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Outcomes of autologous hematopoietic cell transplantation in myeloma patients aged >/=75 years
Bashir, Q., Chamoun, K., Milton, D. R., Khan, M., Ahmed, S., Mehta, R., Popat, U. R., Kebriaei, P., Nieto, Y., Oran, B., et al
Leukemia & lymphoma. 2019;:1-8
Abstract
There is limited data on the outcomes of autologous hematopoietic cell transplantation (auto-HCT) in myeloma patients, 75 or older. We retrospectively analyzed all myeloma patients (n = 72), aged ≥75, who underwent auto-HCT at our center between January 1, 2000, and December 31, 2015. All patients received melphalan ≥140 mg m(-2) conditioning. At day-100, the cumulative incidence of non-relapse mortality was 1%. The overall response rate was 91% with 29% achieving complete/stringent complete remission. The median progression-free survival (PFS) was 31.4 months, and median overall survival (OS) was 72.8 months. The presence of high-risk cytogenetic abnormalities was associated with inferior PFS (p = 0.005) and OS (p = 0.005), while international staging system stage III was identified as a negative prognostic factor for OS (p = 0.002 vs. stage II). We conclude that auto-HCT can be safely performed in myeloma patients 75 and older and is associated with encouraging response rates.
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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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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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Outcome of Multiple Myeloma With Chromosome 1q Gain and 1p Deletion After Autologous Hematopoietic Stem Cell Transplantation: propensity-score matched analysis: Outcome of 1q+/1p- MM pts after auto-HCT
Varma, A., Sui, D., Milton, D. R., Tang, G., Saini, N., Hasan, O., Mukherjee, A., Joseph, J. J., Bashir, Q., Rondon, G., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
BACKGROUND The gain/amplification CKS1B gene at chromosome region 1q21 (1q+) is one of the most common genetic aberrations in multiple myeloma (MM). Amplification of CKS1B is frequently associated with the deletion of CDKN2C gene at chromosome region 1p32 (1p-), which is also associated with inferior outcomes. METHODS In this retrospective study, we evaluated the outcomes of patients with 1q+ and/or 1p- after high-dose therapy and auto-HCT. From January 2006 to December 2015, 1491 newly diagnosed MM patients underwent upfront high-dose therapy and auto-HCT at our institution. Out of those, 899 had the fluorescent in situ hybridization (FISH) data available. FISH was performed at diagnosis and before the start of induction in 686 (76%) patients, and after the initiation of induction therapy in 213 (24%) patients. We identified 100 patients with 1q+ and/or 1p- by FISH from the cohort of 899 patients. A control group (N=287) with diploid cytogenetics and normal FISH panel was selected from the same cohort. From the above two cohorts, using a propensity-score matched analysis, we identified matched controls for 85 of the 100 patients with 1q+/1p-. Patients were matched for age at auto-HCT, sex, international staging system stage, induction regimen, creatinine level, disease status at auto-HCT, conditioning regimen and maintenance therapy. RESULTS Sixty-seven (79%), 4 (5%) and 14 (16%) patients had 1q+, 1p- or both 1q+ and 1p-, respectively. There was no significant difference in induction therapy, preparative regimen, or maintenance therapy between the 1q+/1p- and control groups. The median follow-up time for all patients was 29.2 months (range: 0.29 -84.96). The cumulative incidence of 100-day non-relapse mortality was 1.2% and 0% for the 1q+/1p- and the control groups, respectively. Forty-two patients (50%) in the 1q+/1p- group achieved complete response compared to 40 patients (47%) in the control group. The estimated 3-year progression-free survival (PFS) and overall survival (OS) rates for the 1q+/1p- and the control groups were 41% and 79%, and 56% and 86%, respectively. Patients in the 1q+/1p- group experienced significant increased risk of progression or death compared with the control group (HR 2.21, CI 1.18-4.16, P=0.014). No significant association between OS in the two groups were observed. The outcome of the 1q+/1p- alone (with no additional high-risk cytogenetics) and the propensity-score matched control groups was also compared. Median PFS for the 1q+/1p- alone subgroup was 26.6 months, compared to 38.8 months for the control group (HR 1.9, CI 0.9-4.08, P=0.09). The median OS had not reached for the 1q+1/p- alone subgroup and was 81.1 months for the control group (HR 1.25, CI 0.3-4.6, P=0.73) CONCLUSION 1q+/1p- abnormalities with amplification of CKS1B and deletion of CDKN2C genes were associated with shorter PFS when compared to a propensity-score matched group of patients with diploid cytogenetics and normal a FISH panel. The outcomes of 1q+1/p- MM patients have improved with the use of more effective induction, conditioning, and maintenance therapy compared to historical controls, but they still need more effective therapeutic approaches to fully overcome the negative impact of 1q+1/p-.
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The Effect of Conditioning Regimen Dose Reduction in Obese Patients Undergoing Autologous Hematopoietic Cell Transplantation
Brunstein, C. G., Pasquini, M. C., Kim, S., Fei, M., Adekola, K., Ahmed, I., Aljurf, M., Agrawal, V., Auletta, J. J., Battiwalla, M., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
Abstract
There are limited data on whether to adjust high-dose chemotherapy prior to autologous hematopoietic cell transplant (autoHCT) in obese patients. This study explores the effects of dose adjustment on the outcomes of obese patients, defined as body mass index (BMI) ≥ 30 kg/m(2). Dose adjustment was defined as a reduction in standard dosing of ≥ 20%, based on ideal, reported dosing and actual weights. We included two groups of US patients who had received autoHCT between 2008 and 2014. Specifically, we included patients with multiple myeloma (MM, n=1696) treated with high-dose melphalan; and we included patients with Hodgkin or non-Hodgkin lymphomas (n=781) who received carmustine, etoposide, cytarabine, and melphalan (BEAM) conditioning. Chemotherapy dose was adjusted in 1324 (78%) patients with MM and 608 (78%) patients with lymphoma. Age, sex, BMI, race, performance score, co-morbidity index, and disease features (stage at diagnosis, disease status and time to transplant) were similar between dose groups. In multivariate analyses for MM, adjusting for melphalan dose and for center effect had no impact on overall survival (p=0.894) and treatment-related mortality (TRM) (p=0.62), progression (p=0.12), and progression-free survival (p=0.178). In multivariate analyses for lymphoma, adjusting chemotherapy doses did not affect survival (p=0.176), TRM (p=0.802), relapse (p=0.633) or PFS (p=0.812). No center effect was observed in lymphoma. This study demonstrates that adjusting chemotherapy dose prior to autoHCT in obese patients with MM and lymphoma does not influence mortality. These results do not support adjusting chemotherapy dose in this population.
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Updated Results of Rituximab Pre- and Post-BEAM with or without 90Yttrium-Ibritumomab Tiuxetan during Autologous Transplant for Diffuse Large B-Cell Lymphoma
Chahoud, J., Sui, D., Erwin, W. D., Gulbis, A. M., Korbling, M., Zhang, M., Ahmed, S., Alatrash, G., Anderlini, P., Ciurea, S. O., et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2018
Abstract
PURPOSE We evaluated the effect on long-term survival of adding rituximab (R) to BEAM (carmustine, etoposide, cytarabine, and melphalan) conditioning with or without yttrium-90 ibritumomab tiuxetan (90YIT) in patients with relapsed diffuse large B-cell lymphoma (DLBCL) undergoing autologous stem cell transplant (ASCT). EXPERIMENTAL DESIGN Patients were enrolled on three consecutive phase 2 clinical trials. Patients received two doses of rituximab (375 mg/m2 and 1000 mg/m2) during mobilization of stem cells, followed by 1000 mg/m2 on days +1 and +8 after ASCT with R-BEAM or 90YIT-R-BEAM (90YIT dose of 0.4 mCi/kg) conditioning. Results: One hundred thirteen patients were enrolled, with 73 receiving R-BEAM and 40 receiving 90YIT-R-BEAM. All patients had a prior exposure to rituximab. The median follow-up intervals for survivors were 11.8, 8.1, and 4.2 years in the three trials, respectively. The 5-year disease-free survival (DFS) rates were 62% for R-BEAM and 65% for 90YIT-R-BEAM (P =0.82). The 5-year overall survival rates were 73%, and 77%, respectively (P = 0.65). In patients with de novo DLBCL, survival outcomes of the germinal center/activated b-cell histologic subtypes were similar with 5-year OS rates (P = 0.52) and DFS rates (P = 0.64), irrespective of their time of relapse (< vs. > 1 year) after initial induction chemotherapy (P = 0.97). Conclusions:Administering ASCT with rituximab during stem cell collection and immediately after transplantation induces long-term disease remission and abolishes the negative prognostic impact of cell-of-origin in patients with relapsed DLBCL. The addition of 90YIT does not confer a further survival benefit.