Category: 3. Business

Treatment with oral decitabine/cedazuridine (Inqovi) plus venetoclax (Venclexta) demonstrated high response activity and encouraging survival outcomes in patients with treatment-naive high-risk myelodysplastic syndromes (HR-MDS) or chronic myelomonocytic leukemia (CMML), according to results from a single-center phase 1/2 trial (NCT04655755).¹

The findings, presented at the 2025 ASH Annual Meeting and Exposition, showed that patients treated with the regimen (n = 69) achieved an overall response rate (ORR) of 91% per International Working Group (IWG) 2006 criteria, including a 45% complete remission (CR) rate and a 46% marrow CR (mCR) rate. Responses occurred early, with a median time to first response of 1 cycle (range, 1-3) and a median of 1 cycle to best response (range, 1-5). Patients received a median of 3 cycles (range, 1-25). Response classification using updated IWG 2023 and ELN 2022 criteria showed consistent depth of remission, with CR rates of 54% and 64%, respectively.

The median overall survival (OS) for the full cohort reached 30 months, with 1- and 3-year OS rates of 68.8% and 40.7%, respectively. Median event-free survival (EFS) was 21.2 months, and the respective 1- and 3-year EFS rates were 60.7% and 32.6%. The median duration of response had not yet been reached (NR; 95% CI, 29-NR) at a median follow-up of 25 months (95% CI, 20-33).

“Decitabine/cedazuridine with venetoclax is a feasible and safe combination for [patients with] HR-MDS and CMML,” lead study author Alex Bataller, MD, PhD, explained in his presentation of the data. “This combination is associated with a high ORR, [and responses] occur early in the treatment. The median OS of patients treated with decitabine/cedazuridine and venetoclax is 30 months, with a high proportion of patients undergoing hematopoietic stem cell transplantation [HSCT].”

Bataller currently serves as an assistant professor in the Department of Leukemia, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center in Houston.

A total of 38 patients proceeded to HSCT, with best responses comprising CR (n = 18), mCR (n = 19), and no response (n = 1). The median number of cycles prior to HSCT was 2 (range, 1-11). The median OS among the HSCT subgroup was NR, with 1- and 3-year OS rates of 70.4% and 50.7%, respectively. Six patients experienced disease progression or transformation to acute myeloid leukemia after HSCT, and 8 patients died in CR following HSCT.

What was the design and patient enrolment criteria of the trial?

The phase 1/2 clinical trial evaluating oral decitabine/cedazuridine with venetoclax in treatment-naive HR-MDS or CMML with excess blasts was designed as a single-center, open-label, dose-escalation and -expansion study. Patient enrollment at MD Anderson occurred between January 2021 and August 2024.²

Eligible participants included individuals with previously untreated HR-MDS, defined by an International Prognostic Staging System (IPSS) intermediate-2 or high-risk category, or CMML with excess blasts. The study was structured in two phases.¹ Phase 1 followed a standard 3+3 dose-escalation design to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Two dose levels were evaluated:

• Dose level 0: decitabine/cedazuridine 35 mg/100 mg for 5 days plus venetoclax at 200 mg for 14 days (3 patients; no dose-limiting toxicities [DLTs] observed)
• Dose level +1: decitabine/cedazuridine 35 mg/100 mg for 5 days plus venetoclax at 400 mg for 14 days (6 patients; no DLTs observed)

Based on the absence of DLTs, dose level +1 was declared the RP2D.

Phase 2 focused on assessing the efficacy of the RP2D, enrolling 60 additional patients treated with decitabine/cedazuridine 35 mg/100 mg for 5 days in combination with venetoclax at 400 mg for 14 days per cycle.

In total, 74 patients were screened, and 69 were enrolled across both phases of the trial. The design supports a systematic evaluation of safety, tolerability, and preliminary efficacy of oral decitabine/cedazuridine combined with venetoclax.

Which baseline clinical and molecular features characterized the study population?

The median age at enrollment was 71 years (range, 21-94), and 71% of participants were male. Patients had a median bone marrow blast level of 12% (range, 6%-18%).

Most patients carried a WHO 2016 diagnosis of MDS (86%), 13% had CMML, and 1 patient (1%) had atypical CML. Cytogenetic risk based on revised IPSS (IPSS-R) criteria further underscored the high-risk nature of the cohort: 39% had good-risk cytogenetics, 25% had intermediate risk, 12% had poor risk, and 25% had very poor risk. Therapy-related neoplasms were present in 22% of patients.

Among those with MDS, IPSS-R risk classifications revealed that 59% were categorized as very high risk, 29% as high risk, and 12% as intermediate risk. Modified IPSS scoring aligned with this pattern, with 61% of patients classified as very high risk, 32% as high risk, and 7% as moderate-high risk.

What was the safety profile observed with the combination of decitabine/cedazuridine and venetoclax in patients with high-risk MDS and CMML?

Grade 3 adverse effects (AEs) occurred in 78% of patients; the rates of grade 4 and grade 5 AEs were 91% and 12%, respectively.

Cytopenias were the most frequent high-grade toxicities. Grade 3 anemia occurred in 42% of patients, and grade 4 thrombocytopenia and neutropenia occurred in 65% and 71%, respectively. Febrile neutropenia was observed in 19% of patients. Serious infectious complications included grade 3 to 5 sepsis (12% grade 3; 3% grade 4; 6% grade 5) and pneumonia (9% grade 3; 3% grade 5). Additional infectious effects,such as viremia and skin infections occurred in 9% of patients each.

“Infection prophylaxis and dose modifications are crucial to prevent excessive toxicity of this combination,” Bataller emphasized in his presentation. Seventy-five percent of patients underwent dose reductions during treatment.

References

1. Bataller A, Bouligny IM, Bazinet A, et al. Oral decitabine/cedazuridine in combination with venetoclax in treatment-naïve high-risk MDS or CMML: updates of a phase 1/2 clinical trial. Blood. 2025;146(suppl 1):237. doi:10.1182/blood-2025-237
2. Venetoclax in combination with ASTX727 for the treatment of treatment-naive high-risk myelodysplastic syndrome or chronic myelomonocytic leukemia. ClinicalTrials.gov. Updated October 3, 2025. Accessed December 7, 2025. https://www.clinicaltrials.gov/study/NCT04655755

The all-antibody–based doublet comprising teclistamab-cqyv (Tecvayli) and daratumumab (Darzalex) produced deep responses, high minimal residual disease (MRD) negativity rates, and was well-tolerated when administered as frontline treatment to elderly patients with transplant-ineligible, newly diagnosed multiple myeloma, according to results from cohort A of the phase 2 IFM2021-01 trial (NCT05572229).¹

Results presented during the 2025 ASH Annual Meeting showed that with a median follow-up of 10.3 months, all 37 patients in the intention-to-treat (ITT) population achieved a very good partial response (VGPR) or better with the doublet as their best response. This included a VGPR rate of 32%, a complete response (CR) rate of 8%, and a stringent CR (sCR) rate of 59%. The VGPR or better rate after 4 cycles was 79%, and the overall response rate (ORR) after 4 cycles was 95%; partial response, VGPR, and CR rates were 16%, 76%, and 3%, respectively.

Moreover, all evaluable patients (n = 27) achieved MRD negativity at a sensitivity of 10^-6 by next-generation sequencing (NGS) at 6 months. This rate was 73% for patients in the ITT population who underwent MRD evaluation by NGS.

[Additionally], the progression-free survival [PFS] and overall survival [OS] rates were 100%, and there [were no instances of] grade 3 or higher cytokine release syndrome or immune effector cell–associated neurotoxicity syndrome [observed],” Salomon Manier, MD, PhD, an associate professor in the Department of Hematology at Lille University Hospital in France, stated in his oral presentation of the data. “These results support further exploration of frontline combinations of BCMA/CD3 bispecific antibodies plus anti-CD38 monoclonal antibodies in phase 3 clinical trials.”

What was the rationale for evaluating this all-antibody regimen in the front line for patients with newly diagnosed multiple myeloma?

The current standard-of-care for elderly patients with newly diagnosed multiple myeloma include daratumumab-containing triplet and anti-CD38 antibody–based quadruplet regimens. Although these regimens prolong survival and produce MRD negativity rates at 10^-5 between 32% to 61%, many patients will ultimately relapse; accordingly, further optimization is key.

“Recently, the combination of teclistamab and daratumumab has demonstrated strong efficacy in the late-relapsed setting [as well as] the early-relapsed setting,” Manier shared.

Initial results from cohort 1 (n = 26) of the safety-run-in portion of the phase 3 MajesTEC-7 trial (NCT05552222) showed that, at a median follow-up of 13.8 months (range, 2.0-15.4), teclistamab administered in combination with daratumumab and hyaluronidase-fihj (Darzalex Faspro) plus lenalidomide (Revlimid) produced a VGPR or better rate of 92.3% and a 12-month PFS rate of 96.2%.² Moreover, the phase 3 MajesTEC-3 trial (NCT05083169) recently met its primary PFS end point after approximately 3 years of follow-up with teclistamab plus daratumumab and hyaluronidase vs investigator’s choice of therapy in patients with relapsed/refractory multiple myeloma who had received 1 to 3 prior treatment lines.³

“We hypothesized that a doublet regimen with [just] teclistamab and daratumumab…would be effective and limit toxicity in elderly patients with newly diagnosed multiple myeloma,” he said.

How was IFM2021-01 designed?

IFM2021-01 is an open-label, multicenter, single-arm, phase 2 study evaluating 2 doublets in the frontline setting for transplant-ineligible patients with newly diagnosed multiple myeloma: teclistamab plus daratumumab (Cohort A) and teclistamab plus lenalidomide (Cohort B; n = 37).¹ Patients are also required to be older than 65 years of age and have an ECOG performance status (PS) between 0 and 2.

In cohort A, teclistamab is administered subcutaneously (SC) in 2 step-up doses, followed by a 1.5 mg/kg dose on days 8 and 15 of cycle 1, and maintenance dosing at 3 mg/kg every 4 weeks thereafter. SC daratumumab is administered weekly at a dose of 1800 mg for 8 weeks, every 2 weeks for 16 weeks, and every 4 weeks thereafter.

Following an amendment to the study protocol, teclistamab is now administered at a dose of 3 mg/kg every 8 weeks after cycle 13 if patients achieved a CR or better; treatment interruption was permitted if patients sustained MRD negativity for 2 years. A prespecified safety and efficacy analysis was conducted after 18 patients received at least 2 cycles.

The primary end point in cohort A is the rate of VGPR or better after 4 cycles. Secondary end points include response rates, PFS, OS, time to next treatment, MRD negativity at 10^-6 by NGS at 6 months, sustained MRD 10^-6 ,and treatment-emergent adverse effects (TEAEs).

What should be known about the baseline characteristics of patients in this study?

Overall, the patient population in cohort 1 was representative of the larger transplant-ineligible, newly diagnosed population.

The median age was 73 years (range, 66-87), with the majority of patients between 70 to 75 years of age (49%), and 32% of patients being 75 years or older. Most patients were female (54%), had an ECOG PS of 1 (65%), had stage II disease (51%), did not have extramedullary disease (95%), and had a creatinine clearance of 60 mL/min or greater (62%). According to the International Myeloma Working Group Frailty score, 44% of patients were fit, 33% were intermediate, and 22% were frail. Types of measurable disease included immunoglobulin G (59%), immunoglobulin A (22%), and serum-free light chain only (19%).

The majority of patients had standard cytogenetic risk (68%). Among patients with high-risk disease (32%), mutations included 1q gains (38%); 17p deletions (14%); TP53 mutations (10%); t(4;14), t(14;16), and t(14;20) mutations (3% each); and 1p32 deletions (7%).

As of the data cutoff date of November 4, 2025, 36 patients remain on treatment, with only 1 patient having discontinued treatment due to AEs. The median duration of treatment was 10.3 months (range Q1-Q3, 9.3-16.6), and patients received a median of 12 total treatment cycles (range, 10-18). The median relative dose intensity was 95% (range, 89%-100%) for teclistamab and 96.6% for daratumumab (range, 90.5%-100%).

What did additional assessments of tumor burden biomarkers show?

Additional assessment of tumor burden biomarkers using clonotypic mass spectroscopy at 6 months showed a deep decrease of chronotypes and soluble BCMA at 6 months.

“Only 3 patients had a chronotype below 5 mg, which is considered the equivalent of emergency negativity at 10^-5,” Manier shared, noting that, “ of course, we need to consider that this is an early time point in regards to the elution of the monoclonal components.”

Additionally, flow cytometry indicated immune remodeling at 6 months, with an increase in terminal effector memory T-cells and a decrease in regulatory T cells and natural killer cells.

“[This increase in memory T-cells] reflects the continuous antigen exposure; the [decrease in regulatory T cells and natural killer cells] is likely due to the combination with dartumumab,” Manier added. “That can explain the synergy between the 2 drugs.”

What was the safety profile of this doublet?

In the ITT population, the incidence of grade 3 or higher AEs and serious AEs was 78% and 27%, respectively. No grade 5 AEs were observed. Hematologic AEs included lymphopenia (57%), neutropenia (43%), anemia (5%), and thrombocytopenia (3%). Non-hematologic AEs included infection (14%), hepatic cytolysis (5%), and skin rash (5%). AEs of special interest included infections (any-grade 65%; grade 1/2, 52%; grade 3 or higher, 14%); CRS (59%; grade 1, 35%; grade 2, 24%), injection site reactions (19%, all grade 1/2), and second primary malignancies (3%, all grade 1/2). The cumulative incidence of grade 3/4 infections was spread across time.

“One important thing is that we had a strong recommendation in the trial to give immunoglobulin supplementation systematically to all patients as soon as cycle 1…so 95% of the patients received an immunoglobulin supplementation,” Manier reported. “The median cycle of initiation of this supplementation was indeed cycle 1, and this was able to maintain the level of IgG around 7 g/L across the course of treatment.”

Additionally, systematic monitoring of cytomegalovirus (CMV) by PCR every 3 months showed that there was no correlation with CMV reactivation and the count of CD4 T cells.

Disclosures: Manier has served as a consultant for Abbvie, Adaptive Biotechnology, Amgen, Celgene/BMS, GSK, Janssen, Novartis, Regeneron, Roche, Sanofi, and Takeda; he has also received research funding from Celgene/BMS and Janssen.

References

1. Ahn I, Parrondo R, Thompson M, et al. A phase 2 Study of teclistamab in combination with daratumumab in elderly patients with newly diagnosed multiple myeloma: The IFM2021-01 teclille trial, cohort a. Blood. 2025;146(suppl 1):85. doi:10.1182/blood-2025-85
2. Tecvayli and Talvey – MajesTEC-7 (MMY3005) study. J&J Medical Connect. Updated July 31, 2025. Accessed December 7, 2025. https://www.jnjmedicalconnect.com/products/tecvayli/medical-content/tecvayli-and-talvey-majestec7-mmy3005-study#Touzeau2024
3. Tecvayli plus Darzalex Faspro combination regimen significantly improves progression-free survival and overall survival versus standard of care. News Release. Johnson&Johnson. October 16, 2025. Accessed December 7, 2025. https://www.jnj.com/media-center/press-releases/tecvayli-plus-darzalex-faspro-combination-regimen-significantly-improves-progression-free-survival-and-overall-survival-versus-standard-of-care

Pirtobrutinib (Jaypirca)demonstrated noninferiority in overall response rate (ORR) compared with ibrutinib (Imbruvica) in patients with BTK inhibitor–naive chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) in both the relapsed/refractory (R/R) and treatment-naive settings, according to findings from the phase 3 BRUIN CLL-314 trial (NCT05254743). The results from this head-to-head comparison also showed a progression-free survival (PFS) trend in favor of pirtobrutinib, according to Jennifer Woyach, MD, who presented the findings at the 2025 ASH Annual Meeting.¹

In the ITT population of patients with either R/R or treatment-naive CLL/SLL, the ORR was 87% in patients randomized to pirtobrutinib (n = 331) vs 78.5% in those randomized to ibrutinib (n = 331; P = .0035). The ORR ratio was 1.1080 (95% CI, 1.034–1.187; P value for noninferiority <.0001). The best overall response with pirtobrutinib vs ibrutinib, respectively, was complete remission (CR) or CR with incomplete hematologic recovery (CRi) of 4.8% vs 2.4%, partial remission (PR) or nodular partial remission (nPR) of 82.2% vs 76.1%, partial remission with lymphocytosis (PR-L) of 2.4% vs 3.9%, stable disease (SD) of 5.4% vs 10.9%, and progressive disease (PD) of 1.5% vs 1.2%.

In the treatment-naive population, the ORR was 92.9% in patients randomized to pirtobrutinib (n = 112) vs 85.8% in those randomized to ibrutinib (n = 113; P = .0886). The ORR ratio was 1.0797 (95% CI, 0.989–1.179). The best overall response with pirtobrutinib vs ibrutinib, respectively, was CR/CRi of 7.1% vs 3.5%, PR/nPR of 85.7% vs 82.3%, PR-L of 0.9% vs 2.7%, SD of 2.7% vs 4.4%, and no cases of PD.

In the R/R population, the ORR was 84.0% in patients randomized to pirtobrutinib (n = 219) vs 74.8% in those randomized to ibrutinib (n = 218; P = .0886). The ORR ratio was 1.1233 (95% CI, 1.020–1.237; P value for noninferiority <.0001). The best overall response with pirtobrutinib vs ibrutinib, respectively, was CR/CRi of 3.7% vs 1.8%, PR/nPR of 80.4% vs 72.9%, PR-L of 3.2% vs 4.6%, SD of 6.8% vs 14.2%, and PD of 2.3% vs 1.8%

“Pirtobrutinib demonstrated consistently higher ORR than ibrutinib across all patients, including treatment-naive and R/R populations,” said Woyach, director of the Division of Hematology, The Ohio State University Comprehensive Cancer Center.

PFS data, while immature, showed a trend in favor of pirtobrutinib. In the ITT population, at a median follow-up of 22.0 months with pirtobrutinib and 19.7 months with ibrutinib, the 18-month PFS rates per investigator assessment were 86.9% vs 82.3%, respectively (HR, 0.569; 95% CI 0.388–0.834; nominal P value = .0034). In the R/R population, at a median follow-up of 18.4 months with pirtobrutinib and 15.8 months with ibrutinib, the investigator-assessed 18-month PFS rates were 81.7% vs 79.2%, respectively (HR, 0.729; 95% CI, 0.471–1.128; nominal P value =.1563). And in the treatment-naive population, at a median follow-up of 22.5 months with pirtobrutinib and 22.4 months with ibrutinib, the investigator-assessed 18-month PFS rates were 95.3% vs 87.6%, respectively (HR, 0.239; 95% CI, 0.098–0.586; nominal P value =.0007).

“Early trends in PFS favored pirtobrutinib among all patients and in the R/R and treatment-naive populations,” said Woyach, adding that, “The most pronounced effect [was] in the treatment-naive population, which had the longest follow-up at this data cutoff.”

Safety in BRUIN CLL-314

Regarding safety, the most common all grade treatment-emergent adverse events (TEAEs) with pirtobrutinib vs ibrutinib were neutropenia (22.7% vs 17.8%), upper respiratory tract infection (17.9% vs 19.4%), anemia (15.2% vs 14.2%), pneumonia (13.6% vs 15.1%), and diarrhea (13.3% vs 19.1%). The most common grade ≥3 TEAEs with pirtobrutinib vs ibrutinib were mostly similar: neutropenia (17.3% vs 13.2%), pneumonia (6.4% vs 8.6%), anemia (5.8% vs 3.7%).

Rates of all-grade (10.6% vs 15.1%) and grade ≥3 (3.3% vs 4.9%) hypertension were lower with pirtobrutinib vs ibrutinib. One patient developed Richter Transformation with pirtobrutinib vs 4 patients with ibrutinib.

“Pirtobrutinib was well tolerated with fewer dose reductions and discontinuations due to TEAEs than ibrutinib,” said Woyach.

She said that adverse events of special interest were mostly low-grade and consistent with prior studies of pirtobrutinib. Grade ≥3 neutropenia (25.2% vs 17.5%) and anemia (6.1% vs 3.7%) were higher with pirtobrutinib vs ibrutinib; however, grade ≥3 thrombocytopenia was lower with pirtobrutinib (3.6% vs 4.0%).

All-grade incidence of atrial fibrillation/flutter (2.4% vs 13.5%) was substantially lower with pirtobrutinib versus ibrutinib, particularly among patients aged ≥75 years (4.5% vs 21.4%).

BRUIN CLL-314 Design and Patient Characteristics

The phase 3 BRUIN CLL-314 study accrued patients with BTK inhibitor–naïve CLL/SLL, including both patients with treatment-naive and R/R disease. Overall, there were 662 patients (ITT population) randomized in a 1:1 ratio to pirtobrutinib (n = 331) or ibrutinib (n = 331) between August 18, 2022, and June 17, 2024. The median age was 67 years in both the pirtobrutinib (range, 39–90) and ibrutinib (range, 34–86) arms, and the median number of prior therapies in both arms was 1. In the ITT population, 225 patients were treatment-naive and 437 patients were R/R.

In patients with evaluable samples, 68% (n = 199/293) vs 66% (n = 183/277) of patients in the pirtobrutinib vs ibrutinib cohorts had unmutated IGHV. Further, 40% (n = 104/259) vs 34% (n = 78/227) and 15% (n = 50/331) vs 16% (n = 52/331) had complex karyotype ≥3 abnormalities and del(17p), respectively.

Pirtobrutinib was administered orally at 200 mg/daily and ibrutinib was administered orally at 420 mg/daily. The primary end point was non-inferiority of ORR in the ITT population or R/R population. The key secondary end point was superiority of PFS in the ITT population or R/R population.

Significance and Next Steps

CLL-314 is the first trial comparing pirtobrutinib and ibrutinib in treatment-naive patients and patients with BTK inhibitor–naive R/R CLL/SLL.

Pirtobrutinib is currently approved by the FDA for patients with R/R CLL/SLL who have previously received a BTK inhibitor.² When the PFS data from the BRUIN CLL-314 study fully mature, it is hoped that the trend favoring pirtobrutinib will be upheld and can lead to a regulatory filing for use of the agent in earlier CLL/SLL lines.

REFERENCES

1. Woyach J, Qiu L, Grosicki S, et al. Pirtobrutinib vs ibrutinib in treatment-naïve and relapsed/refractory CLL/SLL: Results from the first randomized phase III study comparing a non-covalent and covalent BTK inhibitor. Blood. 2025;146(suppl 1): 683. doi:10.1182/blood-2025-683

2. FDA grants traditional approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. Food and Drug Administration. Published December 3, 2025. Accessed December 7, 2025. https://tinyurl.com/46522682