression and to kill EBV-infected cells in combination with anti-herpesviral drugs. Our study included short-chain fatty acids (sodium butyrate and valproic acid); hydroxamic acids [Oxamflatin, Scriptaid, Suberoyl anilide hydroxamic acid (SAHA), Panobinostat (LBH589) and Belinostat (PXD101)]; the benzamide MS275; cyclic tetrapeptide Apicidin, and newly-identified HDAC inhibitor Largazole, which was originally isolated from a marine cyanobacterium. We assayed the induction of lytic phase in EBV-positive lymphoma cell lines exposed to different HDACi for 24–48 hrs, then quantitated the expression of EBV TK and other EBV transcripts by RT-PCR analysis. To determine tumor cytotoxic activity of the combination of HDACi and GCV, EBV+ lymphoma cells were exposed to a range of concentrations of HDACi and GCV for 3 days and then to GCV alone for another 3 days. Efficacy of a particular HDACi in the combination treatment approach was then determined by enumerating living cells. With the exception of SAHA and PXD101, the other HDACi had synergistic activity with anti-viral agents in killing EBV+ lymphoma cells. The hydroxamic acid LBH589, the benzamide MS275, and synthetic largazole derivatives 234a and 234b were 104 to 105-times more potent in killing EBV+ lymphoma cells in presence of GCV, compared to sodium butyrate. The effective concentration of LBH589 was in the range of 50–100 nM, MS275 at 200–500 nM and Largazole 234a and 234b at 100–200 nM. Of note, at these concentrations, the drugs as single agents produced no growth inhibitory activity in the tumor cells. LBH589, MS275 and Largazole 234a and 234b also strongly induced EBV-TK expression in the tumor cells. The effectiveness of these HDACi compounds at such low concentrations makes them potentially applicable as sensitizers to anti-viral therapeutics for the treatment of EBV-associated lymphomas. Our finding therefore provides an intriguing possibility that these novel HDACi may be used as an alternative therapeutic option, in combination with nucleoside antivirals, for the treatment of EBV-associated tumors. Disclosures: Faller: HemaQuest Pharmaceuticals: Consultancy, Equity Ownership. Perrine:HemaQuest Pharmaceuticals, Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Williams:HemaQuest Pharmaceuticals: Consultancy, Equity Ownership. Berenson:HemaQuest Pharmaceuticals, Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.
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Sankaranarayanan, N., K. Alleman, K. Charpentier, M. Brown, A. Lally, M. Lawlor, B. Cooper, D. Hull, and K. V. Ranga. "CYTOMEGALOVIRUS IMMUNE GLOBULIN (Ig) ALONE DOES NOT PREVENT SEROCONVERSION IN CMV MISMATCHED KIDNEY TRANSPLANT RECIPIENTS RECEIVING NON-LYTIC INDUCTION THERAPY." Transplantation 78 (July 2004): 483. http://dx.doi.org/10.1097/00007890-200407271-01299.
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Feng, Wen-hai, Eva Westphal, Amy Mauser, Nancy Raab-Traub, Margaret L. Gulley, Pierre Busson, and Shannon C. Kenney. "Use of Adenovirus Vectors Expressing Epstein-Barr Virus (EBV) Immediate-Early Protein BZLF1 or BRLF1 To Treat EBV-Positive Tumors." Journal of Virology 76, no. 21 (November 1, 2002): 10951–59. http://dx.doi.org/10.1128/jvi.76.21.10951-10959.2002.
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ABSTRACT The Epstein-Barr virus (EBV) genome is present in a variety of tumor types, including virtually all undifferentiated nasopharyngeal carcinomas (NPC) and a portion of gastric carcinomas. The uniform presence of the EBV genome in certain tumors (versus only a very small number of normal B cells) suggests that novel therapies which specifically target EBV-positive cells for destruction might be effective for treating such tumors. Although the great majority of EBV-positive tumor cells are infected with one of the latent forms of EBV infection, expression of either viral immediate-early protein (BZLF1 or BRLF1) is sufficient to convert the virus to the lytic form of infection. Induction of the lytic form of EBV infection could potentially result in death of the tumor cell. Here we have examined the efficacy of adenovirus vectors expressing the BZLF1 or BRLF1 proteins for treatment of EBV-positive epithelial tumors. The BZLF1 and BRLF1 vectors induced preferential killing of EBV-positive, versus EBV-negative, gastric carcinoma cells in vitro. Infection of C18 NPC tumors (grown in nude mice) with either the BZLF1 or BRLF1 vector, but not a control adenovirus vector, induced expression of early lytic EBV genes in tumor cells. Injection of C18 tumors with the BZLF1 or BRLF1 adenovirus vector, but not the control vector, also significantly inhibited growth of the tumors in nude mice. The addition of ganciclovir did not significantly affect the antitumor effect of the BZLF1 and BRLF1 adenovirus vectors. These results suggest a potential cancer therapy against EBV-related tumors.
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Lotzová, E., C. A. Savary, and R. B. Herberman. "Induction of NK cell activity against fresh human leukemia in culture with interleukin 2." Journal of Immunology 138, no. 8 (April 15, 1987): 2718–27. http://dx.doi.org/10.4049/jimmunol.138.8.2718.
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Abstract Natural killer (NK) cells have been implicated in defense against malignancies, especially leukemia. Because patients with leukemia and preleukemic disorders manifest low NK activity, it is possible that NK cell impairment may contribute to leukemogenesis. In view of this possibility, it was important to characterize the NK cell defect of leukemic patients and to design new approaches for its correction. Analysis of the mechanism of NK cell defect demonstrated that NK cells of leukemic patients were impaired in their tumor-binding and lytic activity and did not display ability to recycle or to produce cytotoxic factor. However, deficient NK activity could be corrected by culture of peripheral blood effector cells with IL 2. IL 2-activated NK cells manifested restoration of all measured parameters of the cytotoxic mechanism, as exemplified by normalized tumor-binding and lytic activity, as well as the rate of lysis and ability to recycle. Importantly, such in vitro stimulated cytotoxic cells displayed reactivity against fresh leukemic cells of autologous as well as allogeneic origin. Another interesting observation from these studies was that the NK activity was also induced in the leukemic bone marrow, a tissue with a very low frequency of cytotoxic NK cells. It is important to note that cultured NK cells did not represent a stationary cell population, but proliferated in vitro quite actively (doubling time 3 to 6 days) for at least 5 wk. Characterization of the in vitro generated cytotoxic cells indicated that these cells displayed large granular lymphocyte morphology and CD16 and Leu-19 cell surface phenotype. Our data demonstrate that the NK cell defect of leukemic patients is not a permanent phenomenon, but can be reversed in culture with IL 2, and that fully cytotoxic NK cells can be maintained and expanded in vitro. Thus, it is reasonable to suggest that adoptive transfer of autologous NK cells to the patients may represent a promising new therapy for treatment of leukemia.
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Di Filippo, Michela Di, Paulina Hennig, Tugay Karakaya, Marta Slaufova, and Hans-Dietmar Beer. "NLRP1 in Cutaneous SCCs: An Example of the Complex Roles of Inflammasomes in Cancer Development." International Journal of Molecular Sciences 23, no. 20 (October 14, 2022): 12308. http://dx.doi.org/10.3390/ijms232012308.
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Protein complexes termed inflammasomes ensure tissue protection from pathogenic and sterile stressors by induction of inflammation. This is mediated by different caspase-1-induced downstream pathways, including activation of the pro-inflammatory cytokines proIL-1β and -18, induction of a lytic type of cell death, and regulation of the release of other pro-inflammatory molecules. Aberrant inflammasome activation underlies the pathology of numerous (auto)inflammatory diseases. Furthermore, inflammasomes support or suppress tumor development in a complex cell-type- and stage-dependent manner. In human keratinocytes and skin, NLRP1 is the central inflammasome sensor activated by cellular perturbation induced, for example, by UVB radiation. UVB represents the main inducer of skin cancer, which is the most common type of malignancy in humans. Recent evidence demonstrates that activation of NLRP1 in human skin supports the development of cutaneous squamous cell carcinomas (cSCCs) by inducing skin inflammation. In contrast, the NLRP1 inflammasome pathway is restrained in established cSCCs, suggesting that, at this stage, the protein complex has a tumor suppressor role. A better understanding of the complex functions of NLRP1 in the development of cSCCs and in general of inflammasomes in cancer might pave the way for novel strategies for cancer prevention and therapy. These strategies might include stage-specific modulation of inflammasome activation or its downstream pathways by mono- or combination therapy.
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Tazawa, Hiroshi, Joe Hasei, Shuya Yano, Shunsuke Kagawa, Toshifumi Ozaki, and Toshiyoshi Fujiwara. "Bone and Soft-Tissue Sarcoma: A New Target for Telomerase-Specific Oncolytic Virotherapy." Cancers 12, no. 2 (February 18, 2020): 478. http://dx.doi.org/10.3390/cancers12020478.
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Adenovirus serotype 5 (Ad5) is widely and frequently used as a virus vector in cancer gene therapy and oncolytic virotherapy. Oncolytic virotherapy is a novel antitumor treatment for inducing lytic cell death in tumor cells without affecting normal cells. Based on the Ad5 genome, we have generated three types of telomerase-specific replication-competent oncolytic adenoviruses: OBP-301 (Telomelysin), green fluorescent protein (GFP)-expressing OBP-401 (TelomeScan), and tumor suppressor p53-armed OBP-702. These viruses drive the expression of the adenoviral E1A and E1B genes under the control of the hTERT (human telomerase reverse transcriptase-encoding gene) promoter, providing tumor-specific virus replication. This review focuses on the therapeutic potential of three hTERT promoter-driven oncolytic adenoviruses against bone and soft-tissue sarcoma cells with telomerase activity. OBP-301 induces the antitumor effect in monotherapy or combination therapy with chemotherapeutic drugs via induction of autophagy and apoptosis. OBP-401 enables visualization of sarcoma cells within normal tissues by serving as a tumor-specific labeling reagent for fluorescence-guided surgery via induction of GFP expression. OBP-702 exhibits a profound antitumor effect in OBP-301-resistant sarcoma cells via activation of the p53 signaling pathway. Taken together, telomerase-specific oncolytic adenoviruses are promising antitumor reagents that are expected to provide novel therapeutic options for the treatment of bone and soft-tissue sarcomas.
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Bhatt, Shruti, Brittany Ashlock, Ngoc Toomey, Enrique Mesri, Juan Carlos Ramos, and Izidore S. Lossos. "Synergistic Preclinical Activity of Bortezomib with Suberoylanilide Hydroxamic Acid (SAHA) in Primary Effusion Lymphoma (PEL)." Blood 118, no. 21 (November 18, 2011): 1650. http://dx.doi.org/10.1182/blood.v118.21.1650.1650.
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Abstract Abstract 1650 Primary effusion lymphoma (PEL) is an aggressive subtype of non-Hodgkin lymphoma typically presenting as effusions in the serous body cavities without a contiguous tumor mass. PEL may develop in elderly immunosuppressed HIV-negative individuals but more commonly affects HIV-positive patients, accounting for 4% of all lymphomas in this population. Kaposi's sarcoma-associated herpesvirus (KSHV) is directly implicated in the pathogenesis of PEL, however in most patients the malignant B cells are also coinfected with Epstein-Barr virus which may facilitate transformation. Current chemotherapeutic approaches result in dismal outcome of PEL patients with a median survival of only 6 months. Consequently, development of new therapeutic approaches is urgently needed. Recently we reported development of the UM-PEL1 direct xenograft mice model reproducing human PEL (Sarosiek, PNAS 2010) in which bortezomib (BORT) induced virus lytic reactivation leading to malignant B cell death and transient remission of the PEL in vivo. Further improvement on this monotherapy is warranted. Recent studies have shown that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase (HDAC) inhibitor is a highly effective viral lytic-cycle inducer. As herpesviruses are dependent on the proteasome for replication and mature viral production, induction of lytic replication with concomitant inhibition of the proteasome may provide a highly targeted strategy for eradicating KSHV infected cells without leading to increased viremia. Consequently, we hypothesized that combining BORT with SAHA may act synergistically in PEL tumors. Incubation of human PEL cell lines, UM-PEL1, BC1, BC3 and BC5 with BORT-SAHA resulted in increased apoptotis compared to individual treatment with BORT or SAHA, as assayed by flow cytometry using YO-PRO/PI staining. Concordantly, a statistically significant decrease in UM-PEL1 cell proliferation and viability, as examined by an MTT assay, was observed at 48 and 72 hours following combination therapy as compared to untreated cells or cells treated individually with BORT or SAHA. Cell cycle analysis demonstrated that BORT-SAHA combination induced more pronounced G1 cell cycle arrest and apoptosis as compared to individual treatments. SAHA induced a more robust KSHV lytic reactivation compared to BORT. Intriguingly, the BORT-SAHA combination led to an increased expression of the master lytic transactivator RTA and thymidine kinase, however the late lytic gene, K8.1, showed reduced mRNA expression relative to the individual SAHA treatment. These findings were further confirmed by immunofluorescence staining of the K8.1 protein suggesting that BORT could inhibit mature virion production in lytically reactivated malignant B-cells. To comprehensively examine the activity of the BORT-SAHA combination compared to individual BORT or SAHA treatments in vivo, we used UM-PEL1 direct xenograft model. Mice receiving intraperitoneal BORT-SAHA combination showed statistically significant prolonged survival compared to all the control treatments (p<0.001). Since PEL cells are known to be highly dependent on NF-κB for survival, we examined whether the apoptosis induced by the combination treatment was due to the inhibition of this pro-survival pathway. In contrast to our previous observations that individual BORT treatment did not alter NF-κB activity, the in vivo addition of SAHA led to NF-κB inhibition as demonstrated by gel shift assay. Moreover, Western blotting demonstrated downregulation of anti-apoptotic genes, upregulation of pro-apoptotic genes along with the rise in the p53, p21 and increased acetylation of histone 3 in the combination treated mice versus BORT alone. Further, RTA and early lytic gene expression confirmed our in vitro findings that KSHV lytic reactivation is enhanced in the BORT-SAHA treated mice compared to individual treatments. However, transcription of all late lytic genes tested (gB, K8.1, gM, ORF38, ORF67, ORF68) was uniformly inhibited in the animals treated with the BORT-SAHA as compared to SAHA alone, suggesting that the virus was unable to complete the full replicative cycle. In conclusion, this study demonstrates strong pre-clinical activity of the combination of proteasome inhibitor with HDAC inhibitor as a potent anti-PEL therapy that triggers apoptosis by prompting KSHV lytic reactivation without increasing infectious virus production. Disclosures: No relevant conflicts of interest to declare.
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Nalbandyan, Karen, Daniel Benharroch, Benzion Samueli, Michael Kafka, and Anna Gourevitch. "Multiple Myeloma with Foamy Mott Cells." Case Reports in Hematology 2021 (August 10, 2021): 1–4. http://dx.doi.org/10.1155/2021/7391895.
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Intracytoplasmic assorted vacuoles containing immunoglobulin collections are occasionally seen in multiple myeloma. When abundant, they impart a foamy appearance to the tumor cells, which is a potential source for diagnostic pitfalls. Herein, we report the case of a patient who presented with skeletal pain and CT confirmed lytic lesions. A bone marrow biopsy revealed multiple myeloma with unusual foamy Mott cells. The patient was subsequently treated with four cycles of cyclophosphamide, bortezomib, and dexamethasone induction therapy, followed by 3 cycles of lenalidomide with dexamethasone. A biopsy performed following initial biological and immunomodulatory drugs revealed different morphological and clonal characteristics. These features were modified again, five years later, and again, after two years of close monitoring. Hematopathologists should be aware of this morphologic variant of myeloma as well as for the capacity of clonal characteristics, such as light chain monotype, to fluctuate subsequent to treatment.
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Raza, Shahzad, Rachael A. Safyan, Evan Rosenbaum, Alex S. Bowman, and Suzanne Lentzsch. "Optimizing current and emerging therapies in multiple myeloma: a guide for the hematologist." Therapeutic Advances in Hematology 8, no. 2 (December 9, 2016): 55–70. http://dx.doi.org/10.1177/2040620716680548.
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Multiple myeloma (MM) is the second most common hematologic malignancy. The diagnosis of MM requires ⩾10% clonal plasma cells in the bone marrow or biopsy-proven plasmacytoma, plus evidence of end-organ damage (hypercalcemia, renal failure, anemia, and lytic bone lesions). The definition of MM has recently been expanded to include a ⩾60% clonal plasma cell burden in the bone marrow, serum involved/uninvolved light chain ratio of ⩾100, or more than one focal lesion on magnetic resonance imaging ⩾5 mm in the absence of end-organ damage. MM is an incurable malignancy previously associated with poor survival rates. However, over the past two decades, the introduction of novel treatment options has resulted in a dramatic improvement in response rates and overall survival (OS). The combination of a proteasome inhibitor and an immunomodulator (IMiD) is the preferred induction treatment for newly diagnosed transplant-eligible MM patients. After induction, high-dose therapy with autologous stem cell transplant (ASCT) is still the standard of care for these patients. In patients who are transplant ineligible, dose adjusted IMiDs or proteasome inhibitor-based combinations are the preferred treatment option. With the recent approval of novel drugs like carfilzomib, ixazomib, pomalidomide, panobinostat, and monoclonal antibodies (elotuzumab and daratumumab), as well as improved understanding of risk stratification, management of comorbidities and treatment side effects, clinicians can optimize anti-MM therapy, particularly in relapse/refractory MM patients. In this review, we outline the current therapeutic approach to the management of MM.
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Faller, Douglas V., Sajal Ghosh, Tatyana Feldman, Adam Lerner, Judith Smith, Andre Goy, Ronald Berenson, and Susan Perrine. "Short-Term Exposure to Arginine Butyrate, in Combination with Ganciclovir, Is as Effective as Continuous Exposure for Virus-Targeted Therapy of EBV-Positive Lymphomas." Blood 114, no. 22 (November 20, 2009): 4754. http://dx.doi.org/10.1182/blood.v114.22.4754.4754.
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Abstract Abstract 4754 Antiviral drugs alone have been unsuccessful in the treatment of Epstein-Barr virus (EBV)-associated malignancies because the virus maintains a latent state of replication in these tumors. In recent years, we developed a novel therapeutic approach wherein the early lytic phase of the virus is induced prior to the use of cytotoxic antiviral drugs. Butyrate derivatives induce an early lytic pattern of EBV gene expression in patient-derived EBV-positive lymphoblastoid cell lines and, together with the nucleoside analog ganciclovir (GCV), effectively reduce or eliminate tumor growth in humans. In a completed Phase 1/2 trial in which patients with relapsed or refractory EBV-associated lymphoid malignancies were treated with 3 weeks of Arginine Butyrate combined with GCV, tumor responses (CR and PR) occurred in 10 of 15 patients. Butyrate requires administration by prolonged intravenous infusion, which is challenging over long time periods. In the Phase 1/2 clinical trial, tumor responses were observed within a few days of starting therapy. We therefore investigated whether brief or discontinuous exposure to Butyrate is also capable of initiating early lytic-phase gene expression and thymidine kinase induction, and sensitizing EBV-positive lymphoma cells to ganciclovir-mediated cell growth arrest and apoptosis. Multiple daily 6-hr exposures of the EBV-positive Burkitt's lymphoma cell line P3HR1 to butyrate induced sustained expression of the EBV TK and lytic-phase protein BMRF. Discontinuous exposure to butyrate in combination with ganciclovir also induced a similar level of tumor cell death as did continuous treatment, as measured by serial enumeration of viable cells, MTT cell proliferation assays, and measurement of cellular DNA content. Based on these observations, we have initiated a new clinical trial utilizing a 5-day infusion of Arginine Butyrate and 21 days of GCV/valganciclovir for treatment of patients with EBV-positive lymphoid malignancies. The first patient enrolled, with Rituximab-refractory EBV-positive PTLD following a cord stem cell transplant for Hodgkin's Disease, has been treated on this protocol. The therapy was well-tolerated and resulted in rapid resolution of fever and cough of several weeks duration, and a rapid decrease of markedly elevated LDH levels to the normal range. At the end of the first cycle, 4 of 6 target lesions resolved completely, and two additional lesions decreased in size. High EBV, CMV and HHV6 viral loads became undetectable. This response has been durable for 2 months. These findings together suggest that a shorter, more patient-accessible regimen of this virus-targeted therapeutic strategy may be efficacious, and the clinical trial is continuing. Disclosures: Faller: HemaQuest Pharmaceuticals: Consultancy, Equity Ownership, Patents & Royalties, Research Funding. Off Label Use: The use of Ganciclovir, administered in combination with Arginine Butyrate as an inducer of viral TK,to induce apoptosis in EBV-lymphoma and EBV lymphoproliferative disease. Ghosh:HemaQuest Pharmaceuticals: Research Funding. Lerner:HemaQuest Pharmaceuticals: Consultancy. Berenson:HemaQuest Pharmaceuticals: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Perrine:HemaQuest Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties, Research Funding.
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Moore, Stacy M., Jennifer S. Cannon, Yvette C. Tanhehco, Fayez M. Hamzeh, and Richard F. Ambinder. "Induction of Epstein-Barr Virus Kinases To Sensitize Tumor Cells to Nucleoside Analogues." Antimicrobial Agents and Chemotherapy 45, no. 7 (July 1, 2001): 2082–91. http://dx.doi.org/10.1128/aac.45.7.2082-2091.2001.
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ABSTRACT The presence of Epstein-Barr virus (EBV) in the tumor cells of some EBV-associated malignancies may facilitate selective killing of these tumor cells. We show that treatment of an EBV+ Burkitt's lymphoma cell line with 5-azacytidine led to a dose-dependent induction of EBV lytic antigen expression, including expression of the viral thymidine kinase (TK) and phosphotransferase (PT). Azacytidine treatment for 24 h modestly sensitized the cell line to all nucleosides tested. To better characterize EBV TK with regard to various nucleoside analogues, we expressed EBV TK in stable cell clones. Two EBV TK-expressing clones were moderately sensitive to high doses of acyclovir and penciclovir (PCV) (62.5 to 500 μM) and to lower doses of ganciclovir (GCV) and bromovinyldeoxyuridine (BVdU) (10 to 100 μM) compared to a control clone and were shown to phosphorylate GCV. Similar experiments in a transient overexpression system showed more killing of cells transfected with the EBV TK expression vector than of cells transfected with the control mutant vector (50 μM GCV for 4 days). A putative PT was also studied in the transient transfection system and appeared similar to the TK in phosphorylating GCV and conferring sensitivity to GCV, but not in BVdU- or PCV-mediated cell killing. Induction of EBV kinases in combination with agents such as GCV merits further evaluation as an alternative strategy to gene therapy for selective killing of EBV-infected cells.
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Chapoval, Andrei I., Jane A. Fuller, Sergey G. Kremlev, Sonya J. Kamdar, and Robert Evans. "Combination Chemotherapy and IL-15 Administration Induce Permanent Tumor Regression in a Mouse Lung Tumor Model: NK and T Cell-Mediated Effects Antagonized by B Cells." Journal of Immunology 161, no. 12 (December 15, 1998): 6977–84. http://dx.doi.org/10.4049/jimmunol.161.12.6977.
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Abstract Previous studies have demonstrated that IL-15 administration after cyclophosphamide (CY) injection of C57BL/6J mice bearing the i.m. 76-9 rhabdomyosarcoma resulted in a significant prolongation of life. In the present study, we investigated the immune response against the 76-9 experimental lung metastases after CY + IL-15 therapy. Administration of CY + IL-15, but not IL-15 alone, induced prolongation of life and cures in 32% of mice bearing established experimental pulmonary metastases of 76-9 tumor. The CY + IL-15 therapy resulted in increased levels of NK1.1+/LGL-1+ cells, and CD8+/CD44+ T cells in PBL. In vitro cytotoxic assay of PBL indicated the induction of lymphokine-activated killer cell activity, but no evident tumor-specific class I-restricted lytic activity. Survival studies showed that the presence of NK and T lymphocytes is necessary for successful CY + IL-15 therapy. Experiments using knockout mice implied that either αβ or γδ T cells were required for an antitumor effect induced by CY + IL-15 therapy. However, mice lacking in both αβ and γδ T cells failed to respond to combination therapy. Cured B6 and αβ or γδ T cell-deficient mice were immune to rechallenge with 76-9, but not B16LM tumor. B cell-deficient mice showed a significant improvement in the survival rate both after CY and combination CY + IL-15 therapy compared with normal B6 mice. Overall, the data suggest that the interaction of NK cells with tumor-specific αβ or γδ T lymphocytes is necessary for successful therapy, while B cells appear to suppress the antitumor effects of CY + IL-15 therapy.
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Drayson, Mark, Gulnaz Begum, Supratik Basu, Sudhaker Makkuni, Janet Dunn, Nicola Barth, and J. Anthony Child. "Effects of paraprotein heavy and light chain types and free light chain load on survival in myeloma: an analysis of patients receiving conventional-dose chemotherapy in Medical Research Council UK multiple myeloma trials." Blood 108, no. 6 (September 15, 2006): 2013–19. http://dx.doi.org/10.1182/blood-2006-03-008953.
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AbstractWhile investigating 2592 patients enrolled in multicenter myeloma trials, we found light chain–only (LCO) patients had worse median survival times (1.9 years) than patients with IgA and IgG paraproteins (2.3 and 2.5 years, respectively) (P < .001). However, IgA and IgG patients with levels of LC excretion similar to those of LCO patients also had poor survival times because of renal failure, resulting in worse survival during induction therapy and at relapse with no difference in progression-free survival between LCO and IgG patients. LC excretion was higher for λ than for κ types, but there was no difference in survival between the 2 LC types when stratified for level of LC excretion, indicating that care of renal function is vital to improving the survival of any patient with LC excretion. LCO patients were younger (P = .001), had worse performance status (P = .001), and had more lytic lesions (P < .001), perhaps reflecting late and missed diagnoses in younger and older LCO patients, respectively. No differences were observed between IgA and IgG patients in presentation characteristics, response, or survival from disease progression. The worse survival of IgA patients was attributed to shorter progression-free survival (median, 1.2 vs 1.6 years; P < .001), which is important for maintenance therapy.
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Stevens, Servi J. C., Christian M. Zwaan, Sandra A. W. M. Verkuijlen, and Jaap M. Middeldorp. "Epstein-Barr virus (EBV) serology for predicting distant metastases in a white juvenile patient with nasopharyngeal carcinoma and no clinical response to EBV lytic induction therapy." Head & Neck 28, no. 11 (2006): 1040–45. http://dx.doi.org/10.1002/hed.20466.
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Arnason, Jon E., and Lourdes M. Mendez. "Induction Therapy for Gamma-Heavy Chain Disease with Bortezomib and Dexamethasone: A Case Report." Blood 120, no. 21 (November 16, 2012): 5051. http://dx.doi.org/10.1182/blood.v120.21.5051.5051.
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Abstract Abstract 5051 Heavy chain diseases (HCD) are rare B-cell lymphoproliferative disorders characterized by production of a monoclonal immunoglobulin without a light chain. Three subtypes are known based on the type of monoclonal immunoglobulin produced ie. alpha-heavy chain, gamma-heavy chain and mu-heavy chain disease in order of decreasing frequency. Here we report a case of gamma-heavy chain disease in a previously healthy 48 year old African American man, which demonstrated clinical and pathologic response to treatment with bortezomib and dexamethasone. The patient was transferred to our institution for work-up of persistent high fever, hypotension and eosinophilia after a thorough negative infectious and rheumatologic work-up spanning two outside hospital admissions. The patient had originally presented with two months of constitutional symptoms and cough refractory to antibiotics and prednisone. His outside hospital admissions were notable for an RCA NSTEMI (an unexpectedly large thrombus was noted on cardiac catheterization), eosinophilia and persistent fevers to 105 degrees Fahrenheit. Imaging studies included a CT torso and tagged WBC scan which were unrevealing but for mild splenomegaly of 15 cm and notably did not show lymphadenopathy, masses or evidence for infection. The fevers transiently abated with an empiric course of steroids but recurred accompanied by shock, which responded to a pulse of high dose methylprednisolone. Ultimately he was felt to have primary adrenal insufficiency without evidence of infiltrative disease on dedicated CT. On presentation to our hospital, his initial labs showed WBC 5. 3 K/uL (83% neutrophils, 10% lymphocytes, 3% monocytes, 4% eosinophils), Hb 11. 2 g/dL, platelets 173 K/uL. Comprehensive chemistry profile was unremarkable. SPEP/IFE of the serum and urine revealed a monoclonal gamma-heavy chain without associated light chain. The total IgG was elevated at 2522 mg/dL, IgA was mildly depressed at 57 mg/dL and IgM was normal at 147 mg/dL; the monoclonal protein itself could not be quantitated; hence, total serum IgG was followed. The patient underwent a bone marrow biopsy and aspiration which showed trilineage hematopoiesis, marked esosinophilia, no evidence of leukemia or lymphoma, 10% CD138+ plasma cells, with the overwhelming majority staining for IgG but not for kappa or lambda. A skeletal survey was negative for lytic lesions. The findings were felt to be consistent with a plasma cell dyscrasia associated gamma-heavy chain disease. The observed eosinophilia was felt to be reactive to the gamma-heavy chain disease as has been previously described. In the literature, gamma heavy chain disease is reported to most commonly present as a lymphoplasmacytic process and the finding of a plasma cell dyscrasia appears to be an unusual presentation of what is already a rare disease. We decided to tailor the treatment to the finding of a plasma cell dyscrasia. Therefore the patient was started on bortezomib 1. 3 mg/m2 SC D1, 4, 8, 11 and dexamethasone 20 mg PO D1, 2, 4, 5, 8, 9, 11, 12 of a 21 day cycle. His treatment was complicated by paroxysmal atrial tachycardia; a cardiac MRI did not reveal evidence of infiltrative cardiomyopathy. After 4 cycles of bortezomib and dexamethasone, the patient's total IgG had normalized at 1265 mg/dL and though a monoclonal gamma heavy chain was still detected by IFE of the serum and urine, a repeat bone marrow biopsy and aspiration was without morphologic evidence of the heavy chain plasma cell dyscrasia. The patient reported feeling subjectively improved with abatement of his malaise and fatigue and without further episodes of fever. Interestingly, the parameter that most seemed to correlate with his clinical status was eosinophilia which also decreased from a peak of 61% (absolute eosinophil count of 5063/uL) to 8–19% after 4 cycles with bortezomib and dexamethasone. Secondary eosinophilia has been reported in the literature in a subset of gamma HCD patients. The patient further underwent stem-cell mobilization in preparation for auto stem cell transplant with high dose Cytoxan, after which the eosinophilia completely resolved. There are only approximately 120 cases of gamma HCD described in the literature. To our knowledge, this is the first reported case of plasma cell dyscrasia associated gamma HCD responding to treatment with bortezomib and dexamethasone. Disclosures: No relevant conflicts of interest to declare.
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Dugan, James, Bradley M. Haverkos, Ludmila Katherine Martin, Marisa F. Martin, Mark E. Lustberg, John T. Patton, Gerard Nuovo, et al. "Epstein-Barr Virus Kinase-Targeted Therapy for Primary Central Nervous System Post-Transplant Lymphoproliferative Disorder." Blood 124, no. 21 (December 6, 2014): 1750. http://dx.doi.org/10.1182/blood.v124.21.1750.1750.
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Abstract BACKGROUND: Primary central nervous system post-transplant lymphoproliferative disorder (PCNS-PTLD) is a rare complication of solid organ transplant, with no standard therapy. Epstein-Barr virus (EBV) is ubiquitous making the virus a candidate therapeutic target. For virus targeted therapy to be effective, antiviral agents must be phosphorylated by lytic-phase kinases BXLF1 and BGLF4. We hypothesized that lytic kinases would be constitutively expressed in PCNS-PTLD and that antiviral therapy would prove an attractive therapeutic alternative to high dose methotrexate-based regimens in patients who often have impaired organ function and poor performance status. METHODS: We investigated the safety and efficacy of EBV-kinase targeted therapy with zidovudine (AZT), ganciclovir (GCV), rituximab, and dexamethasone in patients with PCNS-PTLD. Patients with biopsy-proven PCNS-PTLD following solid organ transplantation were eligible for treatment. Immune suppression was reduced in all patients prior to treatment. Induction therapy consisted of 14 days of AZT 1500 mg IV BID, GCV 5 mg/kg IV BID, dexamethasone 10 mg IV BID and rituximab 375 mg/m2 once weekly for four weeks. Maintenance antiviral therapy was initiated on day 15 with valganciclovir 450 mg and AZT 300 mg, both twice daily. Responses were evaluated by serial brain MRIs beginning 4 weeks after initiation of treatment. Brain biopsy specimens were evaluated for expression of BGLF4 and BXLF1 by in situ hybridization or immunohistochemistry. To test the hypothesis that expression of EBV kinases conferred sensitivity to antiviral therapy, 293T cells were transfected with cDNAs (or control vectors) encoding for full length BXLF1 and/or BGLF4. Transiently transfected cells were tested for expression by immunoblot and drug sensitivity to AZT/GCV was performed by MTS and flow cytometry assays. RESULTS: Twelve patients (7 M, 5 F) with a median age of 49 were treated from 1998-2014. Transplant history included kidney (N=11), pancreas (N=2), and liver (N=1). Histology data included diffuse large B-cell lymphoma (N=7) and grade III lymphomatoid granulomatosis (N=5). EBV positivity (EBER-ISH) and CD20 expression were documented in all cases. All patients completed induction therapy. Median follow-up time and median duration of maintenance therapy were 28 months (range 2 - 143). The mean progression free survival (PFS) was 33.8 months. Overall response rate (ORR) was 83.3%. Eight patients achieved a complete response (CR) within a median time of 2 months (range 0.75 – 6 months). Two patients had a partial response (PR) with an average time to response of 1.25 months. Two patients (2/12) had progressive disease (PD). Causes of death included septic shock (n=3), pulmonary embolism (n=1), and poor functional status requiring hospice (n=1). One patient had PD at the time of death. Median overall survival (OS) was 29 months (range 2 – 143 months). Grade 3-4 toxicity was primarily hematologic, including anemia (N=4), thrombocytopenia (N=2), and neutropenia (N=5). Toxicity in the maintenance phase was generally reversible with holding therapy. Three patients required discontinuation of AZT during maintenance treatment for transfusion-dependent anemia persisting after holding AZT for 7 days or neutropenia coinciding with systemic infection. One patient had AZT discontinued due to nausea and vomiting that led to acute kidney injury. Evaluation of BXLF1, BGLF4 and LMP1 was completed in 7 patients and found to be positive in all cases. LMP1 and kinase expression occurred in mutually exclusive regions of the tumor. Expression of BXLF1 and BGLF4 led to enhanced sensitization of 293T cells to antiviral-induced growth inhibition and apoptosis. CONCLUSIONS: EBV-kinase targeted therapy with AZT, GCV, rituximab and dexamethasone appears to be effective treatment for patients with EBV+ PCNS-PTLD. We demonstrated durable responses without disease recurrence and minimal toxicity. Expression of BXLF1 and BGLF4 kinases provides a mechanistic rationale for an antiviral approach to this disease and an attractive option to replace high dose chemotherapeutic regimens with less toxic targeted therapy in patients with compromised transplant organ function. A multi-center phase II trial is in development to further investigate this regimen in patients with immune deficiency-related CNS EBV-LPD. Figure 1 Figure 1. Disclosures Porcu: Infinity: Research Funding; Seattle genetics: Research Funding; Actelion: Honoraria; Celgene: Honoraria; United States Cutaneous Lymphoma Consortium: Membership on an entity's Board of Directors or advisory committees; Cutaneous Lymphoma Foundation: Membership on an entity's Board of Directors or advisory committees.
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Chatterjee, Anushila, Julia L. E. Willett, Gary M. Dunny, and Breck A. Duerkop. "Phage infection and sub-lethal antibiotic exposure mediate Enterococcus faecalis type VII secretion system dependent inhibition of bystander bacteria." PLOS Genetics 17, no. 1 (January 7, 2021): e1009204. http://dx.doi.org/10.1371/journal.pgen.1009204.
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Bacteriophages (phages) are being considered as alternative therapeutics for the treatment of multidrug resistant bacterial infections. Considering phages have narrow host-ranges, it is generally accepted that therapeutic phages will have a marginal impact on non-target bacteria. We have discovered that lytic phage infection induces transcription of type VIIb secretion system (T7SS) genes in the pathobiont Enterococcus faecalis. Membrane damage during phage infection induces T7SS gene expression resulting in cell contact dependent antagonism of different Gram positive bystander bacteria. Deletion of essB, a T7SS structural component, abrogates phage-mediated killing of bystanders. A predicted immunity gene confers protection against T7SS mediated inhibition, and disruption of its upstream LXG toxin gene rescues growth of E. faecalis and Staphylococcus aureus bystanders. Phage induction of T7SS gene expression and bystander inhibition requires IreK, a serine/threonine kinase, and OG1RF_11099, a predicted GntR-family transcription factor. Additionally, sub-lethal doses of membrane targeting and DNA damaging antibiotics activated T7SS expression independent of phage infection, triggering T7SS antibacterial activity against bystander bacteria. Our findings highlight how phage infection and antibiotic exposure of a target bacterium can affect non-target bystander bacteria and implies that therapies beyond antibiotics, such as phage therapy, could impose collateral damage to polymicrobial communities.
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Fu, D., J. Chong, C. Foss, J. Fox, S. Wang, G. Green, J. Chen, M. V. Lemas, M. Pomper, and R. Ambinder. "Imaging and therapy for Epstein-Barr virus-associated gastric cancer." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 4644. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.4644.
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4644 Background: Epstein-Barr virus (EBV) has been identified in a wide variety of malignancies, including gastric carcinomas. The virus encodes kinases that phosphorylate nucleoside analogs such as 2’-deoxy-2’-fluoro-5-iodo-1-beta-D- arabinofuranosyluracil (FIAU). We hypothesized that it might be possible to use the viral enzyme to specifically concentrate [125I]FIAU or [131I] FIAU in tumor cells harboring virus and thus deliver imaging and therapeutic radiation. Bortezomib is a potent stimulator of viral kinase expression in EBV tumor cell lines. Methods: We imaged lytic induction in vivo and evaluated the effect of [131I] FIAU on human cancer xenografts in SCID mice. These include a tumor line engineered to constitutively express the EBV thymide kinase (EBVTK), and a control engineered with a sham vector (SHAM), as well one EBV-associated human gastric tumor (KT tumor). Mice were treated with buffer, bortezomib (2μg/g), or radiolabeled FIAU or radiolabeled FIAU and bortezomib in combination. For imaging, mice, [125I]-FIAU and SPECT/CT were used. For therapy, 131I-FIAU was used and tumor dimensions were monitored with calipers. Results: SPECT/CT imaging with [125I]-FIAU of tumor-bearing SCID mice showed selective concentration of radiotracer in tumor tissue in EBVTK (3/3) and in EBV-associated KT tumors (3/3) when animals were pretreated with bortezomib. Treatment with buffer had no effect on 3 EBVTK tumors and 3 SHAM tumors all of which increased in volume. Treatment with 1.6 mCi of [131I]-FIAU alone led to tumor response in 3/3 mice with EBVTK tumors and 0/3 mice with SHAM tumors. Treatment with [131I]-FIAU alone had no effect on EBV KT tumor xenografts (0/3) and all tumors increased in volume. Treatment with bortezomib induced modest responses in all KT tumors. However, treatment with bortezomib and [131I]-FIAU led to marked tumor regression (>80%) in EBV-associated KT tumors (3/3). Conclusions: Treatment with bortezomib leads to selective concentration of radiolabeled FIAU in the EBV-associated tumor xenografts. In combination with [131I]-FIAU it leads to tumor regression. No significant financial relationships to disclose.
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Sauer, Sandra, Andreas Marco Fischer, Andrea Fraenzle, Christina Kunz, Maximilian Merz, Patrick Wuchter, Martina Schmaus, Anthony D. Ho, Hartmut Goldschmidt, and Jens Hillengass. "Impact of Radiation Therapy on Stem Cell Harvest in Multiple Myeloma." Blood 124, no. 21 (December 6, 2014): 5822. http://dx.doi.org/10.1182/blood.v124.21.5822.5822.
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Abstract Background: Bone disease is a hallmark of multiple myeloma (MM) and destructive osteolytic bone lesions affect more than 80 % of patients resulting in pain, spinal cord compression and a reduced quality of life. Local radiation therapy (RT) is generally used to achieve rapid improvement of bone pain, control of local tumor growth and recalcification of osseous lesions. However, patients with a high tumor burden, eligible for high dose therapy and autologous stem cell transplantation (ASCT) require systemic treatment with three to four cycles of induction therapy followed by stem cell harvest and high dose therapy. So far, it remains uncertain, if RT prior to mobilization influences stem cell harvest in newly diagnosed patients with MM. Methods: We retrospectively analyzed the impact of RT on stem cell harvest and outcome in 168 transplant-eligible patients with newly diagnosed symptomatic MM (median age 57 years, range 28-73 years). All patients received RT to symptomatic lytic bone lesions before (n=114) or after (n=54) stem cell harvest and high dose therapy. A median of three cycles induction therapy was applied followed by mobilization therapy before stem cell harvest and high dose therapy. We analyzed, whether RT before stem cell collection influenced the number of leukaphereses needed to achieve stem cell yield, the number of stem cells collected per leukapheresis and the total number of collected stem cells. Additionally, we investigated if timing of RT influenced progression-free (PFS) and overall survival (OS) after high-dose therapy and ASCT. Results: Patients receiving RT before stem cell harvest needed more than one leukapheresis to collect the planned number of stem cells (before: 68.8%; after: 44.2%; p=0.09). The median number of stem cells collected per leukapheresis was significantly lower in patients treated with RT before harvest (before: 2.6 x 106 CD34+ cells per kg / bodyweight, after: 3.8 x 106 CD34+ cells per kg / bodyweight; p<0.001). Also the total median number of collected stem cells was significantly lower in the group treated with RT before stem cell harvest (before: 9.0 x 106 CD34+ cells per kg/bodyweight, after: 10.3 x 106CD34+ cells per kg/bodyweight; p<0.02). Patients treated with RT after stem cell harvest showed a longer PFS (48.9 months) compared to the group receiving RT before harvest (36.3 months; p=0.09). No effect on OS was observed. Conclusion: We demonstrate that RT before stem cell harvest negatively influences stem cell collection in patients with symptomatic MM. Furthermore, we observed a negative trend towards shorter PFS in the group treated with RT before stem cell collection. Therefore, we suggest applying RT after stem cell mobilization in transplant-eligible patients with MM if clinically possible. Disclosures Wuchter: Sanofi: Honoraria; ETICHO: Consultancy, Honoraria. Goldschmidt:Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau; Polyphor: Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Chugai: Research Funding, Speakers Bureau; Onyx: Consultancy, Speakers Bureau; Millenium: Consultancy, Speakers Bureau.
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Hattori, Yutaka, Shin-ichiro Okamoto, Wenlin Du, Taketo Yamada, Naoki Shimada, Kunio Matsumoto, Morihiko Sagawa, and Yasuo Ikeda. "Hepatocyte Growth Factor-Producing Multiple Myeloma (HGF myeloma) Is a Distinct Clinical Entity and Needs for Molecular Targeted Therapy." Blood 112, no. 11 (November 16, 2008): 1717. http://dx.doi.org/10.1182/blood.v112.11.1717.1717.
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Abstract Background and Objective: Disease control of refractory or relapsed multiple myeloma (MM) remains a therapeutic challenge. Classification of the patients in the molecular basis and development of targeted therapy are crucial to overcome the situation. We previously reported that 20–30% of MM cells produce hepatocyte growth factor (HGF), and its serum concentration was specifically elevated in symptomatic MM patients. The purpose of this study is to elucidate the clinical characteristics of HGF-producing MM (HGF myeloma) and to explore a novel therapy. Patients & Methods: Serum concentrations of HGF obtained from 76 patients with MM were measured by ELIZA. Less than 0.3μg/L was considered as a normal range. Association of serum HGF levels with various clinical parameters for disease activity was examined, including age, ISS stage, type of M protein, hemoglobin level, serum creatinine, Ca, β2M, albumin, LDH, CRP, bone marrow MM cell %, chromosomal abnormality, presence of lytic bone lesion and extramedullar plasmacytoma. Phase 2 thalidomide monotherapy was also conducted in 56 patients with refractory MM. HGF-specific competitive inhibitor, NK4 protein, was used for in vitro experiments such as growth inhibition by MTT assay, induction of apoptosis by flow cytometer and activation of intracellular signaling molecules by Western blot analysis. Recombinant adenovirus containing NK4 cDNA (AdCMV.NK4) was intramuscularly injected into lcr/scid-mice bearing tumors derived from HGFproducing KMS11 and 34 cells. Results: Elevated serum HGF level was significantly associated with the presence of anemia (p=0.03) and lytic bone lesion (p=0.009). Seven out of eight patients with high CRP levels without infection and five out of nine patients with extramedullar plasmacytoma also demonstrated elevated serum HGF level. Furthermore, in thalidomide monotherapy for refractory MM, increase in pre- and posttreatment serum HGF level was significant poor prognostic factors for overall survival (OS) in univariate analyses, p=0.025 and 0.01, respectively. Elevation of post-treatment HGF level was also independent poor prognostic factor for OS in multivariate analysis. We next examined the possibility of molecular targeted therapy of HGF using NK4. NK4 protein stabilized the growth of HGF-producing MM cell lines and primary bone marrow MM cells in vitro. NK4 also increased in annexin V+ apoptotic cell fraction and regulated the activation of c-Met, ERK1/2, STAT3, and AKT-1. AdCMV.NK4 significantly delayed growth of KMS 11 and 34-derived tumors in vivo. Histological examination revealed that AdCMV.NK4 induced apoptosis of the tumor cells, accompanied by a reduction in neovascularization in the tumors. AdCMV.NK4 injection prolonged survival of KMS 11 tumor-bearing mice. Conclusion: HGF myeloma is characterized by increased disease activity such as anemia, bone lesion, high CRP level and extramedullar plasmacytoma and also by shorter survival by conventional therapy including thalidomide, and it should be recognized as a distinct clinical entity. Since NK4 showed direct anti-myeloma effect as well as anti-angiogenic activity against HGF-producing MM cells, molecular targeted therapy, for example using NK4, is to be established to improve the therapeutic outcome of HGF myloma.
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Shah, Gunjan L., Meier Hsu, Sean Devlin, David J. Chung, Hani Hassoun, Guenther Koehne, Neha S. Korde, et al. "Autologous Hematopoietic Stem Cell Transplantation Overcomes Primary Refractory Disease in Multiple Myeloma Patients Treated with Novel Agents." Blood 126, no. 23 (December 3, 2015): 1996. http://dx.doi.org/10.1182/blood.v126.23.1996.1996.
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Abstract Introduction: Autologous hematopoietic stem cell transplantation (Auto HSCT) has been shown to prolong progression free (PFS) and overall survival (OS) in patients with multiple myeloma (MM), with the depth of response pre-transplant previously correlated with PFS, but not OS. Even in patients receiving proteasome inhibition and immunomodulatory agents as induction, up to 25% of newly diagnosed patients achieve less than a partial response (PR). We aimed to evaluate outcomes after Auto HSCT for patients with primary refractory MM. Methods: Between 1/2009 and 12/2012, we identified 95 newly diagnosed symptomatic MM patients treated at our institution with novel agent induction regimens and upfront Auto HSCT. Based on IMWG criteria, patients were separated into those achieving >= PR (CR, VGPR, PR) and those who are primary refractory (PrRef) as defined by stable or progressive disease (SD/PD) to first line therapy. Characteristics were compared by the Fisher's Exact test. PFS and OS were calculated in a landmark analysis from transplant and estimated by Kaplan-Meier methods and compared by the log rank test. Results: Sixteen patients (17%) had PrRef disease, with a median age of 53 vs 59 yrs in those who achieved >=PR (p=0.04). Demographic and clinical characteristics were otherwise not statistically different between the two groups: 56 vs 65% were male; 69 vs 80% Caucasian; 69 vs 48% had ISS Stage I disease with 19 vs 14% having high risk cytogenetics; 81 vs 84% had lytic lesions; and 31 vs 51% had extramedullary disease at diagnosis in PrRef pts vs >PR pts, respectively. All patients received induction regimens including either bortezomib (44 vs 38%), lenalidomide (31 vs 24%), or both (25 vs 37%) (p=0.68). Compared with 32% of >=PR pts, 94% of the PrRef pts were treated with additional therapy prior to Auto HSCT (p<0.001), with 5/15 achieving VGPR, 6/15 PR, and 4/15 SD/PD prior to Auto HSCT. Tandem Auto HSCT was performed in two PrRef vs one >= PR patient. Response to Auto HSCT was a 38 vs 58%, 25 vs 25%, 38 vs 14%, and 0 vs 4% for CR, VGPR, PR, and SD/PD, in PrRef vs responding pts respectively (p=0.19). Maintenance therapy, primarily with lenalidomide, was given to 69 vs 78% (p=0.52). Median PFS from transplant was 41 months (95% CI 16 - not reached ) in PrRef pts compared to 53 months, (95%CI: 31 - not reached) in >=PR pts (p=0.51). With a median follow-up of 36.5 months (range 9.5-63 months) in surviving patients, median OS from transplant was not reached in either group (p=0.77)(Figures 1 and 2). For the PrRef pts, 3-yr OS from transplant was 77% (95%CI 43-92%) compared to 87% (95%CI 77-93%) in >=PR pts. Conclusion: A small portion of MM patients have primary refractory disease after induction therapy with bortezomib and lenalidomide. Demographic and disease characteristics, other than age, were not able to differentiate these patients. However, Auto HSCT was an effective therapy regardless of response to novel agent based induction therapy. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Hassoun: Celgene: Research Funding; Novartis: Consultancy; Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Lesokhin:Efranat: Consultancy; Aduro: Consultancy; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Genentech: Research Funding. Landgren:BMJ Publishing: Honoraria; BMJ Publishing: Consultancy; Onyx: Research Funding; International Myeloma Foundation: Research Funding; Onyx: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Medscape: Honoraria; Celgene: Consultancy; Bristol-Myers Squibb: Consultancy; Medscape: Consultancy; Onyx: Consultancy. Landau:Onyx: Honoraria, Research Funding; Spectrum Pharmaceuticals: Honoraria; Takeda: Research Funding; Prothena: Consultancy, Honoraria; Janssen: Consultancy; Janssen: Consultancy. Giralt:SANOFI: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; TAKEDA: Consultancy, Honoraria, Research Funding.
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Keruakous, Amany, Silas Day, Azra Borogovac, Jennifer L. Holter, Adam Steven Asch, and Carrie Yuen. "Predictors of response to upfront bortezomib, lenalidomide and dexamethasone (VRd) in multiple myeloma." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e20507-e20507. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e20507.
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e20507 Background: Achievement of response to less than very good partial response (VGPR) after initial induction is an adverse prognostic factor for progression free survival (PFS) in multiple myeloma (MM). Triplet regimen has been demonstrated to be more effective as compared to doublets, with VRd being the preferred induction regimen in newly diagnosed multiple myeloma (NDMM) based on SWOG077 (43.5% VGPR or better). However, recent studies using quadruple combination, daratumumab-VRd, has shown deep response with 63% reached stringent complete remission (sCR) and CR. Balancing efficacy and toxicity in selecting induction regimen in treatment of MM is a challenge due to advanced age and comorbidity. Biomarkers that guided selection based on prediction for efficacy would be clinically useful. In this study we hypothesized that there is a subgroup of patients with MM that would not benefit from upfront VRd could be identified by biologic factors. Methods: For this retrospective study, we selected a cohort of patients with NDMM who were treated with upfront VRd to be evaluated for response after 3-6 cycles of treatment. We identified variables of risk classification that included cytogenetics, ISS stage, immunoglobulin subtype, light chain restriction, pre-treatment albumin level, bone marrow disease burden, end-organ involvement (hypercalcemia, anemia, renal insufficiency and lytic bone lesions), and presence of extra medullary disease. We analyzed the correlation between variables and response to therapy using Chi Square (Fisher’s Exact) test. Results: Among 175 patients treated in our institution starting April 2011 through May 2018, 120 patients received bortezomib-based regimen with 80% (96 subjects) received VRd and 20% (24 subjects) received Vd, with median age of 60.5 (39-74). After 3-6 cycles of VRd, 50% of patients achieved VGPR or better (48/96), 43% achieved partial response (PR) (43/96), 5% did not respond (5/96). Our data showed that immunoglobulin subtype has statistical significant impact on response to VRd; with increased incidence of VGPR or better in IgA myeloma (79%) as compared to IgG myeloma (37%) (P-Value < 0.0006). In IgG myeloma, we showed increased proportion of patients with PR (56%). Additionally, all 5 patients who did not respond to VRd had IgG myeloma. Other variables did not show statistically significant impact to response to upfront VRd. Conclusions: We conclude that IgG subtype MM predicts suboptimal response with VRd. Thus other regimens or four-drug regimen should be considered for upfront therapy in IgG subtype of MM.
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Mohan, Meera, Rohan Samant, Larry J. Suva, Corey O. Montgomery, Daisy V. Alapat, Roy Morello, Frits van Rhee, et al. "Re-Mineralization of Large Pelvic Lytic Lesions By CT Imaging in Patients with Multiple Myeloma: The Arkansas Experience." Blood 126, no. 23 (December 3, 2015): 4193. http://dx.doi.org/10.1182/blood.v126.23.4193.4193.
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Abstract INTRODUCTION Profound osteolytic lesions are a hallmark of multiple myeloma (MM) bone disease. Bone destruction is associated with severely unbalanced bone remodeling, secondary to the secretion of osteoclast activating factors and significant osteoblast suppression. Lytic lesions of the pelvis are relatively common in MM patients and contribute to increase morbidity due to the high risk of fracture that frequently demands surgical intervention. Since we observed significant improvements in the pelvic CT of patients following total therapy 4 (TT4) we retrospectively analyzed the appearance on pelvic osteolytic lesions by CT during TT4 treatment for myeloma. METHODS The UAMS Myeloma data base was interrogated to identify patients enrolled on the TT4 trial. TT4 is a protocol designed for low risk MM patients as defined by a baseline plasma cell GEP score < than 0.66. The treatment protocol includes two induction chemotherapy cycles followed by tandem autologous bone marrow transplantation, two consolidation cycles and 3 years of maintenance. During treatment, patients were exposed to alkylating agents, IMIDS and proteasome inhibitor agents as well as bisphosphonates. Baseline pelvic osteolytic lesions with > 1 cm in minimal diameter identified by PET/CT or CT of the pelvis were compared to the most recent radiological study available for the same subject. All identified cases were reviewed by radiology faculty to confirm the baseline and follow-up reported findings. Radiological findings were correlated with disease status, molecular subgroup, PET scanning and MRI. RESULTS Sixty-three (63) patients, with a median age of 62 years, were identified for this analysis. Baseline patient characteristics are shown in Table 1. With a median follow up of 41 months, CT studies indicate that 44% (28/63) of patients with large baseline pelvic lytic lesions achieved re-accumulation of radio-dense mineralized tissue at the lytic site. Sixty-eight percent of such patients reached at least VGPR. The average size of the lytic lesions that re-mineralized was 4.0 cm (minimum 1.3 cm - maximum 10 cm). Baseline GEP-defined molecular subgroups and cytogenetic distribution was not different from the entire patient population of TT4. CONCLUSION This study clearly shows that mineral redeposition in large pelvic lytic lesions of MM patients on TT4 is achievable in a significant proportion of individuals. We observed that the amount of re-mineralization was prominent in pelvic lytic lesions with cortical bone destruction. Since flat bones, such as the pelvis, are formed via intramembranous ossification further investigation of the mechanism responsible for this effect is warranted at skeletal sites with different regenerative capacity. These data also suggest that, contrary to much dogma, MM bone lesions can regain matrix mineralization capacity. Table 1. Baseline Patient Characteristics n/N (%) Male 43/63 (69%) IgA Isotype 11/63 (17.5%) IgD Isotype 1/63 (1.6%) IgG Isotype 36/63 (57.1%) Nonsecretory 1/63 (1.6%) Light Chain Isotype 14/63 (22.2%) LDH > = 190 U/L 8/63 (12.7%) Abnormal Cytogenetics 44/63 (69.8%) GEP CD-1 subgroup 4/64 (6.3%) GEP CD-2 subgroup 17/64 (26.6%) GEP HY subgroup 24/64 (37.5%) GEP LB subgroup 8/64 (12.5%) GEP MF subgroup 1/64 (1.6%) GEP MS subgroup 2/64 (3.1%) GEP PR subgroup 5/64 (7.8%) Disclosures Mohan: University of Arkansas for Medical Sciences: Employment. Samant:University of Arkansas for Medical Sciences: Employment. Suva:University of Arkansas for Medical Sciences: Employment. Montgomery:University of Arkansas for Medical Sciences: Employment. Alapat:University of Arkansas for Medical Sciences: Employment. Morello:University of Arkansas for Medical Sciences: Employment. van Rhee:University of Arkansa for Medical Sciences: Employment. Waheed:University of Arkansas for Medical Sciences: Employment. Thanendrarajan:University of Arkansas for Medical Sciences: Employment. Schinke:University of Arkansas for Medical Sciences: Employment. Heuck:Millenium: Other: Advisory Board; Celgene: Consultancy; Foundation Medicine: Honoraria; Janssen: Other: Advisory Board; University of Arkansas for Medical Sciences: Employment. Jethava:University of Arkansas for Medical Sciences: Employment. Johann:University of Arkansas for Medical Sciences: Employment. Barlogie:University of Arkansas for Medical Sciences: Employment. Davies:University of Arkansas for Medical Sciences: Employment; Celgene: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Onyx: Consultancy. Morgan:CancerNet: Honoraria; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; University of Arkansas for Medical Sciences: Employment; MMRF: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Weismann Institute: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zangari:Novartis: Research Funding; Millennium: Research Funding; Onyx: Research Funding; University of Arkansas for Medical Sciences: Employment.
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Yan, Wenqiang, Huishou Fan, Jingyu Xu, Jiahui Liu, Chenxing Du, Shuhui Deng, Weiwei Sui, Yan Xu, Lugui Qiu, and Gang An. "Real-World Retrospective Study of 46 Patients with Macrofocal Multiple Myeloma (MFMM)." Blood 138, Supplement 1 (November 5, 2021): 3765. http://dx.doi.org/10.1182/blood-2021-149464.
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Abstract Real-world retrospective study of 46 patients with Macrofocal multiple myeloma (MFMM) Introduction: Multiple myeloma is a clonal plasma cell malignant neoplasm characterized by bone disease and marrow involvement. However, we found that some myeloma patients presented multiple lytic lesions, but didn't meet the diagnostic criteria of at least 10% clonal plasma cells in the bone marrow. And these patients were always diagnosed with myeloma by biopsy-proven plasmacytomas. This special myeloma entity has been called macrofocal multiple myeloma (MFMM) [1-2]. Considering that the data of this rare myeloma entity are limited, it is of great significance to investigate the clinical characteristics, genetic abnormality, treatment response and prognosis of MFMM patients. Methods: Based on the definition (BMPCs<20% and multiple lytic lesions/plasmacytomas, without anemia, renal insufficiency or hypercalcemia) [3]，we identified 46 MFMM patients among 791 myeloma patients(5.8%) diagnosed at out hospital between January 2013 and December 2019. In the same period with same therapies, other 92 typical myeloma patients were selected as the control group. Results: Patient characteristics and comparisons between MFMM patients and the control group are depicted in Table 1. Of the 46 MFMM patients, 82.6% were <65 years and 73.9% had at least 4 lytic lesions. And the incidence of plasmacytomas in MFMM patients was significantly higher than the control group (43.5% vs 18.5%, p<0.05). According to the international staging (ISS) and the Revised ISS, advanced stage patients in the MFMM group was less common than controls (p<0.05). Regarding to the cytogenetics, the high-risk features was infrequent in patients with MFMM compared to typical myeloma patients (15.8% vs 32.2%, p=0.058). And t (11;14) could be observed in 32.4% MFMM patients and 9.4% myeloma patients (p<0.05). The treatment patterns of the two groups were similar; about 30% of the patients received ASCT, and 80% patients received proteasome-inhibitors based regimen as the induction therapy. Concerning about the best response to treatment, the CR rate of the MFMM group was significantly higher than the controls (78.2% vs 60.8%, p<0.05). As of June 2021, the median follow-up time was 37.9 months. The median progression-free survival in the study and control groups were 77.5 vs 39.8 months, respectively (p<0.05). The overall survival (OS) of MFMM patients was significantly longer than typical myeloma patients during the same period with similar therapies (not reached vs 68.2m, p<0.05). Conclusion: In conclusion, Macrofocal multiple myeloma is a special entity of MM, which is characterized with multiple lytic lesions, more extramedullary diseases, less bone marrow infiltration, and fewer adverse features. And the MFMM patient could achieve deep remission and prolonged OS in the era of novel agents. References: [1] Dimopoulos MA, Pouli A, Anagnostopoulos A, et al. Macrofocal multiple myeloma in young patients: a distinct entity with favorable prognosis. Leuk Lymphoma. 2006;47(8):1553-1556. [2] Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15(12):e538-e548. [3] Katodritou E, Kastritis E, Gatt M, et al. Real-world data on incidence, clinical characteristics and outcome of patients with macrofocal multiple myeloma (MFMM) in the era of novel therapies: A study of the Greco-Israeli collaborative myeloma working group. Am J Hematol. 2020;95(5):465-471. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Biran, Noa, Vesna Najfeld, Emily Bagiella, Sundar Jagannath, and Ajai Chari. "Patients with Newly Diagnosed Multiple Myeloma and a Gain of the Long Arms of Chromosome 1 Have Inferior Outcomes, Including Early Onset Extramedullary Disease, Despite the Use of Novel Triplet Regimens." Blood 120, no. 21 (November 16, 2012): 4996. http://dx.doi.org/10.1182/blood.v120.21.4996.4996.
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Abstract Abstract 4996 BACKGROUND: In patients with newly diagnosed multiple myeloma (MM), a gain of the long arms of chromosome 1 is found in approximately 20% of patients by cytogenetics and 40% by FISH. A few studies have not found these abnormalities to be predictive of inferior progression free survival (PFS) and overall survival (OS) on multivariate analysis. The many studies that have were prior to the use of novel therapies in induction. Currently, testing for a gain or amplification of 1q21 locus is not included in the high risk genetic abnormalities by the International Myeloma Working Group (IMWG). Recently, two groups have reported inferior outcomes with bortezomib based induction regimens followed by high dose melphalan consolidation and maintenance therapy. The gain of 1q21 was either detected by cytogenetics or gene expression profiling (GEP70) at the University of Arkansas (Waheed et al, Cancer 2011) or by FISH in CD138 selected cells by the HOVON group (Neben et al, JCO 2012). However, the outcomes of these patients when treated with a bortezomib, lenalidomide, and dexamethasone induction regimen, which is associated with an overall response rate (ORR) of 100% and VGPR or better rate of 74% is unknown (Richardson et al. Blood 2010). Here, we describe the poor outcomes of patients with newly diagnosed MM with gain of 1q21 by FISH in unselected bone marrow aspirates despite novel agent triplet therapy. METHODS: The inclusion criteria for this IRB approved retrospective study were patients with symptomatic MM starting in June of 2008 who had a gain of 1q21 by FISH in 200 bone marrow interphase cells at the time of diagnosis. Patients with 1q amplification had at least 3 or more copies. PFS and OS were calculated by Kaplan-Meier analyses. RESULTS: 23 patients met the inclusion criteria. The median age was 59. 7 (range 46–71) and twenty patients (87%) were DS III at diagnosis, 13/23(57%) were ISS Stage 3. 6/23 (26%) had hypercalcemia, 8/23 (35%) had renal insufficiency, and 19/23 (83%) had anemia. Lytic lesions were present in 17/23 (74%) of patients at diagnosis. Of note, while 4 patients had deletion 13 by cytogenetics only 2 patients had other high risk findings, one with t(4;14) and another with deletion 17. All patients were treated with novel agent induction therapy. 19/23 (83%) were treated with triplet regimens (bortezomib, dexamethasone, and either lenalidomide or cyclophosphamide i. e. VRD or VCD). Disappointingly, primary induction failure, defined by PD or SD after 3–4 cycles, was observed in 30% of all patients. Of the 17 patients who received upfront triplet VRD or VCD therapy (with or without HDM plus SCR) the overall response rate (ORR) was only 77% (13/17), and 47% (8/17) achieved VGPR or better. More specifically, 3/17 (18%) had CR, 5/17 (29%) had VGPR, 5/17 (29%) had PR, 1/17 (6%) had SD and 1/19 (6%) had PD. Of the 4 patients who received novel doublet therapy (VD or RD) upfront, only 1 had a VGPR, one had SD and 2 had PD. The responses noted were not very durable, with a median PFS of 14 months. Although 3 patients have died (after 11–13 months from diagnosis), the median OS has not been reached with a median follow up of 13 months. Plasmacytomas of the bone with soft tissue expansion were present in 48% of the patients and 3 of 23 (13%) had spinal cord compression. Extra-osseous MM within 3 months of diagnosis was observed in 5/23 (22%) patients and 4/5 did not have any other high risk cytogenetics. Three patients (13%) had CNS MM at median of 5. 3 months after diagnosis. One patient had concomitant parenchymal brain lesions, myleomatous meningitis, and intra spinal cord disease. CONCLUSIONS: Even in the era of novel agent induction therapies, in our series of newly diagnosed 23 patients with a gain of 1q21, the failure rate of induction was 30% with a median PFS of 14 months. Moreover, these patients had a particularly aggressive clinical course with both medullary and extramedullary plasmacytomas, suggesting that PET-CTs, rather than just skeletal surveys should be considered for initial staging and monitoring. Also, given an unusually high incidence (13%) of early onset CNS disease, prompt CSF evaluation and brain MRI should be performed on patients with neurologic symptoms or signs. We recommend that gain or amplification of q21 identified either by FISH (even without CD138 selection – as demonstrated here) or GEP be prospectively studied in patients with newly diagnosed MM with consideration of novel therapeutic approaches. Disclosures: No relevant conflicts of interest to declare.
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Eleutherakis Papaiakovou, Evangelos, Evangelos Terpos, Nikolaos Kanellias, Magdalini Migkou, Maria Gavriatopoulou, Ioannis Ntanasis-Stathopoulos, Despina Fotiou, et al. "Impact of Daratumumab-Containing Induction on Stem Cell Mobilization and Collection, Engraftment and Hospitalization Parameters Among Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplantation." Blood 138, Supplement 1 (November 5, 2021): 3886. http://dx.doi.org/10.1182/blood-2021-149499.
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Abstract Introduction: Advances in induction regimens have significantly improved depth of response and duration of remission in multiple myeloma (MM) patients who are eligible for high-dose therapy and autologous stem cell transplantation (ASCT). Proteasome inhibitor-based induction regimens are standard as part of induction and it has been shown not to have any detrimental effect on stem cell (SC) collection and engraftment. Daratumumab (DARA) is an IgG1k monoclonal antibody directed against CD38 with potent antimyeloma activity. Based on the results of prospective studies DARA is now approved as part of induction therapy. Available data indicate a potential impact of DARA on SC collection but there is limited data on engraftment, duration of hospitalization and infection risk. In this retrospective analysis we evaluated the effect of DARA-based induction on ASCT parameters. Methods: The analysis included consecutive newly diagnosed MM patients that received ASCT between 2016 and 2020, as part of their upfront treatment regimen in our institution (Department of Clinical Therapeutics, Athens, Greece). Per institutional protocol, after 4-6 cycles of induction, pts received low dose cyclophosphamide (2.5 g/m2) followed by G-CSF (10 mcg/Kg/day) to mobilize and collect SCs. Plerixafor was administered on-demand in case of poor mobilization and insufficient first day collection. Large volume leukapheresis was performed in pts with low CD34+ counts in order to increase CD34+ yield. Pts received G-CSF 480 μcg once daily from day +4 after SC reinfusion to ANC >1500/mm3. All pts received antiviral and antifungal but no anti-bacterial prophylaxis. Results: 200 eligible pts were included in the analysis; 40 (20%) pts received DARA as part of PI-based upfront treatment and 160 (80%) pts received PI-based upfront treatment without DARA. Baseline demographics (age, gender, performance status) and disease characteristics (ISS and R-ISS stage, cytopenias, eGFR, lytic bone disease etc) were not different between the two groups. Response after induction was also similar (CR+VGPR rate was 93% vs 95% for non-DARA and DARA-containing regimens respectively). Use of DARA at induction was associated with lower total mean number of collected CD 34+ SCs (10.48 x 10^6/kg vs 16.58 x 10^6/kg, p<0.0001), or SC collection on day 1 (7.99 x 10^6/kg vs 16.27 x 10^6/kg, p<0.0001). Fewer pts in the DARA-treated group achieved the planned yield of at least 5 X 10^6 CD34+/kg, compared to DARA-untreated group (87.5 % vs 96.2%, p=0.047). DARA-treated pts required more often additional SC mobilization with on demand administration of plerixafor (42.5% vs 7.6%, p<0.0001). In order to compensate for a poorer mobilization and lower quality graft (CD34% 0.66% vs 1.26% in apheresis product, p<0.0001) DARA-treated group underwent more often >1 day of SC collection (37.5% vs 6.3%, P <0.0001), resulting in longer duration of collections (689 vs 452 min, p<0.0001) and larger total apheresis volumes (723 vs 557 ml, p<0.0001). However, 97% and 98% of pts in the two groups respectively were able to move to at least a single ASCT. Following ASCT, DARA-treated pts had a slightly delayed hematopoietic recovery (11 vs 10 days to PMN>500/mm3, p<0.001 and 12 vs 11 days for PLT counts> 25x10^9/mm3, p<0.001) and required more transfusions (2 vs 1 for RBCs, p=0.031 and 4 vs 2 for platelets, p<0.001). Rates of neutropenic fever were higher (80% vs 67%, p=0.182), required antibiotics for longer duration (10 vs 8 days, p=0.042) and more often 2 or more lines of antibiotic therapy (53% vs 39%, p=0.003), experienced more often septic shock (12.5% vs 1.3%, p=0.003) and as a results DARA-treated pts had a slightly prolonged hospitalization (21 vs 19 days, p=0.02). However, D100 mortality was not statistically different (<2% in both groups). Conclusion: DARA-containing induction before ASCT is associated with poorer mobilization and frequent need for use of plerixafor. However, similar percentage of patients can move to at least a single ASCT. The use of DARA-containing induction was also associated with slightly increased risk of infectious complications, antibiotics use and blood product transfusions but no increase in the risk of D100 mortality. These data point to the need for certain modifications to ASCT protocol for patients treated with DARA-containing regimens at induction, such as preemptive use of plerixafor, and perhaps prophylactic antibiotics. Disclosures Terpos: Amgen: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding. Gavriatopoulou: Takeda: Honoraria; Karyopharm: Honoraria; Sanofi: Honoraria; GSK: Honoraria; Genesis: Honoraria; Janssen: Honoraria; Amgen: Honoraria. Dimopoulos: Amgen: Honoraria; BMS: Honoraria; Janssen: Honoraria; Takeda: Honoraria; BeiGene: Honoraria. Kastritis: Takeda: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Honoraria; Janssen: Consultancy, Honoraria, Research Funding.
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Bagal, Bhausaheb, Hasmukh Jain, Uma Dangi, Manju Sengar, Sadhana Kannan, Venkatesh Rangarajan, Hari Menon, and Navin Khattry. "Pretransplant PET Positivity Predicts Early Relapse with Poor Outcome in Patients of Multiple Myeloma Undergoing Autologous Stem Cell Transplantation." Blood 124, no. 21 (December 6, 2014): 3997. http://dx.doi.org/10.1182/blood.v124.21.3997.3997.
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Abstract Background: Multiple Myeloma is a heterogeneous disease with few patients enjoying overall survival up to a decade while others dying within few years from diagnosis. Multiple staging systems and risk stratification models based on clinical features, laboratory parameters and cytogenetics have been used to predict the response to therapy and outcomes. Positron emission tomography integrated with computerised tomography (PET-CT) offers several advantages as compared to conventional bone imaging modalities in terms of ability to assess extramedulary disease, detection of bone marrow involvement and extent of active disease. Especially important is ability of PET-CT to assess treatment response in terms of FDG activity as bone changes like lytic lesions may persist long on conventional imaging even when disease is in remission. There is scarce data on potential role of PET-CT in response evaluation and prognostication in patients with multiple myeloma. We prospectively analysed the prognostic relevance of PET-CT done prior to autologous stem cell transplant (ASCT). Method: Consecutive patients of multiple myeloma who underwent ASCT between March 2011 and June 2014 were included in this study. All patients received standard novel agent based induction regimen, bortezomib based in 38 patients and lenalidomide based in 5 patients. Patients were evaluated for response by using international myeloma working group (IMWG) criteria after 4-6 cycles of induction regimen. Subsequently patient's stem cells were harvested from peripheral blood by chemomobilization with cyclophosphamide along with G-CSF. All patients underwent PET-CT immediately pretransplant along with response evaluation by IMWG criteria. PET-CT was considered to be negative if there were no FDG avid lytic lesion and no FDG avid extramedulary disease/soft tissue component was seen. Conditioning regimen used for ASCT were melphalan- 200mg/m2 in 37 patients, reduced doses of melphalan (100-140 mg/m2) in 2 patients or bortezomib- melphalan in 4 patients. Post transplant response evaluation was done at 3 months from transplant and at 3 monthly interval thereafter by SIEP, immunofixation, 24 hours urine BJP, and serum free light chain assay. Probabilities of overall survival and progression free survival were estimated using the Kaplan–Meier method and were compared by log rank test. Results: Forty three patients of multiple myeloma underwent ASCT during the study period. The median age of patients at diagnosis was 49 years and 31 (72 %) were male. As per International Staging System, 15 were stage I, 9 were stage II and 14 were stage III disease at time of diagnosis. After induction therapy, 17 patients achieved CR, 13 patients achieved VGPR, 10 patients had PR while 3 patients had progressive disease (PD) pretransplant. Simultaneously done PET-CT was positive in 15 (34%) patients while it was negative in remaining. At a median follow up of 2.6 years from diagnosis 8 patients had progression of disease and 3 patients have died because of disease progression. So as to evaluate the prognostic utility of PET-CT, patients were grouped into four groups as follows- group 1 - CR/VGPR and PET-CT- negative, group 2 - CR/VGPR and PET-CT- positive, group 3 - PR/PD and PET-CT- negative, group 4 - PR/PD and PET-CT- positive as shown in table 1. Table 1: Pretransplant response according to IMWG criteria and PET-CT. PET negative pretransplant PET positive pretransplant Pre transplant CR/VGPR 25 5 Pretransplant PR/PD. 3 10 At a median follow up of 1.68 years post transplant, 4 patients from group 1 and 4 patients from group 4 have progressed. The estimated probability of overall survival and progression free survival from transplant by Kaplan–Meier method at 3 year is 92 % and 62 % respectively. The time to progression after transplant was significantly short in group 4 as compared to group 1 (median time to progression of 6 months versus 26 months; p=0.001). Out of 8 patients who have relapsed post transplant, 3 patients who were PET-CT positive pretransplant have died while all the 4 patients who were PET negative pretransplant are alive. Conclusion: Pretransplant PET-CT positivity predicts early relapse after ASCT. Survival of such patients is poor after relapse post ASCT. These findings needs validation in larger cohort of patients with longer follow up. Disclosures No relevant conflicts of interest to declare.
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Korde, Neha S., Dickran Kazandjian, Mark Roschewski, Sham Mailankody, Malin Hultcrantz, Constance M. Yuan, Maryalice Stetler-Stevenson, et al. "Longitudinal 18f-FDG-PET-CT Analysis in Newly Diagnosed Multiple Myeloma (NDMM) Patients Following Carfilzomib, Lenalidomide, Dexamethasone Induction and Lenalidomide Maintenance (CRd-R)." Blood 128, no. 22 (December 2, 2016): 3274. http://dx.doi.org/10.1182/blood.v128.22.3274.3274.
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Abstract Introduction: Multiple myeloma (MM) is a patchy bone marrow based malignancy of plasma cells, resulting in painful bone lytic lesions that can be visualized by 18F-FDG-PET-CT. We treated 45 NDMM patients with CRd-R therapy that resulted in high rates of minimal residual disease (MRD) negativity (62%)(Korde et al. JAMA Onc 2015). In this study, we assessed longitudinal FDG response through lenalidomide (Len) maintenance period and aimed to correlate with clinical findings and MRD status. Methods: The details of treatment received, study design and patients' characteristics have already been published. As part of the study design, all patients had serial PET imaging at baseline, after achievement of CR and/or at completion of 8 cycles of CRd, and at year-1 and -2 of Len maintenance, or termination of protocol therapy. Whole body (vertex to toes) static FDG imaging was performed at 1-hour post injection, implemented according to institutional practice. Focal lesions on FGD were defined as: increased uptake (above background reference) within the bone, (excluding articular regions due to high prevalence and likelihood of confounding arthritic disease), maximum standardized uptake value (SUV) >1.5 for lesion size on CT ranging from 0.5-1.0 cm, or maximum SUV >2.5 for lesions >1.0 cm. Results: At baseline, 37/45(82.2%) patients had FDG-positive lesions and 8/45(17.8%) were negative. Median follow-up for longitudinal analysis is 30.1 months. Among initial FDG-negative patients, 7/8 (87.5%) patients remained negative throughout follow-up; 1/8 (12.5%) patients developed a sclerotic FDG-positive lesion deemed not to be progression (rib 5 SUV 1.7). Among the 37 patients with baseline FDG-positive lesions, 12/37(32.4%) patients had complete resolution of FDG-PET-CTs (FDG-responders); 25/37(67.5%) remained FDG-long-term positive at time of last protocol scan. Eight of the 25(32%) FDG-long-term positive patients met IMWG criteria for progression, compared to 0/12 FDG-responders (p value=0.04). For patients with available data, MRD negative status after initial CRd (prior to Len maintenance) was not associated with long-term PET-CT response [19/24(79.2%) vs. 8/11(72.7%), FDG-long-term positive vs. FDG-responders, p=NS]. For the remaining FDG-long-term positive patients not meeting progression criteria, all 17 patients had low-positive persistent FDG with decreased or partial SUV response that decreased over time while on Len maintenance. Conclusions: In patients receiving CRd followed by long-term Len maintenance, 68% of baseline FDG-positive patients have persistent longitudinal FDG-positive myeloma lesions. While there is an increased risk of clinical progression among these patients, the majority showed low-positive FDG lesion uptake that decreased over time with long-term Len maintenance. Long-term resolution of FDG-positive lesions is not associated with MRD status after initial CRd therapy. Further follow-up is needed to examine the significance of persistent FDG-positive lesions in relationship to residual disease and mechanisms of resistance. Figure Figure. Disclosures Korde: Medscape: Honoraria. Hassoun:Takeda: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy; Binding Site: Research Funding. Landgren:Medscape Myeloma Program: Honoraria; BMS: Honoraria; Merck: Honoraria; Takeda: Honoraria; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.
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Barillé-Nion, Sophie, Bart Barlogie, Régis Bataille, P. Leif Bergsagel, Joshua Epstein, Robert G. Fenton, Joth Jacobson, W. Michael Kuehl, John Shaughnessy, and Guido Tricot. "Advances in Biology and Therapy of Multiple Myeloma." Hematology 2003, no. 1 (January 1, 2003): 248–78. http://dx.doi.org/10.1182/asheducation-2003.1.248.
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Abstract Even during this past year, further advances have been made in understanding the molecular genetics of the disease, the mechanisms involved in the generation of myeloma-associated bone disease and elucidation of critical signaling pathways as therapeutic targets. New agents (thalidomide, Revimid, Velcade) providing effective salvage therapy for end-stage myeloma, have broadened the therapeutic armamentarium markedly. As evidenced in Section I by Drs. Kuehl and Bergsagel, five recurrent primary translocations resulting from errors in IgH switch recombination during B-cell development in germinal centers involve 11q13 (cyclin D1), 4p16.3 (FGFR3 and MMSET), 6p21 (cyclin D3), 16q23 (c-maf), and 20q11 (mafB), which account for about 40% of all myeloma tumors. Based on gene expression profiling data from two laboratories, the authors propose 5 multiple myeloma (MM) subtypes defined by the expression of translocation oncogenes and cyclins (TC molecular classification of MM) with different prognostic implications. In Section II, Drs. Barillé-Nion and Bataille review new insights into osteoclast activation through the RANK Ligand/OPG and MIP-1 chemokine axes and osteoblast inactivation in the context of recent data on DKK1. The observation that myeloma cells enhance the formation of osteoclasts whose activity or products, in turn, are essential for the survival and growth of myeloma cells forms the basis for a new treatment paradigm aimed at reducing the RANKL/OPG ratio by treatment with RANKL inhibitors and/or MIP inhibitors. In Section III, Dr. Fenton reviews apoptotic pathways as they relate to MM therapy. Defects in the mitochrondrial intrinsic pathway result from imbalances in expression levels of Bcl-2, Bcl-XL and Mcl-1. Mcl-1 is a candidate target gene for rapid induction of apoptosis by flavoperidol. Antisense oglionucleotides (ASO) lead to the rapid induction of caspace activity and apoptosis, which was potentiated by dexamethasone. Similar clinical trials with Bcl-2 ASO molecules alone and in combination with doxorubicin and dexamethasone or thalidomide showed promising results. The extrinsic pathway can be activated upon binding of the ligand TRAIL. OPG, released by osteoblasts and other stromal cells, can act as a decoy receptor for TRAIL, thereby blocking its apoptosis-inducing activity. MM cells inhibit OPG release by stromal cells, thereby promoting osteoclast activation and lytic bone disease (by enhancing RANKL availability) while at the same time exposing themselves to higher levels of ambient TRAIL. Thus, as a recurring theme, the relative levels of pro- versus anti-apoptotic molecules that act in a cell autonomous manner or in the milieu of the bone marrow microenvironment determine the outcome of potentially lethal signals. In Section IV, Dr. Barlogie and colleagues review data on single and tandem autotransplants for newly diagnosed myeloma. CR rates of 60%–70% can be reached with tandem transplants extending median survival to ~7 years. Dose adjustments of melphalan in the setting of renal failure and age > 70 may be required to reduce mucositis and other toxicities in such patients, especially in the context of amyloidosis with cardiac involvement. In Total Therapy II the Arkansas group is evaluating the role of added thalidomide in a randomized trial design. While data are still blinded as to the contribution of thalidomide, the overriding adverse importance of cytogenetic abnormalities, previously reported for Total Therapy I, also pertain to this successor trial. In these two-thirds of patients without cytogenetic abnormalities, Total Therapy II effected a doubling of the 4-year EFS estimate from 37% to 75% (P < .0001) and increased the 4-year OS estimate from 63% to 84% (P = .0009). The well-documented graft-vs-MM effect of allotransplants can be more safely examined in the context of non-myeloablative regimens, applied as consolidation after a single autologous transplant with melphalan 200 mg/m2, have been found to be much better tolerated than standard myeloablative conditioning regimens and yielding promising results even in the high-risk entity of MM with cytogenetic abnormalities. For previously treated patients, the thalidomide congener Revimid and the proteasome inhibitor Velcade both are active in advanced and refractory MM (~30% PR). Gene expression profiling (GEP) has unraveled distinct MM subtypes with different response and survival expectations, can distinguish the presence of or future development of bone disease, and, through serial investigations, can elucidate mechanisms of actions of new agents also in the context of the bone marrow microenvironment. By providing prognostically relevant distinction of MM subgroups, GEP should aid in the development of individualized treatment for MM.
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Girnius, Saulius Kazmiems, Habte Aragaw Yimer, Sudhir Manda, Christopher A. Yasenchak, Veena Charu, Roger M. Lyons, Suman Kambhampati, et al. "Long-term proteasome inhibition in US community multiple myeloma (MM) patients (pts) following in-class transition (iCT) from parenteral bortezomib (V) to oral ixazomib (I): Updated real-world (RW) data from US MM-6." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e19332-e19332. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e19332.
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e19332 Background: US MM-6 is investigating iCT from parenteral V-based induction to all-oral I-lenalidomide-dexamethasone (IRd) with the aim of increasing proteasome inhibitor (PI)-based treatment adherence/duration while maintaining quality of life (QoL) & further improving outcomes in the diverse US community population. Methods: 21 US community sites, including VA hospitals, are enrolling non-transplant-eligible newly diagnosed MM pts with ≥stable disease after 3 cycles of V-based therapy to receive IRd. Pts use mobile & digital devices to collect actigraphy (activity/sleep) data, complete QoL & treatment satisfaction questionnaires, & self-report medication adherence. Primary endpoint: progression-free survival (PFS); key secondary endpoints include: response rates & duration of therapy. Results: As of Nov 18, 2019, 84 pts had been treated (median age 73 [range 49–90] yrs; 44% ≥75 yrs; 49% male; 15% black/African American; 10% Hispanic/Latino; 35% International Staging System stage III disease; 42% lytic bone disease). Comorbidities included hypertension (57%), anemia (44%), fatigue (43%), & peripheral neuropathy (13%). 85% of pts were receiving VRd at the time of iCT. 62% of pts are still on therapy & enrollment is ongoing. After initiating iCT, ≥complete response (CR) rate increased from 4% to 26% (Table). At 8 mos median follow-up, 6 pts had progressed & there were 2 on-study deaths. The 12-mo PFS rate was 86% (95% CI, 73–93) from the start of V-based regimen & from the start of IRd. During IRd treatment, 92% of pts had treatment-emergent adverse events (TEAEs) (48% grade [G] ≥3). G3 TEAEs (≥5% of pts) were diarrhea (7%), pneumonia (6%), syncope (6%), & anemia (5%). TEAEs led to study drug discontinuation in 7% of pts; 36% had serious TEAEs. I/R/d dose was adjusted due to AEs in 39%/39%/29% of pts. Medication adherence (cycles 1–5) was ‘excellent’/‘very good’ in ≥78% of pts reporting adherence. QoL/treatment satisfaction were maintained in pts completing questionnaires. Actigraphy data showed normal activity levels & sleep durations. Conclusions: US MM-6 pts are representative of the RW US MM population & results show that iCT to an oral PI may permit prolonged PI-based therapy with promising efficacy & without impacting pts’ QoL or treatment satisfaction. Clinical trial information: NCT03173092 . [Table: see text]
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Martin, Ludmila Katherine, Mark E. Lustberg, Fengting Yan, John T. Patton, Pierluigi Porcu, Gerard Nuovo, Robert Cavaliere, and Robert A. Baiocchi. "Successful Treatment of Primary Central Nervous System Post-Transplant Lymphoproliferative Disorder (PCNS-PTLD) with Zidovudine (AZT), Ganciclovir (GCV), Rituximab and Dexamethasone: A Single-Institution Case Series." Blood 118, no. 21 (November 18, 2011): 3067. http://dx.doi.org/10.1182/blood.v118.21.3067.3067.
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Abstract Abstract 3067 BACKGROUND: Primary central nervous system post-transplant lymphoproliferative disorder (PCNS PTLD) is a rare complication of solid organ transplantation, with no standard therapy. Most PCNS PTLDs are associated with Epstein-Barr virus (EBV) infection, thus EBV could serve as a potentially attractive therapeutic target. For EBV-targeted antiviral therapy to be effective, antiviral agents must be phosphorylated by lytic-phase EBV kinases BXLF1/vTK and BGLF4. We hypothesized that PCNS-PTLDs would express viral kinases and that antiviral therapy would prove an attractive therapeutic alternative to high dose methotrexate-based chemotherapy for patients who often have impaired organ function and poor performance status. METHODS: We investigated the safety and efficacy of EBV-targeted therapy with zidovudine (AZT), ganciclovir (GCV), rituximab, and dexamethasone in patients with PCNS PTLD, as well as the relationship of viral protein kinase expression with response to therapy. Patients with biopsy-proven PCNS PTLD following solid organ transplantation were eligible for treatment. Induction therapy consisted of AZT 1500 mg IV, and GCV 5 mg/kg IV, dexamethasone 10 mg IV, twice daily on days 1–14 and 4 weekly doses of rituximab 375 mg/m2 on days 1, 8, 15, and 22. Maintenance therapy was initiated on day 15 with valganciclovir 500 mg twice daily, and AZT 300 mg twice daily until disease progression or intolerable toxicity. Treatment was adjusted for hematologic toxicity and impaired liver and kidney function. Responses were evaluated by serial brain MRIs beginning 4 weeks after initiation of treatment. Brain biopsy specimens were evaluated for expression of viral kinases BGLF4 and BXLF1/vTK by in situ hybridization. RESULTS: Eight patients (5 M, 3 F) with a median age of 49 were treated at our institution from 1999–2011. Transplant history included kidney (N=7), and kidney + pancreas (N=1). Pathology data was available for all patients and included diffuse-large B-cell lymphoma (N=4), grade III lymphomatoid granulomatosis (N=2), and B-cell lymphoma, not further classifiable (N=2). EBV positivity (EBER) and CD20 expression was documented in all cases. Evaluation of BXLF1/vTK and BGLF4 was completed in 4 patients and found to be positive. Areas of tumor expressing viral kinases did not express LMP1. Immune suppression was reduced in all patients prior to treatment. All patients completed induction therapy. Median duration of maintenance therapy was 16.6 months. At the time of analysis, 6 patients were still alive and disease free (median duration of follow-up = 19.6 months, inter-quartile range = 10.6 – 28.3). All 8 patients achieved a complete response by MRI criteria with a median duration to response of 2 months (inter-quartile range = 1.5 – 4 months). Two patients died with survival times of 3 and 143 months after diagnosis. No patients had documented disease progression. Thus far, median duration of progression free survival has been 17.1 months (inter-quartile range = 7 – 31 months). Patient 1 was disease-free for 141 months but developed and died from complications of colon cancer. Patient 8 died of multi-organ failure related to pneumonia and septic shock, which was considered non-treatment-related, 3 months after initiation of therapy. At that time, a brain MRI showed evidence of complete response. Grade 3–4 toxicity was primarily hematologic, including anemia (N=4), thrombocytopenia (N=3), leukopenia (N=5) and neutropenia (N=4). Toxicity in the maintenance phase was generally reversible within 7 days of holding therapy. One patient required discontinuation of AZT during maintenance treatment for persistent, transfusion-dependent anemia. CONCLUSIONS: EBV-targeted therapy with AZT, GCV, rituximab and dexamethasone appears to be safe for the treatment of EBV+ PCNS PTLD, with promising evidence of activity. Responses were generally rapid and durable. Expression of BXLF1/vTK and BGLF4 kinases provides mechanistic rationale for an antiviral approach for this disease. Given the lack of effective standard therapy for these patients, this regimen deserves further investigation. Unanswered questions include the optimum length of maintenance therapy that is still effective while minimizing toxicity, and whether rituximab is necessary to achieve the responses observed. A multi-center phase II trial is in development to further investigate this regimen. Disclosures: Off Label Use: We will discuss the use of zidovudine and ganciclovir to treat primary CNS lymphoma in transplant patients.
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Bayraktar, Ulas D., Roberto Ochoa, Soley Bayraktar, Maria Matsangou, and Juan Carlos Ramos. "High-Dose Methotrexate and Azidothymidine in Combination with Alternating DA-EPOCH Is An Effective Regimen for the Treatment of EBV-Related Plasmablastic Lymphoma." Blood 114, no. 22 (November 20, 2009): 4753. http://dx.doi.org/10.1182/blood.v114.22.4753.4753.
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Abstract Abstract 4753 Introduction Plasmablastic lymphoma (PBL) is an aggressive and generally fatal, rare type of B-cell non-Hodgkin's lymphoma (NHL) with predilection to sino-oral mucosa. PBL is usually associated with human immunodeficiency virus (HIV) and displays an unusual phenotype lacking the expression of B-cell surface antigens. PBLs are infected by Epstein Barr virus (EBV) in approximately 80% of cases and exhibit a restricted pattern of EBV gene expression as they do not typically express latent membrane proteins (LMPs), which enforce viral latency. Azidothymidine (AZT), a thymidine analogue, is an excellent substrate for EBV thymidine kinase, and is capable of inducing EBV lytic gene expression and apoptosis in primary Type I latency EBV+ Burkitt lymphoma (BL) cell lines. AZT was initially developed as an antineoplastic agent but was found to have low efficacy due to poor affinity to human DNA polymerase and low incorporation into DNA. The chemotherapy drug methotrexate (MTX), which also induces gamma-herpes virus lytic induction, inhibits thymidylate synthase thus blocking de novo synthesis of dTMP increasing the likelihood of AZT incorporation into DNA. Indeed, the combination of high-dose MTX and AZT was found to be clinically efficacious in HIV-infected patients with aggressive relapsed NHL. Similarly, at the University of Miami, we have found this drug combination to be highly effective when used in patients with aggressive gamma-herpes virus lymphomas including EBV+ BL and human herpes virus 8 (HHV-8) related primary effusion lymphoma (solid PEL). We report here the role of high dose MTX plus intravenous AZT with alternating infusional EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and adriamycin) in the treatment of HIV associated EBV+ plasmablastic lymphoma. Methods Three HIV+ patients with biopsy proven, EBV-encoded RNA (EBER)+ PBL in sino-oral mucosa were treated with high dose methotrexate (4.5 g/m2 IV on day 1) and AZT 1.5 g IV infusion q12 hours (days 1-3) alternating with dose-adjusted (DA) EPOCH chemotherapy for 6-8 cycles as first line therapy. Patients were started/kept on HAART and were administered prophylactic intrathecal MTX±cytarabine. Responses were evaluated by oral exam and CT scans. Results Selected characteristics of patients are demonstrated in Table. Only Patient 2 was on HAART at the time of diagnosis. Patient 1 had intracranial extension of the large left maxillary lesion through sphenoid sinus with negative CSF cytology. All patients treated with HD-MTX/AZT and alternating EPOCH as above achieved a complete remission (CR). Patient 1 achieved CR after the 3rd cycle. However, 19 days after the 4th cycle he was found to have local recurrence, which was thought to be secondary to poor chemotherapy penetration to necrotic oral palate tissue, and was administered a total of 4620 cGy intensity-modulated radiotherapy to head and neck region followed by consolidation with the same chemotherapy regimen for 4 more cycles. He remains alive and free of disease after 14 months. Patient 2 and 3 received a total of 6 cycles of chemotherapy and remain disease-free after 12 and 13 months, respectively. No grade ≥3 toxicities were encountered during the treatment. Conclusion The combination of high dose MTX and AZT plus alternating DA-EPOCH chemotherapy is a tolerable and effective treatment for HIV related EBV+ plasmablastic lymphomas. The combination of MTX and AZT is a highly active, EBV lytic inducing and targeted regimen which deserves further investigation in the treatment of gamma-herpes virus associated malignancies. Disclosures: No relevant conflicts of interest to declare.
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Baltathakis, Ioannis, Evangelos Terpos, Sosana Delimpasi, Konstantinos Liapis, Fotios Panitsas, Efstathios Kastritis, Anna Christoforidou, et al. "The Combination of the Proteasome Inhibitor Bortezomib with Doxorubicin and Dexamethasone (PAD Regimen) as Front-Line Therapy In Newly Diagnosed, High-Risk Multiple Myeloma: Results of a Phase II Prospective Multicenter Study." Blood 116, no. 21 (November 19, 2010): 3052. http://dx.doi.org/10.1182/blood.v116.21.3052.3052.
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Abstract Abstract 3052 The combination of bortezomib, doxorubicin, and dexamethasone (PAD) has shown efficacy in both relapsed/refractory and untreated, symptomatic multiple myeloma (MM). The activity of this regimen is largely attributed to the recognized synergy between bortezomib and doxorubicin. Bortezomib is capable of reversing resistance to chemotherapy in MM with adverse prognostic features (high-risk myeloma), which has an unfavorable outcome with conventional chemotherapy followed by high-dose therapy and autologous stem cell transplantation (ASCT). In addition, disease status prior to ASCT has prognostic significance for survival, underscoring the need for highly efficient remission induction strategies. In a prospectively designed phase II trial, we focused on the efficacy and safety of the PAD combination as front-line treatment for high-risk myeloma. The study recruited patients aged ≤70 years with newly diagnosed, symptomatic MM with high-risk features (defined by at least one of the following criteria: ISS stage II/III according to serum albumin and beta2-microglobulin, and/or detection of 13q deletion by FISH or conventional karyotyping). Between 2005 and 2008, 40 patients were enrolled in the protocol. The median age of patients was 59 years (range: 41–70 years), and 27 (67.5%) were male. Each 21-day cycle of PAD included bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 plus doxorubicin 9 mg/m2 on days 1–4, and dexamethasone 40 mg on days 1–4 and 8–11. According to protocol, patients received 4 induction cycles of PAD before proceeding to stem cell harvest and ASCT. Acyclovir and ciprofloxacin prophylaxis were routinely used. Patients were evaluated for toxicity at each cycle and for response after the end of the fourth cycle. The primary study endpoint was the response rate at the end of induction (assessed by the International Myeloma Working Group uniform response criteria, 2006). Secondary endpoints were toxicity, progression-free survival (PFS), overall survival (OS), ability to mobilize stem cells, and response after ASCT. ISS stage was I in 2 patients (5%), II in 18 (45%), and III in 20 (50%). Nine out of 40 patients (22.5%) presented with renal failure (creatinine >2mg/dl) due to myeloma at diagnosis. Deletion 13q was detected in 19 patients. Bone disease was present in 30 patients (75%) at diagnosis, and 19 (47.5%) had ≥3 lytic lesions on plain skeleton radiograms. Median patient follow-up time was 28.3 months (range, 1.4–49.3). All patients completed the 4 cycles of PAD, with the exception of one who died during the 2nd cycle. The overall response rate assessed after the 4th cycle of PAD was 95%. Complete remission (CR) was achieved in 12/39 (31%), very good partial remission (VGPR) in 15/39 (38.5%), and PR in 10/39 (25.5%). Thirty-one patients were considered eligible for ASCT, and an adequate stem cell harvest was achieved in all. Following ASCT, CR rate reached 52% (16/31) with a CR+VGPR rate of 84% (26/31). PFS was 67% at 2.1 years, and calculated OS was 81.4% at 4 years (Figures 1 and 2). Factors associated with shorter OS were beta2-microglobulin ≥5.5 mg/L (p=0.03), and ISS stage III (p=0.03). By assessment of the glomerular filtration rate (GFR), a significant improvement in renal function was demonstrated after induction with PAD (median GFR pre- and post-induction: 59.7 versus 82.1 ml/min, respectively; p<0.001). Improvement in kidney function was observed irrespective of the type of response. There was only one treatment-related death secondary to infection. Toxicities were manageable in general, and included grade 3–4 neutropenia in 8/40 patients (20%), grade 3–4 thrombocytopenia in 4/40 (10%), and grade 3 peripheral neuropathy in 4/40 (10%). No grade 4 peripheral neuropathy was encountered. We conclude that the PAD regimen is very effective, and produces high-quality responses in a substantial proportion of patients with newly diagnosed, high-risk MM (CR+VGPR: 69.5%). PAD is well tolerated and does not compromise stem cell mobilization and harvest. Upfront treatment with 4 cycles of PAD followed by ASCT resulted in notable PFS and OS rates in this patient group with adverse-prognosis MM. PAD was shown to be particularly beneficial in patients with renal impairment at diagnosis due to myeloma. Disclosures: Baltathakis: Janssen-Cilag: Research Funding. Terpos:Janssen-Cilag: Honoraria. Delimpasi:Janssen-Cilag: Research Funding. Dimopoulos:Janssen-Cilag: Honoraria. Harhalakis:Janssen-Cilag: Research Funding.
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Rosiñol, Laura, Raquel Jiménez-Segura, Ana Isabel Teruel, Javier De La Rubia, Maria Victoria Mateos, Miguel T. Hernandez, Dolores Hernández, et al. "Characteristics and Outcome Of 66 Patients With Extramedullary Plasmacytomas (EMPs) Included In a Phase III Pethema/GEM Study Of Induction Therapy Prior Autologous Stem Cell Transplantation (ASCT) In Multiple Myeloma (MM)." Blood 122, no. 21 (November 15, 2013): 3188. http://dx.doi.org/10.1182/blood.v122.21.3188.3188.
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Abstract Introduction In April 2006, the Spanish Myeloma Group (PETHEMA/GEM) initiated a randomized phase III trial (GEM05menos65) comparing induction with thalidomide/dexamethasone (TD) vs. bortezomiv/thalidomide/dexamethasone (VTD) vs. VBMCP/VBAD/Bortezomib (VBMCP/VBAD/B) in patients 65 years-old or younger with newly diagnosed symptomatic MM followed by ASCT with MEL-200 and maintenance therapy with interferon vs, thalidomide alone or bortezomib/thalidomide. The results of the overall series has been previously published. However, the efficacy of novel agents in patients with extramedullary disease is not well stablished. Primary end points to describe the characteristics and outcome of patients with EMPs homogeneously treated in the GEM05menos65 trial. Patients and Methods TD consisted of thalidomide 200 mg daily (escalating doses in the first cycle) and dexamethasone 40 mg on days 1-4 and 9-12 at 4-week intervals for 6 cycles. The VTD regimen was identical to TD plus i.v. bortezomib 1.3 mg/m2 on days 1,4,8,11 of each cycle. Combination chemotherapy plus bortezomib consisted of 4 cycles of VBMCP/VBAD on an alternating basis followed by 2 cycles of i.v. bortezomib (1.3 mg/m2 on days 1,4,8, and 11 every 3 weeks). The duration of the induction therapy was 24 weeks in all arms. From April 6, 2006 to August 5, 2009 the 390 planned patients entered the study. 66 patients (17%) had extramedullary plasmacytomas (median age: 54 years, M: 33, F: 33). The isotype was IgG: 41, IgA 11, Bence-Jones: 10, IgD:4; kappa:41, lambda: 25.The stage according to the ISS was I in 27 patients, II in 26 and III in 13 patients. The location of the EMPs was soft-tissue masses arising from lytic lesions in 60 patients, testicular mass with no contact with bone in 1 case and was not specified in 6 cases. Nine patients had multiple extraosseous plasmacytomas. 17 patients received induction therapy with VBMCP/VBAD/B, 23 with TD and 26 with VTD. Results Cytogenetic information was available in 51 out of the 66 cases with EMPs and 12 of them (23%) showed high-risk cytogenetics. There were no differences in the incidence of high-risk cytogenetics (t(4;14), t(14;16) and del 17p) in patients with and without EMPs (23% vs 21%). The incidence of t(4;14) in patients with and without EMP was 16% vs 23%, respectively. The incidence of del 17p was 10% and 6% in patients with and without EMPs.The IFE negative CR rate was significantly higher with VTD as compared to TD (42% vs 13%, p=0.02) while there was no significantly differences among VTD and VBMCP/VBAD/B (42% vs 29%, p=NS). Patients with EMP had a significantly higher rate of PD during induction therapy as compared to patients without EMPs (24% vs 11%, p=0.01). This higher rate of PD in patients with EMP was observed in the 3 induction arms (VBMCP/VBAD/B 24% vs 9%, TD 40% vs 19%, VTD 12% vs 6%). 43 patients received ASCT as part of the treatment design. On an intention to treat basis, the pos-ASCT CR rate was higher with VTD arm compared to TD (50% vs 22%, p=0.07) but not significantly different from VBMCP/VBAD/B (50% vs 41%, p=0.7). After a median follow-up of 46 months, there was no significant differences in PFS between patients with or without EMP (26.9 vs 39.9 months, p=0.47). Although the difference did not reach statistical significance, there was a trend towards a shorter PFS for patients with EMPs with high-risk cytogenetics (median 12.1 vs. 28.3 months, p=0.13). In patients with EMPS, the PFS was not reached in the VTD arm versus 26.9 months with VBMCP/VAB/B and 22.8 moths with TD. The OS was significantly shorter in patients with EMPs as compared to patients without EMPs (median 69.9 months vs not reached, p=0.02) Conclusion 1) In the present study the frequency of EMPs was 17%, 2) the incidence of high-risk cytogenetics in patients with EMPs was similar to that observed in patients with no extramedullary disease, 3) patients with EMPs had a higher rate of progressive disease irrespective of the induction arm as compared to patients without EMPs, being VTD the best treatment option, 4) finally, the OS was significantly shorter in patients with EMPs. Disclosures: Rosiñol: Janssen: Honoraria; Celgene: Honoraria. De La Rubia:Janssen: Honoraria; Celgene: Honoraria. Mateos:Jansen: Honoraria; Celgene: Honoraria. Tomas:MedImmune: Research Funding. Gutiérrez:Jansen: Honoraria; Celgene: Honoraria. San Miguel:Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millenium: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Lahuerta:Janssen: Honoraria; Celgene: Honoraria. Blade:Janssen: Honoraria; Celgene: Honoraria.
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Hill, Elizabeth, Neha Korde, Candis Morrison, Alexander Dew, Ashley Carpenter, Monica Epstein, Crystal Lu, et al. "The Role of 18f-FDG-PET/CT in Characterizing Depth of Response in High Risk Smoldering Multiple Myeloma Patients Treated with Carfilzomib, Lenalidomide, and Dexamethasone (KRd)." Blood 136, Supplement 1 (November 5, 2020): 11–12. http://dx.doi.org/10.1182/blood-2020-136182.
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Introduction A direct association exists between minimal residual disease (MRD) negativity and prolonged survival in multiple myeloma (MM) (Landgren et al, BMT 2016). 18F-fluoro-deoxy-glucose (FDG) positron emission tomography-computed tomography (PET/CT) is a recommended monitoring technique for patients with MM as persistence of FDG uptake after induction therapy, prior to maintenance, is an independent risk factor for progression. Therefore PET/CT and MRD detection in the bone marrow are complementary prognostic tools prior to initiation of maintenance therapy. In patients with smoldering multiple myeloma (SMM), the presence of a focal FDG-avid lesion without underlying osteolytic lesion on PET/CT is associated with rapid progression to MM. However, little is known about the prognostic value of PET/CT for SMM patients receiving treatment. Herein, we show that treatment of high risk (HR)-SMM with carfilzomib, lenalidomide, and dexamethasone with lenalidomide maintenance (KRd-R) leads to sustained remissions detected on PET/CT imaging. Methods Trial design including key results for KRd-R in HR-SMM (NCT01572480) has been submitted to the meeting separately (abstract ID: 136148). As part of the study design, all eligible patients had bone marrow biopsies with multicolor flow cytometry (MRD sensitivity, 10-5) and whole-body PET/CT performed at baseline and at key time points, including achievement of complete response (CR) or completion of KRd induction (8 cycles), after 1 and 2 years of -R maintenance, and annually thereafter. PET/CTs were evaluated by nuclear medicine radiologists blinded to flow cytometry and considered positive if at least one focal hypermetabolic (above background reference) lesion and/or heterogenous bone marrow involvement were present, as defined by the IMWG (Hillengass et al. Lancet Oncol 2019). Results As of data cutoff, 46 patients had completed at least 8 cycles of therapy and had 2 sequential PET/CTs performed. By the end of induction therapy, no patient developed progressive disease and the overall response rate was 100%. Approximately 72% of patients with baseline negative PET/CTs remained negative, 11% of patients had resolution of previous focal/heterogenous FDG avidity, 15% of patients had decrease or stable focal/ heterogenous lesions, and 2% developed new focal lesions. Table 1 shows the results at subsequent time points of one and two years of maintenance therapy. Throughout this time period, one patient developed a lytic lesion after 1 year of maintenance therapy. However, 3 patients had either resolution or decrease in focal/heterogenous lesions. Specifically, after 8 cycles of combination therapy, 33 patients (70.2%, 95% CI 55.9 - 81.4%) had a response of MRD negative CR based on bone marrow flow cytometry and 26 patients (55.3%; 95% CI 41.2-68.6%) had a negative PET/CT in addition to MRD negative CR (Table 2). Conclusions It is important to evaluate the tools used in MM response assessment specifically in the SMM population as more studies report results of treatment in this population. MRD information can be used as a biomarker to evaluate the efficacy of different treatment strategies. This study demonstrates an exceptionally high rate of concordance between MRD negativity by flow cytometry and negative PET/CT after 8 cycles of KRd. However, 15% of patients were MRD negative yet had positive findings on PET/CT. While these lesions were not biopsy proven, some resolved during maintenance therapy. Further follow-up is needed to determine whether early MRD negativity in bone marrow with negative PET/CT correlates to longer overall survival and decreased progression to MM compared to those patients with a positive PET/CT. The use of PET/CT imaging may increase our understanding in assessing depth response to treatment in HR-SMM patients and be an important outcome predictor. Disclosures Korde: Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Landgren:Adaptive: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Glenmark: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Karyopharma: Research Funding; Binding Site: Consultancy, Honoraria; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; BMS: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; Glenmark: Consultancy, Honoraria, Research Funding; Juno: Consultancy, Honoraria; Seattle Genetics: Research Funding; Pfizer: Consultancy, Honoraria; Merck: Other; Karyopharma: Research Funding; Binding Site: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Merck: Other.
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Zuccolotto, G., A. Penna, IM Montagner, D. Carpanese, and A. Rosato. "P06.09 Anti-hPSMA CAR engineered NK-92 cells: An off-the-shelf cellular therapeutic for targeted elimination of prostate cancer cells." Journal for ImmunoTherapy of Cancer 8, Suppl 2 (October 2020): A45.1—A45. http://dx.doi.org/10.1136/jitc-2020-itoc7.88.
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BackgroundAdoptive cell therapy of malignant diseases takes advantages of the cellular immune system to recognize and destroy cancer cells. Despite the remarkable success in B cell malignancies after adoptive transfer of CD19 CAR T cells, CAR T cell therapy in solid tumors has shown less encouraging clinical results, above all caused by tumor escape mechanisms.In order to overcome such limitations, NK-92, a permanent and IL-2-dependent cell line with a high cytotoxicity in vitro, has been engineered in preclinical models with CAR. In this project, we exploited a CAR directed against the human antigen hPSMA that is overexpressed in prostate tumors. This project aimed at transducing NK-92 cell line to obtain a hPSMA-specific CAR NK-92 cell population, to be thereafter characterized in vitro and in vivo for antigen-specific functional activity.Materials and MethodsNK-92 cell line was transduced with a lentiviral vector (LV) carrying a CAR anti-hPSMA. The cell population obtained was then sorted and analyzed for degranulation capacity, IFNγ production and lytic activity against hPSMA+ (PC3-hPSMA, LNCaP) or hPSMA-tumor cell lines. In vivo therapeutic efficacy of CAR-transduced NK-92 was evaluated initially using Winn-Assay and than in subcutaneous and orthotopic tumor models.ResultsCAR-expressing LV efficiently transduced NK-92 cells, which in turn produced cytokines, degranulated and exerted a relevant cytotoxic upon challenge with PSMA+ prostate tumor cells, irrespective of 10 Gy γ-irradiation. In all the in vivo, tumor models CAR-transduced NK-92 shown a statistically significant inhibition of tumor growth.ConclusionsChimeric antigen receptor-engineered NK-92 could offer a valid and cost-effective alternative to primary CAR NK or T cells, in particular in cases, where a suitable donor is not available or the sophisticated infrastructure needed for cell isolation, expansion and genetic modification is missing. This work demonstrates that CAR-engineered NK-92 cells display a high and specific recognition of hPSMA+ PC both in vitro as is in vivo, and could represent an efficient strategy as a new therapeutic intervention against prostate carcinoma, thus paving the way to an Off-The-Shelf cellular therapeutic for targeted elimination of cancer cells and induction of protective antitumor immunity.Disclosure InformationG. Zuccolotto: None. A. Penna: None. I.M. Montagner: None. D. Carpanese: None. A. Rosato: None.