Andrew D Zelenetz

Memorial Sloan-Kettering Cancer Center, New York, New York, United States

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Publications (222)1712.69 Total impact

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    ABSTRACT: Background: Double-hit lymphomas (DHLs) are collectively defined as B-cell non-Hodgkin lymphomas harboring rearrangements of MYC as well as B-cell lymphoma 2 (BCL2) and/or B-cell lymphoma 6 (BCL6). To the authors' knowledge, the impact of specific oncogene rearrangements on outcomes of patients with DHL who are treated with immunochemotherapy has not been previously described. Methods: The authors identified patients whose diagnostic tissue specimens underwent metaphase karyotyping or fluorescence in situ hybridization for MYC as well as both BCL2 and BCL6 rearrangements. Cohorts were defined by the presence (+) or absence (-) of rearrangements: MYC+/BCL2+/BCL6- (BCL2-DHL), MYC+/BCL2-/BCL6+ (BCL6-DHL), and MYC+/BCL2+/BCL6+ (triple-hit lymphoma; THL). Results: A total of 117 patients were included in the current analysis (76 BCL2-DHL patients, 16 BCL6-DHL patients, and 25 THL patients). Compared with patients with BCL2-DHL, those with BCL6-DHL were more likely to be classified as having a non-germinal center cell of origin, presented with extranodal disease, and appeared to achieve higher rates of complete response despite receiving intensive induction therapy less frequently. However, patients with BCL6-DHL experienced a shorter median overall survival if achieving an initial complete response compared with patients with BCL2-DHL. Patients with THL experienced survival outcomes similar to those of patients with BCL2-DHL. Conclusions: Recognition of the specific oncogene rearrangements may be of prognostic value and potentially guide future therapeutic strategies for patients with DHL. Cancer 2015. © 2015 American Cancer Society.
    Cancer 11/2015; DOI:10.1002/cncr.29781 · 4.89 Impact Factor
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    ABSTRACT: Idelalisib is a first-in-class oral inhibitor of PI3Kδ that has shown substantial activity in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). To evaluate idelalisib as initial therapy, 64 treatment-naïve older patients with CLL or small lymphocytic leukemia (median age: 71 years, range: 65 - 90 years) were treated with rituximab 375 mg/m(2) weekly x 8 and idelalisib 150 mg bid continuously for 48 weeks. Patients completing 48 weeks without progression could continue to receive idelalisib on an extension study. The median time on treatment was 22.4 months (range: 0.8 - 45.8+). The overall response rate (ORR) was 97%, including 19% complete responses. The ORR was 100% in patients with del(17p)/TP53 mutations and 97% in those with unmutated IGHV. Progression-free survival was 83% at 36 months. The most frequent (>30%) adverse events (any grade) were diarrhea (including colitis) (64%), rash (58%), pyrexia (42%), nausea (38%), chills (36%), cough (33%), and fatigue (31%). Elevated ALT/AST was seen in 67% of patients (23% Grade ≥3). In conclusion, the combination of idelalisib and rituximab was highly active, resulting in durable disease control in treatment-naïve older patients with CLL. These results support the further development of idelalisib as initial treatment for CLL. ( identifier: NCT01203930).
    Blood 10/2015; DOI:10.1182/blood-2015-03-630947 · 10.45 Impact Factor
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    ABSTRACT: BACKGROUND: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. METHODS: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. RESULTS: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl (2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE =0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. CONCLUSION: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
    JNCI Journal of the National Cancer Institute 10/2015; 107(12). DOI:10.1093/jnci/djv279 · 12.58 Impact Factor
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    ABSTRACT: Therapeutic options for limited-stage diffuse large B cell lymphoma (DLBCL) include short- or full-course R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) ± radiotherapy. The optimal treatment remains unclear. The prognostic value of cell-of-origin (COO) in early stage DLBCL is unknown. Patients with limited-stage DLBCL (stage I or stage II, non-bulky) treated with R-CHOP ± involved field radiotherapy (IFRT) from 1999 to 2012 were included. COO by the Hans algorithm was analysed in a subset of patients. Of 261 patients, 30% were stage I (N = 82), 37% stage IE (N = 96), <1% stage IXEE (N = 1), 18% stage II (N = 46) and 14% stage IIE (N = 37). The stage-modified International Prognostic Index stratified patients into prognostically relevant groups. There was no significant difference in progression-free survival (PFS) or overall survival (OS) for patients in the germinal centre B-cell-like (GCB; n = 65) and non-GCB cohorts (n = 22). Seventeen patients received R-CHOP × 3-4 cycles (Arm A), 147 received R-CHOP × 3-4 cycles + IFRT (Arm B), 48 received R-CHOP × 6 cycles (Arm C), and 50 received R-CHOP × 6 cycles + IFRT (Arm D). The outcomes were excellent, with 5-year PFS of 82% and 5-year OS of 93%, and were similar across the 4 treatment groups. In the rituximab era, outcomes for limited-stage DLBCL, regardless of treatment approach, were excellent. Baseline COO was not a significant prognostic factor in patients treated with short-course R-CHOP + IFRT.
    British Journal of Haematology 10/2015; DOI:10.1111/bjh.13766 · 4.71 Impact Factor
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    ABSTRACT: Background: Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma, with median age at diagnosis in the seventh decade. FL in young adults (YA), defined as diagnosis at≤40 years, is uncommon. No standard approaches exist guiding treatment of YA FL, and little is known about their disease characteristics and outcomes. To gain further insight into YA FL, we analyzed the National LymphoCare Study (NLCS) to describe characteristics, initial treatments, and outcomes in this population versus patients aged>40 years. Patients and methods: Using the NLCS database, we stratified FL patients by age: 18-40 (YA), 41-60, 61-70, 71-80, and>80 years. Survival probability was estimated using Kaplan-Meier methodology. We examined associations between age and survival using hazard ratios and 95% confidence intervals (CI) from multivariable Cox models. Results: Of 2652 eligible FL patients in the NLCS, 164 (6%) were YA. Of YA patients, 69% had advanced disease, 80% had low-grade histology, 50% had good-risk disease according to the Follicular Lymphoma International Prognostic Index (FLIPI). Nineteen percent underwent observation, 12% received rituximab monotherapy, 46% received chemo-immunotherapy (in 59% of these: R-CHOP [rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone]). With median follow-up of 8 years, overall survival (OS) at 2, 5, and 8 years was 98% (95% CI 93-99), 94% (95% CI 89-97), and 90% (95% CI 83-94), respectively. Median progression-free survival (PFS) was 7.3 years (95% CI 5.6-not reached). Conclusions: In one of the largest cohorts of YA FL patients treated in the rituximab era, disease characteristics and outcomes were similar to patients aged 41-60 years; with favorable OS and PFS in YA. Longer-term outcomes and YA-specific survivorship concerns should be considered when defining management. These data may not support the need for more aggressive therapies in YA FL.
    Annals of Oncology 09/2015; DOI:10.1093/annonc/mdv375 · 7.04 Impact Factor
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    ABSTRACT: Abstract PURPOSE: Obinutuzumab (GA101), a novel glycoengineered type II anti-CD20 monoclonal antibody, demonstrated responses in single-arm studies of patients with relapsed/refractory non-Hodgkin lymphoma. This is the first prospective, randomized study comparing safety and efficacy of obinutuzumab with rituximab in relapsed indolent lymphoma. The primary end point of this study was the overall response rate (ORR) in patients with follicular lymphoma after induction and safety in patients with indolent lymphoma. PATIENTS AND METHODS: A total of 175 patients with relapsed CD20+ indolent lymphoma requiring therapy and with previous response to a rituximab-containing regimen were randomly assigned (1:1) to four once-per-week infusions of either obinutuzumab (1,000 mg) or rituximab (375 mg/m2). Patients without evidence of disease progression after induction therapy received obinutuzumab or rituximab maintenance therapy every 2 months for up to 2 years. RESULTS: Among patients with follicular lymphoma (n = 149), ORR seemed higher for obinutuzumab than rituximab (44.6% v 33.3%; P = .08). This observation was also demonstrated by a blinded independent review panel that measured a higher ORR for obinutuzumab (44.6% v 26.7%; P = .01). However, this difference did not translate into an improvement in progression-free survival. No new safety signals were observed for obinutuzumab, and the incidence of adverse events was balanced between arms, with the exception of infusion-related reactions and cough, which were higher in the obinutuzumab arm. CONCLUSION: Obinutuzumab demonstrated a higher ORR without appreciable differences in safety compared with rituximab. However, the clinical benefit of obinutuzumab in this setting remains unclear and should be evaluated within phase III trials.
    Journal of Clinical Oncology 08/2015; 33(30). DOI:10.1200/JCO.2014.59.2139 · 18.43 Impact Factor

  • Cancer Research 08/2015; 75(15 Supplement):2371-2371. DOI:10.1158/1538-7445.AM2015-2371 · 9.33 Impact Factor
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    Mayo Clinic Proceedings 07/2015; 90(8). DOI:10.1016/j.mayocp.2015.06.001 · 6.26 Impact Factor
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    ABSTRACT: Relapsed and refractory (rel/ref) mantle cell lymphoma (MCL) portend a dismal prognosis. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents the only potentially curative therapy in this setting. We analyzed the survival outcomes of 29 recipients of non-myeloablative allo-HSCT for rel/ref MCL, and studied possible prognostic factors in this setting. The cumulative incidences of disease progression and non-relapse mortality at 3 years were 28% (95% confidence interval (CI): 13-46%) and 29% (95% CI: 13-47%), respectively. The cumulative incidence of grade II-IV acute GvHD at days +100 and +180 was 34% (95% CI: 18-52%) and 45% (95% CI: 26-62%), respectively. With a median follow-up in survivors of 53 (range 24-83) months, the 3-year overall survival (OS) and PFS were 54% (95% CI: 38-76%) and 41% (95% CI: 26-64%), respectively. In vivo T-cell depletion with alemtuzumab (n=6) was associated with inferior 3-year PFS (0% vs 51%, P=0.007) and OS (17% vs 64%, P=0.014). Conversely, a second-line international prognostic index (sIPI) at transplantation equal to 0 (no risk factors) was associated with an improved 3-year PFS (52% vs 22%, P=0.020) and OS (71% vs 22%, P=0.006) compared with sIPI ⩾1. Performing an allo-HSCT before 2007 was associated with a decreased 3-year OS (25% vs 76%, P=0.015) but not with a significantly inferior PFS (17% vs 59%, P=0.058). In this single-center series, we report encouraging results with allo-HSCT for patients with rel/ref MCL. High alemtuzumab doses should probably be avoided in this context.Bone Marrow Transplantation advance online publication, 6 July 2015; doi:10.1038/bmt.2015.156.
    Bone marrow transplantation 07/2015; 50(10). DOI:10.1038/bmt.2015.156 · 3.57 Impact Factor
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    ABSTRACT: Twenty percent of patients with follicular lymphoma (FL) experience progression of disease (POD) within 2 years of initial chemoimmunotherapy. We analyzed data from the National LymphoCare Study to identify whether prognostic FL factors are associated with early POD and whether patients with early POD are at high risk for death. In total, 588 patients with stage 2 to 4 FL received first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Two groups were defined: patients with early POD 2 years or less after diagnosis and those without POD within 2 years, the reference group. An independent validation set, 147 patients with FL who received first-line R-CHOP, was analyzed for reproducibility. Of 588 patients, 19% (n = 110) had early POD, 71% (n = 420) were in the reference group, 8% (n = 46) were lost to follow-up, and 2% (n = 12) died without POD less than 2 years after diagnosis. Five-year overall survival was lower in the early-POD group than in the reference group (50% v 90%). This trend was maintained after we adjusted for FL International Prognostic Index (hazard ratio, 6.44; 95% CI, 4.33 to 9.58). Results were similar for the validation set (FL International Prognostic Index-adjusted hazard ratio, 19.8). In patients with FL who received first-line R-CHOP, POD within 2 years after diagnosis was associated with poor outcomes and should be further validated as a standard end point of chemoimmunotherapy trials of untreated FL. This high-risk FL population warrants further study in directed prospective clinical trials. © 2015 by American Society of Clinical Oncology.
    Journal of Clinical Oncology 06/2015; 33(23). DOI:10.1200/JCO.2014.59.7534 · 18.43 Impact Factor
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    ABSTRACT: Purpose To determine the prognostic value of performing fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) before allogeneic and autologous stem cell transplantation (SCT) in patients with aggressive lymphoma. Materials and Methods A HIPAA-compliant retrospective review was performed under institutional review board waiver. Patients with aggressive lymphoma underwent allogeneic or autologous SCT between January 2005 and December 2010. FDG PET/CT was performed within the 3 months prior to transplantation. PET/CT images were evaluated for lesions with FDG avidity greater than that of the background liver. The relationship between pretransplantation PET and progression-free survival (PFS), disease-specific survival (DSS), and overall survival (OS) was assessed with Kaplan-Meier curves and a corresponding log-rank test for categorical variables and Cox regression for continuous variables. Results A total of 175 patients were identified, of whom 73 underwent FDG PET/CT before allogeneic SCT and 102 underwent FDG PET/CT before autologous SCT. Before allogeneic SCT, 23 of 73 patients (32%) had FDG-avid lesions, and before autologous SCT, 11 of 102 patients (11%) had FDG-avid lesions. For allogeneic SCT, the 2-year PFS estimate was 68% (95% confidence interval [CI]: 56%, 82%) in patients without FDG-avid lesions, but only 35% (95% CI: 20%, 61%) for patients with FDG-avid lesions (P = .014). For autologous SCT, the 2-year PFS was 72% (95% CI: 64%, 82%) in patients without FDG-avid lesions, but only 18% (95% CI: 5%, 64%) for patients with FDG-avid lesions (P < .0001). Similar differences were seen in OS and DSS. The risk for posttransplantation recurrence correlated with higher lesional maximum standardized uptake values: for PFS, P < .0001 to P = .01; for DSS, P < .0001 to P = .002; and for OS, P < .0001 to P = .015. Conclusion Performing FDG PET/CT before SCT in patients with aggressive lymphoma has prognostic value. The presence of FDG-avid lesions at PET/CT before allogeneic or autologous SCT indicates aggressive lymphoma, which has a low likelihood of being cured. (©) RSNA, 2015.
    Radiology 06/2015; DOI:10.1148/radiol.2015142556 · 6.87 Impact Factor

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    ABSTRACT: Much has changed in the treatment of cancer since the first NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) were rolled out for 8 different tumor types in November 1996. NCCN Guidelines now include involved algorithms often containing multiple treatment alternatives and detailed pathways of care that depend on more-specific patient characteristics and molecular tumor diagnostics. With 47 different individual NCCN panels, all members of the cancer care team are now better informed than ever to guide patients through the often complex decision-making required to improve the odds of successful outcomes. At the NCCN 20th Annual Conference, a distinguished panel assembled to take a closer look at these invaluable clinical practice guidelines, first glancing backward to how it all started and then forward to explore the key ingredients of trustworthy guidelines. Copyright © 2015 by the National Comprehensive Cancer Network.
    Journal of the National Comprehensive Cancer Network: JNCCN 05/2015; 13(5 Suppl):640-2. · 4.18 Impact Factor
  • Andrew D Zelenetz ·
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    ABSTRACT: As targeted therapy in B-cell lymphomas rapidly expands beyond anti-CD20 monoclonal antibodies, many newer types of agents are in various stages of development. During his presentation at the NCCN 20th Annual Conference, Dr. Andrew D. Zelenetz explored many of them, including the newer immunoconjugates, the Bruton's tyrosine kinase inhibitor ibrutinib, agents targeting apoptosis such as venetoclax (ABT-199), the immunomodulator lenalidomide, and novel immune checkpoint inhibitors such as nivolumab. To improve outcomes in patients with B-cell lymphomas, these therapies either target the tumor cells and their pathways or focus on the microenvironment and immune modulation. Copyright © 2015 by the National Comprehensive Cancer Network.
    Journal of the National Comprehensive Cancer Network: JNCCN 05/2015; 13(5 Suppl):666-9. · 4.18 Impact Factor
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    ABSTRACT: Data from the National LymphoCare Study (a prospective, multicentre registry that enrolled follicular lymphoma (FL) patients from 2004 to 2007) were used to determine disease characteristics, treatment patterns, outcomes and prognosis for elderly FL (eFL) patients. Of 2650 FL patients, 209 (8%) were aged >80 years; these eFL patients more commonly had grade 3 disease, less frequently received chemoimmunotherapy and anthracyclines, and had lower response rates when compared to younger patients. With a median follow-up of 6.9 years, 5-year overall survival (OS) for eFL patients was 59%; 38% of deaths were lymphoma-related. No treatment produced superior OS among eFL patients. In multivariate Cox models, anaemia, B-symptoms and male sex predicted worse OS (P < 0·01); a prognostic index of these factors (0, 1 or ≥2 present) predicted OS [hazard ratio (95% CI): ≥2 vs. 0, 4·72 (2·38-9·33); 1 vs. 0, 2·63 (1·39-4·98)], with a higher concordance index (0·63) versus the Follicular Lymphoma International Prognostic Index (0·55). The index was validated in an independent cohort. In the largest prospective US-based eFL cohort, no optimal therapy was identified and nearly 40% of deaths were lymphoma-related, representing baseline outcomes in the modern era. © 2015 John Wiley & Sons Ltd.
    British Journal of Haematology 04/2015; 170(1). DOI:10.1111/bjh.13399 · 4.71 Impact Factor
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    ABSTRACT: The role of consolidation radiotherapy was examined for patients with diffuse large B-cell lymphoma who were treated at institutions of the National Comprehensive Cancer Network during the rituximab era. Failure-free survival (FFS) and overall survival (OS) were analyzed in terms of patient and treatment characteristics. Potential associations were investigated with univariate and multivariate survival analysis and matched pair analysis. There were 841 patients, and most (710 or 84%) received 6 to 8 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); 293 (35%) received consolidation radiation therapy (RT). Failure occurred for 181 patients: 126 patients (70%) who did not receive RT and 55 patients (30%) who did. At 5 years, both OS and FFS rates were better for patients who had received RT versus those who did not (OS, 91% vs 83% [P = .01]; FFS, 83% vs 76% [P = .05]). A matched pair analysis (217 pairs matched by age, stage, International Prognostic Index [IPI] score, B symptoms, disease bulk, and response to chemotherapy) showed that the receipt of RT improved OS (hazard ratio [HR], 0.53 [P = .07]) and FFS (HR, 0.77 [P = .34]) for patients with stage III/IV disease, but too few events took place among those with stage I/II disease for meaningful comparisons (HR for OS, 0.94 [P = .89]; HR for FFS, 1.81 [P = .15]). A multivariate analysis suggested that the IPI score and the response to chemotherapy had the greatest influence on outcomes. There was a trend of higher OS and FFS rates for patients who had received consolidation RT after R-CHOP (especially for patients with stage III/IV disease), but the difference did not reach statistical significance. Cancer 2014. © 2014 American Cancer Society. © 2014 American Cancer Society.
    Cancer 04/2015; 121(7). DOI:10.1002/cncr.29113 · 4.89 Impact Factor
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    ABSTRACT: High-dose chemotherapy and autologous stem cell transplantation HDT-ASCT is the standard of care for chemosensitive relapsed and refractory diffuse large B-cell lymphoma (rel/ref DLBCL). Interim restaging with functional imaging by positron emission tomography using fluorine-18-deoxyglucose (FDG-PET) has not been established following salvage chemotherapy (ST) prior to HDT-ASCT by modern criteria. Herein, we evaluated 129 patients with rel/ref DLBCL proceeding to HDT-ASCT with ST response assessment by FDG-PET according to the contemporary Deauville 5-point scale. Patients achieving Deauville 1-3 to ST experienced superior progression-free (PFS) and overall (OS) survival of 77% (95% CI: 65-86%) and 86% (75-92%) compared to patients achieving Deauville 4 of 49% (34-62%) and 54% (39-58%) at 3 years, respectively (p<0.001). No other pre-HDT-ASCT risk factors significantly impacted PFS or OS. Despite achieving remission to ST, patients with Deauville 4 should be the focus of risk-adapted investigational therapies. Copyright © 2015 American Society of Hematology.
    Blood 03/2015; 125(16). DOI:10.1182/blood-2014-10-606939 · 10.45 Impact Factor
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    ABSTRACT: Abstract Idelalisib is a first-in-class selective, oral, phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor approved for the treatment of several types of blood cancers. Idelalisib has demonstrated significant efficacy and a tolerable safety profile in clinical trials; however, the US prescribing information contains a black box warning for fatal and/or severe diarrhea or colitis, hepatotoxicity, pneumonitis, and intestinal perforation. An expert panel was convened to review the pathology of these treatment-emergent adverse events (TEAEs) to propose key management tools for patients receiving idelalisib therapy. This article provides an overview of idelalisib TEAEs reported in clinical trials, and a summary of the panel's recommendations for identification and management of idelalisib treatment-emergent diarrhea or colitis as well as a discussion of transaminitis and pneumonitis. For idelalisib-related diarrhea or colitis (including unresolved grade 2 and grade ≥3), after exclusion of infectious causes, the panel recommends individualized treatment with budesonide or oral or intravenous steroid therapy.
    Leukemia and Lymphoma 03/2015; 56(10):1-20. DOI:10.3109/10428194.2015.1022770 · 2.89 Impact Factor
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    ABSTRACT: Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are different manifestations of the same disease, which are managed in the same way. The advent of novel monoclonal antibodies (ofatumumab and obinutuzumab) led to the development of effective chemoimmunotherapy regimens. The recently approved small molecule kinase inhibitors (ibrutinib and idelalisib) are effective treatment options for CLL in elderly patients with decreased tolerance for aggressive regimens and in patients with poor prognostic features who do not benefit from conventional chemoimmunotherapy regimens. This portion of the NCCN Guidelines for Non-Hodgkin's Lymphomas describes the recent specific to the incorporation of recently approved targeted therapies for the management of patients with newly diagnosed and relapsed or refractory CLL/SLL. Copyright © 2015 by the National Comprehensive Cancer Network.
    Journal of the National Comprehensive Cancer Network: JNCCN 03/2015; 13(3):326-62. · 4.18 Impact Factor
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    ABSTRACT: Background: Pre-transplantation 18F-fluorodeoxyglucose (FDG) PET-negativity is one of the strongest predictors of outcome after high-dose therapy and autologous stem-cell transplant (HDT/ASCT) for patients with relapsed or refractory Hodgkin's lymphoma. In this study, we assessed the feasibility and activity of PET-adapted salvage therapy with brentuximab vedotin, followed by augmented ifosfamide, carboplatin, and etoposide (ICE). Methods: In this non-randomised, open-label, single-centre, phase 2 trial, we enrolled patients with relapsed or refractory Hodgkin's lymphoma who had failed one previous doxorubicin-containing chemotherapy regimen. All patients received weekly infusions of 1·2 mg/kg brentuximab vedotin on days 1, 8, and 15 for two 28 day cycles. After completion of brentuximab vedotin treatment, patients received a PET scan. Patients who achieved PET-negative status (a Deauville score of 1 or 2) proceeded directly to HDT/ASCT; those with persistent abnormalities on PET received two cycles of augmented ICE (augICE; two doses of ifosfamide 5000 mg/m2 in combination with mesna 5000 mg/m2 continuous infusion over 24 h, days 1 and 2; one dose of carboplatin AUC 5, day 3; three doses of etoposide 200 mg/m2 every 12 h, day 1) before consideration for HDT/ASCT. Only patients with persistent abnormalities on PET after brentuximab vedotin received augICE; however, all patients in the intention-to-treat population were assessed for the primary outcome, which was the proportion of patients who were PET-negative after brentuximab vedotin alone or brentuximab vedotin followed by augICE. This study is registered with, number NCT01508312, and is no longer accruing patients. Findings: Between Jan 5, 2012, and Oct 4, 2013, we enrolled 46 patients. One patient was deemed ineligible, and not evaluable, before treatment initiation owing to having nodular, lymphocyte-predominant Hodgkin's lymphoma and thus 45 patients received treatment. After brentuximab vedotin, 12 patients (27%, 95% CI 13-40) were PET-negative and proceeded to HDT/ASCT. 33 (73%, 95% CI 60-86) patients were PET-positive after brentuximab vedotin; one PET-positive patient withdrew consent, therefore 32 PET-positive patients received augICE, 22 (69%, 95% CI 53-85) of whom were PET-negative. Overall, 34 patients (76%, 95% CI 62-89) achieved PET-negativity. All 44 patients who completed treatment as per protocol proceeded to receive HDT/ASCT. Brentuximab vedotin was well tolerated and associated with few grade 3-4 adverse events including hyperglycaemia (two [4%] patients, grade 3), nausea (one [2%], grade 3), hypoglycaemia (one [2%], grade 3 and one [2%], grade 4), and hypocalcaemia (one [2%], grade 3 and one [2%], grade 4). Interpretation: PET-adapted sequential salvage therapy with brentuximab vedotin followed by augICE resulted in a high proportion of patients with relapsed or refractory Hodgkin's lymphoma achieving PET-negativity, and therefore could optimise the chance of cure after HDT/ASCT. Funding: Seattle Genetics.
    The Lancet Oncology 02/2015; 16(3). DOI:10.1016/S1470-2045(15)70013-6 · 24.69 Impact Factor

Publication Stats

8k Citations
1,712.69 Total Impact Points


  • 1991-2015
    • Memorial Sloan-Kettering Cancer Center
      • • Lymphoma Service
      • • Department of Medicine
      • • Hematology Service
      • • Department of Pathology
      • • Division of Molecular Biology
      • • Department of Surgery
      New York, New York, United States
  • 2014
    • Columbia University
      New York, New York, United States
  • 2010
    • American University of Beirut
      • Department of Internal Medicine
      Beirut, Mohafazat Beyrouth, Lebanon
  • 2009
    • New York Presbyterian Hospital
      New York City, New York, United States
  • 2001
    • Memorial Hospital, TN
      Chattanooga, Tennessee, United States
  • 1990-1993
    • Stanford Medicine
      • • Division of Oncology
      • • Department of Medicine
      • • Stanford School of Medicine
      Stanford, California, United States