Issues in Haematological Malignancy 2010 Prof. A H Goldstone CBE

1. Issues in Haematological Malignancy 2010Prof. A H Goldstone CBE

2. AML • ALL • CML • CLL • Myeloma • Lymphoma

3. There is more that can be achieved almost everywhere and the PCTs and Insurance Companies are running scared

4. The patient over 70 years starts to get proper treatment!

5. AML – Acute Myeloid Leukaemia • The elderly still do badly • Targeted therapy anti CD33 (Mylotarg) • RIC transplant for the older patient - (50-65)

6. ALL – Acute Lymphoblastic Leukaemia • Adults still do badly • Kids 90% survival • Adults 35% survival • Antibody treatment arrives • Rituximab may also be useful in ALL • More transplant!- • Unrelated donors transplant increasing • RIC (reduced intensity conditioning)

7. CML – Chronic Myeloid Leukaemia • Arrival of tyrosine kinase inhibitors (TKIs) • Imatinib (Glivec) “wonder drug” now produces 90% 10 year survival • Probably needs to be continued indefinitely £25K/yr • Very few patients now need transplanting

8. CLL – Chronic Lymphocyte Leukaemia • Strategy moves from “suppression” to induction of remission • FCR (Fludarabine, Cyclophosphamide, Rituximab) • More complex treatment, more immunosuppression, more commitment of patient • Younger patients should be considered for transplant – this disease is sometime CURABLE!

9. Myeloma • Drugs begin to be effective • Thalidomide • Bortezomib (Velcade) • Lenalidomide (Revlimid) • Side effects are considerable and need close monitoring • Outlook now increased from 2-3 yrs to 6-8 yrs • Every patient of whatever age worthy of consideration of first line therapy

10. So you thought Lymphoma was a rare disease – not any more

11. Lymphoma is:- • The most common blood cancer, more common than leukaemia and myeloma • Most common cause of blood cancer death • 5th leading cause of cancer death in men, 4th in women • Causes 11% of childhood cancers • Increasing 4%/year

12. Non-Hodgkin’s Lymphoma Incidence and Mortality Rates

13. Age-specific incidence rate (case numbers per 100,000 per year) for cases of NHL collected from geographically defined areas of the UK 1984-1993

14. Lymphoma – A growing problem Increasing incidence of NHL Non-Hodgkin's Lymphoma Hodgkin's Lymphoma Australian Institute of Health and Welfare 2000

15. The following table gives the estimated numbers of new cases and deaths for each common cancer type:

16. Approximately 1.5 million people worldwide are living with non-Hodgkin’s lymphoma (NHL) • It is estimated that 300,000 people die each year from the disease

17. Facts and Figures • 1 new case of lymphoma is diagnosed every 9 minutes* • 1 in 50 people will develop lymphoma* • 81% increase in incidence of NHL between 1973-1990 • Overall survival at 5 years is 50%-60% for all non-Hodgkin’s lymphomas • *US statistics • Ries LAG, et al. SEER Cancer Statistics Review, 1975-2000, National Cancer Institute. Bethesda, MD • Cancer Facts & Figures 2004, www.cancer.org

18. Lymphoma: Current Challenges Müller A et al. Ann Hematol. 2005;84:1-12; Hagemeister FB. New agents in the treatment of lymphomas: which ones will succeed. Available at: www.cmeinteractive.cancerconsultants.com/ShowArticle.aspx?ArticleID=2. • Continued increase in incidence 3-4% increase in annual incidence of NHL over last 2-3 decades • Diverse disease made up of numerous subtypes. Careful patient selection necessary to maximize treatment benefit • Despite improvements in outcomes over the past decade, some subgroups of NHL, in particular, remain difficult to treat • Development of newer treatment strategies critical to improving outcomes

19. Non-Hodgkin Lymphoma: Incidence Other subtypes with a frequency ≤ 2% (9%) Peripheral T-cell (6%) Follicular lymphoma (22%) Mantle cell (6%) Small lymphocytic lymphoma (6%) Composite lymphomas (13%) Marginal zone B-cell lymphoma MALT type (5%) Marginal zone B-cell lymphoma nodal type (1%) Diffuse B-cell lymphoma (31%) Lymphoplasmacytic lymphoma (1%) Armitage et al. J Clin Oncol. 1998;16:2780-2795.

20. Low Public Awareness of Lymphoma According to a study of lymphoma patients carried out in 2003: • Prior to diagnosis almost all respondents (97.5%) had been unaware of non-Hodgkin’s lymphoma • Many patients with non-Hodgkin’s lymphoma do not have an accurate understanding of the disease • Up to 35% of respondents were vague about the body parts affected by non-Hodgkin’s lymphoma • Half of respondents were unaware of their specific diagnosis

21. Cause-specific Survival of NHL Study Patients (1974–1995) 100 80 60 40 20 0 Cumulative survival (%) Aggressive NHL Indolent NHL 0 5 10 15 20 25 30 Time (years)

22. Other reasons for incidence of NHL • Many are age-related • Auto-immune disease • Environmental chemicals

23. Lymphomas associated with host susceptibility factors • Enteropathy – associated T-cell Lymphoma - Genetics - Gliadin allergy • Extranodal and systemic EBV + T/Non-Hodgkin’s Lymphoma - Genetics • Hepatosplenic T-cell Lymphoma - Immunosuppression + chronic autogenic stimulation • Burkitt - Malaria + HIV • Post transplant Lymphoma - Iatrogenic immunosuppression

24. HIV – associated Lymphomas • DLBC • Primary CNS Lymphoma • Burkitt • Primary Effusion Lymphoma • 600 fold increase for immunoblastic Lymphoma • 14 fold xs for low grade Non-Hodgkin’s Lymphoma • Hodgkin’s Lymphoma

25. Lymphoma associated with Infectious Agents • Nasal, cutaneous NK/T EBV • Adult T-cell leukaemia Lymphoma HTLV1 • Marginal zone H.pylori, campylobacter, Hepatitis C • Primary effusion Lymphoma HHV-8/KSHV

26. A Cancer in Disguise • Symptoms are commonly seen in other, less serious illnesses, such as influenza or other viral infections and are often overlooked • Symptoms can appear anywhere in the body

27. Diagnosis of NHL • Physical examination • Chest X-ray • Ultrasound • CT scan & PET Scan • Bone marrow biopsy • Blood test, incl. cell surface marker phenotype Sometimes: • Cytogenetics • Gene rearrangement • Liver biopsy • MRI

28. The greatest increase is in skin Lymphoma

29. NHL and occupation

30. CAUTION • Is the rise apparent and not real? • Are we just better at finding and diagnosing?

31. New diagnostic and therapeutic areas in Lymphoma • PET scanning - diagnosis - activity - prognosis • Immunohistochemistry • Targeted therapies - eg Rituximab • Stem cell transplantation

32. The Rationale for Transplant in Lymphoma Auto • Dose Conventional Allo • DOSE • ALLO EFFECT Mini-Allo • DOSE • ALLO EFFECT

33. PET+ve after 2# ABVD predictive of treatment failure in HL PET-2-ve: 2yr FFS 96% (n=161) PET-2+ve: 2yr FFS 14% (n=41) Gallamini et al, ASH 2006 (n=202)

34. Hodgkin Lymphoma • Normally 5 x less frequent than NHL • More frequent also in HIV patients • Now 2 subtypes - Classical - NLPH (nodular lymphocytic predominant)

35. Radiotherapy in Hodgkin’s • Much less frequently used today • Major problem with Breast Cancer after “Mantle” field • Chemo more toxic short term but less toxic long term • Fertility issues with new escalated chemo • Issues of “Survivorship”

36. Why Targeted Therapies? • Need to improve outcomes for all types of lymphoma -Improve cure rate for aggressive lymphomas -Maintain remission for indolent disease -Eradicate minimal residual disease -Decrease relapse rate for all lymphoma • Lymphoma frequently associated with deregulated cellular pathways of differentiation, proliferation or survival -Molecules involved in these aberrations provide rational targets for selective therapies • Agents generally well tolerated and easily combined with other therapies (eg, chemotherapy, radiotherapy) Coiffier B. Semin Oncol. 2004;31(1 suppl 2):7-11.

37. Targeting the Cell Surface slg CD19 CD20 CD22 DR B Lymphocyte

38. Major Themes • Effectiveness without toxicity. • Dose escalation • Exploitation of passive & active immunotherapy

39. The ongoing management of the patient with active disease is vital • Lymphoma, Myeloma + CLL are of major importance in this regard • “Living with Cancer” has truly arrived in many haematological malignancies