In this How I Treat podcast episode, Laura Michaelis, MD interviews Sung-Yun Pai, MD about their recently published article in Blood journal "How I treat Wiskott-Alrich syndrome". They highlight recent updates in treatment, including new risk-benefit calculations due to safer treatments and longer follow-ups. Challenges include late diagnosis, lack of well-matched donors, and limited gene therapy availability. They emphasize the importance of early referral to specialized centers and the need for discussions about curative intent therapies, including transplant and gene therapy. The conversation also covers the complexities of gene therapy, such as the need for better conditioning agents and the challenges of achieving full correction in all cell types.

In this week's episode we'll learn about targeting the tissue factor pathway inhibitor with a monoclonal antibody to rebalance HEMOSTASIS in hemophilia A and B. In the phase 3 BASIS trial, the monoclonal antibody marstacimab reduced bleeding events, and was generally well tolerated, with no unanticipated side effects. After that: matched-donor allogeneic CD19 CAR-T for adult B-ALL. Given after allogeneic transplantation, CAR-donor lymphocyte infusion after lymphodepleting chemotherapy was associated with favorable efficacy and a tolerable safety profile. Finally: a new prognostic index for mycosis fungoides and Sézary syndrome. Comprised of four prognostic factors, the “CLIPI” could enable more personalized treatment of cutaneous lymphomas, identifying patients who may benefit from intensified treatment.

Featured Articles

• Marstacimab prophylaxis in hemophilia A/B without inhibitors: results from the phase 3 BASIS trial
• Matched donor allogeneic CAR-T for adult B-ALL: toxicity, efficacy, repeat dosing, and the importance of lymphodepletion
• A new prognostic index (CLIPI) for advanced cutaneous lymphoma enables precise patient risk stratification

In this week's episode, we’ll learn more about relationships between Epstein-Barr virus genomic variants and human diseases, including hematological malignancies; the presence and timing of somatic GATA1 mutations and their relationship to a Down syndrome-specific form of leukemia; and new definitions for high-risk multiple myeloma that emphasize the presence of two or more high-risk cytogenetic abnormalities.

Featured Articles:

• Association of Epstein-Barr virus genomic alterations with human pathologies
• Clinical significance of preleukemic somatic GATA1 mutations in children with Down syndrome
• Biallelic antigen escape is a mechanism of resistance to anti-CD38 antibodies in multiple myeloma

In this Review Series episode, Associate Editor Dr. Hervé Dombret speaks with Dr. Mark Litzow about the latest immunotherapy advances for Acute Lymphoblastic Leukemia (ALL). The discussion highlights innovative treatments like blinatumomab and inotuzumab, which are showing remarkable success in clinical trials, including an 85% three-year survival rate and over 90% complete remission in elderly patients. Researchers are focusing on reducing chemotherapy intensity, developing personalized treatment approaches, and identifying optimal immunotherapy strategies for different ALL subtypes. The conversation underscores a promising shift towards more targeted, less toxic treatments that could significantly improve patient outcomes across various age groups and disease characteristics. These emerging therapies represent a potential paradigm shift in ALL treatment, offering hope for more effective and less aggressive therapeutic interventions.

Read Dr. Litzow's paper “Incorporation of immunotherapy into frontline treatment for adults with B-cell precursor acute lymphoblastic leukemia” or find the whole review series on acute lymphoblastic leukemia in volume 145 issue 14 of Blood Journal.

In this week's episode we'll learn about Azacitidine in VEXAS 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 matching. 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.

Featured Articles

• Efficacy and safety of azacitidine for VEXAS syndrome: a large-scale retrospective study from FRENVEX
• Array genotyping of transfusion-relevant blood cell antigens in 6946 ancestrally diverse study participants
• Loss of BAP1 defines a unique subtype of TP53-mutated de novo AML and confers sensitivity to BCL-xL inhibitors

In this week's episode we'll learn about persistent changes in immune profiles in patients who have had diffuse large B-cell lymphoma, or DLBCL, and other cancers; that plasminogen activation and plasmin activity do not appear to play a role in routine physiological prevention of venous thromboembolism, or VTE; and about a novel mechanism that makes hematological malignancies carrying epigenetic mutations susceptible to PARP inhibitors.

Featured Articles:

• Large B-cell lymphoma imprints a dysfunctional immune phenotype that persists years after treatment
• Plasminogen activation and plasmin activity are not required to prevent venous thrombosis/thromboembolism
• Transposable elements as novel therapeutic targets for PARPi-induced synthetic lethality in PcG-mutated blood cancer

In this week's episode, we'll learn about how TET2 is often mutated in myeloid malignancies and clonal hematopoiesis. In new work, expansion of Tet2-mutant HSPCs was dependent on Ncoa4, the cargo receptor mediating ferritinophagy. We’ll iron out the implications. After that: a double-oh-seven license to kill in T-cell leukemia/lymphoma. WU-CART-007 is an off-the-shelf CAR T product with manageable safety and encouraging efficacy. With further work, it could become a new option for patients in urgent need of therapy. Finally: a comprehensive genetic study of classical Hodgkin lymphoma using circulating tumor DNA. This new research provides novel and complex insights on genetic subtypes, prognostic biomarkers, neoantigens in the disease environment, and more.

Featured Articles:

• An in vivo barcoded CRISPR-Cas9 screen identifies Ncoa4-mediated ferritinophagy as a dependence in Tet2-deficient hematopoiesis
• Phase 1/2 trial of anti-CD7 allogeneic WU-CART-007 for patients with relapsed/refractory T-cell malignancies
• A comprehensive genetic study of classic Hodgkin lymphoma using circulating tumor DNA

In this week's episode we'll learn about targeting NPM1 in acute myeloid leukemia. Researchers report the first clinical evidence of a menin inhibitor inducing complete remissions in AML with a NPM1 mutation. This validates NPM1 as a new therapeutic target in AML, alongside FLT3, IDH1/2, and KMT2A. Also on the podcast: targeting CD137 to prevent graft-versus-host disease. In nonhuman primates, a single dose of a CD137 antibody-drug conjugate provided long-term protection, with one important caveat: the potential for viral reactivation.

Featured Articles:

• Menin inhibition with revumenib for NPM1-mutated relapsed or refractory acute myeloid leukemia: the AUGMENT-101 study
• A single dose of a CD137 antibody–drug conjugate protects rhesus macaque allogeneic HCT recipients against acute GVHD