Ruxolitinib shows efficacy for certain patients with chronic neutrophilic leukemia, atypical CML
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Ruxolitinib induced responses in about one-third of a cohort of patients with chronic neutrophilic leukemia and atypical chronic myeloid leukemia, according to results of a single-arm phase 2 study published in Journal of Clinical Oncology.
The JAK1/JAK2 inhibitor also appeared well-tolerated among these patients.
“Chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML) are rare BCR-ABL1-negative myeloid neoplasms,” Kim-Hien T. Dao, PhD, DO, assistant professor of medicine at Oregon Health & Science University, and colleagues wrote. “The 2016 WHO diagnostic criteria for CNL and aCML incorporate recurrent genetic markers, which provide diagnostic clarity for these diseases. In particular, colony-stimulating factor-3 receptor (CSF3R) mutations are present in the vast majority of patients with CNL, whereas RAS pathway-centric mutations are common in aCML and other myelodysplastic syndrome/myeloproliferative neoplasm overlap neoplasms.”
No standard of care or approved therapy exists for CNL and aCML; however, allogeneic hematopoietic stem cell transplantation usually is recommended for those eligible. Median survival for both diseases is about 2 years, with hemorrhage, marrow failure and blastic transformation among common causes of death.
Although nontransplant therapies have not been used extensively among this patient population, previous studies in mouse models showed inhibition of JAK1 and JAK2 significantly alleviate oncogenic CSF3R, leukocytosis, splenomegaly and death.
This prompted Dao and colleagues to evaluate the efficacy and safety of ruxolitinib (Jakafi, Incyte) among 21 patients with CNL (median age, 74 years; 52.4% women) and 23 patients with aCML (median age, 67 years; 30.4% women).
Overall hematologic response rate, including complete or partial response, by the end of six 28-day treatment cycles among the first 25 patients enrolled served as the study’s primary endpoint.
Grade 3 or higher adverse events, spleen volume, symptom assessment, genetic correlates of response and 2-year OS served as secondary endpoints.
Results showed an ORR of 32% among the first 25 enrolled patients, which included eight partial responses (CNL, n = 7; aCML, n = 1). Researchers observed an ORR of 35% among all 44 patients, including 11 partial responses (CNL, n = 9; aCML, n = 2) and four complete responses, all among patients with CNL. Among these patients, 50% had oncogenic CSF3R mutations.
Mean absolute allele burden reduction of CSF3R-T618I after six cycles appeared greatest among those who achieved complete response compared with partial or no response.
Researchers followed all patients who did not die or undergo subsequent transplant for at least 2 years (median follow-up, 38.4 months). Median OS was 18.8 months (95% CI, 15.3-25.2) for all patients, 15.6 months for nonresponders and 23.1 months for responders. The most common cause of death was disease progression (n = 13).
Grade 3 or higher adverse events included anemia (34%) and thrombocytopenia (14%). Researchers noted no serious adverse events attributable to ruxolitinib.
“Studies in cell lines, primary colony assays and in vivo models suggest ruxolitinib targets signaling downstream of oncogenic CSF3R,” Dao and colleagues wrote. “Our clinical study provides evidence that ruxolitinib is a treatment option for a subset of patients with CNL and aCML.” – by John DeRosier
Disclosures: Dao reports a consultant/advisory role with and honoraria and research funding from Incyte. Please see the study for all other authors’ relevant financial disclosures.
Perspective
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Jonathan M. Gerber , MD
Although rare, CNL and aCML represent significant clinical challenges. The prognosis is quite poor for both diseases, and the rarity of these conditions has precluded clinical trials. Other than allogeneic HSCT and occasional durable responses to interferon alfa, there has been no effective therapy for either disease. Further complicating matters, most patients with these leukemias present at a relatively advanced age, limiting allogeneic HSCT as a viable option.
Researchers here present what is effectively the largest clinical trial of CNL and aCML to date. Based on the 2013 discovery by Maxson and colleagues of the sensitivity of CSF3R mutations to JAK-STAT inhibition in CNL and aCML, Dao and colleagues treated these patients with the JAK1/2 inhibitor ruxolitinib. Although the ORR to ruxolitinib was somewhat disappointing at only 35% and most responses were of only limited duration, many patients did appear to derive some benefit. Notably, four patients achieved complete remission, two of which were durable, including a molecular compete response. Additionally, six patients were successfully bridged to allogeneic HSCT. Responses appeared to correlate with a diagnosis of CNL — as opposed to aCML — and/or the presence of CSF3R mutations. Interestingly, the durable remissions occurred in patients without detectable mutations in other genes.
These results are quite consistent with the more extensive experience in standard (BCR/ABL-positive) CML — namely, treatment early in the course of the disease is far more effective than after progression to an advanced phase. Ruxolitinib appears particularly promising for patients with CNL with CSF3R mutations but prior to the acquisition of additional mutations in other key genes, which may confer more aggressive disease biology and resistance. Unfortunately, the vast majority of CNL and, especially, aCML cases present at a more advanced stage and/or lack a targetable CSF3R mutation altogether; thus, these leukemias still represent a very much unmet need.
It remains to be seen whether combination therapies incorporating ruxolitinib may be able to overcome the limitations of single-agent therapy. Logical combinatorial options include hypomethylating agents, venetoclax (Venclexta; AbbVie, Genentech) and immunotherapy, all of which have shown promising activity in other myeloid diseases. Other, novel inhibitors of the JAK-STAT pathway may represent additional options. Even as a single agent, ruxolitinib may still prove useful in advanced cases as a bridge to a potentially curative allogeneic HSCT for appropriate candidates and perhaps post-transplant maintenance therapy. Earlier diagnosis may also provide an opportunity to intervene at a more susceptible point in the disease.
Although there is much work yet to be done in the treatment of CNL and aCML, the evolving molecular understanding of these diseases and the advent of novel therapies offer genuine hope for patients with these difficult-to-treat diseases.
Reference:
Maxson JE, et al. N Engl J Med. 2013;doi:10.1056/NEJMoa1214514.
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