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

Hodgkin Lymphoma Board Review

Brad Kahl, MD

11/18/03

Hodgkin Lymphoma

Epidemiology Biology Classification Approach to the Patient

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

Trends in Cancer Mortality Rates, Men, 1973-1996

-80%

-70%

-60%

-50%

-40%

-30%

-20%

-10%

0%Testicular

Hodgkin's

Stomach

Mouth

Bladder

Larynx

Bladder

Colorectal

Pancreas

Leukemia

Trends in Cancer Mortality Rates, Women, 1973-

1996

-70%

-60%

-50%

-40%

-30%

-20%

-10%

0%Hodgkin's

Cervical

Stomach

Thyroid

Colorectal

Uterus

Mouth

Bladder

Ovary

Breast

Leukemia

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)

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

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

Reed-Sternberg Cell

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

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 death malignant transformation

– unclear how this occurs; ? EBV

– unclear how cells end up with RS phenotype

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

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

Nodular Lymphocyte Predominant Hodgkin Lymphoma




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%.

Classic Hodgkin Lymphoma

Nodular Sclerosing Hodgkin Lymphoma

Mixed Cellularity Hodgkin Lymphoma

Nodular Lymphocyte Rich Classical Hodgkin Lymphoma

Lymphocyte Depleted Hodgkin Lymphoma

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**

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 III Involvement of lymph node regions on both sides of the diaphragm

Stage IV Multifocal involvement of 1 extralymphatic sites ± associated lymph nodes or isolated extralymphatic organ involvement with distant nodal involvement

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.

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

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)


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/mm3

lymphocyte count < 600/mm3

(Hasenclever et al, NEJM 339,1506-1514;1998)


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

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

Hodgkin Lymphoma

Results of Treatmentstage 5 year overall survival

–I 90%

–II 90%

–III 80%

–IV 65%

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




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




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

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)

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)

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

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

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

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

Hodgkin Lymphoma: Stem Cell Transplant

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


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


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%


Things to avoid– excessive XRT

maximum acceptable dose to fetus 10 Gy

– anti-metabolites methotrexate

– regimens heavy in alkylating agents MOPP

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

Documents

hd slide

classic hodgkin lymphoma

mono slide

patient slide

nlp hodgkin lymphoma

rs phenotype slide

reedsternberg cell slide

surface immunoglobulin