Severe Cytopenia Research Articles

Current status and perspectives of hematopoietic cell transplantation in patients with paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare complement-driven acquired hemolytic anemia with specific presentations of hemoglobinuria, abdominal pain, fatigue, and thrombosis. To review the current therapeutic strategies for PNH, including anti-complement therapy and allogeneic hematopoietic cell transplantation (alloHCT), focusing on the tailoring of the approach to the disease subtype. The outcome of alloHCT varies depending on disease severity, thrombotic history, and response to prior therapies. Non-transplant PNH therapies include anti-C5 monoclonal antibodies that reduce terminal complement activation (eculizumab, ravulizumab, and crovalimab) and proximal complement pathway inhibitors such as pegcetacoplan (C3 inhibitor), iptacopan (complement factor B inhibitor), and danicopan (complement factor D inhibitor). Although complement inhibitors have revolutionized treatment, alloHCT remains the only curative therapy, particularly for patients who are refractory to medical management or have severe cytopenia. This review outlines the conditioning regimens used in alloHCT and summarizes recent studies showing that overall survival rates improve with less toxic conditioning protocols. AlloHCT can be used to manage PNH, particularly in patients who are resistant to or without access to complement-targeted therapies. Any potential cure offered by alloHCT must be counterbalanced by the significant procedure risks, including graft-versus-host disease and transplant-related mortality, particularly in patients with comorbidities. In the case of severe aplastic anemia with an associated PNH clone, immunoablative protocols based on anti-thymocyte globulin serotherapy with fludarabine and cyclophosphamide are recommended. The use of reduced toxicity protocols with fludarabine has been well-documented in patients with classic PNH. A treosulfan/fludarabine-based regimen is recommended; however, there is no consensus on optimal drug selection.

How I Manage Patients with Unexplained Cytopenia.

The term "unexplained cytopenia" is used to describe a condition characterized by peripheral blood (PB) cytopenia that cannot be attributed to identifiable causes using conventional tests or to any concomitant diseases. Unexplained cytopenia requires clinical attention and further investigation to identify individuals at risk of developing a hematologic neoplasm. The available evidence suggests that somatic mutation analysis may effectively complement the diagnostic work-up and clinical management of unexplained cytopenia. Indeed, the presence or absence of somatic mutation(s) in myeloid genes shows high positive and negative predictive values for myeloid neoplasms (MN). Mutation analysis is also crucial for identifying patients with clonal cytopenia of undetermined significance (CCUS), a condition at increased risk of developing a MN. Recently, clinical/molecular prognostic models have been developed, providing valuable tools for the personalization of clinical and molecular surveillance. Most patients with CCUS show mild cytopenia and do not require therapeutic intervention. Currently, there is no treatment approved for CCUS, and transfusion therapy is the sole therapeutic option for patients with severe symptomatic cytopenia. However, this field has been emerging as a domain of active clinical investigation. This article presents four case studies of patients with unexplained cytopenia, which hematologists may encounter in their clinical practice.

Clonal T cell populations scarcely impair patients with rheumatic diseases: a prospective long-term follow up study

BackgroundClonal T cell populations are frequently detected in patients with rheumatic diseases. The relevance of this finding is often uncertain, as the clinical spectrum can range from being asymptomatic to T cell leukemia. Former studies suggested that certain anti-rheumatic drugs might influence the course of the clonal T cell populations.MethodsA prospective long-term follow up study was performed including patients with rheumatic diseases and clonal T cell populations. Clinical features, adverse events, especially infections and cytopenias, and immunosuppressive medication were assessed. T cell populations were characterized by polymerase chain reaction, flow cytometry and stimulated cell cultures.Results28 Patients with rheumatoid arthritis, spondyloarthritis, or giant cell arteritis were prospectively followed for up to 7.6 years. Severe infections or cytopenias (10.7% autoimmune neutropenias) were rare. The clonal T cell populations mostly persisted over time, the tumor burden decreased in the long-term. The cytokine secretion in stimulated T cell cultures did not differ in the subgroup of RA patients with versus without clonal T cells.ConclusionClonal T cell populations in patients with rheumatic diseases are common, but are rarely harmful. Feared neutropenia, infections or progression into T cell leukemia could not be detected in the long-term in our cohort.

Severe cytopenia after chimeric antigen receptor-T cell driven by large granular lymphocytes and responsive to steroids.

Immune effector cell-associated hematotoxicity (ICAHT) is a common toxicity associated with an important morbidity after chimeric antigen receptor (CAR)-T-cell therapy. Multiple factors seem to be involved in the development of severe ICAHT, making its management difficult. Here, we report three cases of severe ICAHT after axicabtagene-ciloleucel (axi-cel) for diffuse large B-cell lymphoma showing an expansion of large granular lymphocyte in the bone marrow with a CD3/CD57-positive non-CAR-T immunophenotype. We show that it is possible to treat them with low-dose steroids, obtaining a striking resolution of cytopenias with no deleterious impact on the underlying malignancy.

AML typical mutations (CEBPA, FLT3, NPM1) identify a high-risk chronic myelomonocytic leukemia independent of CPSS molecular

AbstractMutations commonly associated with acute myeloid leukemia (AML), such as CEBPA, FLT3, IDH1/2, and NPM1, are rarely found in chronic myelomonocytic leukemia (CMML), and their prognostic significance in CMML has not been clearly identified. In 127 patients with CMML, we have retrospectively analyzed next-generation sequencing and polymerase chain reaction data from bone marrow samples collected at the time of CMML diagnosis. Seven patients harbored CEBPA mutations, 8 FLT3 mutations, 12 IDH1 mutations, 26 IDH2 mutations, and 11 NPM1 mutations. Patients with CMML harboring CEBPA, FLT3, and/or NPM1 mutations (mutCFN) more frequently had the myeloproliferative subtype, a high prevalence of severe cytopenia, and elevated blast counts. Regardless of their CMML Prognostic Scoring System molecular classification, mutCFN patients with CMML had a poor prognosis, and the multivariate analysis identified mutCFN as an independent marker of overall survival. The genetic profile of these mutCFN patients with CMML closely resembled that of patients with AML, with higher-risk clinical characteristics. Our findings lead us to suggest including the assessment of these mutations in CMML prognostic models and treating these patients with AML-type therapies, including intensive chemotherapy and allogeneic stem cell transplantation, whenever feasible. Furthermore, certain targeted therapies approved for use in AML should be considered.

Systemic lupus erythematosus-related macrophage activation syndrome inducing severe cytopenia successfully treated with anifrolumab: a case report

Systemic lupus erythematosus-related macrophage activation syndrome inducing severe cytopenia successfully treated with anifrolumab: a case report

A multicenter phase 2 clinical trial of low-dose subcutaneous decitabine in myelofibrosis

AbstractMyelofibrosis (MF) in the chronic phase is a challenging disease to treat, and conventional treatment options are geared toward symptom palliation. In this prospective, multicenter, phase 2 trial, 21 patients with MF (18 chronic phase, 2 accelerated phase, and 1 blast phase) were treated with a 10-day schedule of subcutaneous decitabine at 0.3 mg/kg per day. The overall response rate was 33% (95% confidence interval, 15-57), primarily manifested as an improvement in cytopenias. The median duration of response was 7 months (range, 3-44). A high International Prognostic Scoring System risk score, high baseline fetal hemoglobin level, and sustained decrease in circulating CD34+ cell counts were associated with response to decitabine. All patients experienced at least 1 grade 3/4 cytopenia. Nonhematologic toxicities were less frequent, with fatigue, anorexia, and hypocalcemia being the most common. Given the lack of effective therapies in MF with severe cytopenias, this study supports further investigation into the use of hypomethylating agents as single agents or in combination therapies. This trial was registered at www.ClinicalTrials.gov as #NCT00095784.

Addition of Elotuzumab to Backbone Treatment Regimens for Multiple Myeloma: An Updated Meta-Analysis of Randomized Clinical Trials

BackgroundThe efficacy of elotuzumab, an anti-SLAMF7 monoclonal antibody, in treating relapsed/refractory multiple myeloma (RRMM) and newly-diagnosed multiple myeloma (NDMM) has varied in randomized controlled trials (RCTs). Moreover, there is limited data on its real-world application. Patients and MethodsWe conducted a systematic review and meta-analysis of RCTs investigating the addition of elotuzumab to backbone antimyeloma regimens. The primary outcome of interest was progression-free survival (PFS). Secondary efficacy outcomes included overall survival (OS), overall response rate (ORR), and rates of very good partial response or better (VGPR). Key toxicities were also evaluated. ResultsThree RRMM trials (n = 915) and 5 NDMM trials (n = 1790) were included, with 50% of the 2705 patients receiving elotuzumab-containing triplets or quadruplets. In RRMM settings, elotuzumab use significantly improved PFS (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.60-0.82; P < .001; I² = 0%). This benefit was consistent among patients with high-risk cytogenetics (HR, 0.62; 95% CI, 0.43-0.90; P = .01; I² = 0%) and was particularly evident in those previously treated with proteasome inhibitors (PIs) or immunomodulatory drugs (IMiDs). The RRMM cohort also demonstrated better OS, ORR, and ≥VGPR rate. However, the NDMM cohort showed no significant improvements in any efficacy outcomes. Despite an increase in severe (grade ≥3) infections, elotuzumab use did not adversely affect rates of severe cytopenias, severe cardiac disorders, or second primary malignancies. ConclusionOur results suggest that elotuzumab-containing regimens represent valuable therapeutic options for PI/IMiD-exposed patients with RRMM. In contrast, elotuzumab's role in frontline settings remains limited.

Use of Eltrombopag to Improve Thrombocytopenia and Tranfusion Requirement in Anti-CD19 CAR-T Cell-Treated Patients.

Background/Objectives: Immune effector cell-associated hematotoxicity (ICAHT) is a frequent adverse event after chimeric antigen receptor (CAR)-T cell therapy. Grade ≥ 3 thrombocytopenia occurs in around one-third of patients, and many of them become platelet transfusion-dependent. Eltrombopag is a thrombopoietin receptor agonist (TPO-RA) able to accelerate megakaryopoiesis, which has been used successfully in patients with bone marrow failure and immune thrombocytopenia (ITP). Its role in managing thrombocytopenia and other cytopenias in CAR-T cell-treated patients has been scarcely addressed. Our aim was to report the safety and efficacy of this approach in patients included in the Spanish Group for Hematopoietic Transplantation and Cellular Therapy (GETH-TC) registry. Methods: This is a retrospective, multicenter, observational study. Patients who developed platelet transfusion dependence subsequently to CAR-T cells and received eltrombopag to improve platelet counts were recruited in 10 Spanish hospitals. Results: Thirty-eight patients were enrolled and followed up for a median (interquartile range [IQR]) of 175 (99, 489) days since CAR-T cell infusion. At the moment eltrombopag was indicated, 18 patients had thrombocytopenia and another severe cytopenia, while 8 patients had severe pancytopenia. After 32 (14, 38) days on eltrombopag, 29 (76.3%) patients recovered platelet transfusion independence. The number of platelet units transfused correlated with the time needed to restore platelet counts higher than 20 × 109/L (Rho = 0.639, p < 0.001). Non-responders to eltrombopag required more platelet units (58 [29, 69] vs. 12 [6, 26] in responders, p = 0.002). Nineteen out of twenty-three (82.6%) patients recovered from severe neutropenia after 22 (11, 31) days on eltrombopag. Twenty-nine out of thirty-five (82.9%) patients recovered red blood cell (RBC) transfusion independence after 29 (17, 44) days. Seven patients recovered all cell lineages while on treatment. No thromboembolic events were reported. Only two transient toxicities (cholestasis, hyperbilirubinemia) were reported during eltrombopag treatment, none of which compelled permanent drug withdrawal. Conclusions: Eltrombopag could be safely used to manage thrombocytopenia and accelerate transfusion independence in CAR-T cell-treated patients.

Molecular mechanisms promoting long-term cytopenia after BCMA CAR-T therapy in multiple myeloma

AbstractHematologic toxicity is a common side effect of chimeric antigen receptor T-cell (CAR-T) therapies, being particularly severe among patients with relapsed or refractory multiple myeloma (MM). In this study, we characterized 48 patients treated with B-cell maturation antigen (BCMA) CAR-T cells to understand kinetics of cytopenia, identify predictive factors, and determine potential mechanisms underlying these toxicities. We observed that overall incidence of cytopenia was 95.7%, and grade >3 thrombocytopenia and neutropenia, 1 month after infusion, was observed in 57% and 53% of the patients, respectively, being still present after 1 year in 4 and 3 patients, respectively. Baseline cytopenia and high peak inflammatory markers were highly correlated with cytopenia that persisted up to 3 months. To determine potential mechanisms underlying cytopenias, we evaluated the paracrine effect of BCMA CAR-T cells on hematopoietic stem and progenitor cell (HSPC) differentiation using an ex vivo myeloid differentiation model. Phenotypic analysis showed that supernatants from activated CAR-T cells (spCAR) halted HSPC differentiation, promoting more immature phenotypes, which could be prevented with a combination of interferon γ, tumor necrosis factor α/β, transforming growth factor β, interleukin-6 (IL-6) and IL-17 inhibitors. Single-cell RNA sequencing demonstrated upregulation of transcription factors associated with early stages of hematopoietic differentiation in the presence of spCAR (GATA2, RUNX1, CEBPA) and a decrease in the activity of key regulons involved in neutrophil and monocytic maturation (ID2 and MAFB). These results suggest that CAR-T activation induces HSPC maturation arrest through paracrine effects and provides potential treatments to mitigate the severity of this toxicity.

Stem Cell Mobilization Performed with Different Doses of Cytarabine in Plasma Cell Myeloma Patients Relapsing after Previous Autologous Hematopoietic Cell Transplantation-A Multicenter Report by the Polish Myeloma Study Group.

Salvage autologous hematopoietic cell transplantation (auto-HCT) may be used to treat relapse of plasma cell myeloma occurring after previous auto-HCT. When an insufficient number of hematopoietic stem cells have been stored from the initial harvest, remobilization is necessary. Here, we aimed to analyze the efficacy and safety of different doses of cytarabine (total 800 vs. 1600 vs. 2400 mg/m2) for remobilization. Sixty-five patients, 55% male, with a median age at remobilization 63 years, were included. Remobilization was performed with cytarabine_800 in 7, cytarabine_1600 in 36, and cytarabine_2400 in 22 patients. Plerixafor rescue was used in 25% of patients receiving cytarabine_1600 and 27% of those receiving cytarabine_2400. Patients administered cytarabine_800 were not rescued with plerixafor. Remobilization was successful in 80% of patients (57% cytarabine_800; 86% cytarabine_1600; 77% cytarabine_2400; p = 0.199). The yield of collected CD34+ cells did not differ between the different cytarabine doses (p = 0.495). Patients receiving cytarabine_2400 were at the highest risk of developing severe cytopenias, requiring blood product support, or having blood-stream infections. One patient died of septic shock after cytarabine_2400. In summary, remobilization with cytarabine is feasible in most patients. All doses of cytarabine allow for successful remobilization. Cytarabine_2400 is associated with higher toxicity; therefore, lower doses (800 or 1600 mg/m2) seem to be preferable.

Factors before leukapheresis that correlate with severe cytopenia and therapy related myeloid neoplasm post CAR-T.

7038 Background: While chimeric antigen receptor T-cell (CAR-T) therapy has transformed treatment for hematological malignancies, severe (≥ grade 3,Gr 3, CTCAE) cytopenias post CAR-T and therapy related myeloid neoplasms (t-MN) are particularly difficult to manage. Survival after diagnosis of t-MN is dismal. Management of ≥Gr 3 cytopenias that do not recover by month 3 after CAR-T require frequent monitoring and transfusion support. Growth factor and thrombopoietin mimetics have variable success, with stem cell boost emerging as having more consistent success. Evaluation for CAR-T eligibility, prior to leukapheresis, is the critical timepoint where factors identified at this time could inform risks and benefits of CAR-T versus alternative treatment and for consideration of stem cell collection in patients who may benefit from stem cell boost to treat severe cytopenia post CAR-T. Methods: We conducted a retrospective analysis comparing clinical data of patients (pts) with lymphoma (NHL) and multiple myeloma (MM) treated with FDA-approved and investigational CAR-T between 01/2016 – 06/2022 at Mayo Clinic. Prolonged cytopenias were defined as hemoglobin (Hg)&lt;8 g/dL, absolute neutrophil count (ANC)&lt;0.5 x 109/L, and/or platelet count (PLT)&lt;50 x 109/L at 3 months after CAR-T. Pts with progressive disease were excluded from cytopenia analysis. Logistic regression to identify factors correlated with cytopenia and t-MN. Results: Among the 186 pts who received CAR-T, 42 (22%) patients developed severe cytopenia (26/102, 25%, in NHL; 16/84, 19% in MM); 15/186 (8%) had more than 1 concurrent cytopenia. Univariate analysis identified that baseline ferritin and CAR-HEMATOTOX score correlated with cytopenia. Multivariate analysis showed that advanced age (≥ 65 years) (HR 2.69, 95%CI 1.17 – 6.40, P = 0.02) and thrombocytopenia (HR 4.01, 95%CI 1.77 – 9.34, P = 0.001) were associated with severe cytopenia. Twenty (10.7%) patients [8 (40%) males] developed t-MN at a median of 9.5 months (IQR 4.8 – 19.3 months) after CAR-T (14/102, 13% in NHL; 6/84, 7% in MM). Univariate analysis identified ferritin and CAR-HEMATOTOX score correlated with t-NM. Multivariate logistic regression showed advanced age (HR 5.03; 95%CI 1.59-18.7, P= 0.009), hemoglobin ≤ 10 g/dl (HR 3.63, 95%CI 1.04-13.30, P = 0.04), and thrombocytopenia (HR 4.06, 95%CI 1.32-14.2, P 0.02) are significantly associated with development of post-CART t-MN. Conclusions: Advanced age, anemia and thrombocytopenia at the time of evaluation for CAR-T eligibility, prior to leukapheresis, are associated with the development of post-treatment severe cytopenia and t-MN. Larger, multi-center studies are needed to validate these findings.

Real-World Risk of Severe Cytopenias in Multiple Myeloma Patients Sequentially Treated with Immunomodulatory Drugs.

Most multiple myeloma (MM) patients experience cytopenias, likely driven by both disease and treatment-related factors. Immunomodulatory agents (IMiDs), which form the backbone of most anti-myeloma regimens, are known to cause higher grade cytopenias. In this context, the impact of sequential IMiD treatments on cytopenia risk is unknown. We evaluated the cumulative risks of severe cytopenias following second line of therapy (LOT) initiation in 5,573 MM patients in the Flatiron Health database. Patients for whom both LOTs 1 and 2 contained IMiDs were considered "sequentially exposed"; those for whom neither contained IMiDs were "never exposed." For the neutropenia outcome, compared to the never exposed, the sequentially exposed had the highest 1-year risk (risk difference [RD] 12%), followed by those only recently exposed during LOT 2 (RD 8%), then by those with only past exposure during LOT 1 (RD 5%). A similar pattern was observed for leukopenia, but no meaningful differences were observed for anemia or thrombocytopenia. The associations between sequential exposure, versus never, with neutropenia and leukopenia were even stronger among those with a recent cytopenia history. Results suggest that sequential exposure to IMiDs is a risk factor for higher grade cytopenias. These findings have profound clinical implications in choosing newer LOTs with potential risks of cytopenia.

Resolvin E1 improves efferocytosis and rescues severe aplastic anemia in mice

Severe aplastic anemia (SAA) is a rare, fatal disease characterized by severe cytopenias and loss of hematopoietic stem cells (HSCs). Immune-mediated destruction and inflammation are known drivers of SAA, however, the underlying mechanisms driving persistent inflammation are unknown. Current treatments for SAA rely on immunosuppressive therapies or HSC transplantation, however, these treatments are not always effective. Using an established mouse model of SAA, we observed a significant increase in apoptotic cells within the bone marrow (BM) and impaired efferocytosis in SAA mice, relative to radiation controls. Single-cell transcriptomic analysis revealed heterogeneity among BM monocytes and unique populations emerged during SAA characterized by increased inflammatory signatures and significantly increased expression of Sirpa and Cd47. CD47, a “don’t eat me” signal, was increased on both live and apoptotic BM cells, concurrent with markedly increased expression of signal regulatory protein alpha (SIRPα) on monocytes. Functionally, SIRPα blockade improved cell clearance and reduced accumulation of CD47-positive apoptotic cells. Lipidomic analysis revealed a reduction in the precursors of specialized pro-resolving lipid mediators (SPMs) and increased prostaglandins in the BM during SAA, indicative of impaired inflammation resolution. Specifically, 18-HEPE, a precursor of E-series resolvins, was significantly reduced in SAA-induced mice relative to radiation controls. Treatment of SAA mice with Resolvin E1 (RvE1) improved efferocytic function, BM cellularity, platelet output, and survival. Our data suggest that impaired efferocytosis and inflammation resolution contributes to SAA progression and demonstrate that SPMs, such as RvE1, offer new and/or complementary treatments for SAA that do not rely on immune suppression.

Prolonged cytopenias after immune effector cell therapy and lymphodepletion in patients with leukemia, lymphoma and solid tumors

Background aimsThe success of chimeric antigen receptor (CAR) T-cell therapy in treating B-cell malignancies has led to the evaluation of CAR T-cells targeting a variety of other malignancies. Although the efficacy of CAR T-cells is enhanced when administered post-lymphodepleting chemotherapy, this can trigger bone marrow suppression and sustained cytopenia after CD19.CAR T-cell therapy. Additionally, systemic inflammation associated with CAR T-cell activity may contribute to myelosuppression. Cytopenias, such as neutropenia and thrombocytopenia, elevate the risk of severe infections and bleeding, respectively. However, data on the incidence of prolonged cytopenias after immune effector therapy in the solid tumor context remain limited. ObjectiveWe compared the incidence of prolonged cytopenias after immune effector therapy including genetically modified T-cells, virus-specific T-cells (VSTs) and NKT-cells, as well non-gene-modified VSTs for leukemia, lymphoma, and solid tumors (ST) to identify associated risk factors. MethodsA retrospective analysis was conducted of 112 pediatric and adult patients with relapsed and/or refractory cancers who received lymphodepleting chemotherapy followed by immune effector therapy. Patients treated with 13 distinct immune effector cell therapies through 11 single-center clinical trials and 2 commercial products over a 6-year period were categorized into 3 types of malignancies: leukemia, lymphoma and ST. We obtained baseline patient characteristics and adverse events data for each participant, and tracked neutrophil and platelet counts following lymphodepletion. ResultsOf 112 patients, 104 (92.9%) experienced cytopenias and 88 (79%) experienced severe cytopenias. Patients with leukemia experienced significantly longer durations of severe neutropenia (median duration of 14 days) compared with patients with lymphoma (7 days) or ST (11 days) (P = 0.002). Patients with leukemia also had a higher incidence of severe thrombocytopenia (74.1%), compared with lymphoma (46%, P = 0.03) and ST (14.3%, P < 0.0001). Prolonged cytopenias were significantly associated with disease type (63% of patients with leukemia, 44% of patients with lymphoma, and 22.9% of patients with ST, P = 0.006), prior hematopoietic stem cell transplant (HSCT) (66.7% with prior HSCT versus 38.3% without prior HSCT, P = 0.039), and development of immune effector cell-associated neurotoxicity syndrome (ICANS) (75% with ICANS versus 38% without ICANS, P = 0.027). There was no significant association between prolonged cytopenias and cytokine release syndrome. ConclusionsImmune effector recipients often experience significant cytopenias due to marrow suppression following lymphodepletion regardless of disease, but prolonged severe cytopenias are significantly less common after treatment of patients with lymphoma and solid tumors.

Treatment of post-allogeneic hematopoietic stem cell transplant cytopenias with sequential doses of multipotent mesenchymal stromal/stem cells

Background aimsCytopenias after allogeneic stem cell transplantation (allo-SCT) are a common complication, the underlying pathogenic mechanisms of which remain incompletely understood. Multipotent mesenchymal stromal/stem cell (MSC) therapy has been successfully employed in the treatment of immune-related disorders and can aid in the restoration of the hematopoietic niche. MethodsA phase II clinical trial to assess the efficacy and safety of administering four sequential doses of ex-vivo expanded bone marrow MSCs from a third-party donor to patients with persistent severe cytopenias after allo-SCT was performed. ResultsThe overall response rate on day 90 was 75% among the 27 evaluable patients (comprising 12 complete responses, 8 partial responses, and 7 with no response). The median time to respond was 14.5 days. Responses were observed across different profiles, including single or multiple affected lineages, primary or secondary timing, and potential immune-mediated or post-infectious pathophysiology versus idiopathic origin. With a median follow-up for surviving patients of 85 months after MSC infusion, 53% of patients are alive. Notably, no adverse events related to MSC therapy were reported. ConclusionsIn summary, the sequential infusion of third-party MSCs emerges as a viable and safe therapeutic option, exhibiting potential benefits for patients experiencing cytopenias following allo-SCT.

Metronomic cyclophosphamide for bone marrow carcinomatosis in metastatic castration-resistant prostate cancer

PurposeIn some patients with prostate cancer, bone marrow carcinomatosis develops later in the course of the disease, which has a poor prognosis. These are often heavily pretreated patients in the castration-resistant situation for whom there are no other therapeutic options, because either all available systemic therapies have already been used or the use of one is not possible due to the cytopenias associated with bone marrow carcinomatosis. In our literature search, there are no data on this treatment in the setting available, especially no clinical trial or even randomized data. This case series is to determine the clinical efficacy of metronomic cyclophosphamide in patients with metastatic castration-resistant prostate cancer and bone marrow carcinomatosis, particularly with regard to stabilization of the blood count (thrombocytopenias) and thus the possibility of further (more toxic) lines of therapy.MethodsRetrospective unicenter analysis was performed on eleven patients between 54 and 84 years of age on metronomic cyclophosphamide for bone marrow carcinomatosis in metastatic castration-resistant prostate cancer treated at a Swiss cancer center between 2014 and 2023.ResultsEleven patients received metronomic cyclophosphamide for varying periods of time; the majority had severe cytopenias (especially thrombocytopenias). Partially hematologic stabilization was achieved with administration of further systemic therapies.ConclusionOur case series demonstrates that the use of metronomic cyclophosphamide allows hematologic stabilization for months, benefiting patients who had already received all available therapies for metastatic castration-resistant prostate cancer. Alternatively, it may act as bridging therapy to allow consecutive administration of more toxic therapies with proven survival benefit.

Transfusion needs after CAR T-cell therapy for large B-cell lymphoma: predictive factors and outcome (a DESCAR-T study)

AbstractChimeric antigen receptor (CAR) T-cells targeting CD19 have been approved for the treatment of relapse/refractory large B-cell lymphoma. Hematotoxicity is the most frequent CAR T-cell–related adverse event. Transfusion support is a surrogate marker of severe cytopenias. Transfusion affects patients’ quality of life, presents specific toxicities, and is known to affect immunity through the so-called transfusion-related immunomodulation that may affect CAR T-cell efficacy. We analyzed data from 671 patients from the French DESCAR-T registry for whom exhaustive transfusion data were available. Overall, 401 (59.8%) and 378 (56.3%) patients received transfusion in the 6-month period before and after CAR T-cell infusion, respectively. The number of patients receiving transfusion and the mean number of transfused products increased during the 6-month period before CAR T-cell infusion, peaked during the first month after infusion (early phase), and decreased over time. Predictive factors for transfusion at the early phase were age >60 years, ECOG PS ≥2, treatment with axicabtagene ciloleucel, pre–CAR T-cell transfusions, and CAR-HEMATOTOX score ≥2. Predictive factors for late transfusion (between 1 and 6 months after infusion) were pre–CAR T-cell transfusions, CAR-HEMATOTOX score ≥2, ICANS ≥3 (for red blood cells [RBC] transfusion), and tocilizumab use (for platelets transfusion). Early transfusions and late platelets (but not RBC) transfusions were associated with a shorter progression-free survival and overall survival. Lymphoma-related mortality and nonrelapse mortality were both increased in the transfused population. Our data shed light on the mechanisms of early and late cytopenia and on the potential impact of transfusions on CAR T-cell efficacy and toxicity.

Comparative efficacy and hematologic safety of different dosages of JAK inhibitors in the treatment of myelofibrosis: a network meta-analysis.

Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by bone marrow fibrosis associated with substantial morbidity and mortality. The therapeutic landscape for MF has advanced with the development of Janus kinase inhibitors (JAKis) like ruxolitinib (RUX), fedratinib (FED), pacritinib (PAC), and momelotinib (MMB), aiming to alleviate symptoms and enhance patient comfort. A network meta-analysis was conducted to assess the efficacy and safety of eleven JAKi treatment regimens across nine randomized controlled trials (RCTs) with a total of 2340 participants. Outcomes were evaluated in terms of spleen volume reduction (SVR), total symptom score reduction (TSSR), hematological safety profiles, and overall survival (OS). RUX and MMB were superior in achieving SVR and TSSR, with significant dose-response relationships observed. PAC and MMB were associated with a decreased risk of grade 3/4 anemia and thrombocytopenia compared to other JAKis. However, no substantial benefits in OS were observed with newer JAKis compared to RUX. The poorer OS outcomes with certain PAC dosages were likely influenced by baseline patient characteristics, particularly severe cytopenias. The introduction of JAKis significantly changed the treatment of MF. This meta-analysis reaffirms the core role of RUX and positions MMB as a potentially powerful alternative for treating symptoms and reducing spleen size. Meanwhile, MMB and PAC have a positive effect on anemia in MF while FED is more tolerable for patients with thrombocytopenia. However, it should be noted that these results are influenced by baseline patient characteristics, particularly cytopenias, which affects both management and overall survival. Therefore, there is an urgent need for personalized dosing strategies to optimize the balance between efficacy and safety, with careful consideration of patient-specific factors. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023424179.

Clinical impacts of severe thrombocytopenia in the first cycle of azacitidine monotherapy and cytogenetics in patients with myelodysplastic syndrome: The Kyoto Conditional Survival Scoring System.

Azacitidine (AZA) has been one of the standard treatments for transplantation-ineligible patients with myelodysplastic syndrome (MDS); however, hematological toxicities frequently cause treatment interruption in the early phase of the therapy. The present study conducted a multicenter retrospective study to investigate the prognostic impacts of various factors, including factors included in the Revised International Prognostic Scoring System (IPSS-R) and severe cytopenia in the early phase of AZA monotherapy in 212 patients with MDS. Severe cytopenia was evaluated after the initiation of therapy by absolute neutrophil counts on the 29th day after AZA (ANC29) initiation, and red cell concentrates (RCC) and platelet concentrate (PC) transfusion units required within 28 days from the start of AZA, designated in the present study as RCC28 and PC28, respectively. The survival period was determined from the 29th day of AZA treatment to death from any cause as the conditional survival period after the first cycle of AZA (CS-AZA1). Multivariate analysis demonstrated that severe thrombocytopenia defined by >30 units of PC28 and very poor risk cytogenetics according to IPSS-R were independent prognostic factors for CS-AZA1. The Kyoto Conditional Survival Scoring System was subsequently developed by incorporating severe thrombocytopenia defined by PC28 and very poor risk cytogenetics, which successfully stratified the risks of the patients in CS-AZA1. In conclusion, extreme PC transfusion dependency during the first cycle of AZA and very poor risk cytogenetics are important prognostic factors in AZA monotherapy for MDS.