Post-polycythemia Vera Myelofibrosis Research Articles

Miliary TB and COVID-19 Coinfection in a Patient With a History of Post-polycythemia Vera Myelofibrosis Treated With Ruxolitinib: A Case Report

Miliary TB and COVID-19 Coinfection in a Patient With a History of Post-polycythemia Vera Myelofibrosis Treated With Ruxolitinib: A Case Report

Evolving landscape of JAK inhibition in myelofibrosis: monotherapy and combinations.

Myeloproliferative neoplasms (MPNs) are characterized by clonal myeloproliferation in 1 or more of the hematopoietic stem cell lineages. Primary myelofibrosis (MF), post-polycythemia vera MF, and post-essential thrombocythemia MF have the worst prognosis and are characterized by the presence of cytokine-mediated symptom complex, splenomegaly, progressive marrow failure, and clonal instability, leading to leukemic transformation. The key therapeutic aims encompass the management of symptoms, splenomegaly, and anemia and the improvement of survivals. These therapeutic aims have evolved with the availability of Jak inhibitors and novel agents, making disease modification potentially achievable. Novel agents may potentially target MPN stem cells, epigenetic alterations, signaling pathways, and apoptotic pathways. In this case-based review, we outline our approach to the management of MF and discuss the therapeutic landscape of MF, highlighting the utility of Jak inhibitors and novel Jak inhibitor-based combinations.

Ropeginterferon Alfa-2b for Pre-Fibrotic Primary Myelofibrosis and DIPSS Low/Intermediate-1 Risk Myelofibrosis: Durable Responses and Evidence of Disease Modification

Background Most patients with primary myelofibrosis (PMF) in pre-/early fibrotic stage (pre-PMF) and at low or intermediate-1 risk by the dynamic international prognostic scoring system (DIPSS) will progress to higher risks or overt MF. There is currently no consensus on the optimal treatment for these patients. Ropeginterferon alfa 2b (ropeg) is a next-generation monopegylated interferon alfa-2b developed specifically to treat myeloproliferative neoplasms (MPN). Aims P1101MF is an on-going multicenter phase 2 study of ropeg in patients with pre-PMF and DIPSS low/intermediate-risk PMF. Methods Key eligibility included morphologically confirmed pre-PMF, overt PMF, post-polycythemia vera MF (PPV-MF) or post-essential thrombocythaemia MF (PET-MF), DIPSS low/intermediate-1 risk, and the need for cytoreduction. The primary outcome were responses in haemoglobin (Hb, from 10 g/dL to upper reference range), white blood cell (WBC, < 10 x 10 9/L) and platelet (≤ 400 x 10 9/L) at 24 and 48 weeks. Secondary outcomes included adverse events (AEs), changes in mutant allele frequencies (MAF) of driver and non-driver genes as assessed by droplet digital polymerase chain reaction (ddPCR), quality-of-life (QOL), cytokine profiles and bone marrow morphology. Patients received ropeg at a dose of 250 mcg at week 1, followed by 350 mcg at week 2 and 500 mcg every 2 weeks from week 4 onwards. Results At the data cut-off of 30 June 2023, 37 men and 29 women with a median age of 59 (range: 30-86) years were enrolled. The diagnoses were pre-PMF (=46, 69.6%); overt PMF (N=6, 9.1%); PPV-MF (N=5, 7.5%); and PET-MF (N=9, 13.6%). Mutational profile of driver genes was JAK2V617F (N=46, 69.6%); CALR mutations (type 1/type-1 like, N=13, 19.7%; type 2/type 2-like, N=4, 6.1%); MPL mutation (N=1, 1.5%); and triple-negative (N=3, 4.5%). The median time from diagnosis to treatment was 5.8 (1-271) months. The median baseline parameters were white blood cell count (WBC): 6.49 (3.25-33.95) x 10 9/L; haemoglobin (Hb): 12.5 (7.1-15.9) g/dL; platelet count: 495 (113-1114) x 10 9/L; and lactate dehydrogenase: 277 (136-1146) IU/L. The median follow-up was 69 (4-69) weeks, with 61 patients (92%) and 51 patients (77%) having completed 24 and 48 weeks of treatment respectively. Responses in Hb, WBC and platelet were 75%, 82% and 74% respectively at 24 weeks, and 82%, 80% and 71% respectively at 48 weeks. Reduction of MAF at 24 and 48 weeks was achieved for JAK2V617F in 50% (19/38) of patients (≥50%, N=10, 26%; complete, N=3, 8%) and 79% (22/28) of patients (≥50%, N=6, 21%; complete, N=1, 4%) respectively; and for CALR in 44% (7/16) of patients (≥50%, N=1, 6%) and 50% (5/10) of patients (≥50%, N=1, 10%) respectively. Forty-six patients (69.6%) had bone marrow biopsies serially performed, with 42 patients (91%) having stable/improved marrow fibrosis. Eight patients (17.4%) had resolution of marrow fibrosis by 48 weeks. There were 5 discontinuations (personal reasons, N=1; intractable pruritus, N=1; symptom/spleen size progression, N=3). Disease progression (pre-PMF to overt PMF; development of accelerated/blast phase) was not observed. Non-haematological AEs included transaminitis (grade 1-2, N=34); malaise (grade 1-2, N=27; grade 3-4, N=1) and hair loss (grade 1-2, N=21). The most common haematological AE was anaemia (grade 1-2, N=15; grade 3-4, N=6). Conclusion: Ropeg was well-tolerated, effective in cytoreduction and induced molecular and morphologic responses in patients with pre-PMF and low/intermediate-1-risk MF.

CPX-351 in Patients with Newly Diagnosed Post Myeloproliferative Neoplasms Acute Myeloid Leukemia

Background Progression of myeloproliferative neoplasms (MPNs) including polycythemia Vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) to acute myeloid leukemia (post MPN AML) is associated with a poor prognosis. Studies evaluating intensive chemotherapy showed response rates ranging between 40% and 50% and a median event-free survival (EFS) of 3-4 months. CPX-351 (Vyxeos) is a new formulation of cytarabine and daunorubicin encapsulated at a fixed 5:1 molar-ratio in liposomes that exploits molar ratio-dependent drug-drug synergy to enhance antileukemic efficacy. Induction therapy with CPX-351 is associated with a 47.7% response rate and significantly improved overall survival (OS) when compared to standard ICT (“7+3”) in older patients with newly diagnosed secondary AML (sAML) (Lancet, JCO 2018). However, patients with post MPN AML were not eligible in that trial. We report here the preliminary results of a prospective trial evaluating the effects of CPX351 in this difficult-to-treat patient population. Methods We designed an open label multicenter phase II non-randomized study to evaluate CPX-351 in post MPN AML. Patients received one to two induction cycles with CPX-351 100 U/m2 on days 1, 3, and 5. Patients in CR/CRi after induction cycle(s) received up to 2 courses of consolidation therapy with CPX-351 65 U/m2 on days 1 and 3 (or on day 1 only in case of unacceptable toxicity). The primary objective was to evaluate the complete remission rate (including CR and CR with incomplete hematological recovery, CRi) after one or two induction cycles with CPX-351. Results In this interim analysis, we present the results for the first 29 patients (14 males and 15 females). The median age was 67 (50-78). Prior MPN before leukemic transformation was ET in 13 (44.8%), PV in 1 (3.4%), PMF in 9 (31%), post ET myelofibrosis in 4 (13.8%) and post PV myelofibrosis in 2 (6.9%) patients. Median hemoglobin, platelet count and white blood cell count were 8.7g/dL (6.2-14.7), 9G/L (7-771) and 6 G/L (1.5-77.3), respectively. BM involvement showed a median of 40% blasts (8-96%). Cytogenetics was favorable, intermediate, unfavorable, or missing in 1 (3.4%), 9 (31%), 17 (58.6%), 2 (6.9%) of cases. Twelve patients (41.3%) achieved a complete response (CR) or a complete response with incomplete hematologic recovery (CRi) after 1 or 2 induction cycles; two patients (6.9%) had a partial response, and 15 patients (51.7%) failed. Minimal residual disease analysis for responding patients is on-going. At the time of analysis, 5 patients transitioned to an allogenic stem cell transplantation. Time for neutrophil count recovery (>0.5G/L) was 26 days (0-41) after the first induction cycle. Mean time for platelet recovery (>50G/L) was 27 days (14-54). Main severe adverse events (grade 3-4) consisted in infections (8, 27.6%), cardiac toxicities (2 tamponades, 6.9%), and expected hematological toxicities. We registered 7 deaths (6 associated with treatment failure and 1 occurring on day-56 of induction-1 related to a fungal infection). With a median follow up of 3.5 months, estimated OS and EFS were 7.1 months. Conclusion CPX-351 showed encouraging response rates and survival with a manageable safety profile. The study continues to accrue patients and results of the entire planned study group (42 patients) will be presented.

PXS5505-MF-101: A Phase 1/2a Study to Evaluate Safety, Pharmacokinetics and Pharmacodynamics of Pxs-5505 in Patients with Primary, Post-Polycythemia Vera or Post-Essential Thrombocythemia Myelofibrosis

Background: Myelofibrosis (MF) is characterized by a progressive increase in extracellular matrix in the bone marrow (BM) associated with decreased production of hematopoietic cells. Though Janus kinase (JAK) inhibitors provide clinical benefit in patients (pts) with MF, they have no direct effect on BM fibrosis (BMF) and thereby limited disease modifying effects. MF is associated with elevated expression of most lysyl oxidase (LOX) isoforms which cross link collagen and elastin. PXS-5505 is a pan-LOX inhibitor that prevents the cross-linking of collagen and elastin and exhibits anti-fibrotic effects in murine models of MF. PXS5505-MF-101 is an ongoing multi-center phase 1/2a study of PXS-5505 in pts with primary, post-polycythemia vera (PV) or post-essential thrombocythemia (ET) MF. (NCT04676529) The study started with two phases: Dose Escalation (DEP) and Cohort Expansion (CEP). The DEP has been completed, establishing a dose of 200mg BID to carry forward into the CEP. During the CEP, up to 24 pts are to be treated for 6 months. Preliminary data from the CEP is presented here. Methods: Study objectives are to determine PXS-5505 safety/tolerability, pharmacokinetics (PK) and pharmacodynamics (PD), BMF changes, spleen volume and MF symptoms (MFSAF). Eligible pts must have primary or post-ET/PV MF of Int-2/high risk; relapsed/refractory or intolerant/ineligible to available JAK inhibitors and have symptomatic disease. Results: At data cutoff (30/Jun/2023), 21 pts have enrolled in the CEP (7 F and 14 M); age 60-86 yrs (median 72 yrs); of these, 10 have completed 24 weeks of Rx and 20 pts have completed ≥1-month Rx. 8 pts had post-ET MF, 5 post-PV MF and 8 PMF; 9 pts have withdrawn from the CEP. Total drug exposure in the CEP is 372 weeks, median 162 days (min 25, max 191). Preliminary CEP PK data are consistent with the DEP with steady state reached by Day 28 with no accumulation observed past this point. The PD data from the DEP demonstrated excellent inhibition of LOX as measured by LOX and LOXL2 target engagement (data previously presented) and this level of inhibition continues to be observed in CEP. [Figure 1] All 9 pts completing 24 weeks PXS-5505 with baseline (BL) biopsies available showed stable reticulin fibrosis at each visit; collagen fibrosis was reduced in 5/9 pts. [Figure 2] Hematological parameters were stable; 7/10 pts had stable/improved hemoglobin and 8/10 had stable/improved platelets over 24 weeks including 3 pts with Grade 4 thrombocytopenia at BL. 4/10 pts had improvements in MF-SAF TSS of ≥20% with 2/10 pts of ≥40% at 24 weeks. No SVR35 responses were seen. There has been 1 fatal AE (febrile neutropenia) on Rx, and 2 post-Rx discontinuation/completion (sepsis, acute myocardial infarction), all unrelated. There have been 6 Rx related adverse events (TRAEs); 2 Grade 1 (vomiting, urticaria), 2 Grade 2 (purpura, hypomagnesaemia), 1 Grade 3 (platelet count decreased), 1 Grade 4 (anemia, noted as leading to drug withdrawal). There have been no serious TRAEs reported. Enrolment into the CEP continues and an additional cohort is planned using PXS-5505 as an add-on to Ruxolitinib Rx. Conclusion: PXS-5505 has been well tolerated with no dose limiting toxicity or serious TRAEs. PD results indicate excellent LOX inhibition at the 200mg BID level. Further, there are preliminary indications of disease modification characterized by stable/improved blood counts and an improvement in collagen fibrosis. These results are encouraging given the poor prognosis seen after Ruxolitinib discontinuation in pts with MF and warrant continued investigation in an earlier Rx setting.

Efficacy and Safety of Fedratinib in Patients with Myelofibrosis Previously Treated with Ruxolitinib: Results from the Phase 3 Randomized FREEDOM2 Study

Introduction Patients (pts) with myelofibrosis (MF) treated with the Janus kinase inhibitor (JAKi) ruxolitinib (RUX) show spleen volume reduction (SVR) and symptom reduction. However, most develop RUX intolerance or relapsed/refractory (R/R) disease and survival rates after RUX discontinuation are poor. Fedratinib (FEDR) delivered SVR and symptom reduction in the JAKARTA2 and FREEDOM studies (C Harrison et al. Am J Hematol 2020; V Gupta et al. Blood 2022). FREEDOM2 (NCT03952039) was a phase 3, open-label, randomized study to evaluate the safety and efficacy of FEDR compared with best available therapy (BAT) in pts with MF previously treated with RUX. Methods Pts aged ≥ 18 years with primary, post-polycythemia vera, or post-essential thrombocythemia MF with Dynamic International Prognostic Scoring System (DIPSS) score ≥ intermediate-2, splenomegaly (≥ 450 cm 3), platelets ≥ 50 x 10 9/L, peripheral blood myeloblasts < 5%, and normal baseline thiamine, R/R or intolerant to RUX, were randomized 2:1 to FEDR 400 mg/day or BAT in 28-day cycles, with stratification by spleen size, platelet count, and RUX R/R vs intolerant. Crossover to FEDR was permitted for progressive disease or after cycle 6 (EOC6) response assessment. Pts were treated until intolerance or lack of efficacy and followed-up every 3 months until death, withdrawal of consent, or study closure. The primary endpoint was SVR ≥ 35% (SVR35) at EOC6; secondary endpoints included symptom response (≥ 50% reduction in total symptom score measured by Myelofibrosis Symptom Assessment Form), SVR ≥ 25% (SVR25), durability of SVR and symptom response, and safety. Results Overall, 201 pts were initially randomized and treated, 134 and 67 pts in the FEDR and BAT arms, respectively; subsequently, 46 (68.7%) pts from the BAT arm crossed over to FEDR. Median (interquartile range) age was 70 (64-74) years, 52.2% were male, and most had primary MF (54.7%) and intermediate-2 DIPSS risk (76.1%). Assessed by aggregated group, most pts in the BAT arm received RUX (70.1%), hydroxyurea (10.4%), or RUX plus hydroxyurea (7.5%). At the data cutoff of December 27, 2022 (median follow-up, 15 months), pts receiving FEDR had significantly higher rates of SVR35 at EOC6 compared with BAT (35.8% vs 6.0%; P < 0.0001), as well as superior SVR25 at EOC6 and SVR35 during the full treatment course ( Table, Figure). SVR35 benefit with FEDR was observed across subgroups. The FEDR arm also showed higher rates of symptom response at EOC6 compared with BAT (34.1% vs 16.9%; P = 0.0033; Table). Median treatment duration was 43 weeks of FEDR and 24.7 weeks of BAT. During the first 6 cycles in the safety population: 70 (52.2%) pts on FEDR and 20 (29.9%) pts on BAT had dose interruption/reduction; median time to first reduction/interruption was 44.0 days for FEDR and 56.5 days for BAT. Treatment-emergent adverse events (TEAEs) leading to permanent treatment discontinuation occurred in 13 (9.7%) and 4 (6.0%) pts in the FEDR and BAT arms, respectively, during the first 6 cycles. During the first 6 cycles, 132 (98.5%) pts on FEDR and 65 (97.0%) pts on BAT had ≥ 1 TEAE; treatment-related AEs (TRAEs) occurred in 109 (81.3%) and 23 (34.3%) pts in the FEDR and BAT arms, respectively. The most frequently occurring TRAEs with FEDR were diarrhea (38.1% FEDR vs 0.0% BAT) and nausea (32.1% FEDR vs 1.5% BAT); most cases were grade 1/2. Grade 3/4 TRAEs occurred in 52 (38.8%) pts in FEDR and 8 (11.9%) pts in BAT arms, most frequently thrombocytopenia (11.9% FEDR vs 3.0% BAT) and anemia (9.0% FEDR vs 9.0% BAT). In the FEDR arm, 22 (16.4%) pts had thiamine levels below normal range, compared with 2 (3.0%) pts receiving BAT; most cases occurred prior to the study amendment of prophylactic thiamine supplementation. There was a single grade 1 case of suspected Wernicke's encephalopathy in the FEDR arm during cycle 3, which resolved fully 24 hours after thiamine supplementation (0 cases in BAT arm). Two pts each in FEDR and BAT arms had TRAEs of infection. Conclusions In this phase 3 randomized study in pts with MF and prior RUX treatment, FEDR demonstrated superior SVR and symptom response rates compared with BAT. Most pts on BAT received RUX, highlighting a clinical need for an alternative JAKi. Differences in AE and discontinuation rates in the first 6 cycles are consistent with other studies comparing JAKi with BAT. AE mitigation strategies were effective and no new safety concerns for FEDR were identified. Study support Bristol Myers Squibb

Real-world clinical characteristics of post-essential thrombocythemia and post-polycythemia vera myelofibrosis.

There are few prospective studies on patients with post-essential thrombocythemia myelofibrosis (PET-MF) and post-polycythemia vera myelofibrosis (PPV-MF). Therefore, we conducted a nationwide longitudinal prospective survey to clarify the clinical characteristics of these diseases. A total of 197 PET-MF and 117 PPV-MF patients diagnosed between 2012 and 2021 were analyzed. The median age at diagnosis was 70.0years for both diseases. The time from diagnosis of ET or PV to that of MF was 9.6 and 10.4years, respectively, with no significant difference. Patients with PPV-MF had higher hemoglobin levels and white blood cell counts than those with PET-MF, whereas those with PET-MF had higher platelet counts than those with PPV-MF. Although splenomegaly was more frequent in patients with PPV-MF at diagnosis, there was no difference in the frequency of constitutional symptoms. Ruxolitinib was the most common treatment administered to 74.6% and 83.8% of patients with PET-MF and PPV-MF, respectively. Patients with PET-MF and PPV-MF had similar prognoses, with 3-year overall survival (OS) of 0.742 in PET-MF and 0.768 in PPV-MF patients. In both diseases, leukemic transformation was the leading cause of death, followed by infection. The 3-year OS for patients with PET/PPV-MF and primary MF diagnosed during the same period was 0.754 and 0.626, respectively, with no significant difference. This survey provides real-world clinical features and prognostic data on secondary myelofibrosis in the ruxolitinib era.

Modulation of TGF-β Superfamily Signaling By Ker-050 Demonstrated Potential to Treat Myelofibrosis and Mitigate Ruxolitinib-Associated Cytopenia

Background: Myelofibrosis (MF) is a disorder characterized by unrestrained proliferation of myeloid precursors and dysfunctional Janus kinase (JAK) signaling. Fibroblast proliferation, bone remodeling, and marrow fibrosis within the osteohematopoietic niche (OHN) result in ineffective and extramedullary hematopoiesis. Clinical manifestations include anemia, splenomegaly, and often disabling symptoms. JAK inhibitors, such as ruxolitinib, have been shown to improve spleen size and symptoms but are associated with dose-limiting cytopenia, reducing their utility for many patients. KER-050 is an investigational, modified activin receptor type IIA ligand trap designed to inhibit select TGF-β superfamily ligands (activins A, B, GDFs 8, 11) to address ineffective hematopoiesis by promoting differentiation of erythroid and megakaryocytic precursors. Here, we present new data from an ongoing Phase 2 study (NCT05037760) evaluating KER-050 as a monotherapy and in combination with ruxolitinib in participants with MF. Methods: This ongoing Phase 2 study is evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of KER-050 administered with or without ruxolitinib in participants with anemia and primary MF, post-essential thrombocythemia MF, or post-polycythemia vera MF. Part 1 involves parallel dose escalation arms (1A: monotherapy, 1B: combination with ruxolitinib) to identify the dose(s) of KER-050 to be evaluated in Part 2. Data are presented as of the data cutoff date of April 3, 2023. Results: A total of 24 participants were enrolled (n=12 in Arm 1A and n=12 in 1B). One participant recently enrolled in Arm 1B at dose level III (3.0 mg/kg) had limited exposure at the time of data cutoff and is not included in the PD findings reported below. All participants met the criteria for higher-risk disease by DIPSS and 41.7% met IWG 2013 transfusion-dependent (TD) criteria (Table 1). The median duration of KER-050 treatment was 116 days (range 26 to 474), with 62.5% of participants ongoing as of the cutoff date. Most participants (91.7%) had at least 1 treatment-emergent adverse event (TEAE). No dose-limiting toxicities and no treatment-related severe or serious TEAEs have been observed. Most frequently observed TEAEs in ≥15% of participants were fatigue (including asthenia) (37.5%), and diarrhea (20.8%). Mean increases in hemoglobin (Hgb), reticulocytes, and soluble transferrin receptor (sTfR) were observed over the first 12 weeks of treatment in non-TD (NTD) participants for whom changes in markers of erythropoiesis were less confounded by ongoing transfusions (Figure 1). Overall, 7 of 13 (53.8%) NTD participants achieved a mean Hgb increase of ≥1.0 g/dL over the first 12 weeks and 2 of 13 (15.4%) achieved an increase of ≥1.5 g/dL. Increases in Hgb were also observed among TD participants, with 3/10 (30%) having a Hgb increase ≥1 g/dL over the first 12 weeks and one participant achieving a transfusion reduction ≥50% over at least 12 weeks (data not shown). For this participant (dose level I, Arm 1B), transfusion burden decreased from 9 red blood cell (RBC) units/12 weeks at baseline to 2 RBC units/12 weeks. Another participant (dose level I, Arm 1B), who received 4 RBC units/12 weeks at baseline, achieved a 20-week transfusion-free period with concomitant increases in Hgb, sTfR and platelets. Across treatment arms, platelet values were generally maintained if not increased. Additionally, for one participant receiving KER-050 monotherapy (dose level I), spleen size decreased by 38% from 2569 cm 3 at baseline to 1592 cm 3 at 24 weeks, coinciding with a 55% reduction in MF-SAF-TSS score from 56 to 25. Summary: Preliminary data from this ongoing Phase 2 study suggest that KER-050 is generally well tolerated and support the potential of KER-050 to improve key aspects of MF, including cytopenia, spleen size, and symptoms. Despite data being limited thus far to the 2 lowest dose levels, encouraging increases in markers of hematopoiesis have been observed as well as an initial case of reduced spleen size in a participant receiving KER-050 monotherapy. Updated analyses available at the time of presentation will provide further insight into the potential of KER-050 to treat MF and mitigate ruxolitinib-associated cytopenia.

Pelabresib in Combination with Ruxolitinib for Janus Kinase Inhibitor Treatment-Naïve Patients with Myelofibrosis: Results of the MANIFEST-2 Randomized, Double-Blind, Phase 3 Study

Background Myelofibrosis (MF) is characterized by bone marrow fibrosis, anemia, splenomegaly and MF-associated symptoms. These hallmarks result from dysregulation of the JAK/STAT pathway and BET-mediated MF target gene modulation. Pelabresib (CPI-0610; pela) is an investigational oral small-molecule drug designed to inhibit BET-mediated gene transcription involved in MF pathogenesis. Preclinical data support the potential of combining pela with therapiesthat target overlapping pathways, such as JAK/STAT, to improve response by inhibiting the molecular drivers of MF. The Phase 3 MANIFEST-2 trial was initiated based on compelling data from Arm 3 of the ongoing Phase 2 MANIFEST study (NCT02158858), which is evaluating the combination of pela and ruxolitinib (rux) in JAK inhibitor (JAKi) treatment-naïve patients (pts) with MF. In Arm 3 of MANIFEST, primary endpoint analyses at 24 Weeks (Wks) for the 84 pts enrolled reported SVR35 (≥35% reduction in spleen volume from baseline) in 68% of pts and TSS50 (≥50% reduction in Total Symptom Score [TSS] from baseline) in 56% of pts (Mascarenhas, et al. 2023). Aims MANIFEST-2 (NCT04603495) is a global, Phase 3, randomized, double-blind, active-control study of pela + rux versus placebo + rux in JAKi treatment-naïve pts with primary MF, post-polycythemia vera MF or post-essential thrombocythemia MF. The aim of this study is to evaluate the efficacy and safety of pela + rux. Here we present the study design and baseline patient stratification for MANIFEST-2. Results from the primary analysis of MANIFEST-2 will be presented at the ASH Annual Meeting 2023. Methods The MANIFEST-2 study schema is shown in Figure 1. Key eligibility criteria include a DIPSS score of Intermediate-1 (Int-1) or higher, platelet count ≥100 × 10 9/L, spleen volume ≥450 cm 3 by CT or MRI, ≥2 symptoms with an average score ≥3 or a TSS of ≥10 using the MFSAF v4.0, peripheral blast count <5% and an ECOG performance status ≤2. Patient randomization was stratified by DIPSS risk category (Int-1 vs Int-2 vs High), platelet count (>200 × 10 9/L vs 100-200 × 10 9/L) and spleen volume (≥1800 cm 3 vs <1800 cm 3). Double-blind treatment of pela (125-175 mg) or placebo was administered once daily for 14 consecutive days, followed by a 7-day break, which is considered one cycle of treatment. Rux (5-25 mg) was administered twice daily based on platelet counts and spleen response for all 21 days of the cycle. The primary endpoint is SVR35 response at Wk 24. Secondary endpoints include TSS50, percentage change in TSS, safety, pharmacokinetics, changes in bone marrow fibrosis, progression-free survival, overall survival, conversion from transfusion dependence to independence and rate of red blood cell transfusion for the first 24 wks. Results A total of 591 pts were screened at 138 sites. Following the screening process, 431 pts from North America, Europe, Asia and Australia were randomized. The number of pts assigned to each randomization stratum are presented in Table 1; the majority of pts presented with DIPSS Int-1 or -2, had a platelet count above 200 × 10 9/L and spleen volume below 1800 cm 3. The study opened for enrolment in November 2020; the first patient received their initial treatment on April 22, 2021, and the last patient received their first treatment on March 2, 2023. The last patient is expected to reach the 24-wk primary endpoint on August 31, 2023, following which a primary analysis will occur. As of June 27, 2023 there were 383 pts ongoing in the study. Conclusion The Phase 3 MANIFEST-2 study was initiated based on compelling data from the ongoing Phase 2 MANIFEST study, in which the combination of pela and rux in Arm 3 demonstrated significant clinical activity and disease-modifying potential without clinically relevant treatment-limiting toxicity. MANIFEST-2 has completed recruitment and will provide definitive efficacy results of combination therapy in JAKi treatment-naïve pts with MF. As DIPSS Int-1 pts have been excluded or underrepresented in prior randomized trials in MF, MANIFEST-2 will also provide important insights in assessing the benefits of starting treatment at an earlier stage of the disease. Primary results from the pivotal Phase 3 MANIFEST-2 trial of pela and rux versus placebo and rux in JAKi treatment-naïve pts may have the potential to influence the MF treatment paradigm and will be presented at the ASH Annual Meeting 2023.

Role of Next Generation Immune Checkpoint Inhibitor (ICI) Therapy in Philadelphia Negative Classic Myeloproliferative Neoplasm (MPN): Review of the Literature.

The Philadelphia chromosome-negative (Ph-) myeloproliferative neoplasms (MPNs), which include essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), are enduring and well-known conditions. These disorders are characterized by the abnormal growth of one or more hematopoietic cell lineages in the body's stem cells, leading to the enlargement of organs and the manifestation of constitutional symptoms. Numerous studies have provided evidence indicating that the pathogenesis of these diseases involves the dysregulation of the immune system and the presence of chronic inflammation, both of which are significant factors. Lately, the treatment of cancer including hematological malignancy has progressed on the agents aiming for the immune system, cytokine environment, immunotherapy agents, and targeted immune therapy. Immune checkpoints are the molecules that regulate T cell function in the tumor microenvironment (TME). The first line of primary immune checkpoints are programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte antigen-4 (CTLA-4). Immune checkpoint inhibitor therapy (ICIT) exerts its anti-tumor actions by blocking the inhibitory pathways in T cells and has reformed cancer treatment. Despite the impressive clinical success of ICIT, tumor internal resistance poses a challenge for oncologists leading to a low response rate in solid tumors and hematological malignancies. A Phase II trial on nivolumab for patients with post-essential thrombocythemia myelofibrosis, primary myelofibrosis, or post-polycythemia myelofibrosis was performed (Identifier: NCT02421354). This trial tested the efficacy of a PD-1 blockade agent, namely nivolumab, but was terminated prematurely due to adverse events and lack of efficacy. A multicenter, Phase II, single-arm open-label study was conducted including pembrolizumab in patients with primary thrombocythemia, post-essential thrombocythemia or post-polycythemia vera myelofibrosis that were ineligible for or were previously treated with ruxolitinib. This study showed that pembrolizumab treatment did not have many adverse events, but there were no pertinent clinical responses hence it was terminated after the first stage was completed. To avail the benefits from immunotherapy, the paradigm has shifted to new immune checkpoints in the TME such as lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin and mucin domain 3 (TIM-3), T cell immunoglobulin and ITIM domain (TIGIT), V-domain immunoglobulin-containing suppressor of T cell activation (VISTA), and human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) forming the basis of next-generation ICIT. The primary aim of this article is to underscore and elucidate the significance of next-generation ICIT in the context of MPN. Specifically, we aim to explore the potential of monoclonal antibodies as targeted immunotherapy and the development of vaccines targeting specific MPN epitopes, with the intent of augmenting tumor-related immune responses. It is anticipated that these therapeutic modalities rooted in immunotherapy will not only expand but also enhance the existing treatment regimens for patients afflicted with MPN. Preliminary studies from our laboratory showed over-expressed MDSC and over-expressed VISTA in MDSC, and in progenitor and immune cells directing the need for more clinical trials using next-generation ICI in the treatment of MPN.

Myeloid sarcoma of the larynx as manifestation of the terminal stage of myeloproliferative disease

A rare clinical observation of advanced myeloid sarcoma developed through blast transformation of post-polycythemia vera myelofibrosis as extramedullary manifestation of acute myeloid leukemia affecting larynx, laryngopharynx, trachea, soft tissues of the neck, pleura, and skeletal bones is presented.

Novel therapeutics for myelofibrosis.

Myelofibrosis (MF) includes primary MF, post-essential thrombocythemia MF, and post-polycythemia vera MF. MF is a progressive myeloid neoplasm characterized by ineffective clonal hematopoiesis, extramedullary hematopoiesis, a reactive bone marrow environment resulting in reticulin deposition and fibrosis, and a propensity for leukemia transformation. The identification of driver mutations in JAK2, CALR, and MPL has contributed to a better understanding of disease pathogenesis and has led to the development of MF-specific therapies, such as JAK2 inhibitors. Despite the fact that ruxolitinib and fedratinib have been clinically developed and approved, their use is limited due to adverse effects such as anemia and thrombocytopenia. Recently, pacritinib has been approved for a group of thrombocytopenic patients with significant unmet clinical needs. In symptomatic and anemic patients with prior JAK inhibitor exposure, momelotinib was superior to danazol in preventing exacerbation of anemia and in controlling MF-associated signs and symptoms, such as spleen size. Although the development of JAK inhibitors is remarkable, modifying the natural course of the disease remains a priority. Therefore, many novel treatments are currently under clinical development. Agents targeting bromodomain and extra-terminal protein, anti-apoptotic protein Bcl-xL, and phosphatidylinositol-3-kinase delta have been studied in combination with JAK inhibitors. These combinations have been employed in both the frontline and "add-on" approaches. In addition, several agents are being studied as monotherapies for ruxolitinib-resistant or -ineligible patients. We reviewed several new MF treatments in the advanced stages of clinical development and treatment options for cytopenic patients.

Post-Polycythemia Vera Myelofibrosis (PPV- MF)-A Case Report of a Patient Transplanted after an Adverse Reaction to Covid Vaccination

Post-Polycythemia Vera Myelofibrosis (PPV- MF)-A Case Report of a Patient Transplanted after an Adverse Reaction to Covid Vaccination

Safety and Effectiveness of Ruxolitinib in Real-World Patients with Myelofibrosis: A 2-Year Observational Study from Taiwan

Introduction Ruxolitinib (RUX) is an approved JAK1/JAK2 inhibitor for the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF), and post-essential thrombocythemia myelofibrosis (PET-MF), but real-world safety and efficacy of RUX in Taiwan are not well understood. This study was conducted to evaluate the safety and efficacy of treatment with RUX with intermediate-2 or high risk PMF, PPV-MF or PET-MF in routine clinical practice. Method This 2-year, single-arm, multicenter, post-marketing surveillance registry collected data on the safety, tolerability, efficacy, and other clinical information of adult patients (pts) aged ≥20 years with a confirmed diagnosis of intermediate-2 or high-risk PMF, PPV-MF, or PET-MF who either received RUX or starting RUX in accordance with the general clinical practice in Taiwan. Primary endpoint included collection of adverse events (AEs), AE of special interest (AESIs; anemia, thrombocytopenia, leukocytosis, hepatitis B virus (HBV) infection or reactivation, tuberculosis (TB) infection, and other infections), and serious adverse events (SAEs) throughout the study. Key secondary endpoints included treatment duration, discontinuation rates, dosage of prescribed RUX, Myeloproliferative Neoplasm symptom assessment form (MPN-10) score after study entry and change in spleen size, specifically in naïve patients who were eligible for spleen response evaluation. Results A total of 99 (51% PMF, 22.4% PPV-MF, and 26.5% PET-MF) pts were recruited, of which 38 (38.4%) pts discontinued due to consent withdrawal (n=11), death (n=10), discontinued prescription of RUX for 3 months (n=4), AEs (n = 2), unsatisfactory therapeutic effect (n=2), administrative problems (n=1), disease progression (n=1), required immediate stem cell transplantation (n=1), and others (n=6). Median age was 68.1 (range: 38.3-87.2) years and gender ratio was balanced, with 97 Taiwanese pts (98.0%). Median disease duration was 13.9 months (range: 0-967.6 months) and 70.7% and 28.3% of pts were identified with the risk of intermediate-2 or high using IPSS/DIPSS risk assessment, respectively. Majority of the recruited pts were RUX pre-treated (n=75; 75.8%) and 24.2% (n=24) pts were RUX-naïve at baseline. During the study, 88 pts (89.8%) had 673 AEs, and 44 (44.9%) experienced 159 SAEs. Half of the pts (55.1%) had moderate or severe SAEs and 39 pts recovered. Over 80% of SAEs (n=131) were not related to RUX. Major AESIs were anemia (29.6%) and thrombocytopenia (20.4%). There were no HBV infection or reactivation reported; 2% of pts had TB while 3% of pts had herpes zoster infections. The major reported infection was pneumonia (20.4%). Key safety data are summarized in Table 1. Most pts had their AEs resolved (77.6%), while 10 deaths occurred due to AEs (10.2%). Majority of the pts (41.8%) received a daily dose of RUX 20 mg at the enrolment, with an average mean daily dose of 22.7±9.2 mg (Figure 1). For naïve pts, mean initial dose was 18.8 ± 8.50 mg and gradually titrated up to 22.3 ± 8.69 mg at 3 months and to 24.0 ± 9.17 mg at 6 months. Among 98 pts, 13.3% pts whose platelet counts between 100-200×103/μL and 21.4% pts whose platelet counts were >200×103/μL were treated with RUX 5-10 mg twice daily. Among 27 RUX pre-treated patients (mean RUX duration before study entry: 17.0 ± 20.98 months), spleen size by palpation was relatively stable throughout the study period. For the 7 RUX naïve pts, the mean spleen size change from baseline was -15.9 %± 28.72 at 12 weeks, -30.8% ± 31.28 at 24 weeks, -54.2% ± 41.93 at 48 weeks and -52.0% ± 36.41 at 96 weeks. However, it should be interpreted with caution due to the small pt pool. A total of 65 pts (65.7%) had >50% improvement in the symptom response by MPN-10 during 2-year study period. . Conclusion This is the first real-world study in Taiwan to evaluate safety and efficacy with RUX in patients with MF. It was observed that physicians employed a conservative strategy for a lower starting dose with gradual titration resulting in comparable safety profile, but lower incidences of thrombocytopenia compared to published clinical trials. The majority of pts reported continuous symptomatic improvement and a small number of RUX naïve pts had pronounced spleen size reduction. Further investigations are required to evaluate whether optimal dose of RUX or titration speed would improve spleen response. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy and Safety of Ropeginterferon Alfa-2b for Pre-Fibrotic Primary Myelofibrosis and DIPSS Low/Intermediate-1 Risk Myelofibrosis

Most patients with early/pre-fibrotic primary myelofibrosis (pre-PMF) and dynamic international prognostic scoring system (DIPSS) low or intermediate-1 risk myelofibrosis (MF) progress to overt PMF or higher risk MF. There is currently no consensus on the optimal treatment strategies in these patients. Ropeginterferon alfa 2b (P1101) is a next generation monopegylated interferon alfa-2b developed specifically to treat myeloproliferative neoplasms (MPN). The P1101MF study is a multicenter phase 2 study of P1101 for patients with pre-PMF and DIPSS low/intermediate-1 risk MF (NCT04988815). Key eligibility included the need for cytoreduction, morphologically confirmed pre-PMF, overt PMF, post-polycythemia vera MF (PPV-MF) or post-essential thrombocythemia MF (PET-MF), and DIPSS low/intermediate-1 risk category. The primary outcome was the clinicohematologic complete response (CHCR) rate at 24 and 48 weeks. Secondary outcomes included adverse events (AEs), changes in allele burden of driver genes and other non-driver mutations, changes in quality-of-life (QOL), changes in cytokine profiles and changes in bone marrow morphology. Patients received P1101 at a starting dose of 250mcg followed by 350mcg at week 2 and 500mcg every 2 weeks from week 4 onwards. At the data cut-off of 28 July 2022, 56 patients (33 men, 23 women) with a median age of 58 (range: 30-87) were enrolled. Thirty eight patients (68%) had pre-PMF, 5 (9%) had overt PMF, 3 (5%) had PPV-MF and 10 (18%) had PET-MF. Next-generation sequencing (NGS) in 53 patients showed JAK2V617F in 39 patients (74%), CALR mutations in 13 patients (25%) and MPL mutation in 1 patient (2%). On day 1, the mean white blood cell (WBC) count, hemoglobin concentration, platelet count, and lactate dehydrogenase (LDH) level were 9.4 x 109/L (range: 3.3-33.95), 12.5 g/dL (range: 7.1-15.9), 520 x 109/L (range: 113-1038) and 359 IU/L (range: 136-1146) respectively. The median duration of follow-up was 24 (2-28) weeks. Forty-six and 30 patients completed 12 and 24 weeks of treatment respectively. At 12 and 24 weeks the CHCR rate was 74% and 67%, respectively. At 24 weeks, 36 (92%) of 39 JAK2V617F mutated patients had stable or improved JAK2V617F allele burden by droplet digital polymerase reaction (ddPCR). Three patients (8%) had >50% reduction in the JAK2V617F allele burden with one patient achieving undetectable JAK2V617F from week 16 onwards. Disease progression or blastic transformation were not observed during the study. The most common AEs were malaise (N=22, 39%; Grade 1-2, N=21; Grade 3-4, N=1), anemia (N=12, 21%; Grade 1-2, N=8; Grade 3-4, N=4), muscle pain (N=11, 20%; Grade 1-2, N=11; Grade 3-4, N=0) and hair loss (N=10, 18%; Grade 1-2, N=10; Grade 3-4; N=0) . There were no treatment discontinuations, safety signals or deaths related to treatment. In summary, P1101 was well-tolerated, effective in cytoreduction and induced molecular responses. The recruitment of patients is ongoing.

Modulation of TGF-β Superfamily Signaling to Treat Myelofibrosis and Mitigate JAK Inhibitor Toxicity: A Report on the Phase 2 Study of Ker-050 in Participants with Myelofibrosis

Background: Myelofibrosis (MF) is a disorder characterized by unrestrained proliferation of myeloid precursors and dysfunctional Janus kinase (JAK) signaling. Hyperplastic and dysplastic megakaryocyte expansion in MF releases inflammatory cytokines. These cytokines promote fibroblast proliferation, bone remodeling, and marrow fibrosis, disrupting the osteohematopoietic niche and leading to ineffective and extramedullary hematopoiesis (Vainchenker et al. 2017). Clinical manifestations include splenomegaly, anemia, and often disabling constitutional symptoms. JAK inhibitors, such as ruxolitinib, have been shown to improve spleen size and symptoms, but are associated with dose-limiting anemia and thrombocytopenia, reducing their utility for many patients (Verstovsek et al. 2012). KER-050 is an investigational product designed to alter signaling of TGF-β superfamily ligands, restoring balance to the osteohematopoietic niche and promoting differentiation of erythroid and megakaryocytic precursors. It is a modified activin receptor type IIA ligand trap that inhibits TGF-β superfamily ligands, including activins A and B and growth and differentiation factors (GDFs) 8 and 11. Preclinical studies have demonstrated that KER-050 induces erythropoiesis, increases platelet counts, improves bone mass, and prevents fibrosis. A preclinical study previously presented demonstrated that RKER-050 can reverse ruxolitinib-associated reductions in hemoglobin, hematocrit, and red blood cell count, indicating potential for KER-050 to mitigate ruxolitinib toxicity. In two clinical studies, including an ongoing study in participants with myelodysplastic syndromes (MDS), KER-050 has been well-tolerated. Accumulated clinical data demonstrate that KER-050 can stimulate erythropoiesis and thrombopoiesis in both healthy post-menopausal women and MDS participants with ineffective hematopoiesis. Here we present data from the first clinical study of KER-050 in participants with MF (NCT05037760). The objective of this study is to evaluate the potential of KER-050 as monotherapy and in combination with ruxolitinib to treat the underlying pathology of MF and mitigate JAK inhibitor-associated cytopenias. Methods: This ongoing Phase 2 open-label study is evaluating the safety, tolerability, pharmacokinetics PK), pharmacodynamics (PD), and efficacy of KER-050 administered with or without ruxolitinib in participants with primary myelofibrosis (PMF), post-essential thrombocythemia myelofibrosis (post-ET MF), and post-polycythemia vera myelofibrosis (post-PV MF) who have anemia (hemoglobin ≤ 10 g/dL or receiving transfusions). Part 1 involves parallel dose escalation arms (1A: monotherapy, 1B: combination with ruxolitinib) to evaluate the safety and tolerability of KER-050 and identify the dose(s) of KER-050 to be evaluated in Part 2 (Figure 1). Changes in hemoglobin, transfusion burden, spleen size, the Myelofibrosis Symptom Assessment Form Total Symptom Score (MF-SAF-TSS), PK and incidence of accelerated MF and acute myeloid leukemia are assessed as secondary endpoints. This study is also evaluating markers of multilineage hematopoiesis, bone remodeling, iron metabolism, inflammation, and marrow fibrosis. Frequency of ruxolitinib dose modification and quality of life will be explored. Results: Preliminary results from Part 1 will be presented. At the time of this writing, 5 patients have received KER-050 on study, 3 in Arm 1A and 2 in Arm 1B. Three participants have completed the dose-limiting toxicity (DLT) assessment period and no DLTs have been experienced. Data evaluated to date indicate a PD effect consistent with previous preclinical and clinical studies of KER-050. Summary: KER-050 is designed to alter TGF-β superfamily signaling, restoring balance to the osteohematopoietic niche and promoting multilineage hematopoietic differentiation. Here we present data from the first study of KER-050 in participants with MF evaluating the potential for KER-050 to impact key aspects of the MF disease state (anemia, spleen size, symptoms, progression), as monotherapy and in combination with ruxolitinib. The potential for KER-050 to mitigate ruxolitinib toxicity and related dose-reductions is being investigated. Exploratory analyses of the KER-050 impact on inflammation, bone remodeling, iron metabolism, and marrow fibrosis, as available, will be shared. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Siremadlin, a Human Double Minute-2 (HDM2) Inhibitor, Added to Ruxolitinib after Suboptimal Response to Ruxolitinib Alone in Patients with Myelofibrosis: Results from Part 1 of the Phase 1/2 Adore Study

Introduction Ruxolitinib (RUX), a first-in-class Janus kinase (JAK)1/JAK2 inhibitor, is the standard of care for myelofibrosis (MF). However, ~50% patients (pts) discontinue RUX after ~3 years, including a third due to lack/loss of spleen response. Targeting additional pathogenic signaling pathways may provide superior disease control and potentially address underlying causes of disease. JAK2 mutations in MF induce expression of HDM2, which degrades tumor suppressor protein p53. Siremadlin (SIR), a potent and selective HDM2 inhibitor, restores p53-mediated apoptosis, which may promote clonal regression and spleen volume reduction (SVR). ADORE (NCT04097821) is a three-part phase 1/2 platform study assessing RUX in combination with 5 novel compounds, including SIR. We report results from the Part 1 (phase 1b) dose escalation cohort of SIR added to existing stable dose of RUX after suboptimal response to RUX alone. Methods Eligible pts had a diagnosis of primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF, splenomegaly (a palpable spleen ≥5 cm from the left costal margin or spleen volume ≥450 cm3 by MRI/CT scan), hemoglobin (Hb) level <11 g/dL (earlier protocol: <10 g/dL), and platelet count ≥75 × 109/L. Pts must have received RUX for ≥12 weeks (wks) (earlier protocol: ≥24 wks) and at a stable dose for ≥4 wks (earlier protocol: ≥8 wks) prior to first combination dose. Part 1 objective was to characterize the safety, tolerability, and recommended phase 2 dose (RP2D) of SIR added to RUX. Primary endpoint was incidence and severity of dose-limiting toxicities (DLT) within first 2 cycles; secondary objectives included characterization of the pharmacokinetic (PK) profile. Preliminary efficacy (change in spleen volume by MRI/CT scan from baseline [BL]), total symptom score (TSS) by MFSAF v4.0 and biomarkers were also explored. Pts were allocated to add SIR 20mg, 30mg or 40mg (orally once daily; days 1-5/28-day cycle) to their stable RUX dose (5-25mg twice daily). Adverse events (AEs) were coded by MedDRA and graded by CTCAE v5.0. Results In Part 1 SIR 20mg, 30mg and 40mg cohorts, 1/7, 9/10 and 1/6 pts were ongoing at data cut-off (April 13, 2022) respectively. The number of pts with DLTs after 2 cycles per number of evaluable pts was 0/6 at 20mg, 1/7 at 30mg (grade [G] 4 neutropenia and G4 thrombocytopenia in same pt), and 2/5 at 40mg (G3 and G4 thrombocytopenia). The most common AEs were gastrointestinal (GI) and hematologic (Table). RP2D was SIR 30mg/day. At 30mg, 5 pts experienced SIR-related GI toxicity; all events were G≤2; all lasted ≤4 days except for 1 case controlled with medication; 2 pts required concomitant medication for nausea, however, none discontinued treatment due to GI AEs. The most common hematologic AEs at 30mg were anemia, neutropenia, and thrombocytopenia. Two pts discontinued SIR 30mg due to G3 neutropenia and thrombocytopenia (for 1 pt) and G3 neutropenia (for 1 pt). At 30mg, 4/10 pts had completed a spleen volume assessment at 24 wks at time of data cut-off and all achieved SVR ≥35% from BL. At 20mg, 1/7 pts had SVR ≥35% at 24 wks. At 40mg, 3 pts discontinued prior to or did not complete spleen volume assessment at wk 24, limiting the availability of efficacy data (Figure). Symptom burden was low at BL across cohorts and subsequent TSS changes were highly variable between pts. SIR exposure increased with dose, with no relevant PK interactions between RUX and SIR observed. SIR increased growth/differentiation factor-15 (GDF15) expression, indicating target TP53 engagement. All pts were TP53 wildtype at BL. At data cut-off, SIR treatment resulted in the emergence of TP53 mutant clones in 1/7 pts at 20mg, 0/10 pts at 30mg and 1/6 pts at 40mg, at very low variant allele frequency (0.02-0.06) with unknown clinical significance. At 24 wks, 4/7 SIR-treated pts with available data had a decrease in JAK2 V617F mutational burden from BL (range 1.85-20.0%). Conclusions The RP2D of SIR is established as 30mg orally once daily on days 1-5/28-day cycle when added to the existing stable dose of RUX in pts with suboptimal response to prior RUX treatment. The addition of SIR 30mg was well tolerated, with low-G short-duration GI toxicity in contrast to an expected HDM2 inhibitor class effect. Other AEs were consistent with known RUX safety profile. Good tolerability at 30mg allowed pts to remain on SIR + RUX and to achieve robust spleen volume responses at 24 wks. The study was sponsored by Novartis Pharmaceuticals. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase 1 Dose-Escalation Study of the Oral Epichaperome Inhibitor, Zelavespib (ZEL) in Combination with Ruxolitinib (RUX), in Patients with Relapsed Myelofibrosis: Results of the Dose Escalation Stage

Background: ZEL (PU-H71) is an oral synthetic purine-scaffold epichaperome inhibitor that selectively binds to epichaperome complexes found in cancer cells via the altered ATP binding site of disease-associated heat shock protein (HSP90). ZEL has shown efficacy in cell line and mouse models of myeloproliferative neoplasm (MPN) and specifically myelofibrosis (MF) by disrupting JAK2 protein stability, resulting in dose-dependent inhibition of cell growth and signaling. JAK2 inhibitors are the only currently approved class of therapies for intermediate/higher risk MF, but there is still an urgent unmet medical need for 2nd line and beyond therapies. An emerging approach is the add-on/add-back strategy, with the addition of the second/novel agent in the setting of suboptimal response to JAKi monotherapy. In a prior trial of ZEL as IV monotherapy in an advanced malignancy study (including both solid and hematologic malignancies), ZEL demonstrated clinical activity in patients with lymphoma and MF. Based on this efficacy signal, the tolerability profile of ZEL in hematological malignancies, and the potential for synergy between mechanisms of action, a study with ZEL in combination with RUX was initiated. The present phase 1 study is the first to establish the safety, MTD, and preliminary efficacy of oral ZEL when added to RUX in MF (NCT03935555). Methods: Patients with primary, post-polycythemia vera or post-essential thrombocythemia MF were eligible if age ≥18 years, ECOG performance status ≤2, treatment with RUX >3 months prior to start with persistent or worsening splenomegaly and disease-related symptoms (by MPN-SAF TSS), adequate cardiac, hepatic and renal function, platelets ≥ 25,000/uL, ANC ≥500/uL, and no active ocular pathology. Oral solution of ZEL was administered daily in continuous 21-day cycles in combination with each patient's stable baseline RUX dose. The initial dose of ZEL was 50 mg with each subsequent cohort dose-escalating by 50 mg QD increments. DLTs were assessed in Cycle 1 (21 days). Response was assessed by IWG-MRT and ELN criteria. Results: Eleven patients have been enrolled: 3 patients each in the 50 and 100 mg cohorts, and 5 in the 150 mg cohort following DLT-driven cohort expansion. Median age was 69 years (range 59-78). Baseline RUX dose ranged from 5-25 mg bid, with a median of 15 mg. Median number of ZEL cycles administered was 4 (range 1-25). Most AEs were Gr 1 and 2 and the most frequent were abdominal pain, diarrhea and fatigue. Gr 4 thrombocytopenia in 2 patients (150 mg) met DLT criteria with platelet nadirs of 7K and 22K during cycle 1. One patient (150 mg with symptomatic improvement) developed Grade 3 bone marrow hypoplasia after 22 cycles of treatment, an SAE judged by the Investigator to be related to treatment. To date, 2 patients (1 each at 100 and 150 mg) demonstrated symptom improvement without significant reduction in spleen size. One patient (50 mg) had stable disease maintained for 20 cycles and successfully bridged to allogeneic stem cell transplant. Allele burden, cytokine profiles, flow cytometry for biomarkers, and PK analyses are in progress and will be presented. Conclusions: The ZEL dose 100 mg QD was well tolerated and was selected as the RP2D in combination with RUX. Although ZEL has not been shown to cause myelosuppression as monotherapy, further evaluation is necessary to understand possible effects on bone marrow and megakaryocyte function when used in combination with RUX. Further exploration of the therapeutic potential of oral ZEL in the treatment of MF and other MPNs, as monotherapy and with RUX, is warranted.

Phase 1/2a Study to Evaluate Safety, Pharmacokinetic and Pharmacodynamic Dose Escalation and Expansion Study of Pxs-5505 in Patients with Primary, Post-Polycythemia Vera or Post-Essential Thrombocythemia Myelofibrosis

Background: Janus kinase (JAK) inhibitors for myelofibrosis (MF) treatment have provided major clinical benefits, but do not improve cytopenias and demonstrate only modest effects on bone marrow fibrosis (BMF). High discontinuation rates are observed due to loss of therapeutic effect or drug induced toxicity. Reducing BMF may normalize the hematopoietic environment and improve symptoms of MF, particularly blood cell counts. Limited therapeutic options highlight the need for novel, effective therapies for primary MF (PMF). Lysyl oxidases (LOX) are a family of enzymes responsible for the critical post-translational modification essential for the biogenesis of cross-linked collagen and elastin, which form the basis of reticulin in bone marrow (BM). Importantly, several members of the lysyl oxidase family are upregulated in MF providing a rationale to therapeutically inhibit all lysyl oxidases. PXS-5505 is a pan-lysyl oxidase inhibitor that prevents the cross-linking of collagen and elastin and consequently exhibits anti-fibrotic effects in murine models of MF. PXS5505-MF-101 is an ongoing, multi-center, open-label phase 1/2a study evaluating the safety and tolerability of PXS-5505 in patients with primary, post-polycythemia vera (PV) or post-essential thrombocythemia (ET) myelofibrosis (NCT04676529). Herein, we present the study design and preliminary data from the dose escalation phase of this study. Methods: The primary objective is to determine the safety and tolerability of PXS-5505In patients with MF. Secondary objectives include determination of appropriate dose, pharmacokinetics (PK) and pharmacodynamics (PD), changes in BMF using European Consensus, spleen volume and MF symptoms (MFSAF). Efficacy endpoints are exploratory. Eligible patients must have PMF or post-ET/PV MF of intermediate/high risk, relapsed/refractory, intolerant or not eligible to available JAK inhibitors (ruxolitinib, febratinib), including those with severe thrombocytopenia, and requiring therapy for symptomatic disease. Patients participating in the DEP required BM biopsy within 6 months of the re-initiation of treatment with PXS-5505. For patients entering the CEP a BM biopsy must have been performed within 3 months prior to Day 1 treatment. The study consists of two phases: Dose Escalation Phase (DEP) and Cohort Expansion Phase (CEP). The DEP followed a 3+3 design with a starting dose of 100 mg PXS-5505 twice daily (BID) for 4 weeks (Level 1), escalating to 150 mg BID (Level 2) and to 200 mg BID (Level 3). The DEP was to determine the maximum tolerated dose (MTD) or if all doses were well tolerated, the dose which provided the highest target engagement PK and PD measures during dose escalation (Day 0, week 1 and week 4) included, maximum plasma concentration (C1hr=Cmax), minimum plasma concentration (Cmin) and LOX and LOXL2 inhibition in plasma which would subsequently be the dose selected for the CEP. Intra patient dose escalation was allowed and patients participating in the DEP phase were able to continue on the CEP up to 6 months of therapy. During the CEP, 24 patients will be treated at the dose determined from the DEP phase. At data cutoff (21 July 2022) the DEP was completed and enrollment for the CEP continues. Results: Five patients were enrolled in the DEP. This included three patients with post ET MF, one patient with post PV MF and one patient with post ET MF. The median age was 71 years (range, 60-77) and all were female. There were no suspected unexpected serious adverse reactions (SUSAR) or dose limiting toxicities during the dose escalation phase. One patient terminated early following transformation to AML (24 days post treatment initiation). Interim PK data from the DEP phase demonstrated that PK properties in patients were similar to PK in healthy volunteers as previously reported at all dose levels (ACTRN12619000332123). At the 200mg BID level the mean (trough) LOX inhibition was 94% and 91% (days 7 and 28), respectively (Figure 1). Similarly, the mean (trough) LOXL2 inhibition was 94% and 93% (days 7 and 28), respectively. Enrolment in the CEP continues and preliminary data will be presented. Conclusion: These findings indicate that excellent targeted LOX and LOXL2 inhibition is being achieved at the 200mg BID level which has been selected as the recommended dose for the currently ongoing expansion phase with no dose limiting toxicity seen. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase Ib Dose-finding Study of Panobinostat and Ruxolitinib in Myelofibrosis.

A Phase Ib Dose-finding Study of Panobinostat and Ruxolitinib in Myelofibrosis.