Curative Therapies Still Needed for First and Second Line Treatment of MPNs

Srdan Verstovsek, MD, PhD

Srdan Verstovsek, MD, PhD

JAK inhibition for the treatment myeloproliferative neoplasms (MPNs), in the frontline setting for myelofibrosis (MF) and in the second-line setting for polycythemia vera (PV), may remain standard treatments despite the emergence of new agents, said Srdan Verstovsek, MD, PhD. This is because although the approved therapies are active in these patient populations, they are not curative.

The COMFORT 1 and 2 trials showed that ruxolitinib (Jakafi), the approved frontline treatment for MF, prolonged survival and resulted in a decrease in cytokine levels, which improved disease-related symptoms. The overall reduction in the risk of death was 33% (HR, 0.67;P= .06). However, ruxolitinib did not help with bone marrow fibrosis.

In the phase III RESPONSE and RESPONSE-2 trials, treating patients with PV with ruxolitinib after stem cell transplant significantly controlled symptoms and reduced spleen volume. Since the trial, having ruxolitinib in the second-line setting has also improved quality of life, hematocrit, white blood cells, platelet count, and the occurrence of thromboembolic events in patients with PV.

Therecent approval of fedratinib(Inrebic) offers another option for the treatment of MF. The data show that fedratinib is just as active as ruxolitinib in patients with MF. Verstovsek, an expert in the space, believes that more clinical trials should be run to address the neurological and gastrointestinal toxicities associated with the drug. Oncologists will also have to learn to balance toxicity and safety with JAK inhibition, as these profiles differ depending on the drug.

In addition to managing toxicity and safety, Verstovsek recommended that community oncologists pay as much attention to the duration of response and quality of life as they do to the response itself. Knowing how long the benefit will last can help physicians prescribe the appropriate dose and achieve the best outcome for the patient.

To date, even with the availability of ruxolitinib and newly approved fedratinib, stem cell transplant is the only curative therapy for MF, and the development of new curative therapies is encouraged.

In an interview withTargeted Oncology, Verstovsek, medical oncologist, and professor, Department of Leukemia, The University of Texas MD Anderson Cancer Center, discussed the treatment of MPNs in the community setting and how the field can improve. He also encouraged community oncologist to incorporate quality-of-life measurements and prognostic scoring systems when treating these patients.

TARGETED ONCOLOGY: What was your overall discussion on MF and PV during your presentation at SOHO?

Verstovsek:PV and MF are 2 different types of MPNs. In PV, we do not worry about survival and we treat people for thrombotic risk. We decrease it in a selective group of patients by utilizing cytoreductive therapy called hydroxyurea (Hydrea). The majority of people with PV require hydroxyurea to control high red blood cells count, platelets, and white blood cells. If that does not work, then ruxolitinib, a JAK inhibitor, has been approved as a full-fledged therapy for the second-line treatment of PV.

The definitions of failure to hydroxyurea are critical for understanding when to interrupt the hydroxyurea and change [therapies]. The goals of therapy with hydroxyurea that are easiest to understand are to control red blood cells, white cells, platelets, symptoms and [spleen size]. Five factors need to be controlled.

Unfortunately, most of us are preoccupied with the blood cell count and not looking at the quality of life, which is also important for the patients. Hydroxyurea, for example, is not very good at controlling the quality of life. If you have a patient who is experiencing good control of their blood cell counts but having a bad quality of life, that is not satisfactory. That is one of the reasons why my presentation was on emphasizing the complexity of the benefit that we need to look for and identifying cases like I've been describing, where there is potential to switch to a medication that could help.

[In my view], uncontrolled red blood cell count, white cells, and platelets, progressive increased in spleen size, and, most importantly for me as a physician, uncontrolled quality of life would be good reasons to consider switching from hydroxyurea to ruxolitinib.

For MF, we know what ruxolitinib does. It's approved for the first-line treatment of MF as a therapy for 2 problems, which are enlarged symptomatic splenomegaly and bad quality of life. Ruxolitinib helps the majority of [these patients]. But, the recent information from multiple sources indicates that early intervention matters. We don’t need to wait for the spleen to be extraordinarily big or quality of life to be bad. Early intervention helps and not only for patients. It also affects the durability of life because with early intervention we can control the spleen much better. There is less myelosuppression when the patients are earlier on in the phase of life with MF, they have less anemia and thrombocytopenia, so one can prescribe a better dose of ruxolitinib, and affect the spleen much more. Spleen decrease is the most important factor for the durability of the benefit and life. So, early intervention is paramount.

TARGETED ONCOLOGY:How are you currently using ruxolitinib in light of the recent approval of fedratinib in patients with MF? Which agent do you use in what setting and why?

Verstovsek:We are fortunate to have a second medication approved for patients with MF, and that is another JAK inhibitor, fedratinib. It appears to be as active as ruxolitinib, although nobody has compared one to the other in a prospective randomized [trial]. But it seems to be as active as ruxolitinib in the 2 aspects where ruxolitinib does well, which is for spleen and symptoms. There are some differences in the toxicity profile. It seems that fedratinib has some issues with neurological and gastrointestinal toxicity, which can be controlled or monitored.

This is to say that in the frontline setting, when we have newly diagnosed patients with MF in need of therapy, with JAK inhibitors I do not anticipate the standard approach to change much. Ruxolitinib has been around since 2011, and I think that will remain as the frontline therapy. I see a good reason to utilize fedratinib in a subgroup of patients after ruxolitinib, particularly in those that are failing because of progressive increase in spleen and still have good red blood cells, platelets, and white cells. Fedratinib is good for spleen and symptoms, but it does cause a significant degree of myelosuppression, just as ruxolitinib does.

I see a role for fedratinib in the second-line setting in patients with big spleen and good bone marrow reserve.

TARGETED ONCOLOGY:What advice would you give to community oncologists regarding these 2 JAK inhibitors?

Verstovsek:The goal of therapy is to control the signs and symptoms of MF and that can be very well achieved, either with ruxolitinib or fedratinib, that is now approved and available to all of us in the community setting.

The primary goal is to balance between the toxicity and the safety. But one also needs to understand that the degree of spleen reduction, at least as much as we know from the use of ruxolitinib, is the determining factor of how long the benefit is going to last. To optimize the dose of either medication to the maximum safe dose at the beginning of treatment is the goal that is not always realized or appreciated because we see that people feel better and we are happy with that. But, optimizing the medication in the first 6 months, when most things happen, both good and bad, can have the maximum benefit on the spleen because there is a correlation between the dose and spleen response. For that happiness to last long and life to last long, we need to optimize the dose to get the spleen as small as possible. If there was one message that I would like to project for the utility of these medications, this would be the one.

TARGETED ONCOLOGY:Can you discuss your presentation on impact of molecular signature and prognostication in MPNs?

Verstovsek:The large part of our efforts in the development of new therapies for MF is understanding the prognosis. Although at the moment we have a limited number of medications to give, the prognosis of patients is still valuable to do. It relates to our ability to project who will have a shorter life expectancy of less than 5 years, in order to refer that patient to bone marrow transplant. Prognostication is intimately involved with our ability to perhaps cure patients with a more aggressive approach like a transplant.

In that regard, with the advent of genetic testing, we now understand that MF is a complex disease. It's not only dependent on JAK/STAT pathway activation, which is present in all of the patients. The results are dependent on multiple other genetic abnormalities aside from the driver mutations that activate the JAK/STAT pathway. Other mutations may have a role in any other cellular activities regardless of the JAK/STAT pathway. These additional mutations have prognostic significance. The advent of the combinations of genetic information, karyotypic information—which are abnormalities in chromosomes—and the standard blood cell count symptoms and age of the patients led to the evolution of our understanding of [a patient's] risk of death. With improvements in widespread testing, we can be better at referring patients to transplant.  

The other side of the coin is to understand whether these genetic complexities affect the utility of the medication itself. For JAK inhibitors, there may be an effect on how they perform in controlling symptoms or spleen size in patients with MF. That's why they are used. It seems that there is a correlation between the overall benefit and the genetic complexity in the person that is taking the pill.

The same pattern of genetic complexity influencing the outcome has been shown after the failure of frontline therapy with a JAK inhibitor. Once the patient fails, they have a good outcome, and we realized that the main reason for failing is clonal evolution. People are genetically different, and that seems to be the main cause of failure and progression, and that leads to an untimely death.

Prognostication at multiple levels is becoming important in everyday practice.

TARGETED ONCOLOGY:What do you want physicians to know about prognostication in MPNs?

Verstovsek:Prognostication is valuable for referring patients to transplant and trying to identify patients that have a shorter life expectancy. We should be aggressive in attempting to implement different prognostic scoring systems and referring the patient to transplant, yet, we do not do that.

The large effort to understand the common practice in the community setting led to the discovery that a large portion of the patients don't even have any kind of informative talk about their prognosis. They're just treated for whatever they suffer from, and nobody ever actually mentions the word prognosis. Even when the prognosis is tackled during discussions with patients in the community setting, many times the prognostic scoring systems that are readily available are not implemented. Many times, it's just about the physician’s impression of the outcome of the patient, based on his or her intuition. That is not the way to do medical care. You should be more careful and utilize what is readily available to us online. The National Comprehensive Cancer Network guidelines are, in large part, devoted to prognostication. Prognostic scoring systems are there for us all to use and use for everybody so that medically, we can do a better job.

TARGETED ONCOLOGY: What are your final thoughts about the availability of therapies in this field?

Verstovsek:The field of MF and MPNs, in general, is an active field where we realize that JAK inhibitors are not the ultimate answer to problems that [patients] experience in their lives when they live with these conditions. The JAK inhibitors can certainly control the signs and symptoms, but they do not cure anybody. Perhaps they can prolong life for a few years.

The field is active in identifying other abnormalities and other ways of controlling the malignancy and perhaps eliminating it [through] immune pathways, epigenetic control, antifibrotics, and transcriptions factors. It's a very active field, and I would encourage my colleagues in the field to refer patients for clinical studies, either at the time of diagnosis or later. Participation in clinical studies is the only way for us to develop new medications beyond JAK inhibitors.

Reference:

Guerra VA, Verstovsek S. Identification for and Management of Patients with PV and MF with Ruxolitinib.Clin Lymphoma Myeloma Leuk. 2019;19(suppl 1):S10-S11. doi: 10.1016/j.clml.2019.07.399.