I’m a haematologist with special interest in myeloproliferative neoplasms, particularly myelofibrosis. Myelofibrosis is an advanced myeloproliferative neoplasm characterised by fibrosis in the marrow and extramedullary haematopoiesis with the massive splenomegaly. Patients with myelofibrosis do experience debilitating symptoms related to the disease itself and also due to massive splenomegaly.
The current standard of care for patients with myelofibrosis is treatment with drugs called JAK inhibitors. There are two agents that are currently approved for treatment of myelofibrosis that are JAK inhibitors – one is a drug called ruxolitinib and the other drug is called fedratinib. These agents are very effective in the treatment of myelofibrosis, they improve the quality of life, decrease the spleen size and also alleviate many of the symptoms associated with myelofibrosis. However, a number of patients have inadequate response to these drugs and also develop progressive increase in spleen size after an initial response. At present there are no approved agents for treatment of myelofibrosis and there are a number of investigational agents for patients that fail JAK inhibitors.
A few years ago our group at Huntsman Cancer Hospital, University of Utah, published a paper in Clinical Cancer Research that was actually my Fellowship research project. We did a library screen utilising a short hairpin RNA on an NPM cell line and we came across this protein called Ran as one of the top hits in our genetic screen. Ran is involved with another protein called XPO1 and together they are responsible for nucleocytoplasmic transport, transporting tumour suppressor proteins outside of the nucleus.
So when we found this gene we further investigated a pharmacological agent called selinexor which blocks this protein, XP01. Selinexor is an oral small molecule inhibitor of XP01 and has shown broad activity in a variety of cancers. It’s a drug that is currently approved in the United States for the treatment of multiple myeloma and also diffuse large B-cell lymphoma. We further did preclinical studies and found that JAK2 positive cell lines are very sensitive to inhibition by selinexor and we also showed that selinexor preferentially, or selectively I should say, decreased proliferation and increased the cell killing of cells derived from myelofibrosis patients compared to normal cord blood cells.
Based on this preclinical data we conducted a study to evaluate the safety and efficacy of selinexor in myelofibrosis patients that were either refractory or intolerant to JAK inhibitors. This was a single centre investigator-initiated study. We initially designed the study to enrol 24 patients. It’s a prospective open label single arm study and the patient population are patients with a diagnosis of either primary myelofibrosis or post-PV or post-ET myelofibrosis. All these patients should be either refractory or intolerant to JAK inhibitors. We defined refractoriness to JAK inhibitors as persistent splenomegaly and symptoms of myelofibrosis after at least three months of JAK inhibitor. Then we also defined intolerance to JAK inhibitors as any side effects that led to discontinuation of these drugs.
These patients were treated with oral selinexor at a dose of 60-80mg once a week as a starting dose. The drug was continued until progression. We evaluated response to oral once a week selinexor by utilising MRI scans to estimate the spleen volume.
The primary endpoint of this study is spleen volume response rate which is basically defined as ≥35% reduction in spleen volume from screening to week 24 MRI. We also collected some symptom scores to measure the total symptom burden of these patients and also obtained a bone marrow evaluation, both at screening and also at week 24 to see any changes in the bone marrow fibrosis grade.
We have treated twelve patients so far on this study, seven were men and five were women. The median age was 68 years and the median duration of prior JAK inhibitor therapy was 22 months which is quite long and does indicate that these patients have been prior treated with JAK inhibitors for an extended period of time. Eleven out of twelve patients were considered resistant to the prior JAK inhibitor therapy and many of these patients, I think eight out of twelve patients, had at least one high risk molecular mutation.
What we observed was that single agent oral weekly selinexor induced very impressive rates of spleen response in these patients that were previously refractory to JAK inhibitors. 30% of the patients had a spleen volume response rate of more than 35% at week 24 and 40% of the patients had a spleen volume response rate of more than 35% at any time during the study. 60% of the patients had at least 25% reduction in spleen volume on the study.
The other interesting finding is that we also observed improvement in anaemia in some of these patients. For example, four out of eight patients who had haemoglobin of less than 10g at screening had an improvement in haemoglobin. More interestingly, of two patients who had transfusion dependent anaemia one patient became transfusion independent and remained without requiring transfusions for almost two years on selinexor. So these were very impressive findings, particularly that, outside of the JAK inhibitors, a single agent demonstrating responses both in terms of spleen and also in terms of improvement in haemoglobin.
The other key finding, I would say, is that we have observed a reduction in the white blood cell count and LDH, which reflect the underlying myeloproliferative activity, very quickly after starting selinexor. These two parameters remained under control during the whole time on selinexor treatment.
In terms of the side effects, we did observe weight loss as the most common side effect. The majority of the patients were able to tolerate with dose adjustment and the weight loss was manageable. However, one patient had to stop the treatment because of the weight loss. We also observed fatigue and dizziness in some of the patients. Ten patients of the twelve required a dose reduction because of the side effects but in terms of the side effects leading to discontinuation of the drug we had three patients who stopped the drug because of side effects, one due to fatigue and two due to weight loss.
Overall the patients remained on selinexor for a good period of time. The median treatment duration of selinexor in these patients was 11 months and there were three patients who were able to continue the drug beyond 18 months. So this indicates that despite some of these side effects that patients were able to stay on the treatment for an extended period of time. More importantly, these side effects, particularly fatigue and nausea and dizziness, improved over time on treatment. We haven’t really observed any serious organ-related side effects on treatment.
The other interesting finding is that we examined paired bone marrow samples at screening and at week 24 in ten patients. We didn’t see any change in the grade of reticulin fibrosis, however, we had one patient who had a bone marrow evaluation done at week 22, which is almost one and a half years after starting treatment with selinexor. In this patient we observed a reduction in the grade of reticulin fibrosis from grade 3 to grade 1 so this does indicate that the selinexor has a potential disease modification effect on myelofibrosis and perhaps we need an extended treatment duration to observe these changes in the bone marrow. So we are planning to collect additional bone marrow evaluations from some of the patients who are still on selinexor beyond 18 months.
In myelofibrosis after failure of JAK inhibitors there is a huge unmet need. We have a number of agents that are currently in development and some of those are, for example, navitoclax, which is a BCL-2 inhibitor, has some promising data. There is another drug called [??] that also has promising data. But I strongly believe that selinexor has shown a single agent activity outside of the JAK inhibitor class of drugs. We are trying to determine the right population that would benefit from selinexor, either up front or after failure of JAK inhibitors. So there are two multicentre, multinational studies, registration studies, are currently ongoing, we are also participating in those studies. One of the studies is looking into combining selinexor with ruxolitinib in newly diagnosed patients that are not previously treated with JAK inhibitors. We are also doing another study in patients who are previously treated with JAK inhibitors and were either refractory or intolerant and get randomised data on selinexor versus physician’s choice.
These studies hopefully will accrue patients faster and we can determine the efficacy of selinexor in a randomised fashion in both JAK2 refractory and also a JAK2 naïve setting in combination with JAK inhibitors.
Myelofibrosis has been a difficult disease. The only cure at present is an allogeneic stem cell transplant but many patients don’t qualify for a transplant, either due to age or comorbidities. But also there are a number of long-term complications of allotransplant, particularly chronic graft versus host disease. So it’s really important to find effective treatments for patients with myelofibrosis that can add to the drugs that we already have for these patients. My hope is that we will find effective treatments that could potentially transform the landscape of myelofibrosis treatment and make this disease into more a chronic illness, even if it’s not curable, with improved quality of life and also an extended survival for these patients.
