Novel Targets Outside of JAK Inhibition Inching into Myelofibrosis Treatment Landscape

August 31, 2020

Experts in myeloproliferative neoplasms find janus kinase inhibitors to be particularly important to the armamentarium for the treatment of myelofibrosis. With only 2 FDA-approved agents, fedratinib and ruxolitinib, and the inevitability that not all patients will derive benefit, and some will develop resistance, the option of moving beyond JAK inhibition is widely discussed.

Experts in myeloproliferative neoplasms find janus kinase (JAK) inhibitors to be particularly important to the armamentarium for the treatment of myelofibrosis (MF). With only 2 FDA-approved agents, fedratinib (Inrebic) and ruxolitinib (Jakafi), and the inevitability that not all patients will derive benefit, and some will develop resistance, the option of moving beyond JAK inhibition is widely discussed.

During a presentation at the 1st annual Texas Virtual MPN Workshop, Naveen Pemmaraju, MD, associate professor, Department of Leukemia, University of Texas MD Anderson Cancer Center discussed the novel therapies beyond JAK inhibitors that are making their way into the treatment landscape of MF.1

Currently, novel agents are showing promise in phase 3 clinical trials, include pacritinib (SB1518) in the phase 3 PACIFICA study (NCT03165734), momelitinib (formerly GS-0387) is being evaluated in the phase III MOMENTUM study (NCT04173494), and fedratinib, although approved in the frontline setting, is now being evaluated as second-line treatment.

Modern JAK Inhibition Combinations

Ruxolitinib remains the standard-of-care treatment for patients with MF, even with the emergence of novel therapies, Pemmaraju noted. To improve upon outcomes in the patient population, ruxolitinib is now being rechallenged in patients or combined with other drugs. One study for which data were published in a 2018 issue of Blood, explored the addition of ruxolitinib to the chemotherapy agent azacitidineazacitidine (Vidaza).

The phase 2 study of ruxolitinib plus azacitidineazacitidine included 44 patients with MF whose median age was 66 years (range, 48-87 years). At baseline, 36 patients (82%) had intermediate-2 (int-2)/high IPSS score, 29 patients (66%) had splenomegaly, and 24 patients (55%) were positive for a JAK V61F mutation.

Thirty-nine patients were evaluable for response. The median follow-up time was 20.4 months (range, 0.5-3.7). The results showed objective response in 33 patients (72%) which included 2 partial responses and clinical improvement in 31 patients. The median time to response was 1.8 months (range, 0.7-19 months). In addition, the combination of ruxolitinib and azacitidine led to spleen response in 21 (61%) of the 34 patients who had splenomegaly > 5cm. In 3 other patients whose splenomegaly was 5 to 10 cm at baseline, there was a 50% reduction in spleen size following treatment with the ruxolitinib combination.

Another phase 2 clinical trial evaluated treatment with ruxolitinib plus navitoclax in patients with JAK2-resistant MF (NCT03373877). The combination demonstrated clinical activity in these patients, according to findings presented at the 2019 American Society of Hematology Annual Meeting. In 30% of the study population, there was a spleen volume response of greater than 35%. In addition, there was a 65% reduction in symptoms and 35% of patients had a reduction in total symptom score (TTS) of more than 50%.

Pemmeraju also noted an ongoing phase 1b study of ruxolitinib plus PU-H71 in patients with MF and polycythemia vera (PV, NCT03373877). In addition, the add-on strategy is being explored with lenalidomide (Revlimid), thalidomide (Thalomid), pracinostat, CPI-0610, sotatercept (ACE-011) plus luspatercept (Reblozyl), as well as in combination with a PI3k (phosphoinositide 3-kinase) inhibitors and interferon inhibitors.

Possible Modern JAK Inhibition Strategies

Targeting JAK is no longer the only strategy available for MF in 2020, Pemmaraju explained. Research has shown that there are possibilities for targeting apoptosis and cell death pathways, telomerase, hematopoietic stem cell, and microenvironments, the TP53 pathway, and targeting fibrosis, cytokines, epigenetics, and other pathways.

In relation to targeting apoptosis and cell death pathways, the phase 2 study of single-agent LCL-161 (NCT02098161) investigated 50 patients with primarily relapsed/refractory MF. A phase 2 open-label study of navitoclax alone or in combination with ruxolitinib (NCT03222609) is also testing out this strategy. The telomerase inhibitor, imtelestat, was also studied in this patient population in phase 2 study (NCT02426086).

There are 2 ongoing trials (NCT02268253 and NCT03373877) investigating the targeting of hematopoietic stem cell/microenvironment. One study is also assessing the targeting of the TP53 pathway in patients with MPNs as well as post-MPN acute myeloid leukemia (AML). Other trials that Pemmaraju mentioned that are investigating fibrosis, cytokines, epigenetics, and other pathways as targets include the phase 2 study of pentraxin (PRM-151, NCT01981850), as well as the studies of sotatercept/luspatercept, alisertib (MLN8237), CPI-0610, and PSD1 inhibition.

Promise of MF Treatment Beyond JAK Inhibition

Multiple treatment strategies have shown positive results in clinical trials as treatment of patients with high-risk MF, Pemmaraju shared. First, he shared results of the phase 1/2 trial of a novel CD123-directed therapy, which was designed to address the CD123 expression seen in many myeloid malignancies, including MF.

Tagraxofusp

In the phase 1/2 trial of tagraxofusp, 32 patients were included in the safety analysis for the study, and more than 10% experienced treatment-related adverse events (TRAEs). The most common TRAEs of any grade were hypoalbuminemia (25%), headache (16%), alanine aminotransferase increased (16%), anemia (14%), and thrombocytopenia (14%).

At baseline, 18 patients had splenomegaly ≥ 5 cm, and of those patients, 10 (56%) had spleen reductions. Additionally, 2 patients had spleen reductions of greater than 50%. Among patients with thrombocytopenia and platelet counts <100 × 109/L 8 patients (62%) had spleen size reduction as did 4 patients (57%) with thrombocytopenia and platelets < 50 × 109/L. Subjects with monocytosis whose monocytes were ≥ 1 × 109/L. In addition, 46% of the 24 patients evaluated to efficacy had a reduction in their TTS.

In terms of survival, the median OS observed was 30.5 months at a median follow-up time of 27 months (range, 0.6-50.3 months).

According to Pemmaraju, the subsets of patients with MF who had thrombocytopenia, monocytosis, or accelerated phase disease are areas of ongoing research.

LCL161

LCL161 was the second agent Pemmaraju noted as a potential new treatment for high-risk MF. The agent was assessed in a phase 2 clinical trial which was launched to address the unfavorable survival outcomes in the patient population. In addition, no JAK inhibitors are approved by the FDA as treatment of this particular group of patients with MF.

In 50 patients, the objective response rate was 30%, leading clinical improvements in 11 patients with symptoms, 6 patients with anemia, and 1 pain with splenomegaly. Additionally, 1 patient achieved a cytogenetic remission.

The survival data show that 34 patients (68%) were still alive at data cutoff. The median duration of response was 1.4 months (95% CI, 0.9-9.1 months). There was also a number of longer-term responses (n = 8) who experienced a response for 1 year or more. At data cutoff, long-term responses were ongoing in 4 patients. The median OS was not reached in the study.

Based on these data, Pemmaraju stated that LCL161 may be a viable option for older patients, those who failed prior JAK inhibitors, and those with thrombocytopenia that limit entry into clinical trials.

Luspatercept

Data presented previously at the 2018 American Society of Hematology (ASH) Annual Meeting showed that a phase 2 study of luspatercept was positive for its primary and secondary end points of transfusion independence.1,2

In a cohort of 22 patients who were not receiving ruxolitinib and had no red blood cell transfusion for 12 consecutive weeks, 14% achieved the primary end point and 18% achieved the secondary end point. In a separate cohort of 21 patients who were not receiving ruxolitinib and had been transfusion dependent for 12 consecutive weeks, 10% were positive for the primary end point and 38% were positive for the secondary end point. In the cohort of 14 patients who were receiving a stable dose of ruxolitinib and were transfusion independent of 12 consecutive weeks, 21% reached the primary end point and 64% achieved the secondary end point. Finally, in the cohort of 19 patients who received a stable dose of ruxolitinib but were transfusion-dependent for 12 consecutive weeks, 32% achieved the primary end point and 53% achieved the secondary end point.

CPI-0610

Preliminary results for CPI-0610 were also presented at ASH in 2019. In the phase 2 study CPI-0610 was combined with ruxolitinib in treatment-naïve patients with MF.1,3

Compared with baseline measurements, an 80% SVR35 (spleen volume reduction) response was observed at week 12, demonstrating a median change from baseline of -49.7% (range, -80.8% to -17.0%). Responses were also observed in high-risk patients including 86.7% of those with DIPSS Dynamic Prognostic Scoring System (DIPPS) ≥int-2, 80% with hemoglobin < 10g/dL, and 53.3% of patients with high molecular risk (HMR) positivity.

In terms of total symptom score (TSS) improvement, it was observed that 71.4% of patients had a TSS response at week 12, and this included the treatment naïve population with an improvement of 45.9%.

Navitoclax

In another phase 2 study, navitoclax with or without ruxolitinib demonstrated promise in patients with primary of secondary MF. The drug specifically helped patients overcome resistance to ruxolitinib which resulted in splenomegaly improvement.1,4

Out of 30 patients assessed, SVR35 at week 24 was 43% in 13 patients and 30% in 9 patients. In addition, resolutions of palpable splenomegaly were observed in 53% of patients. Twenty-five percent of patients also demonstrated reductions in bone marrow fibrosis per local assessment.

Imetelstat

A randomized phase 2 study of imetelstat as treatment of patients with intermediate-2 or high-risk MF who were relapsed or refractory to JAK inhibition induced responses and a survival benefit.1,5

In a pool of 107 patients, 6 patients (10%) had ≥ 35% SVR at week 24 and 23 patients (37%) had a ≥ 10% SVR at week 24.

Imetelstat also achieved a median OS of 19.9 months (95% CI, 17.1-not evaluable [NE]) when administered at a dose of 4.7 mg.kg and the median OS climbed to 29.9 months (95% CI, 22.8-NE) when Imetelstat was administered at 9.4 mg/kg.

Pemmaraju noted that a review of the existing and ongoing research on targeting beyond JAK inhibition in patients with MF was recently published in Current Hematologic Malignancy Reports. The paper states that because of the different mechanisms of action other the novel therapies in MPNs, they can improve outcomes in the field when use alone or in combination with ruxolitinib.6

References:

1. Pemmaraju N, et al. Novel Targeted Therapies Beyond JAK Inhibitors. Presented at: Texas Virtual MPN Workshop; August 27–28, 2020; Virtual.

2. Gerds AT, Vannucchi AM, Passamonti F, et al. A Phase 2 Study of Luspatercept in Patients with Myelofibrosis-Associated Anemia. Blood. 2019;34(supplement_1):557. doi: 10.1182/blood-2019-122546

3. Mascarenhas J, Kremyanskaya M, Hoffman R, et al. MANIFEST, a Phase 2 Study of CPI-0610, a bromodomain and extraterminal domain inhibitor (beti), as monotherapy or "add-on" to ruxolitinib, in patients with refractory or intolerant advanced myelofibrosis. Blood. 2019; 134 (Supplement_1): 670. doi: /10.1182/blood-2019-127119

4. Harrison CN, Garcia JS, Mesa RS, et al. Results from a phase 2 study of navitoclax in combination with ruxolitinib in patients with primary or secondary myelofibrosis. Blood. 2019;134(supplement_1):671. doi: 10.1182/blood-2019-130158

5. Mascarenhas J, Komrokji RS, Cavo M, et al. Imetelstat is effective treatment for patients with intermediate-2 or high-risk myelofibrosis who have relapsed on or are refractory to janus kinase inhibitor therapy: results of a phase 2 randomized study of two dose levels. Blood. 2018;132(supplement_1):685. doi: 10.1182/blood-2018-99-115163

6. Economides, M.P., Verstovsek, S. & Pemmaraju, N. Novel therapies in myeloproliferative neoplasms (mpn): beyond jak inhibitors. Curr Hematol Malig Rep. 2019;14, 460–468. doi: 10.1007/s11899-019-00538-4