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IACH News of the Month: Hematopoietic Stem Cell Transplantation (HCT) |
November 4, 2025
Prepared by Dr. Fabio A. Torres |
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The number of additional high molecular risk mutations predicts outcome after hematopoietic stem cell transplantation in primary and secondary myelofibrosis [retrospective cohort] |
Highlights: The number of high-molecular risk mutations in myelofibrosis (MF) has a significant impact on several post-transplant outcomes. Myeloid mutations in ASXL1, EZH2, SRSF2, IDH1/2, and U2AF2 genes are defined as high-molecular-risk (HMR) mutations in MF. The effect of these mutations on post-transplant outcomes is unclear. A retrospective cohort of 50 patients (aged 36-67 years) with primary and secondary MF who underwent allogeneic transplantation was analyzed. Next-generation sequencing analysis data was available for all patients to enable the study of the effect of additional detrimental mutations included in the HMR mutations on post-transplant outcomes. 17 patients (34%) had primary MFR and 33 (66%) had secondary MF. With a median follow-up of 1.9 years (range, 0.1-14.5), the 3-year overall survival (OS) and progression-free survival (PFS) were 58% and 50%, respectively. Patients with ≥ 2 HMR mutations had poor outcomes compared with patients with none or only one HMR mutation. The 3-year OS, PFS, and non-relapse mortality (NRM) for patients in the former group were 20, 20, and 50% vs. 67, 56, and 17% in patients with none or only one HMR mutation. In the univariate analysis, mutations in DNMT3A, EZH2, and TP53 had a significant impact on outcomes, but no effect was observed for ASXL1. In the multivariate analysis, the presence of ≥ 2 mutations was associated with inferior OS (hazard ratio [HR]: 34.5, p = 0.002), PFS (HR: 46.4, p = 0.0009), and NRM (HR: 144, p = 0.028). Also, DNMT3A mutations were associated with a reduced OS (HR: 5.48, p = 0.03) and PFS (HR: 5.17, p = 0.02). In the transplant setting, the presence of≥ 2 HMR mutations in MF, and specifically DNMT3A mutations, signifies a poor prognosis and may have several prognostic implications. These results require confirmation by larger series. |
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Transplant conditioning intensity (TCI) score predicts allo-HCT outcomes in patients with myelofibrosis: a study of the Chronic Malignancies Working Party of EBMT [retrospective cohort] |
Highlights: The Transplant Conditioning Intensity (TCI) index is an alternative tool for stratifying the conditioning intensity in myelofibrosis (MF) patients undergoing allogeneic hematopoietic cell transplantation (allo-HSCT) and shows good performance for predicting relapse risk and non-relapse mortality (NRM) compared to the traditional classification of myeloablative (MAC) or reduced intensity conditioning (RIC). The intensity of the conditioning regimen in allo-HSCT is classically defined as MAC or RIC. The TCI index is an alternative tool for stratifying the conditioning intensity that has been validated in several cohorts. This study evaluated the performance of this index in MF patients undergoing allo-HSCT compared to the classical classification (MAC or RIC regimen). The primary objective was to assess the association of TCI with outcomes after allo-HSCT: overall survival (OS), progression-free survival (PFS), cumulative incidence of relapse (CIR), and NRM. 2454 patients were included in the final analysis: 1339 (55%), 987 (40%), and 128 (5%) patients were categorized as receiving low (TCI-low), intermediate (TCI-int), and high (TCI-high) intensity regimens, respectively, according to the TCI score, corresponding to 1719 patients with RIC (70%) and 735 patients with MAC (30%) regimens. In multivariate analysis, the use of TCI-int/high regimens was not associated with different OS (hazard ratio [HR]: 1.12, 95% confidence interval [CI]: 0.97–1.30, p = 0.13) or PFS (HR: 1.00, 95% CI: 0.88–1.14, p = 0.95) as compared to TCI-low regimens, but was associated with a lower risk of relapse (HR: 0.74, 95% CI: 0.61–0.91, p = 0.004), and higher risk of NRM (HR: 1.24, 95% CI: 1.04–1.48, p = 0.02). There were no significant differences in OS, PFS, CIR, or NRM in patients receiving MAC regimens compared to RIC. In conclusion, it does appear that the TCI index may be more useful in discriminating transplant outcomes compared to the traditional MAC/RIC classification in patients with MF. Patients conditioned with TCI-int/high regimens had lower CIR but higher NRM rates than those conditioned with TCI-low regimens.
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Outcomes after Melphalan-Based Reduced Intensity Allogeneic Hematopoietic Cell Transplantation in Renal Impairment [Retrospective cohort] |
Highlights: The optimization of pre-hematopoietic stem cell transplant (HCT) of the renal function in patients with renal impairment could decrease the impact and toxicity following melphalan-based reduced-intensity conditioning (RIC). The impact of renal impairment on outcomes and toxicities following melphalan-based RIC is not well described. A single-center retrospective study evaluated the impact of renal impairment on transplant outcomes following fludarabine/melphalan RIC. Graft-versus-host disease (GVHD) prophylaxis with tacrolimus or sirolimus without methotrexate was included. With respect to the renal function assessment, the patients were divided into two groups according to chronic kidney disease (CKD) staging from the National Kidney Foundation: creatinine clearance (CrCl) <90 mL/min and CrCl ≥90 mL/min, measured by pre-transplant 24-hour urine collection. The primary endpoint of this study was 4-year non-relapse mortality (NRM). To evaluate the complications related to melphalan toxicity, the composite endpoint melphalan-induced severe GVHD and gastrointestinal toxicity-free survival (MGTFS) was used. Overall, 561 patients (aged 55-74 years) were included, and patients with CrCl <90 mL/min had more GI toxicity vs. those with CrCl ≥90 mL/min (nausea/vomiting grade 3: 49% vs. 38%, respectively, p = 0.04, and diarrhea grade 3: 52% vs. 43%, respectively, p = 0.08). Also, the first group experienced more mucositis grade 3 (35% vs. 29% and grade 4: 4% vs. 0%, respectively, p = 0.07). MGTFS at day +30 was higher for patients with CrCl ≥90 mL/min vs. CrCl <90 mL/min (hazard ratio [HR]: 1.5, 95% confidence interval [CI]: 1.2 to 1.8, p < 0.01). There were no statistically significant differences in incidence of GVHD between the groups. At 4 years, NRM in patients with baseline CrCl <90 mL/min was significantly higher than those with CrCl <90 mL/min (HR: 1.7, 95% CI: 1.3 to 2.4, p< 0.01). In conclusion, the baseline renal impairment in transplant patients who received fludarabine/melphalan RIC correlated with a higher frequency and severity of all melphalan-related adverse events and contributed to a higher NRM in this population. MGTFS quantified the early effect of fludarabine/melphalan RIC-related toxicities on post-HCT survival in this renally impaired HCT population. |
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Mold Invasive Fungal Infection in Hematopoietic Cell Transplant With Post-Transplant Cyclophosphamide and Posaconazole Prophylaxis [retrospective cohort] |
Highlights: In allogeneic hematopoietic cell transplant (HCT) patients with post-transplantation cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis, probable/proven mold invasive fungal infection (IFI) was associated with worse overall survival (OS). Recently, with the introduction of PTCy-based GVHD prophylaxis, there has been a higher incidence of mold IFIs compared to calcineurin inhibitor-based prophylaxis. However, it is necessary to characterize the clinical impact of mold IFI in patients with PTCy-based GVHD prophylaxis under primary posaconazole prophylaxis. For this reason, a retrospective analysis of Spanish patients with hematological malignancies at a single center who underwent allogeneic HCT from a matched sibling donor, matched unrelated donor, and haploidentical donor was performed to evaluate the incidence and risk factors related to this complication. The patients received PTCy-based GVHD prophylaxis with PTCy, sirolimus, and mycophenolate mofetil. Posaconazole 300 mg was prescribed daily from day +7 until day +90, and for all patients receiving steroids for GVHD. The primary endpoint was the cumulative incidence of mold IFI. Of a total of 435 patients, 26 (6%) experienced 26 episodes of mold IFI, of which 16 (61%) were classified as possible IFI, 8 (31%) as probable, and 2 (8%) as proven. At day +100 and at 2 years, there were no statistically significant differences in incidence by donor type for overall, probable/proven, or possible IFI. In univariate analysis, an HCT-specific comorbidity index (HCT-CI) score > 0 and grade II-IV acute GVHD were associated with a significantly higher risk of mold IFI. Probable/proven mold IFI was associated with inferior OS in multivariate analysis (hazard ratio: 3.99, 95% confidence interval, 1.53 to 10.4). In conclusion, the incidence of mold IFI in the PTCy and posaconazole prophylaxis era is low, but higher HCT-CI scores and acute GVHD are critical risk factors for the development of this infectious complication. |
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Outcomes of primary graft failure in acute myeloid leukemia patients following unrelated transplantation with post-transplant cyclophosphamide: a study from the ALWP/EBMT |
Highlights: A low incidence of primary graft failure (pGF) was observed in patients with acute myeloid leukemia (AML) who underwent a hematopoietic stem cell transplantation (HSCT) from a matched unrelated donor (UD) with post-transplant cyclophosphamide (PTCy)-based anti-graft-versus-host disease (GVHD) prophylaxis. Several risk factors are described for the development of pGF: human leukocyte antigen (HLA)-mismatching, non-myeloablative conditioning, low dose of infused hematopoietic stem cells, cord blood transplantation, among others. With the advent of PTCy-based anti-GVHD prophylaxis, limited data exist on incidence and risk factors for pGF in the setting of PTCy. Some reports describe delayed immune reconstitution and delayed neutrophil engraftment with PTCy, so it is important to determine the effect of PTCy on the incidence of pGF in the scenario of UD HSCT. A retrospective, multicenter study evaluated this question in 141 patients with AML (from an initial sample of 2497 eligible patients) who underwent an HSCT from an 8 to 10/10 HLA-matched UD with PTCy AND who failed to achieve an absolute neutrophil count (ANC) ≥ 0.5 × 109 /L by day +30 and were alive without 2nd HSCT. HSCT from umbilical cord blood, sibling, and haploidentical donor was excluded. Of these 141 patients, 109 (77.3%) recovered within the 30 consecutive days. One-year relapse incidence, leukemia-free survival, and overall survival post-pGF were: 22.4% (95% confidence interval [CI], 15.2–30.3%), 55% (95% CI, 45.8–64.1%), and 59% (95% CI, 49.1–67.5%), respectively. In conclusion, this study demonstrated a low incidence of pGF (5.6%) in the setting of UD HSCT with PTCy as GVHD prophylaxis. The impairment of the proliferation of alloreactive T-cells without affecting T-regulatory cells induced by PTCy could be of clinical importance in avoiding this complication in UD-HSCT recipients. |
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