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Azacitidine holds promise in VEXAS syndrome; a step forward in precision blood matching; identifying a new vulnerability in TP53-mutated AML
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Welcome to the September 18, 2025 episode of Blood Podcast, your source for innovative ideas and cutting edge information. Our topics are based on articles published in Blood A Journal of the American Society of Hematology. First on today's podcast Azacytidine invexis syndrome treatment can provide responses in patients with this complex autoinflammatory disorder, but relapse rates were high, so long term therapy may be required to maintain disease control. After that, a step forward in precision blood High throughput array genotyping enables extended matching to reduce antibody formation. The results show the potential for reducing harm in regularly transfused patients. Finally, identifying a new vulnerability in TP53 mutated AML loss of the tumor suppressor BAP1 defines a unique subtype of TP53 mutated de novo AML. BAP1 loss also confers sensitivity to BCL XL inhibitors in vivo, Opening a new therapeutic avenue. Let's start with Efficacy and safety of Azacytidine and Vex's syndrome, a large scale retrospective study from Frenvex, the the French vexis group. The first author is Vincent Jacquier of Hospital Saint Antoine in Paris. This report provides encouraging data on the treatment of vexis, a severe and complex monogenic disorder associated with significant morbidity and mortality. This recently defined condition provides a unifying diagnosis for a small group of patients with overlapping hemologic, autoimmune and inflammatory manifestations. Vexis affects approximately 1 in 4,000 men over the age of 50 and and rare cases have been reported in women. This disorder is caused by a somatic mutation in the UBA1 gene in hematopoietic progenitor cells. Patients exhibit a variety of inflammatory and autoimmune disorders plus hematologic abnormalities including cytopenias, vacuoles and bone marrow progenitors and in up to 50% of cases, MDs altogether. That's Vexis V for the vacuoles in myeloid and erythroid precurs, e for the E1 enzyme encoded by UBA1, X for X linked A autoinflammatory and S. Vexis was first described in 2020. In 2022 it was incorporated into the major disease classification systems for hematological neoplasms. Today, the syndrome itself is well characterized, but the optimal therapeutic approach is not defined. Corticosteroids can be effective frontline therapy. Steroid sparing strategies include JAK inhibitors, IL6 inhibitors and IL1 inhibitors, though each has limited efficacy. One potentially promising treatment is azacytidine, a hypomethylating agent with an important role in the management of MDS in vexis. Data have been limited to case studies and small series and one prospective trial of 12 patients, the majority of whom had responses to treatment. Now Jacquier and co authors describe their experience with azacitine in a large retrospective Multicenter study of 88 patients who had received at least one cycle of azacytidine. Although Vexis was first defined in 2020, this study includes cases dating back as far as 2009. That's because investigators were able to perform DNA sequencing of archival samples. They re adjudicated patients diagnosed with mds, only including them in the study if they had characteristic mutations in UBA1. The authors described the response to treatment in two categories the AN inflammatory response based on improvement in markers of inflammation, clinical symptoms and steroid requirement, or a hematological response based on standard MDS criteria. Results show that the majority of patients had an inflammatory response to azacytidine treatment. Inflammatory Response rates were 41% at 6 months and 54% at 12 months. A total of 50 patients, or 61% achieved inflammatory response. Relapse free survival on azacitine was 90% at 1 year and 85% at 5 years. Twelve responders discontinued azacitine however, nine relapsed after a median of 3.1 years. Re exposure to azacitine was effective, restoring inflammatory responses in four out of five cases. Researchers also reported hematological responses 65% of patients treated with azacitine achieved red blood cell transfusion independence, 69% had hematologic improvements in the erythroid lineage and 77% in the platelet lineage. 65% of patients had a molecular response defined as a reduction in UBA1 variant allele frequency of 25% or more. In nearly half of the cases, the variant allele frequency dropped below 2%. Of note, infections are a challenge in vexis. Opportunistic infections, either from the disease itself or its treatment, are a major source of morbidity and mortality, and in this study, 34% of patients experienced infections. Authors say this study establishes a clear rationale for testing azacytidine in larger prospective trials for patients with vexis and investigating ways to mitigate relapse and infections. These observations are echoed in a commentary by David P. Steensma of Ajax Therapeutics in Cambridge, Massachusetts, and Rinal M. Patnaik of Mayo Clinic, Rochester, Minnesota. In their commentary, Steenzma and Pat Naik write that the high rate of response and durability of improvements seen with azacitine is encouraging. The study also emphasizes the need, they say, for standardized response criteria. Other major questions remain unanswered. For example, when should azacitine be used as a bridge to potentially curative allogeneic hematopoietic cell transplant? Moreover, several prospective studies of other treatments for vexis are ongoing. That includes two studies of pacritinib, a JAK inhibitor. However, the authors conclude, most patients will be treated outside the context of a clinical trial. Accordingly, reports such as the Frenvex series are helpful. Commentary Authors say these new data will help inform clinicians on azacitidine, which represents an attractive approach to treating this syndrome. Next on the podcast Array genotyping of transfusion relevant blood cell antigens in 6946 ancestrally diverse subjects this work is from Nicholas S. Gleadal and co authors from the University of Cambridge in the UK and other institutions. Gleedal et al describe a high throughput array that allows for simultaneous typing of erythroid, platelet leukocyte and neutrophil antigens. They say this typing strategy is remarkably accurate and highly reproducible. It could be a major step forward in transfusion medicine, particularly in patients who require frequent blood transfusions where alloimmunization is a major concern. This transfusion hazard involves the formation of antibodies to erythrocyte antigens present in the donor but absent in the recipient. Alloimmunization can lead to potentially serious transfusion reactions, hyperhemolysis, especially in sickle cell disease, difficulties in finding compatible blood, disruptions in chronic transfusion programs and higher costs of care. Alloimmunization is a consequence of limited antigen matching despite transfusion from ABO and RHD compatible blood. Up to 5% of recipients experience alloimmunization due to other blood group antigens. With chronic transfusions, risks range from 17 to 43%, depending on factors such as transfusion frequency and use of extended matching. The risk can be reduced by matching for C, C, E, E and K antigens however, this guidance is not always followed. Moreover, blood is not routinely matched for other human erythroid antigens that can induce antibody formation. Similarly, frequent platelet transfusions can result in the formation of alloantibodies to human leukocyte antigens and in some cases, human platelet antigens, rendering standard platelet selection ineffective. Antibodies against human neutrophil antigens can cause transfusion related acute lung injury, while transfusing blood mismatched for HLA may lead to increased rejection in kidney transplant recipients. These concerns highlight the value and challenge of comprehensively matching patients and donors, and researchers hypothesize that extended genotyping of blood group antigens could significantly reduce alloimmunization rates, improving transfusion outcomes. However, comprehensive matching is not simple for hea. Serologic typing has been the gold standard. By contrast, DNA based methods are preferred for hpa, HNA and hla, and not all HEA types are easy to evaluate. For several clinically relevant HEA types, reagents are unavailable. Scarce or unreliable DNA based tests for HEAs are available, yet these cover only a limited number of HEA types. That patch work is a challenge that has sparked technological innovation. The agents for change is the Blood Transfusion genomics consortium, or BCG. An international collaboration between 18 institutions. The BGC has designed and tested what they call a universal blood donor typing array. This platform provides automated, high throughput simultaneous typing of human erythroid, platelet, leukocyte and neutrophil antigens. According to authors, it's designed to support selection of blood products that are matched beyond ABO and rh. The platform also includes markers of genetic ancestry, blood product quality and donor health, such as hemochromatosis associated HFE variants. In the present study, Glidal et al evaluated the use of this high throughput array for extended blood cell antigen typing in samples from 6946 donors, all genotyped in accredited laboratories. The donors were primarily of European descent but also admixed American, African, South Asian and East Asian, among others. They report that the platform enabled extensive blood cell antigen typing with high reproducibility. Genotype reproducibility was greater than 99% for 17,244 variants that translated into a concordance across genotypes of 99.98% for HEA, 99.90% for HPA, and 99.93% for HLA. When compared with previous clinical typing data, the concordance was 99.9% for HCA, 99.6% for HPA, and 99.1% for HLA. The platform also detected seven variant RHDL alleles, a gypb deletion underlying the EU phenotype and 14 high frequency antigen negative types. Beyond blood typing, hereditary hemochromatosis associated HFE variants were identified in 276 donors. Authors conclude that this genotyping platform can reliably and accurately type a wide range of blood cell antigens across patients from diverse ancestries and by reducing harm through extended matching, this assay could potentially improve transfusion outcomes. According to authors of a related commentary, the future of blood group typing may indeed be quote all in one place. That's the title of the commentary authored by Aline Flock, affiliated with Paris East Craith University and Thierry Peyrard with Universit Parisite and University of the Antilles. They write that extensive donor typing strategies may significantly increase the likelihood of identifying compatible donors. Toward that end, the automated high throughput genotyping array described by Gleedal et al. Could alleviate cost and scalability factors that have limited donor typing strategies in the past. This array also sets the stage for future research. Side by side, erythroid and leukocyte typing may provide new insights on the association between HLA alleles and alloimmunization. Furthermore, commentary authors conclude the markers of genetic ancestry, donor health, and product quality available through the assay may enable correlation with recipient outcomes in the future. Finally, on today's podcast, Loss of BAP1 defines a unique subtype of TP53 mutated de novo AML and confers sensitivity to BCL XL inhibitors. This article is by Jacqueline Andrikovich Cohen Lapp and Alexandros Tatsos, all from George Washington University in Washington, DC. Mutations in the tumor suppressor TP53 confer chemotherapy resistance and poor prognosis. These mutations are frequently associated with complex karyotypes, yet they rarely co occur with other known drivers of myeloid transformation. TP53 mutations are relatively uncommon in acute myeloid leukemia, found in roughly 10% of cases. By contrast, biallelic TP53 mutation is a hallmark of pure erythroid leukemias, and acute erythroid leukemias, which have fewer nucleated erythroid cells, can also harbor TP53 mutations, conferring the same poor prognosis. Interestingly, the progression of TP53 mutated pre leukemic blasts to overt AML has been linked to erythroid immunophenotypes and inflammatory features. However, what sparks this transformation remains unclear. It may be something beyond TP53 mutations. The case of Li Fraumeni syndrome is instructive in that regard. Li fraumeni occurs due to germline mutations in TP53, yet few patients with Li fraumeni will go on to develop aml. That suggests additional genetic hits are needed to make that myeloid transformation that brings us to the new report from Andrakovich and colleagues who aimed to identify genetic alterations that cooperate with TP53 deficiency to promote myeloid transformation. Their work specifically implicates BRCA1 associated protein 1 in the process. BAP1 is a DE ubiquitinating enzyme that regulates DNA damage response and epigenetic processes. It plays a role in multiple cellular processes including proliferation and differentiation, metabolism and survival. In the present study, loss of BAP1 appears to be a cooperative event occurring alongside TP53 deficiency that transforms erythroid primed multipotent progenitors. The work also reveals a specific vulnerability in BAP1TP53 deficient erythroleukemias that may be amenable to pharmacotherapy. The findings as published in blood reveal that BAP1 loss occurs in about 1/3 of TP53 mutated AMLs. BAP1 loss was associated with an erythroid primed gene gene expression signature. Furthermore, co occurring loss of BAP1 was associated with a poor prognosis over and above the poor prognosis conferred by TP53 mutation. A key finding is that compound loss of BAP1 and TP53 transforms a heterogeneous population of erythroid primed multipotent progenitors in transgenic mouse models. Loss of BAP1 combined with loss of TRP53, the mouse equivalent of p53, caused transplantable erythroleukemia and occasionally mixed AML. Authors say these variable disease phenotypes mirrored the heterogeneity of human disease. Similarly, induced depletion of BAP1 and TRP53 in adult mice led to erythroleukemia. When those transformed were transplanted, they demonstrated robust leukemic reconstitution and competitive advantage upon transplantation. Sequencing of hematopoietic progenitors revealed that BAP1 loss triggered a pro inflammatory response and cooperated with TRP53 deficiency to transform erythroid primed multipotent progenitors. In further work, BAP1 deficient erythroleukemia was shown to be dependent on expression of BCL21. This is the gene that encodes BCLXL, an anti apoptotic protein, and interestingly, targeting this protein not only reduced leukemic burden but also partially restored erythropoiesis. Treatment with a selective and potent BCL XL inhibitor inhibited proliferation of human and mouse erythroleukemia cells. By contrast, nonerythroid cell lines were resistant to treatment. Similarly, treatment with a pan BCL inhibitor potently induced cell death in human and murine erythroleukemia resistant to venetoclax, the inhibitor of BCL2. In effect, loss of BAP1 and TP53 defines a BCL XL dependent erythroleukemia. That's the conclusion of COMMENTARY authors Tsu Chi Ho and Reuben Kapoor, both from Indiana University School of Medicine. In their commentary, Hu and Kapoor laud the mechanistic insights of the study. They also point to this selective dependency on BCL xl, which reinforces the translational relevance of the findings. However, several research challenges stand in the way of clinical translation. Beyond this pivotal groundwork, the efficacy of BCL XL inhibition needs to be further validated in human AML samples with similar genotypes. The long term effects of BCL XL inhibition need to be elucidated. Nevertheless, Andrakovich et al have made a significant contribution by uncovering pathogenic mechanisms underlying TP53 mutated erythroleukemia and by identifying a new therapeutic vulnerability. Commentary authors say they have opened new avenues for clinical intervention that could improve outcomes in these patients facing disease with a poor prognosis. You have been listening to the Blood Podcast. The articles mentioned in this podcast can be found@bloodjournal.org and are linked in the show notes of this episode. Be sure to join us next week for another episode. Thank you for listening.