Second Allogeneic Hematopoietic Cell Transplantation for Relapsed Adult Acute Myeloid Leukemia

Highlight(s): Active leukemia at the time of the second hematopoietic cell transplantation (HCT2) and early relapse (≤6 months) after the first hematopoietic cell transplantation are major adverse prognostic factors in patients with acute myeloid leukemia who underwent HCT2.

Acute myeloid leukemia (AML) is the most frequent indication in Europe for allogeneic hematopoietic cell transplantation (allo-HCT). Allo-HCT is the most optimal post-remission treatment for relapse prevention due to a potent graft-versus-leukemia effect, irrespective of underlying AML cytogenetic subcategories and measurable residual disease (MRD). Treatment options for patients experiencing AML recurrence after first HCT (HCT1) are limited. Donor lymphocyte infusions and a second allo-HCT (HCT2) are the only therapeutic modalities with demonstrated curative potential in this scenario.

For this reason, a retrospective analysis at the Fred Hutchinson Cancer Center/University of Washington evaluated the outcomes and associated prognostic factors after HCT2. The primary endpoints were relapse and non-relapse mortality (NRM). Utilizing the 2022 European LeukemiaNet criteria, the cytogenetic risk at diagnosis was determined.  Clinical and laboratory pre-conditioning data before HCT2 were used to compute the treatment-related mortality (TRM) score and the HCT-specific comorbidity index (HCT-CI). MRD testing by multiparameter flow cytometry was performed as part of the pre-HCT work-up and any detectable level of MRD was considered positive. Between April 2006 and June 2022, 73 patients with relapsed AML and 8 patients with myelodysplastic neoplasm/AML were studied. At the time of HCT2, 43 (53%) patients were in morphologic remission with MRD-negativity, 16 (20%) in morphologic remission with MRD-positivity, and 22 (27%) had active disease (i.e. bone marrow blasts ≥5% and/or extramedullary disease). Three-year estimates for relapse, relapse-free survival (RFS), and overall survival (OS) were 37% (95% confidence interval: 27-48%), 32% (23-44%), and 35% (26-47%). The rate of NRM at 100 days and 18 months was 20% (12-29%) and 28% (19-39%), respectively.

After multivariable adjustment, active disease was associated with a higher risk of relapse (hazard ratio [HR]: 3.19, p=0.006) and shorter RFS (HR: 2.41, p=0.008) as well as OS (HR: 2.17, p=0.027) compared to transplant in morphologic remission without evidence of MRD. A relapse-free interval <6 months after HCT1 was associated with a higher risk of relapse (HR: 5.86, p<0.001) and shorter RFS (HR: 2.86; p=0.001) and OS (HR: 2.45, p=0.003). A high HCT-CI score (≥4 points) was associated with increased NRM (HR: 4.30, p=0.035), shorter RFS (HR: 3.87, p=0.003) and OS (HR: 3.74, p=0.006). In conclusion, patients with recurrent AML who are eligible for HCT2 have significant adverse prognostic markers, including persistence of active disease before a second transplant, early relapse following the first allograft, and high HCT-CI score. In AML, pre-HCT MRD may also influence prognosis before HCT2. 

How risky is a second allogeneic stem cell transplantation?

Highlight(s): Second allogeneic hematopoietic cell transplantation is a valid option in patients with hematologic malignancy relapse, especially in younger and healthier patients. Compared to historic cohorts, better outcomes were observed in a contemporary retrospective cohort.

In patients treated with allogeneic hematopoietic cell transplantation(allo-HCT) for malignant disease who suffer from a relapse after the transplantation, the role of second allo-HCT (HCT2) is often uncertain. Reduced intensity conditioning for second allografts may be preferable and little data exists to suggest that a new donor will improve disease control by inducing a stronger graft-versus-leukemia effect. Also, a high treatment-related mortality incidence of ~40% after HCT2 before 2009 has been reported. In a recent retrospective multicenter analysis using the data set of the European Bone Marrow Transplant (EBMT) registry, patients who underwent an HCT2 between 2011 and 2021 were analyzed. Study endpoints were non-relapse mortality (NRM), overall survival (OS), progression-free survival (PFS), relapse incidence (RI), and incidence and severity of acute and chronic GVHD. 

3356 second allo-HCTs met the inclusion criteria. The median age at HCT2 was 48 years. Myeloablative conditioning was used in 44%. Most frequent donor types were matched unrelated 10/10 (35%), haploidentical (22%), and identical siblings (18%). 79.1% of patients receiving HCT2 from haploidentical donors received post-transplantation cyclophosphamide as GVHD prophylaxis. Median follow-up was 3.7 (95% confidence interval [95% CI]: 3.4–4) years after HCT2. The 2-year incidence of NRM, OS, RI, PFS, acute GHVD, and chronic GHVD were 22.1% (95% CI: 20.6–23.6), 38.2% (95% CI: 36.4–39.9), 50% (95% CI: 48.1–51.8), 28% 95% CI: 26.3–29.7), 23.8% (95% CI: 22.2–25.4), and 29.9% (95% CI: 28.2–31.6), respectively. Several risk factors for NRM were identified: the time of HCT2 (hazard ratio [HR]: 1.07, 95% CI:1.04–1.11; p<0.001) for every five-year increase; low Karnofsky performance score (≥90 vs. <90; HR: 0.64, 95% CI: 0.53–0.77; p<0.001); sex (females exhibiting a lower risk than males; HR: 0.83, 95% CI: 0.69–1; p=0.048); donor type (haploidentical: HR: 1.50, 95% CI: 1.02–2.21; p=0.039 and unrelated: HR: 1.43, CI 95%: 1.01–2.02; p=0.043) showing higher risks compared to matched sibling donors; previous GVHD before the HCT2 increased NRM risk (HR: 1.28, 95% CI: 1.07 to 1.54; p=0.009); and a very high disease risk index (DRI) significantly elevated the NRM risk (HR: 1.97, 95% CI: 1.20–3.23; p=0.007) relatively to low DRI. Longer delays from first allo-HCT to relapse were associated with a decreased NRM risk (HR: 0.94, 95%CI: 0.90 to 0.98; p=0.002) for every year increase; recent year of transplant: 5 years increment (HR: 0.82, 95% CI 95%: 0.70–0.96; p=0.013); and total body irradiation  were associated with a decreased risk of NRM (HR: 0.67, 95% CI: 0.53 to 0.84; p<0.001). The risk factors for decreased PFS and OS with HCT2 were essentially the same as those for NRM. After HCT2, relapse accounted for 63% of all deaths, making it the most common cause of mortality. GVHD and infections were the primary NRM causes of mortality. In this study, NRM following HCT2 demonstrated improvement in comparison to historic cohorts.

Efficacy of Autologous and Allogeneic Hematopoietic Cell Transplantation in Adults with Acute Promyelocytic Leukemia

Highlight(s): Allogeneic hematopoietic cell transplantation (allo-HCT) and autologous hematopoietic cell transplantation (auto-HCT) are valid as treatment modalities for relapsed acute promyelocytic leukemia. However, a higher non-relapse mortality with allo-HCT and a comparable relapse rate for auto-HCT and allo-HCT are important considerations with these treatments.

There are no randomized trials to evaluate the efficacy and safety of the different modalities of HCT in refractory/relapsed acute promyelocytic leukemia (APL). To assess this question, a systematic review/meta-analysis was conducted. The authors included 23 of the 1158 studies. The inclusion criteria were that studies must include 10 or more patients, be in full manuscript form, and evaluate the use of allo-HCT or auto-HCT for the sole purpose of treating relapsed and/or refractory APL. The primary endpoint of the meta-analysis was to evaluate the body of evidence regarding allogeneic HCT (allo-HCT) or autologous HCT (auto-HCT) in relapsed APL.

There were no limitations based on language, country of origin, date of study, type of study (prospective or retrospective), or whether it was a single-center, multicenter, or registry data study. Studies including HCT as a consolidative strategy in first remission were excluded. Heterogeneity among the pertinent studies was assessed using the I² statistic; moderate heterogeneity was defined by I² > 30%, and high heterogeneity by I² > 60%. Pooled outcomes based on benefits were: 3-year event-free survival (EFS), progression-free survival (PFS), and overall survival (OS), and based on risks were: non-relapse mortality (NRM) and relapse.

Based on results from separate meta-analyses, the pooled rates of EFS (71% versus 54%), PFS (63% versus 43%), and OS (82% versus 58%) are higher after auto-HCT, but the heterogeneity among these studies was high. For auto-HCT, the NRM rate was 5% compared to 29% for allo-HCT. Regarding disease relapse post-HCT, the meta-analysis suggests similar pooled relapse rates with the 2 treatment modalities (allo-HCT, 23%; auto-HCT, 24%). These results support the recent society recommendations (US National Comprehensive Cancer Network and European LeukemiaNet)  for transplant in relapsed APL. Higher NRM with allo-HCT should be taken into consideration when choosing this treatment option.

Post-Transplant Cyclophosphamide–Based Graft-Versus-Host Disease Prophylaxis Attenuates Disparity in Outcomes Between Use of Matched or Mismatched Unrelated Donors

Highlight(s): Post-transplant cyclophosphamide (PTCy) increases donor availability for patients with an indication of allogeneic hematopoietic cell transplantation (allo-HCT).

In the past, hematopoietic stem cell transplantation (HCT) using single-locus HLA mismatched unrelated donor (MMUD) resulted in inferior survival rates because of increased graft-versus-host disease (GVHD), infections, and graft failure when performed with standard calcineurin inhibitor (CNI)-based GVHD prophylaxis. Administration of post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis improves outcomes after haploidentical donor HCT. There is a scarcity of contemporary, large-scale studies comparing matched and MMUD HCT outcomes with new GVHD prophylaxis schemes.

A recent cohort study evaluated recent data from the Center for International Blood and Marrow Transplant Research (CIBMTR) database. Included were adults patients who underwent first allogeneic HCT from January 2017 through June 2021 with a diagnosis of acute leukemia (71%) or myelodysplastic  syndromes. The primary endpoint was to evaluate the efficacy of PTCy for improving HCT outcomes with HLA-matched unrelated donor (MUD) and mismatched unrelated donor (MMUD) HCT when compared with CNI-based prophylaxis. Three-year overall survival (OS) and GVHD-free, relapse-free survival (GRFS) were compared between adult transplant recipients with either PTCy- or CNI-based prophylaxis. CNI-based transplants included the use of either cyclosporine or tacrolimus with other adjunctive agents. PTCy regimens included a CNI or sirolimus with or without mycophenolate mofetil (MMF) and antithymocyte globulin (ATG). Cox regression was used to examine the independent effect of HLA match/ GVHD prophylaxis on OS and GFRS, controlling for other clinical factors. In this study, 10,025 HCT recipients (7,272 recipients of MUD with CNI, 1,681 MUD with PTCy, 613 MMUD with CNI, and 459 MMUD with PTCy) were analyzed. When comparing recipients using PTCy, MUD HCT and MMUD HCT had similar OS (hazard ratio [HR]: 0.96 [95% CI, 0.82-1.18]; p= 0.60) and GRFS (HR: 0.90 [95% CI, 0.79 to 1.02]; p= 0.11).

Compared with patients receiving MUD HCT with CNI-based prophylaxis, recipients of PTCy-based-MUD HCT had improved OS (HR: 0.88 [95% CI, 0.80 to 0.96]; p= 0.0041). GRFS was improved with PTCy after either MUD (HR: 0.61 [95% CI, 0.57 to 0.66]; p< 0.0001) or MMUD transplants (HR: 0.68 [95% CI, 0.60 to 0.76]; p< .0001). In conclusion, this study demonstrates comparable outcomes between MUD HCT and MMUD HCT when using PTCy, suggesting that MMUDs are a suitable donor option if an MUD is not available.

Autologous transplant vs. CAR-T therapy in patients with DLBCL treated while in complete remission

Highlight(s): Treatment with autologous hematopoietic stem cell transplantation (HCT) is linked to better clinical outcomes than with chimeric antigen receptor T-cell (CAR-T) therapy in patients with relapsed diffuse large B-cell lymphoma who achieve a complete remission.

In diffuse large B-cell lymphoma (DLBCL), autologous HCT (auto-HCT) is still considered the standard of care for patients with late relapse in partial remission (PR) or complete remission (CR) after salvage therapy and could be an optional treatment for patients with early relapse (within 12 months) or primary refractory disease when CAR-T therapy is not available. In a retrospective observational study comparing auto-HCT (2015–2021) vs. CAR-T (2018–2021), the authors evaluated the efficacy of these therapies in patients with chemosensitive relapsed DLBCL after attaining a CR.  Primary endpoints included progression-free survival (PFS) and overall survival (OS). Secondary endpoints were relapse rate and non-relapse mortality (NRM). CR status before auto-HCT or CAR-T therapy was defined per Lugano working group classification and determined by local radiologic assessments. Included were 360 patients with LBCL who received auto-HCT (n = 281) or CAR-T (n = 79) while in a CR. Median follow-up was 49.7 months for the auto-HCT and 24.7 months for the CAR-T cohort. The PFS and OS in the two cohorts were compared using the Kaplan-Meier estimator and log-rank tests. In patients with early treatment failure, auto-HCT was associated with a superior 2-year PFS (70.9% vs. 48.3%; p<0.001), lower 2-year cumulative incidence of relapse (22.8% vs. 45.9%; p<0.001) and trend for higher 2-year OS (82.4% vs. 66.1% ; p = 0.076). In the multivariable analysis, treatment with auto-HCT was associated with a superior PFS (hazard ratio [HR]: 1.83, [95% CI, 1.27–2.63]; p= 0.0011) and lower incidence of relapse (HR: 2.18 [95% CI, 1.48-3.2]; p<0.0001) compared to CAR-T. There was no significant difference between auto-HCT and CAR-T groups for NRM (HR: 0.59 [95% CI, 0.19–1.83]; p = 0.36) and OS (HR: 1.44 [95% CI: 0.91–2.28]; p = 0.12). The most common causes of death in both groups were related to disease progression (auto-HCT: 60% and CAR-T: 68%) and infections (auto-HCT: 15.3% and CAR-T: 8%). Based on these findings, the authors suggest that auto-HCT should continue to be the standard of care for transplant-eligible patients with late relapsed DLBCL as there is currently no evidence that CAR-T therapy improves outcomes.

PTCy vs CNI–based GVHD prophylaxis in HLA-matched transplants for Hodgkin lymphoma: a study of the LWP of the EBMT

Highlight(s): Posttransplant cyclophosphamide (PTCy) yields superior outcomes compared with calcineurin inhibitor (CNI)-based prophylaxis in adult patients with Hodgkin lymphoma (HL) undergoing hematopoietic stem cell transplantation (HSCT) from HLA-matched donors.

This study compared the outcomes of patients with HL undergoing HSCT from HLA-matched donors who received graft-versus-host disease (GVHD) prophylaxis with either PTCy  or conventional CNI-based regimens, using data reported in the European Society for Blood and Marrow Transplantation (EBMT) database between 2015 and 2022. Among the cohort, 270 recipients received conventional CNI-based prophylaxis and 176 received PTCy prophylaxis. The latter was associated with delayed hematopoietic recovery but also with a lower risk of chronic (25% vs. 43%; p <0.001) and extensive chronic GVHD(13% vs. 28%; p=0.003) compared with the CNI-based cohort. The 2-year cumulative incidence of non-relapse mortality and relapse was 11% vs. 17% (p= 0.12) and 17% vs. 30% (p=0.007) for PTCy- and CNI-based, respectively. The 2-year overall survival (OS), progression-free survival (PFS), and GVHD-free, relapse-free survival (GRFS) were all significantly better in the PTCy group compared with the CNI-based group: 85% vs. 72% (p=0.005), 72% vs. 53% (p<0.001), and 59% vs. 31% (p<0.001), respectively. In multivariable analysis, PTCy was associated with a lower risk of chronic and extensive chronic GVHD, reduced relapse, and better OS, PFS, and GRFS than the CNI-based platform.

Haploidentical transplantation in primary refractory/relapsed secondary vs de novo AML: from the ALWP/EBMT

Highlight(s): Outcomes of haploidentical hematopoietic stem cell transplantation (Haplo-HSCT) with posttransplant cyclophosphamide (PTCy) are similar for primary refractory/relapsed secondary vs. de novo acute myeloid leukemia (AML).

This study compared the outcomes of Haplo-HSCT with PTCy in 719 patients with primary refractory (PR) or first relapse (Rel) secondary AML (sAML; n = 129) vs. those with de novo AML (n = 590), who received HSCT between 2010 and 2022. A higher percentage of patients with sAML vs. de novo AML had PR disease (73.6% vs. 58.6%; p=0.002). In 81.4% of patients with sAML , the antecedent hematological disorder was myelodysplastic syndrome. Engraftment was 83.5% vs. 88.4% in sAML and de novo AML, respectively (p=0.13). In multivariate analysis, Haplo-HSCT outcomes did not differ significantly between the groups: non-relapse mortality hazard ratio (HR), 1.38 (95% confidence interval [CI], 0.96-1.98; p= 0.083), relapse incidence HR, 0.68 (95% CI, 0.47-1.00; p=0.051). The HRs for leukemia-free survival, overall survival, and graft-versus-host disease-free, and relapse–free survival were 0.99 (95% CI, 0.76-1.28; p = 0.94), 0.99 (95% CI, 0.77-1.29; p = 0.97), and 0.99 (95% CI, 0.77-1.27; p = 0.94), respectively.

Isocitrate dehydrogenase (IDH) 1 and 2 mutations predict better outcome in patients with acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation: a study of the ALWP of the EBMT

Highlight(s):  isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) mutations are associated with improved outcomes in patients with  acute myeloid leukemia (AML) undergoing allogeneic hematopoietic cell transplantation (allo-HCT) in first complete remission (CR1).

The impact of IDH1 and IDH2 mutations in AML patients undergoing allo-HCT in CR1 was evaluated in 1515 adult patients. 15.91% (n = 241) carried IDH1 mutation (mIDH1), and 26.27% (n = 398) IDH2 mutation (mIDH2) and 57.82% (n = 876) had no-IDH mutation. NPM1 was frequently encountered with mIDH1 (no-IDH group, n = 217, 24.8%, mIDH1, n = 103, 42.7%, mIDH2, n = 111, 27.9%, p < 0.0001). At day 180, the cumulative incidence (CI) of grade II-IV acute graft-versus-host disease (GVHD) was significantly lower in mIDH1 and mIDH2 compared to no-IDH groups (Hazard ratio [HR] = 0.66 (95% confidence interval [95% CI] 0.47–0.91), p = 0.011; HR = 0.73 (95% CI 0.56–0.96), p = 0.025, respectively). In the mIDH1 group, overall survival (OS) was improved compared to no-IDH (HR = 0.68 (95% CI 0.48–0.94), p = 0.021), whereas mIDH2 was associated with lower incidence of relapse (HR = 0.49 (95% CI 0.34–0.7), p < 0.001), improved leukemia free survival (HR = 0.7 (95% CI 0.55–0.9), p = 0.004) and OS (HR = 0.74 (95% CI 0.56–0.97), p = 0.027). In the subgroup of NPM1 wild type, only IDH2 was associated with improved outcomes.

Human Leukocyte Antigen Mismatching and Survival in Contemporary Hematopoietic Cell Transplantation for Hematologic Malignancies

Highlight(s): Optimized human leukocyte antigen (HLA) matching should still be considered in modern hematopoietic cell transplantation (HCT). Class I but not class II HLA mismatches, especially at the antigen and peptide-binding motif (PBM) level, are associated with inferior survival in contemporary unrelated  HCT. These effects are not significantly different between non-posttransplant cyclophosphamide (PTCy) compared with PTCy transplants.

The study included 17,292 unrelated HCTs with 6-locus high-resolution HLA typing, performed mainly for acute leukemia or related myeloid neoplasms between 2016 and 2020, including 1,523 transplants with PTCy.  Overall survival (OS) was lower in HLA mismatched compared with fully matched transplants (hazard ratio [HR], 1.23; 99% confidence interval [CI], 1.14 to 1.33; p < 0.001). This was driven by class I HLA-A, HLA-B, HLA-C (HR, 1.29; 99% CI, 1.19 to 1.41; p < 0.001) but not class II HLA-DRB1 and HLA-DQB1 (HR, 1.07; 99% CI, 0.93 to 1.23; p = 0.19). Class I antigen-level mismatches were associated with worse OS than allele-level mismatches (HR, 1.36; 99% CI, 1.24 to 1.49; p < 0.001), as were class I graft-versus-host PBM mismatches compared with matches (HR, 1.42; 99% CI, 1.28 to 1.59; p < 0.001). The use of PTCy improved graft-versus-host disease-free, relapse-free survival compared with conventional prophylaxis in HLA-matched transplants (HR, 0.77; 99% CI, 0.66 to 0.9; p < 0.001). HLA mismatching increased mortality in PTCy transplants (HR, 1.32; 99% CI, 1.04 to 1.68; p = 0.003) similarly as in non-PTCy transplants (interaction p = 0.43).

Transplantation in Adult Patients with Epstein-Barr Virus-Associated Hemophagocytic Lymphohistiocytosis: Yes or No?

Highlight(s): Hematopoietic stem cell transplantation (HSCT) is recommended for patients who obtained partial response (PR) after initial treatment.  A wait-and-see strategy could be adopted for patients who achieved complete response (CR) after initial treatment, but with the risk of failing to achieve a second CR.

In this study, a total of 356 adult Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) patients were evaluated. Eighty-eight received HSCT. Four received salvage HSCT. The 5-year overall survival (OS) rate of the HSCT group was 48.7% (vs. 16.2% in non-transplanted patients, p<0.001). There was no difference in OS between patients who received transplantation at first complete remission (CR1) and those at first partial remission (PR1) nor between patients at CR1 and CR2. Patients who received transplantation at PR2 had inferior survival. The rate of reaching CR2 was significantly higher in patients with CR1 than PR1 (p=0.014). Higher soluble CD25 levels (an indicator of T cell activation), higher EBV DNA loads in plasma (>600 copies/mL) after HSCT, poorer remission status, more advanced acute graft-versus-host disease (GVHD), and the absence of localized chronic GVHD were associated with an inferior prognosis (p<0.05).

Melphalan Dose in Combination with Fludarabine Affects GI Toxicity and GVHD after Allogeneic Transplantation in Acute Myeloid Leukemia and Myelodysplastic Syndromes

Highlight(s): When used in combination with Fludarabine as conditioning for allogeneic hematopoietic cell transplant (Allo-HCT ) for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), a Melphalan dose of 100mg/m2 resulted in lower rates of graft-vs¬¬-host disease (GvHD) and similar non-relapse mortality when compared to 140mgm2.

Fludarabine (Flu) and Melphalan (Mel) are frequently used reduced intensity-conditioning regimens. However, there are limited data on the impact of the Mel dose on toxicity and clinical outcomes of Allo-HCT. The authors compared the impact of Mel 100mg/m2 (Mel-100) vs. Mel 140mg/m2 (Mel-140) in a cohort of 345 patients with AML or MDS who underwent 8/8 HLA-matched Allo-HCT. All patients received Flu (40mg/m2 daily on day -5 through -2, adjusted to renal function) and Mel (100mg/m2 or 140mg/m2 as a single dose on day -2 or split dose over 2 days on day -3 and -2). GvHD prophylaxis consisted of tacrolimus (Tac) and Sirolimus (Siro), Tac and Methotrexate, or post-transplant cyclophosphamide (PTCy) with mycophenolate mofetil (MMF) plus Tac or Siro.  

283 and 62 patients received Mel 140mg/m2 and 100mg/m2, respectively. Patients received conditioning between 2008 and 2020. 61% of patients had a diagnosis of AML (including 53% with adverse-risk cytogenetics  based on the 2017 European LeukemiaNet classification). Baseline characteristics were balanced, except for higher use of PTCy-based GvHD prophylaxis in the Mel-100 group (53% vs. 3.2%, p<0.001).  Patients who received Mel-100 had lower rates of any grade gastrointestinal (GI) toxicity (40.3% vs. 67.8%, p<0.001), day 100 grade II-IV acute GvHD (21.0% vs. 43.1%, p=0.001) and 2-year chronic GvHD (17.4% vs. 27.1%, p=0.033) when compared to those who received Mel-140. In multivariable analysis, Mel-140 resulted in higher risks of GI toxicity (hazard ratio [HR] = 1.83, p=0.013), grade II-IV acute GvHD (HR=2.35, p=0.003), and moderate/severe chronic GvHD (HR=3.13, p=0.007). The total dose of Mel had no independent impact on oral mucositis, non-relapse mortality, relapse-free survival, or overall survival. 

The authors conclude that these findings support the use of Mel-100 in combination with Flu as a reduced-intensity conditioning regimen, acknowledging the current study's limitations and requiring independent validation. 

A Multicenter Phase II Trial of Ruxolitinib for Treatment of Corticosteroid Refractory Sclerotic Chronic Graft-Versus-Host Disease

Highlight(s): The use of Ruxolitinib for refractory sclerotic chronic graft-versus-host disease (cGvHD) resulted in a response of skin and/or joints in 49% of patients (95% Confidence Interval [CI], 34 to 64). It was associated with low (2.2%) non-relapse mortality (NRM) and a failure-free survival (FFS) of 77% at 12 months. 

Sclerotic cGvHD is associated with high rates of patient morbidity as it is associated with a poor health-related quality of life, pain, and high rates of disability, and lacks specific treatment, with small retrospective cohorts using rituximab or Bruton’s tyrosine kinase inhibitors. Based on previous data on cGvHD suggesting the activity of Ruxolitinib, the efficacy of Ruxolitinib in sclerotic cGvHD was evaluated in a phase II multicenter single-arm trial. 

47 patients with sclerotic cGvHD refractory to corticosteroid and at least another additional line of treatment, were treated with Ruxolitinib for at least 6 months. The primary endpoint was complete or partial response (PR) in the skin or joint according to the 2014 National Institute of Health cGvHD  Consensus criteria. Included patients used Ruxolitinib for a median of 11 months. PR in skin and/or joints was noted in 49% (95% CI, 34 to 64) at 6 months, with 45% having joint and fascia response and 19% having skin response. Overall cGVHD PR was noted in 47% (95% CI, 32 to 61). Improvement in Lee Symptom Scale summary and skin subscale scores was reported in 38% of patients. With a cumulative incidence of treatment failure of 20.8% (95% CI, 10.0 to 34.1), NRM of 2.2% (95% CI, 0.17 to 10.3), and no recurrent malignancy, FFS was 77.1% (95% CI, 61.3 to 87.0) at 12 months. Ruxolitinib had a similar safety profile to previous reports, without new signals.

The authors conclude Ruxolitinib was associated with high rates of skin and joint responses, in addition to overall cGvHD response in these patients and was associated with improvement in patient-reported outcomes and represents an effective treatment option for refractory sclerotic cGvHD.

Long-term outcomes of peripheral blood stem cell unrelated donors mobilized with filgrastim

Highlight(s): In a cohort of  donors who underwent peripheral blood stem cell collection mobilized with filgrastim, there were no differences in the rate of myeloid, lymphoid, other cancer, autoimmune disease, or thrombotic events compared to a control cohort of bone marrow stem cell donors.

Allogeneic stem cell transplant (Allo-SCT) represents a cornerstone of treatment for many hematological malignancies and often means a long-term cure. Collection of stem cells can be achieved either through direct bone marrow (BM) harvest or peripheral blood after mobilization with chemotherapy or G-CSF (filgrastim). Peripheral blood stem cell (PSBC) collection using filgrastim has increased, with a lack of information on long-term safety. The authors report the long-term presence of hematological and other secondary neoplasia, thrombosis and autoimmune disease of unrelated donor (either BM or PBSC) patients   who were followed prospectively as part of the National Marrow Donor Program (NMDP) registry and completed biennial surveys to report new diagnoses of malignancy, autoimmune, or thrombotic (MAT) events over ~10 years until the study conclusion.

21653 donors (14530 PBSCs and 7123 BM) were included (66%  of donors contacted). The incidence rate of myeloid disorders per 100 000 person-years in donors of PBSCs was 2.53 (95% confidence interval [CI], 0.82-7.84) and in donors of BM, it was 4.13 (95% CI, 1.33-12.8). The incidence rate ratio of PBSCs/BM donors was 0.61 (95% CI, 0.12-3.03; p=0.55). The incidence of autoimmunity, and thrombosis did not differ between the donor types. This comprehensive study of the long-term effects of filgrastim in unrelated donors of PBSCs provides strong evidence that donors who receive filgrastim are not at an increased risk of these events compared with BM donors. 

The authors conclude that there are no differences in long-term safety for unrelated donors between BM and PBSC mobilized with filgrastim. These findings are reassuring and encouraging regarding the safety of this approach for current donors undergoing stem cell mobilization and individuals considering joining stem cell registries.

First-line treatment of severe aplastic anemia: immunosuppressive therapy plus eltrombopag versus haploidentical hematopoietic stem cell transplantation, a multicenter prospective study

Highlight(s): The use of immunosuppression plus eltrombopag (EPAG) resulted in higher overall survival (OS) but lower failure-free survival (FFS), slower hematopoietic recovery, and lower health-related quality of life  (HRQoL) when compared to haploidentical allogeneic stem cell transplant (Haplo-SCT) as first-line treatment for patients with severe aplastic anemia (SAA) and no available match related donor (MRD). 

MRD allogenic stem cell transplant (Allo-SCT) is considered the preferred first line treatment with patients with SAA under 40 years, even with the introduction of EPAG to immunosuppressive therapy (IST). However, up to two thirds of patients do not have an available MRD, and Haplo-SCT has been used after failure with IST+EPAG and more recently as first line in SAA, but there is a lack of a prospective direct comparison between the two regimens. 

The authors report a prospective multi-institutional cohort of 268 patients diagnosed with SAA and treated with IST+EPAG (n=121) or Haplo-SCT (n= 147). Patients with congenital bone marrow failure syndrome, myelodysplastic syndrome, paroxysmal nocturnal hemoglobinuria, age >60 years, or those with an available MRD were excluded. Patients were recommended for treatment with EPAG+ITS as first line, but those with haploidentical donors were offered Haplo-SCT.  Patients were treated with standard IST (cyclosporine A with goal level of 200-250 ng/mL in adults and 150-200 ng/mL in children, rabbit antithymocyte globulin (rATG) or porcine anti-human lymphocyte immunoglobulin) and EPAG 50mg/day and increased depending on response with a maximal dose of 150mg/day. Patients treated with Haplo-SCT received conditioning with busulfan, cyclophosphamide and rATG. 

86.3% of patients in the Haplo-SCT group and 24.1% of patients in the IST + EPAG group achieved normal complete blood count (CBC) (p < 0.001) after 6 months of treatment. The time to achieve transfusion independence and absolute neutrophil count ≥ 1.0 × 109/L were shorter in the Haplo-SCT group than in the IST + EPAG group (p < 0.05). In the IST + EPAG and Haplo-SCT groups, 3-year OS was 92.4 ± 2.4% and 82.8 ± 3.1% (p = 0.017), whereas 3-year FFS was 69.4 ± 4.2% and 81.6 ± 3.2% (p  = 0.002), respectively. Similar results were observed in patients aged <40 years. Among patients ≥40 years of age, there was no difference in 3-year OS (88.6 ± 4.8% vs. 82.4 ± 8.1%, p=0.517) between the IST + EPAG and Haplo-SCT groups, whereas 3-year FFS was lower in the IST + EPAG group (58.7 ± 7.5% vs. 82.4 ± 8.1%, p = 0.043). Treatment-related mortality was higher in the Haplo-SCT (17 vs. 7.4%, p = 0.019) due to excess transplant-related complications (8 cases of graft-versus-host disease, 6 patients from intracranial hemorrhage, two patients from graft failure and thrombotic microangiopathy in Haplo-SCT). Subgroup analysis for populations aged <40 years indicated that SAA patients benefited more from IST + EPAG, and very SAA benefited more from Haplo-SCT. Patients treated with Haplo-SCT had a significantly better HRQoL than those treated with IST + EPAG (p <0.0001). Multivariate analysis showed that first-line Haplo-SCT was associated with normal CBC at 6 months, better FFS and led to a better HRQoL (p<0.001) when compared to IST+EPAG.

Based on these results, the improved OS seen with IST+EPAG contrasts with higher rates of response and long-term control seen in the Haplo-SCT group. The authors suggest that efforts should be made to improve treatment-related mortality in Haplo-SCT derived from graft-versus-host disease. They also suggest that the best regimen may be impacted by patient-specific factors such as age, access to suitable donors, and social/economic considerations that may influence decisions. 

Early Toxicity and Efficacy of Four Different Conditioning Regimens for Autologous Hematopoietic Cell Transplantation in Patients With Lymphoma: Impact of Drug Shortages in a Resource-Constrained Country

Highlight(s): Carmustine-based regimens (BEAM , CBV) are better tolerated and have similar efficacy and overall survival, progression-free survival when compared to non-carmustine based regimens (BuMel, BendaEAM) as conditioning for autologous stem cell transplants for relapsed refractory lymphoma. 

High-dose chemotherapy followed by autologous hematopoietic stem cell transplant (Auto-SCT) has been the cornerstone of treatment for patients with relapsed or refractory (R/R) lymphomas, even with the recent introduction of CD19 chimeric antigen receptor (CAR) T-cells. BEAM (carmustine, etoposide, cytarabine and melphalan) has been the predominant conditioning regimen due to its efficacy and safety; however, a shortage in medication access can lead to the need for alternative regimens. 

This study aimed to compare the toxicity and transplant outcomes following BEAM, CBV (carmustine, etoposide, cyclophosphamide), BuMel (busulfan, melphalan), and BendaEAM (bendamustine, etoposide, cytarabine, melphalan). We retrospectively analyzed data from 213 patients (CBV 65, BuMel 42, BEAM 68, BendaEAM 38) with R/R lymphomas undergoing Auto-SCT between 2014 and 2020. Among grade III to IV toxicities, oral mucositis was more frequently observed with BuMel (45%) and BendaEAM (24%) compared to BEAM (15%) and CVB (6%, p≤0.001). Diarrhea was more familiar with BendaEAM (42%) and less frequent with BuMel (7%, p=0.01). Acute kidney injury was only found after BendaEAM (11%). Febrile neutropenia and infectious complications were more frequent following BendaEAM. Frequencies of other treatment-related toxicities did not significantly differ according to conditioning type. BendaEAM (odds ratio [OR] 3.07, p =0.01) and BuMel (OR 4.27, p=0.002) were independently associated with higher grade III to IV toxicity up to day +100. However, the four regimens had no significant differences in relapse/progression, non-relapse mortality, progression-free survival, or overall survival. BuMel and BendaEAM were associated with a higher rate of grade III to IV toxicity. Carmustine-based regimens appeared to be less toxic and safer; however, there were no significant differences in transplant outcomes. The authors conclude that although these regimens are appropriate options with similar efficacy, a shortage of certain medications may lead to the use of regimens associated with higher toxicity.