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Prophylactic maintenance with venetoclax/azacitidine after reduced intensity conditioning allo-transplant for high risk MDS and AML
Garcia, J. S., Kim, H. T., Murdock, H. M., Ansuinelli, M., Brock, J., Cutler, C. S., Gooptu, M., Ho, V. T., Koreth, J., Nikiforow, S., et al
Blood advances. 2024
Abstract
We conducted a phase 1 trial assessing safety and efficacy of prophylactic maintenance therapy with venetoclax and azacitidine (Ven/Aza) in patients with high risk myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) undergoing reduced intensity allogeneic hematopoietic stem cell transplantation following venetoclax and FluBu2-conditioning (Ven/FluBu2 allo-SCT) with tacrolimus and methotrexate as graft-versus-host disease (GVHD) prophylaxis. Among 27 patients who underwent Ven/FluBu2 allo-SCT (55.6% prior venetoclax exposure and 96% molecular measurable residual disease (MRD)-positive), 22 received maintenance therapy with azacitidine 36 mg/m2 intravenously on days 1-5 and venetoclax 400 mg by mouth on days 1-14 on one of two schedules (42-day cycles x 8 or 28-day cycles x 12). During maintenance, the most common grade 3/4 adverse events were leukopenia, neutropenia and thrombocytopenia, which were transient and manageable. Infections were uncommon (n=4, all grade 1-2). The 1-year and 2-year moderate/severe chronic GVHD rates were 4% (95% CI, 0.3-18%) and 22% (95% CI, 9-40%). After a median follow-up of 25-months among survivors, median overall survival (OS) was not reached. In the 22 patients who received Ven/Aza maintenance, the 2-year OS, progression-free survival, non-relapse mortality, and cumulative incidence of relapse rates were 67% (95% CI, 43-83%), 59% (95% CI, 36-76%), 0%, and 41% (95% CI, 20-61%), respectively. Immune monitoring demonstrated no significant impact on T cell expansion, but identified reduced B cell expansion compared to controls. This study demonstrates prophylactic Ven/Aza maintenance can be safely administered in high risk MDS/AML patients, but a randomized study is required to properly assess any potential benefit. (NCT03613532).
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Safety and Efficacy of Hizentra® Following Pediatric Hematopoietic Cell Transplant for Treatment of Primary Immunodeficiencies
Patel, N. C., Torgerson, T., Thakar, M. S., Younger, M. E. M., Sriaroon, P., Pozos, T. C., Buckley, R. H., Morris, D., Vilkama, D., Heimall, J.
Journal of clinical immunology. 2023
Abstract
Primary immunodeficiency disease (PIDD) comprises a group of disorders of immune function. Some of the most severe PIDD can be treated with hematopoietic cell transplant (HCT). Hizentra® is a 20% liquid IgG product approved for subcutaneous administration in adults and children greater than 2 years of age with PIDD-associated antibody deficiency. Limited information is available on the use of Hizentra® in children following HCT for PIDD. A multicenter retrospective chart review demonstrated 37 infants and children (median age 70.1 [range 12.0 to 176.4] months) with PIDD treated by HCT who received Hizentra® infusions over a median duration of 31 (range 4-96) months post-transplant. The most common indication for HCT was IL2RG SCID (n = 16). Thirty-two patients switched from IVIG to SCIG administration, due to one or more of the following reasons: patient/caregiver (n = 17) or physician (n = 12) preference, discontinuation of central venous catheter (n = 16), desire for home infusion (n = 12), improved IgG serum levels following lower levels on IVIG (n = 10), and loss of venous access (n = 8). Serious bacterial infections occurred at a rate of 0.041 per patient-year while on therapy. Weight percentile increased by a mean of 16% during the observation period, with females demonstrating the largest gains. Mild local reactions were observed in 24%; 76% had no local reactions. One serious adverse event (death from sepsis) was reported. Hizentra® was discontinued in 15 (41%) patients, most commonly due to recovery of B cell function (n = 11). These data demonstrate that Hizentra® is a safe and effective option in children who have received HCT for PIDD.
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Allogeneic blood or marrow transplantation with haploidentical donor and post-transplantation cyclophosphamide in patients with myelofibrosis: a multicenter study
Kunte, S., Rybicki, L., Viswabandya, A., Tamari, R., Bashey, A., Keyzner, A., Iqbal, M., Grunwald, M. R., Dholaria, B., Elmariah, H., et al
Leukemia. 2022;36(3):856-864
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Abstract
We report the results from a multicenter retrospective study of 69 adult patients who underwent haploidentical blood or marrow transplantation (haplo-BMT) with post-transplantation cyclophosphamide (PTCy) for chronic phase myelofibrosis. The median age at BMT was 63 years (range, 41-74). Conditioning regimens were reduced intensity in 54% and nonmyeloablative in 39%. Peripheral blood grafts were used in 86%. The median follow-up was 23.1 months (range, 1.6-75.7). At 3 years, the overall survival, relapse-free survival (RFS), and graft-versus-host-disease (GVHD)-free-RFS were 72% (95% CI 59-81), 44% (95% CI 29-59), and 30% (95% CI 17-43). Cumulative incidences of non-relapse mortality and relapse were 23% (95% CI 14-34) and 31% (95% CI 17-47) at 3 years. Spleen size ≥22 cm or prior splenectomy (HR 6.37, 95% CI 2.02-20.1, P = 0.002), and bone marrow grafts (HR 4.92, 95% CI 1.68-14.4, P = 0.004) were associated with increased incidence of relapse. Cumulative incidence of acute GVHD grade 3-4 was 10% at 3 months and extensive chronic GVHD was 8%. Neutrophil engraftment was reported in 94% patients, at a median of 20 days (range, 14-70). In conclusion, haplo-BMT with PTCy is feasible in patients with myelofibrosis. Splenomegaly ≥22 cm and bone marrow grafts were associated with a higher incidence of relapse in this study.
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Treatment and outcomes of patients with light chain amyloidosis who received a second line of therapy post autologous stem cell transplantation
Al Saleh, A. S., Ebraheem, M. S., Sidiqi, M. H., Dispenzieri, A., Muchtar, E., Buadi, F. K., Warsame, R., Lacy, M. Q., Dingli, D., Gonsalves, W. I., et al
Blood cancer journal. 2022;12(4):59
Abstract
We retrospectively reviewed 292 patients who received a second line of therapy post ASCT for their light chain amyloidosis. Most patients (40%) were treated with an alkylator + PI ± dex or PI ± dex followed by an alkylator + 2nd-gen IMiD ± dex or 2nd-gen IMiD ± dex (26%), an alkylator ± steroid or steroid monotherapy (19%), a 2nd-gen IMiD + PI ± dex (6%), an alkylator + thalidomide ± dex (5%), or daratumumab-based therapy (4%). The rate of CR or VGPR was 70% among the daratumumab-based group, 62% in the alkylator + PI ± dex or PI ± dex group, 55% in the alkylator + 2nd-gen IMiD ± dex or 2nd-gen IMiD ± dex group, 47% in the 2nd-gen IMiD + PI ± dex group, 24% in the alkylator ± steroid or steroid monotherapy group, and 18% in the alkylator + thalidomide ± dex group. The median OS was NR for the 2nd-gen IMiD + PI ± dex group and the daratumumab group, 130.4 months in the alkylator + 2nd-gen IMiD ± dex or 2nd-gen IMiD ± dex group, 100 months for the alkylator + PI ± dex or PI ± dex group, 36 months for the alkylator ± steroid or steroid monotherapy group, and 21 months for the alkylator + thalidomide ± dex group (P < 0.0001). The median OS was 100 months in patients who received melphalan 200 mg/m(2) compared to 41 months in the 140 mg/m(2) group (P < 0.0001). In conclusion, patients receiving novel therapy post ASCT and melphalan conditioning dosing at 200 mg/m(2) at diagnosis had better outcomes.
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Eprenetapopt Plus Azacitidine After Allogeneic Hematopoietic Stem-Cell Transplantation for TP53-Mutant Acute Myeloid Leukemia and Myelodysplastic Syndromes
Mishra, A., Tamari, R., DeZern, A. E., Byrne, M. T., Gooptu, M., Chen, Y. B., Deeg, H. J., Sallman, D., Gallacher, P., Wennborg, A., et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2022;:Jco2200181
Abstract
PURPOSE Outcomes are poor in TP53-mutant (mTP53) acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), even after allogeneic hematopoietic stem-cell transplant (HCT). Eprenetapopt (APR-246) is a first-in-class, small-molecule p53 reactivator. PATIENTS AND METHODS We conducted a phase II, multicenter, open-label trial to assess efficacy and safety of eprenetapopt combined with azacitidine as maintenance therapy after HCT (ClinicalTrials.gov identifier: NCT03931291). Patients with mTP53 MDS or AML received up to 12 cycles of eprenetapopt 3.7 g once daily intravenously on days 1-4 and azacitidine 36 mg/m(2) once daily intravenously/subcutaneously on days 1-5 in 28-day cycles. The primary outcomes were relapse-free survival (RFS) and safety. RESULTS Of the 84 patients screened for eligibility before HCT, 55 received a transplant. Thirty-three patients ultimately received maintenance treatment (14 AML and 19 MDS); the median age was 65 (range 40-74) years. The median number of eprenetapopt cycles was 7 (range 1-12). With a median follow-up of 14.5 months, the median RFS was 12.5 months (95% CI, 9.6 to not estimable) and the 1-year RFS probability was 59.9% (95% CI, 41 to 74). With a median follow-up of 17.0 months, the median overall survival (OS) was 20.6 months (95% CI, 14.2 to not estimable) and the 1-year OS probability was 78.8% (95% CI, 60.6 to 89.3). Thirty-day and 60-day mortalities from the first dose were 0% and 6% (n = 2), respectively. Acute and chronic (all grade) graft-versus-host disease adverse events were reported in 12% (n = 4) and 33% (n = 11) of patients, respectively. CONCLUSION In patients with mTP53 AML and MDS, post-HCT maintenance therapy with eprenetapopt combined with azacitidine was well tolerated. RFS and OS outcomes were encouraging in this high-risk population.
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Impact of spleen size and splenectomy on outcomes of allogeneic hematopoietic cell transplantation for myelofibrosis: A retrospective analysis by the chronic malignancies working party on behalf of European Society for Blood and Marrow Transplantation (EBMT)
Polverelli, N., Mauff, K., Kröger, N., Robin, M., Beelen, D., Beauvais, D., Chevallier, P., Mohty, M., Passweg, J., Rubio, M. T., et al
American Journal of Hematology. 2021;96(1):69-79
Abstract
The role of spleen size and splenectomy for the prediction of post-allogeneic hematopoietic stem cell transplant (allo-HCT) outcome in myelofibrosis remains under debate. In EBMT registry, we identified a cohort of 1195 myelofibrosis patients transplanted between 2000-2017 after either fludarabine-busulfan or fludarabine-melphalan regimens. Overall, splenectomy was performed in 202 (16.9%) patients and its use decreased over time (28.3% in 2000-2009 vs 14.1% in 2010-2017 period). By multivariate analysis, splenectomy was associated with less NRM (HR 0.64, 95% CI 0.44-0.93, P = .018) but increased risk of relapse (HR 1.43, 95% CI 1.01-2.02, P = .042), with no significant impact on OS (HR 0.86, 95% CI 0.67-1.12, P = .274). However, in subset analysis comparing the impact of splenectomy vs specific spleen sizes, for patients with progressive disease, an improved survival was seen in splenectomised subjects compared to those patients with a palpable spleen length ≥ 15 cm (HR 0.44, 95% CI 0.28-0.69, P < .001), caused by a significant reduction in NRM (HR 0.26, 95% CI 0.14-0.49, P < .001), without significantly increased relapse risk (HR 1.47, 95% CI 0.87-2.49, P = .147). Overall, despite the possible biases typical of retrospective cohorts, this study highlights the potential detrimental effect of massive splenomegaly in transplant outcome and supports the role of splenectomy for myelofibrosis patients with progressive disease and large splenomegaly.
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Inefficacy of Immunosuppressive Therapy for Severe Aplastic Anemia Progressing From Non-SAA: Improved Outcome After Allogeneic Hematopoietic Stem Cell Transplantation
Liu, L., Zhao, X., Miao, M., Zhang, Y., Jiao, W., Lei, M., Zhou, H., Wang, Q., Cai, Y., Zhao, L., et al
Frontiers in oncology. 2021;11:739561
Abstract
BACKGROUND AND AIMS This study aimed at comparing the efficacy and safety of severe aplastic anemia (SAA) cases that had met the criteria for SAA at the time of diagnosis (group A) with SAA that had progressed from non-SAA (NSAA) (group B), both undergoing first-line immunosuppressive therapy (IST). Additionally, group B was compared with SAA that had progressed from NSAA and who had been treated by allogeneic hematopoietic stem cell transplantation (allo-HSCT) (group C). METHODS We retrospectively compared 608 consecutive patients in group A (n = 232), group B (n = 229) and group C (n = 147) between June 2002 and December 2019. Six months after treatment, the rate of overall response and the fraction of patients who had achieved normal blood values, treatment-related mortality (TRM), secondary clonal disease, 5-year overall survival (OS) and failure-free survival (FFS) were indirectly compared between group A and group B, group B and group C. RESULTS Six months after treatment, the rate of overall response and the fraction of patients who had achieved normal blood values in group A was higher than in group B (65.24% vs. 40.54%, P < 0.0001; 23.33% vs. 2.25%, P < 0.0001); the same was true for group C (92.50% vs. 2.25%, P < 0.0001). The rate of relapse in group B was higher than in group C (P < 0.0001), but there were no differences in TRM and secondary clonal disease (P > 0.05). There were no differences in estimated 5-year OS between groups A and B (83.8% ± 2.6% vs. 85.8% ± 2.6%, P = 0.837), or between B and C (85.8% ± 2.6% vs. 77.9% ± 3.4%, P = 0.051). The estimated 5-year FFS in groups A and C was higher than for group B (57.1% ± 3.3% vs. 39.7% ± 3.4%, P < 0.001; 76.7% ± 3.5% vs. 39.7% ± 3.4%, P < 0.0001). CONCLUSION These results indicate that IST is less effective in SAA progressing from non-SAA but allo-HSCT can improve outcomes.
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Impact of consolidation therapy post autologous stem cell transplant in patients with light chain amyloidosis
Al Saleh, A. S., Sidiqi, M. H., Sidana, S., Muchtar, E., Dispenzieri, A., Dingli, D., Lacy, M. Q., Warsame, R. M., Gonsalves, W. I., Kourelis, T. V., et al
American journal of hematology. 2019
Abstract
The role of consolidation post autologous stem cell transplant in light chain amyloidosis is not well defined. We retrospectively identified patients who had light chain amyloidosis and underwent autologous stem cell transplant at the Mayo Clinic. Consolidation was defined as any treatment given after the day 100 evaluation post transplant to maintain or deepen the response. We identified 471 patients, of whom 72 (15%) received consolidation. Patient receiving consolidation had more advanced disease (Mayo 2012 stage ≥II in 67% vs. 52%, P=0.02) and had lower day 100 response rates (very good partial response or better: 35% vs.84%, P<0.0001). After consolidation, rates of very good partial response improved from 24% to 28% and rates of complete response improved from 11% to 40%. Patients with less than very good partial response who received consolidation had better progression free survival (median of 22.4 vs. 8.8 months, P <0.0001) and the benefit was greater in those who deepened their response (median of 41 vs.8.8 months, P<0.0001). In patients with less than very good partial response, there was a trend for better overall survival in patients with less than very good partial response who responded to consolidation (median of 125.8 vs. 74.4 months, P=0.07). In patients who achieved very good partial response or better at day 100 post autologous stem cell transplant, consolidation did not improve progression free or overall survival. Consolidation after autologous stem cell transplant for light chain amyloidosis improves progression fee survival for patients who achieve less than very good partial response. This article is protected by copyright. All rights reserved.
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Long-term event-free and overall survival after risk-adapted melphalan and SCT for systemic light chain amyloidosis
Landau, H., Smith, M., Landry, C., Chou, J. F., Devlin, S. M., Hassoun, H., Bello, C., Giralt, S., Comenzo, R. L.
Leukemia. 2017;31(1):136-142
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Abstract
Stem cell transplantation (SCT), an effective therapy for amyloid light chain (AL) amyloidosis patients, is associated with low treatment-related mortality (TRM) with appropriate patient selection and risk-adapted dosing of melphalan (RA-SCT). Consolidation after SCT increases hematologic complete response (CR) rates and may improve overall survival (OS) for patients with