Venetoclax plus decitabine as a bridge to allogeneic hematopoietic stem-cell transplantation in older patients with acute myeloid leukemia (VEN-DEC GITMO): final report of a multicenter, single-arm, phase 2 trial [Clinical trial] 

Highlight(s): Venetoclax plus decitabine induction can significantly enhance the feasibility of allogeneic hematopoietic stem-cell transplantation (HSCT) in older patients with acute myeloid leukemia (AML) who are deemed fit for transplantation. Longer follow-up and phase 3 trials are crucial to address some unresolved questions. 

This is an ongoing phase 2 trial ((VEN-DEC GITMO; NCT04476199), assessing the efficacy of venetoclax plus decitabine as a bridge to allogeneic HSCT in patients aged ≥60 and <75 years, with newly diagnosed AML categorized as intermediate or high risk according to 2016 WHO and 2017 European LeukemiaNet, an ECOG performance status of less than 2, and considered fit for allogeneic HSCT. The primary endpoint was the proportion of patients who had allogeneic HSCT performed during first complete remission. 93 patients were enrolled and started venetoclax plus decitabine induction (44 [47%] at intermediate risk and 49 [53%] at high risk). The median follow-up was 236 days (interquartile range 121–506). 64 (69%) of 93 patients achieved complete remission and 53 (57%) underwent allogeneic HSCT in full remission. 53 (83%) of 64 with a complete remission underwent allogeneic HSCT. Five (8%) of 64 patients in complete remission relapsed before transplantation and four died consequently. Adverse events (grade ≥3) occurred in 49 (53%) of 93 patients. The most common adverse events were infections (including pneumonia, bacterial sepsis, and SARS-CoV-2 causing seven deaths among 28 [57%] of 49 patients), neutropenia (17 [35%]), thrombocytopenia (two [4%], including one fatal CNS bleeding), and cardiac events (four [8%], including one fatal heart failure). No treatment-related deaths were observed. 51(55%) of 93 patients during cycle one and 36 (44%) of 81 during cycle two, received less than 50% of the cumulative venetoclax dose, 36 (57%) of 64 received less than 75% of the expected dose of venetoclax during cycle three, and 24 (64%) of 37 during cycle four. 38 (64%) of 59 patients in complete remission were minimal residual disease-negative by multi-parametric flow cytometry before allogeneic HSCT. 

Risk of Bleeding in Essential Thrombocythemia Patients with Extreme Thrombocytosis [Retrospective study]

Highlight(s): No difference in the cumulative incidence of bleeding and thrombosis in essential thrombocythemia (ET) patients with vs. without extreme thrombocytosis (ExT). 

This retrospective study analyzed the risk of bleeding and thrombosis in ExT vs. non-ExT ET patients at the Dana Farber Cancer Institute and Massachusetts General Hospital from 2014-2022, to inform treatment decisions. The first major bleed, clinically relevant non-major bleed (CRNMB), and thrombotic event were extracted from medical records. 128 (28%) ExT patients and 323 (72%) non-ExT patients were identified. Cumulative incidence of bleeding was not different in ExT vs. non-ExT patients (21% vs. 13%, p=0.28 for major bleeding; 16% vs. 15%, p=0.50 for CRNMB). Very-low and low thrombotic risk ExT patients were more likely to be cytoreduced compared to very-low and low-risk non-ExT patients (69% vs. 50%, p=0.060 for very-low risk; 83% vs. 53%, p=0.0059 for low risk). However, we found no differences in bleeding between ExT and non-ExT patients when restricting the risk of bleeding from diagnosis to cytoreduction start date (28% vs. 19%, p=0.29 for major bleed; 24% vs. 22%, p=0.75 for CRNMB). The cumulative incidence of thrombosis was also not different between ExT and non-ExT patients (28% vs. 25%, p=0.98). This suggests that cytoreduction may not be necessary to reduce bleeding risk based only on a platelet count of 1 million. Von Willebrand activity levels <30% were not significantly associated with bleeding, although the number of patients with von Willebrand levels <30% was small. The authors identified novel risk factors for bleeding in ET patients including diabetes mellitus and the DNMT3A mutation. 

Pomalidomide for Epistaxis in Hereditary Hemorrhagic Telangiectasia [Clinical trial]  

Highlight(s): this placebo-controlled trial provides evidence of the efficacy and safety of pomalidomide for hereditary hemorrhagic telangiectasia (HHT)- related epistaxis, whether similar effects are evident in patients with gastrointestinal bleeding or patients with pulmonary, liver, or brain arteriovenous malformations is uncertain. 

This was a phase 3 placebo-controlled (NCT03910244) trial in patients with HHT as defined by the Curaçao criteria. 144 patients were randomly assigned in a 2:1 ratio to receive pomalidomide (n=95) at a dose of 4 mg daily or matching placebo (n=49) for 24 weeks. The primary outcome was the change from baseline through week 24 in the Epistaxis Severity Score (a validated bleeding score in HHT; ranging from 0 to 10, with higher scores indicating worse bleeding). A reduction of 0.71 points or more is considered clinically significant. The baseline mean (±standard deviation) Epistaxis Severity Score was 5.0±1.5, a finding consistent with moderate-to-severe epistaxis. At 24 weeks, the mean difference between the pomalidomide group and the placebo group in the change from baseline in the Epistaxis Severity Score was −0.94 points (95% confidence interval [CI], −1.57 to −0.31; p=0.004). The mean difference in the changes in the HHT-specific quality-of-life score between the groups was −1.4 points (95% CI, −2.6 to −0.3). Adverse events that were more common in the pomalidomide group than in the placebo group included neutropenia, constipation, and rash. Lower doses of pomalidomide might have had similar efficacy with fewer toxic effects. No appreciable differences between groups were seen concerning the use of concomitant medications (e.g., tranexamic acid or epsilon aminocaproic acid) or interventional procedures. 

Intensive induction chemotherapy vs hypomethylating agents in combination with venetoclax in NPM1-mutant AML [Retrospective study]

Highlight(s): Overall survival (OS) of patients aged ≥60 years with nucleophosmin 1 (NPM1)-mutant acute myeloid leukemia (AML) was similar with intensive induction chemotherapy (IC) vs. hypomethylating agents plus venetoclax(HMA/VEN). 

This was an international, multicenter retrospective cohort study of 221 patients (147 IC and 74 HMA/VEN) with previously untreated NPM1-mutant AML. Composite complete remission (cCR) (defined as CR + CR with incomplete count recovery) rate was similar for IC and HMA/VEN (cCR, 85% vs. 74%, respectively; p= 0.067). Although OS was significantly improved with IC in unselected patients compared with HMA/VEN (24-month OS, 59% [95% confidence interval (CI), 52-69%] vs. 38% [95% CI, 27-55%]; p= 0.013), this improvement was not statistically significant among patients aged 60-75 years (60% [95% CI, 52-70%] vs. 44% [95% CI, 29-66%]; p= 0.069) and patients who received an allogeneic stem cell transplant (70% [95% CI, 58-85%] vs. 66% [95% CI, 44-100%]; p= 0.56). Subgroup analyses suggested that patients with normal cytogenetics (24-month OS, 65% [95% CI, 56-74%] with IC vs. 40% [95% CI, 26-60%] with HMA/VEN; p= 0.009) and without FLT3 internal tandem duplication mutations might benefit from IC compared with HMA/VEN (24-month OS, 68% [95% CI, 59- 79%] vs. 43% [95% CI, 29-63%]; p= 0.008). In multivariable analysis, OS was not statistically different between patients treated with IC and HMA/VEN (hazard ratio for death with HMA/ VEN vs. IC, 0.71; 95% CI, 0.40-1.27; p= 0.25). Measurable residual disease (MRD) status was not uniformly available.

Transformation of marginal zone lymphoma to Hodgkin lymphoma [Case series study]

Highlight(s): Marginal zone lymphoma (MZL) transformation to Hodgkin Lymphoma (HL) is rare, and data on this event are heterogeneous. Whether this represents transformation of MZL or co-occurrence is unknown. Here are results from the largest reported series.

A total of 10 patients with transformation from MZL to HL were identified, including 6 patients initially diagnosed with splenic MZL (SMZL), 3 with extranodal MZL (EMZL), and 1 with nodal MZL (NMZL). Transformation occurred within 10 years in most patients (90%) at a median of 93 months. Given the absence of molecular clonality studies, it cannot be excluded that the cases of HL may be de novo primary malignancies.  At the time of transformation to HL, most patients presented with advanced disease.  The median follow-up after transformation was 62.5 months (range, 9-116). Three achieved a complete response following treatment with RICE (rituximab, ifosfamide, carboplatin, etoposide)/ BEAM (carmustine, etoposide, cytarabine, melphalan) + autologous hematopoietic cell transplantation (n = 1), BV-AVD (brentuximab vedotin, doxorubicin, vinblastine, dacarbazine; n = 1), and ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine; n = 1). The median overall survival (OS) from the time of transformation was 12 months (range, 4.6-67) with a median progression-free survival from transformation of 9.7 months (range, 2-67). The median OS  from initial diagnosis was 102.5 months (range, 19-161). None of the patients had MZL relapse after transformation to HL. Five patients were alive and 3 were deceased (all 3 died due to lymphoma). 

Multiomics analysis of IgM monoclonal gammopathies reveals epigenetic influence on oncogenesis via DNA methylation [Basic and prospective research]

Highlight: This study demonstrates differential DNA methylation in immunoglobulin M (IgM) gammopathies and specifically between Waldenström macroglobulinemia (WM) and IgM-monoclonal gammopathy of undetermined significance (IgM-MGUS). 

In this study, a multiomics prospective analysis was conducted integrating DNA methylation, RNA sequencing (RNA-seq), and whole-exome sequencing data in 34 subjects (23 with WM, 6 with IgM-MGUS, and 5 normal controls). Analysis was focused on defining differences between IgM gammopathies (WM/IgM-MGUS) compared with controls, specifically between WM and IgM-MGUS. Between groups, genome-wide DNA methylation analysis demonstrated a significant number of differentially methylated regions that were annotated according to genomic region. Next, the integration of RNA-seq data was performed to identify potentially epigenetically deregulated pathways. The authors found that pathways involved in the cell cycle, metabolism, cytokine/immune signaling, cytoskeleton, tumor microenvironment, and intracellular signaling were differentially activated and potentially epigenetically regulated. Importantly, there was a positive enrichment of the CXCR4 signaling pathway along with several interleukin (interleukin 6 [IL-6], IL-8, and IL-15) signaling pathways in WM compared with IgM-MGUS. Further assessment of known tumor suppressor genes and oncogenes uncovered differential promoter methylation of several targets with concordant change in gene expression, including CCND1 and CD79B. The graph in the accompanying commentary (see Figure in original comment by B. Barwick, Link 2) illustrates the different IgM gammopathy profiles/clusters, and their relationship to the epigenetic spectrum.

Measurable Residual Disease by Mass Spectrometry and Next-Generation Flow to Assess Treatment Response in Myeloma [Retrospective study]

Highlight(s): In transplant-eligible multiple myeloma (MM) patients, measurable residual disease (MRD) by next-generation flow (NGF) and mass spectrometry (MS) achieve similar prognostic value in single time point assessments and kinetics. 

In the context of the GEM2012MENOS65 and GEM2014MAIN trials, the authors of this study compared the performance of quantitative immunoprecipitation mass-spectrometry (QIP-MS; EXENT® System; The Binding Site, part of Thermo Fisher Scientific, Birmingham, UK) in serum with NGF cytometry in bone marrow to assess MRD in paired samples obtained post-induction, transplant, consolidation and after 24 cycles of maintenance. QIP-MS identified the M-spike in 59% of cases (109/185) post-induction, 42% (72/173) post-autologous stem cell transplant, 34% (60/178) post-consolidation, and 24% (39/164) at the end of treatment, whereas NGF was positive in 69% (128/185), 50% (87/173), 44% (79/178), and 29% (48/164) of cases, respectively. 

Thus, NGF detected MRD more frequently than QIP-MS, both during active treatment and maintenance. When considering NGF as a reference, the estimated negative predictive value of MS was found to be 65% post-induction, 73% post-ASCT, 73% post-consolidation, and 86% after two years of maintenance. At each time point, both NGF and QIP-MS were able to segregate two groups of patients with significantly different progression-free survival; when the evolution of the results obtained with either method was considered, maintaining or converting to MRD negativity was associated with longer survival, significantly better when compared to sustaining or converting to MRD positivity. Of note, the reemergence of MRD by QIP-MS was associated with a high risk of imminent clinical progression.  The minimally invasive nature of MRD monitoring by MS represents a breakthrough in high-sensitive response assessment in MM. 

Axatilimab in Recurrent or Refractory Chronic Graft-versus-Host Disease [Clinical trial]

Highlight(s): The AGAVE-201 study (NCT04710576) showed that single-agent therapy with axatilimab is effective for many patients with recurrent or refractory chronic graft-versus-host disease (cGVHD), including those in whom standard-of-care therapies failed. 

These results were previously discussed at the “Highlights 29th European Hematology Association Hybrid Congress (EHA2024; 13 to 16 June, Madrid, Spain)” (link to newsletter June 23, 2024). The original study is now published in the NEJM, accompanied by an editorial commentary by S. Sarantopoulos and another editorial in the section “Science behind the study” by M. Mohty. 
In this phase 2, multinational, pivotal, randomized study, the authors evaluated axatilimab (a humanized antibody that targets the colony-stimulating factor 1 receptor [CSF1R]–dependent monocytes and macrophages) at three different doses in 241 patients with recurrent or refractory cGVHD. Patients were randomly assigned to receive axatilimab, administered intravenously, at a dose of 0.3 mg per kilogram of body weight every 2 weeks (0.3-mg dose group; n=80), at a dose of 1 mg per kilogram every 2 weeks (1-mg dose group; n=81), or at a dose of 3 mg per kilogram every 4 weeks (3-mg dose group; n=80). The primary end point was the overall response (complete or partial response) in the first six cycles. 
An overall response was observed in 74% (95% confidence interval [CI], 63 to 83) of the patients in the 0.3-mg dose group, 67% (95% CI, 55 to 77) of the patients in the 1-mg dose group, and 50% (95% CI, 39 to 61) of the patients in the 3-mg dose group. A reduction of more than 5 points on the modified Lee Symptom Scale was reported in 60%, 69%, and 41% of the patients in the three dose groups, respectively. The most common adverse events were dose-dependent transient laboratory abnormalities related to CSF1R blockade. Adverse events leading to discontinuation of axatilimab occurred in 6% of the patients in the 0.3-mg dose group, 22% in the 1-mg dose group, and 18% in the 3-mg dose group.