In this How I Treat series episode Blood Associate Editor, Dr. Jason Gotlib speaks with Drs. Aaron Gerds, Andreas Reiter, and Claire Harrison. The conversation focuses on the work and contributions of these authors to How I Treat Myeloproliferative Neoplasms, and exciting advances in the treatment and management of MPNs.

See the full How I Treat series in volume 145 issue 16 of Blood.

In this week's episode we'll learn about the role of autologous transplant for relapsed myeloma. In an updated analysis of the GMMG ReLApsE trial, salvage autologous transplant offered no survival benefit compared to control chemotherapy. These findings may have clinical implications in an era of alternative, and highly effective, treatment options. After that: Response to DDAVP, or desmopressin, in bleeding disorders. This study is the first large scale meta-analysis to assess the response rate to DDAVP in bleeding disorders. Authors provide new insights into determinants of response, which vary according to the disease type. Finally, turning to diffuse large B cell lymphoma. Germinal center B cells depend on the activity of DOT1 and EZH2 to maintain their pro-proliferative identity. New research shows that combined treatment with DOT1L and EZH2 inhibitors has synergistic activity in vitro.

Featured Articles:

• Salvage autologous transplant in relapsed multiple myeloma: long-term follow-up of the phase 3 GMMG ReLApsE trial
• DDAVP response and its determinants in bleeding disorders: a systematic review and meta-analysis
• Targeting DOT1L and EZH2 synergizes in breaking the germinal center identity of diffuse large B-cell lymphoma

In this week's episode we’ll learn about the role of interleukin-1 signaling in the bone marrow microenvironment in the development of myelodysplastic syndromes, the immune checkpoint regulator VISTA as a potential target for preventing graft-vs-host disease, and epcoritamab plus gemcitabine and oxaliplatin in transplant-ineligible relapsed/refractory diffuse large B-cell lymphoma.

Featured Articles:

• IL-1R1 and IL-18 signals regulate mesenchymal stromal cells in an aged murine model of myelodysplastic syndromes
• Targeting cell-surface VISTA expression on allospecific naïve T cells promotes tolerance
• Epcoritamab plus GemOx in transplant-ineligible relapsed/refractory DLBCL: results from the EPCORE NHL-2 trial

In this week's episode we'll learn about tracking the functional profile of aging platelets. Researchers demonstrate that over time, platelet function shifts away from hemostasis and toward a more immunomodulatory role. These finding could have important implications for transfusion medicine and certain platelet-related disease states. After that, use of odronextamab, a CD20×CD3 bispecific antibody, in patients with diffuse large B-cell lymphoma, or DLBCL, progressing after CAR T cell therapy. The study is the first to evaluate the efficacy and safety of this therapy in the post-CAR T cell treatment setting. Finally, we will recap findings from a study of a novel CAR T-cell product that utilizes specificity to two antigens common in diffuse large B-cell lymphoma.

Featured Articles:

• Aging platelets shift their hemostatic properties to inflammatory functions
• Odronextamab monotherapy in R/R DLBCL after progression with CAR T-cell therapy: primary analysis of the ELM-1 study
• Dissection of single-cell landscapes for the development of chimeric antigen receptor T cells in Hodgkin lymphoma

In this bonus episode of the Blood podcast, we'll hear from Dr. Nicole Thornton, senior author of the article “Deletions in the MAL gene result in loss of Mal protein, defining the rare inherited AnWj-negative blood group phenotype”, speaks with Blood Associate Editor Dr. Erica Wood about the discovery of the genetic basis for the inherited AnWj-negative blood group phenotype. The discovery that Mal protein is expressed on red blood cell membranes of AnWj-positive, but not AnWj-negative individuals, and that homozygous deletion in MAL causes the AnWj-negative blood group phenotype, helps answer a decades-old mystery related to the high prevalence red blood cell antigen AnWj and forms the basis of a new blood group system. 

In this week's episode, we’ll learn more about using itacitinib for the prevention of graft vs host disease in haploidentical transplants, diagnosis and management of purpura fulminans, and results of a systematic review seeking evidence for sickle cell crisis-associated mortality in individuals with sickle cell trait.

 
Featured Articles:

• Itacitinib for prevention of graft-versus-host disease and cytokine release syndrome in haploidentical transplantation
• How I diagnose and treat acute infection–associated purpura fulminans
• Sickle cell trait does not cause “sickle cell crisis” leading to exertion-related death: a systematic review

In today's episode, we'll discuss time-limited triplet therapy in relapsed or refractory CLL. Zanubrutinib, venetoclax and obinutuzumab induced deep remissions, and was well tolerated, even in very high-risk patients, and those with prior exposure to targeted therapies. After that: researchers chronicle the development of a patient-reported outcome measure for sclerosis associated with chronic GVHD—graft-versus-host disease. The new symptom scale—currently undergoing validation studies—may provide valuable information regarding severity, functional impact, and response to therapy. Finally, a study of changes in population dynamic rates that underlie inflammation-associated myeloid bias. The work demonstrates the use of mathematical models to deliver critical biological insights and uncover underlying mechanisms.

Featured Articles:

• MRD-guided zanubrutinib, venetoclax, and obinutuzumab in relapsed CLL: primary end point analysis from the CLL2-BZAG trial
• Development of the Lee Symptom Scale–Skin Sclerosis for chronic GVHD–associated sclerosis
• Population dynamics modeling reveals that myeloid bias involves both HSC differentiation and progenitor proliferation biases

In this week's episode we’ll learn more about azacitidine-venetoclax combination therapy for first-line treatment of high-risk myelodysplastic syndromes; a new risk-scoring system for post-CAR T-cell hematotoxicity in B-cell acute lymphoblastic leukemia, also known as B-ALL; and a novel mechanism for inotuzumab ozogamicin resistance in B-ALL.

Featured Articles:

• Efficacy and safety of venetoclax plus azacitidine for patients with treatment-naive high-risk myelodysplastic syndromes
• Development of ALL-Hematotox: predicting post-CAR T-cell hematotoxicity in B-cell acute lymphoblastic leukemia
• DNTT-mediated DNA damage response drives inotuzumab ozogamicin resistance in B-cell acute lymphoblastic leukemia

In this week's podcast, a potential new therapeutic target in beta-thalassemia. The E3 ubiquitin ligase AMBRA1 promotes autophagic clearance of free alpha-globin. Researchers describe mutations in the AMBRA1 gene that impair this clearance, exacerbating ineffective erythropoiesis and disease severity. After that: targeting MYD88 mutations. Lasalocid-A is a compound that selectively binds to the MYD88 L265P mutant protein, which is found in a range of B-cell lymphomas. New research shows its potential to inhibit tumor growth, overcome ibrutinib resistance, and synergize with venetoclax. Finally: air pollution is linked to an increased risk of venous thromboembolism in a prospective, community-based cohort study. The findings highlight the harms of pollution, and support the case for global efforts to improve public health.

Featured Articles:

• Mutations in AMBRA1 aggravate β-thalassemia by impairing autophagy-mediated clearance of free α-globin
• Lasalocid A selectively induces the degradation of MYD88 in lymphomas harboring the MYD88 L265P mutation
• Air pollution is associated with increased risk of venous thromboembolism: the Multi-Ethnic Study of Atherosclerosis

In this week's episode we’ll learn more about the significance of hypercalcemia in monoclonal gammopathy of undetermined significance, the role of neutrophil gelatinase-associated lipocalin in hemostasis, and the feasibility of combining CD19-targeted NK- or T-cell therapy with anti-CD19 monoclonal antibodies.

Featured Articles:

• Approaching Hypercalcemia in Gammopathy of Undetermined Significance: Insights from the iStopMM study 
• Deficiency of neutrophil gelatinase-associated lipocalin elicits Hemophilia-like bleeding and clotting disorder 
• Anti-CD19 antibody cotreatment enhances serial killing activity of anti-CD19 CAR-T/-NK cells and reduces trogocytosis