BackgroundRuxolitinib improves splenomegaly and symptoms in patients with intermediate-2 or high-risk myelofibrosis; however, nearly half develop grade 3/4 anemia and/or thrombocytopenia, necessitating dose reductions and/or transfusions. We report findings from an open-label phase 2 study exploring a dose-escalation strategy aimed at preserving clinical benefit while reducing hematological adverse events early in ruxolitinib treatment.MethodsPatients with myelofibrosis received ruxolitinib 10 mg twice daily (BID), with incremental increases of 5 mg BID at weeks 12 and 18 for lack of efficacy (maximum, 20 mg BID). Symptom severity was measured using the Myelofibrosis Symptom Assessment Form Total Symptom Score (MFSAF TSS).ResultsForty-five patients were enrolled, 68.9% of whom had a Dynamic International Prognostic Scoring System score of 1 to 2 (i.e., intermediate-1 disease risk). Median percentage change in spleen volume from baseline to week 24 was − 17.3% (≥ 10% reduction achieved by 26 patients [57.8%]), with a clear dose response. Median percentage change in MFSAF TSS from baseline at week 24 was − 45.6%, also with a dose response. The most frequent treatment-emergent adverse events were anemia (26.7%), fatigue (22.2%), and arthralgias (20.0%). Grade 3/4 anemia (20.0%) and dose decreases due to anemia (11.1%) or thrombocytopenia (6.7%) were infrequent.ConclusionsA dose-escalation approach may mitigate worsening anemia during early ruxolitinib therapy in some patients with myelofibrosis.Trial registrationClinicalTrials.gov identifier, NCT01445769. Registered September 23, 2011.

7030 Background: Myelofibrosis(MF) is characterized by splenomegaly, burdensome symptoms, progressive bone marrow (BM) fibrosis, and shortened survival. Ruxolitinib (Rux), an oral, FDA-approved JAK1/JAK2 inhibitor, has demonstrated improvements in spleen volume, symptoms, and survival in patients (pts) with MF. This study was conducted to explore possible effects of long-term Rux treatment on BM morphology in MF. Methods: Trephine biopsies were obtained at baseline, 24 (67 pts), and 48 (17 pts) months (mo) from the cohort of MF patients treated at MD Anderson Cancer Center who participated in a phase I/II trial of Rux (NCT00509899). The clinical outcomes from this trial have been published previously [Verstovsek, NEJM 2010]. Two of the authors (JT and HMK) independently evaluated the World Health Organization (WHO)-defined BM fibrosis grade (0-3). Reviewers were blinded to pts characteristics and outcomes and consensus decided discordant scores. For demonstrative purposes, WHO BM fibrosis grading was also determined for a control cohort of pts treated with hydroxyurea (HU) for 24 (31 pts) and 48 (20 pts) mo. Changes in BM fibrosis grade vs. baseline were calculated for 24 and 48 mo, and categorized as improvement, stabilization, and worsening for each patient. Results: A higher percentage of Rux-treated pts showed stabilization or improvement of BM fibrosis at both 24 and 48 mo than the HU-treated pts. Worsening was greater in the HU-treated cohort at both time points. Conclusions: This exploratory analysis of long-term exposure to Rux in MF provides the first indication that JAK inhibitor therapy may be able to meaningfully retard advancement of BM fibrosis. A comparable effect was not seen with long-term HU therapy. Additional research is needed to further elucidate these findings. Clinical trial information: NCT00509899. [Table: see text]

Ruxolitinib is the first Janus kinase (JAK) inhibitor approved for the treatment of myelofibrosis, where its efficacy is often associated with cytopenia. It is possible that the severity of cytopenia is in part driven by C max. A once‐daily sustained‐release (SR) formulation of ruxolitinib was therefore developed to decrease the C max/C min ratio relative to twice‐daily immediate‐release (IR) ruxolitinib. An SR formulation was identified based on pharmacokinetic evaluation in a phase 1 study in healthy adults (N = 9). This was followed by an open‐label phase 2 study in patients with myelofibrosis (N = 41). Ruxolitinib SR treatment was well tolerated with blood cell counts relatively unchanged through week 16. In terms of efficacy, 7 patients (17.1%) had clinical improvement and 33 (80.5%) had stable disease. While this study has raised the possibility of an increased therapeutic index for ruxolitinib via an SR formulation, further studies are required to validate the hypothesis.

Background: Induction chemotherapy followed by autologous stem cell transplantation (ASCT) is considered a standard of care for appropriate patients with newly diagnosed multiple myeloma (MM), but with the rapid expansion of available treatments, the role of ASCT has been questioned. Numerous studies have shown an improvement in complete response (CR) and progression free survival (PFS) with ASCT but our study is a cost comparison between novel agents and ASCT. We aimed to compare the cost effectiveness of ASCT versus non-transplant regimens in relation to PFS. Methods: We queried the Healthcare Cost and Utilization Project's Nationwide Inpatient Sample (NIS) between 2008 and 2013 using the ICD-9 code 203.00 for MM and V42.81 for ASCT in the primary and secondary diagnosis fields. The analysis included patients who were 18 years or older. We monitored the trends in ASCT with regards to cost of a transplant admission and length of stay (LOS). Cost of hospitalization was adjusted for inflation in reference to the year 2011 and cost to charge ratio. Literature regarding common treatment regimens, response rates, duration of treatment, and PFS was reviewed. The assumption was made that transplant eligible patients that did not undergo transplant would be treated as though they were transplant ineligible. Gay et al 2015 showed a 43.4-month (mo) median PFS with 4 cycles of Rd followed by ASCT and lenalidomide maintenance until progression or toxicity. The cost of novel regimens was estimated using the one month commercial cost described by Roy et al and wholesale acquisition costs for new agents not described by the study which were adjusted using adjunct cost described by the study. A standard weight of 70 kg was used for agents requiring dose calculations. The cost of novel agents for an equivalent duration of 43.4 mo was estimated. Results: A total of 44778 (weighted n=9039) hospitalizations for MM (Male 55.9%, Caucasian 57.9%, peak incidence 65-79 yrs) occurred from 2008-2013. The average length of stay during ASCT admission was 11.4 +/- 0.4 days with a cost of $109,856 +/-5749.83. There has been a 16.89% decrease in LOS and 1.99% increase in the cost of ASCT (p<0.05). Gay et al showed a 43.4 mo PFS with 4 cycles Rd ($46,216) followed by ASCT ($109,856) and lenalidomide maintenance (~35.4 mo $564,453 adjusted for cost of office visits and lab work) for a total of $720,525 Conclusion: Rd + ASCT + R maintenance is efficacious for the treatment of newly diagnosed MM. The cost associated with the induction and transplant represents only 22% of the total cost, whereas lenalidomide maintenance makes up 78%. Considering secondary risks and the cost involved with lenolidomide maintenance, further investigation is warranted regarding the optimal duration of maintenance therapy and resultant progression free survival. It also raises the need for alternative options for maintenance therapy. Bortezomib and ixazomib are both more cost effective options and studies are in progress to assess their efficacy in PFS in the maintenance setting. Studies using novel agents for induction prior to ASCT are ongoing and have yet to reach an optimal duration of therapy. Table 1 shows that most of the novel agents used in combination regimens are more expensive that ASCT. Although most patients would not remain on one of these regimens for 43.4 mo, they would presumably progress through multiple lines of therapy during the 43.4 mo of PFS that ASCT provides. In an era of cost consciousness, ASCT should continue to be an integral component of MM treatment. Disclosures No relevant conflicts of interest to declare.

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