Giuseppina Uccello

Circulating miRNA markers show promise as new prognosticators for multiple myeloma

1Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA 2Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy 3Molecular Virology, Comprehensive Cancer Center, The Ohio State University, Columbus, OHIO, USA 4Lymphoma & Genomics Research Program, Institute of Oncology Research IOR, Via Vela 6, 6500 Bellinzona, Switzerland 5Department of Clinical and Biological Sciences, Division of Geriatric, S. Luigi Gonzaga Hospital, University of Torino, Italy 6Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture (PZ), Italy 7Italian Multiple Myeloma Network, GIMEMA, Italy 8Abramson Cancer Center, Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, PA, USA

Validation of the CLL-IPI and comparison with the MDACC prognostic index in newly diagnosed patients

To the editor: Recently, an international collaboration collected information from ∼3500 chronic lymphocytic leukemia (CLL) patients to develop a comprehensive tool for predicting overall survival (OS) (the international prognostic index for patients with chronic lymphocytic leukemia [CLL-IPI]).[

Venetoclax for the treatment of chronic lymphocytic leukemia

ABSTRACT Introduction: Venetoclax, an orally bioavailable inhibitor of BCL-2, was approved in 2016 by the United States Food and Drug Administration (FDA) for the treatment of chronic lymphocytic leukemia (CLL) patients with 17p deletion [del(17p)], who have received at least one prior therapy. Areas covered: We focus on the mechanism of action of venetoclax and on the clinical trial data that led to the approval of venetoclax for CLL patients. We also review the studies in which this drug has being explored in combination with other anti-CLL drugs. Expert opinion: Data from early clinical trials have shown that venetoclax, as a single agent, is highly effective for relapsed/refractory CLL patients, including those cases with high-risk features. Furthermore, venetoclax seems to be an appropriate option for patients who progress on B-cell receptor (BCR) pathway kinase inhibitors. Venetoclax is also safe, with the most common serious adverse events being neutropenia. The risk of tumor lysis syndrome (TLS) can be reduced by a slow dose ramp-up, careful monitoring, and adequate prophylaxis. Ongoing trials will further clarify the safety and efficacy of venetoclax in combination with other drugs in both relapsed/refractory and untreated CLL patients.

Lenalidomide and low-dose dexamethasone (Rd) versus bortezomib, melphalan, prednisone (VMP) in elderly newly diagnosed multiple myeloma patients: A comparison of two prospective trials.

There are currently no direct head‐to‐head clinical trials evaluating bortezomib‐melphalan‐prednisone (VMP) versus lenalidomide and low‐dose dexamethasone (Rd). VMP (257 cases) and Rd (222 cases) arms of two randomized phase III trials were employed to assess the treatment influence on outcome in untreated elderly MM patients.

Validation of a biological score to predict response in chronic lymphocytic leukemia patients treated front-line with bendamustine and rituximab

During the the last two decades several biological prognostic markers have been identified in chronic lymphocytic leukemia (CLL) [1]. Some, like the IGHV mutational status and TP53 disruption, are also predictive of response to chemoimmunotherapy [2–6]. Rossi et al. reported an observational retrospective analysis on 404 CLL patients treated front-line with fludarabine-cyclophosphamide-rituximab (FCR) [6]. Based on the IGHV mutational status and FISH cytogenetics, patients were stratified into low risk (mutated IGHV and no adverse FISH cytogenetics [del(17p), del(11q)]), intermediate risk (unmutated IGHV and/or del11q in the absence of del17p), and high risk (del17p independent of co-occurring del11q or unmutated IGHV). This simple biologically based prognostic score based on the combination of three widely utilized biomarkers allowed to stratify patients with a significantly different progression-free survival (PFS) and overall survival (OS) after FCR treatment. In addition, they also demonstrated that low-risk patients had a durable remissions after FCR, with a life expectancy overlapping that observed in the age-matched general population [6]. Similarly, Laurenti et al. recently published a retrospective study on 102 patients with CLL treated front-line with chlorambucil-rituximab [7]. This analysis also showed that the above-mentioned biological score could distinguish patients with a different PFS. A trend toward a better OS was also observed. With the aim of investigating whether this biological score could also segregate CLL patients treated with bendamustine-rituximab (BR), we performed a retrospective study on previously untreated CLL patients who received BR as primary therapy. The cohort included 418 patients with progressive CLL from 34 different hematology centers (29 Italian, 3 Israeli, 1 German, and 1 American) who received at least one dose of BR as front-line treatment during the period 2008–2014; 279 of the 418 patients have been included in a previous multicenter study which reported on the front-line treatment of CLL patients with BR outside of clinical trials [8]. Relative survival, defined as the ratio between the actuarial survival observed in the CLL cohort and the expected survival of the general population matched by sex, age, nationality, and calendar year of starting BR was calculated using the Ederer II method. Expected survival estimates were calculated according to Italian, Israel, German, and American life expectancy tables (Human Mortality Database; http://www. mortality.org/, accessed 18 September 2017). Observed and expected survivals were compared using the Fisher test. Data analysis was carried out by STATA 13.1 (by StataCorp 4905 Lakeway Drive College Station, TX 77845, USA) (further details are in the Supplemental Appendix). The main clinical characteristics of the 418 patients are summarized in Table 1. After a median follow-up of 25 months, 86 patients progressed and 56 died, accounting for an estimated 2-year PFS of 73.2% and a 2-year OS of 88.9%. These results are similar to data of a multicenter prospective phase II trial enrolling 117 CLL patients who received BR as first-line therapy. Fisher et al. recorded a 2-year event-free survival of about 70% and a 2-year OS of 90% [3]. In 285 of the 418 cases complete molecular data were available (Table 1 * Massimo Gentile massim.gentile@tiscali.it

Clinical relevance of hypogammaglobulinemia, clinical and biologic variables on the infection risk and outcome of patients with stage A chronic lymphocytic leukemia

The prognostic effect of hypogammaglobulinemia (HGG), clinical and biologic characteristics on the infection risk and outcome has been retrospectively analyzed in 899 patients with stage A chronic lymphocytic leukemia (CLL). Low levels of IgG were recorded in 19.9% of patients at presentation, low levels of IgM and/or IgA in 10.4% and an additional 20% of patients developed HGG during the course of the disease. Before the start of any treatment, 160 (12.9%) patients experienced at least one grade ≥3 infection requiring a systemic anti-infective treatment and/or hospitalization. While IgG levels at diagnosis were not associated with an increased risk of grade ≥3 infection or with an adverse outcome, a significantly increased rate of grade ≥3 infections was recorded in patients with unmutated IGHV (p=0.011) and unfavorable FISH aberrations (p=0.009). Late onset HGG, more frequently recorded in patients with Rai stage I-II (p=0.001) and unmutated IGHV (p=0.001), was also associated with a higher rate of severe infections (p=0.002). These data indicate that, stage A patients with clinical and biologic characteristics of a more aggressive disease develop more frequently late onset HGG, grade ≥3 infections and require a closer clinical monitoring.

Ponatinib-Induced Graft-versus-Host Disease/Graft-versus-Leukemia Effect in a Patient with Philadelphia-Positive Acute Lymphoblastic Leukemia without the T315I Mutation Relapsing after Allogeneic Transplant.

We describe the case of a patient with Philadelphia-positive acute lymphoblastic leukemia treated with dasatinib plus steroids as first-line therapy, who achieved a major molecular response (MMR) before undergoing matched, unrelated donor allogeneic stem cell transplant. Eleven months after the transplant, she experienced molecular relapse. Mutational screening showed negativity for the T315I mutation, The patient underwent a salvage chemotherapy regimen with clofarabine + cyclophosphamide + steroids and ponatinib (clofarabine 70 mg i.v., days 1-5, cyclophosphamide 700 mg i.v., days 1-5, and ponatinib 45 mg p.o., daily starting at day 15). We observed a rapid decrease in minimal residual disease on molecular assessment with an MMR of P190-BCR-ABL/ABL = 0.01% confirmed by bone marrow revaluations at days +23, +59, +108, and +191 after the first day of salvage chemotherapy. After starting ponatinib, the patient experienced skin graft-versus-host disease, suggesting that the efficacy of ponatinib could be related not only to the direct antileukemic effect but also to its ability to promote an indirect graft-versus-leukemia effect. Ponatinib treatment was well tolerated and considered safe with easily manageable side effects.

Pomalidomide in multiple myeloma

The recent introduction of novel agents (thalidomide, lenalidomide, and bortezomib) has impacted favorably on the survival of multiple myeloma (MM) patients. However, prognosis is poor for those who relapse or are refractory (RR) to lenalidomide and bortezomib [1]. Pomalidomide, a third-generation IMiD, was approved in 2013 by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in combination with low-dose dexamethasone for MM patients who have received at least two prior therapies, including both lenalidomide and bortezomib, and whose disease progressed after the last treatment. Herein, we review the current knowledge regarding the clinical use of pomalidomide in MM (Tables 1 and 2).