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The recent serious challenges in patient management resulting from the COVID-19 pandemic have emphasised the need to optimise therapy for immunosuppressed patients. HCL- SB V, sb a provisional entity in the latest WHO classification, accounts for 10-20% of HCL patients and 0-5% of B-cell chronic lymphoid malignancies, and corresponds to approximately 60-75 new HCL- SB V sb patients each year in the United States. Keywords: guidelines; diagnosis; hairy cell leukaemia EN guidelines diagnosis hairy cell leukaemia 11 14 4 04/01/21 20210401 NES 210401 A European viewpoint (Xavier Troussard) The British Society for Haematology presents very useful and instructive guidelines for the diagnosis and management of hairy cell leukaemia (HCL) and hairy cell variant (HCL- SB V sb ).1 HCL-like disorders are well-defined entities although overlaps exist between HCL, variant forms of HCL (HCL- SB V sb ), splenic diffuse red pulp lymphoma (SDRPL) and splenic marginal zone lymphoma (SMZL). In newly diagnosed patients, PNAs remain the treatment of choice, but relapses occur in some patients. [Extracted from the article]

Aims: Lenalidomide is an immunomodulatory imide drug used broadly in the treatment of multiple myeloma and lymphoma. It continues to be evaluated in chronic lymphocytic leukaemia (CLL) at lower doses due to dose‐related toxicities including tumour flare and tumour lysis syndrome. This study aimed to develop a population pharmacokinetic model for lenalidomide in multiple cancers, including CLL, to identify any disease‐related differences in disposition. Methods: Lenalidomide concentrations from 4 clinical trials were collated (1999 samples, 125 subjects), covering 4 cancers (multiple myeloma, CLL, acute myeloid leukaemia and acute lymphoblastic leukaemia) and a large dose range (2.5–75 mg). A population pharmacokinetic model was developed with NONMEM and patient demographics were tested as covariates. Results: The data were best fitted by a 1‐compartment kinetic model with absorption described by 7 transit compartments. Clearance and volume of distribution were allometrically scaled for fat‐free mass. The population parameter estimates for apparent clearance, apparent volume of distribution and transit rate constant were 12 L/h (10.8–13.6), 68.8 L (61.8–76.3), and 13.5 h−1 (11.9–36.8) respectively. Patients with impaired renal function (creatinine clearance <30 mL/min) exhibited a 22% reduction in lenalidomide clearance compared to patients with creatinine clearance of 90 mL/min. Cancer type had no discernible effect on lenalidomide disposition. Conclusions: This is the first report of a lenalidomide population pharmacokinetic model to evaluate lenalidomide pharmacokinetics in patients with CLL and compare its pharmacokinetics with other B‐cell malignancies. As no differences in pharmacokinetics were found between the observed cancer‐types, the unique toxicities observed in CLL may be due to disease‐specific pharmacodynamics. [ABSTRACT FROM AUTHOR]

Problem: Many students entering professional degree programs, particularly M.D., Ph.D., and M.D./Ph.D., are not well prepared regarding the breadth of scientific knowledge required, communication skills, research experience, reading and understanding the scientific literature, and significant shadowing (for M.D.-related professions). In addition, physician scientists are a needed and necessary part of the academic research environment but are dwindling in numbers. Intervention: In response to predictions of critical shortages of clinician investigators and the lack of proper preparation as undergraduates for these professions, the Biomedical Science (BMS) undergraduate major was created at The Ohio State University to attract incoming college freshmen with interests in scientific research and the healthcare professions. The intent of this major was to graduate an elite cohort of highly talented individuals who would pursue careers in the healthcare professions, biomedical research, or both. Context: Students were admitted to the BMS major through an application and interview process. Admitted cohorts were small, comprising 22 to 26 students, and received a high degree of individualized professional academic advising and mentoring. The curriculum included a minimum of 4 semesters (or 2 years) of supervised research experience designed to enable students to gain skills in clinical and basic science investigation. In addition to covering the prerequisites for medicine and advanced degrees in health professions, the integrated BMS coursework emphasized research literacy as well as skills related to work as a healthcare professional, with additional emphasis on independent learning, teamwork to solve complex problems, and both oral and written communication skills. Supported by Ohio State's Department of Internal Medicine, a unique clinical internship provided selected students with insights into potential careers as physician scientists. Outcome: In this educational case report, we describe the BMS undergraduate major and its outcomes after 10 years of implementation. Major outcomes include the strength of the major's matriculates (average ACT score = 32.6; average high school class percentile rank = 95.5) and the high percentage of BMS students who pursued graduate/professional degrees (91%; n = 110). Other markers of success include the strong focus on research, which resulted in 120 articles published by graduates to date (range = 0-12/student; 43% with at least 1 peer-reviewed journal article). Lessons Learned: Based on its successes, adoption of a similar program at other academic medical centers would help feed the pipeline of well-trained health professionals and biomedical researchers. [ABSTRACT FROM AUTHOR]

The article presents case study of a 52-year-old man with splenomegaly and lymphocytosis and was diagnosed with variant hairy cell leukemia (vHCL). It is mentioned that the patient was administered with trametinib for the treatment of IGHV4-34 and MAP2K1-mutation. The article further adds that the patient experienced disease relapse after allogeneic transplantation and developed skin nodules and generalized skin rash.

Patients with chronic lymphocytic leukemia (CLL) who receive chemoimmunotherapy and do not achieve complete remission experience significantly shortened progression-free interval (PFS). Additionally, the majority of patients treated for relapsed disease demonstrate evidence of measurable disease. Eradication of minimal residual disease (MRD) results in improved PFS and overall survival. Maintenance therapy might result in eradication of MRD and improve response duration but might be associated with an increase in incidence of infectious complications. Flavopiridol is a broad cyclin-dependent kinase (CDK) inhibitor with established safety and efficacy in patients with relapsed CLL, particularly patients with high-risk cytogenetic features. A pharmacologically derived schedule was utilized as consolidation therapy in this phase I study to assess the safety and feasibility of outpatient therapy with flavopiridol in patients with low tumor burden. Flavopiridol was administered as a 30-min loading dose of 30 mg/m(2) followed by a 4-h infusion of 30 mg/m(2) once weekly for 3 weeks every 5 weeks (1 cycle) for planned 2 cycles in ten patients. Therapy was extremely well tolerated and no patient developed acute tumor lysis syndrome. The most common toxicities were gastrointestinal. Of the patients, 22 % improved their response from a PR to CR. Eighty-eight percent experienced a reduction in tumor burden as measured by extent of bone marrow involvement including patients with del17p and complex karyotype. The study establishes the safety and efficacy of flavopiridol as consolidation therapy after chemoimmunotherapy for patients with CLL. Further evaluation is required in larger trials for the utility of CDK inhibitors as consolidation or maintenance strategies.Registration number at ClinicalTrials.gov: NCT00377104. [ABSTRACT FROM AUTHOR]

Fludarabine (F) and cyclophosphamide (C) remain backbones of up-front chemotherapy regimens for chronic lymphocytic leukemia (CLL). We report long-term follow-up of a randomized F vs. FC trial in untreated CLL#. With median follow-up of 88 months, estimated median progression-free survival (PFS) was 19.3 vs. 48.1 months for F (n= 109) and FC (n= 118), respectively (p< 0.0001), and median overall survival (OS) was 88.0 vs. 79.1 months (p= 0.96). In multivariable analyses, variables associated with inferior PFS and OS respectively were age (p= 0.002,p< 0.001), Rai stage (p= 0.006,p= 0.02) and sex (p = 0.03, PFS only). Del(17)(p13.1) predicted shorter PFS and OS (p < 0.0001 for each), as did del(11q)(22.3) (p< 0.0001,p= 0.005, respectively), trisomy 12 with mutatedNotch1(p= 0.003,p= 0.03, respectively) and unmutatedIGHV(p= 0.009,p= 0.002, respectively), all relative to patients without these features. These data confirm results from shorter follow-up and further justify targeted therapies for CLL. [ABSTRACT FROM AUTHOR]

We previously reported that bortezomib indirectly modulates transcription of DNA methyltransferase 1 (DNMT). We designed a phase I study of azacitidine (a direct DNMT inhibitor) plus bortezomib in acute myeloid leukemia (AML) to determine safety and tolerability. Twenty-three adults with relapsed/refractory AML received azacitidine 75 mg/m2 daily on days 1-7. Bortezomib was dose escalated from 0.7 mg/m2 on days 2 and 5 to 1.3 mg/m2 on days 2, 5, 9 and 12. The target dose was reached without dose limiting toxicities. Infection and/or febrile neutropenia were frequent. Patients received a median of 2 cycles of therapy (range, 1-12+). Five of 23 patients achieved remission, including two with morphologic and cytogenetic complete response (CR) and three with CR and incomplete count recovery (CRi). Of CR/CRi responders with cytogenetic abnormalities at baseline, three of four achieved cytogenetic CR. The combination of azacitidine and bortezomib was tolerable and active in this cohort of poor-risk previously treated patients with AML. [ABSTRACT FROM AUTHOR]

We hypothesized that GTI-2040, a 20-mer oligonucleotide complementary to the R2 subunit mRNA of ribonucleotide reductase, combined with high dose cytarabine (HiDAC) would result in enhanced cytotoxicity by favoring Ara-CTP DNA incorporation. In a phase I dose escalation trial, adults (≥ 60 years) with refractory or relapsed acute myeloid leukemia (AML) received daily HiDAC plus infusional GTI-2040. Using a novel assay, evidence of intracellular drug accumulation and target R2 down-regulation was observed. GTI-2040/HiDAC can be administered safely. However, with no complete remissions observed, alternative doses and schedules may need to be investigated to achieve clinical activity in older patients with AML. [ABSTRACT FROM AUTHOR]

Protein arginine methyltransferase-5 (PRMT5) is a Type II arginine methyltransferase that regulates various cellular functions. We hypothesized that PRMT5 plays a role in regulating the growth of human melanoma cells. Immunohistochemical analysis indicated significant upregulation of PRMT5 in human melanocytic nevi, malignant melanomas and metastatic melanomas as compared to normal epidermis. Furthermore, nuclear PRMT5 was significantly decreased in metastatic melanomas as compared to primary cutaneous melanomas. In human metastatic melanoma cell lines, PRMT5 was predominantly cytoplasmic, and associated with its enzymatic cofactor Mep50, but not STAT3 or cyclin D1. However, histologic examination of tumor xenografts from athymic mice revealed heterogeneous nuclear and cytoplasmic PRMT5 expression. Depletion of PRMT5 via siRNA inhibited proliferation in a subset of melanoma cell lines, while it accelerated growth of others. Loss of PRMT5 also led to reduced expression of MITF (microphthalmia-associated transcription factor), a melanocyte-lineage specific oncogene, and increased expression of the cell cycle regulator p27Kip1. These results are the first to report elevated PRMT5 expression in human melanoma specimens and indicate this protein may regulate MITF and p27Kip1 expression in human melanoma cells. [ABSTRACT FROM AUTHOR]

This phase I study was conducted to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) of the heat shock protein 90 (HSP90) inhibitor 17-allyamino-17-demethoxygeldanamycin (17-AAG) in combination with bortezomib, and to provide pharmacokinetic data in relapsed or refractory acute myeloid leukemia (AML). Eleven patients were enrolled. The MTD was 17-AAG 150 mg/m2 and bortezomib 0.7 mg/m2. Hepatic toxicity and cardiac toxicity were dose limiting. Co-administration on day 4 led to a decrease in clearance ( p = 0.005) and increase in AUC ( p = 0.032) of 17-amino-17-demethoxygeldanamycin (17-AG), not observed when 17-AAG was administered alone. Pharmacokinetic parameters of patients who developed toxicities and those who did not were not different. The combination of 17-AAG and bortezomib led to toxicity without measurable response in patients with relapsed or refractory AML. Pharmacokinetic data provide insight for studies of related agents in AML. Next-generation HSP90 inhibitors are appealing for further development in this area. [ABSTRACT FROM AUTHOR]

Background: Activating mutations [internal tandem duplication (ITD)] or overexpression of the FMS-like tyrosine kinase receptor-3 (FLT3) gene are associated with poor outcome in acute myeloid leukemia (AML) patients, underscoring the need for novel therapeutic approaches. The natural product silvestrol has potent antitumor activity in several malignancies, but its therapeutic impact on distinct molecular high-risk AML subsets remains to be fully investigated. We examined here the preclinical activity of silvestrol in FLT3-ITD and FLT3 wild-type (wt) AML. Methods: Silvestrol in vitro anti-leukemic activity was examined by colorimetric cell viability assay, colony-forming and flow cytometry assays assessing growth inhibition and apoptosis, respectively. Pharmacological activity of silvestrol on FLT3 mRNA translation, mRNA and protein expression was determined by RNA-immunoprecipitation, qRT-PCR and immunoblot analyses, respectively. Silvestrol in vivo efficacy was investigated using MV4-11 leukemiaengrafted mice. Results: Silvestrol shows antileukemia activity at nanomolar concentrations both in FLT3-wt overexpressing (THP-1) and FLT3-ITD (MV4-11) expressing AML cell lines (IC50 = 3.8 and 2.7 nM, respectively) and patients' primary blasts [IC50 = ~12 nM (FLT3-wt) and ~5 nM (FLT3-ITD)]. Silvestrol increased apoptosis (~4fold, P = 0.0001), and inhibited colony-formation (100%, P < 0.0001) in primary blasts. Silvestrol efficiently inhibited FLT3 translation reducing FLT3 protein expression by 80-90% and decreased miR-155 levels (~60%), a frequently co-regulated onco-miR in FLT3- ITD-positive AML. The median survival of silvestrol-treated vs vehicle-treated mice was 63 vs 29 days postengraftment, respectively (P < 0.0001). Conclusions: Silvestrol exhibits significant in vivo and in vitro antileukemic activities in AML through a novel mechanism resulting in inhibition of FLT3 and miR-155 expression. These encouraging results warrant a rapid translation of silvestrol for clinical testing in AML. [ABSTRACT FROM AUTHOR]

Bioactive components from dietary supplements such as curcumin may represent attractive agents for cancer prevention or treatment. DNA methylation plays a critical role in acute myeloid leukemia (AML) development, and presents an excellent target for treatment of this disease. However, it remains largely unknown how curcumin, a component of the popular Indian spice turmeric, plays a role in DNA hypomethylation to reactivate silenced tumor suppressor genes and to present a potential treatment option for AML. Here we show that curcumin down-regulates DNMT1 expression in AML cell lines, both in vitro and in vivo, and in primary AML cells ex vivo. Mechanistically, curcumin reduced the expression of positive regulators of DNMT1, p65 and Sp1, which correlated with a reduction in binding of these transcription factors to the DNMT1 promoter in AML cell lines. This curcumin-mediated down-regulation of DNMT1 expression was concomitant with p15INK4B tumor suppressor gene reactivation, hypomethylation of the p15INK4B promoter, G1 cell cycle arrest, and induction of tumor cell apoptosis in vitro. In mice implanted with the human AML MV4–11 cell line, administration of curcumin resulted in remarkable suppression of AML tumor growth. Collectively, our data indicate that curcumin shows promise as a potential treatment for AML, and our findings provide a basis for future studies to test the clinical efficacy of curcumin – whether used as a single agent or as an adjuvant – for AML treatment. [ABSTRACT FROM AUTHOR]

Decitabine (DAC) is used for treatment of patients with myelodysplastic syndromes and acute myeloid leukemia (AML). Following cellular uptake, DAC is activated to DAC-triphosphate (TP) and incorporated into DNA. Once incorporated into the DNA, DAC-TP binds and inactivates DNA methyltransferases (DNMTs), thereby leading to hypomethylation and re-expression of epigenetically silenced tumor suppressor genes and ultimately antileukemia activity. However, direct evidence of in vivo DAC-TP occurrence in DAC-treated patients has been difficult to demonstrate due to a lack of suitable validated analytical methodology. Thus, we developed and validated a nonradioactive sensitive and specific LC-MS/MS assay for quantification of DAC-TP. The assay is linear from 50 to 1,000 nM and from 1 to 10 µM and has a lower limit of quantitation of 50 nM and a coefficient of variation for both withinand between-day precision <20%. Following DAC treatment, we detected DAC-TP in parental and DAC-resistant AML cells (in vitro) and bone marrow (BM) and spleen of normal and leukemic mice (in vivo). Downregulation of DNMTs and correlation of DAC-TP concentration with proteins involved in mechanisms of DAC resistance were also demonstrated. The clinical applicability of this method was proven by measuring DAC-TP level in BM and blood mononuclear cells from DAC-treated AML patients. Higher levels are seemingly associated with clinical response. Monitoring the DAC-TP intracellular level may serve as a novel pharmacological endpoint for designing more effective DACbased regimens. [ABSTRACT FROM AUTHOR]

Complex karyotype ( CK) on metaphase cytogenetics discriminates poor outcome in chronic lymphocytic leukaemia ( CLL) patients undergoing salvage treatment; we hypothesized that it might provide prognostic information for patients undergoing allogeneic stem cell transplant. Fifty-one CLL patients were analysed following transplant; 18-month overall survival ( OS), event-free survival ( EFS) and cumulative incidence of progression estimates were 35%, 14% and 63%, respectively, in patients with CK ( n = 19) versus 83%, 68% and 29% in patients without ( n = 32) ( P ≤ 0·0001, P ≤ 0·0001, and P = 0·02). In patients with high-risk interphase cytogenetics, CK remained predictive of worse OS ( P = 0·02) and EFS ( P = 0·009). These findings support further evaluation of metaphase karyotype in transplant risk assessment. [ABSTRACT FROM AUTHOR]

Hairy cell leukemia (HCL) was once considered an untreatable form of chronic lymphoid malignancy. Based upon the recognition of the importance of adenosine deaminase to the normal B cell survival and proliferation, a hypothesis was developed that temporary inhibition of this enzyme might be therapeutically successful in treating chronic B cell leukemias. Pentostatin was initially explored in patients with refractory chronic lymphocytic leukemia (CLL). Both pentostatin and cladribine, purine nucleoside analogs, have been utilized to successfully treat HCL. The high degree of complete and durable remission observed with either agent resulted in many believing that the treatment of this rare disease had been fully optimized. However, a considerable number of patients will relapse. While tremendous progress has been made in initial management, the issues related to optimal therapy, timing of initiation of treatment, and discovery of novel agents that may be effective in those who have relapsed are important. Investigational agents currently being explored in chronic lymphocytic leukemia may also have benefit for those patients who have relapsed or are resistant to therapy of hairy cell leukemia. Many important questions remain (e.g. importance of minimal residual disease) and will require international collaboration to fully address these unanswered questions. The Hairy Cell Leukemia Consortium was established to address these unanswered questions. [ABSTRACT FROM AUTHOR]

Background: Flavopiridol is a cyclin-dependent kinase inhibitor in phase II clinical development for treatment of various forms of cancer. When administered with a pharmacokinetically (PK)-directed dosing schedule, flavopiridol exhibited striking activity in patients with refractory chronic lymphocytic leukemia. This study aimed to evaluate pharmacogenetic factors associated with inter-individual variability in pharmacokinetics and outcomes associated with flavopiridol therapy. Methodology/Principal Findings: Thirty-five patients who received single-agent flavopiridol via the PK-directed schedule were genotyped for 189 polymorphisms in genes encoding 56 drug metabolizing enzymes and transporters. Genotypes were evaluated in univariate and multivariate analyses as covariates in a population PK model. Transport of flavopiridol and its glucuronide metabolite was evaluated in uptake assays in HEK-293 and MDCK-II cells transiently transfected with SLCO1B1. Polymorphisms in ABCC2, ABCG2, UGT1A1, UGT1A9, and SLCO1B1 were found to significantly correlate with flavopiridol PK in univariate analysis. Transport assay results indicated both flavopiridol and flavopiridol-glucuronide are substrates of the SLCO1B1/OATP1B1 transporter. Covariates incorporated into the final population PK model included bilirubin, SLCO1B1 rs11045819 and ABCC2 rs8187710. Associations were also observed between genotype and response. To validate these findings, a second set of data with 51 patients was evaluated, and overall trends for associations between PK and PGx were found to be consistent. Conclusions/Significance: Polymorphisms in transport genes were found to be associated with flavopiridol disposition and outcomes. Observed clinical associations with SLCO1B1 were functionally validated indicating for the first time its relevance as a transporter of flavopiridol and its glucuronide metabolite. A second 51-patient dataset indicated similar trends between genotype in the SLCO1B1 and other candidate genes, thus providing support for these findings. Further study in larger patient populations will be necessary to fully characterize and validate the clinical impact of polymorphisms in SLCO1B1 and other transporter and metabolizing enzyme genes on outcomes from flavopiridol therapy. [ABSTRACT FROM AUTHOR]

Targeting aberrant DNA hypermethylation in chronic lymphocytic leukaemia (CLL) and non-Hodgkin lymphoma (NHL) with decitabine may reverse epigenetic silencing in B-cell malignancies. Twenty patients were enrolled in two phase I trials to determine the minimum effective pharmacological dose of decitabine in patients with relapsed/refractory CLL ( n = 16) and NHL ( n = 4). Patients received 1–3 cycles of decitabine. Dose-limiting toxicity (DLT) was observed in 2 of 4 CLL and 2 of 2 NHL patients receiving decitabine at 15 mg/m2 per d days 1–10, consisting of grade 3–4 thrombocytopenia and hyperbilirubinaemia. Six patients with CLL received decitabine at 10 mg/m2 per d days 1–10 without DLT; however, re-expression of methylated genes or changes in global DNA methylation were not observed. Therefore, a 5-day decitabine schedule was examined. With 15 mg/m2 per d decitabine days 1–5, DLT occurred in 2 of 6 CLL and 2 of 2 NHL patients, consisting of grade 3–4 neutropenia, thrombocytopenia, and febrile neutropenia. Eight patients had stable disease. In 17 patients, there were no significant changes in genome-wide methylation or in target gene re-expression. In conclusion, dose-limiting myelosuppression and infectious complications prevented dose escalation of decitabine to levels associated with changes in global methylation or gene re-expression in CLL and NHL. [ABSTRACT FROM AUTHOR]

Background: While deacetylase (DAC) inhibitors show promise for the treatment of B-cell malignancies, those introduced to date are weak inhibitors of class I and II DACs or potent inhibitors of class I DAC only, and have shown suboptimal activity or unacceptable toxicities. We therefore investigated the novel DAC inhibitor AR-42 to determine its efficacy in B-cell malignancies. Principal Findings: In mantle cell lymphoma (JeKo-1), Burkitt's lymphoma (Raji), and acute lymphoblastic leukemia (697) cell lines, the 48-hr IC50 (50% growth inhibitory concentration) of AR-42 is 0.61 μM or less. In chronic lymphocytic leukemia (CLL) patient cells, the 48-hr LC50 (concentration lethal to 50%) of AR-42 is 0.76 μM. AR-42 produces dose- and time-dependent acetylation both of histones and tubulin, and induces caspase-dependent apoptosis that is not reduced in the presence of stromal cells. AR-42 also sensitizes CLL cells to TNF-Related Apoptosis Inducing Ligand (TRAIL), potentially through reduction of c-FLIP. AR-42 significantly reduced leukocyte counts and/or prolonged survival in three separate mouse models of B-cell malignancy without evidence of toxicity. Conclusions/Significance: Together, these data demonstrate that AR-42 has in vitro and in vivo efficacy at tolerable doses. These results strongly support upcoming phase I testing of AR-42 in B-cell malignancies. [ABSTRACT FROM AUTHOR]

A phase I study to determine the maximum tolerated dose (MTD) of bortezomib (B) when combined with weekly paclitaxel in patients with advanced solid tumors. Eligible patients received escalating doses of intravenous (IV) bortezomib (0.6–2 mg/m2) on days 2 and 9 and IV paclitaxel at 100 mg/m2 on days 1 and 8 of a 21-day cycle. Dose escalation was based on two end-points: not exceeding 80% 20S-proteasome inhibition (20-S PI) and the development of dose-limiting toxicity defined as grade 3 or greater non-hematologic or grade 4 hematologic toxicities. Forty-five patients with advanced solid tumors and a median of 3 prior chemotherapy regimens (range 0–9), received 318 doses (median 5, range 1–34) of bortezomib and paclitaxel. Dose-related inhibition of 20-S PI was observed with a maximum inhibition of 70–80% at the MTD of 1.8 mg/m2 of bortezomib. At the MTD ( N = 9) the following toxicities were observed: grade 4 neutropenia without fever ( n = 2) and cerebrovascular ischemia ( n = 1); grade 3 neutropenia ( n = 3), diarrhea ( n = 2), nausea ( n = 1), and fatigue ( n = 1); grade 2 fatigue ( n = 5), diarrhea ( n = 4), and dyspnea ( n = 2). There was one partial response in a patient with an eccrine porocarcinoma. Stabilization of disease was observed in 7 (16%) patients, 3 of whom had advanced pancreatic cancer. Sequential paclitaxel and bortezomib in previously treated patients with advanced solid tumors resulted in acceptable toxicity and no evidence of interaction. The recommended phase II dose of bortezomib in combination with weekly paclitaxel was 1.8 mg/m2. [ABSTRACT FROM AUTHOR]

The article presents a study which evaluates the use of the combination of pentostatin (P), cyclophosphamide (C), and rituximab (R) in the treatment patients with untreated B-cell chronic lymphocyte leukemia (CCL). The study involves conducting a P and R phase 2 trial without C, using a higher dosage of P on 33 patients. The results reveal that the overall response rate was 76%, which determine that increasing P dosage does not eliminate the need of C in the CCL chemoimmunotherapy.

A phase II clinical trial with single-agent decitabine was conducted in older patients (⩾60 years) with previously untreated acute myebid leukemia (AML) who were not candidates for or who refused intensive chemotherapy. Subjects received low-dose decitabine at 20 mg/m2 i.v. over 1 h on days 1 to 10. Fifty-three subjects enrolled with a median age of 74 years (range, 60-85). Nineteen (36%) had antecedent hernatologic disorder or therapy-related AML; 16 had complex karyotypes (⩾3 abnormalities). The complete remission rate was 47% (n = 25), achieved after a median of three cycles of therapy. Nine additional subjects had no morphologic evidence of disease with incomplete count recovery, for an overall response rate of 64% (n = 34). Complete remission was achieved in 52% of subjects presenting with normal karyotype and in 50% of those with complex karyotypes. Median overall and disease-free survival durations were 55 and 46 weeks, respectively. Death within 30 days of initiation of treatment occurred in one subject (2%), death within 8 weeks in 15% of subjects. Given the DNA hypomethylating effect of decitabine, we examined the relationship of clinical response and pretreatment level of miR-29b, previously shown to target DNA methyltransferases. Higher levels of miR-29b were associated with clinical response (P = 0.02). In conclusion, this schedule of decitabine was highly active and well tolerated in this poor-risk cohort of older AML patients. Levels of miR-29b should be validated as a predictive factor for stratification of older AML patients to decitabine treatment. [ABSTRACT FROM AUTHOR]

Apolizumab (Hu1D10), a humanized monoclonal anti- Human leukocyte antigen -DR β-chain antibody, mediates apoptosis of chronic lymphocytic leukemia (CLL) cells in vitro. We conducted a phase I/II dose-escalation study of thrice-weekly apolizumab (1.5, 3.0, 5.0 mg/kg/dose) for 4 weeks in relapsed CLL. Two of six patients at 5.0 mg/kg/dose developed treatment-related dose-limiting toxicity (aseptic meningitis, hemolytic uremia). Other toxicities included infusion toxicity, urticaria, and headache. Eleven patients were enrolled in a phase I/II expansion to evaluate the maximum tolerated dose (MTD) of 3.0 mg/kg/dose. In total, 23 patients were enrolled (22 CLL, 1 ALL). Nineteen patients with CLL were treated at or above the MTD. One partial response was observed, and three patients had stable disease exceeding 6 months. Pharmacokinetic analysis demonstrated a dose-dependent Cmax increase and serum antibody accumulation after week 1 of therapy. Given the toxicity and lack of efficacy in this and other trials in lymphoma and solid tumors, further development of apolizumab was discontinued. [ABSTRACT FROM AUTHOR]

Enormous progress has been made in the management of patients with hairy cell leukemia (HCL) over the past 50 years since this disease was initially described in 1958. The introduction of the two commonly used purine nucleoside analogs (pentostatin and cladribine, respectively) has independently changed the natural history of this rare malignancy. Both agents are equivalent in terms of response and long-term results. Advances in therapy are being further pursued with inclusion of monoclonal antibodies (e.g. rituximab) and other immunotherapeutic approaches. Patients with this disease now can live a near normal life expectancy, but the disease has not yet been cured. Clinical trials must continue to address the remaining unanswered questions. [ABSTRACT FROM AUTHOR]

Serum levels of pro-[vascular endothelial growth factor (VEGF)] and anti-[thrombospondin-1 (TSP)] angiogenic cytokines were prospectively measured in a phase II trial of chemoimmunotherapy (CIT) for chronic lymphocytic leukaemia (CLL) patients ( n = 56). Pretreatment VEGF levels were lower among patients who achieved complete remission (CR) or nodular partial remission (nPR) relative to those with partial remission (PR) or stable/progressive disease (median 122·0 pg/ml vs. 246·8 pg/ml; P = 0·03). VEGF:TSP ratio was lower (anti-angiogenic phenotype) among patients who achieved CR/nPR. The pretreatment VEGF:TSP ratio also correlated with overall survival ( P = 0·008). A pro-angiogenic profile appears associated with diminished response and inferior survival in CLL patients receiving CIT. [ABSTRACT FROM AUTHOR]

Treatment options for chronic lymphocytic leukaemia (CLL) are limited and eventually fail because of the development of toxicities or drug resistance. Thus, identification of new therapeutic strategies and targets is a high priority. The semisynthetic geldanamycin derivative 17-allylamino-17-demethoxygeldanamycin (17-AAG) inhibits heat shock protein 90 (Hsp90) binding to client proteins, thereby leading to their degradation. We demonstrate that at biologically active and clinically attainable levels (1 μmol/l), 17-AAG treatment of CLL B cells in vitro causes modest apoptosis as well as decreased AKT protein levels. Given the potential activation of AKT following antibody therapy in CLL, we evaluated the combination of 17-AAG and rituximab. These agents produced synergistic cytotoxicity of CLL cells in vitro. However, rituximab-mediated antibody-dependent cellular cytotoxicity was modestly reduced with 17-AAG, and complement-dependent cytotoxicity was not altered. We conclude that the combination of Hsp90 inhibitors with therapeutic antibodies, such as rituximab may represent a novel strategy to enhance therapeutic response in CLL. Furthermore, our data indicates that AKT and Hsp70 protein levels are relevant pharmacodynamic endpoints to monitor the in vivo effect of 17-AAG therapy. [ABSTRACT FROM AUTHOR]

Protein arginine methyltransferase PRMT5 interacts with human SWI/SNF complexes and methylates histones H3R8 and H4R3. To elucidate the role of PRMT5 in human cancer, we analyzed PRMT5 expression in normal human B lymphocytes and a panel of lymphoid cancer cell lines as well as mantle cell lymphoma (MCL) clinical samples. We show that PRMT5 protein levels are elevated in all cancer cells, including clinical samples examined despite its low rate of transcription and messenger RNA stability. Remarkably, polysome profiling revealed that PRMT5 mRNA is translated more efficiently in Mino and JeKo MCL cells than in normal B cells, and that decreased miR-92b and miR-96 expression augments PRMT5 translation. Consequently, global methylation of H3R8 and H4R3 is increased and is accompanied by repression of suppressor of tumorigenecity 7 (ST7) in lymphoid cancer cells. Furthermore, knockdown of PRMT5 expression reduces proliferation of transformed JeKo and Raji cells. Thus, our studies indicate that aberrant expression of PRMT5 leads to altered epigenetic modification of chromatin, which in turn impacts transcriptional performance of anti-cancer genes and growth of transformed lymphoid cells. [ABSTRACT FROM AUTHOR]

The article discusses a study about the relation between hyperglycemia and hospital mortality in patients with acute myeloid leukemia (AML). Under the study, hospitalization, glucose exposure and outcomes of 283 adult patients were analyzed. Results show that hyperglycemia during a patient's hospitalization leads to an increase in hospital mortality. It adds that sepsis does not play a main role for the negative impacts of hyperglycemia on hospital mortality.

The article discusses a study on the safety and efficacy of pentostatin, cyclophosphamide and rituximab (PCR) as first-line treatment for patients with chronic lymphocytic leukemia. The study also examined how age, creatinine clearance (CrCl), Β-2 microglobulin (B2M), and performance status (PS) relate to the efficacy and tolerability of this pentostatin-based chemoimmunotherapy regimen.

This In Memoriam reflects on the life and legacy of Dr. Clara D. Bloomfield, whose work in leukemia research will have a truly lasting effect. [ABSTRACT FROM AUTHOR]

In an attempt to exploit bcl-2 overexpression and aberrant p53 function, two frequently encountered aberrations that predict marked treatment resistance and worse prognosis in patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma (NHL), we combined theophylline, pentostatin, and chlorambucil at two dose levels (cohort I: 30 mg/m2; cohort II: 20 mg/m2) on a 21-day cycle for up to six courses. We employed a phase I/II design to determine feasibility, define the maximum tolerated dose (MTD), and explore the impact of biologic modulation on response and time to progression (TTP) in 20 patients with relapsed or refractory CLL and NHL. Eight patients were enrolled in cohort I. They demonstrated a response rate (RR) of 28% and a 16.5-month TTP after receiving a median of two cycles. A 50% RR was observed in this cohort when patients with adverse histologies were excluded. Because of myelotoxicity, this dose level defined the MTD, and de-escalation occurred. All 12 patients in cohort II received 20 mg/m2 chlorambucil. A 50% RR and an 18-month TTP were observed after a median of 5.5 cycles. An RR of 47% and a complete remission (CR) of 5% were observed for the entire group, although responses and TTP varied greatly by histology. Significant activity was observed in patients with B-cell CLL and follicular lymphoma (FL). RR and TTP for fludarabine-sensitive/naïve and fludarabine-refractory (FR) B-cell CLL patients were 66 vs 25% and 20 vs 8.5 months, respectively. Both FL patients responded (one with partial remission and one with CR), with a 22.5-monthly median TTP. For responding patients, median TTP and overall survival (OS) was 21 and 69 months, respectively, compared to a median TTP of 2 months and an OS of 13.5 months for nonresponders. The combination of pentostatin, chlorambucil, and theophylline is the active regimen in patients with FL and B-cell CLL. [ABSTRACT FROM AUTHOR]

Background: Immune-compromised individuals are at increased risk for developing aggressive Epstein-Barr virus (EBV)-associated lymphoproliferative disorders after primary EBV infection or for reactivation of a preexisting latent EBV infection. We evaluated the effect of depsipeptide, a histone deacetylase inhibitor, on EBV-positive lymphoblastoid cell lines (LCLs) and Burkitt lymphoma cell lines in a mouse model and explored its mechanism of action in vitro. Methods: We studied EBV-transformed LCLs, which express a latent III (Lat-III) viral gene profile, as do some EBV-positive lymphoproliferative malignancies, and Burkitt lymphoma cell lines, which express a Lat-I viral gene profile. Cell lines were used to characterize depsipeptide-induced apoptosis, which was evaluated by flow cytometry. Flow cytometry, western blot analyses, and histone deacetylase inhibitors were used to investigate components of prodeath and survival pathways in vitro. We studied depsipeptide's effects on survival with a mouse xenograft model of EBV-positive human B-cell tumors (groups of 10 mice). All statistical tests were two-sided. Results: Depsipeptide (5 mg/m² of body surface area) treatment was associated with statistically significantly improved survival of mice carrying Lat-III EBV-positive LCL tumors, compared with that of control-treated mice (day 30: for depsipeptide-treated mice, 90% survival, 95% confidence interval [CI] = 73.2% to 100%; for control-treated mice, 20% survival, 95% CI = 5.79% to 69.1%; P<.001), but it was not associated with survival of mice carrying Lat-I EBV-positive Burkitt lymphoma tumors. Depsipeptide induced apoptosis in 64% of LCLs and in 14 % of EBV-positive Burkitt lymphoma cells in vitro. Depsipeptide-treated LCL cultures had two distinct cell populations—one sensitive and one resistant to depsipeptide. Depsipeptide-mediated apoptosis was associated with a 12-fold increased level of active caspase 3, but some apoptosis persisted despite z-VAD-fmk treatment to inhibit caspase activity. Depsipeptide-resistant LCLs expressed higher levels of latent membrane protein 1 (LMP1; P = .017), BCL2 (P = .032), and nuclear factor κB (NF-κB) (P<.001) than depsipeptide-sensitive LCLs; this resistance was circumvented by treatment with PS-1145, an inhibitor of NF-κB activation (P<.001). Conclusions: Apoptosis is induced by depsipeptide via caspase-dependent and -independent pathways in Lat-III EBV-positive LCLs and is enhanced by inhibiting NF-κB activity. Depsipeptide as a treatment for Lat-III EBV-associated lymphoproliferative disorders should be explored further in clinical trials. [ABSTRACT FROM AUTHOR]

Investigates the induction of apoptosis in human B-cell chronic lymphocytic leukemia (CLL) cells by carboxyamido-triazole (CAI), a novel 'static' signal transduction inhibitor. Patient characteristics; Role of tumor reduction and disease stabilization in CLL; Detection of apoptosis in CLL cells.

A review of 84 patients with cutaneous leishmaniasis treated with sodium stibogluconate (Pentostam) at our institution revealed that three had developed herpes zoster during or shortly after receiving therapy. Because zoster has been associated with depressed cellular immunity, we prospectively followed serial lymphocyte subpopulations in eight patients with cutaneous leishmaniasis who received Pentostam. By day 7 of therapy, the white blood cell count had fallen by a median of 1.15/mm3, the total lymphocyte count by a median of 804/mm3, and the CD4+ lymphocyte count by a median of 306/mm3 (67% of baseline; confidence interval, 52%–78%). An in vitro cell-viability assay demonstrated that Pentostam is not toxic to human mononuclear cells. The administration of Pentostam for the treatment of cutaneous leishmaniasis results in lymphopenia that may be related to the subsequent occurrence of herpes zoster. [ABSTRACT FROM PUBLISHER]