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IACH News of the Month: Hematopoietic Stem Cell Transplantation (HCT) |
February 27, 2026
Prepared by Dr. Fabio A. Torres and Dr. Mateo Mejía S. |
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Transplantation in Patients with Lower-Risk MDS: A Prospective Phase 2 Trial Based on Donor Availability. |
Highlights: Allogeneic hematopoietic stem cell transplantation (HSCT) did not improve overall survival (OS) compared to non-transplant therapy in patients with lower-risk myelodysplastic syndrome (MDS) who had additional poor prognostic features: intermediate or higher revised International Prognostic Scoring System (IPSS-R) risk, severe cytopenias, or failure of two lines of therapy. An international expert panel has confirmed the indication of HSCT in high-risk MDS and in lower-risk MDS (LR-MDS) when they have or acquire specific poor prognostic features, including genetic alterations, failure to respond to usual treatment, life-threatening cytopenias, and high transfusion burden. A prospective, controlled, non-randomized, multicenter, phase 2 clinical trial (MDS-ALLO-RISK) evaluated OS at 36 months in patients with a low or intermediate-1 risk IPSS scores and at least 1 of the following additional criteria: intermediate or higher IPSS-R risk, thrombocytopenia <20 × 109 /L, neutropenia <0.5 × 109 /L, or failure to 2 lines of therapy. A total of 77 patients (median age: 62.5 years) were enrolled and stratified by the presence of a matched HLA donor: 62 in the donor arm and 15 without a donor. The 3-year OS was 57.6% (95% confidence interval [CI], 46.2-71.7) in the donor arm and 64.3% (95% CI, 43.5-95.0) in the no-donor arm (hazard ratio [HR] 0.75; 95% CI, 0.31-1.82; p=0.53). Based on the univariable analysis, platelet count, IPSS-R, and the HCT-specific comorbidity index were selected to weight the donor group and compare both groups using propensity score matching. The HR for death was estimated at 0.82 (95% CI, 0.36-1.89; p=0.65), confirming the absence of effect on survival. Non-relapse mortality at 3 years was higher in the donor arm: 24.7% (95% CI, 14.6- 36.1) compared to the no-donor group: 7.2% (95% CI, 0.4-29). The trial was stopped early due to slow enrollment and futility. These results do not support HSCT in patients with LR-MDS. The risks of transplantation may outweigh the benefits, and there is a need for strategies to improve post-transplant outcomes before HSCT can be justified in this population. |
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Menin inhibition enhances graft-versus-leukemia effects by T-cell activation and endogenous retrovirus induction in AML [Basic research]. |
Highlights: Menin inhibition increases major histocompatibility complex II (MHC-II) expression on acute myeloid leukemia (AML) cells, enhancing their susceptibility to T-cell–mediated killing after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Additionally, menin inhibition induces expression of human endogenous retroviruses (HERVs), leading to interferon-stimulated gene activation and further upregulation of MHC-II. In Germany, several investigators tested the hypothesis that menin inhibition after allo-HSCT could reduce the immune escape in human and murine AML cells. MV4;11 cells (lysine methyltransferase 2A [KMT2A]-AFF1 rearranged cell line) exhibited a potent response to menin inhibitor treatment, indicated by a reduction of HOXA9 and MEIS1 protein expression. An increase throughout all samples in HLA-DR/-DQ/-DP expression (MHC-II gene) was seen upon menin inhibition in both KMT2A-rearranged and nucleophosmin 1-mutated primary human AML cells. The impact on immune effector functions was also evaluated in T cells isolated from human peripheral blood. At 6 days after T-cell receptor activation and initiation of menin inhibitor treatment, naïve cell signatures were significantly enriched in terms of effector functions and cytotoxicity (including effector memory re-expressing CD45RA-, T-helper 17-, and TNF-states in CD4+ T cells, and natural killer-like, effector memory re-expressing CD45RA-, and cytotoxic T-cell 17-states in CD8+ T cells), compared with the dimethyl sulfoxide treated controls. Moreover, in a preclinical setting, the impact on MHC-II expression and survival in a murine AML model driven by a KMT2A partial tandem duplication and FLT3-ITD mutation was evaluated in the presence of menin inhibition. Menin inhibition increased MHC-II expression on AML cells in vitro, and improved survival in leukemia-bearing mice that received allo-HSCT and allogeneic T cells. Finally, pharmacologic blockade of the menin-KMT2A interaction augments graft-versus-leukemia (GVL) effects in AML by enhancing T-cell activation and inducing HERV expression, which triggers interferon-stimulated gene upregulation and further enhances MHC-II and the HLA class II transactivator (CIITA) pathways. These mechanisms collectively result in a more robust GVL response and improved AML cell clearance post-transplant, providing a rationale for clinical trials of menin inhibitors as maintenance therapy after allo-HCT in AML.
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Blinatumomab exposure prior to allogeneic stem cell transplantation is associated with increased Epstein-Barr virus reactivation [Retrospective cohort] |
Highlights: Blinatumomab exposure before allogeneic hematopoietic stem cell transplantation (allo-HSCT) is independently associated with a higher incidence of Epstein-Barr virus (EBV) reactivation, likely due to profound B-cell depletion and impaired immune control of latent EBV. This association underscores the importance of EBV monitoring and consideration of preemptive strategies in patients receiving blinatumomab before transplantation. The potent B-cell-depleting effect of blinatumomab, a bispecific CD19/CD3 T-cell engager, achieves high complete remission rates and measurable residual disease (MRD) negativity. However, a high rate of infections has been reported with its use, and in allo-HSCT patients, blinatumomab could increase the viral infection rates, primarily Epstein-Barr virus (EBV) and cytomegalovirus (CMV). A retrospective study investigated viral reactivation in two cohorts: 97 patients with B-cell acute lymphoid leukemia who received blinatumomab before allo-HSCT and 194 controls without prior blinatumomab exposure. Plasma CMV and EBV DNA were monitored by real-time quantitative PCR twice per week for the first 100 days after allo-HSCT, followed by once weekly from 100 to 180 days. By day 100 post allo-HSCT, the group that had received blinatumomab exhibited a significantly higher cumulative incidence of EBV viremia compared with controls (41.5%, 95% confidence interval [CI], 31.5–51.1% vs. 26.4%, 95% CI, 20.4–32.8%; p=0.009) without difference in the onset of post-transplant lymphoproliferative disorder (PTLD) (p=0.736). No differences in CMV, common herpesviruses, or polyomavirus reactivation rates were observed between groups. The multivariable analysis demonstrated a higher risk for EBV viremia with blinatumomab recipients and acute graft-versus-host disease (GVHD) ≥grade III. In conclusion, blinatumomab may contribute to EBV reactivation by depleting normal B cells. The increased risk is particularly relevant for patients with additional risk factors for EBV reactivation, such as use of anti-thymocyte globulin, haploidentical donors, and the presence of GVHD. Early detection and intervention for EBV reactivation, such as reduction of immunosuppression or use of rituximab, remain critical to prevent progression to PTLD and improve transplant outcomes. |
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Immune-related toxicity profile after haematopoietic stem cell transplantation in patients with B-ALL given combination immunotherapy with rituximab, inotuzumab and blinatumomab [Letter to the editor] |
Highlights: The use of a combined sequential immunotherapy with rituximab, inotuzumab, and blinatumomab can lead to profound B-cell depletion, increasing the risk of infectious complications, including viral reactivations such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV) reactivation, as well as hypogammaglobulinemia and delayed B-cell reconstitution. A sequential treatment with immunotherapy for relapsed B-cell acute lymphoid leukemia (B-ALL) in a paediatric population, such as the Pedi-cRIB regimen, can achieve durable remission when used as a salvage regimen before hematopoietic stem cell transplantation (HSCT). Pedi-cRIB incorporates rituximab, inotuzumab and blinatumomab with vincristine, cyclophosphamide and dexamethasone. Regarding the safety and adverse effects of this combined immunotherapy, data on post-transplant immune reconstitution are lacking. In a communication to the editor published in the British Journal of Haematology, four out of five pediatric patients were evaluated for immune reconstitution following the Pedi-cRIB scheme and consolidation with HSCT (one patient had died on day 17 post-transplant). At the time of the analysis, the median follow-up duration after HSCT was 1109 days (range, 836–1355 days). All patients had undetectable CD19+ B lymphocytes before transplantation due to B-cell aplasia resulting from the combined immunotherapy. Therefore, they were all supported with intravenous immunoglobulin (Ig) during the peri-transplant period, maintaining IgG levels >400/mL. Evaluation of immune reconstitution was performed with flow cytometry, demonstrating that half of the patients had recovered CD19+ lymphocyte counts by day +100, and all patients had recovered by the time of this report. All patients showed normal lymphocyte proliferative capacity after HSCT (range, 268–734 days). Concerning viral reactivations, one patient had a high level of EBV DNA (14200 copies/mL) 12 months following transplantation. Still, there were no signs of post-transplant lymphoproliferative disorder, and EBV DNA returned to a low, detectable level after four weekly cycles of rituximab. The same patient also developed CMV reactivation 1 week after transplantation, with CMV viraemia and pneumonitis, which resolved with ganciclovir. All but one patient had adenovirus viraemia 5-12 months after transplant. All were treated successfully. None of the patients experienced invasive fungal infections. Combination immunotherapy with rituximab, inotuzumab, and blinatumomab is effective in achieving deep remissions and facilitating HSCT in B-ALL. However, it requires vigilant monitoring for immune-related toxicities, especially viral reactivation and hypogammaglobulinemia. The regimen does not appear to increase graft-versus-host disease or engraftment complications, but infectious risks necessitate tailored surveillance and prophylactic strategies peri- and post-transplant. |
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Survival in adults with high-risk TA-TMA: a comparative analysis of narsoplimab vs supportive care [Retrospective study] |
Highlights: Narsoplimab treatment in adults with high-risk transplant-associated thrombotic microangiopathy (TA-TMA) is associated with a significant reduction in mortality compared to supportive care. Complement activation by endothelial injury associated with hematopoietic stem cell transplant is associated with the development and pathophysiology of TA-TMA. Narsoplimab is a monoclonal antibody that binds to, and blocks mannan-binding lectin-associated serine protease 2 (MASP-2), a key enzyme implicated in complement activation. A comparative study evaluated the overall survival (OS) in patients (aged ≥16 years) with high-risk TA-TMA taken from three cohorts: (1) patients treated with narsoplimab in a single-arm, open-label clinical trial (NCT02222545, n=28) and (2) an expanded access program (EAP; NCT04247906, n=49) were compared to (3) a well-matched external control group from the Kyoto Stem Cell Transplantation Group (KSCTG) registry (n=121: of which 111 patients compared to NCT02222545 patients and the total group of 121 patients compared to the EAP cohort). The narsoplimab EAP provided access to narsoplimab for patients with TA-TMA who, in their physician's opinion, had no other suitable treatment options and no access to a clinical trial. In the survival analyses, the estimated 1-year OS was 41.0% (95% confidence interval [CI], 21.6-60.4) and 58.0% (95% CI, 43.2-72.7) in OMS721-TMA-001 and EAP patients treated with narsoplimab, respectively, vs. 16.9% (95% CI, 10.2-23.7) in the KSCTG TA-TMA control group. The corresponding median OS was estimated at 274+ days for narsoplimab-treated patients compared with 41 days for the KSCTG TA-TMA control cohort. This study provides comparative survival data, demonstrating a 4-fold reduction in the risk of death for narsoplimab-treated patients compared with matched KSCTG controls receiving only supportive care hazard ratio [HR], 0.25; 95% CI, 0.19-0.34; P<0.0001). Similarly, in high-risk patients treated with narsoplimab in the EAP, mortality risk was significantly lower than among high-risk patients from the KSCTG registry (HR 0.38; 95% CI 0.28-0.51; P<0.0001). When narsoplimab-treated patients from the single-arm study and the EAP were compared with KSCTG patients, the HR for mortality was 0.28 (95% CI, 0.22-0.37; P<0.0001). The drug was well tolerated, and no new safety signals were identified. These results support narsoplimab as a potential therapeutic option for high-risk TA-TMA, a condition for which no approved treatments currently exist, and supportive care alone is associated with poor outcomes. |
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PD-1-based combinations before autologous transplant are associated with improved outcomes in classical Hodgkin lymphoma [Retrospective study] |
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Highlights: ● Patients with relapsed/refractory classical Hodgkin lymphoma (cHL) who received PD-1 inhibitor-based salvage therapy before autologous hematopoietic cell transplant (Auto-SCT) achieved a 2-year progression-free survival (PFS) of 88.2% compared to 70.2% with brentuximab vedotin (Bv) and 67.4% with chemotherapy alone (p<0.0001). ● Use of a PD-1 inhibitor before Auto-SCT remained independently associated with improved PFS (hazard ratio 0.33, 95% confidence interval 0.21-0.51, p<0.001) after controlling for pre-Auto-SCT response, number of previous lines, transplant year, time of relapse, and primary refractory status. The article reports the results of a multicenter retrospective study that analyzed 1280 patients with relapsed/refractory cHL who underwent Auto-SCT from 2010-2022 at 6 centers. The study compared outcomes among patients who received PD-1 inhibitor- based regimens (25%), Bv without PD-1 (28%), or chemotherapy alone (47%) prior to Auto-SCT. All patients were naive PD-1 inhibitors. Patients who received PD-1-based salvage demonstrated superior 2-year PFS across all subgroups. Among the 901 patients transplanted in complete metabolic response, those in the PD-1 group achieved a 2-year PFS of 94.4% compared to 78.5% for Bv and 75.0% for chemotherapy (p<0.0001). Importantly, the PD-1 group also showed improved overall survival in this complete response cohort (99.0% vs. 97.6% vs. 94.3%, p<0.002), while other traditional high-risk factors, such as primary refractory disease, extranodal involvement, and multiple lines, lost their prognostic significance when PD-1-based salvage was used. The type of PD-1 combination did not significantly impact outcomes, whether given alone, with chemotherapy, or with Bv. The authors conclude that these findings support the use of PD-1-based combinations as the preferred first salvage approach for patients with relapsed/refractory cHL who have not received frontline PD-1 therapy |
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HCT Pre-App Program: A Telemedicine-based Prehabilitation for Allogeneic Hematopoietic Cell Transplant candidates [Proof of Concept Prospective study] |
Highlights: Frailty has emerged as a key component of allogeneic hematopoietic cell transplant (allo-HCT) candidate assessment and is closely associated with transplant outcomes. A structured telemedicine-based prehabilitation exercise program (HCT Pre-App) delivered remotely by rehabilitation physicians achieved high adherence (76% - 88%) and significantly improved frailty status in allo-HCT candidates, increasing the proportion of fit patients from 34% to 56% at transplant admission (p=0.001), with no exercise-related adverse events. This single-center prospective study evaluated 185 consecutive allo-HCT candidates enrolled in three sequential cohorts between April 2021 and April 2025: patients receiving frailty assessment only, no prehabilitation (No-Prehab, n=76), a home-based program (Pilot-Prehab, n=59), and the HCT Pre-App telemedicine program (Tele-Prehab, n=50). The digital intervention required only one in-person visit, followed by remote supervision via a platform that provided video demonstrations and exercise tracking. Patients completed a median of three structured sessions per week for approximately 6 weeks prior to transplant. The program achieved 90.7% recruitment and 100% acceptance, with adherence of 76% to 88% across all frailty groups (frail, pre-frail, and fit). Prehabilitation significantly improved frailty status at admission compared with baseline. In the Tele-Prehab cohort, the proportion of fit patients increased from 34% to 56%, while frail patient proportions decreased from 12% to 4% (p=0.001). Multivariate analysis confirmed that compared with no intervention, the HCT Pre-App program independently increased the odds of being fit at admission (odds ratio [OR] 3.86, p=0.001) and reduced the odds of frailty at admission (OR 0.17, p=0.031). Pilot-Prehab showed a similar trend. While one-year overall survival was comparable across No-Prehab, Pilot-Prehab and Tele-Prehab cohorts (74.5%, 84.5%, 78.1%, respectively, p=0.367), there was lower non-relapse mortality among rehabilitation patients (14.6%, 5.1%, 5.6%), but this difference was not statistically significant (p=0.075). The authors conclude these findings demonstrate that home-based digital prehabilitation is feasible, safe, and effective in optimizing transplant candidacy, highlighting frailty as a potentially reversible risk factor when addressed through structured exercise interventions. |
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Nivolumab following CAR-T failure in multiple myeloma and non-Hodgkin lymphoma: results of a phase 2 study. |
Highlights: In 20 patients (11 with multiple myeloma [MM], 9 with non-Hodgkin lymphoma [NHL]) who relapsed after chimeric antigen receptor (CAR) T-cell therapy, nivolumab 480 mg IV every 4 weeks yielded an overall response rate (ORR) of 15%. The study did not meet its primary endpoint, and authors conclude that responses to PD-1 blockade following CAR T-cell therapy relapse are uncommon in MM and NHL. Two MM patients achieved remarkably durable responses: they maintained responses for 18.9 and 18.3 months. The 17 non-responders progressed rapidly with a median time to progression of 0.9 months (range 0.2-1.8), following nivolumab initiation, allowing early identification of patients unlikely to benefit. This single-center, open-label phase 2 trial (NCT04205409) enrolled patients with relapsed MM or NHL following progression after any CAR-T product. The primary endpoint was ORR. Prior to nivolumab, 64% of MM patients and 44% of NHL patients had achieved complete response as their best response to CAR T-cell therapy. The ORR was 15% (3/20): 18% for MM (2/11) and 11% for NHL (1/9). The NHL responder achieved partial response for 1.6 months, while the two MM responders maintained partial responses for 18.9 and 18.3 months. Correlative analyses revealed that circulating CAR T-cells were detectable in 6 (30%) patients before nivolumab initiation but demonstrated an exhausted phenotype without expansion despite high PD-1 expression at baseline. Endogenous T-cell activation occurred in all patients regardless of response, suggesting durable MM responses were driven by endogenous T cells rather than CAR T-cell rejuvenation. The most common grade 3+ adverse events were neutropenia (20%), anemia (10), and sepsis (15%). No immune effector cell–associated neurotoxicity syndrome or cytokine release syndrome occurred. The authors conclude that while nivolumab monotherapy following CAR T-cell therapy failure rarely leads to responses, it produces remarkably durable benefit in a minority of MM patients, likely through endogenous T-cell activation. |
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Proposal for Diagnostic Criteria for Manifestations of Chronic Graft-versus-Host Disease in the Central Nervous System [Retrospective Study] |
Highlights: The authors propose three distinct forms of central nervous system chronic graft vs. host disease (CNS-cGVHD): vasculitis-like, demyelinating, and meningoencephalitis. In addition, they suggest a new classification based on likelihood of CNS-cGVHD as unlikely, possible, or probable. Using this approach, the incidence of CNS-cGVHD was 2.5% (19/770 patients) in a retrospective cohort following allogeneic hematopoietic cell transplant (allo-HCT). This retrospective single-center study developed diagnostic criteria for CNS manifestations of cGVHD by analyzing 770 patients who underwent allo-HCT between 2007-2022. Based on the 2020 National Institutes of Health report on atypical cGVHD, the authors proposed three distinct forms of CNS-cGVHD—vasculitis-like, demyelinating, and meningoencephalitis—and created a 10-point scoring system incorporating clinical symptoms, MRI findings, cerebrospinal fluid (CSF) analysis, presence of systemic cGVHD, timing relative to immunosuppression changes, histology, and treatment response. Scores ≥5 indicate ‘probable’ CNS-cGVHD, 3-4 ‘possible’ disease, and <3 ‘unlikely’ disease. The scoring system was applied retrospectively after interdisciplinary review by neurologists and hematologists, with differential diagnoses requiring exclusion as a mandatory criterion. Among 19/770 (2.5%) patients diagnosed with possible (n=6) or probable (n=13) CNS-cGVHD, the median onset was 175 (IQR,148 – 454) days post-transplant, with 63% having concurrent systemic cGVHD and 32% (n=6) experiencing disease after donor lymphocyte infusion. Most patients presented with cognitive impairment (n=15, 79%), altered consciousness (35%), or seizures (n=7, 37%), with abnormal brain MRI in 68% (n=13) and CSF pleocytosis in 76%—notably, no patient had both normal MRI and CSF. First-line treatment with corticosteroids (18/19) achieved response in 63% (n=12), though a median of 2 therapy lines were given and 74% (n=14) ultimately responded to immunosuppression. However, 42% (n=8) developed long-lasting neurological sequelae (predominantly cognitive deficits), and non-relapse mortality reached 42%, with CNS-cGVHD contributing to death in four of the nine patients who died during follow-up. The authors conclude that CNS-cGVHD represents a rare but serious complication requiring high clinical suspicion and interdisciplinary management to optimize outcomes. The classification and scoring system proposed may allow homogenization of larger multicenter studies focused on CNS-cGVHD studies. |
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The impact of age on survival and excess mortality after autologous hematopoietic cell transplantation in newly diagnosed multiple myeloma patients [Retrospective Study] |
Highlights: In this worldwide retrospective analysis of 61,797 newly diagnosed multiple myeloma (MM) patients undergoing autologous hematopoietic cell transplantation (Auto-SCT) between 2013-2017, older age (≥65 years) was significantly associated with inferior overall survival (OS) (3-year OS: 85.9% for age 18-39 and 74.8% for ≥75 years, p<0.001), shorter progression-free survival (PFS), and higher non-relapse mortality (NRM), but not excess mortality or increased relapse risk. Using relative survival methodology to account for general population mortality, excess mortality attributable to myeloma and transplant was similar across all age groups (approximately 13-15% at 3 years), indicating that advanced age alone should not preclude Auto-SCT in carefully selected patients with MM. This retrospective study by the Worldwide Network for Blood and Marrow Transplantation analyzed 61,797 patients from 61 countries who underwent upfront Auto-SCT for MM between 2013-2017. Patients were stratified into five age cohorts: 18-39 years (2.0%), 40-64 years (68.9%), 65-69 years (21.8%), 70-74 years (6.5%), and ≥75 years (0.8%). Older patients had lower percentages of light chain disease, were more likely to have International Staging System (ISS) stage III disease, high-risk cytogenetics, worse Karnofsky performance status (KPS, score ≤90), and higher hematopoietic cell transplantation-specific comorbidity index (HCT-CI), and were more likely to receive reduced-intensity melphalan conditioning (140 mg/m² vs. 200 mg/m²). Regional variations were also notable, with Eastern-mediterranean countries having the youngest median age and the highest proportion of patients aged <40 years (6.4%), while North American centers had the highest median age and most patients were ≥75 years old. Multivariable analyses adjusted for age, sex, year of transplant, M-protein isotype, cytogenetic risk, ISS stage, disease status at transplant, KPS score, HCT-CI, and conditioning regimen. It showed that age ≥65 years was an independent risk factor for inferior OS (hazard ratio [HR] 1.45 for ≥75 vs. 40-64 years, p<0.001), PFS (HR 1.20, p=0.006), and higher NRM (HR 2.11, p<0.001), but not for relapse incidence (HR 1.12, p=0.19). However, when accounting for expected general population mortality using relative survival methodology in 58,620 patients from 34 countries with available mortality tables, excess mortality attributable specifically to MM and its treatment was remarkably similar across all age groups: 13.1%, 15.0%, 14.6%, 15.0%, and 14.1% at 3 years, respectively (p=0.67). Other significant adverse prognostic factors included male sex, relapsed/progressive disease at transplant (HR 4.84 for OS), ISS stage III (HR 2.23), high-risk cytogenetics (HR 2.09), and lower melphalan dose of 140 mg/m². The association between higher melphalan dose (200 mg/m²) and improved outcomes (was stronger in older patients, with significant interactions noted for OS, PFS, and relapse. In older patients, the beneficial association between 200 mg/m2 melphalan and OS, PFS, and relapse was stronger compared to the results obtained from the model without interaction. The authors conclude that these findings support the use of Auto-SCT in carefully selected older patients, including those aged ≥75 years, with an acceptable 1-year NRM of 3.8%, and that the disease-specific mortality risk remains comparable to that of younger patients when general population life expectancy is accounted for, challenging arbitrary age cutoffs for transplant eligibility. |
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