Panch, Sandhya R.

Abstract INTRODUCTION Immune checkpoint inhibitors (ICIs) have emerged as a cornerstone of cancer therapy. However, despite their efficacy, ICIs can cause a unique spectrum of autoimmune toxicities known as immune-related adverse events (irAEs). In contrast to irAEs involving other organ systems, hematologic irAEs such as ICI-associated immune thrombocytopenia (ICI-ITP) are less common. As a result, existing data on ICI-ITP are largely confined to isolated case reports, single-center case series, and pharmacovigilance databases lacking granular clinical data. To address this key knowledge gap, we sought to comprehensively characterize the incidence, risk factors, clinical features, treatments, and outcomes associated with ICI-ITP. METHODS We performed a multicenter cohort study of adult patients who initiated ICI therapy at 29 hospitals across 7 major cancer centers in 11 geographically diverse states in the US between 2016-2023. ICI-ITP was defined as a decline in platelet count to <100 x109/L in the absence of an alternative more plausible etiology of thrombocytopenia. Patients with hematologic malignancies were excluded, as were those who received cytotoxic chemotherapy within 30 days prior to thrombocytopenia onset. For each patient identified as having ICI-ITP, we collected data on demographics, comorbidities, medications, laboratory values, treatments, and outcomes. All data were extracted by manual chart review. To identify risk factors for ICI-ITP and to examine its association with death, for each case of ICI-ITP we also collected data on two control patients who initiated ICI therapy at the same site and in the same year but without development of ICI-ITP. We used multivariable logistic regression to identify independent risk factors for ICI-ITP and its recovery (the latter defined according to criteria established by the ITP International Working Group). We used a multivariable Cox model to examine the association between ICI-ITP and its severity with all-cause mortality. RESULTS We identified a total of 214 patients who developed ICI-ITP among 86,648 examined (0.25%). The incidence was highly consistent across sites (range, 0.15–0.30%). Risk factors for ICI-ITP included simultaneous receipt of two different classes of ICIs, additional irAEs, and a lower baseline platelet count. ICI-ITP developed at a median of 8 weeks (IQR, 4–18) following ICI initiation. The median nadir platelet count was 41 x109/L (IQR, 17–64). Six out of 214 patients (2.8%) developed a major bleed, and 16 patients (7.5%) developed a clinically relevant non-major bleed. Cell-bound anti-platelet antibody testing was positive in 6 of 8 patients (75.0%) for whom it was assessed, and median circulating thrombopoietin levels (201 pg/mL [IQR, 178–295]) were similar to those seen in primary ITP. Treatments used included glucocorticoids (49.5%), immune globulin (18.2%), and thrombopoietin receptor agonists (13.6%). Overall, 161 patients (75.2%) recovered from ICI-ITP at a median of 2 weeks (IQR, 1–5) following ICI-ITP onset. Predictors of recovery included additional irAEs and a higher nadir platelet count. Treatment response was observed in 57.0%, 56.4%, and 58.3% of patients within 60 days following initiation of glucocorticoids, immune globulin, and thrombopoietin receptor agonists, respectively. Of 76 patients rechallenged with an ICI, 23 (30.3%) developed recurrent ICI-ITP at a median of 9 weeks (IQR, 2–15); 17 of these 23 patients (73.9%) recovered. Finally, ICI-ITP and its severity were monotonically associated with a higher risk of death (adjusted hazard ratio 2.96 [95% CI, 2.14–4.08] for those with severe ICI-ITP compared to those without ICI-ITP). CONCLUSION In this multicenter study involving patients treated with ICIs at 29 hospitals across the US, we identified 214 patients with ICI-ITP. For the first time, we characterize in detail the incidence, risk factors, clinical features, treatments, and outcomes of ICI-ITP, a relatively novel disease entity. We found that more than half of patients responded to conventional ITP-directed therapies, and that most patients rechallenged did not develop recurrent ICI-ITP. We also found that ICI-ITP was independently associated with an increased risk of death, including a nearly 3-fold increased risk in those with severe ICI-ITP. These findings highlight ICI-ITP as a rare but clinically significant complication of ICI therapy that hematologists must be equipped to recognize and manage.

Background. Some patients who present with clinical features consistent with idiopathic hypereosinophilic syndrome (HES; absolute eosinophil count (AEC) ≥1.5 x 10 9/L with related end organ damage) are ultimately diagnosed with a myeloid neoplasm. Although FIP1L1::PDGFRA is the most common molecular abnormality in this setting, many other fusion genes, point mutations and cytogenetic abnormalities have been implicated in driving primary (neoplastic) eosinophilia. Given the poor prognosis of these disorders in the absence of treatment and the availability of targeted therapies for many of the driver mutations, it is becoming increasingly important to rapidly identify the underlying genetic alteration. In this regard, the expense and variable sensitivity of molecular diagnostic tests remains problematic. Although clinical features have been reported to distinguish between PDGFRA-associated myeloid neoplasms and D816V KIT-positive systemic mastocytosis with hypereosinophilia, little is known about the clinical phenotypes of other subsets of patients. This multicenter retrospective study aimed to assemble a large cohort of patients with HES secondary to a myeloid neoplasm to explore the utility of clinical and laboratory features in predicting the underlying molecular abnormality. Methods. Retrospective, de-identified data from 16 centers were collected via an online Research Electronic Data Capture repository. Patients and associated data were obtained from in-house research databases and/or electronic medical record searches at each site. Clinical and laboratory data were entered in accordance with local Institutional Review Boards. Inclusion criteria were peripheral blood hypereosinophilia (AEC >1.5 x 10 9/L) on at least two occasions and one of the following: ≥1 confirmed genetic abnormality recurrently associated with primary myeloid neoplasms, other evidence of clonal eosinophilia, or increased blasts (≥2% in the blood or >5% but <20% in the marrow). Patients with acute myeloid leukemia were excluded. Results. A total of 277 patients followed between 1990 and 2022 were included in the analysis. Median length of follow up was 31 months (range <1-356), and 217/277 (78%) were alive at last follow up. The most common genetic abnormality was FIP1L1::PDGFRA (n=131) followed by D816V KIT mutations (n=39) and alterations involving JAK2 (n=22) (Figure 1). Five patients had genetic abnormalities involving two distinct genes recurrently associated with eosinophilic myeloid neoplasms. The overall median age at diagnosis was 55 years (range 12-89) and 79% of the patients were male. When patients with abnormalities involving PDGFRA and PDGFRB were excluded from the analysis, the male predominance was significantly lower at 62% (p<0.001, Fisher's exact test as compared to the data set as a whole). The overall pattern of organ system involvement was similar irrespective of the underlying genetic abnormality with a few notable exceptions. Cardiac involvement was most common in patients with FIP1L1:: PDGFRA, abnormalities involving JAK2 or without pathologic alterations identified (reported in 22%, 32% and 30%, respectively); whereas skin and gastrointestinal involvement, lymphadenopathy and splenomegaly were most frequent in patients with KIT D816V. Laboratory abnormalities also differed between groups. Whereas anemia was the most common blood abnormality (reported in >50% of patients), erythrocytosis was noted primarily in patients with abnormalities involving JAK2. In contrast, circulating blasts were identified in 70% of patient with BCR::ABL1 and 29% of patients with chromosomal abnormalities or KIT D816V, but in <15% of patients in any of the other groups. Whereas peak AEC alone did not discriminate between the different patient groups, the AEC/tryptase ratio was increased in patients with PDGFRA-associated myeloid neoplasms, molecular abnormalities involving JAK2, or chromosomal abnormalities as compared to those with KIT mutations (Figure 2). Conclusions. Despite the limitations of retrospective data analysis, the data from this large multicenter cohort of patients with HES due to a chronic myeloid neoplasm suggest that routine demographic, clinical and laboratory features vary depending on the underlying molecular abnormality. This approach could ultimately help guide empiric therapy when molecular studies are negative or unavailable.

Abstract Allogeneic hematopoietic cell transplantation (allo‐HCT) is a potentially curative treatment for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). While many factors influence the outcomes of allo‐HCT, the independent impact of donor–recipient ABO mismatching remains unclear. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we identified patients aged ≥18 years with AML or ALL who underwent allo‐HCT between 2008 and 2018. Our objectives were to analyze the outcomes of allo‐HCT based on the donor–recipient ABO status (match, minor mismatch, major mismatch, bidirectional mismatch). Among 4946 eligible patients, 2741 patients (55.4%) were ABO matched, 1030 patients (20.8%) had a minor ABO mismatch, 899 patients (18.1%) had a major ABO mismatch, and 276 patients (5.6%) had a bidirectional ABO mismatch. In multivariable analyses, compared to ABO matched allo‐HCT, the presence of a major ABO mismatch was associated with worse overall survival (HR 1.16, 95% CI 1.05–1.29; p = 0.005), inferior platelet engraftment (HR 0.83, 95% CI 0.77–0.90; p < 0.001), and higher primary graft failure (HR 1.60, 95% CI 1.12–2.30, p = 0.01). Relapse, acute graft versus host disease (GVHD) grades III‐IV and chronic GVHD were not significantly associated with ABO status. While donor age was not significantly associated with outcomes, older recipient age was associated with worse survival and non‐relapse mortality. Our study demonstrates that donor–recipient ABO status is independently associated with survival and other post‐transplantation outcomes in acute leukemia. This underscores the importance of considering the ABO status in donor selection algorithms and its impact in acute leukemia.

Abstract Background: Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). While many factors influence the outcomes of allo-HCT in these leukemias, the independent impact of ABO mismatching between the patient and donor remains unclear. Methods: Using the CIBMTR database, we identified adults aged ≥18 years with AML or ALL who underwent allo-HCT from HLA-matched sibling donor (MSD) or 8/8 matched unrelated donor (MUD) between 2008-2018. We excluded patients who underwent transplant from a mismatched donor source or who received an ex-vivo T-cell depleted graft. Patients were stratified into cohorts based on ABO status (match, minor mismatch, major mismatch, bidirectional mismatch). Outcomes such as overall survival (OS), disease free survival (DFS), non-relapse mortality (NRM), relapse, incidence of acute graft versus host disease (GVHD), chronic GVHD, neutrophil engraftment, platelet engraftment and graft failure were evaluated. Survival analysis was done using Kaplan-Meier method and significant predictors were evaluated using Cox-proportional hazard regression method. Multivariate regression model included main effect (ABO status) and covariates (patient age, gender match, disease type, disease status, HCT-CI, Karnofsky performance status, donor type, conditioning intensity/use of TBI, stem cell source, GVHD prophylaxis, ATG/alemtuzumab use, transplant year). Results: Of 4946 patients who met the study criteria, 2741 patients (55.4%) were ABO matched, 1030 patients (20.8%) had minor ABO mismatch, 899 patients (18.1%) had major ABO mismatch and 276 patients (5.6%) had bidirectional ABO mismatch. Graft manipulation for ABO incompatibility was performed in 900 patients (minor ABO mismatch=532; major ABO mismatch=226; bidirectional mismatch=142), however, the information on individual graft manipulation techniques was limited. In multivariable analysis (table 1), major ABO mismatch significantly affected the OS, platelet engraftment and primary graft failure. Compared to ABO matched allo-HCT, major ABO mismatched allo-HCT was associated with worse OS (major mismatch - HR 1.16, 95% CI 1.05-1.29; p=0.005), inferior platelet engraftment (HR 0.83, 95% CI 0.77-0.90; p=&lt;0.001), and higher risk of primary graft failure [4.5% (major mismatch) vs. 3.2% (ABO matched) - HR 1.60, 95% CI 1.12-2.30, p=0.01]. There was a significant interaction between the ABO status and graft type (peripheral blood vs. bone marrow) for the acute GVHD grades 2-4 model, and they are presented separately (table 1). Bidirectional ABO mismatch also significantly impacted the outcomes such as acute GVHD grades 2-4 (in bone marrow stem cell subgroup, HR 0.50, 95%CI 0.27-0.93, p=0.02) in addition to a trend towards inferior survival and NRM (p-value not significant). Other outcomes such as relapse (p=0.41), acute GVHD grades 3-4 (p=0.13), and chronic GVHD (p=0.30) were not significantly influenced by the ABO status. Conclusions: Our study demonstrates that pre-transplant ABO status is an independent predictor of survival and other post-transplant outcomes in a large cohort of patients with AML and ALL undergoing allo-HCT in the recent era. This demonstrates the importance of considering ABO status in the donor selection algorithms and potential strategies to mitigate its adverse impact. Due to the limited information available on graft manipulation strategies, the impact of graft manipulation techniques on the outcomes could not be evaluated and needs to be investigated in future studies. Figure 1 Figure 1. Disclosures Guru Murthy: Techspert: Consultancy; Guidepoint: Consultancy; Cancerexpertnow: Honoraria; Qessential: Consultancy; TG therapeutics: Other: Advisory board; Cardinal Health Inc.: Honoraria. Devine: Magenta Therapeutics: Current Employment, Research Funding; Tmunity: Current Employment, Research Funding; Sanofi: Consultancy, Research Funding; Johnsonand Johnson: Consultancy, Research Funding; Orca Bio: Consultancy, Research Funding; Be the Match: Current Employment; Vor Bio: Research Funding; Kiadis: Consultancy, Research Funding. Farhadfar: Incyte: Consultancy. Sharma: Vertex Pharmaceuticals/CRISPR Therapeutics: Other: Salary support paid to institution; Novartis: Other: Salary support paid to institution; Spotlight Therapeutics: Consultancy; Medexus Inc: Consultancy; CRISPR Therapeutics: Other, Research Funding; Vindico Medical Education: Honoraria. Stefanski: Novartis: Honoraria. Pulsipher: Equillium: Membership on an entity's Board of Directors or advisory committees; Adaptive: Research Funding; Jasper Therapeutics: Honoraria. Shaw: mallinkrodt: Other: payments; Orca bio: Consultancy.