News of the Week

Highlights:

• Low-dose ruxolitinib instead of mycophenolate mofetil within a backbone of antithymocyte globulin (ATG), calcineurin inhibitor, and short-course methotrexate, significantly reduced the cumulative incidence of grade II–IV acute graft-versus-host disease (GVHD) by day 100 after haploidentical haematopoietic stem-cell transplantation (HSCT) (6.8% vs 36.9%; subdistribution hazard ratio [sHR] 0.15, 95% confidence interval [CI] 0.07-0.34; p<0.0001).
• Lower non-relapse mortality (NRM) and improved GVHD-free, relapse-free survival (GRFS), without a significant increase in relapse or infectious complications was also seen in patients treated with low-dose ruxolitinib.

This multicentre, randomised, controlled phase 3 trial conducted at five centers enrolled 215 patients aged 12-70 years undergoing first myeloablative haploidentical HSCT, with 206 included in the modified intention-to-treat population (103 per group). Patients received ATG, a calcineurin inhibitor, and short-course methotrexate, plus either low-dose ruxolitinib (5 mg twice daily, or once daily for those under 50 kg) or standard mycophenolate mofetil. By day 180, grade II-IV acute GVHD occurred in 10.7% of the ruxolitinib group versus 38.8% of the standard group (sHR 0.22, 95% CI 0.12-0.43), and grade III-IV acute GVHD was similarly reduced (4.9% vs 20.4% by day 180). Moderate-to-severe chronic GVHD was also significantly lower with ruxolitinib (5.0% vs 19.1%; sHR 0.24, p=0.0024), and NRM occurred in no ruxolitinib patients versus six standard-prophylaxis patients (sHR 0.16, p=0.014). Relapse incidence did not differ significantly between groups (14 vs 11 patients), nor did overall survival (hazard ratio [HR] 0.76, p=0.49), though GRFS was significantly improved with ruxolitinib (HR 0.37, 95% CI 0.22-0.62; p<0.0001). The most common grade 3-4 adverse events were thrombocytopenia, neutropenia, and anemia, occurring at similar or slightly higher rates with ruxolitinib, while cystitis was more frequent in the standard group; no treatment-related deaths occurred in either arm.

The authors conclude that replacing mycophenolate mofetil with low-dose ruxolitinib substantially reduced acute and moderate-to-severe chronic GVHD after haploidentical HSCT, with manageable toxicity, supporting further evaluation of early JAK1/2 inhibition as a GVHD prevention strategy, though findings require validation in other transplantation platforms and populations given the trial’s ATG-based, single-country design.

Highlights:

• Abnormal serum immunofixation patterns (ASIP) occurred in 31% of patients (18/58) after B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR-T) therapy for relapsed/refractory multiple myeloma, always after achieving the patient’s best response.
• Pre-progression ASIP was associated with a progression-free survival benefit (not reached vs 18.4 months, p=0.023), but this disappeared on landmark analysis at 7 months (25^th percentile of time to ASIP) (p=0.46), indicating that the benefit reflects a survival bias from the late onset of ASIP after CAR-T therapy, rather than a true prognostic effect.

ASIP, which can manifest as oligoclonal bands, is a well-described phenomenon after autologous hematopoietic cell transplant or during myeloma treatment, where a transient monoclonal band of a different isotype than the original myeloma protein emerges.

This retrospective, two-center study included 58 patients treated with ciltacabtagene autoleucel (74%) or idecabtagene vicleucel (26%), with median follow-up of 25 months (interquartile range [IQR], 14-43). ASIP was observed in 18 of 58 patients (31%; 23 total events), with a median time to onset of 9 months (IQR, 7-17) and median duration of 1.38 months (range, 1-12). All 18 ASIP patients achieved a very good partial response (VGPR) or better versus 74% (29 of 40) of those without ASIP (p=0.022), and most ASIP monoclonal proteins were too faint to quantify by electrophoresis. Of 23 ASIP events, 12 (52%) were preceded within 60 days by an immune stimulus (9 infections, 2 vaccinations, 1 with both), and ASIP patients had a significantly higher median number of infections (4 [IQR, 2-6] vs 2 [IQR, 1-3], p=0.021), though without an increased overall infection burden. Mass spectrometry in 6 (33%) ASIP patients uniformly showed negative results with multiple small clones, supporting an oligoclonal/polyclonal rather than neoplastic origin.

The authors conclude that ASIP likely reflects a deeper response and potentially improved humoral reconstitution and/or preservation of nonmalignant plasma cells in response to an immunological stimulus, with no signal of increased relapse or infection risk.

Highlights:

• Arlocabtagene autoleucel (arlo-cel), a G protein–coupled receptor class C group 5 member D (GPRC5D)-targeted chimeric antigen receptor (CAR) T-cell therapy, achieved an overall response rate of 87% (complete response [CR] rate, 53%) in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM), with a median progression-free survival (PFS) of 18.3 months and 1-year overall survival (OS) rate of 90%.
• Toxicity was characterized by low rates of cytokine release syndrome (CRS), with any CRS occurring in 82% of patients but was grade 3/4 in only 5% and low rates of immune effector-cell associated neurotoxicity syndrome (ICANS) in 10% of patients; maximum tolerated dose (MTD) was not reached.

This phase 1, dose-escalation/expansion study enrolled 84 adult patients with RRMM and ≥3 prior antimyeloma regimens (median 5), including an immunomodulatory drug, proteasome inhibitor, and anti-CD38 antibody; 49% had previously received B-cell maturation antigen (BCMA)-targeted therapy. Arlo-cel was given as a single IV infusion at doses of 25 to 450 × 106 CAR T cells. Primary end points were safety and MTD. CRS occurred in 82% of patients, and ICANS in 10%, and other select neurotoxicities in 12%, with frequency appearing dose-dependent (all occurred at a dose of 150× 106 cells. One CRS-related death occurred at the highest dose level. On-target/off-tumor toxicities affecting skin (30%), nails (19%), and oral tissue (32%) were transient, grade 1/2, and mostly resolved without intervention. With a median follow-up of 16.1 months, median duration of response was 18.0 months, and responses deepened over time; Minimal residual disease (MRD) negativity was observed in 85% of MRD-evaluable patients with CR or better. Response rates were comparable regardless of prior BCMA exposure (79% in BCMA-exposed vs 95% in BCMA-naive patients) and across difficult-to-treat subgroups, including extramedullary disease, high-risk cytogenetics, and triple-class- refractory disease.

The authors conclude that arlo-cel demonstrated a manageable safety profile and deep, durable responses and encouraging PFS and OS in heavily pretreated RRMM, supporting continued development in the ongoing phase 2 (QUINTESSENTIAL) and phase 3 (QUINTESSENTIAL-2) trials.

Highlights:

• Human herpesvirus-6 (HHV-6) DNAemia occurred in 69% of 217 post-transplantation cyclophosphamide (PTCy)-based hematopoietic cell transplant (HCT) recipients, with 29% reaching high-level DNAemia (≥4 log₁₀ copies/mL) at a median of 27 days post-HCT.
• Despite frequent detection, only one patient developed HHV-6-associated encephalitis; however, high-level DNAemia was associated with significantly increased rates of otherwise unexplained fever, rash, transaminitis, gastrointestinal symptoms, and both acute (36% vs 18%, p=0.007) and moderate-to-severe chronic (22% vs 8%, p=0.01) graft-versus-host disease (GVHD).

This prospective study monitored weekly whole-blood HHV-6 levels in 217 patients across six PTCy-based allogeneic HCT trials. All HHV-6 viremia spikes precipitously declined spontaneously, though 27% persisted at ≥3 log₁₀ copies/mL for >1 month. During initial spikes, plasma and whole blood HHV-6 levels correlated strongly (Spearman’s ρ=0.85, p<0.0001), and the virus was distributed across multiple leukocyte subsets, most commonly CD4+ T cells (63%). In contrast, patients with HHV-6 persisting beyond one month showed virus almost exclusively within CD4+ T cells and were consistently plasma-negative, suggesting a shift from lytic to latent infection. Patients with HHV-6 spikes had significantly lower day +28 CD4+ T-cell counts (27 vs 56 cells/µL, p=0.0013), though this difference was resolved by day +100. No significant differences in non-relapse mortality or overall survival were observed between patients with and without high-level HHV-6 DNAemia, and antiviral therapy given for concurrent cytomegalovirus infection did not clear HHV-6 DNAemia in most cases.

The authors conclude that while HHV-6 detection is common after PTCy-based HCT, it infrequently causes classic HHV-6-related disease such as encephalitis; instead, it associates with transient self-limited symptoms, may influence CD4+ T-cell immune reconstitution, and could serve as a biomarker for increased GVHD risk, arguing against a routine role for preemptive antiviral therapy.

Highlights:

• Long-term follow-up (nearly 9 years) of two prospective studies evaluating checkpoint inhibitor therapy (CPIT) as consolidation after autologous hematopoietic cell transplantation (auto-HCT) demonstrated durable remissions in high-risk multiple myeloma (MM) and lymphoma.
• Pembrolizumab/lenalidomide/dexamethasone in high-risk MM achieved a median progression-free survival (mPFS) of 27.1 months and median overall survival (mOS) not reached (NR), while ipilimumab/nivolumab produced an mOS of 8.15 years in lymphoma patients and mOS was NR in MM patients, with acceptable long-term safety.

The first study, a phase II single-arm trial, treated 12 high-risk MM patients with pembrolizumab, lenalidomide, and dexamethasone 60-90 days post-transplantation. With a median follow-up of 8.6-8.8 years, mPFS was 27.1 months (95% confidence interval [CI], 19.3-NR) and mOS was NR (95% CI, 53-NR), with 1-, 3-, and 5-year OS rates of 100%, 91.7%, and 58.3%, respectively. On multivariable analysis, 1p deletion (hazard ratio [HR] 11.9, p=0.016) and age ≥65 years (HR 7.1, p=0.028) were associated with increased progression risk; 58% of patients experienced immune-related adverse events (AEs), predominantly grade 1/2, with no treatment-related deaths. The phase IB study treated 35 patients (11 MM, 24 lymphoma) with ipilimumab/nivolumab starting 14-28 days post-transplantation. Among MM patients, mPFS was 17.7 months and mOS was NR (5-year OS, 72.7%). Among lymphoma patients (mixed T-cell lymphoma and diffuse large B-cell lymphoma), mPFS was 22.2 months and mOS was 8.15 years, with age ≥65 years associated with inferior OS (HR 6.17, p=0.017) and PFS (HR 6.35, p=0.025); one patient with T-cell lymphoma died from treatment-related grade 5 pneumonitis, the only grade 4/5 immune-related AE observed.

The authors conclude that CPIT represents a viable short-term consolidative strategy affording durable remissions in high-risk MM and lymphoma after auto-HCT, though the absence of a control group, lack of immune biomarkers, and small sample sizes limit definitive conclusions, supporting the need for future randomized prospective studies.

Highlights:

• The posttransplant cyclophosphamide (PTCy)-based platform successfully broadens donor availability (allowing for haploidentical donors) while maintaining robust, durable donor chimerism and minimal graft-versus-host disease (GVHD).
• Haplo-bone marrow transplant (BMT) with PTCy achieves an excellent overall survival rate of 96% specifically in pediatric and young adult patients with both treatment-naïve (TN) and relapsed/refractory (R/R) severe aplastic anemia (SAA).

SAA is a rare and life-threatening hematologic disorder marked by peripheral pancytopenia and bone marrow hypocellularity. While allogeneic (allo) BMT from a matched sibling donor (MSD) is a preferred treatment, many patients lack such a donor. For those without an MSD, the standard first-line therapy is typically immunosuppressive therapy using antithymocyte globulin (ATG) and cyclosporine. However, this approach is often hindered by high rates of treatment failure, relapse, and clonal evolution. A retrospective study of 31 consecutive pediatric, adolescent, and young adult (AYA) patients with acquired SAA who underwent allo-BMT at the Johns Hopkins Children’s Center between 2014 and 2024, investigated the efficacy of PTCy across the main transplant platforms used for this population. The study included both TN patients and those with R/R SAA (range 2 to 20 years old). A PTCy cohort (n=23) of patients who received reduced-intensity conditioning with either Haplo or MSD using PTCy was compared with a standard-of-care (SOC) cohort (n=8), a contemporaneous institutional control group receiving SOC-MSD transplantation with traditional conditioning and prophylaxis.  The primary endpoints were overall survival (OS), and transfusion independence after BMT. Other endpoints included hematopoietic cell recovery, donor chimerism, GVHD, and infections. The PTCy cohort achieved an OS of 96%. OS did not differ significantly between the PTCy cohort and the SOC-MSD cohort, being 96% and 100%, respectively (p=0.55). The platform resulted in a near-absence of severe GVHD, with no grade 3-4 acute GVHD in the PTCy group. Only one patient (4%) in the PTCy cohort developed chronic GVHD. Most patients in the PTCy group showed 100% donor T-cell chimerism by day 30, which remained stable through day 360. Notably, most patients achieved the primary endpoint of transfusion independence shortly after the procedure, often within 14 to 30 days for both red blood cells and platelets. The authors conclude that while the small sample size precludes making firm comparative conclusions, results indicate that the PTCy platform successfully broadens donor availability to include Haplo donors without compromising safety or survival outcomes in pediatric and AYA patients.

Highlights:

• The traditional complement activation biomarker soluble C5b-9 (sC5b-9) had no significant association with outcomes in adults with transplant-associated thrombotic microangiopathy (TA-TMA).
• Post-transplant cyclophosphamide (PTCy) significantly reduced the incidence of graft-versus-host disease (GVHD) but did not reduce the incidence of TA-TMA. Additionally, in approximately 50% of cases where both complications occurred, the development of TA-TMA actually predated the onset of acute GVHD (aGVHD).

TA-TMA is characterized by endothelial cell activation and injury. TA-TMA is strongly linked to aGVHD. Because TA-TMA is highly destructive and difficult to manage once advanced, there is a critical need to identify pre-hematopoietic stem cell transplantation (HSCT) and post-HSCT biomarkers that can identify high-risk adult patients early enough to guide prophylaxis and treatment. The MIDAS study is a prospective, multicenter cohort study evaluating adult patients (aged ≥18 years) receiving their first allogeneic HSCT. This analysis included 368 patients and involved highly detailed, weekly collection of clinical and biospecimen data through day +100 post-HSCT, followed by periodic follow-up for up to 1 year. The cumulative incidence of overall TA-TMA by day +100 was 44.9% (95% confidence interval [CI], 39.8%–49.9%), and the incidence of severe TA-TMA was 18.5% (95% CI, 14.7%–22.7%). Grade 2 to 4 aGVHD was diagnosed in 146 patients, with 54 patients developing grade 3 to 4 aGVHD. GVHD prophylaxis using PTCy significantly reduced the incidence of aGVHD, but it did not reduce the incidence of TA-TMA. In the multivariable analysis only three baseline variables were independently and significantly associated with the subsequent development of severe TA-TMA: female sex, hazard ratio (HR): 2.16 (95% CI, 1.24–3.76; p=0.0065); serum creatinine, HR: 9.07 per 1 mg/dL increase (95% CI, 4.28–19.25; p<0.0001); and detectable placental growth factor (PLGF), HR: 2.25 (95% CI, 1.34–3.79; p=0.0023). At day +28 post-HSCT, the predictors of severe TA-TMA included: suppression of tumorigenicity 2 (ST2), HR: 2.76 (95% CI, 2.12–3.6; p<0.0001) and soluble FMS-like tyrosine kinase 1 (sFLT-1) levels, HR: 2.59 (95% CI, 1.76–3.81; p<0.0001). sC5b-9 had no significant association with severe TA-TMA or other HSCT outcomes. Pre-HSCT serum creatinine was a highly significant predictor of both non-relapse mortality (HR, 3.97, p=0.0002) and overall survival (HR, 3.26, p=0.01). The authors suggest that higher baseline serum creatinine levels—even when entirely within the normal range—significantly increase the risk of developing severe TA-TMA. These baseline creatinine levels act as a surrogate marker for variable chronic inflammation and biological aging.

Highlights:

• Older age (≥ 65 years) is independently associated with significantly superior posttransplant survival in newly diagnosed acute myeloid leukemia patients treated with venetoclax plus hypomethylating agents.
• Baseline STAG2 and DNMT3A mutations are key independent predictors of superior posttransplant survival.

While venetoclax plus hypomethylating agents (Ven-HMA) is standard frontline treatment for older/unfit patients and is increasingly used to induce remission to facilitate allogeneic hematopoietic stem cell transplant (allo-HSCT), clinical data on posttransplant outcomes for newly diagnosed acute myeloid leukemia patients (ND-AML) following Ven-HMA remain limited. Prior real-world studies analyzing patients undergoing allo-HSCT after Ven-HMA failed to identify any clinical, molecular, or measurable residual disease (MRD)-based predictors of posttransplant outcomes. To address these clinical challenges, a recent study characterized posttransplant survival and relapse, identified clinical and molecular prognostic factors, and developed a clinical risk-stratification model using a retrospective cohort of 111 ND-AML patients who received frontline Ven-HMA followed by allo-HSCT. Patients (58% male, 60% secondary/therapy-related, median age 70 years [range, 37-80]) received a median of 3 cycles (range, 1-11) of Ven-HMA before allo-HSCT. Mutations at the time of diagnosis included RUNX1 (18%), SRSF2 (17%), TP53 (16%), ASXL1, IDH2, K/NRAS, TET2 (14% each), STAG2 (11%), DNMT3A (8%).

The primary endpoints were overall survival (OS) and relapse-free survival (RFS). At a median follow-up of 15 months, 38% of patients have died and 16% experienced posttransplant relapse. Median posttransplant survival was not reached. The overall cohort achieved 1-, 2-, and 3-year OS rates of 69%, 60%, and 57%, respectively. Multivariable analysis identified several critical baseline factors that were independently associated with superior OS and RFS: age ≥65 years (OS: hazard ratio [HR]: 0.38, p<0.01 and RFS: HR: 0.32, p<0.01) and STAG2 mutation (STAG2^MUT) (OS: HR 0.21, p=0.04 and RFS: HR 0.21, p=0.04). DNMT3A mutation (DNMT3A^MUT) showed borderline independent significance for superior OS (HR: 0.21, p=0.05), with a 3-year OS of 88% vs. 54% in wild-type patients (p=0.09). Using the three highly predictive clinical and molecular markers (age, STAG2^MUT, and DNMT3A^MUT status), the authors developed a simple prognostic risk model. Points were assigned for unfavorable features: age<65 years (1 point), STAG2 wild-type (1 point), and DNMT3A wild-type (1 point). This model effectively stratified the cohort into three risk groups with highly statistically significant differences in 3-year OS (p<0.01): low-risk (0–1 point): 89%; intermediate-risk (2 points): 59%; and high-risk (3 points): 19%. The model’s strong predictive performance was successfully maintained when restricting the analysis to the subset of 98 patients who did not receive pretransplant bridging salvage therapy (p<0.01).

Highlights:

• Under a uniform transplant platform combining treosulfan-based conditioning and post-transplant cyclophosphamide (PTCy), major clinical outcomes are highly comparable between haploidentical and 9/10 mismatched unrelated donor (MMUD) transplants.
• While milder or moderate forms of chronic graft-versus-host disease (GVHD) are more common with haploidentical donors, the overall clinical severity is not increased, and this did not translate into higher treatment-related mortality or worse overall survival.

In patients with acute myeloid leukemia (AML) who require an allogeneic hematopoietic stem cell transplant (allo-HSCT) but lack a fully matched donor, PTCy has greatly improved GVHD control, and treosulfan-based conditioning has reduced treatment-related toxicities. However, it remains unclear whether HLA mismatching continues to adversely affect clinical outcomes when these modern, reduced-toxicity protocols are utilized. Direct comparative data comparing haploidentical (half-matched related) donors with 9/10 MMUDs within a uniform platform of treosulfan and PTCy remain scarce. Using the data from the EBMT (European Society for Blood and Marrow Transplantation) registry, the investigators evaluated a multicenter cohort of 275 adult patients (haploidentical-related donor transplants: 206 patients and 9/10 MMUD transplants: 69 patients) with AML in first complete remission who underwent their first transplant between 2012 and 2023. Leukemia-free survival (LFS) was the primary endpoint. Other clinical endpoints included: overall survival (OS), relapse incidence (RI), non-relapse mortality (NRM), GVHD, and GVHD-free, relapse-free survival (GRFS). Within a uniform platform of treosulfan-based conditioning and PTCy, a 9/10 MMUD was independently associated with a significantly lower risk of chronic GVHD than a haploidentical donor (hazard ratio: 0.27, 95% CI 0.1–0.73, p=0.009). However, extensive forms of chronic GVHD did not differ significantly (5.0% vs. 6.0%, p=0.95). Crucially, donor type (haploidentical vs. 9/10 MMUD) was not significantly associated with any primary survival or disease control endpoint in either univariate or multivariable analyses. At 2 years, OS was 73.1% for the haploidentical group and 71.6% for the MMUD group (p=0.96), and at 1 year, LFS was 66.3% after haploidentical transplant and 65.2% after MMUD transplant (p=0.76). There were no differences in RI, NRM, or GRFS. Ultimately, this study suggests that transplant success is increasingly driven by patient-related factors and the specific biological properties of the conditioning and GVHD prophylaxis platforms rather than the degree of HLA matching itself.

Highlights:

• Haploidentical allogeneic hematopoietic stem cell transplantation (allo-HSCT) with post-transplant cyclophosphamide (PTCy) yields overall and disease-free survival rates that are statistically comparable to matched sibling donor (MSD) transplants.
• Graft-versus-host disease (GVHD)-free/relapse-free survival (GRFS) outcomes are equivalent between the haploidentical and MSD groups.

Although Human Leukocyte Antigen (HLA)-MSDs are the preferred donor source for allo-HSCT, they are available to fewer than 30% of patients. Some studies suggest comparable overall survival and relapse rates, while others report significantly higher non-relapse mortality and inferior survival in the haploidentical setting vs. MSD. A recent study evaluated a large cohort of patients to determine whether haploidentical transplants can serve as a comparable therapeutic alternative to the gold-standard MSD transplant when both groups receive a uniform PTCy-based GVHD prophylaxis platform. Using a registry-based study that analyzed clinical data compiled by the Center for International Blood and Marrow Transplant Research (CIBMTR), the researchers evaluated a cohort of 875 adult patients diagnosed with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndromes who underwent their first allo-HSCT and reported to the CIBMTR between 2012 and 2017. The primary objective was to evaluate and compare transplant outcomes between MSD and haploidentical HSCT recipients. Only one statistically significant difference was directly attributable to donor type: neutrophil engraftment. Patients receiving sibling donor grafts achieved faster neutrophil engraftment compared to those receiving haploidentical grafts (hazard ratio [HR]: 1.20; 95% CI: 1.01–1.43; p=0.036). The unadjusted 28-day cumulative incidence of neutrophil engraftment was 96.1% for MSD-PTCy compared to 91.3% for Haplo-PTCy (p<0.001). Adjusting for confounding baseline clinical characteristics in multivariable models showed no statistically significant differences between haploidentical and sibling donor groups for any other major endpoint. Additionally, the use of peripheral blood stem cells over bone marrow grafts was associated with a 2.23-fold higher risk of chronic GVHD (HR: 2.23; p<0.001) and inferior GRFS (HR: 1.24; p=0.008). Probably, donor type alone is no longer the dominant driver of post-transplant outcomes when a uniform PTCy regimen is used.