Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

Current Challenges and New Opportunities in Follicular Lymphoma

554 views

Published on

i3 Health is pleased to make the speaker slides from this activity available for use as a nonaccredited self-study or teaching resource.

Published in: Education
  • Be the first to comment

  • Be the first to like this

Current Challenges and New Opportunities in Follicular Lymphoma

  1. 1. Current Challenges and New Opportunities in Follicular Lymphoma Christopher R. Flowers, MD, MS Director, Lymphoma Program Professor of Hematology and Oncology Emory University
  2. 2. Disclosures Dr. Flowers discloses the following commercial relationships: Consultant: AbbVie, AstraZeneca, Bayer, Celgene (unpaid), Denovo Biopharma, Genentech/Roche (unpaid), Gilead, Karyopharm, OptumRx, Pharmacyclics/Janssen, Spectrum Research Grant: Abbvie, Acerta, BeiGene, Celgene, Genentech/Roche, Gilead, Janssen Pharmaceutical, Millennium/Takeda, Pharmacyclics, TG Therapeutics
  3. 3. Learning Objectives Evaluate predictive and prognostic markers that can inform personalized care plans for patients with FL Assess emerging efficacy and safety data on novel therapies for previously untreated and relapsed/refractory FL Apply strategies to control treatment-related adverse events in patients with FL FL = follicular lymphoma.
  4. 4. 2016 Projected Incidence of Lymphoid Cancer U.S. cancer statistics for lymphoid malignancies by World Health Organization subtypes HL = Hodgkin lymphoma; MZL = marginal zone lymphoma; PTCL = peripheral T-cell lymphoma; MCL = mantle cell lymphoma; BL = Burkitt’s lymphoma; MF = mycosis fungoides; HCL = hairy cell leukemia; LPL = lymphoplasmacytic lymphoma; WM = Waldenstrom macroglobulinemia; DLBCL = diffuse large B-cell lymphoma; PCN = primary central nervous system lymphoma; CLL = chronic lymphocytic leukemia; SLL = small lymphocytic lymphoma. Teras et al, 2016.
  5. 5. Cellular Origin of B-Cell Lymphomas: Most Are Derived From the Germinal Center ABC = activated B-cell; B-CLL = B-cell chronic lymphocytic leukemia; MALT = mucosa-associated lymphoid tissue; GC = germinal center. Küppers et al, 2005. Naive B cell Marginal zone Germinal center Mantle zone Memory B cell Plasmablast DLBCL (ABC type) Primary mediastinal B-cell lymphoma Follicular lymphoma Burkitt’s lymphoma DLBCL (GC type) Lymphocyte-predominant Hodgkin lymphoma Mantle cell lymphoma B-CLL (unmutated V-region genes) GC B cell Splenic marginal- zone lymphoma B-CLL (unmutated V gene) Post-transplant lymphomas Classical Hodgkin lymphoma Lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia Primary effusion lymphoma Multiple myeloma MALT lymphoma B-CLL Hairy cell leukemia Prolymphocytic leukemia Plasma cell
  6. 6. Key Issues in FL Outcomes for most FL populations are favorable >70% 10-year survival Heterogeneous outcomes for individuals Identify/predict patients with very favorable outcomes Establish new end points for drug development Stratify patients expected to have poor survival with chemo-immunotherapy Describe treatment sequences with poor outcomes Define alternative first-line and second-line therapies Determine biology of poor-risk disease ACS, 2018.
  7. 7. Maintenance/consolidation Initial relapse/≥2nd relapse A Management Approach for FL IF = involved field; EF = extended field; RT = radiotherapy. Chen et al, 2012; Flowers, 2014; Nastoupil et al, 2012; NCCN, 2018. Localized Disease Advanced Stage Low Tumor Burden Advanced Stage High Tumor Burden Initial Evaluation IF/EF RT Rituximab ± chemo ± RT Observe (selected cases) Observation Individualized therapy Rituximab ± chemo ± RT Palliative RT First-line therapy
  8. 8. Rituximab Versus Watchful Waiting in Asymptomatic FL aIf CT showed complete remission, bone marrow was assessed for histology and minimal residual disease. Mo = month; CT = computed tomography; CR = complete remission. Ardeshna et al, 2014. Watchful waiting with regular clinic visits (n=187) Rituximab 375 mg/m2 weekly for 4 weeks (n=84) Mo 3 Patients with asymptomatic stage II, III, IV nonbulky FL (N=463) Rituximab 375 mg/m2 weekly for 4 weeks (n=192) Rituximab 375 mg/m2 every 2 months Mo 7 CT scana Regular clinic visits Mo 13 CT scan if clinical CRa Mo 25 CT scana Continued follow-up
  9. 9. 0 1 2 3 4 5 6 7 75 0 1 2 3 4 5 6 7 70 1 2 3 4 5 6 Rituximab Versus Watchful Waiting in Asymptomatic FL: Outcomes HR = hazard ratio; CI = confidence interval; PFS = progression-free survival; OS = overall survival; yrs = years. Ardeshna et al, 2014. 100 50 25 0 HR: 0.21 (95% CI: 0.14–0.31; log-rank P<.0001) Time to Start of NewTreatment NoNewTreatment(%) 100 75 50 25 0 OS Yrs From Randomization 100 75 50 25 0 PFS HR: 0.23 (95% CI: 0.16–0.32; log-rank P<.0001) PFS(%) HR: 0.62 (95% CI: 0.31–1.26; log-rank P=.19) 100 75 50 25 0 0 1 2 3 4 5 6 7 Time to HistologicalTransformation NoHistological Transformation(%) HR: 0.73 (95% CI: 0.34–1.54; log-rank P=.40) OS(%) Yrs From Randomization Watch and wait Maintenance rituximab
  10. 10. Watchful Waiting Versus R-Chemo WW = watchful waiting; R-chemo = rituximab/chemotherapy. Nastoupil et al, 2016. OS PFS
  11. 11. Watchful Waiting Versus Rituximab R-mono = rituximab monotherapy. Nastoupil et al, 2016. OS PFS
  12. 12. Can We Identify Patients With Favorable FL for Watchful Waiting? Nastoupil et al, 2016. Median follow-up: 8.1 years Median OS: not reached <10% (n=34) of WW patients never initiated active therapy 8-year OS estimates were 74% (95% CI: 69%-79%) Predictors of OS Age 61-70 years: HR 3.22 Age >70 years: HR 8.66 Hemoglobin <120 g/L: HR 2.61
  13. 13. Predicting Outcomes With Gene-Expression Profile Score Huet et al, 2018.
  14. 14. Rituximab Maintenance versus Observation in FL GELA = Groupe d'Etude des Lymphomes de l'Adulte; CHOP = cyclophosphamide/doxorubicin/vincristine/prednisone; CVP = cyclophosphamide/vincristine/prednisone; FCM = fludarabine/cyclophosphamide/mitoxantrone; CR = complete response; PR = partial response; q2m = every 2 months; EFS = event-free survival. Salles et al, 2011. GELA PRIMA Phase 3 Study Primary end point: PFS CHOP x 6 + rituximab x 8 CVP x 8 + rituximab x 8 FCM x 6 + rituximab x 8 Patients with previously untreated grade 1-3 FL (N=1,217) CR, PR Maintenance rituximab 375 mg/m2 q2m x 2 yrs Observation Secondary end points: EFS, OS 1.0 0.8 0.6 0.4 0.2 0 0 6 12 18 24 30 36 Progression-FreeRate Months Stratified HR: 0.50 95% CI: 0.39-0.64 P<0.0001 82% 66% Rituximab maintenance (n=505) Observation (n=513) PROGRESSION-FREE SURVIVAL
  15. 15. Bendamustine/Rituximab (BR) vs R-CHOP in Untreated Indolent and Mantle-Cell Lymphomas R-CHOP = rituximab + CHOP; FLIPI = Follicular Lymphoma International Prognostic Index; NR = not reached. Rummel et al, 2012; Rummel et al, 2013; Rummel, Maschmeyer et al, 2017. PFS: Follicular Lymphoma (n=279) 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 12 24 36 48 60 72 84 BR R-CHOP HR 0.61 (95% CI 0.42-0.87) P = 0.0072 96 Months Response BR, n=166 R-CHOP, n=149 P ORR, % 93 91 — CR, % 40 30 0.21 PFS, months 69.5 31.2 0.000015 PFS for FL, months PFS, FLIPI low (1 or 2) PFS, FLIPI high (3-5) NR NR 53 41 47 35 0.0072 0.0428 0.0679 7-year OS, % 76 59.5 —
  16. 16. MAINTAIN: Study Design a261 patients discontinued, including for progressive disease, patient or physician choice, toxicity or infection, rituximab intolerance, or death. Pts = patients; q2w = every 2 weeks. ClinicalTrials.gov, 2018d; Rummel, Buske et al, 2017. Prospective, randomized phase 3 study Primary end point: PFS Secondary end points: response rates, OS, toxicity Pts with stage II (bulky disease >7 cm) or stage III/IV FL (N=611) Rituximab 375 mg/m² q2m (n=178) Observation (n=172) 1:1 (n=350) Bendamustine/ rituximab: 6 cycles Rituximab: 2 cycles Induction a Rituximab q2w (n=552) Maintenancea 2 yrs 2 yrs = 4 yrs Extended Maintenance = 2 yrs
  17. 17. MAINTAIN: PFS (Primary End Point) mPFS = median progression-free survival; NR = not reached. Rummel, Buske et al, 2017. 4 years versus 2 years rituximab maintenance appeared to prolong mPFS in patients treated with BR induction Not statistically significant OS similar arm Mo ProbabilityofPFS HR: 0.63 (95% CI: 0.36-1.11) 4-yr rituximab maintenance: 19 events; mPFS: NR 2-yr rituximab maintenance: 29 events; mPFS: NR 1 0.7 5 0.5 0.2 5 0 0 12 24 36 48 7260
  18. 18. MAINTAIN LDH = lactate dehydrogenase. Rummel et al, 2013; Rummel, Buske et al, 2017. MAINTAIN Patients with BR induction + 2- year rituximab maintenance Patients with 4-year rituximab maintenance censored StiL NHL1-2003 FL patients with BR induction followed by observation Did not include patients from study who received R-CHOP Characteristic MAINTAIN (n=595) NHL1-2003 (n=139) Median age, yrs (range) 61 60 Male, % 49 45 Stage, %  III  IV 29 59 26 69 B-symptoms 36 38 Bone marrow involved 54 60 LDH >240 36 41 FLIPI  Good  Intermediate  Poor 17 32 50 12 51 45 Baseline Patient Characteristics for Current Versus Historical Cross-Study Comparison
  19. 19. MAINTAIN: Cross-Study Comparison mOS = median overall survival. Rummel, Buske et al, 2017. In nonrandomized, cross-study comparison, 2-year rituximab maintenance following BR significantly increased PFS but not OS compared with observation Progression-Free Survival Overall Survival Mos ProbabilityofPFS ProbabilityofOS HR: 1.01 (95% CI: 0.69–1.50; P=0.9456) 2-yr rituximab maintenance (MAINTAIN); mPFS: NR Observation (NHL1-2003); mPFS: 78 mos HR: 0.68 (95% CI: 0.47–0.87; P =0.0074) 2-yr rituximab maintenance (MAINTAIN); mOS: NR Observation (NHL1-2003); mOS: NR 0 12 24 36 48 60 72 84 96 108 120 132 144 168156 1 0.75 0.5 0.25 0 Mos 0 12 24 36 48 60 72 84 96 108 120 132 144 168156 1 0.75 0.5 0.25 0 Progression-Free Survival of 2-Year Post-BR Rituximab Maintenance Versus Observation
  20. 20. MAINTAIN: Second Primary Malignancy Rummel, Buske et al, 2017. Secondary Malignancies 4-Yr Rituximab Maintenance (n=178) 2-Yr Rituximab Maintenance (n=172) Not Randomized (n=261) Pts with second primary malignancy (n=64), n (%) 15 (8) 18 (10) 31 (12) Secondary malignancies (n=73), n  Prostate  Colon/gastric  Lung  Kidney/urothelial  Pancreatic  Breast  Other, including nonmelanoma skin cancer  Myelodysplastic syndromes  Acute myeloid leukemia  Chronic myeloproliferative neoplasia 21 2 2 1 0 0 1 14 0 0 1 18 3 1 0 2 0 2 9 0 1 0 34 0 7 8 1 1 2 12 2 1 0
  21. 21. Supportive Evidence from Other Studies DFS = disease-free survival; BR-R = bendamustine/rituximab followed by maintenance rituximab (MR); BVR-R = bortzomib/bendamustine/rituximab followed by MR; BR-LR = BR followed by lenalidomide/MR. Kahl et al, 2017; Hill et al, 2017; Evens et al, 2017. Maintenance Therapy Following BR (Kahl: BRIGHT) Maintenance Therapy Following BR (Hill) BR/Bortezomib + Lenalidomide Maintenance (Evens: BIONIC) • Investigators’ choice of maintenance • BR with maintenance PFS vs without • HR 0.5; 95% CI 0.26-0.94 • 13 centers, N=640 • BR with maintenance PFS for pts in PR (HR 0.36 CI 0.18-0.71], P=0.003) • However, it did not improve for pts in CR (HR 0.80 [95% 0.38-1.66], P=0.55) • 1-year DFS results no added benefit from lenalidomide • 3-year PFS rates: • BR-R: 76% • BVR-R: 81% • BR-LR: 74%
  22. 22. Maintenance Rituximab After Frontline BR Hill et al, 2017. PFS associated with response to BR
  23. 23. GALLIUM: Phase 3 Study of Obinutuzumab Versus Rituximab for Previously Untreated FL aAll data presented for patients with FL though study also enrolled MZL patients (randomized separately). Tx = treatment; iNHL = indolent non-Hodgkin lymphoma; ECOG = Eastern Cooperative Oncology Group; PS = performance status; EOI = end of induction; IRC = independent review committee; DOR = duration of response; TTNT = time to next treatment; FDG-PET = fluorodeoxyglucose positron emission tomography. Marcus et al, 2016; Sehn et al, 2015. Primary end point: investigator-assessed PFS in FL patients Secondary end points: IRC-assessed PFS (confirmatory), OS, EFS, DFS, DOR, TTNT, CR/ORR at EOI (± FDG-PET), safety N=1,202 • Tx-naive adult patients with CD20+ iNHL, including FL (grade 1–3a)a • Stage III/IV or stage II bulky disease (≥7 cm) • ECOG PS 0–2 Stratified by chemotherapy, FLIPI, and geographic region Induction Maintenance Obinutuzumab (n=539) Rituximab (n=527) Obinutuzumab+ CHOP, CVP, or bendamustine (n=601) Rituximab+ CHOP, CVP, or bendamustine (n=601) For2yearsoruntildisease progression CR or PR at EOI visit Obinutuzumab, in combination with bendamustine, followed by obinutuzumab monotherapy is approved for the treatment of rituximab-relapsed or rituximab-refractory patients with FL (phase 3 GADOLIN study)
  24. 24. GALLIUM: Phase 3 Study of Obinutuzumab/Chemo Versus Rituximab/Chemo for Previously Untreated FL a Investigator-assessed by Revised Response Criteria for Malignant Lymphoma b IRC-assessed c HR 0.71; P=0.0138 d HR 0.75; P=0.21 AEs = adverse events; IRRs = infusion-related reactions. Marcus et al, 2016; Marcus et al, 2017. Obinutuzumab Chemotherapy (n=601) Rituximab + (n=601) ORR % a 88.5 86.9 CR % a 19.5 23.8 PR % a 69.1 63.1 3-y PFS % b, c 81.9 77.9 3-y OS % d 94.0 92.1 Primary End Point: Investigator-Assessed PFS 0.66 Grade 3/4 AEs were more frequent with obinutuzumab and included infection/infestation, cytopenias, IRRs
  25. 25. RELEVANCE Study Fowler et al, 2018. Presented by Nathan Fowler at 2018 ASCO Annual Meeting
  26. 26. RELEVANCE: Study Design GELF = Groupe d’Etude des Lymphomes Folliculaires; R2 = lenalidomide/rituximab; R-B = rituximab/bendamustine; R-CVP = rituximab + CVP; CRu = unconfirmed complete remission. Clinicaltrials.gov, 2018a; Clinicaltrials.gov, 2018b; Brice et al, 1997; Fowler et al, 2018; Salles et al, 2011.
  27. 27. RELEVANCE: Dosing Schedule d = day; wk = week; q8wk = every 8 weeks; q21d = every 21 days; q28d = every 28 days. Fowler et al, 2018. Treatment Period R2 Arm R-Chemo Arm 1 (~6 months) • Lenalidomide: 20 mg/d, d2-22/28 • Rituximab: 375 mg/m2 Investigator/patient choice prior to randomization • R-CHOP (72%) • R-B (23%) • R-CVP (5%) 2 (~1 year) • Lenalidomide: 20 or 10 mg/d per response at 6, 9, or 12 cycles • Rituximab: 375 mg/m2 • Rituximab: 375 mg/m2 3 (~1 year) • Rituximab: 375 mg/m2 • Rituximab: 375 mg/m2 R2: Lenalidomide 20 mg/d, d2-22/28 until CR/CRu at 6, 9, or 12 cycles, then 10 mg/d (total 18 cycles); rituximab (R) 375 mg/m2/wk cycle 1 and d1 cycles 2-6; continued in responders q8wk for 12 cycles R-CHOP: Q21d for 6 cycles: R 375 mg/m2 IV d1, cyclophosphamide 750 mg/m2 d1, doxorubicin 50 mg/m2 IV d1, vincristine 1.4 mg/m2 IV d1, prednisone 100 mg/d PO d1-5. Then R 375 mg/m2 IV d1 q21d for 2 cycles R-B: Q28d for 6 cycles: R 375 mg/m2 IV d1, bendamustine 90 mg/m2 IV d1-2 R-CVP: Q21d for 8 cycles: R 375 mg/m2 IV d1, cyclophosphamide 750 mg/m2 IV d1, vincristine 1.4 mg/m2 IV d1, prednisone 40 mg/d PO d1-5 R maintenance: In responders, R 375 mg/m2 IV d1 of each cycle q8wk
  28. 28. RELEVANCE: Patient Characteristics aFL grade was unspecified or was not within grades 1-3a for 11 patients in each arm; ULN = upper limit of normal. Fowler et al, 2018; Morschhauser et al, 2018. Characteristics R2 (n=513) n (%) R-Chemo (n=517) n (%) Median age, years (range) Age >70 years 59 (30-89) 80 (16) 59 (23-83) 78 (15) Male 251 (49) 251 (49) ECOG PS 0 1 2 Not evaluated 341 (66) 157 (31) 13 (3) 2 (<1) 345 (67) 157 (30) 14 (3) 1 (<1) Ann Arbor stage I/II III/IV 30 (6) 483 (94) 40 (8) 477 (92) Bulky disease (>7 cm) 218 (42) 199 (38) FL gradea 1 or 2 3a 437 (85) 65 (13) 443 (86) 63 (12) FLIPI score Low risk (0-1) Intermediate risk (2) High risk (3-5) 77 (15) 183 (36) 253 (49) 76 (15) 191 (37) 250 (48) Lactate dehydrogenase (>ULN) 156 (30) 137 (26)
  29. 29. RELEVANCE: Response by IRC (ITT) IRC = independent review committee; ITT = intention to treat; ORR = overall response rate. Fowler et al, 2018. 3-year duration of response (IRC): 77% for R2 74% for R-chemo Investigator results were consistent with IRC
  30. 30. Fowler et al, 2018; Morschhauser et al, 2018. RELEVANCE: Interim PFS by IRC Co-Primary End Point: Interim PFS (~50% events) At a median follow-up of 37.9 months, interim PFS was similar in both arms R2 Arm (n=513) R-Chemo Arm (n=517) Events, n (%) 119 (23) 111 (21) 3-year PFS (95% CI) 77% (72%-80%) 78% (74%-82%) HR (95% CI) P value 1.10 (0.85-1.43) 0.48
  31. 31. RELEVANCE: Interim PFS by Investigator Review Inv. = investigator. Fowler et al, 2018; Morschhauser et al, 2018. R2 Arm (n=513) R-Chemo Arm (n=517) Events, n (%) 111 (22) 121 (23) 3-year PFS (95% CI) 77% (72%-80%) 78% (74%-81%) HR (95% CI) P value 0.94 (0.73-1.22) 0.63
  32. 32. RELEVANCE: Prespecified Subgroup Analysis of Interim PFS (IRC) Fowler et al, 2018. Post-hoc analysis showed no differences between R2 and the R-chemo regimens
  33. 33. RELEVANCE: Overall Survival (Immature; ITT) Fowler et al, 2018. R2 Arm (n=513) R-Chemo Arm (n=517) Events, n (%) 38 (7) 31 (6) 3-year OS (95% CI) 94% (91%-96%) 94% (91%-96%) HR (95% CI) 1.16 (0.72-1.86)
  34. 34. RELEVANCE: Treatment-Emergent Adverse Events aHematologic adverse events were based on laboratory tests; all anemia events were grade 1. Cutaneous reactions included preferred terms From the system organ classes of skin and subcutaneous tissues disorders (including rash), gastrointestinal disorders, and general disorders, along with administration site conditions, infections/infestations, and reproductive system and breast disorder. TEAEs = treatment-emergent adverse events. Fowler et al, 2018. a a
  35. 35. RELEVANCE: Neutropenia and Related Complications aIncluding 4 cases of febrile bone marrow aplasia (all in R-chemo arm). ANC = absolute neutrophil count. Fowler et al, 2018. Patients, n (%) R2 (n=507) R-Chemo (n=503) Grade 3/4 neutropeniaa Grade 4 neutropenia 160 (32) 41 (8) 252 (50) 154 (31) Nadir ANC <100/µL 5 (1) 32 (6) Median time to onset of first grade 3/4 lab 3.7 months 0.6 months Grade 3/4 infections associated with grade 3/4 neutropenia 10 (2) 20 (4) Febrile neutropeniaa Febrile neutropenia requiring hospitalization 11 (2) 8 (2) 34 (7) 26 (5) Infections requiring hospitalization 46 (9) 60 (12) Received growth factors 117 (23) 340 (68) Per protocol, patients in the R2 arm had more frequent laboratory assessments than those in the R-chemo arm (Entire Treatment Period)
  36. 36. RELEVANCE: aIncluding 4 cases of febrile bone marrow aplasia (all in R-chemo arm). bMost common other reasons for discontinuation: secondary primary malignancy (SPM), investigator decision, and lost to follow-up. Fowler et al, 2018. Reasons for Discontinuation, n (%) R2 (n=507) R-Chemo (n=503) All discontinuations 157 (31) 146 (29) Progression 64 (13) 71 (14) Toxicity 43 (8) 16 (3) Insufficient responsea 15 (3) 3 (1) Concurrent illness 12 (2) 9 (2) Voluntary discontinuation/consent withdrawal 11 (2) 18 (4) Major protocol violation 1 (<1) 6 (1) Death 0 1 (<1) Otherb 11 (2) 22 (4) 69% of R2 and 71% of R-chemo patients completed treatment Safety-Related Treatment Discontinuations
  37. 37. CHRONOS-1: Trial Design Dreyling et al, 2018. Patients with indolent B-cell NHL (N=142) FL, MZL, SLL, WM Relapsed/refractory to ≥2 prior lines of treatment Rituximab plus an alkylating agent/regimen Copanlisib 60 mg via 1-hour IV on days 1, 8, and 15 on a 28-day cycle Until progression or unacceptable toxicity Primary end point: ORR after ≥4 cycles Secondary end points: DOR, PFS, OS
  38. 38. CHRONOS-1: Copanlisib Efficacy Dreyling et al, 2018. DOR: 14.1 months PFS: 12.5 months OS: 42.6 months
  39. 39. CHRONOS-1: Copanlisib Safety Dreyling et al, 2018. TRAEs led to dose reductions in 25.4% and interruptions in 50.7% Most Common TRAEs All Grades Grade 3 Grade 4 Transient hyperglycemia 50.0% 33.1% 7.0% Transient hypertension 29.6% 23.9% - Neutropenia 28.9% 9.2% 14.8% Diarrhea 35.2% 8.5% - Pneumonitis 6.3% 1.4% -
  40. 40. Management of Common AEs: Febrile Neutropenia MASCC = Multinational Association of Supportive Care in Cancer; CISNE = Clinical Index of Stable Febrile Neutropenia. Taplitz, Kennedy & Flowers, 2018; Taplitz et al, 2018. Initial doses of empirical antibacterial therapy within 1 hour of triage and monitor for ≥4 hours
  41. 41. Management of Common AEs: Febrile Neutropenia (cont.) FN = febrile neutropenia. Taplitz, Kennedy & Flowers, 2018; Taplitz et al, 2018.
  42. 42. Febrile Neutropenia: IDSA Guideline Recommendations IDSA = Infectious Diseases Society of America. Taplitz et al, 2018. Monotherapy with an antipseudomonal β-lactam agent, such as cefepime, a carbapenem (eg, meropenem or imipenem-cilastatin), or piperacillin-tazobactam, is recommended Other antimicrobials (eg, aminoglycosides, fluoroquinolones, vancomycin) may be added to the initial regimen for management of complications (eg, hypotension, pneumonia) or if antimicrobial resistance is suspected or proven Vancomycin (or other agents active against aerobic gram-positive cocci) is not recommended as a standard part of the initial antibiotic regimen for fever and neutropenia These agents should be considered for specific clinical indications, including suspected catheter-related infection, skin or soft-tissue infection, pneumonia, or hemodynamic instability
  43. 43. Febrile Neutropenia: IDSA Guideline Recommendations (cont.) Taplitz et al, 2018. Modifications to initial empirical therapy may be considered for patients at risk for infection particularly if the patient’s condition is unstable or if the patient has positive blood-culture results for resistant bacteria: Methicillin-resistant Staphylococcus aureus (MRSA): Consider adding vancomycin, linezolid, or, in the absence of pneumonia, daptomycin Vancomycin-resistant Enterococcus (VRE): Consider adding linezolid or daptomycin Extended-spectrum β-lactamase (ESBL) gram negative: Consider early use of a carbapenem Klebsiella pneumoniae carbapenemase (KPC): Consider early use of polymyxin-colistin or tigecycline, or a newer β-lactam with activity against resistant gram-negative organisms
  44. 44. Management of Common AEs: Rash LEN = lenalidomide; MDS = myelodysplastic syndromes; MM = multiple myeloma. Tinsley et al, 2015. Non-serious rash is the leading cause of permanent early discontinuation of LEN in patients with MDS treated in the postmarketing setting (similar data not available for patients with MM, FL, or MCL) Most LEN-related rash: mild to moderate in severity Patchy, raised, macular skin lesions Sometimes with localized urticaria Pruritus Mild to moderate rash may be treated with topical corticosteroids and/or oral antihistamines Any grade LEN-related rash should be appropriately managed through awareness of symptoms, appropriate and prompt intervention, and maximizing patient self-reporting of early signs of rash
  45. 45. Performance of Surveillance Imaging for Detecting Relapse FP = false positives; S/Sx = signs and symptoms. Goldman et al, 2017.
  46. 46. Surveillance Images PET = positron emission tomography; PPV = positive predictive value; NPV = negative predictive value. Goldman et al, 2017. CT PET Other TOTAL Total Scans 443 188 25 656 Concerning for 30 (7%) 39 (24%) 2 (8%) 71 (11%) True Positives 9 (2%) 13 (8%) 1 (4%) 23 (4%) Sensitivity 89% 100% 50% 92% Specificity 95% 83% 96% 91% PPV 30% 35% 50% 32% NPV 99.7% 100% 96% 99.6% Performance by Study Type
  47. 47. Link et al, 2018. Probability of Progression-Free Survival After Multiple Treatments Treatment Line Median PFS Years (95% CI) First 6.62 (6.10-7.20) Second 1.50 (1.35-1.70) R-mono 1.50 (1.26-2.11) R-chemo 1.48 (1.08-1.77) Third 0.83 (0.68-1.09) Fourth 0.69 (0.50-0.97) Fifth 0.68 (0.43-0.88)
  48. 48. 20% of Patients With FL Will Experience Disease Progression Within 24 Months of Treatment SWOG = Southwest Oncology Group. Press et al, 2013; Rummel et al, 2013; Salles et al, 2011. This suggests a high-risk group of patients who will relapse early despite different treatment approaches; maintenance 60 R-CHOP 100 80 60 40 20 0 24 30 36 42 48 540 6 12 18 Time (Months) Progression-FreeSurvival(%) 1.0 Event-FreeRate Rituximab Maintenance 0.8 0.6 0.4 0.2 0.0 0 6 12 18 24 30 36 42 48 54 60 Time (Months) Probability 1.0 0.8 0.6 0.4 0.2 0.0 B-R R-CHOP Time (Months) 0 6 12 18 24 30 36 42 48 54 60 SWOG S0016 Rummel et al (2013) PRIMA
  49. 49. OS of Patients With FL Who Relapsed Within 2 Years of R-CHOP (“Early POD”) POD = progression of disease. Casulo et al, 2015. Of 588 patients, 110 were classified as early progressors 12 non-POD deaths within 2 years  2-year OS (95% CI) was 71% (61.5–78.0)  5-year OS (95% CI) was 50% (40.3–58.8) 1.0 0 1 2 3 4 5 6 7 8 9 10 0.0 0.2 0.4 0.6 0.8 Patients at risk: 101 78 69 58 49 45 33 14 6 0 Time (Years) SurvivalProbability 122 Early Progressors 420 420 407 387 363 344 252 144 33 0420Reference = Early = Reference Group
  50. 50. Validation of Early POD: Additional Data Jurinovic et al, 2016.
  51. 51. Validation of Early POD: Additional Data (cont.) MER = Molecular Epidemiology Resource. Maurer et al, 2016.
  52. 52. FLASH: Landmark Analysis on Overall Mortality at 24 Months Post-Trial Registration Casulo et al, 2017. 2 3 4 5 6 7 8 9 10 Years from Trial Registration 0 10 20 30 40 50 60 70 80 90 100 OverallSurvival,% Early Progression NO Early Progression P<0.0001
  53. 53. FLASH: Validating Impact of POD24 on Mortality PS = performance status; β2MG = beta 2 microglobulin ; Hgb = hemoglobin. Casulo et al, 2017. POD24 independently associated with increased risk of death after adjusting for gender, FLIPI and PS, β2MG HR 5.65 ((4.72-6.76), p=<0.0001) For patients with POD24, death more likely in: Age >60 (p=0.0001) High risk FLIPI (p=0.0006) Hgb <12 (p=0.015) Elevated β2MG (p=0.026)
  54. 54. M7-FLIPI Improves Prognostication of FL Patients Receiving Chemoimmunotherapy GLSG = German Low-Grade Lymphoma Study Group; FFS = failure-free survival. Pastore et al, 2015. FLIPI ECOG PS EZH2, ARID1A, MEF2B, EP300, FOX01, CREBBP, and CARD11 5-year FFS (%) 5-year OS FLIPI low/int 76 91 FLIPI high 57 75 M7-FLIPI low 77 90 M7-FLIPI high 38 65
  55. 55. Clinicopathologic, Biologic Models May Identify Some Early Progressors POD24-PI = early progression prognostic index. Pastore et al, 2015. High-risk m7-FLIPI 61% POD24 20% of patients without POD24 assigned high risk POD24-PI Three m7-FLIPI genes + clinical factors More sensitive, less accurate
  56. 56. Clinicopathologic, Biologic Models May Identify Some Early Progressors (cont.) Huet et al, 2018. Low predictor score: Median PFS 10.8 years High predictor score: Median PFS 3.1 years Gene Expression Profiling PRIMA/MAYO/UI/Barcelona 23 gene signature predicts progression High predictor score, centroblast signature worse, enriched POD24
  57. 57. Does Stem Cell Transplantation Benefit FL Patients With Early POD? Auto-HCT = autologous hematopoietic cell transplantation; allo-HCT = allogeneic hematopoietic cell transplantation; CIBMTR = Center for International Blood and Marrow Transplant Research; pts = patients; HLA = human leukocyte antigen. Smith et al, 2018. Auto, HLA-matched related or unrelated donors = 440 pts Progression or disease relapse within 2 years = 553 pts Received rituximab/chemo for first-line therapy = pts FL undergoing auto-HCT or allo-HCT from 2002- in CIBMTR database = 1,690 pts
  58. 58. Does Stem Cell Transplantation Benefit FL Patients With Early POD? (cont.) MUD = matched unrelated donor; MSD = matched sibling donor; NRM = non-relapse mortality. Smith et al, 2018. Non-Relapse Mortality Relapse/Progression AdjustedCumulative Incidence,% Years Auto MUD MSD 100 0 20 40 60 80 0 2 104 6 8 Years 100 0 20 40 60 80 0 2 104 6 8 Auto MUD MSD AdjustedCumulative Incidence,% Auto-HCT MSD (n=105) MUD (n=95) Auto vs MSD Auto vs MUD MSD vs MUD 5-yr NRM 5 (2%-8%) 17 (10%-25%) 33 (23%-43%) p=0.003 p<0.0001 p=0.01 5-yr Relapse 58 (52%-65%) 31 (21%-40%) 23 (14%-32%) p<0.0001 p<0.001 p=0.25
  59. 59. Results Casulo et al, 2015; Smith et al, 2018. Casulo et al, 2015 Months OverallSurvival Smith et al, 2018 OverallSurvival Months 5-year OS Auto-HCT = 70% 5-year OS MSD = 73% 5-year OS MUD = 49% 5-year OS = 34-50%
  60. 60. S1608: Randomized Phase 2 Trial in Early Progressing or Refractory FL Clinicaltrials.gov, 2018c. CHOP + Obinutuzumab (OR bendamustine + obinutuzumab) Lenalidomide + Obinutuzumab Umbrasilib + Obinutuzumab FL progressing within 2 years or refractory to bendamustine-based or R-CHOP therapy n=45 n=45 n=45 Mandatory specimen submission Primary clinical objective: CR by PET/CT Primary translational objective: validation of m7-FLIPI in this high-risk population Stratify Maintenance therapy Lack of CR/early POD
  61. 61. FL: Preferred Sequence of Therapy Huet et al, 2018; Jurinovic et al, 2016; Pastore et al, 2015. Standard-risk FL patients Many strategies produce favorable outcomes High-risk FL patients with early POD (~20%) Consider early transplantation (auto/allo) Consider intergroup clinical trial Need clinicopathological predictors (m7-FLIPI) Computational approaches to define future treatment strategies Low predictor score: Median PFS 10.8 years High predictor score: Median PFS 3.1 years
  62. 62. Case Study 1 LN = lymph node. 68-year-old woman with slightly enlarged LN in her right axilla for about 1.5 years duration She was told about one year ago by a physician at a one-time visit that she didn’t need to worry about it and that he would watch it She also notes having shotty cervical adenopathy for approximately 3 years intermittently She now presents with increased axillary LNs: 5.0 cm right, 3.7 cm left She notes fatigue and night sweats
  63. 63. Case Study 1 (cont.) SUVmax = maximum standard uptake value. Physical examination: Normal; abdomen shows no abnormal hepatosplenomegaly and no palpable masses PET/CT: Lymph nodes: left axillary 4.2 cm, right axillary 5.4 cm Mesenteric LN conglomerate mass measuring 8 x 4.2 cm Cervical and inguinal nodes <2 cm bilaterally Highest SUVmax 5
  64. 64. Case Study 1 (cont.) CBC = complete blood count; WBC = white blood cell count; Hgb = hemoglobin; Plt = platelet; LDH = lactase dehydrogenase. Notable laboratory findings: CBC: WBC: 6,000 Hgb: 13 Plt: 108 LDH: 128 Left axilla excisional node biopsy shows small lymphocytes. There is no evidence of transformation Flow cytometry shows co-expression of CD10, CD19, CD20 t(14;18)
  65. 65. Case Study 1 (cont.) Past medical history: no significant comorbid diseases Family history: Father had DLBCL and died when the disease relapsed A distant cousin had some kind of blood cancer She is worried about this risk of dying from lymphoma and is ready to discuss starting treatment
  66. 66. Case Study 1 (cont.) Based on this patient’s situation, which of the following management options would you recommend? a. Observation b. Rituximab monotherapy c. Bendamustine + rituximab d. Bendamustine + obinutuzumab e. Rituximab-CHOP f. Obinutuzumab-CHOP g. Lenalidomide + rituximab
  67. 67. Case Study 1 (cont.) After completing all cycles of therapy, what would you choose next for this patient? a. Observation b. Rituximab maintenance c. Obinutuzumab maintenance d. Other maintenance e. Surveillance CTs
  68. 68. Case Study 2 58-year-old man who lives in a small town was diagnosed with FL 7 years ago, at which time he was noted to have 1.8- cm lymph nodes in his right neck 18 months ago, it eventually progressed to 5-cm LNs in his bilateral anterior cervical chain, along with other shotty neck lymph nodes and a large LN in his left axilla This was accompanied by 20 lbs of weight loss and drenching night sweats PET/CT at that time that showed the LNs noted and a mesenteric conglomerate of LNs measuring 9 x 4.5 cm Biopsy showed FL; was started on R-CHOP
  69. 69. Case Study 2 (cont.) He completed 6 cycles of therapy and is now completing his first year of maintenance He noted abdominal discomfort; a PET/CT scan performed yesterday shows a 6 x 8 cm abdominal mass with SUV of 7 Your cousin (who is an interventional radiologist) did a biopsy at the time of the PET/CT; your next- door neighbor (who is a hematopathologist) reviewed it this morning and says it is still FL
  70. 70. Case Study 2 (cont.) What is his likelihood of long-term survival? a. Unknown b. Unclear; he needs M7-FLIPI testing c. Unclear; he needs 23-gene panel testing d. 5-year OS expected to be 50% e. 5-year OS (95% CI) expected to be 70%
  71. 71. Key Takeaways Most patients with FL have favorable outcomes and long-term survival; many can undergo observation at diagnosis Patients who require treatment have several first- line treatment options with anti-CD20 monoclonal antibodies and chemotherapy Patients who relapse early have poor outcomes Should be considered for stem cell transplantation and clinical trials
  72. 72. References American Cancer Society (2018). Survival rates and factors that affect prognosis (outlook) for non-Hodgkin lymphoma. Available at: https://www.cancer.org Ardeshna K, Qian W, Smith P, et al (2014). Rituximab versus a watch-and-wait approach in patients with advanced-stage, asymptomatic, non- bulky follicular lymphoma: an open-label randomised phase 3 trial. Lancet Oncol, 15(4):424-435. DOI:10.1016/S1470-2045(14)70027-0 Brice P, Bastion Y, Lepage E, et al (1997). Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: a randomized study from the Groupe d’Etude des Lymphomes Folliculaires. Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol, 15(3):1110-1117. DOI:10.1200/JCO.1997.15.3.1110 Casulo C, Byrtek M, Dawson K, et al (2015). Early relapse of follicular lymphoma after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone defines patients at high risk for death: an analysis from the National Lymphocare Study. J Clin Oncol, 33(23):2516-2522. DOI:10.1200/JCO.2014.59.7534 Casulo C, Friedberg J, Ahn K, et al (2018). Autologous transplantation in follicular lymphoma with early therapy failure: a National Lymphocare Study and Center for International Blood and Marrow Transplant Research analysis. Biol Blood Marrow Transplant, 24(6):1163-1171. DOI:10.1016/j.bbmt.2017.12.771 Casulo C, Le-Rademacher J, Dixon J, et al (2017). Validation of progression of disease in 24 months (POD24) as a robust early clinical endpoint of poor survival in follicular lymphoma: results from the Follicular Lymphoma Analysis of Surrogacy Hypothesis (FLASH) investigation using individual data from 5,453 patients on 13 clinical trials. Blood, 130(suppl_1):412. Chen H, Liu K, Xu L, et al (2012). Administration of imatinib after allogeneic hematopoietic stem cell transplantation may improve disease-free survival for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. J Hematol Oncol, 5:29. DOI:10.1186/1756- 8722-5-29 Clinicaltrials.gov (2018a). Combined rituximab and lenalidomide treatment for untreated patients with follicular lymphoma (RELEVANCE). NLM identifier: NCT01476787. Clinicaltrials.gov (2018b). Obinutuzumab with or without umbralisib, lenalidomide, or combination chemotherapy in treating patients with relapsed or refractory grade I-IIIa follicular lymphoma. NLM identifier: NCT03269669. Clinicaltrials.gov (2018c). A phase 3 open label randomized study to compare the efficacy and safety of rituximab plus lenalidomide (CC-5013) versus rituximab plus chemotherapy followed by rituximab in subjects with previously untreated follicular lymphoma (RELEVANCE). NLM identifier: NCT01650701. Clinicaltrials.gov (2018d). Significance of duration of maintenance therapy with rituximab in non-Hodgkin lymphomas (MAINTAIN). NLM identifier: NCT00877214.
  73. 73. References (cont.) Dreyling M, Santoro A, Mollica L, et al (2018). Long-term efficacy and safety from the copanlisib CHRONOS-1 study in patients with relapsed or refractory indolent B-cell lymphoma. Blood, 132(suppl_1):1595. DOI:10.1182/blood-2018-99-11482 Evens AM, Hong F, Habermann TM, et al (2017). A 3-arm randomized phase II trial with bendamustine/rituximab therapy in untreated high risk (HR) follicular lymphoma (FL): bortezomib induction or novel IMiD continuation (BIONIC) study from the ECOG-ACRIN cancer research group. Blood, 130(suppl_1):482. Fowler N, Morschhauser F, Feugier P, et al (2018). RELEVANCE: phase III randomized study of lenalidomide plus rituximab (R2) versus chemotherapy plus rituximab, followed by rituximab maintenance, in patients with previously untreated follicular lymphoma. J Clin Oncol, 36(suppl_15):7500. Flowers CR (2014). Routine use of maintenance therapy in follicular lymphoma: examine the rationale for maintenance use before uniformly adopting a strategy. Oncology (Williston Park), 28(9):787, 793. Goldman ML, Kim C, Chen Z, et al (2017). Surveillance imaging during first-remission in follicular lymphoma does not impact overall survival. Blood, 130(suppl_1):1501. Gyan E, Foussard C, Bertrand P, et al (2009). High-dose therapy followed by autologous purged stem cell transplantation and doxorubicin- based chemotherapy in patients with advanced follicular lymphoma: a randomized multicenter study by the GOELAMS with final results after a median follow-up of 9 years. Blood, 113(5):995-1001. DOI:10.1182/blood-2008-05-160200 Herold M, Scholz CW, Rothmann F, et al (2015). Long-term follow-up of rituximab plus first-line mitoxantrone, chlorambucil, prednisolone and interferon-alpha as maintenance therapy in follicular lymphoma. J Cancer Res Clin Oncol, 141(9):1689-1695. DOI:10.1007/s00432-015- 1963-9 Herold M, Schulze A, Niederwieser D, et al (2006). Bendamustine, vincristine and prednisone (BOP) versus cyclophosphamide, vincristine and prednisone (COP) in advanced indolent non-Hodgkin's lymphoma and mantle cell lymphoma: results of a randomised phase III trial (OSHO# 19). J Cancer Res Clin Oncol, 132(2):105-112. DOI:10.1007/s00432-005-0023-2 Hiddemann W, Kneba M, Dreyling M, et al (2005). Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood, 106(12):3725-3732. DOI:10.1182/blood-2005-01-0016 Hill BT, Nastoupil L, Winter AM, et al (2017). Maintenance rituximab or observation after frontline treatment with bendamustine-rituximab (BR) for follicular lymphoma: a real world analysis across 13 US cancer centers. Blood, 130 (suppl_1):2779.
  74. 74. References (cont.) Hochster H, Weller E, Gascoyne RD, et al (2009). Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG1496 study. J Clin Oncol, 27(10):1607-1614. DOI:10.1200/JCO.2008.17.1561 Huet S, Tesson B, Jais JP, et al (2018). A gene-expression profiling score for prediction of outcome in patients with follicular lymphoma: a retrospective training and validation analysis in three international cohorts. Lancet, 19(4):549-561. DOI:10.1016/s1470-2045(18)30102- 5 Jurinovic V, Kridel R, Staiger A, et al (2016). Clinicogenetic risk models predict early progression of follicular lymphoma after first-line immunochemotherapy. Blood, 128(8):1112-1120. DOI:10.1182/blood-2016-05-717355 Kahl BS, Burke JM, van der Jagt R, et al (2017). Assessment of maintenance rituximab after first-line bendamustine-rituximab in patients with follicular lymphoma: an analysis from the BRIGHT trial. Blood, 130(suppl_1):484. Kimby E, Östenstad B, Brown P, et al (2015). Two courses of four weekly infusions of rituximab with or without interferon-α2a: final results from a randomized phase III study in symptomatic indolent B-cell lymphomas. Leuk Lymphoma, 56(9):2598-2607. DOI:10.3109/10428194.2015.1014363 Küppers R (2005). Mechanisms of B-cell lymphoma pathogenesis. Nat Rev Cancer 5(4):251-262. Link BK, Day BM, Zhou X, et al (2018). Second-line and subsequent therapy and outcomes for follicular lymphoma in the United States: data from the observational National LymphoCare Study. Br J Haematol. [Epub ahead of print] DOI:10.1111/bjh.15149 Marcus RE, Davies AJ, Ando K, et al (2016). Obinutuzumab-based induction and maintenance prolongs progression-free survival (PFS) in patients with previously untreated follicular lymphoma: primary results of the randomized phase 3 GALLIUM study. Blood, 128(22):6. Marcus R, Davies A, Ando K, et al (2017). Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med, 377:1331-1344. DOI:10.1056/NEJMoa1614598 Marcus R, Imrie K, Belch A, et al (2005). CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood, 105(4):1417-1423. DOI:10.1182/blood-2004-08-3175 Maurer M, Bachy E, Ghesquieres H, et al (2016). Early event status informs subsequent outcome in newly diagnosed follicular lymphoma. Am J Hematol. 91(11):1096-1101. DOI:10.1002/ajh.24492 Morschhauser F, Fowler NH, Feugier P, et al (2018). Rituximab plus lenalidomide in advanced untreated follicular lymphoma. N Engl J Med, 379(10):934-947. DOI:10.1056/NEJMoa1805104
  75. 75. References (cont.) Nastoupil L, Sinha R, Byrtek M, et al (2016). Outcomes following watchful waiting for stage II-IV follicular lymphoma patients in the modern era. Br J Haematol, 172(5):724-734. DOI:10.1111/bjh.13895 Nastoupil L, Sinha R, Hirschey A, et al (2012). Considerations in the initial management of follicular lymphoma. Community Oncol, 9(11):S53- S60. DOI:10.1016/j.cmonc.2012.09.015 Nickenig C, Dreyling M, Hoster E, et al (2006). Combined cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) improves response rates but not survival and has lower hematologic toxicity compared with combined mitoxantrone, chlorambucil, and prednisone (MCP) in follicular and mantle cell lymphomas: results of a prospective randomized trial of the German Low‐Grade Lymphoma Study Group. Cancer, 107(5):1014-1022. DOI:10.1002/cncr.22093 Pastore A, Jurinovic V, Kridel R, et al (2015). Integration of gene mutations in risk prognostication for patients receiving first-line immunochemotherapy for follicular lymphoma: a retrospective analysis of a prospective clinical trial and validation in a population-based registry. Lancet Oncol, 16(9):1111-1122. DOI:10.1016/S1470-2045(15)00169-2 Press OW, Unger JM, Rimsza LM, et al (2013). Phase III randomized intergroup trial of CHOP plus rituximab compared with CHOP chemotherapy plus (131)iodine-tositumomab for previously untreated follicular non-Hodgkin lymphoma: SWOG S0016. J Clin Oncol, 31(3):314-320. DOI:10.1200/JCO.2012.42.4101 Rummel M, Buske C, Hertenstein B, et al (2017). Four versus two years of rituximab maintenance following bendamustine plus rituximab in patients with previously untreated follicular lymphoma: results of the prospective, randomized, multicenter phase 3 study StiL NHL 7- 2008. Blood, 130(suppl_1):483. Rummel MJ, Maschmeyer G, Ganser A, et al (2017). Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent lymphomas: nine-year updated results from the StiL NHL1 study. J Clin Onc, 35(suppl_15):7501- 7501. DOI:10.1200/JCO.2017.35.15_suppl.7501 Rummel MJ, Niederle N, Maschmeyer G, et al (2012). Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent and mantle cell lymphomas: updated results from the StiL NHL1 study. J Clin Oncol (ASCO Annual Meeting Abstracts), 30(suppl). Abstract 3. Rummel MJ, Niederle N, Maschmeyer G, et al (2013). Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet, 381(9873):1203-1210. DOI:10.1016/S0140-6736(12)61763-2
  76. 76. References (cont.) Salles G, Seymour J, Offner F, et al (2011). Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet, 377(9759):42-51. DOI:10.1016/S0140-6736(10)62175-7 Salles G, Mounier N, de Guibert S, et al (2008). Rituximab combined with chemotherapy and interferon in follicular lymphoma patients: results of the GELA-GOELAMS FL2000 study. Blood, 112(13):4824-4831. DOI:10.1182/blood-2008-04-153189 Sehn LH, Chua NS, Mayer J, et al (2015). GADOLIN: primary results from a phase III study of obinutuzumab plus bendamustine compared with bendamustine alone in patients with rituximab-refractory indolent non-Hodgkin lymphoma. J Clin Oncol (ASCO Annual Meeting Abstracts), 33. Abstract LBA8502. Sebban C, Mounier N, Brousse N, et al (2006). Standard chemotherapy with interferon compared with CHOP followed by high-dose therapy with autologous stem cell transplantation in untreated patients with advanced follicular lymphoma: the GELF-94 randomized study from the Groupe d'Etude des Lymphomes de l'Adulte (GELA). Blood, 108:2540-2544. DOI:10.1182/blood-2006-03-013193 Smith SM, Godfrey J, Ahn KW, et al (2018). Autologous transplantation versus allogeneic transplantation in patients with follicular lymphoma experiencing early treatment failure. Cancer, 124(12):2541-2551. DOI:10.1002/cncr.31374 Solal-Céligny P, Lepage E, Brousse N, et al (1998). Doxorubicin-containing regimen with or without interferon alfa-2b for advanced follicular lymphomas: final analysis of survival and toxicity in the Groupe d'Etude des Lymphomes Folliculaires 86 Trial. J Clin Oncol, 16(7):2332- 2338. DOI:10.1200/JCO.1998.16.7.2332 Taplitz RA, Kennedy EB, Bow EJ, et al (2018). Outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology and Infectious Diseases Society of America Clinical Practice Guideline Update Summary. J Clin Oncol, 26(14):1443-1453. DOI:10.1200/JCO.2017.77.6211 Taplitz RA, Kennedy EB & Flowers CR (2018). Antimicrobial prophylaxis for adult patients with cancer-related immunosuppression: ASCO and IDSA Clinical Practice Guideline Update Summary. J Oncol Pract. [Epub ahead of print] DOI:10.1200/JOP.18.00366 Teras L, DeSantis C, Cerhan J, et al (2016). 2016 US lymphoid malignancy statistics by World Health Organization subtypes. CA Cancer J Clin. DOI:10.3322/caac.21357 Tinsley SM, Kurtin SE & Ridgeway JA (2015). Practical management of lenalidomide-related rash. Clin Lymphoma Myeloma Leuk, 15(suppl):S64-S69. DOI:10.1016/j.clml.2015.02.008 Vitolo U, Ladetto M, Gamba E, et al (2007). Front-line brief chemo-immunotherapy rituximab (R)-FND + rituximab consolidation ± rituximab maintenance in elderly patients with untreated advanced stage follicular lymphoma (FL): first interim analysis of a prospective randomized study (ML17638). Blood, 110(11):1278.

×