Graft-versus-Host disease prophylaxis with cyclophosphamide and cyclosporin [Phase 3 clinical trial]

Highlights:

In this study (ALLG BM12 CAST), the combination of post-transplantation cyclophosphamide-cyclosporin (experimental prophylaxis) led to longer graft-versus-host disease (GVHD)-free, relapse-free survival than standard prophylaxis (cyclosporin-methotrexate) after transplantation from a matched related donor with either reduced-intensity or myeloablative conditioning, without a higher incidence of adverse events.

Among 134 patients who underwent randomization, 66 were assigned to receive experimental prophylaxis and 68 to receive standard prophylaxis. GVHD-free, relapse-free survival (primary endpoint) was significantly longer with experimental prophylaxis (median, 26.2 months; 95% confidence interval [CI], 9.1 to not reached) than with standard prophylaxis (median, 6.4 months; 95% CI, 5.6 to 8.3; P<0.001 by a log-rank test). GVHD-free, relapse-free survival at 3 years was 49% (95% CI, 36 to 61) with experimental prophylaxis and 14% (95% CI, 6 to 25) with standard prophylaxis (hazard ratio for GVHD, relapse, or death, 0.42; 95% CI, 0.27 to 0.66). The cumulative incidence of grade III to IV acute GVHD at 3 months was 3% (95% CI, 1 to 10) in the experimental-prophylaxis group and 10% (95% CI, 4 to 19) in the standard prophylaxis group.

Pooled fecal allogenic microbiotherapy for refractory gastrointestinal acute graft-versus-host disease: Results from the Early Access Program in Europe [Phase 3 clinical trial]

Highlights:

Early Access Program data show that MaaT013 is a safe and effective treatment for refractory gastrointestinal acute graft-versus-host disease (GI-aGvHD). Response to MaaT013 correlates with increased overall survival (OS), suggesting a strong, favorable benefit-risk profile.

173 patients (including 2 pediatric: 12 and 15 years old) with steroid-refractory (SR) or dependent (SD) GI-aGvHD were treated with MaaT013. Patients had failed 1 to 6 systemic treatment lines (median 2; 149/173 [86%] received ruxolitinib). Most patients had grade III (49%) or IV (38%) aGvHD. Three MaaT013 enema administrations were planned every 7 +/- 2 days (median 3, 1-3). One MaaT013 dose contains 150 mL of pooled human allogeneic fecal microbiota (≥1.35 x10¹¹ viable bacteria). Response was calculated comparing aGvHD grading at day 28 (D28) to grading at baseline.

At D28, GI-overall response rate (ORR) was 53%: 52 complete response (CR 30%), 28 very good partial response (VGPR 16%), 11 partial response (PR 6%). GI-ORR was higher in grade II & III GvHD patients compared to grade IV (70% grade II, 64% grade III, 32% grade IV) and higher in SD vs. SR (74% vs. 48%). ORR (n=167) for all organs was 50% with 44 CR, 23 VGPR and 16 PR. Median follow-up among surviving patients was 447 days (7-1812.) Overall survival (OS) was significantly higher in patients achieving at least GI-PR at D28 (Responder, R; n=91) compared to patients in treatment failure (Non-responder, NR; n=82): 73% vs. 34% at Month (M)-6, 69% vs. 25% at M-12, and 61% vs. 25% at M-24 (Log-rank P<0.0001). Median survival in R was 355 days vs. 55 days in NR.

MaaT013 displayed a good overall safety profile in the EAP population: 49 serious pharmacovigilance cases were reported in 44 patients, including 33 cases reported in 30 patients possibly related to MaaT013: infections in 21 patients, sepsis in 10, rectal bleeding/ anorectal disorder in 3, C. difficile colitis in 1.

Measurable Residual Disease–Guided Therapy for Chronic Lymphocytic Leukemia [Phase 3 clinical trial]

Highlights:

This multicenter, open-label trial (FLAIR ISRCTN Registry number, ISRCTN01844152) showed that undetectable measurable residual disease (MRD) and extended progression-free survival (PFS) were more common with ibrutinib–venetoclax than with ibrutinib alone or fludarabine–cyclophosphamide–rituximab (FCR) in patients with chronic lymphocytic leukemia (CLL). 

In this study,  786 patients with CLL were randomly assigned to receive ibrutinib–venetoclax (n=260), ibrutinib alone (n=263), or FCR (n=263). The primary endpoints were undetectable MRD in bone marrow within 2 years in the ibrutinib–venetoclax group as compared with the ibrutinib-alone group, and PFS in the ibrutinib–venetoclax group as compared with the FCR group.

A total of 172 of the 260 participants (66.2%) in the ibrutinib–venetoclax group had undetectable measurable residual disease (MRD) in bone marrow within 2 years, as compared with none of the 263 participants in the ibrutinib-alone group (P<0.001) and 127 of the 263 participants (48.3%) in the FCR group. With a median follow-up of 62.2 months, disease progression or death occurred in 18 participants (6.9%) in the ibrutinib–venetoclax group, as compared with 59 (22.4%) in the ibrutinib-alone group (hazard ratio [HR], 0.29; 95% confidence interval [CI], 0.17 to 0.49; P<0.001) and 112 (42.6%) in the FCR group (HR, 0.13; 95% CI, 0.08 to 0.21; P<0.001). PFS at 5 years was 93.9% with ibrutinib–venetoclax, 79.0% with ibrutinib alone, and 58.1% with FCR. Sudden death occurred in 3, 8, and 4 participants in the ibrutinib–venetoclax, ibrutinib-alone, and FCR groups, respectively.

Cyclophosphamide is superior to methotrexate in previously untreated large granular lymphocyte leukemia. Final results of a prospective, multicentric, phase II randomized controlled trial CT01976182

Highlights: 

●      These results make cyclophosphamide (CP) the standard of care for first-line therapy of large granular lymphocyte (LGL) leukemia versus methotrexate (MTX) treatment.

●      There was no difference in terms of toxicity between the two groups (infections, secondary cancers).

Patients received either MTX (10 mg/m²/week) or CP (100 mg/day) for 4 months. Responders (complete response and partial response [CR+PR]) at month (M)4 continued the same treatment until M12 (CP was delivered at 50 mg/day by M8). Non-responders at M4 were randomly assigned to receive either ciclosporin (3 mg/kg/day) or the drug that had not been administered at the first randomization (MTX or CP). Response was assessed using previously published criteria (Lamy, Blood 2014). The primary endpoint was the CR rate at M4.

160 patients were randomized and 150 were evaluable at M4 (135 LGL-T-cell; 15 LGL-NK-cell). 76 patients received MTX and 74 received CP. Both groups were balanced in terms of clinico-biological parameters. The trial was stopped by the sponsor based on the differences observed between the two groups on CR and overall response rate (ORR) at M4. At M4, the CR rate was 12% (9/76) in the MTX group vs. 24% (18/74) in the CP group (P=0.047), and the ORR was 32% (24/76) in the MTX group vs. 73% (54/74) in the CP group (P<0.001), according to the independent committee. MRD assessed by flow cytometry and digital polymerase chain reaction (STAT3) showed a significant difference between responders at M4 and M12 in favor of CP.

Polatuzumab Vedotin, Rituximab, Gemcitabine and Oxaliplatin (Pola-R-Gemox) for Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL): Results from the Randomized Phase III POLARGO trial

Highlights:

●      Polatuzumab-Rituximab-Gemcitabine-Oxaliplatin (Pola-R-GemOx) demonstrated a statistically significant and clinically meaningful benefit in overall survival (OS) and progression-free survival, with a 40% reduction in risk of death relative to Rituximab-Gemcitabine-Oxaliplatin (R-GemOx).

●      Pola-R-GemOx was associated with known risks of individual components, including polyneuropathy (PN) and infection but neither significantly impacted study endpoints. Pola-R-GemOx represents an alternative treatment option for pts with transplant-ineligible R/R DLBCL not previously exposed to polatuzumab vedotin, that avoids the risk of T-cell depleting regimens and their potential deleterious effects on subsequent therapies.

In total, 270 patients (pts) with DLBCL were enrolled (median age, 66 [range 20-89] years), including 176 (65.2%) pts after 1 prior therapy. Of 246 pts with DLBCL NOS, 143 (58.1%) had primary refractory disease. As of November 29, 2024, in the randomized cohort (N=255; median OS follow-up: 24.6 months), a statistically significant OS benefit was observed with Pola-R-GemOx (n=129) vs. R-GemOx (n=126); hazard ratio 0.60, 95% confidence interval [CI]: 0.43-0.83; P=0.0017). Median OS was 19.5 months (95% CI: 13.3-not evaluable) for Pola-R-GemOx vs. 12.5 months (95% CI: 8.9-15.8) for R-GemOx. OS benefit was consistent across most subgroups.

Grade (Gr) 3-4 adverse event (AE)  rates were similar with Pola-R-GemOx vs. R-GemOx (57.0% vs. 58.4%), with higher rates of thrombocytopenia (34.4% vs. 26.4%) and infections (14.1% vs. 8.0%) with Pola-R-GemOx. PN was more common with Pola-R-GemOx vs. R-GemOx (57.0% vs. 28.8%); primarily Gr 1. Gr 5 AEs were higher with Pola-R-GemOx vs. R-GemOx (11.7% vs. 4.0%), primarily driven by infections including COVID-19.

Tafasitamab (Tafa) plus lenalidomide (Len) and rituximab (R) for patients with relapsed or refractory follicular lymphoma (R/R FL): Results from the phase 3 inMIND Study

Highlights: 

●      Tafasitamab (tafa), a humanised CD19-targeting monoclonal antibody (mAb), has been previously approved in combination with lenalidomide (Len) for relapsed/refractory (R/R) diffuse large B-cell lymphoma, based on the L-MIND study.

●      This study (inMIND; NCT04680052) is a double-blind, randomised, placebo (pbo)-controlled, multicentre international trial evaluating efficacy and safety of adding tafa to Len plus rituximab (Len+R) in pts with R/R follicular lymphoma (FL) or R/R marginal zone lymphoma  (MZL).

548 patients (pts) with FL were randomised: tafa arm (n=273) and pbo arm (n=275); pt characteristics were similar between arms. Median number of prior lines of treatment was 1 (range, 1-10), 45% had ≥2 prior lines, 32% had disease progression within 24 months of diagnosis, and 43% were refractory to prior anti-CD20 mAb. At data cutoff, pts in tafa and pbo arms had received a median of 12 and 11 treatment cycles, 19% and 15% were still on treatment, and 81% and 84% had discontinued treatment, primarily due to treatment completion (54% and 43%) or disease progression (11% and 31%), respectively.

At a median follow-up of 14.1 months, adding tafa to Len+R significantly lowered the risk (by 57%) of progression, relapse, or death (primary endpoint) vs. pbo (median investigator-assessed progression-free survival,  22.4 vs. 13.9 months; hazard ratio [95% CI], 0.43 [0.32, 0.58]; P<0.0001). Similar rates of treatment-emergent adverse events (TEAEs: 99% vs. 99%), grade 3 or 4 AEs (71% vs. 70%) and serious AEs (36% vs. 32%) occurred with tafa and pbo.

Benefit was observed in all subgroups analysed. The safety profile was manageable and consistent with expected toxicities. Tafa+Len+R can be administered in community and academic settings and represents a potential new standard of care option for pts with R/R FL.

Azacitidine, Venetoclax, and Revumenib for Newly Diagnosed NPM1-Mutated or KMT2A-Rearranged AML [Phase 1b clinical trial]

Highlights:

●      Azacitidine and venetoclax is a standard frontline treatment regimen for newly diagnosed older adults with acute myeloid leukemia (AML); however, long-term outcomes remain poor.

●      Revumenib is an oral menin inhibitor with clinical activity in AML patients with nucleophosmin-1 mutation (NPM1m) or lysine methyltransferase 2A rearrangements (KMT2Ar).

●      In this study (NCT03013998), the combination of azacitidine, venetoclax, and revumenib was able to be safely administered with high rates of complete remission (CR) to older adults (≥60 years) newly diagnosed with NPM1m or KMT2Ar AML,

Overall, 43 patients were enrolled and treated with in a dose-escalation and expansion study of azacitidine, venetoclax, and revumenib at two dose levels every 12 hours (in combination with strong cytochrome P450 inhibitor azoles). There was no maximum tolerated dose identified. Differentiation syndrome was present in eight (19%) patients, and QTc Fridericia prolongation was present in 19 (44%) patients, and neither required permanent discontinuation of revumenib. The overall response rate with an intention-to-treat population was 88.4% (95% confidence interval [CI], 74.9 to 96.1; NPM1m: 85.3%; KMT2Ar: 100%), the rate of composite CR (CR + CR with partial or incomplete hematologic recovery) was 81.4% (95% CI, 66.6 to 91.6; NPM1m: 79.4%; KMT2Ar: 88.9%), and the rate of CR was 67.4% (95% CI, 51.5 to 80.9; NPM1m: 65%; KMT2Ar: 78%). No patient had refractory disease after 1-2 cycles of treatment. The median time to first response was 28 days, and 84% of responders achieved remission within the first cycle. All 37 patients evaluated had no evidence of measurable residual disease by a centralized flow cytometry assay.

Phase 2 study of talquetamab + teclistamab in patients with relapsed/refractory multiple myeloma and extramedullary disease: REDIRECTT-1 [Phase 2 clinical trial]

Highlights:

●      Patients (pts) with soft tissue plasmacytomas noncontiguous with bone (extramedullary disease [EMD]) have poor outcomes with standard therapies due to low overall response rates (ORRs) and rapid relapses.

●      In this report of the phase 2 RedirecTT-1 study (NCT04586426), talquetamab (Tal; anti-G Protein-coupled receptor class C group 5 member D [GPRC5D]) plus teclistamab (Tec; anti-B-cell maturation antigen [BCMA]) in pts with relapsed/refractory multiple myeloma (RRMM) with EMD, led to a high ORRs and deep, durable responses. No new safety signals were identified.

Prior chimeric antigen receptor (CAR) T-cell therapy (≤20% of pts) and non-BCMA/-GPRC5D bispecific antibody (BsAb) therapy were permitted. Pts received Tal 0.8 mg/kg every 2 weeks (Q2W) + Tec 3.0 mg/kg Q2W, with step-up doses; pts could switch to Q4W dosing at investigator’s discretion after cycle 6 or after cycle 4 with confirmed ≥very good partial response. Response was assessed per International Myeloma Working Group (IMWG) criteria; EMD response was assessed by whole body positron emission tomography-computed tomography (PET-CT) scans.

As of March 2025, 90 pts received Tal + Tec (median follow-up 12.6 months [range 0.5–19.5]). Median age was 65 years; 22% had high-risk cytogenetics, and the median number of plasmacytomas noncontiguous with bone was 2 (range 1–14). Median prior lines of therapy was 4; 20% had prior anti-BCMA CAR T-cell therapy, and 9% had prior BsAbs. ORR (95% confidence interval) was 79% (69.0–86.8), with ≥complete response of 52%; ORR was 83% (58.6–96.4; n=15/18) in pts with prior anti-BCMA CAR T-cell therapy and 75% (34.9–96.8; n=6/8) in pts with prior BsAb therapy. Overall, the 9-month duration of response, progression-free survival, and overall survival was 75%, 64%, and 80%, respectively. Most responders (>90%) deepened or maintained response after switching to Tal 0.8 mg/kg Q4W + Tec 3.0 mg/kg Q4W. No new safety signals were identified, including no exacerbated Tal or Tec adverse events.