Tag Archives: Ruxolitinib

Azacitidine Plus Ruxolitinib Demonstrates ‘Promising’ Efficacy in Myelofibrosis

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Amber Denham

05/31/2024

Azacitidine in combination with ruxolitinib demonstrates promising efficacy for patients with myelofibrosis (MF), according to long-term follow-up results from a phase 2 clinical trial presented at the 2024 American Society of Clinical Oncology (ASCO) Annual meeting.

The trial included adult patients aged ≥18 years with MF intermediate 1 to 2 or high-risk disease, measured by the Dynamic International Prognostic Scoring System (DIPSS). From March 2013 to October 2021, a total of 61 patients were treated in the trial. Patients had a median age of 66 years (46 to 87). The median hemoglobin was 10.1 g/dl (6.8 to 16.2) and bone marrow blasts 2% (0 to 14%). Overall, 14 (23%) patients had BM blasts ≥5%. Furthermore, JAK2 was mutated in 35 (57%) patients and 38 (62%) patients had intermediate-2 or high-risk DIPSS disease.

Study results showed an International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) response occurred in 44 (72%) patients. A clinical improvement was noted in 37 (61%) patients, including IWG-MRT spleen reduction >50% in 28 (61%) of 46 patients with baseline length ≥5 cm below left costal margin, and 31 (61%) of 51 patients with baseline total symptom score (TSS) >12 having a >50% improvement in TSS 50. In addition, a partial response was seen in 4 patients and cytogenetic complete remission in 3 patients.

With a median follow-up of 93 months, median overall survival (OS) was 46 months (95% confidence interval [CI], 25 to 66), median event-free survival was 33 months (95% CI, 24 to 43), and median duration of any objective response was 43 months (95% CI, 24 to 62). It was noted that disease transformation to AML occurred in 14 (23%) patients with a median time to transformation of 19 months. In addition, 20 (33%) patients received a stem cell transplant (SCT), and 11 (55%) patients had intermediate-2/high-risk DIPPS disease. It was observed that patients in the Intermediate-2/high-risk DIPPS group who received a SCT showed a trend towards improved median OS vs those who did not receive a transplant (38 vs 27 months, P = .2).

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Serum Albumin Levels May Predict Survival Among Patients With Myelofibrosis Treated With Ruxolitinib

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Jonathan Goodman, MPhil

Serum albumin may function as a dynamic surrogate marker for clinical outcomes among patients with myelofibrosis treated with ruxolitinib, according to research published in JCO Precision Oncology. The utility of this surrogate measure may, however, vary by a given patient’s treatment status.

Previous work has established ruxolitinib, a JAK inhibitor, as a standard of care among patients with myelofibrosis. Yet although this treatment may help to reduce spleen size and symptom burden, it is unclear whether it improves overall survival (OS) rates.

New models, such as the RR6 model, have aimed to provide a prognostic surrogate measure for OS, though whether these models effectively distinguish high-risk disease from cases where there is no response to treatment is unclear. For this study, researchers aimed to evaluate whether serum albumin — which is linked with an anti-inflammatory response to treatment — is an effective surrogate marker for OS among patients with myelofibrosis.

Overall, data from 396 patients were included. In the cohort, among evaluable patients, 91 had received ruxolitinib while 305 were naïve to treatment, 58% of patients were male sex, and 72% of patients had primary myelofibrosis.

Analysis suggested that serum albumin levels frequently dropped among all patients, though this was less pronounced among patients treated with ruxolitinib. Relatedly, patients with a high serum albumin level at baseline had improved median OS periods (53.5 months) compared to patients with low levels (29.8 months; odds ratio, 1.95; P <.001).

The link between serum albumin levels and OS was independent of variables included in the dynamic international prognostic scoring system, though only among patients who were naïve to ruxolitinib.

Future efforts to incorporate serum albumin with other inflammatory markers into an inflammatory index and assess its relevance in the context of other JAK inhibitors and combinations are ongoing.

Furthermore, among patients treated with ruxolitinib, changes in serum albumin levels predicted OS. Among patients with stable levels or an increase, median OS was 82.7 months, compared with 64.1 months among patients with a decrease (P =.04).

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Parsaclisib Added to Ruxolitinib Decreases Spleen Volume and Improves Symptom Scores in Myelofibrosis

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Kyle Doherty

The PI3Kδ inhibitor parsaclisib added to a stable dose of ruxolitinib (Jakafi) reduced spleen volume and improved symptom scores for patients with myelofibrosis who experienced a suboptimal response to ruxolitinib, according to findings from a phase 2 study (NCT02718300) published in Blood Adv.

Final results of the study revealed that patients who received daily-to-weekly dosing of parsaclisib (n = 32) and those who received all-daily dosing of parsaclisib (n = 42) achieved a decrease in spleen volume of at least 10% at 12 weeks at rates of 28.0% and 59.5%, respectively. Moreover, patients achieved a 50% decrease or more at week 12 in Myelofibrosis Symptom Assessment Form symptom scores at rates of 14% and 28%, respectively; the rates of at least a 50% decrease at week 12 in Myeloproliferative Neoplasms Symptom Assessment Form symptom scores were 18% and 32%, respectively.

“Ruxolitinib reduces spleen volume, improves symptoms, and increases survival in patients with intermediate- or high-risk myelofibrosis. However, suboptimal response may occur, potentially because of signaling via the PI3K/protein kinase B pathway,” Abdulraheem Yacoub, MD, professor of Hematologic Malignancies and Cellular Therapeutics at KU Medical Center in Kansas City, Kansas, and coauthors wrote. “The addition of parsaclisib to stable-dose ruxolitinib can reduce splenomegaly and improve symptoms, with manageable toxicity in patients with myelofibrosis with suboptimal response to ruxolitinib.”

The study authors added that parsaclisib was designed with a different molecular structure than earlier-generation PI3K inhibitors—the orally bioavailable, potent, and highly selective next-generation inhibitor may in turn be able to limit both on- and off-target toxicities that were previously seen.

Additional findings from the study demonstrated that in the overall population evaluable for the primary end point (n = 65), the median change in spleen volume was −163.6 cm3 (range, −735.6 to 10173 cm3), with a median percentage change of −11% (range, −47% to 444%). At week 24, these figures were −192.0 cm3 (range, −2040 to 761.4 cm3) and −10% (range, −89% to 34%) among 49 evaluable patients. The median percentage change was greater among patients who received all-daily dosing compared with those who received daily-to-weekly dosing both at 12 weeks (−15.0% vs −2.0%) and 24 weeks (−19.0% vs −2.5%, respectively).

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A phase I trial of pevonedistat in combination with ruxolitinib for the treatment of myelofibrosis

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March 13, 2024

Tim Kong, Nicole Gaudin, Karyn Gordon, Maggie J. Cox, Amy W. Zhou, and Stephen T. Oh

Abstract

Janus kinase 2 (JAK2) inhibitors such as ruxolitinib have become standard-of-care therapy for patients with myeloproliferative neoplasms (MPNs); however, activation of alternate oncogenic pathways including nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) has limited durable response as single-agent therapy. With the rationale of targeting both pathways, we conducted a phase I dose escalation trial of pevonedistat in combination with ruxolitinib for the treatment of patients with myelofibrosis (NCT03386214). The primary objective was to assess the safety and tolerability of combination therapy with additional objectives of treatment efficacy and alterations of biomarkers. There were no dose-limiting toxicities observed with most adverse events being limited to grades 1/2. In secondary measures, anemia response was observed in two patients. Pro-inflammatory cytokines and iron parameters were longitudinally assessed, which revealed suppression of interleukin-6 and interferon-gamma in a dose-dependent manner across a subset of patients. These results suggest that combination therapy targeting both JAK2 and NFκB may hold clinical merit for MPN patients.

Addition of Parsaclisib to Ruxolitinib Decreases Spleen Volume and Improves Symptom Scores Among Patients With Myelofibrosis

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Jordan Kadish

02/23/2024

The addition of parsaclisib to stable-dose ruxolitinib treatment decreased spleen volume, improved symptom scores, and yielded acceptable safety among patients with primary or secondary myelofibrosis (MF), according to findings from a phase 2 trial published in Blood Advances.

Abdulraheem Yacoub, MD, The University of Kansas Cancer Center, Kansas City, Kansas, and coauthors explained that although ruxolitinib has demonstrated beneficial results among patients with intermediate- or high-risk myelofibrosis, “suboptimal response may occur, potentially because of signaling via the phosphoinositide 3-kinase (PI3K)/protein kinase B pathway.”

In this phase 2 trial, the study authors aimed to measure the potential benefit of adding PI3Kδ inhibitor parsaclisib to ruxolitinib treatment among patients with primary or secondary myelofibrosis who did not have optimal responses to ruxolitinib alone. The primary end points were dosing, efficacy, and safety of this treatment combination.

All patients included in this study stayed on a stable dose of ruxolitinib. Among these patients, 32 were administered parsaclisib at 10 or 20 mg once daily for 8 weeks, then once weekly afterward (daily-to-weekly dosing). Additionally, 42 patients were administered parsaclisib at 5 or 20 mg once daily for 8 weeks, and then 5 mg once daily afterward (all-daily dosing).

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