[Show abstract][Hide abstract] ABSTRACT: The standard treatment of relapsed/refractory diffuse large B-cell lymphoma (DLBCL) in frail elderly patients has not been established. A variation was made on rituximab (R), cyclophosphamide (C), etoposide (E), procarbazine and prednisone (P), substituting vorinostat (V) for procarbazine. Patients ≥aged 60 years with relapsed/refractory DLBCL, not candidates for autologous stem cell transplantation, were treated R-CVEP [R 375 mg/m2 intravenously (IV), day 1; C 600 mg/m2 IV days 1, 8: E 70 mg/m2 IV day 1, 140 mg/m2 days 2, 3 orally (PO); V (300 vs. 400 mg) PO and P 60 mg/m2 PO days 1–10] every 28 d for six cycles. Quality of life (QoL) was assessed in addition to response. Thirty patients (median age 76 years, 69–88) were enrolled (one died before treatment). Maximum tolerated dose (MTD) for V was 300 mg. For 23 patients at MTD (six phase I + 17 phase II), two were discontinued for toxicity, one withdrew consent, eight achieved complete response (35%), five achieved partial response (22%) and seven progressed (25%). Median overall survival was 17·5 months. Median progression-free survival was 9·2 months. Nine patients are alive. QoL declined during treatment but improved above baseline for patients who completed treatment. In conclusion, R-CVEP was tolerated at MTD and produced durable responses with improved QoL.
British Journal of Haematology 10/2014; 168(5). · 4.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of 3 new genome-wide association studies (GWAS) and 1 previous scan, totaling 3,857 cases and 7,666 controls of European ancestry, with additional genotyping of 9 promising SNPs in 1,359 cases and 4,557 controls. In our multi-stage analysis, five independent SNPs in four loci achieved genome-wide significance marked by rs116446171 at 6p25.3 (EXOC2; P = 2.33 × 10(-21)), rs2523607 at 6p21.33 (HLA-B; P = 2.40 × 10(-10)), rs79480871 at 2p23.3 (NCOA1; P = 4.23 × 10(-8)) and two independent SNPs, rs13255292 and rs4733601, at 8q24.21 (PVT1; P = 9.98 × 10(-13) and 3.63 × 10(-11), respectively). These data provide substantial new evidence for genetic susceptibility to this B cell malignancy and point to pathways involved in immune recognition and immune function in the pathogenesis of DLBCL.
[Show abstract][Hide abstract] ABSTRACT: Patients with double hit lymphoma (DHL), which is characterized by rearrangements of MYC and either BCL2 or BCL6, face poor prognoses. We conducted a retrospective multicenter study of the impact of baseline clinical factors, induction therapy, and stem cell transplant (SCT), on outcomes of 311 patients with previously-untreated DHL. At median follow-up of 23 months, the median progression free survival (PFS) and overall survival (OS) among all patients were 10.9 and 21.9 months, respectively. Forty percent of patients remain disease-free and 49% remain alive at two years. Intensive induction was associated with improved PFS, but not OS, and SCT was not associated with improved OS among patients achieving first complete remission (p=0.14). By multivariate analysis, advanced stage, central nervous system involvement, leukocytosis, and LDH> three times upper limit of normal, were associated with higher risk of death. Correcting for these, intensive induction was associated with improved OS. We developed a novel risk score for DHL, which divides patients into high, intermediate, and low risk groups. In conclusion, a subset of DHL patients may be cured, and some patients may benefit from intensive induction. Further investigations into the roles of SCT and novel agents are needed.
[Show abstract][Hide abstract] ABSTRACT: High-dose therapy and autologous stem cell transplantation (HDT-ASCT) can offer potential long-term remission or cure in patients with non-Hodgkin lymphoma (NHL). Limited experience is available on the safety and efficacy of HDT-ASCT in elderly patients. This is a single-center, retrospective study examining outcomes of HDT-ASCT for 202 NHL patients age 60 years and older between January 2001 and December 2012. Overall survival (OS) and progression-free survival (PFS) were analyzed according to age at HDT-ASCT, hematopoietic cell transplantation comorbidity index (HCT-CI), NHL histology, and remission status at the time of HDT-ASCT. The median age was 65 years (range 60-74) and the majority had either diffuse large B-cell lymphoma (DLBCL, n=73, 37%) or mantle cell lymphoma (MCL, n=69, 34%). One hundred and fifteen patients (57%) had high HCT-CI scores at the time of HDT-ASCT. With a median follow-up of 3.6 years (range 0.4-11.9 years) for survivors, PFS and OS at 3 years were 60% (95% CI: 53-68%) and 73% (95% CI: 67-80%), respectively. Transplant-related mortality (TRM) was 4% both at 100 days and at 1 year post HDT-ASCT. Age and HCT-CI score were not associated with OS or PFS, and high HCT-CI did not correlate with TRM. Seven patients (4%) developed secondary myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) at a median of 35 months (range 6-48) post HDT-ASCT. In this single-center cohort of elderly patients with NHL undergoing HDT-ASCT, this intervention is proved tolerable and effective, with results similar to historic controls in younger patients. Our data suggest that age alone should not preclude HDT-ASCT in elderly patients.
Biology of Blood and Marrow Transplantation 08/2014; · 3.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Molecular and genetic evidence suggests that DNA repair pathways may contribute to lymphoma susceptibility. Several studies have examined the association of DNA repair genes with lymphoma risk, but the findings from these reports have been inconsistent. Here we provide the results of a focused analysis of genetic variation in DNA repair genes and their association with the risk of non-Hodgkin's lymphoma (NHL). With a population of 1,297 NHL cases and 1,946 controls, we have performed a two-stage case/control association analysis of 446 single nucleotide polymorphisms (SNPs) tagging the genetic variation in 81 DNA repair genes. We found the most significant association with NHL risk in the ATM locus for rs227060 (OR = 1.27, 95% CI: 1.13-1.43, p = 6.77×10-5), which remained significant after adjustment for multiple testing. In a subtype-specific analysis, associations were also observed for the ATM locus among both diffuse large B-cell lymphomas (DLBCL) and small lymphocytic lymphomas (SLL), however there was no association observed among follicular lymphomas (FL). In addition, our study provides suggestive evidence of an interaction between SNPs in MRE11A and NBS1 associated with NHL risk (OR = 0.51, 95% CI: 0.34-0.77, p = 0.0002). Finally, an imputation analysis using the 1,000 Genomes Project data combined with a functional prediction analysis revealed the presence of biologically relevant variants that correlate with the observed association signals. While the findings generated here warrant independent validation, the results of our large study suggest that ATM may be a novel locus associated with the risk of multiple subtypes of NHL.
PLoS ONE 07/2014; 9(7):e101685. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) describe a continuum of cancer care in the United States, from initial diagnosis through treatment and referral to hospice beyond treatment. However, in many other countries, there are no regional or national clinical practice guidelines. In 2008, the NCCN-MENA (Middle East and North Africa) project was launched to adapt the NCCN Guidelines to this part of the world. During their joint presentation at the NCCN 19th Annual Conference, Dr. Ali Bazarbachi and Dr. Andrew D. Zelenetz explored the modification process of NCCN Guidelines for MENA and shared examples of how it improved the care of patients with adult T-cell leukemia or lymphoma and younger patients with diffuse large B-cell lymphoma-regardless of where they live.
Journal of the National Comprehensive Cancer Network: JNCCN 05/2014; 12(5 Suppl):838-41. · 4.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: During his presentation at the NCCN 19th Annual Conference, Dr. Andrew D. Zelenetz reviewed the updates to the 2014 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Hodgkin's Lymphomas. Dr. Zelenetz first discussed the updates for diffuse large B-cell lymphoma (DLBCL), focusing primarily on the emergence of MYC-positive DLBCL; the limited role of imaging in early-stage disease; new treatment options; the challenge of tumor heterogeneity; and the impact of cell of origin in the selection of future therapies. Then, on behalf of Dr. Steven Horwitz, Dr. Zelenetz presented the new guidelines for primary cutaneous CD30+ T-cell lymphoproliferative disorders and T-cell large granular lymphocytic leukemia.
Journal of the National Comprehensive Cancer Network: JNCCN 05/2014; 12(5 Suppl):797-800. · 4.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Primary breast diffuse large B-cell lymphoma (DLBCL) is a rare subtype of non-Hodgkin lymphoma (NHL) with limited data on pathology and outcome. A multicentre retrospective study was undertaken to determine prognostic factors and the incidence of central nervous system (CNS) relapses. Data was retrospectively collected on patients from 8 US academic centres. Only patients with stage I/II disease (involvement of breast and localized lymph nodes) were included. Histologies apart from primary DLBCL were excluded. Between 1992 and 2012, 76 patients met the eligibility criteria. Most patients (86%) received chemotherapy, and 69% received immunochemotherapy with rituximab; 65% received radiation therapy and 9% received prophylactic CNS chemotherapy. After a median follow-up of 4·5 years (range 0·6-20·6 years), the Kaplan-Meier estimated median progression-free survival was 10·4 years (95% confidence interval [CI] 5·8-14·9 years), and the median overall survival was 14·6 years (95% CI 10·2-19 years). Twelve patients (16%) had CNS relapse. A low stage-modified International Prognostic Index (IPI) was associated with longer overall survival. Rituximab use was not associated with a survival advantage. Primary breast DLBCL has a high rate of CNS relapse. The stage-modified IPI score is associated with survival.
British Journal of Haematology 01/2014; · 4.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background Patients with relapsed chronic lymphocytic leukemia (CLL) who have clinically significant coexisting medical conditions are less able to undergo standard chemotherapy. Effective therapies with acceptable side-effect profiles are needed for this patient population. Methods In this multicenter, randomized, double-blind, placebo-controlled, phase 3 study, we assessed the efficacy and safety of idelalisib, an oral inhibitor of the delta isoform of phosphatidylinositol 3-kinase, in combination with rituximab versus rituximab plus placebo. We randomly assigned 220 patients with decreased renal function, previous therapy-induced myelosuppression, or major coexisting illnesses to receive rituximab and either idelalisib (at a dose of 150 mg) or placebo twice daily. The primary end point was progression-free survival. At the first prespecified interim analysis, the study was stopped early on the recommendation of the data and safety monitoring board owing to overwhelming efficacy. Results The median progression-free survival was 5.5 months in the placebo group and was not reached in the idelalisib group (hazard ratio for progression or death in the idelalisib group, 0.15; P<0.001). Patients receiving idelalisib versus those receiving placebo had improved rates of overall response (81% vs. 13%; odds ratio, 29.92; P<0.001) and overall survival at 12 months (92% vs. 80%; hazard ratio for death, 0.28; P=0.02). Serious adverse events occurred in 40% of the patients receiving idelalisib and rituximab and in 35% of those receiving placebo and rituximab. Conclusions The combination of idelalisib and rituximab, as compared with placebo and rituximab, significantly improved progression-free survival, response rate, and overall survival among patients with relapsed CLL who were less able to undergo chemotherapy. (Funded by Gilead; ClinicalTrials.gov number, NCT01539512 .).
New England Journal of Medicine 01/2014; · 54.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chronic Lymphocytic Leukemia (CLL) is defined by a perturbed B-cell receptor-mediated signaling machinery. We aimed to model differential signaling behavior between B cells from CLL and healthy individuals to pinpoint modes of dysregulation.
We developed an experimental methodology combining immunophenotyping, multiplexed phosphospecific flow cytometry, and multifactorial statistical modeling. Utilizing patterns of signaling network covariance, we modeled BCR signaling in 67 CLL patients using Partial Least Squares Regression (PLSR). Results from multidimensional modeling were validated using an independent test cohort of 38 patients.
We identified a dynamic and variable imbalance between proximal (pSYK, pBTK) and distal (pPLCγ2, pBLNK, ppERK) phosphoresponses. PLSR identified the relationship between upstream tyrosine kinase SYK and its target, PLCγ2, as maximally predictive and sufficient to distinguish CLL from healthy samples, pointing to this juncture in the signaling pathway as a hallmark of CLL B cells. Specific BCR pathway signaling signatures that correlate with the disease and its degree of aggressiveness were identified. Heterogeneity in the PLSR response variable within the B cell population is both a characteristic mark of healthy samples and predictive of disease aggressiveness.
Single-cell multidimensional analysis of BCR signaling permitted focused analysis of the variability and heterogeneity of signaling behavior from patient-to-patient, and from cell-to-cell. Disruption of the pSYK/pPLCγ2 relationship is uncovered as a robust hallmark of CLL B cell signaling behavior. Together, these observations implicate novel elements of the BCR signal transduction as potential therapeutic targets.
PLoS ONE 01/2014; 9(1):e79987. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The role of the proliferation index (PI) as an outcome predictor in follicular lymphoma (FL) isn't clear. We have previously demonstrated that quantitative image analysis (QIA) is a robust tool for PI determination and the present study aimed to determine the significance of the PI for outcome in low-grade FL. One hundred and twenty-nine patients with grade 1-2 FL were retrospectively analysed. Slides were scanned digitally and follicle/tumour-involved areas were annotated. The intrafollicular PI was estimated by analysing a median of 10 follicles per case. Patients were divided into two groups: PI < 30%, PI ≥ 30% and clinical outcome was analysed. Among the 129 patients analysed, intrafollicular PI ranged from 0·6 to 63·2% with a median of 23·3%. Overall survival was not influenced by PI group. Among those patients initially observed, intrafollicular PI < 30% was associated with longer time to first therapy compared to patients with a PI ≥ 30%. In the group of patients that were treated at diagnosis, PI was not predictive of time to treatment failure (TTTF). Intrafollicular PI is an important predicator of TTFT for patients who are candidates for observation. Further confirmation in an independent cohort of patients is necessary to determine the clinical validity of the results.
British Journal of Haematology 12/2013; · 4.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this prospective phase II trial was to determine the safety and efficacy of a non-myeloablative (NMA) conditioning program incorporating peri-transplant-rituximab in patients with CD20+ B-cell non-Hodgkin lymphoma (B-NHL) receiving an allogeneic stem cell transplant (allo-SCT). Fifty-one adult B-NHL patients, with a median age of 54 years, were treated with cyclophosphamide, fludarabine and 200 cGy of total body irradiation (TBI). Rituximab 375 mg/m2 was given on d-8 and in 4 weekly doses beginning d+21. Equine anti-thymocyte globulin (eATG) was given to recipients of volunteer unrelated donor grafts. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and mycophenolate mofetil and tacrolimus, sirolimus and methotrexate in 8 and 43 patients respectively. Thirty-three patients received grafts from unrelated donors and 18 received grafts from matched related donors. All patients engrafted. Full donor chimerism in bone marrow and peripheral T cells was seen in 92% and 89% of patients respectively at 3 months post-allo-SCT. The cumulative incidence (CI) of grade II-IV acute GVHD (aGVHD) at 6-months was 25% (95% CI: 13-38%) and grade III-IV was 11% (95% CI: 2-20%). The 2-year CI of chronic GVHD (cGVHD) was 29% (95% CI: 15-44%). The 2-year event-free (EFS) and overall (OS) survival for all patients was 72% (95% CI: 59-85%) and 78% (95% CI: 66-90%) respectively. The 2-year EFS for chemosensitive patients was 84% (95% CI: 72- 96%) compared to 30% (95% CI: 2 - 58%) for chemorefractory patients pre-allo-SCT (p<0.001). This NMA regimen, with peri-transplant rituximab, is safe and effective in patients with B-NHL.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 12/2013; · 3.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The International Prognostic Index (IPI) has been the basis for determining prognosis in patients with aggressive non-Hodgkin lymphoma (NHL) for the past 20 years. Using raw clinical data from the National Comprehensive Cancer Network (NCCN) database collected during the rituximab era, we built an enhanced IPI with the goal of improving risk stratification. Adults (n=1,650) with de novo diffuse large B-cell lymphoma (DLBCL) diagnosed over a 10-year period at 7 NCCN cancer centers were included. Clinical features were assessed for their prognostic significance, with statistical efforts to further refine the categorization of age and normalized LDH. This new NCCN-IPI identified 5 predictors (age, LDH, sites of involvement, Ann Arbor stage, ECOG performance status) and assigned a maximum of 8 points. Four risk groups were formed: low (0-1), low-intermediate (2-3), high-intermediate (4-5) and high (6-8). Compared to the IPI, the NCCN-IPI better discriminated low and high risk subgroups (5-year overall survival [OS]: 96% vs 33%) than the IPI (5 year OS: 90% vs 54%), respectively. When validated using an independent cohort from the British Columbia Cancer Agency (n=1,138), it also demonstrated enhanced discrimination for both low and high risk patients. The NCCN-IPI is easy to apply and more powerful than the IPI for predicting survival in the rituximab era.
[Show abstract][Hide abstract] ABSTRACT: Determine the clinical significance of [(18)F]fluorodeoxyglucose (FDG)-avid lesions in patients with lymphoma treated with stem-cell transplantation.
All patients who underwent stem-cell transplantation for lymphoma at Memorial Sloan-Kettering Cancer Center between January 2005 and December 2009 and had post-transplantation FDG positron emission tomography/computed tomography (PET/CT) examinations were included. PET/CT examinations were evaluated for FDG-avid lesions suggestive of disease. Clinical records, biopsy results, and subsequent imaging examinations were evaluated for malignancy.
Two hundred fifty-one patients were identified, 107 with allogeneic and 144 with autologous stem-cell transplantation. Of allogeneic stem-cell transplantation recipients, 50 had FDG-avid lesions suggestive of lymphoma, defined as FDG-avidity greater than liver background. However, only 29 of these 50 demonstrated lymphoma on biopsy, whereas biopsy attempts were benign in the other 21 patients. Sensitivity analysis determined that a 1.5-cm short axis nodal measurement distinguished patients with malignant from nonmalignant biopsies. In 21 of 22 patients with FDG-avid lymph nodes ≤ 1.5 cm, biopsy attempts were benign. In the absence of treatment, these nodes either resolved or were stable on repeat imaging. Disease-free survival of patients with FDG-avid ≤ 1.5 cm lymph nodes was comparable with patients without FDG-avid lesions. In comparison, autologous stem-cell transplantation patients rarely demonstrated FDG-avid lesions suggestive of disease without malignant pathology.
Twenty percent (21 of 107) of patients with an allogeneic stem-cell transplantation demonstrated FDG-avid lymph nodes up to 1.5 cm in short axis on PET/CT, which did not represent active lymphoma. After allogeneic stem-cell transplantation of patients with lymphoma, benign FDG-avid ≤ 1.5 cm lymph nodes can mimic malignancy.
Journal of Clinical Oncology 11/2013; · 17.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Histological transformation (HT) is a major cause of morbidity and mortality in patients with indolent non- Hodgkin lymphoma (NHL). The multicentre National Cancer Comprehensive Network database for NHL provides a unique opportunity to investigate the natural history of HT in the rituximab era. 118 patients with biopsy-confirmed indolent lymphoma and subsequent biopsy-confirmed HT were identified. Treatments for HT included autologous stem-cell transplant (auto-SCT) (n = 50), allogeneic SCT (allo-SCT) (n = 18), and treatment without transplant (n = 50). The 2-year overall survival (OS) for the entire cohort was 68%. For auto-SCT patients aged ≤60 years (n = 24), the 2-year OS was 74%. For non-transplanted patients aged ≤60 years (n = 19), the 2-year OS was 59%. The 2-year OS of patients naïve to chemotherapy prior to HT was superior to patients who were exposed to chemotherapy prior to HT (100% vs. 35%, P = 0·03). In this largest prospective cohort of patients of strictly defined HT in the rituximab era, the natural history of HT appears more favourable than historical studies. Younger patients who were not exposed to chemotherapy prior to HT experienced a prolonged survival even without transplantation. This study serves as a benchmark for future trials of novel approaches for HT in the Rituximab era.
British Journal of Haematology 09/2013; · 4.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Peripheral T-cell lymphomas are aggressive lymphomas that have no standard treatment. Studies suggest that HD-ASCT in the first CR improves outcome. Few data exist regarding allo-HSCT in the first CR.
We retrospectively identified patients (2001-2011) with PTCL-not otherwise specified, angioimmunoblastic T-cell lymphoma, and anaplastic lymphoma kinase-negative anaplastic large cell lymphoma, initially treated with CHOP, CHOP-ICE (ifosfamide, carboplatin, etoposide), or other therapy with the intention to transplant in the first CR. Disease characteristics, therapy, progression-free survival (PFS), and OS were evaluated.
Sixty-five patients were identified. PFS and OS were 38% and 52%, respectively, at 4 years. CHOP and CHOP-ICE regimens had similar outcomes. Treatment with allo-HSCT and HD-ASCT had OS at 4 years of 66% and 67%, respectively. Patients who did not proceed to transplant had OS of 27%. IPI score ≤ 2 and Prognostic Index for T-cell Lymphomas scores ≤ 1 predicted improved outcome. Combined analysis of interim response to CHOP and IPI score also predicted PFS and OS.
Our results support consolidation of first CR with transplantation. The addition of etoposide did not improve outcomes. Baseline IPI and interim response to CHOP can predict outcomes and guide decisions about transplantation in first CR in PTCL. Randomized trials are necessary to confirm the efficacy of this approach.
[Show abstract][Hide abstract] ABSTRACT: Genome-wide association studies (GWAS) have previously identified 13 loci associated with risk of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL). To identify additional CLL susceptibility loci, we conducted the largest meta-analysis for CLL thus far, including four GWAS with a total of 3,100 individuals with CLL (cases) and 7,667 controls. In the meta-analysis, we identified ten independent associated SNPs in nine new loci at 10q23.31 (ACTA2 or FAS (ACTA2/FAS), P = 1.22 × 10(-14)), 18q21.33 (BCL2, P = 7.76 × 10(-11)), 11p15.5 (C11orf21, P = 2.15 × 10(-10)), 4q25 (LEF1, P = 4.24 × 10(-10)), 2q33.1 (CASP10 or CASP8 (CASP10/CASP8), P = 2.50 × 10(-9)), 9p21.3 (CDKN2B-AS1, P = 1.27 × 10(-8)), 18q21.32 (PMAIP1, P = 2.51 × 10(-8)), 15q15.1 (BMF, P = 2.71 × 10(-10)) and 2p22.2 (QPCT, P = 1.68 × 10(-8)), as well as an independent signal at an established locus (2q13, ACOXL, P = 2.08 × 10(-18)). We also found evidence for two additional promising loci below genome-wide significance at 8q22.3 (ODF1, P = 5.40 × 10(-8)) and 5p15.33 (TERT, P = 1.92 × 10(-7)). Although further studies are required, the proximity of several of these loci to genes involved in apoptosis suggests a plausible underlying biological mechanism.