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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.
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2.
Total marrow and lymphoid irradiation as conditioning in haploidentical transplant with posttransplant cyclophosphamide
Al Malki, M. M., Palmer, J., Tsai, N. C., Mokhtari, S., Hui, S., Tsai, W., Aldoss, I., Ali, H., Aribi, A., Cao, T., et al
Blood advances. 2022;6(14):4098-4106
Abstract
Posttransplant cyclophosphamide (PTCy) platform has shown low rates of graft-versus-host disease (GVHD) and nonrelapse mortality (NRM) after haploidentical hematopoietic cell transplantation (HaploHCT). However, because of the limited disease control, relapse rate remains a major cause of treatment failure in high-risk patients. Total marrow and lymphoid irradiation (TMLI) allows for delivery of high radiation to bone marrow and other targeted structures, without increasing off-target radiation exposure and toxicity to end organs. In this phase 1 trial, 31 patients with high-risk and/or active primary refractory leukemias or myelodysplastic syndrome underwent peripheral blood stem cell HaploHCT with TMLI, fludarabine, and cyclophosphamide as the conditioning regimen. Radiation dose was escalated in increments of 200 cGy (1200-2000 cGy). GVHD prophylaxis was PTCy with tacrolimus/mycophenolate mofetil. Grade 2 toxicities by the Bearman scale were mucositis (n = 1), hepatic (n = 3), gastrointestinal (n = 5), and cardiac (n = 2). One patient (1800 cGy) experienced grade 3 pulmonary toxicity (dose-limiting toxicity). At a follow-up duration of 23.9 months for the whole cohort; 2-year NRM was 13%. Cumulative incidence of day 100 grade 2 to 4 and 3 to 4 acute GVHD was 52% and 6%, respectively. Chronic GVHD at 2 years was 35%. For patients treated with 2000 cGy, with a median follow-up duration of 12.3 months, 1-year relapse/progression, progression-free survival, and overall survival rates were 17%, 74%, and 83%, respectively. In conclusion, HaploHCT-TMLI with PTCy was safe and feasible in our high-risk patient population with promising outcomes.
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3.
Anti-CD25 Radioimmunotherapy with BEAM Autologous Hematopoietic Cell Transplantation Conditioning in Hodgkin Lymphoma
Herrera, A. F., Palmer Ph, D. Jm, Adhikarla, V., Yamauchi, D. M., Poku, E. K., Bading, J., Yazaki, P., Dandapani, S., Mei, M. G., Chen, R. W., et al
Blood advances. 2021
Abstract
High-risk relapsed or refractory (R/R) classical Hodgkin lymphoma (HL) is associated with poor outcomes after conventional salvage therapy and autologous hematopoietic cell transplantation (AHCT). Post-AHCT consolidation with brentuximab vedotin (BV) improves progression-free survival (PFS), but with increasing use of BV early in the treatment course, the utility of consolidation is unclear. CD25 is often expressed on Reed-Sternberg cells and in the tumor microenvironment in HL and we hypothesized that the addition of 90Y-antiCD25 (aTac) to BEAM AHCT would be safe and result in a transplantation platform that is agnostic to prior HL-directed therapy. Twenty-five patients with high-risk R/R HL were enrolled onto this phase 1 dose-escalation trial of aTac-BEAM. Following an imaging dose of 111In-antiCD25, 2 patients had altered biodistribution and a third developed an unrelated catheter-associated bacteremia; therefore 22 patients ultimately received therapeutic 90Y-aTac-BEAM AHCT. No dose-limiting toxicities were observed and 0.6mCi/kg was deemed the recommended phase 2 dose, the dose at which the heart wall would not receive > 2500cGy. Toxicities and time to engraftment were similar to those observed with standard AHCT, though 95% of patients developed stomatitis (all grade 1-2 per Bearman toxicity scale). Seven relapses (32%) were observed, most commonly in patients with 3 or more risk factors. The estimated 5-year PFS and overall survival probabilities among 22 evaluable patients were 68% and 95%, respectively, and non-relapse mortality was 0%. aTac-BEAM AHCT was tolerable in patients with high-risk R/R HL and we are further evaluating the efficacy of this approach in a phase 2 trial. The clinical trial was registered at clinicaltrials.gov (NCT01476839).
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4.
Total Body Irradiation and Risk of Breast Cancer After Blood or Marrow Transplantation: A Blood or Marrow Transplantation Survivor Study Report
McDonald, A. M., Chen, Y., Wu, J., Hageman, L., Francisco, L., Kung, M., Wong, F. L., Ness, E., Landier, W., Battles, K., et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2020;:Jco2000231
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Abstract
PURPOSE To examine the association between total body irradiation (TBI) and subsequent breast cancer in women treated with blood or marrow transplantation (BMT) for hematologic malignancies. PATIENTS AND METHODS Participants were drawn from the BMT Survivor Study (BMTSS), a retrospective cohort study that included patients who underwent transplantation between 1974 and 2014 and survived for ≥ 2 years after BMT. Patients with pre-BMT chest radiation or a history of breast cancer were excluded. Participants completed the BMTSS survey, which included details regarding breast cancer diagnosis. Subsequent breast cancer was confirmed by pathology report review or physician notes. Cox proportional hazards models assessed the association between TBI and subsequent breast cancer. Standardized incidence ratios were calculated to determine the excess risk of subsequent breast cancer compared with that in the general population. RESULTS A total of 1,464 female BMT survivors (allogeneic: n = 788; autologous: n = 676) participated, with a median follow-up of 9.3 years from BMT. TBI was used in 660 patients (46%). Thirty-seven women developed subsequent breast cancer (allogeneic: n = 19; autologous: n = 18). Multivariable analysis revealed that exposure to TBI was associated with an increased risk of subsequent breast cancer among allogeneic BMT survivors (hazard ratio [HR], 3.7 [95% CI, 1.2 to 11.8]; P = .03) and autologous BMT survivors (HR, 2.6 [95% CI, 1.0 to 6.8]; P = .048). Pre-BMT exposure to alkylating agents was associated with an increased risk of subsequent breast cancer among autologous BMT survivors (HR, 3.3 [95% CI, 1.0 to 9.0]; P = .05). Compared with that in the general population, exposure to TBI at age < 30 years was associated with a 4.4-fold higher risk of subsequent breast cancer in allogeneic BMT survivors and a 4.6-fold higher risk in autologous BMT survivors. CONCLUSION The association between TBI and subsequent breast cancer, especially among those exposed at a young age, as well as pre-BMT exposure to alkylating agents, should inform breast cancer screening for early detection.
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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.
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6.
Phase I Trial of Total Marrow and Lymphoid Irradiation Transplantation Conditioning in Patients with Relapsed/Refractory Acute Leukemia
Stein, A., Palmer, J., Tsai, N. C., Al Malki, M. M., Aldoss, I., Ali, H., Aribi, A., Farol, L., Karanes, C., Khaled, S., et al
Biology of Blood & Marrow Transplantation. 2017;23(4):618-624
Abstract
Current conditioning regimens provide insufficient disease control in relapsed/refractory acute leukemia patients undergoing hematopoietic stem cell transplantation (HSCT) with active disease. Intensification of chemotherapy and/or total body irradiation (TBI) is not feasible because of excessive toxicity. Total marrow and lymphoid irradiation (TMLI) allows for precise delivery and increased intensity treatment via sculpting radiation to sites with high disease burden or high risk for disease involvement, while sparing normal tissue. We conducted a phase I trial in 51 patients (age range, 16 to 57 years) with relapsed/refractory acute leukemia undergoing HSCT (matched related, matched unrelated, or 1-allele mismatched unrelated) with active disease, combining escalating doses of TMLI (range, 1200 to 2000 cGy) with cyclophosphamide (CY) and etoposide (VP16). The maximum tolerated dose was declared at 2000 cGy, as TMLI simulation studies indicated that >2000 cGy might deliver doses toxic for normal organs at or exceeding those delivered by standard TBI. The post-transplantation nonrelapse mortality (NRM) rate was only 3.9% (95% confidence interval [CI], .7 to 12.0) at day +100 and 8.1% (95% CI, 2.5 to 18.0) at 1 year. The cumulative incidence of grades II to IV acute graft-versus-host disease (GVHD) was 43.1% (95% CI, 29.2 to 56.3) and for grade III and IV, it was 13.7% (95% CI, 6.9 to 27.3). The day +30 complete remission rate for all patients was 88% and was 100% for those treated at 2000 cGy. The overall 1-year survival was 55.5% (95% CI, 40.7 to 68.1). The TMLI/CY/VP16 conditioning regimen is well tolerated at TMLI doses up to 2000 cGy with a low 100-day and 1-year NRM rate and no increased risk of GVHD with higher doses of radiation. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.