Single cell dissection of plasma cell heterogeneity in symptomatic and asymptomatic myeloma

Multiple myeloma, a plasma cell malignancy, is the second most common blood cancer. Despite extensive research, disease heterogeneity is poorly characterized, hampering efforts for early diagnosis and improved treatments. Here, we apply single cell RNA sequencing to study the heterogeneity of 40 individuals along the multiple myeloma progression spectrum, including 11 healthy controls, demonstrating high interindividual variability that can be explained by expression of known multiple myeloma drivers and additional putative factors. We identify extensive subclonal structures for 10 of 29 individuals with multiple myeloma. In asymptomatic individuals with early disease and in those with minimal residual disease post-treatment, we detect rare tumor plasma cells with molecular characteristics similar to those of active myeloma, with possible implications for personalized therapies. Single cell analysis of rare circulating tumor cells allows for accurate liquid biopsy and detection of malignant plasma cells, which reflect bone marrow disease. Our work establishes single cell RNA sequencing for dissecting blood malignancies and devising detailed molecular characterization of tumor cells in symptomatic and asymptomatic patients

Older patients with normal karyotype acute myeloid leukemia have a higher rate of genomic changes compared to young patients as determined by SNP array analysis

10.1016/j.leukres.2011.10.013Leukemia Research364467-473LERE

SH2B3 (LNK) mutations from myeloproliferative neoplasms patients have mild loss of function against wild type JAK2 and JAK2 V617F

10.1111/bjh.12327British Journal of Haematology1616811-820BJHE

Activity and tolerability of nilotinib: A retrospective multicenter analysis of chronic myeloid leukemia patients who are imatinib resistant or intolerant

BACKGROUND: Nilotinib is active in imatinib-resistant and -intolerant chronic myeloid leukemia patients and was recently approved for these indications. METHODS: Data on the efficacy and safety of nilotinib treatment were collected from 2 phase 2 expanded access clinical trials with similar designs (CAMN107AIL01 and ENACT). RESULTS: Of 88 study patients (58 chronic, 11 accelerated, 19 blast crisis), the best responses to nilotinib were complete hematologic response (CHR) in 27%, partial cytogenetic response in 12%, complete cytogenetic response in 14%, and major molecular response in 19%. Patients achieving at least a CHR during imatinib therapy were more likely to respond to nilotinib, and failure to achieve at least a CHR on imatinib therapy was predictive of progression or lack of response to nilotinib (P = .0021). Responses were not statistically different in subgroup analysis, including that of imatinib intolerance compared with imatinib resistance, presence of ABL kinase domain mutations compared with absence of mutations, and previous treatment with another second-generation tyrosine kinase inhibitor compared no prior treatment. The overall survival and progression-free survival rates at 1 year were 83% and 48% for the entire cohort, 93% and 66% in chronic phase, and 64% and 19% in advanced phase. Adverse hematological events included thrombocytopenia (all events, 27%; grade 3-4, 13%) and leukopenia (all events, 18%; grade 3-4, 10%). The majority of the nonhematological events were mild, the most common being rash, infection, bone pain, headache, nausea, and vomiting. CONCLUSIONS: Nilotinib treatment is an efficient and safe therapy for imatinib-resistant or -intolerant patients. Prior response to imatinib therapy is a predictor for the response to nilotinib. © 2010 American Cancer Society

Activity and Tolerability of Nilotinib A Retrospective Multicenter Analysis of Chronic Myeloid Leukemia Patients Who Are Imatinib Resistant or Intolerant

BACKGROUND: Nilotinib is active in imatinib-resistant and -intolerant chronic myeloid leukemia patients and was recently approved for these indications. METHODS: Data on the efficacy and safety of nilotinib treatment were collected from 2 phase 2 expanded access clinical trials with similar designs (CAMN107AIL01 and ENACT). RESULTS: Of 88 study patients (58 chronic, 11 accelerated, 19 blast crisis), the best responses to nilotinib were complete hematologic response (CHR) in 27%, partial cytogenetic response in 12%, complete cytogenetic response in 14%, and major molecular response in 19%. Patients achieving at least a CHR during imatinib therapy were more likely to respond to nilotinib, and failure to achieve at least a CHR on imatinib therapy was predictive of progression or lack of response to nilotinib (P = .0021). Responses were not statistically different in subgroup analysis, including that of imatinib intolerance compared with imatinib resistance, presence of ABL kinase domain mutations compared with absence of mutations, and previous treatment with another second-generation tyrosine kinase inhibitor compared no prior treatment. The overall survival and progression-free survival rates at 1 year were 83% and 48% for the entire cohort, 93% and 66% in chronic phase, and 64% and 19% in advanced phase. Adverse hematological events included thrombocytopenia (all events, 27%; grade 3-4, 13%) and leukopenia (all events, 18%; grade 3-4, 10%). The majority of the nonhematological events were mild, the most common being rash, infection, bone pain, headache, nausea, and vomiting. CONCLUSIONS: Nilotinib treatment is an efficient and safe therapy for imatinib-resistant or -intolerant patients. Prior response to imatinib therapy is a predictor for the response to nilotinib. Cancer 2010;116:4564-72. (C) 2010 American Cancer Society