Haematology+Oncology_News

H aematology & O ncology N ews • Vol. 9 • No. 1 • 2016 12 CONFERENCE COVERAGE

Heavily pretreated myeloma responds to pembrolizumab combo

American Society of Haematology 5–8 December • Orlando, Florida The 57th American Society of Hematology annual meeting, the premier haematology event in malignant and non-malignant haematology, presented the year’s most significant scientific discoveries and relevant key updates in the field, some of which we feature here in our coverage of the meeting. Further in-depth coverage and expert commentaries can be found on www.practiceupdate.com .

rapid 30-minute intravenous infusion without premedication with lenalidomide 25 mg on days 1–21 and dexamethasone 40 mg weekly did not cause any dose-limiting toxicities and was identi- fied as the final MTD, Dr San Miguel said. The regimen is to continue for 24 months or until tumour progression or excessive side effects and was carried forward into the dose-expansion stage in 33 additional patients with a median follow-up of 48 days. Among all 50 patients evaluable for safety, 72% experienced at least one treatment-related adverse event of any grade and 46% (23/50 patients) had grade 3/4 adverse events including neutropenia (22%), thrombocytopenia and anaemia (8% each), hyperglycaemia (6%), and fatigue, muscle spasms, and diarrhoea (2% each). The adverse events were consistent with the individual drug safety profiles, but “the incidence may be underestimated due to the limited drug exposure,” Dr San Miguel cautioned. Immune-mediated adverse events included two cases each of hyper- and hypothyroidism, one case of thyroiditis, and one grade 2 adrenal insufficiency. No cases of colitis or pneumonitis were reported. No dose modifications or treat- ment discontinuations were required to mange the immune-related side effects, he said. No treatment-related deaths occurred. In a second study reported during the same oral myeloma session, pneumonitis cropped up in 10% of heavily pretreated patients with relapsed multi- ple myeloma receiving a slightly different regimen of pembrolizumab plus the IMiD pomalidomide and dexamethasone. The overall response rate in the phase II study was 60% among 27 evaluable patients and 55% in those double-refractory to IMiDs and proteasome inhibitors. reviewed and cases were stratified by disease severity according to the need for second line treatment. A significant increase in the frequency of several damaging variants were identified in genes in the ITP cohort. The most significant associations were detected in the IFNA17 gene, which is involved in transforming growth factor beta secretion and could affect number and function of regulatory T cells. IFNA17 rs9298814 was identified in 26% of cases in the ITP cohort compared to less than 0.01% of controls. In all, 43% of ITP pa- tients had at a presumed deleterious variant of IFNA17. IFNA17 gene variants remained significant in the most severely affected patients, spe- cifically those requiring second line therapy, providing further evidence for this gene’s functional relevance in the pathogenesis and pathophysiology of ITP, Dr Despotovic said. Other genes with known impact on T cell number or function, including DGCR14, SMAD2 and CD83 also contained an in- creased frequency of variants in the European American ITP cohort. IFNLR1 and REL genes were also significantly associated with need for second line ITP therapy. Analysis of this large cohort did not vali- date any of over 20 variants that have been previously published as candidates for ITP susceptibility or evolution to chronic ITP, she added.

the quality of the response was upgraded in 11% with continued treatment, Dr San Miguel said. The rationale for combining PD-1 inhibitors with immunomodulatory drugs (IMiD) lies in recent research showing that lenalidomide reduces PD- ligand 1 and PD-1 expression on multiple myeloma cells as well as on T and myeloid-derived suppres- sor cells, he explained. In addition, lenalidomide enhances checkpoint blockade-induced effector cytokine production inmultiplemyeloma bonemar- row and induces cytotoxicity against myeloma cells. “Lenalidomide will increase the number of T cells and the T-cell activation and anti-PD-1 will release the brake in order to allow these activated T cells to interact with the tumour,” Dr San Miguel said. Patients enrolled in KEYSTONE-023 were heavily pretreated, with 26% previously exposed to pomalidomide, 76% refractory to lenalidomide, 80% refractory to their last line of therapy, and 86% having undergone prior ASCT. Half the pa- tients were double, triple, or quadruple refractory, he noted. The study (Abstract 505) was designed to iden- tify the maximum tolerated dose (MTD) of pem- brolizumab and to assess its safety and tolerability when given with lenalidomide and dexamethasone in patients with multiple myeloma failing at least two prior lines of therapy including a proteasome inhibitor and an IMiD. Their median age was 62 years; 64% were male. In the dose-determination stage, three of six patients treated with pembrolizumab 2 mg/kg plus lenalidomide 25 mg and dexamethasone 40 mg experienced dose-limiting toxicities that resolved without treatment discontinuation. After dose adjustments, a “flat dose” of pem- brolizumab 200 mg given every other week in a

BY PATRICE WENDLING Frontline Medical News

T he one-two punch of combining the pro- grammed cell death-1 (PD-1) inhibitor pem- brolizumab with the immunomodulatory drug lenalidomide and low-dose dexamethasone pro- duced responses in 76% of 17 heavily pretreated patients with relapsed or refractory multiple myeloma in the KEYNOTE-023 study. This included four very good partial responses (24%) and nine partial responses (53%). In nine lenalidomide-refractory patients, the overall response rate was 56%, including two very good partial responses (22%) and three partial responses (33%). The efficacy results are preliminary, but support the continued development of pembrolizumab in patients with multiple myeloma, Dr Jesús San Miguel of Clinica Universidad de Navarra, Pam- plona, Spain, said at the annual meeting of the American Society of Hematology. He closed his presentation with two illustra- tive cases highlighting a rapid response lasting more than a year and a half in a 49-year-old man with myeloma triple-refractory to autologous stem cell transplant (ASCT), lenalidomide, and dexamethasone. The second case involved a patient with double- refractory myeloma and extramedullary disease who achieved a stringent complete response after two cycles of fourth-line pembrolizumab that was associated with a “striking” reduction in lesion volume on computed tomography scans, he said. The median duration of response among the 17 evaluable patients was 9.7 months. The median time to first response was 1.2 months (range 1.0 months to 6.5 months). But some patients require more time and, interestingly,

Genes affecting risk, severity of chronic ITP are identified

according to disease severity, Dr Jenny M. Despotovic reported at the annual meeting of the American Sociey of Haematology. The finding is further evidence for the role of T cell abnormalities in the pathophysiology of chronic ITP. These may be important candidate genes involved in immune regulation and in sus- tained autoimmunity, which appears to be due to generalised immune dysregulation that includes altered T cell balance with a shift

BY MARY JO DALES Frontline Medical News C hildren with chronic immune thrombocy- topenia (ITP) have an increased frequency of damaging variants in genes associated with cellular immunity, notably IFNA17 and IFNLR1, based on the results of whole ge- nome sequencing. The links to IFNA17 and IFNLR1 genes, which are involved in T cell pathways, re- main significant when patients are stratified

toward immune activation (increased Th1/ Th2 ratio) as well as decreased number and impaired function of regulatory T cells, said Dr Despotovic, of Texas Children’s Cancer and Haematology Centres, Baylor College of Medicine, Houston. In their study, Dr Despotovic and her col- leagues performed whole exome sequencing on 262 samples with robust phenotype data from children with chronic ITP in the North American Chronic ITP Registry and the Platelet Disorders Centre at the Weill-Cornell Medical Centre. All but three patients were less than 20 years old at diagnosis; 83% had primary ITP, 10% had Evans syndrome, and 7% had other autoimmune disorders. To identify candidate genes associated with ITP susceptibility, sequencing data were compared for 172 ITP cases of European American ancestry and 5664 controls of Eu- ropean American ancestry with platelet levels over 150 x 10 9 /L in the Atherosclerosis Risk in Communities (ARIC) Study. In a separate analysis, phenotype data for ITP cases were The most significant associations were detected in the IFNA17 gene, which is involved in transforming growth factor beta secretion and could affect number and function of regulatory T cells.

© 2015 American Society of Hematology.