Multiparameter Flow Cytometry Identification of Neoplastic Subclones: A New Biomarker in Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma.

Multiparameter flow cytometry (MFC)-based clonality assessment is a powerful method of diagnosis and follow-up in monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). However, the relevance of intraclonal heterogeneity in immunophenotypic studies remains poorly understood. The main objective of this work was to characterize the different immunophenotypic subclones in MGUS and MM patients and to investigate their correlation with disease stages. An 8-color MFC protocol with 17 markers was used to identify the subclones within the neoplastic compartment of 56 MGUS subjects, 151 newly diagnosed MM patients, 30 MM subjects in complete remission with detectable minimal residual disease, and 36 relapsed/refractory MM patients. Two or more clusters were observed in > 85% of MGUS subjects, 75% of stage I MM patients, and < 15% in stage III. Likewise, a significant correlation between the dominant subclone size, secondary cytogenetic features, and changes in the expression of CD27, CD44, and CD81 was detected. The loss of intraclonal equilibrium may be an important factor related with kinetics and risk of progression not well considered to date in MFC studies. The MFC strategy used in this work can provide useful biomarkers in MGUS and MM.

Successful discontinuation of eltrombopag after complete remission in patients with primary immune thrombocytopenia.

Eltrombopag is effective and safe in immune thrombocytopenia (ITP). Some patients may sustain their platelet response when treatment is withdrawn but the frequency of this phenomenon is unknown. We retrospectively evaluated 260 adult primary ITP patients (165 women and 95 men; median age, 62 years) treated with eltrombopag after a median time from diagnosis of 24 months. Among the 201 patients who achieved a complete remission (platelet count >100 × 10(9) /l), eltrombopag was discontinued in 80 patients. Reasons for eltrombopag discontinuation were: persistent response despite a reduction in dose over time (n = 33), platelet count >400 × 10(9) /l (n = 29), patient's request (n = 5), elevated aspartate aminotransferase (n = 3), diarrhea (n = 3), thrombosis (n = 3), and other reasons (n = 4). Of the 49 evaluable patients, 26 patients showed sustained response after discontinuing eltrombopag without additional ITP therapy, with a median follow-up of 9 (range, 6-25) months. These patients were characterized by a median time since ITP diagnosis of 46.5 months, with 4/26 having ITP < 1 year. Eleven patients were male and their median age was 59 years. They received a median of 4 previous treatment lines and 42% were splenectomized. No predictive factors of sustained response after eltrombopag withdrawal were identified. Platelet response following eltrombopag cessation may be sustained in an important percentage of adult primary ITP patients who achieved CR with eltrombopag. However, reliable markers for predicting which patients will have this response are needed.

Addition of chemotherapy to nivolumab after PD-1 inhibitor failure as bridge to allogeneic stem cell transplantation in classical Hodgkin's lymphoma: report on three cases and literature review.

The poor prognosis of refractory or relapsed (R/R) classical Hodgkin's lymphoma (cHL) after autologous stem cell transplantation has improved greatly due to the introduction of brentuximab vedotin and PD-1 inhibitors. However, the duration of response achieved with these novel agents is too short. The information about the management of patients after anti-PD-1 therapy failure is very limited in cHL, although chemotherapy alone or combined with PD-1 inhibitors has shown encouraging results. We report three cases of heavily pretreated cHL, refractory to nivolumab monotherapy, successfully rescued with the addition of chemotherapy to nivolumab, as a bridge to allogeneic stem cell transplantation (allo-SCT). All three patients presented poor clinical features such as three to four previous lines including brentuximab vedotin and autologous stem cell transplantation, refractoriness to the last line of therapy previous to nivolumab, and rapid disease progression. Notwithstanding these characteristics and nivolumab failure, they achieved a complete response after the addition of chemotherapy, were consolidated with allo-SCT, and still remain in complete response. There are few studies concerning the combination of PD-1 inhibitors and chemotherapy after nivolumab failure, including one retrospective study and one phase II trial with nivolumab plus bendamustine. Therefore, only few patients are consolidated with allo-SCT. However, there are several ongoing trials investigating new combinations of chemotherapy and PD-1 inhibitors in R/R cHL, as well as in first line. All these data suggest that anti-PD-1 therapy may reprogram the immune system, activating and inhibiting effector and immunosuppressive cells, respectively, leading to overtake of chemorefractoriness. Allo-SCT can increase the immune-related events of patients treated with anti-PD-1 previously, consistent on acute graft-versus-host disease, sinusoidal obstruction syndrome, and noninfectious febrile syndrome. In conclusion, the combination of PD-1 inhibitor and chemotherapy may be a feasible therapy after anti-PD-1 treatment failure as a bridge to allo-SCT.