Ivana Gojo

Summary: Calreticulin gene ( CALR ) mutations are seen in 25%–30% of myeloproliferative neoplasms (MPNs). We report outcomes and high‐risk genomic signatures in 149 patients with CALR‐mutated MPN. CALR‐mutated essential thrombocythaemia ( n = 106) progressed to myelofibrosis ( n = 40) at a median of 20.4 years, and 20‐year overall survival (OS) was 81%. In 83 patients with myelofibrosis, the median leukaemia‐free survival (LFS) was 12.9 years, and OS was 13.9 years. Median survival after leukaemia transformation was 6.8 months. High molecular risk (HMR) mutations included ASXL1 , EZH2 , SRSF2 , U2AF1 (Q157), IDH1/2 , TP53 , SETBP1 , KRAS , NRAS and RUNX1 (later five not included in Mutation‐Enhanced International Prognostic Score System [MIPSS70]‐plus v2.0); and were associated with a significantly higher leukaemic transformation, inferior LFS and OS (hazard ratio [HR]: 3.82, 95% confidence interval [CI]: 1.30–11.18); with worst outcomes in patients with ≥2 HMR. Independent of MIPSS70‐plus v2.0, TP53 , KRAS and RUNX1 mutations adversely impacted LFS and OS (HR: 2.87, 95% CI: 1.20–6.88; HR: 3.80, 95% CI: 1.37–10.54; HR: 5.61, 95% CI: 1.53–20.52 respectively). Patients without HMR had a negligible rate of progression. Overall, outcomes are determined not by CALR ‘driver’ mutation, but by the somatic mutations that can emerge during disease evolution. Hence, serial molecular profiling is important for risk stratification. HMR, including TP53 , KRAS and RUNX1 , confer inferior survival and support early transplantation consideration.

PURPOSE: To evaluate the efficacy and safety of the cluster of differentiation 47–targeted antibody magrolimab plus azacitidine (Magro/Aza) versus azacitidine alone in treatment-naïve patients with higher-risk myelodysplastic syndromes (MDS) in the phase III ENHANCE study (ClinicalTrials.gov identifier: NCT04313881 ). METHODS: Based on the Revised International Prognostic Scoring System, patients with intermediate- to very-high-risk MDS were randomly assigned to receive Magro (1 mg/kg on days [D]1 and 4; 15 mg/kg on D8; 30 mg/kg on D11 and D15, and then once per week for five doses, followed by 30 mg/kg maintenance doses once every 2 weeks)/Aza (75 mg/m ² daily on D1-7 or on D1-5 and 8-9 in 28-day cycles) or matched placebo plus azacitidine (Placebo/Aza). Dual primary end points were complete remission (CR) rate (per 2006 International Working Group criteria) and overall survival (OS). RESULTS: At final analysis, 539 patients were randomly assigned to Magro/Aza (n = 268) or Placebo/Aza (n = 271) arms. Baseline characteristics were generally well balanced between treatment arms. In the Magro/Aza versus Placebo/Aza arms, the CR rate was 21.3% versus 23.6% (odds ratio, 0.876 [95% CI, 0.585 to 1.312]; P = .5218), and median OS was 15.9 versus 18.6 months (hazard ratio, 1.203 [95% CI, 0.947 to 1.528]; P = .1299). Magro/Aza had a higher incidence of grade ≥3 adverse events (AEs; 92.8% v 79.2%), AE-associated study drug discontinuations (24.0% v 12.1%), serious AEs (71.9% v 51.5%), and fatal AEs (15.2% v 9.8%) versus Placebo/Aza. CONCLUSION: ENHANCE did not meet the primary end points of CR rate and OS, and showed more frequent severe AEs in patients treated in the Magro/Aza arm.

Ziftomenib - a potent, selective, oral menin inhibitor - is approved as monotherapy for adults with relapsed/refractory (R/R) NPM1-mutated acute myeloid leukemia (NPM1-m AML). The KOMET-007 phase 1 trial investigated clinical activity and tolerability of ziftomenib in combination with standard therapies for R/R and newly diagnosed AML. Here, we report outcomes of adults with R/R NPM1-m AML treated with ziftomenib plus venetoclax/azacitidine. In phase 1a, patients received ziftomenib 200, 400, or 600 mg once daily with standard doses of venetoclax/azacitidine. In phase 1b, ziftomenib 600 mg was selected for expansion. Sixty-seven patients were treated (27 phase 1a; 40 phase 1b). Median age was 66 years, and 55% were men. Median number of prior therapies was 1 (range 1-8); 55% received prior venetoclax and 22% had prior transplantation. Most common (≥20%) grade ≥3 treatment-emergent adverse events were leukopenia (34%), thrombocytopenia (28%), febrile neutropenia and neutropenia (25% each). Six patients developed QTc prolongation (1 ziftomenib-related; grade 1), and 2 experienced differentiation syndrome (grade 3); all events were successfully managed. In patients receiving ziftomenib 600 mg, composite complete remission (CRc) rate was 46% (22/48), with 67% (12/18) achieving central measurable residual disease (MRD) negativity (<0.01% threshold). In venetoclax-naïve and -exposed patients, CRc rates were 70% (16/23) and 24% (6/25), with MRD-negativity rates of 75% (9/12) and 50% (3/6), respectively. Median duration of response was 8.6 months, and median overall survival was not reached. The combination of ziftomenib 600 mg with venetoclax/azacitidine was well tolerated with deep and durable clinical activity in R/R NPM1-m AML. This trial was registered at www.ClinicalTrials.gov as #NCT05735184.

Patients with myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) with high-risk features including TP53 mutations have poor outcomes due to lack of effective therapies. The atypical chemokine surface receptor C-C motif chemokine receptor-like 2 (CCRL2) is overexpressed in MDS and secondary AML (sAML) compared to healthy hematopoietic cells and we recently found that TP53-mutated MDS/AML and AML with erythroid features express the highest levels of this receptor across MDS/AML subtypes. To illustrate the therapeutic potential of CCRL2 as a therapeutic target, we developed an anti-CCRL2 antibody-drug conjugate (ADC) by conjugating an anti-CCRL2 antibody with the cytotoxic drug pyrrolobenzodiazepine (PBD), which causes DNA double-strand breaks leading to cancer cell death. The anti-CCRL2 ADC demonstrated strong CCRL2-selective cytotoxicity against cell lines derived from MDS/AML patients with TP53 mutations and erythroid features, surpassing the cytotoxic effects observed with gemtuzumab and PBD-conjugated anti-CD33 and anti-CD123 ADCs. It also induced apoptosis and suppressed the clonogenicity of primary MDS/AML bone marrow samples without affecting the survival, differentiation and clonogenicity of healthy hematopoietic stem and progenitor cells. This agent also suppressed the leukemic growth of TP53-mutated MDS/AML cell line xenografts, improving mice survival and decreasing the leukemic burden in patient-derived TP53-mutated MDS/AML xenografts. In conclusion, our study introduces CCRL2 as a potential new therapeutic target in high-risk MDS/AML including TP53-mutated subsets.

Outcomes for adults with Philadelphia chromosome positive pre-B cell acute lymphoblastic leukemia (Ph + B-ALL) have improved dramatically, but questions remain regarding the optimal induction regimen and role of allogeneic hematopoietic cell transplantation (alloHCT). We analyzed 60 consecutive patients who received reduced-intensity (RII) or hyper-CVAD induction with continuous, second-generation tyrosine kinase inhibitors (TKIs). Reduced hematologic toxicity occurred after RII. Measurable residual disease (MRD) clearance by multicolor flow cytometry (MFC, 61 vs. 94%, p = 0.02) favored hyper-CVAD, but subsequent MRD-directed blinatumomab negated this difference. Four-year relapse-free survival (RFS) was 72.3% (95% confidence interval: 57.4-91.0%) and 79.8% (65.4-97.3%, p = 0.3) in RII and hyper-CVAD groups, respectively. AlloHCT, predominantly using reduced-intensity conditioning, bone marrow grafts, and post-transplant cyclophosphamide, was the only variable associated with improved overall survival on multivariate analysis. Concurrent chemotherapy and TKIs followed by blinatumomab for MRD positivity and alloHCT, all in less intensive forms, yield excellent outcomes for patients with Ph + B-ALL.

Immune suppression, exhaustion, and senescence are frequently seen throughout disease progression in acute myeloid leukemia (AML). We conducted a phase II study of high-dose cytarabine followed by pembrolizumab 200 mg i.v. on day 14 to examine whether PD-1 inhibition improves clinical responses in relapsed/refractory (R/R) AML. Overall responders could receive pembrolizumab maintenance up to 2 years. Among 37 patients enrolled, the overall response rate, composite complete remission (CRc) rate (primary endpoint), and median overall survival (OS) were 46%, 38%, and 11.1 months, respectively. Patients with refractory/early relapse and those receiving treatment as first salvage had encouraging outcomes (median OS, 13.2 and 11.3 months, respectively). Grade ≥3 immune-related adverse events were rare (14%) and self-limiting. Patients who achieved CRc had a higher frequency of progenitor exhausted CD8+ T cells expressing TCF-1 in the bone marrow prior to treatment. A multifaceted correlative approach of genomic, transcriptomic, and immunophenotypic profiling offers insights on molecular correlates of response and resistance to pembrolizumab.Significance:Immune-checkpoint blockade with pembrolizumab was tolerable and feasible after high-dose cytarabine in R/R AML, with encouraging clinical activity, particularly in refractory AML and those receiving treatment as first salvage regimen. Further study of pembrolizumab and other immune-checkpoint blockade strategies after cytotoxic chemotherapy is warranted in AML.See related commentary by Wei et al., p. 551.This article is highlighted in the In This Issue feature, p. 549