FDA Extends Review Period for Momelotinib NDA in Myelofibrosis

Posted on June 27, 2023June 27, 2023 by mpn_admin

June 16, 2023

Kristi Rosa

The FDA has extended the review period for the new drug application (NDA) seeking the approval of momelotinib as a potential therapeutic option in patients with myelofibrosis.1 The regulatory agency pushed the decision date back by 3 months, to September 16, 2023, to allow for more time to review recently submitted findings.

The application was based on data from the phase 3 MOMENTUM trial (NCT04173494), in which momelotinib significantly improved symptoms, spleen size, and anemia vs danazol in patients with symptomatic and anemic myelofibrosis who received a prior JAK inhibitor.²

Specifically, more patients who received momelotinib (n = 130) experienced a reduction in tumor symptom score (TSS) of 50% or higher at week 24 vs those who were given danazol (n = 65), at 25% and 9%, respectively (proportion difference, 16%; 95% CI, 6%-26%; P = .0095), which met the primary end point of superiority with momelotinib. Moreover, more patients on the investigative arm achieved transfusion independence (TI) at week 24 than those on the control arm, at 30% (95% CI, 22%-39%) and 20% (95% CI, 11%-32%), respectively (noninferiority difference, 14%; 95% CI, 2%-25%; 1-sided P = .0016); TI rates from baseline to week 24 increased by 17% with momelotinib compared with 5% with danazol.

Momelotinib also demonstrated superiority over danazol with regard to splenic response rates at week 24. Thirty-nine percent of patients who received momelotinib experienced a reduction of 25% or more in spleen volume from baseline to week 24 vs 6% in those given danazol (P < .0001); moreover, 22% and 3% of patients, respectively, experienced a reduction of 35% or more (P = .0011).

In a recent news release, GlaxoSmithKline, the drug developer, stated that they were “confident in the momelotinib NDA” and that they “look forward to working with the FDA as they finalize their review.”¹

The international, double-blind, randomized, controlled MOMENTUM trial enrolled patients with a confirmed diagnosis of primary myelofibrosis, post-polycythemia vera myelofibrosis, or post–essential thrombocytopenia myelofibrosis who were at least 18 years of age and who received a prior approved JAK inhibitor for at least 90 days.²

Patients were symptomatic, defined as a TSS of at least 10 at screening; were anemic, defined as a hemoglobin of less than 10 g/dL; a platelet count of more than 25 x 10⁹ cells/L; and had splenomegaly at baseline. Moreover, patients had an ECOG performance status of 0 to 2, and could have had high-risk, intermediate2-risk, or intermediate-1 risk disease by Dynamic International Prognostic Scoring System criteria.

Study participants were randomly assigned 2:1 to momelotinib at 200 mg once daily or danazol at 300 mg twice daily.

The primary end point of the trial was week-24 TSS response rate, which was defined as the proportion of participants achieving a reduction in mean TSS of at least 50% over the 28 days prior to the end of week 24 vs baseline. Important secondary end points comprised week-24 TI rate, 25% splenic response rate at week 24, change in TSS from baseline to week 24, 35% splenic response rate at week 24, and rate of zero transfusions at week 24. Other end points focused on anemia, transfusions, survival, and safety.

A total of 195 patients were enrolled in the trial and were treated. Of those in the momelotinib and danazol arms, 72% and 58% of patients, respectively, completed treatment. The most common reason for early discontinuation in these arms was toxicity (12% vs 17%), followed by patient decision (5% vs 8%).

Data from the study were published in The Lancet and have a data cutoff date of December 3, 2021.

In all patients, the median baseline age was 71 years (interquartile range, 66-76), and most were male (63%) and White (81%). Moreover, the majority of patients had primary myelofibrosis (64%), intermediate-2 risk disease (57%), and harbored a JAK2 mutation (76%). Fourteen of the patients were TI and 50% were dependent. The mean duration of prior JAK inhibition in these patients was 2.6 years, and all patients previously receives ruxolitinib (Jakafi). Five percent of patients had prior fedratinib (Inrebic). The mean TSS at baseline was 27.2, mean hemoglobin was 8.0 g/dL, and the mean platelet count was 144.7 x 10⁹ cells/L.

Additional findings indicated that in the group of patients who were transfusion dependent at baseline (n = 168), 26% and 15% of those in the momelotinib and danazol arms, respectively, achieved TI by the end of week 24.

Momelotinib also proved to be superior to danazol with regard to mean TSS change from baseline to end of week 24, at –11.5 vs –3.9, respectively (least squares mean difference, –6.2; 95% CI, –10.0 to –2.4; P = .0014). This was also true for the rate of zero transfusions to week 24, at 35% (95% CI, 27%-44%) and 17% (95% CI, 9%-28%), respectively (P = .0012). There was also a higher rate of zero transfusions at week 24 in those with hemoglobin at least 8 g/dL vs those with less than 8 g/dL (49% vs 21%) with momelotinib and with danazol (24% vs 9%).

Currently, momelotinib is not approved in any market.¹

References

GSK announces extension of FDA review period of momelotinib. News release. GlaxoSmithKline. June 16, 2023. Accessed June 16, 2023. https://www.gsk.com/en-gb/media/press-releases/gsk-announces-extension-of-fda-review-period-for-momelotinib/
Verstovsek S, Gerds AT, Vannuchi AM, et al. Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM): results from an international, double-blind, randomised, controlled, phase 3 study. Lancet. 2023;401(10373):269-280. doi:10.1016/S0140-6736(22)02036-0

Pacritinib Provides Spleen, Symptom Reduction Regardless of Blood Counts, Association Between SVR and OS in Myelofibrosis

Posted on June 27, 2023June 27, 2023 by mpn_admin

June 16, 2023

Caroline Seymour

Spleen volume reduction (SVR) was associated with overall survival (OS) with pacritinib (Vonjo) in patients with myelofibrosis. Treatment with the JAK2 inhibitor also demonstrated comparable improvements in spleen and symptom response regardless of baseline platelet counts and hemoglobin levels, according to findings from the pivotal phase 3 PERSIST-1 (NCT01773187) and PERSIST-2 (NCT02055781) trials that were presented at the 2023 ASCO Annual Meeting.^1,2

Symptoms of myelofibrosis include marrow fibrosis, splenomegaly, and progressive cytopenia and prior approved agents include ruxolitinib (Jakafi) and fedratinib (Inrebic).

“The previous 2 JAK inhibitors ruxolitinib and fedratinib were for patients at a certain platelet cutoff, so that’s 50 [x 109/L] and above, and pacritinib ended up becoming approved for patients with myelofibrosis with platelets less than 50 [x 109/L], filling that urgent unmet medical need,” Naveen Pemmaraju, MD, associate professor in the Department of Leukemia, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, said in an interview with OncLive^®.

Pacritinib is a JAK1-sparing inhibitor of JAK2/IRAK1/ACVR1 associated with improved SVR vs best available therapy (BAT), including ruxolitinib, in patients with myelofibrosis with platelets below 100 x 109/L in the PERSIST-2 trial. However, the relationship between SVR and OS in patients with thrombocytopenia is not well known. As such, investigators evaluated whether SVR with pacritinib or BAT is associated with improved survival in those with thrombocytopenia.

The analysis included patients from PERSIST-2 who were alive and on study who had received 200 mg of pacritinib twice daily or BAT at week 10 (week-12 SVR window).

In the pivotal PERSIST-2 trial, baseline characteristics in the pacritinib arm for responders (n = 65) and nonresponders (n = 24), respectively, were presented for age (median in years: 66 vs 67), Dynamic International Prognostic Scoring System (DIPSS) high risk (18.5% vs 46%), platelet count (median, 58 x 109/L vs 67 x 109/L), hemoglobin (median, 9.7 g/dL vs 9.3 g/dL), red blood cell transfusion requirement (38% vs 58%), prior JAK2 exposure (45% vs 50%), spleen volume (median, 2573 cm3 vs 2094.5 cm3), and palpable spleen length (median, 15.00 cm vs 12.75 cm).

Responders (n = 28) and nonresponders (n = 56) in the BAT arm had median ages of 66 years and 69 years, respectively. Moreover, 21% and 25% of patients, respectively, had DIPSS high-risk disease, median platelet counts of 68 x 109/L and 47 x 109/L, median hemoglobin of 10.0 g/dL and 9.6 g/dL, red blood cell transfusion requirement in 32% and 54%, prior JAK2 exposure in 64% and 45%, median spleen volume of 2907 cm3 and 2393 cm3, and median palpable spleen length of 12.00 cm and 14.50 cm.

Results showed that at least 10% SVR with pacritinib was prognostic for survival between responders and nonresponders (P <.0001). At least 20% and 35% or more SVRs were also prognostic for survival but to a lesser extent, with P values of .0199 and .3516, respectively. Authors also noted that any degree of SVR was associated with improved survival with pacritinib (HR, 0.08; 95% CI, 0.01-0.51; P = .0007).

Adjusting for baseline spleen volume and red blood cell transfusion requirement in univariate analysis did not affect the survival benefit with pacritinib at the 10% or greater SVR threshold.

Notably, SVR was not associated with survival with BAT at any threshold (SVR ≥10%, P =.4888; SVR ≥20%, P =.9821; SVR ≥35%, P =.8881).

“What is very encouraging is that we’re starting to see disease modification with these JAK inhibitors, not only showing spleen and symptom improvement, but also trying to show OS improvement and that the two can correlate,” Pemmaraju said. “Once we start to see spleen symptom improvement, as well as OS improvement, we can start to try to aim for and achieve disease modification, [which is] what matters to the patient. We’re starting to see that now, as we did with ruxolitinib and perhaps now with the newer JAK inhibitors.”

Additional findings from the analysis indicated that median dose intensity through week 12 was maintained with pacritinib at 200 mg twice daily in all patients who achieved SVR of at least 10%. Of the 28 patients who achieved SVR of at least 10% on BAT, the majority (n = 23) received ruxolitinib prior to the week-12 SVR evaluation. Of these patients, 78% were receiving no more than 10 mg of ruxolitinib twice daily and 43% were receiving no more than 5 mg of ruxolitinib twice daily. Other BATs included hydroxyurea (Hydrea) and prednisone.

Additionally, OS was associated with achieving at least 20% reduction in spleen length with pacritinib (HR, 0.14; 95% CI, 0.02-1.26; P =.0406; OS by spleen length reduction ≥35% and ≥50%, P =.0990 and P =.3008). However, separation of the curves was not as great for prognostication as SVR among responders and nonresponders.

“As pacritinib can be given at full dose regardless of platelet count, it is possible that pacritinib may offer a unique survival advantage for patients with myelofibrosis with moderate or severe thrombocytopenia who achieve ≥10% spleen reduction,” the authors wrote in the poster.

Although pacritinib is approved for use in patients with low platelet counts, clinical studies with the agent have included patients regardless of baseline anemia and thrombocytopenia. As such, another analysis was conducted, pooling the results of the PERSIST-1 and PERSIST-2 trials, to determine dosing patterns and efficacy outcomes by degree of baseline cytopenia.

Results showed that patients maintained median dose intensity of 100% regardless of whether they had baseline platelet counts below or above 100 x 109/L or baseline hemoglobin levels below 8 g/dL, between 8 g/dL and 10 g/dL, or 10 g/dL or above.

Additionally, between 21% and 28% of all patients, regardless of platelet and hemoglobin levels, achieved SVR of at least 35%; between 39% and 44% of patients achieved SVR of at least 25%; between 75.5% and 82% achieved SVR of at least 10%; and between 84% and 93% of patients achieved any spleen volume reduction. Moreover, the depth of the 24-week spleen reduction was similar across all platelet and hemoglobin strata.

Similarly, all patients achieved spleen reduction by week 12, and SVR remained consistent over time across all subgroups. Median hemoglobin also remained stable through week 24 across all hemoglobin thresholds, though some improvement was reported in patients with baseline levels below 8 g/dL.

Any improvement in total symptom score (TSS) was documented in between 80% and 87.5% of patients across all cytopenic groupings, although most patients with baseline hemoglobin below 8 g/dL (62.5%) derived the greatest magnitude in symptom improvement (TSS ≥50). Notably, 12-week TSS improvement occurred with deepening improvement through week 36, particularly in patients with baseline hemoglobin below 8 g/dL.

Regarding Patient Global Impression of Change response across all baseline blood count strata, approximately 80% of patients reported clinical improvement in disease symptoms and approximately 50% of patients classified their symptoms as “much” or “very much” improved at week 24.

“[This study] takes a look at the totality of the pacritinib data across doses across levels of cytopenias among patients and shows that while this drug is best known for its efficacy in cytopenic patients, it shows that the efficacy is about the same in those with higher blood counts as well, or at least it is certainly preserved in those patients as well,” Prithviraj Bose, MD, associate professor in the Department of Leukemia, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, told OncLive^®.

References

Ajufo H, Bewersdorf JP, Harrison C, et al. Spleen volume reduction (SVR) predicts overall survival (OS) in myelofibrosis (MF) patients on pacritinib (PAC) but not best available therapy (BAT): PERSIST-2 landmark OS analysis. J Clin Oncol. 2023;41(suppl 16):7018. doi:10.1200/JCO.2023.41.16_suppl.7018
Bose P, Gagelmann N, Gupta V, et al. Consistency of pacritinib for spleen and symptom reduction in patients with myelofibrosis regardless of cytopenias. J Clin Oncol. 2023;41(suppl 16):7068. doi:10.1200/JCO.2023.41.16_suppl.7068

Jaktinib Bests Hydroxyurea in in Intermediate-2/High-Risk Myelofibrosis

Posted on June 14, 2023June 14, 2023 by mpn_admin

Jun 10, 2023

Kyle Doherty

In a phase 3 study (ZGJAK016; NCT04617028), the novel JAK/ACVR1 inhibitor jaktinib led to a statistically significant improvement in the proportion of patients with a spleen-volume reduction of at least 35% from baseline (SVR35) at week 24 vs hydroxyurea in patients with intermediate-2 or high-risk myelofibrosis.¹

The results were presented at the 2023 EHA Congress and met the primary end point of the trial.

At the April 28, 2022, data cutoff, findings from the interim analysis of the study showed that the 24-week independent review committee (IRC)-assessed SVR35 rate was 72.3% (95% CI, 57.4%-84.4%) in the jaktinib arm (n = 47) compared with 17.4% (95% CI, 5.0%-38.8%) in the hydroxyurea arm (n = 23; P ≤ .0001). Additionally, the best spleen response rates were 80.9% vs 26.1%, respectively (P ≤ .0001). The median maximum percentage change in spleen volume from baseline per IRC assessment were –46.6% vs –18.5%, respectively.

“Three small molecule JAK inhibitors have been approved for myelofibrosis by the FDA, including ruxolitinib [Jakafi], fedratinib [Inrebic], and pacrritinib [Vonjo],” Jie Jin, MD, PhD, a professor of medicine in the Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, in Hangzhou, China, said during the presentation. “Currently in China, ruxolitinib is the only one that is available. Therefore, the treatment [options for] myelofibrosis in China is limited.”

ZGJAK016 was a double-blind, active-controlled, multicenter trial that enrolled adult patients with DIPSS intermediate-2 or high-risk myelofibrosis with an ECOG performance status of 1 or 0. Eligible patients also needed to have a palpable spleen of at least 5 cm below the left costal margin, a platelet count of at least 100 ´ 109/L, and no prior or a maximum of 10 days of treatment with a JAK inhibitor.

Following a 28-day screening period, enrolled patients were randomly assigned 2:1 to receive either jaktinib 100 mg twice daily plus a hydroxyurea placebo or hydroxyurea 0.5 g twice daily plus a jaktinib placebo for four 6-week cycles. At week 24, the extension period began, and patients who achieved SPV35 remained on their initially assigned treatment and those who did not received jaktinib 100 mg twice daily until criteria for termination. Patients were stratified by DIPSS risk status (intermediate-2 vs high-risk).

The primary end point of the study was SVR35 at week 24, measured by MRI or CT imaging and assessed by IRC. Key secondary end points included investigator-assessed SVR35 at week 24, best spleen response rate (defined as achieving SVR35 at any time), proportion of patients with reduction in MPN-SAF Total Symptom Score (TSS) of at least 50%, improvement in terms of anemia, and safety.

The baseline characteristics were well-balanced between the 2 arms; the median age was 63 years (range, 46-76) in the jaktinib arm compared with 62 years (range, 42-74) in the hydroxyurea arm. Most patients in both arms were women (61.7% vs 60.9%), had intermediate-2 DIPSS risk status (89.4% vs 87.0%), did not previously receive a JAK inhibitor (97.9% vs 91.3%), were JAK2 V617F positive (59.6% vs 69.6%), and had primary myelofibrosis (70.2% vs 73.9%). The median spleen volumes upon central review were 1389.7 cm3 (range, 433.6-5070.5) and 1249.1 cm3 (range, 579.6-3011.4), respectively. Additionally, the median platelet count and hemoglobin levels were similar between the 2 arms.

Most patients in the jaktinib arm completed 24 weeks of treatment (89.4%) and entered the extension period (83.0%). In the control arm, these rates were 69.6% and 69.6%, respectively. One patient in the hydroxyurea arm also received open-label jaktinib without unblinding. Four patients died on the jaktinib arm compared with 1 on the hydroxyurea arm; no death was determined to be treatment related.

Additional findings from the study showed that the SVR35 benefit was observed with jaktinib over hydroxyurea across all prespecified subgroups. The greatest differences in SVR35 rate in favor of jaktinib were observed among patients with a baseline MPN-SAF TSS greater than the median (72.0% [95% CI, 35.5%-85.9]), those with a DIPSS risk status of intermediate-2 (66.2% [95% CI, 42.2%-80.4%]), and those whose disease harbored a JAK2 V617F mutation (63.4% [95% CI, 35.0%-81.2%]).

More patients in the jaktinib arm experienced a reduction in MPN-SAF TSS from baseline compared with the hydroxyurea group at every time point examined in the interim analysis. This included week 6 (55.3% vs 34.8%), week 12 (59.6% vs 43.5%), week 18 (66.0% vs 39.1%), and week 24 (63.8% vs 43.5%).

Hemoglobin levels were increased from baseline in the jaktinib arm and decreased in the hydroxyurea arm. Among patients who received jaktinib who required a red blood cell transfusion (n = 7), 5 achieved a decreased in red blood cell transfusion unit of at least 50% by week 24 compared with 2 who received hydroxyurea and required a transfusion (n = 5).

Safety findings demonstrated that nearly all patients in the jaktinib and hydroxyurea arms experienced an any-grade treatment-emergent adverse effect (TEAE), at 97.9% and 100%, respectively. Most patients in both arms experienced a TEAE of grade 3 or higher severity (51.1% vs 60.9%).

Serious TEAEs were present in 27.7% of patients in the jaktinib arm compared with 47.8% in the hydroxyurea arm. TEAEs leading to dose reduction or interruption (23.4% vs 34.8%), as well as those leading to treatment discontinuation (8.5% vs 17.4%), were reported in both arms.

In the jaktinib arm, the most common any-grade TEAEs included thrombocytopenia (40.4%), anemia (38.3%), respiratory tract infections (21.3%), leukopenia (14.9%), fever (12.8%), and reduced blood bilirubin (12.8%). Common grade 3 or higher TEAEs consisted of anemia (25.5%), thrombocytopenia (17.0%), leukopenia (2.1%), neutropenia (2.1%), and decreased lymphocyte count (2.1%).

Comparatively in the hydroxyurea arm, the most common any-grade TEAEs included thrombocytopenia (52.2%), anemia (52.2%), leukopenia (30.4%), neutropenia (26.1%), decreased lymphocyte count (26.1%), and decreased blood bilirubin (26.1%). Grade 3 or higher TEAEs included anemia (43.5%), thrombocytopenia (39.1%), leukopenia (21.7%), neutropenia (21.7%), and decreased lymphocyte count (13.0%).

“At the time of this prespecified interim analysis, jaktinib has demonstrated an improved trend in symptom response vs hydroxyurea,” Jin said. “[Additionally], there were [fewer] cytopenias in the jaktinib group than the hydroxyurea [arm]. Our interim results demonstrate that jaktinib could be a new treatment option for patients with myelofibrosis [who are] DIPSS intermediate-2 or high-risk.”

_Reference

_{Zhang Yi, Zhhuan J, He A, et al. A randomized double-blind phase 3 study of jaktinib versus hydroxyurea in patients with intermediate-2 or high risk myelofibrosis. Hemasphere. 2023;7(suppl 3):S212.}

Ruxolitinib Improves Spleen Volume, TSS in Myelofibrosis Irrespective of Anemia, Transfusion Status

Posted on June 14, 2023June 14, 2023 by mpn_admin

Jun 10, 2023

Gina Mauro

Conference|European Hematology Association Congress

Ruxolitinib was found to improve spleen volume and tumor symptom score in patients with myelofibrosis, irrespective of their anemia and transfusion status, according to data from a post-hoc analysis of the phase 3 COMFORT-I and -II trials.

Ruxolitinib (Jakafi) was found to improve spleen volume and tumor symptom score (TSS) in patients with myelofibrosis, irrespective of their anemia and transfusion status, according to data from a post-hoc analysis of the phase 3 COMFORT-I (NCT00952289) and -II (NCT00934544) trials that were published during the 2023 EHA Congress.¹

Results showed that the reduction in spleen volume of 35% or greater from baseline (SVR35) rates at week 24 in patients with new or worsening anemia up to week 12 were 48.8%, 33.3%, and 41.4%, respectively, for those who were nonanemic, anemic/nontransfusion dependent, and anemic/transfusion dependent at baseline. These rates were 43.2%, 23.1%, and 28.2%, respectively, in patients who did not have new or worsening anemia at week 24.

SVR35 at week 48 was achieved in 42.1%, 44.1%, and 34.6% of patients who had new or worsening anemia and were nonanemic, anemic/nontransfusion dependent, and anemic/transfusion dependent at baseline compared with 42.4%, 22.2%, and 27.3% in those who did not have new or worsening anemia.

A 50% or greater reduction in TSS at week 24 was achieved by 51.1%, 42.1%, and 46.7% of those with new or worsening anemia up to week 12 and who were nonanemic, anemic/nontransfusion dependent, or anemic/transfusion dependent at baseline. In patients who did not have new or worsening anemia up to week 12, these rates were 42.9%, 40.0%, and 54.2%, respectively.

Ruxolitinib, a JAK1/2 inhibitor, is indicated for patients with intermediate- or high-risk myelofibrosis. The FDA approval for ruxolitinib in this setting was based off findings from the COMFORT-I² and COMFORT-II³ trials. Findings showed that ruxolitinib demonstrated a reduction in spleen volume, improved myelofibrosis-related symptoms, and prolonged overall survival. This was in comparison with placebo in COMFORT-I and with best available therapy (BAT) in COMFORT-II.

Transient dose-dependent anemia is a treatment-related adverse effect (TRAE) that has been observed with ruxolitinib. In COMFORT-I, grade 3/4 anemia occurred in 45.2% of patients on ruxolitinib vs 19.2% with placebo. In COMFORT-II, the most frequently reported serious adverse effect in both arms was anemia (5% with ruxolitinib vs 4% with BAT).

Therefore, in the post-hoc analysis presented during the congress, investigators sought to determine how new or worsening anemia from ruxolitinib treatment impacts SVR and TSS in this patient population.¹

Patients were treated with ruxolitinib twice daily with an initial dose based on platelet count. For those with a platelet count of 100 to 200 x 109/L, the dose was 15 mg vs 20 mg for those whose platelet count was above 200 x 109/L. Stratification factors included anemia status at baseline (yes vs no) and transfusion status at baseline (transfusion dependent vs nontransfusion dependent).

Anemia was defined as hemoglobin less than 100 g/L and patients were considered transfusion dependent if they received 2 or more units of red blood cells over 8 to 12 weeks before their first dose of ruxolitinib. Investigators stratified outcomes via presence or absence of new or worsening anemia postbaseline, which was defined as a decrease in hemoglobin of at least 15 g/L or new transfusion requirement at weeks 4, 8, or 12.

Specifically, investigators assessed patients with a reduction in spleen volume of at least 35% from baseline from the pooled COMFORT-I/-II data at weeks 24 and 48, and with at least a 50% reduction in modified Myelofibrosis Symptom Assessment Form TSS at week 24, from the COMFORT-I data.

A total of 277 patients were included in the analysis. Regarding baseline characteristics, the median age ranged from 65.0 to 71.0 years, and between 47% and 56% were male. More than half of patients were baseline nonanemic (n = 154; 55.6%) 19.9% (n = 55) were anemic/nontransfusion dependent, and 24.5% (n = 68) were anemia/transfusion dependent.

References

Al-Ali HK, Mesa R, Hamer-Maansson JE, Braunstein E, Harrison, C. Effect of new or worsening anemia on clinical outcomes in patients with myelofibrosis (MF) treated with ruxolitinib (RUX): a post hoc analysis of the COMFORT-I and -II trials. Presented at: 2023 European Hematology Association Congress; June 8-11, 2023; Frankfurt, Germany. Abstract PB2185.
Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799-807. doi:10.1056/NEJMoa1110557
Harrison C, Kiladjian J-J, Al-Ali HK, et al. JAK Inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366:787-798. doi:10.1056/NEJMoa1110556.

Dr Al-Ali on the Safety and Efficacy of BMS-986158 Plus Ruxolitinib or Fedratinib in Myelofibrosis

Posted on June 14, 2023June 14, 2023 by mpn_admin

Jun 10, 2023

Haifa Kathrin Al-Ali, MD

Conference|European Hematology Association Congress

Haifa Kathrin Al-Ali, MD, discusses the safety and efficacy findings from the dose-escalation portion of the phase 1/2 CA011-023 trial of BMS-986158 in combination with ruxolitinib or fedratinib in patients with intermediate- or high-risk myelofibrosis.

Haifa Kathrin Al-Ali, MD, professor of Translational Oncology and head of the Krukenberg Cancer Center at the University Hospital of Halle (Saale) in Germany, discusses the safety and efficacy findings from the dose-escalation portion of the phase 1/2 CA011-023 trial (NCT04817007) of BMS-986158 in combination with ruxolitinib (Rituxan) or fedratinib (Inrebic) in patients with intermediate- or high-risk myelofibrosis.

BMS-986158 is a potent, oral BET inhibitor. In the dose-escalation phase, the agent was evaluated in combination with ruxolitinib in ruxolitinib-naïve patients for part 1A, and in combination with fedratinib in patients who were refractory/relapsed or intolerant to prior ruxolitinib for part 1B. The dose-expansion portion of the study, which will open for enrollment soon, will evaluate BMS-986158 at the recommended phase 2 dose or the previously tolerated dose in combination with ruxolitinib in parts 2A1 and 2A2, and with or without fedratinib in parts 2B1 and 2B2.

Data from the dose-escalation portion of the trial presented at the 2023 EHA Congress showed that both BMS-986158–based combinations had tolerable safety profiles, Al-Ali says. The most common adverse effects (AEs) included thrombocytopenia and gastrointestinal (GI) toxicities, including diarrhea and nausea. GI AEs were generally mild and did not lead to treatment discontinuation in any patients, according to Al-Ali.

Regarding efficacy, first-line BMS-986158 plus ruxolitinib led to a spleen volume reduction of at least 35% (SVR35) in 73% (95% CI, 39%-94%) of patients at week 12 (n =11), 100% (95% CI, 66%-100%) at week 24 (n = 9), and 80% (95% CI, 28%-100%) at week 48 (n = 5). The mean spleen volume change was –46.7%, –59.9%, and –56.3% at weeks 12, 24, and 48, respectively.

In those given BMS-986158 plus fedratinib in the second-line setting, the SVR35 was 38% (95% CI, 9%-76%) at week 12 (n = 8), 43% (95% CI, 10%-82%) at week 24 (n = 7), and 50% (95% CI, 1%-99%) at week 48 (n = 2). The mean change in spleen volume at weeks 12, 24, and 48 was –29.1%, -30.8%, and -33.0%, respectively.

Evidence for disease modification may have been observed in the form of JAK2 allele burden reduction, which was noted starting in cycle 6 for patients with JAK2 mutations, Al-Ali explains. Additionally, bone marrow fibrosis regression was observed in patients with follow-up bone marrow biopsies, she concludes.

One Patient’s Point of View on “Living” with Myelofibrosis

Posted on November 13, 2019November 14, 2019 by mpn_admin

David told his story at the Cleveland MPN Patient Program in November

On a beautiful fall day in late August 2013, I received a call that changed the course of my life. The voice on the other end told me that they had reviewed my blood counts and determined that I had some sort of leukemia. They had pre-admitted me to the local hospital to meet an oncologist and have the necessary tests. After about two weeks I received my diagnosis of Primary Myelofibrosis, Intermediate 1. I was told that treatment options were limited and the only true cure was allogeneic bone marrow transplan

It is tempting to focus all our energies on our hope in medical interventions. But diagnosis brings fear, denial, anger, & depression. These impact your relationships and can throw you into a downward spiral. Being diagnosed with a life-threatening disease like an MPN is an existential challenge. It raises all the questions: Why are we here? What is life about? What lies beyond this life? How you answer these questions will affect how you deal with your disease and its physical effects.

We are all tempted to be sad and maybe even angry. But you do not have to give in to the negative. You can choose to respond with a positive attitude.

My diagnosis has changed the course of my life – but for the better. Because of myelofibrosis, I realized that I was spending far too much of my time and energy focused on some sort of future achievement. I was super-busy every day and the days passed in a blur. But myelofibrosis woke me up to the truth that life is not about some future achievement. Life is about today. Since my diagnosis, I have come to have a heightened enjoyment of the simple pleasures of daily living.

These last six years have been wonderful and I have enjoyed them more because of my disease. My son and his wife have been kind enough to give us two new grandchildren in the past four years – and I am making the most of that. I’ve made many good friends in the MPN community. I took up motorcycle riding. The more aware I am of my mortality – the more I savor every experience of life.

Your life only comes one day at a time. Today is the day you have – make it into something good. Refuse to let an uncertain future rob you of today’s joys.

David shared his story in the MPN Community Connection Newsletter click here to view

David is the support group coordinator for the northern Pennsylvania/Ohio area, if you are interested in participating you can contact us for more information. Click here to contact us.