Issues in Haematological Issues in Haematological Malignancy 2010Malignancy 2010

Prof. A H Goldstone CBEProf. A H Goldstone CBE

• AMLAML• ALLALL• CMLCML• CLLCLL

• MyelomaMyeloma• LymphomaLymphoma

There is more that can be achieved There is more that can be achieved almost everywhere and the PCTs almost everywhere and the PCTs

and Insurance Companies and Insurance Companies

are running scaredare running scared

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

AML – Acute Myeloid LeukaemiaAML – Acute Myeloid Leukaemia

• The elderly still do badlyThe elderly still do badly

• Targeted therapyTargeted therapy

anti CD33 (Mylotarg)anti CD33 (Mylotarg)

• RIC transplant for the older patient - (50-65)RIC transplant for the older patient - (50-65)

ALL – Acute Lymphoblastic ALL – Acute Lymphoblastic LeukaemiaLeukaemia

• Adults still do badlyAdults still do badly• Kids 90% survivalKids 90% survival• Adults 35% survivalAdults 35% survival

• Antibody treatment arrivesAntibody treatment arrives• Rituximab may also be useful in ALLRituximab may also be useful in ALL

• More transplant!-More transplant!-• Unrelated donors transplant increasingUnrelated donors transplant increasing• RIC (reduced intensity conditioning)RIC (reduced intensity conditioning)

CML – Chronic Myeloid LeukaemiaCML – Chronic Myeloid Leukaemia

• Arrival of tyrosine kinase inhibitors (TKIs)Arrival of tyrosine kinase inhibitors (TKIs)

• Imatinib (Glivec) “wonder drug” now Imatinib (Glivec) “wonder drug” now produces 90% 10 year survivalproduces 90% 10 year survival

• Probably needs to be continued indefinitely Probably needs to be continued indefinitely £25K/yr£25K/yr

• Very few patients now need transplantingVery few patients now need transplanting

CLL – Chronic Lymphocyte CLL – Chronic Lymphocyte LeukaemiaLeukaemia

• Strategy moves from “suppression” to Strategy moves from “suppression” to induction of remissioninduction of remission

• FCR (Fludarabine, Cyclophosphamide, FCR (Fludarabine, Cyclophosphamide, Rituximab)Rituximab)

• More complex treatment, more More complex treatment, more immunosuppression, more commitment of immunosuppression, more commitment of patientpatient

• Younger patients should be considered for Younger patients should be considered for transplant – this disease is sometime transplant – this disease is sometime CURABLE!CURABLE!

MyelomaMyeloma

• Drugs begin to be effectiveDrugs begin to be effective• ThalidomideThalidomide• Bortezomib (Velcade)Bortezomib (Velcade)• Lenalidomide (Revlimid)Lenalidomide (Revlimid)• Side effects are considerable and need close Side effects are considerable and need close

monitoringmonitoring• Outlook now increased from 2-3 yrs to 6-8 Outlook now increased from 2-3 yrs to 6-8

yrsyrs• Every patient of whatever age worthy of Every patient of whatever age worthy of

consideration of first line therapyconsideration of first line therapy

So you thought Lymphoma So you thought Lymphoma was a rare disease – was a rare disease –

not any morenot any more

Lymphoma is:-Lymphoma is:-

• The most common blood cancer, more The most common blood cancer, more common than leukaemia and myelomacommon than leukaemia and myeloma

• Most common cause of blood cancer Most common cause of blood cancer deathdeath

• 55thth leading cause of cancer death in men, leading cause of cancer death in men, 44thth in women in women

• Causes 11% of childhood cancersCauses 11% of childhood cancers

• Increasing 4%/yearIncreasing 4%/year

Non-Hodgkin’s Lymphoma Non-Hodgkin’s Lymphoma Incidence and Mortality RatesIncidence and Mortality Rates

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

areas of the UK 1984-1993areas of the UK 1984-1993

Lymphoma – A growing Lymphoma – A growing problem problem

Increasing incidence of NHLIncreasing incidence of NHL

Non-Hodgkin's Lymphoma

Hodgkin's Lymphoma

Australian Institute of Health

and Welfare 2000

The following table gives the estimated The following table gives the estimated numbers of new cases and deaths for each numbers of new cases and deaths for each

common cancer type:common cancer type:Cancer TypeCancer Type Estimated New Estimated New

CasesCasesEstimated DeathsEstimated Deaths

BladderBladder 68,81068,810 14,10014,100

Breast (Female-Male)Breast (Female-Male) 182,460-1,990182,460-1,990 40,480-45040,480-450

Colon and Rectal Colon and Rectal (Combined)(Combined)

148,810148,810 49,96049,960

EndometrialEndometrial 40,10040,100 7,4707,470

Kidney (Renal Cell) Kidney (Renal Cell) CancerCancer

46,23246,232 11,05911,059

Leukaemia (ALL)Leukaemia (ALL) 44,27044,270 21,71021,710

Lung (Including Lung (Including Bronchus)Bronchus)

215,020215,020 161,840161,840

MelanomaMelanoma 62,48062,480 8,4208,420

Non-Hodgkin’s Non-Hodgkin’s LymphomaLymphoma

66,12066,120 19,16019,160

PancreaticPancreatic 37,68037,680 34,29034,290

ProstateProstate 186,320186,320 28,66028,660

Skin (Nonmelanoma)Skin (Nonmelanoma) >1,000,000>1,000,000 <1,000<1,000

ThyroidThyroid 37,34037,340 1,5901,590

• 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 FiguresFacts and Figures

*US statistics

Ries LAG, et al. SEER Cancer Statistics Review, 1975-2000, National Cancer Institute. Bethesda, MD

Cancer Facts & Figures 2004, www.cancer.org

• 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

Lymphoma: Current ChallengesLymphoma: Current Challenges

• Continued increase in incidence 3-4% Continued increase in incidence 3-4% increase in annual incidence of NHL over last increase in annual incidence of NHL over last 2-3 decades2-3 decades

• Diverse disease made up of numerous Diverse disease made up of numerous subtypes. Careful patient selection necessary subtypes. Careful patient selection necessary to maximize treatment benefitto maximize treatment benefit

• Despite improvements in outcomes over the Despite improvements in outcomes over the past decade, some subgroups of NHL, in past decade, some subgroups of NHL, in particular, remain difficult to treatparticular, remain difficult to treat

• Development of newer treatment strategies Development of newer treatment strategies critical to improving outcomescritical 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: www.cmeinteractive.cancerconsultants.com/ShowArticle.aspx?ArticleID=2.

Non-Hodgkin Lymphoma: Non-Hodgkin Lymphoma: IncidenceIncidence

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;16:2780-2795.

Low Public Awareness of Low Public Awareness of LymphomaLymphoma

According to a study of lymphoma patients carried outin 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 Cause-specific Survival of NHL Study Patients Patients

(1974–1995)(1974–1995)C

um

ula

tive

su

rviv

al (

%)

Time (years)

100

80

60

40

20

00 5 10 15 20 25 30

Aggressive NHL

Indolent NHL

Other reasons for Other reasons for incidence of NHLincidence of NHL

• Many are age-relatedMany are age-related

• Auto-immune diseaseAuto-immune disease

• Environmental chemicalsEnvironmental chemicals

Lymphomas associated with Lymphomas associated with host susceptibility factorshost susceptibility factors

• Enteropathy – associated T-cell Lymphoma Enteropathy – associated T-cell Lymphoma - Genetics - Genetics - Gliadin allergy- Gliadin allergy

• Extranodal and systemic EBV + T/Non-Hodgkin’s Extranodal and systemic EBV + T/Non-Hodgkin’s LymphomaLymphoma

- Genetics- Genetics• Hepatosplenic T-cell Lymphoma Hepatosplenic T-cell Lymphoma

- Immunosuppression + chronic - Immunosuppression + chronic autogenic autogenic stimulation stimulation

• Burkitt Burkitt - Malaria + HIV- Malaria + HIV

• Post transplant Lymphoma Post transplant Lymphoma - Iatrogenic immunosuppression- Iatrogenic immunosuppression

HIV – associated LymphomasHIV – associated Lymphomas• DLBCDLBC

• Primary CNS LymphomaPrimary CNS Lymphoma

• BurkittBurkitt

• Primary Effusion LymphomaPrimary Effusion Lymphoma

• 600 fold increase for immunoblastic Lymphoma 600 fold increase for immunoblastic Lymphoma

• 14 fold xs for low grade Non-Hodgkin’s 14 fold xs for low grade Non-Hodgkin’s LymphomaLymphoma

• Hodgkin’s LymphomaHodgkin’s Lymphoma

Lymphoma associated with Lymphoma associated with Infectious AgentsInfectious Agents

• Nasal, cutaneous NK/TNasal, cutaneous NK/TEBVEBV

• Adult T-cell leukaemia LymphomaAdult T-cell leukaemia LymphomaHTLV1HTLV1

• Marginal zoneMarginal zoneH.pylori, campylobacterH.pylori, campylobacter, Hepatitis C, Hepatitis C

• Primary effusion LymphomaPrimary effusion LymphomaHHV-8/KSHVHHV-8/KSHV

A Cancer in DisguiseA Cancer in Disguise

• Symptoms are commonly seen in other, less Symptoms are commonly seen in other, less serious illnesses, such as influenza or other viral serious illnesses, such as influenza or other viral infections and are often overlookedinfections and are often overlooked

• Symptoms can appear anywhere in the bodySymptoms can appear anywhere in the body

Diagnosis of NHL

• Physical examinationPhysical examination• Chest X-rayChest X-ray• UltrasoundUltrasound• CT scan & PET ScanCT scan & PET Scan• Bone marrow biopsyBone marrow biopsy• Blood test, incl. cell surface marker phenotypeBlood test, incl. cell surface marker phenotype

Sometimes:Sometimes:• CytogeneticsCytogenetics• Gene rearrangementGene rearrangement• Liver biopsyLiver biopsy• MRI MRI

The greatest increase is in The greatest increase is in skin Lymphomaskin Lymphoma

NHL and occupationNHL and occupation

CAUTIONCAUTION

• Is the rise apparent and not real?Is the rise apparent and not real?

• Are we just better at finding and Are we just better at finding and diagnosing?diagnosing?

New diagnostic and therapeutic New diagnostic and therapeutic areas in Lymphomaareas in Lymphoma

• PET scanningPET scanning- - diagnosisdiagnosis- activity- activity- prognosis- prognosis

• ImmunohistochemistryImmunohistochemistry

• Targeted therapiesTargeted therapies- eg Rituximab- eg Rituximab

• Stem cell transplantationStem cell transplantation

The Rationale for Transplant The Rationale for Transplant in Lymphomain Lymphoma

AutoAuto• DoseDose

Conventional AlloConventional Allo• DOSEDOSE• ALLO EFFECTALLO EFFECT

Mini-AlloMini-Allo• DOSEDOSE• ALLO EFFECTALLO EFFECT

PET+ve after 2# ABVD predictive PET+ve after 2# ABVD predictive of treatment failure in HLof 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 LymphomaHodgkin Lymphoma

• Normally 5 x Normally 5 x lessless frequent than NHL frequent than NHL

• More frequent also in HIV patientsMore frequent also in HIV patients

• Now 2 subtypesNow 2 subtypes

- Classical- Classical

- NLPH (nodular lymphocytic - NLPH (nodular lymphocytic predominant)predominant)

Radiotherapy in Hodgkin’sRadiotherapy in Hodgkin’s

• Much less frequently used todayMuch less frequently used today

• Major problem with Breast Cancer after Major problem with Breast Cancer after “Mantle” field“Mantle” field

• Chemo more toxic short term but less toxic Chemo more toxic short term but less toxic long termlong term

• Fertility issues with new escalated chemoFertility issues with new escalated chemo

• Issues of “Survivorship”Issues of “Survivorship”

Why Targeted Therapies?Why Targeted Therapies?• Need to improve outcomes for all types of lymphomaNeed to improve outcomes for all types of lymphoma

-Improve cure rate for aggressive lymphomas-Improve cure rate for aggressive lymphomas

-Maintain remission for indolent disease-Maintain remission for indolent disease

-Eradicate minimal residual disease-Eradicate minimal residual disease

-Decrease relapse rate for all lymphoma-Decrease relapse rate for all lymphoma

• Lymphoma frequently associated with deregulated Lymphoma frequently associated with deregulated cellular pathways of differentiation, proliferation or cellular pathways of differentiation, proliferation or survivalsurvival

-Molecules involved in these aberrations provide -Molecules involved in these aberrations provide rational targets for selective therapiesrational targets for selective therapies

• Agents generally well tolerated and easily combined Agents generally well tolerated and easily combined with other therapies (eg, chemotherapy, radiotherapy)with other therapies (eg, chemotherapy, radiotherapy)

Coiffier B. Semin Oncol. 2004;31(1 suppl 2):7-11.

Targeting the Cell SurfaceTargeting the Cell Surface

slg

DR

CD19 CD20CD22

B Lymphocyte

Major ThemesMajor Themes

• Effectiveness without toxicity.Effectiveness without toxicity.

• Dose escalationDose escalation

• Exploitation of passive & active Exploitation of passive & active immunotherapyimmunotherapy

• The ongoing management of the The ongoing management of the patient with active disease is vitalpatient with active disease is vital

• Lymphoma, Myeloma + CLL are of Lymphoma, Myeloma + CLL are of major importance in this regardmajor importance in this regard

• ““Living with Cancer” has truly Living with Cancer” has truly arrived in many haematological arrived in many haematological malignanciesmalignancies