Evidence-Based Oncology January 2019
Evidence-Based Oncology January 2019
Produced by Samantha DiGrande and Jaime Rosenberg
Updates from annual ASH meeting, December 2018.
Ruxolitinib Results in Better Treatment Response, Less Toxicity in Early Primary MyelofibrosisJaime Rosenberg
For the first time, a study has demonstrated that early primary myelofibrosis (PMF) represents a category of patients who are likely to have better responses and lower toxicities from treatment with ruxolitinib. According to the study, led by Francesca Palandri, MD, PhD, of the Institute of Hematology at the University of Bologna, Italy, presented at the 60th American Society of Hematology Annual Meeting & Exposition, held December 1-4, 2018, in San Diego, California, a World Health Organization (WHO)–defined diagnosis may help better identify patients who may need strict monitoring during treatment with ruxolitinib (Jakafi).
In 2016, WHO criteria labeled early PMF as an individual entity with different clinical and laboratory presentations, as well as a significantly better outcome compared with overt PMF. However, there is a lack of information on the therapeutic effects of ruxolitinib depending on treatment setting.
Aiming to provide data on the differences in baseline clinical and laboratory characteristics, response to treatment, and toxicity between early and overt PMF treated with ruxolitinib, researchers utilized a clinical database in 23 European hematology centers. The database included retrospective data of 537 patients with myelofibrosis (MF) treated with ruxolitinib between January 2011 and July 2018. Spleen and symptom response were documented, and hematologic toxicity and infections were graded.
Of the 199 patients, 59 had a diagnosis of early PMF and 140 had a diagnosis of overt PMF. Median time from diagnosis to ruxolitinib initiation was 22.4 months.
Compared with patients with overt PMF, patients with early PMF started ruxolitinib with higher hemoglobin levels (median, 11.6 vs 10.4 g/dL) and lower circulating blast counts. They were also more frequently at intermediate-1 Dynamic International Prognostic Scoring System risk (69.6% vs 42.5%). The ruxolitinib starting doses and 12-week titrated doses were comparable between the 2 groups.
At 3 months, 43.1% of patients with early PMF achieved a spleen response, and at 6 months 48.9% achieved a spleen response, compared with 27.9% and 31.3% of patients with overt MF respectively. The rate of symptom response was also higher among patients with early PMF at both 3 months (82.5% vs 68.8%) and 6 months (90.0% vs 73.7%).
Toxicities and infections also favored patients with early PMF. In the first 12 months from ruxolitinib initiation, anemia and thrombocytopenia of all grades were observed in 75.6% and 43.1% in patients with overt PMF and in 86.3% and 60.0% of patients, respectively, with early PMF.
At 3 months, anemia was more prevalent among patients with overt PMF (94.7% vs 80.0%), with 32.6% of these patients having grade 3-4 anemia compared with 17.8% in early PMF. Similarly, rates of thrombocytopenia were also higher among patients with overt PMF at 3 months (51.5% vs 36.2%) and at 6 months (52.9% vs 35.8%), with only 2.2% and 2.5% of patients having grade 3-4 thrombocytopenia, respectively.
During treatment, 75 patients had at least one grade 2 or greater infectious episode. Overall, 108 patients discontinued treatment (52.5% of patients with early PMF and 55% of patients with overt PMF). Evolution into acute leukemia occurred in 21 patients.
Overall survival and progression-free survival were comparable between the 2 groups.
Palandri F, Palumbo G, Abruzzese E, et al. Presentation and outcome of 199 patients with 2016 WHO diagnosis of early and overt primary myelofibrosis treated with ruxolitinib. In: Proceedings from the 60th American Society of Hematology Annual Meeting & Exposition; December 1-4, 2018; San Diego, CA. Abstract 3052.
Myelofibrosis Survival After Discontinuing Ruxolitinib Differs Based on Reason for Discontinuation
Ruxolitinib (Jakafi) is the only targeted therapy available for the treatment of myelofibrosis (MF)-related splenomegaly and symptoms, and although 50% of patients with MF achieve significant clinical responses with ruxolitinib, half the responders stop responding over time.
Following failure with ruxolitinib, there are limited treatment options available. Among patients who fail on the treatment, prognosis is unfavorable, particularly among those who started ruxolitinib with advanced-stage disease, according to study results presented at the 60th American Society of Hematology Annual Meeting & Exposition held in San Diego, California.
The results further indicated that discontinuation because of disease evolution into acute leukemia or because of occurrence of a second solid neoplasia significantly reduced life expectancy.
The researchers assessed retrospective data from a clinical database created in 23 European hematology centers. The data included information on 537 patients treated with ruxolitinib from January 2011 to July 2018; information on 442 patients available as of July 15, 2018, was reported.
Spleen and symptom response to treatment were evaluated, and ruxolitinib-related toxicity and infections were graded. Overall survival was estimated from the date of ruxolitinib discontinuation to the date of death or last contact.
After a median follow-up of 30.5 months, 214 of the 442 (48.4%) evaluable patients discontinued ruxolitinib. Among these patients, (20.1%) died while on therapy because of MF progression (34.9%), infection (25.6%), heart disease (16.3%), second neoplasia (7%), hemorrhages (7%), and other causes (9.2%). Among the remaining 171 patients who discontinued ruxolitinib, median follow-up was 11.3 months. Reasons for discontinuation included drug-related toxicity (28.6%), loss or lack of response (23.4%), MF progression (12.3%), acute leukemia (13.4%), allogeneic stem cell transplantation (ASCT) (11.1%), second solid neoplasia (4.1%), and other unrelated causes (7.1%).
After discontinuing ruxolitinib, 68 patients received 1 line of therapy, 21 received 2 lines, and 9 received more than 2 treatments. Additionally, 73 patients did not receive any therapy. Treatments received after ruxolitinib discontinuation, alone or in combination, included hydroxyurea, ASCT, second-generation JAK2 inhibitors, splenectomy, azacytidine/decitabine, chemotherapy, investigational agents, danazole, and erythropoietin-stimulating agents.
A total of 95 patients died following ruxolitinib discontinuation due to MF progression (30.5%), acute leukemia (25.4%), infections (14.7%), second neoplasia (9.5%), hemorrhages (4.2%), heart disease (4.2%), ASCT (4.2%), thrombosis (2.1%), and other causes (5.2%). Median survival time following ruxolitinib among the 171 patients was 22.6 months.
Survival following discontinuation was significantly influenced by Dynamic International Prognostic score category, transfusion dependency, and driver mutation status at baseline.
While receiving therapy, 45 of 153 (29.4%) and 123 of 161 (76.4%) evaluable patients achieved a spleen and symptoms response at any point, but survival was not affected by the previous response to treatment. However, survival significantly varied based on the reason for stopping treatment, with those discontinuing because of acute leukemia evolution or second solid neoplasia having the worst outcome.
Among patients who discontinued treatment in chronic phase, the use of second-generation tyrosine kinase inhibitors and other investigational agents prolonged survival compared with administration of conventional treatments.
Palandri F, Elli E, Polverelli N, et al. Outcome of patients with myelofibrosis after ruxolitinib failure: role of disease status and treatment strategies in 214 patients. In: Proceedings from the 60th American Society of Hematology Annual Meeting & Exposition; December 1-4, 2018; San Diego, CA. Abstract 4277.