The National CML Society

2012 CML UPDATE“What’s New? What’s Coming?”

Luke Akard MDCo-Director Indiana Blood and

Marrow Transplantation Program

Ph + CML Clinical Issues• About 5000 cases per year in the US• Incidence increases with age

– About half of patients are over age 65– More frequent in men: 1.9:1 ration– Incidence 1.5 per 100,000 per year

• Survival has improved over the past decade• Most are asymptomatic, 85% chronic phase at

diagnosis

CML Overview• Malignant bone marrow disease

– Increased numbers of bone marrow cells– Increased numbers of mature white blood cells in the

blood stream, – Often with an increase in the red cells and platelets as

well

• In 1961 the Philadelphia Chromosome was found to be associated with CML

Chromosome analysis—requires cultured cells analyzed in metaphase

DNA

RNA

Protein

CML Overview• Three phases of disease

– Chronic Phase 3-5 years– Accelerated Phase 3-18 months– Blast Phase 3-6 months

• Treatment overview (non-HSCT)– 1970s chemotherapy busulfan, hydroxyurea– 1980’s-1990’s interferon +/- Ara-C– 2000 imatinib– 2006, 2007 dasatinib, nilotinib

IRIS Trial: 5 Year Response to Gleevec

Druker B et al. N Engl J Med 2006;355:2408-2417

IRIS trial data from the first 6 years of Imatinib as initial therapy of CML• At 6 years, 98% of patients will have had a

complete hematologic response, 88% OS• 83% will have had a complete cytogenetic response• What about loss of response or failures?

Year EventsAP/BC

1 3.3% 1.5% 2 7.5 2.8

3 4.8 1.6 4 1.5 0.9

5 0.9 0.6 6 0.4 0.0

Hochhaus et al Blood 110:15a, 2007

Imatinib Has Changed CML Monitoring

Complete hematologic response

Complete cytogenetic response

Major molecular response

Hematologic Response

• Complete CHRPlatelets < 450,000, WBC < 10,000, no immature

granulocytes or basophils, no spleen• Anything less is not complete• LeukemiaNet guidelines for CBC

– Every 2 weeks until CHR confirmed– Every 3 months thereafter

• If not in CHR at 3 months on Gleevec, virtually no chance of responding to it.

Baccarani et al Blood 108:1809, 2006

Cytogenetic Response• Bone Marrow Exam (vs. blood FISH)• Complete: Ph+ 0% CCyR• Partial: Ph+ 1%-35% • Minor: 36%-65%• Minimal: 66%-95%• None: Ph+ >95%• Major: Complete + partial MajCyR• LeukemiaNet guidelines for monitoring

– Baseline then every 6 months until CCyR then every 12 months

IRIS trial data: Cytogenetic Response

• Impact of failure to respond to imatinibSurvival:– No MCyR @ 12 months: 81% vs 97% 5y OS– No CyCR @ 18 months: 90% vs 99% 5y OS– No MCyR @ 18 months: 80% vs. 95% 5y OS

• Future response if stay on imatinib:– No CyR at 6 months, <20% chance CCyR– If PCyR @ 12 months, 64% likely to obtain CCyR– If no MCyR @ 12 months, still 36% obtain CCyr

Fluorescent in situ hybridization (FISH) does not require culturedCells in metaphase

Molecular Response• Complete: no transcript detectable• Major: <=0.10 (3 log or 1000 fold decrease)

– Requires quantitative pcr for bcr-abl to assess falling level

– Can not assess response, other than complete, from qualitative pcr bcr-abl.

• LeukemiaNet guidelines– Check every 3 months – Perform mutational analysis in case of failure or suboptimal

responseBaccarani et al Blood 108:1809, 2006

• Mutation analysis available using – Molecular MD, 2611 SW 3rd Ave. Portland OR 97201 tel 503-459-4975.

Molecular Testing in CML

Tube RNA cDNA

PCR products

1 DayReportExtraction RT

1 DaySequencing

1.0 Day

0.5 Day

0.5 DayLong range PCR

QRT- PCR

0.5 Day

LEVELSQRT-PCR

MUTATIONT315I FRET

MUTATIONSEQ

WT T315I

5%

IRIS study MMR definition*

03/0

506

/05

09/0

512

/05

03/0

604

/0605

/06

0.001

0.01

0.1

1

10

100

Date

BC

R-A

BL

/co

ntr

ol g

en

e (%

) MEDIAN STANDARDIZED BASELINEVALUE ON 30 UNTREATED PATIENTS

3 log reduction from standard baseline

* Hughes et al. NEJM 349; October 9 2003

• 4.5 log• 0.0032%

• 4 log• 0.01%

• 3 log• 0.10%

• Log reduction from

standardized baseline

• International Scale

MMR = 0.1% International Scale

Molecular Response to Imatinib

• IRIS trial 4 year follow-up data– MMoR 53% @ 1 year– CMoR 7% @ 1 year– MMoR 80% @ 4 years– 4 log reduction

• 22% 1 year• 44% 4 years

– If CCyR at 1 year, impact of MMoR• MMoR @ 12 months 100% 5 yr RFS• Less than MMoR @ 12 months 97% 5 yr RFS

Druker et al NEJM 355:2408-17, 2006

Side Effects of Imatinib Decrease Over Time

Superficial edemaNauseaMuscle crampsMusculoskeletal painDiarrheaRashFatigueHeadacheAbdominal pain

18% 15% 23% 21% 23% 14% 11% 12% 15%

5% 3% 7% 6% 5% 2% 3% 3% 3%

Adverse Event, All Grades 2yr 4yr

Kantarjian et al Blood 108:605a, 2006

Pregnancy and Imatinib

• 180 mothers 71% exposed in 1st trimester, 26% in all trimesters

• Outcome known in 125 pregnancies• 63 (50%) normal live infants• 35 elective abortions (3 after fetal defects)• 18 (14%) spontaneous abortions • 12 fetal abnormalities, including 4 cases with bony

defects Pye et al Blood 108:132a, 2006

• Half of pregnancies have progressive disease following interruption of imatinib Ault et al JCO 24:1204, 2006

Failure to respond to Imatinib

3 months6 months

12 months18 monthsAnytime

No HR stable/prog disLess than CHR, no CgR Ph+ > 95%Less than PCgR Ph+>35%Less than CCgRLoss of CHR, loss of CCgR

Suboptimal Response to Gleevec

3 months6 months12 months18 months

Anytime

Less than CHRLess than PCgR Ph+>35%Less than CCgRLess than MMolR 3 logs or moreAdditional chromosome abn in Ph+ cells, loss of MMolR

Why Do Some Patients Fail To Respond To Imatinib?

Multiple Causes For Drug Resistance

1. Mutations in the tyrosine kinase (50-75+%)• Multiple sites of mutation have been found, with T315I being the

most unresponsive to imatinib, dasatinib, and nilotinib

2. Increased transcription of bcr-abl or increased tyrosine kinase activity (10%)

3. Diminished cellular uptake of drug, drug pumps (5%)

4. Bcr-abl independent pathways5. Patients do not take their medication.

Mutant Kinase Domains in bcr-abl

• Over 50 mutations have been identified to date• Some mutations confer only moderate resistance, so

dose escalation can be successful• Evaluating for mutations in imatinib resistance may have

clinical usefulness in the future.

Treatment Options If Imatinib Fails

• Young patients with appropriate bone marrow donors—consider allogeneic transplant

• Four other tyrosine kinase inhibitors with demonstrated benefit for Gleevec failures

Second line TKI Therapy

• Dasatinib Haematologica 95:232,

2010

– 85 patients treated with 70 mg bid or 100 qd– 75% MCyR, 68% CCyR– 90% OS at 2 years

• Nilotinib Blood 117:1141, 2011

– 321 patients failed 600 mg + imatinib– 59% MCyR, 44% CCyR– If CCyR 56% MMR– CCyR durable 84% CCyR at 2 years, OS 87%

Second Line TKI Therapy• Bosutinib Blood 118:4567,

2011

– 200 patients imatinib resistant– 53% MCyR, 41% CCyR– If CCyR 64% MMR– OS 2 years 92%

• Ponatinib early results PACE trial ASH 118:abs 109, 2011

– 3-6 month follow-up, 94% failed > 2 TKI’s– 188 CP patients (48 with T315I mutation)– 46% MCyR, 32% CCyR (51% MCyR, 48% CCyR

with T315I mutation)

Selected Comparisons

FeatureT315I responsesPeripheral edemaPleural effusionsGrade 3-4 hemeMedian dose admininstered

Imatinib020%

<10%20%400 qd

Dasatinib018%

10-35%49%101 mg qd140 mg planed

Nilotinib0<1%

1%29%799 mg qd 800 mg planned

TKI’s: Drug-Drug Interactions

– Inhibitors = Drugs that may ↑ plasma levels of imatinib or nilotinib

• Clarithromycin• Erythromycin• Itraconazole• Ketoconazole

•Inducers = Drugs that may ↓ plasma levels of imatinib or nilotinib

• Carbamazepine

• Dexamethasone• Phenobarbital • Phenytoin• Rifampin• St. John’s wort

•Substrates = Drugs whose plasma levels may be increased by imatinib & nilotinib

– Acetaminophen– Cyclosporine– Dihydropyridine Ca++ channel

blockers– HMG-CoA reductase inhibitors

(eg, simvastatin)– Pimozide– Triazolobenzodiazepines– Warfarin

Grapefruit juice is also an inhibitor of Cytochrome P450- would increase levels of imatinib and nilotinib

Second generation TKI vs. imatinib as initial therapy

Drug CCyR %

Imatinib/drug

MMR %

Imatinib/drug

Progression to AP/BP %

Imatinib/drug

OS %

Imatinb/drug

Nilotinib2 yr dataLancet Oncol 2011

77 / 87 44 / 71 7 / 1 96 / 97

Dasatinib2 yr dataBlood 2012

82 / 86 46 / 64 5/ 2.3 95.2 / 95.3

Bosutinib18 month dataASH 2011 abs 455

68 / 70 27 / 41 5 / 2 95 / 99

Can You Stop Treatment?• Mechanism of action TKI vs. interferon• Stop during pregnancy

– Initial year of treatment vs. planned pregnancy

• Clinical trial Stop Imatinib STIM trial– 100 patients in CMR for at least 2 years– Molecular monitoring monthly X 1 yr, then q 2 mo– 61 relapses (all molecular), 3 after 7 months– 5 did not return to CMR with retreatment

ASH 2011 abs 603

The Future in CML• Can we identify patients who can receive imatinib

without risk as initial therapy– Molecular response at 1, 3, or 6 months

• Can the addition of interferon improve long term outcome?

• European trial suggests may be able to stop treatment after interferon maintenance.

• Will new combinations of treatments work better than tyrosine kinase inhibitors alone? Serial vs. sequential

• T315I mutation trials: HHT, Aurora kinase inhibition MK-0457, new TKI inhibitors KW-2449, XL-228

CML Treatments In Development• Tyrosine kinase inhibitors

– Ponatinib AP24534 multi kinase inhibitor trial (Ariad) T315I plus– DCC-2036 binds to different domain on bcr-abl, active in T315I– Non-ATP binding site inhibitors: AG957, ON 012380, ON01910

• Aurora kinase inhibitors: • Histone deacetylase inhibitors

– SAHA (vorinostat), LAQ 824, LBH 589• Hedgehog pathway inhibitors

– PF-04449913– BMS833923

• Homoharringtonine Omapro—plant alkaloid (Ceflatonin)• CML vaccines: short bcr-abl peptides, PR1 (proteinase 3 a

neutrophilic protease), HSP chaperone proteins

CML Treatment 2012• Newly diagnosed

– 400 mg/d imatinib or nilotinib 400 mg 2x/d or dasatinib 100 mg/d– Clinical trials: duration of therapy, second agents, target response

• Failure to achieve response or progressive disease– Switch to alternative TKI– Omapro if fail more than 2 TKI’s– Allogeneic marrow transplant for appropriate patients– Ponatinib clinical trials– Other clincal trials

• If present with accelerated or blast phase, use higher doses of imatinib or dasatinb and consider early allogeneic marrow transplant

Contact

Luke Akard MD1500 Albany Street

Suite 911Beech Grove IN 56107

317-528-5500Fax 317-782-6316

E-mail lakard@ibmtindy.com

National CML Society Indianapolis

CML Connection Group

http://www.nationalcmlsociety.org/cml-connection-indianapolis