Elliott, Michelle A.

AbstractThe current study was approached with the assumption that response to induction chemotherapy, in acute myeloid leukemia (AML), overshadows pre‐treatment risk variables in predicting survival and therefore be used as an anchor for a simplified risk model. We considered 759 intensively‐treated patients with AML, not promyelocytic: median age 60 years; primary 66%, secondary 25%, and therapy‐related 9%; European LeukemiaNet cytogenetic risk category favorable 8%, intermediate 61%, and adverse 31%. Complete remission with (CR) or without (CRi) count recovery was achieved in 608 (80%) patients. After a median follow‐up of 22 months, 503 deaths, 272 relapses, and 257 allogeneic hematopoietic stem cell transplants (AHSCTs) were recorded. Multivariable analysis identified failure to achieve CR/CRi (HR 3.8, 95% CI 3.1–4.8), adverse karyotype (2.2, 1.8–2.8), and age >55 years (2.1, 1.6–2.7) as main risk factors for survival. HR‐weighted scoring resulted in four‐tiered risk stratification: low (0 points; N = 183), intermediate‐1 (1 point; N = 331), intermediate‐2 (2 points; N = 117), and high (≥3 points; N = 128), with respective median survival (5‐year rate) not reached (68%), 34 (37%), 13 (20%), and 5 (5%) months (p < .001). FLT3‐ITD mutation was associated with inferior survival in intermediate‐1 (p = .004) and TP53 in intermediate‐2 (p = .06) and high (p = .02) risk disease; the latter was fully accounted for by the close association between TP53 mutation and complex/monosomal karyotype while the observations regarding FLT3‐ITD were not affected by treatment with midostaurin. AHSCT had a favorable impact on survival, most apparent in intermediate‐1 (p < .001), intermediate‐2 (p = .03), and high (p = .01) risk disease. The proposed 3‐factor survival model offers a novel prototype that is amenable to further enhancement by molecular information and was validated in an external cohort of 1032 intensively‐treated AML patients.

TPS7080 Background: Myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPN) are classified as a distinct category under the World Health Organization (WHO) classification of myeloid neoplasms. MDS/MPN with RS and thrombocytosis (MDS/MPN-RS-T) and MDS/MPN, unclassifiable with > 15% bone marrow ring sideroblasts (MDS/MPN-U-RS) have similar clinical and pathological characteristics with symptomatic or transfusion-dependent anemia as the predominant morbidity. Luspatercept has been approved in myelodysplastic syndromes with ring sideroblasts (MDS-RS) and MDS/MPN overlap syndromes, based on the phase 3 MEDALIST clinical trial which primarily included MDS-RS patients with an objective erythroid response rate of approximately 40 per cent. In this trial, some MDS-RS patients also experienced an increase in neutrophil and platelet counts. This raises a safety concern for MDS/MPN patients with elevated platelet or WBC counts such as MDS/MPN-RS-T and MDS/MPN-U-RS. Previous studies have shown clinical and biological differences between MDS-RS and MDS/MPN-RS-T, with the latter group at a significantly elevated risk for thrombotic events. Additionally, several MDS/MPN-RS-T patients are on hydroxyurea which may blunt the erythroid response of luspatercept. Therefore, it is imperative to establish the safety and efficacy of luspatercept in this patient group. Methods: This is an investigator-initiated, prospective, phase II study of luspatercept in MDS/MPN overlap neoplasms with ring sideroblasts and thrombocytosis or unclassifiable with ring sideroblasts with 2 arms; hydroxyurea-independent (cohort A) and hydroxyurea-dependent (cohort B). Hydroxyurea and/or aspirin use is allowed as per investigator discretion. The primary goal is to study the efficacy and safety of luspatercept in MDS/MPN-RS-T or MDS/MPN-U-RS with symptomatic anemia. The primary endpoint is to assess erythroid response rate as per the 2015 International Working Group MDS/MPN response criteria. Secondary endpoints include response duration, time to acute myeloid leukemia (AML) transformation, thrombosis rate, AML-free and overall survival. Inclusion criteria include newly diagnosed or relapsed/refractory adult patients with WHO-defined diagnosis of MDS/MPN-RS-T or MDS/MPN-U-RS with symptomatic or transfusion-dependent anemia and unlikely to respond (EPO level > 200 IU/L) or intolerant to erythropoiesis stimulating agent (ESA) therapy. Prior therapy with lenalidomide, hypomethylating agents or immunosuppressive therapy is allowed. The overall plan is to enroll 54 patients across the three Mayo Clinic sites, Minnesota, Arizona and Florida. Enrollment to the trial began in January 2022 with 1 patient enrolled at the time of abstract submission. Clinical trial information: NCT05005182.

Abstract Patients with systemic mastocytosis (SM) are at increased risk for anaphylaxis from vespid and honeybee stings. The response of mastocytosis patients to tick-borne infections has not been reported. A 77-year-old woman hospitalized for progressive symptoms of fever, chills, night sweats, and abdominal pain became obtunded and required intubation, support with pressors, treatment for disseminated intravascular coagulation, and resuscitation from 3 episodes of asystole. During her evaluation, bone marrow biopsy revealed heretofore undiagnosed SM. A history of a tick bite 3 weeks previously was elicited when Ehrlichia chaffeensis infection was diagnosed. Institution of treatment with doxycycline led to gradual recovery. Ehrlichia chaffeensis–induced mast cell degranulation was felt to be responsible for many of her symptoms. This case is a cautionary report of the potential danger of tick-borne infection in patients with SM. How widespread this problem occurs is unknown and will depend on future surveillance in endemic areas.

Abstract Disease Overview Chronic neutrophilic leukemia (CNL) is a rare, often aggressive myeloproliferative neoplasm (MPN) defined by persistent mature neutrophilic leukocytosis, bone marrow granulocyte hyperplasia, and frequent hepatosplenomegaly. The 2013 seminal discovery of oncogenic driver mutations in colony‐stimulating factor 3 receptor ( CSF3R ) in the majority of patients with CNL not only established its molecular pathogenesis but provided a diagnostic biomarker and rationale for pharmacological targeting. Diagnosis In 2016, the World Health Organization (WHO) recognized activating CSF3R mutations as a central diagnostic feature of CNL. Other criteria include leukocytosis of ≥25 × 10 9 /L comprising >80% neutrophils with <10% circulating precursors and rare blasts, and absence of dysplasia or monocytosis, while not fulfilling criteria for other MPN. Management There is currently no standard of care for management of CNL, due in large part to the rarity of disease and dearth of formal clinical trials. Most commonly used therapeutic agents include conventional oral chemotherapy (e.g., hydroxyurea), interferon, and Janus kinase (JAK) inhibitors, while hematopoietic stem cell transplant remains the only potentially curative modality. Disease Updates Increasingly comprehensive genetic profiling in CNL, including new data on clonal evolution, has disclosed a complex genomic landscape with additional mutations and combinations thereof driving disease progression and drug resistance. Although accurate prognostic stratification and therapeutic decision‐making remain challenging in CNL, emerging data on molecular biomarkers and the addition of newer agents, such as JAK inhibitors, to the therapeutic arsenal, are paving the way toward greater standardization and improvement of patient care.

Abstract Background Systemic mastocytosis (SM) is formally classified as advanced, smoldering (SSM), or indolent (ISM). Advanced SM indicates the presence of an associated non-mast cell lineage hematologic neoplasm (SM-AHN) or at least one "C finding" (i.e. features of organopathy from mast cell infiltration); the latter defines aggressive SM (ASM). Both advanced SM and ISM might be associated with MC mediator symptoms (MC-MSs) or urticaria pigmentosa (UP). Current drug therapy for SM is primarily directed at reversing C findings or alleviating symptoms/UP, and includes cladribine, midostaurin, and avapritinib. The former has a long track-record of safety while the latter two are recent additions that target the associated KIT mutation, but with concerning gastrointestinal and neurological side effects. We retrospectively reviewed our experience with cladribine therapy in SM, in order to maintain a proper perspective in making treatment choices. Methods The current study includes 42 patients with SM (22 advanced and 20 indolent/smoldering), recruited from the Mayo Clinic SM database, based on documentation of treatment with cladribine. Conventional criteria were used for diagnosis and classification (Blood 2016;127:2391) and definitions of response (Eur J Clin Invest. 2007 Jun;37(6):435); in the latter regard, we utilized modified Valent criteria that incorporated a minimum of one-month duration to qualify as response. Results Advanced SM: 22 patients (median age 65 years, range 48-80; males 68%) had advanced SM, including 13 SM-AHN, 8 ASM, and 1 mast cell leukemia. Median (range) BM MC burden was 30% (10%-90%), serum tryptase 193 ng/ml (21-1370), hemoglobin 10.6 g/dL (7-15), leukocytes 6 x 10(9)/L (0.5-63), and platelets 115 x 10(9)/L (8-320). KITD816V was detected in 86% of 19 evaluated and abnormal karyotype in 14% of 21 evaluated. 50% of patients had palpable hepatomegaly, 59% palpable splenomegaly, 100% MC-MSs, and 14% UP; 87% displayed at least one C finding. Median time from BM biopsy confirmed diagnosis to initiation of cladribine therapy was 1.5 months (range 0.1-17). 55% of patients received at least 3 cycles of treatment. Overall response (OR) was documented in 17 (77%) patients with similar OR rates in ASM (88%) vs SM-AHN (69%; p=0.32), with median time to response of 3.7 months (range 0.4-9). OR included 45% major response (MR) and 32% partial response (PR). 17 patients were evaluated for BM MC response with 44% showing &gt;50% reduction, in MCs, including 19% with complete resolution. Organomegaly response was complete in 36% and partial in 27%. Tryptase response of &gt;50% was documented in 32%. Cladribine side effects were limited to cytopenias with 36% showing grade 3 or 4 myeloid cytopenia. Median duration of response was 6 months (range 1-67). Six patients, including 5 with SM-AHN, progressed to either AML or MCL. Among the 5 patients who did not respond to cladribine, one with ASM was successfully treated with midostaurin. Indolent or smoldering SM: 20 patients (median age 56 years, range 36-73; males 45%) had ISM (n=17) or SSM (n=3). Median (range) BM MC burden was 13% (5%-60%) and serum tryptase level 49 ng/ml (14-1630). KITD816V was detected in 95% of 19 evaluated patients and abnormal karyotype in 12% of 17 evaluated. All patients displayed MC-MSs and 46% UP. Median time from BM biopsy confirmed diagnosis to initiation of cladribine therapy was 4 months (range 0-92). 85% of patients received at least 3 cycles of cladribine therapy. OR was documented in 14 (70%) patients, including 60% complete or major regression of symptoms or UP, with median time to maximal response of 8.5 months (range 1-98); response rates in patients with UP were similar with 57% complete or major regression; 10 patients were evaluable for BM MC response with 50% showing &gt;50% reduction in MC burden. Serum tryptase response was evaluated in 13 patients with 46% showing &gt;50% reduction in levels. Treatment-emergent cladribine side effects were limited to cytopenias with only 3 (15%) patients experiencing grade 3 or 4 myeloid cytopenia and (n=3; 15%) and 6 (30%) experiencing grade 3 or 4 lymphopenia. Conclusions: The current study confirms the favorable side effect profile and long-term safety of cladribine as a first-line drug of choice for both indolent and advanced SM. Response to cladribine therapy was evident in all aspects of the disease, including MC-associated organopathy, UP, MC-MSs, serum tryptase level and bone marrow MC burden. Disclosures Patnaik: StemLine: Research Funding; Kura Oncology: Research Funding. Al-Kali: Novartis: Research Funding; Astex: Other: Research support to institution.

Abstract Background Clonal cytopenia of undetermined significance (CCUS) is a risk factor for development of myeloid neoplasms (MN) such as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Therapy-related myeloid neoplasm (t-MN) is defined as the development of a MN in the context of prior DNA damaging therapies including chemotherapy, radiation, and immunosuppressive therapies. CCUS diagnosed in the setting of prior DNA damaging therapy (t-CCUS) and its outcomes are not known. The aim of this study was to study clinicopathological features and outcome of t-CCUS and compare it with t-MN. Methods Patients who had received DNA-damaging therapy and subsequently determined to have CCUS or t-MN were identified. The diagnosis of CCUS was made if the patient had non-diagnostic bone marrow biopsy evaluation combined with evidence of pathogenic myeloid somatic genetic alterations using conventional cytogenetics or next generation sequencing (NGS) panel. Pathogenic/likely pathogenic variants (PV) were stratified by DTA (DNMT3A, TET2, and ASXL1) genes vs. others. Event-free survival (EFS) was calculated using interval from t-CCUS to t-MN with death as a competing risk. Overall survival (OS) for t-CCUS and t-MN patients was calculated using interval from t-CCUS or t-MN diagnoses respectively to the last follow up. Statistical analysis was performed using JMP (v14.1, SAS Institute). Results We identified 30 patients with t-CCUS and 259 patients with t-MN. Eleven (37%) t-CCUS patients developed t-MN and were included in both cohorts (Fig. A). Clinical characteristics of t-CCUS patients are shown in Table 1. Briefly, age (median, interquartile range or IQR) at the diagnosis of primary malignancy and t-CCUS was not different between those who developed t-MN and those did not (P=0.09 and 0.378 respectively). There was no difference in hemoglobin, white blood cells, or ANC between the two groups. Patients who developed t-MN had a significantly lower platelet count (68 vs. 130, P&lt;0.01) and higher bone marrow blast percent (2 vs. 0, P=0.04) compared to those who did not. At t-CCUS diagnosis, cytogenetics was abnormal in 11 (37%) patients and none had complex karyotype (CK). Paired cytogenetic analysis at t-CCUS and t-MN was available for 10 patients: 4 had unchanged karyotype at t-MN, whereas 6 had cytogenetic evolution. In contrast, 213 (83%) of 256 t-MN patients with available cytogenetics had abnormalities and 126/256 (49%) had CK. Thus, a significantly higher proportion of patients had CK t-MN compared to t-CCUS (χ 2 26.4, P&lt;0.01). A 42-gene NGS panel identified 36 PV in 21 patients (median 1, range 1-4) at t-CCUS. The most common PV were in TET2 (37.1%), TP53 (11.4%), DNMT3A (8.6%), and ZRSR2 (8.6%) genes. Two patients had paired NGS available at t-CCUS and t-MN: one had BCOR and U2AF1 PV at t-CCUS and acquired an additional NRAS PV at t-MN. The second patient had 2 PV in TP53 at t-CCUS diagnosis, that remained the only PV identified at t-MN. In the t-MN cohort, median number of PV was 2 (range 1-9). The most common PV identified were TP53 (21.5%), TET2 (6.7%), DNMT3A (6.4%), and ASXL1 (6.4%), whereas 4.8% patients had no PV. Three of 22 patients in the t-CCUS cohort had TP53mut, compared to 55 of 157 in the t-MN cohort (χ 2 4, P=0.05). Management strategies for t-CCUS included observation (20), growth factors (4), treatment of primary malignancy (2), immunosuppressives (1), hypomethylating agent followed by allogeneic SCT (1), and others (2). Following t-CCUS, 9 patients progressed to MDS and 2 to AML with a median of 3.5 months (IQR 1.7-43.4). EFS was 43.4 months (IQR 6.8-80.9). The presence of abnormal cytogenetics (Fig. B) and the absence of DTA-mutations (Fig. C) predicted shorter EFS. At last follow up, 12 (40%) deaths were noted. Four (33%) patients died without developing t-MN. Causes of death in the t-CCUS cohort were: t-MN (3), primary malignancy (1), progressive cytopenia without MN (1), infection (1), graft-vs.-host-disease (1), and undetermined (5). t-MN patients had a significantly shorter survival compared to t-CCUS (Fig. D). Conclusion More than 10% of t-MN patients had a precursor t-CCUS. On the other hand, t-CCUS patients are at a high risk of progression to MN. t-MN is characterized by the acquisition of TP53mut, genomic instability, and a significantly shorter survival compared to t-CCUS. The presence of abnormal cytogenetics and the absence of DTA mutations at t-CCUS predict shorter EFS. Figure 1 Figure 1. Disclosures Litzow: Omeros: Other: Advisory Board; AbbVie: Research Funding; Jazz: Other: Advisory Board; Amgen: Research Funding; Astellas: Research Funding; Pluristem: Research Funding; Actinium: Research Funding; Biosight: Other: Data monitoring committee. Patnaik: Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees. Al-Kali: Novartis: Research Funding; Astex: Other: Research support to institution.

Summary We describe our single institution experience with cladribine therapy in 42 patients with systemic mastocytosis (SM): 22 advanced (adv‐SM; median age 65 years, 68% males) and 20 indolent/smouldering SM (ISM/SSM; median age 56 years, 45% males); subcategories included eight aggressive, 13 associated with another haematological neoplasm, one mast cell leukaemia, 17 ISM and three SSM. Overall/major response rates were 77%/45% for adv‐SM and 70%/60% for ISM/SSM, and median (range) duration of response 10 (4–75) and 46 (4–140) months respectively. A >50% reduction in bone marrow mast cell burden and serum tryptase level was documented in 63% and 67% of patients with adv‐SM and 50% and 46% with ISM/SSM respectively. The presence of KIT proto‐oncogene, receptor tyrosine kinase ( KIT ) D816V predicted response in adv‐SM: 17 (90%) of 19 with and none of three without the mutation responded ( P < 0·01). Treatment‐emergent adverse events were mostly limited to transient cytopenias: Grade 3/4 neutropenia, thrombocytopenia, or lymphopenia occurred in 27%, 27% and 27% of patients with adv‐SM, and 5%, 5% and 30% with ISM/SSM respectively. The present study provides practical information that might be considered when making treatment choices between cladribine and newer KIT‐targeted therapies and identifies the absence of KIT D816V as a potential marker of cladribine resistance in advanced SM; the latter observation needs confirmation in a larger study.

SummaryInstitutional database search (1999–2020) for acute myeloid leukaemia (AML) identified 109 cases of myeloid sarcoma (MS), of which 19 were isolated and presented de novo. The latter displayed longer survival (median 78 months), compared to MS with synchronous intramedullary AML (n = 32; median 16 months) and de novo AML without MS (n = 729; median 22 months; P = 0·13). However, the difference in survival was no longer apparent after accounting for bone marrow cytogenetic risk status (P = 0·67). Treatment‐induced MS tumour resolution was not affected by the presence of intramedullary disease (P = 0·61). The current study clarifies the prognosis of de novo isolated MS, in the context of AML.