Severe Cytopenia Research Articles

Evidence of NF-ΚB Pathway Activation in Patients with Advanced, High Molecular Risk Myelofibrosis

Evidence of NF-ΚB Pathway Activation in Patients with Advanced, High Molecular Risk Myelofibrosis

Cyclophosphamide Induces Durable Molecular and Clinical Responses in Patients with Relapsed T-Large Granular Lymphocytic Leukemia (T-LGLL)

T-cell large granular lymphocytic leukemia (T-LGLL) is a clonal proliferation of cytotoxic T-lymphocytes that can result in severe cytopenias. The management of T-LGLL is immune-suppressive therapy, with methotrexate (MTX), cyclophosphamide (Cy), and cyclosporine (CsA) serving as primary frontline agents. While MTX has been the main front line agent to treat T-LGLL, overall response rates (ORR) are less than 40%, with complete response (CR) rates of only 5%. Data from the ECOG5998 (E5998) prospective trial and French cohort studies suggest an improved response with Cy in the 2 nd line setting. Anecdotal evidence suggests that Cy may eradicate the T-LGLL clone, producing complete molecular remission (CMR), which has not been observed with MTX or CsA. The degree to which a CMR can be attained and the lengths of such remissions with Cy remains unknown, particularly in the relapsed setting. We evaluated patients treated with Cy, to assess the duration of response and degree of CMR.We retrospectively evaluated patients treated for T-LGLL with oral Cy. Diagnosis of was based on 2016 World Health Organization Criteria. Patients needed a CD3+ CD8+ population on flow cytometry ≥500 cells/mm 3 and a positive monoclonal T-cell receptor (TCR) by PCR or restriction of TCR-Vbeta on flow cytometry. TCR-Vbeta rearrangement was deemed positive if one or more clone was detected in ≥10% of events. Disease response was defined by the E5998 study criteria. CMR was defined as CR by E5998 criteria and clearance of the TCR PCR gene rearrangement or TCR-VBeta flow cytometry. Time to response (TTR) was measured as time from start of Cy until partial response (PR) or CR, with patients who failed to respond being censored at the end of Cy treatment. Leukemia-free survival (LFS) in patients responding to Cy was measured as time from start of Cy until progression. Patients without progression were censored at last follow up. TTR and LFS were compared across variables using Kaplan-Meier curves with median survival and 95% confidence intervals.A total of 25 patients, with a mean duration of Cy treatment of 8 months, and median follow up time of 19 months, were included in this analysis. Patients were started on 50 mg daily for 2 weeks and then increased to 100 mg if tolerated. Three patients (12%) were treated with Cy as 1 st line, 14 (56%) as 2 nd line, 5 (20%) as 3 rd line, and 3 (12%) as 4 th line. Of the 3 patients that received Cy as 1 st line, none had a response. All refractory patients received MTX prior to Cy. Of the 22 refractory patients, 14 (64%) had a response (6 CR, 8 PR), 7 patients had no response, and 1 could not be determined due to development of multiple myeloma. Of the 6 patients that attained a CR, 50% had a CMR. The median TTR (CR or PR) was 6 months (95% CI: 4-7) while median time to PR was 9 months and median time to CR was 7 months. The median time to CMR was 11 months. In patients that achieved a response, median follow up time was 27 months, with a median LFS of 24 months. Median LFS for those who attained a PR was 20 months, while the median LFS for those who attained a CR was not reached as none progressed (Figure). The median follow-up for patients with a CMR was 17 months with LFS having not been reached due to no progression. There was no significant impact of age, gender, or presence of rheumatoid arthritis (RA) on LFS. Males (48%) had a shorter TTR compared to females (52%) (5 vs 7 months; p=0.05). Patients with RA (28%) also trended towards a shorter TTR (p=0.07).Herein, we demonstrate that patients treated for relapsed T-LGLL with Cy can attain durable remissions, with a prolonged response. Of particular interest is that no patients who attained a CR have relapsed, showing that durable remission is achievable, while no patients that received Cy as 1 st line had a response. Further, in patients that achieved a CR, 50% achieved a CMR which has not been previously demonstrated in the relapsed setting. While limited in cohort size, and additional follow up needed, these data suggest that Cy can produce long term remissions in patients with relapsed T-LGLL and induce CMR. While we demonstrate that CMR is attainable in the relapsed setting, the impact of this on long term disease control compared to clinical CR is unclear. Therefore, we recommend that CMR be used as an endpoint in future studies, particularly prospective trials, to evaluate response to treatment. These data clearly demonstrate that Cy is effective in the setting of relapsed T-LGLL and can induce long term disease control. [Display omitted] DisclosuresBrammer: Seattle Genetics: Speakers Bureau; Kymera Therapeutics: Consultancy; Celgene: Research Funding.

Myelodysplastic Syndromes: Have You Seen Your Patient Beyond His Hemoglobin?

Background: Palliative care (PC) is a patient-centered care model that aims to relief suffering by establishing a plan of care that integrates physical, psychosocial, cultural, familial and spiritual issues during the course of disease's evolution. Thus, PC applies not only to patients who face a diagnosis beyond the possibility of cure, but to all those who experience significant symptoms throughout the course of the disease. Myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid neoplasms characterized by cytopenias and an elevated risk of developing acute leukemia. As MDS display a wide genetic heterogeneity, patients have a variable clinical presentation, ranging from asymptomatic patients to individuals with severe cytopenias and high-risk disease. MDS are more prevalent in the elderly population, which usually experience several morbidities; thus, MDS frequently lead to notable symptoms and deterioration of quality-of-life, making most of them eligible to PC in addition to standard hematologic care. In spite of that, previous studies demonstrated that patients with hematologic malignancies appear to have restricted access to PC services and receive more aggressive therapies at the end of life.Aims: To evaluate eligibility criteria for PC in a cohort of MDS patients and correlate with clinical and laboratory data.Methods: Clinical and demographic data of MDS patients were collected through interviews using a standardized questionnaire: time from diagnosis, number of morbidities, need for seeking the emergency during the last 12mo, delirium events, wounds, dysphagia, recurrent falls, adverse events to medication, quality of communication with the medical team, fears regarding the disease and its complications, religious support, age, gender, monthly household income and level of schooling. Specific PC scores were also applied: Edmonton Symptom Assessment Scale (ESAS) and Palliative Performance Scale (PPS). Clinical and laboratory data were collected: hemoglobin (Hb), platelet and neutrophil counts, Revised International Prognostic Scoring System (IPSS-R) and transfusion burden. Statistical univariate and multivariate analysis were performed. P value <.05 was considered statistically significant. This research was approved by the Institutional and National Review Board; written informed consent was obtained from all subjects.Results:Thirty-six patients were evaluated: median age 68y (21-90), sex 16F/20M. According to ESAS, tiredness and anxiety were the most relevant symptoms in MDS patients [median (min-max)]: pain 0 (0-10), tiredness 4.5 (0-10), drowsiness 1.5 (0-10), nausea 0 (0-7), lack of appetite 0 (0-10), shortness of breath 0 (0-10), depression 0 (0-10), anxiety 3.5 (0-10), best wellbeing 2.5 (0-8). Younger patients (<60y, n=10) had a worse ESAS for best wellbeing (5 (2-8)) when compared to older individuals (≥60y, n=26): (2 (0-7)), p=.007, and tended to have worse ESAS scores for tiredness: 8.5 (0-10) vs 3.5 (0-10), p=.56. Importantly, ESAS for tiredness was not correlated to Hb levels, the number of red blood cell transfusions nor with IPSS-R (all p>.05). ESAS for drowsiness was significantly higher in patients with two (5 (0-10)) and ≥three morbidities (3 (0-8) vs those with only one morbidity (0 (0-10)): p=.01 and p=.03, respectively. ESAS for best wellbeing was better in individuals with higher household income 0 (0-0) vs patients with lower financial resources 3 (0-7), p=.04). PPS median was 90% (60-100%) and negatively correlated with transfusion burden (r=0.407, p=.01) and with the need for seeking the emergency in the past 12mo (r=-0.332, p=.04). Finally, despite facing a potential life-threatening disease, 94.4% of the patients reported that their doctors had never talked to them about aspects related to end-of-life care. Conversely, 75% of them reported fears and doubts regarding this phase.Conclusions: In our casuistic of MDS patients, tiredness was the most important symptom observed. Surprisingly, it was not correlated with Hb levels and transfusion burden, suggesting that Hb levels alone should not be used to justify symptoms. The number of morbidities and lower household income also impacted ESAS scores. Finally, a great part of the patients revealed miscommunication with their hematologists regarding end-of-life planning. Our data indicate that MDS patients might benefit from a PC multidisciplinary team approach. DisclosuresCosta: Novartis: Consultancy.

Long-Term Treatment with Pacritinib on a Compassionate Use Basis in Patients with Advanced Myelofibrosis

Long-Term Treatment with Pacritinib on a Compassionate Use Basis in Patients with Advanced Myelofibrosis

A Phase II Study of 5-Azacytidine (AZA) and Venetoclax As Maintenance Therapy in Patients with Acute Myeloid Leukemia (AML) in Remission

A Phase II Study of 5-Azacytidine (AZA) and Venetoclax As Maintenance Therapy in Patients with Acute Myeloid Leukemia (AML) in Remission

Interim Analysis of the Randomized Phase 1b/3 Study Evaluating the Safety and Efficacy of Tazemetostat Plus Lenalidomide and Rituximab in Patients with Relapsed/Refractory Follicular Lymphoma

Interim Analysis of the Randomized Phase 1b/3 Study Evaluating the Safety and Efficacy of Tazemetostat Plus Lenalidomide and Rituximab in Patients with Relapsed/Refractory Follicular Lymphoma

Decreased Chimeric Antigen Receptor T-Cell Efficacy with Severe or Prolonged Post-Infusion Cytopenias

INTRODUCTIONProlonged cytopenias following Chimeric Antigen Receptor (CAR) T-cell therapy are common. The cytopenias are mainly due to the genotoxic effects of conditioning chemotherapy and systemic inflammatory insult to hematopoietic stem and progenitor cells from CAR T-cell activity. Tocilizumab, an anti-IL6 receptor antibody, reduces cytokine release syndrome (CRS), a clinical manifestation of CAR T inflammatory toxicity. We sought to determine if prophylactic tocilizumab can decrease the risk and/or severity of CRS. We secondarily hypothesized that decreasing the inflammatory injury to hematopoietic stem cells could improve bone marrow function after CAR T. Lastly, we analyzed the association between cytopenias and CAR T efficacy generally.METHODSIn this single-institution, retrospective cohort study, we examined all patients who had received axicabtagene ciloleucel for relapsed/refractory diffuse large B cell lymphoma (DLBCL) between March 2018 and April 2021 (Table 1). Each patient was evaluated for prolonged cytopenias, defined as requiring granulocyte-colony stimulating factor (G-CSF), red blood cell or platelet transfusion beyond day 28 after CAR T infusion. After CAR T infusion, no patient was given any anti-lymphoma therapy prior to collection of blood count data. We compared response to CAR T 6 weeks post-infusion, progression-free survival (PFS), and overall survival (OS) for patients with and without prolonged cytopenias. A univariate regression analysis was performed, and between group differences were calculated using Chi-squared, Fisher's exact tests, and Cox Proportional hazard regression model. Kaplan-Meier and log-rank analyses were used to evaluate the PFS and OS. We also compared patients who did and did not receive prophylactic tocilizumab 36 hours after CAR T infusion for differences in prolonged cytopenias, PFS, OS, and development and severity of CRS and neurotoxicity. CRS and neurotoxicity were graded using the ASTCT consensus grading system.RESULTSThe study included 54 patients, 31 (57.4%) met criteria for prolonged cytopenias. 1 (1.9%) patient died of progressive disease prior to day 28 and was excluded from analysis. All patients who died in this study did so on the basis of progressive lymphoma. Likelihood of no response to CAR T at 6 weeks was higher in patients who needed G-CSF support past day 28 (HR 2.20, p = 0.048), had a hemoglobin nadir less than 8 g/dL (HR 2.61, p = 0.031), were still requiring platelet transfusions after day 28 (HR 2.26, p = 0.038), or had a platelet nadir less than 25,000 per µl during the first 28 days (HR 4.01, p = 0.013, Table 2). For patients who had neutrophil counts below the median at day 28, the median PFS was 4.5 months vs. 17.9 months (HR 2.07, p = 0.035) compared to those above the median. In patients with a platelet nadir less than 25,000 per µl or below the median at day 28 (Figure 1), the median PFS was 4.5 months vs. not reached (HR 3.12, p = 0.003) and 3.9 months vs. not reached (HR 3.85, p = 0.0004) respectively. Median OS was 9.44 months in patients who required G-CSF support past day 28 (HR 2.79, p = 0.022) vs. not reached in those who didn't receive G-CSF past day 28. For patients with an ANC below the median on day 28, median OS was 19.87 months vs not reached (HR 2.65, p = 0.022). In patients with a platelet nadir less than 25,000 per µl or below the median at day 28, the median OS were 7.8 months vs not reached (HR 3.72, p = 0.006) and 7.79 months vs not reached (HR 3.39, p = 0.007) respectively. Among patients who received prophylactic tocilizumab, 12 (54.5%) had prolonged bone marrow failure compared to 19 (57.6%) among those who did not (p = 0.82). PFS, OS, and rates and severity of CRS and neurotoxicity did not differ between the prophylactic tocilizumab groups.CONCLUSIONSIn this study of patients with relapsed/refractory aggressive B-cell lymphomas receiving a CD28 domain-containing CAR T product, severe short-term or prolonged cytopenias were associated with an increased risk of lymphoma progression and death. This effect was not ameliorated by administration of prophylactic tocilizumab, which also did not affect the development or severity of CAR T inflammatory toxicities. Further study is required to determine the mechanistic nature of the relationship between post-infusion cytopenias and CAR T efficacy. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Severe Anemia Is Associated with a Risk of Infection in Patients with Myelodysplastic Syndromes

Introduction: Infections are a well-recognized complication in patients (pts) with myelodysplastic syndromes (MDS) that contribute substantially to the morbidity and mortality particularly in pts suffering from neutropenia. Neutropenia and other immune defects including impaired neutrophil function have been reported to be predisposing factors for severe infections. Furthermore, some of the therapies may worsen neutropenia and lead to an additional risk factor to develop infectious episodes. Since infectious complications are no primary endpoint in clinical trials epidemiological data on infections in large cohorts of MDS pts is sparse.Methods: We performed a retrospective analysis of 3.787 MDS-patients from the Duesseldorf MDS Registry who were diagnosed between 1980 and 2018. Infectious complications were defined as clinical symptoms of infection associated with the need for antibiotic and/or antifungal therapy, and/or the isolation of a pathogen and/or an identifiable site of infection by physical examination. Infectious episodes were categorized as fever of unknown origin, microbiologically or clinically documented infection.Results: Amongst our study cohort, 42% of the pts suffered from at least one infectious complication of any type during the course of their disease. Most infectious diseases were of bacterial origin (34.7%) and in 17% a pathogen was isolated. Pneumonia was the most common site of infection (64%). Pts who experienced at least one infectious episode had a significant poorer overall survival (OS) than pts without such events (21 vs 37 months, p<0.001). Pts with a higher risk disease according to the IPSS-R had fewer infections during the course of the disease than pts with a lower-risk MDS (487 total infections vs 1481, p<0.001). Nevertheless, the presence of any infectious episode lead to an inferior OS in lower-risk (40 vs 29 months, p<0.001) as well as in higher-risk disease (38 vs 24 months, p=0.006).In univariate analyses comparing pts who had no infections versus those who had one or more, pts with older age (>65 years) tended to have a higher incidence of infectious episodes (p<0.001). In addition, patients older than 65 suffering from infections had a shorter OS than patients who did not experience an infectious complication. The difference in OS was highly significant with 16 months for pts suffering from infectious complications compared to 24 months (p<0.001). Likewise, an excruciating higher incidence of infections was noted in MDS pts compared to infections incidence in a non-MDS population in Germany. The risk of a 65-year-old or older MDS pt to suffer from pneumonia was 6.9 times higher compared to a non-MDS pt of the same age.We found a highly significant negative correlation between the depth of cytopenia in all three myeloid lineages and the presence of infections (p<0.001), suggesting that patients with severe cytopenia suffer from infectious episodes more frequently. However, pts with an isolated neutropenia having an absolute neutrophil count below a threshold of 0.8 × 10 9/L and suffering from infectious episodes had no inferior OS than neutropenic pts without any infection (25 vs 32 months, p=0.583). Pts with isolated severe thrombocytopenia with a platelet count <50 × 10 9/L had a similar OS of 26 months for pts with infectious complications. The difference in OS between pts with and without infections was even more pronounced in this group (26 vs 48 months, p=0.002). Still, a low hemoglobin (Hb) level <9g/dl appeared to be the most significant risk factor for pts with infections, resulting in the poorest OAS of only 17 months in pts with isolated anemia suffering from infections. In multivariate analyses, we found that Hb <9g/dl, followed by ANC <0.8 × 10 9/L, were independently associated with the risk to suffer from an infection during the disease. In addition, a Hb <9g/dl was the most important blood count parameter with regard to OS when compared to platelets <50 × 10 9/L, and ANC <0.8 × 10 9/L.Conclusion: The incidence of infections significantly increases in pts with advanced age. MDS-pts in general are more vulnerable for infection-related morbidity and mortality than non-MDS-pts. Low hemoglobin and platelet counts were both found to be associated with a worse prognosis compared to low neutrophil counts. The appearance of at least one infectious episode leads to an inferior DisclosuresNachtkamp: Jazz: Speakers Bureau; bsh medical: Speakers Bureau; Celgene: Other: Travel Support. Kobbe: Celgene: Research Funding. Gattermann: Celgene: Honoraria; Takeda: Research Funding; Novartis: Honoraria. Germing: Novartis: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria, Other: advisory activity, Research Funding; Janssen: Honoraria.

Bendamustine Is a Safe and Effective Regimen for Lymphodepletion before Tisagenlecleucel in Patients with Large B-Cell Lymphomas

Bendamustine Is a Safe and Effective Regimen for Lymphodepletion before Tisagenlecleucel in Patients with Large B-Cell Lymphomas

Low-Dose Weekly Decitabine and Venetoclax in TP53-Mutated Myeloid Malignancies

Decitabine (Dec) and Azacitidine (Aza) that target DNA methyltransferase 1 (DNMT1) are hypomethylating agents (HMAs) approved to treat acute myeloid leukemia (AML) in combination with Venetoclax (Ven). The combination is also used to treat high-risk myelodysplastic syndromes, especially TP53-mutated (TP53mut) cases in which responses to HMA alone are short-lived. In most patients (pts), however, myelosuppression from treatment leads to frequent Ven duration and/or dose-reductions, and/or cycle delays. An approach to decrease HMA-mediated myelosuppression but maintain S-phase dependent DNMT1-targeting, evaluated in a previous clinical trial (https://doi.org/10.1111/bjh.16281), is to administer noncytotoxic doses/concentrations of Dec (0.2 mg/kg; ~5 mg/m 2) by a frequent-distributed schedule of 1X/week. An approach to decrease Ven mediated myelosuppression but maintain cooperation with HMA, shown in pre-clinical studies, is to administer a single-dose prior to HMA. Ven can depolarize mitochondrial membranes; mitochondrial membrane-potential is essential to function of the mitochondrial enzyme DHODH that produces cytidine/deoxycytidine that competes with HMA in cells. Thus, Ven prior to HMA dosing temporarily inhibits de novo pyrimidine synthesis, to counter a major mechanism of resistance to HMA in MDS/AML, without suppressing normal myelopoiesis (https://doi.org/10.1182/blood-2020-143200). We conducted a retrospective analysis of all pts with TP53mut MDS or AML treated with weekly Ven and low-dose subcutaneous Dec at our institution. We analyzed the characteristics of these pts, response to therapy, and outcomes using standard descriptive statistics. Mutational testing was performed using a commercial next-generation sequencing (NGS) panel.Five pts, 3 male and 2 female, with TP53mut MDS or AML were treated with weekly Ven 400 mg on D1 and subcutaneous Dec 0.2 mg/kg on D2, administered weekly in 28 day cycles. Two pts had MDS (1 de novo, 1 treatment related) and 3 pts had AML (1 de novo, 2 secondary from prior MDS). Four pts (80%) received the treatment in frontline, all with poor performance status (PS), and 1 pt (20%) had R/R disease. Median age at diagnosis was 79 years [41-82]. The only young pt had prolonged severe cytopenias after 1 cycle Dec standard dosing during the peak of COVID-19 pandemic so was switched to this regimen. Of the 4 frontline treated pts, 2 pts had high-risk MDS, and 2 pts had adverse risk AML. The R/R pt had high-risk MDS transformed to AML that was refractory to 2 prior lines of therapy: standard Aza/Ven x5 cycles, then standard Vyxeos. Disease cytogenetics were complex in all pts. 60% (3/5) pts had sole TP53mut on NGS, with median variant allelic frequency (VAF) 48% [28-79]. 80% (4/5) pts were transfusion dependent prior to treatment. Median time to initiating therapy was 7 days from initial or refractory diagnosis [3-59] and median follow-up was 7.8 months (mo) [2.9-11.4]. The overall response rate (ORR) was 100%: 4/4 frontline pts had complete remissions (CR), and the 1 R/R pt achieved morphologic leukemia-free state (MLFS). Median time to best response was 2.9 mo. 50% (2/4) pts became transfusion independent. 40% (2/5) pts lost their TP53mut at best response, and another 40% (2/5) pts had significant reductions (83% and 38%) in TP53 mut VAF. The regimen was well tolerated with no pts stopping therapy due to adverse effects (AE) . AE included G3/G4 neutropenia (80%), G1 thrombocytopenia (40%), nausea (20%), fatigue (20%), lower extremity edema (20%), pneumonia (60%), and neutropenic fever (20%) with a median of 1 unplanned hospitalization per pt during follow-up. 60% (3/5) pts remain in CR on continued therapy for a median of 7.8 mo [7.2-9.4] thus far. One pt underwent allogeneic stem cell transplantation, however, died 11.4 mo after conditioning due to transplant related mortality. The R/R pt died after being lost to follow-up 2.9 mo after therapy initiation. No pt had measurable relapse during follow-up.Combination weekly Ven with subcutaneous low-dose Dec is well tolerated yielding high rates of clinical and molecular response in pts with TP53mut MDS/AML. Although small, this case-series extends previous clinical trial proof-of-activity of non-cytotoxic DNMT1-targeting to a high-risk, poor PS, historically chemorefractory patient population. The regimen allowed frequent, sustained exposure to therapy often not possible with standard HMA/Ven regimens. [Display omitted] DisclosuresShastri: Kymera Therapeutics: Research Funding; Guidepoint: Consultancy; GLC: Consultancy; Onclive: Honoraria. Gritsman: iOnctura: Research Funding. Feldman: Glycomimetics: Current Employment, Current holder of stock options in a privately-held company. Verma: Celgene: Consultancy; Acceleron: Consultancy; Novartis: Consultancy; Stelexis: Consultancy, Current equity holder in publicly-traded company; Eli Lilly: Research Funding; Curis: Research Funding; Medpacto: Research Funding; Incyte: Research Funding; GSK: Research Funding; BMS: Research Funding; Stelexis: Current equity holder in publicly-traded company; Throws Exception: Current equity holder in publicly-traded company. Saunthararajah: EpiDestiny: Consultancy, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

Clinical, Immunological, and Molecular Variability of RAG Deficiency: A Retrospective Analysis of 22 RAG Patients

PurposeWe described clinical, immunological, and molecular characterization within a cohort of 22 RAG patients focused on the possible correlation between clinical and genetic data.MethodsImmunological and genetic features were investigated by multiparametric flow cytometry and by Sanger or next generation sequencing (NGS) as appropriate.ResultsPatients represented a broad spectrum of RAG deficiencies: SCID, OS, LS/AS, and CID. Three novel mutations in RAG1 gene and one in RAG2 were reported. The primary symptom at presentation was infections (81.8%). Infections and autoimmunity occurred together in the majority of cases (63.6%). Fifteen out of 22 (68.2%) patients presented autoimmune or inflammatory manifestations. Five patients experienced severe autoimmune cytopenia refractory to different lines of therapy. Total lymphocytes count was reduced or almost lacking in SCID group and higher in OS patients. B lymphocytes were variably detected in LS/AS and CID groups. Eighteen patients underwent HSCT permitting definitive control of autoimmune/hyperinflammatory manifestations in twelve of them (80%).ConclusionWe reinforce the notion that different clinical phenotype can be found in patients with identical mutations even within the same family. Infections may influence genotype–phenotype correlation and function as trigger for immune dysregulation or autoimmune manifestations. Severe and early autoimmune refractory cytopenia is frequent and could be the first symptom of onset. Prompt recognition of RAG deficiency in patients with early onset of autoimmune/hyperinflammatory manifestations could contribute to the choice of a timely and specific treatment preventing the onset of other complications.

Efficacy of lenalidomide in the treatment of myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN-U) with the presence of deletion 5q– and trisomy 8+

Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are very rare clonal myeloid characterized by the simultaneous presence of both of erythrocytic and/orgranulocytic dysplasia with myeloproliferative features. The etiology of the disease remains unknown. The MDS/MPN group is made up of five disorders: chronic myelomonocytic leukemia, atypical chronic myeloid leukemia, juvenile myelomonocytic leukemia, MDS/MPN ring sideroblasts with thrombocytosis and MDS/MPN, un classifiable (MDS/MPN-U). MDS/MPN-U remains the leastcharacterized entity. It accounts less than 5% of all myeloid disorder. The reare currently no well-established diagnostic criteria. The disease is heterogeneous with outclear management strategies. The aim of thispaperis to present a case of a 59-year-old female patient diagnosed with MDS/MPN-U with deletion 5q– and trisomy 8+, whom lenalidomide 10 mg daily has been used as monotherapy. The disease has initially manifested as severe cytopenias, multiple transfusions of blood preparations were required. Currently patientis in the 9th month of treatment. Hemoglobin, platelets and white blood cells returned to normal. The patient completely became independent of transfusion of red blood cell concentrates. No adverse events were observed.

P14.11 Severe treatment-induced myelosuppression is more frequent in female malignant glioma patients and associated with reduced overall survival

Abstract BACKGROUND An association of treatment-related myelotoxicity with female gender has been previously suggested. However, a systematic analysis of the prognostic relevance of radiochemotherapy-related cytopenia involving the different blood cell lineages is lacking. MATERIAL AND METHODS We retrospectively analyzed cytopenia during temozolomide-based concomitant radiochemotherapy (RCT) in 493 glioma patients. Histological grading, molecular pathology, surgical procedures and median overall survival (OS) were recorded. The extent of cytopenia was correlated with gender and outcome. RESULTS Treatment-induced severe cytopenia (leuko-, lympho-, neutro- and thrombocytopenia) occurred much more often in female than in male glioma patients (40.8 vs. 13.9%, p-value &amp;lt;0.0001). In female patients with IDH-wildtype high-grade astrocytomas there was a negative correlation of severe leuko-, lympho- and thrombocytopenia during temozolomide RCT with OS (36 vs. 54, 37 vs. 54 and 36 vs. 57 weeks, respectively; all p-values &amp;lt;0.05). In male patients there was also a trend for this unfavorable effect. Additionally, severe cytopenia correlated with reduced temozolomide dose exposure during RCT (all p-values &amp;lt;0.05 in total cohort) and reduced dose exposure was independently associated with worse OS (p-values &amp;lt;0.05 in the total and female cohort). CONCLUSION Our data confirm that women are at higher risk for treatment-induced cytopenia during RCT which is associated with a significant decrease in OS. From our data, it appears plausible that reduced temozolomide dose exposure during RCT is at least in part responsible for this finding. Immunosuppression of patients with severe cytopenia may be an independent contributor to adverse outcome.

Immune dysregulation syndrome with cytotoxic T‐lymphocyte antigen 4 mutation showing multiple central nervous system lesions

Background Haploinsufficiency of cytotoxic T-lymphocyte antigen 4 (CTLA4) is a primary immunodeficiency disease characterized by hypogammaglobulinemia and diverse autoimmune disorders. Although central nervous system lesions have been described in patients with CTLA4 insufficiency, there have been few reports in the field of neurology. Case presentation A 23-year-old man was referred to Saga University Hospital (Saga, Japan) with dizziness and abnormal head magnetic resonance imaging showing hyperintensity in the left cerebellar hemisphere. He was diagnosed with immune thrombocytopenia and hypogammaglobulinemia at age 8 years. He had repeated mild upper respiratory infections. Neurological events had occurred four times, with a long spinal lesion extending over three vertebral segments. High-dose intravenous methylprednisolone was effective for acute attacks, and low-dose prednisolone prevented relapses for 7 years. When he reached the age of 37 years, he developed severe diarrhea and immune cytopenia, and lost 6 kg in half a year. It was suspected that the patient had primary immunodeficiency due to his history of recurrent infections, hypogammaglobulinemia and severe diarrhea. Genome sequencing showed a heterozygous CTLA4 variant in exon 2. Abatacept therapy with prednisolone and cyclosporine was effective for diarrhea and autoimmune cytopenia. Conclusions A patient with CTLA4 variant might develop multiple central nervous system lesions including longitudinally-extended spinal cord lesions. As there is effective targeted immunotherapy, a complete immunological work-up is required for early diagnosis when a patient presents with central nervous system lesions and multi-organ symptoms.

MM-146: A Real-World Study of Bendamustine Therapy in a Very Heavily Pre-Treated Population of Multiple Myeloma Patients

<h3>Context</h3> Bendamustine is an alkylating agent with activity against multiple myeloma (MM), and in UK clinical practice, its use is predominately limited to patients who have no other therapeutic options. <h3>Objective</h3> Assessment of efficacy and toxicity of bendamustine in the real-world setting. <h3>Design</h3> Retrospective case-review study including patients commenced on bendamustine Jan. 2016–Jan. 2021 (follow-up until May 2021). <h3>Setting</h3> A UK tertiary MM center. <h3>Patients</h3> Twenty-nine patients received bendamustine and corticosteroids, 14 in combination with thalidomide, with a median of 5 prior lines of therapy. Cytogenetic data were available in 19; 95% (18/19) had high-risk-disease at their most recent assessment prior to commencing bendamustine. <h3>Interventions</h3> Bendamustine was given at 60 mg/m² D1,2; dexamethasone/methylprednisolone weekly; thalidomide 50–200mg daily (28-day cycle). <h3>Main Outcomes Measures</h3> Overall response rate (ORR, ≥partial response, PR), clinical benefit rate (CBR, ≥minimal response, MR), progression-free survival (PFS), overall survival (OS), and toxicity. <h3>Results</h3> The median PFS of the cohort was 1.8 months (median follow-up 13 months), and the OS was 4.8 months. Of the 29 patients, 23 were assessable for response (4 completed <1 cycle, 2 had a secretory disease). The ORR was 26% (6/23, all PR), and the CBR was 39% (9/23). Achievement of ≥PR was associated with longer PFS and OS (median PFS 5.3 months <i>vs</i> 1.8 months, p=0.10; OS 14 months <i>vs</i> 4.1 months, p=0.15). Toxicity assessment was performed in the whole cohort. Twenty-eight percent (8/29) had received ≥5 cycles at time of data cut-off and 3 remain on treatment. The reason for stopping therapy was progression in 65% (17/26) and death in 23% (6/26). One patient stopped treatment due to significant cytopenias, 1 due to frailty, and 1 because bendamustine had been used as a bridge to alternative therapy. Thirty-four percent (10/29) only completed ≤1 cycle of therapy, 3 died, 6 progressed, and 1 had severe cytopenias. Fifty-five percent (16/29) required transfusion of platelets and/or red blood cells during their treatment. <h3>Conclusions</h3> In this very heavily pre-treated population, bendamustine was associated with an ORR of 26%, and the overall PFS and OS were short at 1.8 and 4.8 months, respectively. However, achieving ≥PR was associated with a longer PFS and OS (5.3 and 14 months, respectively), suggesting bendamustine may provide a therapeutic option for a subgroup of patients when no others are available.

&lt;i&gt;Ehrlichia chaffeensis&lt;/i&gt;&lt;i&gt;-&lt;/i&gt;associated Hemophagocytic Lymphohistiocytosis: A Case Series and Literature Review

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is an uncommon condition characterized by abnormal, excessive immune activation resulting in severe cytopenias from an uncontrolled inflammatory response. It can be primary/ familial or secondary/sporadic. Infections, particularly viral infections are a common cause of secondary HLH. HLH due to Human monocytic ehrlichiosis (HME) is very rare, hence we are reporting our cases. Objective: To review cases of Ehrlichia-associated HLH at our institution and perform a literature review regarding this entity. Methods: We reviewed cases of Ehrlichia-associated HLH for the previous two years at our institution (Carilion Clinic). We then performed a review of the published literature on it, using Pubmed. Results: Over the past two years, five cases of Ehrlichia-associated HLH were diagnosed at our hospital. The average age of the patients was 67 years with predominantly males. All the patients were pancytopenic, and a majority had abnormal liver function tests. Diagnosis of ehrlichiosis was made by serum polymerase chain reaction (PCR) assay on blood. Patients had further testing done because of lack of clinical improvement. All patients had significantly elevated ferritin levels. Bone marrow biopsy samples of all patients showed findings of hemophagocytosis. All, but one, patients were treated with doxycycline and a combination of etoposide and dexamethasone. Three patients recovered while two died. On review of medical literature, we found a total of only 36 cases of Ehrlichia-associated HLH, including our five cases. There were 19 adults and 17 children. Both population groups showed varying degrees of pancytopenia. Splenomegaly was relatively uncommon, seen in less than one-third of the patients. Ferritin and triglyceride levels were routinely elevated. Bone marrow biopsy showing hemophagocytosis was the confirmatory test in all patients. A significant number of patients, both adults and children, required a combination of doxycycline and chemotherapy (etoposide and dexamethasone) to achieve clinical cure. Children had a better prognosis than adults, with one child and four adults succumbing to their illness. Conclusions: Ehrlichia-associated HLH is a rare but emerging disease entity. In endemic areas, a high degree of suspicion is required to diagnose ehrlichiosis and HLH resulting from it. Early diagnosis and prompt initiation of treatment for HLH is key to a favorable outcome.

MiR-181c regulates MCL1 and cell survival in GATA2 deficient cells.

GATA2 is a transcription factor critical for hematopoiesis. Germline mutations in GATA binding protein 2 (GATA2) led to haploinsufficiency, severe cytopenias of multiple cell lineages, susceptibility to infections and strong propensity to develop myelodysplastic syndrome, and acute myeloid leukemia. Mechanisms of progressive cytopenias remain unclear. MicroRNA (miRNA) represents a unique mechanism of post-transcriptional gene regulation. In this study, miRNA profiles were evaluated and eight miRNAs were found to be differentially expressed (≥2-fold, P ≤ 0.05) in patient-derived cell lines (N=13) in comparison to controls (N=10). miR-9, miR-181a-2-3p, miR-181c, miR-181c-3p, miR-486-3p, and miR-582 showed increased expression, whereas miR-223 and miR-424-3p showed decreased expression. Cell death assays indicated that miR-181c potently induces cell death in lymphoid (Ly-8 and SP-53) and myeloid (HL-60) cell lines. miR-181c was predicted to target myeloid cell leukemia (MCL)1, which was confirmed by transfection assays, resulting in significantly reduced MCL1 mRNA and decreased live cell numbers. Bone marrow analysis of 34 GATA2 patients showed significantly decreased cellularity, CD34-positive cells, monocytes, dendritic cells, NK cells, B cells, and B cell precursors in comparison to healthy controls (N=29; P<0.001 for each), which was accompanied by decreased levels of MCL1 (P<0.05). GATA2 expression led to significant repression of miR-181c expression in transfection experiments. Conversely, knockdown of GATA2 led to increased miR-181c expression. These findings indicate that miR-181c expression is increased and MCL1 levels decreased in GATA2 deficiency cells, and that GATA2 represses miR-181c transcription. Increased miR-181c may contribute to elevated cell death and cytopenia in GATA2 deficiency potentially through down-regulation of MCL1.

New-Onset Severe Cytopenia After CAR-T Cell Therapy: Analysis of 76 Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia.

Although chimeric antigen receptor T (CAR-T) cell therapy has proven to be effective in treating relapsed or refractory B-cell hematological malignancies, severe hematological toxicities remain an intractable issue. This retrospective study assessed the characteristics and risk factors of new-onset severe cytopenia following CAR-T cell infusion in 76 patients with r/r acute lymphoblastic leukemia. The rates of new-onset severe cytopenia were high, including severe neutropenia (SN) (39/56, 70%), severe anemia (SA) (35/66, 53%), and severe thrombocytopenia (ST) (31/64, 48%). Comparatively, cohorts with higher cytokine release syndrome (CRS) grades had higher incidence of severe cytopenia with prolonged duration. Multivariable analyses showed that elevated maximum (max) lg D-dimer and delayed peak time of CRS are independent risk factors for SN recovery; increased max lg IL-10 and delayed CRS recovery are risk factors for SA; high max lg ferritin is a risk factor for ST; and longer period to CRS onset or CRS recovery and higher grade of CRS are risk factors for prolonged hematological toxicities. These observations led to the conclusion that profiles of CRS, including its duration, severity and serum markers are correlated to the incidence and recovery of new-onset severe cytopenia, prompting clinical intervention for post-CAR-T severe cytopenia.

Obinutuzumab (Gazyva) and High-Dose Methylprednisolone (HDMP) Combination for Patients with Chronic Lymphocytic Leukemia (CLL) - a Phase Ib/II Study

Obinutuzumab (Gazyva) and High-Dose Methylprednisolone (HDMP) Combination for Patients with Chronic Lymphocytic Leukemia (CLL) - a Phase Ib/II Study

Outcomes with CD34 stem cell boost for poor graft function after allogeneic hematopoietic stem cell transplantation for hematologic malignancies: A systemic review and meta-analysis.

e19021 Background: Poor graft function (PGF) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation (allo-HCT) characterized by severe multilineage cytopenia in the absence of mixed donor chimerism, relapse, or severe graft-vs-host disease (GVHD). We present a systemic review and meta-analysis aimed to assess the outcomes with stem cell boost (SCB) for PGF in adult allo-HCT patients. Methods: Following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, 752 articles were screened from 4 databases (PubMed, Embase, Cochrane, and Clinical trials.gov) using MeSH terms and keywords for “hematological malignancies”, “hematopoietic stem cell transplantation”, “CD34 antigen(s)” and “treatment outcome(s)” from the date of inception to Jan 2021. After excluding review, duplicate and non-relevant articles, we included 8 studies (1 prospective, 7 retrospective) reporting hematologic complete/overall response rate (CR/ORR), GVHD and overall survival (OS) after SCB for PGF after Allo-HSCT. Quality evaluation was done using the NIH quality assessment tool. Pooled analysis was done using the ‘meta’ package (Schwarzer et al, R programming language) and proportions with 95% confidence intervals (CI) were computed. Inter-study variance was calculated using Der Simonian-Laird Estimator. Results: We identified 217 patients who received SCB for PGF after allo-HCT. Median age, time since transplant and SCB dose were 48 (37-54) years, 133 (113-450) days and 3.43 (1.7-4.9) million CD34 cells/kg respectively. CR and ORR were 71% (95%CI 0.63-0.77, I216%) and 80% (95%CI 0.74-0.85, I20%) respectively. After median follow up of 41.5 (5-77) months, actuarial survival rate (ASR) was 54% (95%CI 0.48-0.61, I20%). OS was reported from 80% (1y) to 40% (9y) Acute and chronic GVHD incidence after SCB was 17% (95% CI 0.12-0.23, I2=0%) and 17% (95% CI 0.08-0.32, I2=72%, n=197) respectively, and 25% (95% CI 0.14-0.39, I2=63%, n=163) deaths were due to relapse (Table). Conclusions: CD34 SCB improves outcomes after PGF after allo-HSCT with acceptable toxicity profile. However, current literature lacks high-quality randomized evidence and there remains an unmet need for prospective studies to address optimal dosing and manipulation of SCB. Outcomes with SCB for PGF after allo-HCT (n=217).[Table: see text]