Baseline Spleen Size Research Articles

P1041: IMPACT OF FEDRATINIB ON SPLEEN VOLUME AND MYELOFIBROSIS SYMPTOMS IN PATIENTS WITH SUBSTANTIAL SPLENOMEGALY: POST HOC ANALYSES FROM THE JAKARTA AND JAKARTA2 TRIALS

Background: In myelofibrosis (MF), splenomegaly is a marker of disease progression, and larger spleen size (SS) is correlated with poorer survival and debilitating symptoms. Fedratinib (FEDR) is an oral, selective Janus kinase 2 (JAK2) inhibitor approved as first-line (1L) treatment (Tx) of patients (pts) with MF and in pts previously treated with ruxolitinib (RUX). In the phase 3, placebo-controlled JAKARTA trial (NCT01437787) and the phase 2, single-arm JAKARTA2 trial (NCT01523171), pts experienced substantial improvements in spleen volume and MF symptoms after receiving 6 FEDR Tx cycles. Given the prognostic impact of splenomegaly, these analyses explore whether these clinical benefits were influenced by pre-Tx SS. Aims: Investigate the efficacy of FEDR 400 mg/d in JAKARTA and JAKARTA2, in pt subgroups defined by baseline (BL) SS. Methods: The JAKARTA trial assessed FEDR 400 mg/d, FEDR 500 mg/d, and placebo in pts with JAK inhibitor-naïve MF, and the JAKARTA2 trial evaluated FEDR 400 mg/d (starting dose) in pts resistant/intolerant to prior RUX. Both studies enrolled pts with intermediate- or high-risk MF, SS >5 cm from the left costal margin by palpation, platelets ≥50×109/L, and ECOG PS ≤2. These post hoc analyses included pts from both studies who were allocated to receive FEDR 400 mg/d (the approved dosage) in continuous 28-d Tx cycles. Pt subgroups were divided according to BL median SS (mSS) in each trial. Changes from BL in spleen volume and Myelofibrosis Symptom Assessment Form (MFSAF) total symptom score (TSS) were measured at the end of cycle 6 (EOC6). Spleen volume was assessed by MRI/CT scan; MFSAF TSS was the sum of 6 MF symptom scores: night sweats, early satiety, pruritus, pain under ribs-left side, abdominal discomfort, and bone/muscle pain. Eligible pts must have had spleen volume and/or TSS data at BL and EOC6. Results: Overall, 96 pts in JAKARTA and 97 pts in JAKARTA2 received FEDR 400 mg/d; mSS (range) at BL was 16 (5–40) cm and 18 (5–36) cm, respectively. In the JAKARTA <mSS and ≥mSS cohorts, median BL spleen volume was 1771 (316–3396) mL and 3329 (983–6430) mL, respectively, and median TSS was 13.0 (0.0–54.9) and 17.2 (0.4–57.0). In JAKARTA2, median BL spleen volume was 1937 (737–4305) mL and 4002 (1821–7815) mL for pts with <mSS and ≥mSS, respectively; BL TSS was 17.2 (0.7–48.0) and 23.6 (1.0–44.0). Overall, 75 (78%) pts in JAKARTA and 51 (53%) pts in JAKARTA2 had spleen volume data available at BL and EOC6; the <mSS and ≥mSS cohorts, comprised 37 and 38 pts, respectively, in JAKARTA, and 31 and 20 pts in JAKARTA2. Median spleen volume reduction (SVR) from BL was similar between the <mSS and ≥mSS cohorts in each trial, and 97% of pts with ≥mSS in both trials achieved some degree of SVR. In JAKARTA, median SVR at EOC6 was −38% (95% CI, −43 to −31) in the <mSS and −40% (95% CI, −40 to −28) in the ≥mSS cohort; in JAKARTA2, median SVR was −37 (95% CI, −43 to −30) in the <mSS and −38.5% (95% CI, −49 to −14) in the ≥mSS cohort. TSS data were available at BL and EOC6 for 71 (74%) pts in JAKARTA and 51 (53%) pts in JAKARTA2. Changes from BL in TSS at EOC6 were similar in the JAKARTA <mSS and ≥mSS cohorts, with median TSS reductions of −49% and −51%, respectively. Median TSS changes at EOC6 in JAKARTA2 were greater for pts with larger spleens, −36% and −49% in the <mSS and ≥mSS cohorts, respectively. Image:Summary/Conclusion: Pts who completed 6 Tx cycles with FEDR 400 mg/d, whether used as 1L MF Tx or after RUX Tx, experienced substantial improvements in spleen volume and MF symptom severity regardless of the extent of splenomegaly at BL.

Spleen and Symptom Responses with Fedratinib (FEDR) in Patients with Myelofibrosis (MF) and Substantial Splenomegaly

Spleen and Symptom Responses with Fedratinib (FEDR) in Patients with Myelofibrosis (MF) and Substantial Splenomegaly

MPN-332: Clinical Benefit of Pelabresib (Cpi-0610) in Combination with Ruxolitinib in JAK Inhibitor Treatment-Naïve Myelofibrosis Patients: Interim Efficacy Subgroup Analysis from Arm 3 of the MANIFEST Phase 2 Study

Context: Pelabresib (CPI-0610), a first-in-class, oral, small-molecule inhibitor of BET proteins (BETi), has potential to promote disease-modifying activity through altered gene regulation of key oncogenic, fibrotic, and inflammatory factors in MF. Treatment with JAKi ruxolitinib (rux) or fedratinib in the frontline setting is associated with approximately 30–40% splenic response (spleen volume reduction ≥ 35% [SVR35]) at 6 months. BETi pelabresib monotherapy demonstrated clinical activity in heavily pre-treated MF pts. Therefore, combination of pelabresib with rux is expected to achieve higher SVR35 response rate in JAKi treatment-naïve MF pts. Objective: Evaluation of pelabresib in combination with rux in JAKi treatment-naïve MF pts. Design: Pts with MF who were not previously treated with JAKi were enrolled in Arm 3 of MANIFEST. The primary endpoint is SVR35 response at wk 24. Pts were treated with pelabresib 125 mg daily on days 1–14 in a 21-day cycle in combination with rux, which was dosed based on the baseline platelet count. Results: As of 29 September 2020, 78 pts were treated, and 66 pts were ongoing. Baseline characteristics were mean age: 67 years; 72% male; primary MF: 54% pts; DIPSS ≥Int-2: 76% pts; IPSS ≥Int-2: 83%; Hgb <10g/dL: 65%; median platelet: 294 x 109/L (range: 100, 1849); median spleen volume: 1719 cc (range: 451, 4782); median TSS: 16 (range: 0, 38); high-molecular-risk mutations: 55%, JAK2 mutation: 72%. At wk 24, 67% (42/63) pts achieved SVR35 (median % change from baseline: -50%; range: -84.4%, 23.7%). Subgroup analysis showed that mean percentage change in spleen volume at wk 24 was consistent across subgroups based on gender, age, risk score, MF subtype, baseline platelet count, and baseline spleen size. Importantly, subgroup analysis based on molecular findings showed a significant benefit regardless of the mutational status, including the presence of ASXL1 mutation, which generally carries a poor prognosis. Pelabresib was generally well tolerated. Conclusions: Pelabresib treatment in combination with rux in JAKi treatment-naïve MF pts resulted in spleen volume reduction that was greater than what would be expected with rux alone, regardless of baseline patient disease and demographic characteristics. Pelabresib (CPI-0610), a first-in-class, oral, small-molecule inhibitor of BET proteins (BETi), has potential to promote disease-modifying activity through altered gene regulation of key oncogenic, fibrotic, and inflammatory factors in MF. Treatment with JAKi ruxolitinib (rux) or fedratinib in the frontline setting is associated with approximately 30–40% splenic response (spleen volume reduction ≥ 35% [SVR35]) at 6 months. BETi pelabresib monotherapy demonstrated clinical activity in heavily pre-treated MF pts. Therefore, combination of pelabresib with rux is expected to achieve higher SVR35 response rate in JAKi treatment-naïve MF pts. Evaluation of pelabresib in combination with rux in JAKi treatment-naïve MF pts. Pts with MF who were not previously treated with JAKi were enrolled in Arm 3 of MANIFEST. The primary endpoint is SVR35 response at wk 24. Pts were treated with pelabresib 125 mg daily on days 1–14 in a 21-day cycle in combination with rux, which was dosed based on the baseline platelet count. As of 29 September 2020, 78 pts were treated, and 66 pts were ongoing. Baseline characteristics were mean age: 67 years; 72% male; primary MF: 54% pts; DIPSS ≥Int-2: 76% pts; IPSS ≥Int-2: 83%; Hgb <10g/dL: 65%; median platelet: 294 x 109/L (range: 100, 1849); median spleen volume: 1719 cc (range: 451, 4782); median TSS: 16 (range: 0, 38); high-molecular-risk mutations: 55%, JAK2 mutation: 72%. At wk 24, 67% (42/63) pts achieved SVR35 (median % change from baseline: -50%; range: -84.4%, 23.7%). Subgroup analysis showed that mean percentage change in spleen volume at wk 24 was consistent across subgroups based on gender, age, risk score, MF subtype, baseline platelet count, and baseline spleen size. Importantly, subgroup analysis based on molecular findings showed a significant benefit regardless of the mutational status, including the presence of ASXL1 mutation, which generally carries a poor prognosis. Pelabresib was generally well tolerated. Pelabresib treatment in combination with rux in JAKi treatment-naïve MF pts resulted in spleen volume reduction that was greater than what would be expected with rux alone, regardless of baseline patient disease and demographic characteristics.

MPN-379: Interim Results from an Ongoing Phase 1/2 Clinical Trial of Tagraxofusp, a CD123-Targeted Therapy, in Patients with Chronic Myelomonocytic Leukemia (CMML)

Background: Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes and myeloproliferative neoplasms (MDS/MPN) with poor outcomes, particularly in the relapsed/ refractory (R/R) setting. Current FDA-approved therapies have limited clinical impact. Clinical outcomes appear particularly poor in patients with proliferative features (high WBC counts, splenomegaly, high symptom burden) and high-risk cytogenetic and/or genomic features. Tagraxofusp (TAG) targets CD123, a biomarker expressed on CMML blasts and clonal monocytes; additionally, there is evidence of microenvironmental clonal plasmacytoid dendritic cells. Collectively, these features provide a rationale to assess the role of TAG in CMML patients. Objectives: To assess safety and efficacy of TAG in patients with CMML refractory/resistant/intolerant to HMAs, hydroxyurea, or intensive chemotherapy. Methods: Multicenter Phase 1/2 trial with TAG being administered as a daily IV infusion at 7, 9, or 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 1 and 12 mcg/kg in stage 2. Results: Twenty-nine patients, including CMML-1 [n=19] and CMML-2 [n=10]; the median age was 70 years (range 42–87). Thirteen patients (45%) had baseline splenomegaly (spleen palpable below the left costal margin [BCM]); nine of these patients had baseline splenomegaly ≥5 cm BCM. The most common treatment-related adverse events (TRAEs, incidence ≥25%) were hypoalbuminemia, thrombocytopenia, and anemia. The most common ≥ grade 3 TRAEs were thrombocytopenia (34%), anemia (17%), and nausea (3%). Capillary leak syndrome was reported in seven patients (4 with grade 1–2; 3 with grade 3). Three patients, all with splenomegaly at baseline, achieved complete bone marrow responses (BMCRs), including one patient who was allografted in CR. Of note, two of these three BMCRs had proliferative CMML with high-risk cytogenetic and genomic features. Analysis of clinical benefit demonstrated a clinical reduction in splenomegaly in all patients with baseline splenomegaly (14/14): 71% (10/14) had spleen size reduction of ≥50%, and 60% (6/10) with baseline spleen size ≥5 cm had spleen size reduction of ≥50%. Conclusions: The interim results represent the clinical efficacy and safety of TAG monotherapy in a cohort of CMML patients, including patients with splenomegaly, a recognized poor prognostic factor in CMML. ( NCT02268253 )

Spleen Size and Function in Sherpa Living High, Sherpa Living Low and Nepalese Lowlanders

High-altitude (HA) natives have evolved some beneficial responses leading to superior work capacity at HA compared to native lowlanders. Our aim was to study two responses potentially protective against hypoxia: the spleen contraction elevating hemoglobin concentration (Hb) and the cardiovascular diving response in Sherpa highlanders, compared to lowlanders. Male participants were recruited from three groups: (1) 21 Sherpa living at HA (SH); (2) seven Sherpa living at low altitude (SL); and (3) ten native Nepalese lowlanders (NL). They performed three apneas spaced by a two-min rest at low altitude (1370 m). Their peripheral oxygen saturation (SpO2), heart rate (HR), and spleen volume were measured across the apnea protocol. Spleen volume at rest was 198 ± 56 mL in SH and 159 ± 35 mL in SL (p = 0.047). The spleen was larger in Sherpa groups compared to the 129 ± 22 mL in NL (p < 0.001 compared to SH; p = 0.046 compared to SL). Spleen contraction occurred in all groups during apnea, but it was greater in Sherpa groups compared to NL (p < 0.001). HR was lower in Sherpa groups compared to NL both during rest (SL: p < 0.001; SH: p = 0.003) and during maximal apneas (SL: p < 0.001; SH: p = 0.06). The apnea-induced HR reduction was 8 ± 8% in SH, 10 ± 4% in SL (NS), and 18 ± 6% in NL (SH: p = 0.005; SL: p = 0.021 compared to NL). Resting SpO2 was similar in all groups. The progressively decreasing baseline spleen size across SH, SL, and NL suggests a role of the spleen at HA and further that both genetic predisposition and environmental exposure determine human spleen size. The similar HR responses of SH and SL suggest that a genetic component is involved in determining the cardiovascular diving response.

Final Results of Phase 2 Clinical Trial of LCL161, a Novel Oral SMAC Mimetic/IAP Antagonist, for Patients with Intermediate to High Risk Myelofibrosis

Final Results of Phase 2 Clinical Trial of LCL161, a Novel Oral SMAC Mimetic/IAP Antagonist, for Patients with Intermediate to High Risk Myelofibrosis

PF672 RESULTS FROM ONGOING PHASE 1/2 CLINICAL TRIAL OF TAGRAXOFUSP (SL‐401) IN PATIENTS WITH RELAPSED/REFRACTORY CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML)

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.

CML patients presenting with priapism: Is there any disparity in outcome?

e18545 Background: Priapism, a urological emergency that needs prompt treatment, is an uncommon presenting feature of chronic myeloid leukemia (CML). CML frequently occurs in younger males and adolescents in developing countries. Occurrence of erectile dysfunction (ED) in this particular age group can severely decrease the quality of life. It is known that immediate treatment of priapism preserves erectile function. The data on the outcome of priapism in CML patients from developing world is limited. Methods: We analysed the CML patients treated at PGIMER Chandigarh from January 2003 to December 2018. Baseline spleen and liver size, hematological parameters, Sokal and Hasford score were documented. Duration of priapism, treatment received by the patients, and response to Imatinib were recorded. The severity of ED was assessed by SHIM (Sexual Health Inventory for Men) score. Results: Twenty-three patients (1.7%) out of total 1350 male CML-CP patients had priapism at diagnosis. The median age was 24 years (range 13 – 50 years); 60.8% patients belonged to 21 – 40 years age group. Median duration of priapism was 8 days (range 2 – 25 days). Splenomegaly and hepatomegaly were found in 91.3% and 56.5% patients, respectively. Baseline median hemoglobin was 9.9 g/dL; TLC was 283000/mm3 and platelet count was 352000/mm3. Based on Sokal score, 4/23, 16/23 and 3/23 patients belonged to low, intermediate and high risk categories, respectively. According to Hasford score, 7/23, 14/23 and 2/23 patients belonged to low, intermediate and high risk categories, respectively. All patients received cytoreductive therapy [hydroxyurea and Imatinib]; 21 patients underwent penile aspiration, 13 patients underwent therapeutic leucapheresis and 8 patients underwent distal penile shunt surgery. Majority of the patients (78.2%) achieved CHR at 6 weeks and 21 patients achieved MMR at 12 months. ED could be assessed in 14 patients on follow up. As per SHIM score, 2/14 and 12/14 patients had moderate and severe ED, respectively. The occurrence and severity of ED was unaffected by leucapheresis or shunt surgery. Conclusions: We found severe ED on follow up among majority of CML-CP patients with priapism at presentation. Despite favourable response to Imatinib, long duration of symptoms and hyperleucocytosis probably contributed to ischemic priapism and severe ED in the study cohort. We conclude that prolonged and untreated priapism in CML-CP patients is a major risk factor for ED. There is a need to sensitise the primary care physicians and surgeons in the developing world regarding this grave complication in CML patients.

Outcome of CML patients with de novo bleeding complications: Do they behave differently?

e18546 Background: Chronic myeloid leukemia (CML) is a clonal hematopoietic neoplasm. A subset of CML patients present may present with unusual bleeding manifestations. There is limited data on the incidence and outcome of such patients on treatment with imatinib. Methods: We analysed the CML patients treated at PGIMER Chandigarh from January 2003 to December 2018. Baseline spleen and liver size, hematological parameters, Sokal and Hasford score, site and severity of bleeding (as per WHO classification) were recorded. The treatment response, occurrence of cytopenias and need for second line TKI were analyzed. Results: Sixty-six patients (2.8%) out of 2350 adult CML patients had bleeding at diagnosis. The median age was 35 years (range 15 – 66 years); 56.1% were males. The median duration of follow up was 79 months (range 6 – 123 months). Splenomegaly and hepatomegaly was found in 89.3% and 65.1% patients, respectively. Baseline median hemoglobin was 9.5 g/dL; TLC was 151600/mm3 and platelet count was 301000/mm3. Based on Sokal score, 15/66, 26/66 and 25/66 patients belonged to low, intermediate and high risk categories, respectively. According to Hasford score, 22/66, 36/66 and 8/66 patients belonged to low, intermediate and high risk categories, respectively. Based on WHO grading, 33/66, 30/66 and 3/66 patients had grade 1, 2 and 3 bleed, respectively. 48 patients had mucocutaneous bleeding [cutaneous 17, gum bleed 16, epistaxis 15], 4 had psoas haematoma, 7 had vaginal bleeding, 3 had ocular bleeding, 6 had GI bleed [upper GI 3, lower GI 3], 3 had hematuria. 74.2% achieved CHR at 6 weeks and 83.3% achieved MMR at 12 months with Imatinib. 18 developed cytopenias which required Imatinib interruption or dose reduction. 18 required Imatinib dose escalation for suboptimal response, 5 patients received second line TKI. Six patients progressed to advanced phase CML (AP/BC) after a median duration of 32 months (range 21 – 49 months). Bleeding manifestations resolved in all patients and there was no recurrence of bleeding on follow up. Conclusions: Bleeding is an uncommon presentation of CML. It might be a harbinger of an increased risk of cytopenias, suboptimal treatment response and disease progression on Imatinib.

Results from Ongoing Phase 1/2 Clinical Trial of Tagraxofusp (SL-401) in Patients with Intermediate or High Risk Relapsed/Refractory Myelofibrosis

Background: Patients with myelofibrosis (MF) that have failed or are intolerant to JAK inhibitors (JAKi) have no standard treatment options. Tagraxofusp (Elzonris™; SL-401) is a novel targeted therapy directed to the interleukin-3 receptor-α (CD123), a target expressed on a variety of malignancies, including certain myeloproliferative neoplasms (MPNs) such as MF. CD123 is also expressed on plasmacytoid dendritic cells (pDCs), which reside in the tumor microenvironment and may play a role in promoting growth of MPNs and other malignancies. Therefore, targeting of CD123-expressing malignant cells and/or neighboring pDCs may offer a novel therapeutic approach. Tagraxofusp has demonstrated high levels of clinical activity against blastic plasmacytoid dendritic cell neoplasm (BPDCN), a CD123+ malignancy derived from pDCs.Methods: This multicenter, two-stage Phase 1/2 trial is enrolling patients with MF that were relapsed, refractory, or unable to tolerate JAKi. Primary objectives include assessment of safety, determining optimal dose/regimen, and evaluating efficacy outcomes. In the Stage 1 dose escalation cohort (completed), tagraxofusp was dosed as a daily IV infusion at 7, 9, and 12 mcg/kg/day, on days 1-3 every 21 days (cycle 1-4), every 28 days (cycles 5-7), and every 42 days (cycles 8+). In Stage 2 (ongoing), patients received the optimal dose determined in Stage 1 (12 mcg/kg/day).Results: As of July 2018, 18 patients with MF received tagraxofusp. Five patients were treated in the second line setting and 12 patients were treated in third-line setting, and beyond. Median age was 69 years (range 55-81); 60% patients were female. Of the 18 patients with DIPSS Plus risk group assessment available, 3 patients (17%) were intermediate-1, 10 patients (55%) were intermediate-2, and 5 patients (28%) were high-risk. Median platelet count was 66 K/uL (range 15-579). 70% (14/20) of patients had baseline platelets <100K/uL, of which 6 patients had platelets <50K/uL at study entry. 89% (17/19) of patients had baseline splenomegaly defined as palpable spleen 5 cm or more below costal margin (BCM) by physical exam. Most common treatment-related adverse events (TRAEs) include hypoalbuminemia and thrombocytopenia (each 27%), and alanine aminotransferase increased, anemia, dizziness, fatigue, headache and nausea (each 20%). Most common ≥grade 3 TRAEs include anemia (20%) and thrombocytopenia and fatigue (each 7%). Capillary leak syndrome was reported in 1 patient (5%; grade 3). 50% (6/12) of evaluable patients, with baseline spleen size 5 cm or more BCM, had a spleen response, of which 33% (4/12) had splenomegaly reduction by 33% or more and 25% (3/12) had splenomegaly reduction by 35% or more. 50% (3/6) of patients with spleen response had treatment duration 8+ months, including 8+, 12+ and 14+ months (all 3 ongoing). Four patients with baseline thrombocytopenia had treatment durations 8+ months, 3 of which are ongoing.Conclusions: Tagraxofusp monotherapy demonstrated improvements in splenomegaly, with a manageable safety profile, in patients with relapsed/refractory MF, an area of unmet medical need. Given CD123 expression on myeloid neoplastic cells and pDCs in the tumor microenvironment, tagraxofusp may offer a novel targeted approach for MF patients. Enrollment continues, and updated safety and efficacy data will be presented. Registrational designs are being evaluated. Clinical trial information: NCT02268253. DisclosuresPemmaraju:celgene: Consultancy, Honoraria; abbvie: Research Funding; cellectis: Research Funding; stemline: Consultancy, Honoraria, Research Funding; samus: Research Funding; novartis: Research Funding; Affymetrix: Research Funding; SagerStrong Foundation: Research Funding; plexxikon: Research Funding; daiichi sankyo: Research Funding. Gupta:Incyte: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Schiller:Pharmacyclics: Research Funding; Celator/Jazz Pharmaceuticals: Research Funding. Lee:LAM Therapeutics: Research Funding; AstraZeneca: Consultancy; Clinipace: Consultancy; Karyopharm Therapeutics Inc: Consultancy; Amgen: Consultancy. Yacoub:Ardelyx, INC.: Equity Ownership; Cara Therapeutics: Equity Ownership; Dynavax: Equity Ownership; Inycte: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Ali:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Sardone:Stemline Therapeutics: Employment, Equity Ownership. Wysowskyj:Stemline Therapeutics: Employment, Equity Ownership. Shemesh:Stemline Therapeutics: Employment, Equity Ownership. Chen:Stemline Therapeutics: Employment, Equity Ownership. Olguin:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics: Employment, Equity Ownership. Dunn:Stemline Therapeutics: Employment, Equity Ownership. Verstovsek:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees. Khoury:Stemline Therapeutics: Research Funding.

Results from Ongoing Phase 1/2 Clinical Trial of Tagraxofusp (SL-401) in Patients with Relapsed/Refractory Chronic Myelomonocytic Leukemia (CMML)

Background: Patients with chronic myelomonocytic leukemia (CMML) have historically had poor outcomes, with overall response rates (ORR) of ~16% for hypomethylating agents (HMA) in first-line registration studies with a median overall survival (OS) of ~4-7 months in the relapsed/refractory (R/R) setting. Allogeneic stem cell transplant is not an option for the majority, due to older age at diagnosis and comorbidities. Tagraxofusp (Elzonris™, SL-401) is a novel targeted therapy directed to the interleukin-3 receptor-α (CD123), a target expressed on a variety of malignancies. In CMML, CD123 is expressed on malignant progenitor cells as well as microenvironmental plasmacytoid dendritic cell (pDC) infiltrates, now shown to be part of the malignant clone (Solary, EHA 2018). We thus hypothesized that therapeutic targeting of CD123-expressing malignant cells and infiltrating clonal pDCs may offer a novel therapeutic approach. Tagraxofusp has already demonstrated high levels of clinical activity against blastic plasmacytoid dendritic cell neoplasm (BPDCN), a CD123+ malignancy derived from pDCs.Methods: This multicenter, two-stage Phase 1/2 trial is enrolling patients with relapsed/refractory (r/r) CMML or other myeloproliferative neoplasms (MPNs). Primary objectives include assessment of safety, determining optimal dose/regimen, and evaluating efficacy outcomes in patients with r/r CMML. In the Stage 1 dose escalation cohort (completed), tagraxofusp was administered as a daily IV infusion at 7, 9, and 12 mcg/kg/day, on days 1-3 every 21 days (cycle 1-4), every 28 days (cycles 5-7), and every 42 days (cycles 8+). In Stage 2 (ongoing), patients received the optimal dose determined in Stage 1 (12 mcg/kg; no MTD reached).Results: As of July 2018, 18 patients with CMML (CMML-1 [n=10]; CMML-2 [n=8]) received tagraxofusp. 13 patients were treated in second-line setting and 5 patients were treated in third-line and beyond, with HMAs being the most commonly administered prior therapy. Median age was 70 years (range 42-80); 78% patients were male. 53% (9/17) of patients had baseline splenomegaly (range: 2 to 22 cm palpable below left costal margin (BCM) by physical exam). Most common treatment-related adverse events (TRAEs) were hypoalbuminemia and nausea (each 38%), vomiting (31%), fatigue, edema, and thrombocytopenia (each 25%). Most common ≥grade 3 TRAEs were thrombocytopenia (13%) and nausea (6%). Capillary leak syndrome was reported in 3 patients (19%; all grade 2). 100% (8/8) of patients with baseline splenomegaly had a spleen response, including 75% (6/8) who had reduction in splenomegaly of 50% or more. 60% (3/5) of patients with baseline spleen size ≥5cm had reduction in splenomegaly of 50% or more. Two patients treated with tagraxofusp achieved bone marrow CRs. 43% (6/14) of evaluable patients had a treatment duration of 6 months or more, including one at 8+ and one at 14+ months.Conclusions: Tagraxofusp monotherapy resulted in significant reductions in spleen sizes along with bone marrow morphological responses in relapsed/refractory patients with CMML, with a manageable safety profile. Given CD123 expression on both neoplastic myeloid cells and pDCs infiltrates, tagraxofusp may offer a novel targeted approach for patients with CMML, an area of unmet medical need. Enrollment continues, and updated safety and efficacy data will be presented. A registrational trial in this patient population is planned. Clinical trial information: NCT02268253. DisclosuresAli:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Gupta:Novartis: Consultancy, Honoraria, Research Funding; Incyte: Research Funding. Schiller:Celator/Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding. Lee:AstraZeneca: Consultancy; Clinipace: Consultancy; Karyopharm Therapeutics Inc: Consultancy; LAM Therapeutics: Research Funding; Amgen: Consultancy. Yacoub:Cara Therapeutics: Equity Ownership; Ardelyx, INC.: Equity Ownership; Dynavax: Equity Ownership; Inycte: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Sardone:Stemline Therapeutics: Employment, Equity Ownership. Wysowskyj:Stemline Therapeutics: Employment, Equity Ownership. Shemesh:Stemline Therapeutics: Employment, Equity Ownership. Chen:Stemline Therapeutics: Employment, Equity Ownership. Olguin:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics: Employment, Equity Ownership. Dunn:Stemline Therapeutics: Employment, Equity Ownership. Verstovsek:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Khoury:Stemline Therapeutics: Research Funding. Pemmaraju:celgene: Consultancy, Honoraria; novartis: Research Funding; Affymetrix: Research Funding; samus: Research Funding; cellectis: Research Funding; daiichi sankyo: Research Funding; stemline: Consultancy, Honoraria, Research Funding; plexxikon: Research Funding; abbvie: Research Funding; SagerStrong Foundation: Research Funding.

Predictive models for splenic response to JAK-inhibitor therapy in patients with myelofibrosis

JAK inhibitors for myelofibrosis (MF) reduce spleen size, control constitutional symptoms, and may improve survival. We studied the clinical characteristics of 548 MF patients treated with JAK inhibitors from 2008 to 2016 to better understand predictors of splenic response. Response was defined as a 50% decrease in spleen size at early (3–4 months on therapy) and late (5–12 months) timepoints after therapy initiation. Early response positively correlated with higher doses of JAK inhibitor, baseline spleen size 5–10 cm, and hemoglobin. Early response negatively correlated with baseline spleen size >20 cm and high WBC. The strongest predictor of late response was whether a patient had a response at the earlier timepoint (OR 8.88). Our response models suggest that clinical factors can be used to predict which patients are more likely to respond to JAK inhibitors, and those who do not achieve an early response, i.e. within 3–4 months, should consider alternative treatments.Trial registration: ClinicalTrials.gov identifier: NCT01773187.Trial registration: ClinicalTrials.gov identifier: NCT02055781.

Momelotinib Treatment-Associated Neuropathy: Prevalence, Risk Factors and Outcome in 100 Patients with Myelofibrosis

Background: Momelotinib (a JAK1 and JAK2 inhibitor) induces both anemia and spleen response in patients with myelofibrosis (MF) (Leukemia 2013;27:1322). The favorable effect on anemia was a distinguishing feature for momelotinib, compared to other JAK inhibitors, but the drug was also associated with treatment-emergent peripheral neuropathy (TE-PN). We examined the natural history and risk factors of momelotinib-associated peripheral neuropathy.Methods: The study patients constitute part of a larger phase-1/2 clinical trial (CCL09101; NCT00935987) using momelotinib for the treatment MF. Toxicity grading was according to the Common Terminology Criteria for Adverse Events (CTCAE) v.4.03. Momelotinib capsules (as opposed to the newer tablet formulation used in the currently ongoing phase-3 study) were used in the current study, which represents a sponsor-independent analysis.Results: 100 patients with MF (median age 66 years; 58% males) were treated at the Mayo Clinic between 11/20/09 and 11/10/10. DIPSS-plus (JCO. 2011;29:392) risk distribution was 63% high, 36% intermediate-2 and 1% intermediate-1. 75% of the patients harbored JAK2V617F and 50% abnormal karyotype. Previous treatment included other JAK inhibitors in 21 patients, thalidomide/lenalidomide/pomalidomide in 31 and hydroxyurea or other cytoreductive agents in 55. History of diabetes was documented in 7% of the patients at baseline and 14 (14%) of the patients had symptoms of PN before starting treatment with momelotinib, all of which were grade-1.Momelotinib was initiated at 100 mg/day in 3 patients, 150 mg/day in 21, 150 mg twice-daily in 20, 200 mg/day in 3, 300 mg/day in 47 and 400 mg/day in 6. The maximum momelotinib dose was 150 mg/day in 6 patients, 150 mg twice-daily in 20, 300 mg/day in 68 and 400 mg/day in 6. Treatment duration was <6 months in 12 patients, 6-12 months in 22, 12-24 months in 19 and >24 months in 47.Median follow-up after the institution of protocol drug therapy was 35 months (range 1-49). During this period, TE-PN was documented in 44 (44%) patients; of these, 42 were in patients without baseline neuropathy. TE-PN involved the feet only in 28 patients, hands only in one patient and both feet and hands in 15 patients. Median (range) for the time of onset of TE-PN was 32 weeks (1-132) and duration of TE-PN 11 months (0-40). All 42 newly-emergent PN were grade-1 sensory while the two patients with grade-1 baseline PN progressed to grade-2. Formal neurological evaluation, which was performed in 9 patients, mostly showed length-dependent sensory-motor large and small fiber neuropathy with axonal features.TE-PN resulted in drug discontinuation in 7 patients and reduction in drug dose in 28 patients. Improvement after drug dose reduction was documented in only one patient and in none of those with drug discontinuation. Progression to grade-2 PN was documented in 3 patients.TE- PN was significantly associated with clinical improvement (CI) with 54% incidence in responders vs 30% in non-responders (p=0.02); however, longer treatment duration was also associated with higher prevalence of TE-PN (p=0.03). In univariate analysis, patients with TE-PN lived longer than those without TE-PN (p=0.048); however, significance was lost during multivariable analysis that included either achievement of CI or treatment duration.Neither the initial (p=0.53) nor maximum (p=0.37) momelotinib dose was correlated with TE-PN, which was also not influenced by JAK2V617F (p>0.99), karyotype (p=0.26), history of diabetes (p=0.39) or previous treatment with JAK inhibitor therapy (p=0.7), thalidomide (p=0.24), lenalidomide (p=0.59), pomalidomide (p=0.63) or hydroxyurea (p=0.56). There were no correlations between TE-PN and age (p=0.37), sex (p=0.37), type of MF (p=0.98), DIPSS-plus score (p=0.07), baseline transfusion dependency (p=0.15), constitutional symptoms (p=0.83) or spleen size (p=0.53). TE-PN did not correlate with hematologic (p=0.14) or extramedullary toxicity other than PN (p=0.41) or lipase/amylase abnormalities (p=0.35).Conclusions: Momelotinib-associated neuropathy in MF might not be reversible in the majority of cases but also does not appear to be progressive. We were not able to identify risk factors for TE-PN, other than duration of treatment, which also explains its apparent association with response/survival. We are currently looking into possible correlations with serum thiamine levels. DisclosuresNo relevant conflicts of interest to declare.

β-Blocker therapy ameliorates hypersplenism due to portal hypertension in children.

Thrombocytopenia due to hypersplenism precludes percutaneous liver biopsy in many cases of chronic liver disease (CLD). The aim of this study was to assess the efficacy of propranolol in correcting platelet counts (>100,000/mm(3)) to ensure percutaneous liver biopsy in children with CLD. From January 2005 to December 2012, 51 consecutive children (mean age 11.5 ± 3.0 years, 34 boys) with CLD who needed liver biopsy but could not be done due to hypersplenism-related thrombocytopenia (platelets <100,000/mm(3) and/or total leukocyte counts <4,000/mm(3) with splenomegaly) were recruited and given a 4-week trial of long-acting propranolol (1.5-2 mg/kg/day). Hemodynamic parameters and splenic artery hemodynamics by Doppler ultrasound were recorded before and after the propranolol trial. Response to therapy was defined as improvement of platelet counts to ≥10(5)/mm(3). Thirty-two (62.7%) children responded to propranolol therapy and their mean platelet counts increased from 57.5 ± 13.0 × 10(3) to 140.7 ± 43.3 × 10(3)/mm(3), p = 0.0001. Liver biopsy could be done in 29. While comparing responders with non-responders, baseline spleen size (7.4 ± 3.3 vs. 12.7 ± 4.5 cm, p = 0.0001) and platelet counts (57.5 ± 13.0 × 10(3) vs. 39.5 ± 14.5 × 10(3), p = 0.0001) were found to be significant. ROC curve suggested a cut-off value of ≤8.5 cm of spleen and ≥53,000 platelets as predictors of response. With propranolol, mean arterial pressure and spleen size reduced (p < 0.05) and splenic artery resistance increased significantly (p = 0.005) in responders. Propranolol corrects thrombocytopenia and makes liver biopsy possible in almost two-thirds of cases by reducing splenic sequestration through splenic artery vasoconstriction. The baseline spleen size and platelet counts determine the effectiveness of therapy. A trial of β-blocker is worth carrying out in cases where liver biopsy is contraindicated due to hypersplenism-related thrombocytopenia.

Baseline Spleen Size and Mutations Involving ASXL1 and SRSF2 Predict Survival and Treatment Response In JAK Inhibitor Treated Myelofibrosis Patients

BackgroundJAK inhibitors (JAKi) currently represent a frontline treatment modality in patients with symptomatic intermediate- or high-risk myelofibrosis (MF). While the efficacy of JAKi in decreasing spleen size and improving disease-related symptoms is well documented, the effect of this drug class on overall survival and risk of leukemic transformation in MF patients is less well understood, primarily due to short follow up in individual patient cohorts. Furthermore, there is scant information on baseline predictors of overall and leukemia-free survival, and also spleen and/or anemia responses, at the onset of JAKi therapy. We conducted a sponsor-independent single-center retrospective review of patients treated with JAKi with long follow up to address the aforementioned issues. Here, we report our findings regarding baseline predictors of clinical outcome and treatment response in MF patients treated with JAKi. MethodsClinical, cytogenetic and molecular data were retrospectively collected on patients treated with one or more JAKi on a clinical trial at the Mayo Clinic, Rochester, MN. Baseline clinical data pertained to the onset of treatment with the first JAKi. Karyotype information was available for all patients. Screening for JAK2V617F, MPLW515, ASXL1, and SRSF2 mutations was performed as previously described (Leukemia. 2013 Apr 26. doi: 10.1038/leu.2013.119). Spleen size was measured by palpation by clinical investigators. Anemia and spleen responses were adjudicated as per IWG criteria (Tefferi, Blood, 2006). Information on survival and leukemic transformation was updated in July 2013. ResultsA total of 157 MF patients were studied (60% male; median age 65 years, range 34-89 years). Ninety seven patients (62%) had primary MF, 42 (27%) post-polycythemia vera MF, and 18 (11%) post-essential thrombocythemia MF. The DIPSS-plus distribution was: Low/Int-1 20 (13%), Int-2 66 (42%), and High 71 (45%). Other characteristics were: JAK2V617F positive 78%, unfavorable karyotype 17%, hemoglobin <10 g/dL 58%, leukocyte count >25 x 109/L 31%, platelet count <100 x 109/L 15%, peripheral blasts ≥1% 69%, red blood cell transfusion-dependent 37%, and constitutional symptoms 56%. Forty one patients (38%) were ASXL1 mutated (n=108) and 20 (18%) SRSF2 mutated (n=110). One hundred and thirty nine patients (89%) were evaluable for spleen response (median spleen size by palpation 19 cm, range 6-32 cm) and 91 (58%) for anemia response by IWG criteria.The first JAKi was momelotinib (CYT387) in 79 patients (50%), ruxolitinib in 51 (33%) and fedratinib (SAR302503) in 27 (17%). Median follow up from first JAKi treatment was 30 months (range 1-67 months); during this period, 72 deaths (46%) and 14 (9%) leukemic transformations have been documented.The median overall survival of the entire cohort was 41 months. Multivariable analysis identified the following DIPSS-plus independent predictors for survival: palpable spleen size >20 cm (HR 2.5), ASXL1 mutated status (HR 3.1) and SRSF2 mutated status (HR 3.8) (all p<0.01) (Figure). In contrast, there was no difference in survival with regards to the first JAKi used for MF treatment (p=0.3).Multivariable analysis identified the following predictors for leukemia-free survival: SRSF2 mutated (HR 9.7), unfavorable karyotype (HR 8.7), and palpable spleen size >20 cm (HR 9.1) (all p<0.01).Predictors of spleen response included baseline spleen size (≤20 cm 56%, >20 cm 34%; p=0.01), with borderline significance for ASXL1 mutation status (unmutated 51%, mutated 31%; p=0.06).Predictors of anemia response included RBC transfusion status at baseline (transfusion dependent 38%, transfusion independent 12%; p<0.01) and JAK2V617F status (unmutated 46%, mutated 22%; p=0.02). ConclusionsLarger baseline spleen size and ASXL1 and SRSF2 mutated status predicted for inferior overall survival, independent of DIPSS-plus, at the onset of first JAKi treatment in MF patients. Similarly, multivariable analysis identified larger baseline spleen size and presence of unfavorable karyotype and SRSF2 mutations as being predictive for inferior leukemia-free survival. Spleen response rates were significantly superior in patients with smaller baseline spleen size and possibly ASXL1 unmutated status. Anemia response rates were significantly higher in patients who were transfusion-dependent at baseline and had JAK2V617F unmutated status. [Display omitted] [Display omitted] Disclosures:Pardanani:Bristol Myers Squibb: Clinical trial support Other; Sanofi: Clinical trial support, Publication support services, Clinical trial support, Publication support services Other; PharmaMar: Clinical trial support, Clinical trial support Other; JW Pharmaceutical Corp.: Clinical trial support, Clinical trial support Other. Off Label Use: Use of Ruxolitinib, Momelotinib, Fedratinib and Pomalidomide for treatment of Myelofibrosis in Clinical Trial setting.

Ruxolitinib Provides Reductions in Splenomegaly Across Subgroups: An Analysis of Spleen Response in the COMFORT-II Study

Abstract▪279▪This icon denotes a clinically relevant abstract Background:COMFORT-II is a randomized, open-label, phase 3 study evaluating the safety and efficacy of ruxolitinib, a potent and selective oral inhibitor of JAK1 and JAK2, in patients with primary myelofibrosis (PMF), post-polycythemia vera-MF (PPV-MF), or post-essential thrombocythemia-MF (PET-MF). Patients who received ruxolitinib had significantly greater reductions in spleen volume compared with those who received best available therapy (BAT). The primary and key secondary endpoints of the study were both met: the proportion of patients achieving ≥35% reduction in spleen volume at week 48 (28.5%, ruxolitinib; 0%, BAT; P <.0001) and week 24 (31.9%, ruxolitinib; 0%, BAT; P <.0001), respectively. Subgroup analysis was performed on both the 48- and 24-week endpoints. Methods:In the COMFORT-II study, 219 patients were randomized (2:1) to receive ruxolitinib (15 or 20 mg twice daily [bid] based on the baseline platelet count [100– 200 × 109/L or >200 × 109/L, respectively]) or BAT of the investigator’s choice. The proportions of ruxolitinib-treated patients achieving the primary and key secondary endpoints were analyzed by subgroup for gender (male or female), age (≤65 or >65 years), starting dose (15 or 20 mg bid), baseline MF type (PMF, PPV-MF, or PET-MF), previous hydroxyurea (hydroxycarbamide) use (yes or no), baseline palpable spleen length (≤10 or >10 cm), baseline spleen volume (>median or ≤median), JAK2V617F mutation (presence or absence), and International Prognostic Scoring System (IPSS) risk category (intermediate-2 or high) (Cervantes F, et al, Blood, 2009;113(13):2895–2901). In addition, the relationships between these factors and spleen volume reduction were investigated by multivariate logistic regression. Results:The proportion of patients in each subgroup with ≥ 35% reduction in spleen volume from baseline at week 48 is shown below (Figure). [Display omitted] BL, baseline; HU, hydroxyurea.The response rate was higher in patients receiving ruxolitinib than in patients receiving BAT in all subgroups; no patients in the BAT group reached a ≥35% reduction in spleen volume at week 48. All subgroups receiving ruxolitinib responded and all subgroup comparisons had overlapping 95% confidence intervals. At week 24, a trend for a higher response rate was observed in patients who received a starting dose of 20 mg bid compared with those who received a starting dose of 15 mg bid; however, the response rates among these patients at week 48 were not different. No significant difference in response rates was observed between patients with the JAK2V617F mutation compared with those without the mutation. Results of the subgroup analysis were confirmed by the multivariate models. A significant effect of the ruxolitinib starting dose was seen when response rates were modeled at week 24 but not when modeled at week 48. Conclusions:Recent findings from the COMFORT-II study show that patients who received ruxolitinib had significantly greater reductions in splenomegaly than did patients who received BAT. In this analysis, ruxolitinib was shown to be more effective than BAT at reducing spleen volume in all patient subgroups regardless of gender, age, mutation status, IPSS risk category, baseline spleen size, MF subtype, or ruxolitinib starting dose. Disclosures:Harrison:Novartis: Honoraria; Incyte: Honoraria; S*Bio: Honoraria; Celgene: Honoraria; Sanofi Aventis: Honoraria. Kiladjian:Novartis: Honoraria; Celgene: Honoraria. Gisslinger:Novartis: Speakers Bureau; Celgene Austria: Research Funding, Speakers Bureau; Aop-Orphan: Speakers Bureau. Niederwieser:Novartis: Speakers Bureau. Passamonti:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Waltzman:Novartis: Employment. Hollaender:Novartis Pharma AG: Employment. Hunter:Incyte Corporation: Employment, Equity Ownership. Levy:Incyte Corporation: Employment, Equity Ownership. Knoops:Novartis: Consultancy. Cervantes:Bristol-Myers-Squibb: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vannucchi:Novartis: Honoraria. Barosi:Novartis: Consultancy.

Consistent Benefit of Ruxolitinib Over Placebo in Spleen Volume Reduction and Symptom Improvement Across Subgroups and Overall Survival Advantage: Results From COMFORT-I

Abstract Abstract 278 Background: Overactive JAK-STAT signaling as a result of gain-of-function mutations (eg, JAK2V617F) and/or high circulating levels of inflammatory cytokines is considered to play a key role in the pathogenesis of myeloproliferative neoplasms. Ruxolitinib, a selective oral inhibitor of JAK1 and JAK2, demonstrated a significant reduction in spleen volume (SV) and improvements in myelofibrosis (MF)-related symptoms in a double-blind placebo-controlled trial (COMFORT-I). The objective of this analysis was to evaluate the efficacy of ruxolitinib across patient (pt) subgroups in COMFORT-I. Methods: Pts with MF were randomized to start placebo or ruxolitinib at a dose of 15 mg or 20 mg PO BID depending on baseline platelet count (100–200 ×109/L or &gt;200 ×109/L, respectively). The dose was optimized for efficacy and safety during treatment. SV change was measured by MRI; MF symptoms were assessed using a daily diary (modified Myelofibrosis Symptom Assessment Form [MFSAF] v2.0) over 1 wk prior to dosing and throughout the 24 wks of dosing. The percent changes from baseline to wk 24 in SV and MFSAF Total Symptom Score (TSS, a measure of combined scores for abdominal discomfort, pain under ribs on left side, early satiety, itching, night sweats, and bone/muscle pain) were compared for ruxolitinib and placebo pts across the following subgroups: MF disease subtype, age, International Prognosis Scoring System (IPSS) risk group, presence/absence of JAK2V617F mutation, baseline hemoglobin, baseline spleen size (palpable spleen length), and baseline TSS. Survival was estimated by Kaplan-Meier method. Changes in SV and TSS Across Subgroups: 309 pts were randomized: 155 to ruxolitinib and 154 to placebo. Ruxolitinib demonstrated consistent benefit compared with placebo in both SV and TSS across all subgroups evaluated (Table). The impact of symptom severity on response was evaluated by baseline TSS quartiles (maximum score for TSS = 60). Ruxolitinib pts with baseline TSS of &lt;8.5, 8.5-&lt;16.5, 16.5-&lt;25.5 and ≥25.5 had mean percent changes in SV of −28.0, −31.4, −31.7 and −34.8, respectively, vs +8.1 for all placebo pts combined. The mean percent change in TSS for these same subgroups was −40.5, −47.2, −48.1 and −48.2 vs +41.8 for all placebo pts combined. These data indicate that pts with modest to marked symptoms all benefit from ruxolitinib therapy in terms of both SV and TSS. Survival Analysis: 13 ruxolitinib and 24 placebo pts died during the study or during extended follow-up (median follow-up of 52 and 51 wks, respectively), representing a hazard ratio (95% CI) of 0.499 (0.254, 0.98) (p=0.0395). For ruxolitinib- and placebo-treated pts, respectively, the probability of survival (95% CI) &gt;48 wks was 0.98 (0.92, 0.99) and 0.90 (0.81, 0.95) for pts with baseline hemoglobin values ≥10 g/dL and 0.84 (0.72, 0.91) and 0.77 (0.63, 0.86) for pts with baseline hemoglobin &lt;10 g/dL. Conclusions: Pts receiving ruxolitinib had higher response rates than placebo based on reductions in SV and improvements in TSS at wk 24 regardless of baseline subgroup: MF disease subtype, age (≤65 or &gt;65 y), IPSS risk group (intermediate-2 or high-risk), presence or absence of JAK2V617F mutation, hemoglobin level (≥10 g/dL or &lt;10 g/dL), palpable spleen length (≤10 cm or &gt;10 cm), and symptom severity (TSS quartile). In addition, the overall survival analysis suggested a benefit with ruxolitinib therapy over placebo. Disclosures: Verstovsek: Incyte: Research Funding. Mesa:Incyte: Research Funding; Lilly: Research Funding; SBio: Research Funding; Astra Zeneca: Research Funding; NS Pharma: Research Funding; Celgene: Research Funding. Gotlib:Incyte: Consultancy, Research Funding. Levy:Incyte: Employment, Equity Ownership. Gupta:Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Catalano:Incyte: Honoraria; Novartis: Honoraria. Deininger:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Genzyme: Research Funding. Miller:Incyte: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau. Winton:Incyte: Consultancy. Arcasoy:Incyte: Research Funding. Lyons:Alexion: Consultancy, Honoraria; Telik: Research Funding; Incyte: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Research Funding. Vaddi:Incyte: Employment. Erickson-Viitanen:Incyte: Employment. Sun:Incyte: Employment. Sandor:Incyte: Employment. Kantarjian:Incyte: Research Funding; Novartis: Consultancy, Research Funding.

Results of a Phase 2 Study of Pacritinib (SB1518), a Novel Oral JAK2 Inhibitor, In Patients with Primary, Post-Polycythemia Vera, and Post-Essential Thrombocythemia Myelofibrosis

Abstract▪282▪This icon denotes a clinically relevant abstract Background:The JAK2V617F mutation has been linked to the pathogenesis of myeloproliferative neoplasia. Pacritinib (SB1518) is a potent inhibitor of both wild-type JAK2 and the JAK2V617F mutant. In previously reported Phase 1 studies, patients with myelofibrosis (MF) who received pacritinib achieved steady-state plasma levels above the IC50 for JAK2 at all doses (100–600 mg/d). Target inhibition, measured by phosphorylation of the STAT3, STAT5, and JAK proteins in PBMCs and whole blood was also shown at all doses. 400 mg/d was chosen as the recommended dose (RD) for Phase 2 study. Aim:The primary endpoint of the Phase 2 study was to assess the spleen response rate, defined as a ≥35% reduction in MRI-measured spleen volume between baseline and Week 24. Methods:Qualifying patients had primary, post-ET, or post-PV MF, with palpable splenomegaly ≥5 cm below the left costal margin. Based on minimal myelosuppression in the Phase 1 trials, no minimum hematology values were required for eligibility. Treatment with pacritinib was on a continuous oral, daily schedule. Disease symptoms were evaluated using the MF-SAF.Results: Patients:Thirty-four MF patients (median age 69; range, 44–84 years) consented and were enrolled, of which 25 (74%) were men. Median PS was 1 with 2 patients having PS >1. Median baseline hemoglobin and platelet count were 10.2 g/dL and 119,000/μL, respectively. Fifteen patients (44%) had platelet counts <100,000/μL, including 7 with counts <50,000/μL. Median baseline spleen size was 14 cm (range 4–30 cm) below the LCM by physical exam, and median spleen volume was 2647 cc (range 404–7817 cc) by MRI. Twenty-six patients (76%) were JAK2V617F mutation-positive. The median time on study is 8.2 months (range, 0.5 to 12.1 months). Safety:Seventeen patients (50%) have discontinued, including 8 (24%) due to AEs (1 each for nausea, sepsis, increased bilirubin, subdural hematoma, allergic reaction, GI bleed, and 2 due to thrombocytopenia), 5 for disease progression and 2 for lack of response. Of the AEs leading to discontinuation, only increased bilirubin, allergic reaction and intermittent nausea were considered possibly drug related. Ten patients required dose reduction for adverse events. One patient required drug discontinuation associated with decreased neutrophils and platelets. This was considered related to worsening disease; otherwise, there were no changes in pacritinib dosing related to impaired hematopoiesis. The most common treatment-related AEs were gastrointestinal, which were generally low grade and easily managed. GI AEs >Grade 2 included Grade 3 diarrhea in 2 patients (6%). Only 1 patient discontinued for GI toxicity. Efficacy:Pacritinib produced meaningful reductions in splenomegaly. Thirty patients (88%) showed reductions in palpable splenomegaly; 15 (44%) showed decreases of ≥50% and 6 (18%) achieved clinical resolution of splenomegaly. Eleven patients (32%) had a ≥35% reduction in splenic volume as measured by MRI. Splenic reduction of 50% by PE correlated with a 25% reduction in spleen volume by MRI. Fourteen patients (41%) had reduction in splenic volume by >25%. Spleen response rates were equivalent among patients with low baseline platelet counts and those with normal baseline counts. All spleen responses are ongoing; consequently a median duration of response has not been reached. Two patients met IWG-MRT criteria for clinical improvement in hemoglobin including 1 who became transfusion independent. At the 6-month visit, a significant reduction (>2 point improvement) was observed for MF-associated symptoms, including abdominal pain, bone pain, early satiety, worst fatigue, inactivity, night sweats and pruritus. Conclusions:Pacritinib shows promising efficacy in alleviating MF-associated splenomegaly and constitutional symptoms at a dose that induces minimal myelosuppression. Once-daily dosing is well tolerated, with manageable GI toxicity as the main side effect. Given the lack of myelosuppression with pacritinib, this JAK2 inhibitor is of particular importance for MF patients with impaired hematopoiesis. Disclosures:Mesa:SBIO: Research Funding.

Exploratory analysis describing ultrasonic (US) evaluation of spleen size during peripheral blood progenitor cell (PBPC) mobilization by filgrastim in normal donors

7102 Background: Filgrastim is used to mobilize CD34+ cells into the peripheral blood that are collected by apheresis for allogeneic transplantation. We prospectively evaluated spleen size during PBPC mobilization Methods: Donors ≥18 yrs eligible to be PBPC donors per institutional guidelines enrolled. Splenic assessments were done before, during, and after PBPC mobilization. Filgrastim dose and schedule and leukapheresis (LK) procedures were per local practice. Spleen size by US was measured in 3 dimensions: longitudinal (craniocaudal), transverse, and diagonal (perpendicular to transverse). Splenic volume was estimated by taking the cross-product of 3 dimensions and multiplying by 0.52, approximating an ellipse volume. Stiff (ASH 2007) reported the primary endpoint, fold change from baseline in splenic volume during mobilization. Exploratory analyses, including a linear regression evaluating the effect of age and baseline spleen size on fold-change, were performed. Results: 309 enrolled, median age 44yrs, 56% male. Median fold volume change from baseline to first LK was 1.47, resolving to near baseline 1 week after last LK. No significant clinical sequelae, including splenic rupture, were reported. Older donors appeared to have the smallest baseline spleen volume and the largest fold change (table). Linear regression analyses indicated age was a significant predictor for both baseline spleen volume (p=0.0031) and spleen volume fold change from baseline at first LK (p=0.0499). Conclusions: During mobilization, spleen volume transiently increased from baseline to day of 1st LK and returned to near baseline 1 week after last LK. Older donors tended to have smaller baseline splenic volume and greater fold changes in spleen size. Preclinical models suggest decreasing hematopoietic stem cell homing after mobilization with aging (Morrison 1996; Wagers 2002), which could result in splenic accumulation of progenitor and stem cells. [Table: see text] [Table: see text]

The JAK Inhibitor, INCB018424, Demonstrates Durable and Marked Clinical Responses in Primary Myelofibrosis (PMF) and Post-Polycythemia/Essential Thrombocythemia Myelofibrosis (Post PV/ETMF).

Background: Myelofibrosis (MF) is characterized by progressive bone marrow dysfunction, extramedullary hematopoiesis, massive splenomegaly, elevated levels of inflammatory cytokines, severe constitutional symptoms, cachexia and premature death. INCB018424 is a potent, selective inhibitor of JAK 1 and 2 which has demonstrated impressive clinical activity in the early portion of a phase 1/2 study in patients with PMF and Post-PV/ET MF.Methods: Following the initial dose escalation phase with a BID schedule (N=11), both twice daily (10 mg BID to 25 mg BID, N=56) and once daily (25 mg QD to 200 mg QD, N= 37) dose regimens were explored. Endpoints included spleen size assessed by manual palpation, constitutional symptoms assessed using the Modified Myelofibrosis Symptom Assessment Form (MFSAF) and JAK2 allele burden. Exercise capacity is being assessed using the Six Minute Walk Test (6MWT), and body mass and composition are being assessed using standard methods. Safety was assessed by collection of adverse events and monitoring of laboratory data.Results: Over 100 patients are currently enrolled in the study, with a mean exposure to drug of > 5 months. Twenty percent of patients have received INCB018424 for > 9 months. INCB018424 is associated with a rapid reduction of splenomegaly in over 93% of patients from a mean baseline spleen size >20 cm, with 50% or greater reduction being observed in 35% of patients dosed with 10 mg BID or 50 mg QD, and 59% of patients dosed with 25mg BID regimens. These declines nearly always occur within the first month of therapy, with further, slower decreases often observed thereafter. In responding patients, spleen size reduction persists for the duration of therapy (currently up to one year follow-up). Constitutional symptoms are reported with high frequency in the study population as assessed by the MFSAF: night sweats, pruritis and fatigue were reported by >60%, >45% and >90% of patients respectively. Improvements in self-assessed symptom scores (mean % improvement of 40% to 60%) occurred by the first assessment at week 2. Activity limitations are also reported by a high proportion of MF patients; 70% of respondents reported impaired ability to exercise or get around, with a mean score >5 on the 11-point MFSAF scale; INCB018424 therapy was associated with rapid (within 2 weeks) and marked (40% or more) improvement in self-assessed score. There was a dose-dependent weight gain, most pronounced in patients with the lowest body mass index (BMI) values at baseline. Profound reductions in inflammatory cytokines were observed by the first evaluation at week 2 in virtually all patients, and were maintained during therapy. INCB018424 is generally well tolerated with the primary toxicity being dose-dependent grade 3 or 4 reversible thrombocytopenia which occurred in 0%, 18% and 32% of patients dosed with 10 mg BID, 50 mg QD or 25 mg BID.Conclusions: INCB18424 shows unprecedented and durable clinical efficacy in reducing spleen size and improving constitutional symptoms in patients with MF. Results from proactive dose modification regimens, assessments of exercise capacity, MRI-based spleen volume assessment and body composition determination will be presented.