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IACH News of the Month: Hematopoietic Stem Cell Transplantation (HCT) |
December 30, 2025
Prepared by Dr. Fabio A. Torres and Dr. Mateo Mejía S. |
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Defining remission following hematopoietic cell transplant for myelofibrosis: an international expert panel consensus [Consensus document]. |
Highlights: For the first time, a consensus definition of post-transplant remission in myelofibrosis (MF) includes the clearance of a driver and/or somatic mutation(s) as a sine qua non condition, with a high agreement between experts. Currently, there are no validated criteria for defining post-hematopoietic stem cell transplant (HCT) remission evaluation of MF. Also, the recent data demonstrate that achieving a molecular driver mutation clearance is associated with long-term disease-free survival and overall survival, unlike other criteria, such as fibrosis, splenomegaly, and cytopenias, that can persist for a year or more after transplant, making it challenging to report HCT outcomes. Through a consensus method among experts, several hematologists from the United States, Canada, and Europe achieved the following definitions of post-transplant response in MF (see Table 1 in original article): ● Molecular Remission (MR): a post-transplant state with an undetectable driver and/or (in case of triple negative disease) somatic mutations measured by highly sensitive single-target or multitarget panel/next generation sequencing assays in either the blood or bone marrow samples. There are three subcategories of MR: ▪ MR with complete remission: Achieve a hematologic recovery, morphologic, and cytogenetic remission, and full donor chimerism. ▪ MR with poor graft function: Poor graft function was defined as an absolute neutrophil count <1.5 × 109 /L, platelet count <30 × 109 /L, and hemoglobin <85 g/L (at least two hematopoietic cell count lines do not meet hematologic remission criteria). ▪ MR with incomplete marrow recovery: These cases must meet the definition of MR and have a good graft function but have either persistent age-adjusted hypo- or hypercellular marrow, persistent fibrosis, or dysplastic megakaryocytes. ● Molecular Persistent Disease (MPD): patients who have measurable molecular disease in the post-HCT period. There are two subcategories: ▪ MPD with persistent cytogenetic abnormalities: Persistence of cytogenetic abnormalities in the absence of molecular persistence would be considered persistent disease. ▪ MPD with persistent mixed chimerism: Persistent mixed chimerism without molecular persistence would not be considered persistent disease. ● Molecular Relapse (MRe): Recurrence of driver mutation(s) or somatic mutations which were previously undetectable on 2 occasions at least 28 days apart. Four subcategories: ▪ MRe with hematologic relapse: Recurrence of cytopenias. ▪ MRe with morphologic relapse. ▪ MRe with cytogenetic relapse: Recurrence of abnormal karyotype (or abnormal fluorescence in situ [FISH]) in the blood or bone marrow after it was previously undetected. ▪ MRe with mixed chimerism: Loss of full donor (>95%) whole blood or CD33+ /CD34+ chimerism after previously established or a decrease in whole blood or CD33+ /CD34+ chimerism from prior assessment. Finally, the authors propose a timing of evaluation for the molecular, histopathological, chimerism, and spleen assessment. In general, the evaluation includes five time points: pretransplant, around day +30, day +100 (bone marrow biopsies and chimerism must be evaluated for the first time post-transplant on this day), day +180, and 1 year post-transplant. |
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Usage of rabbit anti-thymocyte / anti-T-lymphocyte globulins (ATG / ATLG) for hematological malignancies in allogeneic hematopoietic cell transplantation: Best practice recommendations from the EBMT Practice Harmonisation and Guidelines Committee [Consensus document]. |
Highlights: Rabbit anti-thymocyte/anti-T-lymphocyte globulins (ATG/ATLG) continue to be a resource in the science of transplantation that reduces the risk of graft rejection and modulates the immune response, particularly in myeloablative allogeneic hematopoietic stem cell transplant (allo-HSCT) from related or unrelated donors. An expert consensus panel of experts defined recommendations on the use of rabbit ATG/ATLG. The use of this immunosuppressor therapy is particularly useful for graft-versus-host disease (GvHD) prophylaxis in allo-HSCT, especially when peripheral blood is used as the stem cell source. Some recommendations are the following (see Tables 4 and 5 in original article): ● ATG/ATLG is effective in reducing GvHD in matched related and unrelated donor transplants, with optimal dosing being critical. In cord blood transplantation and haploidentical allo-HSCT, it is controversial and remains under investigation. In the case of cord blood transplant, omission of ATG/ATLG is often preferred. In αβT/CD19-depleted transplants, an individualized approach is necessary. ● The choice between ATG vs. ATLG is extremely variable, and the panel did not reach a consensus between these therapies. In general, ATLG dose (30 mg/kg, day -3 to -1) is higher than ATG (2.5–5 mg/kg, day -3 to -1). ● The administration is preferably started early in the day (between 09:00 and 10:30). The infusion rate must be increased slowly (10-20 ml/hour every 30 min) and deliver the total daily dose over a minimum of 6–8 hours. ● On chemotherapy days, administer chemotherapy first, then H1 blocker, steroid, paracetamol, and finally ATG/ATLG. ● For the prevention of allergic reactions and serum sickness, the panel recommends premedication 30-60 minutes before infusion with H1 blocker and steroids (adults: 100 mg of prednisolone). In the case of ATLG, administering a test dose of 1 mg/kg one day before, in four hours, can help to identify severe allergic responses. With each administration, it is necessary to repeat the premedication. ● In case of allergic reaction, stop infusion, administer rescue medication, monitor vital signs, and restart infusion at a reduced rate ≥30 min after symptom resolution. An additional dose of corticosteroid is useful two hours after completion of the dose. ● To prevent bleeding due to thrombocytopenia, check platelet counts pre-infusion and 2 hours post-infusion, consider transfusion before ATG/ATLG if below institutional thresholds. ● Monitor for systemic inflammatory response and always rule out sepsis in case of fever and systemic symptoms/signs related to the infusion of ATG/ATLG. ● Rituximab is not recommended as prophylaxis for post-transplant lymphoproliferative disorder, unless the Epstein-Barr viremia is positive. ● In the setting of second allo-HSCT and re-exposure to ATG/ATLG, switching between these drugs is not recommended to prevent the development of anti-drug antibodies and antibody-mediated failure if a second allo-HSCT is needed.
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Improved outcomes of acute lymphoblastic leukemia after allogeneic blood or marrow transplantation with high-dose post-transplantation cyclophosphamide in the era of more effective pre-transplant therapy [Retrospective cohort]. |
Highlights: In B-cell acute lymphoblastic leukemia, the improvement in the allogeneic hematopoietic stem cell transplant (allo-HSCT) outcomes is due to reductions in relapse secondary to the recent inclusion of immunotherapies and targeted-antigen therapies in pre-transplant therapy. The introduction of new immunotherapies and targeted-antigen therapies in the treatment of acute lymphoblastic leukemia (ALL) has changed the outcomes, yielded better overall survival (OS), relapse-free survival (RFS), and more frequent deeper measurable residual disease (MRD) responses over cytotoxic chemotherapy. Theoretically, these benefits can improve the results after post-allo-HSCT. Also, the improvement of allo-HSCT platforms with high-dose post-transplantation cyclophosphamide (PTCy) has expanded donor options and reduced transplant-related toxicities. An analysis of these issues at the Johns Hopkins transplant database compared outcomes in adult patients with ALL who received allo-HSCT using PTCy (50 mg/kg on days 3 and 4) with respect to two eras: before (ERA1, 2008-2014) and after (ERA2, 2015-2022) the introduction of blinatumomab. Multivariable models were developed to evaluate differences in clinical outcomes between the two eras, including meaningful factors as disease category (Philadelphia-negative B-cell ALL and T-cell ALL vs. Philadelphia-positive [Ph+] B-cell ALL), MRD status, first complete remission with and without salvage therapy, and comorbidities. 251 patients were included. The median follow-up was longer in ERA1 (5.77 years) than in ERA2 (3.2 years). A statistically significant difference was observed with better outcomes for ERA2 with respect to OS (hazard ratio [HR]: 0.54, 95% confidence interval [CI]: 0.35-0.83, p=0.005), RFS HR: 0.52, 95% CI: 0.35-0.76, p=0.001), and cumulative incidence of relapse (CIR) (subdistribution hazard ratio [SDHR]: 0.45, 95% CI: 0.28-0.70, p=0.0005) but without differences in non-relapse mortality (NRM). This improvement in OS, RFS, and CIR was restricted to the B-cell ALL subgroup. Also, pre-transplant MRD persistence was significantly less frequent in B-cell ALL in ERA2 (ERA1: 17.0% vs. ERA2: 4.8%, p=0.005) but not in T-cell ALL (41.7% vs. 28.0%, p=0.47). Blinatumomab and tyrosine kinase inhibitors (TKIs) contributed to these improvements in ERA2, particularly with 2nd/3rd generation TKIs in patients with Ph+ B-cell ALL. These data suggest that B-cell ALL patients should receive immunotherapies (e.g., blinatumomab) and targeted-antigen therapies (TKIs in Ph+ patients) to achieve the deepest level of MRD before transplant, preferably using reduced intensity conditioning and PTCy to reduce NRM and graft-versus-host disease. |
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Long-term benefits of autologous stem cell transplantation versus intensive chemotherapy consolidation for acute myeloid leukemia patients: A propensity score matching analysis from the PETHEMA AML registry [Retrospective cohort]. |
Highlights: Autologous hematopoietic stem cell transplantation (auto-SCT) remains a useful resource for consolidation of the first remission in patients with acute myeloblastic leukemia (AML) and with contraindications for allogeneic stem cell transplant (allo-SCT), particularly in patients with low- and intermediate-risk as classified by the European Leukemia-Net (ELN) classification. Allo-SCT) is the preferred strategy of consolidation in high- and most intermediate-risk AML (as per ELN). However, when allo-SCT is not feasible, the options for consolidation include high-dose intensive chemotherapy (CT: three cycles) or CT (two cycles) intensified with auto-SCT. The benefit of this last strategy remains uncertain. A retrospective cohort of the Spanish Programa Español para Tratamientos en Hematología (PETHEMA) AML registry compared these two strategies in 1272 adult patients with AML who received consolidation therapy with either three cycles of CT (n=615) or two cycles of CT followed by auto-SCT (n=657), without subsequent allo-SCT. A propensity score (PS)-matched cohort was developed with this population for the final analysis. In the PS-matched cohort, median relapse-free survival (RFS) was 62.78 months for the auto-SCT group vs. 34.86 months for the CT group (hazard ratio [HR]: 0.80, 95% confidence interval [CI]: 0.62–1.04, p = 0.092). The median overall survival (OS) was 144.97 months for the auto-SCT group vs.104.96 months for the CT group (HR 0.91, 95% CI: 0.66–1.25, p = 0.563). Among patients with normal karyotype and negative FLT3-ITD mutation, the group of auto-SCT patients had an improved RFS and OS compared to CT patients. In the multivariable analysis performed on the PS-matched cohort, the protective effect of auto-SCT on RFS persisted (HR: 0.47, 95% CI: 0.21–1.07, p = 0.073), but the benefit on OS was not statistically significant (p=0.524). In conclusion, a strategy of auto-SCT is an option of consolidation in patients with AML and contraindications for allo-SCT, particularly in patients aged ≤65 years old, core-binding-factor leukemia, normal karyotype, negative FLT3-ITD mutation, and negative nucleophosmin (NPM1) mutation. |
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High-dose busulfan-melphalan vs melphalan and reinforced VRD for newly diagnosed multiple myeloma [Phase 3 clinical trial]. |
Highlights: ● In 458 transplant-eligible patients with newly diagnosed multiple myeloma (NDMM) treated with reinforced bortezomib, lenalidomide, and dexamethasone (VRD), intravenous busulfan plus melphalan (BUMEL) conditioning did not significantly improve median progression-free survival (PFS) over melphalan 200mg/m2. Overall survival rates were also similar. ● Patients who received BUMEL achieved higher minimal residual disease (MRD)-negative rates (68% vs. 58%, odds ratio [OR] 1.51, p=0.035) and it benefited specific subgroups: patients with international staging system (ISS) II/III, t(14;16), and del(1p) had improved PFS. Those with ISS stage I disease had longer PFS with MEL200 (median PFS not reached at 9 years).
The GEM12 trial randomized 458 patients with NDMM to receive either BUMEL: IV busulfan 3.2 mg/kg days -5, -4,and -3 plus melphalan 140 mg/m²) or MEL200 as conditioning for Auto-SCT after 6 cycles of VRD induction. All patients received consolidation with VRD x 2 cycles after Auto-SCT. After a median follow-up of 101 months (8.4 years), the primary endpoint of PFS showed no significant difference between regimens: median PFS was 89 months for BUMEL and 73.1 months for MEL200 (hazard ratio [HR] 0.89, 95% confidence interval [CI] 0.70-1.14, p=0.3). The 9-year OS was also similar: 67.3% for BUMEL vs. 64.9% for MEL200 (HR 0.96, p=0.8).
The rate of complete response (CR) or better after transplant favored BUMEL (59.1% vs. 53.1%, OR 1.52, 95% CI 1.05-2.2), but not after consolidation (59.1% for BUMEL vs. 53.1% for MEL200, OR 1.28, 95% CI 0.88-1.85). There were no differences in MRD negativity (10⁻⁶ sensitivity) with BUMEL throughout treatment: 34% vs. 31% post-induction, 55% vs. 52% post-transplant, and 58% vs. 56% post-consolidation. However, the achievement of MRD-negative status was higher for BUMEL (68% vs. 58%, OR 1.51, 95% CI 1.03-2.21, p=0.035).
Prespecified subgroup analyses revealed differences. For patients with ISS stage II/III disease (n=282), BUMEL provided benefit with median PFS of 76 months compared to 57 months with MEL200.
Grade 2-4 mucositis occurred in 25.3% with BUMEL vs. 15.4% with MEL200. Infections were more frequent with BUMEL (41% vs. 31%). Veno-occlusive disease occurred in 4 patients in the BUMEL arm and none in the MEL200 arm, but all cases resolved. Two deaths occurred by day 100 in the BUMEL group, due to infection. There were no differences in secondary malignancies and median time to engraftment between groups.
The authors conclude that the reinforced VRD regimen (8 cycles total: 6 induction+2 consolidation) achieved exceptional long-term outcomes, representing the best results reported with a triplet regimen without anti-CD38 monoclonal antibodies. While BUMEL did not improve PFS for the overall population, it provided significant benefits for patients with advanced ISS disease and specific cytogenetic abnormalities. |
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In-vivo B-cell maturation antigen CAR T-cell therapy for relapsed or refractory multiple myeloma [First in human; case series]. |
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Highlights: ● In four patients with relapsed or refractory multiple myeloma (RRMM) treated with ESO-T01, an in vivo manufactured chimeric receptor antigen (CAR) T-cell therapy, two patients achieved a stringent complete response (sCR) and two achieved a partial response (PR) by 2-month follow-up, without requiring apheresis, ex vivo manufacturing, or lymphodepletion. ● All patients developed grade 1-3 cytokine release syndrome (CRS) within the first day, with a second wave of grade 1 CRS occurring between days 8-12. CAR T-cell expansion was comparable to approved ex-vivo CAR T-cell therapies, with peak levels on days 10-17.
In vivo CAR T-cell therapy represents a novel approach that delivers CAR transgene directly to endogenous T cells, eliminating the need for apheresis, ex vivo manufacturing, and lymphodepletion. ESO-T01 is a nanobody-targeted, immune-shielded lentiviral vector engineered to target T cells and express an anti-B-cell maturation antigen (BCMA) single domain antibody CAR.
This case series (from a single hospital in Wuhan, China) reports first-in-human data from four adult patients with heavily pretreated RRMM enrolled in a phase 1 study. They were refractory to immunomodulators and proteasome inhibitors and had measurable disease. Patients received a single intravenous infusion of ESO-T01 at 2.0 × 10⁸ transduction units. All patients developed acute inflammatory reactions and CRS within the first day, managed with supportive care and glucocorticoids. A second wave of grade 1 CRS occurred on days 8-12. CAR T-cells were first detected on days 4-8 and peaked on days 10-17, with levels comparable to approved CAR T-cell therapies. At the 2-month follow-up, patients 1 and 2 achieved an sCR with resolution of extramedullary disease, while patients 3 and 4 achieved PRs with minimal residual disease-negativity in bone marrow.
The authors conclude that ESO-T01 demonstrated promising efficacy in heavily pretreated multiple myeloma, including eradication of extramedullary disease, though larger cohorts and longer follow-up are needed to confirm these findings. |
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Maintenance therapy with romidepsin after autologous stem-cell transplant for peripheral T-cell lymphoma [Prospective Clinical Trial]. |
Highlights: ● In 26 patients with peripheral T-cell lymphoma (PTCL) who underwent autologous hematopoietic stem-cell transplantation (AHCT) in first complete remission (CR1) or first partial remission (PR1) followed by maintenance romidepsin, the estimated 2-year progression-free survival (PFS) was 62% (95% CI, 45-83), which did not meet the primary efficacy endpoint of 70%. ● Maintenance romidepsin was feasible after AHCT, with common toxicities being fatigue (73%), thrombocytopenia (48%), and anemia (48%). Three patients discontinued treatment due to toxicity.
PTCLs are aggressive malignancies with suboptimal outcomes. AHCT consolidation in first remission is a therapeutic strategy that has shown a median intent-to-treat (ITT) PFS of 36% to 48%. Romidepsin is a histone deacetylase inhibitor approved for relapsed/refractory PTCL. This multicenter phase 2 study evaluated maintenance romidepsin therapy after AHCT to improve outcomes.
Twenty-six patients who underwent AHCT in CR1 or PR1 were enrolled, and 7 patients were enrolled in an exploratory cohort with high-risk histology or AHCT after CR or PR 2. The primary endpoint was 2-year PFS, with a predefined efficacy of 70%. Patients received carmustine, etoposide, cytarabine, and melphalan conditioning, followed by romidepsin at 14 mg/m² starting on days 42-80 post-AHCT. The dosing schedule was every 2 weeks until 6 months post-AHCT, every 3 weeks between 6-12 months, and every 4 weeks between 1-2 years post-AHCT. Forty-seven patients consented to the trial and 13 did not receive romidepsin due to relapse before treatment (n=3), cardiac issues (n=3), declined AHCT (n=2), patient refusal before first dose (n=5). One patient received romidepsin but was later reclassified to myeloid sarcoma and removed from the analysis. Of the 26 patients treated in the CR1/PR1 cohort, 11 had angioimmunoblastic T-cell lymphoma and 7 had PTCL-not otherwise specified, as the most common histological subtypes.
With median progression-free follow-up of 32 months (range 24-36), 15 of the first 25 patients remained progression-free at 2 years. The estimated 2-year PFS was 62% (95% CI, 45-83), which did not meet the predefined efficacy endpoint of 70%. The median PFS was not reached. Among all 33 patients treated, the estimated 2-year overall survival was 79%. Most toxicities were hematologic, with grade 3-4 neutropenia in 24% and lymphopenia in 21%. Five patients required dose reduction, and three discontinued due to toxicity.
The authors conclude that although the study did not meet its primary efficacy endpoint, maintenance romidepsin was feasible with an estimated 2-year PFS of 62%, which compares favorably to an ITT historical control rate of 36-44%. |
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Allogeneic hematopoietic stem cell transplantation in germ line DDX41 mutated patients with myeloid malignancies [Retrospective Cohort Study] |
Highlights: ▪ In 83 patients with germ line DDX41 mutations who underwent allogeneic hematopoietic stem cell transplantation (HSCT) for myelodysplastic syndrome/acute myeloid leukemia (MDS/AML), the 2-year leukemia-free survival (LFS) was 68.6% (95% CI, 57.1-77.6) with 2-year non-relapse mortality (NRM) of 21.1%, demonstrating that HSCT is safe in this population without increased toxicity. ▪ Seven cases of DDX41 donor cell leukemia (DCL) were identified among patients who relapsed after related donor transplantation (19.4% of related donor recipients), highlighting the critical need to screen related donors for DDX41 mutations prior to transplantation.
Germ line DDX41 mutations occur in approximately 5% of myeloid malignancies with excess blasts. This multicenter French study reports the largest cohort of post-HSCT outcomes in 83 DDX41-mutated patients (64 AML, 19 MDS) with median follow-up of 4.4 years. The 2-year overall survival (OS) was 73.9%, and cumulative incidence of relapse was 10.2%, with median time to relapse of 28.5 months.
A pair-matched analysis comparing 32 DDX41-mutated with 77 wild-type AML patients showed no significant differences in 6-year LFS (47.9% vs. 52.1%, p=0.84), OS, NRM, or graft-versus-host disease. However, DDX41-mutated patients exhibited a distinct late relapse pattern, with median time to relapse of 50.1 months vs. 7.5 months in wild-type patients. Among 11 patients who relapsed after related donor transplantation, 7 developed DCL with confirmed germ line DDX41 mutations in donors, occurring at a median of 86 months post-transplant.
The authors conclude that HSCT is safe in DDX41-mutated MDS/AML without increased toxicity. Systematic screening of potential related donors for DDX41 mutations is essential to prevent recurrent leukemia arising from the donor. |
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Donor-Recipient Weight Difference in Allogeneic Peripheral Blood Stem Cell Hematopoietic Cell Transplantation [Retrospective Cohort Study] |
Highlights: ▪ In 841 adult patients who underwent allogeneic peripheral blood stem cell (PBSC) transplantation, donor-recipient weight difference showed minimal impact on transplant outcomes, with no significant association with overall survival (OS), relapse-free survival (RFS), relapse, or acute graft-versus-host disease (GVHD). ▪ Use of heavier donors was associated with higher CD34+ cell dose (r=0.2956, P<0.001), increased risk of chronic GVHD (hazard ratio [HR] 1.07, P=0.036), and decreased risk of non-relapse mortality (NRM: HR 0.93, P<0.05), but these effects were modest and likely confounded by stem cell dose rather than weight difference itself.
Outcomes of 841 patients (median age=58, range 18-76 years) who underwent allogeneic PBSC transplantation at Princess Margaret Hospital Cancer Centre, Toronto, between 2018-2023 were analysed. The median donor-recipient weight difference was 1.3 kg (range: -82 to +128 kg). When donor-recipient weight difference was analyzed as a continuous variable, heavier donors provided a higher CD34+ cell dose and were associated with modest increases in chronic GVHD risk and a decreased risk of NRM. However, no significant associations were observed with OS, RFS, cumulative incidence of relapse, or acute GVHD.
When patients were stratified into three groups based on weight difference (donor >20kg lighter, within 20kg, or >20kg heavier), recipients with heavier donors achieved faster neutrophil engraftment and had higher rates of cytomegalovirus reactivation at one year. The associations between donor weight and outcomes appeared to be mediated primarily through CD34+ cell dose, which, in multivariate analysis, was associated with chronic GVHD and CMV reactivation. The authors conclude that donor-recipient weight disparity has limited clinical impact on PBSC transplant outcomes in adults. While heavier donors provide larger grafts with more rapid engraftment, the modest increases in chronic GVHD risk and decreases in NRM are likely explained by differences in stem cell dose and graft composition rather than weight difference per se. |
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