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1
Bashir, Qaiser, Peter Thall, Chitra Hosing, Floralyn L. Mendoza, Eric Han, Michael Wang, Jatin Shah, et al. "Salvage Autologous or Allogeneic Stem Cell Transplantation After the Failure of First Autograft in Patients with Multiple Myeloma." Blood 114, no. 22 (November 20, 2009): 1186. http://dx.doi.org/10.1182/blood.v114.22.1186.1186.
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Abstract Abstract 1186 Poster Board I-208 Background: Almost all patients with multiple myeloma (MM) who receive autologous hematopoietic stem cell transplantation (auto HCT) eventually relapse. The treatment options for these patients include novel agents or second (salvage) auto or allogeneic (allo) HCT. Use of reduced intensity conditioning (RIC) has significantly reduced the transplant-related mortality (TRM) with allo HCT. We evaluated the outcomes of patients who received salvage auto or allo HCT for relapsed MM. Methods: Sixty-two patients (24 females and 38 males), with a median age of 55 years (range: 37-73) received a salvage auto HCT between January 1992 and December 2008, whereas 44 patients (19 females and 25 males), with a median age of 51 years (range 32-65) received salvage allo HCT (12 unrelated and 32 related donor) between October 1988 and December 2006. Among 12 patients with unrelated allo HCT, ten were matched at 10/10 HLA loci, while two patients were mismatched at 1 or 2 loci, respectively. Among 32 patients with related donor allo HCT, 29 matched at 10/10 loci, while 3 patients had one or two antigen mismatches. In the allo HCT group eight patients received myeloablative regimens (MA), while thirty six patients received RIC regimens. MA regimens were fludarabine + melphalan 180 mg/m2 in 4 patients, busulfan + cyclophosphamide in 2 patients, busulfan + melphalan in one patient and TBI-based in another patient. RIC regimens were fludarabine + melphalan ≤140 mg/m2 in 34 patients and cyclophosphamide + fludarabine in 2 patients. Results: Median follow-up for both auto and allo HCT patients was 24 months. Median prior treatment regimens in auto and allo HCT patients were 4 (2-16) and 5 (2-10), respectively. Overall response rates in evaluable patients in auto HCT and allo HCT were 63% and 75%, respectively. Cumulative incidence of grade II-IV acute GVHD was 27% and limited or extensive chronic GVHD was 43% in allo HCT group. One-hundred day TRM in auto HCT and allo HCT groups was 3% and 9%, respectively. Most common causes of nonrelapse mortality were infections (12%) in auto, and acute or chronic GVHD (24%) in allo HCT group. Median progression free survival (PFS) and overall survival (OS) for auto HCT were 15.5 and 43.3 months, and for allo HCT were 6.9 and 14 months, respectively. Patients receiving MA regimens had significantly shorter PFS and OS than patients receiving RIC regimens. Conclusions: Both second auto and allo HCT are feasible for salvage therapy in patients with advanced MM, who had relapsed after an auto HCT. Disease progression remains the major cause of treatment failure. RIC regimens have improved the outcome of allo HCT. Disclosures: No relevant conflicts of interest to declare.
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Orti, Guillermo, Jaime Sanz, Arancha Bermudez, Dolores Caballero, Carmen Martinez, Jordi Sierra, José R. Cabrera Marin, et al. "Outcome of Second Allogeneic SCT Following Relapse of Hematological Malignancies After a First Allogeneic SCT." Blood 118, no. 21 (November 18, 2011): 3056. http://dx.doi.org/10.1182/blood.v118.21.3056.3056.
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Abstract Abstract 3056 Background: Disease relapse is the most frequent cause of treatment failure following allogeneic haematopoietic cell transplantation (allo-HCT), and carries a very poor prognosis. A second allo-HCT may be the only curative option for the majority of these patients. Patient and transplant factors that may associate with the outcome of a second allo-HCT are required for clinical-decision making in such high-risk patients. Aims and Methods: We performed a retrospective analysis of patients receiving a second allo-HCT for disease relapse after a prior allo-HCT reported by GETH centres. Our aim is to analyze our experience in this setting, and to identify factors associated with patient outcome. Results: We present data on 189 patients who underwent a second allo-HCT for disease relapse in Spain up to December 2010 (median year 2004), with a median follow-up for survivors of 54 months (3–224): median age 35 years (range 4–69); 113 male (60%); initial diagnosis AML 77, ALL 45, MDS/MPD 28, CML 23, lymphoprolipherative disorder 12, and others 4. Seventy-five (40%) received myeloablative conditioning. Donors for second allo-HCT were related in 158 cases (84%), and in 33 cases (17%) were new donors different from the donors in the previous allo-HCT. Only 23 cases (12%) had T-cell depletion. Median time from the first to the second allo-HCT was 19 months (1–151). The cumulative incidence of non-relapse mortality was 37%. Median overall survival (OS) was 297 days, with an OS at 1, 3 and 5 years of 39%, 28% and 25%, respectively. Type of donor (related versus unrelated and new donor versus same donor) and type of conditioning (myeloablative versus non-myeloablative) had no association with patient outcome. However, OS was significantly poorer in patients who underwent second allo-HCT in active relapse or progression than in those with low disease burden (complete response, good partial response, or chronic phase; 29% vs 52% at 1 year, 21% vs 39% at 3 years, 17% vs 35% at 3 years, respectively; p=0.001). Also, patients with early relapse after the first allo-HCT who underwent a second allo-HCT <1 year after first HCT also had a poorer OS than those with a later relapse and second allo-HCT (13% vs 53% at 1 year, 7% vs 40% at 3 years, and 5% vs 35% at 5 years, respectively; p<0.001). The impact of these two clinical factors in the outcome remained independent in the multivariate analysis (disease status at second allo-HCT: HR 1.8, 95% CI 1.2–2.6, p=0.002; time to second allo-HCT: HR 3.2, 95% CI 2.2–4.6, p<0.001). Time to second allo-HCT and disease status also have an independent association with the probability of progression free survival in this series (p <0.001 and p =0.001, respectively). In fact, while patients with late relapse who received a second allo-HCT in good response had a very encouraging probability of OS of 49% at 5 years, patients who had an early relapse and required a second allo-HCT in less than 1 year from their first allo-HCT and also had active disease at the time of second allo-HCT had very poor OS of only 8% at 1 year and no one survived beyond 3 years after the second allo-HCT. Conclusions: 25% of patients who relapse after an allo-HCT can achieve long-term survival of 5 or more years following a second allo-HCT. Donor type does not appear to influence the outcome. On the contrary, our data suggest that disease status at HCT and time to relapse between first and second HCT are two significant prognostic factors with independent impact on patient outcome. The indication of a second allo-HCT in this context should be thoroughly discussed for individual cases, in particular for patients with early relapse and refractory disease arriving to second allo-HCT, for whom the probability of prolonged survival is extremely low. Disclosures: No relevant conflicts of interest to declare.
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Gergis, Usama, Nandita Khera, Marie Louise Edwards, Yan Song, Rochelle Sun, Ronit Simantov, Smitha Sivaraman, Rocio Manghani, and James Signorovitch. "Abstract 6 Projected Impact of Omidubicel on Racial and Ethnic Disparities in Allogeneic Hematopoietic Cell Transplant Access and Outcomes for Patients with Hematologic Malignancies in the U.S." Stem Cells Translational Medicine 11, Supplement_1 (September 1, 2022): S8. http://dx.doi.org/10.1093/stcltm/szac057.006.
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Abstract Introduction Patients with hematologic malignancies (HM) who are eligible for allogeneic hematopoietic cell transplant (allo-HCT) often lack an HLA-matched related donor (MRD) and rely on unrelated donors for a matched or mismatched unrelated donor (MUD or MMUD) or on umbilical cord blood (UCB). It is well known that racial minorities are underrepresented in donor registries. Objective Omidubicel, an advanced cell therapy for allo-HCT, demonstrated superior hematopoietic recovery and clinical outcomes compared with standard UCB (NCT02730299). We hypothesized the impact of omidubicel access on racial and ethnic health disparities in a projection model. Methods A model was developed to project allo-HCT access and clinical outcomes in a hypothetical population of 10,000 allo-HCT-eligible US patients with HM lacking an HLA-MRD. Outcomes associated with omidubicel, MUD, MMUD, haploidentical or UCB HCT, or no transplant were assessed by race/ethnic group. Model inputs, including clinical outcomes for each HCT type, were drawn from clinical trials, public CIBMTR and US Department of Health and Human Services data, and published studies. Increasing omidubicel use was modeled, with proportional reductions in other allo-HCT types or no transplant. Results In a modeled population of 10,000 patients, 5,956 (60%) received allo-HCT utilizing current donor sources (MUD, MMUD, haploidentical, UCB) with no omidubicel (status quo). While 80% of white patients underwent allo-HCT, only 40% of Hispanic, 32% of Asian, and 22% of Black patients underwent allo-HCT. Mean time from selecting graft to HCT was 11.5 weeks. Including those not transplanted, 1-year OS was 62% overall, ranging from 56% (Black) to 65% (White). Modeled increases in omidubicel use in eligible patients were associated with higher proportions of patients undergoing allo-HCT, decreased time to HCT, and increased 1-year OS. Improvements were greatest among racial minorities. Assuming 20% omidubicel use, the proportion of patients receiving allo-HCT increased by 71% in Black, 43% in Asian, 30% in Hispanic, and 5% in White patients. Modeled time to allo-HCT improved as well. Discussion Access to omidubicel is projected to decrease time to allo-HCT, improve outcomes overall, with greatest improvements among racial and ethnic groups underserved by the status quo, thus helping to reduce racial disparities and improving health equity in allo-HCT.
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Fenske, Timothy S., Mei-Jie Zhang, Jeanette Carreras, Ernesto Ayala, Linda J. Burns, Amanda Cashen, Luciano J. Costa, et al. "Autologous or Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation for Chemotherapy-Sensitive Mantle-Cell Lymphoma: Analysis of Transplantation Timing and Modality." Journal of Clinical Oncology 32, no. 4 (February 1, 2014): 273–81. http://dx.doi.org/10.1200/jco.2013.49.2454.
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Purpose To examine the outcomes of patients with chemotherapy-sensitive mantle-cell lymphoma (MCL) following a first hematopoietic stem-cell transplantation (HCT), comparing outcomes with autologous (auto) versus reduced-intensity conditioning allogeneic (RIC allo) HCT and with transplantation applied at different times in the disease course. Patients and Methods In all, 519 patients who received transplantations between 1996 and 2007 and were reported to the Center for International Blood and Marrow Transplant Research were analyzed. The early transplantation cohort was defined as those patients in first partial or complete remission with no more than two lines of chemotherapy. The late transplantation cohort was defined as all the remaining patients. Results Auto-HCT and RIC allo-HCT resulted in similar overall survival from transplantation for both the early (at 5 years: 61% auto-HCT v 62% RIC allo-HCT; P = .951) and late cohorts (at 5 years: 44% auto-HCT v 31% RIC allo-HCT; P = .202). In both early and late transplantation cohorts, progression/relapse was lower and nonrelapse mortality was higher in the allo-HCT group. Overall survival and progression-free survival were highest in patients who underwent auto-HCT in first complete response. Multivariate analysis of survival from diagnosis identified a survival benefit favoring early HCT for both auto-HCT and RIC allo-HCT. Conclusion For patients with chemotherapy-sensitive MCL, the optimal timing for HCT is early in the disease course. Outcomes are particularly favorable for patients undergoing auto-HCT in first complete remission. For those unable to achieve complete remission after two lines of chemotherapy or those with relapsed disease, either auto-HCT or RIC allo-HCT may be effective, although the chance for long-term remission and survival is lower.
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Kurosawa, Saiko, Takuhiro Yamaguchi, Shuichi Miyawaki, Naoyuki Uchida, Heiwa Kanamori, Kensuke Usuki, Takuya Yamashita, et al. "A Markov decision analysis of allogeneic hematopoietic cell transplantation versus chemotherapy in patients with acute myeloid leukemia in first remission." Blood 117, no. 7 (February 17, 2011): 2113–20. http://dx.doi.org/10.1182/blood-2010-05-285502.
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Abstract Various prospective trials have been performed to assess the roles of allogeneic hematopoietic cell transplantation (allo-HCT) and chemotherapy in patients with acute myeloid leukemia (AML) in first complete remission (CR1). However, the results have not always been consistent, and there has been a limited evaluation of quality of life (QOL) in these postremission strategies. We performed a Markov decision analysis that enabled us to compare survival outcomes with a QOL evaluation using a database of 2029 adult AML patients who achieved CR1. The Markov decision model compared 2 strategies: allo-HCT or chemotherapy in CR1. Patients who had intermediate- or unfavorable-risk AML had a longer life expectancy when they received allo-HCT in CR1 than patients treated with chemotherapy alone. Likewise, patients who had a suitable related donor who received allo-HCT in CR1 had a longer life expectancy. The life expectancy was shortened to a greater degree by adjustment for QOL in the allo-HCT group. Nevertheless, QOL-adjusted life expectancies in most of the subgroups remained longer in the allo-HCT group than in the chemotherapy group. Our results showed that older patients with a related donor and younger patients with unfavorable cytogenetics benefited the most from allo-HCT in CR1.
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Reichenbach, Dawn K., Benjamin M. Matta, Xiaoli Zhang, Brent Koehn, Lisa Mathews, Michelle J. Smith, Colby J. Feser, Robert Zeiser, Heth Roderick Turnquist, and Bruce R. Blazar. "IL-33 mediated expansion of host ST2+ Treg prior to allogeneic hematopoietic cell transplantation decreases macrophage and effector T cell activation reducing acute GVHD." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 140.33. http://dx.doi.org/10.4049/jimmunol.196.supp.140.33.
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Abstract Graft-versus-host disease (GVHD) is the leading complication and cause of mortality after allogeneic hematopoietic cell transplantation (allo-HCT). Recently, we reported that IL-33 released from tissue damaged during allo-HCT conditioning mediates pro-inflammatory responses by Teffector cells resulting in greater acute GVHD lethality and clinical symptoms in mice. However, IL-33 is a pleiotropic cytokine that mediates both pro-inflammatory and anti-inflammatory responses. We hypothesized that the beneficial effects mediated by IL-33 could be harnessed if IL-33 was present prior to inflammatory mediators released during conditioning. Here, we demonstrate that exogenous IL-33 given peri allo-HCT (days −10 to 4) to recipients of MHC-disparate allo-HCT asserts its immunoregulatory properties reduced GVHD lethality and clinical symptoms compared to non-treated controls. IL-33 treatment peri allo-HCT resulted in the expansion of recipient Treg and suppressive myeloid cells that persisted post irradiation. Host Treg depletion in C57Bl/6 FoxP3-DTR mice by diphtheria toxin given concurrently with peri allo-HCT IL-33 treatment accelerated GVHD symptoms and lethality compared to peri allo-HCT IL-33 treatment alone, demonstrating that host Treg were necessary for GVHD protection. Transfer of Treg deficient in ST2, the IL-33 receptor, afforded less GVHD protection than wild-type Treg. ST2+ Treg controlled macrophage activation and prevented accumulation of Teffector cells in GVHD target tissue. Thus, we demonstrate that peri allo-HCT IL-33 expanded and activated host Treg have potential as a therapeutic modality to prevent and treat GVHD.
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Tyszka, Martyna, Dominika Maciejewska-Markiewicz, Jarosław Biliński, Arkadiusz Lubas, Ewa Stachowska, and Grzegorz W. Basak. "Increased Intestinal Permeability and Stool Zonulin, Calprotectin and Beta-Defensin-2 Concentrations in Allogenic Hematopoietic Cell Transplantation Recipients." International Journal of Molecular Sciences 23, no. 24 (December 15, 2022): 15962. http://dx.doi.org/10.3390/ijms232415962.
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Significant progress has been made in understanding the connection between intestinal barrier function and allogenic hematopoietic cell transplantation (allo-HCT) recipients’ outcomes. The purpose of this study was to further evaluate gut barrier permeability and other potential intestinal barrier disruption markers in the allo-HCT setting. Fifty-one patients were enrolled in the study. Intestinal permeability was assessed with the sugar absorption test and faecal concentrations of the zonulin, calprotectin and beta-defensin-2 levels in the peri-transplantation period. Most patients undergoing allo-HCT in our department had a disrupted intestinal barrier at the baseline, which was associated with older age and higher Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI). Regardless of this, we observed a further increase in gut barrier permeability after allo-HCT in most patients. However, there was no association between permeability assay and other markers (zonulin, calprotectin and beta-defensin-2). Patients with acute GVHD had significantly higher median calprotectin concentrations after allo-HCT compared with the patients without this complication. Our findings indicate that gut barrier damage develops prior to allo-HCT with progression after the procedure and precedes further complications, but did not prove other markers to be useful surrogates of intestinal permeability.
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Hashimoto, Daigo, Andrew Chow, Melanie Greter, Yvonne Saenger, Wing-Hong Kwan, Marylene Leboeuf, Florent Ginhoux, et al. "Pretransplant CSF-1 therapy expands recipient macrophages and ameliorates GVHD after allogeneic hematopoietic cell transplantation." Journal of Experimental Medicine 208, no. 5 (May 2, 2011): 1069–82. http://dx.doi.org/10.1084/jem.20101709.
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Acute graft-versus-host disease (GVHD) results from the attack of host tissues by donor allogeneic T cells and is the most serious limitation of allogeneic hematopoietic cell transplantation (allo-HCT). Host antigen-presenting cells are thought to control the priming of alloreactive T cells and the induction of acute GVHD after allo-HCT. However, whereas the role of host DC in GVHD has been established, the contribution of host macrophages to GVHD has not been clearly addressed. We show that, in contrast to DC, reducing of the host macrophage pool in recipient mice increased donor T cell expansion and aggravated GVHD mortality after allo-HCT. We also show that host macrophages that persist after allo-HCT engulf donor allogeneic T cells and inhibit their proliferation. Conversely, administration of the cytokine CSF-1 before transplant expanded the host macrophage pool, reduced donor T cell expansion, and improved GVHD morbidity and mortality after allo-HCT. This study establishes the unexpected key role of host macrophages in inhibiting GVHD and identifies CSF-1 as a potential prophylactic therapy to limit acute GVHD after allo-HCT in the clinic.
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Rocha, Vanderson, Giancarlo Fatobene, and Dietger Niederwieser. "Increasing access to allogeneic hematopoietic cell transplant: an international perspective." Hematology 2021, no. 1 (December 10, 2021): 264–74. http://dx.doi.org/10.1182/hematology.2021000258.
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Abstract Allogeneic hematopoietic cell transplantation (allo-HCT) is a highly complex, costly procedure for patients with oncologic, hematologic, genetic, and immunologic diseases. Demographics and socioeconomic status as well as donor availability and type of health care system are important factors that influence access to and outcomes following allo-HCT. The last decade has seen an increase in the numbers of allo-HCTs and teams all over the world, with no signs of saturation. More than 80 000 procedures are being performed annually, with 1 million allo-HCTs estimated to take place by the end of 2024. Many factors have contributed to this, including increased numbers of eligible patients (older adults with or without comorbidities) and available donors (unrelated and haploidentical), improved supportive care, and decreased early and late post-HCT mortalities. This increase is also directly linked to macro- and microeconomic indicators that affect health care both regionally and globally. Despite this global increase in the number of allo-HCTs and transplant centers, there is an enormous need for increased access to and improved outcomes following allo-HCT in resource-constrained countries. The reduction of poverty, global economic changes, greater access to information, exchange of technologies, and use of artificial intelligence, mobile health, and telehealth are certainly creating unprecedented opportunities to establish collaborations and share experiences and thus increase patient access to allo-HCT. A specific research agenda to address issues of allo-HCT in resource-constrained settings is urgently warranted.
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Delgado, Julio, Donald W. Milligan, and Peter Dreger. "Allogeneic hematopoietic cell transplantation for chronic lymphocytic leukemia: ready for prime time?" Blood 114, no. 13 (September 24, 2009): 2581–88. http://dx.doi.org/10.1182/blood-2009-05-206821.
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AbstractThe development of reduced intensity conditioning regimens has increased the number of patients diagnosed with chronic lymphocytic leukemia that are referred for allogeneic hematopoietic cell transplantation (allo-HCT). However, given the toxicity of allo-HCT, it should only be offered to eligible patients whose life expectancy is significantly reduced by the disease. Accordingly, the European Group of Blood and Marrow Transplantation has recently identified those patients in whom allo-HCT could be a reasonable therapeutic approach. In this review, we have evaluated the outcome of chronic lymphocytic leukemia patients undergoing allo-HCT, either after conventional or reduced intensity conditioning regimens, in the context of current nontransplantation strategies. We have also analyzed the most important predisposing factors that might interfere with the procedure as well as posttransplantation complications that are particularly common in these patients. Finally, we have addressed the most relevant factors when deciding what patients should be considered for allo-HCT and the timing of the procedure.
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Chen, Robert, Joycelynne M. Palmer, Sandra H. Thomas, Ni-Chun Tsai, Len Farol, Auayporn Nademanee, Stephen J. Forman, and Ajay K. Gopal. "Brentuximab vedotin enables successful reduced-intensity allogeneic hematopoietic cell transplantation in patients with relapsed or refractory Hodgkin lymphoma." Blood 119, no. 26 (June 28, 2012): 6379–81. http://dx.doi.org/10.1182/blood-2012-03-418673.
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Brentuximab vedotin induces an overall response rate of 75% in patients with relapsed/refractory Hodgkin lymphoma, but its impact on future allogeneic transplantation (allo-HCT) is not known. We retrospectively examined the records of 18 patients with relapsed/refractory Hodgkin lymphoma who were treated on brentuximab vedotin clinical trials to evaluate the efficacy and safety of subsequent reduced-intensity allo-HCT. Seventeen patients had previous autologous transplant; 6 were in complete remission, and 8 were in partial remission before allo-HCT with 12 grafts from unrelated or mismatched donors. The 1-year overall survival was 100%, progression-free survival was 92.3%, and nonrelapse mortality was 0% (median follow-up, 14 months). The incidence of acute GVHD was 27.8% and chronic GVHD was 56.3%. Brentuximab vedotin before reduced-intensity allo-HCT does not appear to adversely affect engraftment, GVHD, or survival and may provide sufficient disease control to enable reduced-intensity allo-HCT.
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Akinsete, Adeseye Michael, Michael R. DeBaun, and Adetola A. Kassim. "Sickle Cell Disease Post-Transplant Care Challenges in Nigeria: Systematic Institutional Neglect of Medical Tourism." Blood 134, Supplement_1 (November 13, 2019): 4568. http://dx.doi.org/10.1182/blood-2019-126120.
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Introduction: Allogeneic hematopoietic stem cell transplantation (Allo-HCT) is potentially curative in eligible patients with sickle cell disease (SCD). Long term survival remains a challenge following allo-HCT and factors that predict for longer term complications and late mortality include increased hospitalization within the first 100 days, low socioeconomic status and poor access to healthcare. A new cottage industry of medical tourism associated with allo-HCT has emerged where children and adults with SCD living in Africa are traveling to countries that provide allo-HCT. Recent advances in improved disease-free survival and overall survival has resulted in families seeking curative options outside of their low resource-setting. The decision for allo-HCT is heavily weighed to family preference without regards to post-transplant care in their local environment. Unfortunately, the long-term care required for many children following an allo-HCT transplant is usually not available in their home country. Thus, the family desiring an allo-HCT is put in an awkward situation where they may need to have follow-up care in their primary country at a medical facility where neither the expertise nor the resources are available to manage long-term complications of allo-HCT. To explore the relationship between transplant medical tourism and patients with SCD, we report a case series of children who received their allo-HCT in another country only to return back to Nigeria. Methods: We recently established a post-transplant care clinic at the Lagos University Teaching Hospital, Idi-Araba, Nigeria. This includes a multidisciplinary team of providers, physicians and nurses with expertise in transplant care, and collaboration from Vanderbilt University Medical Center, USA. All cases described received allo-HCT outside Nigeria and returned within 60-100 days post-transplant. Parental preference for curative option was main indication for seeking allo-HCT. Records were obtained through electronic and paper medical records. Results: All the four cases reported had sickle cell anemia (Hb SS). Cases 1-3 received reduced intensity haploidentical HCT with post-transplant cyclophosphamide (Haplo-HCT), using G-mobilized peripheral blood stem cell grafts from parental donors with sickle cell trait. They all received preconditioning with hydroxycarbamide, azacytidine, and hypertransfusion (Table). Case-1 was 2years old, initially evaluated at day +135 post-transplant, complications included grade-II acute GI graft-versus-host disease (GVHD) at day+37 post-transplant, febrile illness and pseudo-membranous colitis requiring repeat endoscopies and prolonged steroid therapy. Case 2 was 5-years-old, seen day+395 post-transplant self-discontinued immunosuppression and antimicrobial prophylaxis with no guidance (despite the original haplo-HCT required a minimum of 12 months of immunosuppression therapy). Similarly, Case 3 was 7-years-old, off immunosuppression prematurely, and yet to commence routine post-transplant immunizations. Case 4 was 5-year-old who received matched related myeloablative bone marrow transplant. He was seen at day +138 post-transplant. He had poor graft function, EBV reactivation requiring Rituximab chemotherapy. Other management challenges encountered by patient's post-transplant include timely monitoring of immunosuppression and graft function, provision of irradiated blood component transfusion support, provision of anti-malaria and anti-helminthic prophylaxis which are endemic locally. Further, no physician to physician contact was made to transfer the patient back to a hematologist or oncologist with knowledge about post-transplant medical care. Discussion: The argument for performing the allo-HCT in children moving back to a low-income country has to be weighed against the availability of a strategy for management of late complications of allo-HCT, such as chronic GVHD, infectious complications related to immune reconstitution, as well as endocrine and chronic metabolic syndromes. Ultimately, the decision to perform an allo-HCT in such situations must be done on a case-by-case basis with a clear contingency plan to manage transplant-related complications for at least 2 years after the procedure at a hospital with adequate transplant expertise and support measures. Disclosures No relevant conflicts of interest to declare.
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Fenske, Timothy S., Tara M. Graff, Kwang Woo Ahn, Alyssa DiGilio, Sonali M. Smith, Anna Sureda, and Mehdi Hamadani. "Reduced-Intensity Allogeneic Hematopoietic Cell Transplantation (allo-HCT) Provides Durable Progression-Free Survival (PFS) in a Subset of Diffuse Large B-Cell Lymphoma (DLBCL) Patients Relapsing after Autologous (auto-) HCT." Blood 126, no. 23 (December 3, 2015): 197. http://dx.doi.org/10.1182/blood.v126.23.197.197.
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Abstract Background: DLBCL relapsing after an auto-HCT has a poor prognosis. Unfortunately this is a common clinical dilemma, since ~50% of auto-HCTs for DLBCL ultimately fail. Allo-HCT is often considered following failure of an auto-HCT; however, limited information is available regarding prognostic factors identifying DLBCL patients likely to benefit from a subsequent allo-HCT. Methods: Adult (≥18 years) DLBCL patients undergoing an alloHCT between 2000-2012, after experiencing disease progression/relapse (P/R) following a prior autoHCT and reported to the CIBMTR were included. Patients undergoing tandem auto-allo HCT and those receiving allo-HCT for indications other than relapsed DLBCL were excluded. Primary outcomes were non-relapse mortality (NRM), P/R, PFS, and overall survival (OS). Cox regression method was used to develop a prognostic model of PFS and OS. Results: Characteristics of 503 patients included in this analysis are shown in Table 1. The 3-yr univariate probabilities of NRM, P/R, PFS and OS were 30%, 38%, 31% and 37% respectively. Factors associated with higher NRM on multivariate analysis (MVA) included chemoresistance disease prior to allo-HCT (RR=1.86; p=0.003), myeloablative conditioning (MAC) (RR=1.99; p=0.0006; within 1st 10months following alloHCT) and unrelated donors (URD) grafts (RR=1.44; p=0.03). Factors associated with P/R on MVA included chemoresistance (RR= 2.25, p<0.0001), Karnofsky performance status (KPS) <80 (RR 1.81, p=0.006), and interval between auto-HCT and allo-HCT of <1 yr (RR=2.28, p<0.0001). Factors associated with inferior PFS on MVA included KPS <80 (RR=1.79, p=0.0005), chemoresistance (RR=2.04, p<0.0001), auto-HCT to allo-HCT interval <1 yr (RR=1.32, p=0.01), and MAC (RR 1.29, p=0.03). Factors associated with worse OS on MVA included KPS <80 (RR1.86, p=0.0003), chemoresistance (RR=1.94, p<0.0001), MAC (RR=1.39, p=0.008). Three adverse prognostic factors were used to construct a prognostic model for PFS, including; (i) KPS <80 (2 points) (ii) Interval between auto-HCT & allo-HCT of <1yr (1 point) and (iii) chemoresistant disease at allo-HCT (2 points). This CIBMTR prognostic model classified patients into three prognostic groups: low risk (0-1 points), intermediate risk (2-3 points), or high risk (4-5 points), predicting 3-yr PFS probabilities of 38% (95% CI=32-44), 19% (95% CI=11-27) and 10% (95% CI=0-22), respectively (Fig 1). The 3-yr OS probabilities in similar order were 43%, 25% and 14% respectively. Conclusion: The CIBMTR prognostic model identifies a subgroup of DLBCL patients relapsing from an auto-HCT who can experience long-term PFS following an allo-HCT. Reduced-intensity conditioning is preferred in this setting. Table.N=503 (%)Median age at alloHCT, years52 (range 19-72)Male gender305 (61)KPS ≥80393 (78)Stage III-IV at diagnosis54%Rituximab prior to HCT72%Median lines of therapy4 (range 1-7)High LDH at HCT34%Time from auto-HCT to allo-HCT, months15 (range 1-198)Disease status at transplantCR175 (35)PR197 (39)Chemorefractory106 (21)Untreated12 (2)Missing13 (3)Type of donorSibling253 (50)URD250 (50)Myeloablative conditioning127 (25)PB graft456 (91)TBI in conditioning133 (26)Median follow up, months55 (range 1-149) Figure 1. Figure 1. Disclosures Smith: Celgene: Consultancy; Pharmacyclics: Consultancy. Sureda:Seattle Genetics Inc.: Research Funding; Takeda: Consultancy, Honoraria, Speakers Bureau.
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Hamadani, Mehdi, Maud Ngoya, Anna Sureda, Qaiser Bashir, Carlos Alejandro Litovich, Hervé Finel, Yue Chen, et al. "Outcome of allogeneic transplantation for mature T-cell lymphomas: impact of donor source and disease characteristics." Blood Advances 6, no. 3 (February 2, 2022): 920–30. http://dx.doi.org/10.1182/bloodadvances.2021005899.
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Abstract Mature T-cell lymphomas constitute the most common indication for allogeneic hematopoietic cell transplantation (allo-HCT) of all lymphomas. Large studies evaluating contemporary outcomes of allo-HCT in mature T-cell lymphomas relative to commonly used donor sources are not available. Included in this registry study were adult patients who had undergone allo-HCT for anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma (AITL), or peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) between 2008 and 2018. Hematopoietic cell transplantation (HCT) platforms compared were posttransplant cyclophosphamide-based haploidentical (haplo-)HCT, matched sibling donor (MSD) HCT, matched unrelated donor HCT with in vivo T-cell depletion (MUD TCD+), and matched unrelated donor HCT without in vivo T-cell depletion (MUD TCD−). Coprimary end points were overall survival (OS) and progression-free survival (PFS); secondary end points included nonrelapse mortality (NRM), and relapse/progression incidence (RI). A total of 1942 patients were eligible (237 haplo-HCT; 911 MSD; 468 MUD TCD+; 326 MUD TCD−). Cohorts were comparable for baseline characteristics with the exception of higher proportions of patients with decreased performance status (PS) and marrow graft recipients in the haplo-HCT group. Using univariate and multivariate comparisons, OS, PFS, RI, and NRM were not significantly different among the haplo-HCT, MSD, MUD TCD+, and MUD TCD− cohorts, with 3-year OS and PFS of 60%, 63%, 59%, and 64%, respectively, and 50%, 50%, 48%, and 52%, respectively. Significant predictors of inferior OS and PFS on multivariate analysis were active disease status at HCT and decreased PS. AITL was associated with significantly reduced relapse risk and better PFS compared with PTCL-NOS. Allo-HCT can provide durable PFS in patients with mature T-cell lymphoma (TCL). Outcomes of haplo-HCT were comparable to those of matched donor allo-HCT.
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Chhabra, Saurabh, Kwang Woo Ahn, Zhen-Huan Hu, Sandeep Jain, Amer Assal, Jan Cerny, Edward A. Copelan, et al. "Myeloablative vs reduced-intensity conditioning allogeneic hematopoietic cell transplantation for chronic myeloid leukemia." Blood Advances 2, no. 21 (November 5, 2018): 2922–36. http://dx.doi.org/10.1182/bloodadvances.2018024844.
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Abstract Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment of chronic myeloid leukemia (CML). Optimal conditioning intensity for allo-HCT for CML in the era of tyrosine kinase inhibitors (TKIs) is unknown. Using the Center for International Blood and Marrow Transplant Research database, we sought to determine whether reduced-intensity/nonmyeloablative conditioning (RIC) allo-HCT and myeloablative conditioning (MAC) result in similar outcomes in CML patients. We evaluated 1395 CML allo-HCT recipients between the ages of 18 and 60 years. The disease status at transplant was divided into the following categories: chronic phase 1, chronic phase 2 or greater, and accelerated phase. Patients in blast phase at transplant and alternative donor transplants were excluded. The primary outcome was overall survival (OS) after allo-HCT. MAC (n = 1204) and RIC allo-HCT recipients (n = 191) from 2007 to 2014 were included. Patient, disease, and transplantation characteristics were similar, with a few exceptions. Multivariable analysis showed no significant difference in OS between MAC and RIC groups. In addition, leukemia-free survival and nonrelapse mortality did not differ significantly between the 2 groups. Compared with MAC, the RIC group had a higher risk of early relapse after allo-HCT (hazard ratio [HR], 1.85; P = .001). The cumulative incidence of chronic graft-versus-host disease (cGVHD) was lower with RIC than with MAC (HR, 0.77; P = .02). RIC provides similar survival and lower cGVHD compared with MAC and therefore may be a reasonable alternative to MAC for CML patients in the TKI era.
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Herbaux, Charles, Jordan Gauthier, Pauline Brice, Elodie Drumez, Loic Ysebaert, Hélène Doyen, Luc Fornecker, et al. "Efficacy and tolerability of nivolumab after allogeneic transplantation for relapsed Hodgkin lymphoma." Blood 129, no. 18 (May 4, 2017): 2471–78. http://dx.doi.org/10.1182/blood-2016-11-749556.
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Herbaux, Charles, Reid Merryman, Steven Devine, Philippe Armand, Roch Houot, Franck Morschhauser, and Bradley Haverkos. "Recommendations for managing PD-1 blockade in the context of allogeneic HCT in Hodgkin lymphoma: taming a necessary evil." Blood 132, no. 1 (July 5, 2018): 9–16. http://dx.doi.org/10.1182/blood-2018-02-811174.
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Abstract PD-1 blockade is an effective therapy in relapsed/refractory (R/R) classical Hodgkin Lymphoma (cHL) who have relapsed after or are ineligible for autologous hematopoietic cell transplantation (HCT). Although single-agent anti-PD-1 monoclonal antibodies (mAb’s) are associated with high response rates and durable remissions, available results to date suggest that a large majority of patients will eventually progress on therapy. Many of these patients are potential candidates for allogeneic HCT (allo-HCT) after receiving anti-PD-1 mAb’s, and allo-HCT remains for now the only treatment with demonstrated curative potential in this setting. However, initial reports suggested that allo-HCT in this setting may be associated with increased risk of early transplant-related toxicity, likely driven by lingering effects of PD-1 blockade. Furthermore, many patients with R/R cHL who undergo allo-HCT will relapse after transplantation, most often with limited treatment options. Here again, PD-1 blockade appears to yield high response rates, but with an increased risk of attendant immune toxicity. Many questions remain regarding the use of PD-1 blockade before or after allo-HCT, especially in relation to the feasibility, outcome, optimal timing, and method of allo-HCT after PD-1 blockade. Despite the scarcity of prospective data, these questions are unavoidable and must be tackled by clinicians in the routine care of patients with advanced cHL. We provide consensus recommendations of a working group based on available data and experience, in an effort to help guide treatment decisions until more definitive data are obtained.
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Moldovianu, Ana-Maria, Ana Manuela Crisan, Zsofia Varady, and Daniel Coriu. "The Difficult-to-Treat del 17 p Patient—A Case Report in Chronic Lymphocytic Leukemia." Medicina 58, no. 1 (December 24, 2021): 33. http://dx.doi.org/10.3390/medicina58010033.
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Chronic lymphocytic leukemia (CLL) treatment strategies have evolved to include mechanism-driven drugs but now raise new questions regarding their optimum timing and sequencing. In high-risk patients, switching from pathway inhibitors to allogeneic stem cell transplantation (allo-HCT) is still a matter of intense debate. We report the case of a CLL patient with 17 p deletion treated with ibrutinib as a bridge to allo-HCT. Early relapse after allo-HCT urged the initiation of salvage therapy, including donor lymphocytes infusions, ibrutinib, and venetoclax. We aim to outline and discuss the potential benefits of novel therapies, the current role of allo-HCT in CLL, drug timing and sequencing, and the unmet need to improve the long-term outcome of high-risk CLL patients.
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Ratner, Lindsay, Jing ‘Daisy’ Zhu, Megan N. Gower, Tejendra Patel, Jordan A. Miller, Amber Cipriani, George A. Stouffer, Daniel J. Crona, and Craig R. Lee. "Pharmacogenomic prescribing opportunities in percutaneous coronary intervention and bone marrow transplant patients." Pharmacogenomics 23, no. 3 (February 2022): 183–94. http://dx.doi.org/10.2217/pgs-2021-0125.
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Aim: To evaluate the potential impact of preemptive multigene pharmacogenomic (PGx) testing on medication prescribing in real-world clinical settings. Patients & methods: Prescription frequencies for 65 medications with actionable PGx recommendations were collected in 215 percutaneous coronary intervention (PCI) and 131 allogeneic hematopoietic cell transplant (allo-HCT) patients. A simulation projected the number of PGx-guided prescribing opportunities. Results: In PCI and allo-HCT patients, respectively, 66.5 and 90.1% were prescribed at least one medication with actionable PGx prescribing recommendations. Simulations projected 26.5 and 41.2 total PGx-guided prescribing opportunities per 100 PCI and allo-HCT patients, respectively, if multigene PGx results were available. Conclusion: A multigene PGx testing strategy offers potential to optimize medication prescribing beyond clopidogrel and tacrolimus in PCI and allo-HCT patients.
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Lacevic, Jasmin, Tea Reljic, Najla El Jurdi, Mohamed A. Kharfan-Dabaja, Taiga Nishihori, Rami S. Komrokji, Ambuj Kumar, and Benjamin Djulbegovic. "Conservative Management Vs. Allogeneic Hematopoietic Cell Transplantation For Polycythemia Vera: A Systematic Review and Decision-Analysis." Blood 122, no. 21 (November 15, 2013): 5372. http://dx.doi.org/10.1182/blood.v122.21.5372.5372.
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Abstract Background Conservative treatment which typically includes phlebotomy or hydroxyurea or other cytoreductive therapy (plus aspirin) (ConsRxAsa) is effective treatment with acceptable complications for management of polycythemia Vera (PV) but is not considered curative [thus resulting in a shorter life expectancy (LE) in comparison to LE in the general population]. On the other hand, an allogeneic hematopoietic cell transplantation (allo-HCT) from a HLA compatible donor is considered a curative treatment option, but is potentially associated with high-risk of life-threatening complications. We sought to answer the question of which of these two treatment options results in better survival. Methods Because there are no direct randomized controlled trials (RCT) addressing the question if ConsRxAsa is superior to allo-HCT, we resorted to a decision-analysis to answer this question. We constructed a Markov model to represent and analyze the decision of ConsRxAsa vs. Allo-HCT. The results of the model were expressed in terms of life expectancy (LE) and survival probabilities. We performed a systematic review (and when possible a meta-analysis) to inform parameters in the model. ConsRxAsa arm was modeled by simulating the natural history of PV. For Allo-HCT arm, we adopted our previously published model (Biol Blood Marrow Transplant 2009;15:1415-21) but modified it to evaluate the effect of both conventional and reduced-intensity allo-HCT performed in chronic phase of PV. Results We identified 165 relevant articles of which only 7 described testing various treatments for PV in RCTs. However, most data used to populate the decision model came from one RCT and one cohort study. Using base case of age of 45 years, we estimated a probability of survival at 10 and 20 years of 86% and 67% for ConsRxAsa versus 55% and 32% for allo-HCT (Fig). This translates into an average LE of 17.1 years for ConsRxAsa vs. 11.6 years for allo-HCT, respectively. Sensitivity analysis according to age, early transplant-related mortality, risk of bleeding or thrombosis did not affect the results. Adopting median age of 65 years and comparing reduced-intensity allo-HCT vs. ConsRxAsa, we found that the average LE was 8.6 years for allo-HCT vs. 12.5 in the conservative treatment arm. Again, conservative treatment remained superior under a wide range of assumptions. Conclusions integration of current best existing evidence into the decision model shows that conservative management of PV appears to provide a better survival compared to offering an allo-HCT in chronic phase of P. Vera. Disclosures: No relevant conflicts of interest to declare.
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Kharfan-Dabaja, Mohamed A., Mehdi Hamadani, Tea Reljic, William I. Bensinger, Benjamin Djulbegovic, and Ambuj Kumar. "Comparative Efficacy of Tandem Autologous Versus Autologous Followed by Allogeneic Hematopoietic Cell Transplantation in Patients with Multiple Myeloma: A Systematic Review and Meta-Analysis." Blood 120, no. 21 (November 16, 2012): 4519. http://dx.doi.org/10.1182/blood.v120.21.4519.4519.
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Abstract Abstract 4519 Background: Despite advances in our understanding of clinical, genetic, and molecular aspects of multiple myeloma (MM) coupled with availability of more effective therapies, it remains an incurable disease. Combining cytoreduction from high-dose (chemo- or chemoradio-) therapy with adoptive immunotherapy forms the basis of an autologous-allogeneic (auto-allo) hematopoietic cell transplantation (HCT) strategy. However, when an auto-allo HCT approach is compared to tandem autologous (auto-auto) HCT, conflicting results have been reported. Accordingly, we performed a systematic review of published studies comparing auto-auto HCT with auto-allo HCT in patients with newly diagnosed MM. Methods: A systematic search of MEDLINE thru Nov 5, 2011, and pertinent conference proceedings, was conducted. Included studies allocated newly diagnosed MM patients to auto-allo HCT if an HLA-matched sibling donor was available versus auto-auto if sibling donor was not available (biologic randomization). Independent, dual data extraction was performed. Pooling of data from similar outcomes was done using the random-effects model. Results: Our search identified 152 publications, of which five (manuscript=four, abstract=one) met inclusion criteria. The five included trials enrolled 1538 patients (auto-allo=565, auto-auto=973). At least a very good partial response was assessed in one study (522 patients) and did not differ among the treatment arms [risk ratio (RR) (95% CI) = 0.97 (0.87–1.09), p=0.66]; but complete remission, assessed in five studies (1130 patients), was higher in the auto-allo HCT arm [RR(95% CI) =1.65 (1.25–2.19), p=0.0005]. Event-free survival did not differ among auto-allo HCT group versus auto-auto HCT group on per-protocol analysis [hazard ratio (HR) (95% CI) = 0.78 (0.58–1.05)), p=0.11] of three trials (409 patients), or ITT analysis [HR(95% CI) = 0.83 (0.60–1.15), p=0.26] in three trials (1229 patients). Overall survival (OS) did not differ among these treatment arms whether analyzed on per-protocol [HR(95% CI) = 0.88 (0.33–2.35), p=0.79] in two trials (214 patients), or by ITT [HR(95% CI) = 0.80 (0.48–1.32), p=0.39] analysis in three trials (1229 patients). Non-relapse mortality (NRM) was worse with auto-allo HCT [RR(95%CI) = 3.55 (2.17–5.80), p<0.00001] in four trials (1047 patients). Conclusion: Despite higher CR rates, there is no apparent improvement in OS with auto-allo HCT; but this approach results in higher NRM in patients with newly diagnosed MM. Disclosures: No relevant conflicts of interest to declare.
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Kurosawa, Saiko, Takuhiro Yamaguchi, Naoyuki Uchida, Shuichi Miyawaki, Heiwa Kanamori, Kensuke Usuki, Takuya Yamashita, et al. "A Markov Decision Analysis of Post-Remission Strategies in 2029 Patients with AML in First Remission (CR1): Should We Perform Allogeneic Hematopoietic Cell Transplantation in CR1?." Blood 114, no. 22 (November 20, 2009): 2281. http://dx.doi.org/10.1182/blood.v114.22.2281.2281.
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Abstract Abstract 2281 Poster Board II-258 Background: A decision analysis using the Markov process is a flexible and convenient analytical method that tracks the clinical events that occur after a certain decision with different probabilities and utilities over time. To address the role of allogeneic hematopoietic cell transplantation (allo-HCT) for acute myeloid leukemia (AML) in CR1, we performed a Markov decision analysis using newly collected clinical data from 2029 patients. Methods: Probabilities and other outcome data were derived from a database of adult AML patients that was constructed from case report files collected for this study. We included patients who were diagnosed with AML other than M3 between 1999 and 2006, aged 16 to 70 years, and who had achieved CR1 after 1 or 2 courses of induction chemotherapy. Using the software package TreeAge Pro 2009, we constructed a Markov decision model that compared 2 strategies: allo-HCT in CR1 (HCT group) and no allo-HCT in CR1 (CTx group). Possible health states considered in each decision included, for the HCT group, 1) no relapse without chronic GVHD, 2) no relapse with chronic GVHD, 3) relapse, and 4) dead, and, for the CTx group, 1) no relapse, 2) relapse, 3) second remission, 4) after salvage allo-HCT, and 5) dead. Quality-of-life (QOL) adjustments were made by incorporating time trade-off utilities that were derived from a questionnaire to 12 physicians who were familiar with the treatment of AML. The cycle length between state transitions was set at 3 months. Results: A total of 2029 patients were eligible for this analysis. The median age was 50 years, and the median follow-up of the surviving patients was 4.10 years. The proportions of patients with favorable, intermediate, unfavorable and unknown cytogenetic risk by SWOG criteria were 20%, 54%, 17% and 9%, respectively. Therapies performed at CR1 were allo-HCT in 494 patients (24%) and chemotherapy in 1535 patients (76%). Among 1076 patients whose HLA typing was performed for allo-HCT in CR1, 431 had HLA-matched or 1-antigen-mismatched related donors. Life expectancy and quality-adjusted life expectancy for the HCT and CTx groups in each risk category are summarized in Table 1. Life expectancy of the HCT group was longer than that of the CTx group (4.96 years vs. 4.44 years). However, quality-adjusted life expectancy of the HCT group was comparable to that of the CTx group (4.06 years vs. 3.98 years) due to a larger reduction of expected life length in the HCT group after QOL adjustment. In a subset analysis of the CTx group, patients with more favorable cytogenetic risk had a longer life expectancy. Whereas allo-HCT in CR1 was associated with a shorter life expectancy in patients with favorable-risk AML, allo-HCT in CR1 was associated with a longer life expectancy in those with intermediate-risk or unfavorable-risk AML. Adjustment for QOL did not change the preferred decision in the intermediate- and unfavorable-risk groups, although the survival advantages for allo-HCT in CR1 were less than those without QOL adjustment. In a subset of patients who had related donors, both life expectancy and quality-adjusted life expectancy were longer in the HCT group. Conclusion: The results of our decision analysis using the Markov process indicated that patients with intermediate- or unfavorable-risk AML have a longer life expectancy and quality-adjusted life expectancy with a decision of allo-HCT in CR1. Our results also showed that a Markov decision analysis that incorporates QOL may be useful as a decision-making tool for patients who might be candidates for allo-HCT. Disclosures: No relevant conflicts of interest to declare.
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Huang, Haiwen, Qiangli Wang, Ting Xu, Xiaochen Chen, Zhengming Jin, and Wu Depei. "Frontline Allogeneic and Autologous Hematopoietic Cell Transplant for Peripheral T-Cell Lymphomas (PTCLs): A Comparison Study Between Conventional Chemotherapy and Hematopoietic Cell Transplant from a Chinese Center." Blood 126, no. 23 (December 3, 2015): 4381. http://dx.doi.org/10.1182/blood.v126.23.4381.4381.
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Abstract Purpose We present the result of a comparison study between conventional chemotherapy and HCT for Peripheral T-cell lymphomas (PTCLs) in our center, especially the comparison between allo-HCT and auto-HCT. Patients and Methods From July 2007 to July 2014, 112 cases were analyzed retrospectively. All 112 patients were high risk group (IPI®3-4), 52 patients received conventional chemotherapy alone and 60 patients underwent HCT. In HCT group, Twenty-one (36.5%) patients received allo-HCT and thirty-nine patients (63.5%) received auto-HCT. Before receiving transplantation, 40 patients were in complete remission (CR), 2 patients were in partial remission (PR) and 18 patients were in refractory or relapse (NR). In the 18 NR patients, 11 patients accepted allo-HCT and 7 patients accepted auto-HCT. Patients¡¯ baseline characteristics were listed in Table 1 and Table 2. Results In this study, the longest follow-up time was 76 months and the shortest follow-up time was only two months. After chemotherapy, 31/52 patients achieved complete remission (CR)£¬5/52 patients achieved PR and 16/52 patients were not remission£¡§NR). The overall response rate was 69.2%. However, 14 patients suffered relapse in 36 responding patients, the recurrence rate was close to 50%. In allo-HCT group, 19/21 patients achieved CR and 2/21 patients died of severe infection within 100 days after HCT. In auto-HCT patients, 35/39 patients achieved CR and 4/39 patients were in NR. 7 patients experienced relapse after auto-HCT. After a median follow-up of 33.5 months, the K-M analysis showed that the 5-year PFS for HCT and chemotherapy were 60% and 30% (p =0.006), the 5-year OS were 65% and 33% (p =0.007). The difference between the two groups was significant The 5-year PFS for auto-HCT and allo-HCT were 61% and 60% (p=0.724). The 5-year OS were 62% and 61% (p=0.724). In transplant group, the 5-year OS for patients who were CR or NR before transplantation were 81% and 53% (p=0.303). The one-year cumulative TRM of allo-HCT and auto-HCT were 22.5% and 7.8% (p=0.250). For patients whose ages are below 50, the 2-year PFS for HCT and chemotherapy were 62.7% and 34.8% (p=0.017), the 3-year OS were 71.2% and 36.7% (p=0.033). The one-year TRM of HCT and chemotherapy were 15.5% and 12.4% (p=0.203). For patients more than 50 years old, the 1-year OS for HCT and chemotherapy were 85.7% and 66.5% (p=0.384). And the one-year TRM of HCT and chemotherapy were 28.6% and 33.3% (p=0.352). Conclusion The majorities of PTCL patients are at high risk and have a high recurrence rate after conventional chemotherapy alone. Our results suggest that HCT is superior to conventional chemotherapy in long-term survival for PTCLs and HCT is feasible for high-risk patients with low TRM, especially in the young patients. Therefore, HCT should be considered to be the first-line therapy in high risk PTCL patients. As to PFS and OS, there seems to be no difference between auto-HCT and allo-HCT. While before transplantation, there are more NR and relapsed patients in allo-HCT group, we recommend allo-HCT for refractory and relapsed patients. Table 1. Patient characteristics Parameters Chemotherapy HCT p value Number 52 60 Gender(female/male) 16/36 16/44 0.521 Median Age 45 29 0.003 Histological subtypes N PTCL-NOS 9 17 ALK-negative ALCL 15 15 AITL 15 17 NK/T 13 11 High risk factors B-symptoms 27 25 0.436 IPI score ®3 52 60 1.000 Ann Arbor III-IV stage 40 40 0.376 Evaluated LDH 40 42 0.546 Response to chemotherapy N CR 31 40 PR 5 2 NR 16 18 Responses to transplantation N N CR 54 PR 0 NR 4 Uncertain 2 Table 2. Patient characteristics of transplantation group Parameters Auto-HCT Allo-HCT Number 39 21 Histological subtypes PTCL-NOS 12 4 ALK-negative ALCL 13 4 AITL 7 9 NK/T 7 4 Conditioning regimen BEAM 39 0 BUCY 0 11 TBI+BUCY 0 10 Donor source N Matched unrelated donor 8 Matched sibling donor 4 Haploid donor 8 Cord blood 1 Disease status before HCT CR 30 10 PR 2 0 NR 7 11 Disease status after HCT CR 35 19 PR 0 0 NR 4 0 uncertain 0 2 Disclosures No relevant conflicts of interest to declare.
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Hoffman, Stephanie, Pavan Reddy, John Martin Magenau, Attaphol Pawarode, Brian Parkin, Sarah Marie Anand, Monalisa Ghosh, John Joseph Maciejewski, Darren Patrick King, and Mary Riwes. "Long-term follow-up of adult hematopoietic stem cell transplant recipients diagnosed with COVID-19." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e19028-e19028. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e19028.
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e19028 Background: Long-term complications of COVID-19 in hematopoietic stem cell transplant (HCT) recipients are unknown. Recent studies have described short term outcomes of COVID-19 infection post allogeneic (allo) and autologous (auto) HCT. In this study we provide long term follow-up of the outcomes of COVID-19 infection in allo and auto HCT recipients. Methods: We performed a retrospective study of adult patients who have received allo or auto HCT and were subsequently diagnosed with COVID-19 infection between March-December 2020. We summarized patient characteristics, laboratory and treatment data related to COVID-19 infection in these patients. Results: In this study, we provide long-term follow-up of over 7 months. Fifteen patients were identified for inclusion (allo n = 12, auto n = 3). Median follow-up was 7.8 months (range 1.9-10.7) for surviving patients. Median age at COVID-19 diagnosis was 55 years (range 24-77). Most patients were > 1 year out from transplant (allo n = 10, auto n = 1, 73%). Two patients (allo n = 1, auto n = 1, 13%) had undergone transplant within the preceding month. Most allo patients (n = 11, 73%) had received myeloablative conditioning. At the time of COVID-19 diagnosis, 9 allo patients (75%) were on immunosuppression (IS) (n = 7 for chronic graft-versus-host-disease (GVHD); n = 2 for GVHD prophylaxis). Eleven patients (73%) required hospitalization (allo n = 9, auto n = 2). Per the National Institutes of Health definitions of COVID-19 illness severity, 3 patients had critical disease (allo n = 2, auto n = 1, 20%), 5 severe (allo n = 5, 33%), 3 moderate (allo n = 2, auto n = 1, 20%), and 4 mild (allo n = 3, auto n = 1, 27%). All patients with chronic GVHD required hospitalization. Two patients died (allo n = 1, auto n = 1, 13%)—both had critical COVID-19 infections, were > 65 years old, > 3 years out from transplant, and had significant comorbidities. The allo patient was receiving prednisone < 1 mg/kg for chronic lung GVHD at COVID-19 diagnosis. Two allo patients developed either acute GVHD or chronic GVHD exacerbation within 3 months of their infection. One patient developed biopsy-proven acute GVHD (max grade III) 3 weeks after her infection and another patient developed a severe exacerbation of chronic GVHD within 3 months—both continue to require multi-modal IS. The remaining 7 patients with chronic GVHD have been maintained on either stable or tapered IS. Conclusions: Given the effect of COVID-19 infection, its impact on HCT recipients is important to define. The majority of HCT patients who contracted moderate-critical COVID-19 infections in our study were either on IS or had significant comorbidities. Our observational data points to the importance of long-term follow-up in HCT patients. Future studies are needed to delineate whether there is a relationship between COVID-19 infection and GVHD development or exacerbation. The role of vaccination in HCT recipients remains to be explored.
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Peled, Jonathan U., Sean M. Devlin, Anna Staffas, Melissa Lumish, Raya Khanin, Eric R. Littmann, Lilan Ling, et al. "Intestinal Microbiota and Relapse After Hematopoietic-Cell Transplantation." Journal of Clinical Oncology 35, no. 15 (May 20, 2017): 1650–59. http://dx.doi.org/10.1200/jco.2016.70.3348.
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Purpose The major causes of mortality after allogeneic hematopoietic-cell transplantation (allo-HCT) are relapse, graft-versus-host disease (GVHD), and infection. We have reported previously that alterations in the intestinal flora are associated with GVHD, bacteremia, and reduced overall survival after allo-HCT. Because intestinal bacteria are potent modulators of systemic immune responses, including antitumor effects, we hypothesized that components of the intestinal flora could be associated with relapse after allo-HCT. Methods The intestinal microbiota of 541 patients admitted for allo-HCT was profiled by means of 16S ribosomal sequencing of prospectively collected stool samples. We examined the relationship between abundance of microbiota species or groups of related species and relapse/progression of disease during 2 years of follow-up time after allo-HCT by using cause-specific proportional hazards in a retrospective discovery-validation cohort study. Results Higher abundance of a bacterial group composed mostly of Eubacterium limosum in the validation set was associated with a decreased risk of relapse/progression of disease (hazard ratio [HR], 0.82 per 10-fold increase in abundance; 95% CI, 0.71 to 0.95; P = .009). When the patients were categorized according to presence or absence of this bacterial group, presence also was associated with less relapse/progression of disease (HR, 0.52; 95% CI, 0.31 to 0.87; P = .01). The 2-year cumulative incidences of relapse/progression among patients with and without this group of bacteria were 19.8% and 33.8%, respectively. These associations remained significant in multivariable models and were strongest among recipients of T-cell–replete allografts. Conclusion We found associations between the abundance of a group of bacteria in the intestinal flora and relapse/progression of disease after allo-HCT. These might serve as potential biomarkers or therapeutic targets to prevent relapse and improve survival after allo-HCT.
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Bartoszewicz, Natalia, Krzysztof Czyżewski, Robert Dębski, Anna Krenska, Ewa Demidowicz, Monika Richert-Przygońska, Mariusz Wysocki, and Jan Styczyński. "Efficacy of keratinocyte growth factor in prevention of oral mucositis in children undergoing allogeneic hematopoietic cell transplantation." Acta Haematologica Polonica 51, no. 3 (September 16, 2020): 172–78. http://dx.doi.org/10.2478/ahp-2020-0030.
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AbstractIntroductionOral mucositis is regarded by patients as one of the worst and debilitating complications of conditioning and hematopoietic cell transplantation (HCT). Prevention of mucositis is one of the priorities of supportive therapy during and after conditioning.ObjectivesThe primary objective of the study was the analysis of efficacy of keratinocyte growth factor (KGF, palifermin) used in prophylaxis of oral mucositis in patients undergoing allo-HCT. The secondary objectives of the study included the analysis of the influence of palifermin on clinical course of oral mucositis and early transplant outcomes, as well as analysis of the contraindications of palifermin in patients undergoing allo-HCT.Patients and methodsA total number of 253 allo-HCT performed between 2003 and 2018 in patients aged 0–19 years in a single center were analyzed. Overall, in 161 HCTs, palifermin was administered.ResultsPatients receiving KGF were transplanted earlier in the context of calendar year, and more often received ATG, mainly due to the higher rate of unrelated donor transplants. Allo-HCT patients who were administered palifermin had shorter time of mucositis (median: 9 vs. 13 days, p < 0.001), lower mucositis grade (median: 2° vs. 3°; p < 0.001), shorter period of total parenteral nutrition (median: 19 vs. 22 days; p = 0.018), and lower incidence of episodes of febrile neutropenia (median: 39.1% vs. 83.1%; p < 0.001).ConclusionsThe use of palifermin has decreased duration and severity of oral mucositis in children after allo-HCT. Palifermin is a safe and well-tolerated compound in children undergoing allo-HCT.
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Choi, Sung Won, Erin Gatza, Guoqing Hou, Yaping Sun, Joel Whitfield, Yeohan Song, Katherine Oravecz-Wilson, Isao Tawara, Charles A. Dinarello, and Pavan Reddy. "Histone deacetylase inhibition regulates inflammation and enhances Tregs after allogeneic hematopoietic cell transplantation in humans." Blood 125, no. 5 (January 29, 2015): 815–19. http://dx.doi.org/10.1182/blood-2014-10-605238.
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Key Points HDAC inhibition reduced proinflammatory cytokines and increased regulatory T-cell number and function after allo-HCT. HDAC inhibition enhanced signal transducer and activator of transcription 3 acetylation and induced indoleamine-2,3-dioxygenase after allo-HCT.
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He, Kuang, Zhenke Wu, Hideaki Fujiwara, Steven Whitesall, Cynthia K. Zajac, Sung Won Choi, Pavan Reddy, and Muneesh Tewari. "Computational analysis of continuous body temperature provides early discrimination of graft-versus-host disease in mice." Blood Advances 3, no. 23 (December 6, 2019): 3977–81. http://dx.doi.org/10.1182/bloodadvances.2019000613.
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Key Points Unsupervised machine learning analysis of continuous body temperature data revealed early signals of aGVHD in allo-HCT mice. Continuous measurement of body temperature is promising for early prediction of aGVHD in human allo-HCT patients.
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Nawas, Mariam T., Miriam Sanchez-Escamilla, Sean M. Devlin, Molly A. Maloy, Sergio A. Giralt, Miguel-Angel Perales, and Michael Scordo. "Dynamic Easix Scores Closely Predict Non-Relapse Mortality after Allogeneic Hematopoietic Cell Transplantation." Blood 134, Supplement_1 (November 13, 2019): 1971. http://dx.doi.org/10.1182/blood-2019-125834.
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Background: Endothelial Activation and Stress Index (EASIX) was developed as a simple surrogate of endothelial dysfunction and when evaluated pre-allogeneic hematopoietic cell transplantation (allo-HCT), is one of the strongest tools for predicting non-relapse mortality (NRM). In several datasets, we have found that high EASIX scores at days +30 and +100 post allo-HCT and at the onset of graft-versus-host disease (GVHD) are associated with higher NRM and poorer overall survival (OS) (data unpublished). These data demonstrate that EASIX analyzed as a categorical variable at specific landmarks is associated with outcomes after allo-HCT. However, the trend of EASIX scores has never been evaluated as a continuous variable over time. We hypothesized that defining the natural history of changes in EASIX post-HCT would help us identify an optimal time point at which EASIX has the highest discrimination for NRM. We also sought to determine whether changes in EASIX over time may be a more informative marker of NRM. Methods: We evaluated 509 adult patients who received an unmodified or ex-vivo CD34+-selected allo-HCT between April 2008 and December 2016. One hundred and forty-nine patients underwent unmodified, reduced intensity or nonmyeloablative allo-HCT with uniform GVHD prophylaxis of sirolimus/tacrolimus and low-dose methotrexate. Three hundred and sixty patients underwent myeloablative allo-HCT with ex-vivo CD34+ selection (CliniMACS® CD34 Reagent System) as GVHD prophylaxis. The EASIX score (LDH*creatinine/platelet count) was calculated at continuous timepoints from baseline [day -30 to day -10] until 1-year post-HCT. For each longitudinal evaluation, the concordance of EASIX was estimated for NRM events occurring in the subsequent 180 days. A log transformation using base 2 (log2) was applied to all EASIX variables to reduce skew. A one-unit increase in log2 EASIX is associated with a doubling (one-fold increase) of EASIX on the original scale. Disease relapse or death were considered competing risks for NRM. Results: Patient and HCT characteristics are detailed in Table 1. Median age at HCT was 56 years (range 19-78) and 59% of patients were males. The majority of unmodified allo-HCT were done for non-Hodgkin lymphoma (69%), while the majority of CD34-selected allo-HCTs were done for acute leukemia (61%). Most patients had sensitive disease at time of HCT (CR=61%; PR=13%). All patients except two received peripheral blood mobilized allografts. HCT-CI was 0 in 24% of patients, 1-2 in 32% and ≥ 3 in 44%. Sixty-eight patients experienced NRM within 1-year post-HCT. Causes of death in these patients were infection (41%), GVHD (29%), toxicity/organ failure (24%) and other (6%). Among all patients, EASIX scores rise rapidly early post-HCT and peak day +8 followed by sharp decline until day +40. Thereafter, EASIX scores tend to downtrend, but remain above baseline for the duration of the first year post-HCT (Figure 1). EASIX discrimination of 180-day NRM increases from time of allo-HCT until day +180 to +210, when concordance is highest (concordance index=0.85) (Figure 2). Overall, the ability of the EASIX score to discriminate NRM event times is similar when EASIX is analyzed as a categorical variable at landmark timepoints and as change from pre-HCT baseline EASIX score. In the first days post-HCT, EASIX values rise to a similar degree in patients regardless of whether they experience NRM or relapse in the following 180 days. Later in the post allo-HCT course, patients who do not experience NRM, including patients who relapse, have consistently lower EASIX scores compared to those who experience NRM in the following 180 days (Figure 3). Conclusions: Our data are the first to characterize the continuous trend of EASIX scores after allo-HCT, demonstrating that EASIX scores are highly dynamic and have variable concordance with NRM when analyzed longitudinally. While pre-HCT EASIX can be used to help guide allo-HCT treatment decisions prior to allo-HCT, evaluation of the dynamic changes in EASIX scores may better predict risk of NRM over time as patients acquire additional endothelial injury and toxicities after HCT. Assessment of dynamic EASIX scores may be useful in guiding novel investigative approaches to reduce the risk of toxicities and NRM along the allo-HCT journey. Disclosures Giralt: Actinium: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy; Takeda: Consultancy, Research Funding; Kite: Consultancy; Miltenyi: Research Funding. Perales:Miltenyi: Research Funding; Kyte/Gilead: Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Medigene: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; NexImmune: Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Scordo:McKinsey & Company: Consultancy; Angiocrine Bioscience, Inc.: Consultancy.
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Htut, Myo, Anita D'Souza, Benedetto Bruno, Mei-Jie Zhang, Mingwei Fei, Cristina Gasparetto, Yago Nieto, Amrita Krishnan, and Parmeswaran Hari. "Survival after Relapse Following Tandem Allogeneic Vs. Tandem Autologous Hematopoietic Cell Transplantation (HCT) for Myeloma (MM)." Blood 128, no. 22 (December 2, 2016): 833. http://dx.doi.org/10.1182/blood.v128.22.833.833.
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Abstract Background: Five large prospective trials have shown a lack of improvement in OS from an autologous-allogeneic (auto-allo) HCT approach in MM, whereas 3 trials have demonstrated benefit. In long term follow up of the randomized EBMT-NMAM2000 trial, Gahrton et al* reported that overall survival (OS) after relapse among the auto-allo cohort was superior compared to auto-auto recipients. Objective: Compare OS rates after relapse from upfront auto-allo vs. auto-auto HCT. Eligibility: Recipients (N-1679) of either an upfront tandem autologous (n=1110) or auto-allo HCT (n=569) reported to the CIBMTR. Eligibility included age ≤70, planned tandem HCT and recipients of subsequent allo HCT following relapse were excluded. HLA-matched related (96%) and unrelated grafts (4%) were included. Methods: Cox proportional hazards (PH) regression modeling was used in multivariate analysis of OS after relapse with the clock starting at relapse, and events included death from any cause. Surviving patients were censored at the time of last contact. Results/Discussion: 404 patients relapsed in the auto-auto group and 178 patients in the auto-allo group (Table 1). Median time from diagnosis to 1st HCT was 8 months for auto-allo patients and 7 months for auto-auto patient with most patients receiving 1-2 lines of chemotherapy before 1st HCT (73% in auto-allo and 90% in auto-auto groups). Among auto-allo patients, 46% of relapses occurred in < 6 months from 2nd HSCT, compared to 26% in the auto-auto group suggesting that the auto-allo pts were a higher risk group. The median follow-up after relapse for the auto-allo and auto-auto groups were 102 and 99 months respectively. In univariate survival analysis, patients in the auto-allo group had a similar probability of survival (48%) at 5 years post relapse, compared with the auto-auto arm (41%) (Table-2). 101 patients in auto-allo patients died due to MM (69%) vs. 229 (83%) deaths in auto-auto groups due to MM. In multivariate analysis, a pattern of differential time dependent risk was observed. Both cohorts had a similar risk of death in the 1st year after relapse (HR of 0.72; p=0.12). However, for time points beyond 12 months after relapse, patients in the auto-allo group had superior OS compared with auto-auto cohort (HR for death in auto-auto =1.55; p=0.0052) (Figure-1). Other significant co-variates associated with superior survival were enrollment in a clinical trial for HCT, male sex and novel agent (lenalidomide/bortezomib) use in induction prior to HCT. Conclusion: We extend the post relapse survival findings reported by Gahrton et al in allogeneic HCT with matched sibling donors in a larger real world population of related and unrelated grafts. Despite a higher risk population with increased risk of early relapse undergoing tandem auto-allo HCT, we observed a long term reduction in post relapse mortality. This likely reflects an improved response to salvage therapy due to the donor derived immunologic milieu that potentiates the immune effects of agents such as lenalidomide and pomalidomide. With the availability of other agents that modulate immune mediated disease control such a daratumumab (reduction in T and B regulatory subsets) and check point inhibitors; we anticipate that post allo transplant immune manipulation can further augment these benefits. Table 1 Patients' Baseline characteristics * Gahrton et al. EBMT-NMAM2000 study (Blood 2013; 121 (25):5055-63) Table 1. Patients' Baseline characteristics. / * Gahrton et al. EBMT-NMAM2000 study (Blood 2013; 121 (25):5055-63) Table 2 Univariate survival analysis of patients who relapsed post tandem transplant (time 0 at time of relapse) Table 2. Univariate survival analysis of patients who relapsed post tandem transplant (time 0 at time of relapse) Figure 1 Adjusted overall survival for post relapse patients Figure 1. Adjusted overall survival for post relapse patients Disclosures Krishnan: celgene: Consultancy, Speakers Bureau; takeda: Consultancy, Speakers Bureau; janssen: Consultancy, Speakers Bureau; onyx: Speakers Bureau.
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Chen, Robert, Joycelynne Palmer, Leslie Popplewell, Jessica Shen, Eileen Smith, Maria Delioukina, Neil Kogut, Joseph Rosenthal, Stephen J. Forman, and Auayporn P. Nademanee. "Allogeneic Hematopoietic Cell Transplantation (allo-HCT) Can Induce Durable Remission in Heavily Pretreated Relapsed Hodgkin Lymphoma. (HL)." Blood 114, no. 22 (November 20, 2009): 1192. http://dx.doi.org/10.1182/blood.v114.22.1192.1192.
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Abstract Abstract 1192 Poster Board I-214 Background: Even though Hodgkin lymphoma (HL) is a curable disease, about, 20-30% patients are either refractory to induction chemotherapy or relapse post treatment. High dose chemotherapy and autologous HCT has been shown to be an effective salvage therapy for patients with relapsed HL. However, relapse continues to occur after auto-HCT, especially in patients with chemoresistant or poor-risk features at relapse. The prognosis of these patients is poor with limited options of treatment. Although allo-HCT offers both cytoreduction and potential graft-versus-tumor effect, its use in relapsed HL has been limited by non-relapse mortality (NRM) and patient co-morbidities induced by numerous prior treatments. To examine the potential impact of allo-HCT on survival and disease outcomes, we performed retrospective analysis of allo-HCT in relapsed/refractory HL to determine if allo-HCT can induce long-term remission in heavily pretreated relapsed HL. Results: Between January 2003 and December 2008, 29 patients with relapsed HL underwent allo-HCT at City of Hope National Medical Center. The median age was 37 (range: 14-63). 20 (69%) patients were chemosensitive at time of allo-HCT. 17 (59%) patients had prior auto-HCT. 16 (55%) patients received matched siblings and 13 (45%) received unrelated donor cells. 20 (69%) patients had prior radiation treatments. The median number of prior regimens was 5 (range: 2-8). 23 (79%) patients underwent a non-myeloablative conditioning regimen while 6 (21%) patients had a myeloablative regimen. 14 (48%) patients received Tacrolimus/Sirolimus as graft versus host disease prophylaxis and 15 (52%) patients received a combination of Cellcept/CsA, Cellcept/CsA/MTX, Tacrolimus/MTX, or Tacrolimus/Sirolimus/MTX. With a median follow up of 31.9 months (range: 9.7-69.1) for surviving patients, the results show: Conclusion: Allogeneic hematopoietic cell transplantation in heavily pretreated relapsed Hodgkin's lymphoma is feasible, tolerable, and can induce durable clinical remissions. Disclosures: No relevant conflicts of interest to declare.
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Tamaki, Masaharu, Kazuaki Kameda, Shun-ichi Kimura, Naonori Harada, Naoyuki Uchida, Noriko Doki, Masatsugu Tanaka, et al. "Deletion of Y chromosome before allogeneic hematopoietic stem cell transplantation in male recipients with female donors." Blood Advances 6, no. 6 (March 17, 2022): 1895–903. http://dx.doi.org/10.1182/bloodadvances.2021006456.
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Abstract The graft-versus-leukemia (GVL) effect is one of the curative mechanisms of allogeneic hematopoietic stem cell transplantation (allo-HCT). H-Y antigens, which are encoded by Y chromosome, are important targets of the GVL effect. Thus, deletion of the Y chromosome (del[Y]) might cause the GVL effect to deteriorate in a transplantation involving a female donor and male recipient, although the clinical significance of the del(Y) group remains to be elucidated. In this study, we evaluated adult male patients who underwent allo-HCT between 2010 and 2019 in Japan. There were 155 cases in the del(Y) group and 4149 cases without del(Y) who underwent female-to-male allo-HCT. Del(Y) was significantly associated with inferior overall survival (hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.00-1.53; P = .049) and an increased risk of relapse (HR, 1.40; 95% CI, 1.08-1.80; P = .0098) in multivariate analyses. There was no significant difference in nonrelapse mortality between recipients with and without del(Y) (HR, 1.08; 95% CI, 0.769-1.51; P = .67). In contrast, del(Y) was not significantly associated with any clinical outcomes in the cohort of male-to-male allo-HCT. A higher incidence of relapse might have been caused by attenuation of the GVL effect resulting from a lack of H-Y antigens. Because a GVL effect resulting from sex mismatch may not be expected in men with del(Y) who undergo allo-HCT with a female donor, additional post–allo-HCT strategies might be required to prevent disease relapse.
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Chopra, Martin, Marlene Biehl, Tim Steinfatt, Andreas Brandl, Juliane Kums, Jorge Amich, Martin Vaeth, et al. "Exogenous TNFR2 activation protects from acute GvHD via host T reg cell expansion." Journal of Experimental Medicine 213, no. 9 (August 15, 2016): 1881–900. http://dx.doi.org/10.1084/jem.20151563.
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Donor CD4+Foxp3+ regulatory T cells (T reg cells) suppress graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HCT [allo-HCT]). Current clinical study protocols rely on the ex vivo expansion of donor T reg cells and their infusion in high numbers. In this study, we present a novel strategy for inhibiting GvHD that is based on the in vivo expansion of recipient T reg cells before allo-HCT, exploiting the crucial role of tumor necrosis factor receptor 2 (TNFR2) in T reg cell biology. Expanding radiation-resistant host T reg cells in recipient mice using a mouse TNFR2-selective agonist before allo-HCT significantly prolonged survival and reduced GvHD severity in a TNFR2- and T reg cell–dependent manner. The beneficial effects of transplanted T cells against leukemia cells and infectious pathogens remained unaffected. A corresponding human TNFR2-specific agonist expanded human T reg cells in vitro. These observations indicate the potential of our strategy to protect allo-HCT patients from acute GvHD by expanding T reg cells via selective TNFR2 activation in vivo.
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Bashir, Qaiser, Wei Wei, Alexandre Chiattone, Gabriela Rondon, Simrit Parmar, Nina Shah, Ernesto Harold Booc, et al. "Allogeneic Hematopoietic Cell Transplantation for Multiple Myeloma." Blood 116, no. 21 (November 19, 2010): 4569. http://dx.doi.org/10.1182/blood.v116.21.4569.4569.
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Abstract Abstract 4569 Background: Allogeneic hematopoietic cell transplantation (allo HCT) is a potentially curative therapy for multiple myeloma (MM), but has high treatment-mortality (TRM). In addition, disease relapse occurs in a significant number of patients. We sought to evaluate if the recent advances in the field of HCT and MM have impacted the results of allo HCT for MM. We present the results of allo HCT performed at a single center over last 25 years. Methods: 149 patients with MM who underwent allo HCT between 11/1985 and 6/2010 using myeloablative (MA) N= 52, or reduced intensity conditioning (RIC) N=97 at our institution were retrospectively analyzed. Results: Patient characteristics and pertinent outcomes are summarized in the Table. 62 (42%) were female. Median age was 50 (28-70) years. Median follow up is 2.4 years [11.3 years for the patients who received allo HCT prior to year 2000(<2000); 2 years for the patients who received allo HCT in the year 2000 and onwards (≥2000)]. TRM at 2 year was 37%. TRM was significantly lower for year ≥2000, recipients of RIC regimens, recipients of peripheral blood stem cells (HPC-A), and disease status at transplant PR or better. There was no difference between TRM for patients above or below age 50 years (p 0.08). Grade II-IV acute and limited or extensive chronic graft-versus host disease was seen in 31%, and 37% patients, respectively. Progression free survival (PFS) at 2 year and 5 year was 23% (95% CI: 16–30) and 15% (95% CI: 9–21), respectively. Overall survival (OS) at 2 year and 5 year was 40% (95% CI: 32–48) and 21% (95% CI: 13–29), respectively. At the time of last follow up 40 patients are still alive and 28 are in remissionn, longest for 166 months. On univariate analysis the OS was significantly better for year ≥2000 versus year <2000; recipients of HPC-A versus HPC-M; primary responsive disease versus relapse or primary refractory disease at HCT; disease status at HCT PR or better; and patients without poor risk cytogenetic features at diagnosis. OS was longer in patients who received maintenance therapy post allo HCT (N=12) versus the patients who did not, although it did not reach statistical significance (2.9 years versus 8.4 months; p 0.06). Conclusion: Allo HCT for MM can offer long term disease control in a subset of MM patients. TRM has declined and outcomes have significantly improved over the last decade. Maintenance therapy may have a role post allo HCT. Disclosures: Shah: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Research Funding. Weber:novartis-unpaid consultant: Consultancy; Merck- unpaid consultant: Consultancy; celgene- none for at least 2 years: Honoraria; millenium-none for 2 years: Honoraria; celgene, Millenium, Merck: Research Funding. Qazilbash:Celgene: Speakers Bureau.
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Bejanyan, Nelli, Claudio G. Brunstein, Qing Cao, Aleksandr Lazaryan, Xianghua Luo, Julie Curtsinger, Rohtesh S. Mehta, et al. "Delayed immune reconstitution after allogeneic transplantation increases the risks of mortality and chronic GVHD." Blood Advances 2, no. 8 (April 20, 2018): 909–22. http://dx.doi.org/10.1182/bloodadvances.2017014464.
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Key Points UCB recipients have slower T-cell reconstitution but more robust NK and B-cell recovery after allo-HCT than MSD recipients. Delayed CD4+ total and naive T-cell reconstitution after allo-HCT increases the risk of infection, mortality, and chronic GVHD.
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Nabergoj, Mitja, Junfeng Wang, Marie Robin, Nicolaus Kröger, Emanuele Angelucci, Xavier Poire, Jakob R. Passweg, et al. "Outcomes Following Second Allogenic Haematopoietic Cell Transplantation in Patients with Myelofibrosis: A Retrospective Study on Behalf of the Chronic Malignancies Working Party of EBMT." Blood 134, Supplement_1 (November 13, 2019): 698. http://dx.doi.org/10.1182/blood-2019-125802.
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Introduction: The only curative treatment for myelofibrosis (MF) remains allogenic haematopoietic cell transplantation (allo-HCT) although the risks of non-relapse mortality (NRM), relapse and graft rejection need to be taken into consideration. Therapeutic approaches following relapse after allo-HCT include symptom-directed management, chemotherapy, JAK2 inhibitors, adoptive immunotherapeutic approaches with donor lymphocyte infusion (DLI) and, in a minority, a second allo-HCT. Frequently, due to the advanced age of the recipient, early relapses, and numerous complications, 2nd allo-HCT can only be considered in a limited number of patients. Few studies evaluating the role of 2nd allo-HCT in MF following 1st relapse or primary/secondary graft rejection have been published to date. Methods and results: Patient selection was performed by identifying adult patients who underwent 2nd allo-HCT for MF between 2010-2017: 216 patients were analyzed; 64% were male, 78% had primary MF (PMF) and 22% secondary MF (sMF). Median age at the time of 2nd allo-HCT was 57 years, and median time from 1st allo-HCT was 8 months. Of this cohort, 56% of patients received a 2nd allo-HCT for relapse, 31% for graft failure and the reason was missing in 13%. A greater proportion was transplanted within 1 year from 1st allo-HCT (61 %) whilst 39% had 2nd allo-HCT > 1 year. A reduced Karnofsky performance status (KPS<90) was noted in 50% of patients. Conditioning regimens were reduced-intensity (RIC) in 72% and myeloablative (MAC) in 19% of patients, respectively. Donors were related in 38% and unrelated in 62%. T-cell depletion was reported in 46% of patients. In 31% of patients, the same donor as utilized for the first allo-HCT episode was recruited, whilst an alternative donor was utilized in 54% of cases. Sustained engraftment was achieved in 69% of the cohort, with a significant proportion of patients experiencing either primary (13%) or secondary (12%) graft failure, details were lacking for 13%. Median follow-up was 40 months and for the entire cohort the 2-year overall survival (OS) was 49%. Univariate analysis of gender, age (older or younger than 55 yrs), disease type (pMF vs sMF), donor type (same vs alternative, matched vs unrelated), conditioning intensity (MAC vs RIC) and ATG exposure did not highlight any significant effects on OS rates. Of note, patients undergoing a 2nd allo-HCT for graft failure showed significantly worse outcome compared to those transplanted for relapse with a 2-year OS of 34% and 52%, respectively (p=0.02). In addition, performance status had a significant effect on OS; those with a KPS<90 had an OS of 40% compared to those with a KPS≥90 (61%, p=0.03). Patients transplanted ≤12 months from 1st allo-HCT had significantly worse 2-year OS compared to those transplanted later (43% for ≤12 months, 57% for >12 months, p=0.02). The 2-year relapse-free-survival (RFS) for the entire cohort was 44%. Only time elapsed from the 1st allo-HCT to 2nd was significantly associated with 2-year RFS (41% for ≤12 months, 49% for >12 months, p=0.05). Of note, the 2-year OS and RFS were comparable following use of the same or a different donor. The 2-year cumulative incidence of relapse and NRM were 22 and 34%, respectively. The time interval from 1st to 2nd allo-HCT appeared to be highly significant for NRM with patients transplanted ≤12 months having a higher 2-year NRM compared to those transplanted >12 months (40 vs 24%, respectively, p=0.008). A trend for higher NRM was the reason for 2nd allo-HCT: patients transplanted for graft rejection had a 2-year NRM of 45% compared to 31% for those with relapse (p=0.06). Conclusions: This analysis supports the utilization of a 2nd allo-HCT for patients with MF who have presented with graft failure or relapse following a 1st allo-HCT. In univariate analysis, overall outcome appears worse in patients being transplanted after graft failure as well as for those transplanted within 1 year after 1st allo-HCT, due to increased NRM. Of note, the use of either the original or a different donor are associated with similar outcomes. Further work is required to elucidate other risk factors, GVHD rates and to define the optimal conditioning regimen in this setting. Table. Disclosures Robin: Novartis Neovii: Research Funding. Kröger:Sanofi-Aventis: Honoraria; Riemser: Research Funding; Novartis: Honoraria, Research Funding; Neovii: Honoraria, Research Funding; Medac: Honoraria; JAZZ: Honoraria; DKMS: Research Funding; Celgene: Honoraria, Research Funding. Angelucci:Celgene: Honoraria, Other: Participation in DMC; BlueBirdBio: Other: Local advisory board; Jazz Pharmaceuticals: Other: Local advisory board; Roche: Other: Local advisory board; Vertex Pharmaceuticals Incorp., and CRISPR Therapeutics: Other: Participation in DMC; Novatis: Honoraria, Other: Chair Steering Committee TELESTO protocol. Dreger:AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Riemser, Roche: Consultancy; AbbVie, Gilead, Novartis, Riemser, Roche: Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; Neovii, Riemser: Research Funding. Platzbecker:Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Rambaldi:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Italfarmaco: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Omeros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mayer:AOP Orphan Pharmaceuticals AG: Research Funding. Ladetto:ADC Therapeutics: Honoraria; Pfizer: Honoraria, Speakers Bureau; Celgene: Honoraria; J&J: Honoraria; Roche: Honoraria; AbbVie: Honoraria; Acerta: Honoraria, Speakers Bureau. Hernandez Boluda:Incyte: Other: Travel expenses paid. McLornan:Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Novartis: Honoraria. Chalandon:Incyte Biosciences: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria.
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Burke, Michael, Barb Trotz, Qing Cao, Brenda Weigel, Ashish Kumar, Angela Smith, and Michael Verneris. "Allogeneic Hematopoietic Cell Transplantation (Allo-HCT) for Treatment of Pediatric Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (ALL)." Blood 114, no. 22 (November 20, 2009): 3377. http://dx.doi.org/10.1182/blood.v114.22.3377.3377.
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Abstract Abstract 3377 Poster Board III-265 Introduction: Allo-HCT with best available donor for children with Philadelphia positive (Ph+) ALL has previously been considered standard practice. Since the introduction of imatinib into the treatment of this disease, the role of allo-HCT is more uncertain. Patients and Methods: We investigated the impact of remission status, graft source, and imatinib use on transplant outcomes for thirty-seven children with Ph+ ALL who received an allo-HCT at the University of Minnesota between 1990 and 2006. The median age at HCT was 7.47 (range; 1.4 -16.4) years. Thirteen patients received imatinib therapy pre and/or post-HCT (imatinib group) and 24 patients, received either no imatinib (n=23) or only after post-HCT relapse (n=1) (non-imatinib group). Results: There was no difference in disease-free survival (DFS) or relapse between the imatinib and non-imatinib groups at 3 years (62% / 15% vs. 53% / 26%; p=0.99; 0.81, respectively). There was no significant difference in transplant outcomes between matched related donor or unrelated donor (umbilical cord blood or matched unrelated marrow) recipients whereas patients receiving allo-HCT in first remission (CR1) had superior DFS and less relapse compared to patients transplanted in ≥CR2 (71% / 16% vs. 29% / 36%; p=0.01; p=0.05). Conclusions: Based on this retrospective analysis at a single institution, the use of imatinib either pre and/or post-transplant does not appear to significantly impact outcomes for children with Ph+ ALL and allo-HCT with the best available donor should be encouraged in CR1. Disclosures: No relevant conflicts of interest to declare.
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Siyahian, Aida, Heeyoung Kim, Jennifer Berano Teh, Howard Chang, Liezl Atencio, Alicia Gonzales, F. Lennie Wong, Ryotaro Nakamura, Canlan Sun, and Saro Armenian. "Incidence and Predictors of Late-Occurring Central Nervous System Complications in Allogeneic Hematopoietic Cell Transplant Survivors." Blood 128, no. 22 (December 2, 2016): 5799. http://dx.doi.org/10.1182/blood.v128.22.5799.5799.
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Abstract Introduction: Advances in treatment strategies and supportive care have resulted in a growing number of survivors of allogeneic hematopoietic cell transplantation (allo-HCT). In this population, central nervous system (CNS) complications represent a major cause of morbidity and mortality in the immediate post-HCT setting. However, there is a paucity of knowledge regarding the incidence and risk factors for CNS complications developing years after HCT. Potential mediators of late-occurring CNS toxicity could include previous exposure to radiation or drugs (e.g. fludarabine, Busulfan, and calcineurin inhibitors), infections resulting from immunodeficiency or tissue barrier breakthrough, bleeding due to thrombocytopenia, or CNS recurrence of primary malignancy. The current report addresses the existing gap in literature by comprehensively evaluating the role of demographic, HCT-related therapeutic exposures, graft versus host disease (GVHD) and its management, as well as post-HCT comorbidities in the development of late-occurring (>1 year) CNS complications after allo-HCT. Methods: A retrospective cohort study design was used to describe the cumulative incidence of CNS complications (Common Terminology of Adverse Events Grade 3-5: seizure disorder, stroke, encephalopathy), and to examine the role of demographic, disease-related and conditioning factors in 1,543 one-year survivors who underwent allo-HCT at City of Hope between 1995 and 2010. Next, a nested case-control approach (1:2 match: age at HCT, sex, length of follow-up) was used to evaluate the role of post-HCT exposures and comorbidities on long term risk. Cumulative incidence was calculated taking into consideration the competing risk of death. Multivariable regression analysis was used to calculate hazard ratios (HR) and odds ratios (OR), as well as 95% confidence intervals (CI), adjusted for relevant covariates. Results: Median follow-up for the entire cohort was 5.2 years (range: 1-18.9 years), representing 9,850 person-years of follow-up. Fifty-five survivors developed 83 CNS complications at a median of 2.5 years (range: 1-14.4 years) from allo-HCT; 53% were female; underlying diagnoses at allo-HCT: ALL (29%), AML (20%), Lymphoma (15%), CML (12%), other (24%); HCT conditioning: busulfan/cytoxan (11%), total body irradiation/etoposide (25%), fludarabine/melphalan (36%), other (29%). Ten-year cumulative incidence of CNS complications was highest (9.9%) for females who underwent allo-HCT for ALL (Figure). Diagnosis of ALL (HR: 2.3 [CI 1.1-4.7]), and conditioning with fludarabine/melphalan (HR: 5.3 [CI 1.2-23.6]) were significant predictors of CNS complications, independent of age. Post-HCT risk factors: Multivariable regression analysis adjusting for disease relapse and GVHD status revealed a significantly higher risk of CNS complications in survivors who were on mycophenolate mofetil or sirolimus (OR: 4.5 [CI 1.4-15.1]), who developed hypertension (OR: 3.5 [CI 1.3-9.3]), or thrombocytopenia (OR: 3.1 [CI 1.2-8.1]) in the years following allo-HCT. Five-year overall survival was significantly worse in patients who developed CNS complications when compared to those who did not (53.8% vs. 73.6%, p<0.001). Conclusions: Patients undergoing allo-HCT for ALL or those receiving conditioning with fludarabine/melphalan as part of reduced-intensity conditioning had a significantly higher risk of late CNS complications; females with ALL had the highest risk over time. Post-HCT hypertension, thrombocytopenia, and use of mycophenolate mofetil or sirolimus are important risk factors for late-occurring CNS toxicity. Taken together these data form the basis for identifying high-risk individuals for targeted surveillance, as well as vigilant management of post-HCT risk factors. Figure Figure. Disclosures No relevant conflicts of interest to declare.
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Lin, Jianfeng, and Scott G. Filler. "Fungal dysbiosis and survival after allo-HCT." Nature Microbiology 6, no. 12 (November 11, 2021): 1473–74. http://dx.doi.org/10.1038/s41564-021-00986-w.
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Khan, Faisal, Sarah Sy, Polly Louie, Robyn Lee, Douglas A. Stewart, James A. Russell, and Jan Storek. "Genomic Instability Is Frequent in Oral and Rare in Nasal Mucosal Cells of Allogeneic HCT Recipients." Blood 112, no. 11 (November 16, 2008): 2140. http://dx.doi.org/10.1182/blood.v112.11.2140.2140.
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Abstract Genomic Instability (GI), appraised by microsatellite length alteration, is a precancerous or cancerous condition. We hypothesized that genomic instability is frequent in oral but not nasal mucosal cells of HCT recipients as oral but not nasal carcinoma is frequent in long-term HCT survivors.We examined epithelial cells from buccal and nasal mucosa of 35 subjects for the presence of GI at 15 microsatellite loci spanning 14 human autosomes. The study population included long-term allo-HCT survivors (4–22 yrs, n=18) and short-term allo-HCT survivors (2–3 months, n=5), and long-term auto-HCT survivors (4–12 yrs, n=5). Controls also included 5 patients treated with intensive chemotherapy and 2 healthy volunteers. DNA extracted from peripheral blood leukocytes and cells of nasal and buccal mucosa was PCR amplified for a panel of 15 Short tandem repeat (STR) markers (ABI-Identifiler TM). The amplicons were subjected to capillary electrophoresis and fragment size analysis was performed to identify novel allele peaks (one that was absent in donor and recipient blood pre-transplant but present in recipient mucosa post-transplant) indicative of microsatellite instability (MSI). MSI was observed in buccal mucosal cells of 56% long-term survivors of allo-HCT; the number of STR loci showing novel allele peaks ranged from 1–6 (median=3). None of the short-term survivors of allo-HCT, long-term survivors of auto-HCT, or control individuals showed MSI in the buccal mucosal cells. Only one allogeneic HCT survivor showed MSI (at one STR locus) in nasal mucosal cells. No genomic alterations were observed in blood leukocytes of any of the above patients or controls. In conclusion, genomic instability is frequently observed in long-term allo-HCT suvivors in oral mucosal cells but rarely in nasal mucosal cells. The facts that oral but not nasal mucosa is frequently involved in chronic GVHD and that MSI was not detected in recipients of auto-HCT suggest that graft-vs-host reaction induces genomic instability.
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Shadman, Mazyar, Jordan Gauthier, Kevin A. Hay, Jenna M. Voutsinas, Filippo Milano, Ang Li, Alexandre V. Hirayama, et al. "Safety of allogeneic hematopoietic cell transplant in adults after CD19-targeted CAR T-cell therapy." Blood Advances 3, no. 20 (October 22, 2019): 3062–69. http://dx.doi.org/10.1182/bloodadvances.2019000593.
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Key Points The toxicity of allo-HCT in patients with prior CAR-T therapy was not higher than what is expected in these high-risk patients. In ALL patients, there seems to be a benefit from earlier utilization of allo-HCT after CAR-T therapy.
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Stavrik, Sonja Genadieva, and Anna Sureda. "Stem-Cell Transplantation in Adult Patients with Relapsed/Refractory Hodgkin Lymphoma." Transplantology 2, no. 4 (October 3, 2021): 396–411. http://dx.doi.org/10.3390/transplantology2040038.
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Although the majority of patients with Hodgkin lymphoma (HL) are cured with initial therapy, in 85–90% of early stage and 70–80% of advanced-stage disease cases, relapse remains a major problem. Autologous stem-cell transplantation (auto-HCT) after salvage chemotherapy is currently considered to be the standard of care for patients who relapse after first-line chemotherapy or for whom first-line treatment fails. The curative capacity of auto-HCT has been improving with the introduction of new drug-based salvage strategies and consolidation strategies after auto-HCT. Allogeneic stem-cell transplantation (allo-HCT) represents a reasonable treatment option for young patients who relapse or progress after auto-HCT and have chemosensitive disease at the time of transplantation. Allo-HCT is a valid treatment strategy for patients with relapse/refractory HL (r/r HL) because the results have improved over time, mainly with the safe combination of allo-HCT and new drugs. Bearing in mind that outcomes after haploidentical stem-cell transplantation (haplo-HCT) are comparable with those for matched sibling donors and matched unrelated donors, haplo-HCT is now the preferred alternative donor source for patients with r/r HL without a donor or when there is urgency to find a donor if a matched related donor is not present. The development of new drugs such as anti-CD 30 monoclonal antibodies and checkpoint inhibitors (CPI) for relapsed or refractory HL has demonstrated high response rates and durable remissions, and challenged the role and timing of HCT. The treatment of patients with HL who develop disease recurrence or progression after allo-HCT remains a real challenge and an unmet need.
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Kurosawa, Saiko, Kimikazu Yakushijin, Takuhiro Yamaguchi, Yoshiko Atsuta, Tokiko Nagamura-Inoue, Hideki Akiyama, Shuichi Taniguchi, et al. "Changes In Incidence and Causes of Non-Relapse Mortality (NRM) After Allogeneic Hematopoietic Cell Transplantation (allo-HCT): Are Transplants Improving?" Blood 116, no. 21 (November 19, 2010): 901. http://dx.doi.org/10.1182/blood.v116.21.901.901.
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Abstract Abstract 901 Background: Many changes have been made to reduce NRM after allo-HCT. While an improvement in NRM has been demonstrated in younger patients who are in remission, NRM has not been examined in other settings, such as in older patients or allo-HCT in non-remission. Therefore, we retrospectively assessed changes in the incidence and causes of NRM over the last 12 years in allo-HCT patients. Methods: We analyzed a nationwide registry database to estimate the incidence of NRM and overall survival (OS) in patients aged 16 years or older who had acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL) or myelodysplastic syndrome (MDS) and received the first allo-HCT from 1997 to 2008. We compared the NRM incidence after allo-HCT in three consecutive four-year periods (1997-2000, 2001–2004, and 2005–2008) for younger patients (16-49 years), and in the later two periods for older patients (≥50 years). Analyses were separately performed for standard-risk and high-risk patients. The standard-risk group included patients with acute leukemia/MDS in remission or untreated low-risk MDS (RA/RARS), and the high-risk group included those who were not in remission at allo-HCT. Subgroup analyses were performed based on patient age and donor source: HLA-matched/1-Ag mismatched related donor (related donor) versus unrelated bone marrow (BM) or cord blood (CB) donor (alternative donor). Results: A total of 10003 patients with a median age of 42 years were analyzed and the median follow-up of surviving patients was 37 months (0-154). The proportion of AML, ALL, and MDS patients was 53%, 28%, and 19%, respectively. A total of 2003, 3424, and 4576 allo-HCT were performed in 1997–2000, 2001–2004, and 2005–2008, respectively. The number and proportion of patients aged 50 years or older (n=227, 11%; n=1061, 31%; n=1907, 42%), the use of a reduced-intensity conditioning regimen (n=34, 2%; n=697, 20%; n=1244, 27%) and allo-HCT from an unrelated CB donor (n=42, 2%; n=582, 17%; n=990, 22%) increased over the three periods. An analysis of standard-risk patients (n=6280) showed that the incidence of NRM was 23% at 3 years after allo-HCT. Older patients had a significantly higher NRM than younger patients (31% vs 20%, p<0.001). The donor source significantly affected the incidence of NRM, and unrelated CB had the highest risk of NRM (related, 17%; unrelated BM, 26%; unrelated CB, 32%, p<0.001). The highest incidence of NRM was seen in 2001–2004 (25%) and the lowest incidence was seen in the most recent period, 2005–2008 (22%). A subgroup analysis of younger patients who received allo-HCT from a related donor showed that there was no significant improvement in NRM, and this was 12–15%. In younger patients who received allo-HCT from an alternative donor, the NRM incidence significantly decreased over the three periods (30%, 24%, and 22%, p<0.001) mainly due to a reduced risk of death associated with GVHD, organ failure and lung complications, and OS also significantly improved (58%, 59%, and 64%, p=0.008). In older patients who received allo-HCT from a related donor, NRM significantly improved in 2005–2008 compared to 2001–2004 (29% vs 18%, p<0.001). However, due to the increase in the incidence of relapse in 2005–2008, this decreased NRM did not lead to an improvement of OS (51% vs 55%, p=0.21). In older patients who received allo-HCT from an alternative donor, NRM and OS significantly improved in 2005–2008 compared to 2001–2004 (NRM, 43% vs 31%, p<0.001; OS, 40% vs 51%, p<0.001). The reduction in NRM was mainly due to a significant decrease in death associated with GVHD and infection. In the analysis of high-risk patients (n=3723), the incidence of NRM was generally higher than that in the standard-risk group (34% vs 23% at 3 years, p<0.001). High-risk patients who received allo-HCT from an alternative donor had a significantly lower NRM in the later periods, which led to an improvement in OS. Multivariate analysis indicated that the period of 2005–2008, younger age, and the application of a related donor were independently associated with a lower risk of NRM in both the standard- and high-risk groups. Conclusions: NRM and OS have recently improved, especially for allo-HCT from unrelated BM or CB donors. These advances were observed not only in younger patients but also in older patients. Although allo-HCT in non-remission was generally associated with a higher risk of NRM, we observed a similar trend regarding the improvement of NRM and OS. Disclosures: No relevant conflicts of interest to declare.
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Uhl, Franziska M., Sophia Chen, David O’Sullivan, Joy Edwards-Hicks, Gesa Richter, Eileen Haring, Geoffroy Andrieux, et al. "Metabolic reprogramming of donor T cells enhances graft-versus-leukemia effects in mice and humans." Science Translational Medicine 12, no. 567 (October 28, 2020): eabb8969. http://dx.doi.org/10.1126/scitranslmed.abb8969.
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Acute myeloid leukemia (AML) relapse after allogeneic hematopoietic cell transplantation (allo-HCT) has a dismal prognosis. We found that T cells of patients relapsing with AML after allo-HCT exhibited reduced glycolysis and interferon-γ production. Functional studies in multiple mouse models of leukemia showed that leukemia-derived lactic acid (LA) interfered with T cell glycolysis and proliferation. Mechanistically, LA reduced intracellular pH in T cells, led to lower transcription of glycolysis-related enzymes, and decreased activity of essential metabolic pathways. Metabolic reprogramming by sodium bicarbonate (NaBi) reversed the LA-induced low intracellular pH, restored metabolite concentrations, led to incorporation of LA into the tricarboxylic acid cycle as an additional energy source, and enhanced graft-versus-leukemia activity of murine and human T cells. NaBi treatment of post–allo-HCT patients with relapsed AML improved metabolic fitness and interferon-γ production in T cells. Overall, we show that metabolic reprogramming of donor T cells is a pharmacological strategy for patients with relapsed AML after allo-HCT.
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Docampo, Melissa D., Marina B. da Silva, Amina Lazrak, Katherine B. Nichols, Sophia R. Lieberman, Ann E. Slingerland, Gabriel K. Armijo, et al. "Alloreactive T cells deficient of the short-chain fatty acid receptor GPR109A induce less graft-versus-host disease." Blood 139, no. 15 (April 14, 2022): 2392–405. http://dx.doi.org/10.1182/blood.2021010719.
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Abstract The intestinal microbiota is essential for the fermentation of dietary fiber into short-chain fatty acids (SCFA) such as butyrate, acetate, and propionate. SCFAs can bind to the G-protein-coupled receptors GPR43 and GPR109A (HCAR2), with varying affinities to promote cellular effects in metabolism or changes in immune function. We explored the role of GPR109A as the main receptor for butyrate in mouse models of allogeneic hematopoietic cell transplantation (allo-HCT) and graft-versus-host disease (GVHD). Deletion of GPR109A in allo-HCT recipients did not affect GVHD, but transplantation of T cells from GPR109A knockout (KO) (Gpr109a−/−) mice into allo-HCT recipient mice significantly reduced GVHD morbidity and mortality compared with recipients of wild-type (WT) T cells. Recipients of Gpr109a−/− T cells exhibited less GVHD-associated target organ pathology and decreased proliferation and homing of alloreactive T cells to target tissues. Although Gpr109a−/− T cells did not exhibit immune deficits at a steady state, following allo-activation, Gpr109a−/− T cells underwent increased apoptosis and were impaired mitochondrial oxidative phosphorylation, which was reversible through antioxidant treatment with N-acetylcysteine (NAC). In conclusion, we found that GPR109A expression by allo-activated T cells is essential for metabolic homeostasis and expansion, which are necessary features to induce GVHD after allo-HCT.
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Norasetthada, L., M. B. Maris, B. M. Sandmaier, T. Gooley, S. Forman, E. Agura, R. T. Maziarz, et al. "HLA-Matched Related (MRD) or Unrelated Donor (URD) Non-Myeloablative Hematopoietic Cell Transplantation (HCT) for Patients (pts) with Refractory and Relapsed Aggressive Non Hodgkin Lymphoma (NHL)." Blood 104, no. 11 (November 16, 2004): 2307. http://dx.doi.org/10.1182/blood.v104.11.2307.2307.
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Abstract There are few treatment options for pts with relapsed aggressive T and B cell NHL after failure of auto HCT and subsequent high dose allo HCT has resulted in high rates of non-relapse mortality (NRM). We evaluated utility of allo HCT after non-myeloablative conditioning for these pts to reduce NRM risks while exploiting graft versus tumor (GVT) effects. Between 12/1999 and 2/2004, 42 pts, median age 50 (range, 17–66) years, with refractory or relapsed aggressive NHL [diffuse large B cell (DLBCL) (n=32), T-cell anaplastic large cell (ALCL) (n=4), T-cell lymphoblastic (n=3), T- cell immunoblastic (n=2) and Burkitt’s (n=1)] were studied. Median time from dx to allo HCT and number of prior regimens were 40 (range, 7–222) months and 4 (range, 1–6), respectively. Twenty-seven pts (62%) had previous auto HCT: 24 had relapsed while 3 had planned auto HCT for cytoreduction before allo HCT. Median time from auto to allo HCT was 15 (range, 2–29) months. Allo conditioning consisted of 2 Gy TBI alone (n = 3 MRD) or with added fludarabine (90 mg/m2) (n = 39; 26 MRD, 13 URD) followed by mycophenolate mofetil and cyclosporin. PBSC (n = 41) or marrow (n = 1) were infused from MRD (n = 29) or URD (n = 13). At HCT, 18 pts were in complete remission (CR) and 24 had measurable disease [10 partial remission (PR) 14 untreated relapse and refractory]. All pts engrafted (see table). The overall incidences of grades II, III and IV acute GVHD were 33%, 15% and 4%, respectively. 2-year probability of chronic GVHD was 57%. Early death from aspergillosis occurred in 2 pts. Of the 18 pts given HCT in CR, 13 (72%) remained in CR after HCT, while 64% of pts (7/11) who were in PR and 23% of pts (3/13) who had relapsed/refractory disease at HCT, achieved CR. The overall response rate was 46%. Of the 24 pts who had relapsed after auto HCT, 2 died early, 11 (46%) achieved CR and 11 progressed after allo HCT. With a median follow up of 19 (range, 6–50) months, 20 of 42 pts (48%) (12 MRD, 8 URD) were alive: 18 in CR (43%) (10 MRD, 8 URD) and 2 with progressive disease. Twenty two pts died a median of 5 (range, 3–26) months after HCT: 14 from relapse and 8 from non-relapse causes (7/8 from infections + GVHD). Day 100, and 1-year NRM* were 10% and 15%, respectively. One year overall* (OS) and progression free survivals* (PFS), and relapse rates* were 63% (MRD: 62%; URD: 85%), 49% (MRD: 45%; URD: 62%) and 36% (MRD: 34%; URD: 38%), respectively. Allo HCT after non-myeloablative conditioning offers a therapeutic option for pts with relapsed aggressive NHL including those in relapse after auto HCT, especially when the disease can be cytoreduced before HCT. All pts (n=42) MRD (n=29) URD (n=13) Rel : Relapse; Ref : Refractory;*Cumulative probability Disease status at HCT 18 CR, 10 PR, 10 Rel, 4 Ref 12 CR, 8 PR, 6 Rel, 3 Ref 6 CR, 2 PR, 4 Rel, 1 Ref Overall response rate 11/24 (46%);(10 CR, 1 PR) 8/17 (47%);(7 CR, 1 PR) 3/7 (43%); (3 CR) CR at HCT, sustained CR 13/18 (72%) 8/12 (67%) 5/6 (83%) PR at HCT, sustained CR 7/11 (64%) 5/9 (56%) 2/2 (100%) Rel or Ref at HCT, sustained CR 3/13 (23%) 2/8 (25%) 1/5 (20%) Living pts status 18 CR, 2 PD 10 CR, 2 PD 8 CR Day 100 NRM* 10% 14% 0% 1 year NRM* 15% 21% 0% 1 year OS* 63% 62% 63% 1 year PFS* 49% 45% 62% 1 year Rel rate* 36% 34% 38%
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Haverkos, Bradley M., Diana Abbott, Mehdi Hamadani, Philippe Armand, Mary E. Flowers, Reid Merryman, Manali Kamdar, et al. "PD-1 blockade for relapsed lymphoma post–allogeneic hematopoietic cell transplant: high response rate but frequent GVHD." Blood 130, no. 2 (July 13, 2017): 221–28. http://dx.doi.org/10.1182/blood-2017-01-761346.
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Key Points Checkpoint blockade via anti–PD-1 mAbs was associated with a high overall response rate in relapsed Hodgkin lymphoma allo-HCT patients. Checkpoint blockade via anti–PD-1 mAbs after allo-HCT can be complicated by rapid onset of severe and treatment-refractory GVHD.
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Wirk, Baldeep, Barry E. Storer, David G. Maloney, Ajay K. Gopal, Ryan D. Cassaday, Rachel Salit, Paul V. O'Donnell, Brenda M. Sandmaier, and Mary E. D. Flowers. "Analysis of Pre-Transplant Therapy with Brentuximab Vedotin for Relapsed/Refractory Hodgkin Lymphoma on Outcomes of Reduced Intensity Conditioned Allogeneic Hematopoietic Cell Transplantation." Blood 126, no. 23 (December 3, 2015): 4406. http://dx.doi.org/10.1182/blood.v126.23.4406.4406.
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Abstract Background: The impact of prior salvage therapy with brentuximab vedotin (BV) for relapsed/ refractory Hodgkin lymphoma (HL) on long-term outcomes after reduced intensity conditioned (RIC) allogeneic hematopoietic cell transplantation (allo-HCT) is unknown. Early studies (Chen et al Biol Blood Marrow Transplant 2014; 20: 1864-1868) suggested an improved 2-year progression free survival (PFS) with BV salvage given before allo-HCT compared to patients without prior BV treatment. In the current study, we analyzed the impact of prior therapy on the incidence of chronic graft-versus-host disease (cGVHD) and other major outcomes in patients, who received an RIC allo-HCT for relapsed HL. Methods: This is a retrospective study of relapsed/refractory HL patients who had RIC allo-HCT between 2005-2014 at the Fred Hutchison Cancer Research Center. Patients were grouped according to prior history of salvage therapy with or without BV pre allo-HCT. Baseline patient characteristics are shown in the Table. Results: Of the 62 consecutive allo-HCT recipients in this study, 25 had prior therapy with BV (BV group) and 37 received other chemotherapy alone (No BV group) for relapsed HL before allo-HCT. More patients in the BV group were in complete remission at allo-HCT (Table). The 100 day acute GVHD and 5 year cGVHD incidence for the BV vs. no BV group were 58% (95% confidence intervals [CI]: 39%-78%) vs. 65% (95% CI: 50%-80%), p=0.6 and 46% (95% CI: 26%-67%) vs. 51% (95% CI: 35%-68%), p=0.66, respectively. The 5 year non-relapse mortality and relapse/ progression for the BV vs. no BV group were 8% (95% CI: 1%-19%) vs. 25% (95% CI: 11%-38%), p=0.13 and 46% (95% CI: 24%-67%) vs. 38% (95% CI: 22%-53%), p0.98. The 5 year PFS and overall survival for BV vs. no BV group were 46% (95% CI: 25%-68%) vs. 38% (95% CI: 22%-53%), p=0.44 and 78% (95% CI: 60%-95%) vs. 56% (95% CI: 40%-72%), p=0.14. The major cause of death in both groups was relapsed HL. Conclusion: With longer follow-up, similar incidences of cGVHD, PFS and OS were observed in patients who received salvage therapy for relapsed/refractory HL prior to allo-HCT with or without BV. Any potential differences in cGVHD and other major outcomes need to be tested in a larger population. Table 1. Characteristics Prior treatment with Brentuximab vedotin Yes N=25 No N=37 Median age, years (range) 27 (14-47) 32 (17-64) Disease stage at diagnosis, n (%) I II III IV 2 (8)11 (44)7 (28)5 (20) 0 (0)15 (41)12 (32)10 (27) Prior history of local radiation pre allo-HCT 20 (80) 29 (78) No. of prior lines of therapies pre allo-HCT 4 (2 - 10) 3 (2 - 7 ) Prior autologous HCT, n (%) 0 1 2 (tandem auto) 1 (4) 21 (84) 3 (12) 0 (0) 35 (96) 2 (4) Disease status at allo-HCT, n (%) Complete remission Partial remission Progressive disease 9 (36) 13 (52) 3 (12) 7 (19)20 (54)10 (27) Median interval from diagnosis to allo-HCT, months (range) 33 (10.7-222) 30.7 (5-292) Graft type, n (%) Bone Marrow Peripheral blood stem cells 9 (36) 16 (64) 15 (41) 22 (59) Donor type, n (%) Haploidentical Matched related Matched unrelated Mismatch unrelated 16 (64) 5 (20) 4 (16) 0 (0) 17 (46) 14 (38) 5 (14) 1 (2) Conditioning for allo-HCT, n (%) FLU/CY/TBI (2 Gy) FLU/TBI (2 Gy) FLU/TBI (3 Gy) TBI (2 Gy) 16 (64) 6 (24) 1 (4) 2 (8) 17 (46) 15 (40) 0 (0) 5 (14) GVHD prophylaxis, n (%) CNI/MMF/post transplant CY CNI+MMF+/- other 16 (64) 9 (36) 17 (46)20 (54) Median follow-up, months (range) 34 (4 - 99) 84 (34 - 121) Abbrev: FLU fludarabine, CY cyclophosphamide, TBI total body irradiation,CNI calcineurin inhibitor, MMF mycophenolate mofetil Disclosures Maloney: Seattle Genetics: Honoraria; Roche/Genentech: Honoraria; Janssen Scientific Affairs: Honoraria; Juno Therapeutics: Research Funding. Gopal:Gilead, Spectrum, Pfizer, Janssen, Seattle Genetics: Consultancy; Spectrum, Pfizer, BioMarin, Cephalon/Teva, Emergent/Abbott. Gilead, Janssen., Merck, Milennium, Piramal, Seattle Genetics, Giogen Idec, BMS: Research Funding; Millennium, Seattle Genetics, Sanofi-Aventis: Honoraria. Cassaday:Seattle Genetics: Research Funding; Pfizer: Research Funding. Sandmaier:Gilliad: Honoraria; ArevaMed: Honoraria; Jazz Pharmaceutical: Honoraria; Seattle Genetics: Honoraria; Abmit: Research Funding; Bellicum: Research Funding.
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Melody, Megan Elizabeth, Chimere Bruning, Rachel Mack, Kimberley Parrott, Richard Taylor, James M. Foran, Vivek Roy, et al. "Patient perceptions of palliative care in the process of allogeneic hematopoietic cell transplantation." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e24082-e24082. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e24082.
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e24082 Background: Allogeneic hematopoietic cell transplantation (allo-HCT) is associated with significant short- and long-term sequelae that affect patients’ overall quality of life (QoL) and their physical and psychological well-being. Studies have shown improvement in patient QoL and physician satisfaction with palliative care involvement in the allo-HCT process. However, patient and physician perceptions regarding palliative care often impact timely referral. We conducted a prospective study to examine patient perceptions of palliative care both before and after palliative care consultation during evaluation for allo-HCT. Methods: This is a prospective, single-center study, of patients > 18 years of age, who were referred for a palliative care consultation as part of standard evaluation for allo-HCT. Patients were administered a pre- and post-visit internally derived questionnaire to assess their understanding and comfort level with palliative care. The primary objective of this study was to examine patient perceptions of palliative care consultation during evaluation for allo-HCT. Primary end point was the change in patient pre- and post- questionnaire responses. Secondary endpoint was the completion of advance care planning documentation pre- and post- consultation. Results: We enrolled 32 patients (male = 14) undergoing evaluation for allo-HCT with a primary diagnosis of AML (n = 8), NHL (n = 8), MDS (n = 7), ALL (n = 2), and other (n = 7). Following consultation with palliative care there was a statistically significant increase in patient understanding of the reason for the appointment, p = 0.0006. There was also a significant increase in patient’s knowledge of palliative care, with only 28% describing their knowledge as “good” or “excellent” prior to consultation and 79.3% after consultation, p < 0.0001. There was an observed positive, non-statistically significant, trend in patient comfort level with palliative medicine with only 20.7% (n = 6) describing their comfort as “high” or “very high” prior to consultation and 51.7% (n = 15) after consultation, p = 0.60. There was a higher rate of completion of advance care planning documentation following consultation with palliative medicine 56.3% vs 71.4%, p = 0.042. Conclusions: Palliative care consultation prior to allo-HCT increases a patient’s understanding of the role of palliative medicine as part of their allo-HCT and improves advance care planning. These findings need to be validated in a larger, multicenter, patient cohort.
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Chen, Feng, Depei Wu, Ran Wang, Xianghua Huang, Xiaozhong Li, and Chaoxing Huang. "Histopathology of Chronic Kidney Disease after Allogeneic Hematopoietic Cell Transplantation: A Multi-Center Observational Study of Kidney Biopsies." Blood 134, Supplement_1 (November 13, 2019): 5696. http://dx.doi.org/10.1182/blood-2019-128121.
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Background Renal dysfunction is a common complication of allogeneic hematopoietic cell transplantation (Allo-HCT) with proven negative impact on early and long-term mortality. The cumulative incidence of chronic kidney disease(CKD) after Allo- HCT varies from 13~60% in adult studies to as high as 62% in children. So far, most knowledge on chronic renal impairment in the context of Allo-HCT is based on clinical and laboratory findings. Causes of CKD are diverse, usually overlapping, and poorly understood. Kidney biopsies are performed in less than 5% patients with CKD, the pathophysiology of idiopathic CKD remains obscure. We conducted a multi-center clinicopathologic study of Allo-HCT patients with CKD to described the histopathologic spectrum of renal manifestations. Methods and Results Between 2005 and 2018, 24 recipients(17 males and 7 females) of Allo-HCT underwent kidney biopsy for either proteinuria or deterioration of kidney function at four centers. The median age was 43.8 (7.2~54.3) years, and the median time from Allo-HCT to kidney biopsy was 17.2(2.0~74.6)months. Evidence for GVHD was found in 20 (83.3%) patients. Among the 24 patients, 10 patients had a large amount of proteinuria (24-hour urine protein > 3.5 g/L), and 12 patients had elevated serum creatinine (Scr >110μmol/l). The most common pathological findings of kidney biopsy were GVHD (n=8), membranous nephropathy (MN, n=5), thrombotic microangiopathy (TMA, n=4), BK virus nephropathy (n=2), and we also found ischemic nephropathy, chronic interstitial nephritis, minimal change disease (MCD), GVHD with TMA, MN with focal segmental glomerular sclerosis (FSGS), MCD with acute tubular injury, BK virus nephropathy combined with calcineurin inhibitor nephrotoxicity in one case. The follow-up data showed 3 died of recurrent malignancy, 6 loss to follow-up , the median follow-up time was 18.3(12.3~120.2)months. Of the 18 patients, 8 (44.4%) had an estimated glomerular filtration rate (eGFR) of less than 60 ml/(min1.73m2), 5 (27.8%) still had moderate proteinuria. Conclusions A wide spectrum of renal pathologic findings can be observed in Allo-HCT patients. Either severe proteinuria or elevated serum creatinine were common presentations in this unique setting, which can be due to GVHD , MN, TMA, BK virus nephropathy , MCD, FSGS, and overlapping lesions. Kidney biopsies are necessary to establish the underlying cause of CKD in Allo-HCT patients. Disclosures No relevant conflicts of interest to declare.