Comparative Efficacy and Safety of Once Versus Twice Weekly Carfilzomib Based Therapies in Relapsed Refractory Multiple Myeloma- a Systematic Review

Introduction: Carfilzomib use as a single agent or in combination has been shown to improve outcomes in relapsed refractory multiple myeloma (RRMM). Traditionally, carfilzomib has been administered in twice-weekly dosage schemes as compared to the newly approved once-weekly dosage scheme. The once-weekly dosing of carfilzomib is thought to provide same efficacy and has been evaluated in many clinical trials. We have performed a systematic review of comparative efficacy and toxicity profiles of once and twice-weekly carfilzomib dosing schemes in RRMM. Materials and methods: Systematic review was done according to PRISMA statement. PubMed, Embase, AdisInsight, & Clinicaltrials.gov databases were searched, without any filters, using the search terms "Multiple Myeloma" AND "Kyprolis" OR "Carfilzomib". Most recent reports of phase I/II/III clinical trials reporting the clinical efficacy and/or safety of carfilzomib in RRMM were considered for inclusion. After screening of 267 articles, 16 clinical trials (N=2393) evaluating twice-weekly carfilzomib and 4 trials (N=418) evaluating once-weekly dosing schedule were considered for inclusion. Results Once versus (vs.) twice-weekly carfilzomib regimens were evaluated in a total of 406 and 1869 patients, respectively. In our discussion, group-1 refers to patients receiving once weekly carfilzomib while group-2 refers to twice weekly dosing schedule group. For the evaluated population, high risk cytogenetics were reported in 15% (n=60) patients in group-1 and in 17% (n= 317) patients in group-2. The median no. of prior lines of therapy ranged 1-8 in group-1 as compared to 1-20 in group-2. All studies reported the patient responses according to International Myeloma Working Group (IWMG) response criteria. The cumulative overall response rate (ORR) was better in group 1: 70.4% (n= 286) vs. 48% (n= 896). Similarly, more patients in group-1 achieved stringent complete response (sCR) or complete response (CR): 11.5% (n= 47) patients in group 1 vs. 5.2% (n= 99) patients in group 2. The response rates were also non-inferior in group-1 for other responses as overall. In group-1, 30% (n= 123) patients achieved very good partial response (VGPR) compared to 21% (n=389) patients in group-2. The partial response (PR) rate was 28.5% (n= 116) vs. 22% (n= 412) in groups 1 and 2 respectively The rate of minimal response (MR) achievement was comparable in both groups: 5% (n= 21) in group-1 vs. 8% (n= 154) patients in group-2. But lesser proportion of patients in group-1 went on to develop progression of myeloma disease [5.6% (n= 23) vs. 15.6% (n= 293)]. Stable disease (SD) state was achieved by 12.3% (n=50) patients in group-1 compared to 20% (n= 379) patients in group-2. Owing to phase-1 design of most clinical trials evaluating the once-weekly dosing schedule, the survival data is immature at present, but the median progression free survival (PFS) ranged from 1 day to 12.6 months in group-1 while in group 2 it ranged from 3.7-44.4 months. (Table-1) The toxicity profiles were also comparable for both dosing schedules. The most common hematological adverse events (AEs) were anemia and thrombocytopenia and their incidences were 15.7% (n= 64) vs. 25.5% (n= 477) and 13.3% (n= 54) vs. 23.1% (n= 432) in groups 1 and 2 respectively. The most common non-hematological AEs were infections, fatigue, and nausea that were reported in 22% (n= 89), 19% (n= 77), and 17.4% (n= 71) patients in group 1, and 14.5% (n= 272), 19.3% (n= 362), and 19.1% (n= 357) patients in group 2, respectively. Overall, grade 3 or above cardiac AEs were reported in 3.4% (n= 14) patients in group 1 and 3.3% (63/1869) patients in group 2. The most common cardiac AE was hypertension which constituted 50% (n= 7) and 64% (n= 40) of all grade 3 or more cardiac AEs in groups 1 and 2, respectively. Conclusion Achievement of objective response rates for once-weekly carfilzomib appears to be better or at-least similar to twice-weekly carfilzomib regimens. There is paucity of prospective studies comparing once vs. twice-weekly carfilzomib in RRMM which highlights the need for more clinical trials evaluating this regimen. Apart from efficacy and safety profile, once-weekly carfilzomib dosing also carries the potential of becoming a preferred option in terms of lesser financial burden and number of patient visits to the infusion centers. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Reduction in the utilization of prednisone or methotrexate in Canadian claims data following initiation of etanercept in pediatric patients with juvenile idiopathic arthritis

Background In adult patients with arthritis, use of the tumor necrosis factor (TNF) inhibitor etanercept (ETN) is often associated with a reduction in the utilization of co-medications, particularly steroids. Comparatively little is known about the utilization of co-medications when ETN is initiated in pediatric patients with juvenile idiopathic arthritis (JIA). Methods This study analyzed Canadian longitudinal claims level data spanning January 2007 to April 2017. Data were collated from the IQVIA Private Drug Plan, Ontario Public Drug Plan, and the Quebec Public Drug Plan (Régie de l’assurance maladie du Québec) databases. Patients < 18 years of age were indexed when filling a prescription for ETN between January 2008 and January 2016. Those who met the inclusion and exclusion criteria were assessed for methotrexate (MTX), and prednisone (PRD) use in the 6 months prior to and 12 months following initiation of ETN. Results Longitudinal claims data for 330 biologic-naive pediatric patients initiating ETN therapy were included. The majority of patients were female (67%), aged 10–17 years (64%), and with a drug history consistent with JIA (96%). Most patients were from Quebec (36%) or Ontario (33%). Dosing of ETN was weight-based with a mean dosage over the first year of 31 mg per week. ETN dosing was relatively consistent over the first year. In total, 222 (67%) patients did not use MTX and 223 (68%) did not use PRD before or after starting ETN. A total of 17% (18/103) of MTX-treated and 50% (46/92) of PRD-treated patients discontinued use of those medications upon initiation of ETN treatment. In patients continuing MTX or PRD, significant reductions in the weekly dosage from 14.3 to 6.8 mg per week for MTX and from 56 to 23 mg per week for PRD were observed (P < 0.01). Conclusions This study of Canadian claims-level data is the first large prespecified analysis of co-medication utilization following the initiation of ETN therapy in pediatric patients. A decline in both MTX and PRD use and dosage was observed and may be associated with benefits related to safety, tolerability, and overall healthcare costs.

PATIENTS WITH ≥ 20 X 109/L PLATELETS AT BASELINE MAY HAVE A PROMPT RESPONSE TO ROMIPLOSTIM DURING THE EARLY PHASE OF TREATMENT: AN ITALIAN SINGLE-INSTITUTION EXPERIENCE

Patients with chronic immune thrombocytopenia treated with romiplostim may benefit from a higher starting dose when a rapid increase in count is needed, but it could be avoided in those with a prompt response to the standard dosage. We hypothesized that a platelet count ≥ 20 x 109/l at baseline could distinguish subjects with such response from those with a delayed one during the early phase of treatment. Our work is a retrospective and single-institution analysis comparing the median platelet count, the median weekly dosage of romiplostim and the median number of weekly platelet counts < 50 x 109/l between patients with a baseline ≥ 20 x 109/l platelets (n=10, 2 splenectomized) and those with a lower one (n=8, 3 splenectomized) during the first month of treatment with romiplostim. The results show a higher median platelet count (79,5 vs 40,5 x 109/l, p=0,002) and a lower median dose of romiplostim (1 vs 2 mcg/kg/week, p=0,01) in subjects with a baseline ≥ 20 x 109/l platelets, who also had a trend of less weekly counts < 50 x 109/l platelets (1 vs 2, p=0,054). These data suggest that patients with ≥ 20 x 109/l platelets at baseline may achieve a prompt response with the standard dose of romiplostim, but further and larger data are needed in order to assess whether it can be considered in clinical practice.

Imatinib at Weekly Dosage May Induce and Maintain Haematologic and Molecular Remission in Chronic Eosinophilic Leukemia Harbouring FIP1L1-PDGFRA Fusion Gene- An Extended Follow-up Study.

Background. A small proportion of patients with hypereosinophilic syndrome (HES) demonstrate the presence of an interstitial deletion in chromosome 4 leading to the creation of the imatinib-responsive fusion gene- FIP1L1-PDGFRA (F/P). Recently, we showed that a single weekly dose of imatinib is sufficient to induce and maintain remission of chronic eosinophilic leukemia (CEL) with detectable F/P transcript. Here, we present data from 12 patients CEL and HES, 11 of which were F/P positive, who achieved a rapid complete haematologic remission (CHR) with daily imatinib treatment and remission was then maintained with a weekly imatinib schedule. Design and methods. Twelve patients, 11 out of 12 with detectable F/P were treated with imatinib at the initial doses varies between 100–400mg. There were 10 male and 2 female with a median age of 57 years (19–80). Median time to start imatinib was 23 months (1–204 months). The imatinib dose was de-escalated while patients remained in haematologic remission. As a response maintenance, once weekly imatinib was established in all cases. Results. All studied patients achieved a complete haematologic remission (CHR) and 100% of cases with detectable F/P fusion gene before imatinib, demonstrated a molecular remission determined by reverse transcriptase polymerase chain reaction (RT-PCR) analysis. The breakpoints occured within exon 12 of PDGFRA whereas breakpoints dispersed across the FIP1L1 locus occuring between exons 10 and 13. Median time to achieve CHR was 13 days (4–90), and median time to molecular remission was 9 months (4–24). As a remission maintenance, imatinib doses were set at 100mg weekly in 9 pts and 200mg weekly in 3. With a median follow-up of 21 months (8–49 months) all pts remain in CHR. The FIP1L1-PDGFRA is undetectable in 11 patients by RT-PCR. Conclusions. Imatinib at weekly dosage may induce and maintain remission in patient with CEL expressing F/P fusion gene. This strategy appears to be safe and cost savings.