LYMPHOMA IN OLDER PEOPLE. Ama Rohatiner, St. Bartholomew s Hospital, Londonj

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1 LYMPHOMA IN OLDER PEOPLE Ama Rohatiner, St. Bartholomew s Hospital, Londonj

2 LYMPHOMA IN OLDER PEOPLE PERSPECTIVES HALF OF ALL NEWLY-DIAGNOSED PTS. WITH LYMPHOMA ARE >60 MAY REQUIRE DIFFERENT MANAGEMENT - other illnesses - may alter tolerance to treatment for lymphoma

3 LYMPHOMA IN OLDER PEOPLE PERSPECTIVES ctd. INCIDENCE LIFE EXPECTANCY

4 FOLLICULAR LYMPHOMA 22% 'THE REST' LARGE B-CELL LYMPHOMA 31% CD20+ International Classification Project, JCO 1998, 16, 2782 International Classification Project, JCO 1998,16,2782,

5 EFFECT OF AGE ON SURVIVAL Rx: CAP/BOP Age no. of pts. CR rate 5-y survival % death from other causes <60y 45 76% 62% 2% > % 34% 22% p value Deaths = not due to lymphoma, not treatment-related Vose et al, JCO 1988;6:

6 LYMPHOMA IN OLDER PEOPLE DLBC: PROGNOSTIC FACTORS (I.P.I.) Factor Relative risk Age (<60 vs.>60) 1.96 LDH 1.85 Perf. Status (0,1 vs.2-4) 1.80 Stage (I/II vs. III/IV) 1.47 No. of extranodal sites (<1vs>1) 1.48 Shipp et al, Blood 1994; 303:

7 LYMPHOMA IN OLDER PEOPLE AGE-ADJUSTED PROGNOSTIC INDEX (I.P.I.) STAGE (I/II vs. III/IV) LDH PERF. STATUS (0,1 vs.2-4) Shipp et al, Blood 1994; 303:

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9 LYMPHOMA IN OLDER PEOPLE POTENTIAL SOLUTION: DOSE REDUCTION? AGE(years) % of full dose CR rate(%) med. Survival (mos.) A < > > TRY NOT TO, IF POSSIBLE - OUTCOME A LOT WORSE Dixon et al. (SWOG) JCO 1986;4:

10 WHICH REGIMEN? CONCLUSIONS FROM 18 RANDOMISED TRIALS ANTHRACYCLINES HELP ( be mindful of potential cardiotoxicity) STANDARD TREATMENT = CHOP LYMPHOMA IS PREDOMINANT CAUSE OF DEATH SOME PTS. - TREATMENT WITH PALLIATIVE INTENT* *person s s wishes

11 HAEMATOLOGICAL TOXICITY (9 studies) Pts. aged >70 Treated with CHOP/CHOP- like regimen >40% developed Grade 3/4 neutropenia 21% - 47% developed dneutropenic sepsis Death from infection: 5% - 30% Balducci and Lyman, JCO 2001;19:

12 HAEMATOLOGICAL TOXICITY ADDING G-CSF HELPS AT SBH - USED FOR SPECIFIC PTS. and >70 ALWAYS FOLLOWING 1 EPISODE OF NEUTROPENIC SEPSIS

13 LOCALISED DISEASE: TREATMENT ORIGINALLY RADIOTHERAPY 33% CHEMOTHERAPY + RADIOTHERAPY CHEMOTHERAPY

14 LOCALISED DISEASE (Miller et al. NEJM 1998;339:21). RandomisationR CHOP X 3 + IF RT - 5y Ov. Surv. 82% CHOP X 8-5y Ov.Surv.72% BUT AT 10 YEARS - DIFFERENCE NO LONGER SIGNIFICANT Horning et al, ASH 2001

15 DLBC LYMPHOMA: LOCALISED DISEASE PTS. AGED >60 IPI SCORE 0 Pts.>60 CHOP x 4 270pts. Randomisation CHOP x 4 +RT 292pts. NO DIFFERENCE IN SURVIVAL(p = 0.4) MIN. FOLLOW-UP = 5.8Y

16 DLBC LYMPHOMA: LOCALISED DISEASE WHAT CAN WE CONCLUDE? CHEMOTHERAPY ALONE BETTER - AND SIMPLER

17 2/3 MAJORITY PRESENT WITH DISSEMINATED DISEASE

18 STRATEGIES TO IMPROVE SURVIVAL TAKE CHOP and: SHORTEN TREATMENT INTERVAL ADD ANTI-CD20 (Rituximab)

19 DIFFUSE LARGE B-CELL LYMPHOMA SHORTENING TREATMENT INTERVAL CHOP -21 vs CHOP -14 PTS. AGED >60 YRS EFS AND SURVIVAL BETTER WITH CHOP -14 N.B. BEFORE RITUXIMAB Pfreundschuh et al, Blood 2004, 104 : 626

20 SHORTENING INTER-CYCLE TIME: WHAT CAN WE CONCLUDE? APPEARS TO HELP - SO NOW IN U.K. NATIONAL RANDOMISED TRIAL COMPARING R + CHOP, EVERY 21 or 14 DAYS

21 ADDITION OF RITUXIMAB INCTR(UK) St. Bartholomew s Hospital, Ehrlich h P : On immunity it with London special reference to cell life. Proc. R. Soc. Lond. (Biol) 1890

22 CHOP + RITUXIMAB FRENCH STUDY U.S. STUDY EUROPEAN STUDY

23 ADDING RITUXIMAB CHOP + RITUXIMAB CR RATE EVENT-FREE SURVIVAL SURVIVAL Coiffier et al, NEJM, 346:235,2002

24 ility Surviva al probab CHOP ± rituximab as first-line Rx 7-year follow-up, Overall Survival R-CHOP CHOP 0 p = Coiffier B et al, ASCO 2007 Years

25 CHOP ± rituximab: OS by bcl-2 expression Bcl-2 ve p = 0.27 Bcl-2+ve p < obability R-CHOP 0.8 CHOP Survival pr0.6 0 p < Years robability Survival pr0.6 0 p < R-CHOP CHOP Years Coiffier B et al ASCO 2007

26 ADDING RITUXIMAB ctd. U.S. INTERGROUP STUDY : PATIENTS AGED > 60 CHOP RITUXIMAB Rand. CR/PR CHOP + rituximab N.F.T Habermann et al,j. Clin Oncol 24:3121,

27 U.S. INTERGROUP STUDY 632 PATIENTS AGED > 60 NO DIFFERENCE IN RESPONSE RATE NO DIFFERENCE IN SURVIVAL NB. STUDY NOT DESIGNED TO COMPARE CHOP with CHOP + R Habermann et al, J. Clin Oncol 24:3121,2006

28 RITUXIMAB AS MAINTENANCE THERAPY Median follow-up 5.55 years Treatment Median failure-free survival (years) p CHOP + Maint.R 5.2 CHOP + obs R-CHOP + Maint.R 5.2 R-CHOP + obs Morrison VA, et al. ASCO 2007

29 ADDING RITUXIMAB - U.S. STUDY WHAT CAN WE CONCLUDE? OVERALL: RITUXIMAB HELPED (FFS) MAINTENANCE NOT HELPFUL IN PTS. WHO RECEIVED RITUXIMAB AS PART OF INITIAL Rx

30 - ADDING RITUXIMAB ctd. 6 x CHOP Gy (Bulk, E) 8 x CHOP-14 Random + 36 Gy (Bulk, E) 2 x 2 factorial 6 x CHOP-14 design + 36 Gy (Bulk, E) + 8 x rituximab Pfreundschuh M, et al. ASH x CHOP Gy (Bulk, E) + 8 x rituximab

31 EVENT-FREE SURVIVAL Pr roportion : 6 x CHOP-14 2: 8 x CHOP-14 1, 2: p = : 6 x CHOP x R 1, 3: p < , 4: p< : 8 x CHOP x R 3, 4: p = Time (months) Pfreundschuh M, ASH 2006

32 OVERALL SURVIVAL Pr roportion : 6 x CHOP-14 1, 2: p = : 8 x CHOP-14 1, 3: p = : 6 x CHOP x R 1, 4: p = : 8 x CHOP x R 3, 4: p = Time (months) Pfreundschuh M, et al ASH 2006

33 ADDING RITUXIMAB:WHAT CAN WE CONCLUDE? IMPROVES OUTCOME PROBLEM: PRICE PRECLUDES MOST PEOPLE FROM RECEIVING IT

34 COST (TO N.H.S. in U.K.)* for a PERSON 1.8 sq.m 4 INFUSIONS = 5,776 *APPROVED AS PART OF 1st LINE TREATMENT FOR FOLLICULAR and DIFFUSE LARGE B-CELL LYMPHOMAS

35 ADDING RITUXIMAB:SOLUTIONS? PROPOSAL FOR INTERNATIONAL RANDOMISED PHASE III STUDY (INCTR) + MOLECULAR ADD-ON STUDIES (SBH) ASK ROCHE TO EMULATE NOVARTIS (CML)?

36 CNS PROPHYLAXIS (i/t MTX) - SBH IF INVOLVEMENT OF : B.M.,TESTIS, POST-NASAL SPACE WALDEYER S RING IF: RAISED LDH and 2 or >2 EXTRA-NODAL SITES HIGH I.P.I. SCORE(3 or >3 RISK FCTORS) (PTS. WHO ARE HIV+ve)

37 EXPERIMENTAL SOLUTIONS? Se (no.34) Selenium - discovered by Jons Berselius in 1817

38 DIFFUSE LARGE B CELL LYMPHOMA SELENIUM AND CANCER SELENIUM CAN: PREVENT CANCER (EPIDEMIOLOGICAL AND INTERVENTIONAL STUDIES FROM CHINA) INDUCE APOPTOSIS AND AUGMENT CHEMOTHERAPY- INDUCED CELL DEATH IN CELL LINES St. Bartholomew s Hospital REDUCE TOXICITY OF CHEMOTHERAPY Roswell Park Memorial Institute

39 OVERALL SURVIVAL BY SERUM SELENIUM AT PRESENTATION 100 PATIENTS WITH HIGH-GRADE G LYMPHOMA N = 23 CUM MULATIVE % SURVIVING p = N = Last et al, JCO, July 15, 2003 TIME (YEARS)

40 DLBC LYMPHOMA : SELENIUM SBH: SOON TO BEGIN: RANDOMISED STUDY TO EVALUATE THE EFFECT OF ADDING SELENIUM TO RICE IN YOUNGER PTS. WITH RECURRENT DLBC LYMPHOMA HIGH-DOSE THERAPY AIM: TO INCREASE EFFICACY AND REDUCE TOXICITY DISCUSSION: OLDER PTS.

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