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Radiation Therapy Can Be Safely Incorporated into Pretransplantation Treatment Regimens for Patients with Multiple Myeloma
Damron, E. P., Qazilbash, M. H., Fang, P. Q., Wu, S. Y., Dabaja, B. S., Rondon, G., Hosing, C., Champlin, R. E., Bashir, Q., Shpall, E. J., et al
Transplantation and cellular therapy. 2023;29(1):37.e1-37.e7
Abstract
Primary treatment of multiple myeloma (MM) often involves systemic induction therapy (SIT) followed by autologous stem cell transplantation (ASCT). Radiation therapy (RT) is sometimes used for palliation; however, many practitioners avoid RT out of concern that future peripheral blood progenitor cell (PBPC) collection required for ASCT may be compromised. In this study, we retrospectively examined the possible effect of RT on PBPC collection. We reviewed the charts of 732 patients with MM treated with RT at our institution from 1999 to 2017, including patients who received RT prior to PBPC collection for planned ASCT. RT plans (both MM and non-MM RT) were reviewed to estimate the percentage of bone marrow (BM) treated using published estimates of skeletal BM distribution. Statistics were performed using Pearson correlation and the t-test. The 732 MM patients included 485 planned for ASCT; of these, 223 received RT prior to PBPC collection and were included in the final cohort. The median age at PBPC collection was 59 years (range, 33 to 80 years). For SIT, patients received combination regimens including the following agents: bortezomib (142 patients; 64%), lenalidomide (111 patients; 50%), and alkylators (46 patients; 21%). Nine patients (4%) received dexamethasone alone. The median cumulative %BM treated per patient was 6.7 (range .0 to 47.4). The median RT dose was 24 Gy (range, 10.0 to 75.6 Gy). Mobilization was performed using granulocyte-colony stimulating factor (G-CSF) alone (189 patients; 85%), G-CSF with plerixafor (15 patients; 7%), or chemotherapy (19 patients; 9%). A median of 7.8 × 10(6) CD34(+)/kg PBPCs (range, .5 to 54.8× 10(6) CD34(+)/kg) were collected in a median of 3 (range, 1 to 9) apheresis procedures. One hundred ninety-six patients (99%) collected ≥2.0 × 10(6) CD34(+)/kg PBPCs, and 166 (83%) collected >5.0 × 10(6) CD34(+)/kg PBPCs. The number of PBPCs collected was not associated with %BM treated (P = .15) or RT dose (P = .56). The number of apheresis procedures performed was not associated with %BM treated (P = .54) or RT dose (P = .85). The amount of PBPCs collected did not differ significantly between patients receiving RT to the pelvis/sacrum (P = .20) and those receiving RT to the spine (P = .13). The time to platelet engraftment was longer for patients with higher %BM treated (P = .02). Eleven patients did not undergo a confirmed ASCT, owing to patient preference (3 patients), trial therapy (1 patient), comorbidities (1 patient), election for hospice (1 patient), inadequate collection (4 patients), or inadequate follow-up (1 patient). In our study cohort, RT prior to ASCT did not impair successful ASCT. RT must be carefully planned and delivered to ensure safe incorporation into pre-ASCT treatment regimens.
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Vorinostat combined with Busulfan, Fludarabine, and Clofarabine Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Leukemia: Long-term Study Outcomes
Alatrash, G., Saberian, C., Bassett, R., Thall, P. F., Ledesma, C., Lu, Y., Daher, M., Valdez, B. C., Kawedia, J., Popat, U., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Conditioning regimens play a major role in determining disease outcomes following allogeneic hematopoietic stem cell transplantation (allo-HSCT). The use of intravenous (IV) busulfan (Bu) as part of the conditioning chemotherapy has been shown to be effective in controlling disease relapse. However, disease relapse remains a major cause of death following allo-HSCT. OBJECTIVE To determine the long-term outcomes of vorinostat with IV Bu plus dual nucleoside analogs clofarabine (Clo) and fludarabine (Flu) in the conditioning regimen for patients undergoing allo-HSCT. STUDY DESIGN This was a rapid dose escalation phase I/II study designed to determine whether the addition of vorinostat would improve the efficacy of standard IV Bu Flu Clo conditioning regimen. This report presents the long-term disease outcomes of this combination in 68 patients with high risk leukemia, including 31 (46%) with acute lymphoblastic leukemia (ALL) and 37 (54%) with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). RESULTS Fifty-eight patients (85%) were in morphologic complete remission at time of transplant and 38 patients (56%) received matched unrelated donor grafts. Over the median follow up of 37.6 months, among the 68 patients, 29 (43%) died, and the non-relapse mortality (NRM) rate was 22% (n=15). Median overall survival (OS) and median NRM were not reached. Nineteen patients (28%) experienced disease progression. Median PFS was 36.8 months. Thirty-seven patients (57%) developed grade 2-4 acute GVHD and 20 patients (31%) developed chronic GVHD. CONCLUSION Our results suggest a lack of benefit from adding a short course of vorinostat to IV Bu/Flu/Clo conditioning regimen for leukemia patients undergoing allo- HSCT.
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3.
Radiation Therapy can be Safely Incorporated Into Pre-Transplant Treatment Regimens for Patients With Multiple Myeloma
Damron, E. P., Qazilbash, M., Fang, P., Wu, S. Y., Dabaja, B., Rondon, G., Hosing, C., Champlin, R., Bashir, Q., Shpall, E. J., et al
International journal of radiation oncology, biology, physics. 2021;111(3s):S81
Abstract
PURPOSE/OBJECTIVE(S): Primary treatment of multiple myeloma (MM) often involves systemic induction therapy (SIT) followed by autologous stem cell transplant (ASCT). Radiation therapy (RT) is sometimes used for palliation; however, many practitioners avoid RT out of concern that future peripheral blood progenitor cell (PBPC) collection required for ASCT may be compromised. We retrospectively examined the possible effect of RT on PBPC collection. MATERIALS/METHODS We reviewed the charts of 732 MM patients (pts) seen from 1997-2016 at our institution and included pts who received RT prior to PBPC collection for planned ASCT. RT plans (both MM and non-MM RT) were reviewed to estimate the percentage (%) bone marrow (BM) treated using published estimates of skeletal BM distribution. Statistics were performed using Pearson correlations and t-tests. RESULTS Of 732 MM pts, ASCT was planned for 485 pts; of these, 223 pts received RT prior to PBPC collection and were included in the final cohort. 133 pts (60%) were male. Median age at PBPC collection was 59 years (range 33-80). For SIT, pts received combination regimens including the following agents: bortezomib (142 pts, 64%); lenalidomide (111 pts, 50%); alkylators (46 pts, 21%). Nine pts (4%) received dexamethasone alone. RT plans and/or a description of the fields, were available to estimate treated BM% for 221 pts. The median cumulative BM% treated per pt was 6.7 (range 0.0-47.4). The median RT dose was 24 Gy (range 10.0-75.6 Gy). Mobilization was performed using granulocyte-colony stimulating factor (G-CSF) alone (189 pts, 85%), G-CSF with plerixafor (15 pts, 7%), or chemotherapy (19 pts, 8%). PBPC collection data was available for 199 pts. A median of 7.8?×?10(6) CD34(+)/kg PBPCs (range 0.5-54.8) were collected in a median of 3 (1-9) apheresis procedures. 196 pts (99%) collected more than 2.0?×?10(6) CD34(+)/kg (minimum PBPC no. required for engraftment), and 167 pts (84%) collected more than 5.0?×?10(6) CD34(+)/kg (preferred no. of PBPCs collected). The number of PBPCs collected was not associated with BM% treated (P?=?0.15) or RT dose (P?=?0.56). The number of apheresis procedures performed was not associated with BM% treated (P?=?0.54) or RT dose (P?=?0.85). The number of PBPCs collected did not differ significantly for pts receiving RT to the pelvis (P?=?0.96), lumbar spine (P?=?0.35), or thoracic spine (P?=?0.059). Time to platelet engraftment was longer for patients with higher %BM treated (P?=?0.02). Eleven pts did not undergo a confirmed ASCT due to: pt preference (3 pts), trial therapy (1 pt), comorbidities (1 pt), election for hospice (1 pt), inadequate collection (4 pts) and inadequate follow up (1 pt). CONCLUSION Among pts with MM, RT prior to ASCT did not prevent adequate PBPC collection or impair successful ASCT. RT must be carefully planned and delivered to ensure safe incorporation into pre-ASCT treatment regimens.
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4.
Busulfan and melphalan conditioning is superior to melphalan alone in autologous stem cell transplantation for high-risk MM
Saini, N., Bashir, Q., Milton, D. R., Tang, G., Delgado, R., Rondon, G., Popat, U. R., Hosing, C. M., Nieto, Y., Kebriaei, P., et al
Blood advances. 2020;4(19):4834-4837
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Optimizing the Conditioning Regimen for HCT in Myelofibrosis: Long-term Results of a Prospective Phase II Clinical Trial
Popat, U., Mehta, R. S., Bassett, R., Kongtim, P., Chen, J., Alousi, A. M., Anderlini, P., Ciurea, S., Hosing, C., Jones, R., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
BACKGROUND Optimal conditioning regimen for older patients with myelofibrosis undergoing allogeneic hematopoietic cell transplantation (HCT) is not known. Likewise, role of dose intensity is not clear. METHODS We conducted a non-randomized prospective phase II trial using low-dose, later escalated to high-dose (MAC) busulfan with fludarabine (Bu-Flu) in myelofibrosis patients up to 74 years. First 15 patients received intravenous busulfan 130 mg/m(2)/day on days -3 and -2 ("low dose"); 31 received high dose - either 100 mg/m(2)/day (days -5 to -2; n=4) or pharmacokinetic-guided area under the curve of 4,000 mumol.min (days -5 to -2; n=27). Primary endpoint was day 100 non-relapse mortality (NRM). FINDINGS Median age was 58 years (interquartile range (IQR) 53-63). Dynamic international prognostic scoring system (DIPSS)-plus was intermediate (n=28) or high (n=18). Donors were related (n=19) or unrelated (n=27). Cumulative incidence of NRM was 9.7% (95% confidence interval (CI) 0-20.3) at day 100 and at 3 years in the high dose, while it was 0% in the low dose group at day 100, and increased to 20% (95% CI 0-41.9) at 3 years. With a median follow up of 5.1 years (IQR 3.8-6), 3-year relapse was 32.3% (95% CI 15.4-49.1) in high dose versus 53.3% (95% CI 26.6-80.1) in low dose; event-free survival was 58% (95% CI 43-78%) versus 27% (95% CI 12-62%), and overall survival was 74% (95% CI 60-91%) versus 60% (95% CI 40-91%) respectively. In multivariate analysis, high dose busulfan had a trend towards lower relapse (Hazard ratio (HR) 0.44, 95% CI, 0.18-1.07, p=0.07), with no impact on NRM. INTERPRETATION Intensifying Bu-Flu regimen using pharmacokinetic-monitoring appears promising in reducing relapse without increasing non-relapse mortality. FUNDING The study was supported partly by Otsuka pharmaceutical and partly by the Cancer Center Support Grant (NCI Grant P30 CA016672).
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Impact of Donor Type and Melphalan Dose on Allogeneic Transplant Outcomes for Patients with Lymphoma
Saini, N. Y., Saliba, R. M., Rondon, G., Maadani, F., Popat, U., Hosing, C. M., Betul, O., Bashir, Q., Olson, A., Nieto, Y., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
We analyzed 186 patients with lymphoma who received allogeneic stem cell transplant (ASCT) with fludarabine-melphalan (FM) conditioning and different donors [25 haploidentical (HD), 98 matched unrelated (MUD), and 63 matched related (MRD)] at our institution between 09/2009-01/2018. Patients received fludarabine 160 mg/m(2) (40 mg/m(2)/day x 4 days) in combination with one dose of melphalan 140 mg/m(2) (FM140) or 100 mg/m2 (FM100). Engraftment was similar between the 3 groups (92%, 89%, and 98%, respectively; p=0.7). The 6-months cumulative incidence of grade III-IV aGVHD was 4%, 14% and 8% (p=NS), and 3-year chronic GVHD was 5%, 16% and 26% (p=NS) for HD, MUD and MRD groups, respectively. The 3-year non-relapse mortality and relapse were 31%, 32% and 10% (HD vs. MUD, p=0.9, HD vs. MRD, p=0.02), and 15%, 21% and 39% (HD vs. MUD, p=0.4, HD vs. MRD, p=0.04) for HD, MUD and MRD groups, respectively. At 3 years, PFS was 59%, 44% and 46% (p=NS), OS was 52%, 54% and 67% (p=NS) and GVHD-free, relapse-free survival (GRFS) 39%, 31%, 24% for HD, MUD transplants (p=NS). No differences in the 3-year PFS [57% vs. 43% (p=0.3)] and OS [64% vs. 58% (p=0.7)] were seen for patients receiving FM100 versus FM140. In conclusion, HD transplants have similar outcomes compared with HLA matched transplants in patients with lymphoma, and FM100 appears to be at least as effective conditioning as FM140 regimen.
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Is There an Optimal Conditioning for Older Patients with AML Receiving Allogeneic Hematopoietic Cell Transplantation?
Ciurea, S. O., Kongtim, P., Varma, A., Rondon, G., Chen, J., Srour, S., Bashir, Q., Alousi, A., Mehta, R. S., Oran, B., et al
Blood. 2019
Abstract
The optimal conditioning regimen for older patients with AML remains unclear. Here we compared outcomes of AML patients above 60 years receiving AHCT at our institution. All 404 consecutively treated patients received one of the following conditioning regimens: 1) fludarabine + melphalan 100mg/m2 (FM100), 2) fludarabine + melphalan 140mg/m2 (FM140), 3) fludarabine + IV busulfan AUC{greater than or equal to}5,000/day x 4 days (Bu{greater than or equal to}20000), and 4) fludarabine + IV busulfan AUC 4,000/day x 4 days (Bu16000) were included. A propensity score analysis (PSA) was used to compare outcomes between these 4 groups. Among the 4 conditioning regimens, FM100 group had a significantly better long-term survival with 5-year progression-free survival (PFS) of 49% vs. 30%, 34% and 23%, respectively. The benefit of FM100 regimen resulted primarily from a lower non-relapse mortality associated with this regimen, effect more pronounced in patients with lower performance status. The PSA confirmed that FM100 was associated with better post-transplant survival, while no significantly differences were seen between other regimen groups. In conclusion, older patients with AML benefit from a reduced-intensity conditioning regimen with lower melphalan doses (FM100), which was associated with better survival despite the fact that was primarily used in patients who could not receive more intense conditioning regimen.
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8.
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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Allogeneic Transplantation after Myeloablative Rituximab/BEAM +/- Bortezomib for Patients with Relapsed/Refractory Lymphoid Malignancies: 5-Year Follow-up Results
Chamoun, K., Milton, D. R., Ledesma, C., Young, K. H., Jabbour, E. J., Alatrash, G., Anderlini, P., Bashir, Q., Ciurea, S. O., Marin, D., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
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Editor's Choice
Abstract
Although bortezomib and rituximab have synergistic activity in patients with lymphoma, and can both attenuate graft-versus-host disease (GVHD), the drugs have not been used together in patients undergoing allogeneic stem-cell transplantation (alloSCT). In this phase 1/2 trial, we assessed the safety and activity of bortezomib added to the rituximab (R) plus BEAM (carmustine, etoposide, cytarabine, melphalan) regimen in patients with relapsed lymphoma undergoing alloSCT. Primary GVHD prophylaxis consisted of tacrolimus and methotrexate. Bortezomib (1 - 1.3 mg/m(2) per dose) was administered intravenously on days -13, -6, -1, and +2. We performed inverse probability weighting analysis to compare GVHD and survival results to a historical control group that received R-BEAM without bortezomib. Thirty-nine patients were assessable for toxic effects and response. The median age was 54 years. The most common diagnosis was diffuse large B-cell lymphoma (41%). Twenty-two patients (56%) and 17 patients (44%) received their transplants from matched related and unrelated matched donors, respectively. The maximum tolerated bortezomib dose was 1 mg/m(2). The weighted cumulative incidences of grade II-IV and grade III or IV acute GVHD were 50% and 34%, respectively; these incidences and survival rates were not significantly different from those of the control group. Median survival has not been reached in patients age ≤50 years and who had a long follow-up time of 60.7 months. The R-BEAM regimen has a survival benefit in lymphoma patients age ≤50 years undergoing alloSCT. The addition of bortezomib has no impact on survival or incidence of GVHD.
PICO Summary
Population
Patients with relapsed lymphoma undergoing allo-SCT
Intervention
Bortezomib added to the rituximab plus BEAM (carmustine, etoposide, cytarabine, melphalan) regimen (n=39)
Comparison
Historical control group that received R-BEAM without bortezomib.
Outcome
The R-BEAM regimen has a survival benefit in lymphoma patients age </=50 years undergoing alloSCT. The addition of bortezomib has no impact on survival or incidence of GVHD.
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10.
Amifostine reduces gastro-intestinal toxicity after autologous transplantation for multiple myeloma
Malek, E., Gupta, V., Creger, R., Caimi, P., Vatsayan, A., Covut, F., Bashir, Q., Champlin, R., Delgado, R., Rondon, G., et al
Leukemia & lymphoma. 2018;59(8):1905-1912
Abstract
High-dose melphalan (HDM) followed by autologous hematopoietic cell transplantation (auto-HCT) remains the standard-of-care therapy for multiple myeloma (MM) even with the availability of proteasome inhibitors and immunomodulatory drugs. Gastrointestinal (GI) toxicity is the main cause of morbidity after HDM. Amifostine, a cytoprotective agent, may reduce HDM-associated GI toxicity. We conducted a case control study comparing HDM + auto-HCT with or without amifostine for MM patients. One hundred and seven patients treated at University Hospitals Cleveland Medical Center who received pre-transplant amifostine were compared to 114 patients treated at MD Anderson Cancer Center without use of this agent. Amifostine 740 mg/m(2) was administered as a bolus infusion at 24 h and 15 min before HDM. Patients' characteristics were similar in both the groups. Amifostine therapy was well tolerated without any significant adverse effects. Grade II or greater oral mucositis (27.1% vs 47.4%; p = .002), nausea (31.8% vs. 86.0%; p = .0001), vomiting (18.7% vs. 52.6%; p = .0001) and diarrhea (56.1% vs. 72.7%; p = .006) occurred less frequently in the amifostine-treated group. There was no discernable effect of amifostine on engraftment, progression-free or overall survival. Our results indicate that amifostine decreases GI toxicity while preserving anti-myeloma efficacy of HDM and auto-HCT.