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The Simplified Comorbidity Index predicts non-relapse mortality in reduced-intensity conditioning allogeneic haematopoietic cell transplantation
Elias, S., Brown, S., Devlin, S. M., Barker, J. N., Cho, C., Chung, D. J., Dahi, P. B., Giralt, S., Gyurkocza, B., Jakubowski, A. A., et al
British journal of haematology. 2023
Abstract
Comorbidity assessment before allogeneic haematopoietic cell transplantation (allo-HCT) is essential for estimating non-relapse mortality (NRM) risk. We previously developed the Simplified Comorbidity Index (SCI), which captures a small number of 'high-yield' comorbidities and older age. The SCI was predictive of NRM in myeloablative CD34-selected allo-HCT. Here, we evaluated the SCI in a single-centre cohort of 327 patients receiving reduced-intensity conditioning followed by unmanipulated allografts from HLA-matched donors. Among the SCI factors, age above 60, mild renal impairment, moderate pulmonary disease and cardiac disease were most frequent. SCI scores ranged from 0 to 8, with 39%, 20%, 20% and 21% having scores of 0-1, 2, 3 and ≥4 respectively. Corresponding cumulative incidences of 3-year NRM were 11%, 16%, 22% and 27%; p = 0.03. In multivariable models, higher SCI scores were associated with incremental risks of all-cause mortality and NRM. The SCI had an area under the receiver operating characteristic curve of 65.9%, 64.1% and 62.9% for predicting 1-, 2- and 3-year NRM versus 58.4%, 60.4% and 59.3% with the haematopoietic cell transplantation comorbidity index. These results demonstrate for the first time that the SCI is predictive of NRM in patients receiving allo-HCT from HLA-matched donors after reduced-intensity conditioning.
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Survival with Axicabtagene Ciloleucel in Large B-Cell Lymphoma
Westin, J. R., Oluwole, O. O., Kersten, M. J., Miklos, D. B., Perales, M. A., Ghobadi, A., Rapoport, A. P., Sureda, A., Jacobson, C. A., Farooq, U., et al
The New England journal of medicine. 2023
Abstract
BACKGROUND In an analysis of the primary outcome of this phase 3 trial, patients with early relapsed or refractory large B-cell lymphoma who received axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor T-cell therapy, as second-line treatment had significantly longer event-free survival than those who received standard care. Data were needed on longer-term outcomes. METHODS In this trial, we randomly assigned patients with early relapsed or refractory large B-cell lymphoma in a 1:1 ratio to receive either axi-cel or standard care (two to three cycles of chemoimmunotherapy followed by high-dose chemotherapy with autologous stem-cell transplantation in patients who had a response). The primary outcome was event-free survival, and key secondary outcomes were response and overall survival. Here, we report the results of the prespecified overall survival analysis at 5 years after the first patient underwent randomization. RESULTS A total of 359 patients underwent randomization to receive axi-cel (180 patients) or standard care (179 patients). At a median follow-up of 47.2 months, death had been reported in 82 patients in the axi-cel group and in 95 patients in the standard-care group. The median overall survival was not reached in the axi-cel group and was 31.1 months in the standard-care group; the estimated 4-year overall survival was 54.6% and 46.0%, respectively (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.54 to 0.98; P = 0.03 by stratified two-sided log-rank test). This increased survival with axi-cel was observed in the intention-to-treat population, which included 74% of patients with primary refractory disease and other high-risk features. The median investigator-assessed progression-free survival was 14.7 months in the axi-cel group and 3.7 months in the standard-care group, with estimated 4-year percentages of 41.8% and 24.4%, respectively (hazard ratio, 0.51; 95% CI, 0.38 to 0.67). No new treatment-related deaths had occurred since the primary analysis of event-free survival. CONCLUSIONS At a median follow-up of 47.2 months, axi-cel as second-line treatment for patients with early relapsed or refractory large B-cell lymphoma resulted in significantly longer overall survival than standard care. (Funded by Kite; ZUMA-7 ClinicalTrials.gov number, NCT03391466.).
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3.
Association between busulfan exposure and survival in patients undergoing a CD34+ selected stem cell transplantation
Tamari, R., Scordo, M., Kunvarjee, B., Proli, A., Lin, A., Flynn, J. R., Cho, C., Devlin, S. M., Klein, E., Boulad, F., et al
Blood advances. 2023
Abstract
Busulfan is an alkylating drug routinely used in conditioning regimens for allogeneic hematopoetic cell transplantation (allo-HCT). A myeloablative conditioning regimen including busulfan is commonly used in patients undergoing a T cell depleted (TCD), allo-HCT, but data on the optimal busulfan pharmacokinetic (PK) exposure in this setting are limited. Between 2012 and 2019, busulfan PK was performed to target a area-under-curve (AUC) exposure of 55-66mg*h/L over 3 days using an non-compartmental analysis (NCA) model (Phoenix WinNonLin, Certara USA, Princeton, NJ). We retrospectively re-estimated busulfan exposure following the published population PK (popPK) model (InsightRX, Inc, 2021) and correlated it with outcomes. To define an optimal exposure, univariable models were performed with P splines wherein hazard ratio plots were drawn and thresholds were found graphically as the points where the confidence interval crossed 1. Cox proportional hazard models and competing risk models were used for analyses. 176 patients were included with a median age 59 years (2-71). Using the popPK model, the median cumulative busulfan exposure was 63.4 mg*h/L (46.3-90.7). The optimal threshold was at the upper limit of the lowest quartile (59.5 mg*h/L). 5-yr overall survival with busulfan exposure ≥59.5 vs. <59.5 mg*h/L was 67% (95% CI 59-76%) vs. 40% (95% CI 53%-68%), respectively, p=0.02, and this association remained in a multivariate -analyses (HR 0.5, 95% 0.29, 0.88, p=0.02). In patients undergoing a TCD allo-HCT, busulfan exposure is significantly associated with overall survival. Using a published popPK model to optimize exposure may significantly improve OS.
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4.
Reduced Intensity Compared to Non-myeloablative Conditioning in Patients with Non-Hodgkin Lymphoma undergoing Allogeneic Hematopoietic Stem Cell Transplantation
Nath, K., Peterson, K., Brown, S., Devlin, S., Rodriguez, N., Barker, J., Giralt, S., Gyurkocza, B., Jakubowski, A., Papadopoulos, E., et al
Transplantation and cellular therapy. 2023
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Editor's Choice
Abstract
BACKGROUND . Reduced intensity (RIC) and non-myeloablative (NMA) conditioning are preferred for patients with non-Hodgkin lymphoma (NHL) receiving allogeneic hematopoietic stem cell transplantation (allo-HCT). Although prior studies have suggested that higher-intensity regimens within RIC-NMA conditioning are associated with inferior outcomes in patients with NHL, the optimal conditioning regimen remains unknown. OBJECTIVES AND STUDY DESIGN . We performed a retrospective single-center analysis to determine outcomes of adult patients with B- and T-cell NHL who underwent allo-HCT and received either RIC or NMA conditioning between March 2008 - December 2019. RIC regimens included fludarabine-cyclophosphamide-thiotepa-4Gy-total body irradiation (Flu-Cy-TT-4Gy-TBI), fludarabine-melphalan (Flu-Mel), fludarabine-cyclophosphamide-4Gy-total body irradiation (Flu-Cy-4Gy-TBI) and fludarabine-busulfan-4 (Flu-Bu-4). The NMA regimen included fludarabine-cyclophosphamide-2Gy-total body irradiation (Flu-Cy-2Gy-TBI). The primary outcome was overall survival. Secondary outcomes included progression-free survival, non-relapse mortality and the incidence of acute and chronic graft-vs-host-disease (GvHD). RESULTS . Of 279 transplanted patients (median age, 58 years), 110 received RIC (55% Flu-Mel, 38% Flu-Cy-TT-4Gy-TBI, 6% Flu-Bu-4, 1% Flu-Cy-4Gy-TBI) and 169 received NMA conditioning with Flu-Cy-2Gy-TBI. With a median of 64 months of follow-up from allo-HCT, there was no significant difference in overall survival between the NMA and RIC groups (median not reached [NR] vs 103 months, respectively. P = 0.1), and this was maintained on multivariable analysis. Similarly, after adjustment for all independently significant covariates (age, Karnofsky performance status, HCT-CI, disease histology), the regression analysis showed no significant difference in progression-free survival with RIC compared to NMA conditioning (hazard ratio [HR] 1.38; 95% CI 0.92 - 2.09, P = 0.24). On univariable analysis, there was no significant difference in non-relapse mortality between RIC and NMA conditioning (100-day estimates: 10.0% vs. 1.8%, respectively, P = 0.5). After adjustment for age, ethnicity, Karnofsky performance score, HCT-CI, GvHD prophylaxis and donor source, RIC conditioning was associated with a significantly higher incidence of non-relapse mortality compared to NMA conditioning (HR 2.61, 95% CI 1.04 - 6.52, P = 0.039). On multivariable analysis, compared with the Flu-Cy-2Gy-TBI regimen, the RIC cohort had higher rates of grade II-IV (HR, 2.25; 95% CI, 1.31 - 3.86; P = 0.002) and grade III-IV acute GvHD (HR, 5.62; 95% CI, 2.03 - 15.6; P < 0.001). CONCLUSION . The findings of this study suggest that NMA conditioning with Flu-Cy-TBI-2Gy may be considered over more intensive RIC regimens for patients with NHL undergoing allo-HCT.
PICO Summary
Population
Adults with B- or T-cell non-Hodgkin lymphoma who underwent allogeneic stem cell transplant (allo-HSCT) at a single centre in USA (n=279)
Intervention
Reduced intensity conditioning (RIC) with or without total body irradiation (n=110)
Comparison
Non-myeloablative (NMA) conditioning (n=169)
Outcome
With a median of 64 months of follow-up from allo-HCT, there was no significant difference in overall survival between the NMA and RIC groups (median not reached [NR] vs 103 months, respectively), and this was maintained on multivariable analysis. Similarly, after adjustment for all independently significant covariates (age, Karnofsky performance status, HCT-CI, disease histology), the regression analysis showed no significant difference in progression-free survival with RIC compared to NMA conditioning (hazard ratio [HR] 1.38; 95% CI 0.92 - 2.09). On univariable analysis, there was no significant difference in non-relapse mortality between RIC and NMA conditioning (100-day estimates: 10.0% vs. 1.8%, respectively). After adjustment for age, ethnicity, Karnofsky performance score, HCT-CI, GvHD prophylaxis and donor source, RIC conditioning was associated with a significantly higher incidence of non-relapse mortality compared to NMA conditioning (HR 2.61, 95% CI 1.04 - 6.52). On multivariable analysis, compared with the Flu-Cy-2Gy-TBI regimen, the RIC cohort had higher rates of grade II-IV (HR, 2.25; 95% CI, 1.31 - 3.86) and grade III-IV acute GvHD (HR, 5.62; 95% CI, 2.03 - 15.6).
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Ionizing radiation exposure after allogeneic hematopoietic cell transplantation
Cho, C., Maloy, M. A., Devlin, S. M., Aras, O., Dauer, L. T., Jakubowski, A. A., Papadopoulos, E. B., Perales, M. A., Rappaport, T. S., Giralt, S. A.
Bone marrow transplantation. 2022
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Conditioning regimens are associated with distinct patterns of microbiota injury in allogeneic hematopoietic cell transplantation
Shouval, R., Waters, N. R., Gomes, A. L. C., Zuanelli Brambilla, C., Fei, T., Devlin, S. M., Nguyen, C. L., Markey, K. A., Dai, A., Slingerland, J. B., et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2022
Abstract
PURPOSE The gut microbiota is subject to multiple insults in allogeneic-hematopoietic cell transplantation (allo-HCT) recipients. We hypothesized that preparative conditioning regimens contribute to microbiota perturbation in allo-HCT. EXPERIMENTAL DESIGN This was a retrospective study that evaluated the relationship between conditioning regimens exposure in 1,188 allo-HCT recipients and the gut microbiome. Stool samples collected from 20 days before transplantation up to 30 days after were profiled using 16S rRNA sequencing. Microbiota injury was quantified by changes in α-diversity. RESULTS We identified distinct patterns of microbiota injury that varied by conditioning regimen. Diversity loss was graded into three levels of conditioning-associated microbiota injury (CMBI) in a multivariable model that included antibiotic exposures. High-intensity regimens, such as total body irradiation (TBI)-thiotepa-cyclophosphamide, were associated with the greatest injury loss (CMBI III). In contrast, the non-myeloablative regimen fludarabine-cyclophosphamide with low-dose TBI (Flu/Cy/TBI200) had a low-grade injury (CMBI I). The risk of acute graft-versus-host disease correlated with CMBI degree. Pre-transplant microbial compositions were best preserved with Flu/Cy/TBI200, whereas other regimens were associated with loss of commensal bacteria and expansion of Enterococcus. CONCLUSIONS Our findings support an interaction between conditioning at the regimen level and the extent of microbiota injury.
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7.
Evaluation of Melphalan Exposure in Lymphoma Patients Undergoing BEAM and Autologous Hematopoietic Cell Transplant
Dahi, P. B., Lin, A., Scordo, M., Flynn, J. R., Devlin, S. M., Ruiz, J. D., DeRespiris, L., Carlow, D., Cho, C., Lahoud, O. B., et al
Transplantation and cellular therapy. 2022
Abstract
High dose melphalan is one of the main cytotoxic DNA alkylating agents and is used in many transplant conditioning regimens. Studies have shown a wide range of drug exposure when a traditional weight-based dose of melphalan is used. The optimal melphalan dose in BEAM [carmustine (B), etoposide (E), cytarabine (A), melphalan (M)], which results in maximum efficacy with acceptable toxicity, is unknown. In this pharmacokinetic (PK) analysis of 105 patients with lymphoma undergoing BEAM-autologous hematopoietic cell transplantation (AHCT), we initially estimated melphalan exposure as area-under-the-curve (AUC) by a non-compartmental analysis, and subsequently compared it with a newly developed two-compartment population-PK model. The two models correlated closely with each other. We found that the traditional fixed weight-based dosing of propylene glycol-free (captisol-enabled) melphalan in BEAM results in a wide variation in exposure as estimated by both models. Higher melphalan exposure was significantly associated with increased metabolic toxicities but did not seem to impact progression-free survival. While our study suggests a melphalan AUC of 8 mg*h/L to be a potential target in BEAM, larger prospective studies using personalized PK-directed melphalan dosing are needed to determine the optimal melphalan exposure in lymphomas.
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Reduced-intensity conditioning hematopoietic stem cell transplantation for chronic lymphocytic leukemia and Richter's transformation
Lahoud, O. B., Devlin, S. M., Maloy, M. A., Roeker, L. E., Dahi, P. B., Ponce, D. M., Gyurkocza, B., Koehne, G., Young, J. W., Castro-Malaspina, H. R., et al
Blood advances. 2021;5(14):2879-2889
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Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) may potentially cure patients with chronic lymphocytic leukemia (CLL) and Richter's transformation (CLL-RT) or CLL without RT, but the impact of novel agents on HSCT is unclear. CLL-RT patients have a grave prognosis, and their outcomes after HSCT are uncertain. We conducted a retrospective analysis of all 58 CLL patients, including 23 CLL-RT patients, who underwent reduced intensity conditioning (RIC) HSCT at Memorial Sloan Kettering Cancer Center (New York, NY) between September 2006 and April 2017. With a median follow-up of 68 months (range, 24-147 months), 5-year progression-free survival (PFS) was 40% (95% confidence interval [CI], 28%-56%), and overall survival (OS) was 58% (95% CI, 48%-74%). The 1-year graft-versus-host disease/relapse-free survival (GRFS) was 38% (95% CI, 25%-50%). Patients with CLL-RT and CLL patients without RT had comparable outcomes. In both cohorts, treatment-sensitive response and ≤3 previous lines of therapy produced superior PFS and OS. Outcomes were agnostic to adverse cytogenetic and molecular features. Novel agents did not have a negative impact on HSCT outcomes. Total body irradiation (TBI)-containing RIC yielded inferior PFS, OS, and GRFS. CLL-RT patients older than age 55 years who had an HSCT Comorbidity Index score of ≥2 demonstrated inferior OS. This study, which is the largest series of RIC-HSCT for patients with CLL-RT, provides evidence supporting RIC-HSCT in early remission courses for patients with CLL-RT and poor-risk CLL patients. TBI-containing RIC should be considered with caution.
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Toxicities of high-dose chemotherapy and autologous hematopoietic cell transplantation in older patients with lymphoma
Dahi, P. B., Lee, J., Devlin, S. M., Ruiz, J., Maloy, M., Rondon-Clavo, C., Petrlik, E., Tamari, R., Shah, G., Scordo, M., et al
Blood advances. 2021;5(12):2608-2618
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Abstract
High-dose chemotherapy and autologous hematopoietic cell transplantation is an effective consolidation therapy in lymphoma; however, its use in elderly patients has been limited because of concerns for greater toxicity in this group. We investigated the toxicities of carmustine, etoposide, cytarabine, and melphalan (BEAM) and autologous hematopoietic cell transplantation (AHCT) in 346 patients in 2 age groups: 279 patients aged 60 to 69 years and 67 patients aged ≥70 years. The majority developed severe toxicities; the most common were febrile neutropenia, gastrointestinal, infections, and cardiovascular. Older patients were at higher risk for grade ≥3 cardiovascular toxicities (hazard ratio [HR], 3.36; 95% confidence interval [CI], 2.25-5.00; P < .001) and skin toxicities (HR, 2.45; 95% CI, 1.08-5.54, P = .032). In the older group, nonrelapse mortality at 100 days and at 2 years was 2.99% (95% CI, 0.55-9.32) and 6.2% (95% CI, 1.97-13.95), respectively, vs 1.79% (95% CI, 0.68-3.92) and 2.91% (95% CI, 1.37-5.42), respectively, in the younger group. When adjusting for the number of grade ≥3 toxicities within the first 100 days, older patients had a 1.71-fold (95% CI, 1.08-2.71) increased risk for progression or death relative to younger patients. Although BEAM followed by AHCT is effective, it is associated with significant organ toxicities, especially in patients aged ≥70 years. Interventions to mitigate toxicities while maintaining efficacy are much needed.
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Fractionated Infusion of Hematopoietic Progenitor Cells Does Not Improve Neutrophil Recovery or Survival in Allograft Recipients
Tamari, R., Brown, S., Devlin, S. M., Kosuri, S., Maloy, M. A., Ponce, D. M., Sauter, C., Shaffer, B., Dahi, P., Young, J. W., et al
Transplantation and cellular therapy. 2021
Abstract
BACKGROUND Allogeneic hematopoietic cell transplantation (HCT) offers a potentially curative therapy in patients with hematologic malignancies; however, non-relapse mortality (NRM) remains a concern. Strategies to improve neutrophil recovery and immune reconstitution are needed to decrease NRM. Murine models of allogeneic HCT suggest that fractionated hematopoietic progenitor cell (HPC) infusion may improve engraftment through improved access of HPCs to a viable hematopoietic niche. OBJECTIVES The primary objective was to determine the impact of fractionated versus unfractionated (bulk) infusions of HPCs on the time to achieve neutrophil engraftment. Secondary objectives included the effect of fractionated vs. bulk infusion of HPC on platelet engraftment, immune reconstitution, the incidence of acute graft-versus-host disease (GVHD; grade II-IV), NRM and overall survival (OS). STUDY DESIGN In this randomized phase 2 study, patients with hematologic malignancies undergoing allogeneic HCT were randomized to receive HPC infusion as a bulk (Bulk Arm) or in fractions (Fractionated Arm): 4 × 10E6 CD34+ cells/kg recipient weight infused on day 0, with the remaining HPCs CD34+ cell selected then infused on days 2, 4 and 6 post-HCT, in equally distributed aliquots. Randomization was stratified by type of transplant, unmodified (i.e. T cell replete graft) vs. CD34+ cell selected (T cell depleted graft). Patients whose donor failed to collect at least 7 × 10E6 CD34+ cells/kg recipient weight received bulk HPC infusions regardless of randomization, for safety. These patients continued HCT on study but were replaced until each arm reached the pre-specified accrual target. Per protocol, these patients were not included in this modified intent to treat analysis. RESULTS One hundred and sixteen patients were enrolled. Donors of 42 patients failed to mobilize the minimum CD34+ cell dose (7 × 10E6 cells/kg recipient weight) and were excluded from the analysis. Of the 74 evaluable patients, 38 were randomized to the Bulk Arm and 36 to the Fractionated Arm. All patients engrafted. Median time to ANC of ≥ 500 was 11 days on both arms. Day +180 median CD4+ cell count was 179 cells/µl in the Bulk Arm and 111 cells/µl in the Fractionated Arm (p=0.779). The cumulative incidences of grades II-IV acute GVHD on post-transplant day 100 were 32% vs. 17% in pts in the Bulk vs. Fractionated Infusion Arms, respectively (p=0.131). Two patients on the Bulk Infusion arm experienced grades 3-4 GVHD, while none on the Fractionated Infusion arm. The 4-year OS was 60% and 62% for patients in the Bulk vs. Fractionated Arms (p=0.414), respectively. The 4-year cumulative incidences of NRM and relapse were similar. CONCLUSIONS fractionated infusion of HPCs in allotransplant recipients did not impact neutrophil or CD4+ cell recovery, NRM, relapse or OS when compared to bulk HPC infusion. We also observed that, with current mobilization techniques, it was unlikely that more than 60% of healthy donors would be able to collect more than 7 × 10(6) CD34+ cells/kg recipient weight for adult recipients.