SUMMARY Poly (ADP-ribose) polymerase inhibitors (PARPis) are clinically effective predominantly for BRCA-mutant tumors. We introduce a mechanism-based strategy to enhance PARPi efficacy based on DNA damage-related binding between DNA methyltransferases (DNMTs) and PARP1. In AML and breast cancer cells, DNMT inhibitors (DNMTis) alone covalently bind DNMTs into DNA and increase PARP1 tightly bound into chromatin. Low doses of DNMTis plus PARPis, versus each drug alone, increase PARPi efficacy, increasing amplitude and retention of PARP1 directly at laser-induced DNA damage sites. This correlates with increased DNA damage, synergistic tumor cytotoxicity, blunting of self-renewal and strong anti-tumor responses in unfavorable AML subtypes and BRCA wild-type breast cancer cells. Our combinatorial approach introduces a strategy to enhance efficacy of PARPis in treating cancer.

• This is the first trial to investigate PD-1 inhibitor, pembrolizumab, and an IMiD (pomalidomide) in MM with promising clinical efficacy.• PD-L1 expression on myeloma cells and PD-1 on marrow infiltrating T lymphocytes are potential biomarkers for efficacy of PD-1 blockade. 33%]); median duration of response was 14.7 months. At median follow-up of 15.6 months, progression-free survival (PFS) was 17.4 months and overall survival was not reached. Analyses of pretreatment marrow samples revealed a trend for increased expression of PD-L1 in responding patients and longer PFS with increased T-lymphocyte infiltrates, irrespective of PD-1 expression. Pembrolizumab, pomalidomide, and low-dose dexamethasone have acceptable safety and durable responses in RRMM patients. This trial was registered at www.clincialtrials.gov as

To determine whether primary plasma cell leukemia (PPCL) remains a high-risk multiple myeloma feature in the context of contemporary therapy and gene expression profiling (GEP), we reviewed records of 1474 patients with myeloma who were enrolled in Total Therapy protocols or treated identically off protocol. 27 patients (1.8%) were classified as having PPCL. As a group, these patients more often had low hemoglobin, high beta-2-microglobulin, high lactate dehydrogenase, low albumin, and cytogenetic abnormalities. Among 866 patients with GEP results, the PPCL group more often had disease that was classified as high risk, and in CD-1 and MF molecular subgroups. Regardless of the therapeutic protocol, patients with PPCL had shorter median overall survival (1.8 years), progression-free survival (0.8 years), and complete response duration (1.3 years) than the remainder whose clinical outcomes had improved markedly with successive protocols. Multivariate analyses of pretreatment parameters showed that PPCL was a highly significant independent adverse feature linked to overall survival, progression-free survival, and complete response duration. In GEP analyses, 203 gene probes distinguished PPCL from non-PPCL; the identified genes were involved the LXR/RXR activation, inositol metabolism, hepatic fibrosis/hepatic stellate-cell activation, and LPS/IL-1-mediated inhibition of RXR function pathways. Different treatment approaches building on these genomic differences may improve the grave outcome of patients with PPCL.

No abstract

Hypopigmented mycosis fungoides is an uncommon clinical variant of cutaneous T-cell lymphoma. We hypothesized that hypomelanosis in hypopigmented mycosis fungoides may have a similar mechanism as in vitiligo, a condition in which it is believed that alterations in expression of CD117 (stem cell factor receptor/KIT protein) on epidermal melanocytes and abnormal interactions between melanocytes and surrounding keratinocytes may play a pathogenic role. To test the hypothesis that similar mechanisms might also explain hypopigmentation in hypopigmented mycosis fungoides, skin specimens from five cases each of hypopigmented mycosis fungoides and vitiligo were studied immunohistochemically for immunophenotype of the infiltrating cells, CD117 (expressed by epidermal melanocytes), and pan melanoma cocktail of antigens (gp100, tyrosinase, and MART-1) expression; cases of conventional mycosis fungoides and normal skin were studied in parallel as controls. Our findings confirm a predominance of CD8 þ neoplastic T cells in hypopigmented mycosis fungoides. Similarly, the epidermal lymphocytic infiltrate in vitiligo was also composed of CD8 þ cytotoxic T cells, in contrast to an epidermal infiltrate composed of CD4 þ T cells in conventional mycosis fungoides. The average number of epidermal CD117 expressing cells followed the same pattern of decreased expression in hypopigmented mycosis fungoides as in vitiligo, whereas the levels in conventional mycosis fungoides were higher, and similar to that observed in normal skin. Furthermore, a decreased number of melanocytes per high-power field of the length of the biopsy was present in hypopigmented mycosis fungoides and vitiligo, as compared with either conventional mycosis fungoides or normal skin, suggesting a correlation between decreased expression of CD117 and decreased number of melanocytes. We propose that decreased expression of CD117 and its downstream events in melanocytes may be initiated by cytotoxic effects of melanosomal-antigen-specific CD8 þ neoplastic T lymphocytes, resulting in destabilization of CD117 and leading to dysfunction and/or loss of melanocytes in the epidermis of hypopigmented mycosis fungoides.