Short regimen of rituximab plus lenalidomide in follicular lymphoma patients in need of first-line therapy

Abstract The SAKK 35/10 phase 2 trial, developed by the Swiss Group for Clinical Cancer Research and the Nordic Lymphoma Group, compared the activity of rituximab vs rituximab plus lenalidomide in untreated follicular lymphoma patients in need of systemic therapy. Patients were randomized to rituximab (375 mg/m2 IV on day 1 of weeks 1-4 and repeated during weeks 12-15 in responding patients) or rituximab (same schedule) in combination with lenalidomide (15 mg orally daily for 18 weeks). Primary end point was complete response (CR)/unconfirmed CR (CRu) rate at 6 months. In total, 77 patients were allocated to rituximab monotherapy and 77 to the combination (47% poor-risk Follicular Lymphoma International Prognostic Index score in each arm). A significantly higher CR/CRu rate at 6 months was documented in the combination arm by the investigators (36%; 95% confidence interval [CI], 26%-48% vs 25%; 95% CI, 16%-36%) and confirmed by an independent response review of computed tomography scans only (61%; 95% CI, 49%-72% vs 36%; 95% CI, 26%-48%). After a median follow-up of 4 years, significantly higher 30-month CR/CRu rates and longer progression-free survival (PFS) and time to next treatment (TTNT) were observed for the combination. Overall survival (OS) rates were similar in both arms (≥90%). Toxicity grade ≥3 was more common in the combination arm (56% vs 22% of patients), mainly represented by neutropenia (23% vs 7%). Addition of lenalidomide to rituximab significantly improved CR/CRu rates, PFS, and TTNT, with expected higher, but manageable toxicity. The excellent OS in both arms suggests that chemotherapy-free strategies should be further explored. This trial was registered at www.clinicaltrials.gov as #NCT01307605.

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The Follicular Lymphoma International Prognostic Index (FLIPI) as Part of a Proposed Prognostic Model for Follicular Lymphoma Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation (ASCT).

Blood ◽

10.1182/blood.v104.11.12.12 ◽

2004 ◽

Vol 104 (11) ◽

pp. 12-12 ◽

Cited By ~ 1

Author(s):

Grant E. Keeney ◽

Theodore A. Gooley ◽

Oliver W. Press ◽

John M. Pagel ◽

Stephen H. Petersdorf ◽

...

Keyword(s):

Follicular Lymphoma ◽

International Prognostic Index ◽

Prognostic Index ◽

Progression Free Survival ◽

B Cell Lymphoma ◽

Median Number ◽

Hematopoietic Stem ◽

Prior Chemotherapy ◽

Five Factors ◽

Grade 3

Abstract The FLIPI has recently been demonstrated to correlate with survival in patients (pts) with newly diagnosed follicular lymphoma (FL). No such index has been developed or evaluated to predict outcome for FL pts in the setting of myeloablative therapy and ASCT, despite data suggesting that ASCT may improve overall and progression-free survival (PFS). We examined the factors that contribute to the FLIPI as well as other factors assessed at time of transplant for their association with overall survival (OS) in 189 pts undergoing ASCT for FL. Baseline characteristics included: median age = 47 years (range, 24 – 64), stage III–IV = 94%, >4 nodal areas = 7.7%, elevated LDH = 30%, >5 cm maximal bulk of disease = 18%, chemoresistant disease = 13%, median number of prior chemotherapy regimens = 2. The FL histologies included: Grade 1 (49%), Grade 2 (31%), Grade 3 (13%), and transformation to diffuse large B-cell lymphoma (6%). Patients were conditioned with chemotherapy-only (21%), chemo+TBI (45%), or radioimmunotherapy +/− chemo (34%). Among all pts, the five-year estimated OS and PFS are 58% and 39%, respectively, with a median follow-up among surviving pts of 8 years (range, 1 – 18). The five factors that were found to be most significantly associated with OS include two FLIPI factors [age, hazard ratio for death (HR) = 1.37 per ten-year increase in age; elevated LDH, HR = 1.57] and three other clinical factors [>1 maximal extranodal site of disease, HR = 1.67; ≥2 prior chemotherapy regimens, HR = 1.99; chemoresistant disease, HR = 2.8]. Patients with 0 – 1 adverse factors (with age dichotomized as < 45 vs. ≥ 45) had an estimated 5-year OS of 79%, those with 2 factors 50%, 3 factors 41%, 4 or 5 factors 13% (Figure). Although prospective validation of this proposed model is required, this approach may be used to counsel FL pts regarding expected outcome following ASCT, to compare data between trials, and to design future studies. Figure Figure

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Randomized Trial of Lenalidomide Alone Versus Lenalidomide Plus Rituximab in Patients With Recurrent Follicular Lymphoma: CALGB 50401 (Alliance)

Journal of Clinical Oncology ◽

10.1200/jco.2014.59.9258 ◽

2015 ◽

Vol 33 (31) ◽

pp. 3635-3640 ◽

Cited By ~ 99

Author(s):

John P. Leonard ◽

Sin-Ho Jung ◽

Jeffrey Johnson ◽

Brandelyn N. Pitcher ◽

Nancy L. Bartlett ◽

...

Keyword(s):

Adverse Events ◽

Follicular Lymphoma ◽

International Prognostic Index ◽

Prognostic Index ◽

Dose Intensity ◽

Complete Response ◽

Time To Progression ◽

Non Hodgkin Lymphoma ◽

Grade 3 ◽

Group B

Purpose Lenalidomide and rituximab (LR) are active agents in follicular lymphoma (FL). Combination regimens have not been previously assessed in randomized studies. Patients and Methods The Cancer and Leukemia Group B (Alliance) 50401 trial is a randomized phase II trial studying rituximab (375 mg/m2 weekly for 4 weeks), lenalidomide (15 mg per day on days 1 to 21, followed by 7 days of rest, in cycle 1 and then 20 mg per day on days 1 to 21, followed by 7 days of rest, in cycles 2 to 12), or LR. The rituximab-alone arm was discontinued as a result of poor accrual. Eligibility included recurrent FL and prior rituximab with time to progression of ≥ 6 months from last dose. Aspirin or heparin was recommended for patients at high thrombosis risk. Results Ninety-one patients (lenalidomide, n = 45; LR, n = 46) received treatment; median age was 63 years (range, 34 to 89 years), and 58% were intermediate or high risk according to the Follicular Lymphoma International Prognostic Index. In the lenalidomide and LR arms, grade 3 to 4 adverse events occurred in 58% and 53% of patients, with 9% and 11% of patients experiencing grade 4 toxicity, respectively; grade 3 to 4 adverse events included neutropenia (16% v 20%, respectively), fatigue (9% v 13%, respectively), and thrombosis (16% [n = 7] v 4% [n = 2], respectively; P = .157). Thirty-six percent of lenalidomide patients and 63% of LR patients completed 12 cycles. Lenalidomide alone was associated with more treatment failures, with 22% of patients discontinuing treatment as a result of adverse events. Dose-intensity exceeded 80% in both arms. Overall response rate was 53% (20% complete response) and 76% (39% complete response) for lenalidomide alone and LR, respectively (P = .029). At the median follow-up of 2.5 years, median time to progression was 1.1 year for lenalidomide alone and 2 years for LR (P = .0023). Conclusion LR is more active than lenalidomide alone in recurrent FL with similar toxicity, warranting further study in B-cell non-Hodgkin lymphoma as a platform for addition of novel agents.

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Ofatumumab monotherapy in rituximab-refractory follicular lymphoma: results from a multicenter study

Blood ◽

10.1182/blood-2011-09-378323 ◽

2012 ◽

Vol 119 (16) ◽

pp. 3698-3704 ◽

Cited By ~ 97

Author(s):

Myron S. Czuczman ◽

Luis Fayad ◽

Vincent Delwail ◽

Guillaume Cartron ◽

Eric Jacobsen ◽

...

Keyword(s):

Follicular Lymphoma ◽

Overall Response Rate ◽

Response Rate ◽

International Prognostic Index ◽

Prognostic Index ◽

Progression Free Survival ◽

Free Survival ◽

Overall Response ◽

Median Progression Free Survival ◽

Grade 3

Abstract New treatments are required for rituximab-refractory follicular lymphoma (FL). In the present study, patients with rituximab-refractory FL received 8 weekly infusions of ofatumumab (CD20 mAb; dose 1, 300 mg and doses 2-8, 500 or 1000 mg; N = 116). The median age of these patients was 61 years, 47% had high-risk Follicular Lymphoma International Prognostic Index scores, 65% were chemotherapy-refractory, and the median number of prior therapies was 4. The overall response rate was 13% and 10% for the 500-mg and 1000-mg arms, respectively. Among 27 patients refractory to rituximab monotherapy, the overall response rate was 22%. The median progression-free survival was 5.8 months. Forty-six percent of patients demonstrated tumor reduction 3 months after therapy initiation, and the median progression-free survival for these patients was 9.1 months. The most common adverse events included infections, rash, urticaria, fatigue, and pruritus. Three patients experienced grade 3 infusion-related reactions, none of which were considered serious events. Grade 3-4 neutropenia, leukopenia, anemia, and thrombocytopenia occurred in a subset of patients. Ofatumumab was well tolerated and modestly active in this heavily pretreated, rituximab-refractory population and is therefore now being studied in less refractory FL and in combination with other agents in various B-cell neoplasms. The present study was registered at www.clinicaltrials.gov as NCT00394836.

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Fractionated 90Y-Ibritumomab Tiuxetan Radioimmunotherapy As an Initial Therapy of Follicular Lymphoma: An International Phase II Study in Patients Requiring Treatment According to GELF/BNLI Criteria

Journal of Clinical Oncology ◽

10.1200/jco.2013.50.3110 ◽

2014 ◽

Vol 32 (3) ◽

pp. 212-218 ◽

Cited By ~ 37

Author(s):

Tim M. Illidge ◽

Sam Mayes ◽

Ruth Pettengell ◽

Andrew T. Bates ◽

Mike Bayne ◽

...

Keyword(s):

Follicular Lymphoma ◽

Phase Ii ◽

International Prognostic Index ◽

Prognostic Index ◽

Progression Free Survival ◽

Complete Response ◽

Initial Therapy ◽

Hematologic Toxicity ◽

Ibritumomab Tiuxetan ◽

Free Survival

Purpose We report an international, multicenter phase II trial to evaluate the efficacy and toxicity of fractionated 90Y-ibritumomab tiuxetan (90Y-IT) as initial therapy of follicular lymphoma (FL). Patients and Methods A total of 74 patients, with a median age of 61 years (range, 28 to 80 years), were recruited requiring initial therapy by Groupe d'Etude des Lymphomes Folliculaires (GELF)/British National Lymphoma Investigation (BNLI) criteria. Among them, 78% had stage III-IV disease, 32% intermediate, and 44% high-risk (according to FL International Prognostic Index). Treatment consisted of two doses of 90Y-IT (11.1 MBq/kg) administered 8 to 12 weeks apart. Patients with more than 20% lymphoma infiltration of bone marrow (BM) received one infusion per week for 4 consecutive weeks of rituximab (375 mg/m2) and proceeded to fractionated radioimmunotherapy (RIT) only if a repeat BM biopsy demonstrated clearing of lymphoma to less than 20% involvement. The primary end point was end of treatment response of the intention-to-treat population. Secondary objectives were safety and progression-free survival (PFS). Results Initial overall response rate (ORR) was 94.4% (68 of 72 patients) with combined complete response (CR/CRu) of 58.3% (42 of 72 patients). Nine patients subsequently improved response making an ORR of 95.8% (69 of 72 patients) and CR/CRu of 69.4% (50 of 72 patients). At a median follow-up of 3.1 years (range, 0.2 to 5.2 years) estimated 3-year PFS is 58%, treatment-free survival 66%, and overall survival 95%. Median PFS is 40.2 months. Thirty patients have experienced disease progression and 24 have required further treatment. The treatment was well tolerated with few (2.8%) grade 3 or 4 infectious episodes or adverse events and manageable hematologic toxicity. Conclusion Fractionated RIT using 90Y-IT is an effective initial treatment for advanced-stage FL in patients with higher tumor burden requiring treatment.

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Abbreviated Chemotherapy With Fludarabine Followed by Tositumomab and Iodine I 131 Tositumomab for Untreated Follicular Lymphoma

Journal of Clinical Oncology ◽

10.1200/jco.2005.14.803 ◽

2005 ◽

Vol 23 (24) ◽

pp. 5696-5704 ◽

Cited By ~ 112

Author(s):

John P. Leonard ◽

Morton Coleman ◽

Lale Kostakoglu ◽

Amy Chadburn ◽

Ethel Cesarman ◽

...

Keyword(s):

Bone Marrow ◽

Follicular Lymphoma ◽

Standard Dose ◽

Bone Marrow Involvement ◽

International Prognostic Index ◽

Prognostic Index ◽

Progression Free Survival ◽

Complete Response ◽

To Receive

Purpose To evaluate the safety and efficacy of a sequential chemotherapy plus radioimmunotherapy (RIT) regimen in previously untreated follicular non-Hodgkin's lymphoma. Patients and Methods Thirty-five patients received an abbreviated course (three cycles) of fludarabine followed 6 to 8 weeks later by tositumomab and iodine I 131 tositumomab. Results After fludarabine, 31 (89%) of 35 patients responded, with three (9%) of 31 patients achieving a complete response (CR). After the full regimen of fludarabine and iodine I 131 tositumomab, all 35 patients responded; 30 (86%) of 35 patients achieved CR, and five (14%) of 35 achieved partial response. After a median follow-up of 58 months, the median progression-free survival (PFS) had not been reached (95% CI, 27 months to not reached), but it will be at least 48 months. The 5-year estimated PFS rate is 60%. Baseline Follicular Lymphoma International Prognostic Index (FLIPI) was significantly associated (P = .003) with PFS. Five of six patients with more than 25% bone marrow involvement at baseline achieved adequate bone marrow cytoreduction to receive standard-dose iodine I 131 tositumomab. Ten (77%) of 13 patients with baseline bone marrow Bcl-2 positivity demonstrated molecular remissions at month 12. Toxicities were manageable and principally hematologic. Two (6%) of 35 patients developed human antimurine antibodies (HAMA) after RIT. Conclusion Use of abbreviated fludarabine before iodine I 131 tositumomab can reduce bone marrow involvement, when needed, to allow the use of RIT and can suppress HAMA responses. This sequential treatment regimen is highly effective as front-line therapy for follicular lymphoma, particularly for low- or intermediate-risk FLIPI patients.

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The architectural pattern of FOXP3-positive T cells in follicular lymphoma is an independent predictor of survival and histologic transformation

Blood ◽

10.1182/blood-2009-07-235598 ◽

2010 ◽

Vol 115 (2) ◽

pp. 289-295 ◽

Cited By ~ 113

Author(s):

Pedro Farinha ◽

Abdulwahab Al-Tourah ◽

Karamjit Gill ◽

Richard Klasa ◽

Joseph M. Connors ◽

...

Keyword(s):

T Cells ◽

Follicular Lymphoma ◽

International Prognostic Index ◽

Prognostic Index ◽

Progression Free Survival ◽

Tissue Microarrays ◽

Index Score ◽

Cell Distribution ◽

Cell Content ◽

International Prognostic Index Score

Abstract Previous studies of follicular lymphoma (FL) patients treated heterogeneously have suggested that decreased numbers of regulatory T cells correlates with improved survival. We studied advanced-stage FL patients from a single institution phase 2 trial. All patients were treated uniformly with multiagent chemotherapy and radiation. Tissue microarrays were constructed using diagnostic biopsies available in 105 patients and stained with CD4, CD8, CD25, and forkhead/winged helix transcription factor 3 (FOXP3) antibodies. Both cell content and cell distribution were evaluated. For all antibodies, there were cases with a predominant intrafollicular or perifollicular localization of cells (follicular pattern) while others displayed a diffuse pattern. The median follow-up of living patients was 17.1 years. The International Prognostic Index score predicted overall survival (OS; P = .004) but not risk of transformation (RT). Cell content did not impact survival, while immunoarchitectural patterns of CD4/CD8 were significant for progression-free survival (PFS; P = .056), CD25 for both PFS and OS (P = .002 and P = .024, respectively), and FOXP3+ predicted PFS, OS, and RT (P = .001, P < .001 and p = .002, respectively). A Cox multivariate model showed both International Prognostic Index score and FOXP3+ pattern were independent predictors of OS (P = .008 and P < .001, respectively), while only FOXP3+ pattern predicted RT (P = .004). We conclude that FOXP3+ cell distribution significantly predicts survival and RT in FL.

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Phase III Study of R-CVP Compared With Cyclophosphamide, Vincristine, and Prednisone Alone in Patients With Previously Untreated Advanced Follicular Lymphoma

Journal of Clinical Oncology ◽

10.1200/jco.2007.13.5376 ◽

2008 ◽

Vol 26 (28) ◽

pp. 4579-4586 ◽

Cited By ~ 422

Author(s):

Robert Marcus ◽

Kevin Imrie ◽

Philippe Solal-Celigny ◽

John V. Catalano ◽

Anna Dmoszynska ◽

...

Keyword(s):

Follicular Lymphoma ◽

International Prognostic Index ◽

Prognostic Index ◽

Response Duration ◽

Complete Response ◽

Phase Iii ◽

Term Outcome ◽

Bulky Disease ◽

Long Term Outcome ◽

Trial Treatment

PurposeTo compare the long-term outcome of patients with previously untreated follicular lymphoma (FL) needing therapy, after treatment with cyclophosphamide, vincristine and prednisone (CVP) versus CVP plus rituximab (R-CVP) and to evaluate the predictive value of known prognostic factors after treatment with R-CVP.Patients and MethodsPatients with previously untreated CD20-positive stage III/IV FL were randomly assigned to eight cycles of R-CVP (n = 159) or CVP alone (n = 162). The median follow-up period was 53 months.ResultsThe primary end point—time to treatment failure (TTF), which included patients without a response after four cycles as an event—was significantly prolonged in patients receiving R-CVP versus CVP (P < .0001). Improvements in all other end points, including overall and complete response rates (P < .0001), time to progression (TTP; P < .0001), response duration (P < .0001), time to next antilymphoma treatment (P < .0001), and overall survival (OS; P = .029; 4-year OS: 83% v 77%;) were achieved with R-CVP versus CVP alone. Univariate analyses demonstrated an improvement in TTP with R-CVP versus CVP irrespective of the Follicular Lymphoma International Prognostic Index (FLIPI) subgroup, the International Prognostic Index (IPI) subgroup, baseline histology, and the presence or absence of B symptoms or bulky disease. By multivariate analysis, FLIPI retains a strong predictive power for TTP in the presence of the trial treatment effect.ConclusionAnalysis of all outcome measures, including OS, confirm the benefit of adding R to CVP in the front-line treatment of FL.

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R-FND Followed by Radioimmunotherapy for High-Risk Follicular Lymphoma

Blood ◽

10.1182/blood.v112.11.3056.3056 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3056-3056 ◽

Cited By ~ 7

Author(s):

Peter McLaughlin ◽

Sattva Neelapu ◽

Michelle Fanale ◽

Maria Rodriguez ◽

Ana Ayala ◽

...

Keyword(s):

High Risk ◽

Follicular Lymphoma ◽

International Prognostic Index ◽

Prognostic Index ◽

Ibritumomab Tiuxetan ◽

Free Survival ◽

Grade 3 ◽

Anti Cd20 ◽

Better Than

Abstract Follicular lymphoma (FL) patients, (pts) with high-risk features using the FL International Prognostic Index (FLIPI) have an expected 5-year survival of only about 50% with conventional therapy. With the incorporation of anti-CD20 monoclonal antibody (mAb) therapy, results are improving (e.g., Buske, Blood2006; 108: 1504). Starting in 2003, we have treated high-risk (FLIPI ≥3) FL pts with R-FND (rituximab, fludarabine, mitoxantrone, dexamethasone) for 4 cycles, followed by radioimmunotherapy (RIT) with ibritumomab tiuxetan, and subsequent rituximab maintenance. Results for the first 35 pts are: complete (CR) and partial (PR) remission 83% and 14%; 3-year overall (OS) and failure-free survival (FFS) 89% and 74% (median follow-up 24 mo.). RIT converted 5 PR pts to CR. Toxicity was mainly hematologic. Five pts did not receive RIT, one because of neutropenia after R-FND. Following RIT, platelet and neutrophil nadirs were 28 and 0.3, occurring at 4–7 weeks. 16 pts required transfusions, and 27 received growth factors. 13 pts had infections, only 2 of which were grade 3. Recovery occurred by 3 weeks in most, with prolonged cytopenias in 6. There has been 1 case of myelodysplasia. In conclusion, the additional complexity of this RIT intensification strategy is warranted in this high-risk FL population, resulting in OS and FFS outcomes that are better than non-mAb therapies, and at least as good as published chemotherapy-rituximab combination therapy.

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A pooled analysis of 1,144 patients with HIV-associated lymphoma: Assessment of lymphoma-, HIV-, and treatment-specific factors on clinical outcomes.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.8005 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 8005-8005 ◽

Cited By ~ 1

Author(s):

Stefan K. Barta ◽

Xiaonan Xue ◽

Roni Tamari ◽

Jeanette Y Lee ◽

Nicolas Mounier ◽

...

Keyword(s):

International Prognostic Index ◽

Prognostic Index ◽

Progression Free Survival ◽

Complete Response ◽

Initial Therapy ◽

Pooled Analysis ◽

Cd4 Count ◽

Therapeutic Interventions ◽

Hiv Viral Load ◽

Clinical Phase

8005 Background: Non-Hodgkin Lymphoma (NHL) remains the most common malignancy in patients with HIV. Outcomes have significantly improved over the last decade, but there is no accepted consensus regarding the optimal initial therapeutic approach. Our objective was to assess the effects of clinical factors on response and survival. Methods: We performed a systematic review to search for prospective clinical phase II or III trials that assessed therapeutic interventions for HIV-associated NHL and assembled individual patient data from 16 trials published between 2000 and 2011 including 1144 patients (median N=62/trial, range 17-195). Treatment factors included type of chemotherapy (CHOP, N=642; EPOCH, N=178; CDE, N=191; intensive regimens, N=155) and rituximab use (N=542). Endpoints included complete response (CR), progression-free survival (PFS), and overall survival (OS). We used logistic regression and Cox proportional hazard models adjusted for age, sex, age-adjusted International Prognostic Index (IPI), baseline CD4 count, baseline HIV viral load, use of concurrent antiretroviral therapy, and histology. Odds ratios (OR) > 1 for CR denote improved CR, and hazard ratios (HR) < 1 indicate reduced risk of progression or death. Results: Among the lymphoma- and HIV-specific covariates evaluated, only a higher IPI score was associated with inferior CR rate, PFS and OS (p<0.001). Rituximab was associated with a higher CR rate (OR 1.75; p=0.017), better PFS (HR 0.39, p<0.001) and OS (HR 0.39, p<0.001); patients with a higher baseline CD4 count benefited more from rituximab (HR for OS 0.57 if baseline CD4 count ≥100/ul vs. <100/ul; p<0.001). For all histologies, initial therapy with the EPOCH regimen resulted in a better CR rate (OR 1.78, p=0.039), PFS (HR 0.61, p=0.032) and OS (HR 0.47, p<0.001) when compared to CHOP. Conclusions: In this pooled analysis including 1144 patients with HIV-associated NHL, the addition of rituximab to chemotherapy was associated with significantly improved CR rate, PFS, and OS, specifically for patients with a baseline CD4 count ≥100/uL. Treatment with infusional EPOCH was also more effective than CHOP.

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Polypharmacy and potentially inappropriate medication use in older patients with aggressive non-Hodgkin lymphoma (NHL) leads to inferior survival and increased treatment-related toxicities.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.10039 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 10039-10039 ◽

Cited By ~ 1

Author(s):

Richard Jirui Lin ◽

Helen Ma ◽

Robin Guo ◽

Michael L. Grossbard ◽

Andrea B. Troxel ◽

...

Keyword(s):

Older Patients ◽

Inappropriate Medication ◽

International Prognostic Index ◽

Tumor Biology ◽

Prognostic Index ◽

Dose Intensity ◽

Progression Free Survival ◽

Rank Test ◽

Potentially Inappropriate Medications ◽

Grade 3

10039 Background: Survival outcomes for older patients with aggressive NHL are disproportionally inferior to those of younger patients. While differences in tumor biology may play a role, older patients are often frail with comorbidities, polypharmacy, and use potentially inappropriate medications (PIM) such as anticholinergics and benzodiazepines. Methods: Using Cox proportional hazard and logistic regression models, we analyzed all aggressive NHL patients age ≥60 treated at our two affiliated hospitals from 2009-2014 to examine the association of polypharmacy and PIM use with progression-free survival (PFS), overall survival (OS), and treatment-related toxicities. Results: In this updated and final analysis, we included 171 patients with complete records from these two hospitals. They share similar demographic, clinical, and laboratory characteristics except for higher International Prognostic Index (IPI) in patients from one hospital. The median age was 70 years (range 65-77). At the time of diagnosis, 46% of patients used more than 4 medications (polypharmacy) and 47% used at least one PIM. Only 43% of patients received first-line chemotherapy of adequate relative dose intensity (>85% dosage), and 65% experienced ≥grade 3 toxicities. Polypharmacy and PIM use were associated with shortened PFS and OS by log-rank test. Most importantly, PIM use remained an independent predictor of PFS, OS, and ≥ grade 3 toxicities in multivariable analyses (Table). Conclusions: This is the first report of significantly adverse survival impacts of polypharmacy and PIM use in older patients with aggressive NHL, presumably from drug-drug interactions that increase toxicities and impair the delivery of adequate chemotherapy dosage. Our findings support the use of evidence-based geriatric principles to guide meticulous medication management to improve outcome disparity for these patients. [Table: see text]

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