Key Ideas

Newer data are steadily narrowing the population that benefits from intensive chemotherapy in acute leukemia. In fit older adults with adverse-risk AML, lower-intensity azacitidine-venetoclax now rivals or outperforms intensive induction based on the results of the PARADIGM study. Venetoclax added to azacitidine, however, has not improved survival in higher-risk MDS. And in older adults with acute lymphoblastic leukemia (ALL), dose-reduced and “chemotherapy-free” regimens are closing a survival gap that has persisted for decades.

A Shifting Definition of "Fit for Chemotherapy" in AML

For decades, the central question in newly diagnosed acute myeloid leukemia (AML) has been which patients are fit enough for intensive induction chemotherapy. The phase 2 PARADIGM trial, presented as a plenary abstract at the 2025 American Society of Hematology (ASH) Annual Meeting, asked a different question: among patients who are fit for intensive chemotherapy, which of them might do just as well, or better, with a gentler approach?

The randomized study enrolled 172 previously untreated, transplant-eligible adults and compared azacitidine plus venetoclax against conventional intensive induction (7+3 or CPX-351).[1] Key exclusion criteria include several favorable-risk AML subtypes and those with FLT3-ITD or TKD mutations; thus, the enrolled population skewed toward adverse-risk disease with a median age in the mid-60s, so the results speak most directly to older adults with higher-risk AML rather than to younger or favorable-risk patients.

Event-free survival (EFS), the primary endpoint, favored azacitidine-venetoclax with a median EFS of roughly 14.5 months versus 6.2 months with intensive chemotherapy.[1] Response rates and rates of proceeding to allogeneic transplant were also higher with the lower-intensity regimen, while rates of infection, bleeding, and 60-day mortality were higher with intensive chemotherapy. Overall survival did not differ significantly between arms, likely reflecting the availability of effective salvage options and crossover in practice.

The takeaway for older, transplant-eligible adults with intermediate- or adverse-risk, FLT3 wild-type AML is that azacitidine-venetoclax is a reasonable frontline alternative to intensive induction, with the goal of inducing remission and moving efficiently to allogeneic transplant, which remains the therapy most closely linked to long-term survival in this group. Patients with favorable-risk subtypes, such as core-binding factor AML or NPM1-mutated AML, who can be cured with chemotherapy alone without transplant, are treated differently and generally still receive intensive induction.

Venetoclax Falls Short of Expectations in Higher-Risk MDS

Higher-risk myelodysplastic syndrome (MDS), typically defined by increased marrow blasts, high-risk cytogenetics, or severe cytopenias, has for years been treated with a hypomethylating agent alone, most commonly azacitidine or decitabine. Given venetoclax's success in AML, it was reasonable to ask whether adding it to azacitidine would improve outcomes in higher-risk MDS as well.

The phase 3 VERONA trial randomized 509 patients with treatment-naive higher-risk MDS (IPSS-R score greater than 3, not immediately eligible for transplant) to azacitidine plus either venetoclax or placebo, with overall survival as the primary endpoint.[2] The results, presented in 2025, showed no meaningful difference: median overall survival was approximately 22 months in both the azacitidine + venetoclax arm and the azacitidine + placebo arm, with the survival curves essentially overlapping. A forest plot analysis found no subgroup, including patients with blast counts in the 10 to 19 percent range, that derived a clear survival benefit. The venetoclax combination also carried a higher rate of neutropenic fever and cytopenias, without improving the rate of complete remission, the rate of transplant, or how quickly patients reached transplant.

The clinical implication is a more selective role for venetoclax in higher-risk MDS going forward. For most patients, the priority remains identifying transplant candidates early and coordinating with transplant colleagues, since allogeneic transplant is the only potentially curative option, including for patients with TP53-mutated disease, where outcomes remain the most challenging.

For patients whose disease carries an IDH2 mutation, a more targeted option is now available through the National Cancer Institute's myeloMATCH initiative, a multi-cooperative-group effort that assigns patients with AML and MDS to trials matched to their molecular profile. One active myeloMATCH substudy is comparing the IDH2 inhibitor enasidenib added to standard hypomethylating therapy against hypomethylating therapy alone in IDH2-mutated higher-risk MDS. With myeloMATCH now open at a large number of sites nationally, checking whether a patient's higher-risk MDS qualifies for one of its molecularly matched substudies is worth doing before defaulting to standard therapy.

Closing the Survival Gap in Older Adults With ALL

Outcomes in acute lymphoblastic leukemia (ALL) have improved dramatically in adolescents and young adults through pediatric-inspired chemotherapy regimens, but that progress has not translated as well to older adults, largely because the toxicity of those regimens, particularly from asparaginase, is harder to tolerate with age. Registry data confirm that survival gains in ALL patients over 60 have lagged well behind those seen in younger patients.

Several approaches are narrowing that gap:

Dose-Reduced Pediatric-Inspired Chemotherapy

A dose-reduced version of the CALGB 10403 pediatric-inspired regimen (RD-10403), which caps peg-asparaginase at roughly a quarter to half of the young-adult dose, produced a 3-year overall survival of 55% in a cohort of older adults with Philadelphia chromosome-negative (Ph-) ALL, compared with a historical benchmark of roughly 15% to 20% for 3- to 5-year survival in this population.[3] About 40% of patients experienced a grade 3 toxicity, but most were manageable, and follow-up work suggests even lower asparaginase doses can still reach therapeutic drug levels.

Mini-Hyper-CVD Plus Venetoclax

For both B-cell and T-cell ALL, mini-hyper-CVD (an attenuated version of the hyper-CVAD chemotherapy backbone) combined with venetoclax has shown durable remissions in newly diagnosed patients, with reported 3-year overall survival in the range of 60% to 70% in small early cohorts.[4] This regimen offers a phenotype-agnostic option that can be utilized for both Ph- B-cell and T-cell ALL.

Chemotherapy-Free Antibody-Based Therapy for B-Cell ALL

For older adults specifically with Ph- B-cell ALL, the Alliance A041703 trial tested a completely chemotherapy-free approach: two cycles of the CD22-directed antibody-drug conjugate inotuzumab ozogamicin followed by four cycles of the CD19-directed bispecific T-cell engager blinatumomab, with intrathecal chemotherapy for central nervous system prophylaxis.[5] Complete remission rates exceeded 90%, and 3-year overall survival was reported at roughly 60%,[8] compared with a historical benchmark of approximately 20% for patients over 60.

Taken together, for phenotype-agnostic approaches, dose-reduced pediatric-inspired chemotherapy or mini-hyper-CVD plus venetoclax are increasingly used; for older adults specifically with B-cell ALL, the chemotherapy-free inotuzumab-then-blinatumomab sequence is an increasingly attractive first-line option.

Philadelphia Chromosome-Positive ALL: A Genuine Success Story

Philadelphia chromosome-positive (Ph-positive) ALL is enriched in older adults, accounting for roughly half of ALL cases in patients over 60, and it has undergone one of the more remarkable transformations in acute leukemia care over the past two decades, moving from a high-risk ALL subtype to one of the best-surviving, largely through combining tyrosine kinase inhibitors (TKIs) with immunotherapy in place of intensive chemotherapy.

Early chemotherapy-free approaches combined the second-generation TKI dasatinib with the bispecific antibody blinatumomab and reported response rates above 90%, with 3-year overall survival around 87% and 4-year overall survival around 80%.[6],[9] Substituting the more potent TKI ponatinib for dasatinib has produced even higher survival, with estimated 3-year overall survival around 90% in updated series from a single center, alongside high rates of molecular response and MRD negativity.[7] The main vulnerabilities of this approach are late central nervous system relapses, particularly in patients with a high white blood cell count at diagnosis, along with cardiovascular toxicities associated with ponatinib that require monitoring.

Newer combinations are now testing dual TKI plus blinatumomab,[10] and an early University of Chicago-led effort combining inotuzumab ozogamicin with a TKI has reported deep remission rates similar to TKI-blinatumomab approaches, with roughly 80% two-year overall survival in preliminary follow-up.[11] Inotuzumab's once-weekly, three-dose-per-cycle schedule offers an alternative approach for patients that may have logistical barriers to receiving blinatumomab-based therapy. For all of these regimens, central nervous system prophylaxis with roughly 15 to 16 intrathecal chemotherapy treatments over the first 18 months of treatment remains an important component of care.

For Patients

Treatment for acute leukemias and related blood cancers is moving away from a one-size-fits-all approach built around intensive chemotherapy, and toward regimens tailored to age, fitness, and the specific genetic features of a person's disease.

For older adults with AML who are otherwise healthy enough for intensive chemotherapy, a gentler combination of azacitidine and venetoclax now performs as well as, or better than, traditional intensive chemotherapy for many higher-risk cases, with fewer serious infections and less time in the hospital. That said, patients with certain favorable genetic subtypes of AML may still do best with traditional intensive chemotherapy, since it can cure the disease without a transplant.

For higher-risk MDS, a recent large clinical trial found that adding venetoclax to standard therapy did not improve survival, so the standard hypomethylating-agent therapy remains appropriate for most patients, with allogeneic stem cell transplant, when possible, offering the best chance at long-term disease control. Patients whose MDS carries a specific mutation called IDH2 may be eligible for a nationwide clinical trial network called myeloMATCH, which matches patients to trials based on their tumor's genetic profile, so it is worth asking whether a diagnosis qualifies.

For older adults with ALL, several newer regimens, some combining lower doses of chemotherapy with an oral pill (venetoclax), and others replacing chemotherapy altogether with antibody-based therapies (inotuzumab ozogamicin and blinatumomab), are meaningfully improving survival compared with what was possible even five to ten years ago. For a specific subtype called Philadelphia chromosome-positive ALL, combining a targeted pill with antibody-based immunotherapy has turned what used to be the highest-risk form of this leukemia into one of the more treatable ones, with many patients now surviving several years or more.

Anyone facing one of these diagnoses should ask their care team which of these newer, less-toxic options may apply to their specific case, and whether a clinical trial, including myeloMATCH for eligible MDS and AML patients, might be available to them.

Key Takeaways

  • In fit, transplant-eligible older adults with intermediate- or adverse-risk AML, azacitidine plus venetoclax now offers event-free survival roughly double that of intensive chemotherapy, with fewer infections and less hospitalization.

  • Favorable-risk AML subtypes, such as core-binding factor AML, generally still warrant intensive chemotherapy since they can be cured without transplant.

  • Adding venetoclax to azacitidine did not improve survival in higher-risk MDS in the phase 3 VERONA trial; hypomethylating-agent therapy alone, plus early transplant evaluation, remains standard for most patients.

  • Patients with IDH2-mutated higher-risk MDS may be candidates for a molecularly matched clinical trial through the myeloMATCH initiative.

  • Dose-reduced pediatric-inspired chemotherapy, mini-hyper-CVD plus venetoclax, and chemotherapy-free inotuzumab-then-blinatumomab are each improving survival in older adults with ALL compared with historical outcomes.

  • Philadelphia chromosome-positive ALL, once the highest-risk ALL subtype, now has 3-year overall survival approaching 90% with TKI-plus-immunotherapy regimens, though late CNS relapse and cardiovascular toxicity require ongoing monitoring.

References

  1. Fathi A, Perl A, Fell G, et al. 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. Presented at: 2025 ASH Annual Meeting & Exposition; December 6-9, 2025; Orlando, FL. Abstract 6.

  2. Garcia-Manero G, Platzbecker U, Fenaux P, et al. Primary analysis of the randomized, phase 3 VERONA study of venetoclax with azacitidine versus placebo with azacitidine in patients with treatment-naive, intermediate and higher-risk myelodysplastic syndromes. Presented at: Society of Hematologic Oncology (SOHO) 2025 Annual Meeting; September 3-6, 2025; Houston, TX. Abstract MDS-1497.

  3. Patel AA, et al. Efficacy and tolerability of a modified pediatric-inspired intensive regimen (RD-10403) for acute lymphoblastic leukemia in older adults. eJHaem. 2021.

  4. Short NJ, Kantarjian H, et al. Mini-hyper-CVD plus venetoclax for treatment of older adults with newly diagnosed Philadelphia chromosome-negative ALL. Presented at ASH Annual Meeting.

  5. Wieduwilt MJ, Yin J, Kour O, et al. Inotuzumab ozogamicin then blinatumomab for older adults with newly diagnosed B-cell ALL: Alliance A041703 cohort 1 results. J Clin Oncol. 2025;43(32):3526-3535.

  6. Foà R, Bassan R, Vitale A, et al. Dasatinib-blinatumomab for Ph-positive acute lymphoblastic leukemia in adults. N Engl J Med. 2020;383(17):1613-1623.

  7. Kantarjian H, Short NJ, Haddad FG, et al. Results of the simultaneous combination of ponatinib and blinatumomab in Philadelphia chromosome-positive ALL. J Clin Oncol. 2024;42(35):4246-4251.

  8. Wieduwilt MJ, Yin J, Kour O, et al. Inotuzumab ozogamicin then blinatumomab for older adults with newly diagnosed, Ph-negative, CD22-positive, B-cell acute lymphoblastic leukemia: extended follow-up of Alliance for Clinical Trials in Oncology A041703 cohort 1 reveals durable remission and survival. Blood. 2025;146(Suppl 1):444.

  9. Advani AS, Moseley A, O'Dwyer KM, et al. Dasatinib/prednisone induction followed by blinatumomab/dasatinib in Ph+ acute lymphoblastic leukemia. Blood Adv. 2023;7(7):1279-1285.

  10. Luskin MR, Murakami MA, Keating JH, et al. A phase I study of asciminib in combination with dasatinib, prednisone, and blinatumomab for Ph-positive acute leukemia in adults. J Clin Oncol. 2025;43(16_suppl):6509.

  11. Patel A, Duvall A, Saygin C, et al. Primary efficacy analysis of phase II study investigating tyrosine kinase inhibitor (TKI) and inotuzumab ozogamicin-based therapy for newly diagnosed Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Blood. 2025;146(Suppl 1):441.