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8-chloro-adenosine (8-Cl-Ado) is currently in phase-I clinical trials for acute myeloid leukaemia and chronic lymphocytic leukaemia ( CLL). Previously, we demonstrated that treatment with 8-Cl-Ado leads to diminished ATP levels. We hypothesized that AMP-activated protein kinase ( AMPK) signalling would be initiated in these cells, leading to induction of autophagy. AMPK activation and induction of autophagy were demonstrated during preclinical incubations in CLL cells with the analogues. Importantly, we extended similar observations in CLL lymphocytes during an 8-Cl-Ado phase-I trial. In conclusion, 8-Cl-Ado treatment induces autophagy in CLL lymphocytes in vitro as well as in vivo during clinical trial. [ABSTRACT FROM AUTHOR]

The Pim proteins are Ser/Thr kinases over-expressed in several hematological malignancies such as chronic lymphocytic leukemia (CLL) and some solid cancers like prostate cancer. Several small molecules have been developed to inhibit these kinases. In prostate cancer cell lines, the Pim kinase inhibitor SMI-4a and the Bcl-2 antagonist ABT-737 resulted in synergistic cytotoxicity. Akin to prostate cancer cells, CLL lymphocytes over-express Pim and Bcl-2 proteins. It was hypothesized that similar cytotoxic interaction should be observed in CLL. This study evaluated thein vitrocytotoxic effect of three Pim kinase inhibitors (AZD1208, SGI-1776 and SMI-4a) combined with Bcl-2 antagonists (ABT-737 or ABT-199) in malignant CLL lymphocytes. Data indicated Pim kinase inhibitors in combination with ABT-737 or ABT-199 resulted mostly in additive cytotoxicity with a few synergistic responses; however, the extent of synergism was less robust than that observed previously in prostate cancer cell lines treated with SMI-4a and ABT-737. [ABSTRACT FROM PUBLISHER]

BACKGROUND Little is known regarding racial disparities in characteristics and outcomes among patients with chronic lymphocytic leukemia (CLL). METHODS The characteristics and outcomes of untreated African American (AA) patients with CLL (n = 84) were analyzed and compared with a reference nonblack (NB) patient population (n = 1571). RESULTS At the time of presentation, AA patients had lower median hemoglobin levels (12.9 g/dL vs 13.7 g/dL), higher β2 microglobulin levels (2.7 mg/dL vs 2.4 mg/dL), greater frequency of constitutional symptoms (27% vs 10%), unmutated immunoglobulin heavy-chain variable region ( IGHV) mutation status (65% vs 47%), ζ-chain-associated protein kinase 70 (ZAP70) expression (58% vs 32%), and deletion of chromosome 17p or chromosome 11q (28% vs 17%; P ≤ 02 for each comparison). Fifty-one percent of AA patients and 39% of NB patients required first-line therapy and 91% and 88%, respectively, received chemoimmunotherapy. Overall response rates to treatment were 85% for AA patients and 94% for NB patients ( P = .06); and the complete response rates were 56% and 58%, respectively ( P = .87). The median survival of AA patients was shorter compared with that of NB patients (event-free survival: 36 months vs 61 months; P = .007; overall survival: 152 months vs not reached; P = .0001). AA race was an independent predictor of shorter event-free and overall survival in multivariable regression models. CONCLUSIONS The current results indicated that AA patients with CLL have more unfavorable prognostic characteristics and shorter survival compared with their NB counterparts. Cancer 2013;119:3177-3185. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

We evaluated long-term outcomes of 60 patients with chronic lymphocytic leukemia treated with an initial therapy of lenalidomide. At a median follow-up of 4 years, time-to-treatment failure has not been reached and overall survival is 82%. Thirty-five (58%) patients had a response lasting >36 months (long-term responders [LTRs]). Best LTR responses consisted of 25 (71%) complete remissions and 10 (29%) partial remissions. In addition to clinical responses, an increase in IgA, IgG, and IgM levels of >50% from baseline was reported in 61 %, 45%, and 42% of LTRs. Normalization in the percentage of CD4+ and CD8+ cells and T-cell numbers was observed in 48%, 71 % and 99% of LTRs. Compared with other patients in the study, LTRs had lower baseline plasma levels of p-2-microglobulin, were more likely to have trisomy 12, and less likely to have deletion 17p [ABSTRACT FROM AUTHOR]

Backgrounds: Approximately 1,000 microRNAs (miRs) are present in the human genome; however, little is known about the regulation of miR transcription. Because miR levels are deregulated in chronic lymphocytic leukemia (CLL) and signal transducer and activator of transcription (STAT)-3 is constitutively activated in CLL, we sought to determine whether STAT3 affects the transcription of miR genes in CLL cells. Methods: We used publically available data from the ENCODE project to identify putative STAT3 binding sites in the promoters of miR genes. Then we transfected CLL cells with STAT3-shRNA or with an empty vector, and to determine which miRs are differentially expressed, we used a miR microarray approach followed by validation of the microarray results for 6 miRs using quantitative real-time polymerase chain reaction (qRT-PCR). Results: We identified putative STAT3 binding sites in 160 promoter regions of 200 miRs, including miR-21, miR-29, and miR-155, whose levels have been reported to be upregulated in CLL. Levels of 72 miRs were downregulated (n = 63) or upregulated (n = 9). qRT-PCR confirmed the array data in 5 of 6 miRs. Conclusions: The presence of activated STAT3 has a profound effect on miR expression in CLL cells. [ABSTRACT FROM AUTHOR]

A recent phase III trial demonstrated improved progression-free survival (PFS) and overall survival (OS) associated with adding rituximab to fludarabine and cyclophosphamide (R-FC) compared to FC in treatment of previously untreated chronic lymphocytic leukemia (CLL). A cost-effectiveness analysis of R-FC over FC was performed from a US third-party payer perspective over a lifetime horizon in the base case. One-way, two-way and probabilistic sensitivity analyses were conducted to assess the robustness of the results. A secondary analysis was performed by also considering a societal perspective. R-FC was associated with an incremental 1.15 quality-adjusted life-years (QALYs) compared to FC and resulted in an incremental cost-effectiveness ratio of $$23 530 per QALY in the base case and $$31 513 per QALY considering a societal perspective. Results were most sensitive to time horizon, discount rate and unit drug cost for rituximab. Within the limitations of modeling long-term outcomes, R-FC is cost-effective for previously untreated CLL. [ABSTRACT FROM AUTHOR]

The t(14;19)(q32;q13) involving the IGH@ and BCL3 loci is an infrequent cytogenetic abnormality detected in B-cell malignancies. We describe the clinicopathologic, cytogenetic, and molecular genetic characteristics of 14 cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) with t(14;19)(q32;q13). All patients (10 men and 4 women) had lymphocytosis; 10 had lymphadenopathy. Blood and bone marrow lymphocytes were predominantly small, but cytologically and immunophenotypically atypical. In all cases, t(14;19) was found in the neoplastic stem line; it was the sole abnormality in 4. Ten cases showed additional cytogenetic abnormalities, including trisomy 12 in 9 and complex karyotypes in 7. Fluorescence in situ hybridization demonstrated IGH@/BCL3 fusion gene in all cases. In all cases, the IGHV genes were unmutated, but only 7 expressed ZAP70. Seven cases preferentially used IGHV4-39. Our results indicate that t(14;19)(q32;q13) identifies a subset of CLL/SLL with distinctive clinicopathologic and genetic features. Furthermore, t(14;19) may represent an early, possibly primary, genetic event. [ABSTRACT FROM AUTHOR]

The article presents a research on the application of intravenous (iv) bolus alemtuzumab combined with rituximab in patients with chronic lymphocytic leukemia (CLL) through continous intravenous infusion (civ) and subcutaneous (sc) injection. It says that civ, sc alemtuzumab, and iv rituximab was explored in CLL patients. The results suggest that the combination of civ and sc alemtuzumab, along with rituximab, achieved maximum response rate after a 4-week treatment period in 73% of patients.

The article presents a study on the activity of Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) messenger RNA expression in the bone marrow and peripheral blood of patients with chronic lymphocytic leukemia (CLL). The study used direct isothermal mRNA amplification method to detect EBV LMP1 mRNA expression in the peripheral blood of 98 healthy patients and 135 patients with CLL. Results show that 19 of the 135 CLL cases have EBV LMP1 mRNA transcripts, but only 1% in the healthy ones.

Cancer is a genetic disease in which the interplay between alterations in protein-coding genes and non-coding RNAs (ncRNAs) plays a fundamental role. In recent years, the full coding component of the human genome was sequenced in various cancers, whereas such attempts related to ncRNAs are still fragmentary. We screened genomic DNAs for sequence variations in 148 microRNAs (miRNAs) and ultraconserved regions (UCRs) loci in patients with chronic lymphocytic leukemia (CLL) or colorectal cancer (CRC) by Sanger technique and further tried to elucidate the functional consequences of some of these variations. We found sequence variations in miRNAs in both sporadic and familial CLL cases, mutations of UCRs in CLLs and CRCs and, in certain instances, detected functional effects of these variations. Furthermore, by integrating our data with previously published data on miRNA sequence variations, we have created a catalog of DNA sequence variations in miRNAs/ultraconserved genes in human cancers. These findings argue that ncRNAs are targeted by both germ line and somatic mutations as well as by single-nucleotide polymorphisms with functional significance for human tumorigenesis. Sequence variations in ncRNA loci are frequent and some have functional and biological significance. Such information can be exploited to further investigate on a genome-wide scale the frequency of genetic variations in ncRNAs and their functional meaning, as well as for the development of new diagnostic and prognostic markers for leukemias and carcinomas. [ABSTRACT FROM PUBLISHER]

The article offers information on the treatment for fludarabine-refractory chronic lymphocytic leukemia (CLL). Cumulative evidence proposes that allogeneic stem cell transplantation is an effective therapeutic strategy for patients who are not responding to fludarabine. It states that chemoimmunotherapy regimen that includes rituximab or alemtuzuman and allogeneic stem cell transplantation ameliorate the prognosis of fludarabine-refractory CLL.

CD20 is an important therapeutic target in chronic lymphocytic leukaemia (CLL). In order to examine the relationship between CD20 expression and cytogenetic abnormalities, we correlated the fluorescent in-situ hybridization (FISH) genetic subtype of 510 treatment-naïve patients with CD20 expression as measured by quantitative flow cytometry. Patients were classified using the Dohner hierarchial classification. The median numbers of CD20 antigen sites by FISH subtypes were: 17p- ( n = 26), 9341 per cell; 11q- ( n = 42), 5886 per cell; +12 ( n = 93), 23 603 per cell; negative FISH ( n = 153), 8828 per cell; and 13q- ( n = 196), 10 781 per cell. Compared to cases with negative FISH, 11q- cases had significantly lower CD20 expression ( P = 0·001), and +12 cases had significantly higher CD20 expression ( P < 0·001). The significance of trisomy 12 and high CD20 expression was maintained after multivariate analysis accounting for other disease characteristics. Fifty-nine patients received the combination of rituximab and granulocyte-macrophage colony-stimulating factor as frontline therapy; responses were observed in 13 of 14 (93%) patients with +12, in two of four (50%) patients with 11q-, and in 30 of 41 (73%) patients with negative FISH, 13q- or 17p- CLL. Leukemic CD20 expression differed significantly between FISH subtypes. Patients with trisomy 12 CLL showed strong leukemic cell CD20 expression and had a high rate of response to rituximab-based therapy. [ABSTRACT FROM AUTHOR]

Monoclonal antibodies have led to a profound shift in the therapeutic landscape of chronic lymphocytic leukemia (CLL). Alemtuzumab and rituximab remain the most active antibodies, and their single-agent activity has been established in previously untreated and relapsed patients with CLL. Higher response rates and a better quality of response through eradication of minimal residual disease have been reported with monoclonal antibody combinations. Chemoimmunotherapy regimens are being actively explored in frontline CLL therapy, and numerous combination regimens have been investigated in relapse. New and more effective therapies are shifting the focus from palliation to treatment algorithms with curative attempt. Challenges for monoclonal antibody combinations in the future include: (1) defining appropriate patient populations for combination therapies; (2) assessing the impact of pretreatment biologic prognostic factors; (3) enhancing eradication of minimal residual disease; and (4) reassessing response criteria in CLL. [Copyright &y& Elsevier]

The objective of this study was to assess the incidence and the clinical significance of Epstein-Barr virus (EBV) in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Patients with CLL/SLL who presented at The University of Texas M. D. Anderson Cancer Center over a 2-year period and had available marrow paraffin blocks were studied for evidence of EBV infection using a highly specific in-situ hybridization assay for detection of EBV encoded RNA (EBERs). Results were analysed in relation to other presenting characteristics and outcome. Thirty-two patients were examined. EBERs were detected in the bone marrow of 12 of 32 (38%) CLL/SLL marrows vs 0 of 20 normal marrows ( p = 0.002). EBERs were observed in sporadic granulocytes alone or in addition to its presence in lymphocytes in nine of the 12 EBV-positive patients. EBERs were detected less frequently in patients with Rai stage 0 – 1 disease (20%) compared with Rai stage 2 – 4 (66%; p = 0.008). EBER-positive patients tended to have higher lactate dehydrogenase levels ( p = 0.053). The 10-year survival rate was 22% vs 58% for patients with and without discernible EBERs (log-rank, p = 0.08). Evidence of EBV infection was found in 38% of patients with CLL/SLL. Despite the small number of patients tested, discernable EBERs were significantly more common in individuals with more advanced Rai stage and there was a trend toward shorter survival in patients in whom EBV EBERs were discerned. Larger studies are needed to determine the prognostic value and role of EBV infection in patients with CLL/SLL. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukemia (CLL) is a common malignancy often managed by the practicing oncologist rather than at a tertiary referral center. Since no standard treatment has been shown to be curative, patients are frequently observed without treatment for many years. In the past, first-line therapy with an alkylating agent, particularly chlorambucil, was standard when treatment became necessary. Because of its superior activity in achieving remission and extending the time to relapse and disease progression compared with alkylating agents, the purine nucleoside analog fludarabine is now commonly used as first-line treatment. Historically, salvage treatment with combination chemotherapy included an alkylating agent, anthracycline, vinca alkyloid, and/or corticosteroid. Currently, salvage regimens often incorporate a purine nucleoside analog and an alkylating agent. Two monoclonal antibodies, rituximab and alemtuzumab, have become available and have made further advances in both first-line and salvage treatment of patients with CLL. In this article we review the agents and regimens that have been studied as salvage treatment of CLL. With the development of purine nucleoside analogs and monoclonal antibodies, incremental progress has been made in the therapy of previously treated patients with CLL. Newer strategies will aim to further improve the complete remission rate, which may have a positive impact on survival. [ABSTRACT FROM AUTHOR]

Purpose. Amifostine is an organic thiophosphate that may selectively protect normal tissues from the toxicities of chemotherapy. The combination of fludarabine and cyclophosphamide (FC) is highly active in patients with chronic lymphocytic leukemia (CLL). Infection is a serious toxicity of the FC regimen. Methods. Amifostine was added to the FC regimen in a phase II study of 46 patients with CLL. Patients received FCA (fludarabine 30 mg/m2 i.v. daily for 3 days, cyclophosphamide 300 mg/m2 i.v. daily for 3 days, and amifostine 500 mg i.v. over 15 min daily for 3 days starting 30 min before cyclophosphamide) at intervals of 4–6 weeks for a maximum of six courses. Results. Patients receiving FCA had equivalent rates of sepsis, early death, objective response and survival to those observed in a prior series of 78 patients treated with FC. Amifostine-associated toxicities included nausea, vomiting, and hypotension. Conclusion. The study amifostine regimen did not reduce the toxicity or activity of the FC regimen in patients with CLL. [ABSTRACT FROM AUTHOR]

Sixty-two adults with previously treated acute leukemia were treated with 4'-(9-acridinylamino) methanesulfon-m-anisidide (AMSA) with a total dose of 150 mg to 1320 mg/m2 of body surface area given over 3 to 14 days intravenously. Of the 56 patients who received an adequate trial, 13 achieved a complete remission and six had a partial remission. The best therapeutic results were observed when AMSA was used at a dose level of 75 to 90 mg/m2 per day for 7 days, which resulted in nine complete remissions among 30 patients. Eleven of 38 patients with myeloblastic leukemia achieved complete remission, and three of 13 with lymphoblastic disease achieved partial remission. Complete remissions were observed in nine of 39 patients who were refractory to cytarabine and anthracyclines, indicating a lack of cross-resistance between these drugs and AMSA. The median duration of remission was 12 weeks, and the median survival of responders was 28.5 weeks. The major toxicity of AMSA therapy was severe myelosuppression resulting in frequent infections during induction therapy. Our results indicate that AMSA has significant activity against refractory adult acute leukemia and deserves further evaluation. [ABSTRACT FROM AUTHOR]

We evaluated the activity and tolerability of alemtuzumab given as a continuous infusion for 7 d followed by subcutaneous administration for 11 wk as salvage therapy for 10 patients with fludarabine-refractory chronic lymphocytic leukemia. The continuous infusion of alemtuzumab was well tolerated. The typical infusion reaction seen with intravenous alemtuzumab was abolished. Two patients achieved a partial response with an overall response rate of 20%. Alemtuzumab levels were measured in four patients and detectable levels were obtained in three. Clinical activity needs to be confirmed in a larger patient population. [ABSTRACT FROM AUTHOR]

The immunomodulatory drug lenalidomide is currently being evaluated for its antineoplastic properties in treating hematologic malignancies. However, its potential role in augmenting immune reactions against opportunistic infections has not been explored. We report the rapid resolution of chronic Mycobacterium marinum infection in a patient following initiation of lenalidomide therapy for chronic lymphocytic leukemia. [ABSTRACT FROM AUTHOR]

This study evaluated the efficacy of allogeneic bone marrow transplantation (AlloBMT) in eight patients who had chronic lymphocytic leukaemia (CLL) in Richter's transformation. Five patients were in resistant relapse and three others were in sensitive or untreated relapse. Three out of eight patients (38%) were alive and in remission at 14 months, 47 months and 67 months respectively. Two of these three patients, including one with an unrelated-donor transplant and a prior, unsuccessful autologous transplantation, received a non-myeloablative preparative regimen. These data suggest that, compared with conventional chemotherapy, AlloBMT improves the prognosis for patients with Richter's syndrome. Further study of a larger number of patients is needed to confirm these results. [ABSTRACT FROM AUTHOR]

Ofatumumab (Arzerra; Genmab/GlaxoSmithKline) — a fully human cytolytic monoclonal antibody that is specific for CD20 — was approved by the US FDA for the treatment of chronic lymphocytic leukaemia in October 2009. [ABSTRACT FROM AUTHOR]

Describes the prognostic importance of pretreatment bone marrow cytogenetic studies in adults with acute lymphocytic leukemia (ALL) at a single institution, with an identical treatment program. Way that the patients had documented morphologic diagnosis of ALL; Performance of cytogenetic analysis using the Giemsa banding technique; Conclusion that the pretreatment bone marrow karyotype is an important part of the evaluation of adults with acute lymphocytic leukemia and provides significant prognostic information.

To the Editor: It is not surprising that Burger et al. (Dec. 17 issue)(1) report positive results in the Study of Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia (RESONATE-2), a randomized trial of ibrutinib versus chlorambucil in older patients with chronic lymphocytic leukemia (CLL). Chlorambucil has served as a comparator in trials of bendamustine, alemtuzumab, ofatumumab, and obinutuzumab, and longer durations of progression-free survival have been reported with each agent.(2)-(5) In addition, these trials have shown longer durations of overall survival with the use of ibrutinib and obinutuzumab.(1),(2) We reviewed our experience in the Connect . . . [ABSTRACT FROM AUTHOR]

Deletion of chromosome 17p with a loss of p53 is an unfavorable cytogenetic change in chronic lymphocytic leukemia (CLL) with poor clinical outcome. Since p53 affects mitochondrial function and integrity, we examined possible mitochondrial changes in CLL mice with TCL1-Tg/p53 −/− and TCL1-Tg/p53 +/+ genotypes and in primary leukemia cells from CLL patients with or without 17p-deletion. Although the expression of mitochondrial COX1, ND2, and ND6 decreased in p53 −/− CLL cells, there was an increase in mitochondrial biogenesis as evidenced by higher mitochondrial mass and mtDNA copy number associated with an elevated expression of TFAM and PGC-1α. Surprisingly, the overall mitochondrial respiratory activity and maximum reserved capacity increased in p53 −/− CLL cells. Our study suggests that leukemia cells lacking p53 seem able to maintain respiratory function by compensatory increase in mitochondrial biogenesis. [ABSTRACT FROM AUTHOR]

Accurate identification of patients likely to achieve long-progression-free survival (PFS) after chemoimmunotherapy is essential given the availability of less toxic alternatives, such as ibrutinib. Fludarabine, cyclophosphamide, and rituximab (FCR) achieved a high response rate, but continued relapses were seen in initial reports. We reviewed the original 300 patient phase 2 FCR study to identify long-term disease-free survivors. Minimal residual disease (MRD) was assessed posttreatment by a polymerase chain reaction-based ligase chain reaction assay (sensitivity 0.01%). At the median follow-up of 12.8 years, PFS was 30.9% (median PFS, 6.4 years). The 12.8-year PFS was 53.9% for patients with mutated immunoglobulin heavy chain variable (IGHV) gene (IGHV-M) and 8.7%for patientswith unmutated IGHV (IGHV-UM). 50.7% of patients with IGHV-M achieved MRD-negativity posttreatment; of these, PFS was 79.8% at 12.8 years. A plateau was seen on the PFS curve in patientswith IGHV-M, with no relapses beyond 10.4 years in 42 patients (total follow-up 105.4 patient-years). Onmultivariable analysis, IGHV-UM(hazard ratio, 3.37 [2.18-5.21]; P < .001) and del(17p) by conventional karyotyping (hazard ratio, 7.96 [1.02- 61.92];P=.048)were significantly associated with inferior PFS. Fifteen patients with IGHV-Mhad 4-colorMRDflowcytometry (sensitivity 0.01%) performed in peripheral blood, at amedian of 12.8 years posttreatment (range, 9.5-14.7). All were MRD-negative. The high rate of very long-term PFS in patients with IGHV-M after FCR argues for the continued use of chemoimmunotherapy in this patient subgroup outside clinical trials; alternative strategiesmaybepreferred inpatientswithIGHV-UM, tolimit long-term toxicity. [ABSTRACT FROM AUTHOR]

The fludarabine and cyclophosphamide couplet has become the backbone of the chronic lymphocytic leukemia (CLL) standard of care. Although this is an effective treatment, it results in untoward toxicity. Bendamustine is a newly approved and better-tolerated alkylating agent. We hypothesized that similar to cyclophosphamide, bendamustine induced DNA damage will be inhibited by fludarabine, resuiting in increased cytotoxicity. To test this hypothesis and the role of the stromai microenvironment in this process, we treated CLL lymphocytes in vitro with each drug alone and in combination. Simuitaneous or prior addition of fludarabine to bendamustine resulted in maximum cytotoxicity assayed by 3,3'-dihexyloxacarbocyanine iodine negativity, annexin positivity, and poly (adenosine 5'-diphosphate-ribose) polymerase cleavage. Cytotoxicity eiicited by combination of both agents was similar in these malignant B cells cultured either in suspension or on marrow stroma cells. Cell death was associated with DNA damage response, which was determined by phosphorylation of H2AX and unscheduled DNA synthesis. H2AX activation was maximum with the drug combination, and unscheduled DNA synthesis induced by bendamustine was blocked by fludarabine. in parallel, ATM, Chk2, and p53 were phosphorylated and PUMA was induced. Cell death was caspase independent; however, caspases did decrease levels of Mcl-1 survival protein. These data provide a rationale for combining fiudarabine with bendamustine for patients with CLL. [ABSTRACT FROM AUTHOR]

In chronic lymphocytic leukemia (CLL), stimulation of the B-cell receptor (BCR) triggers survival signals. Because in various cells activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway provides cells with survival advantage, we wondered whether BCR stimulation activates the JAK/STAT pathway in CLL cells. To stimulate the BCR we incubated CLL cells with anti-IgM antibodies. Anti-IgM antibodies induced transient tyrosine phosphorylation and nuclear localization of phosphorylated (p) STAT3. Immunoprecipitation studies revealed that anti-JAK2 antibodies coimmunoprecipitated pSTAT3 and pJAK2 in IgM-stimulated but not unstimulated CLL cells, suggesting that activation of the BCR induces activation of JAK2, which phosphorylates STAT3. Incubation of CLL cells with the JAK1/2 inhibitor ruxolitinib inhibited IgM-induced STAT3 phosphorylation and induced apoptosis of IgM-stimulated but not unstimulated CLL cells in a dose- and time-dependent manner. Whether ruxolitinib treatment would benefit patients with CLL remains to be determined. [ABSTRACT FROM AUTHOR]

Standardized criteria for diagnosis and response evaluation in chronic lymphocytic leukemia (CLL) are essential to achieve comparability of results and improvement of clinical care. With the increasing range of therapeutic options, the treatment context is important when defining refractory CLL. Refractory CLL has been defined as no response or response lasting ≤ 6 months from last therapy. This subgroup has a very poor outcome, and many trials use this group as an entry point for early drug development. With the intensification of first-line regimens, the proportion of patients with refractory CLL using these criteria decreases. This has immediate consequences for recruitment of patients into trials as well as salvage strategies. Conversely, patients who are not refractory according to the traditional definition but who have suboptimal or short response to intense therapy also have a very poor outcome. In this Perspective, we discuss recent results that may lead to a reassessment of risk categories in CLL focusing on fit patients who are eligible for all treatment options. We cover aspects of the history and biologic basis for refractory CLL and will focus on how emerging data on treatment failure from large trials using chemoimmunotherapy may help to define risk groups in CLL. [ABSTRACT FROM AUTHOR]

Abstract: Randomized trials demonstrated the superiority of chemoimmunotherapy over chemotherapy in the frontline treatment of CLL. Based on favorable experience with the addition of mitoxantrone (M) to fludarabine (F) plus cyclophosphamide (C), we designed a pilot study testing the combination of FCM plus rituximab (R). Thirty patients with previously untreated, symptomatic CLL, <70 years, and beta-2-microglobulin

Abstract: Systemic mastocytosis may be primary or be associated with other hematological malignancies, most commonly myeloid neoplasms. In contrast, the association of systemic mastocytosis with lymphoid neoplasms is comparatively rare, and in the absence of appropriate clinical vigilance the diagnosis may be missed. We report a case of aggressive systemic mastocytosis associated with chronic lymphocytic leukemia (SM-CLL), placing particular emphasis on the investigational algorithm used in establishing this diagnosis, and discussing key clinical considerations in the initiation of therapy. [Copyright &y& Elsevier]

: ObjectiveTo investigate the graft-vs-leukemia effect of allogeneic stem cell transplantation after a nonablative conditioning regimen as treatment for patients with chronic lymphocytic leukemia.: Patients and MethodsPatients were eligible to treatment if they were refractory or recurred after a prior response to fludarabine. Seventeen patients were treated. All patients received a preparative regimen of fludarabine (30 mg/m2 daily for 3 days) and intravenous cyclophosphamide (750 mg/m2 daily for 3 days). Ten patients received rituximab in addition to chemotherapy. The median time from diagnosis to transplant was 67 months. Nine of 17 patients had refractory disease.: ResultsAll patients had engraftment of donor cells. Eleven (65%) did not require platelet transfusions. Ten patients with persistent disease underwent immunomanipulation to augment GVL effects including immunosuppression withdrawal and donor lymphocyte infusion with or without rituximab treatment. Seven of these 10 patients had a complete response and 2 had a partial response; 8 of these 9 responders had received rituximab with their immunomanipulation process. The final response was complete remission in 12 and partial remission in 4 patients for an overall response rate of 94%. Overall survival was 100% for patients who received the combined chemo-rituximab conditioning regimen, vs 14% for those who received chemotherapy alone (p = 0.03).: ConclusionOur results indicate that a pronounced GVL effect occurs after nonmyeloablative allogeneic hematopoietic transplantation for advanced CLL. This activity might be facilitated by rituximab. Prospective controlled trials are needed to define the role of nonablative allogeneic hematopoietic transplantation for treatment of this disease. [Copyright &y& Elsevier]

Background: The course of chronic lymphocytic leukemia (CLL) is variable. In aggressive disease, the CLL cells usually express an unmutated immunoglobulin heavy-chain variable-region gene (IgV) and the 70-kD zeta-associated protein (ZAP-70), whereas in indolent disease, the CLL cells usually express mutated IgV but lack expression of ZAP-70. Methods: We evaluated the CLL B cells from 307 patients with CLL for ZAP-70 and mutations in the rearranged IgV gene. We then investigated the association between the results and the time from diagnosis to initial therapy. Results: We found that ZAP-70 was expressed above a defined threshold level in 117 of the 164 patients with an unmutated IgV gene (71 percent), but in only 24 of the 143 patients with a mutated IgV gene (17 percent, P<0.001). Among the patients with ZAP-70–positive CLL cells, the median time from diagnosis to initial therapy in those who had an unmutated IgV gene (2.8 years) was not significantly different from the median time in those who had a mutated IgV gene (4.2 years, P=0.07). However, the median time from diagnosis to initial treatment in each of these groups was significantly shorter than the time in patients with ZAP-70–negative CLL cells who had either mutated or unmutated IgV genes (P<0.001). The median time from diagnosis to initial therapy among patients who did not have ZAP-70 was 11.0 years in those with a mutated IgV gene and 7.1 years in those with an unmutated IgV gene (P<0.001). Conclusions: Although the presence of an unmutated IgV gene is strongly associated with the expression of ZAP-70, ZAP-70 is a stronger predictor of the need for treatment in B-cell CLL. N Engl J Med 2004;351:893-901. [ABSTRACT FROM AUTHOR]