Allogeneic transplantation for Ph+ acute lymphoblastic leukemia with posttransplantation cyclophosphamide
Blood advances. 2020;4(20):5078-5088
Allogeneic blood or marrow transplantation (alloBMT) is standard of care for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in first complete remission (CR1). The routine pretransplant and posttransplant use of tyrosine kinase inhibitors (TKIs) has dramatically improved outcomes, but the optimal conditioning regimen, donor type, and TKI remain undefined. The bone marrow transplant database at Johns Hopkins was queried for adult patients with de novo Ph+ ALL who received alloBMT using posttransplantation cyclophosphamide (PTCy) as a component of graft-versus-host disease (GVHD) prophylaxis from 2008 to 2018. Among transplants for Ph+ ALL, 69 (85%) were performed in CR1, and 12 (15%) were performed in second or greater remission (CR2+). The majority of transplants (58%) were HLA haploidentical. Nearly all patients (91.4%) initiated TKI posttransplant. For patients in CR1, the 5-year relapse-free survival (RFS) was 66%. The use of nonmyeloablative conditioning, absence of measurable residual disease (MRD) according to flow cytometry at transplant, and the use of dasatinib vs imatinib at diagnosis were associated with improved overall survival (OS) and RFS. Neither donor type nor recipient age ≥60 years affected RFS. When analyzing all transplants, alloBMT in CR1 (vs CR2+) and the absence of pretransplant MRD were associated with improved RFS. Most relapses were associated with the emergence of kinase domain mutations. The cumulative incidence of grade 3 to 4 acute GVHD at 1 year was 9%, and moderate to severe chronic GVHD at 2 years was 8%. Nonmyeloablative alloBMT with PTCy for Ph+ ALL in an MRD-negative CR1 after initial treatment with dasatinib yields favorable outcomes.
Adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) undergoing allogeneic transplantation (n=76)
Myeloablative conditioning in first complete remission (CR1 MAC, n=26); Non-myeloablative conditioning in first complete remission (CR1 NMAC, n=43)
Patients in second or subsequent remission (CR2+, n=12)
For patients in CR1, the 5-year relapse-free survival (RFS) was 66%. The use of nonmyeloablative conditioning, absence of measurable residual disease (MRD) according to flow cytometry at transplant, and the use of dasatinib vs imatinib at diagnosis were associated with improved overall survival (OS) and RFS. Neither donor type nor recipient age ≥60 years affected RFS. When analyzing all transplants, alloBMT in CR1 (vs CR2+) and the absence of pretransplant MRD were associated with improved RFS. Most relapses were associated with the emergence of kinase domain mutations. The cumulative incidence of grade 3 to 4 acute GVHD at 1 year was 9%, and moderate to severe chronic GVHD at 2 years was 8%.
Does early chimerism testing predict outcomes after allogeneic hematopoietic stem cell transplantation?
Leukemia & lymphoma. 2020;:1-3
Reduced intensity conditioning for acute myeloid leukemia using melphalan- vs busulfan-based regimens: a CIBMTR report
Blood advances. 2020;4(13):3180-3190
There is a lack of large comparative study on the outcomes of reduced intensity conditioning (RIC) in acute myeloid leukemia (AML) transplantation using fludarabine/busulfan (FB) and fludarabine/melphalan (FM) regimens. Adult AML patients from Center for International Blood and Marrow Transplant Research who received first RIC allo-transplant between 2001 and 2015 were studied. Patients were excluded if they received cord blood or identical twin transplant, total body irradiation in conditioning, or graft-versus-host disease (GVHD) prophylaxis with in vitro T-cell depletion. Primary outcome was overall survival (OS), secondary end points were leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and GVHD. Multivariate survival model was used with adjustment for patient, leukemia, and transplant-related factors. A total of 622 patients received FM and 791 received FB RIC. Compared with FB, the FM group had fewer transplant in complete remission (CR), fewer matched sibling donors, and less usage of anti-thymocyte globulin or alemtuzumab. More patients in the FM group received marrow grafts and had transplantation before 2005. OS was significantly lower within the first 3 months posttransplant in the FM group (hazard ratio [HR] = 1.82, P < .001), but was marginally superior beyond 3 months (HR = 0.87, P = .05). LFS was better with FM compared with FB (HR = 0.89, P = .05). NRM was significantly increased in the FM group during the first 3 months of posttransplant (HR = 3.85, P < .001). Long-term relapse was lower with FM (HR = 0.65, P < .001). Analysis restricted to patients with CR showed comparable results. In conclusion, compared with FB, the FM RIC showed a marginally superior long-term OS and LFS and a lower relapse rate. A lower OS early posttransplant within 3 months was largely the result of a higher early NRM.
Adult AML patients from Center for International Blood and Marrow Transplant Research who received first RIC allo-transplant between 2001 and 2015 (n=1413)
Fludarabine/busulfan reduced intensity conditioning regimen (FB, n=791)
Fludarabine/melphalan reduced intensity conditioning regimen (FM, n=622)
Compared with FB, the FM group had fewer transplant in complete remission (CR), fewer matched sibling donors, and less usage of anti-thymocyte globulin or alemtuzumab. More patients in the FM group received marrow grafts and had transplantation before 2005. OS was significantly lower within the first 3 months posttransplant in the FM group (hazard ratio [HR] = 1.82), but was marginally superior beyond 3 months (HR = 0.87). LFS was better with FM compared with FB (HR = 0.89). NRM was significantly increased in the FM group during the first 3 months of posttransplant (HR = 3.85). Long-term relapse was lower with FM (HR = 0.65). Analysis restricted to patients with CR showed comparable results.
Favorable outcomes of COVID-19 in recipients of hematopoietic cell transplantation
The Journal of clinical investigation. 2020
BACKGROUND Understanding outcomes and immunologic characteristics of cellular therapy recipients with SARS-CoV-2 is critical to performing these potentially life-saving therapies in the COVID-19 era. In this study of recipients of allogeneic (Allo) and autologous (Auto) hematopoietic cell transplant and CD19-directed chimeric antigen receptor T cell therapy (CAR-T) at Memorial Sloan Kettering Cancer Center, we aimed to identify clinical variables associated with COVID-19 severity and assess lymphocyte populations. METHODS We retrospectively investigated patients diagnosed between March 15th and May 7th, 2020. In a subset of patients, lymphocyte immunophenotyping, quantitative real-time PCR from nasopharyngeal swabs, and SARS-CoV-2 antibody status were available. RESULTS We identified 77 SARS-CoV-2 + cellular therapy recipients (Allo = 35, Auto = 37, CAR-T = 5; median time from cellular therapy 782 days (IQR 354,1611). Overall survival at 30 days was 78%. Clinical variables significantly associated with the composite endpoint of non-rebreather or higher oxygen requirement and death (n events = 25/77) included number of co-morbidities (HR 5.41, P = 0.004), infiltrates (HR 3.08, P = 0.032), and neutropenia (HR 1.15, P = 0.04). Worsening graft-versus-host-disease was not identified among Allo subjects. Immune profiling revealed reductions and rapid recovery in lymphocyte populations across lymphocyte subsets. Antibody responses were seen in a subset of patients. CONCLUSION In this series of Allo, Auto, and CAR-T recipients, we report overall favorable clinical outcomes for COVID-19 patients without active malignancy and provide preliminary insights into the lymphocyte populations that are key for the anti-viral response and immune reconstitution. FUNDING NIH P01 CA23766, NIH/NCI P30 CA008748.
Hematopoietic Cell Transplantation in the Treatment of Newly Diagnosed Adult Acute Myeloid Leukemia: An Evidence-Based Review from the American Society of Transplantation and Cellular Therapy
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
The role of hematopoietic cell transplantation (HCT) in the management of newly diagnosed adult acute myeloid leukemia (AML) is reviewed and critically evaluated in this evidence-based review. An AML expert panel, consistent of both transplant and non-transplant experts was invited to develop clinically relevant frequently asked questions covering disease- and HCT-related topics. A systematic literature review was conducted to generate core recommendations that were graded based on the quality and strength of underlying evidence based on the standardized criteria established by American Society of Transplantation and Cellular Therapy Steering Committee for evidence-based reviews. Allogeneic HCT offers a survival benefit in patients with intermediate and high-risk AML and is currently a part of standard clinical care. We recommend the preferential use of myeloablative conditioning in eligible patients. A haploidentical related donor marrow graft is preferred over a cord blood unit in the absence of a fully HLA-matched donor. The evolving role of allogeneic HCT in the context of measurable residual disease monitoring and recent therapeutic advances in AML with regards to maintenance therapy after HCT are also discussed.
Survival following allogeneic transplant in patients with myelofibrosis
Blood advances. 2020;4(9):1965-1973
Allogeneic hematopoietic cell transplantation (HCT) is the only curative therapy for myelofibrosis (MF). In this large multicenter retrospective study, overall survival (OS) in MF patients treated with allogeneic HCT (551 patients) and without HCT (non-HCT) (1377 patients) was analyzed with Cox proportional hazards model. Survival analysis stratified by the Dynamic International Prognostic Scoring System (DIPSS) revealed that the first year of treatment arm assignment, due to upfront risk of transplant-related mortality (TRM), HCT was associated with inferior OS compared with non-HCT (non-HCT vs HCT: DIPSS intermediate 1 [Int-1]: hazard ratio [HR] = 0.26, P < .0001; DIPSS-Int-2 and higher: HR, 0.39, P < .0001). Similarly, in the DIPSS low-risk MF group, due to upfront TRM risk, OS was superior with non-HCT therapies compared with HCT in the first-year post treatment arm assignment (HR, 0.16, P = .006). However, after 1 year, OS was not significantly different (HR, 1.38, P = .451). Beyond 1 year of treatment arm assignment, an OS advantage with HCT therapy in Int-1 and higher DIPSS score patients was observed (non-HCT vs HCT: DIPSS-Int-1: HR, 2.64, P < .0001; DIPSS-Int-2 and higher: HR, 2.55, P < .0001). In conclusion, long-term OS advantage with HCT was observed for patients with Int-1 or higher risk MF, but at the cost of early TRM. The magnitude of OS benefit with HCT increased as DIPSS risk score increased and became apparent with longer follow-up.
Clinical outcomes with low dose anti-thymocyte globulin in patients undergoing matched unrelated donor allogeneic hematopoietic cell transplantation
Leukemia & lymphoma. 2020;:1-7
Anti-thymocyte globulin (ATG) has been associated with decreased rates graft versus host disease (GVHD) but with a potential risk of increasing risk of infection and relapse. We retrospectively studied the impact of single dose low dose (2.5 mg/kg) ATG in patients undergoing allogenic hematopoietic cell transplantation (HCT) from 8/8 matched unrelated donors (MUD). Of the total 209 patients identified, 129 received ATG. At baseline, the ATG group had more intermediate and high disease risk index (DRI) (64.6% vs. 54.3%) (28.3% vs. 23.7%) p < .001, respectively, and who received reduced intensity or non-myeloablative conditioning (RIC) (69.0% vs. 47.5%, p .003). There was no significant difference in the overall survival (OS) HR = 1.3, 95% CI [0.99, 1.0], p = .350 or relapse-free survival (RFS) HR = 1.2, 95% CI [0.74, 1.8], p = .526 between the two groups. Patients receiving ATG had a lower incidence of chronic GVHD (cGVHD) (10.1% vs. 25%, p = .007) and less moderate to severe cGVHD (8.5% vs. 25%, p = .002). ATG was associated with a reduced incidence of moderate to severe cGVHD OR = 0.28, 95% CI [0.12, 0.61], p < .01. There was no difference in the incidence of Epstein-Barr Virus (EBV) or cytomegalovirus (CMV) reactivation, CMV disease, invasive fungal infection, or grade III-IV acute GVHD (aGVHD). Our study shows that low dose ATG results in similar OS and RFS with lower rates of cGVHD. Additional prospective studies are needed to confirm these findings.
Early post-transplantation factors predict survival outcomes in patients undergoing allogeneic hematopoietic cell transplantation for myelofibrosis
Blood cancer journal. 2020;10(3):36
Factors predicting allogeneic hematopoietic cell transplantation (HCT) outcomes in myelofibrosis in the early post-HCT period have not been defined thus far. We attempt to study such factors that can help identify patients at a higher risk of relapse or death. This retrospective study included 79 patients who underwent first HCT for myelofibrosis at three centers between 2005 and 2016. Univariate analysis showed that red blood cell (RBC) transfusion dependence (HR 9.02, 95% CI 4.0-20.35), platelet transfusion dependence (HR 8.17, 95%CI 3.83-17.37), 100% donor chimerism in CD33 + cells (HR 0.21, 95%CI 0.07-0.62), unfavorable molecular status (HR 4.41, 95%CI 1.87-10.39), normal spleen size (HR 0.42, 95%CI 0.19-0.94), grade ≥ 2 bone marrow fibrosis (vs. grade ≤ 1; HR 2.7, 95%CI 1.1-6.93) and poor graft function (HR 2.6, 95%CI 1.22-5.53) at day +100 were statistically significantly associated with relapse-free survival (RFS). RBC transfusion dependence and unfavorable molecular status were also statistically significant in the multivariate analysis. Patients in whom both of these factors were present had a significantly worse RFS when compared to those with one or none. While limited by a small sample size, we demonstrate the significance of transfusion dependence and molecular status at day +100 in predicting outcomes.
Utilization of Chimeric Antigen Receptor (CAR) T Cell Therapy in Clinical Practice for Relapsed/Refractory Aggressive B cell non-Hodgkin Lymphoma: An Expert Panel Opinion from the American Society for Transplantation and Cellular Therapy
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Axicabtagene ciloleucel (YESCARTA(R), Kite Pharma, a Gilead Company) and tisagenlecleucel (KYMRIAH(R), Novartis Pharmaceuticals Corp.) are two CD19-directed chimeric antigen receptor T cell (CD19 CAR T) products that are currently approved by the U.S. Food and Drug Administration, the European Medicines Agency, Health Canada, Ministry of Health, Labor and Welfare (Japan) and Therapeutic Goods Administration (Australia) for treatment of specific subtypes of relapsed/ refractory aggressive B cell non-Hodgkin lymphoma (NHL). While this approval has been transformative in the use of cellular immunotherapy in lymphoma, there are concerns regarding appropriate utilization of this novel therapy, as well as short- and long-term toxicities. To address these issues, representatives of American Society of Transplantation and Cellular Therapy (ASTCT) convened to recognize and address key issues surrounding the clinical application of CD19 CAR T cell therapy in B cell lymphomas, in collaboration with worldwide experts and members of International Society of Cell and Gene Therapy (ISCT), American Society of Hematology (ASH), Foundation for the Accreditation of Cellular Therapy (FACT) and European Society for Blood and Marrow Transplantation (EBMT). The aim of this article is to provide consensus opinion from experts in the fields of hematopoietic cell transplantation, cellular immunotherapy, and lymphoma regarding key clinical questions pertinent to the utilization of CD19 CAR T for the treatment of NHL. As the clinical practice using CAR T cells grows worldwide, we anticipate that this guidance will be relevant for hematology/oncology physicians who care for patients with lymphomas.
Early fluctuations in busulfan levels with therapeutic dose monitoring during allogeneic stem cell transplantation: do they matter?
Leukemia & lymphoma. 2019;:1-8
Therapeutic dose monitoring is widely adopted for determination of busulfan (Bu) dose for use as a conditioning regimen. However, while dose adjustments are being incorporated, transient fluctuations of Bu levels may occur. We aim to understand if these fluctuations affect clinical outcomes of these patients. We compared outcomes in patients in whom the absolute dose changes and fluctuation of AUC were ≥ median% versus < median%. Rates of sinusoidal obstructive syndrome, grades 2-4/grades 3-4 acute and chronic graft versus host disease were not different between the two cohorts. The Kaplan-Meier curves for overall survival showed no significant differences. Six patients required >50% dose adjustment and four had a fluctuation in AUC of >50%. One of these patients died of sinusoidal obstruction syndrome and two died of infections. In our study, the transient fluctuations in Bu levels did not affect clinical outcomes; hence obviating the need for test dose strategy.