Philadephia chromosomal positive acute lymphoblastic leukemia

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Philadephia chromosomal positive acute lymphoblastic leukemia

  1. 1. Philadephia chromosomal positive acute lymphoblastic leukemia Jiong HU Blood & Marrow Transplantation Center, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine
  2. 2. 1. Role of TKI: overview 2. Dose of chemotherapy with TKI 3. SCT with TKI: allo-SCT and pre/post-SCT TKI auto-SCT 4. Elderly
  3. 3. about 25% adult cases of ALL - randomized controlled trials of therapy unusual - poor outcome with standard combination chemotherapy -Two major developments - tyrosine kinase inhibitors (TKI) - myeloablative allogeneic HSCT Background
  4. 4. Tyrosine kinase inhibitors (TKI) Khan S. US Pharm. 2012;37(5)(Oncology suppl):3-7 Stock W. Leukemia & Lymphoma, 2010; 51(2): 188-198 Agent FDA approved dose Mechanism Mutation Imatinib 600mg/day - ABL inhibitor -Substrate of Pgp; Uptake by OCT-1 P loop mutation Dasatinib 140mg/day - SRC/ABL inhibitior, more potent than IM - Not substrate of Pgp, penetration across the blood-brain barrier T315I Nilotinib 150-200mg twice daily More potent than IM /
  5. 5. Tyrosine kinase inhibitors (TKI) Josep-Maria Ribera Leukemia & Lymphoma, 2012; Early Online: 1–7
  6. 6. - Induction: TKIs added upfront , during or after induction chemotherapy CR rates based on morphology and conventional cytogenetics over 90% with major molecular response of 30 ~50% - Consolidation: including TKIs and allogeneic HSCT when possible - Overall outcome 40~60% of patients achieved prolonged remissions significant improve compare to pre-TKI era - No rationale for omitting TKIs from treatment though no data from randomized clinical trials Tyrosine kinase inhibitors (TKI) Josep-Maria Ribera Leukemia & Lymphoma, 2012; Early Online: 1–7
  7. 7. 1. TKI in the treatment of ph+ ALL 2. Dose of chemotherapy with TKI 3. SCT with TKI: allo-SCT and pre/post-SCT TKI auto-SCT 4. Elderly
  8. 8. - Reduction of cytotoxic agents or even increasing dose of TKIs early studies for patients not eligible for intensive therapy or SCT due to advanced age TKIs (imatinib or dasatinib) combined with minimal chemotherapy achieved 100% CR without induction fatalities Intensity of chemotherapy in TKI era Josep-Maria Ribera Leukemia & Lymphoma, 2012; Early Online: 1–7
  9. 9. - EWALL-Ph-01 Study (2007~2010): 71 pts with median age 69.2 (58-83) and FU of 3.3 years - Treatment: Induction: Dasatinib 140mg QD (100mg >70y) + weekly VCR 1mg + DEX 40mg 2 days (20mg >70y) x 4 weeks Consolidation: Dasatinib 100mg/d sequentially with MTX 1g/m² IV d1 (500 mg/m² >70y) + L-ASP 10,000UI/m² IM d2 (5,000 UI/m² >70y) for cycles 1, 3, 5 or cytarabine 1g/m²/12h d1, d3, d5 (500 mg/m² >70y) for cycles 2, 4 and 6. Maintenance: Dasatinib sequentially with 6-MP/MTX every other month and DEX/VCR every 2 months up to 24 months followed by dasatinib alone until relapse or death TKI + chemotherapy: EWALL study ASH 2012 abstract
  10. 10. - CR: 67/71 (94%) - BCR-ABL/ABL ≤0.1% 54%; undetectable (<4.5 log) 22% - RFS(censored at HSCT) and OS(non-censored): 42.7% (26.9-58.5) and 44.7% (31.8-57.5) - Safety: 3 pts died in induction; 60 pts (84%) received consolidation and 8 died in CR -Relapses: 29 relapsed (median 9 months, range 3-34) and 24 pts died; T315I in 63%; F317L in 7%; V299L in 4% and no mutation in 7% ASH 2012 abstract TKI + chemotherapy: EWALL study
  11. 11. ASH 2012 abstract Additional chromosomal abnormality (ACA) at induction and molecular response were prognostic factors TKI + chemotherapy: EWALL study
  12. 12. TKI + chemotherapy: EWALL study British Journal of Haematology Volume 158, Issue 4, pages 506–514, 2012 - 32 adults Ph+ ALL (18~60 years) with pediatric-based chemo + imatinib - CR: 94% - Toxicity: III-IV infections, neuropathy, myopathy and liver function abnormalities; major treatment delays and dose reductions - Median and 3-year OS: 40.7 months and 53%; Median and 3- year EFS: 30.1 months and 50% - Imatinib + pediatric-based regimen results in high response, considerable toxicity and high non-relapse mortality post-HSCT
  13. 13. - Prospective randomized study - Patients: 18-60 years untreated Ph+ ALL - Induction: arm A (IM-based): IM 800mg on D1-28 + VCR (2mg, D1, 8, 15, 22) + DEX(40mg D1-2, 8-9, 15-16, and 22-23); arm B (IM/HyperCVAD): IM 800mg on D1-14 + HyperCVAD - Consolidation: 1 cycle of MTX (1g/m2, D1) + AraC (3g/m2/12h, D2~3) + IM 800mg D1-14 followed by allo-SCT or autologous SCT ASH 2012 abstract TKI + chemotherapy: Graaph-2005 study
  14. 14. - Patients:270 randomized and 265 were evaluable (133 arm A, 132 arm B; median age, 47 years; median follow-up, 40 months) ASH 2012 abstract Arm A n=133 Arm B n=132 P value CR rate cycle 1 98% 89% 0.003 cycle 2 98% 91% 0.006 Induction Death 1 9 0.01 MRD response major response 44% 46% NS undetectable 10% 10% NS Transplantation 80 allo/17 auto 77allo/17 auto NS 3-year EFS 46% 38% NS 3-year OS 53% 49% NS TKI + chemotherapy: Graaph-2005 study
  15. 15. - Front-line TKIs with chemo yields high response rate - TKI + reduced dose chemo followed by Allo-HSCT and/or Auto- HSCT: comparable outcome to TKI + intensive chemo - Role of intensified chemo must be reconsidered except for patients not undergoing SCT . TKI + chemo: Summary
  16. 16. 1. TKI in the treatment of ph+ ALL 2. Dose of chemotherapy with TKI 3. SCT with TKI: allo-SCT and pre/post-SCT TKI auto-SCT 4. Elderly
  17. 17. - Allogeneic transplantation: considered as the only curative option in the pre TKI era searching for suitable donor transplantation mortality - Autologous transplantation: usually associated with high relapse rate limited to patients achieved undetectable transcripts . Role of stem cell transplantation in TKI era
  18. 18. - Impact of TKI on leukemia stem cells (LSC): imatinib and novel TKIs such as nilotinib and dasatinibas combined with cytotoxic agents improved response, molecular remission and overall outcome in vitro experiments suggested that TKIs have antiproliferative but no cytotoxic effect on most primitive ALL LSCs none TKIs in clinical use are able to kill most primitive LSCs LSCs lead to relapse . Role of stem cell transplantation in TKI era World J Stem Cells 2012 June 26; 4(6): 44-52
  19. 19. Therapy with TKI results in the depletion of cycling leukemia cells without eliminating the Leukemia stem cells (LSCs), then the latter can regenerate the tumor after that therapy is halted. World J Stem Cells 2012 June 26; 4(6): 44-52 Role of stem cell transplantation in TKI era
  20. 20. Allo-SCT in pre TKI era: International ALL Trial MRC UKALLXII/ECOG2993 Blood August 1, 2008 vol. 112 no. 3 903-909 267 adult ALL without TKI as front-line therapy
  21. 21. Allo-SCT in post TKI era: GMALL study ASH 2010, 147 - Prospective multicenter GMALL study: 335 newly diagnosed Ph+ ALL - Treatment: imatinib 600mg daily with chemotherapy (different starting time and duration) - CR rate: 85.7~89.4% - For all patients in CR1, 219 patients (66.4%)underwent SCT 3-year and 7 year OS: 57% and 52% - For patients did not undergo SCT in CR1: median OS of 9.4 months; 3-year OS 14% SCT in CR1remains the treatment of choice even in patients who achieve a good molecular response to initial therapy with TKI and chemo
  22. 22. ph+ALL: allo-HSCT combined with TKI - pre-transplantation TKI improve CR rate and MRD response - post-transplantation TKI prevention and treatment of relapse Leukemia & Lymphoma, 2012; Early Online: 1–7
  23. 23. MDACC study - Retrospective study: adult 102; pediatric 11 - Sib donor (n=60), unrelated (n=40), cord blood (n=12), haplo (n=1) - CR1(n=71),CR2(n=11), NR(n=31) -TKI as front-line therapy n=67;Post-transplantation TKI maintenance n=32 - Median FU: 5 years(1.1-20.4) - OS:CR1 43% vs. other 16%, P=.002 - Pre-transplantation TKI not associated with outcome (uni/mutlivariate analysis) Biology of Blood and Marrow Transplantation Volume 18, Issue 4 , Pages 584-592, 2012
  24. 24. JALSG study Leukemia (2011) 25, 41–47 - Retrospective analysis between 2002~2005 - 100 newly-diagnosed adult ph+ALL with imatinib + chemo as front-line therapy 97 CR achieved and 51 received allo-HSCT vs. historical control (n=122) allo-HSCT in CR1 without TKI treatment - 3-year OS: Imatinib+HSCT 65%;control HSCT 44%;P=0.005 - 3-year DFS/3-year RR much improved in Imatinib+HSCT group P=0.005 - TRM not significantly different (P=0.27)
  25. 25. JALSG study Leukemia (2011) 25, 41–47
  26. 26. Imatinib GRAAPH-2003 Study Biology of Blood and Marrow Transplantation Volume 19, Issue 1 , Pages 150-155, 2013
  27. 27. Biology of Blood and Marrow Transplantation Volume 19, Issue 1 , Pages 150-155, 2013 Imatinib GRAAPH-2003 Study 4-year OS ,95%CI 4-year DFS ,95%CI CIR% TRM in CR LALA-94 N=103 20 (14-26) 20(14-28) 42(34-50) 16 GRAAPH2003 N=43 52(36-66) * 43(27-58) * 24(14-40) 11 * p=0.001~0.002 In Ph+ ALL, the addition of imatinib to chemo followed by auto or allo-HSCT is associated with an improved long-term outcome.
  28. 28. Pre-SCT IM: GMALL study ASH 2010, 147 - Treatment: Arm 1: IM starting between IND and conso 1, then after conso1 (n=51); Arm 2: IM starting 2nd half of IND and throughout conso1 (n=105); Arm 3: IM starting and throughout conso1 (n=179) until SCT
  29. 29. Pre-SCT IM: GMALL study ASH 2010, 147 A1 A2 A3 No pts N=51 N=105 N=179 CR rate / 89.4% 85.7% ED / NR / 5.8% / 4.8% 11.3% / 3% PCR negative * 4.2% 12.5% 33% OS 31% 40% 50% Pre-SCT rel 11.8% 8.7% 4% Post-SCT rel 30.8% 24.3% 11.3% Post-SCT NRM 33.3% 25.7% 20.8% earlier and prolonged IM is associated with superior treatment outcomes after SCT
  30. 30. J Hematology Oncology 2012 - n=82 ph+ALL with allo-HSCT: regimen TBI+Cy or BU-based - 62 pts received post-transplantation Imatinib starting D+70; 10(16.1%) stop due to AEs - DFS:IM group 81.5% vs. no IM group 33.5% (p=0.000) with the median follow-up of 31 months (range, 2.5-76 months) and 24.5 months (range, 4–72 months) - Multivariate analysis: post-transplantation Imatinib as independent prognostic factor DFS (p=0.000) and OS (p=0.000) PKU Study
  31. 31. PKU Study J Hematology Oncology 2012 Selection bias: more patients in the non IM group present poor prognostic factor such as severe gut GVHD, pancytopenia.
  32. 32. J Hematology Oncology 2012 PKU Study
  33. 33. prophylaxis Pre-emptive P value No pts 26 29 Allo-SCT CR1 23; CR2 3 CR1 27; CR2 2 IM treatment 24/26 14/29 Median D of IM D+ 48 D+70 Follow-up 30 months 32 months Alive in CR 82% 78% MRD + 10/26, 40% 20/29; 69% 0.046 Duration of MRD- CR 26.5 months 6.8 months 0.065 5-year OS 80% 74.5% 0.84 ASH 2011 abstract Post-allo-HSCT TKI: GMALL randomized study
  34. 34. Post-allo-HSCT TKI: GMALL randomized study ASH 2011 abstract - Prophylactic imatinib treatment significantly reduces the molecular relapse after SCT - Both prophylactic / pre-emptive strategies are associated with a low rate of hematologic relapse, durable remissions and excellent long-term outcome - MRD+ prior to and early after SCT in small subset of patients associated with poor prognosis even with post-transplant imatinib
  35. 35. • Pre-transplantation TKI - TKI improve remission rate and improve MRD response - Pre-transplantation TKI improve post-transplantation outcome remains to be determined • Post-transplantation TKI - Benefit need confirmation in prospective study - Tolerability of post-transplantation TKI - Optimal dose, duration of TKI treatment TKI + allo-HSCT: Summary
  36. 36. Autologous SCT • TKI + sequential chemotherapy would result in significant leukemia cell cytoreduction leading to molecular remission in Ph+ ALL • collection of normal hematopoietic stem cells uncontaminated by residual BCR/ABL+ lymphoblasts • reduce the likelihood of relapse after auto-SCT • Post-transplant maintenance with TKIs
  37. 37. Autologous SCT: CALGB study10001 • 58 ph+ ALL with 3-4 cycels of imatinib (400 mg twice daily) plus sequential chemotherapy followed auto-SCT or allo-SCT from a matched sibling donor by TBI/etoposide based conditioning • 15 allo-SCT from sib donor, 19 atuo-SCT, other from unrelated donors or alternative therapy • Imatinib + chemotherapy resulted RT-PCR negative stem cells: 9/19 complete molecular response(CMR); 4/19 major molecular response (MMR) and 6 not evaluable. ASH 2012 abstract
  38. 38. Autologous SCT: CALGB study10001 • RT-PCR status (CMR vs. MMR) had no effect on OS or DFS after auto-SCT (P=0.77 for DFS and P=0.50 for OS). • Day +120 MRD auto-SCT: DFS and OS longer in patients with MMR (n=8) than no MMR (n=6, P=0.045 and P=0.011). • Median follow up of 5.1 years: 9/19 (47%) auto-SCT and 7/15 (47%) allo-SCT remain alive in continuous CR. • 10 relapsed (8 with auto-SCT and 2 with allo-SCT) • DFS (median, 5.5 vs 4.1 years; P=0.84) and OS (median, 6.0 years vs. not reached at >6 years; P=0.90) similar for auto- or allo-SCT ASH 2012 abstract
  39. 39. Autologous SCT: EBMT study • 171 auto-SCT in CR1 between 1996-2010 • Median patient age 48.3 (19-65) years • Conditioning regimen: TBI (63%) or chemotherapy (37%). • Peripheral blood as source of stem cells in 84% • Median follow-up of 2 years • 2-year OS 45% (+/-4%) and LFS 32% (+/-4%) • RI and NRM 54% (+/-4%) and 13% (+/-3%), • 2-year LFS increased from 22% (1996-2000) to 32% (2001- 2006) and 54% (2007-2010) p<0.001 • RI decreased from 65% to 47% and 46% (p=0.01) ASH 2012 abstract
  40. 40. Autologous SCT: EBMT study ASH 2012 abstract
  41. 41. Autologous SCT: summary • In the era of TKIs, auto-SCT may be considered potentially curative option for patients without sibling donors • Advantage: more profound responses achieved with TKIs post-transplant maintenance remains to be determined
  42. 42. 1. TKI in the treatment of ph+ ALL 2. Dose of chemotherapy with TKI 3. SCT with TKI: allo-SCT and pre/post-SCT TKI auto-SCT 4. Elderly
  43. 43. Elderly ph+ ALL • TKI + minimal chemo as induction resulted in high initial response • Post-remission therapy: - Myeloablative SCT not feasible - non-myeloablative or auto-SCT can be considered in fit patients - TKI + chemo
  44. 44. Elderly ph+ ALL: PETHEMA study Prephase Dexamethasone 10 mg/m2, i.v., days −5 to −1 Induction 1 Vincristine 1 mg (fixed dose), i.v., days 1, 8, 14, 22 Imatinib 400 mg/d, p.o. Dexamethasone 10 mg/m2, i.v., days 1, 2, 8, 9, 15, 16 Maintenance Mercaptopurine 50 mg/m2, p.o., daily Methotrexate 20 mg/m2, i.m., weekly Imatinib 400 mg/d, p.o. Reinduction cycles Dexamethasone 40 mg (fixed dose) p.o./i.v., days 1, 2 (every 3 months, 1st year) Vincristine 1 mg (fixed dose), i.v., day 1 (every 3 months, 1st year) Maintenance-2 Imatinib 400 mg/d, p.o. (3rd year) British Journal of Haematology Volume 159, Issue 4, pages 485–488, November 2012
  45. 45. Elderly ph+ ALL: PETHEMA study - 32 newly diagnosed ph+ ALL - median age 65 (56-82) - Induction response: 26 CR (84%); ED 4 (13%); NR 1 (3%) - Post-remission: death in CR 2/26 (8%), relapse 9/26 (35%), alive in CR1 15/32 (47%) - CR duration: median 37 months (13~43) - Median OS: 22 months - Median EFS: 21 months; 4-year EFS: 38% British Journal of Haematology Volume 159, Issue 4, pages 485–488, November 2012
  46. 46. Conclusions • Use of TKIs resulted in higher CR rate (95~100%) even with minimal chemotherapy • TKI-containing therapy followed by myeloablative allo-HSCT resulted in long-term survival of 50~60% in young adults; promising results also in non-myeloablative HSCT or alternative donor • Auto-HSCT can be reconsidered in case of profound or complete molecular response without suitable donor • TKI + chemo without SCT: - intensified chemo + TKI considered for young/fit patients - TKI + chemo in elderly remained to be improved • Optimal dose / duration of TKI remained to be determined

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