Cytopenias In Patients Research Articles

Consistency of Spleen and Symptom Reduction Regardless of Cytopenia in Patients With Myelofibrosis Treated With Pacritinib

BackgroundPacritinib is a JAK2/IRAK1/ACVR1 inhibitor that is approved in the United States for the treatment of patients with myelofibrosis who have a platelet count < 50 × 109/L. Phase 3 clinical studies of pacritinib included patients across a wide range of baseline platelet and hemoglobin levels. Patients and MethodsIn order to assess the impact of baseline blood counts on pacritinib efficacy, an analysis of efficacy outcomes by baseline platelet and hemoglobin levels was performed using data pooled from 2 Phase 3 studies of pacritinib in patients with MF (PERSIST-1 and PERSIST-2). ResultsOf 276 patients evaluable for spleen response, spleen volume reduction occurred consistently across platelet subgroups (< 100 × 109/L or ≥ 100 × 109/L) and hemoglobin subgroups (< 8 g/dL, ≥ 8 to < 10 g/dL, or > 10 g/dL), with no diminution in treatment effect in patients with severe thrombocytopenia or anemia. Among 159 patients evaluable for symptoms response, improvement in total symptom score (TTS) was similar across platelet subgroups. A ≥ 50% improvement of TSS occurred more frequently in patients with baseline hemoglobin < 8 g/dL compared with those with baseline hemoglobin ≥ 8 to < 10 g/dL or > 10 g/dL. Patients with baseline hemoglobin < 8 g/dL also experienced improved hemoglobin sustained over 24 weeks, whereas subgroups with less severe anemia had stable hemoglobin levels over time. Symptom improvement as assessed using the Patient Global Impression of Change instrument was generally consistent across platelet and hemoglobin subgroups. ConclusionPacritinib demonstrates consistent efficacy in patients with MF regardless of baseline platelet and hemoglobin counts.

Clonal Hematopoiesis in Patients With Neuroendocrine Tumor Treated With Lutetium-177 and the Risk of Thrombocytopenia: A Prospective Study.

Thrombocytopenia is a relatively common dose-limiting toxicity during peptide receptor radionuclide therapy (PRRT) in patients with NET. Although uncommon, some patients develop persistent cytopenia and eventually therapy-related myeloid neoplasm (t-MN), which has a dismal prognosis. As the indications for PRRT are expanding, it is important to investigate factors that may predict cytopenias during/after PRRT. We prospectively evaluated the prevalence of clonal hematopoiesis (CH) and cytopenia in patients with NET undergoing PRRT. Patients with metastatic NET with plan to receive four cycles of lutetium-177 were enrolled. CH was evaluated before PRRT using a panel of 220 genes with a targeted depth of ≥1,000×. Patients were followed during PRRT and every 3 months thereafter. Of 37 patients enrolled, the median age was 68 years and 51.4% were male. Previous treatment exposures included alkylating agents in 30%, platinum agents in 8%, and external radiation in 13%. CH was detected in 35.1% using a variant allele frequency (VAF) cutoff of ≥2% and 45.9% with a VAF of ≥1%. The most common mutations were in age-related genes (DNMT3A, TET2). CH was not associated with anemia or neutropenia; however, it was associated with lower platelet count at baseline and more time spent in a thrombocytopenic state during/after PRRT. Five patients had bone marrow biopsies (BMBs) because of sustained hematologic dysfunction post-PRRT, and of those, diagnoses included clonal cytopenia of undetermined significance (CCUS) in three and idiopathic cytopenia of undetermined significance (ICUS) in two. CH is present in 35.1% of patients with NET and is associated with thrombocytopenia risk during PRRT. Future studies with long-term follow-up will delineate whether CH might be a predictor for higher risk of t-MN after PRRT.

Phase 1b trial of IRAK 1/4 inhibition for low-risk myelodysplastic syndrome refractory/resistant to prior therapies.

TPS6591 Background: Chronic stimulation of both the interleukin-1 receptor (IL-1R) and toll-like receptors (TLRs) in myeloid progenitors is thought to promote a proinflammatory environment in the bone marrow that causes persistent cytopenia in patients with low-risk myelodysplastic syndrome (LR-MDS). The serine/threonine kinases IRAK1 and IRAK4 are critical for the signaling downstream of IL-1R and most TLRs promote production of proinflammatory cytokines and NLRP3 inflammasome-driven pyroptosis, leading to bone marrow inflammation and cell death. IRAK1/4 is a potential target for inhibition for the treatment of LR-MDS by decreasing inflammation and cell death within the bone marrow, allowing for restoration of hematopoiesis. R289 is a prodrug for R835, a potent and selective inhibitor of IRAK1 and IRAK4 kinases. The safety and pharmacokinetic properties of R289/R835 were evaluated in a phase 1 study in healthy volunteers (Study C-906289-001). R289 was well tolerated with no serious or severe adverse events (AEs) reported. Most AEs were mild and transient; the most common AEs (mild/moderate) were headache and GI disturbance. Overall, the study supported the further evaluation of R289. An open-label, phase 1b study to determine the tolerability and preliminary efficacy of R289 for patients with LR-MDS refractory to prior therapies is currently enrolling patients. Methods: The R289 phase 1b open label, single arm, multi-center study (NCT05308264) includes a dose escalation phase (up to 24 patients) and a dose expansion phase (up to 10 patients). Inclusion criteria for both phases: patients ≥18 years with a definitive diagnosis of LR-MDS. Exclusion criteria include prior MDS treatment(s) within 4 weeks of study treatment. Dose Escalation Phase: A 3+3 dose escalation design will be used to determine the maximum tolerated dose (MTD). An initial R289 dose of 250 mg qd, will be given orally, with or without food, progressing to 1 g qd with dose limiting toxicity (DLT) assessed at each dose level. The DLT evaluation period will be 28 days. After completion, patients without DLTs may remain at their respective dose levels if clinical benefit continues without toxicity. Dose Expansion Phase: R289 will be administered to up to 10 additional patients with LR-MDS at a dose not exceeding the MTD in the dose escalation phase. The primary endpoint is safety and tolerability of R289. Secondary endpoints include preliminary efficacy and pharmacokinetics of R289. Statistical analyses will be primarily descriptive. The trial is currently ongoing at 9 US sites. Clinical trial information: NCT05308264 .

Investigation of the correlation between platelet antibodies and peripheral blood cytopenia in patients with hepatocellular carcinoma

The primary triggers that stimulate the body to generate platelet antibodies via immune mechanisms encompass events such as pregnancy, transplantation, and blood transfusion. Interestingly, our findings revealed that a subset of male patients with hepatocellular carcinoma (HCC), despite having no history of transplantation or blood transfusion, has shown positive results in platelet antibody screenings. This hints at the possibility that certain factors, potentially related to the tumor itself or its treatment, may affect antibody production. To delve the causes we initiated this study. We employed a case–control study approach to analyze potential influential factors leading to the positive results via univariate and multivariate regression analysis. We utilized Kendall’s tau-b correlation to examine the relationship between the strength of platelet antibodies and peripheral blood cytopenia. Antitumor medication emerged as an independent risk factor for positive results in HCC patients, and the strength of platelet antibodies positively correlated with the severity of anemia and thrombocytopenia. Without history of blood transfusion, transplantation, pregnancy, those HCC patients underwent recent tumor medication therapy are experiencing peripheral erythrocytopenia or thrombocytopenia, for them platelet antibody screenings holds potential clinical value for prevention and treatment of complications like drug-immune-related anemia and/or bleeding.

Secondary hemophagocytic lymphohistiocytosis in pediatric patients with visceral leishmaniasis and Epstein-Barr virus infection.

Visceral leishmaniasis-associated hemophagocytic lymphohistiocytosis (VL-HLH) is indistinguishable from those of HLH of other etiologies due to the overlap symptoms, posing a serious threat to life. In this study, we aimed to provide insights for early diagnosis and improve outcomes in pediatric patients with VL-HLH. We retrospectively analyzed the clinical and laboratory data of 10 pediatric patients with VL-HLH and 58 pediatric patients with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH). The median time from symptom onset to cytopenia in patients with VL-HLH and EBV-HLH was 11 days (interquartile range, 7-15 days) and five days (interquartile range, 3.75-9.25 days) (P = 0.005). Both groups showed liver injury and increased lactate dehydrogenase levels; however the levels of aspartate aminotransferase, alanine aminotransferase, direct bilirubin, and lactate dehydrogenase in patients with VL-HLH were significantly lower than those in patients with EBV-HLH (P < 0.05). The fibrinogen and triglyceride levels were almost normal in VL-HLH patients but were significantly altered in EBV-HLH cases ( P < 0.05). The positive rate of first bone marrow microscopy examination, anti-rK39IgG detection, and blood metagenomic next-generation sequencing was 50%, 100%, and 100%, respectively. After VL diagnosis, eight patients were treated with sodium stibogluconate and two were treated with liposomal amphotericin B. All the patients with VL-HLH recovered. Our study demonstrates that regular triglyceride and fibrinogen levels in pediatric patients with VL-HLH may help in differential diagnosis from EBV-HLH. VL-HLH is milder than EBV-HLH, with less severe liver injury and inflammatory responses, and timely treatment with antileishmanial agents is essential to improve the outcomes of pediatric patients with VL-HLH.

Clinical Outcomes, Survival, and Predictors in Lower-Risk Myelodysplastic Syndrome Patients Treated with Cyclosporine A

Plain Language SummaryTherapeutic options to improve myelodysplastic syndrome (MDS)-related cytopenias in patients with lower-risk MDS are limited, and cyclosporin A (CSA) is an available option. We retrospectively assessed the effects of CSA on patients with lower-risk MDS at Shuguang Hospital affiliated with Shanghai University of Traditional Chinese Medicine. After statistical analysis, we found that more patients treated with CSA improved cytopenias than those treated without CSA. Patients with hypocellular marrow were more likely to get responses to CSA. Hypocellular marrow was defined as marrow cellularity of <30%. However, CSA did not delay disease progression and prolong survival span. The results of this study suggest that CSA is a safe treatment and can significantly improve cytopenias of a substantial proportion of patients with lower-risk MDS, especially in individuals with hypocellular bone marrow.

Assessing Pancytopenia in Leukemia Patients through flow Cytometry and ELISA to Evaluate the Complete Blood Counts and Cluster of Differentiation Markers

To diagnose cases involving pancytopenia or leukopenia, a comprehensive assessment of various factors is necessary, including blood count, peripheral blood, and bone marrow analysis, immunophenotyping, and cytogenetics. This study aims to examine the complete blood count parameters and CD markers in Sudanese patients with leukemia and pancytopenia, utilizing flow cytometry and ELISA techniques. This study is a laboratory-based addressing the assessment of the target population (acute Leukaemia with pancytopenia) by complete blood count, flow cytometry, and ELISA techniques. The research group was comprised of patients who were diagnosed with acute leukemia and had pancytopenia before undergoing treatment. Another group of patients with acute leukemia but without pancytopenia was also included. In addition, there was a control group consisting of healthy individuals who volunteered for the study. Essentially, the control group was made up of healthy individuals who were not affected by acute leukemia or pancytopenia. In our study, we enrolled a total of 150 participants, comprising three groups: 50 cases of acute leukemia, 50 patients with acute leukemia who subsequently developed pancytopenia, and 50 healthy volunteers. The majority of participants were female, constituting 56% of the sample (84 individuals), while the most prevalent age group represented was individuals aged 65, accounting for 43.3% of the participants. Our analysis revealed a statistically significant correlation between age and both leukemia and leukemia with pancytopenia, with a p-value of 0.00. Furthermore, the presence of either AML or ALL also exhibited a substantial association with the disease, indicated by a p-value of 0.00. Specifically, the use of a flow cytometer allowed us to identify the presence of CD3 with a p-value of 0.00 and CD4 with a slightly higher p-value of 0.04. Improvement of patient management by introducing effective tools for predicting prognosis is the key to success in managing diseases. We recommend that flowcytometry be used routinely to diagnose leukemia and leukemia with cytopenia in patients at all stages of the disease.

Next-generation therapy for lower-risk MDS.

Myelodysplastic syndromes (MDS) are malignant myeloid neoplasms characterized by ineffective clonal hematopoiesis leading to peripheral blood cytopenia and a variable risk of transformation to acute myeloid leukemia. In lower-risk (LR) MDS, as defined by prognostic scoring systems recently updated with the addition of a mutation profile, therapeutic options aim to reduce cytopenia, mainly anemia. Although options for reducing the transfusion burden have recently been improved, erythropoiesis-stimulating agents (ESAs), lenalidomide, hypomethylating agents, and, more recently, luspatercept have shown efficacy in rarely more than 50% of patients with a duration of response often far inferior to the patient's life expectancy. Nevertheless, several new therapies are currently under investigation aiming at improving cytopenia in patients with LR-MDS, mostly by targeting different biological pathways. Targeting ligands of the transforming growth factor β pathway has led to the approval of luspatercept in LR-MDS with ring sideroblasts or SF3B1 mutation, potentially replacing first-line ESAs in this population. Here, we also discuss the evolving standard of care for the treatment of LR-MDS and explore some of the most promising next-generation agents under investigation.

Intravital Microscopy to Study the Effect of Matrix Metalloproteinase Inhibition on Acute Myeloid Leukemia Cell Migration in the Bone Marrow.

Hematopoiesis is the process through which all mature blood cells are formed and takes place in the bone marrow (BM). Acute myeloid leukemia (AML) is a blood cancer of the myeloid lineage. AML progression causes drastic remodeling of the BM microenvironment, making it no longer supportive of healthy hematopoiesis and leading to clinical cytopenia in patients. Understanding the mechanisms by which AML cells shape the BM to their benefit would lead to the development of new therapeutic strategies. While the role of extracellular matrix (ECM) in solid cancer has been extensively studied during decades, its role in the BM and in leukemia progression has only begun to be acknowledged. In this context, intravital microscopy (IVM) gives the unique insight of direct in vivo observation of AML cell behavior in their environment during disease progression and/or upon drug treatments. Here we describe our protocol for visualizing and analyzing MLL-AF9 AML cell dynamics upon systemic inhibition of matrix metalloproteinases (MMP), combining confocal and two-photon microscopy and focusing on cell migration.

Autoimmune cytopenias in patients with malignant lymphoma: A multicenter report by the Polish Lymphoma Research Group.

Autoimmune cytopenias (ACs), including immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA) and autoimmune granulocytopenia, are rare complications observed in lymphoma patients. They may appear before, during or after lymphoma diagnosis, whether the patients had disease progression or not. This study aims to correlate ACs with lymphoma type, disease course and prognosis. We performed a multicenter retrospective analysis of adult patients with malignant lymphoma and ACs coexistence diagnosed and treated in centers aligned with the Polish Lymphoma Research Group (PLRG). The analysis covers the years 2016-2022 and included 51 patients comprised of 23 women and 28 men. Of these, 35 patients were diagnosed with AIHA, 15 patients with ITP and 1 patient with both AIHA and ITP. The most common type of lymphoma was Hodgkin lymphoma (HL) (12 patients) and diffuse large B-cell lymphoma (DLBCL) (14 patients). At the time of diagnosis, 31 (61%) of patients had stage 4 of HL or DLBCL, according to Ann Arbor classification. In total, the response to treatment was evaluated in 50 patients, with 25 being in complete remission and 6 in partial remission. We observed that B cell symptoms (p = 0.036), bone marrow involvement (p = 0.073), splenomegaly (p = 0.025), and more than 2 lines of treatment were more common in AIHA compared to ITP patients. Conversely, eucopenia (p = 0.056) and ACs without lymphoma progression (p = 0.002) were more often diagnosed in ITP patients. In the study group, relapsed and refractory disease was observed more often, and shorter overall survival (OS) was noted in patients with DLBCL. We found that AC is associated with a worse prognosis in comparison to the general population of lymphoma patients. There were no differences in response to AC therapy. To have more accurate data, a larger group, as part of a multicenter study, should be evaluated.

Phase 1b Trial of Irak 1/4 Inhibition for Low-Risk Myelodysplastic Syndrome Refractory/Resistant to Prior Therapies: A Trial in Progress

Background and Significance: Chronic stimulation of both the interleukin-1 receptor (IL-1R) and toll-like receptors (TLRs) in myeloid progenitors is thought to promote a proinflammatory environment in the bone marrow that causes persistent cytopenia in patients with low-risk myelodysplastic syndrome (LR-MDS). The serine/threonine kinases IRAK1 and IRAK4 are critical for the signaling downstream of IL-1R and most TLRs that promotes production of proinflammatory cytokines and NLRP3 inflammasome-driven pyroptosis, leading to bone marrow inflammation and cell death. Therefore, inhibition of IRAK1/4 is a potential target for the treatment of LR-MDS by decreasing inflammation and cell death within the bone marrow, allowing for restoration of hematopoiesis. R289 is a prodrug that is converted to the active drug R835 in the gastrointestinal (GI) tract. R835 is a potent and selective inhibitor of IRAK1 and IRAK4 kinases that inhibits TLR and IL-1R-dependent proinflammatory cytokine production in multiple cell types. In vivo, R835 blocks TLR4 and IL-1R-dependent systemic cytokine release in mice. The safety and pharmacokinetic properties of R289/R835 were evaluated in a phase 1 study in healthy volunteers (Study C-906289-001). R289 was well tolerated with no serious or severe adverse events (AEs) reported. Most AEs were mild and transient; the most common AEs (mild/moderate) were headache and GI disturbance. Overall, the phase 1 trial results supported the further study of R289. An open-label phase 1b study to determine the tolerability and preliminary efficacy of R289 for patients with LR-MDS refractory to prior therapies is currently recruiting patients. Study Design and Methods: The R289 phase 1b study (NCT05308264) is an open label, single arm, multi-center study, which includes a dose escalation phase (up to 12 patients) and a dose expansion phase (up to 10 patients). Inclusion criteria for both phases will include patients ≥18 years with a definitive diagnosis of low-risk MDS (International Prognostic Scoring System-R ≤3.5) and ≤5% bone marrow myeloblasts. Patients must be relapsed or refractory/resistant or intolerant to prior MDS therapies. Exclusion criteria include prior MDS treatment(s) within 4 weeks of study treatment, clinically significant anemia (from iron deficiency, hemolysis, or GI bleeding), and chronic myelomonocytic leukemia. Dose Escalation Phase: A 3+3 dose escalation design will be used to determine the maximum tolerated dose (MTD). An initial R289 dose of 250 mg qd, will be given orally, with or without food, progressing to 500 mg qd with dose limiting toxicity (DLT) assessed at both doses. The DLT evaluation period will be 28 days. After completion, patients not experiencing DLTs may remain at their respective dose levels as long as they demonstrate continued clinical benefit without toxicity. Dose Expansion Phase: Up to 10 additional patients with LR-MDS will be enrolled, with R289 administered to all patients at a dose not exceeding the MTD determined in the dose escalation phase. The primary endpoint of the study is safety and tolerability of R289, assessed by incidence of AEs, discontinuation/interruption of R289 due to AEs, and incidence of DLTs. Secondary endpoints include preliminary efficacy, assessed by red blood cell transfusion independence by Week 24 (% achieving ≥50% reduction in transfusions), and pharmacokinetics of R289. Change from baseline in plasma biomarkers, including C-reactive protein and TNFα, and bone marrow biomarkers will be assessed. Statistical analyses will be primarily descriptive. Tabulations will be produced for disposition, demographics, disease characteristics, safety, pharmacokinetics, pharmacodynamics, and clinical activity. For analyses of clinical activity, such as proportion of patients with RBC transfusion independence, complete responder rate, overall response rate, and proportion of subjects with hematologic improvements, the summary will be produced separately for the dose escalation phase and dose expansion phase. For the dose escalation phase, data will be summarized by dose level and overall. The trial is currently recruiting at 9 US sites. The study has enrolled 7 patients in the dose escalation phase.

Bone Marrow Assessment in Liver Cirrhosis Patients with Otherwise Unexplained Peripheral Blood Cytopenia

We performed a retrospective single-center analysis to investigate the diagnostic yield of bone marrow puncture in patients with liver cirrhosis and cytopenia. Liver cirrhosis patients receiving bone marrow aspiration or biopsy for the diagnostic work-up of otherwise unexplained peripheral blood cytopenia at our institution between 2004 and 2020 were enrolled in this study. We evaluated findings from cytologic, histologic and immunologic assessment and final diagnostic outcomes. A total of 118 patients with a median age of 55 years and a median Child–Pugh score of B (8 points) were enrolled. The main etiologies of liver cirrhosis were viral hepatitis (B and C) or chronic alcohol consumption. The majority of patients (60%) exhibited concurrent anemia, leukocytopenia and thrombocytopenia. Bone marrow assessment revealed normal, unspecific or reactive alterations in 117 out of 118 patients (99%). One patient was diagnosed with myelodysplastic syndrome. Our findings suggest that peripheral blood cytopenia in patients with liver cirrhosis is rarely associated with a primary bone marrow pathology.

Cytopenia after CAR‑T cell therapy: Analysis of 63patients with relapsed and refractory B‑cell non‑Hodgkin lymphoma.

The present study aimed to determine the clinical characteristics of cytopenia in patients with relapsed and refractory B-cell non-Hodgkin lymphoma (B-NHL) who were treated with chimeric antigen receptor T-cell (CAR-T) therapy. Thus, a total of 63 patients with relapsed and refractory B-NHL who underwent CAR-T therapy between March 2017 and October 2021 were retrospectively selected for analysis. Neutropenia, anemia and thrombocytopenia at grade ≥3 occurred in 48 (76.19%), 16 (25.39%) and 15 (23.80%) cases, respectively. The results of a multivariate analysis demonstrated that the baseline absolute neutrophil count (ANC) and hemoglobin concentration were independent risk factors for grade ≥3 cytopenia. A total of 3 patients died early and were therefore excluded from the present study. Furthermore, cell recovery was examined at day +28 after infusion; 21 patients (35%) did not recover from cytopenia and 39 patients (65%) recovered. A multivariate analysis demonstrated that the baseline ANC <2.29×109/l, baseline hemoglobin <114.50 g/l and baseline IL-6 >21.43 pg/l were independent risk factors affecting hemocyte recovery. In conclusion, patients with relapsed and refractory B-NHL exhibited an increased incidence of grade ≥3 hematologic toxicity following CAR-T cell therapy, while baseline blood cell and IL-6 levels are independent risk factors for hemocyte recovery.

Phase 1b clinical study of IRAK 1/4 inhibition for low-risk myelodysplastic syndromes refractory/resistant to prior therapies.

TPS7085 Background: Chronic stimulation of both interleukin-1 receptor (IL-1R) and toll-like receptors (TLRs) in myeloid progenitors is thought to cause a bone marrow proinflammatory environment responsible for persistent cytopenia in patients with low-risk (LR)-MDS. IRAK1 and IRAK4 are serine/threonine kinases that are critical for the downstream signaling of IL-1R and most TLRs resulting in the production of proinflammatory cytokines and NLRP3 inflammasome-driven pyroptosis leading to bone marrow inflammation and cell death. Thus, IRAK1/4 inhibition is a potential target for the treatment of LR-MDS by decreasing inflammation and cell death within the bone marrow allowing the restoration of hematopoiesis. R289 is a prodrug that is converted to the active drug R835 in the gastrointestinal (GI) tract. R835 is a potent and selective inhibitor of IRAK1 and IRAK4 kinases and inhibits TLR and IL-1R-dependent proinflammatory cytokine production in multiple cell types. In vivo, R835 blocks TLR4 and IL-1R-dependent systemic cytokine release in mice. The safety and pharmacokinetic properties of R289/R835 were evaluated in a phase 1 healthy volunteer study (Study C-906289-001). R289 was well tolerated with no serious or severe adverse events (AEs) reported. Most AEs were mild and transient; the most common AEs (mild/moderate) were headache and GI disturbance. Overall, the trial supported the advancement of R289 into further studies. An open-label Phase 1b study to determine the tolerability and preliminary efficacy of R289 for patients with LR-MDS refractory to prior therapies is currently enrolling patients. Methods: The current study (NCT05308264) includes a dose escalation phase (up to 12 patients) and a dose expansion phase (up to 10 patients). Inclusion criteria for both phases will include patients ≥18 years with a definitive diagnosis of LR-MDS. Exclusion criteria will include prior treatment for MDS that concluded &lt;4 weeks prior to study treatment. Dose Escalation Phase: Dose escalation will utilize a 3+3 design to determine the maximum tolerated dose (MTD). R289 tablets can be taken orally with or without food. Dose limiting toxicity (DLT) will be assessed at each dose level. The DLT evaluation period will be 28 days. After completion of the DLT evaluation period, patients who do not experience DLTs may remain on treatment at their respective dose level if they continue to demonstrate clinical benefit without toxicity. Dose Expansion Phase: Up to 10 additional patients with LR-MDS will be enrolled; the primary endpoint of the study will be the safety and tolerability of R289. The secondary endpoints will include an assessment of preliminary efficacy and characterization of the pharmacokinetics of R289. R289 will be administered to all patients at a dose not to exceed the MTD determined in the Dose Escalation Phase. The trial is currently recruiting at 8 US sites. Clinical trial information: NCT05308264 .

Efficacy and Safety of CD34+ Stem Cell Boost for Delayed Hematopoietic Recovery After BCMA Directed CAR T-cell Therapy

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized treatment outcomes for patients with relapsed refractory multiple myeloma (RRMM). Despite supportive care with growth factors and thrombopoietin (TPO) mimetics, nearly half of the patients experience severe and prolonged cytopenias after CAR T infusion, which have become a major therapeutic challenge for patients with RRMM. Given the successful use of CD34+ autologous hematopoietic stem cells for treatment of non- or delayed engraftment after allogeneic and autologous stem cell transplantations, there is a need to explore the role of previously stored autologous stem cells as a boost for post-CAR T cytopenias in RRMM. We performed a multicenter retrospective analysis of adult patients with RRMM who received previously collected and stored CD34+ stem cell boosts after CAR T-cell therapy between 2 July 2020 and 18 January 2023. Indications for boost were determined per physician discretion and primarily included cytopenias and related complications. Overall, a total of 19 patients received stem cell boost, at a median dose of 2.75 × 106 CD34+ cells/kg (range 1.76-7.38), given at a median of 53 days (range 24-126) after CAR T infusion. Eighteen (95%) patients successfully recovered hematopoiesis after stem cell boost with median time for neutrophil, platelet, and hemoglobin engraftment of 14 (range 9-39), 17 (range 12-39), and 23 (range 6-34) days after the boost, respectively. Stem cell boosts were well tolerated, with no patients experiencing infusion reactions. Although infections were common and severe before stem cell boost, only 1 patient experienced a new infection after boost. All patients had experienced independence from use of growth factors, TPO agonists, and transfusions at the last follow-up. Autologous stem cell boosts can be effectively and safely used to promote hematopoietic recovery for post-CAR T cytopenias in patients with RRMM. Stem cell boosts can be a very effective rescue measure for post-CAR T cytopenias and related complications, as well as supportive care needs.

344 - Impact of Cytopenias in Patients Treated with Ruxolitinib Versus Best Available Therapy for Steroid-Refractory Acute Graft-Versus-Host Disease: A REACH2 Post Hoc Analysis

344 - Impact of Cytopenias in Patients Treated with Ruxolitinib Versus Best Available Therapy for Steroid-Refractory Acute Graft-Versus-Host Disease: A REACH2 Post Hoc Analysis

Early Cytopenias and Infections Following Chimeric Antigen Receptor T-Cell Therapy: A Single Center Experience

Background: Chimeric antigen receptor (CAR) T-cell therapy has shown promising responses in various hematologic malignancies. Cytopenias including anemia, neutropenia, and thrombocytopenia are common and manageable toxicities in the first 90 days after CAR T-cell therapy. Factors contributing to hematopoietic recovery following CAR T-cell therapy have not been well studied. Objective: Characterize the cytopenias, potential associated risk factors, incidence and management of infections, utilization of granulocyte-colony stimulating factor (G-CSF), thrombopoietin receptor (TPO) agonists, stem cell boosts, and immunoglobulin (IVIG) in the first 90 days after CAR T-cell infusion. Methods: This retrospective, single center chart review included 49 patients with various hematologic malignancies (non-Hodgkin lymphoma, acute lymphoblastic leukemia, multiple myeloma) treated with CAR T-cell therapy between March 2019 and July 2022. White blood cell count, absolute lymphocyte count, absolute neutrophil count, hemoglobin, platelet counts, and inflammatory markers were recorded at apheresis, lymphodepletion (day -5), day 0, +7, +14, +21, +30, +60, and +90. Cytopenias were documented using CTCAE grading system. Hypogammaglobulinemia (IgG<400 mg/dL) and infections by day +30 and day +90 were evaluated. Administration of GCSF, TPO-agonist, and IVIG up to day +90 were recorded. Recovery of immune repertoire using bone marrow biopsy and immunodeficiency panel results were included when available. Responses to CAR T were documented using disease specific disease response criteria. Cytokine release syndrome (CRS) and immune effector cell associated neurologic syndrome (ICANS) were graded using the ASTCT consensus criteria. The data was censored at date of progression, death or day +90 post CAR T-cell infusion. Results: Forty-nine patients received CAR T-cell therapy including axicabtagene ciloleucel (n = 6), tisagenlecleucel (n = 13), brexucabtagene autoleucel (n = 9), lisocabtagene maraleucel (n = 11), idecabtagene vicleucel (n = 10) from March 2019 to March 2022. Patient characteristics for all patients and those with and without grade 3-4 cytopenias at day +90 are seen in Table 1. The incidences of grade 3-4 lymphopenia, neutropenia, anemia, and thrombocytopenia at day 0 were 96%, 35%, 18%, and 20%; at day 30 the incidences were 38%, 40%, 19%, and 33%; at day +90 the incidences were 21%, 18%, 4%, and 11%, respectively with further characterization in Figure 1. Day +90 overall response rate and complete response rates were 49% and 43%, respectively with no significant differences between patients with and without cytopenias on day+90. Any grade CRS and ICANS were seen in 76% and 33% of the patients with grade 3+ CRS and ICANS seen in 2% and 10% of the patients, respectively. No significant differences were observed in the incidence of cytopenias in patients with any grades or grade 3+ CRS and ICANS. Infections occurred in 39% of patients and were severe, requiring hospitalization and intravenous treatment in 14%. The median time to infection was 8 days post infusion with 63% of infections having a bacterial source and 52% a viral source. None of the patients with cytopenias developed underlying myelodysplastic syndrome post CAR T. No cytopenia or infection related deaths were noted. Per physician discretion, GCSF was administered to 21 patients with median time to initiation of 23 days (range 14-140 days) and median duration of use of 33 days, with four patients having ongoing use at the time of last follow up. TPO-agonists were administered to nine patients. Eighteen patients received IVIG. Six patients received a stem cell boost due to prolonged cytopenia at a median of 54 days post CAR T-cell infusion and led to successful recovery of cytopenias. Further statistical analysis is under consideration to assess patient and disease related factors that may contribute to delayed hematopoietic recovery and associated complications of infections, bleeding and transfusions and will be available for the meeting. Conclusion: Cytopenias commonly persist through day +90 days post CAR T-cell therapy. Infections are common but manageable. The use of GCSF, TPO agonists, and IVIG appeared safe and did not worsen CRS or ICANS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical and Mechanistic Relationship of T-Cell Large Granular LymphocyticLeukemia (TLGL) andmonoclonal Gammopathy of Undetermined Significance(MGUS)

Introduction: The incidental finding of asymptomatic clonal expansion of plasma cells (MGUS), and T cells (TCUS) is not uncommon and its prevalence increases with age. While the propensity of such conditions to progress to multiple myeloma (MM) and TLGL, respectively is not fully elucidated, we observed in our clinical practice an intertwine between TLGL and MGUS, suggesting a possible mechanistic relationship. Per definition, MGUS should be asymptomatic and without cytopenia, the presence of which would upstage this condition. Thus, most often cytopenias in patients (pts) with MGUS and TLGL coexistence have been primarily attributed to the autoimmune sequelae of the T cell clonopathy. However, TLGL can also be asymptomatic in 20-50% of cases. In such a scenario the identification of the culprit etiology of cytopenia is crucial for the selection of proper therapies. Moreover, understanding the relationship between MGUS and TLGL may provide important lessons regarding the nature of the latter. One could stipulate that TLGL cells are the closest natural equivalent to the chimeric antigen receptor T cells (CART) and naturally arise from the immune trigger provided by clonal plasma cells. The initially polyclonal CTL responses may subsequently evolve to a clonal process, in particular upon acquisition of STAT3 mutations, ultimately controlling the MGUS clone. Alternatively, both humoral and CTL responses are triggered by the same offending agent and its persistence leads to the selection of dominant MGUS and TLGL clones as markers of an overshooting immune response. Methods/Results: We accrued a cohort of 280 pts with TLGL and explored both deep clinical and genomic phenotypes on 171 informative pts for whom complete data was available. Overall, pts had a median age of 67 years (IQR 58-73) with almost 1.09 M:F ratio. Among them, 23% had a concomitant plasma cell dyscrasia, with the majority being MGUS (19%), whereas only 2% and 1% of pts presented with Waldenstrom's macroglobulinemia/lymphoplasmacytic lymphoma (WM-LPL) and MM, respectively. Of note, no MGUS was found in TLGL pts <50 years, suggesting other pathogenetic drivers in younger cases. Overall, TLGL/MGUS had IgG (63%), IgM (25%) and IgA (9%) monoclonal protein phenotypes. In addition, polyclonal hypergammaglobulinemia was present in another 12% of pts. Whereas the overall expected MM evolution is 1-2% per year in typical MGUS, at a median follow up time of 12.5 years (8-17) only 1 MGUS/TLGL case progressed to MM as opposed to the estimated 3-4 pts. Furthermore, while the median overall survival (OS) of pts with MGUS has been reported as 8 years in historical cohorts, in our TLGL/MGUS cases reached 19 years. Looking at clinical characteristics, 13.5% of pts were asymptomatic, 61% had anemia, 53% neutropenia, and 34.5% thrombocytopenia. Anemia (76% vs 58%, p=.04), and bilineage cytopenia (38% vs 22%, p=.04) were more common in pts with co-associated MGUS. Gender, age distribution and disease-specific features such as TLGL counts (median 1785 vs 1680/µL), presence of STAT3 mutations (26% vs 33%) and co-occurring rheumatoid arthritis (15% vs 14%) did not differ between the two groups. Overall response rate (ORR) to T cell-directed therapy achieved 87% in pts with TLGL vs 64% in pts with concomitant MGUS (p=.0017). Indeed, because of the higher refractoriness rate in the latter group (median line of therapies 4 vs 3 in non-MGUS cases), 6 of these immunosuppression-refractory pts received bortezomib-dexamethasone resulting in a 67% ORR with a median time-to-next-treatment of 6.5 months (3-11). These observations argue against TLGL being the culprit of cytopenia in all TLGL/MGUS, suggesting that the monoclonal protein may have a specificity against myeloid or erythroid precursors. Conclusion: Our study shed light on the intertwining relation of the TLGL/MGUS clinical dyad. Rather than a coincidental finding in older pts, such clinical presentation may represent the first paradigmatic example of natural CART cells, analogous to those currently used in MM clinical practice. Finally, the etiology of cytopenias in TLGL need to be cautiously investigated, not automatically assuming a relation to TLGL. To further dissect such complicated dynamics, we are investigating a large cohort of MGUS pts for the presence of TCUS/TLGL and assessing the specificity of polyclonal and monoclonal proteins in MGUS pts with cytopenia using 2 million 12-mers peptide arrays.

Real-World Analysis of Cytopenias after Chimeric Antigen Receptor T-Cell Therapy: A Comparison of BCMA and CD19 Based Outcomes

Introduction: Chimeric Antigen Receptor (CAR) T-cell therapy is now approved as a second-line treatment for relapsed/refractory diffuse large B cell lymphoma (DLBCL), multiple myeloma (MM), and acute lymphoblastic leukemia. B-cell maturation antigen (BCMA) and CD19 CAR-T therapies are associated with substantial hematological toxicity, potentially causing complications in the post-CAR-T setting. It is unclear if cytopenia rates differ between CAR-T therapies. We evaluated differences in cytopenia, transfusion support, and associated outcomes in patients receiving CAR-T therapy for MM and non-Hodgkin's lymphoma (NHL) at our institution. Methods: We performed a retrospective analysis of patients diagnosed with MM and NHL from 2012-2022 who subsequently relapsed and received CAR-T-cell therapy at the Winship Cancer Institute at Emory University. Patients were excluded if they underwent apheresis but had not received infusion or had manufacturing failure. We compared rates of grade 3/4 cytopenias based on CIBMTR criteria and supportive care at day 0, 3mo, 6mo, and 1 year as well as date of hematological recovery. Day 0 was defined as onset of grade 3/4 cytopenia after CAR-T therapy. Hematological recovery was defined as sustained hemoglobin >8g/dL, platelets >50,000/µL, and ANC >1000/mm3 without need for support. Differences between groups were determined using Fisher's exact test and Kruskal-Wallis Test where appropriate. PFS and overall survival (OS) were estimated using the Kaplan-Meier method from CAR-T infusion to progression or death for those events and last contact for those censored. Statistical analysis was performed using SAS with significance at the 0.05 level. Results: Of 35 patients, 24 received BCMA and 11 received CD19 CAR-T therapy. Median age at CAR-T infusion for all patients was 58 years (36-78). Most patients were male (66.7%) and of white race (57.1%) [Table 1]. Overall, 4 patients (11.4%) had an initial ECOG ≥2. Twenty-one patients (87.5%) had penta-refractory MM disease with extramedullary involvement in 25%. All patients with NHL had stage 4 disease with bone marrow involvement in 33.3%. Eight patients had DLBCL (72.7%), 1 double hit lymphoma (18.2%), and 2 mantle cell lymphoma (9.1%). Six patients received tisa-cel, 2 axi-cel, 2 brexu-cel, and 1 liso-cel. The MM cohort underwent significantly more autologous transplantations as a prior line of therapy (p<0.001). Patients with NHL received CAR-T at a later median age (p=0.006). Median follow-up for the MM and NHL cohort was 2.38 years and 0.2 years respectively. There was no difference in time from last therapy to CAR-T infusion (p=0.171) nor days of hospitalization (p=0.681). Almost all patients (95.8%) achieved hematological recovery after infusion with similar recovery rates between groups (p=0.536). Median time to grade 3/4 anemia recovery was 6 days (1-90), neutropenia recovery at 15 days (1-336), and thrombocytopenia recovery at 28 days (14-277). Time to grade 3/4 anemia, neutropenia, and thrombocytopenia was 1 day (0-11), 2 days (0-11) and 2 days (0-15) respectively. Most patients required supportive care with growth factors (34.6%), packed red cells (57.7%), and platelets (23.1%) without significant group differences [Table 2]. One patient with MM received TPO. Prolonged grade 3/4 cytopenia rates were significant with 17.1% at 3mo, 22.9% at 6mo and 8.7% at 1 year. Both groups had similar rates of grade 3/4 cytopenia at day 0, 3mo, 6mo, and 1 year. The MM cohort had higher rates of infection (p<0.001). Rates of CRS (p=0.226) and neurotoxicity (p=0.063) were similar. Fourteen patients with MM (58.3%) and 3 patients with NHL (27.3%) progressed post-CAR-T. Median PFS overall was 1.7 years, 2 years (95%CI: 1, 3) in the MM group, and not reached (NR) (0.2, NA) in the NHL group. Median OS overall was NR, NR in MM (2.5, NA) and NR in NHL (0.3, NA). Grade 3/4 neutropenia and thrombocytopenia were not associated with survival at any time interval. Onset of grade 3/4 cytopenia were not associated with histopathological characteristics, inflammatory markers, or CRS/ICANS. Conclusions: This real-world study demonstrates comparable rates of upfront and prolonged cytopenia in patients receiving BCMA and CD19 CAR-T therapies. Over 20% of patients had prolonged, ongoing grade 3/4 cytopenias requiring supportive care at the 3-6mo mark. Further follow-up and larger prospective studies are needed to validate these findings. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Linezolid Exposure Is Associated with Cytopenias in Patients Treated for Multidrug-Resistant Tuberculosis.

Although linezolid is effective for multidrug-resistant TB (MDR-TB) tuberculosis treatment, it is associated with cytopenias after 4 weeks of administration. Data on toxicities with long-term use of linezolid and drug pharmacodynamics in MDR-TB treatment are limited, and concerns about toxicity present barriers to wider implementation. This was a secondary analysis of a prospective cohort study of patients treated for MDR-TB in the country of Georgia from 2015 to 2017. Intensive blood sampling 4 to 6 weeks after treatment initiation with linezolid 600 mg daily was performed for pharmacokinetic (PK) analysis, including linezolid trough concentration (Cmin) and area under the curve from 0 to 24 hours (AUC0-24). Linezolid exposure was defined using literature-reported thresholds. Cytopenias were defined using an NIH adverse event (AE) scale. Logistic regression was used to evaluate the relationship between linezolid exposure and cytopenias. Among 76 patients receiving linezolid in their baseline treatment regimen and who had PK data available, cytopenia AEs occurred in 30 (39.5%) for an incidence rate of 46 per 100 person-years. The median duration of linezolid therapy was 526 days. No patients required dose reduction or interruption due to cytopenias. Median linezolid Cmin was 0.235 mg/L (interquartile range [IQR], 0.069 to 0.529), and median AUC0-24 was 89.6 mg·h/L (IQR, 69.2 to 116.2). Cytopenias were associated with linezolid PK parameters (Cmin > 2 mg/L and AUC0-24 > 160 mg·h/L). Cytopenias occurred frequently with long-term use of linezolid 600 mg/day and were associated with PK parameters but did not result in the need for treatment interruption in the management of a cohort of patients with MDR-TB.