Pardanani, Animesh

Abstract Abstract 430 Background: The Dynamic International Prognostic Scoring System (DIPSS-plus) uses eight risk factors to predict overall survival (OS) in primary myelofibrosis (PMF): unfavorable karyotype, peripheral blood (PB) blast count ≥1%, platelet count <100 × 109/L, white blood cell count (WBC) >25 × 109/L, hemoglobin level <10 g/dL, red blood cell transfusion need, constitutional symptoms, and age >65 years (JCO 2011;29:392). Among these risk factors, karyotype holds a dominant role in predicting both overall (OS) and leukemia-free (LFS) survival (Blood 2011;118:4595). More recently, certain PMF-associated somatic mutations (IDH, EZH2, ASXL1, SRSF2) have been reported (in print or at recent meetings) to carry prognostic relevance for OS or LFS in PMF while other mutations (JAK2, MPL, TET2, SF3B1) did not. The purpose of the current study was to examine the individual and combined prognostic relevance of the former in the context of cytogenetic risk stratification and DIPSS-plus. Methods: An updated Mayo Clinic database of 1008 karyotypically- and DIPSS-plus-annotated patients with PMF was used to identify study patients in whom DNA at time of referral was available for mutation analysis. OS and LFS were calculated from the time of referral, which was also the time of study sample collection. Results: In an ongoing project, a total of 397 PMF patients have so far been studied for IDH1/2 (n=367), SRSF2 (n=355), ASXL1 (n=260) and EZH2 (n=43) mutations. The corresponding mutational frequencies were 5.4% (20/367), 14.4% (51/355), 31.2% (81/260) and 7% (3/43). These mutations were not exclusive of either each other or JAK2 or MPL mutations and a significant clustering was noted between SRSF2 and IDH mutations; IDH mutational frequency was 21% (10/48) in SRSF2-mutated versus 3% (9/279) in unmutated cases (P<0.0001). Mutational hotspots were P95 in exon 1 for SRSF2 and exons 1, 2 and 5 for ASXL1. OS and LFS effect have so far been examined for ASXL1, SRSF2 and IDH 1/2 mutations; in univariate analysis, all three mutations significantly affected OS (ASXL1 RR 1.9, 95% CI 1.4–2.7; SRSF2 RR 1.7, 95% CI 1.2–2.5; IDH 1/2 RR 1.8, 95% CI 1.1–3.1) whereas only IDH 1/2 (RR 5.5, 95% CI 2.5–11.8) and SRSF2 (RR 3.5, 95% CI 1.7–7.0) but not ASXL1 (p=0.29) mutations affected LFS. The observed prognostic relevance for OS was sustained during multivariable analysis that included ASXL1 with either SRSF2 or IDH mutations, as co-variates, whereas both IDH and SRSF2 mutations remained significant for LFS. Based on the above observations, study patients were classified into two groups: i) unmutated for ASXL1, SRSF2 and IDH1/2 (all unmutated; n=146) and ii) mutated for at least one of the three mutations (one or more mutated; n=130); the latter group constituted 62%, 52%, 18% and 27% of DIPSS-plus high, intermediate-2, intermediate-1and low risk patients, respectively (p<0.0001). The corresponding rates for patients with favorable and unfavorable karyotype were 47% and 43% (p=0.7) and for normal vs. abnormal karyotype were 53% and 36% (p=0.008). The “all unmutated group”, compared to the “one or more mutated group” enjoyed a significantly superior OS (RR 0.5, 95% CI 0.4–0.7) and LFS (RR 0.3, 95% CI 0.2–0.7) that was DIPSS-plus-independent for OS (p=0.03) and karyotype-independent for LFS (p=0.004). The prognostic value of distinguishing “all unmutated” from “one or more mutated” patient groups was most evident for DIPSS-plus intermediate-2 or lower risk groups (p=0.002) and its added value for high-risk group was limited (p=0.23) (Figure). Conclusions: A concomitant analysis strategy reveals that SRSF2, ASXL1 and IDH mutations carry inter-independent prognostic relevance for overall or leukemia-free survival in PMF. Any one of these three mutations is more likely to occur in patients with normal karyotype and such an event predicts shortened survival that is not accounted for by DIPSS-plus and a higher risk of leukemic transformation that is independent of karyotype. The current study suggests that such information might be useful in treatment decisions involving intermediate-2 or lower risk patients. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 755 Background: TG101348 is a potent, orally bioavailable, JAK2-selective small molecule inhibitor, that is currently being evaluated in a Phase I study for the treatment of myelofibrosis. Data from the dose escalation cohort (n=28; 30-800mg administered as a single daily dose) showed dose-linear plasma exposure, with mean elimination T1/2 at steady state ranging from 20 to 52 hours. The dose-limiting toxicity was asymptomatic grade 3 or 4 amylasemia/lipasemia that was reversible, and the maximum tolerated dose (MTD) was 680mg. The most frequent non-hematological toxicities were mild nausea, vomiting, and/or diarrhea that were easily controlled or resolved spontaneously. Grade 3/4 neutropenia and thrombocytopenia were observed in 14% and 25% of patients, respectively. TG101348 had activity in reducing spleen size, leukocyte count, and JAK2V617F (VF) allele burden. Here, we present updated results with a focus on data from the dose confirmation cohort who initiated treatment at a dose of 680mg/day. Results: Fifty nine patients (median age=66 years; range 43-86) have been treated – 28 in the dose escalation phase, and 31 in the dose confirmation phase. Overall, 44 patients had PMF, 12 post-PV MF, and 3 post-ET MF; 86% were VF-positive. Median palpable spleen size was 18cm and 22 patients were RBC transfusion-requiring at study enrollment. After a median follow-up of 12 weeks (range <1-76), 18 (31%) patients have discontinued treatment due to toxicity (n=7; thrombocytopenia=3, neutropenia=1), comorbidities (n=5), withdrawal of consent (n=4), or non-compliance/lack of response (1 each). The remaining 41 patients are currently at the following dose levels: 680mg (n=14), 520-600mg (n=16), 360-440mg (n=10), and 240mg (n=1). The cumulative drug exposure to date is 362 patient-months; exposure at or above MTD (≥680mg) is 154 patient-months. Forty patients (68%) started treatment at ≥680mg. Toxicity: TG101348 is well tolerated. Of the patients who started at ≥680mg, Gr3/4 neutropenia was observed in 15/0% and Gr3/4 thrombocytopenia in 20/10%. Twenty four (60%) patients did not require RBC transfusions at baseline (median Hgb=9.6g/dL; range 7.4-13.1); of these, 42% and 8% of patients developed Gr3 and Gr4 anemia, respectively. The majority of patients who started at ≥680mg developed mild nausea (1 Gr3), vomiting (1 Gr3), and/or diarrhea (3 Gr3) that were self-limited or easily controlled. Other non-hematological toxicities included Gr1/2 transaminitis (38%), Gr1/2 serum creatinine elevation (38%), and asymptomatic hyperlipasemia (33%). Efficacy: Thirty three patients who started at ≥680mg have completed at least 3 cycles of treatment; at 3 months, reduction in palpable spleen size (baseline median=18cms; range 6-32) was at least 50% in 22 (67%) patients; the spleen became non-palpable in 9 (27%) patients. All 21 patients with leukocytosis at baseline (WBC range 11 to 203 ×109/L) who started at ≥680mg have experienced a marked reduction in their WBC count (range 4 to 90); 70% had a normal WBC count at their last follow-up visit. Overall, 48 of the 51 VF-positive patients completed at least 1 cycle and were evaluable for response in VF allele burden; at last available follow-up, the median decrease in granulocyte mutant allele burden was 48%; 21 (44%) patients have had a ≥50% reduction, and in the group who started treatment at ≥680mg, 48% have had a ≥50% reduction. Of those evaluable, there was clinically significant benefit or resolution of constitutional symptoms, including early satiety, fatigue, cough, pruritus, and night sweats. Conclusions: TG101348 continues to be well tolerated in patients with myelofibrosis. Spleen and leukocyte responses are frequent, observed early, and produce substantial clinical benefit for patients. These responses are associated with significant decrease in VF allele burden and point to activity of TG101348 against the malignant clone in myelofibrosis. Disclosures: Pardanani: TargeGen: Research Funding; Cytopia: Research Funding. Off Label Use: Data from ongoing clinical trial will be presented. Gotlib:TargeGen: Research Funding. Jamieson:Merck: Research Funding; Pfizer: Research Funding; Wintherix: Consultancy; TargeGen: Research Funding; Celgene: Research Funding. Cortes:Targegen: Research Funding. Stone:Cephalon: ad hoc advisory board. Silverman:TargeGen: Consultancy. Shorr:TargeGen: Employment, Equity Ownership. Gilliland:Merck: Employment. Tefferi:TargeGen: Research Funding.

Abstract Abstract 423 Background: Cytogenetic abnormalities at diagnosis are seen in 20–70% of patients with myelodysplastic syndromes (MDS). The International Prognostic Scoring System -revised (IPSS-R) classifies these cytogenetic abnormalities into five prognostic groups: very good (del(11q), ΠY with overall survival (OS) of 61 months); good (normal, del(20q), del(5q), del(12p) with OS 49 months); intermediate (+8,7q-, i(17q),+19,+21 with OS 26 months); poor (der(3)q21/q26, −7, complex with 3 abnormalities with OS 16 months); and very poor (complex with >3 abnormalities with OS of 6 months) (Schanz J, JCO 2012, Greenberg P, Blood 2012). Monosomal karyotype (MK) is defined as the presence of two or more autosomal monosomies or a single monosomy associated with a structural abnormality. We have previously shown that MK identifies a prognostically worse subgroup of MDS patients with a complex karyotype (Patnaik M, Leukemia 2010). Objectives: Methods: The Mayo Clinic database for MDS was used to identify patients in whom bone marrow histologic and cytogenetic information was obtained at the time of diagnosis. WHO criteria were used for MDS diagnosis and leukemic transformation. Results: i) Patient characteristics: A total of 1,014 patients met the above-stipulated criteria. Median age of the cohort was 71 years (range: 18–98 years) with 684 (67%) males. 819 patients (81%) had primary MDS with 195 cases (19%) of therapy-related MDS. 759 patients (75%) are dead at a median follow-up of 18 months (range: 0–223 months) with leukemic transformation documented in 125 cases (12%). IPSS-R risk distribution was as follows: very low (n=149, 15%), good (n=261, 26%), intermediate (n=221, 22%), high (n=131, 13%), and very high (n=252, 25%). ii) IPSS-R karyotype (Entire cohort; n=1,014): The five cytogenetic groups by IPSS-R were as follows: very good (n=43, 4%), good (n=577, 57%), intermediate (n=187, 18%), poor (n=83, 8%), and very poor (n=124, 12%). We evaluated the prognostic impact of the above groups by Kaplan Meier and Cox proportional hazards analysis. OS for the five cytogenetic groups was as follows: good (36 months), very good (28 months), intermediate (20 months), poor (13 months), and very poor (6 months) (Figure 1). OS of patients with very good karyotype was significantly better than patients with very poor and poor karyotype (p<0.0001, RR 3.2 and p=0.04, RR 1.6 respectively) but similar to patients with intermediate and good karyotype (p=0.22 and 0.28 respectively). iii) IPSS-R karyotype (Primary MDS; n=819): Cytogenetic risk groups by IPSS-R were as follows: very good (n=38, 5%), good (n=512, 63%), intermediate (n=153, 19%), poor (n=46, 6%), and very poor (n=70, 9%). OS of the five groups was as follows: good (39 months), very good (23 months), intermediate (21.5 months), poor (14.5 months), and very poor (6.5 months). OS of patients with very good karyotype was significantly better than patients with very poor karyotype (p=0.0002, RR 2.5) but similar to patients with poor, intermediate and good karyotype (p=0.23, 0.26 and 0.18 respectively). iv) Monosomal karyotype: MK was identified in 153 (15%) cases of which 4 cases were intermediate, 42 poor, and 107 very poor by IPSS-R. OS of patients with MK was similar to those with very poor karyotype (6 months). In addition, OS of patients with very poor without MK was akin to patients with poor without MK (p=0.21). Furthermore, among primary MDS we identified 83 (8%) cases of MK of which 4 were intermediate, 21 were poor, and 58 very poor by IPSS-R. We confirmed that OS of patients with MK was similar to patients with very poor karyotype (6.5 months). Moreover, survival of patients with very poor without MK was similar to patients with poor without MK (p=0.51). Conclusions: In this independent analysis of 1,014 patients with MDS, IPSS-R cytogenetic risk characterization failed to discriminate between very good, good and intermediate prognostic groups. In addition, patients with very poor without MK have a similar prognosis to patients with poor without MK and should be included in the poor category whereas the presence of MK should warrant inclusion into the very poor risk category. Disclosures: No relevant conflicts of interest to declare.

Abstract INTRODUCTION: Erdheim-Chester Disease (ECD) is a rare hematologic disease manifesting as granulomatous or fibrotic infiltration of long bones and non-skeletal tissues by non-Langerhans foamy histiocytic (CD68+, CD1a-, S100-) cells. The clinical presentation can be diverse and any organ can be affected. It is estimated that less than 500 cases have been reported in the literature. METHODS: We retrospectively reviewed the medical records of patients evaluated at Mayo Clinic from January 2001 to May 2014. A tissue biopsy review by pathologists at Mayo Clinic was necessary for inclusion in the study. In all cases, the diagnosis of ECD was confirmed using clinical criteria in conjunction with histopathologic findings. Clinical data such as patient characteristics, disease presentation, management strategies, treatment responses, and survival time were collected. RESULTS: Forty-five patients with confirmed ECD were included in our study. The median age at diagnosis was 53 years (range, 32-78), while the median age of onset of symptoms prior to diagnosis was 24 months (range, 1-180). There was a male predilection with a male to female ratio of 2.4. The duration of follow-up ranged from 1-168 months (median, 20). At the time of last follow-up, 38 patients were alive and 5 were dead, while the vital statuses of 2 patients were unknown. The median and mean survival times from the time of diagnosis were 150 and 130 months respectively. The median survival time from the time of symptom onset was not reached and mean time was 154 months (Figures 1A and 1B). Bone pain was the most common presenting symptom (27%). Other common presentations included diabetes insipidus (24%), abdominal pain (22%), B symptoms (13%), visual changes (13%), renal failure/obstruction (11%), pleural effusion (9%), other neurologic symptoms (9%), ataxia (7%), pericardial effusion (7%), edema (7%), dyspnea (7%), and hypertension (7%). The organs/sites involved were bone (80%), central nervous system (59%), kidneys (56%), lungs (38%), retroperitoneum (33%), heart (22%), sinuses (22%), bone marrow (14%), adrenal glands (13%), liver (11%), spleen (11%), and skin (16%). Only 18 (40%) patients had the diagnosis established by the first biopsy. The rest required multiple biopsies before the diagnosis was confirmed (median, 2; range, 1-5). Testing for BRAF V600Ewas performed in 12 patients and 8 (67%) tested positive for the mutation. Eight patients have not required ECD-specific treatment so far. Of the 37 patients who required treatment, the median number of treatments received was 2 (range, 1-7). The systemic treatments received and their response rates are summarized in Table 1. Four patients received radiotherapy but none responded. At the time of the last follow up, 5 patients with BRAFV600E were receiving treatment with vemurafenib or dabrafenib. However, follow-up is insufficient for proper assessment of response. CONCLUSIONS: ECD is an extremely rare diagnosis as exemplified in our retrospective analysis. The diagnosis is often challenging due to protean and diverse clinical presentation as well as frequent inconclusive initial biopsies. There is usually a long-latency period of smoldering symptoms leading to definitive diagnosis. A high level of suspicion is essential in order to make the diagnosis and BRAFmutation analysis should be considered an integral part of work up even if biopsy is non-diagnostic. Traditional oncologic systemic therapies and even novel rheumatologic anti-inflammatory agents generally have limited objective activity. BRAF inhibitors offer a novel treatment option and results of prospective studies are eagerly awaited. Abstract 1405. Table 1: Summary of Response to Various Treatment Modalities in Patients with ECD Therapeutic Agent Number of Patients Treated Response (%) Complete Response Partial Response Stable Disease No response Corticosteroids 11 0 0 9 91 Methotrexate 9 0 0 11 89 Cyclophosphamide 4 0 0 25 75 2-CDA 12 8 17 25 50 Interferon-α 8 0 29 14 57 Vinorelbine 4 0 50 0 50 Tumor necrosis-α factor Inhibitors 7 0 0 14 86 Interleukin-1 Receptor Antagonists 6 17 17 0 67 Tamoxifen 2 0 50 0 50 Radiotherapy 4 0 0 0 100 Figure 1 Figure 1. Disclosures Off Label Use: We report among all treatments utilized at our institution for ECD including the use of steroids, immunosupressants, TNF blockers, interleukin-1 receptor antagonists, and BRAF inhibitors in patients with Erdheim Chester Disease. These treatments, though supported by other reports in the literature, have not been explicitly approved by the FDA for ECD..

Abstract Abstract 3790 Background: Chronic myelomonocytic leukemia (CMML) is a clonal stem cell disorder characterized by: persistent peripheral blood (PB) monocytosis (>1 × 10(9)/L), absence of BCR-ABL1 fusion, absence of rearrangement of the PDGFRA/B genes, <20% bone marrow (BM) & PB blasts, and dysplasia involving one or more myeloid cell lines. It is clinically considered to be an overlapping syndrome with myelodysplastic and myeloproliferative features. The natural history and prognostic features of CMML are not well defined with the MD Anderson prognostic score (MDAPS) and the Spanish risk stratification by cytogenetics being the two major prognostic tools currently being used in clinical practice. Methods: 227 patients with WHO defined CMML were seen at the Mayo Clinic from 1997 through 2007. All patients underwent bone marrow (BM) examination and cytogenetic evaluation at diagnosis. We evaluated the prognostic relevance of several clinical and laboratory parameters including those previously identified by the MDAPS (Blood 2002;99:840) and the Spanish cytogenetic risk stratification (Haematologica 2011;96:375). Results: Among the 227 study patients, 153 (67%) were males and median age was 71 years (range, 17–90 years). There were 192 (85%) patients with CMML-1 & the remainder had CMML-2. At a median follow-up of 15 months, 166 (73%) deaths and 33 (14.5%) leukemic transformations were documented. Median survivals were 22 months for CMML-1 and 14 months for CMML-2. In univariate analysis, significant risk factors for survival included decreased hemoglobin level, decreased platelet count and increased levels of white blood cells (WBC), absolute neutrophils (ANC), absolute monocytes (AMC), absolute lymphocytes (ALC), PB blasts, BM blasts and presence of circulating immature myeloid cells (IMC; inclusive of PB blasts). However, on multivariable analysis that included the aforementioned Spanish cytogenetic risk stratification, only increased AMC (>10 × 10(9)/L, RR 2.5, 95% CI 1.7–3.8), presence of circulating IMC (RR 2.0, 95% CI 1.4–2.7), decreased hemoglobin (<10 g/dL; RR 1.6, 99% CI 1.2–2.2), and decreased platelet count (<100 × 10(9)/L; RR 1.4, 99% CI 1.0–1.9) retained significance. Using these four independent risk factors, we prepared a new prognostic risk model that performed better than both the MDAPS and the Spanish cytogenetic risk models (Figure). The Mayo risk model was also predictive of leukemic transformation: high risk RR 4.9 (95% CI 1.9–12.8) and intermediate risk RR 2.6 (1.1–5.9). Individual parameters of independent significance for leukemic transformation included PB blast count and AMC >10 × 10(9)/L. Conclusions: Absolute monocyte count is the strongest predictor of survival in CMML. Other independent risk factors include circulating immature myeloid cells, anemia and thrombocytopenia. A risk model based on these four risk factors is effective in predicting both overall and leukemia-free survival and outperforms both the MDAPS and risk stratification by cytogenetics. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 756 Background: Myelofibrosis (MF) is the most serious of chronic myeloproliferative neoplasms (MPNs) for which there is no approved therapy. Exaggerated JAK2 signaling, either by gain-of-function mutations (eg, JAK2V617F) or high circulating levels of JAK1/2 activating cytokines (eg, interleukin [IL]-6), is believed to play a key role in MPN pathogenesis. INCB018424 (424), a selective oral inhibitor of JAK1/2, has demonstrated clinical benefits including reduction of splenomegaly and improvement of symptoms in a Phase I/II trial in MF patients. Thrombocytopenia was identified as the dose limiting toxicity occurring in 30% of patients at 25mg BID. Methods: Patients with primary, post-PV or post-ET MF were enrolled in the study. Following the characterization of multiple dosing regimens, an individually optimized dose regimen strategy was developed, based on available efficacy and safety data. In a subset of patients, spleen volume change was measured by MRI at 1, 3 and 6 months of treatment in order to establish an objective measure of spleen response. The impact of 424 on MF associated symptoms was assessed using a validated instrument, MFSAF (Mesa et al., Leukemia Research 2009). As a surrogate marker of functional benefit, exercise capacity was assessed with a standardized 6-minute walk test (6MWT) at baseline, 1, 3 and 6 months of therapy. Results: 155 patients were enrolled in the study, with median duration of treatment of 1+ years and the duration of drug exposure of >150 patient years (76 patients received >1 year of therapy). Clinical responses have been maintained over the entire duration of treatment and most patients remain on therapy (115 of 155 patients; 74%). Progression to AML occurred in 3 patients, which is below the expected frequency based on published data (Barosi et al., Blood 2007). SAEs related to 424 occurred in 12 patients, and are generally related to bone marrow suppression or return of or exacerbation of signs and symptoms of MF when therapy is discontinued. Further optimization of the dosing regimen utilized baseline platelet count to determine the starting dose (10 or 15mg BID) and allowed dose titration after 1 and 2 months of therapy; most patients were optimized to 15 or 20mg BID. This approach significantly reduced the incidence of thrombocytopenia (<5%, N=35), while providing equivalent efficacy to higher dose regimens. With an optimized dosing regimen, spleen volume reduction was evident as early as 1 month, and durable over 6 months, of therapy (33 % median decrease after 6 months, N=23). Eleven of 23 (48%) of patients achieved ≥ 35% reduction (equivalent to IWG clinical improvement criteria of 50% reduction by palpation) from baseline in spleen volume at month 6. MF patients have impaired exercise capacity at baseline (decreased 6MWT performance by 60-90 meters vs. age-matched controls). Treatment with 424 resulted in improved 6MWT performance, with median increase from baseline of 33, 58 and 70 meters after 1,3 or 6 months of therapy, respectively. Rapid and durable reduction of a total symptom score based on key symptoms (fatigue, abdominal discomfort/pain, bone/muscle pain, night sweats and pruritus) was noted (51 % and 58% of patients achieving 50% reduction in the total score following 1 and 6 months of treatment, respectively). Improvement in symptoms coincided with a rapid and sustained reduction in pro-inflammatory cytokines, including IL-1b, IL-1ra, IL-6 and TNFa, without tachyphylaxis to therapy. Finally, spleen response was associated with greater improvements in total symptom score, exercise capacity, and reduced fatigue (see Table). Conclusion: An optimized dosing regimen of INCB018424 resulted in sustained clinical, symptomatic and functional benefits in MF patients with an improved hematological safety profile compared to a 25 mg BID regimen. Safety and efficacy of 424 in MF patients is further supported by the follow-up data of >1 yr of 424 therapy. Disclosures: Verstovsek: Incyte: Research Funding. Bradley:Incyte Corporation: Employment, Equity Ownership. Erickson-Viitanen:Incyte Corporation: Employment, Equity Ownership. Vaddi:Incyte Corporation: Employment, Equity Ownership. Levy:Incyte Corporation: Employment, Equity Ownership.

Background:Patients with myelofibrosis (MF) who fail or are intolerant to JAK inhibitors (JAKi) have limited treatment options. Tagraxofusp is a targeted therapy directed to CD123 that was approved by the US FDA for the treatment of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN). CD123 is expressed on a variety of malignancies including BPDCN, acute myeloid leukemia (AML), and certain myeloproliferative neoplasms (MPN), including MF. Moreover, CD123+ plasmacytoid dendritic cells (pDCs), the cell of origin of BPDCN, have been detected in the microenvironment of certain myeloid neoplasms, including MF, where they may play a tumor‐promoting role.1,2,3 Notably, pDCs share a common precursor cell with monocytes, and monocytosis has been reported as a poor prognostic factor, associated with rapid disease progression and shortened survival, suggesting an accelerated disease phase in MF.4 As such, tagraxofusp may offer a novel and rational therapeutic approach in patients with relapsed/refractory MF, including patients with monocytosis.Aims:Primary objectives include assessment of safety, determining the recommended Phase 2 dose (RP2D) and schedule, and evaluating efficacy in patients with MF who were relapsed, refractory, or unable to tolerate JAKi.Methods:This multicenter, open‐label Phase 1/2 trial is enrolling patients with MF. In the Stage 1 (dose escalation), tagraxofusp was administered as a daily IV infusion at 7, 9, and 12 mcg/kg on days 1–3 every 21 days (cycle 1–4), 28 days (cycles 5–7), and 42 days (cycles 8+). In Stage 2 (expansion), patients are receiving the RP2D (12 mcg/kg).Results:23 patients with MF received tagraxofusp, including 12 patients who received ≥ 3 prior lines of therapy. Median age 69 years (range 55–81), 61% were female, and 30% had baseline monocytosis (≥ 1x109/L). Baseline risk assessment based on the DIPSS Plus risk group assessment showed 1 patient (4%) with intermediate‐1, 12 patients (52%) with intermediate‐2, and 10 patients (44%) with high‐risk. At study entry, the median platelet count was 59 K/uL with 71% of patients had baseline platelets <100 K/uL, of which 8 patients had platelets <50 K/uL. 87% of patients had baseline splenomegaly (spleen palpable ≥ 5 cm below the left costal margin [LCM]). Most common treatment‐related adverse events (TRAEs, incidence ≥ 15%) include headache, hypoalbuminemia, alanine aminotransferase increased and thrombocytopenia. The most common ≥ grade 3 TRAE was thrombocytopenia (8%). Capillary leak syndrome was reported in 1 patient (grade 3). Among the 14 evaluable patients with baseline splenomegaly, 57% had spleen size reductions: 43% (6/14) had reductions of > 25%, of which 3 patients had reductions of ≥ 45%. In 5 patients with baseline splenomegaly and monocytosis, 80% (4/5) had reductions of > 25%, of which 2 had reductions of ≥ 45%. Six patients, including 3 patients with monocytosis and 5 patients with platelets <100 K/uL, had treatment duration of 6 months or more.Summary/Conclusion:Tagraxofusp demonstrated single agent activity, with a predictable and manageable safety profile, in patients with relapsed/refractory MF, including in patients with monocytosis, a poor prognostic factor, both constituting potential areas of unmet medical need. Enrollment continues, and updated trial data will be presented. Registrational trial designs are being evaluated. Trial information: NCT02268253.

Background:Patients with chronic myelomonocytic leukemia (CMML) have historically poor outcomes, with ∼6–7 month median overall survival (OS) in the relapsed/refractory (r/r) setting. Splenomegaly is a major cause of morbidity, is a poor prognostic factor and has emerged as a potential therapeutic target in CMML. Tagraxofusp (SL‐401) is a targeted therapy directed to CD123, a target expressed on CMML blasts, monocytes and neoplastic microenvironmental plasmacytoid dendritic cells (pDCs) that are part of the CMML malignant clone, as well as on a variety of additional malignancies. Tagraxofusp was approved by the US FDA for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) and is being investigated in other CD123‐expressing malignancies.Aims:Primary objectives include assessment of safety, determining the recommended Phase 2 dose (RP2D) and schedule, and evaluating efficacy in patients with CMML.Methods:This multicenter, open‐label, Phase 1/2 clinical trial is enrolling patients with CMML. In Stage 1 (dose escalation), tagraxofusp was administered as a daily IV infusion at 7, 9, and 12 mcg/kg on days 1–3 every 21 days (cycle 1–4), every 28 days (cycles 5–7), and every 42 days (cycles 8 and beyond). In Stage 2 (expansion), patients receive the RP2D (12 mcg/kg).Results:20 patients with CMML (CMML‐1 [n = 12]; CMML‐2 [n = 8]) were treated with tagraxofusp, including 18 in the relapsed/refractory setting, with hypomethylating agents (HMAs) being the most commonly administered prior therapy. Median age was 69 years (range 43–80) and 80% were male. 10 patients (50%) had baseline splenomegaly (defined as spleen palpable below the left costal margin [BCM]), of which 6 had baseline splenomegaly ≥ 5 cm BCM. Most common treatment‐related adverse events (TRAEs, incidence ≥ 20%) were hypoalbuminaemia, thrombocytopenia, nausea, vomiting and fatigue. Most common ≥ grade 3 TRAEs were thrombocytopenia (35%) and nausea (5%). Capillary leak syndrome was reported in 3 patients (grade 1–2). 100% (10/10) of patients with baseline splenomegaly had a spleen response by physical exam: 80% (8/10) had spleen size reduction of ≥ 50% and 67% (4/6) with baseline spleen size ≥ 5 cm had spleen size reduction of ≥ 50%. Three patients treated with tagraxofusp achieved bone marrow complete responses (BMCRs), including 1 patient who was bridged to stem cell transplant in remission on tagraxofusp.Summary/Conclusion:Tagraxofusp demonstrated single agent activity in patients with CMML and splenomegaly, an area of potential unmet medical need. Given the expression of CD123 in CMML, tagraxofusp represents a rational therapeutic approach in this disease. Updated data will be presented, and a registrational trial is planned. Trial information: NCT02268253.