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1.
Impact of thiotepa dose-intensity in primary diffuse large B-cell lymphoma of the central nervous system undergoing autologous hematopoietic cell transplant with thiotepa/carmustine conditioning
Arshad, S., Fang, X., Ahn, K. W., Kaur, M., Scordo, M., Sauter, C. S., Furqan, F., Awan, F. T., Hamadani, M.
Bone marrow transplantation. 2023
Abstract
Thiotepa/carmustine (TT-BCNU) is a commonly used autologous transplant (ASCT) conditioning regimen for primary DLBCL of the CNS (PCNSL). The total thiotepa dose varies among TT-BCNU recipients, with some centers administering a total dose of 20 mg/kg, while others using 10 mg/kg. We retrospectively assessed the impact of thiotepa dose intensity on ASCT outcomes in 218 adult PCNSL patients who underwent a first ASCT with TT-BCNU conditioning and received either a total thiotepa dose of 10 mg/kg (TT-10 group; N = 90), or 20 mg/kg (TT-20 group; N = 128). The median follow-up of survivors was 22 months. The cumulative incidence of 1-year non-relapse mortality (NRM) for TT-10 and TT-20 cohorts were 6% (95%CI = 2-12%) vs. 4% (95%CI = 1-8%), respectively (p = 0.66). The 3-year cumulative incidence of relapse (15% vs. 13%; p = 0.67), progression-free survival (PFS) (71% vs. 80%; p = 0.25) and overall survival (OS) (79% vs. 83%; p = 0.56) were similar in the TT-10 and TT-20 groups, respectively. On multivariate analysis compared to TT-10, the TT-20 cohort was not associated with significantly different risk of NRM (Hazard ration [HR] = 0.77; p = 0.64), relapse/progression (HR = 0.87; p = 0.74), PFS (HR = 0.80; p = 0.48) or OS (HR = 1.10; p = 0.80). In conclusion thiotepa dose-intensity in TT-BCNU conditioning does not impact ASCT outcomes of PCNSL patients.
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2.
Efficacy, safety, and cost of mobilization strategies in multiple myeloma: a prospective, observational study
Dhakal, B., Zhang, M. J., Burns, L. J., Tang, X., Meyer, C., Mau, L. W., Nooka, A. K., Stadtmauer, E., Micallef, I. N., McGuirk, J., et al
Haematologica. 2023;108(8):2249-2254
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3.
Autologous hematopoietic cell transplantation versus whole-brain radiotherapy consolidation in primary central nervous system lymphoma: A systematic review and meta-analysis
Epperla, N., Reljic, T., Chowdhury, S. M., Ferreri, A. J. M., Kumar, A., Hamadani, M.
Hematological oncology. 2022
Abstract
The management of newly diagnosed primary central nervous system lymphoma (PCNSL) includes administration of high-dose methotrexate based regimens followed by consolidation therapy to minimize the risk of relapse. However, the best consolidation strategy (autologous hematopoietic cell transplant [auto-HCT] vs. whole-brain radiotherapy [WBRT]) is controversial. Hence, we performed a systematic review and meta-analysis of all randomized controlled trials that compared auto-HCT versus WBRT consolidation for patients with PCNSL after first-line treatment.The primary outcome was overall survival (OS), while the secondary outcomes included progression-free survival (PFS), response rates (overall response rate [ORR] and complete remission [CR]), relapse rate, treatment-related mortality (TRM), and neuropsychological adverse events. We performed a pooled analysis of the single-arm studies that incorporated auto-HCT or WBRT consolidation and evaluated neurocognitive outcomes. Only two studies met the inclusion criteria (n = 240). There was no significant difference in OS (HR = 1.50; 95% CI = 0.95-2.36), PFS (HR = 0.99; 95% CI = 0.44-2.22), ORR (RR = 1.48; 95% CI = 0.90-2.44), CR rate (RR = 1.21; 95% CI = 0.90-1.63), relapse rate (RR = 0.46; 95% CI = 0.05-4.28), and TRM (RR = 5.67; 95% CI = 1.01-31.91). The neuropsychological tests to assess neurocognitive domains were different and inconsistently reported in the two studies and therefore we were unable to perform a meta-analysis but provide a descriptive assessment. Both the studies showed a significant decline in the attention/executive function (based on the trail making test A and trail making test B) in those receiving WBRT compared to auto-HCT. We found 9 single-arm phase II studies that reported data on outcomes associated with either auto-HCT (5 studies) or WBRT (4 studies) consolidation. Of these, two studies (n = 43) reported data on neurocognitive decline following auto-HCT consolidation. Pooled proportion of patients with neurocognitive decline in these studies was 6% (95% CI, 0%-17%) for those receiving auto-HCT and there was no heterogeneity between studies (I(2) = 0%). Three studies (n = 122) reported data on neurocognitive decline following WBRT consolidation. Pooled proportion of patients with neurocognitive decline in these studies was 43% (95% CI, 11%-78%) for those receiving WBRT and there was high heterogeneity between studies (I(2) = 94%). There was significant heterogeneity between subgroups (p = 0.035). The outcomes were not significantly different in patients with PCNSL receiving auto-HCT or WBRT consolidation therapies, however, there is a higher degree of neurocognitive decline associated with WBRT compared to auto-HCT consolidation. The decision to choose a consolidation strategy needs to be individualized based on age, frailty, and co-morbidities.
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4.
Rap1A, Rap1B, and β-Adrenergic Signaling in Autologous HCT: A Randomized Controlled Trial of Propranolol
Johnson, A. K., Lorimer, E. L., Szabo, A., Wu, R., Shah, N. N., D'Souza, A., Chhabra, S., Hamadani, M., Dhakal, B., Hari, P., et al
The Yale Journal of Biology and Medicine. 2022;95(1):45-56
Abstract
Successful hematopoietic cell transplantation (HCT) depends on rapid engraftment of the progenitor and stem cells that will reestablish hematopoiesis. Rap1A and Rap1B are two closely related small GTPases that may affect platelet and neutrophil engraftment during HCT through their roles in cell adhesion and migration. β-adrenergic signaling may regulate the participation of Rap1A and Rap1B in engraftment through their inhibition or activation. We conducted a correlative study of a randomized controlled trial evaluating the effects of the nonselective β-antagonist propranolol on expression and prenylation of Rap1A and Rap1B during neutrophil and platelet engraftment in 25 individuals receiving an autologous HCT for multiple myeloma. Propranolol was administered for 1 week prior to and 4 weeks following HCT. Blood was collected 7 days (baseline) and 2 days (Day -2) before HCT, and 28 days after HCT (Day +28). Circulating polymorphonuclear cells (PMNC) were isolated and analyzed via immunoblotting to determine levels of prenylated and total Rap1A versus Rap1B. Twelve participants were randomized to the intervention and 13 to the control. Rap1A expression significantly correlated with Rap1B expression. Rap1B expression significantly correlated with slower platelet engraftment; however, this association was not observed in the propranolol-treated group. There were no significant associations between neutrophil engraftment and Rap1A or Rap1B expression. Post hoc exploratory analyses did not reveal an association between social health variables and Rap1A or Rap1B expression. This study identifies a greater regulatory role for Rap1B than Rap1A in platelet engraftment and suggests a possible role for β-adrenergic signaling in modulating Rap1B function during HCT.
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5.
ASTCT Clinical Practice recommendations for transplant and cellular therapies in multiple myeloma
Dhakal, B., Shah, N., Kansagra, A., Kumar, A., Lonial, S., Garfall, A., Cowan, A., Poudyal, B. S., Costello, C., Gay, F., et al
Transplantation and cellular therapy. 2022
Abstract
Over the past decade, therapeutic options in multiple myeloma (MM) have changed dramatically. Given the unprecedented efficacy of novel agents, the role of hematopoietic cell transplantation (HCT) in MM remains under scrutiny. Rapid advances in myeloma immunotherapy including the recent approval of chimeric antigen receptor (CAR) T-cell therapy will impact the MM therapeutic landscape. The American Society for Transplantation and Cellular Therapy (ASTCT) convened an expert panel to formulate clinical practice recommendations for role, timing, and sequencing of autologous (auto-HCT), allogeneic (allo-HCT) and CAR T-cell therapy for patients with newly diagnosed (NDMM) and relapsed/refractory MM (RRMM). The RAND-modified Delphi method was used to generate consensus statements. Twenty consensus statements were generated. The panel endorsed continued use of auto-HCT consolidation for patients with NDMM as a standard-of-care option, whereas in the front line allo-HCT and CAR-T were not recommended outside the setting of clinical trial. For patients not undergoing auto-HCT upfront, the panel recommended its use in first relapse. Lenalidomide as a single agent was recommended for maintenance especially for standard risk patients. In the RRMM setting, the panel recommended the use of CAR-T in patients with 4 or more prior lines of therapy. The panel encouraged allo-HCT in RRMM setting only in the context of clinical trial. The panel found RAND-modified Delphi methodology effective in providing a formal framework for developing consensus recommendations for the timing and sequence of cellular therapies for MM.
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6.
Autologous hematopoietic cell transplantation in diffuse large B-cell limphoma after 3 or more lines of prior therapy: evidence of durable benefit
Mei, M., Hamadani, M., Ahn, K. W., Chen, Y., Kharfan-Dabaja, M. A., Sauter, C., Herrera, A. F.
Haematologica. 2022
Abstract
Not available.
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7.
Post-relapse survival in Waldenstrom macroglobulinemia patients experiencing therapy failure following autologous transplantation
Ahmed, S., Zhao, Q., Hanel, W., Qazilbash, M. H., Patel, K., Narra, R., Kansagra, A., Iqbal, M., Awan, F. T., Christian, B., et al
Hematological oncology. 2021
Abstract
Waldenström macroglobulinemia (WM) is a rare B-cell lymphoproliferative malignancy. Autologous hematopoietic cell transplantation (auto-HCT) is considered in a subset of WM patients with relapsed disease. While registry data has shown a benefit for auto-HCT in relapsed WM, there is a paucity of data on outcomes of patients relapsing after auto-HCT. Eligibility criteria included adult patients with relapsed/refractory WM who underwent auto-HCT between 2007 and 2017. The primary endpoint was post-relapse overall survival (PR-OS). Secondary endpoints were to identify factors prognostic of PR-OS. Of the 48 patients with WM who underwent auto-HCT, 22 (46%) experienced relapse following auto-HCT. Median PR-OS of relapsed WM patients after auto-HCT (n = 22) was not reached (NR) (95% confidence interval [CI]: 17.5 months-NR). Among patients who relapsed <1 year versus =1 year from auto-HCT, the median PR-OS was 18.4 months (95%CI: 0.8-NR) months and NR (95%CI: 17.5-NR), respectively (P=0.06). Of note, disease status at the time of transplant, CR/VGPR versus PR did not appear to impact PR-OS. The median PR-OS was significantly longer in patients who received ibrutinib in the post-transplant setting compared to those who did not (NR vs 18.4 months, 95%CI: 9.1-NR, P=0.02). On univariable analysis, the presence of complex karyotype (RR=4.87, 95% CI=1.22-19.53) and a higher number of prior lines of therapy (RR=1.81, 95% CI=1.23-2.67) were associated with a significantly higher risk of relapse. This is the only study to date that evaluated outcomes of WM patients who relapsed following auto-HCT and provides a benchmark for future trials evaluating survival following auto-HCT relapse. This article is protected by copyright. All rights reserved.
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8.
Budesonide Prophylaxis Reduces the Risk of Engraftment Syndrome After Autologous Hematopoietic Cell Transplantation in Multiple Myeloma
Dhakal, B., Thapa, B., Dong, H., Tarima, S., Chhabra, S., D'Souza, A., Drobyski, W., Abid, M., Shah, N., Fenske, T., et al
Clinical lymphoma, myeloma & leukemia. 2021
Abstract
BACKGROUND Engraftment syndrome (ES) after autologous hematopoietic cell transplantation (AHCT) in multiple myeloma (MM) encompasses a continuum of periengraftment complications characterized by noninfectious fever, rash, diarrhea, and capillary leak features. PATIENTS AND METHODS We analyzed the ES outcomes in 257 consecutive patients MM patients who underwent AHCT at our institution from 12/2017 to 11/2019 with budesonide prophylaxis (3 mg PO daily at day +5 post-AHCT till the time of discharge) (N = 109) and no prophylaxis (N = 148). RESULTS The rates of ES were significantly higher in the no prophylaxis group versus prophylaxis group [69 (46%) vs. 23 (21%); P< .001]. There was no significant difference in length of stay (LOS) [mean 15 (±3.2) vs. 16 (±2.8); P = .27] and 30-day readmission [9 (6%) vs. 8 (7%); P = .81] between the no prophylaxis and prophylaxis groups, respectively. On adjusted analysis, budesonide prophylaxis was associated with a significantly lower risk of developing ES [odds ratio (OR) 0.29 (95% confidence interval [CI], 0.16-0.51); P< .0001]. There was no difference in the 30-day readmission rates [OR 1.12 (95% CI, 0.41-3.03); P = .81], but a trend for shorter LOS in the prophylaxis group [7.3% reduction in LOS (95% CI, -14.4% to 0%); P = .06]. CONCLUSION Budesonide prophylaxis significantly reduces the risk of ES in MM patients undergoing AHCT. These promising results suggest the need for a randomized study investigate the role of budesonide for ES prophylaxis.
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9.
Outcomes Associated With Thiotepa-Based Conditioning in Patients With Primary Central Nervous System Lymphoma After Autologous Hematopoietic Cell Transplant
Scordo, M., Wang, T. P., Ahn, K. W., Chen, Y., Ahmed, S., Awan, F. T., Beitinjaneh, A., Chen, A., Chow, V. A., Dholaria, B., et al
JAMA oncology. 2021
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Editor's Choice
Abstract
IMPORTANCE Primary central nervous system lymphoma (PCNSL) requires induction and consolidation to achieve potential cure. High-dose therapy and autologous hematopoietic cell transplant (AHCT) is an accepted and effective consolidation strategy for PCNSL, but no consensus exists on the optimal conditioning regimens. OBJECTIVE To assess the outcomes in patients with PCNSL undergoing AHCT with the 3 most commonly used conditioning regimens: thiotepa/busulfan/cyclophosphamide (TBC), thiotepa/carmustine (TT-BCNU), and carmustine/etoposide/cytarabine/melphalan (BEAM). DESIGN, SETTING, AND PARTICIPANTS This observational cohort study used registry data from the Center for International Blood and Marrow Transplant Research registry. The Center is a working group of more than 380 transplantation centers worldwide that contributed detailed data on HCT to a statistical center at the Medical College of Wisconsin, Milwaukee. The participant data were from 603 adult patients with PCNSL who underwent AHCT as initial, or subsequent, consolidation between January 2010 and December 2018. Patients were excluded if they had a non-Hodgkin lymphoma subtype other than diffuse large B-cell lymphoma, systemic non-Hodgkin lymphoma, or HIV; received an uncommon conditioning regimen; or were not in partial remission or complete remission prior to AHCT. Statistical analysis was performed from July 5, 2020, to March 1, 2021. INTERVENTIONS Patients received 1 of 3 conditioning regimens: TBC (n?=?263), TT-BCNU (n?=?275), and BEAM (n?=?65). MAIN OUTCOMES AND MEASURES The primary outcome was progression-free survival. Secondary outcomes included hematopoietic recovery, incidence of relapse, nonrelapse mortality, and overall survival. RESULTS Of 603 patients, the mean age was 57 (range, 19-77) years and 318 (53%) were male. The 3-year adjusted progression-free survival rates were higher in the TBC cohort (75%) and TT-BCNU cohort (76%) compared with the BEAM cohort (58%) (P?=?.03) owing to a higher relapse risk in the BEAM cohort (hazard ratio [HR], 4.34; 95% CI, 2.45-7.70; P?.001). In a multivariable regression analysis, compared with the TBC cohort, patients who received TT-BCNU had a higher relapse risk (HR, 1.79; 95% CI, 1.07-2.98; P?=?.03), lower risk of nonrelapse mortality (NRM) (HR, 0.50; 95% CI, 0.29-0.87; P?=?.01), and similar risk of all-cause mortality more than 6 months after HCT (HR, 1.54; 95% CI, 0.93-2.55; P?=?.10). Age of 60 years or older, Karnofsky performance status less than 90, and an HCT-comorbidity index greater than or equal to 3 were associated with lower rates of survival across all 3 cohorts. Subgroup analyses demonstrated that patients aged 60 years and older had considerably higher NRM with TBC. CONCLUSIONS AND RELEVANCE In this cohort study, thiotepa-based conditioning regimen was associated with higher rates of survival compared with BEAM, despite higher rates of early toxic effects and NRM; these findings may assist clinicians in choosing between TBC or TT-BCNU based on patient and disease characteristics.
PICO Summary
Population
Adults with primary central nervous system lymphoma (PCNSL) who underwent autologous transplantation as initial, or subsequent, consolidation and were reported to the CIBMTR registry (n=603)
Intervention
Thiotepa/busulfan/cyclophosphamide conditioning (TBC, n=263), thiotepa/carmustine conditioning (TT-BCNU, n=275)
Comparison
Carmustine/etoposide/cytarabine/melphalan conditioning (BEAM, n=65).
Outcome
The mean age was 57 (range, 19-77) years and 318 (53%) were male. The 3-year adjusted progression-free survival rates were higher in the TBC cohort (75%) and TT-BCNU cohort (76%) compared with the BEAM cohort (58%), owing to a higher relapse risk in the BEAM cohort (hazard ratio [HR], 4.34). In a multivariable regression analysis, compared with the TBC cohort, patients who received TT-BCNU had a higher relapse risk (HR, 1.79), lower risk of nonrelapse mortality (NRM) (HR, 0.50), and similar risk of all-cause mortality more than 6 months after HCT (HR, 1.54). Age of 60 years or older, Karnofsky performance status less than 90, and an HCT-comorbidity index greater than or equal to 3 were associated with lower rates of survival across all 3 cohorts. Subgroup analyses demonstrated that patients aged 60 years and older had considerably higher NRM with TBC.
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10.
Autologous Transplant versus Chimeric Antigen Receptor T-cell Therapy for Relapsed DLBCL in Partial Remission
Shadman, M., Pasquini, M. C., Ahn, K. W., Chen, Y., Turtle, C. J., Hematti, P., Cohen, J. B., Khimani, F., Ganguly, S., Merryman, R. W., et al
Blood. 2021
Abstract
The relative efficacy of autologous hematopoietic cell transplant (auto-HCT) versus chimeric antigen receptor T-cell (CAR-T) therapy in diffuse large B-cell lymphoma (DLBCL) patients who achieve a partial remission (PR) after salvage chemotherapy is not known. Using the Center for International Blood & Marrow Transplant Research registry database, we identified adult DLBCL patients who received either an auto-HCT (2013-2019) or CAR-T treatment with axicabtagene ciloleucel (2018-2019) while in a PR by CT or PET scan. We compared the clinical outcomes between the two cohorts using univariable and multivariable regression models after adjustment for relevant baseline and clinical factors. In the univariable analysis, the 2-year progression-free survival (52% vs. 42% ; p=0.1) and the rate of 100-day non-relapse mortality (4% vs. 2% ; p=0.3) were not different between the 2 cohorts but consolidation with auto-HCT was associated with a lower rate of relapse/progression (40% vs. 53% ; p=0.05) and a superior overall survival (OS) (69% vs. 47% ; p=0.004) at 2-years. In the multivariable regression analysis, treatment with auto-HCT was associated with a significantly lower risk of relapse/progression rate (HR=1.49; p=0.01) and a superior OS (HR=1.63; p=0.008). In patients with DLBCL in a PR after salvage therapy, treatment with auto-HCT was associated with a lower incidence of relapse and a superior OS compared with CAR-T. These data support the role of auto-HCT as the standard-of-care in transplant-eligible patients with relapsed DLBCL in PR after salvage therapy.