Chadi Nabhan

Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: A multicenter retrospective analysis

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 the 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) rates among all patients were 10.9 and 21.9 months, respectively. Forty percent of patients remain disease-free and 49% remain alive at 2 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 = .14). By multivariate analysis, advanced stage, central nervous system involvement, leukocytosis, and LDH >3 times the 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.

A retrospective multicenter analysis of elderly Hodgkin lymphoma: outcomes and prognostic factors in the modern era

We investigated a recent (January 1999 to December 2009) cohort of 95 elderly Hodgkin lymphoma subjects. At diagnosis, median age was 67 years (range, 60-89 years), whereas 61% had significant comorbidity, 26% were unfit, 17% had a geriatric syndrome, and 13% had loss of activities of daily living. Overall response rate to therapy was 85%, whereas incidence of bleomycin lung toxicity was 32% (with associated mortality rate, 25%). With 66-month median follow-up, 2-year and 5-year overall survival were 73% and 58%, respectively (advanced-stage, 63% and 46%, respectively). Most International Prognostic Score factors were not prognostic on univariate analyses, whereas Cox multivariate regression identified 2 risk factors associated with inferior overall survival: (1) age more than 70 years (2.24; 95% CI, 1.16-4.33, P = .02) and (2) loss of activities of daily living (2.71; 95% CI, 1.07-6.84, P = .04). Furthermore, a novel survival model based on number of these risk factors (0, 1, or 2) showed differential 2-year OS of 83%, 70%, and 13%, respectively (P < .0001) and 5-year OS of 73%, 51%, and 0%, respectively (P < .0001).

A Pilot Trial of Rituximab and Alemtuzumab Combination Therapy in Patients with Relapsed and/or Refractory Chronic Lymphocytic Leukemia (CLL)

The treatment of patients with chronic lymphocytic leukemia (CLL) who fail purine analogues is sub optimal. CLL lymphocytes express two antigens, namely CD 20 and CD 52, for which monoclonal antibodies are readily available. Rituximab is a chimeric monoclonal antibody targeted against CD 20, which has some activity in refractory CLL, with primary effect on nodal disease. Alemtuzumab is a humanized anti-CD 52 antibody that is approved for the treatment of CLL in patients who fail alkylating agents and purine analogues. Alemtuzumab has better activity in the peripheral blood and the bone marrow compared to nodal disease. We investigated whether combining both antibodies is safe in refractory CLL. Both antibodies were given to a total of 12 patients divided into 3 cohorts with escalating alemtuzumab doses (3 mg, 10 mg, and 30 mg). The combination was proven to be safe, not toxic, feasible, and active. One patient attained PR by NCI criteria while all other patients had stable disease lasting a median of 101.5 days. All patients normalized their peripheral lymphocytosis within a median of 23.5 days. No treatment-related mortality was identified. No CMV reactivation occurred. Additional studies are needed to investigate the clinical significance of such a combination in this patient population, and whether this combination can be administered safely with systemic chemotherapy. These studies are currently underway.

Chronic Lymphocytic Leukemia: A Clinical Review

IMPORTANCE The most common leukemia is chronic lymphocytic leukemia (CLL). Every year, there are 15 000 new diagnoses and 5000 CLL deaths in the United States. Although therapeutic choices were once limited, treatment of this disease has vastly improved in the last decade. OBJECTIVE Evidence-based review of the diagnosis, staging, and treatment of CLL. EVIDENCE REVIEW PubMed, Cochrane Library, Scopus, and Google Scholar databases were searched through August 28, 2014. English-language peer-reviewed articles published between 2000-2014 were found using the keywords chronic lymphocytic leukemia, upfront therapy, upfront therapies, upfront therapeutic, upfront therapeutics, upfront treatment, front-line treatment, first-line treatment, front-line treatments, first-line treatments, front-line therapy, front-line therapies, randomized, randomized studies, randomized study, clinical trial, clinical trials, phase 3, and phase 3 clinical trial. Abstracts and presentations at scientific meetings were excluded. A total of 277 articles were retrieved, of which 24 met our predefined selection criteria; treatment recommendations were based on subsequent analysis of these 24 articles. FINDINGS The Rai and Binet systems for staging CLL were established in 1975 and 1977, respectively. However, they do not account for new disease categories such as monoclonal B-cell lymphocytosis (peripheral blood clonal lymphocytosis that does not meet other criteria for CLL). Two subsets of CLL are now recognized based on risk stratification involving molecular and cytogenetic analyses. Outcomes are improved by the addition of immunotherapy to combination chemotherapy for initial treatment in all subsets of treated patients. Overall response rates between 75% and 90% and complete responses between 22% and 45% are expected in the current era, with more than 80% of treated patients alive at 3 years. Overall, 5-year survival has increased to 66% from 60% (P < .001) in the past 10 years. CONCLUSIONS AND RELEVANCE Chemoimmunotherapy is the standard first-line option approach for CLL, the most common leukemia observed in adults. Treatment is initiated when the disease becomes symptomatic, and survival is high following treatment.

Analysis of very elderly (≥80 years) non-hodgkin lymphoma: impact of functional status and co-morbidities on outcome.

Data on outcome, prognostic factors, and treatment for very elderly non‐Hodgkin lymphomas (NHL) is sparse. We conducted a multicentre retrospective analysis of NHL patients ≥80 years (at diagnosis) treated between 1999 and 2009. Detailed characteristics were obtained including geriatric syndromes, activities of daily living (ADLs), and co‐morbidities using the Cumulative Illness Rating Scale‐Geriatrics (CIRS‐G). We identified 303 patients: 170 aggressive NHL (84% B cell/16% T cell) and 133 indolent NHL (82% B cell/18% T cell). Median age was 84 years (80–95). A geriatric syndrome was present in 26% of patients, 18% had ≥1 grade 4 CIRS‐G, and 14% had loss of ADLs. At 49‐month median follow‐up, 4‐year progression‐free (PFS) and overall survival (OS) for aggressive NHLs were 31% and 44% respectively (stage I/II: PFS 53% and OS 66%; stage III/IV: PFS 20% and OS 32%; P < 0·0001 and 0·0002, respectively). Four‐year PFS and OS for indolent NHL were 44% and 66% respectively, regardless of stage. Multivariate regression analysis identified two key factors that predicted inferior PFS and OS for both NHL groups: lack of CR and loss of ADLs. Prospective studies for very elderly NHL that incorporate geriatric tools, especially ADLs, are warranted.

Classifying Cytogenetics in Patients with Acute Myelogenous Leukemia in Complete Remission Undergoing Allogeneic Transplantation: A Center for International Blood and Marrow Transplant Research Study

Cytogenetics play a major role in determining the prognosis of patients with acute myelogenous leukemia (AML). However, existing cytogenetics classifications were developed in chemotherapy-treated patients and might not be optimal for patients undergoing allogeneic hematopoietic cell transplantation (HCT). We studied 821 adult patients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) who underwent HCT for AML in first or second complete remission between 1999 and 2004. We compared the ability of the 6 existing classifications to stratify patients by overall survival. We then defined a new scheme specifically applicable to patients undergoing HCT using this patient cohort. Under this scheme, inv(16) is favorable, a complex karyotype (4 or more abnormalities) is adverse, and all other classified abnormalities are intermediate in predicting survival after HCT (5-year overall survival, 64%, 18%, and 50%, respectively; P = .0001). This scheme stratifies patients into 3 groups with similar nonrelapse mortality, but significantly different incidences of relapse, overall and leukemia-free survival. It applies to patients regardless of disease status (first or second complete remission), donor type (matched related or unrelated), or conditioning intensity (myeloablative or reduced intensity). This transplantation-specific classification could be adopted for prognostication purposes and to stratify patients with AML and karyotypic abnormalities entering HCT clinical trials.

Gemcitabine in hematologic malignancies

Gemcitabine is a pyrimidine analogue that showed significant activity in solid malignancies. Gemcitabine acts by inhibiting DNA synthesis through chain termination and ribonucleotide reductase inhibition. During initial phase I and II studies, gemcitabine had a low toxicity profile and was well tolerated as a single agent and in combination therapy. Recently, there has been more interest in studying the activity of gemcitabine in hematologic malignancies. Gemcitabine demonstrated good activity in refractory Hodgkin disease patients, non-Hodgkin lymphoma, cutaneous T-cell lymphoma, and acute leukemias. There is a preponderance of evidence on the activity of gemcitabine in vitro in myeloma and leukemic cell lines. The activity of gemcitabine in these disorders will pave the way for incorporating this agent into the early phases of therapy.

Optimal Sequencing of Ibrutinib, Idelalisib, and Venetoclax in Chronic Lymphocytic Leukemia: Results from a Multi-Center Study of 683 Patients.

Background Ibrutinib, idelalisib, and venetoclax are approved for treating CLL patients in the United States. However, there is no guidance as to their optimal sequence. Patients and methods We conducted a multicenter, retrospective analysis of CLL patients treated with kinase inhibitors (KIs) or venetoclax. We examined demographics, discontinuation reasons, overall response rates (ORR), survival, and post-KI salvage strategies. Primary endpoint was progression-free survival (PFS). Results A total of 683 patients were identified. Baseline characteristics were similar in the ibrutinib and idelalisib groups. ORR to ibrutinib and idelalisib as first KI was 69% and 81%, respectively. With a median follow-up of 17 months (range 1-60), median PFS and OS for the entire cohort were 35 months and not reached. Patients treated with ibrutinib (versus idelalisib) as first KI had a significantly better PFS in all settings; front-line [hazard ratios (HR) 2.8, CI 1.3-6.3, P = 0.01], relapsed-refractory (HR 2.8, CI 1.9-4.1, P < 0.001), del17p (HR 2.0, CI 1.2-3.4, P = 0.008), and complex karyotype (HR 2.5, CI 1.2-5.2, P = 0.02). At the time of initial KI failure, use of an alternate KI or venetoclax had a superior PFS when compared with chemoimmunotherapy. Furthermore, patients who discontinued ibrutinib due to progression or toxicity had marginally improved outcomes if they received venetoclax (ORR 79%) versus idelalisib (ORR 46%) (PFS HR .6, CI.3-1.0, P = 0.06). Conclusions In the largest real-world experience of novel agents in CLL, ibrutinib appears superior to idelalisib as first KI. Furthermore, in the setting of KI failure, alternate KI or venetoclax therapy appear superior to chemoimmunotherapy combinations. The use of venetoclax upon ibrutinib failure might be superior to idelalisib. These data support the need for trials testing sequencing strategies to optimize treatment algorithms.BACKGROUND Ibrutinib, idelalisib, and venetoclax are approved for treating CLL patients in the US. However, there is no guidance as to their optimal sequence. PATIENTS AND METHODS We conducted a multicenter, retrospective analysis of CLL patients treated with kinase inhibitors (KIs) or venetoclax. We examined demographics, discontinuation reasons, overall response rates (ORR), survival, and post-KI salvage strategies. Primary endpoint was progression-free survival (PFS). RESULTS A total of 683 patients were identified. Baseline characteristics were similar in the ibrutinib and idelalisib groups. ORR to ibrutinib and idelalisib as first KI was 69% and 81% respectively. With a median follow up of 17 months (range 1-60), median PFS and OS for the entire cohort were 35 months and not reached. Patients treated with ibrutinib (vs. idelalisib) as first KI had a significantly better PFS in all settings; front-line (HR 2.8, CI1.3-6.3 p=.01), relapsed-refractory (HR 2.8, CI 1.9-4.1 p<.001), del17p (HR 2.0, CI 1.2-3.4 p=.008), and complex karyotype (HR 2.5, CI 1.2-5.2 p=.02). At the time of initial KI failure, use of an alternate KI or venetoclax had a superior PFS as compared to chemoimmunotherapy (CIT). Furthermore, patients who discontinued ibrutinib due to progression or toxicity had marginally improved outcomes if they received venetoclax (ORR 79%) versus idelalisib (ORR 46%) (PFS HR .6, CI.3-1.0, p=.06). CONCLUSIONS In the largest real-world experience of novel agents in CLL, ibrutinib appears superior to idelalisib as first KI. Further, in the setting of KI failure, alternate KI or venetoclax therapy appear superior to CIT combinations. The use of venetoclax upon ibrutinib failure might be superior to idelalisib. These data support the need for trials testing sequencing strategies to optimize treatment algorithms.

MYC-associated and double-hit lymphomas: A review of pathobiology, prognosis, and therapeutic approaches

Aberrant expression of the v‐myc avian myelocytomatosis viral oncogene homolog (MYC) proto‐oncogene has known transformative potential in healthy human cells. Chromosomal MYC rearrangements and consequent MYC overexpression is the defining lesion in Burkitt lymphoma (BL), conferring a highly proliferative state. However, abnormalities of MYC are increasingly appreciated in non‐BL histologies, including diffuse large B‐cell lymphoma (DLBCL) and B‐cell lymphomas intermediate between BL and DLBCL, with a particularly aggressive clinical phenotype. Although there are conflicting data regarding prognostic implications of isolated MYC aberrancy in these non‐BLs, the co‐occurrence of MYC rearrangements and either the antiapoptotic gene B‐cell chronic lymphocytic leukemia/lymphoma 2 (BCL2) or the transcriptional repressor BCL6 leads to an entity termed double‐hit B‐cell lymphoma (DHL) (or triple‐hit if all 3 abnormalities are observed) with a particularly poor prognosis and no established treatment paradigms. Notably, a distinct pattern of gene expression profiling has been noted when MYC is overexpressed in BL compared with other lymphomas, supporting the notion that, although MYC promotes target gene transcription, the target genes vary by disease subtype. The frequency of MYC activity depends on the method of detection and ranges from 5% to 10% using fluorescence in situ hybridization but up to 30% of DLBCL using immunohistochemistry. Standard therapies developed for DLBCL are less effective when the disease is driven by MYC, leading to lower response rates and response durations. An important clinical challenge is to pre‐emptively identify MYC‐associated lymphomas and to subsequently develop trials specifically for this group of patients. However, the design of such studies is complicated by variable definitions of MYC‐associated lymphoid malignancies and the lack of effective therapies to date. The objective if the current review was to evaluate the implications of MYC aberrancy with respect to the B‐cell lymphoma double‐hit and triple‐hit phenotypes and to consider the available data for clinical and practical management. Cancer 2014;120:3884–3895.

Peripheral T-cell lymphomas in a large US multicenter cohort: prognostication in the modern era including impact of frontline therapy

BACKGROUND Optimal frontline therapy for peripheral T-cell lymphoma (PTCL) in the modern era remains unclear. PATIENTS AND METHODS We examined patient characteristics, treatment, and outcomes among 341 newly diagnosed PTCL patients from 2000 to 2011. Outcome was compared with a matched cohort of diffuse large B-cell lymphoma (DLBCL) patients, and prognostic factors were assessed using univariate and multivariate analyses. RESULTS PTCL subtypes included PTCL, not otherwise specified (PTCL-NOS) (31%), anaplastic large T-cell lymphoma (ALCL) (26%), angioimmunoblastic T-cell lymphoma (23%), NK/T-cell lymphoma (7%), acute T-cell leukemia/lymphoma (6%), and other (7%). Median age was 62 years (range 18-95 years), and 74% had stage III-IV disease. Twenty-three (7%) patients received only palliative care whereas 318 received chemotherapy: CHOP-like regimens (70%), hyperCVAD/MA (6%), or other (18%). Thirty-three patients (10%) underwent stem-cell transplantation (SCT) in first remission. The overall response rate was 73% (61% complete); 24% had primary refractory disease. With 39-month median follow-up, 3-year progression-free survival (PFS) and overall survival (OS) were 32% and 52%. PFS and OS for PTCL patients were significantly inferior to matched patients with DLBCL. On multivariate analysis, stage I-II disease was the only significant pretreatment prognostic factor [PFS: hazard ratio (HR) 0.54, 95% confidence interval (CI) 0.34-0.85, P = 0.007; OS: HR 0.42, 95% CI 0.22-0.78, P = 0.006]. ALK positivity in ALCL was prognostic on univariate analysis, but lost significance on multivariate analysis. The most dominant prognostic factor was response to initial therapy (complete response versus other), including adjustment for stage and SCT [PFS: HR 0.19, 95% CI 0.14-0.28, P < 0.0001; OS: HR 0.26, 95% CI 0.17-0.40, P < 0.0001]. No overall survival difference was observed based on choice of upfront regimen or SCT in first remission. CONCLUSIONS This analysis identifies early-stage disease and initial treatment response as dominant prognostic factors in PTCL. No clear benefit was observed for patients undergoing consolidative SCT. Novel therapeutic approaches for PTCL are critically needed.