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Blood Podcast
Time-limited triplet therapy in relapsed/refractory CLL; patient-reported outcomes in chronic GVHD-related sclerosis; myeloid bias mechanisms in hematopoiesis
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Welcome to the March 20, 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, Time Limited Triplet therapy and relapsed or refractory xenubrutinib, 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 symptoms 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. Our first article is MRD guided Xenubrutinib, Venetoclax and Obinutuzumab in Relapsed Primary endpoint analysis from the CLL2BZAG trial. The first author is Moritz Furstenau of the German CLL Study Group at the University of Cologne, Germany. This phase two trial combines the three classes of treatments that have transformed the CLL therapeutic landscape. Xenubrutinib is an inhibitor of bruton tyrosine kinase or BTK, venetoclax is an inhibitor of B cell lymphoma 2 or BCL2 and obinutuzumab is an anti CD20 monoclonal antibody. Combining two of these classes markedly improves patient outcomes. The use of triple combinations is a more recent innovation. Triplets may allow for time limited treatment, helping to avoid acquired resistance and reducing cumulative toxicity. The strongest evidence for triple therapy is in the first line treatment of cll, where triplets have demonstrated high rates of undetectable minimal residual disease or MRD and and prolonged progression free survival. The evidence for triplets is not as extensive in patients with relapsed or refractory cll, many of whom have already been exposed to BTK inhibitors and venetoclax. However, two prior phase 2 studies provide encouraging results. One study evaluated the combination of ibrutinib, venetoclax and obinutuzumab. Post treatment, the undetectable MMRD rate was 50% in 22 patients with relapsed or refractory CLL. The other study from the German CLL Study group published in blood in 2024 evaluated acalabrutinib, venetoclax and obinutuzumab in the relapsed refractory setting. Treatment was MRD guided. The triplet was given until there was evidence of a deep remission. 42 out of 45 patients, 93% achieved undetectable MRD at any time point and the rate of 3 year progression free survival was 85% not now in blood. The German CLL study group provides evidence for another triplet xanubrutinib, venetoclax and obinutuzumab. Following optional debulking with Bendamustine, patients received obinutuzumab, zanubrutinib and venetoclax sequentially initiated over the first three cycles of induction treatment. The total duration of induction was 8 cycles of 28 days. This was followed by maintenance, obinutuzumab, zanubrutinib and venetoclax. Maintenance continued until the patient achieved a complete response plus undetectable MRD in peripheral blood for two consecutive measurements or a total of 24 months. 42 patients were enrolled in the Phase 2 study. 50% of the patients had already received a BTK inhibitor, venetoclax or both. Nearly 40% had a TP53 mutation or deletion. Most patients in the study achieved deep remissions with this MRD guided triplet treatment strategy. The median treatment duration was 14.3 months. 21 of 40 evaluable patients, 52.5% had undetectable MRD at 6 months. Many remissions deepened over time. The best undetectable MMRD rate was 85%, meaning that 85% of patients achieved undetectable MRD at any time point. The best undetectable MRD rate was similar at 80% in patients previously exposed to a BTK inhibitor or venetoclax and also 80% in patients. Patients with TP53 aberrations estimated progression free survival and overall survival at 18 months was 96% and 96.8% respectively. The triple combination was well tolerated over a median observation time of 21.5 months. 26 of the patients had COVID 19. There were two fatal adverse events, COVID 19 and a fungal pneumonia in association with COVID 19. Other common adverse events included thrombocytopenia, neutropenia, diarrhea, infusion related reactions, nausea and fatigue. Also in blood is a commentary called the bright and the dark side of the Moon. The authors are Anna Maria Frustacci and Alessandro Tedeschi of Niiguarda Hospital in Milan, Italy. First, the Bright side of the Moon the present study demonstrates the efficacy of fixed duration therapy in a modern population of relapsed patients. The only fixed duration combination currently approved for previously treated CLL is Venetoclax rituximab, but that's based on the Murano study which doesn't reflect today's patient population in which the majority of patients have been treated only with targeted therapies. The combination was effective independent of previous exposure to targeted agents. Moreover, deep remissions were achieved even in patients with TP53 aberrations. Typically, continuous treatment has been considered the preferred option for these high risk patients. Now the dark side data is lacking on the role of triple combinations in elderly and unfit patients. The median age of patients in this study was 64 years. Similar to other triplet combination studies, the assessment of MRD is not yet standardized. Work must be done to determine the optimal timing and methods for assessment, and it's not clear which patients would benefit the most or least from triple combination regimens. Adding agents increases toxicity, raising the question of whether triplets are feasible for every patient. Nevertheless, this work with Furstenau and co authors is another step forward in our understanding of triplets in relapsed or refractory cll. A time limited triplet strategy can induce deep remissions and allow for discontinuations, limiting toxicity, clonal evolution, resistance and cost. The next article is development of the LI Symptom Scale Skin Sclerosis for chronic GVHD Associated Sclerosis the first author is Emily Baumrin of the University of Pennsylvania in Philadelphia. Sclerosis refers to the abnormal stiffening of tissues or other aspects of anatomy and in the context of chronic gvhd, sclerosis is associated with substantial long term disability. The symptoms are significant, distressing and uncomfortable. Patients report skin and joint tightness, restricted range of motion and poor wound healing, among other symptom. Sclerosis affects 10 to 20% of patients who have undergone hematopoietic cell transplantation and it is a major clinical challenge. Sclerosis responds poorly to currently available therapies. The mainstay is prolonged immunosuppressive therapy, which contributes to morbidity. Even further studies are needed to make meaningful progress. That's the conclusion of a 2020 NIH consensus conference on chronic GVHD. This research gap includes an unmet need for novel therapies. However, developing novel therapies has proven difficult. One major hurdle is the tools used to assess sclerosis in the GVHD context. Clinical trials in GVHD typically use the NIH skin score as a primary endpoint. This is a tool that clinicians use to rate skin manifestations on a scale of 0 to 3. However, the NIH skin score is not sensitive to small changes in sclerosis that can be a problem in chronic GVHD treatment responses are slow and active. Sclerosis is not easily distinguished from structural changes. What else can be done? There's increasing interest in asking patients themselves. Patient reported outcomes or PROs could provide valuable information on sclerosis severity, impact and treatment response. Pros are capable of isolating subtle improvements that go undetected in clinician reports, so a properly developed PRO could help in sclerosis assessment beyond what can be achieved with clinician scoring. To develop a pro, it's not necessary to reinvent the wheel. Several sclerosis related pros are available. Among these is the LI Symptom Scale or LSS for Chronic gvhd. It's the current standard PRO collected in chronic GVHD clinical trials and it includes six items that are relevant to sclerosis. In the current issue of Blood, Baumrin and co authors report on the development and initial validation of the newly proposed LI Symptom Scale, Skin Sclerosis or LSS SCL. This is a pro instrument consisting of 55 items specifically developed for adults with chronic GVHD associated skin sclerosis. Of note, this tool was developed based on a patient interview technique called concept elicitation. Concepts refers to disease symptoms and impacts important to patients and elicitation is the use of open ended questions to draw out responses. So questions were designed to spontaneously elicit concepts, symptoms and impacts. In the context of a semi structured patient interview. Researchers conducted 35 open ended interviews of adults with chronic GVHD and associated sclerosis. They recruited patients until they reached saturation, meaning that additional interviews were not producing new themes. What the researchers found was eye opening. The interviews revealed five overarching skin changes, symptoms, emotional and social functioning, mobility restrictions and activity limitations. But the individual responses revealed deeply personal realities that put a human face on these domains instead of symptoms. One patient said they felt their body getting tighter day by day instead of social functioning. Another patient described heavy social anxiety and being treated as less than human. And instead of mobility restrictions, one patient described the frustration of not being able to get up and greet family members or even pick up a pencil off the floor. Next, the researchers conducted some preliminary content validation, starting with a pool of 54 question items. To test and refine these items, they conducted cognitive briefing interviews with with 25 patients who had chronic GVHD associated sclerosis. Cognitive interviewing is a technique to vet self report questions. By pinpointing problems with comprehension and clarity, errors in measurement and response can be minimized. Based on this phase, researchers were able to make some phrasing changes to improve relevance and comprehension. They also made some item level changes, ultimately resulting in 55 items requiring a median time of 4 minutes for completion. These results support the relevance, comprehensibility and comprehensiveness of the provisional LSS scl, the Lee Symptom Scale, Skin Sclerosis and now further work is underway to validate this PRO with formal psychometric testing in an external cohort. These results are discussed in a commentary by Naila Ljuredi and Steven Z. Pavletic from the National Cancer Institute in Bethesda, Maryland. They describe the LSS SCL PRO as a key addition to assessments for chronic gvhd. It's a promising tool that demonstrates preliminary construct validity. The researchers tried to ensure inclusion of diverse sclerotic disease manifestations. However, the study is limited by a lack of racial diversity 86% were white, about 6% were Hispanic, and about 8% were listed as other race ethnicity. Single center recruitment is another limitation of this group of adult patients seen at the Fred Hutchinson Cancer Center. Nevertheless, commentary authors conclude this newly proposed PRO instrument is a long awaited effort to accelerate progress in this highly morbid form of chronic gvhd. Finally, on today's podcast, Population dynamics modeling reveals myeloid bias involves both HSC differentiation and progenitor proliferation biases. The first author is Apeksha Singh from the University of California in Los Angeles. To better understand this work, we must first understand the term myeloid bias, which refers to an overabundance of myeloid cells. This comes at the expense of lymphoid cells and it can compromise adaptive immunity including vaccine response and infection resistance. Myeloid bias is associated with advanced age and inflammatory diseases. Of note, aging and chronic inflammation are linked to an overabundance of MPPs or multipotent progenitors, which are short term hematopoietic stem cells with limited self renewal capacity. The MPPs are categorized by their differentiation biases. Specifically, MPP3s are primed to generate myeloid cells. The MPP2s are primed for erythrocyte and megakaryocyte generation, and MPP4s are primed for lymphocytes. It's known that MPPs play a critical role in maintaining hematopoiesis. However, it's not fully clear to what extent they contribute to myeloid bias. Is myeloid bias in MPPs solely responsible for changes in the differentiation rates of short term hematopoietic stem cells or are there additional contributory mechanisms? One potential factor to consider is, as previously noted, inflammation. Hematopoietic cells are responsive to cytokines and Toll like receptor ligands, which can induce myeloid cell production given that inflammation link. Singh et al set out to study the population dynamics of myeloid bias in a mouse model of chronic inflammation. This mouse model, called I kappa B, is characterized by elevated NF kappa b activity and an increase in myeloid biased mpps. One interesting aspect of this study is the innovative use of mathematical models. Specifically, the authors developed a mathematical model of hematopoiesis based on a set of ordinary differential equations. Using this model, they were able to analyze hematopoietic stem and progenitor cell counts in bone marrow data from the I kappa B mice. Through this analysis, they determined that short term hematopoietic stem cell differentiation was important but unlikely to be the sole factor accounting for the increase in myeloid biased mpps. The finding inspired further investigation of the mechanisms driving myeloid bias in I kappa B mice. The authors employed single cell RNA sequencing of both I kappa B and wild type HSPCs. They tracked the gradual development of metapoietic stem cells into erythrocyte megakaryocyte myeloid and lymphoid primed progenitors. They fitted a partial differential equations model of population dynamics to these data, and this revealed two important findings. First, fewer hematopoietic stem cells differentiated into the lymphoid lineage, and second, they observed increased expansion of early myeloid primed progenitors, so early expansion among myeloid primed progenitors was also contributing to increased proliferation. There was one other important observation here. Researchers found differential gene expression along lineages confirming increased proliferation in myeloid primed progenitors as important for myeloid bias. Next, researchers transplanted wild type hematopoietic stem and progenitor cells into I kappa B mouse recipients. The changes in cell population dynamics that they had previously observed were once again apparent, showing that an inflamed bone marrow microenvironment was sufficient to drive myeloid bias. Finally, the investigators applied these analyses to single cell RNA sequencing measurements in HSPCs isolated from aged mice and also from human patients with myeloid neoplasms, they saw the same myeloid primed progenitor expansion as in the I kappa B models that suggests common features across different settings of myeloid bias. Together, authors say these analyses demonstrate that inflammatory signaling promotes myeloid bias. This occurs not only through the biasing of hematopoietic stem cell differentia, but also via enhanced expansion of early myeloid primed progenitors. These findings are also reviewed in a commentary called Math Models Expose Myeloid Bias Mechanisms in Hematopoiesis. The authors are Arthur C. Fasoni of the Federal University of Itajuba, Brazil, and Ingmar Glauch of the Dresden University of Technology, Dresden, Germany. Fasoni and Glausch describe the work as an elegant synthesis of mouse data with mechanistic mathematical models. By integrating mathematical modeling and experimental approaches, the researchers show how myeloid bias arises from a combination of hematopoietic stem cell differentiation and progenitor proliferation biases. They say the differential equation based models in the study offer a robust framework for analyzing dynamic data on hematopoiesis. More broadly, the work highlights the potential of mathematical and computational models to provide a more conceptual and mechanistic interpretation of the underlying biology. In fact, this work conjures up a 20 year old quote from the mathematical biologist Joel E. Cohen, who said, mathematics is biology's next microscope, only better. In the age of big data and AI, one might question whether mechanistic mathematical modeling is still relevant. However, the work by Singh and co authors offers an emphatic yes, mathematics is still a microscope, so to speak, for biology. It's a tool that is far from obsolete and may gain even more importance in the future. 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.