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IACH NEWS OF THE WEEK |
Highlights of the 67th American Society of Hematology Annual Meeting and Exposition (#ASH25; December 6-9, 2025, in Orlando, Florida)
Over the past few days we have been attending #ASH25. Here is a summary of some of the most notable contributions. The data mentioned here is based primarily on abstracts and/or full articles, and may differ from the data presented during the event.
December 15, 2025
Prepared by Dr Edwin Uriel Suárez |
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Teclistamab plus Daratumumab in Relapsed or Refractory Multiple Myeloma: MajesTEC-3 study [Phase 3 clinical trial] |
Highlights: In patients with multiple myeloma who had received one to three previous lines of therapy, those in the teclistamab–daratumumab group had significantly longer progression-free survival (PFS; primary endpoint) and overall survival (OS; secondary endpoint). A total of 587 patients underwent randomization (291 to receive teclistamab-daratumumab and 296 to receive daratumumab-pomalidomide-dexamethasone [DPd] or daratumumab-velcade-dexamethasone [DVd]). At a median of 34.5 months, PFS was significantly longer with teclistamab-daratumumab than with DPd or DVd. The estimated 36-month PFS was 83.4% in the teclistamab–daratumumab group and 29.7% in the DPd or DVd group (hazard ratio, 0.17; 95% confidence interval, 0.12 to 0.23; P<0.001). More patients in the teclistamab-daratumumab group than in the DPd or DVd group had a complete response or better (81.8% vs. 32.1%), an overall response (89.0% vs. 75.3%), and minimal residual disease negativity (10-5; 58.4% vs. 17.1%) (P<0.001 for all comparisons). Patients in the teclistamab–daratumumab group had a significantly lower risk of death than those in the DPd or DVd group (P<0.0001 by stratified log-rank test). The estimated 36-month OS was 83.3% (95% CI, 78.3 to 87.2) with teclistamab–daratumumab and 65.0% (95% CI, 58.8 to 70.5) with DPd or DVd. Serious adverse events occurred in 70.7% of the patients in the teclistamab–daratumumab group and in 62.4% of those in the DPd or DVd group; death from adverse events occurred in 7.1% and 5.9%, respectively. Infection prophylaxis, including immune globulin supplementation (a protocol amendment that was adopted in February 2023), antibiotics, and prophylaxis for Pneumocystis jirovecii pneumonia and herpes zoster reactivation, was administered according to institutional guidelines. |
| Link to full paper |
| Link to meeting abstract |
| Link to ClinicalTrials.gov number, NCT05083169 |
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Dual Targeting of Extramedullary Myeloma with Talquetamab and Teclistamab: RedirecTT-1 [Phase 2 clinical trial]. |
Highlights: ● Patients with plasmacytomas that are noncontiguous with bone marrow (true extramedullary myeloma) are at high risk for disease progression or relapse. ● Most patients with drug-resistant, true extramedullary myeloma had a response with talquetamab plus teclistamab. The incidence of adverse events of grade 3 or above was high and was consistent with previous observations for each agent as monotherapy. A total of 90 patients with drug-resistant, true extramedullary myeloma were enrolled in the study and received talquetamab plus teclistamab treatment (median follow-up, 12.6 months). A response occurred in 79% of the patients (95% confidence interval [CI], 69 to 87). Among the patients with a response, the percentage with a response duration of at least 12 months was 64% (95% CI, 48 to 76). At 12 months, progression-free survival was 61% (95% CI, 50 to 71), and overall survival was 74% (95% CI, 63 to 83). Common adverse events of any grade included oral symptoms, such as dysgeusia, dry mouth, and dysphagia (in 87% of the patients); cytokine release syndrome (in 78%); and nonrash skin effects (in 69%). Grade 3 or 4 adverse events (most commonly hematologic events) occurred in 76% of the patients; 31% had grade 3 or 4 infection. A nonfatal adverse event led to discontinuation of one or both agents in 6% of the patients. Among 10 deaths that occurred during follow-up, 5 were due to infection and 5 were considered to be related to the study treatment. |
| Link to full paper |
| Link to meeting abstract |
| Link to ClinicalTrials.gov number, NCT04586426 |
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Minimal residual disease (MRD)-negative outcomes following a novel, in vivo gene therapy generating anti–B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR)-T cells in patients with relapsed and refractory multiple myeloma (RRMM): Preliminary results from inMMyCAR, the first-in-human phase 1 study of KLN-1010. |
Highlights: Here, the authors report the results on the initial three patients treated with KLN-1010 from inMMyCAR, the first sponsored multicenter study of an in vivo chimeric antigen receptor (CAR) T-cell therapy for patients with relapsed and refractory multiple myeloma (RRMM). Designed as an off-the-shelf therapy, KLN-1010 eliminates the need for apheresis, bespoke ex vivo cell manufacturing, or lymphodepleting chemotherapy and may broaden access to CAR T-cell therapies. All patients experienced a measurable residual disease (MRD)-negative response (10-5 or 10-6 sensitivity) at month 1 by a next-generation flow cytometry or sequencing method. All achieved a partial response at month 1 that deepened over time; the best response was a very good partial response at month 3. All remain in response without disease progression. Eligibility required RRMM with measurable disease, adequate end-organ and bone marrow function, and at least 3 prior lines of therapy, including a proteasome inhibitor, (PI) an immunomodulatory drug (IMiD), and an anti-CD38 monoclonal antibody. Patients (N=3) were aged from 61-72 years, and their time from diagnosis was 7.9-9.4 years. All had high-risk cytogenetics and 3-4 prior lines of therapy. Two were refractory to a PI, an IMiD, and anti-CD38 therapy. All were naïve to BCMA-targeted therapies. The time from consent to infusion was 13-18 days. All patients experienced treatment-emergent adverse events, primarily around infusion and during CAR T-cell expansion. Grade 2 cytokine release syndrome was observed in two patients during CAR T-cell expansion. No immune effector cell-associated neurotoxicity syndrome or delayed neurotoxicity were noted. Cytopenias were limited. No patients were observed to have grade ≥3 hematologic toxicity, or treatment-emergent infections at month 1. The patient with the longest follow-up to date maintained MRD negativity (10-6 sensitivity) at month 3. |
| Click for the meeting abtract |
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Tafasitamab, lenalidomide, and rituximab in relapsed or refractory follicular lymphoma (inMIND): a global, phase 3, randomised controlled trial. |
At this #ASH25 meeting, post hoc data were presented that consistently demonstrate clinical benefits. Here are the pivotal study data published this week. Highlights: The addition of tafasitamab (CD19-targeted Fc-enhanced monoclonal antibody) to lenalidomide and rituximab resulted in a statistically significant and clinically meaningful improvement in progression-free survival (primary endpoint), with an acceptable safety profile in patients with relapsed or refractory (R/R) follicular lymphoma. This combination represents a potential new standard-of-care treatment. Adults with R/R follicular lymphoma, who had received at least one previous line of systemic therapy, were eligible for enrolment and randomly assigned (1:1) to receive treatment with up to 12 cycles (28-day cycle length) of tafasitamab (12 mg/kg by intravenous infusion on days 1, 8, 15, and 22 of cycles 1–3 and days 1 and 15 of cycles 4–12) or placebo, both with lenalidomide (20 mg/day orally on days 1–21 of cycles 1–12) and rituximab (375 mg/m² by intravenous infusion on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 2–5). Between April 2021 and August 2023, 548 patients with R/R follicular lymphoma were enrolled and randomly assigned to treatment with either tafasitamab (n=273) or placebo (n=275). The addition of tafasitamab to lenalidomide and rituximab resulted in significantly lower risk of progression, relapse, or death versus placebo (median PFS 22.4 months [95% confidence interval (CI) 19.2 to not evaluable] in the tafasitamab group vs. 13.9 months [95% CI 11.5–16.4] in the placebo group; hazard ratio 0.43 [95% CI 0.32–0.58]; P<0.0001). Most common adverse events occurring in either the tafasitamab group or placebo group were neutropenia (133 [49%] vs. 123 [45%]) and diarrhea (103 [38%] vs. 77 [28%]). There were no deaths due to treatment-related adverse events in the tafasitamab group; two (1%) patients had fatal adverse events related to treatment in the placebo group. |
| Link to full paper |
| Link to meeting abstract |
| Link to ClinicalTrials.gov number, NCT04680052 |
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Epcoritamab, lenalidomide, and rituximab versus lenalidomide and rituximab for relapsed or refractory follicular lymphoma (EPCORE FL-1): a global, open-label, randomised, phase 3 trial. |
Here we summarize EPCORE FL-1 (previously treated follicular lymphoma [FL]), which was published this week in the context of the meeting. Highlights: Lenalidomide and rituximab (R²) is an accepted standard of care in this population. The EPCORE FL-1 trial demonstrated the efficacy (higher overall response rate [ORR] and longer progression-free survival [PFS]) and safety of epcoritamab plus R² versus R² in participants with relapsed or refractory FL after at least one previous line of chemoimmunotherapy. In this multicountry, open-label, phase 3 trial, participants were randomly allocated (1:1) to fixed-duration epcoritamab plus R² or R² for up to 12 cycles. Epcoritamab was administered weekly in cycles 1–3 and every 4 weeks in cycles 4–12, lenalidomide once daily during cycles 1–12 (days 1–21), and rituximab weekly during cycle 1 and monthly in cycles 2–5. The dual primary endpoints were ORR and PFS by independent review committee. The data reported here are from a planned interim analysis carried out after 78% of PFS events had occurred. This study is ongoing (closed to recruitment). Findings Out of 668 participants screened for eligibility across 189 centres in 30 countries, a total of 488 participants were randomly allocated, 243 to epcoritamab plus R² and 245 to R². The trial met its dual primary endpoints, showing superiority of epcoritamab plus R² over R² in ORR and PFS. With a median follow-up of 14.8 months (IQR 11.4–19.0), ORR was 95% (95% confidence interval [CI] 92–97) with epcoritamab plus R² versus 79% (74–84; P<0.0001) with R². PFS was longer with epcoritamab plus R² versus R² (hazard ratio 0·21 [95% CI 0.14–0.31], P<0.0001); estimated 16-month PFS favoured epcoritamab plus R² (85.5% vs. 40.2%). Grade 3 or higher adverse events were more frequent with epcoritamab plus R² (219 [90%] of 243 participants) versus R² (161 [68%] of 238 participants). Cytokine release syndrome was low grade with epcoritamab plus R² (grade 1 in 28 [21%] participants and grade 2 in seven [5%] participants) and manageable, and all events were resolved.
During ASH25, the ongoing phase 3 clinical trial design, EPCORE FL-2 (untreated follicular lymphoma), was presented. Study in the recruitment phase. |
| Link to full paper |
| Link to ClinicalTrials.gov number, NCT05409066 |
| Link to ClinicalTrials.gov number, NCT06191744 |
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A new validated staging system for AL amyloidosis with Stage IIIC defining ultra-poor risk: AL International Staging System (AL-ISS) [Retrospective study]. |
Highlights: The authors validate a new AL amyloidosis staging system, incorporating longitudinal strain (LS) to the biomarker-based (NT-proBNP and Troponin-T [TnT]) staging system in the contemporary treatment era, with robust identification of an ultra-poor risk stage (IIIC). AL International Staging System was derived from a cohort of patients with AL amyloidosis from the UK National Amyloidosis Centre (2015-2019). The model was validated in patient cohorts from Europe, USA (2015-2024) and UK (2020-2024). 2493 patients were included (derivation, n=573; validation n=1920). In a multivariable model for the derivation cohort, LS≥ -9% and cardiac biomarkers at previously validated thresholds (NT-proBNP 332 ng/L and 8500 ng/L and high-sensitivity-TnT >50 ng/L) were independent poor prognostic factors stratifying patients into stages I, II, IIIA, IIIB and IIIC. In the validation cohort, the patient stages were stage I: 317 (17%), II: 782 (41%), IIIA: 551 (29%), IIIB: 174 (9%) and IIIC: 96 (5%), respectively (first-line daratumumab treated: 826; 43%). With a median follow-up of 34 months, median overall survival (OS) was not reached (NR); estimated 1-year, 2-year and 3-year OS was 82%, 74% and 70%, respectively. Median survival for stages I-II, IIIA, IIIB and IIIC were NR, 67, 26 and 7 months (1-year OS IIIC 53% vs. 68% for IIIB in the daratumumab-treated patients), respectively (P<0.001). External validation exhibited good predictive performance. Stage IIIC independently discriminated the poorest outcome across all cohorts. |
| Link to full paper |
| Link to meeting abstract |
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Pirtobrutinib Versus Ibrutinib in Treatment-Naïve and Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma [Phase 3 clinical trial]. |
Highlights: ● Pirtobrutinib, a highly selective, noncovalent Bruton tyrosine kinase inhibitor (BTKi), has shown efficacy and safety in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who received a prior covalent BTKi. ● In patients with CLL/SLL who are BTKi-naïve, treatment with pirtobrutinib was well tolerated and demonstrated non-inferiority to ibrutinib in independent review committee (IRC)-assessed overall response rate (ORR), in both the intention to treat (ITT) and relapsed/refractory (R/R) populations. In this study (BRUIN CLL-314 [LOXO-BTK-20030]) 662 patients were randomly assigned 1:1 to receive pirtobrutinib or ibrutinib. All patients were BTKi-naïve. Primary end points were IRC-ORR among all randomly assigned patients (ITT) and in patients with R/R disease. The study met its primary end points, demonstrating statistically significant noninferiority of IRC-ORR for pirtobrutinib versus (vs.) ibrutinib in both the ITT (87.0% [95% confidence interval (CI), 82.9 to 90.4] vs. 78.5% [95% CI, 73.7 to 82.9]; ORR ratio = 1.11 [95% CI, 1.03 to 1.19]; two-sided P<0.0001) and R/R populations (n=437; 84.0% [95% CI, 78.5 to 88.6] vs. 74.8% [95% CI, 68.5 to 80.4]; ORR ratio = 1.12 [95% CI, 1.02 to 1.24]; two-sided P<0.0001). In treatment-naïve patients (n=225), IRC-ORR was 92.9% (95% CI, 86.4 to 96.9) with pirtobrutinib vs. 85.8% (95% CI, 78.0 to 91.7) with ibrutinib. Cardiac adverse event rates of atrial fibrillation/flutter and hypertension were lower with pirtobrutinib. Real-world studies evaluating sequencing are urgently needed to determine whether upfront pirtobrutinib is preferable to a standard second generation BTK inhibitor, vs. reserving pirtobrutinib for the R/R situation. |
| Link to full paper |
| Link to meeting abstract |
| Link to ClinicalTrials.gov number, NCT05254743 |
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Fixed-Duration versus Continuous Treatment for Chronic Lymphocytic Leukemia [Phase 3 clinical trial]. |
Highlights: ● Treatment of chronic lymphocytic leukemia (CLL) currently consists of two main approaches — continuous therapy with Bruton’s tyrosine kinase inhibitors (BTKi) and fixed-duration regimens combining venetoclax with either CD20 antibodies or BTKi. ● In patients with previously untreated CLL, fixed-duration treatment with venetoclax–obinutuzumab or venetoclax–ibrutinib was noninferior to continuous ibrutinib with regard to investigator-assessed progression-free survival (PFS). In this study (CLL17), a total of 909 patients were assigned to venetoclax–obinutuzumab (303 patients), venetoclax–ibrutinib (305 patients), or ibrutinib (301 patients). The median follow-up was 34.2 months. In this prespecified interim analysis, 3-year PFS was 81.1% in the venetoclax–obinutuzumab group, 79.4% in the venetoclax–ibrutinib group, and 81.0% in the ibrutinib group (hazard ratio for venetoclax–obinutuzumab vs. ibrutinib, 0.87 [98.3% confidence interval [CI], 0.54 to 1.41]; hazard ratio for venetoclax–ibrutinib vs. ibrutinib, 0.84 [98.0% CI, 0.53 to 1.32]); the results for each comparison met the criterion for noninferiority. After the end of treatment, measurable-residual disease in peripheral blood was undetectable in 73.3% of the patients in the venetoclax–obinutuzumab group, 47.2% in the venetoclax–ibrutinib group, and 0% in the ibrutinib group. Three-year overall survival was 91.5%, 96.0%, and 95.7%, respectively. The most common adverse events were infections, gastrointestinal disorders, and cytopenias. |
| Link to full paper |
| Link to meeting abstract |
| Link to ClinicalTrials.gov number, NCT04608318 |
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Results from paradigm - a phase 2 randomized multi-center study comparing azacitidine and venetoclax to conventional induction chemotherapy for newly diagnosed fit adults with acute myeloid leukemia. |
Highlights: Azacitidine plus venetoclax (aza-ven) was associated with significantly improved event-free survival (EFS), as well as higher rates of overall response (OR) and composite remission rate (CRR), vs. induction chemotherapy (IC) in younger, IC-eligible patients. A greater proportion of patients successfully proceeded to hematopoietic stem cell transplantation (HCT) following response to aza-ven than those to IC. Aza-ven led to numerically fewer serious infectious complications, significantly improved quality-of-life and symptom burden during initial therapy, with less time in the hospital and the intensive care unit.
This open-label, multicenter, phase II randomized clinical trial compared the therapeutic activity of conventional IC (7+3 regimen or liposomal daunorubicin and cytarabine [CPX351; Vyxeos]) to aza-ven among IC-eligible patients aged ≥18 years. Patients with core binding factor fusions, FLT3 mutations, or NPM1 mutations (unless aged ≥ 60 years) were excluded. Patients were allowed to proceed to HCT on both arms following response on protocol-directed therapy. As of July 2025, 172 patients were randomized to aza-ven (n=86) or IC (n=86). Median age was 64 years for aza-ven and 65 years for IC patients. The majority of patients were European LeukemiaNetwork 2022 adverse risk (72%), 15% were intermediate-, and 12% favorable-risk. Distribution of risk categories did not differ across arms (P=0.44), nor did the proportions of TP53, NPM1, or IDH1/2 mutations. By intent to treat analysis, the OR rate was significantly higher in the aza-ven arm (88% vs. 62%; P<0.001), as was composite remission rate (CRR; complete response [CR] + CR with partial hematologic recovery + CR with incomplete hematologic recovery) (81% vs. 55%; P<0.001). CR rates for aza-ven and IC were not significantly different (59% vs. 50%; P=0.066). Procession to HCT following response from protocol therapy differed across arms (P=0.009) with 52 patients (61%) in aza-ven and 34 (40%) on IC arms. With a median follow-up of 16 months, 1-year EFS was 53% for aza-ven and 39% for the IC arm. EFS overall was significantly superior in the aza-ven arm (hazard ratio 0.61; P=0.017). Grade 3/4 therapy-related adverse events in ≥10% were mainly hematologic and at similar rates across arms. |
| Link to meeting abstract |
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CDK4/6 inhibition mitigates chemotherapy-induced expansion of TP53-mutant clonal hematopoiesis [Experimental preclinical study]. |
Highlights: These data demonstrate that CDK4/6 inhibition given in conjunction with a variety of chemotherapy regimens and across diverse cancer populations mitigates chemotherapy-related expansion of clonal hematopoiesis (CH) clones with mutations in DNA damage response genes. This finding was also observed in a syngeneic murine model of TP53 mutant CH. This represents the first demonstration in patients of a pharmacologic strategy to block chemotherapy-induced expansion of pre-leukemic TP53-mutant clones. CDK4/6 pharmacologic inhibition has been shown to induce quiescence in normal hematopoietic stem and progenitor cells (HSPCs) and reduce chemotherapy-induced bone marrow suppression without interfering with the anti-tumor efficacy of chemotherapy. Trilaciclib is an intravenously administered, CDK4/6 inhibitor that is FDA-approved to decrease the incidence of chemotherapy-induced myelosuppression in patients with small cell lung cancer (SCLC). In this study, serial blood samples from healthy controls (n=176) and three placebo-controlled randomized clinical trials of trilaciclib including patients with (1) SCLC (n=65) receiving carboplatin and etoposide, (2) metastatic colorectal cancer (n=125) receiving leucovorin/fluorouracil/oxaliplatin/irinotecan plus bevacizumab, and (3) metastatic triple negative breast cancer (n=34) receiving gemcitabine and carboplatin. The authors sequenced peripheral blood genomic DNA at treatment onset and after several rounds of chemotherapy. Across all three clinical trials, DNA damage response CH clones, including TP53, expanded more rapidly with chemotherapy in both trilaciclib groups and placebo groups compared to untreated control individuals. However, CH growth rate was significantly lower in the trilaciclib compared to the placebo arm (P=0.045) To further explore the functional effect of CDK4/6 inhibition, the investigators conducted murine studies using mixed bone marrow cells. The results showed that carboplatin alone markedly expanded P53-mutant hematopoietic cells in blood and bone marrow (from a mean of 18% to 45%), but this effect was blocked when combined with trilaciclib. The growth suppression persisted even after treatment stopped, and combined therapy caused selective apoptosis of TP53-mutant stem cells while sparing normal ones. Further, single-cell RNA sequencing demonstrated that CDK4/6 inhibition induces quiescence in HSPCs and myeloid progenitor cells, counteracting the proliferative advantage of TP53-mutant clones under cytotoxic stress. |
| Link to meeting abstract |
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Ianalumab plus Eltrombopag in Immune Thrombocytopenia [Phase 3 clinical trial]. |
Highlights: ● Current second-line treatments for immune thrombocytopenia (ITP) require long-term administration. ● Ianalumab is a fully human IgG1 monoclonal antibody that binds to and blocks B-cell activating factor (BAFF) receptors, leading to enhanced depletion of B cells through antibody-dependent cellular cytotoxicity and to inhibition of B-cell activation, maturation, proliferation, and survival. ● Ianalumab plus eltrombopag led to a longer time to treatment failure than placebo plus eltrombopag. In this phase 3, randomized, double-blind trial (VAYHIT2), the authors assigned, in a 1:1:1 ratio, adults with primary ITP and an insufficient response or a relapse after first-line glucocorticoid therapy to receive ianalumab at a dose of 9 mg or 3 mg per kilogram of body weight or placebo once monthly for 4 months. Eltrombopag was administered once daily in each group according to local prescribing information; the dose was tapered until discontinuation by the end of week 24 in eligible patients. A total of 152 patients underwent randomization: 50 to the 9-mg ianalumab group, 51 to the 3-mg ianalumab group, and 51 to the placebo group. The estimated probability of being free from treatment failure (primary endpoint) at 12 months was 54% (95% confidence interval [CI], 39 to 67) in the 9-mg group, 51% (95% CI, 36 to 64) in the 3-mg group, and 30% (95% CI, 18 to 43) in the placebo group. The time to treatment failure was significantly longer with ianalumab plus eltrombopag than with placebo plus eltrombopag; the estimated hazard ratio for treatment failure (ianalumab vs. placebo) was 0.55 (P=0.04) in the 9-mg group and 0.58 (P=0.045) in the 3-mg group. The percentage of patients with a stable response at 6 months was significantly higher in the 9-mg group than in the placebo group (62% vs. 39%; P=0.045). The overall frequency of adverse events during the treatment period was generally similar in the three groups. The frequency of serious adverse events was 16% in the 9-mg group, 6% in the 3-mg group, and 4% in the placebo group. |
| Link to full paper |
| Link to meeting abstract |
| Link to ClinicalTrials.gov number, NCT05653219 |
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