Trial in Progress: Phase Ib/II Study of Bcl-2/Bcl-Xl Inhibitor Pelcitoclax (APG-1252) in Patients with Myelofibrosis (MF) That Progressed after Initial Therapy

Background: Pelcitoclax (APG-1252), a novel dual inhibitor of Bcl-2/Bcl-xL, is active as monotherapy in patients with advanced solid tumors and well tolerated up to 240 mg twice weekly (NCT03387332). Preclinical data suggest that cells with Janus-associated kinase-2 (JAK2) mutations, including those associated with bone marrow fibrosis, are dependent on Bcl-2/Bcl-xL for survival and that addition of BH3 mimetics targeting Bcl-2/Bcl-xL induces apoptosis. Furthermore, in JAK2‒mutated cell models, apoptotic synergy is demonstrated when a JAK2 inhibitor and Bcl-2/Bcl-xL inhibitor are combined, as inhibition of Bcl-xL overcomes resistance to JAK2 inhibitors. Taken together, APG-1252 could overcome resistance to JAK2 inhibitors, and the combination could augment clinical benefit in patients with suboptimal responses to JAK2 inhibitor‒based therapy. Study Objectives: The primary objective of this open-label trial is to evaluate the safety and efficacy of APG-1252, as monotherapy and when combined with ruxolitinib, in adults with histologically or cytologically confirmed MF who require therapy and are ineligible for JAK2 inhibitors (and can receive single-agent APG-1252) or have had inadequate responses to ruxolitinib-based therapy (and can receive this treatment plus APG-1252). Secondary objectives include APG-1252 pharmacokinetics, time to response, and duration of response. Exploratory objectives include changes in cytogenetics and molecular mutations, bone marrow fibrosis, and cytokines on treatment. Study Design: The study is divided into Part 1 (APG-1252 monotherapy) and Part 2 (APG-1252 plus ruxolitinib). For Part 1, the key inclusion criterion is ineligibility for JAK2 inhibitors and for Part 2, inadequate responses to prior ruxolitinib-based therapy. A standard 3+3 dose-escalation design is being implemented to determine the maximum tolerated dose (MTD) of APG-1252 monotherapy in Part 1 and APG-1252 combined with ruxolitinib in Part 2. APG-1252 will initially be administered at 160 mg intravenously by 30-minute injection once weekly in a 28-day cycle. The dose can be escalated to a maximum of 240 mg or reduced to a minimum of 80 mg, depending on tolerability. Part 2 will begin once the MTD and recommended phase 2 dose (RP2D) of APG-1252 monotherapy have been determined. In Part 2, ruxolitinib will be administered orally twice daily per the package insert. After the MTD for APG-1252 monotherapy has been determined, no additional patients will be enrolled in Part 1; however, up to 15 to 30 additional patients can be enrolled in Part 2, to further evaluate the safety and anticancer activity of the combination at MTD or RP2D. Patients will continue treatment until disease progression or unacceptable toxicity. Clinical responses are being assessed every 12 weeks according to criteria from the International Working Group‒Myeloproliferative Neoplasms Research and Treatment and European LeukemiaNet panels, while optimal clinical benefit will be evaluated at 24 weeks. Enrollment will be from September 2020 and preliminary results estimated in October 2022. For further information, contact: [email protected]. Registration: ClinicalTrials.gov Identifier NCT04354727. Disclosures Pemmaraju: Pacylex Pharmaceuticals: Consultancy; Roche Diagnostics: Honoraria; LFB Biotechnologies: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; Celgene: Honoraria; AbbVie: Honoraria, Research Funding; MustangBio: Honoraria; Affymetrix: Other: Grant Support, Research Funding; Cellectis: Research Funding; Daiichi Sankyo: Research Funding; Plexxikon: Research Funding; Samus Therapeutics: Research Funding; DAVA Oncology: Honoraria; Blueprint Medicines: Honoraria; Novartis: Honoraria, Research Funding; Incyte Corporation: Honoraria; SagerStrong Foundation: Other: Grant Support. Mudenda:Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company. Wang:Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company. JI:Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company. Lu:Ascentage Pharma Group: Current Employment, Current equity holder in publicly-traded company. Fu:Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company. Liang:Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company. McClain:Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company. Sheladia:Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company. Verstovsek:Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; PharmaEssentia: Research Funding; ItalPharma: Research Funding; AstraZeneca: Research Funding; Protagonist Therapeutics: Research Funding; Promedior: Research Funding; Celgene: Consultancy, Research Funding; NS Pharma: Research Funding; Genentech: Research Funding; CTI Biopharma Corp: Research Funding; Incyte Corporation: Consultancy, Research Funding; Roche: Research Funding; Gilead: Research Funding. Yang:Ascentage Pharma (SuZhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests. Zhai:Ascentage Pharma (SuZhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests.

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NS-018, a Selective JAK2V617F Inhibitor, Improves JAK2V617F-Induced Murine Myelofibrosis Without Decreasing The Erythrocyte Or Platelet Count

Blood ◽

10.1182/blood.v122.21.3847.3847 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3847-3847

Author(s):

Yohei Nakaya ◽

Kotaro Shide ◽

Haruna Naito ◽

Tomoko Niwa ◽

Tatsuya Horio ◽

...

Keyword(s):

Bone Marrow ◽

Hydrogen Bonding ◽

Platelet Count ◽

Carbonyl Group ◽

Wild Type ◽

Bone Marrow Fibrosis ◽

Platelet Counts ◽

Unique Mode ◽

Marrow Fibrosis ◽

Jak2 Inhibitors

Abstract A single somatic mutation, V617F, in Janus kinase 2 (JAK2) is one of the causes of myeloproliferative neoplasms (MPN), including primary myelofibrosis, and the mutant kinase JAK2V617F is a therapeutic target in MPN. However, inhibition of wild-type JAK2 (JAK2WT) can decrease the red blood cell (RBC) or platelet count. Therefore, a JAK2 inhibitor that produces a smaller reduction in the RBC and platelet counts in the therapeutic window would have clinical benefit. NS-018 is a potent and selective inhibitor of JAK2 and Src-family kinases which is currently in an early-phase clinical trial for MPN. To compare the inhibitory effect of NS-018 on JAK2WT and JAK2V617F in the cell, we assessed the antiproliferative activity of NS-018 against Ba/F3 cells expressing murine JAK2WT or JAK2V617F. NS-018 suppressed the growth of Ba/F3-JAK2V617F cells with an IC50 value of 470 nM, whereas it suppressed the growth of Ba/F3-JAK2WT cells stimulated with IL-3 with an IC50value of 2000 nM. Thus, NS-018 showed 4.3-fold selectivity for Ba/F3-JAK2V617F over Ba/F3-JAK2WT cells (V617F/WT ratio). Other JAK2 inhibitors also showed selectivity for Ba/F3-JAK2V617F over Ba/F3-JAK2WT cells, though their selectivity was lower. For example, INCB018424 (ruxolitinib) and TG101348 showed V617F/WT ratios of 2.0 and 1.5, respectively. Among the eight JAK2 inhibitors tested, NS-018 showed the highest selectivity for JAK2V617F cells. NS-018 also inhibited erythroid colony formation in JAK2V617F transgenic mice at significantly lower concentrations than in wild-type mice. To assess the ability of NS-018 to selectively inhibit JAK2V617F-harboring cells in vivo, we established a JAK2V617F bone marrow transplantation (BMT) mouse model. NS-018 was administered by oral gavage twice a day for 40 days at a dose of 50 mg/kg. When assessment was carried out 50 days after the start of the study, NS-018 was found to have significantly prolonged the survival of JAK2V617F BMT mice, decreased their splenomegaly and restored their disrupted splenic architecture. NS-018 also partially suppressed bone marrow fibrosis in JAK2V617F BMT mice. All vehicle-treated mice that had survived to the study endpoint had mild-to-moderate reticulin fibrosis, whereas all mice treated with NS-018 had slight-to-little reticulin fibrosis, except for one mouse with mild fibrosis. Although vehicle-treated JAK2V617F BMT mice showed marked leukocytosis, NS-018 treatment achieved a 95% suppression of this increase. In spite of the marked effects of NS-018 in JAK2V617F BMT mice described above, NS-018 treatment had not decreased the RBC or reticulocyte count after 50 days of administration. JAK2V617F BMT mice showed a 78% decrease in the platelet count compared with control mice, and NS-018 treatment did not further decrease the count. To better understand the ability of NS-018 to preferentially inhibit the mutated form of JAK2, we explored the X-ray co-crystal structure of NS-018 bound to activated JAK2 and focused on the flipped carbonyl group of Gly933, which is located immediately N-terminal to the DFG (Asp-Phe-Gly) motif in the activation loop of JAK2. We identified two kinds of hydrogen-bonding interactions between NS-018 and the carbonyl group of Gly993: water-mediated hydrogen bonding involving a nitrogen atom of NS-018 and a CH•••O hydrogen bond involving an aromatic CH of NS-018. The unique mode of binding of NS-018 to activated JAK2 provides a plausible explanation for its JAK2V617F selectivity. In summary, NS-018 preferentially inhibited the growth of JAK2V617F-harboring cells over JAK2WT-harboring cells. NS-018 was also effective against leukocytosis, splenomegaly, and bone marrow fibrosis, and prolonged survival in JAK2V617F BMT mice with no reduction in the RBC or platelet counts. These characteristics of NS-018 may be explained at least in part by its unique mode of binding to the activated form of JAK2. NS-018 may have therapeutic benefit for MPN patients in virtue of its simultaneous satisfaction of the two requirements of efficacy and reduced hematologic adverse effects. Disclosures: Nakaya: Nippon Shinyaku: Employment. Naito:Nippon Shinyaku: Employment. Niwa:Nippon Shinyaku: Employment. Horio:Nippon Shinyaku: Employment.

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Efficacy, Safety, and Confirmation of the Recommended Phase 2 Dose of Ruxolitinib Plus Panobinostat in Patients with Intermediate or High-Risk Myelofibrosis

Blood ◽

10.1182/blood.v124.21.711.711 ◽

2014 ◽

Vol 124 (21) ◽

pp. 711-711 ◽

Cited By ~ 6

Author(s):

Jean-Jacques Kiladjian ◽

Florian H Heidel ◽

Alessandro M. Vannucchi ◽

Vincent Ribrag ◽

Francesco Passamonti ◽

...

Keyword(s):

Bone Marrow ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Phase Iii ◽

Spleen Volume ◽

Bone Marrow Fibrosis ◽

Advisory Committees ◽

Expansion Phase ◽

Marrow Fibrosis

Abstract Background: Myelofibrosis (MF) is a clonal neoplastic disease resulting in bone marrow fibrosis, splenomegaly, and debilitating constitutional symptoms. The Janus kinase (JAK) pathway is often dysregulated in MF, and agents targeting this pathway have demonstrated efficacy in this disease. Ruxolitinib (RUX), a potent JAK1/JAK2 inhibitor, demonstrated superiority in spleen volume reduction, symptom improvement, and survival compared with the control arm in the phase III COMFORT-I and COMFORT-II studies. Panobinostat (PAN), a potent pan-deacetylase inhibitor (pan-DACi), inhibits JAK signaling through disruption of the interaction of JAK2 with the protein chaperone heat shock protein 90. In phase I/II studies, PAN has shown splenomegaly reduction and improvement of bone marrow fibrosis. The combination of RUX and PAN demonstrated synergistic anti-MF activity in preclinical studies. These preliminary results led to the initiation of a phase Ib study evaluating the combination of RUX and PAN in patients (pts) with MF. The updated results from the expansion phase of this trial are presented here. Methods: Eligible pts had intermediate-1, -2, or high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF by International Prognostic Scoring System criteria, with palpable splenomegaly (≥ 5 cm below the costal margin). The primary objective was determination of the maximum tolerated dose (MTD) and/or recommended phase II dose (RPIID). Secondary objectives included safety, efficacy, and pharmacokinetics. Exploratory endpoints included assessment of improvement in bone marrow fibrosis and reduction of JAK2 V617F allele burden. The treatment schedule was RUX (5-15 mg) twice daily (bid) every day and PAN (10-25 mg) once daily 3 times per week (tiw; days 2, 4, and 6) every other week (qow) in a 28-day cycle. Following dose escalation and identification of the potential RPIID, additional pts were enrolled into the expansion phase and treated at this dose. Results: As of March 14, 2014, a total of 61 pts were enrolled (38 escalation phase and 23 expansion phase). The median duration of exposure to PAN and to RUX was 24.6 weeks and 24.0 weeks, respectively, for pts treated in the expansion phase. Three DLTs were observed in the escalation phase (grade 4 thrombocytopenia [n = 2], grade 3 nausea [n = 1]). No MTD was reached. The RPIID was confirmed to be RUX 15 mg bid and PAN 25 mg tiw qow in May 2014. Among the 34 pts treated at the RPIID, grade 3/4 adverse events (AEs) regardless of causality included anemia (32%), thrombocytopenia (24%), diarrhea (12%), asthenia (9%), and fatigue (9%). AEs led to discontinuation in 6% of pts treated at the RPIID. Two pts treated at the RPIID died due to causes unrelated to study treatment (1 due to myocardial infarction and 1 due to progression of myelofibrosis). Among the pts treated at the RPIID, 79% showed a >50% decrease in palpable spleen length, with 100% decrease (non-palpable spleen) being observed in 53% of pts. Additionally, 48% of pts treated at the RPIID in the expansion phase achieved ≥35% reduction in spleen volume (Figure). These results are similar to those observed for spleen volume response at 24 weeks among pts who received single-agent RUX on the phase III COMFORT-I (41.9%) and COMFORT-II (32%) studies. Conclusions: The combination of the JAK1/JAK2 inhibitor RUX and the pan-DACi PAN was well tolerated and resulted in high rates of reductions in splenomegaly in pts with intermediate- and high-risk MF. Although a relatively larger proportion of patients experienced spleen volume reductions at week 24 as compared to the COMFORT studies, the smaller sample size, shorter follow up times and potential differences in the patient populations preclude definitive comparisons. Similar to COMFORT-I and II trials, hematological AEs, specifically anemia and thrombocytopenia, were the most common AEs observed in pts treated with the combination therapy. Pts continue to be treated in the expansion phase at the RPIID. Updated safety, efficacy, and exploratory analyses on bone marrow fibrosis, JAK V617F allele burden, and biomarkers, including cytokines, will be presented. Figure Change in Spleen Volume in Expansion Phase Figure. Change in Spleen Volume in Expansion Phase Disclosures Kiladjian: Novartis: Honoraria, Research Funding, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Honoraria, Research Funding. Heidel:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ribrag:Celgene: Consultancy; Pharmamar: Consultancy; Epizyme: Research Funding; Bayer: Consultancy, Research Funding; Servier: Consultancy, Honoraria, Research Funding. Conneally:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kindler:Novartis: Consultancy. Acharyya:Novartis: Employment. Gopalakrishna:Novartis: Employment. Ide:Novartis: Employment, Equity Ownership. Loechner:Novartis: Employment. Mu:Novartis: Employment. Harrison:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria; CTI: Consultancy, Honoraria; Gilead: Honoraria; SBio: Consultancy; Shire: Speakers Bureau.

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Efficacy and Safety of Eltrombopag for Treatment of Patients with Myelodysplastic Syndromes after Hypomethylating-Agent Failure: A Phase 2 Clinical Trial

Blood ◽

10.1182/blood.v126.23.1691.1691 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1691-1691 ◽

Cited By ~ 2

Author(s):

Maliha Khan ◽

Bodden Kristy ◽

Tapan Kadia ◽

Alessandra Ferrajoli ◽

Yesid Alvarado ◽

...

Keyword(s):

Clinical Trial ◽

Bone Marrow ◽

Myelodysplastic Syndromes ◽

Research Funding ◽

Phase 2 ◽

Open Label ◽

Bone Marrow Fibrosis ◽

First Response ◽

Transfusion Requirements ◽

Marrow Fibrosis

Abstract Background: Myelodysplastic syndromes (MDS) are malignant clinical disorders characterized by ineffective hematopoiesis, bone marrow dysplasia, peripheral cytopenias and a property to transform into acute myeloid leukemia (AML). Standard of care for MDS includes the hypomethylating agents (HMAs) (i.e. azacitidine, decitabine) to improve quality of life, decrease transfusion requirements and improve clinical outcome. However not all patients (pts) respond to HMAs and even in responding pts, cytopenias may persist. HMA-failure MDS has extremely poor prognosis and currently there are no approved therapeutic options for such pts who are often of advanced age with frequent comorbidities. Objectives: The dual primary objectives of this study evaluate the safety and efficacy of the second-generation thrombopoietin-receptor agonist (TPO-RA) eltrombopag (EPAG) for the treatment of MDS pts at the time of HMA-failure. Secondary objectives include incidence of transformation to AML and evaluation of bone marrow fibrosis during therapy. Methods: Eligible pts for this 2-arm phase 2 open-label clinical trial included adults with MDS after completing >4 HMA cycles with failure to achieve at least a partial response, or the presence of ongoing cytopenias per IWG criteria. Arm A includes eltrombopag monotherapy and Arm B includes eltrombopag with continuation of the HMA at the previous dosing schedule. The starting eltrombopag dose is 200mg orally daily, which can be increased to 300mg in the absence of toxicity. First response is assessed after 2 cycles with each cycle lasting 28 days. The primary efficacy endpoint was overall response rate based on the IWG-2006 criteria. Results: To date, 23 pts with a median age of 72 years (range 42-84 years) have been enrolled. Prior to study entry, pts had received a median of 6 (range 4-25) HMA cycles. Cytogenetics were diploid in 12 (53%), intermediate in 7 (30%), and high risk in 4 (17%) pts by IPSS. Median bone marrow blasts at study start was 3% (range 0-15%). Arm A has enrolled 7 pts with a median age of 74 years; Arm B has enrolled 16 pts with median age of 69 years. In Arm B, ongoing HMA therapy includes azacitidine in 7 (44%) and decitabine in 9 (56%). Nine (39%) pts increased to 300mg EPAG after median of 8 weeks on study. Median total cycles received on study is 5 (1-17); median OS has not been reached. Overall, 16 pts are response-evaluable; 7 pts discontinued prior to the first response assessment at 2 months (4 due to AEs including myalgias/fatigue (n=2), hyperbilirubinemia (n=1), and pneumonia (n=1), 2 per pt request and 1 for pt inability to comply with protocol requirements). Of the 16 response-evaluable pts, 3 (19%) in Arm B demonstrated platelet improvement, including one pt necessitating EPAG dose-reduction to 100mg due to platelet count exceeding 450 x10⁹/L with concomitant ANC recovery at 200mg EPAG dose level. An additional 8 (35%) pts have remained on study for a median of 5 cycles (2-17) with stable disease. Two pts discontinued therapy due to disease progression, including 1 (4%) that progressed to AML. The most common non-hematologic AEs regardless of attribution included hyperbilirubinemia (n=14, 61%), fatigue (n=13, 56%) myalgias (n=11, 48%), fever (7, 30%), dyspnea (7, 30%), nausea (6, 26%) and transaminitis (4, 17%). No significant increase in bone marrow fibrosis has been observed. Conclusion: Eltrombopag orally daily appears to be a safe and beneficial supportive adjunct for pts with MDS while receiving HMA-therapy or after HMA-failure due to persistent cytopenias. Treatment on this study continues and larger prospective clinical trials are needed to confirm these preliminary findings. Disclosures Off Label Use: Eltrombopag for the treatment of MDS-related cytopenias". Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding. DiNardo:Novartis: Research Funding.

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A Phase 2 Study to Evaluate the Efficacy and Safety of Simtuzumab in Adult Subjects with Primary, Post Polycythemia Vera (PV) or Post Essential Thrombocythemia (ET) Myelofibrosis

Blood ◽

10.1182/blood.v126.23.2810.2810 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2810-2810

Author(s):

Srdan Verstovsek ◽

Michael R. Savona ◽

Ruben A. Mesa ◽

Stephen Oh ◽

Hua Dong ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Research Funding ◽

Phase 2 ◽

Fibrosis Score ◽

Bone Marrow Fibrosis ◽

Advisory Committees ◽

Equity Ownership ◽

Stage 1 ◽

Marrow Fibrosis

Abstract Background: Simtuzumab (SIM) is a humanized monoclonal antibody that inhibits lysyl oxidase-like molecule 2 (LOXL2), an extracellular matrix enzyme that catalyzes the covalent cross-linking of collagen and is widely expressed across many fibrotic diseases. In pre-clinical models, inhibition of LOXL2 blocks fibroblast activation, which plays an important role in the development of organ fibrosis. In Phase 1 studies, SIM was well-tolerated in patients (pts) with advanced solid tumors, liver fibrosis, and idiopathic pulmonary fibrosis (IPF). A Phase 2, open-label study to determine the efficacy of SIM alone (Stage 1) and combined with ruxolitinib (rux) (Stage 2) in pts with primary myelofibrosis (PMF) and post-ET/PV MF was initiated. Methods: Eligible pts had intermediate-1, intermediate-2, or high risk disease and Eastern Cooperative Oncology Group performance status of <2. The primary endpoint was rate of clinical response as defined by a reduction in bone marrow fibrosis score following 24 weeks of treatment with SIM. Patients were randomized in a 1:1 ratio to receive 200 mg or 700 mg SIM by intravenous infusion every 2 weeks as monotherapy (Stage 1, n=24) or combined with rux (Stage 2, n=30). Patients received SIM for up to 24 weeks. Bone marrow biopsies and aspirates were performed approximately every 3 months. Bone marrow fibrosis scoring was performed and quantified at local investigator sites using the European Consensus on Grading Bone Marrow Fibrosis. Myelofibrosis symptoms were evaluated using the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) and changes in hematologic parameters and splenomegaly were assessed. Results: Between 7/14/11 and 9/22/14, 54 pts were randomized and treated (200 mg SIM [n=12], 700 mg SIM [n=12], 200 mg SIM/rux [n=15], and 700 mg SIM/rux [n=15]). In Stage 1, 0 subjects (0%) in the SIM 200 mg group and 2 subjects (16.7%; 90% CI 3.0%, 43.8%) in the SIM 700 mg group showed a reduction in bone marrow fibrosis score from Baseline to Week 24. In Stage 2, 1 subject (6.7%; 90% CI 0.3%, 27.9%) in the SIM 200 mg/rux group and 2 subjects (13.3%, 90% CI 2.4%, 36.3%) in the SIM 700 mg/rux group showed a reduction in bone marrow fibrosis score from Baseline to Week 24. In an exploratory analysis, similar numbers of subjects showed increases in bone marrow fibrosis scores. SIM treatment was not associated with meaningful improvements in hematologic parameters or reductions in MPN-SAF score or spleen size. The most frequent adverse events were those commonly associated with MF, including constitutional symptoms and reductions in hematological parameters. Conclusions: SIM treatment alone or in combination with rux is safe but does not reliably reduce bone marrow fibrosis in pts with MF. The reason for reduction of marrow fibrosis in some patients and increase in others is unclear and may be sampling variability. Clinical studies of SIM in IPF and liver fibrosis are ongoing. Disclosures Savona: Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Research Funding; Astex Pharmaceuticals, Inc: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Mesa:Incyte Corporation: Research Funding; CTI Biopharma: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Pfizer: Research Funding; Promedior: Research Funding; Genentech: Research Funding; NS Pharma: Research Funding; Gilead: Research Funding. Oh:CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Dong:Gilead Sciences: Consultancy, Equity Ownership. Thai:Gilead Sciences: Employment, Equity Ownership. Gotlib:Allakos, Inc.: Consultancy.

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The MD Anderson Cancer Center (MDACC) Experience with Ruxolitinib, An Oral JAK1 and JAK2 Inhibitor, in Myelofibrosis: Long-Term Follow-up Outcomes of 107 Patients From a Phase I/II Study,

Blood ◽

10.1182/blood.v118.21.3851.3851 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3851-3851 ◽

Cited By ~ 1

Author(s):

Srdan Verstovsek ◽

Zeev Estrov ◽

Jorge E. Cortes ◽

Deborah A. Thomas ◽

Gautam Borthakur ◽

...

Keyword(s):

Bone Marrow ◽

High Risk ◽

Phase I ◽

Spleen Size ◽

Fibrosis Score ◽

Bone Marrow Fibrosis ◽

Jak2 Inhibitor ◽

Marrow Fibrosis ◽

Parent Trial

Abstract Abstract 3851 Background: Myelofibrosis (MF) is a myeloproliferative neoplasm associated with splenomegaly, debilitating symptoms, cytopenias and progressive bone marrow fibrosis. Survival in MF is poor, and effective therapy is lacking. Ruxolitinib (INCB18424) is a JAK1 and JAK2 inhibitor with established clinical benefit in patients (pts) with MF (Verstovsek S. J Clin Oncol 29: [suppl; abstr 6500], 2011) by reducing spleen size and improving MF symptoms & quality of life. Objective: Aim was to identify potential correlates of overall survival (OS) of MF pts receiving ruxolitinib. This study was based on a subset analysis of an open-label single-arm phase I/II trial (INCB18424–251; NCT00509899). Methods: 158 adult pts with primary or secondary MF were enrolled in the parent trial; most received ruxolitinib at doses of 10–25 mg PO twice daily. This updated analysis focuses on 107 pts enrolled at MDACC: 63 were high, 34 intermediate (int)-2 and 10 int-1 risk, according to the International Prognosis Scoring System (IPSS), and assesses their survival and correlates thereof. For log-rank survival analysis, events were censored at the later of last dose, last visit, or last follow-up date. Results: Efficacy and safety findings of the parent trial have been published (Verstovsek S. N Engl J Med 363:1117, 2010): ruxolitinib treatment led to a rapid and sustained reduction in splenomegaly and improvements in MF symptoms; anemia and thrombocytopenia were the most common adverse events. After a median follow-up of 32 months, 58 of 107 pts (54%) were still receiving therapy. The corresponding overall survival (OS) was 69% (33 pts died, none due to therapy-related reasons: 14 while on therapy/within 30 days (d) of discontinuation (dc), and 19 off-study). Accounting for deaths occurring on the study, the 2-yr actuarial survival of int-2 and high-risk pts was 92% and 88%, respectively. However, the 2-yr survival of 13 int-2 and 21 high-risk pts who had discontinued therapy and were subsequently followed was 32% and 21%, respectively. MF transformed to acute leukemia in 9 pts: 5 while on therapy/within 30 d of dc, and 4 off-study; the transformation rate was 0.036/pt years. Pts with normal baseline cytogenetics did not have better survival than those with aberrations (Hazard ratio [HR]=1.52; p=0.24). However, pts with a baseline bone marrow fibrosis score of 2 had greater survival than those with a score of 3 (HR=2.21; p=0.031). Other evaluable baseline pt characteristics (gender, age, anemia, WBC and splenomegaly, did not affect survival. Surprisingly, high-risk pts (per either IPSS or dynamic IPSS [DIPSS]) did not have significantly worse survival than int-2 pts. Importantly, reduction in palpable spleen length while on ruxolitinib was noted to be the most robust predictor for survival: pts who had a ≥50% reduction in spleen size (n=62) had significantly prolonged survival vs. those with a <25% reduction (n=20) (Fig. 1; HR=4.94; p<0.0001). Conclusions: Most MDACC pts with advanced MF in the phase I/II ruxolitinib study are still receiving therapy, demonstrating an OS of 69% after a median of 32 months. The 2-yr survival of pts who remained on therapy was 3–4-fold greater than those who discontinued therapy. Among baseline pt characteristics, only a lower bone marrow fibrosis score correlated with better survival. Conversely, achievement of ≥50% reduction in spleen size while on ruxolitinib resulted in greater survival (vs. <25% reduction). Our data suggest that the most important factors that influence survival of MF pts receiving ruxolitinib are continuous active therapy and a degree of the spleen response, not pt pretherapy characteristics. Disclosures: Verstovsek: Incyte Corporation: Research Funding.

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Genomic Characterization Provides Diagnostic Clarity in Cases with Overlapping Bone Marrow Fibrosis and Monocytosis

Blood ◽

10.1182/blood-2018-99-117796 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4283-4283

Author(s):

Andrew T Kuykendall ◽

Chetasi Talati ◽

Ling Zhang ◽

Najla Al Ali ◽

Kendra L. Sweet ◽

...

Keyword(s):

Bone Marrow ◽

Research Funding ◽

Monocyte Count ◽

Bone Marrow Fibrosis ◽

Genomic Features ◽

Prognostic Features ◽

Pathologic Features ◽

Trisomy 9 ◽

Disease Specific ◽

Marrow Fibrosis

Abstract Introduction: Chronic myelomonocytic leukemia (CMML) and primary myelofibrosis (MF) are distinct myeloid malignancies with clinical and pathologic features that often overlap. The presence of significant bone marrow fibrosis with concomitant monocytosis can be diagnostically challenging. Distinguishing between these two clinical entities has important prognostic and therapeutic implications. In this study, we aimed to genomically characterize cases with overlapping features of both fibrosis and monocytosis and describe their clinical outcomes. Then, using well-established CMML and MF databases, we aimed to identify disease-specific genomic abnormalities to allow for improved diagnostic characterization. Methods: Including molecularly annotated patients (pts) from our CMML and MF databases, we created 3 cohorts. Cohort 1 was comprised of MF pts without significant monocytosis. Cohort 2 included CMML pts with absent/minimal bone marrow fibrosis. Cohort 3 included CMML pts with fibrosis and MF pts with monocytosis. Significant fibrosis defined as grade 2-3 by European consensus recommendations. Monocytosis defined as an absolute (>800/µL, the upper limit of normal in our laboratory) and relative (>10%) peripheral monocyte count. Cohorts 1 and 2 were compared to establish disease-specific somatic gene mutation patterns. Enriched variables were those that occurred significantly more often with p < 0.05. Specificity threshold of > 95% was used. Blinded pathological review of overlap bone marrow cases revealed concordance with original diagnosis in > 95% of cases. Results: Cohorts 1, 2 and 3 were comprised of 181, 168 and 61 pts, respectively. Among 61 pts in cohort 3, 26 had a prior CMML diagnosis and 35 had prior MF diagnosis. Median OS (mOS) in cohort 1 was 161 months (mo) compared to 35 mo in cohort 2 (p < 0.001) and 42 mo in cohort 3 (p < 0.001). mLFS for cohorts 1, 2, and 3 were not reached, 61 mo and 42 mo, respectively (p < 0.001). We compared molecular and cytogenetic abnormalities between cohort 1 and 2, assessing individual and commonly co-occurring abnormalities. Genomic abnormalities more common in CMML were mutations in TET2 (p < 0.001), RAS (p < 0.001), RUNX1 (p < 0.001), SRSF2 (p < 0.001), CBL (p = 0.05), ASXL1 (p = 0.04), TET2/SRSF2 (p < 0.001), TET2/ASXL1 (p < 0.001), TET2/RUNX1 (p = 0.03), SRSF2/ASXL1 (p = 0.004), and normal karyotype (p = 0.002). Genomic abnormalities more common in MF included driver mutations (i.e. JAK2, MPL, or CALR) (p < 0.001), del 20q (p = 0.03), del 13q (p < 0.001), and trisomy 9 (p = 0.004). Disease-specific abnormalities were those that were enriched in either CMML or MF with a specificity of >95%. CMML-specific abnormalities included RAS mutations and co-mutations in TET2/RUNX1, TET2/SRSF2, and SRSF2/ASXL1. MF-specific genomic abnormalities included del20q, del13q, and trisomy 9. We applied these disease-specific genomic abnormalities to cohort 3 to see if these findings could stratify pts toward a CMML-like genotype or MF-like genotype. Of 61 patients, 29 displayed only CMML-like genomic features (genomic CMML), 7 only MF-like features (genomic MF), 4 had both CMML and MF-specific features (genomic overlap) and 21 genomically undefined. Among those in cohort 3 with clinical MF diagnosis, 16 (46%) were reclassified as genomic CMML, 6 (17%) as genomic MF, 3 (9%) as genomic overlap, and 10 (31%) as genomically undefined. Among those with an original clinical diagnosis of CMML, 1 was redefined as genomic MF. OS for genomic CMML did not differ from genomic MF (p = 0.70). There was a trend for inferior LFS in genomic CMML compared to genomic MF (40 mo vs 59 mo, p = 0.19). Multivariate analysis identified the strongest prognostic features in cohort 3 as age > 70 (OR 9.4, p = 0.05), platelet count < 100,000/µL (OR 4.6, p = 0.02) and degree of bone marrow fibrosis (OR 5.1, p = 0.009). Conclusions: Specific genomic features distinguish CMML from MF. Application of these findings to pts with overlapping clinicopathologic features provides clarity in >50% of cases, primarily reclassifying patients as CMML. Clinically, outcomes in this overlap group with bone marrow fibrosis and monocytosis mirror those of CMML, regardless of genomic assignment; however, the presence of thrombocytopenia and magnitude of bone marrow fibrosis provide further prognostic discrimination. Future studies testing CMML-like therapeutic strategies should be considered in MF with monocytosis. Disclosures Kuykendall: Celgene: Honoraria; Janssen: Consultancy. Sweet:BMS: Honoraria; Celgene: Honoraria, Speakers Bureau; Jazz: Speakers Bureau; Astellas: Consultancy; Phizer: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; Agios: Consultancy; Jazz: Speakers Bureau; Agios: Consultancy; Phizer: Consultancy; Astellas: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Honoraria; Celgene: Honoraria, Speakers Bureau. Sallman:Celgene: Research Funding, Speakers Bureau. List:Celgene: Research Funding. Komrokji:Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau.

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Transcriptional Landscape of the Microenvironment in Bone Marrow Fibrosis at Single Cell Level

Blood ◽

10.1182/blood-2019-126897 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1675-1675

Author(s):

Nils B. Leimkühler ◽

Ronghui Li ◽

Helene Gleitz ◽

Inge Snoeren ◽

Stijn Fuchs ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Research Funding ◽

Cell Level ◽

Bone Marrow Fibrosis ◽

Advisory Committees ◽

Molecular Alterations ◽

Ecm Proteins ◽

Travel Grant ◽

Marrow Fibrosis

Although the molecular alterations in hematopoietic cells which drive the development of myeloproliferative neoplasms (MPN) have been largely defined, reactive cellular alterations in the non-hematopoietic compartment remain rather obscure and have not been studied at single cell level. We therefore profiled enriched non-hematopoietic bone marrow cells by scRNAseq in bone marrow (BM) fibrosis compared to healthy marrow. BM fibrosis was induced by transplantation of hematopoietic stem and progenitor cells (HSPCs) with overexpression of Thrombopoietin (ThPO) into lethally irradiated mice. As ThPO-overexpression robustly leads to reticulin fibrosis in all mice (100%), we were able to study 1) pre-fibrosis (5 weeks after transplantation; reticulin fibrosis grade 0) and 2) manifest bone marrow fibrosis (10 weeks after transplantation, reticulin grade 2-3). The analysis revealed a total of 8 distinct clusters: 1-4) subpopulations of mesenchymal stromal cells (MSC-1: adipogenic, MSC-2: osteogenic, MSC-3: transition, MSC-4: interferonhigh), 5) osteoblastic lineage cells (OLCs), 6) arterial endothelial cells (ECs) and 7-8) Schwann cell precursors (SCP-1: non-myelinating SCPs; SCP-2: myelinating SCPs). Exposure to ThPO overexpressing HSPCs resulted in an overrepresentation of adipogenic MSCs at the expense of all other MSC subclusters. Differential gene expression analysis revealed a functional reprogramming of the "adipogenic" expanding MSCs with down-regulation of hematopoiesis-support and induction of a secretory phenotype including upregulation of various extracellular matrix (ECM) proteins driving fibrosis. Interestingly, only two MSC subclusters gained significant ECM expression indicating myofibroblast differentiation. Expansion of OLCs in BM fibrosis suggested a differentiation of the underrepresented MSC subpopulations into osteolineage cells which was confirmed by pseudotime analysis. Myelinating SCPs, highly expressing interleukin-33 (IL-33), showed the largest expansion in fibrosis. IL-33 is described to play a significant role in solid organ fibrosis by having both pro- and anti-fibrotic effects. Nerve injury triggers the expansion of myelinating and non-myelinating Schwann cells to promote repair, suggesting that mSCPs increase as compensatory and regenerative mechanism for the previously described MPN-induced sympathetic neuropathy. Dissection of cellular and molecular alterations in pre-fibrosis and manifest fibrosis demonstrated that only one MSC subpopulation was already significantly expanded in the pre-fibrotic phase, but only showed minor transcriptional changes. The upregulation of ECM proteins, osteogenesis as well as proinflammatory genes were hallmark features of manifest fibrosis. Interestingly, the overrepresentation of IL-33 expressing mSCPs was more pronounced in the pre-fibrotic phase, indicating that the expansion is a regenerative phenomenon failing in the stages of manifest fibrosis. Our findings were validated in the clinically relevant JAK2(V617F)-induced model of myelofibrosis. In conclusion, we here identified two distinct MSC subsets that are pro-fibrotic and contribute to osteosclerosis in PMF. The functional reprogramming of these MSCs in the bone marrow niche was accompanied by expansion of mSCPs with regenerative capacities, most likely caused by neural damage and Schwann cell death triggered by mutant HSCs. Disclosures Crysandt: Amgem: Other: travel grant; Pfizer: Other: travel grant; Gilead: Other: travel grant; Incyte: Membership on an entity's Board of Directors or advisory committees; celgene: Other: travel grant. Koschmieder:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers-Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, 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, Research Funding; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AOP Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Foundation: Research Funding.

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Thrombopoietic Agents in the Treatment of Childhood Immune Thrombocytopenia (ITP): Clinical Treatment At 2 Centers

Blood ◽

10.1182/blood.v118.21.2230.2230 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2230-2230

Author(s):

Kavitha Ramaswamy ◽

Loan Hsieh ◽

Hatice Melda Ürekli ◽

Diane J. Nugent ◽

James B Bussel

Keyword(s):

Bone Marrow ◽

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Rescue Therapy ◽

Bone Marrow Fibrosis ◽

Advisory Committees ◽

Equity Ownership ◽

The Mean ◽

Marrow Fibrosis

Abstract Abstract 2230 Introduction: Thrombopoietic agents (TPO-A) are widely used in adults for difficult ITP. However only 1 study has been published describing the use of a TPO mimetic (Nplate) in 22 children with ITP. This study is a post hoc analysis of 32 children (<21yr) who received clinical treatment (off study) with either Nplate or Promacta. Methods: All children described are from 2 centers:,Weill Cornell in New York (n=22, 9 on Nplate, 13 on Promacta) and Childrens Hospital Orange County (10, all on Nplate). All patients in this abstract were treated off study although some had previously participated in the AMGEN195 (Pediatric) followed by AMGEN 213 (long term maintenance) studies. Responses (taken from the published study) were defined as platelet count (plt ct) > 50k on 2 consecutive weeks, plt increase ≥ 20k on 2 consecutive weeks, and the percent of weeks at ≤ 50k independent of rescue therapy. Rescue therapy e.g. IVIG, steroids, plt transfusion, resulted in counts being considered “non-responder” for 2 full weeks after initiation of treatment. Bone marrows were evaluated for reticulin fibrosis (RF) using consensus grades 0–3. Several patients had more than one marrow during treatment; in these cases, the most recent on-therapy marrow was used. Results: The median age of patients on Nplate was 10 years of age (2–19) while for those on Promacta it was 16 years (5–19). Of the 32 patients treated with TPO-A, 24 responded with a plt ct ≥ 50k twice; 19/32 received Nplate and 15/19 responded; 13/32 received Promacta and 9/13 responded. Plt increases ≥ 20k were seen in 23 of 32 patients. The number of patients whose platelet count was ≥ 50k for at least 50 percent of visits was 20/32. The mean number of previous treatments for responders to Nplate was 3.2 while for Nplate non-responders it was 2.25. For Promacta, the mean for responders was 2.9 treatments and for non-responders 3 treatments. Younger patients did not seem to respond as well to treatment with either TPO-A (see table). Nplate patients received treatment for a mean of 19.2 weeks; for patients treated with Promacta it was 13.7 weeks. Baseline bone marrows were available in 17 patients of whom 6 had grade 1 reticulin fibrosis (RF). There were 10 children with marrows performed after the start of TPO-A: 2 with RF score=0, 7 with score=1+, and 1 with score=2+ Adverse events (AEs) other than bone marrow fibrosis and bleeding (lack of efficacy) were all 1–2+ and not related to TPO-A. In particular, no thrombosis or development of malignancy was seen. In conclusion, TPO-A were an effective treatment of chronic ITP in the 32 consecutive children retrospectively analyzed here from 2 centers. Younger children in this study seemed not to respond as well as older children, in contrast to small numbers of young children in published data who responded very well. No major changes were seen in the bone marrows but a formal baseline and on therapy study in children is needed to assess this issue. AEs were infrequent and tolerable. Additional studies with both Nplate and Promacta, either planned or in progress, are needed to clarify the response rates, AEs eg bone marrow fibrosis, and effects in subgroups of children. Disclosures: Bussel: Portola: Consultancy; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Cangene: Research Funding; Genzyme: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sysmex: Research Funding.

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Bone Marrow Fibrosis In Immune Thrombocytopenia (ITP) Patients Treated With Thrombopoietin Receptor Agonists (TRA) – a Single Center Long-Term Follow-Up

Blood ◽

10.1182/blood.v122.21.3527.3527 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3527-3527

Author(s):

Waleed Ghanima ◽

Julia Turbiner Geyer ◽

Christina Soo Lee ◽

Attilio Orazi ◽

Leonardo Boiocchi ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Research Funding ◽

Single Center ◽

Duration Of Treatment ◽

Bone Marrow Fibrosis ◽

Advisory Committees ◽

Equity Ownership ◽

Marrow Fibrosis

Abstract Introduction TRAs increase platelet counts by stimulating the TPO-receptor. A known effect of TRA treatment is increased bone marrow fibrosis (MF). This study explored extent of MF, its clinical relevance, and incidence of phenotypic or karyotypic abnormalities in TRA-treated ITP patients. Methods This single-center study was carried out at the Platelet Disorders Center of Weill Cornell Medical College (WCMC), NY, USA. Eligibility criteria were: diagnosis of ITP; treatment with a TRA (romiplostim, eltrombopag, AKR 501 (Eisai) or Shionogi agent), ≥ 1 bone marrow biopsy (BMB) performed during TRA treatment. BMBs were performed every 1–2 years as standard f/u procedure for our ITP patients on TRA. MF grade was assessed from MF-0 to MF-3 according to the European Consensus Grading System in 141 BMBs acquired prior to (n=15), during (n=117) and after (n=9) TRA-treatment from 66 patients. Fifty disease-free staging BMBs served as controls. BMBs were separately reviewed by 3 pathologists to assess the grade of MF and then reviewed concurrently as needed to reach consensus. The study was approved by the IRB of WCMC; informed written consent was obtained from patients. Results Median (Q1-Q3) age at the time of 1st BMB was 38 years (18-63); 34 males 32 females. 32 patients had > 2 on-treatment BMBs. The distribution of MF-grades is shown in the figure. The proportion of MF-0 decreased from 67% in pretreatment biopsies (BM0) to 21% in the first set of BMBs (BM1); in the 15 patients with pre- and on-treatment BMBs there was a significantly higher number of MF-0 in BM0 as compared to BM1 (10/15 vs. 3/15;p=0.016) suggesting that TRAs induce fibrosis in treated patients. In patients with multiple on-treatment BMBs (n=32), first on-treatment BMB was graded as MF-1 in 24. In the last set of biopsies (BM-Last) 8 had progressed to MF-2/3, 12 remained MF-1, and 4 became MF-0 illustrating the unpredictability of the future course of MF from the first on-treatment marrow. Nonetheless, a higher number of MF-2/3 BMB was found in BM-Last as compared to BM1 [10 (31%) vs. 3 (9%) of 32; p=0.039]. In 5 patients with MF-2/3 BMB, TRA were discontinued: on f/u 2 had less fibrosis, 1 remained the same, and 2 are awaiting f/u BMB. BMB was graded MF-0 in 54% and MF-1 in 46% of control BMB; no difference was found in the proportion of MF-0/1 and 2/3 in BM0 compared to controls, but increased MF-2/3 was seen in BM-last compared to controls (p<0.001). At BM-last in patients dichotomized by MF-0/1 vs. MF-2/3, differences in hemoglobin levels (13.6 vs. 12.4 g/dl, respectively), absolute neutrophil counts (4.8 vs. 7 x109/L), platelet counts (92 vs. 123 x109/L), and LDH levels (212 vs. 219 U/L) were not significantly different. Of the following 6 clinical factors: age, duration of disease, duration of treatment, splenectomy status, type and dose of agent; only age was significantly higher in patients with MF-2/3 as opposed to MF0/1 at time of BM-last [57 vs. 38 years; p=0.01]. There was a tendency toward longer duration of treatment in patients with MF-2/3 as compared to MF-0/1 (3.6 y vs. 2.7y; p=0.16). Flow cytometric immunophenotyping of BMB in 89 examinations did not reveal emergence of clonal abnormalities. Cytogenetic analysis in 72 BMBs did not show any clonal karyotypic abnormalities. Conclusions This large single center experience indicates that TRAs induce some degree of MF as supported by: 1) decreasing fraction of MF-0 after initiation of TRA, 2) decreasing fraction of MF-0/1 (normal grades of MF) in subsequent on-treatment BMBs, 3) increasing fraction of MF-2/3 (pathological grades) in patients with multiple on-treatment BMBs. Only older age was associated with higher grades of fibrosis. However, MF remained stable in most patients within the range found in normal individuals. Higher grades of MF (MF-2/3) observed in some patients were not clinically significant based on peripheral blood counts. Overall, since a number of patients developed MF-2 and even MF-3, this suggests a risk of progressive fibrosis in approximately 20% of patients. No neoplastic immunophenotypic or karyotypic abnormalities emerged during treatment with TRAs. Annual or bi-annual follow-up with BMB should be carefully considered in TRA-treated patients. Discontinuation of TRA should be encouraged in those who develop/progress to MF-3 and possibly even MF-2 to avoid potential further progression of MF Disclosures: Bussel: Amgen: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; Genzyme: Research Funding; IgG of America: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; Symphogen: Membership on an entity’s Board of Directors or advisory committees.

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A New Prognostic Model for Response in Myelofibrosis Patients Treated with JAK2 Inhibitors: A Study from Three US Academic Centers

Blood ◽

10.1182/blood.v124.21.1842.1842 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1842-1842 ◽

Cited By ~ 1

Author(s):

Menghrajani Kamal ◽

Philip S. Boonstra ◽

Alissa A. Weber ◽

Cecelia Perkins ◽

Krisstina L. Gowin ◽

...

Keyword(s):

Bone Marrow ◽

Clinical Response ◽

Bone Marrow Biopsy ◽

Risk Score ◽

Initial Dose ◽

Research Funding ◽

Spleen Size ◽

Jak2 Inhibitor ◽

European Consensus ◽

Jak2 Inhibitors

Abstract Background: JAK2 inhibitors have been shown to improve symptoms and produce durable reductions in splenomegaly in patients with myelofibrosis (MF), and ruxolitinib has been shown to improve survival in MF patients (Cervantes et al., 2013; Verstovsek et al., 2013). Current prognostic models such as DIPSS plus (Gangat et al., 2011) predict survival in MF based on clinical, laboratory, and cytogenetic information, but their value in predicting clinical response or survival during treatment with JAK2 inhibitors remains unknown. We hypothesized that clinical features such as bone marrow fibrosis and splenomegaly may have independent effects on therapy response. Therefore, we conducted a retrospective analysis to create a new model to risk stratify patients with respect to their likelihood of responding to oral JAK2-inhibitor therapy. Methods: We studied a cohort of 203 patients with bone marrow biopsy-proven MF seen at University of Michigan, Stanford University, and Mayo Clinic in Scottsdale, AZ. These patients were all treated with ruxolitinib or an experimental JAK2 inhibitor. Our primary endpoint was defined as IWG-MRT criteria for splenic response by palpation (Tefferi et al., 2013). Response in patients with spleen size of less than 5 cm was defined as complete resolution of splenomegaly. Of the 203 patients studied, splenic response was evaluated after 3 months of therapy in 167 patients and after 6 months of therapy in 138 patients; 127 patients were in both groups. A logistic regression was performed to identify factors that would predict clinical response. Results: The following characteristics were significantly associated with spleen response at 3 and 6 months: initial spleen size, European consensus criteria grading of MF on bone marrow biopsy, initial DIPSS plus score, and initial WBC count. Cellularity on marrow biopsy was not significant. We enriched a baseline logistic model of initial dose of oral JAK2 therapy and DIPSS plus score with additional prognostic factors. We found the following clinical characteristics to be jointly associated with splenic response: normalized initial dose of oral JAK2 inhibitor, initial spleen size, DIPSS plus score, degree of fibrosis by European consensus criteria. Duration of disease from time of diagnosis to time of treatment initiation was not prognostic for splenic response. We used this model to calculate the probability of splenic response based on a risk score: Risk score = –1.18(Dose) + 0.09(Initial Spleen Size in cm) + 0.20(DIPSS-plus Points) +0.92 (if fibrosis is MF-3). The probability at 6 months can then be calculated from the risk score as follows: [1/(1+e(risk score-2.6))]. The figure demonstrates the prognostic gain of our model over a model based on DIPSS plus alone. Conclusion: With this observational study, we propose a predictive model which may serve as a clinical tool to identify which patients are most likely to benefit from JAK2 inhibitor-based therapies. Further validation in independent data sets will be required before this model can be more widely applied. Disclosures Mesa: Incyte Corporation, CTI, NPS Pharma, Inc., Gilead Science Inc., Celgene: Research Funding. Gotlib:Incyte: Consultancy, Honoraria, Research Funding, Travel Reimbursement Other; Gilead: Research Funding; Sanofi: Research Funding; Novartis: Research Funding, Travel Reimbursement, Travel Reimbursement Other. Talpaz:ARIAD Pharmaceuticals, Inc., BMS, Sanofi, Incyte, Pfizer: Research Funding.

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