Management of post-autologous transplant relapse in patients with T-cell lymphomas.

Autologous hematopoietic cell transplantation (AHCT) is often used as a consolidation for patients with peripheral T-cell lymphomas (PTCLs) due to the poor prognosis associated with this heterogenous group of disorders. However, a significant number of patients will experience post-AHCT disease relapse. Here, we report a retrospective study of consecutive 124 patients with PTCLs who underwent AHCT from 2008 to 2020. With a median follow-up of 6.01 years following AHCT, 49 patients (40%) experienced disease relapse. As expected, more patients who were not in first complete remission experienced post-AHCT relapse. Following relapse, majority of the patients (70%) receiving systemic therapies intended as bridging to curative allogeneic HCT. However, only 18 (53%) patients eventually underwent allogeneic HCT. The estimated 3-year OS among patients proceeding to allogeneic HCT was 72% (95% CI 46%-87%). Our report details the pattern of post-AHCT relapse and the management of relapsed disease using different therapeutic modalities.

A Pilot Study of UM171-Expanded Cord Blood Grafts for Tandem Auto/Allogeneic Hematopoietic Cell Transplant in High and Ultra-High-Risk Myeloma Patients.

BACKGROUND: Multiple myeloma (MM) remains associated with a poor outcome, particularly in patients with advanced disease and high-risk (HR) cytogenetics. To date, the only curative treatment is allogeneic (allo) hematopoietic cell transplantation (HCT), but high incidences of graft versus host disease (GVHD), non-relapse mortality (NRM) and disease progression remain important obstacles. Cord blood (CB) transplantation has been associated with low rates of relapse and chronic (c) GVHD, but its use has declined because of high incidences of infections, severe acute GVHD and high NRM. In other hematologic malignancies, UM171-expanded CB transplants have led to improved outcomes, allowing for the selection of smaller, better HLA-matched units. OBJECTIVE: We aimed to investigate the safety and feasibility of single UM171-expanded single CB unit transplantation in frontline tandem auto/allo HCT for HR/ultra-HR MM patients. STUDY DESIGN: Newly diagnosed MM patients ≤ 65 years with an ISS stage II/III and del17p, t4,14, t14,16, t14,20, del1p or +1q, R-ISS 3, ≥ 2 cytogenetic abnormalities, or plasma cell leukemia without a sibling donor and availability of a 5-7/8 matched CB graft with ≥ 0.5 x 105 CD34+/kg and ≥ 1.5 x 107 TNCs/kg were eligible to this phase I/II prospective study (ClinicalTrials.gov NCT03441958). After induction and autologous HCT, patients received a reduced intensity conditioning regimen and were infused with 7-day UM171-expanded CD34+ cells, along with the lymphocytes contained in the CD34-negative fraction. The primary endpoints were feasibility of UM171 expansion, safety, kinetics of engraftment, incidences and maximum grades of acute and cGVHD at 1 and 2 years, assessment of measurable residual disease (MRD) and quality of life (QoL). RESULTS: Between 05/2018 and 11/2021, 20 patients were enrolled. One patient had an unsuccessful CB expansion with UM171, leaving 19 patients with a median age of 56 years. Median CD34+ cell dose infused after expansion was 4.62 x 106/kg (range: 0.79-5.76). Median times to achieve absolute neutrophil counts of 0.1 and 0.5 x 109/L were D+6 and D+10.5; median time to reach ≥ 20 x 109/L platelets was D+36. Full donor chimerism was achieved in all cell lineages by D+120 in recipients of reduced intensity conditioning. Cumulative incidences of grade II-IV, grade III-IV acute GVHD and moderate/severe cGVHD at 12 months were 68.4% (95% CI: 46-90), 5.3% (95% CI: 0-16%), and 10.5% (95% CI: 0-25%), respectively. With a median follow-up of 2.9 years (range: 0.46-5.3), cumulative incidences of relapse, PFS, OS and NRM at 3 years were 36.8% (95% CI: 14-59), 47.4% (95% CI: 29-76), 68.4% (95% CI: 50-93) and 15.8% (95%CI: 0-33), respectively. Median time to complete immunosuppression discontinuation was D+238. No unexpected adverse events were observed. Only one of 7 patients alive at 2 years with negative MRD at transplant has relapsed. Non-relapsing patients had a QoL after transplant similar to the general population. SIGNIFICANCE: UM171-expanded CB transplant in HR/ultra-HR myeloma patients is feasible and allows the use of single CB units with a low risk of cGVHD. Patients with negative pre-transplant MRD might benefit most from a UM171-expanded CB transplant.

Outcomes of adults with refractory or relapsed acute myeloid leukemia treated with azacitidine and venetoclax compared to other therapies: a multicenter retrospective study.

This study reports characteristics and outcomes of adults who received Azacitidine-Venetoclax (AZA-VEN) compared to other salvage therapies (NO-AZA-VEN) as first salvage therapy for acute myeloid leukemia (AML). The clinical data of 81 patients with a diagnosis of relapsed or refractory AML were analyzed. The ORR was comparable for both groups (55% vs 57%, p = 0.852). Median OS (6.8 vs 11.2 months, p = 0.053) and median RFS (6.9 vs 11.2 months, p = 0.488) showed a trend in favor of the NO-AZA-VEN group. OS was significantly longer with NO-AZA-VEN for ELN 2022 risk category sub-group, patients under 60 years old, primary AML and for patients who underwent allo-hematopoietic stem cell transplant after salvage therapy. There was no statistical difference in complications of treatment such as febrile neutropenia, intensive care unit stay, septic shock and total parenteral nutrition. Those results do not support the preferential use of AZA-VEN over other regimens in R/R acute myeloid leukemia.

Improved outcomes of UM171-expanded cord blood transplantation compared with other graft sources: real-world evidence.

Cord blood (CB) transplantation is hampered by low cell dose and high nonrelapse mortality (NRM). A phase 1-2 trial of UM171-expanded CB transplants demonstrated safety and favorable preliminary efficacy. The aim of the current analysis was to retrospectively compare results of the phase 1-2 trial with those after unmanipulated CB and matched-unrelated donor (MUD) transplants. Data from recipients of CB and MUD transplants were obtained from the Center for International Blood and Marrow Transplant Research (CIBMTR) database. Patients were directly matched for the number of previous allogeneic hematopoietic stem cell transplants (alloHCT), disease and refined Disease Risk Index. Patients were further matched by propensity score for age, comorbidity index, and performance status. Primary end points included NRM, progression-free survival (PFS), overall survival (OS), and graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) at 1 and 2 years after alloHCT. Overall, 137 patients from CIBMTR (67 CB, 70 MUD) and 22 with UM171-expanded CB were included. NRM at 1 and 2 years was lower, PFS and GRFS at 2 years and OS at 1 year were improved for UM171-expanded CBs compared with CB controls. Compared with MUD controls, UM171 recipients had lower 1- and 2-year NRM, higher 2-year PFS, and higher 1- and 2-year GRFS. Furthermore, UM171-expanded CB recipients experienced less grades 3-4 acute GVHD and chronic GVHD compared with MUD graft recipients. Compared with real-world evidence with CB and MUD alloHCT, this study suggests that UM171-expanded CB recipients may benefit from lower NRM and higher GRFS. This trial was registered at www.clinicaltrials.gov as #NCT02668315.

Bortezomib Maintenance After Allogeneic Transplantation in Newly Diagnosed Myeloma Patients Results in Decreased Incidence and Severity of Chronic GVHD.

Allogeneic hematopoietic cell transplantation (HCT) has curative potential in myeloma but remains hampered by high rates of relapse and chronic graft-versus-host disease (GVHD). We hypothesized that bortezomib (BTZ) as maintenance therapy after allo HCT could not only decrease the incidence of relapse but also the incidence and severity of chronic GVHD. The primary endpoint of this study was to determine whether BTZ maintenance decreases the incidence and severity of chronic GVHD using National Institutes of Health (NIH) criteria. The secondary endpoints were to determine the immunosuppression burden, organ involvement and survival (overall survival, progression-free survival) in patients either receiving or not receiving BTZ. In this retrospective study, we compared the outcome of 46 myeloma patients who received BTZ after upfront tandem auto-allo HCT between 2008 and 2020 to 61 patients without maintenance. We explored the impact of BTZ maintenance on incidence and severity of chronic GVHD using the 2014 NIH criteria. At 2 years, incidences of overall (61.2% versus 83.6%; P = .001), and moderate/severe chronic GVHD (44.5% versus 77.0%; P = .001) were significantly lower in BTZ recipients who had less mouth (43% versus 67%; P = .018) and eyes (9% versus 41%; P = .001) involvement at initial diagnosis. We report a lower use of systemic steroids (45.1% versus 76.4%; P < .001), mycophenolate mofetil (15.5% versus 28.2%; P = .031) and tacrolimus (34.5% versus 70.6%; P < .001) in BTZ recipients. Probability of being alive and off systemic immunosuppressants at 3 years was 77% in BTZ recipients and 56% in controls (P = .046). To date, there is no difference in survival between both groups. In summary, BTZ maintenance improved incidence and severity of chronic GVHD and should be considered as a valid option in myeloma patients receiving upfront tandem auto-allo HCT.

Impact of Implementing a Bendamustine-Based Conditioning Regimen on Outcomes of Autologous Stem Cell Transplantation in Lymphoma while Novel Cellular Therapies Emerge.

With the advent of new cellular and targeted therapies, treatment options for relapsed and refractory (r/R) lymphomas have multiplied, and the optimal approach offering the best outcomes remains a matter of passionate debate. High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is still considered a treatment option for patients with chemosensitive lymphoma when cure is the expected goal. The myeloablative conditioning regimen preceding the stem cell infusion is considered the effective component of this approach. Carmustine (BCNU)-based preparative regimens, such as BEAM and BEAC, are considered the standard of care and have shown efficacy and low nonrelapse mortality (NRM). Comparative studies between conditioning regimens have failed to identify a better option. After a BCNU drug shortage in Canada followed by a steep increase in price, we elected to substitute BCNU for bendamustine (benda) in the preparative regimen. The purpose of this substitution was to improve response while preserving safety and controlling costs. From May 2015 to May 2018, a total of 131 consecutive lymphoma patients received benda-EAM conditioning. These patients were compared with 96 consecutive patients who received BCNU-based conditioning from January 2012 to May 2015. Apart from conditioning, supportive care measures were the same in the 2 groups. Patients receiving benda were older (55.7 years versus 51.1 years; P = .002). The development of grade ≥3 mucositis was more frequent with benda conditioning (39.5% versus 7.8%; P < .001) leading to a greater requirement for parenteral nutrition (48.9% versus 21.9%; P < .001). A transient creatinine increase >1.5 times the upper limit of normal (15.3% versus 4.2%; P < .008) and intensive care unit admission (6.9% versus 1.1%; P < .029) were more frequent with benda; however, there were no between-group differences in cardiac, pulmonary, or liver toxicity and NRM. With a median follow-up of 48 months for the benda group and 60 months for the BCNU group, benda was associated with significantly better progression-free survival (71% versus 61%; P = .040; hazard ratio [HR], 1.6; 95% confidence interval [CI], 1.0 to 2.7) and overall survival (86% vs 71%; P = .0066; HR, 2.6; 95% CI, 1.3 to 5.4) compared with BCNU-based conditioning regimens. While novel therapies emerge, our study demonstrates that benda-EAM is safe and effective and should be considered a valid alternative to BCNU conditioning to improve outcomes of patients with chemosensitive r/R lymphomas undergoing ASCT.

Chimeric antigen receptor T-cell therapy in adults with B-cell acute lymphoblastic leukemia.

Chimeric antigen receptor T-cell (CAR-T) therapy has transformed treatment paradigms for relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) in children and younger adults. We performed a systematic review to investigate the published literature on efficacy and toxicity of CAR-T therapy in adults with r/r B-ALL. We searched MEDLINE, Embase, and the Cochrane Library for prospective interventional studies and included published studies of ≥5 patients with median age at enrollment of ≥18 years. Risk of bias was assessed with a modified Institute of Health Economics tool. A total of 2566 records were assessed; 16 studies involving 489 patients were included in the final analysis. The mean complete remission (CR) rate was 81% and the measurable residual disease (MRD)-negative remission rate was 81% at 4 weeks after CAR-T infusion. With median follow-up across studies of 24 months, the cumulative 12-month probabilities of progression-free survival (PFS) and overall survival (OS) were 37% (95% CI, 26-48) and 57% (95% CI, 49-65), respectively. Relapse occurred in 40.3% of cases; target antigen was retained in 73.2% of relapses. Across studies, any grade of cytokine release syndrome (CRS) occurred in 82% of patients (95% CI, 61-95) and grade 3 or higher CRS in 27% (95% CI, 18-36). Neurotoxicity of any grade occurred in 34% of patients (95% CI, 24-47) and grade 3 or higher in 14% (95% CI, 1-25). In summary, CAR-T therapy achieves high early remission rates in adults with r/r B-ALL and represents a significant improvement over traditional salvage chemotherapy. Relapses are common and durable response remains a challenge.

Real-World Outcomes of Autologous and Allogeneic Hematopoietic Stem Cell Transplantation for Relapsed/Refractory Hodgkin Lymphoma in the Era of Novel Therapies: A Canadian Perspective.

Despite high cure rates with frontline therapy for Hodgkin lymphoma (HL), approximately 30% of patients will relapse or develop primary refractory disease (R/r). Autologous hematopoietic stem cell transplantation (autoHSCT) is the standard of care for R/r disease, and allogeneic HSCT (alloHSCT) is a curative option for patients in second relapse. Novel agents are being incorporated for the treatment of R/r HL, such that the optimal timing of transplantation is currently being challenged. In this rapidly evolving field, we sought to offer a Canadian perspective on the optreatment of R/r HL and demonstrate the role and effectiveness of both autoHSCT and alloHSCT for the treatment of R/r HL. This single-center retrospective study examined outcomes in 89 consecutive patients with R/r HL treated with autoHSCT between January 2007 and December 2019. A total of 17 patients underwent alloHSCT either as a tandem auto-allo approach or as salvage therapy. With a median follow-up of 5.0 years, the estimated 5-year PFS and OS for patients undergoing autoHSCT were 57.5% (95% confidence interval [CI], 45.2% to 68.0%) and 81.3% (95% CI, 70.0% to 88.8%), respectively. Corresponding values for patients who underwent alloHSCT were 76.5% (95% CI, 48.8% to 90.4%) and 82.4% (95% CI, 54.7% to 93.9%). Nonrelapse mortality at 0% at 100 days and 9.4% at 5 years post-autoHSCT and 0% and 5.9%, respectively, post-alloHSCT. The cumulative incidence of acute graft-versus-host disease (GVHD) at day +100 was 35.3% (95% CI, 17.7% to 62.3%), and that of chronic GVHD at 1 year was 23.5% (95% CI, 6.9% to 45.8%). Both autoHSCT and alloHSCT provide robust and prolonged disease control New agents should be used as a bridge to improve the curative potential of these definitive cellular therapies.

Donor Age and Non-Relapse Mortality: Study of Their Association after HLA-Matched Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndrome.

The purpose of this retrospective study was to study the correlation between donor age (DA) and non-relapse mortality (NRM) and relapse incidence (RI) among patients treated with allogeneic hematopoietic cell transplantation (aHCT) for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) in a single Canadian center. Data from 125 consecutive patients transplanted with a matched related or unrelated donor between 2015 and 2020 were analyzed using multivariable models. After a median follow-up of 2.8 years, the cumulative incidences of NRM and relapse were 19% and 35% at 5 years. Despite being independently associated with NRM and relapse-free survival (RFS), DA was not associated with RI. The independent determinants of NRM in addition to DA were patient age and hematopoietic cell transplantation comorbidity index (HCT-CI), independently of donor kinship. The effect of DA on NRM was found to be significantly increased over the age of 50 years. DA was not associated with incidence of acute graft-versus-host disease (aGVHD) but showed an association with the occurrence of chronic GVHD (cGVHD). In conclusion, younger donors should be favored to limit NRM and increase RFS in HLA-matched aHCT. The etiological mechanisms behind the association of DA with higher NRM remain to be elucidated.