Svetlana Trestman

Autoimmune thrombocytopenia in chronic myeloid leukemia treated with interferon-alpha: Differential diagnosis and possible pathogenesis

Interferon-α (INF-α) is an effective anti-neoplastic and anti-viral drug. Treatment with INF-α is frequently complicated by adverse effects, which may rarely be immune mediated. We report 2 patients with Ph+ chronic myeloid leukemia (CML) who developed autoimmune thrombocytopenia while receiving months of treatment with INF-α. This complication responded well to discontinuation of interferon and administration of steroids treatment. Here, we also summarize the literature on INF-α induced autoimmune thrombocytopenia, and discuss differential diagnosis and possible mechanisms involved in the development of thrombocytopenia during therapy with INF-α.

Outcomes of light-chain amyloidosis patients treated with first-line bortezomib: a collaborative retrospective multicenter assessment.

Light‐chain amyloidosis (AL) is associated with low survival rates, particularly in patients with cardiac involvement. We evaluated the outcome of 73 consecutive, non‐selected ‘real‐world’ AL patients, treated with first‐line bortezomib‐based induction, focusing on the benefit of concurrent administration of alkylating agents. Most patients had renal (77%), cardiac (66%), or multiorgan (74%) involvement. Sixty‐eight per cent (n = 50) received alkylating agent (mostly cyclophosphamide). Severe adverse events were seen in 45%, most evident in patients with cardiac involvement, with no increased toxicity in patients receiving an alkylator agent. Hematological response (HemR) was obtained in 77% of patients, including 33% very good partial responses and 19% complete responses. Age <70 yr, lack of cardiac and peripheral neurologic involvement, and co‐administration of an alkylating agent were associated with significantly improved HemR. NYHA cardiac failure staging was the only independent factor affecting overall survival. Administration of an alkylating agent and the achievement of both HemR and organ response were associated with a statistically significant improved survival in those surviving the first 6 months of induction. First‐line bortezomib‐based regimen resulted in favorable response and survival in newly diagnosed patients. Co‐administration of an alkylating agent improved outcome without increasing treatment‐related toxicity.

Divergence in CD19-Mediated Signaling Unfolds Intraclonal Diversity in Chronic Lymphocytic Leukemia, Which Correlates with Disease Progression

Emerging data on intraclonal diversity imply that this phenomenon may play a role in the clinical outcome of patients with chronic lymphocytic leukemia (CLL), where subsets of the CLL clone responding more robustly to external stimuli may gain a growth and survival advantage. In this study, we report intraclonal diversity resolved by responses to CD19 engagement in CLL cells, which can be classified into CD19-responsive (CD19-R) and -nonresponive subpopulations. Engagement of CD19 by anti-CD19 Ab rapidly induced cellular aggregation in the CD19-R CLL cells. The CD19-R CLL cells expressed higher surface levels of CD19 and c-myc mRNA, exhibited distinct morphological features, and were preferentially abolished in rituximab-treated patients. Both subpopulations reacted to sIgM stimulation in a similar manner and exhibited similar levels of Akt and Erk phosphorylation, pointing to functional signaling divergence within the BCR. CD19 unresponsiveness was partially reversible, where nonresponding CD19 cells spontaneously recover their signaling capacity following incubation in vitro, pointing to possible in vivo CD19–signaling attenuating mechanisms. This concept was supported by the lower CD19-R occurrence in bone marrow–derived samples compared with cells derived from the peripheral blood of the same patients. CLL patients with >15.25% of the CD19-R cell fraction had a shorter median time to treatment compared with patients with <15.25% of CD19-R cell fraction. In conclusion, divergence in CD19-mediated signaling unfolds both interpatient and intraclonal diversity in CLL. This signaling diversity is associated with physiological implications, including the location of the cells, their responses to anti-CLL therapeutics, and disease progression.

Serum free immunoglobulin light chain fingerprint identifies a subset of newly diagnosed multiple myeloma patients with worse outcome

Multiple myeloma (MM) is a multi–subclonal malignancy with relatively high heterogeneity. Patients who initially presented with both monoclonal‐protein (MP) and free light chain (FLC) secretion but then relapsed with a light chain escape pattern have been shown to reflect disease clonal evolution and to bare a worse prognosis. We hypothesized that a discordant MP/FLC pattern at diagnosis may reflect a similar clonal evolution that had occurred prior to diagnosis of active myeloma, conferring a worse outcome. We analyzed 255 consecutive newly diagnosed MM patients who received first line bortezomib‐based therapy between 2007 and 2014, hypothesizing that their MP/FLC fingerprint at diagnosis reflects clonal heterogeneity and, therefore, affects outcome. An involved FLC level ≥ 700 mg/L and MP ≥ 2.5 g/L were used as cutoffs for low vs high FLC and MP levels, respectively. Patients were divided into 4 subgroups according to their involved FLC and MP blood levels at diagnosis: HiLC and HiMP for patients with either a predominant FLC or a predominant MP, respectively, and HiLC‐MP and LoLC‐MP when both FLC and MP were increased or decreased, respectively. There were 68 (27%) patients with HiLC, which presented more often with International Staging System‐3 stage (P < .0001). Multivariate analysis showed that HiLC was associated with a 5.1‐fold risk for mortality in a multivariate model (95% confidence interval [CI], 1.34‐19.68). Both HiLC and HiLC‐MP phenotypes were associated with shorter progression‐free survival (hazard ratio of 2.66 [95% CI, 1.33‐5.32] and 2.82 [95% CI, 1.37‐5.83], respectively), independently of other prognostic factors, including the use of autograft. Thus, we identified an LC predominant secretory fingerprint (HiLC phenotype) at diagnosis as a potential independent risk factor that may affect disease control and survival in newly diagnosed MM patients treated with bortezomib‐based induction therapy; this may represent increased subclonal heterogeneity.

Treatment patterns and clinical outcomes in high‐risk newly diagnosed multiple myeloma patients carrying the 17p deletion: An observational multi‐center retrospective study

Del17p is a genomic imbalance occurring in ∼7%‐10% of myeloma at diagnosis newly diagnosed myeloma patients (NDMM) and comprises a poor prognostic factor. The goal of this study is to analyze real world data and outcomes among NDMM patients carrying 17p deletion. We report an observational, retrospective, multicenter study. Sixty consecutive patients diagnosed with multiple myeloma in the 8 participating centers diagnosed between 1/2008 and 1/2016 proven to carry 17p deletion by means of fluorescence in situ hybridization (FISH) were identified. Most received a bortezomib‐based induction, over half underwent autologous hematopoietic cell transplantation (HCT); 30% of the patients gained early access to new novel agents via clinical trials, access programs or private insurance. Overall response rate (ORR) after induction was 85%; 94% for transplant eligible (TE); and 75% for transplant ineligible (NTE), and declined in subsequent treatment lines, 64% achieved ≥ VGPR. Median overall survival (OS) was 43 months; median progression free survival (PFS) was 11 months, 19 months for TE and 7 for NTE. In multivariate analysis: higher M‐Spike, presence of extramedullary disease, and >50% of cells baring del17p were associated with adverse PFS; Autologous HCT and higher hemoglobin were associated with longer PFS; OS was 59 months for patients with early access to newer agents. Older age and higher M‐Spike levels were associated with adverse OS, Autologous HCT was associated with favorable OS, 59.7 vs 28.7 months for NTE patients. Despite the improvement achieved with autologous HCT and new novel agents, the prognosis of patients with 17p deletion is still inferior, emphasizing the need for novel approaches.