Loretta J. Nastoupil

Double hit lymphoma: The MD Anderson Cancer Center clinical experience

We report our experience with 129 cases of double hit lymphoma (DHL), defined as B‐cell lymphoma with translocations and/or extra signals involving MYC plus BCL2 and/or BCL6. All cases were reviewed for histopathological classification. Median age was 62 years (range, 18–85), 84% of patients had advanced‐stage disease, and 87% had an International Prognostic Index score ≥2. Fourteen patients (11%) had a history of low‐grade follicular lymphoma. MYC translocation was present in 81%, and extra signals of MYC in 25% of patients. IGH‐BCL2 translocation was present in 84% and extra signals of BCL2 in 12% of patients. Two‐year event‐free survival (EFS) rates in all patients and patients who received R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), R‐EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin), and R‐HyperCVAD/MA (rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with cytarabine plus methotrexate) were 33%, 25%, 67% and 32%, respectively. In patients achieving complete response with initial therapy (n = 71), 2‐year EFS rates in patients who did (n = 23) or did not (n = 48) receive frontline stem cell transplantation were 68% and 53%, respectively (P = 0·155). The cumulative incidence of central nervous system involvement was 13% at 3 years. Multivariate analysis identified performance status ≥2 and bone marrow involvement as independent adverse prognostic factors for EFS and OS. Further research is needed to identify predictive and/or targetable biological markers and novel therapeutic approaches for DHL patients.

Safety and activity of lenalidomide and rituximab in untreated indolent lymphoma: an open-label, phase 2 trial

BACKGROUND Standard treatments for indolent non-Hodgkin lymphomas are often toxic, and most patients ultimately relapse. Lenalidomide, an immunomodulatory agent, is effective as monotherapy for relapsed indolent non-Hodgkin lymphoma. We assessed the efficacy and safety of lenalidomide plus rituximab in patients with untreated, advanced stage indolent non-Hodgkin lymphoma. METHODS In this phase 2 trial, undertaken at one instution, patients with follicular lymphoma and marginal zone lymphoma were given lenalidomide, orally, at 20 mg/day on days 1-21 of each 28-day cycle. For patients with small lymphocytic lymphoma, dosing began at 10 mg/day to avoid tumour flare, with an escalation of 5 mg/month to 20 mg/day. Rituximab was given at 375 mg/m(2) as an intravenous infusion on day 1 of each cycle. Patients responding after six cycles could continue therapy for up to 12 cycles. The primary endpoint was overall response, defined as the proportion of patients who achieved a partial or complete response; patients were assessed for response if they had any post-baseline tumour assessment. This trial is registered with ClinicalTrials.gov, number NCT00695786. FINDINGS 110 patients with follicular lymphoma (n=50), marginal zone lymphoma (n=30), and small lymphocytic lymphoma (n=30) were enrolled from June 30, 2008, until Aug 12, 2011. 93 of 103 evaluable patients had an overall response (90%, 95% CI 83-95). Complete responses occurred in 65 (63%, 95% CI 53-72) and partial responses in 28 patients (27%, 19-37). Of 46 evaluable patients with follicular lymphoma, 40 (87%) patients had a complete response and five (11%) had a partial response. Of 27 evaluable patients with marginal zone lymphoma, 18 (67%) had a complete response and six (22%) had a partial response. Of 30 evaluable patients with small lymphocytic lymphoma, seven (23%) had a complete response and 17 (57%) had a partial response. The most common grade 3 or 4 adverse events were neutropenia (38 [35%] of 110 patients), muscle pain (ten [9%]), rash (eight [7%]), cough, dyspnoea, or other pulmonary symptoms (five [5%]), fatigue (five [5%]), thrombosis (five [5%]), and thrombocytopenia (four [4%]). INTERPRETATION Lenalidomide plus rituximab is well tolerated and highly active as initial treatment for indolent non-Hodgkin lymphoma. An international phase 3 study (NCT01476787) to compare this regimen with chemotherapy in patients with untreated follicular lymphoma is in progress. FUNDING Celgene Corporation and Richard Spencer Lewis Memorial Foundation and Cancer Center Support Grant.

Complete Surgical Excision Is Essential for the Management of Patients With Breast Implant–Associated Anaplastic Large-Cell Lymphoma

PURPOSE Breast implant-associated anaplastic large-cell lymphoma (BI-ALCL) is a rare type of T-cell lymphoma that arises around breast implants. The optimal management of this disease has not been established. The goal of this study is to evaluate the efficacy of different therapies used in patients with BI-ALCL to determine an optimal treatment approach. PATIENTS AND METHODS In this study, we applied strict criteria to pathologic findings, assessed therapies used, and conducted a clinical follow-up of 87 patients with BI-ALCL, including 50 previously reported in the literature and 37 unreported. A Prentice, Williams, and Peterson model was used to assess the rate of events for each therapeutic intervention. RESULTS The median and mean follow-up times were 45 and 30 months, respectively (range, 3 to 217 months). The median overall survival (OS) time after diagnosis of BI-ALCL was 13 years, and the OS rate was 93% and 89% at 3 and 5 years, respectively. Patients with lymphoma confined by the fibrous capsule surrounding the implant had better event-free survival (EFS) and OS than did patients with lymphoma that had spread beyond the capsule (P = .03). Patients who underwent a complete surgical excision that consisted of total capsulectomy with breast implant removal had better OS (P = .022) and EFS (P = .014) than did patients who received partial capsulectomy, systemic chemotherapy, or radiation therapy. CONCLUSION Surgical management with complete surgical excision is essential to achieve optimal EFS in patients with BI-ALCL.

Lenalidomide, idelalisib, and rituximab are unacceptably toxic in patients with relapsed/refractory indolent lymphoma.

To the editor: Understanding of the tumor microenvironment has led to the development of novel agents for lymphoma, although few studies have combined these as a therapeutic strategy. We report unacceptable toxicity from such a biological triplet. Patients were treated in a multiarm phase 1 study

Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline

Purpose To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events in patients treated with immune checkpoint inhibitor (ICPi) therapy. Methods A multidisciplinary, multi-organizational panel of experts in medical oncology, dermatology, gastroenterology, rheumatology, pulmonology, endocrinology, urology, neurology, hematology, emergency medicine, nursing, trialist, and advocacy was convened to develop the clinical practice guideline. Guideline development involved a systematic review of the literature and an informal consensus process. The systematic review focused on guidelines, systematic reviews and meta-analyses, randomized controlled trials, and case series published from 2000 through 2017. Results The systematic review identified 204 eligible publications. Much of the evidence consisted of systematic reviews of observational data, consensus guidelines, case series, and case reports. Due to the paucity of high-quality evidence on management of immune-related adverse events, recommendations are based on expert consensus. Recommendations Recommendations for specific organ system-based toxicity diagnosis and management are presented. While management varies according to organ system affected, in general, ICPi therapy should be continued with close monitoring for grade 1 toxicities, with the exception of some neurologic, hematologic, and cardiac toxicities. ICPi therapy may be suspended for most grade 2 toxicities, with consideration of resuming when symptoms revert to grade 1 or less. Corticosteroids may be administered. Grade 3 toxicities generally warrant suspension of ICPis and the initiation of high-dose corticosteroids (prednisone 1 to 2 mg/kg/d or methylprednisolone 1 to 2 mg/kg/d). Corticosteroids should be tapered over the course of at least 4 to 6 weeks. Some refractory cases may require infliximab or other immunosuppressive therapy. In general, permanent discontinuation of ICPis is recommended with grade 4 toxicities, with the exception of endocrinopathies that have been controlled by hormone replacement. Additional information is available at www.asco.org/supportive-care-guidelines and www.asco.org/guidelineswiki .

Evaluating cell-of-origin subtype methods for predicting diffuse large B-Cell lymphoma survival: A meta-analysis of gene expression profiling and immunohistochemistry algorithms

BACKGROUND Patients with DLBCL exhibit widely divergent outcomes despite harboring histologically identical tumors. Currently, GEP and IHC algorithms assign patients to 1 of 2 main subtypes: germinal center B cell-like (GCB), or activated B cell-like (ABC), the latter of which historically carries a less favorable prognosis. However, it remains controversial as to whether these prognostic groupings remain valid in the era of rituximab therapy. MATERIALS AND METHODS A systematic literature review identified 24 articles from which meta-analyses were conducted, comparing survival outcomes for patients assigned to either GCB or ABC/non-GCB subtype using GEP and/or Hans, Choi, or Muris IHC algorithms. RESULTS Patients designated as GCB DLBCL using GEP fared significantly better in terms of overall survival than those with ABC DLBCL (hazard ratio, 1.85; P < .0001). In contrast, the Hans and Choi algorithms failed to identify significant differences in overall survival (P = .07 and P = .76, respectively) between GCB and non-GCB groups. CONCLUSIONS Our study illustrates a lack of evidence supporting the use of the Hans and Choi algorithms for stratifying patients into distinct prognostic groups. Rather, GEP remains the preferred method for predicting the course of a patients disease and informing decisions regarding treatment options.

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.

Patterns of failure in advanced stage diffuse large B-cell lymphoma patients after complete response to R-CHOP immunochemotherapy and the emerging role of consolidative radiation therapy.

PURPOSE The role of consolidative radiation therapy (RT) after complete response (CR) to rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for stage III-IV diffuse large B-cell lymphoma (DLBCL) patients is unclear. We aimed to evaluate our institutional experience when consolidative RT is delivered to initial presenting sites or bulky sites in these patients. METHODS AND MATERIALS We identified 211 histologically confirmed stage III-IV DLBCL patients who received R-CHOP from January 2000 to May 2012 at our institution. Patterns of failure for patients who achieved CR to R-CHOP were analyzed. Local control (LC), distant control (DC), progression-free survival (PFS), and overall survival (OS) were estimated using Kaplan-Meier method and compared between patients who received R-CHOP alone versus R-CHOP plus consolidative RT using the log-rank test. Multivariate analyses were also performed using Cox proportional hazards model. RESULTS Detailed treatment records were available for 163 patients. After a median 6 cycles of R-CHOP, 110 patients (67.5%) achieved CR and were entered for analysis. Fourteen patients (12.7%) received consolidative RT. After median follow-up of 32.9 months, 43.8% of patients who received R-CHOP alone failed at the initial sites with or without distant recurrence (DR), whereas isolated DR only occurred in 3.7% of these patients. Consolidative RT was associated with significantly improved LC (91.7% vs 48.8%), DC (92.9% vs 71.9%), PFS (85.1% vs 44.2%), and OS (92.3% vs 68.5%; all Ps<.0001) at 5 years compared with patients with R-CHOP alone. On multivariate analysis, consolidative RT and nonbulky disease were predictive of increased LC and PFS, whereas bone marrow involvement was associated with increased risk of DR and worse OS. Consolidative RT was also associated with marginal improved OS. CONCLUSIONS Forty-four percent of patients with advanced stage DLBCL failed at initial presenting sites after achieving CR to R-CHOP. Incorporation of consolidative RT as part of upfront treatment in these patients was associated with improved LC, PFS, and a trend towards improved OS.

Disparities in the Early Adoption of Chemoimmunotherapy for Diffuse Large B-cell Lymphoma in the United States

Background: Since the 1970s, CHOP chemotherapy has been the standard treatment for patients with diffuse large B-cell lymphoma (DLBCL). In 2002, randomized trials changed this standard by showing that adding rituximab immunotherapy to CHOP improved survival. However, how these results influenced chemoimmunotherapy adoption in clinical practice remains unclear. Methods: Using the National Cancer Database to compare chemoimmunotherapy use with chemotherapy alone, we collected data on demographics, stage, health insurance, area-level socioeconomic status (SES), facility characteristics, and type of treatment for DLBCL patients diagnosed in the United States 2001–2004. Multivariable log binomial models examined associations between race, insurance, and treatment allocation, adjusting for covariates. Results: Among 38,002 patients with DLBCL, 27% received chemoimmunotherapy and 50% chemotherapy alone. Patients who had localized disease, were diagnosed in 2001 or who were black, uninsured/Medicaid insured, or lower SES were less likely to receive any form of chemotherapy (all P < 0.0001). Patients who were diagnosed in 2001 or who were black [relative risk (RR), 0.83; 95% confidence interval (CI), 0.78–0.89], >60 years (RR, 0.94; 95% CI, 0.90–0.98), or had localized disease (RR, 0.89; 95% CI, 0.86–0.92) were less likely to receive chemoimmunotherapy. Receiving treatment at high DLBCL volume teaching/research facilities was associated with the greatest likelihood of chemoimmunotherapy (RR, 1.69; 95% CI, 1.52–1.89). Conclusions: Black DLBCL patients were less likely to receive chemotherapy or chemoimmunotherapy during this period. Impact: This large national cohort study shows disparities in the diffusion of chemoimmunotherapy for DLBCL. Improving DLBCL outcomes will require efforts to extend access to proven advances in therapy to all segments of the population. Cancer Epidemiol Biomarkers Prev; 21(9); 1520–30. ©2012 AACR.

Racial differences in the presentation and outcomes of chronic lymphocytic leukemia and variants in the United States

BACKGROUND Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in the United States, and prolymphocytic leukemia (PLL) is a related, rare chronic lymphoproliferative disorder. METHODS Using the United States Surveillance, Epidemiology and End Results (SEER) data from 13 registries, we examined differences in incidence and survival for CLL, small lymphocytic lymphoma (SLL) and PLL by race. International Classification of Diseases for Oncology 3(rd) edition histology codes 9670, 9823, and 9632-34 were used to identify cases. RESULTS From 1992 to 2007, 30,622 cases of CLL/SLL and 268 cases of PLL were recorded. Males had higher incidence than females (male-to-female incidence rate ratio CLL/SLL 1.89, 95% confidence interval (CI) 1.85-1.94 and PLL 2.47, 95%CI 1.90-3.20). Black patients were diagnosed at younger age compared to white patients (mean age at diagnosis for white versus black patients for CLL/SLL, 70 versus 67 years, P < .001; for PLL, 71 versus 61 years, P < .001). Greater proportion of black patients with SLL presented with B symptoms, extranodal primary site, and advanced disease compared to white patients (P = .003, P = .012, and P = .009 respectively). White patients with CLL/SLL had better survival rates than black patients (5-year relative survival rate 77.1% versus 63.9%, P < .01). In univariate Cox regression models, black race, male gender, age at diagnosis > 65 years, advanced stage, and B-symptoms were predictors of worse survival (P < .01) among CLL/SLL patients. CONCLUSIONS Black patients with CLL/SLL and PLL present at younger age and black patients with CLL/SLL have worse survival than white patients. Epidemiological studies examining the biological variants of these diseases in concert with race are needed to elucidate the etiology of these disparities.