Special supplement from 2024 ASCO Annual Meeting

Abstract number: e1901. Evolving patterns of transplant strategies for mantle cell lymphoma in the era of BTK inhibitors and CAR-T therapy.

Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma. In recent years, the prognosis has improved thanks to Bruton’s tyrosine kinase (BTK) inhibitors and chimeric antigen receptor-T cell (CAR-T) therapy. Whether autologous hematopoietic stem cell transplantation (auto-HCT) after ibrutinib and high-dose cytarabine (HD-ARAC) induction is necessary for this context is unclear. Moreover, CAR-T provides better outcomes than allogeneic-HCT (allo-HCT) in chemorefractory disease and early relapse after auto-HCT. Maddukuri et al., evaluated the outcomes (overall survival [OS] and progression-free survival [PFS]) of transplantation in a retrospective cohort of 71 patients (mainly Caucasian) with MCL at Penn State Cancer Institute between 1993 and 2023. Strategies of transplant included auto-HCT (n=30), allo-HCT (n=32), and CAR-T (n=9). Disease status at transplant was complete remission (CR) 52.1% (n=37), primary induction failure or relapsed/refractory 36.6% (n=26), and partial remission (PR) 11.3% (n=8). Relapsed and refractory MCL (n=4) patients received CAR-T whereas patients achieving CR 1 (n=8) and PR 1 (n=1) received auto-HCT. The median follow-up was 3.1 years. At the follow-up, OS at 1 year and 3 years was 93.3% and 85.9% for auto-HCT, 62.5% and 52.9% for allo-HCT, and 88.9% and 76.2% for CAR-T therapy, respectively (p = 0.007). PFS at 1-year and 3 years was 86.3% and 75.0% for auto-HCT, 50.0% and 43.3% for allo-HCT, and 66.7% and 66.7% for CAR-T therapy (p = 0.03). The primary cause of death was disease progression (n=10) and transplant-related mortality (n=9). In conclusion, CR at the time of transplant improved long-term outcomes in MCL.

Abstract number: 7073. Survival outcomes after autologous stem cell transplantation in T follicular helper type lymphoma.

Peripheral T cell lymphoma comprises a heterogeneous group of generally aggressive lymphomas, of which the most common is T follicular helper-type lymphoma. Patients with Lugano classification stages II-IV or adverse prognostic indicators are eligible for auto-HCT. Allo-HCT is associated with greater toxicity and transplantation-related mortality than auto-HCT. In this retrospective cohort, 218 patients were evaluated between 1997 and 2023 at the MD Anderson Cancer Center, of which 84 (39%) underwent auto-HCT. Survival analysis was performed with Kaplan-Meier curves and comparisons were made using log-rank tests. Most patients had advanced-stage disease (92% with stage III or IV) and elevated lactate dehydrogenase (LDH) (89%). The most common first-line treatments were CHOP (37%) followed by CHOEP (14%) and a combination of brentuximab with either CHP or CHEP (13%). Interestingly, individuals who underwent auto-HCT exhibited a notably greater overall survival (p < 0.01) in comparison to those who did not receive auto-HCT. The cohort's median PFS following initial treatment was 12.5 months, and its median OS was 40.3 months (see Table 1 of original research).

Abstract number: e19043. Survival benefit of autologous transplant (ASCT) for mantle cell lymphoma (MCL) in the California Cancer Registry (CCR).

The addition of ibrutinib to high-dose cytarabine (HD-ARAC) induction followed by intravenous rituximab and ibrutinib maintenance, enhanced front-line treatment of MCL according to the first results of the TRIANGLE prospective trial. However, socioeconomic status is an important consideration for these therapies because for people with low income or a lack of access to medicines in public health facilities, a strategy of transplant could still improve outcomes. Maranzano et al., presented data from the CCR that included MCL patients diagnosed from January 1, 2000, to December 31, 2020. The endpoint was to evaluate the role of ASCT and the influence of social determinants of health (SDH) in a diverse real-world population of MCL patients. Univariate Cox proportional hazards modeling for lymphoma-specific survival (LSS) was performed. Then a stepwise multivariable regression incorporated those variables significant at p ≤ 0.10. Socioeconomic status (SES) variables were reported using census-block group data at diagnosis. Among the patients, 5740 belonged to different ethnic groups: Non-Hispanic (NH) Whites (n = 4038); NH Blacks (n = 175); Hispanics (n = 1057); Asian/Pacific Islanders (n = 400). The overall cohort's median overall survival (OS) was 4.4 years, with a median follow-up of 33 months (IQR 9–76). Patients with ASCT (n=652, 11%) had a better median (OS) than those without ASCT (14.2 years vs. 3.7 years, respectively, p<0.001). At 100 days, the transplant-related mortality (TRM) was 2.5%. Age ≥ 70 years (hazard ratio [HR] 1.71, p<0.001), ASCT (HR 0.54, p<0.001), diagnosis after 2013 (HR 0.78, p<0.001), Charlson comorbidity index (Ref 0; 1-2 HR 1.22, p<0.001; 3+ HR 1.94, p<0.001), married (HR 0.86, p=0.003), NCI/NCCN treatment center (HR 0.77, p<0.001), higher education (top 40% with a high school diploma vs. bottom 20%, HR 0.70, p<0.001), higher overall SES (medium vs. low SES tertile, HR 0.81, p<0.003), and increased community poverty (middle 40% vs. bottom 20%, HR 1.14, p=0.043) were significant predictors of LSS in the multivariable analysis. The authors suggest that ASCT in select patients results in a durable response with low TRM. To prevent worse outcomes, it is important to identify socially disadvantaged patients early in the course of their illness.

Abstract number: e1903. Relapsed Hodgkin lymphoma autologous stem cell transplant long term follow up.

Salvage therapy followed by high-dose chemotherapy and auto-HCT is considered the standard of care for relapsed Hodgkin lymphoma (HL) patients. In this study, the authors reported 30-year outcomes for patients with HL treated with auto-HCT. The cohort included 35 patients who were evaluated between 1992 and 2022. Carmustine, etoposide, and melphalan (CEM, 1992–2005) and carmustine, etoposide, cytarabine, and melphalan (BEAM, 2006 to present) were the preparative regimens. In 2018, 13 patients received brentuximab vedotin as part of their post-transplant consolidation therapy added to BEAM. Nine out of fifteen (60%) patients who received CEM had a complete response (CR). Twenty patients were on BEAM, and 16/20 (80%) of them had a CR (Fisher's exact test, p=0.27). Following a median of 13 years (range 1–23), the actual 10-year rates of disease-free survival (DFS) and overall survival (OS) are 52% and 64%, respectively.

Adverse events included S. epidermidis sepsis (3 patients), E. coli sepsis (3 patients), and esophageal perforation that led to death in 1 patient. In this cohort, the most frequent late complication was cardiomyopathy.

Abstract number: 7032. Epcoritamab + R-DHAX/C in transplant-eligible patients (pts) with high-risk relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL).

Allogeneic hematopoietic cell transplant (allo-HCT) is the sole curative therapy option in DLBCL pts with recurrence after chimeric antigen receptor T-cell (CAR-T) therapy, while autologous (auto)-HCT remains the standard of care for DLBCL pts with chemosensitive initial late relapse. However, many patients don´t receive auto-HCT due to insufficient response to salvage therapy. For this reason, Karimi et al. assessed the effectiveness of epcoritamab (a CD3xCD20 bispecific antibody) in conjunction with rituximab, dexamethasone, cytarabine, and either oxaliplatin or carboplatin (R-DHAX/C) in pts with R/R DLBCL who were eligible for auto-HCT, including high-risk pts (those who progressed within 12 months from the end of first-line therapy or primary refractory). In the absence of a comparator arm, 29 pts eligible for transplant received R-DHAX/C and epcoritamab (2 step-up doses, then 24- or 48-mg full doses) in 21-day cycles (QW, Cycles 1–3). The primary endpoint was the overall response rate (ORR). 24 patients (83%) were classified as high-risk at baseline, 19 patients (66%) as primary refractory illness (no response or recurrence within 6 months of starting therapy), and 3 patients (10%) as having received previous CAR-T therapy.

According to Kaplan-Meier estimates, 60% of patients continued to be progression-free at 24 months, while 90% of pts who proceeded to auto-HCT (n=16) and 60% of pts who continued epcoritamab without ASCT (n=5) remained progression-free. The complete response (CR) rate was 69% and the ORR was 76% (see Table 1 of original research). At 24 months, an estimated 86% of patients were still alive. Without any fatal treatment related adverse events (TEAEs), thrombocytopenia (76%), anemia (59%), nausea (48%), and neutropenia (48%), were the most frequent TEAEs of any grade. In conclusion, this study supports further evaluation of epcoritamab plus R-DHAX/C for the salvage therapy for patients with R/R DLBCL. This scheme followed for auto-HCT eligible patients offers the best ORR in the long-term follow-up.

Donor lymphocyte infusion (DLI) after allogeneic hematopoietic cell transplantation (allo-HCT) for hematological malignancies.

Despite the routine use of DLI at allo-HCT centers worldwide, no true consensus has been defined concerning indications, prerequisites, and application details. Recently, the European Society for Blood and Marrow Transplantation (EBMT) has attempted to provide guidance, in the 2024 version of the EBMT Handbook. Given the absence of prospective data in most publications, these recommendations are mostly based on retrospective studies and expert consensus. Here is a summary of are some of the most relevant key points.

Indications for DLI: 

1.     Prophylactic DLI

·       Common practice

o   High-risk disease (as defined by the European LeukemiaNet 2022 criteria)

o   Transplantation in advanced or refractory disease

o   Ex-vivo lymphodepleted allo-HCT

·       Can be considered

o   Non-myeloablative conditioning

o   Abscence of druggable targets

2.     Pre-emptive DLI

·       Common practice

o   Mixed chimerism

o   Persistent minimal residual disease (MRD)

o   Molecular or cytogenetic relapsed

·       Can be considered

o   Infections

3.     Therapeutic DLI

·       Common practice

o   Hematological relapse

o   Extramedullary relapse

·       Can be considered

o   Post-transplantation lymphoproliferative disease

The interval between two consecutive DLIs in prophylactic settings should be at least 6 weeks, whereas in pre-emptive or therapeutic settings the delay can be shorter (usually 4 weeks is acceptable).

Recommended pre-requisites for DLI: 

At least day 90 days after transplantation (might be amended based on type of donor, graft source, graft-versus-host disease (GVHD) prophylaxis, and conditioning regimens).

·       Absence of infection.

·       No requirement of systemic immunosuppressive medications for 3–6 weeks.

·       Considerations for previous or ongoing GVHD in cases of:

o   Prophylactic DLI: active acute or chronic GVHD is considered an absolute contraindication. A history of cortico-sensitive acute GVHD (grade 2–4), or moderate or severe chronic GVHD, are defined as relative contraindications.

o   Pre-emptive or therapeutic DLI: although a history of acute GVHD (grade 2–4), or moderate or severe chronic GVHD do not serve as a contraindication for DLI, it is crucial to carefully assess the benefit–risk balance with the patient. DLI administration must be approached with utmost caution under these circumstances, depending also on the timing of GVHD episodes in relation to relapse and DLI.

·       A dose escalating regimen should be used if more than one DLI is planned, as this has been shown to reduce the risk of DLI-induced GVHD (Table 1 of the original publication).

Table 2 of the original publication summarized some disease-specific considerations. Essentially, for myeloid neoplasms, sensitivity to DLI is high in myeloproliferative neoplasms and intermediate in acute myeloid leukemia. In lymphoid neoplasms, sensitivity is high for follicular and mantle cell lymphoma, as well as for multiple myeloma, and intermediate for Hodgkin lymphoma and chronic lymphocytic leukemia. It is unknown for T cell lymphomas.

From 50^th Annual Meeting of the EBMT.

The results of the first randomized phase 3 trial (NCT00766779) assessing allogeneic hematopoietic cell transplantation (HCT) in newly diagnosed, older patients (aged 60–75 years) with first complete remission (CR1) acute myeloid leukemia (AML) were recently presented. Patients with a related or unrelated donor were randomly assigned 2:1 to HCT or non-HCT. Following conditioning with fludarabine, 200 Gy total body irradiation, and immunosuppression with cyclosporin/mycophenolate mofetil, HCT was carried out. Local standards were followed in the administration of non-HCT consolidation.  125 patients were randomized (83 to HCT and 42 to non-HCT consolidation). In multivariate analysis adjusted for donor type and cytogenetic risk, after a follow-up of 62 months, 5-year leukemia-free survival (primary endpoint) was 28.8% (95% confidence interval [CI]  20.4–40.6) in the HCT group and 8.9% (95% CI 3.1–25.7) in the non-HCT group (difference 8.9 months [1.3–16.6; p=0.02]). Incidence of relapse was 37.8% in the HCT arm (95% CI 27.2-48.4) and 91.1% in the non-HCT arm (95% CI 80.7-100.0) at 60 months (hazard ratio [HR]: 3.1 [95% CI 1.93-4.98] p=0.001). Treatment related mortality was 26.8% (95% CI 17.1-36.5).

Abstract OS1-02 - HEMATOPOIETIC CELL TRANSPLANTATION FOR PATIENTS OF OLDER AGE WITH AML IN FIRST COMPLETE REMISSION: RESULTS OF A RANDOMIZED PHASE III TRIAL OF THE EBMT. 

Fecal microbiota transplantation for high-risk treatment-naïve acute graft-versus-host disease (GVHD).

Results of an open-label, single-arm, pilot study (NCT04139577), third-party, single-donor fecal microbiota transplantation (FMT) in combination with systemic corticosteroids have been published. Participants with high-risk acute lower gastrointestinal (LGI) graft-versus-host disease (GVHD) were included.  Participants were scheduled to receive 1 induction dose (15 capsules per day for 2 consecutive days), followed by 3 weekly maintenance doses (15 capsules per day on days 8, 15, and 22). The primary end point of the study was feasibility, which would be achieved if ≥80% of participants were able to swallow ≥40 of the 75 scheduled capsules. Ten participants (9 treatment naïve; 1 steroid-refractory) were enrolled and treated. The study met the primary end point, with 9 of 10 participants. At day 28, the overall response rate was 70% (complete response [CR], 60%; partial response [PR], 10%). The organ-specific LGI CR rate at day 28 was 70%. Initial clinical response was observed within 1 week for all responders and clinical responses were durable, without recurrent LGI GVHD in participants achieving CR. At day 28, clinical responders did not require any additional GVHD therapies beyond corticosteroids and FMT. Among responders, the median duration of response was 152 days, and 7 participants had an ongoing GI response at data cut off.  The small size and single-arm design of this study limits the ability to characterize the impact of FMT on clinical responses and microbial measurements because FMT was administered concurrently with corticosteroids. Additionally, all participants received FMT from the same donor, and it is unclear whether similar results would be reproduced with different FMT donors.

Peripheral blood (PB) stem cell versus bone marrow (BM) graft in reduced intensity conditioning (RIC) haploidentical hematopoietic stem cell transplantation (Haplo-SCT) for acute myeloid leukemia (AML) in complete remission (CR).

An analysis of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT) has been published. While PB is associated with a higher incidence of graft-versus-host disease (GVHD), it may induce a stronger graft-versus-leukemia effect compared to BM, notably in AML. The analysis used the EBMT registry database and compared PB (n = 595) versus BM (n = 209) grafts in a large cohort of 804 patients aged of 60 years who underwent Haplo-SCT with post-transplantation cyclophosphamide for AML in first or second CR. The risk of acute GVHD was significantly higher in the PB group (Grade II-IV, hazard ratio [HR]= 1.67, 95% confidence interval [CI] 1.10–2.54, p= 0.01; Grade III-IV, HR= 2.29, 95% CI [1.16–4.54], p= 0.02). No significant difference was observed in chronic GVHD or non-relapse mortality. In the PB group, the risk of relapse was significantly lower than in the BM group (HR= 0.65, 95% CI [0.45–0.94], p= 0.02) and leukemia-free survival was significantly better (HR= 0.76, 95% CI [0.59–0.99], p= 0.04),with a suggestion of improved overall survival (HR = 0.78, 95% CI [0.60– 1.01], p= 0.06).

Improved outcome of allogeneic transplantation (AlloSCT) in older patients treated for myeloid malignancies using post-transplantation cyclophosphamide (PTCy) and reduced duration of immune suppression.  

PTCy in addition to immunosuppression has emerged as a pivotal strategy for graft-versus-host (GvHD) prophylaxis following AlloSCT, however, increased toxicity is a concern in an elderly population and may hinder the benefit of PTCy. The authors of this study report a retrospective cohort of 92 patients aged >65 years who underwent AlloSCT for myeloid malignancies at a single institution using PTCy and abbreviated immunosuppression as their GvHD prophylaxis. The conditioning regimen was selected based on patient age, donor match, patient comorbidities, and fitness. All patients received PTCy (50mg/kg on 2 days) in addition to tacrolimus for 10/10 human leukocyte antigen (HLA)-matched transplant, and tacrolimus and mycophenolate mofetil (MMF) for mismatched or haploidentical donor grafts. Immunosuppression was continued until day +30 to +70 depending on disease status and match of the donor. The most frequent myeloid malignancy was acute myeloid leukemia (71% of patients). The comorbidities in the cohort, represented by HCT-CI scores, were HCT-CI scores of 1 (30%), 2 to 3 (36%) or >3 (34%). Of note, 38% of patients underwent upfront AlloSCT or were transplanted with active disease, and most patients (80%) had matched unrelated donors. The 1- and 2-year cumulative incidences of relapse were 8% and 13%, while treatment-related mortality estimates were 9% at both time points. Acute GVHD grade 3 to 4 occurred in 7% within the first 180 days and severe chronic GVHD in 6% of patients. This all resulted in a 1- and 2-year GVHD-free and relapse-free survival of 74% and 70%, respectively.

Efficacy of autologous (AutoSCT) and allogeneic hematopoietic cell transplantation (AlloSCT) in adults with acute promyelocytic leukemia (APL).

Despite improvements in upfront treatment of APL in adults, relapse disease is still seen in 10% of patients, usually within 36 months after completion of front-line therapy. Both AutoSCT and AlloSCT are options for management of relapsed disease after achieving second complete response (CR2), however there is no direct comparison, and treatment modality of choice depends on site preferences and patient fitness. The authors performed a systematic review followed by a meta-analysis to compare AutoSCT vs. AlloSCT as consolidation in CR2 for relapsed APL. Study selection criteria were predefined and included enrollment of >10 patients and transplant performed as consolidation in CR2. A total of 23 studies were included. Pooled rates of event-free survival (71% vs. 54%), progression-free survival (63% vs. 43%), and overall survival (82% vs. 58%) are higher after AutoSCT, which the authors attribute to higher non-relapse mortality for AlloSCT (29% vs. 5%). Off note, the pooled acute and chronic graft-versus-host disease rate was 34% and 30%, respectively. The authors acknowledge the limitations of their analysis, including the high heterogeneity across studies, lack of consistent predefined endpoints, and inherent differences in both treatment modalities, they conclude that in the absence of a randomized prospective clinical trial comparing AlloSCT and AutoSCT, the results of this meta-analysis show that both treatment modalities are acceptable in patients with relapsed APL.