Philadelphia Chromosome Positive ALL

1. Philadelphia Chromosome Positive ALL Warren Brenner

3. Initial BM core biopsy:100% 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

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 >50 FAB described 3 groups (L1-3) based on morphology and cytochemistry Who classification abandons the distinction of L1-3 morphologies

12. Immunophenotyping

14. Philadelphia Chromosome Positive ALL Overall incidence in adults of 20-25% Increases with age to >40% in patients >50 Most common cytogenetic abnormality detected in adult ALL Bcr/Abl positivity is confined to CD10+ B cell precursor ALL

17. Molecular Basis of Ph+ Chromosome Translocation

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

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

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

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. Table 1. Comparison of Treatment Outcomes According to Disease Subtype in Adults and Children with Acute Lymphoblastic Leukemia.Table 1. Comparison of Treatment Outcomes According to Disease Subtype in Adults and Children with Acute Lymphoblastic Leukemia.

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+)

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

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

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