Philadelphia Chromosome Positive ALL

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Philadelphia Chromosome Positive ALL

• Warren Brenner

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• 56 year old previously healthy female
• Presents with 2 week history of increasing
  fatigue, polydipsia and polyuria
• Initial presentation to OSH reveals new onset
  diabetes, anemia and thrombocytopenia with normal
  physical exam
• WCC 4.5 Hgb 10.9 (normal MCV) Platelets 19K
• CMP WNL
• LDH 1200

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• Initial BM core biopsy100 cellularity with
  extensive replacement by a proliferation of Leder
  negative blasts. No remaining normal
  hematopoetic cells were seen.
• Immunohistochemistry Expression of nuclear TdT,
  cytoplasmic CD79a and cytoplasmic CD34.
  Scattered blasts expressed cytoplasmic
  myeloperoxidase in granular pattern.
• Immunostains for T-cell phenotype were negative.

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• Immunophenotyping by flow cytometry revealed
  CD19 blasts which co-expressed TdT and CD79a.
  The cells were also positive for HLA-DR, CD34 and
  CD10 and lacked expression of CD20, CD33 and CD7
• Diagnosis Acute precursor B-lymphoblastic
  leukemia
• Cytogenetics Philadelphia chromosome positive by
  metaphase karyotyping and FISH

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TdT
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CD79A
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Introduction

• About 5000 cases diagnosed annually in the US
• Represents 20 of adult acute leukemia's
• Bimodal age distribution
• 4-5/100,000 in ages 2-4
• 1/100,000 in adults gt50
• FAB described 3 groups (L1-3) based on morphology
  and cytochemistry
• Who classification abandons the distinction of
  L1-3 morphologies

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Immunophenotyping
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20-30
55-65
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CD19 CD 79a CD22
CD10
Cytoplasmic Ig
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Philadelphia Chromosome Positive ALL

• Overall incidence in adults of 20-25
• Increases with age to gt40 in patients gt50
• Most common cytogenetic abnormality detected in
  adult ALL
• Bcr/Abl positivity is confined to CD10 B cell
  precursor ALL

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Fader et al The Biology and therapy of adult
acute lymphoblastic leukemia Cancer
,2003/vol98/no7
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Fader et al The Biology and therapy of adult
acute lymphoblastic leukemia Cancer
,2003/vol98/no7
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Molecular Basis of Ph Chromosome Translocation
Faderl, S. et al. N Engl J Med 1999341164-172
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Frequency of the Philadelphia Chromosome,
p210Bcr-Abl, and p190Bcr-Abl in Leukemia
Kurzrock, R. et. al. Ann Intern Med
2003138819-830
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Ph ALL

• Prospective PCR testing performed on patients
  with CD10 B cell precursor ALL enrolled on GMALL
  trials 04/89 and 05/93
• 478 patients
• 37 of CD10 B lineage precursor ALL were Ph
• p190 77
• p210 20
• Concurrent Bcr/Abl PCR and cytogenetic analysis
  performed on 212 patients 89 concordance

Gleibner et al, Blood, 1 March 2002.Vol 99, No5
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Probabilities of OS and DFS
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Probabilities of OS and DFS
Gleibner et al, Blood, 1 March 2002.Vol 99, No5
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• No clear SS difference between p190 and p210
  although p210 tended to do worse in all aspects
• Based on former prognostic factors of the GMALL
  studies for survival of CR patients, only WCC and
  especially Ph were independent prognostic factors

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CALGB Experience

• Prospective karyotype analysis on 256 patients
• 29 were Ph( 68 had other abnormalities)
• CR rate did not differ significantly between
  various risk groups - 80
• Ph - median DFS 9 months, probability of CCR at
  5 years was 8
• 11 5 year survival
• 9 long term survivors all underwent allogeneic BMT

Wetzler et al, Blood, Vol 93, No 11,1999
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French Experience

• 443 patients
• 29 Ph of which in 46 was only chromosome
  abnormality
• Median age 45, median wcc 30K
• All were B cell lineage (87 expressed CD10)
• CR rate 59, median EFS 5 months and 3 year EFS
  was 5

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Significance of concurrent chromosome
abnormalities

• 111 patients with Ph ALL enrolled on CALGB
  protocol 8461
• 32 had Ph as only abnormality
• Most common other abnormalities included extra
  der(22)hyperdipoidy, abnormalities of 9p, 21,
  8, -7 and gain of 8q or 1q
• No significant difference between groups in CR
  rate and survival but patients with -7 had very
  low CR rates(25) and patients with der(22) had
  a higher cumulative incidence of relapse

Wetzler et al Additional Cytogenetic
abnormalities in adults with Ph ALL a study of
the CALGB, Br J of hematology, 124, 2750288
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Treatment

• Ph ALL is associated with an extremely poor
  prognosis and generally not curative with
  standard ALL type therapy
• Presently, allogeneic or matched unrelated BMT is
  the only potential curative therapy

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Comparison of Treatment Outcomes According to
Disease Subtype in Adults and Children with Acute
Lymphoblastic Leukemia
Pui, C.-H. et al. N Engl J Med 1998339605-615
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Outcome with conventional chemotherapy for adults
with Ph-positive ALL
Thomas et al treatment of Ph ALL with
hyper-CVAD and imatinib Blood, 15 June 2004.Vol
103, No12
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Bone Marrow Transplantation

• IBMTR data published in 1992 on 67 HLA matched
  allogeneic transplants showed a 38 2 year DFS
  rate.
• Long term f/u of 38 patients transplanted at City
  of Hope/Stanford showed 2 year DFS of 46 in
  patients transplanted in CR1 and 28 for patients
  transplanted beyond CR1

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Unrelated BMT(NMDP) 127 patients with poor risk
ALL (76 were Ph)
Cornelissen etal Unrelated marrow
transplantation for adults with poor risk ALL
strong graft versus-leukemia effect and risk
factors determining outcome Blood, 15 March
2001.Vol 97,No 6
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Cornelissen etal Unrelated marrow
transplantation for adults with poor risk ALL
strong graft versus-leukemia effect and risk
factors determining outcome Blood, 15 March
2001.Vol 97,No 6
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ALL LALA-94 Trial

• Risk adapted post remission strategy
• Role of SCT for high risk ALL
• 1000 patients enrolled between 1994-2002
• Median age 33
• 23 Ph
• Median follow up of 5 years

Thomas, X. et al. J Clin Oncol 224075-4086 2004
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Fig 1. Schema of LALA-94 trial
Thomas, X. et al. J Clin Oncol 224075-4086 2004
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DFS According to Risk Groups
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Results of Transplant

• Median OS 14.2 months for auto
• Median OS 21.5 months for allo
• 3 year OS 17 for auto
• 3 year OS 36 for allo
• 3 year DFS 15 for auto
• 3 year DFS 34 for allo

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Role Of Imatinib

• Selective inhibitor of Bcr-Abl TK, PDGF receptor
  TK and c-kit receptor
• Single agent therapy for previously treated
  relapsed or refractory Ph ALL and CML in
  lymphoid blast crisis were associated with RR of
  40-50 but true CR were rare and median survival
  was only 2-5 months
• HYPER-CVAD and imatinib 20 patients. 100 CR
  rate
• Complete molecular remission in 60
• Median f/u 20 months 75 DFS
• Of the 20 patients 50 underwent allogeneic
  transplant of which only 1 relapsed with median
  f/u of 12 months following transplant
• 6 of 10 patients not undergoing transplant
  remained alive without disease with 20 month
  median f/u

Thomas et al treatment of Ph ALL with
hyper-CVAD and imatinib Blood, 15 June 2004.Vol
103, No12
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Future Questions

• Role of imatinib as first line interim therapy
  prior to transplant
• Role of imatinib in patients with positive
  Bcr/Abl transcripts post transplant
• Clinical trials - CALGB C10001- Looking at
  imatinib pre and post transplant