Audio and slides for this presentation are available on YouTube: http://youtu.be/rAgnoymx0DQ Dr. Ann LaCasce talks about the various treatments for lymphoma, including chemotherapy and radiation therapy methods, as well as the role of clinical trials. This presentation was first given at a lymphoma workshop presented by the Lymphoma Research Foundation (www.lymphoma.org).

1. Overview of Therapy of
Lymphoma
Ann S. LaCasce, MD
Director, Dana-Farber/Partners CancerCare Hematology-Medical Oncology
Fellowship Program
Assistant Professor of Medicine, Harvard Medical School
March 23, 2013

2. Agenda
• History of lymphoma therapy
• Current chemotherapy agents
• Antibody based therapies
• Overview of radiation
• Standard therapy
– Diffuse large B-cell lymphoma
– Indolent lymphoma
– CLL/SLL
– Hodgkin lymphoma
• Clinical trials

3. History of lymphoma
chemotherapy
Nitrogen mustard
Used to treat HL
1942
FDA approves
cyclophosphamide
1959
Farber treats ALL
with methotrexate
1948
POMP induces
remissions in ALL
DeVita et al cure lymphoma
with combination chemo
1970
1965
Rituximab approved
for B-cell NHL
Brentuximab approved
for relapsed HL
and CD30+ T-cell NHL
1997
2011

4. History of cancer

5. Mustard gas
Soldiers exposed
to mustard gas
had destruction of
lymphoid tissue and
bone marrow

6. History of chemotherapy
1940’s pharmacologists
Gillman and Goodman
recruited to investigate
chemical warfare

7. First chemotherapy
• Goodman and Gillman administered
nitrogen mustard to mice with lymphoid
tumors
• In 1942, Gustav Lindskog (thoracic
surgeon) successfully treated a patient
with non-Hodgkin’s lymphoma with
nitrogen mustard

8. Sidney Farber
In 1948, gave aminopterin
(folate antagonist) leading
to first remission in a pediatric
patient with ALL

9. Combination chemotherapy
Frei, Holland, and Freireich
hypothesized strategy for
combination chemotherapy
based on treatment of TB
with multiple drugs to
develop therapy in ALL

10. MOPP for lymphoma
Canellos and DeVita – MOPP which cured patients with
Hodgkin and non-Hodgkin lymphoma

11. Chemotherapy drugsChemotherapy drugs
Chemotherapy drugs kill dividing cells

12. Side effects of chemotherapy
• Kills the body’s normal rapidly dividing
cells:
– Bone marrow (myelosuppression)
– Digestive tract (mucositis)
– Hair follicles (alopecia)

13. Common classes of chemotherapy
in lymphoma
• Alkylators (cytoxan)
• Anthracyclines
(adriamycin)
• Anti-metabolites
(fludarabine)
• Vinca alkaloids
(vincristine, vinblastine)

14. Radiation

15. Discovery of X-ray
Wilhelm Röentgen
1895

16. Marie Curie
Late 1800’s
discovered polonium
and radium and led
first studies of radiation
to treat cancer

17. External beam radiotherapy
(XRT)
Currently delivered via linear accelerators
Causes cellular DNA damage
Use imaging to plan delivery of dose while
sparing normal tissues
Given over days (fractionation) to allow for
recovery of normal cells
Many lymphomas very sensitive to XRT
allowing use of lower doses than in solid
tumors

18. Involved Field Radiation

19. Antibodies,
Kinase inhibitors
Newer therapies

20. B-cellB-cell
CD20 CD20
CD20
Punch holes
Direct killing
How does rituximab work?
Recruit immune
cells

21. Brentuximab Vedotin
Drug (MMAE)
Anti-CD30 antibody
Binds to CD30
MMAE disrupts
microtubule network
Internalized and goes
to lysosome
MMAE is released
CD-30

22. Diffuse large B-cell lymphoma
• CHOP (cytoxan, adriamycin, vincristine,
prednisone) standard treatment since
1970’s
• More aggressive regimens developed
• More toxic
• No more effective
• RCHOP superior to CHOP

23. Indolent lymphomas
• Early stage disease – radiation
• Advanced stage disease:
• Observation
• Rituximab
• Rituximab plus chemotherapy
• Clinical trials

24. Chronic lymphocytic leukemia
• Observation
• Rituximab plus fludarabine with or without
cyclophosphamide
• Chlorambucil with or without rituximab
• Rituximab plus bendamustine
• Clinical trials

25. Hodgkin lymphoma - chemotherapy
• ABVD (adriamycin, bleomycin, vinblastine,
dacarbazine)
• Generally well tolerated
• Typically no infertility
• Does not effect stem cells
• Brentuximab vedotin - relapsed setting with
on-going studies upfront

26. Hodgkin lymphoma - RT
• Used as part of therapy for early stage
disease in some patients
• Used for bulky areas in advanced disease

27. Novel pathways in NHL

28. What is a clinical trial?
• Test the safety and how well a new drug
works in a particular disease
• Test the safety and how well an
established drug works in a new disease
• Compare a new medication to standard
treatment
• Goal for FDA approval of a drug for a
particular use

29. Clinical trials

30. Phase III clinical trial
In cancer studies, typically no
placebo except in certain
circumstances

31. Oversight clinical trials
• Studies may be conducted by pharmaceutical
companies, single or group of investigators
(including cooperative groups)
• Careful oversight to ensure ethical and safe
conduct
• Institutional Review Board (IRB)
– Evaluate protocol
– Review consent form
– Oversee ongoing conduct of trial

32. Summary
• We’ve come a long way since nitrogen
mustard
• Combination chemotherapy remains part of
many lymphoma regimens
• Radiation is also an important modality for
lymphoma
• Rituximab has been a critical addition to
treatment in NHL
• New targeted therapies are under active
investigation