Category Archives: Clinical Trial

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

Posted on by

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

  1. 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
  2. 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

Read more

Pelabresib Provides Clinical Benefit in Hydroxyurea-Refractory or Intolerant High-Risk Essential Thrombocythemia

Posted on by

Caroline Seymour
Conference|European Hematology Association Congress

Treatment with pelabresib monotherapy led to a 60% confirmed complete or partial hematologic response at any time without incurring grade 4 or 5 treatment-related adverse effects in patients with high-risk essential thrombocythemia refractory or intolerant to hydroxyurea.

Treatment with pelabresib monotherapy led to a 60% confirmed complete or partial hematologic response at any time without incurring grade 4 or 5 treatment-related adverse effects (AEs) in patients with high-risk essential thrombocythemia (ET) refractory or intolerant to hydroxyurea, according to preliminary findings from arm 4 of the phase 2 MANIFEST trial (NCT02158858) presented at the 2023 EHA Congress.

At data cutoff of July 29, 2022, 7 of 20 patients had been treated for at least 6 months, and 14 patients continued to receive treatment with pelabresib. The confirmed complete and partial hematologic response rates were 40% and 20%, respectively.

“Pelabresib monotherapy resulted in hematologic response and symptom improvement in patients with high-risk ET who are resistant/intolerant to hydroxyurea,” Francesco Passamonti, MD, lead study author, professor of hematology at the University of Insubria of Varese, and head of the Division of Hematology at the University Hospital of Varese in Italy, said.

ET is a myeloproliferative neoplasm (MPN) defined by progressive thrombocytosis, thrombohemorrhagic events, and systemic symptoms. Despite first-line cytoreductive therapy with hydroxyurea and interferon alfa-2a, resistance and intolerance remain issues for this population, creating an unmet medical need.

Pelabresib is an oral, small molecule inhibitor of BET, which has the potential to downregulate the expression of genes that reside within the pathogenic pathways that underly MPN progression.

MANIFEST in a 4-arm, ongoing, global, open-label, phase 2 study evaluating pelabresib in patients with myelofibrosis and ET. Arm 1 is evaluating pelabresib alone, and arms 2 and 3 are investigating pelabresib plus ruxolitinib (Jakafi), all in patients with myelofibrosis. Arm 1 is evaluating pelabresib monotherapy as second-line therapy in patients with ruxolitinib-refractory or intolerant disease. Arm 2 is evaluating pelabresib as an add-on to ruxolitinib in the second line following suboptimal response or progression. In arm 3, the combination is being evaluated in the frontline in patients with Dynamic International Prognostic Scoring System intermediate-2/high disease.

The study population in arm 4 consisted of patients with high-risk ET refractory or intolerant to hydroxyurea with at least 2 symptoms of average score of 3 or more, or a total symptom score (TSS) of 15 or more per Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) in the past 7 days, and platelets above 600 x 109/L.

Patients were treated with 225 mg of oral pelabresib monotherapy once daily for 14 days in 21-day cycles (n = 21).

The primary end point of this arm of the study was confirmed complete hematologic response at any time. Secondary end points included confirmed partial hematologic response at any time and symptom improvement. Exploratory end points included translational evaluation of Interleukin-8 (IL-8) expression change, cytokines, and mutation status.

Regarding baseline characteristics (n = 20), the median patient age was 64 years (range, 42-83) and most were older than 60 years (60%) and female (60%). Median hemoglobin, platelet count, white blood cell count, and spleen volume was 13 g/dL (range, 10-16), 722 x 109/L (range, 418-1255), 7.9 x 109/L (range, 4-12.3), and 402 cc (range, 124-907), respectively. Spleen was not palpable in 90% of patients, and median TSS was 32.7 (range, 6.9-123). Median prior hydroxyurea duration was 103 months (range, 0.7-245). Most patients had received at least 2 prior lines of therapy (60%). Fifteen percent of patients had prior thrombosis. Twenty percent of patients had myelofibrosis high-molecular risk, with JAK2, CALR, ASXL1, and MPL mutations residing in 45%, 40%, 15%, and 5% of tumors, respectively.

With respect to blood counts over time, the median platelet, white blood cell, and hemoglobin (n = 13) counts at week 12 were 446 x 109/L, 8.2 x 109/L, and 13.0 g/dL, respectively. Sixty percent of patients had platelets no higher than 400 x 109/L over time. Similarly, most patients (95%) did not experience white blood cell counts above 10 x 109/L over time. The median percentage change in platelet and white blood cell counts at week 12 were –40% and 8.2 x 109/L, respectively. Additionally, by week 24 (n = 7), median hemoglobin remained stable at 13.4 g/dL.

TSS was evaluated in 14 patients, showing 50% reduction in TSS50 in MPN-SAF at any time. By week 12, median TSS had been reduced by 31%.

A NF-κB target cytokine panel linked to bone marrow pathogenesis and inflammation was assayed. Included cytokines were CD40, CD40-L, CRP, IL-6, IL-18, IP-10, MMP-2, TNF-α, thrombospondin-1, RANTES, VCAM-1, and VEGF.

“Pelabresib monotherapy demonstrated a durable reduction in NF-κB–driven cytokines associated with bone marrow abnormalities and inflammation,” Passamonti said, reaching close to 40%.

In addition, IL-8 gene expression was evaluated in whole blood prior to and 4 hours after pelabresib administration. Passamonti stated that “rapid reduction in IL-8 gene expression was observed,” with median expression changes of –67% (95% CI, –79% to –56.9%), –69% (95% CI, –76.5% to –12.2%), and –52% (95% CI, –85% to 106.6%) at cycle 1 day 1 (n = 16), cycle 1 day 14 (n = 11), and cycle 3 day 1 (n = 10), respectively.

Furthermore, investigators explained that although variant allele fraction (VAF) levels were maintained in most patients with 30% or fewer driver mutations, 2 of 6 patients with post baseline JAK2 V617F–mutation assessment showed meaningful reduction in VAF from 60% to 20% and 52% to 40%.

Regarding safety, serious AEs occurred in 3 patients, consisting of leukocytosis, thrombocytosis, and eyelid bleeding in 1 patient, infection in another, and dyspnea and pulmonary embolism in the third. Another 3 patients reported treatment-emergent AEs that led to pelabresib discontinuation. No grade 5 AEs occurred.

“Safety results [were] as expected in the underlying population and consistent with the known safety profile of pelabresib,” Passamonti said.

Leukopenia was the only reported hematologic AE (all-grade, 10%). Non-hematologic AEs included nausea (60%), diarrhea (35%), constipation (30%), vomiting (25%), dyspepsia (10%), dysgeusia (35%), ageusia (30%), abdominal pain (25%), rash (20%), respiratory tract infection (15%), weight decrease (15%), muscle spasms (15%), myalgia (10%), headache (10%), insomnia (10%), pruritus (10%), hypertension (10%), fatigue (10%), and arthralgia (10%).

Hemorrhagic and thromboembolic events included pulmonary embolism (grade 3, 5%), deep vein thrombosis (all-grade, 5%), acute myocardial infarction (all grade, 5%), hemorrhagic diarrhea (grade 3, 5%), eyelid bleeding (grade 3, 5%), hematoma (all grade, 5%), hematuria (all grade, 5%), and petechia (all grade, 5%). All cases of thromboembolic events and eyelid bleeding were unrelated to pelabresib.

“These preliminary safety and efficacy results in patients with high-risk essential thrombocythemia continue to provide evidence for the potential clinical benefit of pelabresib in myeloid diseases,” Passamonti concluded.

Reference

Passamonti F, Patriarca A, Knapper S, et al. Pelabresib (CPI-0610) monotherapy in patients with high-risk essential thrombocythemia refractory or intolerant to hydroxyurea: preliminary results from MANIFEST study. Presented at: 2023 EHA Congress; June 8-11, 2023; Frankfurt, Germany. Abstract S168.

Read more

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

Posted on by

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.

Read more

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

Posted on by

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

  1. 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.
  2. 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
  3. 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.

Read more

Rusfertide Offers Durable Hematocrit Control in Phlebotomy-Dependent Polycythemia Vera

Posted on by

June 11, 2023

Caroline Seymour

Rusfertide (PTG-300) demonstrated freedom from phlebotomy, sustained hematocrit control, and 12-week treatment completion in 69.2% (n = 18/26) vs 18.5% (n = 5/27) of patients with phlebotomy-dependent polycythemia vera who received placebo (P = .0003), meeting the primary end point of the phase 2 REVIVE trial (NCT04057040). Findings were presented at the 2023 EHA Congress.

“The REVIVE study demonstrated significantly higher efficacy with rusfertide compared with placebo in subjects with polycythemia vera,” said Marina Kremyanskaya, MD, PhD, lead study author and assistant professor of medicine, hematology, and medical oncology at the Icahn School of Medicine at Mount Sinai in New York, New York, in a presentation of the data. “Current standard-of-care therapy in polycythemia vera does not consistently maintain hematocrit below 45%, thereby potentially increasing the risk of thromboembolic events. Rusfertide has the potential to consistently maintain hematocrit [levels] below 45%.”

Polycythemia vera is a myeloproliferative neoplasm (MPN) that produces red blood cells in excess and is often marked by elevated hematocrit. Hematocrit, when uncontrolled, can lead to higher fatality from cardiovascular causes or thrombotic events. Although guidelines from the National Comprehensive Cancer Network and European LeukemiaNet state that hematocrit should be maintained below 45%, current standard-of-care therapy fails to do so in most patients.

Hepcidin is a peptide hormone that controls iron availability for red blood cell formation. Rusfertide is a novel hepcidin mimetic that mirrors the effects of hepcidin on erythropoiesis, representing a potential add-on therapy to standard therapy with improved activity. This hypothesis was tested in the phase 2 REVIVE trial.

To be eligible for enrollment in the study, patients had to have phlebotomy-dependent polycythemia vera per 2016 World Health Organization criteria, having received at least 3 phlebotomies in 28 weeks with or without concurrent cytoreductive therapy. Additionally, all patients had to be phlebotomized to hematocrit levels below 45% prior to the first dose of rusfertide to standardize the starting hematocrit.

The study consisted of 3 parts: dose finding, blinded randomized withdrawal, and open-label extension. Rusfertide was administered subcutaneously in doses ranging from 10 mg to 120 mg weekly. In part 1, rusfertide was titrated for the first 16 weeks to determine the clinically effective dose. Efficacy was evaluated in weeks 17 to 28. In part 2, patients were randomly assigned 1:1 to receive active or placebo doses of rusfertide in weeks 29 to 41. Study treatment continued in part 3 for up to 3 years.

Safety and efficacy served as key end points of the trial. Efficacy was characterized by the proportion of responders in part 2, defined by the proportion of patients who maintained hematocrit below 45% and the percentage reduction in phlebotomies. Patient outcomes were evaluated with the MPN Symptoms Assessment Form Total Symptom Score.

A total of 70 patients were included in the dose-finding portion of the research. Fifty-nine patients were treated in part 2, 53 of which were included in the primary efficacy analysis set. Fifty-two patients are ongoing treatment in part 3

Regarding baseline characteristics of those included in part 2, most patients were male, above the age of 50 years at diagnosis, had polycythemia vera for approximately 5 years, and received hydroxyurea as the primary means of cytoreductive therapy. Across the arms, 52.7% of patients were high risk and 47.4% were low risk. Body mass index was 30.1 ± 5.76 kg/m2 and 28.7 ± 4.55 kg/m2 in the placebo and rusfertide arms, respectively.

Additional findings demonstrated similar benefit in time to treatment failure with rusfertide in responders (P < .0001), patients ineligible for phlebotomy plus hydroxyurea (P < .0001), and those with hematocrit under 45% (P < .0001).

Kremyanskaya also explained that rusfertide led to meaningful reductions in the need for phlebotomy, both with phlebotomy only (n = 37) and phlebotomy plus cytoreductive therapy (n = 33).

Although the focus of the presentation centered around outcomes in part 2, investigators also evaluated symptom improvement in part 1. Notably, moderate or severe symptoms of problems with concentration (P =.0018), itching (P = .0054), fatigue (P =.0074), and inactivity (P =.0005) were all improved following treatment with rusfertide. Kremyanskaya noted that meaningful comparison of symptom improvement was not possible in part 2 because most patients who were randomized to placebo discontinued prior to the 12-week symptom assessment.

In terms of safety, Kremyanskaya stated that rusfertide was “generally well tolerated.” Treatment-emergent adverse effects (TEAEs) included injection site erythema (64.3%), injection site pain (41.4%), injection site pruritus (40.4%), fatigue (31.4%), injection site mass (25.7%), pruritus (25.7%), arthralgia (24.3%), injection site swelling (24.3%), dizziness (22.9%), headache (22.9%), nausea (22.9%), anemia (20.0%), COVID-19 (20.0%), injection site irritation (18.6%), and injection site bruising (15.7%). Most events were grade 1/2 (83%), and 17% of patients experienced grade 3 events. No grade 5 events occurred.

“Most common TEAEs were injection site reactions, which decreased in incidence with continued treatment,” Kremyanskaya noted. “Additionally, events were localized, grade 1 or 2 in severity, and generally did not lead to treatment discontinuation,”

Two treatment-related events of mild thrombocytosis and recurrent grade 1 injection site erythema led to treatment discontinuation.

Patients who completed the REVIVE study will be eligible to enroll in PTG-300-21, a separate, 2-year follow-on extension trial. The agent is also under evaluation in the phase 3 VERIFY trial (NCT05210790), where it is being compared with placebo in patients with polycythemia vera maintaining hematocrit control and in improving symptoms of disease.

Disclosures: Dr Kremyanskaya reported receiving honoraria and being on the advisory board for Protagonist Therapeutics, Inc.

Reference

Kremyanskaya M, Kuykendall A, Pemmaraju N, et al. Targeted therapy of uncontrolled erythrocytosis in polycythemia vera with the hepcidin mimetic, rusfertide: – blinded randomized withdrawal results of the REVIVE study. Presented at: 2023 EHA Congress; June 8-11, 2023; Frankfurt, Germany. Abstract LBA2710.

Read more

Fedratinib and Ruxolitinib: Advice for Deciding Which Agent to Give and When

Posted on by

The introduction of fedratinib (Inrebic) to the treatment landscape of myelofibrosis (MF) and the challenges that have arisen over deciding between administering fedratinib or ruxolitinib (Jakafi) means more community oncologists should consult specialists when treating these patients, said Andrew Kuykendall, MD.

Research shows that fedratinib and the earlier JAK inhibitor, ruxolitinib have similar efficacy in patients with MF. However, their toxicity profiles differ, and the potential for encephalopathy with fedratinib is an ongoing concern, resulting in a black box warning on the label. Now that the agent is FDA approved for the treatment of MF, oncologists are left with a decision of which JAK inhibitor to give to which patients and when to prescribe them.

How to continue using ruxolitinib now that fedratinib is available remains an unanswered question, said Kuykendall, assistant member, Moffitt Cancer Center; however, experts in treating myeloproliferative neoplasms (MPNs) can be a helpful resource for other oncologists.

Another resource for treatment decision-making is clinical data from the JAKARTA-2 trial, which studied fedratinib in patients with MF who were previously treated with ruxolitinib. Findings from a re-analysis of the study were presented at the 2019 ASCO Annual Meeting and showed that 46 of the 83 assessable patients achieved a spleen response (55%; 95% CI, 44%-66%), meeting the primary endpoint of the study.

The most common adverse events included diarrhea (n = 60), nausea (n = 54), vomiting (n = 40), constipation (n = 20), and others. Additionally, hematologic abnormalities including, grade 3/4 anemia (n = 96), thrombocytopenia (n = 68), and neutropenia (n = 23) were seen. Eighteen patients (19%) discontinued treatment due to adverse events.

These data suggest that fedratinib may be a second-line option for patients who are resistant or sensitive to ruxolitinib. The management of the gastrointestinal (GI)-related toxicities and checking of thymine levels to prevent encephalopathy, however, are newer management concerns that physicians must be aware of when administering fedratinib to patients with MF and is another point when consulting an MPN specialist may come in handy.

Read Targeted Oncology’s interview with Dr. Kuykendall.

Watch Behind the Mystery: Living with Polycythemia Vera

Posted on by

The Lifetime Channel’s The Balancing Act featured a story this week on polycythemia vera (PV), with experts Dr. Richard T. Silver, a professor of medicine at NewYork–Presbyterian/Weill Cornell Medical Center, and Dr. Srdan Verstovsek of the MD Anderson Cancer Center, who discuss the latest inpatient care and clinical trials for PV, as well as the future for those living with PV as a chronic illness. Learn More

Learn more about MPN Clinical Trials