Hagop M. Kantarjian

AUG 2025KantarjianThe Lancet

Acute lymphocytic leukaemia

Acute lymphocytic leukaemia (ALL) is a haematological malignancy of the lymphoid progenitor cells. Enhanced genetic analyses have led to the identification of over 23 subtypes of B-cell and 17 subtypes of T-cell ALL. In parallel, the development of highly sensitive measurable residual disease assays have refined disease monitoring and risk stratification. Breakthroughs in molecular therapeutics and immunotherapies have improved treatment efficacy while reducing toxicity, challenging the traditional notion of 2·5-3 years of intensive chemotherapy. Notable progress includes the use of more potent BCR::ABL1 tyrosine-kinase inhibitors, and antibodies targeting CD19 and CD22 leukaemia surface antigens, which have delivered unprecedented outcomes in BCR::ABL1-positive ALL. Historically, adults have had poorer outcomes than paediatric cases, largely due to the higher prevalence of adverse genetic subtypes and less favourable genetic subtypes. However, development of new therapies has improved overall survival in B-cell ALL to approximately 80-90%, even in adult and infant populations. Chimeric antigen receptor T-cell therapies have also transformed outcomes for children with refractory or relapsed ALL and are now being incorporated into the front-line treatment of adult ALL. These innovations hold the promise of increasing the cure rates while reducing reliance on intensive chemotherapy and allogeneic stem-cell transplantation.

An all-oral triplet regimen (decitabine/cedazuridine, venetoclax, and gilteritinib) for newly diagnosed and relapsed/refractory FLT3-mutated AML and high-risk MDS

Combination of FLT3 inhibitors with azacitidine and venetoclax has promising activity in FLT3 -mutated acute myeloid leukemia (AML). In this phase I/II study, we evaluated the safety and efficacy of an all-oral regimen of decitabine/cedazuridine, venetoclax, and gilteritinib in adults with FLT3 -mutated AML and other myeloid malignancies. A total of 46 patients were enrolled (19 with newly diagnosed [ND] AML and 27 with relapsed/refractory [R/R] disease). The median age was 72 years in ND AML and 67 years in R/R cohort; 38 patients (83%) had FLT3 -ITD mutations. The composite complete remission (CRc) rate was 74% in ND-AML and 42% in R/R-AML, with CR rates of 58% and 21%, respectively. Two nonresponders in the ND group had prior treatment for antecedent myeloid malignancies. The 18-month relapse-free survival and overall survival were 67% and 54% in the ND cohort, respectively. During induction, the median time to ANC ( > 0.5 × 10⁹/L) and platelet ( > 50 ×10⁹/L) recovery was 37 and 27 days, respectively, in ND AML. During consolidation, median treatment durations were 3 days for DEC-C, 7 days for venetoclax, and 28 days for gilteritinib. This all-oral triplet regimen shows promising activity in ND FLT3 -mutated AML; myelosuppression remains a key toxicity requiring dose adjustment.

Dose optimization of single-agent inotuzumab ozogamicin in adults with relapsed/refractory acute lymphoblastic leukemia

Following the approval of inotuzumab ozogamicin (InO) monotherapy for the treatment of adults with relapsed/refractory CD22-positive acute lymphoblastic leukemia, the US Food and Drug Administration issued a post-marketing requirement study due to their concerns that the proposed dose of 1.8 mg/m2/cycle may not be optimal in balancing the safety and efficacy of InO. Here, we provide an overview of single-agent InO dose-optimization strategies, including the rationale for studying a fractionated InO dosing schedule and justification for the approved dosing regimen based on clinical safety and efficacy data, as well as comprehensive exposure–response analyses from InO clinical studies.

Clinical outcomes associated with NPM1 mutations in newly diagnosed acute myeloid leukemia

Retrospective cohort study reveals differential survival across therapy regimens in newly diagnosed NPM1-mutated acute myeloid leukemia, highlighting distinct prognostic risk factors.

AUG 5KantarjianBlood Cancer Journal

Treatment of adult acute lymphoblastic leukemia—a therapeutic revolution in the making

The field of adult acute lymphoblastic leukemia (ALL) is in the midst of a rapidly evolving therapeutic revolution in both Philadelphia-chromosome (Ph)-positive and Ph-negative B-cell ALL [ 1 , 2 , 3 , 4 , 5 ]. In a recent Blood Cancer Journal article from China, Li and colleagues reported on their experience in 132 adults with Ph-positive ALL treated with induction therapy with olverembatinib (third-generation BCR::ABL1 tyrosine kinase inhibitor [TKI]) and reduced intensity chemotherapy [ 6 ]. One hundred and thirty patients (98.5%) achieved a complete remission (CR), and 116 proceeded to consolidation with either allogeneic hematopoietic stem cell transplantation (HSCT; n = 73), or with olverembatinib and immunotherapy ( n = 43): blinatumomab in 28 patients and chimeric antigen receptor (CAR) T-cell therapy in 15 patients. The outcomes were better in the immunotherapy combinations compared with HSCT: 3-month complete molecular response (CMR) rate 95% versus 78%; 3-year event-free survival (EFS) rate 91% versus 74%; 3-year survival rate 94% versus 81% [ 6 ].

JUL 24KantarjianLeukemia

Five-year follow-up of OPTIC: long-term efficacy, safety, and mutation analyses of ponatinib in chronic-phase chronic myeloid leukemia from a randomized phase 2 trial

Randomized trial shows long-term benefit of ponatinib dosing in chronic myeloid leukemia, suggesting improved outcomes for T315I patients.

JUL 21KantarjianCancer

Results of second‐line therapy in adult Philadelphia chromosome‐positive acute lymphoblastic leukemia

Comparison of obecabtagene autoleucel versus an external control arm in adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia

Compares efficacy of obe-cel and external controls, indicating superior remission rates in adults with R/R B-ALL.

Predictors of survival in adults with B-cell acute lymphoblastic leukemia treated with blinatumomab and/or inotuzumab ozogamicin in first salvage

Analyzes survival predictors in adults with B-ALL after blinatumomab and inotuzumab ozogamicin treatment, indicating the role of allo-HSCT.

Decreased TXNRD1 is associated with resistance to tagraxofusp in blastic plasmacytoid dendritic cell neoplasms, as seen in phase II

Phase II trial identifies TXNRD1 levels as a biomarker for resistance to tagraxofusp in BPDCN, suggesting clinical implications.

JUL 4JabbourBlood Cancer Journal

Adult acute lymphoblastic leukemia: incorporation of recent advances into current treatment strategies

Shows improved outcomes in adults with B-cell ALL through advanced therapies, suggesting better survival rates.

JUN 27JabbourBlood Cancer Journal

Inotuzumab ozogamicin therapy for measurable residual disease in adult acute lymphoblastic leukemia

Investigational Clinical Trial Agents versus Conventional Second Salvage Therapies in Patients with Relapsed/Refractory Acute Myeloid Leukemia

PURPOSE: Outcomes in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) remain discouraging despite the rapid expansion of treatment paradigms over the past decade. Clinicians must often decide between conventional salvage treatment regimens or enrollment in clinical trials. EXPERIMENTAL DESIGN: We retrospectively identified 657 patients with AML in second treatment salvage and compared the outcomes of those who received investigational agents (n = 354) with conventional salvage regimens (n = 303). RESULTS: Conventional salvage was associated with higher response rates [complete response (CR) or CR with incomplete count recovery rate: 22% vs. 12%, P = 0.0008] and higher early mortality rates (60-day mortality: 17% vs. 7%, P = 0.0002). There was no difference in rates of bridging to allogeneic stem cell transplant (7% vs. 10%, P = 0.2), event-free survival (EFS; median: 1.5 vs. 2 months, P = 0.9), or overall survival (OS; median: 4.1 vs. 4.5 months, P = 0.8). A subgroup analysis of conventional regimens showed improved EFS (median EFS: 3.6 vs. 1.4 months, P = 0.004) and a trend toward improved OS (median OS: 7.5 vs. 3.8 months, P = 0.06) with the addition of venetoclax in venetoclax-naïve patients. CONCLUSIONS: Enrollment of R/R patients in clinical trials is a suitable alternative to conventional salvage regimens, offering novel therapeutic approaches to improve upon the historically dismal outcomes in this setting.

The All-Oral Combination of Revumenib, Decitabine and Venetoclax for Relapsed or Refractory Acute Myeloid Leukemia (SAVE)

Evaluates oral regimen efficacy in relapsed AML, highlighting high response rates.

Preliminary data from the ongoing Phase 1 study of the menin-MLL inhibitor enzomenib (DSP-5336) in combination with venetoclax and azacitidine in patients with relapsed or refractory Acute Myeloid Leukemia

Phase 1 study shows enzomenib with venetoclax and azacitidine improves responses in R/R AML, indicating a safe treatment approach.

Multimodal assessment of chronic myelomonocytic leukemia with extramedullary involvement reveals RAS pathway activation, adverse outcomes and epithelial-mesenchymal transition

Multimodal assessment reveals adverse outcomes in chronic myelomonocytic leukemia with extramedullary disease, suggesting RAS pathway implications.

RUNX1 mutations define a high-risk biological subset of chronic myelomonocytic leukemia and cooperate with ASXL1 mutations to drive leukemic transformation

Retrospective analysis identifies RUNX1 and ASXL1 mutations predict poor outcomes in chronic myelomonocytic leukemia, suggesting treatment adjustments may be needed.

Impact of uncontrolled hyperglycemia during induction chemotherapy on response and survival outcomes in patients with adult B-cell acute lymphoblastic leukemia (B-ALL) on HCVAD-based regimens

Retrospective study finds that uncontrolled hyperglycemia worsens outcomes in adult B-ALL, suggesting the need for better management.

Outcomes of hypomethylating agent failure in patients with myelodysplastic syndromes

A phase 1/2 study of DS-1594 menin inhibitor in relapsed/refractory acute leukemias

Several menin inhibitors are in development targeting menin dependent leukemias, however available preclinical results show variable level of activity. We report the phase 1 portion (to establish a recommended phase 2 dose [RP2D]) and pharmacokinetic analysis of a phase 1/2 first-in-human clinical trial of DS-1594b menin inhibitor. Eligible patients included adults (≥ 18 years of age) with relapsed/refractory (R/R) acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) including but not restricted to those with KMT2A-rearrangement (r) or NPM1 mutation. Seventeen patients at a median of age 56 years (range, 19-82 years) were treated, 15 (88%) had R/R AML, and 2 (12%) had R/R B-ALL; 9 (53%) had a KMT2A-r but none had an NPM1 mutation. The median prior lines of therapy was 3 (range 1-8) and 5 patients (29%) had received prior menin inhibitors. Five dose escalation cohorts were evaluated; no RP2D was established, and the trial was stopped at phase 1 due to a decision by supporting company due to lack of efficacy at studied dose levels and portfolio realignment. Differentiation syndrome (DS) was seen in 5 patients (29%); 2 in cohort 1 (70 mg twice daily, n = 4) 1 each had grade 1 and grade 4 DS, 3 patients in cohort 2 (50 mg twice daily/100 mg daily, n = 4) of whom 2 had grade 2 and 1 patient had grade 3 DS (considered as dose limiting toxicity). No DS was noted at cohort 3 (20 mg/day), and in subsequent dose-escalation cohorts (cohorts 4 and 5) a lead-in ramp-up dosing starting at 20 mg/day was instituted to improve tolerability. Other relevant treatment emergent adverse events of grade ≥ 3 included infections; pneumonia and febrile neutropenia in 7 patients each (41%), and sepsis in 6 patients (35%). No study drug related deaths were noted. No patient achieved a response, however 4 patients (23%) had > 25% bone marrow blast reduction. Pharmacokinetic analysis showed DS-1594b reached maximum concentration approximately in 2 h with total exposure increasing with escalating doses and reached stead-state by Cycle 1 Day 8. DS-1594b showed limited efficacy at the doses tested but appeared safe with a lead-in dosing approach.