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Blood Podcast
Azacitidine plus venetoclax in high-risk myelodysplastic syndromes, post-CAR T-cell hematotoxicity in B-cell acute lymphoblastic leukemia (B-ALL), and inotuzumab ozogamicin resistance in B-ALL
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Welcome to the March 13, 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. Today we'll learn more about Azacytidine 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 ozogamycin resistance. In Ball, we first examine data in the BLOOD article entitled Efficacy and safety of Venetoclax plus azacytidine for patients with treatment naive high risk myelodyspl syndromes by Jacqueline Garcia of the Dana Farber Cancer Institute in Boston, Massachusetts and colleagues. Patients with higher risk myelodysplastic syndromes or mds have a poor prognosis with a median overall survival of less than two years and a high rate of transformation to acute myeloid leukemia. Higher risk MDS is associated with a high symptom burden as well, including anemia, fatigue and vulnerability to infection. Many patients are transfusion dependent, creating additional quality of life impacts. This disease can be cured with hematopoietic stem cell transplantation however, most patients are ineligible because of performance status and or comorbidities. The current standard of care for transplant ineligible patients with higher risk MDS is monotherapy with one of two hypomethylating agents, azacytidine or dacitabine. The authors of the clinical study that we'll be discussing first investigated a potential new treatment for higher risk MDS that combined azacytidine with the pro apoptotic BCl2 inhibitor venetoclax. Venetoclax is currently FDA approved for chronic lymphocytic leukemia and in combination with azacitidine, dicitabine or low dose cytarabine for older or less fit patients with acute myeloid leukemia. The current paper reported the results of an ongoing phase 1b dose escalation dose expansion study of asacitidine plus venetoclax in patients with previously untreated higher risk MDS. As originally designed, patients were to receive 400 or 800 milligrams of venetoclax daily for all 28 days of a 28 day cycle with azacitine given on 7 days of the cycle. However, 2 of the initial 10 patients treated with this regimen developed fatal sepsis, prompting the researchers to scale back Venetoclax administration to only 14 of the 28 days. Here, the authors report efficacy and safety results for patients treated with the recommended phase 2 dose of 400 mg of venetoclax given orally on days 1 to 14. The azacytidine dose was 75 mg per square meter administered on 7 days of each cycle. Patients were enrolled if they had an International Prognostic scoring system or IPSS score of 1.5 or higher or a revised IPSS score of greater than 3 and could not have more than 20% bone marrow blasts at baseline. One hundred and seven patients received the recommended Phase 2 dose 86% of them had a high or very high risk revised IPSS score. Median bone marrow blast count was 11%. About 70% of the patients were 75 years or older. Median follow up was just under 32 months. At data cutoff, 29.9% of patients had reached complete remission or CR. Responses were seen across all subgroups, including patients with high risk cytogenetics and patients with TP53 mutations. Median overall survival was 26.0 months. Patients with TP53 mutations had a numerically shorter overall survival of only 11.2 months. 59 of the 107 patients were transfusion dependent at baseline 24 or about 40% of these patients became transfusion independent. 80% of the patients who were transfusion independent at baseline remained so about half of 104 evaluable patients showed hematologic improvement. 42% of the overall cohort went on to receive stem cell transplant as their next immediate treatment. 94% of patients who received the recommended phase 2 dose had at least one grade 3 or 4 treatment emergent adverse event. These were primarily hematologic, including most commonly neutropenia, thrombocytopenia, febrile neutropenia, and anemia. Gastrointestinal adverse events were also common but were primarily grades one or two. Infections occurred in 40.2% of patients, including 12 cases of pneumonia, seven of which were serious. Serious adverse events also included six cases each of cellulitis, diverticulitis, and sepsis. 59 patients died during the study, including 23 or about 20% who died from progressive disease. One death was considered possibly related to venetoclax and two were considered possibly related to azacitine. In their discussion, the authors noted that their results compare favorably with historical outcomes for azacitine monotherapy, including higher overall survival and a longer median duration of cr. The rate of AML progression was also relatively low at 12%. Many patients had hematologic improvement and or became transfusion independent, potentially improving quality of life as well. Azacytidine venetoclax combination therapy is under further investigation in newly diagnosed higher risk MDS in the ongoing Phase three Verona trial. In an accompanying commentary, Sangeetha Venugopal and Mikhail Sekaris of the University of Miami in Miami, Florida, expressed cautious optimism that this new combination therapy might represent a badly needed alternative to stem cell transplant for patients with higher risk MDs. They noted, however, that the high rate of toxicities seen in the current study may be a limitation. They suggested that it might be worthwhile to explore whether venetoclax dosing might be reduced even further to improve safety without sacrificing efficacy, particularly for patients aged 80 years or older. Next up, we'll discuss findings from the Blood article entitled Development of all Hematotox Predicting Post CAR T cell hematotoxicity in B Cell Acute lymphoblastic Leukemia by Monica S. Nair of the National Cancer Institute in Bethesda, Maryland and colleagues. Chimeric antigen receptor or CAR T cell therapies have led to improved outcomes for patients with B ALL in recent years. While beneficial in many cases, these therapies are also associated with substantial post treatment toxicities that must be monitored and managed. Many patients who receive these therapies develop immune effector cell associated hematotoxicity, which often manifests as neutropenia and or thrombocytopenia. In some patients these cytopenias are mild and transient, while in others they are severe and long lasting. Severe prolonged neutropenia, defined as an absolute neutrophil count or ANC of less than 500 per microliter for 14 or more days, is of particular importance in these patients as it makes them highly vulnerable to infection and associated adverse outcomes. Recently, researchers developed a scoring system known as CAR Hematotox or CAR HT that helps to predict the risk of severe prolonged cytopenias in patients with B cell malignancies. This score was developed using data from patients with diffuse large B cell lymphoma, mantle cell lymphoma, and multiple myeloma in B all. However, post CAR T cell cytopenias are less well characterized and it was unknown whether this scoring system might also apply to this condition. The authors of the second paper that we'll be discussing investigated these questions by retrospectively analyzing data from patients with relapsed refractory b, all from four National Cancer Institute phase 1 trials testing CAR T cell therapies. The authors identified 156 pediatric patients with relapsed refractory B, all who were treated with CD19 or CD22 targeted CAR T cell therapies across the four trials between 2012 and 2023. These patients had received a median of five prior lines of therapy, and about half had relapsed following allogeneic hematopoietic stem cell transplant. About half of these patients had high bone marrow involvement at baseline, defined as more than 25% blasts. 65% of the cohort were considered to have a high disease burden. Sufficient data were available to analyze cytopenias occurring in the first 30 days after car T cell therapy. The median duration of severe neutropenia was 13 days. About half of patients in experienced severe prolonged neutropenia during the 30 days. Of 146 patients who were evaluable for both ANC and platelet counts, 62% had grade three or four neutropenia and 40% had grade three or four thrombocytopenia. Only 39% of patients showed both ANC and platelet recovery by the end of the 30 days. Interestingly, applying the CAR HT index to the full patient group identified 87% of patients as high risk, substantially higher than the 49% who experienced severe prolonged neutropenia. This finding meant that CAR HT did not discriminate well between patients who were more or less likely to experience severe hematotoxicity. The authors identified two key differences between B ALL and the other B cell malignanc in which CAR HT was developed. One difference is ferritin level, which is substantially higher on average in patients with B all. High ferritin is a predictor of poorer outcomes in B cell malignancies and is included as a risk factor in CAR ht. The other difference is bone marrow involvement, which is more common in B all. A high bone marrow disease burden is associated with longer post CAR T cell cytopenias across B cell malignancies. Given these differences, the authors created a new risk scoring system for B ALL that substituted the extent of bone marrow involvement for ferritin levels as a risk factor. This new scoring system, called all hematotox or ALLHT, identified 47% of the patients with B ALL as high risk for severe prolonged cytopenias. The remainder of the patients were categorized as low risk. The patients identified as high risk had a median of 26 days of neutropenia compared with four days for the low risk group. The high risk patients also had a shorter median overall survival of 9.8 months compared with 24 months for the low risk group. As external validation, the authors applied ALLHT to two other relapsed refractory B, all cohorts, one treated with a mix of CAR T cell therapies at Memorial Sloan Kettering and the other at Seattle Children's Hospital. Here, too, the new risk score was able to identify high risk groups who were more likely to have had severe prolonged neutropenia, had a greater number of days with neutropenia, and who had reduced overall survival compared with low risk patients. In an accompanying commentary, Regina M. Myers of the University of Pennsylvania in Philadelphia and Michael A. Pulsifer of the University of Utah in Salt Lake City, Utah, praised the rigorous methodology in which this new scoring system was developed. They also recognized this work as an important first step in understanding post car T cell cytopen in patients with relapsed refractory B all. They noted that because this study only looked at the first 30 days post treatment, it does not shed light on late developing cytopenias, which are also clinically important. Studies involving larger groups of patients will also be needed to fully characterize the nature and risk of post CAR T cell cytopenias in these patients. In the final part of today's podcast, we'll discuss findings in the Blood article entitled DNTT Mediated DNA Damage response drives Inotuzumab Ozogamycin Resistance in B Cell Acute Lymphoblastic Leukemia by Carolyn S. Escherich of Heinrich Heine University in Dusseldorf, Germany, and colleagues. Inertuzumab ozogomycin, also called INO, is an FDA approved therapy for treating relapsed refractory CD22 positive B all. This antibody drug, conjugate, links a CD22 targeted antibody with the cytotoxic drug calecheomycin. It kills leukemia cells by latching onto the CD22 protein present on the external cell membrane of B All blasts, leading to internalization and release of calichiomycin. Calichiomycin subsequently enters the nucleus where it induces double stranded DNA breaks, activates DNA damage signaling pathways, and ultimately causes cell death by apoptosis. INO is associated with high complete remission rates on the order of 60 to 80% in patients with relapsed refractory B ALL. Recently, studies have also shown high complete remission rates for newly diagnosed patients. Although it is not currently approved in that setting. However, not all patients respond to this therapy at the outset and the duration of remission is variable. The reason Trial data reveal evidence of both primary and secondary resistance to ino. In addition, many patients show evidence of minimal residual disease after INO based therapy. Several mechanisms of inoresistance have been identified. These include loss or downregulation of the CD22 target epitope BCL2 pathway, alterations that decrease apoptosis and loss of function mutations in genes such as TP53 that participate in DNA damage response signaling. The authors of the third paper we'll be discussing set out to further investigate the molecular mechanisms of inoresistance in B all. They began their studies with a comprehensive genome wide CRISPR Cas9 knockout screen in a CD22 positive B all cell line. This screen identified three top genes whose knockout led to inoresistance loss of the gene encoding the CD22 target epitope, loss of the BAC1 gene which participates in mitochondria dependent apoptosis signaling and loss of a novel resistance gene known as dntt. The DNTT gene encodes a protein called DNA nucleotidyxotransferase. This protein, also called dntt, is a DNA polymerase involved in the repair of double stranded DNA breaks. Using non homologous end joining, the study authors investigated DNTT protein expression more comprehensively as a previously uncharacterized determinant of INO resistance. Again using crispr, they knocked out DNTT expression in three human leukemia cell lines. These DNTT negative cell lines were resistant to INO levels that killed the parent wild type cell lines. The DNTT negative cell lines were also resistant to calichiomycin alone as well as several other drugs such as mitoxantrone and etoposide that also induced double stranded DNA breaks. DNTT knockout did not affect resistance to drugs that induce single strand breaks or to nucleobase analogs. The authors used whole transcriptome sequencing to investigate changes in RNA expression induced in these cell lines by 24 hours of exposure to INO. In wild type leukemia cells, exposure to INO strongly activated expression of genes involved in DNA damage response signaling. This upregulation was markedly attenuated in the DNTT negative cells. Protein expression studies identified specific proteins involved in the DNA damage response including H2A histone family member X and the cyclin dependent kinase CDKN1A, whose expression was increased in wild type cells exposed to INO but blunted or delayed in DNTT negative cells. Loss of DNTT also led to reduced cell cycle arrest and apoptotic priming in cells exposed to ino. The authors used patient derived B ALL cells to investigate the effects of DNTT expression in models a step closer to human patients. In B ALL cells from newly diagnosed patients, natural variation in DNTT expression correlated with ex vivo measures of INO sensitivity. In a xenograft model, a mixture of DNTT negative and wild type B ALL cells were injected into severely immunodeficient mice. The proportion of DNTT negative blasts increased rapidly in response to INO treatment, doubling or nearly tripling depending on INO dose. The authors also investigated DNTT expression in blasts from pediatric patients before and after receiving INO monotherapy. In a phase 2 trial, 21 of 26 patients showed DNTT downregulation after inotherapy. By contrast, only 4 of the 26 patients showed partial or complete loss of CD22 expression. Given these findings, the authors concluded that DNTT is an important mediator of inoresistance in B all that warrants further investigation. This protein might also eventually serve as a biomarker for for inoresistance in patients. In an accompanying commentary, Philippe Rousselot of the Universite Versailles Paris Sacle in Gift sur Yivet, France, acknowledged DNTT downregulation as a new and important form of INO resistance. He noted that ongoing development of INO combinations may help mitigate the risk of resistance associated with INO monotherapy. For a list of additional authors, as well as more detailed articles and commentaries on which this podcast is based, please go to bloodjournal. Org. Be sure to join us next week for another episode of Blood Podcast. Thank you for listening.