Targeted Therapy Combinations With JAK inhibition Show Early Promise for Myelofibrosis

Lucia Masarova, MD

Patients with myelofibrosis have complicated pathology and multiple pathways, creating the opportunity to use multiple targeted agents for treatment, but also leading to greater potential for resistance to monotherapy, according to Lucia Masarova, MD.

During the Texas Virtual MPN Workshop, Lucia Masarova, MD, an assistant professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, presented data exploring combinations with ruxolitinib (Jakafi) and novel targeted therapies for patients with myelofibrosis that may potentially improve outcomes and help to overcome mechanisms of resistance.¹

These novel agents include navitoclax, a BCL-xL/BCL-2 inhibitor; CPI-0610, a brodomodomain and extraterminal (BET) inhibitor; azacitadine, a DNA methyltransferase inhibitor; and parsaclisib (INCB0504465), a PI3K inhibitor. She focused on data presented at the American Society of Hematology (ASH) 2019 Annual Meeting and European Hematology Association (EHA) 2020 Annual Congress.

CPI-0610

Of these agents, Masarova described CPI-0610 as one of the most important. This drug has the potential to be a best-in-class BET inhibitor. It’s a potent and selective BET inhibitor that has the potential for disease modification in this setting, as it alters the gene expression at transcriptional start cites and gene enhancers. By inhibiting BET proteins, it downregulates pro-inflammatory cytokines through the NF-KB pathway, inhibits megakaryocyte differentiation, and inhibits TGF-β target genes. When using this agent, Masarova said, there will hopefully be improved outcomes in patients while avoiding treatment resistance.

CPI-0610 is currently being studied in a phase 2 clinical trial called MANIFEST (NCT02158858) in patients with myelofibrosis, the initial results of which were presented at EHA 2020.²,³ Masarova spoke about 2 out of the 3 arms of the trial: the combination of CPI-0610 and ruxolitinib in patients who responded suboptimally to ruxolitinib alone and in patients receiving the combination as frontline therapy.

Patients who responded suboptimally to ruxolitinib (Arm 2) were divided into cohort 2A and 2B, which were based on transfusion dependency. The primary end points were spleen volume reduction (SVR) and packed red blood cell independency. Patients receiving frontline therapy (Arm 3) had anemia and their primary end point was SVR by 24 weeks.

“Overall, the combination has been well tolerated in suboptimal responders as well as in the frontline approach,” Masarova said in her presentation.

Arm 2 enrolled 70 patients, 44 in cohort 2A and 26 in cohort 2B, and treatment is ongoing in 44 patients. The median duration of ruxolitinib was 28 weeks and 76% of patients had treatment with ruxolitinib for 6 or more months. There were 74% of patients with a hemoglobin of less than 10 g/dL.²

Patients in this arm had a discontinuation rate of 37%; 10% was due to treatment-emergent adverse events (AEs) and 10% was because of myelofibrosis preimplantation genetic diagnosis (PGD). Grade 3 or higher AEs included thrombocytopenia at 24.4%, anemia at 8.5%, gastrointestinal toxicity at 8.4%, fatigue at 5.7%, and respiratory tract infection at 4.3%.

“Up to 35% of patients were able to convert from transfusion dependence into transfusion independence, and best SVR by 35% or more has been achieved in about 20% of all patients in both [cohorts] regardless of transfusion dependency at the enrollment,” Masarova said. There were improvements in total symptom score (TSS) of 50% observed in 46.2% for patients in cohort 2A and 36.8% in cohort 2B.

In Arm 3, there were 64 patients enrolled, 30 of which were evaluated for the first end point in April 2020. There are 57 patients still receiving therapy. The median duration of treatment with ruxolitinib was 24 weeks. Prior to week 24, the median dose of ruxolitinib was 10 mg twice a day and the median dose of CPI-0610 was 125 mg daily. There were 64% of patients with a hemoglobin of less than 10 g/dL.³

This arm had an 11% discontinuation rate, 6% of which were due to treatment-emergent AEs and 0% were for myelofibrosis PGD. Grade 3 or higher AEs consisted of anemia at 17%, thrombocytopenia at 4.7%, and respiratory tract infection at 4.7%.

An SVR of 35% was achieved in 63.3% of patients at 24 weeks in Arm 3, with a median SVR of 52.9%, and TSS improvement of 50% at 24 weeks was achieved in 58.6%, with a median of 64%.

“These results are definitely superior to single-agent ruxolitinib in the approval cohort studies.”

Azacitidine

Azacitadine has also been investigated in a phase 2 study (NCT01787487) with ruxolitinib, with updates presented at ASH 2019.⁴ Sixty patients with previously untreated myelofibrosis were enrolled and 18 are still receiving treatment. Thus far, there have been a median of 47 cycles of therapy administered and a median follow-up of 35 months as of November 2019. The median duration of ruxolitinib was 28 months.

The overall response rate per the 2013 International Working Group-Myeloproliferative Neoplasms Research and Treatment criteria was 75%. Seventy-four percent of patients had more than 50% reduction in palpable spleen at any time and 63% had more than 50% reduction as of week 24. After azacitidine was given for a median of 3 months, there were responses in 26% and the median duration of response had not yet been reached.

For bone marrow morphology, there was an improvement of over 50% at any time in the study. This improvement was sustained in all but 1 patient over a 28-month period.

Patients in this trial had new grade 3 or higher AEs of thrombocytopenia at 22%, neutropenia at 18%, and anemia at 17%. There was 1 non-hematologic AE of grade 3 or higher of infections at 8%.

Navitoclax

In another phase 2 trial presented at EHA, navitoclax was looked it in combination with ruxolitinib in patients with relapsed/refractory myelofibrosis.⁵ This drug causes cell death by apoptosis through binding to BCL-xL, BCL-2, and BCL-W. The investigators thought that it had the potential to halt the growth of fibrosis.

“By using a BCL-xL and BCL-2 inhibitor with ruxolitinib, we can possibly achieve enhanced efficacy and overcome ruxolitinib resistance,” Masarova explained.

Patients with chronic myelofibrosis who were taking ruxolitinib for 12 weeks or more and were on a stable dose for 8 weeks or more, who had palpable splenomegaly of over 5 cm below costal margins, were included on the trial. The primary end point was SVR percentage change at 24 weeks. Patients received doses ranging from 50 mg daily up to 300 mg daily to find the maximum tolerated dose of navitoclax.

Of the 36 patients enrolled, 34 were evaluable as of February 2020. The median duration of ruxolitinib was about 15.5 months. There were 70.6% of patients who were able to receive the maximum dose of navitoclax, and the median dosage of ruxolitinib and navitoclax was 20 mg daily and 176 mg daily, respectively. A reduction in the dose of navitoclax was required in 82.4% of patients; this was mainly due to thrombocytopenia in 58.8% of patients.

Forty-one percent of patients went off navitoclax entirely, 8.8% because of AEs and 11.8% because of myelofibrosis PGD. The most common grade 3 or higher treatment-emergent AEs were thrombocytopenia at 53%, anemia at 32%, and diarrhea at 6%. Masarova said the thrombocytopenia was manageable with dose reduction.

At week 24, an SVR of 35% was achieved in 26.5% of patients with a median of 26.6% reduction overall. A TSS improvement of 50% was achieved in 30% of patients, and there was a median change from 13.7% to 6.2% at 24 weeks.

Parsaclisib

The phase 2 study for parsaclisib, a novel potent, highly selective PI3K-δ inhibitor, studied patients with relapsed/refractory myelofibrosis with platelet counts of 50 or more. These patients had suboptimal response to ruxolitinib after receiving it for 6 months or more and receiving a stable dose for 8 weeks or more prior to enrollment. Patients also had palpable spleen volume of over 10 cm or 5 to 10 cm with myeloproliferative neoplasm symptoms. The primary end point was SVR at 12 weeks.⁶

Patients were treated in either a daily/weekly schedule with 10 or 20 mg of parsaclisib every day for 8 weeks and then the same dose every week after, or an all-daily schedule of 5 or 20 mg of parsaclisib every day for 8 weeks and 5 mg every day after.

As presented at EHA 2020, 53 patients enrolled on the study had a median duration of ruxolitinib of 28 weeks. Ruxolitinib duration prior to enrollment was a median of 18 months. There were 47 patients evaluable for SVR and TSS at 12 weeks.

The discontinuation rate was 38%, 11% due to treatment-emergent AEs and 21% due to myelofibrosis PGD. AEs led to discontinuation in 54% of patients who received the daily/weekly dosing schedule and 5% in the all-daily dosing schedule. The most common grade 3 or higher treatment-emergent AEs were thrombocytopenia at 30% and diarrhea, nausea, fatigue, fall, back pain, and dyspnea all at 3%.

By week 12, 24% of patients who received all-daily dosing had SVR of 25% versus 3% of patients on daily/weekly dosing. A median of almost 40% of patients achieved reduction in TSS by 12 weeks on daily dosing and 14% on daily/weekly dosing.

“In conclusion, the combination of targeted agents and ruxolitinib [is] a very exciting topic these days. [They] possibly improve efficacy of single-agent and reduce or overcome resistance that could come from single-agent ruxolitinib,” Masarova said.

_References:

_{1. Masarova L. Targeted therapies in combination with JAK inhibitor. Slides presented at: Texas Virtual MPN Workshop; August 27-28, 2020.}

_{2. Verstovsek S, Mascarenhas J, Kremyanskaya M, et al. CPI-0610, bromodomain and extraterminal domain protein (BET) inhibitor, as 'add-on' to ruxolitinib (RUX), in advanced myelofibrosis patients with suboptimal response: update of MANIFEST phase 2 study. Presented at: 2020 EHA Virtual Congress; June 11-21, 2020. Abstract EP1083.}

_{3. Mascarenhas J, Harrison C, Patriarca A, et al. CPI-0610, bromodomain and extraterminal domain protein (BET) inhibitor, in combination with ruxolitinib, in jak inhibitor treatment naïve myelofibrosis patients: update of MANIFEST phase 2 study. Presented at: 2020 EHA Virtual Congress; June 11-21, 2020. Abstract EP1084.}

_{4. Masarova L, Verstovsek S, Bose P, et al. Phase 2 study of ruxolitinib (RUX) in combination with 5-azacitidine (AZA) in patients (pts) with myelofibrosis. Blood. 2019;134(suppl 1):1656. doi:10.1182/blood-2019-130691}

_{5. Harrison C, Garcia JS, Mesa R, et al. Navitoclax in combination with ruxolitinib in patients with primary or secondary myelofibrosis: a phase 2 study. Presented at: 2020 EHA Virtual Congress; June 11-21, 2020. Abstract EP1081.}

_{6. Yacoub A, Wang ES, Rampal RK, et al. Addition of parsaclisib, a pi3kdelta inhibitor, in patients (PTS) with suboptimal response to ruxolitinib (RUX): a phase 2 study in pts with myelofibrosis (MF). Presented at: 2020 EHA Virtual Congress; June 11-21, 2020. Abstract S216.}