ONCAlert | Upfront Therapy for mRCC
News  >  

Expert Addresses Challenges Associated With Allogeneic Transplant in Myelofibrosis

Danielle Ternyila
Published Online:8:55 PM, Tue March 24, 2020
Tania Jain, MBBS
Tania Jain, MBBS
The only curative treatment available for patients with myelofibrosis (MF) is allogeneic stem cell transplantation (SCT), despite more drugs becoming available in this disease setting. Physicians also continue to face a number of challenges in this setting.

While transplant may be the best option for cure in most patients with MF, the process is not perfect, says Tania Jain, MBBS. Patients may develop further morbidities when undergoing transplant, which is also associated with mortality. Graft-versus-host-disease is a known complication of allogeneic SCT as well.

The current standard frontline option for GVHD remains corticosteroids. Although many clinical trials are evaluating the potential for combination regimens, corticosteroids still remain most effective as monotherapy.

Ruxolitinib (Jakafi), a JAK2 inhibitor, has been approved by the FDA for the treatment of patients with acute GVHD who are steroid-refractory, based on results from the REACH1 and further validated in the REACH2 clinical trials. In REACH1, the phase II study, ruxolitinib induced a 57% objective response rate at day 28 in this patient population.

In an interview with Targeted Oncology, Jain, assistant professor at Johns Hopkins University, discussed the role of transplant as treatment of patients with MF and the challenges that remain in this space. She also spoke to the treatment options for patients with GVHD.

TARGETED ONCOLOGY: What is the role of SCT in MF, and in what patients is this an available treatment option?

JainMF, as we know, is a disorder of the bone marrow and for most of those, allogeneic SCT is the only potentially curative treatment. We now have more drugs in the MF space that can improve the symptoms and splenomegaly, and even cytopenias to some extent. However, none of them are curative options, and none of them change the natural history of MF, which is to transition into acute myeloid leukemia (AML). That is where the role of allogeneic SCT comes in.

Out of the patients that are seen in clinic, we consider most of them for an allogeneic SCT if they are eligible and if they have a high-risk disease. The indications for allogeneic SCT in general include patients with intermediate- to high-risk by the DIPPS Plus scoring system or if they are having a lot of issues with transfusion dependence and transfusion requirements.

As we are learning more and more about the rule of molecular mutations in prognosticating the disease process, that has come into role in terms of using the MIPSS70 or MIPSS70 version 2.0 of the scoring system. Those are some of the factors that we use to identify patients who would require SCT, and we use the usual screening for the patient for identifying their age, organ function, etc., to see if they are good candidates for SCT. Usually, about half of the patients are eligible.

TARGETED ONCOLOGY: How do these molecular mutations play a role in transplant?

JainWe know that some of the mutations, for example, AXL1, EZH2, SRSF2, and IDH1/2 have been shown to have a higher risk in patients with MF. That means they have a lower leukemia-free survival and lower OS. Those are the patients we tend to consider allogeneic SCT in sooner compared to others.

TARGETED ONCOLOGY: What challenges still remain in this space?

JainThe first challenge is the referral of patients to a transplant center. Just like in multiple myeloma and other malignancies, a lot of times these patients are not considered for an allogeneic SCT and are not referred to a transplant center for evaluation. The second challenge is that our transplant process, even though we do it with an intention to cure, is a far from perfect process. It has associated morbidities and associated mortality from the transplant itself, so that is a challenge.

Specifically, in MF, these patients have had a chronic malignancy for years before they go to transplant usually. Along the way, they develop comorbidities associated with MF, such as splenomegaly, decreased performance status, pulmonary hypertension, and other things. That makes them less optimal of a candidate going into transplant. Hence the results in them having inferior outcomes after transplant compared to some other malignancies.

There is a lot of work to be done in terms of trying to improve survival after allogeneic SCT in these patients because this is what we have to offer for cure for the time to come. Even with the drugs in the pipeline, I don’t think any at this time are offering anything curative to change the burden of the disease or the natural history of the disease.

TARGETED ONCOLOGY: What are the different options after a patient relapses following transplant?

JainThere are a few things we can do, and it depends on what type of relapse it is. For example, if you are seeing molecular relapse, so the JAK is positive again or another driver mutation, we have considered donor lymphocyte infusion, which is getting a lymphocyte product from the same donor again. That is associated with some responses, but it is also an increased risk of GVHD. That needs to be considered.

Other options are dependent upon the disease status at that time. Some people will come back as AML, and that would require more AML-directed therapies. You can always put patients back on a JAK inhibitor if you are trying to target splenomegaly and symptoms if that is what is bothering the patients.

Rarely, which I emphasize rarely, patients are considered for the second transplant if they are young and an appropriate candidate for something like that.

TARGETED ONCOLOGY: With the concern of GVHD, how do you manage this?

JainGVHD is a known and unique complication of an allogeneic SCT process. Acute GVHD can present as a skin rash or upper/lower gastrointestinal symptoms, or liver disease. It results from potential tissue injury that happens from the conditioning, resulting in an increase in the cytokine release and causes inflammation in these organs. The treatment is directed to improve that inflammation. The mainstay of treatment, or the first-line at this time, is primarily corticosteroids. Some studies have looked at adding something to steroids, but at this time we don’t have anything that does better in addition to steroids compared with steroids alone. The first-line has so far remained high-dose corticosteroids at a dose of 2 mg/kg or sometimes 1 mg/kg if it is just upper gastrointestinal involvement or skin involvement.

TARGETED ONCOLOGY: What has been your experience with ruxolitinib?

JainIn the second-line setting, we now have the approval of ruxolitinib, a JAK2 inhibitor when the JAK pathway is involved in the GVHD, and we have seen some success in patients who are steroid-refractory.

We have used ruxolitinib in some patients with steroid-refractory acute GVHD, grade 2 to 4 mostly. You see more responses in grade 2, as you would expect compared to patients with grade 3 and grade 4, and that is consistent with what the REACH1 data also showed and the REACH2 trial. We do see responses, but there is a concern for infections and cytopenias with ruxolitinib. That has to be kept in mind as you are treating patients.

Copyright © TargetedOnc 2020 Intellisphere, LLC. All Rights Reserved.