Evaluating the Hedgehog Inhibitor Glasdegib in Patients With Heavily Pretreated Myelofibrosis

In a phase Ib/II trial of patients with myelofibrosis whose disease did not respond to JAK inhibitors, treatment with the hedgehog inhibitor glasdegib did not significantly improve symptom burden or reduce spleen volume, according to study results presented by Aaron T. Gerds, MD, of the Cleveland Clinic Taussig Cancer Institute in Cleveland, Ohio, at the 2017 ASCO Annual Meeting.

However, the authors shared anecdotal evidence of patient-reported symptom improvement, suggesting that certain patient-reported outcomes may be more sensitive indicators of treatment benefit than the standard endpoints of spleen volume reduction (SVR) and total symptom score (TSS).

“Maybe we should rethink how we assess [treatment response] in heavily pretreated patients and possibly change the goal,” Dr. Gerds told ASH Clinical News. “Perhaps a 50 percent reduction in symptom burden is not meaningful for some patients – maybe all they need is a 20 percent reduction to be more functional and have better quality of life.”

Dr. Gerds presented interim results of the study at the 2017 ASCO Annual Meeting. At the time of the presentation, 21 patients (mean age = 69.3 years; range = 58-83 years) with primary/secondary myelofibrosis who had previously been treated with at least one JAK inhibitor (including ruxolitinib) were enrolled. Fifteen percent of patients had received two previous JAK inhibitors, and 52 percent were refractory to previous JAK inhibitor therapy.

Spleen volume and symptom burden (measured by TSS) were assessed at baseline; primary efficacy endpoints were the proportion of patients with ≥35 percent SVR and ≥50 percent reduction in TSS from baseline to week 24.

Patients received glasdegib 100 mg orally in 28-day cycles, and the median duration of treatment was 85 days (range = 22-343 days).

No patients achieved the primary endpoint of SVR; five patients did experience a mild decrease in spleen volume, but the greatest reduction was only 21.4 percent. No progressive disease was reported before day 71 of treatment.

At baseline, patients reported mostly mild symptoms, with four reporting severe symptoms (primarily severe fatigue). At week 24, only one patient met the efficacy endpoint for reduction in symptom burden. Notably, that patient had severe baseline symptoms. The authors also reported that three and four patients, respectively, achieved TSS reductions of 30 percent and 20 percent.

“Early on, the symptoms stayed the same, and they actually improved as the study went on,” Dr. Gerds noted, with patients reporting substantial improvements on certain TSS components, including spleen-related symptoms (52% reduction), inactivity (58% reduction), and fatigue (36% reduction). “But very few patients met the endpoint for symptom burden reduction.”

The most common adverse events (AEs; occurring in ≥20% of patients) were:

  • dysgeusia (n=13)
  • muscle spasm (n=12)
  • alopecia (n=8)
  • decreased appetite (n=7)
  • fatigue (n=7)
  • lipase increase (n=5)
  • weight decrease (n=5)

Except for one case of fatigue, no AEs were considered serious.

Overall, the results associated with glasdegib do not compare favorably with those of the JAK inhibitor ruxolitinib, the only myelofibrosis treatment approved by the U.S. Food and Drug Administration. Despite negative results, the study highlights new directions for myelofibrosis clinical research.

“Ruxolitinib can improve symptoms by shrinking the spleen and reducing cytokine levels, but, to the best of our knowledge, it doesn’t change the disease biology, it doesn’t reduce the fibrosis, and it doesn’t reduce the mutant allele burden to a significant degree,” said Dr. Gerds. “Preclinical models of glasdegib emphasize where we’re going with myelofibrosis treatment. … We’re looking for different ways to uproot the disease from the bone marrow.”

The study is limited by its single-arm design and small population. Also, Dr. Gerds noted that, given that symptom improvement was noted only anecdotally, “we might not have been doing the quality-of-life surveys as often as we should have” to evaluate glasdegib’s impact on patient-reported outcomes.

Dr. Gerds reports research funding from Pfizer.


Gerds AT, Tauchi T, Ritchie EK, et al. Phase I/II trial of glasdegib in patients with primary or secondary myelofibrosis. Abstract #7061. Presented at the 2017 ASCO Annual Meeting, June 5, 2017; Chicago, Illinois.