Philadelphia Chromosome Positive ALL Warren Brenner 56 year

1
Philadelphia Chromosome Positive ALL

• Warren Brenner

2

• 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

3

• 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.

4

• 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

5
(No Transcript)
6
TdT
7
CD79A
8
(No Transcript)
9
(No Transcript)
10
(No Transcript)
11
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

12
Immunophenotyping
5
20-30
55-65
13
CD19 CD 79a CD22
CD10
Cytoplasmic Ig
14
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

15
Fader et al The Biology and therapy of adult
acute lymphoblastic leukemia Cancer
,2003/vol98/no7
16
Fader et al The Biology and therapy of adult
acute lymphoblastic leukemia Cancer
,2003/vol98/no7
17
Molecular Basis of Ph Chromosome Translocation
Faderl, S. et al. N Engl J Med 1999341164-172
18
Frequency of the Philadelphia Chromosome,
p210Bcr-Abl, and p190Bcr-Abl in Leukemia
Kurzrock, R. et. al. Ann Intern Med
2003138819-830
19
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
20
(No Transcript)
21
Probabilities of OS and DFS
22
Probabilities of OS and DFS
Gleibner et al, Blood, 1 March 2002.Vol 99, No5
23

• 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

24
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
25
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

26
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
27
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

28
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
29
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
30
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

31
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
32
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
33
(No Transcript)
34
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
35
Fig 1. Schema of LALA-94 trial
Thomas, X. et al. J Clin Oncol 224075-4086 2004
36
DFS According to Risk Groups
37
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

38
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
39
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