Philadephia chromosomal positive acute lymphoblastic leukemia Jiong HU

Philadephia chromosomal positive acute lymphoblastic leukemia Jiong HU Blood & Marrow Transplantation Center, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine

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

Background 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

Tyrosine kinase inhibitors (TKI) Agent FDA approved dose Mechanism Mutation Imatinib 600 mg/day - ABL inhibitor P loop mutation -Substrate of Pgp; Uptake by OCT-1 Dasatinib 140 mg/day - SRC/ABL inhibitior, more potent than IM - Not substrate of Pgp, penetration across the blood-brain barrier Nilotinib 150 -200 mg twice More potent than IM daily T 315 I / Khan S. US Pharm. 2012; 37(5)(Oncology suppl): 3 -7 Stock W. Leukemia & Lymphoma, 2010; 51(2): 188 -198

Tyrosine kinase inhibitors (TKI) Josep-Maria Ribera Leukemia & Lymphoma, 2012; Early Online: 1– 7

Tyrosine kinase inhibitors (TKI) - 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 Josep-Maria Ribera Leukemia & Lymphoma, 2012; Early Online: 1– 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

Intensity of chemotherapy in TKI era - 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 Josep-Maria Ribera Leukemia & Lymphoma, 2012; Early Online: 1– 7

TKI + chemotherapy: EWALL study - EWALL-Ph-01 Study (2007~2010): 71 pts with median age 69. 2 (58 -83) and FU of 3. 3 years - Treatment: Induction: Dasatinib 140 mg QD (100 mg >70 y) + weekly VCR 1 mg + DEX 40 mg 2 days (20 mg >70 y) x 4 weeks Consolidation: Dasatinib 100 mg/d sequentially with MTX 1 g/m² IV d 1 (500 mg/m² >70 y) + L-ASP 10, 000 UI/m² IM d 2 (5, 000 UI/m² >70 y) for cycles 1, 3, 5 or cytarabine 1 g/m²/12 h d 1, d 3, d 5 (500 mg/m² >70 y) 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 ASH 2012 abstract

TKI + chemotherapy: EWALL study - 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; T 315 I in 63%; F 317 L in 7%; V 299 L in 4% and no mutation in 7% ASH 2012 abstract

TKI + chemotherapy: EWALL study Additional chromosomal abnormality (ACA) at induction and molecular response were prognostic factors ASH 2012 abstract

TKI + chemotherapy: EWALL study - 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 British Journal of Haematology Volume 158, Issue 4, pages 506– 514, 2012

TKI + chemotherapy: Graaph-2005 study - Prospective randomized study - Patients: 18 -60 years untreated Ph+ ALL - Induction: arm A (IM-based): IM 800 mg on D 1 -28 + VCR (2 mg, D 1, 8, 15, 22) + DEX(40 mg D 1 -2, 8 -9, 15 -16, and 22 -23); arm B (IM/Hyper. CVAD): IM 800 mg on D 1 -14 + Hyper. CVAD - Consolidation: 1 cycle of MTX (1 g/m 2, D 1) + Ara. C (3 g/m 2/12 h, D 2~3) + IM 800 mg D 1 -14 followed by allo-SCT or autologous SCT ASH 2012 abstract

TKI + chemotherapy: Graaph-2005 study - Patients: 270 randomized and 265 were evaluable (133 arm A, 132 arm B; median age, 47 years; median follow-up, 40 months) Arm A n=133 Arm B n=132 P value CR rate cycle 1 98% 89% 0. 003 cycle 2 98% 91% 0. 006 1 9 0. 01 major response 44% 46% NS undetectable 10% NS Transplantation 80 allo/17 auto 77 allo/17 auto NS 3 -year EFS 46% 38% NS 3 -year OS 53% 49% NS Induction Death MRD response ASH 2012 abstract

TKI + chemo: Summary - 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

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

Role of stem cell transplantation in TKI era - 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 - 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 lead to relapse World J Stem Cells 2012 June 26; 4(6): 44 -52

Role of stem cell transplantation in TKI era 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

Allo-SCT in pre TKI era: International ALL Trial MRC UKALLXII/ECOG 2993 267 adult ALL without TKI as front-line therapy Blood August 1, 2008 vol. 112 no. 3 903 -909

Allo-SCT in post TKI era: GMALL study - Prospective multicenter GMALL study: 335 newly diagnosed Ph+ ALL - Treatment: imatinib 600 mg daily with chemotherapy (different starting time and duration) - CR rate: 85. 7~89. 4% - For all patients in CR 1, 219 patients (66. 4%) underwent SCT 3 -year and 7 year OS: 57% and 52% - For patients did not undergo SCT in CR 1: median OS of 9. 4 months; 3 -year OS 14% SCT in CR 1 remains the treatment of choice even in patients who achieve a good molecular response to initial therapy with TKI and chemo ASH 2010, 147

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

MDACC study - Retrospective study: adult 102; pediatric 11 - Sib donor (n=60), unrelated (n=40), cord blood (n=12), haplo (n=1) - CR 1(n=71), CR 2(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：CR 1 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

JALSG study - 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 CR 1 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) Leukemia (2011) 25, 41– 47

JALSG study Leukemia (2011) 25, 41– 47

Imatinib GRAAPH-2003 Study Biology of Blood and Marrow Transplantation Volume 19, Issue 1 , Pages 150 -155, 2013

Imatinib GRAAPH-2003 Study LALA-94 N=103 GRAAPH 2003 N=43 4 -year OS , 95%CI 4 -year DFS , 95%CI CIR% TRM in CR 20 (14 -26) 20(14 -28) 42(34 -50) 16 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. Biology of Blood and Marrow Transplantation Volume 19, Issue 1 , Pages 150 -155, 2013

Pre-SCT IM: GMALL study - Treatment: Arm 1: IM starting between IND and conso 1, then after conso 1 (n=51); Arm 2: IM starting 2 nd half of IND and throughout conso 1 (n=105); Arm 3: IM starting and throughout conso 1 (n=179) until SCT ASH 2010, 147

Pre-SCT IM: GMALL study No pts CR rate ED / NR A 1 N=51 / / A 2 N=105 89. 4% 5. 8% / 4. 8% A 3 N=179 85. 7% 11. 3% / 3% PCR negative * OS Pre-SCT rel 4. 2% 31% 11. 8% 12. 5% 40% 8. 7% 33% 50% 4% Post-SCT rel Post-SCT NRM 30. 8% 33. 3% 24. 3% 25. 7% 11. 3% 20. 8% earlier and prolonged IM is associated with superior treatment outcomes after SCT ASH 2010, 147

PKU Study - 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) J Hematology Oncology 2012

PKU Study Selection bias: more patients in the non IM group present poor prognostic factor such as severe gut GVHD, pancytopenia. J Hematology Oncology 2012

PKU Study J Hematology Oncology 2012

Post-allo-HSCT TKI: GMALL randomized study No pts Allo-SCT IM treatment Median D of IM Follow-up Alive in CR MRD + Duration of MRD- CR 5 -year OS prophylaxis 26 CR 1 23; CR 2 3 24/26 Pre-emptive 29 CR 1 27; CR 2 2 14/29 D+ 48 30 months 82% 10/26, 40% 26. 5 months 80% D+70 32 months 78% 20/29; 69% 6. 8 months 74. 5% P value 0. 046 0. 065 0. 84 ASH 2011 abstract

Post-allo-HSCT TKI: GMALL randomized study - 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 ASH 2011 abstract

TKI + allo-HSCT: Summary • 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

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

Autologous SCT: CALGB study 10001 • 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

Autologous SCT: CALGB study 10001 • 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

Autologous SCT: EBMT study 171 auto-SCT in CR 1 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% (20012006) and 54% (2007 -2010) p<0. 001 • RI decreased from 65% to 47% and 46% (p=0. 01) • • ASH 2012 abstract

Autologous SCT: EBMT study ASH 2012 abstract

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

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

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

Elderly ph+ ALL: PETHEMA study Prephase Induction 1 Maintenance Dexamethasone Vincristine Imatinib Dexamethasone Mercaptopurine Methotrexate Imatinib Dexamethasone Reinduction cycles Vincristine Maintenance-2 Imatinib 10 mg/m 2, i. v. , days − 5 to − 1 1 mg (fixed dose), i. v. , days 1, 8, 14, 22 400 mg/d, p. o. 10 mg/m 2, i. v. , days 1, 2, 8, 9, 15, 16 50 mg/m 2, p. o. , daily 20 mg/m 2, i. m. , weekly 400 mg/d, p. o. 40 mg (fixed dose) p. o. /i. v. , days 1, 2 (every 3 months, 1 st year) 1 mg (fixed dose), i. v. , day 1 (every 3 months, 1 st year) 400 mg/d, p. o. (3 rd year) British Journal of Haematology Volume 159, Issue 4, pages 485– 488, November 2012

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 CR 1 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

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