12/7/2012 1 12/7/2012 Chronic Myeloid Leukemia Chronic Myeloid - - PDF document

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Neil Shah, MD PhD Division of Hematology/Oncology UCSF School of Medicine San Francisco, California

Chronic Myeloid Leukemia Diagnosis and Treatment Update Chronic Myeloid Leukemia Diagnosis and Treatment Update CML - clinical features CML - clinical features

• approximately 4500 new US cases per year
• median age at presentation: 53 years
• men comprise approximately 60 percent of cases
• disease is clinically divided into two general phases

chronic phase accelerated/ blast crisis phase

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CML - chronic phase CML - chronic phase

• approximately 40 percent of patients are without

symptoms (fatigue)

• 85 percent of newly diagnosed CML cases are in

chronic phase

• median duration of chronic phase (prior to 2000)

approximately 4-6 years

After 2000 - unknown, greater than 10 years

• interventions can lead to durable responses in chronic

phase

Medical therapy (interferon, TKIs) Stem cell transplantation

Clinical Course: Phases of CML

Chronic phase Median 4–6 years stabilization Accelerated phase Median duration up to 1 year Blastic phase (blast crisis) Median survival 3–6 months Advanced phases Cooperating mutations* *loss of p53; trisomy 8; second Ph; PAX5 deletion; others

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The Philadelphia chromosome is nearly always The Philadelphia chromosome is nearly always detected in patients with CML detected in patients with CML The Philadelphia chromosome is nearly always The Philadelphia chromosome is nearly always detected in patients with CML detected in patients with CML

Forrest et al, 2008; Bakshi et al, 2008; Image courtesy of Larry Beauregard, Jr., PhD.

46,XX,t(9;22)(q34;q11.2)

Ph chromosome Ph chromosome BCR BCR-

• ABL

ABL (activated activated tyrosine kinase) tyrosine kinase) BCR BCR ABL ABL

CML CML

The Philadelphia (Ph) Chromosome Results in the BCR-ABL Fusion Gene The Philadelphia (Ph) Chromosome Results in the BCR-ABL Fusion Gene

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CML - diagnosis CML - diagnosis

• Bone marrow biopsy should be performed at the time
• f suspected diagnosis
• The presence of the Philadelphia chromosome

translocation or other strong evidence of the BCR- ABL fusion gene is required to make the diagnosis of CML

CML was the first cancer to be treated with a tyrosine kinase inhibitor (TKI) CML was the first cancer to be treated with a tyrosine kinase inhibitor (TKI)

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Imatinib (Gleevec) - Clinical Efficacy

Phase III Trials (Chronic Phase CML)

Treatment

Imatinib Hematologic Major Cytogenetic

Response Rate (%)

55 20 Interferon + Ara-C 83 94

O

• Brien et al, NEJM, 2003

FDA Approval, May 2001

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IMATINIB AS FRONTLINE THERAPY FOR CML IMATINIB AS FRONTLINE THERAPY FOR CML

7-

• 8 year update of newly

8 year update of newly-

• diagnosed

diagnosed Chronic Phase CML patients treated Chronic Phase CML patients treated with 400 mg daily imatinib with 400 mg daily imatinib

OBrien et al. ASH 2008, Abstract 186

• Overall Survival (ITT Principle): Imatinib Arm

Estimated overall survival at 8 years is 85% (93% considering only CML-related deaths) Survival: deaths associated with CML Overall Survival % Without Event 10 20 30 40 50 60 70 80 90 100 Months Since Randomization

12 24 36 48 60 72 84 96

Deininger et al. ASH 2009, Abstract 1126

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Sustained CCyR

• n study: 53%

No CCyR: 17%* Lost CCyR: 15%* Safety: 5%* Lost regained CCyR: 3% CCyR +

• ther: 7%

Expectations on Imatinib: IRIS 8-Yr Update Shows 37% Have Unacceptable Outcome

*Unacceptable outcome. Deininger M, et al. ASH 2009. Abstract 1126.

• Most Frequently Reported AEs: First-Line Imatinib

Most Common Adverse Events (by 5 Years) All Grade AEs Patients, % Grade 3/4 AE

• s

Patients %

Superficial Edema 60 2 Nausea 50 1 Muscle cramps 49 2 Musculoskeletal pain 47 5 Diarrhea 45 3 Rash/skin problems 40 3 Fatigue 39 2 Headache 37 <1 Abdominal pain 37 4 Joint pain 31 3

• Only Serious Adverse Events (SAEs) were collected after 2005
• Grade 3/4 adverse events decreased in incidence after years 1-2

OBrien et al. ASH 2008, Abstract 186

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Long-Term Adherence to Imatinib Is Critical for Achieving Molecular Response

Adherence to imatinib tracked for 3 months in 87 consecutive CML patients with CCyR using microelectronic monitoring devices

Marin D, et al. J Clin Oncol. 2010;28:2381-2388.

MMR CMR

Probability of MMR 0.8 1.0 Mos Since Start of Imatinib Therapy 0.6 0.4 0.2 6 12 18 24 30 36 42 48 54 60 66 72 P < .001 Adherence > 90% (n = 64) Adherence 90% (n = 23) Probability of CMR 0.8 1.0 Mos Since Start of Imatinib Therapy 0.6 0.4 0.2 6 12 18 24 30 36 42 48 54 60 66 72 P = .002 Adherence > 90% (n = 64) Adherence 90% (n = 23)

Imatinib - Conclusions Imatinib - Conclusions

• Imatinib is effective for a large proportion of chronic phase

CML patients

• 85% overall survival with imatinib exceeds that of all other

CML therapies, with 7% patients dying from CML after eight years

• 82% of patients treated with imatinib achieved a CCyR

55% of all imatinib randomized patients are still on study

treatment, and nearly all of these are in CCyR

• Responses are typically durable, and the annual risk of

progression generally decreases with time

• Adherence appears to be critical for achieving optimal

responses

• While many patients have side effects, there have been no

new concerning safety findings with long term follow-up

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Chronic Phase CML – response definitions Chronic Phase CML – response definitions

• Complete hematologic response: normal white blood

cell count and differential, platelet count not elevated

• Complete cytogenetic response (CCyR): lack of Ph

chromosome in at least 20 bone marrow metaphases

Major cytogenetic response (MCyR): 35% Ph

metaphases

• Major molecular response (MMR): three log (1000-

fold) reduction in BCR-ABL transcript level from baseline

Complete molecular response (CMR): BCR-ABL

no longer detectable by PCR

NCCN – monitoring guidelines NCCN – monitoring guidelines

• Complete blood count and differential should be

performed regularly

• Molecular monitoring of BCR-ABL levels in the blood

by PCR should be performed every three months for at least the first 3 years after initiating treatment

• Bone marrow biopsy should be performed:

If a one-log reduction level in BCR-ABL is not

achieved at 3 months

After 12 months, in any patient who has not had a

documented CCyR or MMR

In the event of loss of response (one-log increase

in PCR) or disease transformation

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Why do some patients not achieve deep responses on imatinib? Why do some patients lose an initial response despite continuing imatinib? Why do some patients not achieve deep responses on imatinib? Why do some patients lose an initial response despite continuing imatinib? Imatinib Failure - Causes Imatinib Failure - Causes

• Drug-resistant mutations in BCR-ABL develop (most common)

Close to 100 different drug-resistant mutations have been

identified in patients with resistant disease

• BCR-ABL overexpression develops
• Apparent lack of normal hematopoietic stem cells
• Non-adherence to treatment
• Undefined mechanisms

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Imatinib Failure – Treatment Options Imatinib Failure – Treatment Options

• Second-generation TKIs

Dasatinib Nilotinib Bosutinib

• These drugs are vulnerable to about 5 drug-resistant

mutations

• These drugs are ineffective against the imatinib-resistant

T315I mutation

• Omacetaxine (protein synthesis inhibitor)
• Interferon
• Stem cell transplantation
• Clinical trial

Imatinib Failure – Response Rates Imatinib Failure – Response Rates

• TKIs:

Dasatinib: 50% CCyR; 42% MMR Nilotinib: 45% CCyR; 28% MMR Bosutinib: 41% CCyR; 31% MMR

• These drugs are vulnerable to about 5 drug-resistant

mutations

• These drugs are ineffective against the imatinib-resistant

T315I mutation

• Omacetaxine (protein synthesis inhibitor) in T315I+ patients:

16% CCyR; 13% MMR

• Interferon (anecdotal experience)
• Stem cell transplantation
• Clinical trial (ponatinib, active against T315I mutation)

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Second Generation TKIs for Previously Untreated CP-CML Second Generation TKIs for Previously Untreated CP-CML

• Nilotinib and dasatinib are superior to imatinib for

achieving rapid complete cytogenetic and major molecular responses in patients with newly diagnosed chronic phase CML

• Nilotinib and dasatinib are clinically vulnerable to fewer

drug-resistant mutations, and appear to protect against disease transformation better than imatinib

• The tolerability of nilotinib and dasatinib appears to be

equivalent to imatinib

• Many CML specialists prefer initiating second

generation TKIs in newly diagnosed chronic phase CML patients

Discussing Your Disease With Your Health Care Provider Discussing Your Disease With Your Health Care Provider

• Ensure that you have had all recommended diagnostic tests

(bone marrow biopsy, etc) prior to initiating treatment

• Realize that there is a choice of TKIs for first line treatment

(imatinib, nilotinib, dasatinib)

• If you are encountering bothersome treatment-related side

effects, there are many treatment alternatives

• Ensure that your disease is being adequately monitored, and

treatment is changed if you do not meet treatment milestones (1-log reduction in BCR-ABL transcript level or MCyR at 3 months, MMR or CCyR at 12 months), or if there is loss of response despite continuing to take medication

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In Most Cases, Chronic Phase CML is a Chronic Condition In Most Cases, Chronic Phase CML is a Chronic Condition

• Realize that the expected treatment outlook for chronic phase

CML patients is very favorable, provided that adequate response can be achieved and maintained

It is expected that most patients can expect to live a normal

lifespan on TKI therapy

• From a psychological perspective, prepare yourself for a

marathon rather than a sprint

• If you are responding well to treatment but are experiencing

quality of life issues, realize that there are many treatment

• ptions

Communicate concerns with your health care provider

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