Transplantation for MPNs and CML: Who and When?

Bart Scott, MD

With a number of effective targeted therapies now available for patients with myeloproliferative neoplasms and chronic myeloid leukemia (CML), patient selection for transplantation should rely heavily on prognostic scoring, according to Bart Scott, MD. “It’s important to balance transplant’s curative potential with toxicity concerns and the disease’s natural progression,” he said during a "How I Treat" session at the second annual ASH Meeting on Hematologic Malignancies.

Scott, an assistant professor at the Fred Hutchinson Cancer Research Center in Seattle, focused on myelofibrosis (MF) first, noting that the optimal timing of hematopoietic cell transplantation (HCT) in MF is when the patient is considered to be at intermediate (Int-2) or high risk by the DIPSS scale.

Scott has found busulfan (Bu)-based pretransplant conditioning regimen to be the ideal. “Our typical four-day regimen is generally well-tolerated,” he said, adding that the Fred Hutchinson protocol has begun to shift toward giving Bu before cyclophosphamide. “But we are always improving.”

In considering the impact of molecular drivers, those with wild-type CALR mutations do better, regardless of HCT, Scott noted. Regarding the impact of a JAK2V617F mutation, some data suggest that patients with mutations do better than those with wild-type disease. “But these patients might also be affected by earlier diagnosis and interventions,” he said.

The FDA approved the JAK2 inhibitor ruxolitinib (Jakafi) in November 2011 as a treatment for patients with intermediate and high-risk MF, including primary MF, post-polycythemia vera MF, and post-essential thrombocythemia MF. The approval was based on findings from 2 randomized trials in patients with intermediate or high risk MF. In the first study, ruxolitinib was superior to placebo and in the second the drug beat best available therapy. In both studies, ruxolitinib showed superior spleen volime reduction of ≥35%.

JAK2 inhibitors could have an impact on the MF treatment pathway, Scott explained. There is a reduction in splenomegaly, increased weight and performance status, and a potential survival improvement seen with JAK2 inhibition. However, patients may defer transplant longer, due to these benefits, which could lead to complications down the road. Additionally, questions still remain regarding an optimal withdrawal strategy for ruxolitinib prior to transplant.

Scott also addressed the issue of whether patients should undergo splenectomy, calling it “controversial.” He noted the existence of both pros and cons in considering splenectomy. Possible benefits include a slightly improved engraftment, improved nutritional status, and improved quality of life. Possible reasons not to do it include the surgical risk—“the patient may not make it to transplant,” he noted—as well as recovery time that delays transplant and the fact that the spleen will shrink after transplant, anyway.

“It’s hard to know the best course because the degree of splenomegaly is probably related to the severity of the underlying disease,” he said. “We just need more data.”

Scott then turned his attention to HCT in CML, reviewing the World Health Organization’s definition of the phases of CML as chronic stable, accelerated, and blast crisis. Transplant has slowly been utilized less in this setting, he noted. In some cases, HCT is still appropriate, specifically for patients in the chronic stable phase who are intolerant to all TKIs, have failed two TKIs, or if they have a T315I alteration and ponatinib is not an option.

Patients in the accelerated phase should move to transplant if they experience TKI failure. Patients in blast crisis should be transplanted after completing a TKI-containing regimen, Scott said.

Despite what Scott referred to as the “demise of the allogeneic transplant in CML due to FDA approval of imatinib,” the most appropriate type of transplant is still a matter of discussion. He still prefers allogeneic transplant in unrelated donor patients until about 55 years of age; apart from this rather select group, his preference is to perform ablative transplant on those patients who can tolerate it. For older, sicker patients in the chronic phase, non-myeloablative transplantation is his preference.

As to transplant timing, Scott suggests a 3-month trial of salvage treatment first for patients in the chronic phase before proceeding to transplant. His preference is to transplant patients in the accelerated or blast crisis phases as soon as a donor becomes available.