Hodgkin Lymphoma – Disease

Specific Biology and Treatment

Options

John Kuruvilla
My Disclaimer
• This is where I work…
 Objectives
• Pathobiology – what makes HL different
• Diagnosis
• Staging
• Treatment Philosophy and Approach
– Primary Treatment
– Second-line Therapy
• Summary and Recommendations
• A look forward…
 Hodgkin Lymphoma – Incidence and Prevalence

Total Male Female

New HL Cases - Canada 775 436 339

HL Deaths - Canada 131 72 59
ESTIMATES FOR EUROPE and NORTH AMERICA
Incidence - 3 / 100 000
Prevalence 350 000
Lifetime Risk 1 / 250

Canadian Cancer Society 2001

Current Lymphoma Classification is
based on relating disease to normal
cell types and development
 Hodgkin Lymphoma - Pathology
• Background of
inflammatory cells,
eosinophils, fibrosis
• Reed-Sternberg cell is
the “malignant cell”
• Immunophenotype
shows CD30+ CD15+
• Cell of origin recently
shown to be a B
lymphocyte

Lazarchick, J. ASH Image Bank 2009;2009:9-00002

Subtypes based on Pathology
• Classical HL
– Nodular Sclerosis – 55%
– Mixed Cellularity – 25%
– Lymphocyte Rich – 5%
– Lymphocyte Deplete – 1-2%
• Lymphocyte Predominant HL – 5%
Diagnosis – gold standard is biopsy!
• Fine needle aspirate (FNA) – quick, easy no OR
but…
• Excisional LN biopsy
– Lymph node architecture
– Enough tissue to do additional testing
• Diagnostic sample should be reviewed by expert
hematopathologist
 Staging – Really simple
• Standard staging includes:
– A history and physical exam
– Bloodwork (usually CBC and chemistry tests)
– CT scans (neck, chest, abdomen and pelvis)
– Functional imaging (gallium or PET scan)
– Bone marrow aspirate and biopsy (if stage III/IV
disease or B symptoms)
Staging of Lymphoma – Ann Arbor
System
Stage I Stage II Stage III Stage IV

• A – absence of any “B” symptoms

• B – Unexplained fever, drenching sweats or weight loss
• Bulky > 10 cm mass on imaging
 Prognostic Score in HL discriminates
Overall Survival

Age >45
Stage IV
Male
Albumin < 40
WBC > 15
ALC < 0.6
HB < 105

Moccia JCO 2012

 Decisions regarding Therapy
• Modified for specific instances but not individualized
yet

• Balance potential toxicity against effectiveness

• Remission ≠ Cure – why?

– Remission is just a state at a specific time
– Cure is remission maintained forever
Treatment Philosophy in Hodgkin
Lymphoma
• Cure!
• In circumstances where cure rate is high
– ie. localized disease – minimize late effects
• When cure rate is not as high
– Consider more intensive treatment

IS MORE BETTER?
 Chemotherapy
• Works typically through a DNA damaging
mechanism – affects all growing cells
– Lymphoma Cells
– Blood Cells
– Lining of GI Tract
– Hair
• A systemic therapy – treatment travels everywhere
through the bloodstream
ABVD – Typical HL Chemotherapy
• ABVD is given every 2 weeks (A and B parts)
– 1 cycle = 2 treatments and is given over 4 weeks
– Adriamycin 25 mg/m2
– Bleomycin 10 u/m2
– Vinbastine 6 mg/m2
– Dacarbazine 375 mg/m2
 Radiation
• Applies to localized disease
• May not be used in all types of aggressive NHL
• Generally treatment is given daily for 4 weeks
(Monday to Friday X 4 weeks = 20 treatments or
“fractions”)
• Side effects based on the area that is being
radiated (skin and tissue beneath it)
• Doses of radiation are lower than those used in
solid cancers
Common Radiation Fields
 Combined modality Therapy
• Chemotherapy + Radiation = Combined Modality
Therapy
• This is our current standard treatment of localized
(limited stage) HL
• We do not routinely use radiation as part of the
treatment of widespread (advanced stage) HL but
may consider for bulky site of disease
 Hodgkin Lymphoma

• Cure rate in limited stage disease is 80-95%

• Cure rate in advanced stage disease is 65-80%
• Treatment has evolved over 30-40 years based on
application of multiple clinical trials
– Radiation initially then combination chemotherapy
– Subsequently more multi-drug regimens (MOPP or
MOPP/ABV) and now ABVD
 Limited HL – less treatment is just as
effective

• 2 cycles of ABVD and lower dose radiation is just

as effective as 4 cycles of ABVD and more RT
Engert NEJM 2010
 Limited HL – Less toxic treatment is
just as effective

• 4 cycles of ABVD and radiation is just as effective as 4 cycles of 7

drug chemotherapy and RT
Engert NEJM 2010
 Limited HL – Radiation may help
maintain remission

Meyer et al. JCO 2005

 Concerns about more intensive
regimens in HL
• Acute toxicities
– Low blood counts
– higher rates of transfusion and infection
• Late Toxicity
– Infertility
– Second Cancers
• Need longer follow-up to accurately understand
frequencies of late effects
– Other multi-drug regimen studies have NOT shown
benefits
 Treatment algorithm in Hodgkin
Lymphoma
• Limited stage disease (short course ABVD)
– Minimize toxicity
– Recommend radiation but balance toxicity (second
cancer, heart disease) against disease recurrence
• Smaller radiation field, lower dose
• Advanced stage disease (longer course ABVD)
– Lymphoma recurrence remains an important
concern
– More aggressive chemotherapy?
 What happens if primary treatment
doesn’t work?
• A minority of patients with HL!
– Primary refractory disease – lymphoma grows on
treatment or within 3 months of completion
– Relapsed disease – lymphoma grows after 3 months
of treatment
• Lymphoma is behaving aggressively – signs that
cancer cells have developed drug/radiation
resistance
– But this can be overcome – different drugs and
doses
 GHSG Transplant Trial – Autologous Transplant
improves Outcome in relapsed HL

Schmitz et al. Lancet 2002

 Transplant strategies vary center to center

• No studies demonstrate the superiority of one

approach over another – variation in:
– Type of second-line chemotherapy (ICE, GDP)
– Technique of mobilizing peripheral blood stem cells
– High dose therapy regimen of the transplant
– Role of radiation as part of second-line treatment

• Generally, lymphoma needs to respond to second-

line chemotherapy for transplant to be successful
A (Canadian) Transplant Strategy
• Second-line chemotherapy (GDP)
– Gemcitabine 1000 mg/2 day 1 and 8
– Dexamethasone 40 mg days 1-4
– Cisplatin 75 mg/m2 day 1
• Stem Cell Mobilization
– Cyclophosphamide 2 g/m 2 day 1
– Etoposide 200 mg/m 2 days 1-3
– Neupogen 10 ug/kg starting day 6
• High Dose Chemotherapy
– Etoposide 60 mg/kg day -4
– Melphalan 180 mg/m2day –3
– Stem Cell Infusion Day 0
PMH Treatment Policy – Limited Stage
Hodgkin Lymphoma
• Definition
– Stage IA (non Bulky)
– Stage II A (non Bulky)
• Treatment
– ABVD chemotherapy 2-4 cycles + Involved Field
Radiation (30 Gy) depending on amount of disease
and some lab parameters
PMH Treatment Policy – Advanced
Stage Hodgkin Lymphoma
• Definition
– Stage III or IV
– Any Stage with B symptoms
– Bulky Disease
• Treatment
– ABVD chemotherapy X 6-8 cycles
– Radiation if bulky site
PMH Treatment Policy – Relapsed /
Refractory Hodgkin Lymphoma
• ASCT eligible patients
– Second-line chemotherapy with GDP
– Mobilization of stem cells
– ASCT procedure
– Consider radiation if bulky disease pre-ASCT
• Non-ASCT eligible patients
– Alternate chemotherapy regimen
– Radiation
Summary – The Fundamentals of HL
• Confirm the diagnosis
• Accurate Staging
• Treatment is chemotherapy based (ABVD)
– Remember to think about radiation if the disease is
localized
• Second chance of cure with ASCT