Management of Advanced Phase CML

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Management of Advanced Phase CML

• Mike Martin, MD

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Outline

• Review of advanced CML
• Imatinib naïve disease
• Imatinib resistant or intolerant disease
• Impact of clonal evolution
• Ongoing trials
• Summary

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Pathophysiology

• Constitutive activation of ABL leads to genomic
  and epigenetic instability
• Is any abnormal ABL safe? Low level BCRABL
  transcripts eventually lead to progression
  despite imatinib?
• Stereotyped acquisition of further chromosomal
  abnormalities
• Trisomy 8, isochromosome 17
• Progress into an accelerated phase
• Pre-TKI median duration was 6-18 months
• Short, terminal BP with myeloid, lymphoid or
  undifferentiated morphology

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Historic Treatment

• 80/20 Myeloid undifferiented v. Lymphoid
• MBP CR rates 10-30, median OS 2-3 months
• LBP CR rates 30-60, medain OS 6-9 months
• Sudden BC
• Less than 3 months from CHR
• Only 2 in first 2 years after diagnosis
• Generally in low-risk individuals
• 25 of BC
• 21 Lymphoid over Myeloid

Kantarjian HM, Keating MJ, Talpaz M et al.
Chronic myelogenous leukemia in blast crisis.
Analysis of 242 patients. Am J Med. 1987 83
445-54.
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Definitions of disease states (WHO)

• Accelerated Phase
• Blasts 10-19 in PB or BM
• PB basophils gt20
• Persistent thrombocytopenia or thrombocytosis
• Increasing spleen size and WBC count un
  responsive to therapy
• Cytogenetic evidence of clonal evolution

• Blast Phase
• gt 20 blasts in PB or BM
• Extramedullary blast proliferation
• Large foci or clusters of blasts in the bone
  marrow biopsy

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Response criteria
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Response Criteria

• IRIS trial MCyR by 12 months predicted OS
  regardless of therapy
• CCyR independently predicts OS and is the most
  important prognostic indicator
• Achieving a hematologic response is a
  prerequisite for a cytogenetic response

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Traditional Chemotherapy
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MBP only
Low-dose AraC lt1gm/m2 (5 studies) Intermediate-d
ose AraC 1-3gm/m2 (5 studies) High-dose AraC
9-36mg/m2 (6 studies) Combinations often include
an anthracycline and/or vincristine, etoposide or
carboplatin
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and 2 from MDACC both with at least 1gm/m2 AraC
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Decitabine

• 123 patients
• 64 BP, 51 AP, and 8 CP
• 100mg/m2 q12h x5 days x13 pts
• 75mg/m2 q12h x5 days x 33 pts
• 50mg/m2 q12h x5 days x 84 pts
• Dosing punch line no impact of dose intensity on
  response

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TRM was 3 Febrile neutropenia in 37 Documented
infections in 34 going onto receive an Allo NR
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Decitabine 2nd study

• 35 patients
• Imatinib resistant
• 15mg/m2 x5 days a week for two weeks

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Decitabine vs. Traditional Therapy

• MDACC retrospective review of MP-CML
• 162 patients
• 90 intensive therapy
• 31 decitabine
• 41 other single agents
• 10 only received HU
• Decitabine group was older but otherwise no
  statistical differences
• 71 older than 50 versus 37 in the intensive
  therapy arm

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Imatinib naive
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Imatinib in CML-BP
Imatinib doses ranged from 300 to 1000mg daily
in both studies Myeloid responses were slightly
more durable than lymphoid 9 went on to receive
Allo transplant
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Sawyers et al Imatinib in BP
Imatinib dosed at 600 800mg daily
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Imatinib plus etoposide/mitoxantrone and
cytarabine maintenance in MBP
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Imatinib (600-800mg daily) is the preferred first
line therapy in advanced phase CML
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Imatinib resistant or intolerant
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Dasatinib (Talpaz et al, NEJM 2006)

• Promiscuous inhibitor
• Phase I
• Any phase CML or Phi ALL
• Imatinib resistant or intolerant
• 84 patients enrolled

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Response were short lived with the majority of
the patients relapsing in less than 12 and 6
months, respectively No data on going on to
Tx (one mentioned in the results)
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Dasatinib Phase II in MBP or LBP
With 8 months of median follow-up Percentage
going on to receive BMT not reported
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Nilotinib Phase I
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Nilotinib Phase II trial

• Minimal cross-intolerance with imatinib
• Thrombocytopenia only lab abnml intolerance
• CML-AP
• 400mg BID with dose-escalation for lack of
  response to 600mg BID

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Imatinib plus chemotherapy

• Imatinib (600mg) plus idarubicin biweekly and
  daily cytarabine
• 19 patients in MBP
• 17 had failed single agent imatinib
• In addition they had failed a median of 5 prior
  therapies

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Imatinib, idarubicin plus cytarabine
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Decitabine plus imatinib

• Decitabine 15mg/m2 daily x5 days x2 weeks
• Imatinib 600mg daily continuously
• 28 patients
• 25 imatinib resistant
• 32 FN

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Dasatinib (70mg BID) is the preferred second line
therapy in advanced phase CML
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3rd line TKIs?
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Nilotinib (400mg BID dose-escalated to 600mg BID
for lack of response)
Patients resistant or intolerant of both imatinib
and dasatinib Commons AEs include cytopenias,
low PO4 and high Bilirubin
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Bosutinib (500mg/day)
41 pts with CML-AP, 35 pts with CML-BP and 21
with Phi ALL Src and ABL TKI, similar to
dasatinib
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None of the responses to these agents are
durable allogeneic stem cell transplantation is
only hope for long term survival
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Allogeneic Transplantation

• Only curative option for advanced disease
• GVL prominent
• Long term survival and relapse based on stage at
  time of transplantation
• Early CP 57 5-year OS, 10 5-year relapse rate
• NMDP analysis of over 1400 patients
• 3-year relapse rates
• CP 6
• AP 25
• 2nd CP 27
• BP 56

Hansen JA, Gooley TA, Martin PJ, et al. Bone
marrow transplants from unrelated donors for
patients with chronic myeloid leukemia. NEJM.
1998 338 962-8. McGlave PB, Shu XO, Wen W, et
al. Unrelated donor marrow transplantation for
chronic myelogenous leukemia 9 years experience
of the National Marrow Donor Program. Blood.
2000 95 2219-25.
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Other agents
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HHT

• Inhibits protein synthesis
• Phase I trial of s.c. administration
• 8 patients in BP and 2 in AP
• Some minor activity described

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Aurora Kinase inhibitors

• AKs involved in regulation of mitotic chromosome
  segregation and cytokinesis
• MK-0457
• Small molecule AK inhibitor
• Also blocks JAK2
• Active in vitro v. T315I mutants
• Brief report in Blood Jan 2007 describes in vivo
  activity in 3 patients with advanced disease and
  the mutation

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Clonal evolution
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Definitions of disease states (WHO)

• Accelerated Phase
• Blasts 10-19 in PB or BM
• PB basophils gt20
• Persistent thrombocytopenia or thrombocytosis
• Increasing spleen size and WBC count un
  responsive to therapy
• Cytogenetic evidence of clonal evolution

• Blast Phase
• gt 20 blasts in PB or BM
• Extramedullary blast proliferation
• Large foci or clusters of blasts in the bone
  marrow biopsy

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Impact of clonal evolution

• Defined as the acquisition of chromosomal
  abnormalities
• In the Phi clone
• Criteria for accelerated phase
• BcrAbl independent proliferation?
• 71 patients treated with 600mg day (ODwyer ME et
  al Blood 2002)

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Imatinib 400-600mg daily
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AP and Clonal evolution second generation TKIs
(n60)
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Conclusions about CE

• Clone still relies heavily on ABL kinase
• Poor prognostic marker when combined with other
  features of advanced disease

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CNS disease
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• CNS EML more common with lymphoid
• Rare with myeloid
• Imatinib does NOT cross the BBB
• Dasatinib does
• In vitro and small case series are encouraging
• Bosutinib also cross the BBB
• Role for lyposomal cytarabine, etc not fully
  defined

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Ongoing trials
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Acknowledgements

• Geoffrey Uy, MD
• John F. DiPersio, MD PhD