Abstract
Background: Patients (pts) with higher-risk (HR)-MDS in whom HMAs fail have a dismal prognosis with a median overall survival (OS) of <6 months. Immune tolerance and evasion by malignant cells have been recognized as important mechanisms of progression in cancers including MDS. Immune checkpoint inhibition with the anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab improved outcomes in pts with solid tumors by overcoming this resistance mechanism. We hypothesized that CTLA-4 blockade in pts with HR-MDS post HMAs failure would be tolerable and lead to meaningful clinical responses.
Methods: In an investigator-initiated, CTEP-sponsored phase 1b study, eligible pts with HR-MDS (defined by Intermediate-2 or high IPSS score, or intermediate-1 with ≥5% blasts in bone marrow [BM] or transfusion needs) who had primary or secondary failure of HMAs (≥4 cycles) received ipilimumab monotherapy at 2 dose levels (DL); DL1 used 3mg/kg and DL2 used 10mg/kg. In the induction phase [Figure 1], 4 doses were administered at 3-week intervals. Responding Pts and those with stable disease (SD) at end of induction received a maintenance phase with 4 more doses of ipilimumab administered at 3-month intervals (study total is 8 doses). BM biopsies were obtained at baseline, post cycles 2, 4, and before each maintenance dose. The primary objectives were to determine the tolerability of ipilimumab and identify the optimal dose for dose expansion. Toxicities were graded according to CTCAE 4.0 criteria. Responses were evaluated using International Working Group 2006 criteria at end of induction and before each maintenance dose. Overall survival (OS) was calculated from first dose of ipilimumab until death using Kaplan-Meier methods with censoring at time of allogeneic stem cell transplantation (alloSCT) or cutoff date for data collection on 6/30/2015.
Results: Eleven pts were enrolled on the dose-escalation part of the study; 6 on DL1 and 5 on DL2. Median age was 63 years (range, 50-79). Five pts had received 2 prior lines of therapy (including HMAs) while 6 pts had received only HMAs; median number of HMAs cycles 5; range, 4-18. Five pts had a normal karyotype while each of the following categories were present in one pt: del5q, del7q, complex, trisomy 8 (2 pts unsuccessful karyotyping). At baseline, 4 pts were platelet transfusion-dependent and 5 were red blood cell transfusion-dependent. Median platelet count was 25×10⁹/L (range, 12-61×10⁹/L), median white blood cell count was 1.5×10⁹/L (range, 1.05-7.6×10⁹/L), median absolute neutrophil count was 0.28×10⁹/L (range, 0.06-4.7×10⁹/L), median hemoglobin was 9.4 gm/dL (range 7.6-10.8 gm/dL), and median BM blast percentage was 9% (range, 2-30%). All pts in DL1 received ≥2 ipilimumab doses; 2 received 6 or 8 doses. Three of 6 pts in DL1 developed grade 3 immune-related adverse events (IRAEs) while 4 of 5 pts at DL2 developed grade 3 IRAEs. Four pts (36%) experienced no IRAEs (3 at DL1 and 1 at DL2). All IRAEs were reversible with stopping ipilimumab +/- initiation of systemic steroids. No pt died due to an IRAE and all patients were successfully weaned from steroids. The spectrum of IRAEs was similar to that of ipilimumab use in pts with solid malignancies (rash, hepatitis, and diarrhea/colitis). Overall no pts had objective responses. Three pts (27.3%) had SD for >6 months; one had a prolonged SD after an IRAE, and one experienced an ongoing SD for >16 months. Three pts underwent alloSCT post ipilimumab without any additional toxicities and remain in complete remission at 2, 12 and 18 months post alloSCT, respectively. Median and mean OS for entire cohort (censoring at time of alloSCT) was 368 and 352 days, respectively (95%CI for mean OS, 264-440 days) [Figure 2]. Correlative studies evaluating dynamic changes in T-cell subsets, myeloid derived suppressor cells, cytokine levels, and T-cell receptor repertoire are in progress.
Conclusions: Monotherapy withanti-CTLA-4 antibody ipilimumabat 3mg/kg is tolerable and can lead to prolonged disease stabilization. This dose is currently being evaluated further in a dose-expansion multi-center study. AlloSCT appears feasible post ipilimumab use but further data are needed. These results provide rationale for further exploration of immune checkpoint inhibition therapy in pts with MDS.
Figure 1. Administration schedule Figure 1. Administration schedule Figure 2. Overall survival from first dose (censored at alloSCT or 6/30/2015). Figure 2. Overall survival from first dose (censored at alloSCT or 6/30/2015).
Disclosures
Off Label Use: Ipilimumab for MDS. Gore:Celgene: Consultancy, Honoraria, Research Funding.
Modulation of temozolomide dose differentially affects T-cell response to immune checkpoint inhibition
