1. Hodgkin Lymphoma Board Review Brad Kahl, MD 11/18/03

2. Hodgkin Lymphoma  Epidemiology  Biology  Classification  Approach to the Patient

3. Hodgkin Lymphoma  Epidemiology –14% of malignant lymphomas –0.5% of all malignancies –approximately 8000 new cases/yr in US –approximately 1500 deaths/yr –over past 30 years  age adjusted incidence rates declined appreciably  mortality rates declined substantially

4. Trends in Cancer Mortality Rates, Men, 1973-1996

5. Trends in Cancer Mortality Rates, Women, 1973- 1996

6. Hodgkin Lymphoma  Epidemiology –men > women –whites > blacks > Asians –no clear risk factors, several implicated  woodworking, farming  familial risk –Concordance for HD in twins  10/179 in monozygotic vs 0/187 in dizygotic twins (Mack et al, NEJM 1995)

7. Hodgkin Lymphoma  Risk Factors con’t –HIV  increases risk for HD 8 fold –HD not an AIDS defining illness  NHL 113x  KS 310x –Unclear why risk for NHL so much greater in HIV patients compared to HD

8. Hodgkin Lymphoma  Epstein Barr Virus –EBV DNA found in 50% RS cells –pathogen or passenger –Increased risk for HD after infectious mono (Hjalgrim et al, NEJM 2003) –Absolute risk 1/1000 –Median incubation time from mono to EBV+ HD 4.1 years –No increased risk for EBV- HD after mono

9. Reed-Sternberg Cell

10. Hodgkin Biology  Hodgkin’s Disease –Reed-Sternberg cell is the malignant cell  1% of cells in a biopsy specimen  potent cytokine producing cell (at least 12 cytokines)  cytokines appear to drive the disease process –remainder of cells are background inflammatory cells  lymphocytes, plasma cells, macrophages, eosinophils –RS cell as the malignant cell  origin only worked out within the past 5 years

11. Hodgkin Biology  RS is a “crippled” germinal center B cell –does not have normal B cell surface antigens –micromanipulation of single RS followed by PCR demonstrates clonally rearranged, but non functional immunoglobulin genes  somatic mutations result in stop codon (no sIg)  no apoptotic deathmalignant transformation –unclear how this occurs; ? EBV –unclear how cells end up with RS phenotype

12. Hodgkin Lymphoma Classification  “Classic” Hodgkin’s Disease  nodular sclerosis  mixed cellularity  lymphocyte depleted (very rare)  classical lymphocyte rich –HRS cells CD30 and CD15 positive  nodular lymphocyte predominant –HRS cells (L&H cells) have B cell markers  CD 20 and surface Immunoglobulin

13. NLP Hodgkin Lymphoma  differs from classical HD clinically and histopathlogically –preference for peripheral nodal sites –early stage distribution –late median time to recurrence –late recurrences common –low mortality from HD –L&H cells  express CD 20 (B cell marker)  express surface Ig

14. Nodular Lymphocyte Predominant Hodgkin Lymphoma

17.  Management –No consensus  often treated like classical hodgkins  My view is “do not overtreat” as cure is unlikely and as many deaths from second malignancies as from LPHD (possible related to HD therapy)  I believe watch and wait is reasonable  Often can do IFRT to problem areas as they appear  Rituximab effective in relapse with ORR 85-100%.

18. Classic Hodgkin Lymphoma

19. Nodular Sclerosing Hodgkin Lymphoma

20. Mixed Cellularity Hodgkin Lymphoma

21. Nodular Lymphocyte Rich Classical Hodgkin Lymphoma

22. Lymphocyte Depleted Hodgkin Lymphoma

23. Hodgkin Lymphoma: approach to patient  staging evaluation  H & P  CBC, diff, plts  ESR, LDH, albumin, LFT’s, Cr  CT scans chest/abd/pelvis, CXR  bone marrow evaluation (for stage IIB and higher)  PET scan may be helpful  PFTs, LVEF when clinically indicated  Fertility counseling  **lymphangiogram or laparotomy**

24. Cancer. 1982;49:2112. Modified Ann Arbor Staging Stage I Involvement of a single lymph node region Stage II Involvement of  2 lymph node regions on the same side of the diaphragm Stage IIIInvolvement of lymph node regions on both sides of the diaphragm Stage IVMultifocal involvement of  1 extralymphatic sites ± associated lymph nodes or isolated extralymphatic organ involvement with distant nodal involvement

25. Ann Arbor Staging System for Hodgkin's Disease and Non-Hodgkin's Lymphoma Stage I Stage II Stage III Stage IV Reprinted with permission. Adapted from Skarin. Dana-Farber Cancer Institute Atlas of Diagnostic Oncology. 1991.

27. Modified Ann Arbor Staging  “E” designation for extranodal disease  B symptoms  recurrent drenching night sweats during previous month  unexplained, persistent, or recurrent fever with temps above 38 C during the previous month  unexplained weight loss of more than 10% of the body weight during the previous 6 months  Criteria for bulk –10 cm nodal mass –mediastinal mass > 1/3 thorax diameter

28. Hodgkin Lymphoma: Prognostic Factors  Adverse prognostic features for stage I & II (EORTC data)  more than 3 nodal sites  bulky adenopathy  ESR > 50  B symptoms  invasion into critical organs  male  age > 40  MC or LD subtype –should probably not receive XRT alone if any of the above present (excessive relapse rate)

29. Hodgkin Lymphoma: Prognostic Factors  Independent adverse prognostic factors –advanced stage (III-IV)  male sex  age > 45  albumin < 4 gm/dl  HgB < 10.5 mg/dl  stage IV disease  WBC count > 15,000/mm 3  lymphocyte count < 600/mm 3 (Hasenclever et al, NEJM 339,1506-1514;1998)

30. Hodgkin Lymphoma: Prognostic Factors

31. Hodgkin Lymphoma: Biologic Prognostic Factors  Favorable –EBV in tumor cells  Unfavorable –Tissue eosinophila (NSHD) –Lymphocyte depletion (NSHD) –RS atypia (NSHD) –Bcl-2 overexpression –P53 –High proliferative rate

32. Hodgkin Lymphoma  Treatment –approach depends upon stage, prognostic factors, and co-morbidities –Stage I-II  consider XRT, chemotherapy, or combined therapy –Bulky stage I-II  combined modality therapy, usually 6 cycles of chemotherapy –Stage III-IV  ABVD x 6-8 cycles gold standard

33. Hodgkin Lymphoma  Results of Treatment stage5 year overall survival –I90% –II90% –III80% –IV65%

34. Hodgkin Lymphoma: Treatment of limited stage disease  Current general consensus is to administer CMT –ABVD x 4 (consider 6 cycles for bulk) –Followed by IFRT –Definite trend towards limiting the radiation field and possibly lowering the radiation dose due to concern over late effects –Data from 2 large trials  #1: Institute Nazionale Tumori –Enrolled patients with stage I, IIA, IIA bulky, and IIEA –Data presented at 2001 ASH meeting

35. Hodgkin Lymphoma: Treatment of limited stage disease

37.  Study #2: Engart et al, JCO Oct 2003. –Included patients with limited stage HD and at least one risk factor  Bulky mediastinal disease  Extranodal disease  Massive splenic disease  ESR > 50 and no B symptoms  ESR > 30 and B symptoms  More that 2 lymph node regions

38. Hodgkin Lymphoma: Treatment of limited stage disease

40.  More acute toxicities in EFRT  Late toxicities (second CA, cardiac, pulmonary) not statistically different –Trend worse in EFRT arm –Longer follow up will needed  Conclusion from trials 1 and 2 –4 cycles of chemotherapy plus IFRT equally effective to treatment plans including larger radiation fields

41. Hodgkin Lymphoma  Excess death rate (relative)* (SEER data) –2 years: 5.6% –5 years: 8.8% –10 years:14.3% –15 years: 19.4% –20 years:23.9% *compared to age and sex matched control (deaths other than from Hodgkins)

42. Hodgkin Lymphoma: Late Complications  Radiotherapy appears to confer the most late risk –Actuarial rate of second CA 1%/year with no plateau –In one study the 25 year cumulative risk of breast CA was 16.3%  Current major focus of current clinical trials to to maintain high cure rate while minimizing late complication  shorter courses of chemotherapy with lower radiation doses in smaller fields  elimination of radiotherapy (some argue for this already)

43. Hodgkin Lymphoma  Current EORTC trial for stage I-II patients –EBVP x 6 + 36 Gy IF –EBVP x 6 + 20 Gy IF –EBVP x 6 (arm closed do to excessive relapse)  Current GHSG trial for stage I-II patients –ABVD x 4 + 30 Gy IF –ABVD x 4 + 20 GY IF –ABVD x 2 + 30 Gy IF –ABVD x 2 + 20 GY IF

44. Hodgkin Lymphoma: Late Complications  Other Late Complications –depends upon treatment modality utilized  XRT vs. MOPP vs. ABVD vs. CMT –issues depends upon the age of patient  relative risks higher in younger patients  absolute risks higher in older patients –Risks of leukemia and infertility appear substantially lower using ABVD rather than MOPP  Infertility 20% vs. 50-70% –Pulmonary-Bleomycin, Cardiac-adriamycin

45. Hodgkin Lymphoma: Advanced Disease  More straightforward right now –ABVD is standard –Treat until CR + 2 cycles up to maximum of 8 –No role for routine XRT after chemo  (Aleman et al, NEJM June 2003) –Common practice is to administer consolidative XRT to bulky mediastinal disease after chemo  Stanford V, BEACOPP being compared to ABVD in prospective clinical trials currently

46. Hodgkin Lymphoma: Stem Cell Transplant  Reserved for patients who relapse after chemotherapy (autologous) –Superior to additional conventional chemotherapy in RCT  (Schmitz et al, Lancet 2002)  Upfront transplant for poor prognosis disease does not appear superior (2 trials)  Beneficial for the small group of patients with primary refractory HD

47. Hodgkin Lymphoma: Stem Cell Transplant

48. Lymphoma and Pregnancy  4th most common malignancy among pregnant females (breast > cervical > ovarian)  no good evidence that pregnancy has a prognostic influence on the lymphoma (except Burkitts)  Staging Issues –CT scans and radioisotope scans contraindicated –rely on PE, labs, CXR, US, MRI, and marrow

49. Lymphoma and Pregnancy  Therapy during pregnancy –choices will vary on case by case basis –type of lymphoma, gestational age, personal beliefs –therapeutic abortion vs watchful waiting vs limited XRT vs chemotherapy  Indolent NHL (rare) and some Hodgkins –will be able to defer therapy until after delivery

50. Lymphoma and Pregnancy  Aggressive NHL and Hodgkins requiring therapy –2nd and 3rd trimester  data suggests can give combination chemotherapy with minimal risk to fetus (CHOP or ABVD)  need to plan delivery to avoid neutropenia and thrombocytopenia –1st trimester (most difficult situation)  consider therapeutic abortion  risk of fetal malformation with combination chemo approximately 20%

51. Lymphoma and Pregnancy  Things to avoid –excessive XRT  maximum acceptable dose to fetus 10 Gy –anti-metabolites  methotrexate –regimens heavy in alkylating agents  MOPP