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Approaches to the management of adults with acute lymphoblastic leukemia

Approaches to the management of adults with acute lymphoblastic leukemia. Dr. Santiago Pavlovsky Scientific Director Angelica Ocampo Hospitalisation and Clinical Research Center - FUNDALEU Buenos Aires - Argentina.

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Approaches to the management of adults with acute lymphoblastic leukemia

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  1. Approaches to the management of adults with acute lymphoblastic leukemia Dr. Santiago Pavlovsky Scientific Director Angelica Ocampo Hospitalisation and Clinical Research Center - FUNDALEU Buenos Aires - Argentina

  2. WHO histological classification of precursor B-cell, T cell, and mature B-cell neoplasms • Precursor B lymphoblastic leukemia/lymphoma: 70-85% adults ALL FAB: L1, L2; 10-15% lymphoblastic lymphoma. Phenotype:TdT (+), CD19 (+), CD22 (+), CD20 (+), CD79a+, S Ig (-). Cytogenetic:t (9;22) BCR/ABL (30%), t (4;11) gene ALL1/ AF4 ( 36%) • Precursor T lymphoblastic leukemia/lymphoma: 25% adults ALL FAB: L1, L2; 85-90% Lymphoblastic Lymphoma. Phenotype: CD3 (+), CD4 (+), CD5 (+), CD7 (+), CD8 (+). Cytogenetic: MYC (8q 24.1) • Mature B-cell leukemia/lymphoma: 2-4% adults ALL FAB: L3, CD19 (+), CD20 (+), CD22 (+), TdT (-), S IgM (+), Ki-67 >95% of cells; t (8;14) (q24;q32) oncogene c-MYC. 2-3% are adult Burkitt ´s lymphoma.

  3. Adverse prognostic factors in adults ALL • Time to CR > 4 weeks. Late responders • Age > 35 years old. • Leukocyte > 30.000/mm3 • Immunophenotype: Pro B (B-lin., CD10-) Early T (T-lin., CD1a-, sCD3-) Mature T (T-lin., CD1a-, sCD3+) • Cytogenetics: t (9;22) BCR/ABL t (4;11) ALL1/AF4 • MRD (+) after induction and consolidation positive.

  4. Treatment strategy in the 80`s and 90`s BFM based for adults ALL • Induction: Prednisone-vincristine-daunorubicin- L-asparaginase for four weeks. • Consolidation: High-dose (CPM, Ara-C, Mtx) rotational of brief duration. • G-CSF: Reduce duration of neutropenia and early mortality (4% vs 11%). • CNS prophylaxis: High-dose MTX and TIT (ara-C- MTX-DMT). • Maintenance: 6MP+MTX with pulses for 18-24 mo. • Allo-BMT: For high-risk patients <45 years old.

  5. Results of recents adult ALL trials Group Year No Pts Age %CR %LFS %OSV • GMALL 02/84 1993 562 28 75 39 (7y) 49 • FGTALL 1993 581 33 76 32 (4y) • MRC-UKALL 1997 618 >15 82 29 (5y) 29 • PETHEMA -93 1998 108 28 86 41 (4y) 47 • MRC/ECOG 1999 920 -- 89 • MDACC 2000 204 39 91 38 (5y) 39(5y) • GMALL 05/93 2001 1163 35 83 44(3y) 47(3y) • GIMENA 0288 2002 794 28 82 33 (9y) 27 (9y) • LALA-94 2004 922 33 84 30 (5y) 33 (5y) • CALGB 19802 2005 163 40 79 32 (3y) 36 (3y) • Total 6035 75-91 34 (5y) 36 (5y)

  6. Results of therapy in adults ALL according to GATLA protocols Trial Years Consol No Pts %CR %DFS %OSV 5 years 1/79 to 2/82 No 135 80 15 1 24 2 3/82 to 6/87 Yes 144 79 30 38 7/87 to 7/00 Yes 190 80 36 43 8/00 to 8/05 Yes 100 80 30 (4y) 36 (4y) 1: P=0.004 2: P=0.005 Lluesma-Goñalons M, Pavlovsky S, et al: Ann Oncol 2:33-39,1991

  7. EFS in favourable risk (WBC < 30,000/mm3 and age < 35 years) in adults ALL. GATLA P<0.001 48% 45% 18% Months

  8. EFS in unfauvorable risk according to protocol in adults ALL. GATLA 1979 to 2005 P=0.290 25% 19% 13% Months

  9. Pediatric vs adults therapeutic trials in adolescent (15-21 ys) with ALL Protocol Country Type No pts %CR %EFS FRALLE-93 France1 Pediatr 77 94 67 LALA-94 Adults 100 83 41 CCG USA2 Pediatr 196 96 64 CALGB Adults 103 93 38 • Boissel N et al: J Clin Oncol 21:774-780,2003 • Stock W, et al: Blood 96:476a,suppl,2000

  10. A randomized controled trial of filgastrin (G-CSF) during induction and consolidation therapy for 198 adults ALL. CALGB 91111 G-CSF Placebo P Induction: PMN >1000/mm3 days 16 22 <0.001 Hospital days 22 28 =0.02 Consolidation: PMN >1000/mm3 days 6 9 Median DFS (ys) 2.3 1.7 =0.53 Median OSV (ys) 2.4 1.8 =0.25 Conclusion: G-CSF improve neutrophil recovery but not affect the outcome. RA Larson et al: Blood 92:1556-1564,1998

  11. Comparison of chemotherapy versus Allo-BMT for adults ALL in first complete remission. • Therapy Chemo Allo-BMT P< • Source GALLSG IBMTR • No Centers 44 98 • No Pts 484 234 • % Relapses 9 ys 66 30 0.0001 • % LFS 9 ys 32 34 0.02 Zhang MJ et al: Ann Intern Med 123:428-431,1995

  12. Allo versus auto transplantation in adults ALL. A GOELAMS trial. • Eligible 198 pts, median age 33 yrs, CR rate 86% • Transplant Allo Auto P= • No Pts (<50 ys) 41 106 • TRM at 6 mo 15% 3% • DFS at 6 ys 75% 33% 0.0004 • OSV at 6 ys 75% 40% 0.0027 M Hunault et al: Blood 104:3028-3037,2004

  13. Comparison of intensive chemo, Allo or Auto SCT as post-remision Tx for adults with high-risk ALL. PETHEMA ALL-93 trial High-risk: age 30-50 ys or WBC>25x109/L or t(9;22, t(4;14) Eligible: 222 pts, CR 183 pts (82%), 5 ys DFS: 35%,OSV 34% Chemo AlloSCT AutoSCT P= No/Rand 36/48 57/84 31/50 %relapse 46 62 57 N.S. %DFS 5 ys 44 35 33 N.S. %OSV 5 ys 50 35 37 N.S. JM Ribera et al. Haematol 90:1346-1356,2005

  14. Therapy for Mature B-cell adults ALL Protocol Center No Pts %CR %LFS %SV 5ys Ref B-NHL83 * GALLSG 24 63 50 49 1 B-NHL86 * GALLSG 35 74 71 51 1 Prot 9251 CALGB 24 75 66 52 2 Hyper-CVAD MDACC 26 81 61 49 3 Hyp-CVAD-R MDACC 31 86 88 89 4 • Short intensive therapy with six short alternately cycles A and B with high-dose MTX, CPM, or Ifosfamide, VM26 and Ara-C plus TIT. 1) Hoelzer D et al: Blood 87:495-508,1996 2) Lee EJ, et al: J Clin Oncol 19:4014-4022,2001 3) Thomas DA et al: J Clin Oncol 17:2461,1999 4) Thomas DA et al. Blood 106:47a,Abstr 149,2005

  15. Historical comparison of Imatinib plus chemo (I-C) vs chemo (C) only preceding stem cell transplantation in newly diagnosed Ph´+ ALL • Pre-SCT therapy Chemo Chemo+Imatinib P • No Pts 31 29 • % CR 82 79 NS • % relapse prior SCT 42 3.5 =0.002 • % DFS 38 76 =0.001 Seok L et al. Blood 104:Abstr 2740,2004

  16. Outcome in naive adults BCR-ABL + ALL treated with Imatinib plus intensive chemotherapy. • Therapy MDACC1 JALSG2 UKALL3 GRA ALL4 • No Patients 35 80 27 29 • % CHR 94 96 89 69 % C Mol R 24 78 • No BMT 13 (36%) 15 (63%) 15 (56%) • DFS 78% (3ys) 45% (2yr) 56% (1yr) 57% (1yr) • OSV 58% (2yr) 59% (1yr) 71% (1yr) • Historical DFS after BMT without Imatinib: 30-40% 1) DA Thomas et al. Blood 106:520a,Abstr 1830,2005 2) M Janada et al. Blood 106:Abstr 1827,2005 3) B Patel B et al. Blood 106:523a,Abstr 1839,2005 4) A Delannoy et al. Blood 106: Abstr 146,2005 (Pts >54 ys)

  17. Imatinib given concurrenttly versus subsequent to induction and consolidation in newly diagnosis adults Ph`+ ALL • Imatinib 600 mg subsequent concurrent • No patients 48 46 • Log reduction 1.5 log 3.9 log • BCR/ABL neg PCR 10% 50% • % CR 96% • Grade III-IV toxicity lower higher OG Ottmann et al. Blood 104;No 11,abstr 685,2004

  18. Facts of Imatinib in BCR-ABL positive adults ALL • In 56 relapse/refractory patients Imatinib alone produced a 60% ORR with 19% CR. The TTP and OSV was 2.2 and 4.9 months respectively. (OG Ottmann et al: Blood 100:1965,2002) • Imatinib not cross the blood brain barrier and has a significant risk of CNS relapse without CNS prophylaxis. • Daily dose of Imatinib should be 600-800 mg. • As first line imatinib plus chemo produce 85-95% of CR. • Concurrent Imatinib /chemo is clearly superior than sequential or alternating, based on Q-RT-PCR determinations of BCR-ABL transcript levels.

  19. Target therapy in association with chemotherapy according to phenotype and BCR-ABL in adults ALL. Phenotype BCR-ABL CD20 CD52 Therapy T-Precursor Negative Negat. >10%+ Chemo+Alentuz Positive Negat. Negat. Chemo+Imatinib B-Precursor Posit. Negat. Chemo+Ritux. Negative Negat. Negat. Chemo only Negat. >10%+ Chemo+Alentuz Mature B Negative Posit. Chemo+Ritux.

  20. Conclusions • The largest advances in treatment of adults ALL were derived from the introduction of multiagent BFM like regimen on induction, consolidation and maintenance. • The ALL strategy must be perform according to cytological classification Precursor B or T cells or B mature cells . • MRD-based early response by flow cytometry or immunoglobulin H gene analysis identify the majority of patients at risk to relapse, and safe others from inadequately toxic therapy. • The use of Imatinib with chemo on induction and consolidation improve the prognosis of BCR/ABL positive adult ALL.

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