Issues in Haematological Malignancy 2010 Prof. A H Goldstone CBE

AML AML ALL ALL CML CML CLL CLL Myeloma Myeloma Lymphoma Lymphoma

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

The patient over 70 years starts to get proper treatment!

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

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

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

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

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

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

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

Non-Hodgkin’s Lymphoma Incidence and Mortality Rates

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

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

The following table gives the estimated numbers of new cases and deaths for each common cancer type: Cancer Type Estimated New Cases Estimated Deaths Bladder68,81014,100 Breast (Female-Male) 182,460-1,99040, Colon and Rectal (Combined) 148,81049,960 Endometrial40,1007,470 Kidney (Renal Cell) Cancer 46,23211,059 Leukaemia (ALL) 44,27021,710 Lung (Including Bronchus) 215,020161,840 Melanoma62,4808,420 Non-Hodgkin’s Lymphoma 66,12019,160 Pancreatic37,68034,290 Prostate186,32028,660 Skin (Nonmelanoma) >1,000,000<1,000 Thyroid37,3401,590

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

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

Lymphoma: Current Challenges Continued increase in incidence 3-4% increase in annual incidence of NHL over last 2-3 decades 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 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 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 Development of newer treatment strategies critical to improving outcomes 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:

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

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

Cause-specific Survival of NHL Study Patients (1974–1995) Cumulative survival (%) Time (years) Aggressive NHL Indolent NHL

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

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

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

Lymphoma associated with Infectious Agents Nasal, cutaneous NK/TNasal, cutaneous NK/TEBV Adult T-cell leukaemia LymphomaAdult T-cell leukaemia LymphomaHTLV1 Marginal zoneMarginal zone H.pylori, campylobacter, Hepatitis C Primary effusion LymphomaPrimary effusion LymphomaHHV-8/KSHV

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 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 Symptoms can appear anywhere in the body

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

The greatest increase is in skin Lymphoma

NHL and occupation

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

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

The Rationale for Transplant in Lymphoma Auto Dose Dose Conventional Allo DOSE DOSE ALLO EFFECT ALLO EFFECTMini-Allo DOSE DOSE ALLO EFFECT ALLO EFFECT

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)

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

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

Why Targeted Therapies? Need to improve outcomes for all types of lymphoma 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 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) Agents generally well tolerated and easily combined with other therapies (eg, chemotherapy, radiotherapy) Coiffier B. Semin Oncol. 2004;31(1 suppl 2):7-11.

Targeting the Cell Surface slg DR CD19 CD20 CD22 B Lymphocyte

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

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