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Autologous stem cell transplant in fit patients with refractory or early relapsed diffuse large B-cell lymphoma that responded to salvage chemotherapy
Tun, A. M., Wang, Y., Maliske, S., Micallef, I., Inwards, D. J., Habermann, T. M., Porrata, L., Paludo, J., Bisneto, J. V., Rosenthal, A., et al
Haematologica. 2024
Abstract
Chimeric antigen receptor T-cell (CAR-T) therapy is the new standard of care in fit patients with refractory or early relapsed diffuse large B-cell lymphoma (DLBCL). However, there may still be a role for salvage chemotherapy (ST) and autologous stem cell transplant (ASCT) in certain circumstances (eg, lack of CAR-T resources, chemosensitive relapses, etc). We retrospectively studied 230 patients with refractory or early relapsed DLBCL who underwent ST and ASCT. Median line of ST was 1 (range 1-3). Best response before ASCT was complete response (CR) in 106 (46%) and partial response (PR) in 124 (54%) patients. Median follow-up after ASCT was 89.4 months. The median progression-free (PFS) and overall survival (OS) were 16.1 and 43.3 months, respectively. Patients relapsing between 6 to 12 months after frontline therapy had numerically better median PFS (29.6 months) and OS (88.5 months). Patients who required 1 line of ST, compared to those requiring >1 line, had better median PFS (37.9 vs 3.9 months; P = 0.0005) and OS (68.3 vs 12.0 months; P = 0.0005). Patients who achieved CR had better median PFS (71.1 vs 6.3 months; P.
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Outcomes of Patients With Classic Hodgkin Lymphoma Who Relapsed After Autologous Stem Cell Transplant
Tun, A. M., Wang, Y., Matin, A., Inwards, D. J., Habermann, T. M., Micallef, I., Johnston, P. B., Porrata, L., Paludo, J., Bisneto, J. V., et al
HemaSphere. 2023;7(4):e869
Abstract
Immune checkpoint inhibitors (ICIs) and brentuximab vedotin (BV) are novel agents for classic Hodgkin lymphoma, including relapse after autologous stem cell transplant (ASCT). However, their impact on survival post-ASCT relapse, in comparison with conventional therapy, is less known due to the lack of randomized controlled trials. Clinical characteristics and outcomes of 115 patients with relapse (or progression) after ASCT are studied. After a median follow-up of 8.59 years from post-ASCT relapse, the median progression-free survival (PFS) and overall survival (OS) were 0.91 and 5.07 years, respectively. Median lines of therapy after post-ASCT relapse was 2 (range, 1-12). The median PFS was not reached (NR) versus 1.11 versus 0.50 versus 0.85 versus 0.78 years (P = 0.006) and OS was NR versus 7.60 versus 3.08 versus 3.51 versus 3.17 years (P = 0.28) in patients first treated with ICIs versus BV versus investigational agents versus chemotherapy versus radiation therapy (RT). First-line treatment with novel agents (ie, ICIs and BV) was associated with superior outcomes compared with investigational agents and chemotherapy/RT with a median PFS of 1.65 versus 0.50 versus 0.79 years (P = 0.003) and a median OS of 7.60 versus 3.08 versus 3.32 years (P = 0.08). Regardless of lines of therapy, the treatment with ICIs had the most favorable outcome with a median PFS and OS of 3.98 and NR years, respectively. Allogeneic stem cell transplant (allo-SCT) was done in 23 patients (20%), and the median post-allo-SCT PFS and OS were 1.31 and 2.35 years, respectively. In conclusion, survival following post-ASCT relapse improves significantly when patients receive novel agents.
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3.
Long-term outcome of immunologic autograft engineering
Porrata, L. F., Inwards, D. J., Ansell, S. M., Micallef, I. N., Johnston, P. B., Villasboas, J. C., Paludo, J., Markovic, S. N.
EJHaem. 2022;3(2):488-491
Abstract
Our phase III trial reported that autograft-absolute lymphocyte count (A-ALC) improved survival post-autologous peripheral blood hematopoietic stem cell transplantation (APBHSCT) for a short-term follow-up of 2 years. We evaluated retrospectively in our phase III trial patients that the A-ALC still confers survival benefit with a longer follow-up. With a median follow-up of 127.6 months, patients infused with an A-ALC ≥ 0.5 × 10(9) cells/kg experienced better overall survival (HR = 0.392, 95% confidence of interval [CI]: 0.224-0.687, p < 0.001) and progression-free survival (HR = 0.413, 95% CI: 0.253-0.677), p < 0.0004). This study supports that A-ALC provides long-term survival benefit post APBHSCT.
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4.
Long-Term Health-Related Quality of Life of Autologous Hematopoietic Cell Transplantation Patients and Nontransplant Patients With Aggressive Lymphoma: A Prospective Cohort Analysis
Strouse, C. S., Larson, M. C., Ehlers, S. L., Yost, K. J., Maurer, M. J., Ansell, S. M., Inwards, D. J., Johnston, P. B., Micallef, I. N., Link, B. K., et al
JCO oncology practice. 2022;:Op2100694
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Abstract
PURPOSE This study assessed the long-term quality of life (QOL) of patients with aggressive lymphoma subtypes treated with autologous hematopoietic cell transplant (autoHCT) compared with those without history of transplant. METHODS Patient-reported QOL measures were prospectively gathered from patients enrolled in the Iowa/Mayo Specialized Program of Research Excellence Molecular Epidemiology Resource cohort with aggressive lymphoma subtypes. QOL was measured using the Functional Assessment of Cancer Therapy-General (FACT-G), Functional Assessment of Chronic Illness Therapy-Fatigue Scale, State-Trait Anxiety Inventory (STAI), and Profile of Mood States instruments and with a numeric rating scale for overall QOL and spiritual QOL. The autoHCT group and no HCT groups were compared at 3 years (FU3) and 6 years (FU6) after lymphoma diagnosis. RESULTS In total, 980 patients with lymphoma (106 autoHCT and 874 no HCT) diagnosed between 2002 and 2013 were included for analysis. The mean FACT-G total score was similar in the autoHCT and no HCT groups at FU3 (89.9 v 90.1, P = .64) and also at FU6 (91.5 v 89.6, P = .44). No differences between the autoHCT and no HCT groups were identified in the FACT subscales. The STAI identified lower anxiety in the autoHCT group by mean STAI1 (state) at FU3 (30.1 v 33.4, P < .01) and by mean STAI2 (trait) at FU6 (30.1 v 33.5, P = .02). No other clinically meaningful differences were identified between the two groups using the other QOL instruments. CONCLUSION Patients remaining in remission at 3 and 6 years after diagnosis had a high level of QOL with no significant differences associated with history of treatment with autoHCT.
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5.
Progression-Free Survival at 24 Months as A Landmark After Autologous Stem Cell Transplant in Relapsed or Refractory Diffuse Large B-cell Lymphoma
Tun, A. M., Maliske, S., Wang, Y., Inwards, D. J., Habermann, T. M., Micallef, I., Porrata, L., Paludo, J., Bisneto, J. V., Rosenthal, A., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) who achieve progression-free survival (PFS) at 24 months (PFS24) following immunochemotherapy (IC) have excellent overall survival (OS) comparable to that of the age- and sex-matched general population. However, a similar landmark has not been established for patients with relapsed or refractory (RR) DLBCL following frontline IC who are subsequently treated with salvage therapy followed by autologous stem cell transplant (ASCT). OBJECTIVE To evaluate the role of PFS24 as a landmark after ASCT in patients with RR DLBCL. STUDY DESIGN Patients with RR DLBCL after frontline R-CHOP or R-CHOP-like IC who underwent salvage therapy and ASCT at Mayo Clinic between July 2000 and December 2017 and University of Iowa between April 2003 and April 2020 were identified from institutional lymphoma and transplant databases. Clinical characteristics, treatment information, and outcome data were abstracted. PFS, OS, and post-ASCT relapse survival (PRS) were analyzed using Kaplan-Meier method, and cumulative incidences of relapse vs non-relapse mortality and different causes of death were compared accounting for competing events. RESULTS A total of 437 patients were identified. Median age at ASCT was 61 years (range 19-78), and 280 (64%) were male. After a median post-ASCT follow up of 8.0 years (95% CI 7.2-8.7), 215 patients had a relapse (or disease progression), 180 within 2 years and 35 after 2 years. For the entire cohort, post-ASCT relapse rate was much higher than non-relapse mortality rate (48.1 vs 9.1% at 5-years). Median PFS and OS after ASCT was 2.7 and 5.4 years, respectively. Lymphoma was the primary cause of death after ASCT. In contrast, for patients who had achieved PFS24 (n=220), rates of post-PFS24 relapse and non-relapse mortality were similar (14.8% and 12.3% at 5-years). Median PFS and OS after achieving PFS24 was 10.0 and 11.5 years, respectively. Lymphoma related and unrelated death rates were similar after achieving PFS24. For all patients who had a post-ASCT relapse, median PRS was 0.7 (95% CI 0.5-0.9) years, and late relapse (>2 vs ≤2 years after ASCT) was associated with better PRS (median 2.3 [1.7-4.8] vs 0.5 [0.3-0.7] years, p<0.001). CONCLUSION PFS24 is an important landmark associated with post-ASCT outcomes in patients with RR DLBCL following frontline IC.
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Infused autograft-absolute lymphocyte count predicts superior survival in Diffuse Large B-Cell Lymphoma patients post-autologous peripheral blood hematopoietic stem cell transplantation: a matched-control study
Porrata, L. F., Burglaster, E. A., Winters, J. L., Jacob, E., Inwards, D. J., Ansell, S. M., Micallef, I. N., Johnston, P. B., Villasboas, J., Paludo, J., et al
Transplantation and cellular therapy. 2021
Abstract
BACKGROUND Our group published a double phase III trial showing that patients infused with an autograft absolute lymphocyte count (A-ALC) = 0.5?×?10(9) cells/kg experienced superior survival post- autologous peripheral blood hematopoietic stem cell transplantation (APBHSCT). Based on the results from our phase III study as well as published retrospective studies, on April 1, 2017, our Bone Marrow Transplant Program changed our standard practice to collect an A-ALC = 0.5?×?10(9) cells/kg in addition to stem cells for lymphoma patients undergoing APBHSCT. OBJECTIVE The primary objective of the study was to continue to assess the prognostic ability of A-ALC by evaluation overall survival (OS) and progression-free survival (PFS) of diffuse large B-cell lymphoma (DLBCL) patients that underwent APBHSCT after April 1, 2017 compared with matched control groups in a 1:1:1 ratio with DLBCL patients infused with an A-ALC < 0.5?×?10(9) cells/kg and A-ALC = 0.5?×?10(9) cells/kg prior to April 1, 2017. STUDY DESIGN Using the GREEDY algorithm, 85 DLBCL patients (cases) infused with an A-ALC = 0.5?×?10(9) cells/kg after April 1, 2017 were matched in a 1:1:1 ratio with control groups of DLBCL patients transplanted prior to April 1, 2017: control 1: patients infused with an A-ALC < 0.5?×?10(9) cells/kg and control 2: patients infused with an A-ALC = 0.5?×?10(9) cells/kg prior April 1, 2017. Groups were matched regarding gender, age, stage, lactate dehydrogenase (LDH), performance status, extra-nodal disease, international prognostic index (IPI), and disease status prior to APBHSCT (complete response or partial response). Survival follow-up was truncated at 3 years from the date of transplant. RESULTS Cases, control 1 and control 2 were balanced to age (p?=?0.8); gender (p?=?0.9); LDH (p?=?0.6); performance status (p?=?0.5); extra-nodal disease (p?=?0.2); IPI (p?=?0.6); and disease status prior to APBHSCT (p =0.2). Cases and control 2 showed superior OS and PFS compared with control 1. Multivariate analysis including all patients continue to show that A-ALC = 0.5?×?10(9) cells/kg as an independent predictor for OS (HR?=?0.382, 95% CI?=?0.241-0.605, p < 0.0001) and PFS (HR?=?0.437, 95% CI?=?0.279-0.629, p < 0.0001). CONCLUSION Our match-control study continues to support the results of published retrospective studies and our Phase III study showing that the infusion of A-ALC is a prognostic factor for survival of DLBCL patients undergoing APBHSCT. Our studies support the practice of not only collecting enough stem cells for hematologic engraftment, but also enough immune effector cells (i.e., A-ALC) to improve clinical outcomes in DLBCL patients post-APBHSCT.
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7.
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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8.
Effect of time to relapse on overall survival in patients with mantle cell lymphoma following autologous haematopoietic cell transplantation
Riedell, P. A., Hamadani, M., Ahn, K. W., Litovich, C., Brunstein, C. G., Cashen, A. F., Cohen, J. B., Epperla, N., Hill, B. T., Im, A., et al
British journal of haematology. 2021
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Abstract
In young and fit patients with mantle cell lymphoma (MCL), intensive induction therapy followed by a consolidative autologous haematopoietic cell transplant (autoHCT) is the standard of care in the front-line setting. Recently, time-to-event analysis has emerged as an important risk assessment tool in lymphoma, though its impact in MCL is not well defined. We utilized the Center for International Blood and Marrow Transplant Research database to evaluate the effect of post-autoHCT time to relapse on overall survival (OS) over time in 461 patients who underwent autoHCT within 12 months of MCL diagnosis. On multivariate analysis, the impact of relapse on OS was greatest at the six-month [hazard ratio (HR) = 7·68], 12-month (HR = 6·68), and 18-month (HR = 5·81) landmark timepoints. Using a dynamic landmark model we demonstrate that adjusted OS at five years following each landmark timepoint improved with time for relapsing and non-relapsing patients. Furthermore, early relapse (<18 months) following autoHCT defines a high-risk group with inferior post-relapse OS. This retrospective analysis highlights the impact of time to relapse on OS in MCL patients undergoing up-front autoHCT and emphasizes the need to consider novel therapeutic approaches for patients suffering early relapse.
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ASTCT, CIBMTR, and EBMT clinical practice recommendations for transplant and cellular therapies in mantle cell lymphoma
Munshi, P. N., Hamadani, M., Kumar, A., Dreger, P., Friedberg, J. W., Dreyling, M., Kahl, B., Jerkeman, M., Kharfan-Dabaja, M. A., Locke, F. L., et al
Bone marrow transplantation. 2021
Abstract
Autologous (auto-) or allogeneic (allo-) hematopoietic cell transplantation (HCT) are accepted treatment modalities for mantle cell lymphoma (MCL). Recently, chimeric antigen receptor (CAR) T-cell therapy received approval for MCL; however, its exact place and sequence in relation to HCT is unclear. The ASTCT, CIBMTR, and the EBMT, jointly convened an expert panel to formulate consensus recommendations for role, timing, and sequencing of auto-, allo-HCT, and CAR T-cell therapy for patients with newly diagnosed and relapsed/refractory (R/R) MCL. The RAND-modified Delphi method was used to generate consensus statements. Seventeen consensus statements were generated; in the first-line setting auto-HCT consolidation represents standard-of-care in eligible patients, whereas there is no clear role of allo-HCT or CAR T-cell therapy, outside of a clinical trial. In the R/R setting, the preferential option is CAR T-cell therapy especially in MCL failing or intolerant to at least one Bruton's tyrosine kinase inhibitor, while allo-HCT is recommended if CAR T-cell therapy has failed or is not feasible. In the absence of contemporary evidence-based data, 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 MCL.
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Characteristics of late transplant-associated thrombotic microangiopathy (TA-TMA) in patients who underwent allogeneic hematopoietic stem cell transplantation
Heybeli, C., Sridharan, M., Alkhateeb, H. B., Villasboas Bisneto, J. J., Buadi, F. K., Chen, D., Dingli, D., Dispenzieri, A., Gertz, M. A., Go, R. S., et al
American journal of hematology. 2020