Adding Navitoclax to Ruxolitinib Shows Potential in JAK-Resistant Myelofibrosis

Naveen Pemmaraju, MD

A phase 2 clinical trial (NCT03222609) demonstrated encouraging results with the addition of navitoclax to the JAK inhibitor ruxolitinib (Jakafi) in patients with myelofibrosis (MF) who were no longer receiving benefit from prior ruxolitinib. This add-back strategy induced clinically meaningful improvements in spleen volume and total symptom score, which were independent of high-molecular-risk mutations or high numbers of total gene mutations at baseline.

Preclinical studies demonstrated that dual inhibition of Bcl-1/Bcl-xL and JAK2 could enhance malignant cell death compared with JAK2 inhibition alone, and this combination is thought to overcome acquired resistance to single-agent JAK inhibitor therapy. This study aimed to explore the clinical responses of navitoclax plus ruxolitinib in this patient population.

These findings were presented during the 2020 American Society of Hematology (ASH) Annual Meeting, which explored the results of 34 patients who had been enrolled and received at least 1 dose of the combination regimen as of the data cutoff date. The single-arm open-label study included patients with either primary or secondary MF with splenomegaly who either failed ruxolitinib or had a suboptimal response after 12 weeks of continuous treatment.

In an interview with Targeted Oncology, Naveen Pemmaraju, MD, associate professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discussed the potential role of an add-back strategy as treatment of patients with MF who no longer benefited from prior ruxolitinib.

TARGETED ONCOLOGY: What is the prognosis like for patients with MF, and what options are available after these patients fail ruxolitinib?

Pemmaraju: Patients with MF are experiencing a very new era [of treatments]. Previously we thought of MF as exclusively a chronic disease, but what we're finding out now is patients who failed the only frontline available targeted class, the JAK inhibitors, some of these patients experience very poor outcomes, including overall survival. There have been several studies that have come out from the United States and now Europe that survival among a lot of these patients with MF may be 2 years or less if they experienced clonal evolution after frontline JAK inhibitor ruxolitinib. I think it reminds us that relapsed/refractory MF can be, in fact, a life-threatening condition and a little bit more of an acute than a chronic situation. To frame 2020 as we head into 2021, patients with MF after ruxolitinib or fedratinib, the 2 JAK inhibitors approved, there are no standard approved therapies, so there's no standard approach. The 3 approaches outside of stem cell transplant have been either to change up the JAK inhibitor, to add in or add back a second agent, or change it up completely and go to a novel agent. I think this is the framework for patients with MF after frontline JAK inhibitor failure or suboptimal response.

TARGETED ONCOLOGY: What was the rationale for the addition of the navitoclax to ruxolitinib for this study?

Pemmaraju: In the background of ruxolitinib failure or suboptimal response, as I mentioned, there are several strategies that 1 can follow. One that's emerging over the last few years is that add on or add back strategy. In this strategy, the concept or hypothesis is to keep the JAK inhibitor on and add in the second agent after a certain period of time to see if there's additive synergistic, combinatorically effect. Several of these strategies are ongoing with bromodomain inhibitors, PI3k inhibitors, hypomethylating agents, and now with Bcl-xL with navitoclax. That's the study that I presented at ASH.

The rationale and background are interesting. It turns out that possibly in MPNs and MF, this pathway of Bcl-xL may be upregulated or overexpressed, and that may be a bit different from some of the other myeloid malignancies where Bcl-2 plays a more prominent role. Everyone is familiar with Bcl-2 with venetoclax (Venclexta), but there is a drug not FDA-approved, known as navitoclax, which targets primarily Bcl-xL. The concept, at least preclinically in the lab, is that if you can administer navitoclax, either alone or in combination with the JAK inhibitor, this may serve to overcome JAK resistance and may work well with the JAK inhibitor to lead to clinical benefit in patients, so that's the preclinical rationale for this study.

TARGETED ONCOLOGY: How do high-risk molecular mutations factor into the study before we get into the results?

Pemmaraju: What we're learning from several of the groups that are putting together these scoring systems is that outside of the big 3, which is JAK2, CALR, and MPL, which essentially make up close to 90% or more of the mutations seen in the MPN. There are what's called additional or non-driver major molecular mutations, and some of these have prognostic significance. Some of them include more familiar ones, such as ASXL1, but some of them also include some of these unclear mutations. In the setting of high-risk molecular mutations, a lot of the new scoring systems, for example, the MIPSS70, which has just come out recently, will include several of these, so ASXL1, IDH1/2, EZH2, and SRSF2. Several of these mutations are considered high risk, and so those can be plugged into scoring systems or in the clinic, in terms of clinical terms, they may predict for someone who has a higher chance of transformation to leukemia or a less positive outcome.

TARGETED ONCOLOGY: What were the results that were presented during the 2020 ASH Annual Meeting?

Pemmaraju: At ASH, I was able to be the leading presenter for our group that was looking at this ongoing phase 2 study of ruxolitinib plus navitoclax in patients who have had a suboptimal response to ruxolitinib alone in MF, and so just over 30 patients have been treated. This abstract focused on some novel findings, which are really in the setting of high-risk molecular mutations and cytokine profiling that was built from the beginning.

I think in terms of high-risk molecular mutations, it was notable that more than just over half the patients actually had not only high-risk mutations but also had 2 or more of these mutations, and still, the addition of the navitoclax, by and large, yielded clinical benefit for the majority of these patients. That's very nice to know that even in the presence of high-risk mutations, the combination trial is still working to give clinical benefit.

The second finding is that of cytokines. It's been known that MF has an upregulation of these cytokines, and so we showed that several of the cytokines that were expected from before were elevated, but I think also the new interesting data are that there were a couple of new cytokines that we found that were upregulated in the setting of MF and may be modulated by the combination. I think these new cytokines need to be further investigated, not only on this ongoing study, so it'll be important to see what the significance is because those have not been known, and to also ask other groups around the world to look into their datasets, their studies, and trials to see if they're finding the same thing. The implication would be, can you develop a new broader cytokine panel to build into these studies to see if it correlates with symptom burden, with spleen size reduction, and potentially even other outcomes later on? I think this is an exciting emerging clinical translational correlative work that still needs validation as we move forward.

TARGETED ONCOLOGY: Are there any plans to further that research?

Pemmaraju: In terms of future directions, there are actually several that kind of stick out to me in 2021 as we move into this new year. One is while this add back strategy is promising and encouraging, it's still very new. I think the important thing to look out for is toxicities and side effects. With all of these newer agents, there's a potential for thrombocytopenia, so lowering of the platelet counts, which can already happen with the JAK inhibitor. We know about these. We need to monitor doses, regimens, platelet levels, and these are built into these protocols, so monitoring for older and new toxicities, I think, is number 1.

Second is how do we measure success in the post-JAK inhibitor frontline setting? In the frontline setting for JAK inhibitors, we look at things such as spleen and symptom burden. I think these are very important, but as we move into this second-line and beyond setting, I would advocate that we need to consider not only those important factors, but maybe other factors such as progression-free survival, event-free survival, even overall survival because again, as I mentioned earlier, some of these patients have a bit more of an acute course rather than a chronic core, so maybe a course that might be measured in only years rather than decades for many of our patients.

I think a third factor is the scientific understanding of MF itself. As I mentioned, this cytokine [finding], which has been known for a decade or longer, but what are the exact cytokines that are upregulated or downregulated, with the various newer therapies with and without JAK inhibitors? Then to continue the search for novel biomarkers, new clinical translational lab correlates that we can build into studies or find retrospectively. That can give us more clues for a patient's benefit to these newer drugs. I think these are kind of the exciting directions that I see for 2021 in our field.