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Myeloablative Fractionated Busulfan with Fludarabine in Older Patients: Long Term Disease-Specific Outcomes of a Prospective Phase II Clinical Trial
Mehta, R. S., Bassett, R., Chen, J., Valdez, B. C., Kawedia, J., Alousi, A. M., Anderlini, P., Al-Atrash, G., Bashir, Q., Ciurea, S. O., et al
Transplantation and cellular therapy. 2021
Abstract
BACKGROUND Compared to reduced-intensity conditioning regimen, myeloablative conditioning (MAC) for hematopoietic stem cell transplantation (HCT) reduces relapse but is avoided in older patients due to higher non-relapse mortality (NRM). To meet the need for a myeloablative regimen for older patients, we developed a novel fludarabine and busulfan MAC regimen. We fractionated the dose of busulfan and gave it for six days over a two-week period and demonstrated the feasibility and safety of this approach. However, the disease-specific efficacy of this regimen is not known. OBJECTIVES The purpose of this study was to estimate the efficacy of fractionated busulfan regimen by estimating diseases specific survival outcomes. STUDY DESIGN The conditioning regimen consisted of busulfan and fludarabine. On days -13 and -12 before HCT, patients received 80mg/m(2) busulfan intravenously (IV) daily in an outpatient clinic. Additional chemotherapy was administered during inpatient treatment from day -6 through day -3, including fludarabine 40mg/m(2) and busulfan IV once daily. The dosing of busulfan was determined from PK analyses to achieve for the course a target AUC of 20,000±12% µmol.min, which is close to the average exposure of myeloablative dose of busulfan. 150 patients with high-risk hematological malignancies up to 75 years were enrolled on this prospective phase II study. The objective was to evaluate NRM, relapse, survival, the rates of graft-versus-host disease (GVHD), and long-term complications. RESULTS The median age of the patient population was 61 years (interquartile range, 55-67). The most common diagnoses were acute myeloid leukemia (AML; N=59, 39.3%), myelodysplastic syndrome (MDS; n=29, 19.3%), and myelofibrosis (MF; N=22, 14.7%). Most had an unrelated donor (n=93, 62%) and received peripheral blood graft (n=110, 73.3%). Over half had an HCT-Specific Comorbidity Index of =3 (n=79, 52.7%). The median follow-up among survivors was 43.4 months (IQR, 38.9-50.4). In patients with AML in complete remission, MDS, and myelofibrosis, 3 year OS was 66.7% (95% CI, 50.2-88.5%), 43.6% (95% CI, 28.6-66.4%), and 59.1% (95% CI, 41.7-83.7%) respectively. The cumulative incidence of NRM was 22% (15.3%-28.7%), extensive chronic GVHD was 27% (95% CI, 20-34%), bronchiolitis obliterans was 4.7% (95% CI, 1.3-8.1%), and secondary malignancies was 8.7% (95% CI, 4.1-13.2%) at 3 years. CONCLUSION Lengthening the duration of busulfan (fractionation) permits safe delivery of myeloablative conditioning in older patients, leading to prolonged survival.
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Randomized phase II trial of extracorporeal phototherapy and steroids vs. steroids alone for newly diagnosed acute GVHD
Mehta, R. S., Bassett, R., Rondon, G., Overman, B. J., Popat, U. R., Hosing, C. M., Rezvani, K., Qazilbash, M. H., Anderlini, P., Jones, R. B., et al
Bone marrow transplantation. 2021
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Editor's Choice
Abstract
Steroids remain the initial therapy for acute graft-vs.-host disease (AGVHD). Strategies to improve response and minimize steroid exposure are needed. We report results of a randomized, adaptive, Bayesian-designed, phase II trial of prednisone with or without extracorporeal photopheresis (ECP) as an initial therapy for patients with newly diagnosed AGVHD. The primary endpoint was success at day 56 defined as: alive, in remission, achieving AGVHD response without additional therapy, and on <1?mg/kg at day 28 and <0.5?mg/kg on day 56 of steroids. Eighty-one patients were randomized to the ECP arm (n?=?51) or steroids alone (n?=?30). Median age was 54 years (range: 17-75); 90% had grade II AGVHD and 10% had grades III and IV AGVHD, with skin (85%), upper (22%)/lower (22%) gastrointestinal, and liver (10%) involvement. The ECP arm had a higher probability of success (0.815) and exceeded the predefined threshold for determining the investigational arm promising. ECP was potentially more beneficial than steroids-alone in skin-only AGVHD (response rate: 72% vs. 57%, respectively) than for visceral-organ AGVHD (47% vs. 43%, respectively). The addition of ECP to steroids may result in higher GVHD response as initial therapy for AGVHD, especially for patients with skin-only involvement.
PICO Summary
Population
Patients with newly-diagnosed acute graft-versus-host disease (AGVHD, n=81)
Intervention
Prednisone with extracorporeal photopheresis (ECP, n=51)
Comparison
Prednisone alone (n=30)
Outcome
The ECP arm had a higher probability of success (0.815) and exceeded the predefined threshold for determining the investigational arm promising. ECP was potentially more beneficial than steroids-alone in skin-only AGVHD (response rate: 72% vs. 57%, respectively) than for visceral-organ AGVHD (47% vs. 43%, respectively).
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Myeloablative conditioning using timed-sequential busulfan plus fludarabine in older patients with acute myeloid leukemia: long term results of a prospective phase II clinical trial
Mehta, R. S., Bassett, R., Olson, A., Chen, J., Ahmed, S., Alousi, A. M., Anderlini, P., Al-Atrash, G., Bashir, Q., Ciurea, S. O., et al
Haematologica. 2019
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Conditioning with busulfan plus melphalan versus melphalan alone before autologous haemopoietic cell transplantation for multiple myeloma: an open-label, randomised, phase 3 trial
Bashir, Q., Thall, P. F., Milton, D. R., Fox, P. S., Kawedia, J. D., Kebriaei, P., Shah, N., Patel, K., Andersson, B. S., Nieto, Y. L., et al
The Lancet. Haematology. 2019
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Editor's Choice
Abstract
BACKGROUND Retrospective studies suggest that conditioning therapy with busulfan plus melphalan could result in longer progression-free survival compared with melphalan alone in patients with multiple myeloma undergoing autologous haemopoietic cell transplantation (auto-HCT). We aimed to test this hypothesis in a randomised trial. METHODS The primary objective of the study was to compare progression-free survival with conditioning of busulfan plus melphalan with melphalan alone in patients with multiple myeloma. Patients with newly diagnosed multiple myeloma who were eligible for cell transplantation, aged 70 years or younger, with at least stable disease, were randomly assigned (1:1) to treatment. Patients received either busulfan plus melphalan, with a test dose of busulfan 32 mg/m(2) followed by pharmacokinetically adjusted doses on days -7, -6, -5, and -4 to achieve a target daily area under the curve (AUC) of 5000 mmol-minute and melphalan 70 mg/m(2) per day on days -2 and -1 (total melphalan dose 140 mg/m(2)), or a melphalan dose of 200 mg/m(2) on day -2. Randomisation was performed via a Clinical Trial Conduct Website at the University of Texas MD Anderson Cancer Center. The accrual is complete and final results are presented here. The study is registered with ClinicalTrials.gov, number NCT01413178. FINDINGS Between Oct 12, 2011, and March 22, 2017, 205 patients were assessed for eligibility and randomly assigned to treatment. The primary analysis of progression-free survival was measured in 202 patients who received treatment: 104 patients in the busulfan plus melphalan group and 98 patients in the melphalan alone group. 90 days after auto-HCT, 102 (98%) of 104 patients given busulfan plus melphalan and 95 (97%) of 98 patients given melphalan alone achieved partial response or better. The median follow-up in the busulfan plus melphalan group was 22.6 months (IQR 15.2-47.1) and 20.2 months (IQR 8.8-46.6) in the melphalan alone group. Median progression-free survival was 64.7 months (32.9-64.7) with busulfan plus melphalan versus 43.5 months (19.9-not estimated) with melphalan alone (hazard ratio 0.53 [95% CI 0.30-0.91]; p=0.022). There were no treatment-related deaths by day 100 in either group. Grade 2-3 mucositis was observed in 77 (74%) of 104 patients in the busulfan plus melphalan group versus 14 (14%) of 98 patients in the melphalan alone group. INTERPRETATION These findings, if confirmed in other ongoing studies, suggest that busulfan plus melphalan could replace melphalan alone as the conditioning regimen for auto-HCT in patients with newly diagnosed myeloma. FUNDING This study was funded in part by the National Institutes of Health (NIH) through MD Anderson's Cancer Center Support Grant (CA016672).
PICO Summary
Population
Patients with newly diagnosed multiple myeloma who were eligible for cell transplantation, aged 70 years or younger, with at least stable disease (n=202)
Intervention
Busulfan plus mephalan conditioning prior to autologous transplantation (n=104)
Comparison
Melphalan conditioning alone (n=98)
Outcome
Median progression-free survival was 64.7 months with busulfan plus melphalan versus 43.5 months with melphalan alone. There were no treatment-related deaths by day 100 in either group. Grade 2-3 mucositis was observed in 77 (74%) of 104 patients in the busulfan plus melphalan group versus 14 (14%) of 98 patients in the melphalan alone group.
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Feasibility of Lenalidomide Therapy for Persistent Chronic Lymphocytic Leukemia after Allogeneic Transplantation
Khouri, M. R., Jabbour, E. J., Gulbis, A. M., Turturro, F., Ledesma, C., Korbling, M., Samuels, B. I., Ahmed, S., Alousi, A. M., Ciurea, S. O., et al
Biology of Blood & Marrow Transplantation. 2017;23(8):1405-1410
Abstract
In patients with chronic lymphocytic leukemia (CLL), persistence of disease after allogeneic stem cell transplantation (alloSCT) can result in poor outcomes. In an effort to improve these outcomes, patients with persistent CLL who were 90 to 100 days beyond alloSCT with no evidence of graft-versus-host-disease (GVHD) were randomized to receive lenalidomide or standard care (withdrawal of immunosuppression followed by donor lymphocyte infusion). Lenalidomide was initiated at 5mg every other day and increased to 10mg daily, if tolerated, in each patient. Of 38 patients enrolled, 17 (45%) met the eligibility criteria for randomization. Of these 17 patients, 8 were randomized to undergo lenalidomide therapy. Five (62%) patients had to stop taking the drug because of toxicity. The main reason for drug discontinuation was acute GVHD in 43% of patients. This incidence was 11% in the patients who were randomized to not receive lenalidomide. With a median follow-up of 2.6 years, the median survival was 3.4 years for those receiving lenalidomide. This was not reached in patients randomized to not receive lenalidomide and in patients in complete remission who were not randomized. These results suggested that treatments other than lenalidomide are needed for persistent CLL after alloSCT.