-
1.
Total Marrow and Lymphoid Irradiation with Post-Transplant Cyclophosphamide for Patients with AML in Remission
Stein, A. S., Malki, M. M. A., Yang, D., Palmer, J. M., Tsai, N. C., Aldoss, I., Ali, H., Aribi, A., Artz, A., Dandapani, S., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Graft versus host disease (GVHD) has remained the main cause of post-transplantation mortality and morbidity after allogeneic hematopoietic cell transplantation (alloHCT), adding significant economic burden and affecting quality of life. It would be desirable to reduce the rate of GVHD among patients in complete remission (CR) without increasing the risk of relapse. OBJECTIVE In this study, we have tested a novel conditioning regimen of total marrow and lymphoid irradiation (TMLI) at 2000 cGy, together with post-transplant cyclophosphamide (PTCy) for patients with acute myeloid leukemia in first or second CR, to attenuate the risk of chronic GVHD by using PTCy, while using escalated targeted radiation conditioning before allografting to offset the possible increased risk of relapse. The primary objective was to evaluate the safety/feasibility of combining a TMLI transplant conditioning regimen with a post-transplant high dose cyclophosphamide (PTCy)-based GVHD prophylaxis strategy, through the assessment of adverse events in terms of type, frequency, severity, attribution, time course, duration, and complications, including acute GVHD, infection, and delayed neutrophil/platelet engraftment. Secondary objectives included estimation of non-relapse mortality (NRM), OS, relapse-free survival, acute and chronic GVHD, and GVHD-relapse-free survival (GRFS). STUDY DESIGN A patient safety lead-in was first conducted to ensure there were no unexpected toxicities and was expanded on the basis of lack of dose limiting toxicities (DLTs). The patient safety lead-in segment followed 3+3 dose expansion/(de-)escalation rules based on observed toxicity through day +30; the starting dose of TMLI was 2000 cGy, and a de-escalation to 1800 cGy was considered. After the safety lead-in segment, an expansion cohort of up to 12 additional patients was to be studied. TMLI was administered on days -4 to 0, delivered in 200 cGy fractions twice daily. The radiation dose delivered to the liver and brain was kept at 1200 cGy. Cyclophosphamide was given on days +3 and +4 after alloHCT, 50 mg/kg each day for GVHD prevention; tacrolimus was given until day +90 and then tapered. RESULTS Among 18 patients with a median age of 40 years (range 19-56), the highest grade toxicities were grade 2 Bearman bladder toxicity and stomatitis. No grade 3-4 Bearman toxicities or toxicity-related deaths were observed. The cumulative incidence of acute GVHD (aGVHD) grade 2-4 and moderate-to-severe chronic GVHD were 11•1% and 11•9%, respectively. At a median follow up of 24•5 months, two-year estimates of OS and relapse-free survival were 86•7% and 83•3%, respectively. Disease relapse at 2 years was 16•7%. The estimates of NRM at 2 years was 0%. The GVHD-/relapse-free survival (GRFS) rate at 2 years was 59•3% (95%CI: 28•8-80•3). CONCLUSION This chemotherapy-free conditioning regimen, together with PTCy and tacrolimus, is safe, with no NRM. Preliminary results suggest an improved GRFS rate.
-
2.
Burden of Long-Term Morbidity Borne by Survivors of Acute Myeloid Leukemia Treated With Blood or Marrow Transplantation: The Results of the BMT Survivor Study
Armenian, S. H., Chen, Y., Hageman, L., Wu, J., Landier, W., Bosworth, A., Francisco, L., Schlichting, E., Bhatia, R., Salzman, D., et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2022;:Jco2102829
-
-
-
Free full text
-
-
Editor's Choice
Abstract
PURPOSE Blood or marrow transplantation (BMT) is an integral part of consolidation and/or salvage therapy for patients with acute myeloid leukemia (AML). With the growing population of AML survivors, there is a need to understand the quality of their survival. MATERIALS AND METHODS This multisite study included 1,369 2-year survivors who underwent BMT for AML between 1974 and 2014 at age ≥ 21 years and 1,310 siblings. Using Common Terminology Criteria for Adverse Events, severe/life-threatening and fatal chronic health conditions were identified. Multivariable regression analysis was used to compare the risk of severe/life-threatening conditions and health status between survivors and siblings, and to identify risk factors for health conditions among BMT survivors. RESULTS The prevalence of severe/life-threatening conditions was 54.9% in BMT survivors compared with 28.5% in siblings (P < .001), yielding 3.8-fold higher odds of severe/life-threatening conditions (95% CI, 3.1 to 4.7) among the BMT survivors. The most prevalent conditions included subsequent neoplasms, diabetes, cataracts, venous thromboembolism, and joint replacement. Survivors were more likely to report poor general health (odds ratio [OR], 3.8; 95% CI, 2.8 to 5.1), activity limitation (OR, 3.7; 95% CI, 3.0 to 4.5), and functional impairment (OR, 2.9; 95% CI, 2.3 to 3.6). Among BMT recipients, the 20-year cumulative incidence of severe/life-threatening/fatal conditions was 68%. History of chronic graft-versus-host disease was associated with a higher risk of pulmonary disease (hazard ratio [HR], 3.1; 95% CI, 1.0 to 9.3), cataract (HR, 2.6; 95% CI, 1.4 to 3.8), and venous thromboembolism (HR, 2.3; 95% CI, 1.3 to 4.7). Relapse-related mortality (RRM) plateaued at 30%, whereas non-RRM increased to 50% at 30 years. CONCLUSION The burden of severe/life-threatening conditions is substantially higher in BMT recipients when compared with an unaffected comparison group, contributing to an increasing incidence of non-RRM over time. Chronic graft-versus-host disease was an important risk factor for severe/life-threatening/fatal conditions among BMT recipients, informing the need for close monitoring to anticipate and manage morbidity.
PICO Summary
Population
People who were treated for acute myeloid leukaemia (AML) between 1974 and 2014 and their siblings (n=2679)
Intervention
Single bone marrow transplant at 21 years or younger and surviving at least 2 years (BMT surviviors, n=1369)
Comparison
Nearest age siblings of the cohort of transplant survivors (siblings, n=1310)
Outcome
The prevalence of severe/life-threatening conditions was 54.9% in BMT survivors compared with 28.5% in siblings, yielding 3.8-fold higher odds of severe/life-threatening conditions (95% CI, 3.1 to 4.7) among the BMT survivors. The most prevalent conditions included subsequent neoplasms, diabetes, cataracts, venous thromboembolism, and joint replacement. Survivors were more likely to report poor general health (odds ratio [OR], 3.8; 95% CI, 2.8 to 5.1), activity limitation (OR, 3.7; 95% CI, 3.0 to 4.5), and functional impairment (OR, 2.9; 95% CI, 2.3 to 3.6). Among BMT recipients, the 20-year cumulative incidence of severe/life-threatening/fatal conditions was 68%. History of chronic graft-versus-host disease was associated with a higher risk of pulmonary disease (hazard ratio [HR], 3.1; 95% CI, 1.0 to 9.3), cataract (HR, 2.6; 95% CI, 1.4 to 3.8), and venous thromboembolism (HR, 2.3; 95% CI, 1.3 to 4.7). Relapse-related mortality (RRM) plateaued at 30%, whereas non-RRM increased to 50% at 30 years.
-
3.
Outcome of allogeneic hematopoietic cell transplantation after venetoclax and hypomethylating agent therapy for acute myeloid leukemia
Sandhu, K. S., Dadwal, S., Yang, D., Mei, M., Palmer, J., Salhotra, A., Al Malki, M., Aribi, A., Ali, H., Khaled, S., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
The combination of hypomethylating agents with the selective Bcl-2 inhibitor venetoclax (HMA-VEN) has emerged as a highly active regimen in acute myeloid leukemia (AML) both in the upfront as well as relapsed/refractory (r/r) setting. We report our early experience with a cohort of patients who were able to proceed to allogeneic hematopoietic cell transplantation (alloHCT) after HMA-VEN therapy. Thirty two AML patients (19 r/r and 13 de novo) with a median age of 62 years underwent alloHCT after HMA-VEN therapy. Twenty two (68.8%) were in CR/CRi at time of HCT. With a median follow up of 14.4 months, the 1-year overall survival was 62.5% and disease-free survival was 43.8%. The 1-year non relapse mortality rate was 18.8 % and cumulative incidence of relapse was 37.5 %. Among patients who underwent alloHCT in CR, the 1-year OS was 77.3% and cumulative incidence of NRM was 9.1%. Cumulative incidence of Grade II-IV acute GVHD was 43.8%. We conclude that HCT post HMA-VEN is associated with favorable allogeneic HCT outcomes in newly diagnosed older AML patients as well as those with r/r AML.
-
4.
Long term outcomes of patients with Acute Myeloid Leukemia treated with myeloablative FTBI based conditioning with Tacrolimus and sirolimus based GVHD prophylaxis regimen: 6 year follow up from Single Center
Salhotra, A., Hui, S., Yang, D., Mokhtari, S., Mei, M., Al Malki, M. M., Aldoss, I., Ali, H., Sandhu, K. S., Aribi, A., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
Cyclophosphamide/etoposide combined with fractionated total body irradiation (FTBI) or intravenous busulfan, has been the main conditioning regimens for allogeneic hematopoietic cell transplantation (alloHCT) for young patients with acute myeloid leukemia (AML) eligible for myeloablative conditioning regimens (MAC). Recent data has suggested that intravenous busulfan could be the preferred myeloablative regimen in patients with myeloid malignancies. However, busulfan-based regimens are associated with higher rates of sinusoidal obstruction syndrome. Here, we are reporting long-term survival outcomes of AML patients receiving FTBI combined with cyclophosphamide or etoposide before alloHCT at City of Hope. We obtained a retrospective review of a prospectively maintained institutional registry of clinical outcomes in 167 AML patients (median age =41 years, range: 18-57) in CR1/2, who underwent alloHCT from 2005-2015 at our center. Eligible patients received MAC with FTBI (1320 cGy) and cyclophosphamide (120 mg/kg) for unrelated donor (MUD) or etoposide (60 mg/kg) for related donors. Graft-versus-host disease (GVHD) prophylaxis was tacrolimus and sirolimus. In this retrospective study, 6-year overall survival was 60%, and non-relapse mortality was 15%. GRFS rate at 1 and 2 years was 45% and 39%, respectively. We also described late metabolic effects and cumulative incidence of secondary malignancies (9.5%) in this report. Overall, in this young adult patient population, our results compare favorably to chemotherapy- (intravenous Busulfan-) based conditioning regimens without significant long term toxicity arising from TBI-based regimen.
-
5.
Favorable outcomes for allogeneic hematopoietic cell transplantation in elderly patients with NPM1-mutated and FLT3-ITD-negative acute myeloid leukemia
Aldoss, I., Nakamura, R., Yang, D., Salhotra, A., Stein, A. S., Pullarkat, V., Forman, S. J., Marcucci, G.
Bone marrow transplantation. 2019
-
6.
Haematopoietic cell transplantation for blastic plasmacytoid dendritic cell neoplasm: a North American multicentre collaborative study
Kharfan-Dabaja, M. A., Al Malki, M. M., Deotare, U., Raj, R. V., El-Jurdi, N., Majhail, N., Cherry, M. A., Bashir, Q., Darrah, J., Nishihori, T., et al
British Journal of Haematology. 2017;179(5):781-789
Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is incurable with conventional therapies. Limited retrospective data have shown durable remissions after haematopoietic cell transplantation (HCT) [allogeneic (allo) or autologous (auto)]. We conducted a multicentre retrospective study in BPDCN patients treated with allo-HCT and auto-HCT at 8 centres in the United States and Canada. Primary endpoint was overall survival (OS). The population consisted of 45 consecutive patients who received an allo-HCT (n = 37) or an auto-HCT (n = 8) regardless of age, pre-transplant therapies, or remission status at transplantation. Allo-HCT recipients were younger (50 (14-74) vs. 67 (45-72) years, P = 0.01) and had 1-year and 3-year OS of 68% [95% confidence interval (CI) = 49-81%] and 58% (95% CI = 38-75%), respectively. Allo-HCT in first complete remission (CR1) yielded superior 3-year OS (versus not in CR1) [74% (95% CI = 48-89%) vs. 0, P < 0.0001]. Allo-HCT outcomes were not impacted by regimen intensity [3-year OS for myeloablative conditioning = 61% (95% CI = 28-83%) vs. reduced-intensity conditioning = 55% (95% CI = 28-76%)]. One-year OS for auto-HCT recipients was 11% (95% CI = 8-50%). These results demonstrate efficacy of allo-HCT in BPDCN, especially in patients in CR1. Pertaining to auto-HCT, our results suggest lack of efficacy against BPDCN, but this observation is limited by the small sample size. Larger prospective studies are needed to better define the role of HCT in BPDCN.Copyright © 2017 John Wiley & Sons Ltd.
-
7.
US Intergroup Study of Chemotherapy Plus Dasatinib and Allogeneic Stem Cell Transplant in Philadelphia Chromosome Positive ALL
Ravandi, F., Othus, M., O'Brien, S. M., Forman, S. J., Ha, C. S., Wong, J. Y. C., Tallman, M. S., Paietta, E., Racevskis, J., Uy, G. L., et al
Blood Advances. 2016;1(3):250-259
Abstract
This multicenter trial was conducted to determine whether the addition of dasatinib to chemotherapy followed by an allogeneic hematopoietic cell transplant (HCT) in patients with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) was feasible. Patients >= 18 and <= 60 years of age with newly diagnosed Ph+ ALL received up to 8 cycles of alternating hyperCVAD and high dose cytarabine and methotrexate with dasatinib. Patients with an available matched sibling or unrelated donor underwent an allogeneic HCT in first complete remission (CR1) followed by daily dasatinib starting from day 100. Others received maintenance therapy with vincristine and prednisone for 2 years and dasatinib indefinitely. 97 patients (94 evaluable) with median age of 44 years (range, 20 - 60) and median WBC at presentation of 10 x 109/L (range, 1 - 410 x 109/L) were accrued. 83 (88%) patients achieved CR or CR with incomplete count recovery (CRi) and 41 underwent ASCT in CR1. Median follow-up is 36 months (range, 9 - 63). For the overall population, overall survival (OS), event-free survival (EFS), and relapse-free survival (RFS) at 3 years were 69%, 55%, and 62%, respectively. The 12-month RFS and OS after transplant were 71% and 87%, respectively. Landmark analysis at 175 days from the time of CR/CRi (longest time to HCT), showed statistically superior advantages for RFS and OS (p=0.038 and 0.037, respectively) for the transplanted patients. Addition of dasatinib to chemotherapy and HCT for younger patients with Ph+ ALL is feasible and warrants further testing. CONFLICT OF INTEREST DISCLOSURES No COI information to disclose: Partow Kebriaei, Laura Kinsbury, Richard Little, Janis Racevskis, Naoko Takebe, Honoraria: Uma Borate, self, Alexion, Novartis, Amgen; Elisabeth Paietta, self, Amgen; Susan O'Brien, self, Gilead, Pharmacyclics, Janssen; Jerald Radich, self, Novartis, BMS, Ariad; Farhad Ravandi, self, BMS, Ariad; Martin Tall, self, St. Vincent's Hospital, Hartford Hospital, Lundbeck Canada; Jeffrey Wong, self, Accuray, Inc. Consulting or Advisory Role: Fred Appelbaum, self, Igenica, Amgen, Pfizer, Neumedicine, Celator; Uma Borate, self, Alexion, Novartis, Suneisis; Harry Erba, self, Novartis, Incyte, Celgene, Amgen, Ariad, Seattle Genetics, Sunesis, Pfizer, Janssen, Daiichi Sankyo; Megan Othus, self, Glycomemetics, Celgene (DSMB both); Elisabeth Paietta, self, Amgen; Susan O'Brien, self, Amgen, Celgene, CLL Global Research Foundation, GSK; Jerald Radich, self, Novartis, BMS, Ariad; Farhad Ravandi, self, Ariad; Martin Tallman, self, Bioline, Biosight, Agios; Travel, Accommodations, Expenses: Uma Borate, self, Novartis, Alexion, Amgen and Jazz (as part of speakers' bureau); Elisabeth Paietta, self, Amgen; Susan O'Brien, self (company pending); Mary Horowitz, self, Novartis; Jerald Radich, self, Novartis, BMS; Jeffrey Wong, self, Accuray, Inc. Research Funding: Harry Erba, institution, Celator, Millennium/Takeda, Seattle Genetics, Astellas, Amgen, Agio, Juno, Janssen; Mary Horowitz, self, Sobi Pharmaceuticals; Hagop Kantarjian, institution, Ariad, BMS, Pfizer, Amgen, Novartis; Jerald Radich, self, Novartis; Susan O'Brien, self/institution, Acerta, TG Therapeutics, Regeneron, Gilead, Pharmacyclics, ProNAi; Farhad Ravandi, self/institution, BMS; Martin Tallman, self, Bioline, Epizyme, Arog; Jeffrey Wong, institution, Accuray, Inc. Speakers' Bureau: Uma Borate, self, Novartis, Alexion, Amgen and Jazz; Harry Erba, self, Novartis, Incyte, Celgene; Stock or Other Ownership: Fred Appelbaum, self, Adaptive Biotechnology; Patents, Royalties, Other Intellectual Property: Chul Ha, self, has patents but no royalty arrangements (patents held by Dr. Chul and his institution) Other Relationship: Harry Erba, self, Gyclomemetics Inc., (DSMB Chair)