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Chimeric antigen receptors (CAR)-modified T cells are an emerging therapeutic tool for chronic lymphocytic leukemia (CLL). However, in patients with CLL, well-known T-cell defects and the inhibitory properties of the tumor microenvironment (TME) hinder the efficacy of CAR T cells. We explored a novel approach combining CARs with lenalidomide, an immunomodulatory drug that tempers the immunosuppressive activity of the CLL TME. T cells from patients with CLL were engineered to express a CAR specific for CD23, a promising target antigen. Lenalidomide maintained the in vitro effector functions of CD23.CAR+ T cells effector functions in terms of antigen-specific cytotoxicity, cytokine release and proliferation. Overall, lenalidomide preserved functional CAR T-CLL cell immune synapses. In a Rag2−/−γc−/−-based xenograft model of CLL, we demonstrated that, when combined with low-dose lenalidomide, CD23.CAR+ T cells efficiently migrated to leukemic sites and delayed disease progression when compared to CD23.CAR+ T cells given with rhIL-2. These observations underline the therapeutic potential of this novel CAR-based combination strategy in CLL. [ABSTRACT FROM AUTHOR]

High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (DH/TH-HGBL) still miss an in-depth genomic characterization. To identify accompanying genetic events, we performed a pilot study on 7 cases by applying DNA microarray and targeted NGS sequencing. Interestingly, the genetic background of DH/TH-HGBL is largely overlapping with that of other high-grade/poor prognosis lymphomas. Namely, copy number abnormalities were trisomy of chromosome 7 and chromosome 8q gain, encompassing MYC. Among gene variants, those affecting transcription factors (MYC, FOXO1), epigenetic modulators (KMT2D, EZH2 and CREEBP), and anti-apoptotic gene (BCL2), were recurrent. MYC and BCL2 were mutated in 3 and 5 cases, respectively. In addition, mutations of FOXO1, previously reported in Diffuse Large B-Cell Lymphomas, were also detected. Clarifying the genomic background of this subset of high-risk lymphomas will pave the way for the clinical use of new biomarkers to: (1) monitor treatment response and; (2) consider alternative targeted therapies. [ABSTRACT FROM AUTHOR]

To characterize the effect of glasdegib on cardiac repolarization (QTc) in patients with advanced cancer. A concentration–QTc model was developed using data from two glasdegib single-agent, dose-escalation trials. Triplicate electrocardiogram was performed at pre-specified timepoints paired with pharmacokinetic blood collections after a single dose and at steady-state. Changes in QTc from baseline were predicted by model-based simulations at the clinical dose (100 mg QD) and in a supratherapeutic setting. Glasdegib did not affect the heart rate, but had a positive effect on the corrected QT interval, described by a linear mixed-effects model with ΔQTcF (QTc using Fridericia's formula) as the dependent variable with glasdegib plasma concentrations from doses of 5–640 mg QD. The predicted mean QTcF change (upper bound of the 95% CI) was 5.30 (6.24) msec for the therapeutic 100-mg QD dose; at supratherapeutic concentrations (40% and 100% increase over the therapeutic Cmax), it was 7.42 (8.74) and 12.09 (14.25) msec, respectively. The relationship of glasdegib exposure and QTc was well characterized by the model. The effect of glasdegib on the QTc interval did not cross the threshold of clinical concern for an oncology drug. ClinicalTrials.gov ID: NCT01286467 and NCT00953758. [ABSTRACT FROM AUTHOR]

Objectives: Detectable minimal residual disease (MRD) after therapy for acute lymphoblastic leukemia (ALL) is the strongest predictor of hematologic relapse. This study evaluated outcomes of patients with B-cell precursor ALL with MRD of ≥10−4 Methods: Study population was from ALL study groups in Europe managed in national study protocols 2000–2014. MRD was measured by polymerase chain reaction or flow cytometry. Patients were age ≥15 years at initial ALL diagnosis. Patients were excluded if exposed to blinatumomab within 18 months of baseline or prior alloHSCT. Results: Of 272 patients in CR1, baseline MRD was ≥10−1, 10−2 to <10−1, 10−3 to <10−2, and 10−4 to <10−3 in 15 (6%), 71 (26%), 109 (40%), and 77 (28%) patients, respectively. Median duration of complete remission (DoR) was 18.5 months (95% confidence interval [CI], 11.9–27.2), median relapse-free survival (RFS) was 12.4 months (95% CI, 10.0–19.0) and median overall survival (OS) was 32.5 months (95% CI, 23.6–48.0). Lower baseline MRD level (P ≤.0003) and white blood cell count <30,000/µL at diagnosis (P ≤.0053) were strong predictors for better RFS and DoR. Allogeneic hematopoietic stem cell transplantation (alloHSCT) was associated with longer RFS (hazard ratio [HR], 0.59; 95% CI, 0.41–0.84) and DoR (HR, 0.43; 95% CI, 0.29–0.64); the association with OS was not significant (HR, 0.72; 95% CI, 0.50–1.05). Discussion: In conclusion, RFS, DoR, and OS are relatively short in patients with MRD-positive ALL, particularly at higher MRD levels. AlloHSCT may improve survival but has limitations. Alternative approaches are needed to improve outcomes in MRD-positive ALL. [ABSTRACT FROM AUTHOR]

An exploratory analysis of 75 follicular lymphoma patients treated with obinutuzumab or rituximab induction therapy (IT) for 4 weeks in the phase II GAUSS study aimed to determine whether positron emission tomography (PET) results could predict progression-free survival (PFS) and tumor response. The proportion of patients with a PFS event (progression or death) was higher in those who were PET-positive after IT (assessed using Deauville five-point scale criteria; 35/52, 67%) than PET-negative (5/20, 25%); the hazard ratio for progression or death was 0.25 (95%CI: 0.01–0.64;p = 0.0018). A significant association was also found when PET results were assessed using International Harmonization Project and European Organisation for Research and Treatment of Cancer criteria. Change between baseline and end of IT in values of standardized uptake value and other PET parameters were associated with PFS and response. Validation of these results in prospective studies of larger cohorts is warranted. [ABSTRACT FROM AUTHOR]

Following the 53rd annual meeting of the American Society of Hematology (ASH) in San Diego in December 2011, a group of clinical and laboratory investigators convened for the 6th Post-ASH International Workshop on Chronic Myeloid Leukemia (CML) and Myeloproliferative Neoplasms (MPN). The Workshop took place on 13-14 December at the Estancia, La Jolla, California, USA. This report summarizes the most recent advances in the biology and therapy of CML that were presented at the ASH meeting and discussed at the Workshop. Preclinical studies focused on the CML stem cell and its niche, and on early results of deep sequencing of CML genomes. Clinical advances include updates on second- and third-generation tyrosine kinase inhibitors (TKIs), molecular monitoring, TKI discontinuation studies and new therapeutic agents. A report summarizing the pertinent advances in MPN has been published separately. [ABSTRACT FROM AUTHOR]

We retrospectively analyzed the data of 337 patients with cytogenetically normal (CN) acute myeloid leukemia (AML), aged ≤ 65 years (training set). A prognostic index score (PIS) was calculated by totaling the score derived from the regression coefficients of each clinical variable, significantly associated with prognosis by multivariate analysis. The variables that were independent prognostic factors for event-free survival (EFS) and overall survival (OS) in the training set were: age ≥ 50 years, secondary AML and white blood cell count (WBC) ≥ 20 × 109/L. The patients of the training set were stratified into three groups: low-, intermediate- and high-risk. The median EFS was 25, 12 and 7 months in the low-, intermediate- and high-risk groups (p < 0.0001), respectively. The median OS was not reached in the low-risk group and was 19 and 10 months in the intermediate- and high-risk groups (p < 0.0001). This PIS was validated in a series of 193 patients with CN-AML. The median EFS was 66, 16, and 3 months (p < 0.0001) and the median OS was 66, 16, and 5 months in the three risk groups, respectively (p < 0.0001). This PIS may be useful for clinical decision-making in CN-AML and may be prospectively integrated with the newest biological markers which at present are not routinely assessed and need prognostic validation. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the efficacy of combined treatment with rituximab and subcutaneous cladribine in patients with newly diagnosed and relapsed chronic lymphocytic leukemia (CLL). Forty-three patients with active CLL or small lymphocytic lymphoma received rituximab 375 mg/m2 on day 1 and cladribine 0.1 mg/kg subcutaneously on days 2–6. The treatment was repeated every 4 weeks for a total of four cycles. Sixteen patients were pretreated. The overall response rate was 88% (50% complete remission and 38% partial remission). The median time to treatment failure was 37.9 months. Grade 4 neutropenia developed in 5% of patients. The data indicate that combination therapy with rituximab and cladribine is a valuable and safe treatment for patients with CLL. [ABSTRACT FROM AUTHOR]

Imatinib has revolutionized the treatment of patients with chronic myeloid leukemia (CML). However, some patients may experience resistance or intolerance to imatinib over time. For these patients, two excellent therapeutic options are available. Dasatinib, approved in 2006 for the treatment of patients with CML in all phases who experience imatinib resistance or intolerance, has displayed significant efficacy, with a 2-year follow-up showing durable hematologic and cytogenetic responses, as well as prolonged progression-free and overall survival. Nilotinib was approved in 2007 for the treatment of patients with CML in chronic phase or CML in accelerated phase, resistant or intolerant to prior therapy including imatinib, based on strong efficacy as well as a favorable safety profile. Several factors, including mutation status, patient history, and existing comorbidities can impact the decision to use dasatinib or nilotinib, or pursue other options such as allogeneic stem cell transplant. The purpose of this review article is to shed light on a further consideration when deciding which agent to use, based on the efficacy and safety of dasatinib and nilotinib. This consideration involves the differences in both the imatinib-resistant and -intolerant patients enrolled in the pivotal studies for each agent, as well as other trial criteria. [ABSTRACT FROM AUTHOR]

Here, we present the results of a randomised clinical trial carried out between 1998 and 2004, evaluating the possible role of radiotherapy (RT) as consolidation treatment after induction chemotherapy (CT) in diffuse large B-cell (DLBC) gastric lymphoma. Fifty-four patients were enrolled and all received anthracycline containing regimens as induction CT. Patients were evaluated after four to six cycles and those in complete remission (CR) were randomised to receive gastric involved field (IF) RT or two addition cycles of the same CT. Forty-five patients (83%) were randomised after the induction CT. Clinical results of patients allocated to the RT arm showed a significant reduction in incidence of local relapse versus patients who received CT alone. However, overall survival was not different between the two arms. Our results confirm that CT could be considered as first line therapy for newly diagnosed gastric DLBC lymphoma; IF RT delivered in those patients achieving CR after induction CT is able to prevent local relapse. [ABSTRACT FROM AUTHOR]

The JAK2V617F mutation occurs in 50% of patients with essential thrombocythemia (ET). We investigated the correlation between the JAK2V617F mutation and clinical and laboratory characteristics, thrombohemorrhagic risk and incidence of disease evolution in 275 patients with ET followed for a median follow-up of 7 years. JAK2V617F mutation was detected in 175 patients (64%), of whom 173 were heterozygous. Patients with the mutation were older and displayed higher hemoglobin and hematocrit levels, but lower platelet count. Cytotoxic treatment requirement was similar in the two groups, but patients with the mutation showed better responses. Incidence of thrombosis and disease evolution was comparable. JAK2 mutational status assessment was valuable to distinguish two populations of patients with ET, showing distinctive hematologic and clinical features. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which discusses a study on the impact of additional cytogenetic abnormalities (ACA) on the response and survival of patients with late chronic phase chronic myeloid leukemia (CML), who were treated with the Bcr-Abl tyrosine kinase imatinib mesylate.

Chronic myeloid leukemia (CML) is the first human malignancy for which the promise of targeted therapy has come true. CML is invariably associated with a specific genetic lesion - the t(9;22) chromosomal translocation. As a consequence of this translocation, a BCR-ABL fusion gene is formed on the 22q- derivative (traditionally known as the Philadelphia chromosome) and the deregulated tyrosine kinase activity of the protein encoded by this gene has been shown to be both necessary and sufficient for initiation and maintenance of the disease. Imatinib mesylate, an orally available tyrosine kinase inhibitor that targets Bcr-Abl, entered clinical evaluation in 1998. Its efficacy surpassed almost everyone's predictions, and the observation of high response rates and favorable toxicity profile associated with imatinib therapy led to its approval as first-line treatment for all newly diagnosed CML patients over an exceptionally short period of time. The 6-year results of the Phase III trial have recently been reported and confirm durability of responses and declining incidence of adverse events over time, although, at present, occurrence of unexpected side effects in the long term cannot be excluded. Although imatinib does 'cure' CML and has to be administered chronically to patients, it has revolutionized both outcome and quality of life CML patients. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) remains the most common form of leukemia and the most common cause of leukemia death. Although conventional chemotherapy can cure between 25 and 45% of AML patients, the majority of patients die after relapse or of complications associated with treatment. Thus, more specific and less toxic treatments for AML patients are needed, especially for elderly patients. An indispensable prerequisite to investigate tailored approaches for AML is the recent progress in the understanding the molecular features that distinguish leukemia progenitors from normal hematopoietic counterparts and the identification of a variety of dysregulated molecular pathways. This in turn would allow the identification of tumor-specific characteristics that provide a rational basis for the development of more tailored, and hence potentially more effective and less toxic, therapeutic approaches. In this review, we describe some of the signaling pathways that are aberrantly regulated in AML, with a specific focus on their pathogenetic and therapeutic significance, and we examine some recent therapies directed against these targets, used in clinical trial for relapsed patients or unfit for conventional chemotherapy. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented that discusses the diagnostic and therapeutic challenges involved in an extramedullary myeloid tumour of the stomach and duodenum without acute myeloblastic leukemia.

The (1;19)(q23;p13) translocation, leading to the production of the E2A/PBX1 fusion transcript, is one of the most common translocations in pediatric B-lineage acute lymphoblastic leukemia (ALL). It was assumed to be associated with a poor clinical outcome, although intensive therapy and bone marrow transplantation have been shown to be able to overcome the negative prognostic impact. Only few data are available concerning t(1;19)(q23;p13) in adult ALL. In particular, the prognostic significance of this genetic aberration is not yet clear. We describe three cases of adult ALL carrying the t(1;19)(q23;p13), who were all characterized by an aggressive clinical course and short survival, and discuss the molecular features of the disease as recently identified by gene expression profiling. [ABSTRACT FROM AUTHOR]

Antibody-targeted chemotherapy is a promising approach in patients with hematological malignancies. In particular, gemtuzumab ozogamicin (GO, formerly CMA-676), an anti-CD33 antibody linked to calicheamicin, has been approved for the treatment of elderly patients with acute myeloid leukemia (AML) in relapse. Nevertheless, no data are until now available concerning the possible efficacy of GO for myeloid sarcomas (MS). We treated with GO 24 AML patients, in 5 cases presenting with myeloid sarcomas of the skin or bones. The overall complete response rate was 21%. The median duration of response was 6 months. Four out of the 5 patients with myeloid sarcoma showed a regression of the masses, in two cases also obtaining a clearance of marrow blasts. The most common adverse events included thrombocytopenia, neutropenia, infections, elevation of bilirubin and hepatic transaminases. Notably, severe bleeding occurred in 5 cases (21%). VOD was documented in 1 case. We conclude that GO is effective as a single agent in AML and myeloid sarcomas. Further data are required to clarify the possible correlation between GO administration and occurrence of bleeding. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) patients with core binding factor abnormalities [inv(16) or t(8;21)] have a relatively good prognosis, especially patients with inv(16) when treated with high-dose cytosine arabinoside (AraC) containing regimens, whereas in the case of t(8;21) evidences in favor of such regimen are contrasting. We previously demonstrated that blast cells from inv(16)-positive AML patients are characterized by an increased sensitivity to AraC with higher incorporation of 3 H AraC into DNA and the increase of induced apoptosis in vitro . In the present study we tested the sensitivity of leukemic cells from 15 t(8;21)-positive AML patients to AraC and compared it with the results obtained from cells of 74 patients with inv(16), "intermediate" or "unfavourable" karyotype at diagnosis (for a total of 89 patients). The incorporation of 3 H AraC into DNA in cells with t(8;21) was significantly lower than in cells with inv(16) ( P  = 0.02) or normal karyotype ( P  = 0.04). Interestingly, the incorporation of the drug into DNA in t(8;21) cells was similar to those with "unfavourable" karyotype. Furthermore, AraC induced apoptosis in t(8;21)-positive AML cells was not increased. These data suggest that the mechanism of response to chemotherapy for t(8;21)-positive cells is probably different then in AML cells with inv(16), underlining the possible importance for patients carrying the t(8;21) of repeated high-dose regimens and not necessarily of high-dose AraC based ones. [ABSTRACT FROM AUTHOR]

Evaluates the cytogenetic response of patients with chronic myeloid leukemia treated with alpha-interferon. Feasibility of peripheral blood stem cell mobilization induced by granulocyte-colony stimulating factor (G-CSF); Patient tolerance for G-CSF; Number of patients who achieved karyotypic remission before mobilization.

The article discusses the development of acute myeloid leukemia in patient with ataxia telangiectasia (AT). It is noted that two-thirds of patients with AT experience severe to moderate immunodeficiency while more than 50 percent show compartmental immunoglobulin deficit. The author also highlights the need for more information to determine the appropriate dosages of chemotherapy to reduce toxicities and remission rates in AT patients with myeloid leukemia.

Despite aggressive approaches, including second transplant, donor lymphocyte infusion and several new agents, the prognosis of acute lymphoid leukemia (ALL) patients relapsing after stem-cell transplantation (SCT) remains poor. Monoclonal-antibodies (moAb) could provide a useful tool in this setting. In particular, anti-CD52 moAb is useful in lymphoid malignancies. We thus treated as compassionate with campath-1H 3 ALL patients relapsed after SCT. In 2 cases we observed a reduction of peripheral blood and/or bone marrow blasts. In 1 case a GVHD grade reduction was observed. Larger trials are required in order to define the role of campath-1H in ALL. [ABSTRACT FROM AUTHOR]

Essential thrombocythemia (ET) is a chronic myeloproliferative disorder characterised by the absence of the Philadelphia (Ph+) chromosome. Recent studies have reported controversial results relating to BCR-ABL rearrangements in ET patients. We studied 44 Ph-negative ET patients with the RT-PCR technique at diagnosis or during the follow-up. None of them showed any of the BCR-ABL transcript actually described by others in ET; neither the “classical” P210 nor the P190 or P230 variants. Our results confirm the absence of BCR-ABL abnormalities in Ph-negative ET patients. [ABSTRACT FROM AUTHOR]

Visceral fungal infections are a serious complication during chemotherapy in acute myeloid leukemia patients. In particular, aspergillus species are often responsible for severe infections in these patients. The lung, with at least four different histo-pathological patterns, and the nasal sinuses are the sites most frequently involved by this agent. Both types of infection can be lethal, the invasion of major bronchial vessels, and the colonisation of the central nervous system through the ethmoid bone both possible dramatic events. Recovery of ANC and prompt systemic specific antifungal treatments are then necessary in order to control the process. At present, intravenous deoxicholate amphotericin B (fungizoneB) is the most frequently employed schedule for the treatment of these infections, and nephrotoxicity and infusion related chills are the principal adverse effects. These two drugs have also been tested as an aerosol in order to increase the pulmonary concentration and reduce their systemic toxicity. Moreover, the successful direct instillation of antifungal agents into a pulmonary aspergillus has been described. In some cases, lung surgery can be proposed for isolated aspergillomas, while granulocyte transfusions have also been utilised in case of invasive mycosis.