Abstract: Myeloid and erythroid precursor vacuolation is a common dysplastic finding associated with myeloid malignancies, toxins, drug, and nutritional deficiencies. It has been described as a core morphologic feature in VEXAS (vacuoles, E1 enzyme, X‐linked, autoinflammatory, somatic) syndrome. We sought to determine the number of cases attributable to VEXAS syndrome in bone marrow biopsies and aspirates (BAMB) reporting myeloid precursor vacuolation. We reviewed 1318 individual BAMB reports from January 2020 to July 2021 where “vacuole(s),” “vacuolation,” or “vacuolated” was reported. Bone marrow biopsies with vacuolation confined to blasts or those completed as routine workup prior to stem cell transplant or post induction chemotherapy for AML (acute myeloid leukemia) were excluded. Myeloid and erythroid precursor vacuolation was noted in 219 reports representing 210 patients. The most common etiology was myelodysplastic syndrome (MDS) (38.6%), AML (16.7%), lymphoproliferative disorders and multiple myeloma (7.6%), drug or toxin exposure (5.2%) myeloproliferative neoplasm (MPN) or MPN/MDS overlap syndrome (4.3%). VEXAS syndrome was determined to be the etiology in 2.9% of patients. Two additional cases of VEXAS syndrome with bone marrow biopsies reported in the specified time frame did not explicitly report myeloid or erythroid precursor vacuolation but were identified based on clinical suspicion and repeat BAMB review. Myeloid and erythroid precursor vacuolation is a dysplastic feature attributable to VEXAS syndrome in at least 2.9% of cases. Standardized reporting of vacuolization, triaging of molecular sequencing and optimal treatment of this disorder are critical issues facing those seeing patients with suspected VEXAS syndrome.

Abstract: Myelofibrosis (MF)‐associated constitutional symptoms can severely impact health‐related quality of life. Clinical trials in MF traditionally measure symptom response to treatment as a landmark endpoint of total symptom score (TSS) reduction ≥50% from baseline. However, this dichotomous assessment provides a limited view of clinically relevant symptomatic changes. Herein we evaluated longitudinal change from baseline in TSS over the continuous 24‐week period and individual symptom scores to obtain a more comprehensive understanding of symptom benefits experienced by patients with MF receiving therapy. Methods Longitudinal symptom change was evaluated using mixed‐effect model repeated measure (MMRM) methodology with individual item‐level analyses to complement the interpretation of the landmark symptom results in the completed phase III SIMPLIFY studies of momelotinib in MF. MMRM compared mean change in TSS from baseline with Week 24 using data from all patient visits. Generalized estimating equations were used to estimate item‐level odds ratios using multiple predictive imputations for missing data. Results Momelotinib and ruxolitinib groups reported similar overall symptom improvements, with a TSS difference of 〈 1.5 points between groups for each post‐baseline visit in SIMPLIFY‐1. In SIMPLIFY‐2, the improvement in TSS observed in momelotinib‐treated patients was consistent with that observed in SIMPLIFY‐1, whereas progressive TSS deterioration was observed with control. Item‐level scores were heterogeneous in both studies. A similar and greater proportion of momelotinib‐treated patients were categorized as “improved” or “stable” compared with control in SIMPLIFY‐1 and SIMPLIFY‐2, respectively. Odds ratios for between‐group comparison ranged from 0.75 to 1.21 in SIMPLIFY‐1, demonstrating similarity in likelihood of symptom improvement. In SIMPLIFY‐2, the likelihood of symptom improvement in each item was higher in the momelotinib arm. Conclusions These findings suggest that momelotinib provides clinically relevant symptom benefits in the JAK inhibitor‐naïve and JAK inhibitor‐exposed settings.

Abstract: Anemia is a frequent manifestation of myelofibrosis (MF) and there is an unmet need for effective treatments in anemic MF patients. The REALISE phase 2 study (NCT02966353) evaluated the efficacy and safety of a novel ruxolitinib dosing strategy with a reduced starting dose with delayed up-titration in anemic MF patients. Fifty-one patients with primary MF (66.7%), post-essential thrombocythemia MF (21.6%), or post-polycythemia vera MF (11.8%) with palpable splenomegaly and hemoglobin 〈 10 g/dl were included. Median age was 67 (45–88) years, 41.2% were female, and 18% were transfusion-dependent. Patients received 10 mg ruxolitinib b.i.d. for the first 12 weeks, then up-titrations of up to 25 mg b.i.d. were permitted, based on efficacy and platelet counts. Overall, 70% of patients achieved a ≥50% reduction in palpable spleen length at any time during the study. The most frequent adverse events leading to dose interruption/adjustment were thrombocytopenia (17.6%) and anemia (11.8%). Patients who had a dose increase had greater spleen size and higher white blood cell counts at baseline. Median hemoglobin levels remained stable and transfusion requirements did not increase compared with baseline. These results reinforce the notion that it is unnecessary to delay or withhold ruxolitinib because of co-existent or treatment-emergent anemia.

Abstract: Introduction Allogeneic hematopoietic cell transplantation (HCT) remains the only potentially curative therapy for myelofibrosis (MF). However, despite improvements in donor availability, most patients receive non-HCT therapy in the form of conventional drugs (e.g. hydroxyurea), or more recently, JAK inhibitor therapy (JAKi). For a proportion of patients, JAKi offers durable clinical benefit in the form of symptom improvement, reduction in splenomegaly and improved quality of life. The role of HCT in the JAKi era has not been well studied, and despite recent advances in the understanding of the pathogenesis and refinement of prognostic scoring systems,real-world decision making remains challenging. The goal of this study was to compare the outcomes of patients who received upfront JAKi vs. HCT for MF in dynamic international prognostic scoring system (DIPSS)-stratified categories. Methods This multicentre study included adult patients up to age 70 years with primary or secondary MF in chronic phase who were first seen at one of the eight participating centres in Canada and the United States between January 1, 2012 and December 31, 2017. The primary outcome was overall survival (OS) in patients with DIPSS int-1 risk or higher who received JAKi vs. HCT. To compare the planned, upfront treatment strategy, patients who received a short-course of JAKi as bridging therapy prior to HCT ( & lt; 6 months or documented plan of care) were analysed in the HCT group. Similarly, patients who were treated with JAKi, but received a HCT following JAKi failure ( & gt;12 months or documented progression) were analysed in the JAKi group. To minimize selection and lead-time bias, OS was calculated from the start of JAKi and date of transplant, respectively. Patients who were transplanted for accelerated- or blast-phase disease were not included in the analysis. OS was calculated using the Kaplan-Meier method and differences were tested using the log-rank test. Results Between 2012 and 2017, 506 patients with MF were seen at the study centres and 311 received JAKi or HCT. Of these, 174 (56%) had PMF and 137 (44%) had post-ET or post-PV MF. An upfront HCT strategy was used in 86 patients and an upfront JAKi strategy was used in 225 patients. Of those, 53 patients went on to receive HCT following JAKi failure. The median duration of follow up of survivors was 32.8 (1.2 - 99.2) months. The median OS of MF patients with DIPSS int-1 or higher was 65.3 (95% CI: 55.7 - 76.4) months for patients treated with an upfront JAKi strategy and 89.4 (95% CI: 20.4 - not reached) months for those treated with an upfront HCT strategy (p=0.018, Figure). The survival of patients with int-1 risk disease was 0.78 (95% CI: 0.69 - 0.88) in the JAKi group vs. 0.60 (95% CI: 0.43 - 0.83) in the HCT group at 36 months and 0.68 (95% CI: 0.57-0.82) in the JAKi group vs. 0.60 (95% CI: 0.43-0.83) in the HCT group at 60 months. Given the small number of patients with DIPSS high risk, these patients were combined with the int-2 cohort for analysis. The survival of patients with int-2/high risk disease was 0.58 (95% CI: 0.49 - 0.69) in the JAKi group vs. 0.49 (95% CI: 0.36 - 0.65) in the HCT group at 36 months and 0.37 (95% CI: 0.24-0.55) in the JAKi group vs. 0.45 (95% CI: 0.32-0.62) in the HCT group at 60 months (Table). Conclusions Previous studies, which included many patients treated in the era before widespread availability of JAKi, supported an upfront HCT strategy in patients with higher risk MF. While these agents have not demonstrated consistent disease-modifying effects, many patients do experience durable clinical benefit in the form of symptom improvement and reduction in spleen size. In our study, there was no clear benefit of upfront HCT. The median OS of patients who received HCT upfront was longer than that of patients who were treated with upfront JAKi, but upfront HCT was associated with early mortality and the OS benefit was not apparent until after 5 years. An inherent limitation of this study is a lack of data on potentially important comorbid conditions which may have contributed to selection bias. However, to our knowledge this is the largest study to compare upfront HCT and JAKi strategies in patients with higher risk MF, making these findings relevant to modern clinical practice in the JAKi era. A delayed transplant approach may be appropriate for selected patients who are deriving clinical benefit from JAKi. Defining the optimal timing for HCT in higher risk MF remains a question for future research. Disclosures Maze: Pfizer: Consultancy; Novartis: Honoraria; Takeda: Research Funding. Arcasoy:CTI Biopharma: Research Funding; Samus Therapeutics: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Janssen: Research Funding. Yacoub:Dynavax: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Cara Therapeutics: Current equity holder in publicly-traded company; Hylapharm: Current equity holder in private company; Incyte: Speakers Bureau; Agios: Honoraria, Speakers Bureau; Novartis: Speakers Bureau; Roche: Other: Support of parent study and funding of editorial support. McNamara:Novartis: Honoraria. Foltz:Celgene: Membership on an entity's Board of Directors or advisory committees; Constellation: Research Funding; Incyte: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gupta:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol MyersSquibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Incyte: Honoraria, Research Funding.

Abstract: Background: Few studies have objectively assessed the value of routine clinical, laboratory and radiological evaluation to detect recurrence of Hodgkin lymphoma. The optimal follow up of patients (pts) in complete remission following initial therapy has not been defined. Methods: We identified 99 adult pts with Hodgkin lymphoma, who received treatment and follow up supervised by the British Columbia Cancer Agency and relapsed between Jan 1990 and April 2004. Pts who did not achieve complete remission or had a second hematological malignancy were excluded. Pts were followed with clinical assessment, chest radiograph, CBC and alk phos every 3 m for 2 y, then every 6 m for 3 y, then annually. Routine CT scans were recommended every 6 m for 3 y then annually for 2 y. Relapses were categorized as identified by pt (symptoms, new palpable disease) or by physician (routine physical examination or radiological or laboratory studies in asymptomatic pts). Results: Median age at original diagnosis was 28 y (range 14–73). 86 pts initally had advanced and 13 limited stage disease. Primary treatment was chemotherapy +/− radiation in 93 pts and radiation alone in 6 pts. 10 pts had autologous SCT for primary refractory disease. Median follow up from diagnosis was 82 months (range 12–241). Median time to first relapse from completion of treatment was 14 months (range 2–142). Of the 99 relapses, 75 (76%) were identified by the pt and 24 (24%) by the physician. Pt systemic symptoms of relapse were: fatigue 13 pts; alcohol induced pain 3; weight loss 11; pruritis 9; night sweats 19; fever 6. Local symptoms were shortness of breath 8; chest pain 8; back pain 9; abd pain 3. 29 pts had more than 1 symptom. 44 pts noted a new lymph node or mass and 1 pt had leg swelling. 24 relapses were detected by physician: 14 on CXR, 7 on CT scan, 1 on lymphangiogram and 2 on physical exam. No asymptomatic relapses were identified by laboratory abnormalities alone. 2 of the 13 relapses in pts with initially limited stage disease (18%) were detected by physician (1 CXR and 1 CT chest), vs 22 of 86 (26%) in advanced disease. 78% of relapses occurred within 36 months of completing initial treatment. Patient vs Physician Detected Relapses by Follow up Period Time from therapy completion Patient Detected Relapse Physician Detected Relapse Total # Relapses & lt; 12 months 37 (80%) 9 (20%) 46 12–35 months 19 (61%) 12 (39%) 31 ≥ 36 months 19 (86%) 3 (14%) 22 All Relapses 75 (76%) 24 (24%) 99 80% of relapses within 12 months of therapy completion were detected by pts despite more intensive physician surveillance in this period. The proportion of physician detected relapses was greatest 12–36 months after completion of treatment, possibly due to relapse with more slowly progressive disease amenable to detection on periodic routine testing while it is still being carried on relatively frequently. The 22% of relapses occurring in the period of less frequent surveillance, greater than 3 years after treatment, were primarily detected by pts. Conclusions: 76% of Hodgkin lymphoma relapses were detected by the pt and 78% of relapses occurred within 3 years of therapy completion. Asymptomatic relapse was detected on physical exam and radiological studies but not laboratory testing. The highest proportion of physician detected relapses occurred 12–35 months after treatment. Annual routine follow up beyond 36 months contributed minimally to relapse detection, identifying only 3% of total relapses.

Abstract: Timely diagnosis of patients (pts) with polycythemia vera (PV) and essential thrombocythemia (ET) is important given the risks of thrombotic and hemorrhagic complications, disease progression and associated symptoms.  Pts often present initially to primary care physicians, who may have limited previous experience with PV/ET given the low prevalence.  Little is known about the timeliness of referral or diagnostic testing after identification of abnormal blood test results or if delays in diagnosis affect patient outcomes. Objectives To determine the time from initial lab abnormality to referral, diagnosis and treatment of pts with PV and ET. Methods Pts at a single Canadian academic institution newly diagnosed with PV or ET from Jan 2010 to May 2013 were identified.  Retrospective data was collected including demographics, lab values, diagnostic testing and treatments. Results Demographics: 26 pts with PV and 34 with ET were identified.  Median age was 67.5 (44-89) y for PV and 66.5 (34-92) y for ET. Delay in Referral and Diagnosis: 98% of pts were referred directly to a hematologist by their primary care physician.  69% of PV pts were referred within 30 days and 92% within 90 days of initial lab abnormality.  Median time from referral to diagnosis was 98 (0-221) days.  41% of ET pts were referred within 30 days and 56% within 90 days of initial lab abnormality.  Median time from referral to diagnosis was 121 (8-638) days.  PV pts were referred sooner, median 20 (0-187) days, than ET pts, median 67 (0-3743) days (p=0.01).  The median delay from referral until hematology assessment was 51 days for PV compared to 78 days for ET (p=0.08).  After assessment by the hematologist, it required a median of 35 days to make a diagnosis of PV and 25 days for a diagnosis of ET (p=0.31). Referrals by platelet (plt) count: There was a trend to earlier referral of ET pts with higher platelet (plt) counts.  15/20 (75%) ET pts with plt count 〉 600 were referred within 90 days of initial lab abnormality whereas only 4/14 (29%) of pts with plt count 450-600 were referred within 90 days (p=0.056). Treatment of PV pts: 22/26 (85%) pts received phlebotomy at or after referral at the direction of a hematologist.  Average delay in referral (and phlebotomy initiation) for patients treated with phlebotomy was 32 days.  13/26 (50%) pts were initiated on treatment with hydroxyurea within 2 months of diagnosis.  Average delay in diagnosis (and hydroxyurea initiation) in this subgroup was 142 days.   11/26 (42%) pts were receiving ASA prior to the initial hematological consultation.  12/26 (46%) were initiated on ASA at or shortly after hematological consultation.  Average delay to hematology consultation (and ASA initiation) was 90 days in this subgroup. Treatment of ET pts: 8/34 (24%) pts were initiated on treatment with hydroxyurea within 2 months of diagnosis.  Average delay in diagnosis (and hydroxyurea initiation) in this subgroup was 790 days. 17/34 (50%) pts were receiving ASA prior to the initial hematological consultation.  15/34 (44%) were initiated on ASA at or shortly after hematological consultation.  Average delay to hematology consultation (and ASA initiation) was 355 days in this subgroup. No thrombotic or major hemorrhagic complications occurred in any PV/ET pts between the time of initial lab abnormality and diagnosis. Discussion This study demonstrates the marked variability in time from lab abnormality to referral and diagnosis for PV/ET pts.  Primary care providers were more likely to promptly refer PV pts than ET pts, and particularly tended to overlook referral and investigation of pts with modestly elevated plt counts of 450-600.  This is a concern, as risk of thrombosis in ET pts is independent of plt count.  Delays were also apparent in wait times for hematology appointments and subsequent diagnostic tests.   The delay in diagnosis led to a delay in initiation of therapy to reduce risk of thrombosis in both PV and ET pts.  Possible strategies to expedite diagnosis include targeted education of primary care physicians focusing on identification of lab features of PV/ET.  Directive comments on lab reports by community hematopathologists may also facilitate prompt referral and investigation. Disclosures: No relevant conflicts of interest to declare.

Abstract: BACKGROUND: Ruxolitinib (RUX) is a potent JAK1/JAK2 inhibitor that demonstrated improvements in splenomegaly and disease-related symptoms, as well as improved survival, in patients (pts) with intermediate (Int)-2- or high-risk myelofibrosis (MF), and has proved superior to placebo and best available therapy in the phase 3 COMFORT studies. JUMP is an expanded-access phase 3b trial designed to assess the safety and efficacy of RUX in pts with MF and includes patients with no access to RUX outside a clinical trial. As of Dec 2014, final enrollment was 2233 pts in 26 countries. METHODS: Eligible pts had Int-2- or high-risk MF with or without splenomegaly, or Int-1-risk MF with a palpable spleen (≥ 5 cm from the costal margin). Pts received starting doses of RUX based on platelet counts at baseline (5 mg twice daily [bid; ≥ 50 to 〈 100 × 109/L], 15 mg bid [100 to 200 × 109/L] , or 20 mg bid [ 〉 200 × 109/L]). The primary endpoint was assessment of safety and tolerability of RUX. Additional analyses included changes in palpable spleen length and symptom scores as measured by the FACT-Lymphoma total score (FACT-Lym TS). The final analysis will be performed after all pts have completed 24 months of treatment or discontinued the study. RESULTS: This analysis includes 1869 pts (primary MF, 59.1%; n = 1105) who started treatment ≥ 1 year before the data cutoff date (01 Jan 2015). At baseline, median age was 67 y (range, 18-89 y); 54.1% were male; median palpable spleen length was 12 cm below the costal margin; 87 pts did not have splenomegaly. Median hemoglobin (Hb) was 106 g/L, and 38.9% of pts had Hb levels ˂ 100 g/L; median platelet count was 257 × 109/L; mean FACT-Lym TS and FACIT-Fatigue score were 113.7 and 33.2, respectively. At data cutoff, 37.0% of pts remained on treatment; 26.1% had completed treatment per protocol. Primary reasons for discontinuation included adverse events (AEs; 17.4%), disease progression (8.2%), and death (3.4%). Median exposure was 13.6 months; the median average daily dose was 36.7 mg for pts starting at 20 mg bid (n = 1168; 62.5%) and 23.2 mg for pts starting at 15 mg bid (n = 559; 29.9%). The majority of pts (66.0%) had dose modifications, and 26.2% had a dose interruption. Grade 3/4 hematologic AEs included anemia (34.0%), thrombocytopenia (14.9%), and neutropenia (3.9%), which led to discontinuation in 2.2%, 3.3%, and 0.2% of pts, respectively. The most common nonhematologic AEs (≥ 10%) were pyrexia (14.5%), asthenia (13.8%), diarrhea (12.4%), and fatigue (10.3%), and were primarily grade 1/2; grade 3/4 AEs were low overall (≤ 2%), except pneumonia (3.9%), which led to discontinuation in 9 pts (0.5%). Rates of infections were low; all-grade infections ≥ 5% included pneumonia (6.2%), urinary tract infection (5.7%), and nasopharyngitis (5.3%). Tuberculosis was reported in 5 pts (0.3%; grade 3/4, 0.1%); hepatitis B was reported in 1 pt (0.1%; grade 3/4, 0.1%). At wk 24 and 48, 57.2% (742/1297) and 62.0% (588/949) of pts with baseline splenomegaly achieved a ≥ 50% reduction from baseline in palpable spleen length; 22.9% (297/1297) and 19.0% (180/949) had 25% to 50% reductions, respectively. Most pts (70.5%; 1208/1713) experienced a ≥ 50% reduction at any time; 23.3% (399/1713) had complete resolution of splenomegaly (Figure). At wk 24 and 48, 96.6% (57/59) and 91.5% (43/47) of evaluable pts without splenomegaly at baseline continued to have a nonpalpable spleen; 1.7% (1/59) and 4.3% (2/47) had a spleen that was 0-5 cm, and 1.7% (1/59) and 4.3% (2/47) had a spleen ≥ 5 cm. A large proportion of pts achieved a response (ie, a clinically significant improvement) on the FACT-Lym TS and FACIT-Fatigue at wk 24 (43.0% [525/1220] ; 47.1% [593/1258]) and wk 48 (43.2% [368/852] ; 45.7% [396/867]). Similar responses were seen in pts without a palpable spleen (FACT-Lym TS: wk 24, 44.0% [22/50] ; wk 48, 36.1% [13/36]; FACIT-Fatigue: wk 24, 49.1% [27/55] ; wk 48, 35.1% [13/37]). CONCLUSIONS: To date, JUMP includes the largest cohort of pts with MF treated with RUX. Consistent with previous findings, anemia and thrombocytopenia were the most common AEs but rarely led to discontinuation. As observed previously, most pts experienced reductions in splenomegaly and symptoms with RUX treatment. Clinically meaningful improvements in symptoms were also seen in pts with no palpable spleen, a pt group not included in the COMFORT studies. Overall, the safety and efficacy profile of RUX in JUMP is consistent with that in the phase 3 COMFORT studies. Disclosures Palumbo: Novartis: Honoraria, Other: Advisory Board. Le Coutre:Novartis: Honoraria. Al-Ali:Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Ullrich:Novartis: Honoraria. Brittain:Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pierre Fabre: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Foltz:Promedior: Research Funding; Gilead: Research Funding; Novartis: Honoraria, Research Funding. Raanani:Bristol-Myers Squibb: Other: Advisory Board; Novartis: Other: Advisory Board, Research Funding; Ariad: Other: Advisory Board; Pfizer: Other: Advisory Board. Gupta:Incyte: Honoraria, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ghosh:Novartis Pharmaceuticals Corporation: Employment. Tannir:Novartis Pharma AG: Employment. Perez Ronco:Novartis Pharma AG: Employment. Vannucchi:Novartis: Other: Research Funding paid to institution (University of Florence), Research Funding; Shire: Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.