Choice of upfront treatment in the management of diffuse large B-cell lymphoma and follicular lymphoma

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1 Choice of upfront treatment in the management of diffuse large B-cell lymphoma and follicular lymphoma Ryan Lynch MD Assistant Professor, University of Washington Assistant Member, Fred Hutchinson Cancer Research Center Seattle, Washington

2 Goals/outline Diffuse large B-cell lymphoma (DLBCL) Integrating components of IPI score with pathology information to create evidence-based treatment approach Hint: It isn t always R-CHOP x 6 Follicular lymphoma Approach to deciding which patients require systemic and/or local therapy If so, what should be used?

3 DLBCL background Most common lymphoma subtype 25% of non Hodgkin lymphomas (NHL) in developed world Possibly more frequent in Central and South America (up to 40%) Chemo-immunotherapy is curative in about 60% of patients R-CHOP x 6 every 21 days is standard

4 R-CHOP x 6 is superior to CHOP x 6 GELA, RICOVER-60, and MINT studies all demonstrated superiority of R-CHOP to CHOP GELA Subsequent studies over the past 10+ years have failed to find a standard that is superior in an unselected DLBCL population Feugier et al. JCO 2005

5 Alive (%) Dose dense therapy superior in older patients in pre-rituximab era CHOP-21 (n = 178) 40.6 CHOP-14 (n = 172) Yr OS, % CHOP-14 CHOP Pfreundschuh M, et al. Blood. 2004;104:

6 but no difference in the rituximab era Progression-free survival Cunningham et al Lancet 2013

7 What about a next generation anti-cd20 antibody? Obinutuzumab (Gazyva) Mossner et al Blood 2010

8 No difference between G-CHOP and R-CHOP Progression-free survival Vitolo et al. JCO 2017

9 Dose adjusted EPOCH-R Drug Route DL-2 DL-1 DL1 DL2 DL3 DL4 DL5 DL6 Prednisone PO 60 (mg/m 2 BID) Day 1-5 Rituximab IV 375 (mg/m 2 ) Day 1 Vincristine CIV 0.4 (mg/m 2 /day) Day 1-4 Etoposide CIV (mg/m 2 /day) Day 1-4 Doxorubicin CIV (mg/m 2 /day) Day 1-4 Cyclophosphamide (mg/m 2 ) Day 5 IV GCSF Day 7 onward until ANC > 1000/μL SC 300 μg/day (if <75 kg) or 480 μg/day (if 75 kg) Dose escalated for next cycle if ANC > 500/uL De-escalate if ANC < 500/uL for 3 days or platelets < 25K/uL at any time Goal to maximize chemotherapy intensity in patients who can tolerate it DL -1-2: Original protocol did not reduce etoposide and doxorubicin, but reasonable to do so

10 CALGB R-CHOP x 6 vs. DA-EPOCH-R x 6 Randomized phase III study Untreated, newly diagnosed stage II-IV DLBCL (stage I PMBCL), ECOG PS 0-2, LVEF > 45%, tumor biopsies available, no CNS disease (N = 465) DA-EPOCH-R R-CHOP 6 cycles Primary endpoint: EFS Secondary endpoints: RR OS Safety *Included CNS prophylaxis if BM/testicular involvement or elevated LDH plus 2 extranodal sites. Prophylaxis: MTX IT x 4 doses on Day 1 of Cycles 3-6. Wilson WH, et al. ASH Abstract 469. Wilson WH, et al. Blood. 2002;99:

11 CALGB Results No significant difference in response rates between treatment arms Subset analysis pending Wilson WH, et al. ASH Abstract 469.

12 EFS (%) OS (%) CALGB 50303: No difference in EFS and OS EFS OS HR: 1.14 (95% CI: ; P =.4386) HR: 1.18 (95% CI: ; P =.42) 20 0 R-CHOP DA-EPOCH-R Yrs 20 0 R-CHOP DA-EPOCH-R Yrs *Median follow-up 5 yrs Wilson WH, et al. ASH Abstract 469.

13 CALGB/Alliance 50303: Increased toxicity with EPOCH-R Wilson WH, et al. ASH Abstract 469.

14 SWOG 9704: ASCT in CR/PR1 (IPI 3-5) Improved PFS, but no OS benefit Stiff et al. N Engl J Med 2013

15 I didn t come here to tell you to give R-CHOP x 6 to every patient with aggressive B-cell NHL

16 R-CHOP x 6 remains standard for untreated in unselected patients DLBCL However, DLBCL is a heterogeneous disease, and much has been learned since CALGB was designed in 2005 Subsets of patients may benefit from altered approach

17 International Prognostic Index (IPI) Age > 60 Performance status > 1 LDH elevated Extranodal sites > 1 Stage III/IV Validated in rituximab era as predictor of outcome Ziepert et al JCO 2010

18 Age > 60 Performance status > 1 LDH elevated Extranodal sites > 1 Stage III/IV

19 How to approach a new diagnosis of DLBCL Age > 60 Performance status > 1 Pathology/FISH LDH elevated Extranodal sites > 1 Stage III/IV

20 How to approach a new diagnosis of DLBCL Age > 60 Performance status > 1 Pathology/FISH LDH elevated Extranodal sites > 1 Stage III/IV

21 Can early stage DLBCL patients receive abbreviated therapy?

22 In pre-rituximab era, abbreviated chemo-rt superior to chemo alone CHOP x 3 + RT N= 401 CHOP x 8 Miller NEJM 339:21, 1998

23 Abbreviated chemo/rt for early stage DLBCL in rituximab era Retrospective data (Odejide et al 2015) and phase II data (Persky et al 2008) show excellent outcomes with R-CHOP x RT UNFOLDER EFS benefit to 6 R-CHOP + RT in >7.5 cm lesions Lysa no benefit to RT in non-bulky disease with R-CHOP 4-6 Adapted from Ng et al JCO 2016

24 How to approach a new diagnosis of DLBCL Age > 60 Performance status > 1 Pathology/FISH LDH elevated Extranodal sites > 1 Stage III/IV

25 Limited data in elderly (age > 80) SEER data R-CHOP associated with improved survival on multivariate analysis R-mini-CHOP ~50% dosing, including doxorubicin 2 year OS 59% TRM 8.1% Williams et al. Cancer 2015 Peyrade et al Lancet Oncol 2011

26 Poor performance status or heart failure R-CEOP a reasonable option for a patient with decreased ejection fraction or co-morbidities Adjust dose to ensure patient tolerance R-CVP palliative in most patients

27 How to approach a new diagnosis of DLBCL Age > 60 Performance status > 1 Pathology/FISH LDH elevated Extranodal sites > 1 Stage III/IV

28 WHO 2016 Update High grade B-cell lymphoma (HGBL), with MYC and BCL2 and/or BCL6 rearrangements Double (DHL) or triple-hit lymphomas (THL) Gene rearrangements by FISH/cytogenetics (not protein expression) HGBL, not otherwise specified Similar to entity previously called BCLU or Burkitt-like Blastoid appearance but lack specific features of BL, MCL, or B- LBL Swerdlow et al Blood 2016

29 High grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6 Also known as double hit lymphoma (DHL) DHL associated with inferior outcomes with R- CHOP Double protein/expressor lymphoma (DEL) Increased IHC staining for MYC (>40%) and BCL2 (>50%) Outcomes with R-CHOP Johnson NA, et al: J Clin Oncol 30:3452-9, 2012

30 Should we use intensified regimens in DHL and DEL?

31 R-CHOP vs Intensified Regimens in DHL Petrich et al. Blood 2014;124:

32 Petrich et al. Blood 2014;124: DHL: PFS by Induction Regimen

33 Prospective study DA-EPOCH-R x 6 in MYC rearranged DLBCL No prospective or randomized evidence to support the use of DA- EPOCH-R in DEL Prospective phase II DA-EPOCH-R x 6 cycles Dunleavy K, et al: ASH 2014 Median follow up 14 months 52 patients All patients with MYC rearrangement, 45% with concurrent BCL2 rearrangement

34 Primary mediastinal (thymic) B-cell lymphoma is a Median age 35 Females > males (2:1) distinct subtype Dominant mediastinal mass with direct extranodal extension or involvement of neighboring lymph node chains Less common advanced stage or BM involvement Path: bands of sclerosis, often with CD30+, can resemble Hodgkin lymphoma Surface immunoglobulin neg, but CD19+, CD20+, CD79a+

35 DA-EPOCH-R upfront in PMBCL NCI 51 patients (prospective) Median follow up 5 years Stanford 17 patients (retrospective) Median follow up 3 years Dunleavy K, et al: N Engl J Med 368: , 2013

36 Primary mediastinal large B-cell lymphoma Limited stage R-CHOP x 6 + IFRT DA-EPOCH-R x 6 without RT Advanced stage DA-EPOCH-R x 6 Refractory or relapsed disease very challenging to treat

37 ABC vs. GCB Cell of origin is important in DLBCL Activated B-cell type (ABC) vs. germinal center B-cell type (GCB) However, no randomized data to support escalated regimens beyond R- CHOP, though studies are ongoing Gutierrez-Garcia G, et al. Blood 2011; 117:4836

38 DLBCL: Other induction regimens under study Ibrutinib + R-CHOP: (phase III)- ABC subtype only Lenalidomide + R-CHOP: (phase III)-ABC subtype only Brentuximab-vedotin + R-CHP CD30+ (at least 1%) phase III closed due to poor accrual

39 Summary MYC rearranged/dhl/thl: DA-EPOCH-R or Burkitt-like regimen (R- CODOX-M/R-IVAC) DEL: controversial. R-CHOP vs. DA-EPOCH-R (I like clinical trials) High grade B-cell lymphoma NOS: DA-EPOCH-R vs. Burkitt-like regimen ABC DLBCL: R-CHOP x 6 (for now) Challenges in translating promising phase II data into successful phase III randomized clinical trials!

40 How to approach a new diagnosis of DLBCL Age > 60 Performance status > 1 Pathology/FISH LDH elevated Extranodal sites > 1 Stage III/IV

41 Who needs CNS prophylaxis Highly aggressive B-cell NHL Lymphoblastic lymphoma Burkitt lymphoma Intravascular DLBCL CD5+ DLBCL MYC rearranged DLBCL (including DHL and THL) Double expressor DLBCL (IHC, BCL2 > 50%, MYC > 40%)

42 Who needs CNS prophylaxis DLBCL Elevated LDH and > 1 extranodal site Involvement of the testes, orbit, breast or epidural space Bone marrow involvement CNS IPI score

43 CNS IPI Patients with score of 4-6 (CNS relapse risk >5%) should receive CNS prophylaxis Number of Factors 0-1 < CNS Relapse Risk (%) Schmitz et al. JCO 2016

44 What to use for CNS prophylaxis? Should be incorporated into regimen for high risk histologies (R- CODOX-M/R-IVAC, R-hyper-CVAD) Burkitt, lymphoblastic, select cases of high grade B-cell lymphoma NOS (younger patients) Mid-cycle IV methotrexate (3.5 g/m2) x 3 vs. intrathecal Consider IV for high risk DLBCL patients (Abutting CNS, sinus involvement, many risk factors) Intrathecal methotrexate 12 mg x 4 cycles likely sufficient for most cases No prospective data

45 Other considerations Bulky disease Allopurinol 300 mg once or twice per day started at least 1-2 days prior to treatment and continuing for at least 1 week Oral hydration High risk patients should be admitted and monitored with serial labs and rasburicase PRN Baseline Hepatitis B, C, and HIV testing HIV entire lectures can be dedicated to this topic alone and choice of therapy can be different Hepatitis B risk of reactivation prophylaxis needed! Baseline Echo EF of at least 50% for doxorubicin Can substitute etoposide for depressed EF

46 Summary Stage I/II: R-CHOP x 3 + RT or R-CHOP x 6 reasonable Site > 7.5 cm R-CHOP x 6 and consider RT Age > 80 or poor performance status Consider R-mini-CHOP or R-CEOP (if depressed EF) Aggressive histologies PMBCL, DHL/THL, MYC rearranged, HGBCL: Intensified regimen CNS prophylaxis Don t forget to use on patients with risk factors!

47 Follicular lymphoma Most common subtype of indolent B-cell NHL Nodular growth pattern effaces normal lymphoid architecture 85% of patients have t(14;18) translocation Most common immunophenotype CD10+, CD19+, CD20+, BCL6+, BCL2+, CD5-, CD23- FL treatment is rarely curative Patients living longer (manage like a chronic disease) Median OS in rituximab era has not been reached (Tan et al JCO 2013)

48 Follicular Lymphoma - Grading Grade 1-2 Grade 1 (follicular small cleaved cell) ~45% < 15% centroblasts Grade 2 (follicular mixed small & large cell) ~27% Grade 3 (follicular large cell) ~27% Images courtesy of J. Connors, MD from slide adapted from Ajay Gopal MD

49 Grade 3 Follicular Lymphoma Feature Grade 3A Grade 3B Centrocytes Present Absent Diffuse areas Absent Present BM involvement Frequent Uncommon CD10 100% 50% BCL2 ~75% ~75% t(14;18) 73% 13% BCL6 rearrangements 18% 44% Controversial area, Grade 3A generally treated like FL Less controversial: Grade 3B treated like DLBCL Ott et al, Blood 2002 May 15;99(10): (Horn et al. Haematologica Sep;96(9): doi:

50 Indications for treatment: GELF criteria Tumor bulk One site > 7 cm, or 3 sites > 3 cm Systemic symptoms Splenomegaly Vital organ compromise Effusions Circulating lymphoma cells > 5000/uL Cytopenias (Neutrophils < 1000/uL, Platelets < 100K / ul Histologic Transformation treat like DLBCL

51 Stage I/II follicular lymphoma No randomized trials RT alone may be curative Stanford experience: 40% 10 year relapse free survival Most retrospective analyses used higher doses, but Gy likely sufficient Concurrent RT with rituximab +/- chemo unlikely to provide added benefit (mixed retrospective data) Systemic therapy alone (rituximab +/- chemo reserved for symptomatic patients with a contraindication to definitive RT Site of disease Age of patient/risk of secondary malignancy Mac Manus MP,. J Clin Oncol 14: , 1996

52 Early stage FL: observation No initial therapy 43 evaluable patients Median age= 58 yrs Median OS= 19 yrs 10yr OS = 86% 10yr treatment-free survival=56% Advani et al JCO 2004

53 Should I treat asymptomatic advanced FL?

54 Advanced stage asymptomatic FL: Chlorambucil vs Observation Median Survival p=0.84 Observation 6.7 yr Asymptomatic Stage III/IV FL n=309 Chl 10mg/day 5.9 yrs 19% did not require treatment at 10 years! Ardeshna et al, Lancet. 2003

55 Asymptomatic advanced stage FL: Rituximab vs Observation Time to next therapy Overall Survival 46% did not need treatment at 3 yrs! No improvement in QOL 1:1:1 randomization, with induction only arm eventually closed Rituximab induction 375 mg/m2 weekly x 4 Maintenance every 2 months x 2 years Ardeshna et al Lancet Oncol Apr;15(4):

56 Evolution of the management of symptomatic advanced stage FL in the rituximab era TTF PFS R-FM R-CHOP R-CVP Least toxic: R-CVP->R-CHOP->R-FM: Most Toxic Federico et al. JCO 2013

57 Is there benefit to maintenance rituximab? Untreated advanced stage FL 6 cycles R-CHOP, then randomized to maintenance vs. observation Median f/u 72 months PFS benefit, but no OS benefit Salles G et al, Lancet 2013

58 PFS STIL and BRIGHT trials R-bendamustine vs. R-CHOP in follicular lymphoma without transformation PFS benefit STIL Time (Months) BRIGHT trial R-B noninferior to R-CHOP/R-CVP by primary endpoint of CR rate Less toxicity with R-B vs. R-CHOP Flinn IW, et al: Blood 123: , 2014 Rummel MJ, et al: Lancet 381: , 2013

59 OS PFS End of Induction FDG-PET is associated with improved outcome PET - PET + p<.001 PET - PET + p=.001 Trotman et al. J Clin Oncol Aug 10;29(23):

60 Impact of 2 year initial TTP on OS after R-CHOP Risk of progression over time Survival by early (< 2 year) vs late progression High-early relapse risk POD: progression of disease Casulo et al. J Clin Oncol Aug 10;33(23):

61 Histologic transformation of follicular lymphoma Occurs at rate of 2-3%/year Transformation after previous anthracycline-based chemotherapy is associated with poor outcomes Single-agent rituximab or R-bendamustine considered inadequate R-CHOP is considered standard in naïve patients Consider platinum-containing regimens in those who previous received CHOP-like regimen (R-ICE, R-DHAP) Role of auto-hsct is controversial (no randomized evidence in rituximab era)

62 Histologic transformation of follicular lymphoma Outcomes similar between HT and de novo DLBCL with R-CHOP Anthracycline use prior to transformation associated with worse outcomes Link BK, et al: J Clin Oncol 31:3272-8, 2013

63 Role of auto HSCT after HT of follicular lymphoma Retrospective review of PRIMA trial suggests that patients who have HT after previous immunochemotherapy may benefit from auto HSCT as part of salvage No clear benefit for those who relapse with persistent FL histology

64 Other notes FL is rarely cured goal of treatment is to relieve symptoms and maximize reimssion duration/treatment-free interval Minimize toxicity High index of suspicion for transformation Bulk, rapid growth of single site, site more FDG avid than others Adjust therapy based on prognosis Age Comorbidities Early treatment does not prolong survival or prevent histologic transformation

65 Early stage: RT potentially curative Summary Advanced Stage Observe if no indication for treatment Grade 1-2: Low Tumor Burden- Rituximab alone or R-Bendamustine High-tumor Burden- R-Bendamustine Grade 3 Grade 3A: R-bendamustine (low threshold to escalate) Grade 3B: R-CHOP Histologic transformation R-CHOP or anthracycline based therapy (if not already received) I do not prefer R-maintenance due to lack of OS benefit (but still controversial)? Increased risk of death/infection, GALLIUM study

66 Questions? Thank you!