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Hana Safah MDProfessor of Medicine

Tulane University School of Medicine Director of the SCT program, Tulane Medical Center

The speaker has no financial relationships with a commercial interest to disclose and no conflicts of interest to resolve.

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Overview of CML� Epidemiology

� Diagnosis

� Treatment options

� Managing patients under therapy

Epidemiology of CML� 15% of adult leukemia

� About 5,920 new cases estimated in 2013

� 610 deaths in 2013

� 1.1 per 100,000

� Median age is 67 years

� No clear genetic or environmental risk factors; there may be an increased risk with radiation exposure

� Fatal until 1980s

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Clues to the diagnosis of CML� Unexplained & persistent leukocytosis

� Unexplained thrombocytosis 30-50%

� Leukocyte alkaline phosphatase decreased

� Vitamin B12 increased

� Increased uric acid & LDH

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Bone marrow biopsy

� Hyper cellular marrow, 75-90%

� Myeloid to erythroid ratio 10-30:1

� WBC maturation stages present with myeloid predominance

� Megakaryocytes increased and may be dysplastic

� Fibrosis may be seen with disease progression

The Philadelphia chromosome� Chromosome translocation t(9;22)(q34;q11)

� BCR-ABL: fusion between BCR gene on chr 22 and ABLgene on chr 9 (p210 protein with deregulated tyrosine kinase activity in CML, p190 in ALL)

� 95% of CML patients have the Ph chromosome by Karyotype or FISH

� 30-40% of the 5% negative for Ph chr, are positive by PCR for BCR-ABL gene

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Philadelphia chromosome� BCR-ABL:

1. ABL protein becomes constitutively active as a protein tyrosine kinase enzyme

2. DNA protein binding activity of ABL is attenuated

3. The binding of ABL to the cytoskeletal actin microfilament is enhanced which increases proliferation, affects differentiation, and blocks apoptosis

� Hence the potential of tyrosine kinase inhibitor therapy

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Phases of CMLChronic Phase� 25-60% are asymptomatic

� Fatigue

� Left upper quadrant pain/mass

� Weight loss

� Splenomegaly in 30-70%

� Hyper viscosity: visual or mental status changes and priapism

� Median survival of untreated patients: 3.5-5 years

Accelerated phase� 10-19% blasts, PB or BM

� Platelets <100 x109/L (not related to therapy)

� ≥ 20% basophils in peripheral blood

� Clonal evolution

� Increasing in spleen size and increase in WBC count unresponsive to therapy

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Blast phase� ≥ 20% blasts in bone marrow, peripheral blood or both

� Extramedullary infiltrates with leukemic cells

� OS 3-6 months

� 70% have myeloid phenotype (25% have lymphoid phenotype and 5% are undifferentiated).

Prognostic factors� Age

� Spleen size

� WBC

� Platelet count

� Blast, eosinophil, basophil % in peripheral blood

� Deletion of chromosome 9, which is seen in 10-15%, is associated with a worse prognosis

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Prognostic groupslow, intermediate, high:

Sokol score: age in years, spleen size, platelet count, blast cells. More commonly used especially in imatinib trials.

Hasford score: age, spleen size, platelet count, blasts, basophils, eosinophil count

Can calculate at www.icsg.unibo.it/rrcalc.asp

Both predict the probability of response to tyrosine kinase inhibitors

Trends in cancer treatment:

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Historical Treatment � Hydroxyurea : to control the WBC count.

� Interferon alpha: 70-80% may achieve a complete hematologic response. 40-60% have cytogenetic response

� Interferon + Cytarabine: showed higher response than IFN alone

Imatinib (Gleevec)

Dasatinib (Sprycel)

Nilotinib (Tasigna)

Bosutinib (Bosulif)

Ponatinib ( Iclusig)

OtherOmacetaxin ( Synribo)

Allogeneic Stem Cell transplantation

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CML

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Imatinib� Selective inhibitor of BCR-ABL tyrosine kinase

� Also inhibits PDGF-R (platelet derived growth factor receptor) & cKIT

� Effective in all phases of CML

� Oral therapy, 400 mg/day in chronic phase, 600 mg/day in blast crisis & accelerated phases

� Approved by FDA 12/2002 for 1st line treatment of CML based on IRIS

Imatinib� IRIS trial NEJM 2003: Randomized imatinib vs. IFN +

cytarabine in chronic CML

� Imatinib was associated with lower toxicity and better quality of life

� 19 month CCyR 73.8 vs. 8.5% favoring Imatinib

� Only 7% of patients progressed to accelerated or blast crisis

� Overall survival 89% at 60 months

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Imatinib toxicity� Nausea

� Peripheral/ peri-orbital edema

� Diarrhea

� Rash

� Fatigue

� Muscle cramps

� Myelosuppresion: neutropenia in 45%, thrombocytopenia in 25%, anemia 10%

� CHF: 1.7%

Imatinib failure� Primary resistance, failure to achieve hematologic

remission at 3 months

� 15-25% may have cytogenetic resistance (no cytogenetic response at 6 months, or major cytogenetic response at 12 months or complete cytogenetic response at 18 months)

� 40-60% is due to mutation of ABL

� T3151 is the most resistant mutation

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Treatment of Imatinib failure� Increase dose up to 800 mg QD

� More effective in those who had previously achieved cytogenetic response with prior standard dose

� Second generation TKI

Dasatinib� 2nd generation BCR-ABL kinase inhibitor

� 325 x more potent than imatinib , dual inhibitor of ABL and SRC family of kinases, active against the active and inactive conformation of the ABL gene

� active against all mutations in vitro except the T315I

� FDA approved it in October 2010 as first line therapy, chronic phase CML

� Chronic phase: 100 mg daily. AP and BC: 140 mg daily

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Dasatinib� START –C trial: Chronic phase, imatinib resistant or

intolerant, at 24 month follow up: 91% CHR, 53% CCyR, 47% MMR. OS 94%,

� START- A trial: Accelerated phase, imatinib resistant or intolerant patients, 12 PFS 66%, OS 82%

� START B trial: CML in blast crisis. PFS 6.7 months, OS 11.8 months

� Naïve CML Patients: 519 patients randomized to dasatinib100 mg vs. imatinib 400 mg PO daily, at 12 months, CCyR dasatinib 77% vs. Imatinib 66% (P=0.001)

Adverse effects of dasatinib� Reversible inhibition of platelet aggregation

� Pleural effusions (29% of chronic CML, 50% of accelerated CML, 33% with blast phase CML)

� Prior cardiac history or HTN are risk factors for pleural effusion, also 70 mg BID dosing

� Lymphocytosis with clonal expansion of NK/T cells

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Nilotinib� Selective inhibitor of BCR-ABL tyrosine kinase

� 20-50 x more potent than imatinib resistant cell lines, 3-7 x more potent in sensitive lines

� FDA approved October 2007 (400 mg BID) for chronic & accelerated CML resistant or intolerant to imatinib

� FDA approved June 2010 (300 mg BID) for newly diagnosed chronic CML

Nilotinib� phase III multicenter study compared nilotinib 300 mg or

400 mg BID vs. imatinib 400 mg QD in newly diagnosed chronic CML

� MMR 43% at 300 mg vs. 43% at 400 mg for nilotinib vs. 22% for imatinib at 12 months

� CCyR 80% 300 mg vs. 78% 400 mg for Nilotinib vs. 65% for imatinib at 12 months

� Patients with high Sokal risk, the MMR rate at 3 years was 67% for nilotinib vs. 39% for imatinib with a lower progression rate

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Nilotinib� Phase II study in blast phase CML showed responses, but

they were not durable

� If used in the 2nd line setting, performance status & prior cytogenetic response to imatinib are associated with a better prognosis on 2nd generations TKIs

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Nilotinib toxicity� QT prolongation & sudden cardiac death: a black box

warning. Monitor EKG, avoid other drugs that prolong QT, replace electrolyte abnormalities prior to start

� Rare fluid retention, edema, muscle cramps

� Neutropenia, thrombocytopenia grade 3-4 in 29%

� Asymptomatic increase in lipase, bilirubin, glucose, hypophosphatemia

� Peripheral arterial occlusive disease (PAOD)

Bosutinib� Dual ABL/SRC Kinases

� Active against mutations that are resistant to imatinib, dasatinib, and nilotinib except for T315I and minimal inhibition of KIT and PDGFR

� Not recommended as first line therapy

� As second line of therapy in resistant/ intolerant CP-CML: CHR 86%, MCyR 53%, CCyR 41% at 24 months

� Effective in AP-CML and BP-CML

� Approved for all phases of CML , resistant or intolerant to prior TKI.

� QTc prolongation, diarrhea , otherwise well tolerated.

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Ponatinib� Multi-targeted Kinase inhibitor

� Active against many kinase domain mutations including T315I

� CCyR, in patient intolerant/ resistant in CP-CML were 46%, AP-CML 50% and 30% in BP-CML, response rate was higher in the T315I patients

� Approved for all phases of CML , resistant or intolerant to prior TKI.

� Arterial thrombosis, PE, MI, hepatotoxicity, pancreatitis

Test Recommendation

Bone marrow cytogenetics2 • At diagnosis to establish the disease phase. If collection of bone marrow is not feasible, FISH on peripheral blood specimen using dual probes for the BCR and ABL genes is an acceptable method of confirming the diagnosis of CML.

• At 3 months from initation of therapy , if QPCR using IS is not available• At 12 months from initation of therapy, if there is no CCyR or MMR.• At 18 months form initiation of therapy, if not in MMR and lack of CCyR at 12

months• Rising levels of BCR-ABL transcript (1-log increase) without a MMR.

Quantitative RT-PCR(QPCR)

• At diagnosis.

• Every 3 months when a patient is responding to treatment. After CCyR has been achieved, every 3 months for 3 years and every 3-6 months thereafter.

• If there is a rising level of BCR-ABL transcript (1-log increase) with a MMR, QPCR analysis should be repeated in 1-3 months.

BCR-ABL kinasedomain mutationanalysis

• Chronic phase� inadequate initial response (failure to achieve PCyR or BCR-

ABL/ABL ≤ 10% (IS) at 3 months or CCyR at 12 and 18 months).� Any sign of loss of response ( Hematologic or cytogenetic relapse)• Disease progression to accelerated or blast phase.

Version 1, 2014, 09/09/13 NCCN, Network, Inc.

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Follow-up Response Treatment Recommendations

3 months

FCR-ABL/ABL ≤ 10% (IS) or PCyR

BCR-ABL/ABL ≥ 10% (IS) or less than PCyR1,2

Continue the same dose of TKI

Switch to alternate TKI3

Evaluate for allogeneic HSCT depending on response to TKI therapy.

12 months

CCyR

PCyR1

Minor or no cytogenetic response 1-2

Cytogenetic relapse 1-2

Continue the same dose of TKI

Switch to alternate TKI (preferred)3Continue same dose of TKIDose escalation of imatinib to maximum of 800 mg, as tolerated (if not a candidate for dasatinib, nilotinib, bosutinib, ponatinib or omacetaxine)

Switch to alternate TKI (preferred)3

Evaluate for allogeneic HSCT depending on response to TKI therapy

Switch to alternate TKI (preferred)3Dose escalation of imatinib to a maximum of 800 mg, as tolerated (if not a candidate for dasatinib, nilotinib, bosutinib, ponatinib or omacetaxine)

Evaluate for allogeneic HSCT depending on response to TKI therapy

18 months

CCyR

PCyR or cytogenetic relapse 1-2

Continue the same dose of TKI

Switch to alternate TKIEvaluate for allogeneic HSCT depending on response to TKI therapy

Version 1, 2014, 09/09/13 NCCN, Network, Inc

Treatment Options Based on BCR-ABL Kinase Domain Mutation Status

Mutation Treatment Options

T3151 Ponatinib (preferred) or omacetaxine, HSCT or clinical trial

V299L Consider ponatinib, nilotinib or omacetacine4

T315A Consider ponatinib, nilotinib, imatinib5 , bosutinib, or omacetaxine4

F317L/V/I/C Consider ponatinib, nilotinib, bosutinib or omacetaxine4

Y253H, E255K/V, F359V/C/I

Consider ponatinib, dasatinib, bosutinib or omacetaxine4

Any other mutation Consider ponatinib, high-dose imatinib6 , dasatinib, nilotinib, bosutinib or omacetaxine4

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NCCN guidelines key points� Imatinib, nilotinib, dasatinib are all category 1

recommendations for 1st line treatment in chronic phase

� 2nd generation TKIs may be better for intermediate or high risk patients

� If patient has failed 1st line treatment with a 2nd generation TKI, use the alternate 2nd generation TKI as opposed to imatinib

� Patients with T3151 mutations should be considered for clinical trials or stem cell transplant

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Allogeneic Stem Cell Transplantation� Potentially curative

� More successful in first chronic phase as opposed to accelerated, blast phase ; 5-yr OS 75%,40%, 10%

� Faithfull monitoring of disease not to miss the chronic phase window.

� GVHD is the major morbidity

Years

0 2 61 3 4 5

Probability of Survival after HLA-identical Sibling Donor Transplants for CML,

1998-2009- By Disease Status and Transplant Year -

0

20

40

60

80

100

10

30

50

70

90

0

20

40

60

80

100

10

30

50

70

90

Pro

bability o

f Surv

ival, %

P < 0.0001

SUM-WW11_29.pptSlide 30

CP, 1998-2000 (N=2,291)

AP, 1998-2000 (N=300)

CP, 2001-2009 (N=2,524)

AP, 2001-2009 (N=333)

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Indications for allogeneic SCT� Not a 1st line therapy of chronic CML due to excellent

results with TKIs

� Appropriate for patient with T315I mutations and other BCR-ABL mutations that are resistant to all TKIs

� Disease progression to accelerated phase and blast phase, de novo or on TKI therapy ( use alternate TKI as a bridge to SCT)

� Intolerant to all TKIs

� 2-yr OS : 44% ( T315I) vs. 76% (TKI intolerance with out the mutation)

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BCR-ABL positivity post transplant

� Timing of testing is important: if positive 6-12 months post transplant, there is a high rate of relapse (42% if positive vs. 3% PCR negative), 8% if positive > 36 months

� But late PCR + may have lower risk of relapse (14 %)

� Study of 379 patients with CML alive at >18 months post transplant showed 90 (24%) had at least 1 positive BCR-ABL (Radich et al)

TKIs and allogeneic SCT� Imatinib has shown a complete hematologic response in

>70% with cytogenetic response in 58% after failure of BMT

� Imatinib probably not helpful if patients failed it prior to transplant

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TKIs and allogeneic SCT� Consider dasatinib or nilotinib if imatinib used prior to

transplant

� TKIs may be used as maintenance for 1 yr post transplant for CML in Accelerated phase/blast phase to prevent relapse

Donor lymphocyte infusion (DLI)� Induces durable molecular remission

� More helpful in chronic phase vs. advanced phases

� Disease free survival appears higher with donor lymphocyte infusion vs. imatinib, but needs to be confirmed in randomized clinical trials

� Risk of graft vs. host disease and aplasia

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Causes of Death after Transplants

performed in2008-2009

Autologous

Infection (8%)

Other (16%)

Organ Failure (2%)

New Malignancy (1%)

Primary Disease (73%)

Unrelated Donor

Infection (16%)

Other (29%)Organ

Failure (6%)

Primary Disease(33%)

New Malignancy (1%)

GVHD (15%)

SUM-WW11_17.pptSlide 18

HLA-identical Sibling

Infection (12%)

Other (21%)

Primary Disease (47%)

GVHD (14%)

Organ Failure (4%)

New Malignancy (1%)

0

20

40

60

80

100

AML ALL CML MDS/MPS Aplastic

Anemia

Immune

Deficiency

SUM-WW11_16.ppt

100-day Mortality after Unrelated Donor Transplants,

2008-2009

Slide 17

Early Disease

Intermediate Disease

Advanced Disease

Chronic Phase

Accelerated Phase

Blast Phase

Other

Mort

ality

, %

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0

20

40

60

80

100

AML ALL CML MDS/MPS Aplastic

Anemia

Immune

Deficiency

SUM-WW11_15.ppt

100-day Mortality after HLA-identical Sibling Transplants,

2008-2009

Slide 16

Early Disease

Intermediate Disease

Advanced Disease

Chronic Phase

Accelerated Phase

Blast Phase

Other

Mort

ality

, %

Infectious complication

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Marrow and Blood TransplantationComplications: GVHD� Acute GVHD become apparent in the first few weeks

following transplantation

-Affects 10% - 80% of allogeneic transplant recipients

-Graded from I-IV according to number of organs involved

� Chronic GVHD become apparent at 100 to 400 days post transplant

-Affect 30% - 50% of allogeneic transplant recipients

-Classified as “limited” or “extensive” organ involvement

Djubegovic B, et al.Cancer Contol.2003

ASH Education Book, Jan 1, 2008

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Guidelines for screening for common cancers after SCT

Site Screening recommendationsBreast Mammogram annually starting at age 40†; begin at age 25 or 8 years after radiation,

which ever occurs later, in women who have received ≥ 20 Gy to the chest region

Cervix PAP smear every year (for regular PAP test) or every 2 years (for liquid-based PAP test); after age 30, if patient has had 3 consecutive normal tests, may screen every 2-3 years†

Colorectal Beginning at age 50, fecal occult blood annually and/or flexible sigmoidoscopyevery 5 years, or double contrast barium enema every 5 years, or colonoscopy every 10 years; certain high-risk groups (e.g., patients with inflammatory bowel disease) may need earlier initiation and more frequent screening†

Lung Yearly pulmonary exam with imaging as appropriateOral Yearly oral cavity examThyroid Yearly thyroid examSkin Skin exam as a part of periodic health exam†

*Adapted from Children’s Oncology Group25 and EBMT/CIBMTR/ASBMT Guidelines42

† Similar to American Cancer Society recommendations forgeneral population cancer screening

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Solid Cancers� 3 -5 years, increases with time

� Incidence at 5, 10, and 15yrs is 0.7%, 2.2%, and 6.7% compared to 0.3%, 0.6% and 0.8% in general population

� Risk Factor

� Young age, TBI, cGvHD (severity and >24 months use of immunosuppression)

� TBI solid cancers (Breast 17% in 25 yrs, thyroid, melanoma)

� cGvHD: cancer of the bucal mucosa, squamous cell cancer

PTLD � Incidence 1-2%, 80% within the 1st year

� Arises in donor cells

� Early benign, polymorphic, monomorphic PTLD and Hodgkin’s Lymphoma –PTLD

� Risk Factors: EBV, T-Cell depletion, ATG, a GVHD, Graft from mismatched unrelated donor, cGvHD (>1yr)

� Follow copies of EBV, >1000 preemptive Rituximab

� 50-80% Response with Rituximab

� Multiple extra nodal disease and late onset, R-CHOP

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MDS/AML� 5-15% in Autologous SCT, 2-5 years (11q23, 5q and 7q)

� Risk factors, alkylating agents, TBI in conditioning regimen

� <1% post allo PBSCT

Lingering Questions……� Are tyrosine kinase inhibitors better than allogeneic stem cell

transplant in terms of survival?

� Will 2nd generation TKIs have an improved survival benefit compared to imatinib?

� Cost of therapy vs. cancer survival?

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Nowell & Hungerford (photo from Penn Medicine)