Efficacy and safety of azacitidine in VEXAS syndrome: a large-scale retrospective
study from the FRENVEX

Highlights:

●      VEXAS (Vacuoles, E1 Enzyme, X-Linked, Autoinflammatory, Somatic) syndrome is a severe monogenic disorder caused by somatic UBA1 mutations, characterized by inflammation, cytopenias and frequent association with myelodysplastic neoplasms (MDS).

●      This study showed that azacitidine (AZA) can provide sustainable inflammatory, hematological, and molecular responses during treatment of VEXAS syndrome.

This multicenter retrospective study assessed AZA efficacy and safety in 88 genetically confirmed VEXAS patients from the FRENVEX (French VEXAS) group, 80% meeting World Health Association 2022 MDS criteria. Inflammatory response rates were 41% at 6 months and 54% at 12 months, regardless of MDS status. A total of 50 (61%) patients achieved inflammatory response, with 70% occurring at 6 months, suggesting a delayed median response. Among responders, relapse-free survival on AZA was 90% at 1 year and 85% at 5 years. Of the 12 responders who discontinued AZA, 9 relapsed after a median of 3.1 years (range: 0.4–5.6), with effective re-exposure in 4 of 5 patients. Hematological responses included red blood cell transfusion independence in 65% and platelet improvement in 77% of patients. Molecular response, defined as a ≥25% reduction in UBA1 variant allele frequency (VAF), was observed in 65% of patients, all of whom achieved inflammatory and hematological responses; and VAF dropped below 2% in 43% of cases. Infections (34%) and cytopenias (36%) were common, particularly during the first three cycles. Likewise, we recall the Spanish case series study of 4 patients with VEXAS without MDS, where AZA had positive disease-modifying results (See the News of the Week- January 20, 2025).

Sustained bone marrow and imaging MRD negativity for 3 years drives discontinuation of maintenance post-ASCT in myeloma [Prospective cohort] 

Highlight:  

This study demonstrated the utility of testing measurable residual disease (MRD, which involves detecting low levels of malignant plasma cells in the bone marrow and performing a positron emission tomography/computed tomography scan) to determine if maintenance lenalidomide therapy could be discontinued in selected patients with multiple myeloma (MM) after induction therapy, autologous hematopoietic cell transplant (ASCT), and single-agent lenalidomide.

The conversion to MRD positivity, the treatment-free survival (TFS), and the progression-free survival (PFS)  were evaluated in 52 patients with MM who discontinued lenalidomide maintenance after achieving sustained bone marrow and imaging MRD negativity for 3 years. The median follow-up from lenalidomide discontinuation was 3 years. Overall, 12 (23%) patients obtained MRD positivity and restarted lenalidomide maintenance. Only 4 (7.6%) patients progressed; 3 had a biochemical progression and 1 had a clinical progression. The overall median PFS was not reached, whereas the 7-year PFS from diagnosis was 90.2%. The 1-, 2-, and 3-year TFS rates were 93.9%, 91.6%, and 75.8%, respectively, whereas the 1-, 2-, and 3-year landmark PFS rates from maintenance discontinuation (study entrance) were 96.0%, 96.0%, and 92.9%, respectively. There were no statistically significant associations among age, sex, Second Revision International Staging System, type of induction therapy, and use of consolidation therapy and the effect outcomes of PFS and TFS. Thus, in the era of modern antimyeloma treatments, a subgroup of patients may remain treatment free while in complete remission without jeopardizing disease response.

Adult Acute Lymphoblastic Leukemia: 2025 Update on Diagnosis, Therapy, and Monitoring [Critical Review]

Kantarjian et al. have recently published several reviews of acute lymphoblastic leukemia (ALL). Below are some key points from the review in the American Journal of Hematology.

Key points:

●      Although ALL is the most common pediatric cancer, it is a rare disease overall. Current treatment relies on multiagent chemotherapy administered over 2–3 years, resulting in long-term survival in 80%–90% in pediatric patients compared to 40%–50% in adult patients, depending upon patient-and disease-specific characteristics.

●      Philadelphia Chromosome (Ph)-positive B-Cell ALL: the treatment and outcome of this historically considered poor risk subtype were drastically changed with the advent of the BCR::ABL1 tyrosine kinase inhibitors (TKIs). The combination of a TKI with a backbone of multiagent chemotherapy, or more recently blinatumomab, is the mainstay of therapy, resulting in 5-year survival rates of 80+%. Achieving a complete molecular remission, particularly by next generation sequencing, is an important prognostic indicator, which may identify patients who may avoid allogeneic stem cell transplantation (SCT). See Figure 1 in the original article.

●      Ph-Negative B-Cell ALL: The treatment approach was historically composed of a chemotherapy backbone (either pediatric-inspired, or Hyper-CVAD based). Novel agents including inotuzumab ozogamicin and blinatumomab are being incorporated into these regimens to improve the rates of measurable residual disease negativity and long-term outcomes. While differences in long-term survival rates differ between age groups, such as adolescents and young adults compared to older adults (≥ 60 years), with these immunotherapy-chemotherapy regimens, the 4-year survival rates have improved to 80%–85% among patients who are able to receive these treatments. The use of inotuzumab ozogamicin and blinatumomab in lieu of intensive chemotherapy in this population has improved safety and efficacy in patients ≥ 60 years old. Clinical trials incorporating chimeric antigen receptor (CAR) T-cell therapy into treatment for older patients are in progress. See Figure 2 in the original article.

●      T-Cell ALL: Combination chemotherapy regimens incorporating pegylated asparaginase and nelarabine are the standard for patients with T-cell ALL. Early T-cell precursor (ETP) ALL is a high-risk subgroup for which allogeneic SCT should be considered. Inclusion of the BCL-2 inhibitor venetoclax into treatment for patients with ETP-ALL may be beneficial and is currently being investigated.

●      The desired goals are to achieve cure rates comparable to those in pediatric ALL and to reduce or eliminate the need for prolonged intensive/maintenance chemotherapy and associated toxicities.

Fitness assessment in acute myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet [Consensus]

This panel developed 21 recommendations related to the evaluation of the fitness of patients with acute myeloid leukemia.

Key recommendations: 

●      Ineligibility for intensive treatment does not exclude eligibility for allo-stem cell transplant after achieving complete remission following non-intensive treatment

●      For mitigating disease-related symptoms, antileukemic therapy should be considered even with unattainable curative intent.

●      Fitness refers to a comprehensive evaluation of: age, performance status (PS), comorbidities, and functional capacity. See Table 5 in the original article for “Available tools for comprehensive geriatric assessment”.

●      Age, as a single parameter, should not be considered for the definition of fitness.

●      For patients aged >75 years, eligibility for intensive chemotherapy (IC) should be evaluated carefully.

○      Given that only a small proportion of patients aged >75 years can benefit from IC and considering the lack of clinical trials focusing exclusively on intensively treated patients in this age group, careful evaluation of eligibility for IC is needed for patients aged >75 years. It is crucial to also consider the patient’s quality-of-life (QoL) expectations, psychosocial circumstances, and willingness to undergo IC.

○      PS should be determined during treatment planning. Nevertheless, considering its subjective nature and limited sensitivity, a geriatric assessment is particularly useful for patients with a PS score of >2 to inform decisions about treatment intensity. For patients with a PS score of >3, the decision between active treatment and supportive therapy alone should be made on a case-by-case basis.

●      A comprehensive approach that considers both patient- and disease-related factors is recommended. Because diagnostic workup may require time, patients with clinically stable disease may wait up to 3 weeks from diagnosis to treatment. Patients should be informed that the time spent on comprehensive assessments is critical for tailoring the most effective treatment plan.

●      Although not reaching a consensus, 67% of the panelists agreed that early palliative care (EPC) should be standard of care, even for patients receiving IC, to improve QoL, and treatment outcome. EPC should be integrated at diagnosis, tailored to the patient’s goals, preferences, and expectations, with a focus on symptom management and psychosocial support.

FDA Oncologic Drugs Advisory Committee (ODAC) Votes Against the Applicability of STARGLO Data for U.S. Patients With DLBCL [Meeting Drug approval] 

Following the discussion, eight out of nine ODAC members voted that the STARGLO trial (NCT04408638) findings (evaluating the efficacy and safety of glofitamab in combination with gemcitabine plus oxaliplatin (Glofit-GemOx) compared with rituximab in combination with gemcitabine plus oxaliplatin (R-GemOx) in patients with R/R DLBCL) could not be reliably translated to a United States population. Of 274 patients, this global trial enrolled only 9% of patients (n=25) in the U.S.

See the summary of this clinical trial in a previous IACH news of the week entry (Highlights 29th European Hematology Association Hybrid Congress [EHA2024; 13 to 16 June, Madrid, Spain]).

FDA ODAC Votes in Support of DARZALEX FASPRO for High-Risk Smoldering Myeloma [Meeting Drug approval]

The U.S. Food and Drug Administration’s Oncologic Drugs Advisory Committee (ODAC) voted 6-2 in favor of the benefit-risk profile of DARZALEX (daratumumab) as a single-agent therapy for adults with high risk-smoldering multiple myeloma, based on the phase 3 AQUILA clinical trial (NCT03301220). See the summary of this study in a previous IACH news of the week post (Highlights of the 66th American Society of Hematology Annual Meeting and Exposition [#ASH24; December 7-10, 2024, in San Diego, California)].

If approved, DARZALEX FASPRO could transform care for thousands of patients annually diagnosed with HR-SMM in the U.S., offering a chance to act before irreversible complications occur.

Hoffbrand's Postgraduate Haematology, 8th Edition [Book]

This new edition of the “Hoffbrand” book, a publication dating back to 1972, has been published by Adam J. Mead (Editor), Michael A. Laffan (Editor), Graham P. Collins (Editor), Deborah Hay (Editor), A. Victor Hoffbrand (Consulting Editor). This 8^th edition promises to continue the tradition of excellence with a fully updated text. It is an indispensable resource.

The table of contents is available in the link below.