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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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Characteristics of Distress and Support Group Participation in Caregivers of Older Allogeneic Hematopoietic Cell Transplantation Patients: A Single Institution Retrospective Review
Elko, T. A., Brown, S., Lobaugh, S., Devlin, S., Jakubowski, A. A., Perales, M. A., Maloy, M. A., Applebaum, A. J., Giralt, S. A., Levy, L., et al
Journal of the advanced practitioner in oncology. 2023;14(2):127-137
Abstract
Older patients with hematologic malignancies are increasingly considered for allogeneic hematopoietic cell transplant (allo-HCT). However, older patients often have increased comorbidities and thus may require an increased level of post-transplant care. These factors can contribute to increased caregiver distress, which has been associated with worsened health outcomes for caregivers and patients. To examine predictors of caregiver distress and support group participation in caregivers of older allo-HCT patients, we retrospectively reviewed charts of 208 patients aged 60 and older who underwent their first allo-HCT at our institution from 2014 through 2016. We systematically characterized and identified the incidence of caregiver distress and attendance in a caregiver support group from the start of conditioning through 1 year post allo-HCT. Evidence of caregiver distress and support group participation was recorded by reviewing clinical and/or social work documentation. We found that 20 caregivers (10%) endorsed stress and 44 caregivers (21%) attended our support group at least once. A patient's prior history of psychiatric diagnosis (p = .046) or the use of potentially inappropriate medications for older adults (p = .046) was found to be associated with caregiver stress. Caregivers who were spouses or partners of patients (p = .048) or caregivers of married patients were more likely to attend the support group (p = .007). While limited by retrospective design and likely underreporting, this study reveals factors associated with caregiver distress in the older allo-HCT caregiver population. This information can help providers identify caregivers at risk for distress and improve caregiver resources, which may improve both caregiver and patient outcomes.
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Patterns of CMV Infection After Letermovir Withdrawal in Recipients of Post-Transplant Cyclophosphamide Based Transplant
Lin, A., Brown, S., Chinapen, S., Lee, Y. J., Seo, S. K., Ponce, D. M., Shahid, Z., Giralt, S. A., Papanicolaou, G. A., Perales, M. A., et al
Blood advances. 2023
Abstract
Reactivation of latent cytomegalovirus (CMV) is increased in CMV seropositive (CMV+) recipients of allogeneic hematopoietic cell transplantation (allo HCT) using post-transplant cyclophosphamide (PT-Cy) based graft versus host disease prophylaxis. Letermovir, a novel DNA terminase complex inhibitor, reduces the incidence of clinically significant CMV infection (csCMVi) in this population; however, parameters that predict csCMVi after letermovir withdrawal are not well described. Here, we examined clinical and immunological parameters in 294 recipients of PT-Cy based allo HCT, including 157 CMV+ patients of whom 80 completed letermovir prophylaxis without csCMVi, and subsequently stopped letermovir. In this population, the median duration of letermovir exposure was 203 days (interquartile range (IQR): 160 - 250 days). After letermovir withdrawal, the 90-day cumulative incidence of csCMVi was 23.0% (14.3 - 32.8). There were no episodes of CMV end-organ disease. Hypo-gammaglobulinemia prior to letermovir discontinuation was predictive of csCMVi (hazard ratio: 0.33, 95% confidence interval: 0.12-0.93, p = 0.03), whereas T-cell and B-cell reconstitution prior to letermovir withdrawal were not predictive of csCMVi. Higher numbers of NK cells were found prior to letermovir withdrawal in patients that experienced csCMVi (median 202 versus 160, p = 0.03). In CMV+ recipients, CD3+CD4-CD8+ T-cell reconstitution was faster in CMV+ patients regardless of letermovir exposure. Taken together, these data suggest that csCMVi after letermovir withdrawal was frequent in patients treated with PT-Cy, despite prolonged exposure. Strategies to boost CMV specific adaptive immunity in patients with persistent hypo-gammaglobulinemia is a logical pathway to reduce csCMVi after letermovir withdrawal.
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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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5.
Improved GRFS after posttransplant cyclophosphamide-based vs ATG-based HLA-mismatched unrelated donor transplant
Jimenez Jimenez, A. M., Komanduri, K., Brown, S., Wang, T. P., Pereira, D. L., Goodman, M., Beitinjaneh, A., Lekakis, L. J., Chinapen, S., Devlin, S. M., et al
Blood advances. 2022
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Editor's Choice
Abstract
A common method to prevent graft versus host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT) from an HLA-mismatched unrelated donor (MMUD) is tacrolimus, methotrexate and anti-thymocyte globulin (ATG). The use of post-transplant cyclophosphamide (PTCy) demonstrated promise in a prospective trial for MMUD HCT. We compared one-year GVHD-free, relapse-free survival (GRFS) in 128 recipients of tacrolimus/methotrexate/ATG (ATG group, N = 46) with PTCy, mycophenolate mofetil, and tacrolimus or sirolimus (PTCy group, N = 82) based prophylaxis after MMUD HCT. Patients receiving HCT from a MMUD mismatched at ≥ 1 locus among HLA-A, -B, -C, and -DRB1 were included. The two groups were well matched for HCT indication, high-risk disease, and HCT comorbidity index, whereas more patients on PTCy received bone marrow (50% versus 26%, P = 0.01) and >1 locus HLA-mismatched grafts (30.5% vs. 2.2%, P = 0.001). The one-year GRFS was 16% (95% confidence interval: 8% - 31%) versus 54% (44% - 66%, P < 0.001) in the ATG and PTCy groups, respectively. The multivariable-adjusted hazard ratio (HR) for GRFS was 0.34 (0.21 - 0.55, P < 0.001) with the use of PTCy. The one-year overall survival (OS) in the ATG group was 45% (32% - 62%) versus 75% (66% - 85%) in the PTCy group (P < 0.001). Relapse incidence was similar. One-year non-relapse mortality was greater after ATG-based prophylaxis: (38%, 23% - 52%; versus 16%, 9% - 25%; P < 0.001). In summary, PTCy based prophylaxis resulted in superior GRFS and OS in recipients of MMUD.
PICO Summary
Population
Adults from 11 centres in USA, transplanted from a mismatched unrelated donor, mismatched at ≥ 1 locus among HLA-A, -B, -C, and -DRB1.
Intervention
Methotrexate 5 to 15 mg/m2 IV, on days 1, 3, 6, and 11 post-HCT, peritransplant dose-adjusted tacrolimus, and 5 to 7.5 mg/kg rabbit ATG, before allograft infusion. (ATG group, n= 46)
Comparison
50 mg/kg IV cyclophosphamide on days 3 and 4, post-allograft infusion (PTCy group, n= 82)
Outcome
The one-year GRFS was 16% (95% confidence interval: 8% - 31%) versus 54% (44% - 66%,) in the ATG and PTCy groups, respectively. The multivariable-adjusted hazard ratio (HR) for GRFS was 0.34 (0.21 - 0.55) with the use of PTCy. The one-year overall survival (OS) in the ATG group was 45% (32% - 62%) versus 75% (66% - 85%) in the PTCy group. Relapse incidence was similar. One-year non-relapse mortality was greater after ATG-based prophylaxis: (38%, 23% - 52%; versus 16%, 9% - 25%).
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High-dose Bendamustine, Etoposide, Cytarabine and Melphalan (BeEAM) Conditioning Prior to Autologous Transplantation for Patients with Multiple Myeloma
Solomon, S. R., Brown, S., Shegda, N., Jackson, K. C., Zhang, X., Bashey, A., Holland, H. K., Morris, L. E., Solh, M.
Transplantation and cellular therapy. 2022
Abstract
Single-agent high-dose melphalan (Mel) followed by autologous stem cell transplantation (ASCT) remains a standard of care in eligible patients with multiple myeloma (MM), and efforts to improve transplant outcomes by intensifying transplant conditioning have mostly failed. Bendamustine combines both alkylating and antimetabolite properties, can induce responses in MM resistant to other alkylators and represents a promising agent to combine with Mel prior to ASCT. We performed a phase II study to test the safety and efficacy of the high-dose chemotherapy combination of bendamustine, etoposide, cytarabine and melphalan (BeEAM) in newly diagnosed MM patients up to 70 years of age. The primary study endpoint was day +100 complete response rate. Sixty-five patients with a median (range) age of 59 (40, 69) years were transplanted from 2015-2020. Other characteristics included KPS<80%, HCT-CI≥3, ISS III, and high-risk FISH in 35%, 46%, 26% and 44% respectively. ASCT following BeEAM was well tolerated, and there were no non-relapse deaths through one-year post-transplant. Although at least one non-hematologic grade 3 toxicity was reported in 58 (89%) patients (including grade 3 febrile neutropenia in 48% and stomatitis/esophagitis in 28%), there were no grade ≥3 renal or hepatic toxicity and no grade ≥4 non-hematologic toxicity. Day +100 response rate was ≥CR1 and ≥VGPR1 in 40% and 89%, respectively. With a median f/u of 44 (13, 70) months, 3-year overall survival was 92%, 96% and 90% for all patients and those with standard- and high-risk FISH respectively. Corresponding values for 3-year progression-free survival was 57%, 72% and 40% respectively. When BeEAM-conditioned patients were compared to historical Mel-conditioned cohort, no significant differences were noted in relapse or survival outcomes in univariate or multivariable analysis. In summary, BeEAM was shown to be a safe and effective conditioning regimen prior to up-front autologous transplant for MM. Although the BeEAM regimen does not appear to offer a significant advantage over single-agent Mel, further studies combining bendamustine and melphalan is the front-line setting may be warranted.
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CD34-selected allogeneic hematopoietic cell transplantation for chronic myeloid leukemia in the tyrosine kinase era
Vaughn, J. L., Brown, S., Papadopoulos, E. B., Jakubowski, A. A., Tamari, R., Giralt, S. A., Ponce, D. M., Cho, C., Perales, M. A., Shaffer, B. C., et al
Bone marrow transplantation. 2022
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8.
Impact of omitting post-transplant minidose-methotrexate doses in allogeneic hematopoietic cell transplantation
Lin, A., Brown, S., Maloy, M., Ruiz, J. D., Devlin, S., DeRespiris, L., Proli, A., Jakubowski, A. A., Papadopoulos, E. B., Sauter, C. S., et al
Leukemia & lymphoma. 2022;:1-8
Abstract
Given prophylactic methotrexate (MTX) is often held in the setting of toxicity we investigated the impact of omitting minidose-MTX dose(s). Outcomes were compared between patients who had 1-3 doses omitted and those who received all four planned doses of minidose-MTX. Of 370 consecutive patients, 50 had MTX dose(s) omitted. When MTX was omitted, initial management was mycophenolate mofetil (MMF; 36/50 patients) with or without corticosteroids (14/50 patients). Rates of grade 3-4 acute GVHD were similar between groups. Omission of minidose-MTX resulted in an increased risk of chronic GVHD (cGVHD; HR 2.27; p = .024) and decreased overall survival (HR 1.61; p = .024). However, other transplant-related outcomes were comparable. In summary, omission of minidose-MTX doses was not associated with an increased risk of acute GVHD when an alternative was added (e.g. MMF ± corticosteroids). This did not abrogate the increased risk of cGVHD or decreased overall survival.
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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.
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10.
Prospective phase 2 trial of ixazomib after nonmyeloablative haploidentical peripheral blood stem cell transplant
Solomon, S. R., Solh, M., Zhang, X., Brown, S., Jackson, K. C., Holland, H. K., Morris, L. E., Bashey, A.
Blood advances. 2020;4(15):3669-3676
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Abstract
Proteasome inhibition results in extensive immunomodulatory effects that augment natural killer cell cytotoxicity and inhibit aspects of T-cell, B-cell, and dendritic cell function. We performed a phase 2 study that examined the effects of ixazomib for graft-versus-host disease (GVHD) prophylaxis (up to 12 cycles) with posttransplant cyclophosphamide and tacrolimus after standard nonmyeloablative haploidentical donor transplantation (HIDT). Ixazomib was started on day +5 (4 mg on days 1, 8, and 15 of a 28-day cycle), with dose reductions allowed in future cycles for toxicity. All patients received peripheral blood stem cells. Twenty-five patients were enrolled with a median age of 62 years (range, 35-77 years) who had acute leukemia (4), myelodysplastic syndrome (7), non-Hodgkin lymphoma/Hodgkin lymphoma/chronic lymphocytic leukemia (8), and myeloma (6). The hematopoietic cell transplant comorbidity index was ≥3 in 68% of the patients. After a median follow-up of 33.5 months, the cumulative incidence of relapse/progression at 1 year was 24% and 44% at 3 years, which failed to meet the statistically predefined goal of decreasing 1-year risk of relapse. Engraftment occurred in all patients with no secondary graft failure, and 3-year nonrelapse mortality (NRM) was 12%. Cumulative incidence of grade 3 to 4 acute GVHD was 8%, whereas moderate-to-severe chronic GVHD occurred in 19%. Nineteen patients survive with an estimated 1-year overall survival (OS) of 84% and 3-year OS of 74%. Hematologic and cutaneous toxicities were common but manageable. The substitution of ixazomib for mycophenolate mofetil (MMF) post-HIDT results in reliable engraftment, comparable rates of clinically significant GVHD, relapse and NRM, and favorable OS. This trial was registered at www.clinicaltrials.gov as # NCT02169791.