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1.  Chronic lymphocytic leukemia patients with high-risk genomic features have inferior outcome on successive CALGB trials with alemtuzumab consolidation: subgroup analysis from CALGB 19901 and CALGB 10101 
Leukemia & lymphoma  2013;54(12):10.3109/10428194.2013.788179.
Alemtuzumab consolidation has been investigated to improve remission duration after fludarabine-based induction for chronic lymphocytic leukemia (CLL). The impact on genomic high-risk disease remains unknown. CALGB 19901 and 10101 enrolled previously untreated patients to receive alemtuzumab consolidation after fludarabine-based induction. Immunoglobulin heavy chain gene mutation status (IGVH) and interphase cytogenetics were assessed retrospectively. Treatment response with these alemtuzumab-containing regimens was similar, regardless of genomic risk, except for patients harboring del(17p), where few complete remissions were observed. PFS was similar between IGVH groups, but OS was inferior in IGVH unmutated patients (P=0.03). Cytogenetic risk group was associated with PFS and OS (P=0.01 for both), with similarly short PFS in del(17p) and del(11q) and particularly short OS in del(17p) patients. Cytogenetic risk group remained signficantly associated with PFS and OS when controlling for other prognostic factors (PFS: P=0.009; OS: P=0.02), as did the negative association of IGVH unmutated disease with OS (P=0.004). Results were similar when restricting to patients who received at least one dose of alemtuzumab consolidation, demonstrating limited ability to overcome the poor outcome associated with high-risk genetic features.
doi:10.3109/10428194.2013.788179
PMCID: PMC3766417  PMID: 23547837
CLL; alemtuzumab; clinical trial; cytogenetics; immunoglobulin genes
2.  Addition of Infliximab to Standard Acute Graft-versus-Host Disease Prophylaxis Following Allogeneic Peripheral Blood Cell Transplantation 
Infliximab, a chimeric monoclonal antibody against tumor necrosis factor-α, has shown activity against steroid refractory acute graft-versus-host disease (GVHD). We conducted a prospective trial of infliximab for the prophylaxis of acute GVHD. Patients older than 20 years undergoing myeloablative allogeneic stem cell transplantation for hematologic malignancies were eligible. GVHD prophylaxis consisted of infliximab given one day prior to conditioning and then on days 0, +7, +14, +28 and +42, together with standard cyclosporine and methotrexate. Nineteen patients with a median age of 53 years were enrolled. All patients received peripheral blood allografts from matched sibling (n=14) or unrelated donors (n=5). Results were compared with a matched historical control group (n=30) treated contemporaneously at our institution. The cumulative incidences of grades II–IV acute GVHD in the infliximab and control groups were 36.8% and 36.6% respectively (p=0.77). Rates of chronic GVHD were 78% and 61% respectively (p=0.22). Significantly more bacterial and invasive fungal infections were observed in the infliximab group (p=0.01 and p=0.02 respectively). Kaplan-Meier estimates of 2 year overall survival and progression free survival for patients receiving infliximab were 42% and 36% respectively. The corresponding numbers for patients in the control group were 46% and 43% respectively. The addition of infliximab to standard GVHD prophylaxis did not lower the risk of GVHD and was associated with an increased risk of bacterial and invasive fungal infections.
doi:10.1016/j.bbmt.2008.04.006
PMCID: PMC4100722  PMID: 18541197
Hematopoietic stem cell transplantation; Allogeneic; Graft-versus-Host Disease; Steroid refractory; Infliximab; Tumor necrosis factor; unrelated donor
3.  A Phase I/II Study of Etanercept and Rituximab in Patients with Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma 
Leukemia  2009;23(5):912-918.
Rituximab has modest activity in relapsed Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) but is associated with TNF-α release that can cause CLL proliferation and inhibit apoptosis. We examined whether disruption of TNF-α by etanercept improves response to rituximab in CLL. Eligible patients had previously treated CLL with performance status 0–3. Patients received etanercept 25 mg subcutaneously twice weekly (weeks 1–5) and rituximab 375 mg/m2 intravenously thrice weekly (weeks 2–5) using a phase I/II design. Primary endpoints were response and toxicity. The 36 enrolled patients had a median of 2 prior treatments; 50% were fludarabine-refractory, and 22% had del(17p13.1). Of the 34 response-evaluable patients, ten (29%) responded, including 9 partial responses and 1 complete remission. Response was not affected by prior rituximab nor fludarabine-refractory status, but no patients with del(17p13.1) responded. Median PFS for responders was 9.0 months (range 1–43). Ten patients have had treatment-free intervals exceeding 12 months, including four who have remained untreated for 32, 43, 46 and 56 months. Adverse events were mild, including mild infusion reactions, transient cytopenias and grade 3 infections in 14%. The combination of etanercept and thrice weekly rituximab produces durable remissions in non-del(17p13.1) CLL patients and is well tolerated.
doi:10.1038/leu.2008.385
PMCID: PMC4099250  PMID: 19225537
Rituximab; Etanercept; chronic lymphocytic leukemia
4.  Improved non-relapse mortality and infection rate with lower dose of antithymocyte globulin in patients undergoing reduced intensity conditioning allogeneic transplantation for hematologic malignancies 
Purpose
We sought to reduce the risk of infectious complications and non-relapse mortality (NRM) associated with the use of antithymocyte globulin (ATG) without compromising control of acute graft-versus-host disease (GVHD) in patients undergoing reduced intensity conditioning (RIC) transplantation.
Methods
As part of an ongoing quality improvement effort, we lowered the dose of rabbit ATG from 7.5 mg/kg of ATG (R-ATG) (n=39) to 6.0 mg/kg of ATG (r-ATG) (n=33) in association with fludarabine and busulfan RIC transplantation and then monitored patients for adverse events, relapse, and survival.
Results
Of the 72 mostly high risk (82%) patients studied, 89% received unrelated donor allografts, 25% of which were HLA-mismatched. No differences in post-transplantation full donor-cell chimerism rates were observed between the two ATG-dose groups (p>0.05). When R-ATG vs. r-ATG patients were compared, we observed no significant difference in the cumulative incidence of grade II–IV acute GVHD (32% vs. 27%; p-=0.73) or grade III–IV acute GVHD (23% vs. 11%; p=0.28). However, the r-ATG group had significantly less CMV reactivation (64% vs. 30%; p=0.005) and bacterial infections (56% vs. 18%; p=0.001), a better 1-year cumulative incidence of NRM (18% vs. 3%; p=0.03) and a trend for better 1-year overall survival (64% vs. 84%; p=0.07) compared to R-ATG patients.
Conclusions
A seemingly modest reduction in the dose of rabbit ATG did not compromise control of acute GVHD or achievement of donor chimerism but led to a significant decrease in the risk of serious infections and NRM in high risk RIC allograft recipients.
doi:10.1016/j.bbmt.2009.07.006
PMCID: PMC3953136  PMID: 19822302
Fludarabine; busulfan; thymoglobulin; antithymocyte globulin; allogeneic stem cell transplantation; graft-versus-host disease
5.  Impact of Age on Outcomes After Initial Therapy With Chemotherapy and Different Chemoimmunotherapy Regimens in Patients With Chronic Lymphocytic Leukemia: Results of Sequential Cancer and Leukemia Group B Studies 
Journal of Clinical Oncology  2012;31(4):440-447.
Purpose
Chronic lymphocytic leukemia (CLL) is a disease of the elderly, yet few clinical trials include a significant number of older patients, and outcomes after specific therapies can be different depending on age.
Patients and Methods
We examined patients enrolled onto successive first-line CALGB CLL trials to determine whether efficacy of regimens varied by age, focusing on ideal chemotherapy choice and benefit of immunotherapy addition to chemotherapy in older patients. Regimens included chlorambucil, fludarabine, fludarabine plus rituximab (FR), fludarabine with consolidation alemtuzumab, and FR with consolidation alemtuzumab.
Results
A total of 663 patients were evaluated for response, progression-free survival (PFS), and overall survival (OS) by age group. Interaction effects of fludarabine versus chlorambucil by age group (PFS, P = .046; OS, P = .006) showed that among patients younger than 70 years, PFS and OS was improved with fludarabine over chlorambucil (PFS: hazard ratio [HR] = 0.6, 95% CI, 0.5 to 0.8; OS: HR = 0.7, 95% CI, 0.5 to 0.9), but not in older adults (PFS, HR = 1.0, 95% CI, 0.6 to 1.7; OS: HR = 1.5, 95% CI, 0.9 to 2.3). In contrast, FR improved outcomes relative to fludarabine, irrespective of age (PFS: HR = 0.6, 95% CI, 0.4 to 0.7; OS: HR = 0.7, 95% CI, 0.5 to 0.9). Alemtuzumab consolidation did not provide benefit over similar regimens without alemtuzumab (P > .20), irrespective of age.
Conclusion
These data support the use of chlorambucil as an acceptable treatment for many older patients with CLL and suggest rituximab is beneficial regardless of age. These findings bear relevance to both routine care of CLL patients 70 years and older and also future clinical trials in this population.
doi:10.1200/JCO.2011.41.5646
PMCID: PMC3731920  PMID: 23233702
6.  Prolonged myelosuppression with clofarabine in the treatment of patients with relapsed or refractory, aggressive non-Hodgkin lymphoma 
Leukemia & lymphoma  2009;50(3):349-356.
We evaluated the safety and efficacy of the purine nucleoside analogue, clofarabine, in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). Six patients with DLBCL (n = 5) or MCL (n = 1) and a median age of 68 years were treated with 40 mg/m2 clofarabine IV over 2 h for 5 days, repeated every 28 days, for 1–2 cycles. The overall response rate was 50% (complete response = 1, complete response unconfirmed = 1, partial response = 1). Median progression-free survival was 3.5 months (range 1.5–10 months) and the median overall survival was 7.8 months (range 3–31 months). Grade 3–4 neutropenia and thrombocytopenia was universal, with a median of 34 (range 19–55) and 77 (range 0–275) days required for neutrophil and platelet recovery. Grade 3 non-hematologic toxicities included transaminitis, febrile neutropenia, non-neutropenic infections and orthostatic hypotension. Further accrual to the study was terminated due to prolonged Grade 3–4 myelosuppression and orthostatic hypotension in five of six patients. Clofarabine exhibits evidence of single agent activity in relapsed or refractory DLBCL. However, further study with novel administration schedules that maintain this efficacy and limit toxicity is warranted.
doi:10.1080/10428190902730227
PMCID: PMC3695225  PMID: 19263294
Clofarabine; diffuse large B cell lymphoma; mantle cell lymphoma; nucleoside analogues; myelosuppression
7.  Phase II trial of rituximab and bortezomib in patients with relapsed or refractory mantle cell and follicular lymphoma 
Cancer  2010;117(11):10.1002/cncr.25792.
Background
In vitro studies in mantle cell lymphoma (MCL) cell lines and patient-derived cells have demonstrated synergistic apoptosis with combined rituximab and bortezomib (R-bortezomib), compared to single agent bortezomib. Therefore, we evaluated R-bortezomib in a preclinical model and in a phase II clinical trial.
Methods
A Hu-MCL-SCID model engrafted with the Jeko cell line was treated with R-bortezomib, bortezomib, or rituximab. Twenty-five patients with relapsed follicular (n=11) and MCL (n=14) received 375 mg/m2 rituximab days 1 and 8 and 1.3-1.5 mg/m2 bortezomib days 1, 4, 8, and 11 every 21 days for a median of 3 cycles (range, 1-5).
Results
R-bortezomib resulted in a statistically significant improvement in overall survival in Hu-MCL-SCID mice. In the clinical trial, the overall response rate (ORR) in 25 patients was 40%, with an ORR of 55% and 29% in patients with follicular and MCL, respectively. The estimated 2-year progression-free survival (PFS) was 24% (95% CI 10%, 53%) in all patients and 60% (95% CI 20%, 85%) in responding patients. Thirteen patients (52%) developed grade 3 neurotoxicity consisting of constipation/ileus, sensory or motor neuropathy, or orthostatic hypotension. Patients heterozygous for the CD32a (Fcγ receptor IIa) 131 histidine (H) to arginine (R) polymorphism had a significantly decreased PFS (p=0.009) after R-bortezomib compared to HH and RR homozygotes.
Conclusion
R-bortezomib has significant activity in patients with relapsed or refractory follicular and MCL, although an unexpectedly high incidence of grade 3 neurologic toxicity is a potential limiting factor with this combination.
doi:10.1002/cncr.25792
PMCID: PMC3116936  PMID: 24048792
rituximab; bortezomib; neuropathy; mantle cell lymphoma; follicular lymphoma
8.  Consolidation Therapy With Subcutaneous Alemtuzumab After Fludarabine and Rituximab Induction Therapy for Previously Untreated Chronic Lymphocytic Leukemia: Final Analysis of CALGB 10101 
Journal of Clinical Oncology  2010;28(29):4500-4506.
Purpose
To determine if alemtuzumab consolidation improves response rate and progression-free survival (PFS) after induction chemoimmunotherapy in previously untreated symptomatic patients with chronic lymphocytic leukemia.
Patients and Methods
Patients (n = 102) received fludarabine 25 mg/m2 intravenously days 1 to 5 and rituximab 50 mg/m2 day 1, 325 mg/m2 day 3, and 375 mg/m2 day 5 of cycle 1 and then 375 mg/m2 day 1 of cycles 2 to 6; fludarabine plus rituximab (FR) administration was repeated every 28 days for six cycles. Three months after completion of FR, patients with stable disease or better response received subcutaneous alemtuzumab 3 mg day 1, 10 mg day 3, and 30 mg day 5 and then 30 mg three times per week for 5 weeks.
Results
Overall response (OR), complete response (CR), and partial response (PR) rates were 90%, 29%, and 61% after FR, respectively; 15% of patients were minimal residual disease (MRD) negative. Of 102 patients, 58 received alemtuzumab; 28 (61%) of 46 patients achieving PR after FR attained CR after alemtuzumab. By intent to treat (n = 102), OR and CR rates were 90% and 57% after alemtuzumab, respectively; 42% of patients became MRD negative. With median follow-up of 36 months, median PFS was 36 months, 2-year PFS was 72%, and 2-year OS was 86%. In patients achieving CR after FR, alemtuzumab was associated with five deaths resulting from infection (viral and Listeria meningitis and Legionella, cytomegalovirus, and Pneumocystis pneumonias), which occurred up to 7 months after last therapy. The study was amended to exclude CR patients from receiving alemtuzumab.
Conclusion
Alemtuzumab consolidation improved CR and MRD-negative rates after FR induction but caused serious infections in patients who had already achieved CR after induction and did not improve 2-year PFS or survival.
doi:10.1200/JCO.2010.29.7978
PMCID: PMC2988639  PMID: 20697069
9.  Pentostatin and Rituximab Therapy for Previously Untreated B-CLL 
Cancer  2010;116(9):2180-2187.
We have shown that the combination of pentostatin (P), cyclophosphamide (C) and rituximab (R) achieves an overall response (OR) rate >90% with more than 40% complete responses (CR) in patients with untreated CLL. To evaluate if the tolerability of this regimen could be enhanced without sacrificing efficacy, we conducted a phase II trial of P and R without cyclophosphamide, using a higher P dose (4 mg/m2). Among the 33 patients enrolled, 82% were male, median age was 65 (9 patients ≥70 years) and 64% were Rai stage III-IV. The OR rate was 76% with 9 CR (27%), 5 nPR, and 11 PRs. At the time of this analysis, 29/33 patients are still alive and the median follow up for patients still alive is 14 months (range: 1-34.8 months). Four (12%) patients experienced grade 3 or higher hematologic toxicity and 5 (15%) experienced grade 3 or higher non-hematologic toxicity. Comparison of this trial to our previous PCR trial showed that patients treated with PCR had a higher OR rate (91% vs. 76%) and CR rate (41% vs. 27%) compared to patients treated with PR. Median treatment-free survival for all accrued patients was notably longer in PCR treated patients compared to PR (30 vs. 16 months). These findings suggest that increasing the dose of the purine nucleoside analogue does not eliminate the need for cyclophosphamide in chemoimmunotherapy for treatment of CLL.
doi:10.1002/cncr.25028
PMCID: PMC2919331  PMID: 20187101
pentostatin; rituximab; cyclophosphamide; chemoimmunotherapy; response rates; B-CLL
10.  Flavopiridol, Fludarabine, and Rituximab in Mantle Cell Lymphoma and Indolent B-Cell Lymphoproliferative Disorders 
Journal of Clinical Oncology  2009;28(3):418-423.
Purpose
Flavopiridol downmodulates antiapoptotic proteins associated with resistance to fludarabine and rituximab and is effective against p53-mutated chronic lymphocytic leukemia (CLL). We conducted a phase I study of flavopiridol, fludarabine, and rituximab (FFR) in patients with mantle-cell lymphoma (MCL), indolent B-cell non-Hodgkin's lymphomas (B-NHL), and CLL to determine the activity of FFR.
Patients and Methods
Therapy included fludarabine 25 mg/m2 intravenously (IV) days 1 to 5 and rituximab 375 mg/m2 day 1 every 28 days for 6 cycles. We administered flavopiridol 50 mg/m2 by 1-hour IV bolus (IVB) day 1 (n = 15); day 1 to 2 (n = 6); 20 mg/m2 30-minute IVB + 20 mg/m2 4-hour IV infusion (n = 3); or 30 mg/m2 + 30 mg/m2 (n = 14).
Results
Thirty-eight patients (median age, 62 years) with MCL (n = 10); indolent B-NHL including follicular (n = 9), marginal zone (n = 4), lymphoplasmacytic (n = 1), or small lymphocytic lymphoma (n = 3); and CLL (n = 11), were enrolled. Twenty-two patients were previously untreated; 16 had received one to two prior therapies. Two patients in cohort 2 developed grade 3 dose-limiting toxicity (seizures, renal insufficiency). The median number of treatment cycles was 4, with cytopenias (n = 10) and fatigue (n = 3) the most common reasons for early discontinuation. Overall response rate was 82% (complete response, 50%; unconfirmed complete response, 5%; partial response, 26%), including 80% of patients with MCL (median age, 68; seven complete responses, one partial response). Median progression-free survival (PFS) was 25.6 months. Median PFS of patients with nonblastoid variant MCL (n = 8) was 35.9 months.
Conclusion
FFR was active in MCL, indolent B-NHL, and CLL and should be studied for older patients with MCL who are not candidates for aggressive chemotherapy.
doi:10.1200/JCO.2009.24.1570
PMCID: PMC2815704  PMID: 20008633
11.  Phase II Study of Flavopiridol in Relapsed Chronic Lymphocytic Leukemia Demonstrating High Response Rates in Genetically High-Risk Disease 
Journal of Clinical Oncology  2009;27(35):6012-6018.
Purpose
Patients with chronic lymphocytic leukemia (CLL) with high-risk genomic features achieve poor outcomes with traditional therapies. A phase I study of a pharmacokinetically derived schedule of flavopiridol suggested promising activity in CLL, irrespective of high-risk features. Given the relevance of these findings to treating genetically high-risk CLL, a prospective confirmatory study was initiated.
Patients and Methods
Patients with relapsed CLL were treated with single-agent flavopiridol, with subsequent addition of dexamethasone to suppress cytokine release syndrome (CRS). High-risk genomic features were prospectively assessed for response to therapy.
Results
Sixty-four patients were enrolled. Median age was 60 years, median number of prior therapies was four, and all patients had received prior purine analog therapy. If patients tolerated treatment during week 1, dose escalation occurred during week 2. Dose escalation did not occur in four patients, as a result of severe tumor lysis syndrome; three of these patients required hemodialysis. Thirty-four patients (53%) achieved response, including 30 partial responses (PRs; 47%), three nodular PRs (5%), and one complete response (1.6%). A majority of high-risk patients responded; 12 (57%) of 21 patients with del(17p13.1) and 14 (50%) of 28 patients with del(11q22.3) responded irrespective of lymph node size. Median progression-free survival among responders was 10 to 12 months across all cytogenetic risk groups. Reducing the number of weekly treatments per cycle from four to three and adding prophylactic dexamethasone, which abrogated interleukin-6 release and CRS (P ≤ .01), resulted in improved tolerability and treatment delivery.
Conclusion
Flavopiridol achieves significant clinical activity in patients with relapsed CLL, including those with high-risk genomic features and bulky lymphadenopathy. Subsequent clinical trials should use the amended treatment schedule developed herein and prophylactic corticosteroids.
doi:10.1200/JCO.2009.22.6944
PMCID: PMC2793044  PMID: 19826119
12.  Flavopiridol Pharmacogenetics: Clinical and Functional Evidence for the Role of SLCO1B1/OATP1B1 in Flavopiridol Disposition 
PLoS ONE  2010;5(11):e13792.
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.
doi:10.1371/journal.pone.0013792
PMCID: PMC2967470  PMID: 21072184
13.  Brief Report: Pre-treatment Angiogenic Cytokines Predict Response to Chemoimmunotherapy in Patients with CLL 
British journal of haematology  2009;146(6):660-664.
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 leukemia (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.
doi:10.1111/j.1365-2141.2009.07811.x
PMCID: PMC2777697  PMID: 19604237
Chronic lymphocytic leukaemia; angiogenesis; therapy; VEGF, prognostic factors
14.  Dic(17;18)(p11.2;p11.2) is a recurring abnormality in chronic lymphocytic leukaemia associated with aggressive disease 
British journal of haematology  2009;148(5):754-759.
Summary
Interphase cytogenetics are commonly used to identify clonal abnormalities in chronic lymphocytic leukemia (CLL) patients but fail to identify recurrent translocations that ultimately can direct more focused molecular characterization. Given the importance of del(17p13.1) in CLL outcome, we performed an extensive review of 1213 patients undergoing metaphase cytogenetics at our institution and identified 16 (1.3%) with a recurrent unbalanced translocation between the p arms of chromosomes 17 and 18 that results in a dicentric chromosome with loss of much of 17p and 18p. The dic(17;18)(p11.2;p11.2) was associated with a complex (three or more unrelated cytogenetic abnormalities) karyotype in 12 patients (75%) at the time that the abnormality was first identified, and eventually associated with a complex karyotype in 94% of patients. IGHV mutational analysis was un-mutated in 88% of cases where evaluation was possible. Except for one patient who was diagnosed with CLL incidentally during a workup for metastatic tonsillar cancer, all patients identified with dic(17;18)(p11.2;p11.2) met criteria for disease treatment, with a median time from diagnosis to first treatment of 15 months. Our data demonstrate that dic(17;18)(p11.2;p11.2) is a novel recurrent cytogenetic abnormality in CLL associated with early age at diagnosis and accelerated disease progression. Future efforts to identify genes disrupted by this translocation are warranted and ongoing.
doi:10.1111/j.1365-2141.2009.08007.x
PMCID: PMC2902554  PMID: 20015097
chronic lymphocytic leukemia; prognostic factors; cytogenetic abnormalities; FISH; dic(17;18)(p11.2;p11.2)
15.  Ofatumumab: a novel monoclonal anti-CD20 antibody 
Ofatumumab, a novel humanized monoclonal anti-CD20 antibody, was recently approved by the FDA for the treatment of fludarabine and alemtuzumab refractory chronic lymphocytic leukemia (CLL). Ofatumumab effectively induces complement-dependent cytotoxicity (CDC) in vitro, and recent studies demonstrated that ofatumumab also effectively mediates antibody-dependent cellular cytotoxicity (ADCC). Pharmacokinetic studies indicated that increased exposure to the antibody correlated with improved clinical outcome in CLL. Thus, pharmacogenomics may be important in identifying which patients are more likely to respond to ofatumumab therapy, although such studies have not yet been performed. Patients with the high-affinity FCGR3a 158 V/V polymorphism may be more likely to respond to therapy, if ADCC is the primary in vivo mechanism of action of ofatumumab. Patients with increased expression of the complement defense proteins CD55 and CD59 may be less likely to respond if ofatumumab works in vivo primarily via CDC. Patients with increased metabolism and clearance of ofatumumab may have lower exposure and be less likely to respond clinically. Thus, pharmacogenomics may determine the responsiveness of patients to ofatumumab therapy.
PMCID: PMC3513208  PMID: 23226042
monoclonal antibody; CD20; CLL; NHL; lymphoma
16.  Pulmonary hypertension in Hodgkin's disease 
Thorax  2007;62(4):371.
doi:10.1136/thx.2006.070029
PMCID: PMC2092463  PMID: 17387215
17.  Update in the management of chronic lymphocytic leukemia 
Advances in the treatment of chronic lymphocytic leukemia (CLL) have improved initial overall response (OR) rates, complete response (CR) rates and progression free survival (PFS). Despite these advances, CLL remains incurable with standard therapies. Thus, there remains a need for more effective therapies in both the upfront and relapsed setting, particularly for patients with high-risk cytogenetic abnormalities such as del(11q22) and del(17p13). The 2008 American Society of Hematology (ASH) Annual Meeting featured several presentations which highlighted the ongoing clinical advances in CLL. The benefit of adding rituximab to purine analog therapy in the upfront setting was demonstrated by a large randomized study which showed that the addition of rituximab to fludarabine and cyclophosphamide (FCR) significantly improved OR, CR and PFS. The improvement in PFS directly resulted from an improved ability to eliminate minimal residual disease (MRD) in the peripheral blood, highlighting the importance of MRD eradication. However, a multi-center study suggested that the high CR rates to chemoimmunotherapy regimens such as FCR obtained in academic centers may not be reproducible when the same regimens are given in the community setting. The immunomodulatory drug lenalidomide is active in relapsed high-risk CLL, but two studies of lenalidomide in previously untreated CLL patients failed to achieve a CR and were associated with significant tumor lysis, tumor flare and hematologic toxicity. In the relapsed setting, a combination study of the bifunctional alkylator bendamustine and rituximab (BR) demonstrated a high OR rate in patients with del(11q22) and del(17p13), indicating that further studies to define's bendamustine activity are warranted in high-risk CLL. Similarly, the CDK inhibitor flavopiridol demonstrated significant clinical activity and durable remissions in heavily treated, refractory CLL patients with high-risk cytogenetic features and bulky lymphadenopathy. The monoclonal anti-CD20 antibody ofatumumab appeared to be superior to rituximab in relapsed CLL patients with bulky nodal disease or high-risk cytogenetic features. Ongoing studies of these agents and other novel therapeutic agents in clinical development hold forth the promise that treatment options for CLL patients will continue to expand and improve.
doi:10.1186/1756-8722-2-29
PMCID: PMC2723130  PMID: 19619273
19.  Development and validation of a sensitive liquid chromatography/mass spectrometry method for quantitation of flavopiridol in plasma enables accurate estimation of pharmacokinetic parameters with a clinically active dosing schedule 
A high-performance liquid chromatographic assay with tandem mass spectrometric detection was developed and validated for quantitation of the broad spectrum kinase inhibitor, flavopiridol, in human plasma. Sample preparation conditions included liquid-liquid extraction in acetonitrile (ACN), drying, and reconstitution in 20/80 water/ACN. Flavopiridol and the internal standard (IS), genistein, were separated by reversed phase chromatography using a C-18 column and a gradient of water with 25 mM ammonium formate and ACN. Electrospray ionization and detection of flavopiridol and genistein were accomplished with single reaction monitoring of m/z 402.09 > 341.02 and 271.09 > 152.90, respectively in positive-ion mode [M+H]+ on a triple quadrupole mass spectrometer. Recovery was greater than 90% throughout the linear range of 3 nM to 1,000 nM. Replicate sample analysis indicated within- and between-run accuracy and precision to be less than 13% throughout the linear range. This method has the lowest LLOQ reported to date for flavopiridol, and it allows for more accurate determination of terminal phase concentrations and improved pharmacokinetic parameter estimation in patients receiving an active dosing schedule of flavopiridol.
doi:10.1016/j.jchromb.2008.04.023
PMCID: PMC2504738  PMID: 18490204
20.  Antibody Therapy for CLL 
Seminars in hematology  2008;45(2):95-103.
The introduction of the monoclonal antibodies rituximab (anti-CD20) and alemtuzumab (anti-CD52) has revolutionized the treatment of chronic lymphocytic leukemia (CLL). Both antibodies were first studied as single agents in relapsed CLL, but rituximab is increasingly used in combination chemoimmunotherapy regimens in previously untreated patients. Phase II studies demonstrated that the addition of rituximab to fludarabine-based chemotherapy improves complete response (CR) rates and progression-free survival (PFS), but long-term survival benefit has not been shown. Alemtuzumab is less commonly used, due to its greater infusion, hematologic and immune toxicity. Subcutaneous (SC) administration significantly reduces infusion toxicity, but hematologic and infectious complications, most notably cytomegalovirus (CMV) reactivation, still occur with SC dosing. Alemtuzumab’s unique clinical properties include its clinical activity in relapsed CLL patients with del(17p13) and its ability to eradicate minimal residual disease (MRD) in bone marrow. Its use as consolidation therapy to eradicate MRD after nucleoside analog therapy is under active study. Several investigational monoclonal antibodies are in preclinical or clinical studies, most notably lumiliximab (anti-CD23) and ofatumumab (HuMax CD20), and are briefly discussed in this review.
doi:10.1053/j.seminhematol.2008.02.001
PMCID: PMC2390995  PMID: 18381104
21.  Expression of TCL-1 as a Potential Prognostic Factor for Treatment Outcome in B-Cell Chronic Lymphocytic Leukemia 
Leukemia research  2007;31(12):1737-1740.
TCL-1 expression is variable in CLL, and no study has examined its association with treatment response. We measured TCL-1 protein in CLL cells from 51 patients who then received pentostatin, cyclophosphamide, and rituximab. TCL-1 expression did not correlate with any pre-treatment characteristics. Lower TCL-1 levels were associated with higher probability of attaining flow cytometry-negative status post-treatment (52% versus 17%, p=0.046). Trends toward improved complete remission rate (49% versus 19%, p=0.064) and progression-free survival (medians: 33 versus 20 months, p=0.199) were noted with lower TCL-1 expression. These data suggest TCL-1 expression may help predict treatment outcome in CLL patients following chemoimmunotherapy, and examination in larger studies is warranted.
doi:10.1016/j.leukres.2007.05.020
PMCID: PMC2225453  PMID: 17659340
Chronic Lymphocytic Leukemia (CLL); TCL-1; prognostic factor; pentostatin; chemoimmunotherapy

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