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: overview2. Dose of chemotherapy with TKI3. SCT with TKI: allo-SCT and pre/post-SCT TKI auto-SCT4. Elderly

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

Tyrosine kinase inhibitors (TKI)

Khan S. US Pharm. 2012;37(5)(Oncology suppl):3-7Stock 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 theblood-brain barrier

T315I

Nilotinib 150-200mg twice daily

More potent than IM /

Tyrosine kinase inhibitors (TKI)

Josep-Maria Ribera Leukemia & Lymphoma, 2012; Early Online: 1–7

- 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

1. TKI in the treatment of ph+ ALL2. Dose of chemotherapy with TKI3. SCT with TKI: allo-SCT and pre/post-SCT TKI auto-SCT4. Elderly

- 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

- 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

- 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

ASH 2012 abstract

Additional chromosomal abnormality (ACA) at induction and molecular response were prognostic factors

TKI + chemotherapy: EWALL study

TKI + chemotherapy: EWALL study

British Journal of HaematologyVolume 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

- 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

- 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

- 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

1. TKI in the treatment of ph+ ALL2. Dose of chemotherapy with TKI3. SCT with TKI: allo-SCT and pre/post-SCT TKI auto-SCT4. Elderly

- 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

LSCs lead to relapse

.

Role of stem cell transplantation in TKI era

World J Stem Cells 2012 June 26; 4(6): 44-52

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

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

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 CR1 remains the treatment of choice even in patients who achieve a good molecular response to initial therapy

with TKI and chemo

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)

- 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

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)

JALSG study

Leukemia (2011) 25, 41–47

Imatinib GRAAPH-2003 Study

Biology of Blood and Marrow TransplantationVolume 19, Issue 1 , Pages 150-155, 2013

Biology of Blood and Marrow TransplantationVolume 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.

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

Pre-SCT IM: GMALL study

ASH 2010, 147

A1 A2 A3No pts N=51 N=105 N=179CR 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

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

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.

J Hematology Oncology 2012

PKU Study

prophylaxis Pre-emptive P valueNo pts 26 29Allo-SCT CR1 23; CR2 3 CR1 27; CR2 2IM treatment 24/26 14/29Median D of IM D+ 48 D+70Follow-up 30 months 32 monthsAlive in CR 82% 78%MRD + 10/26, 40% 20/29; 69% 0.046Duration of MRD- CR 26.5 months 6.8 months 0.0655-year OS 80% 74.5% 0.84

ASH 2011 abstract

Post-allo-HSCT TKI: GMALL randomized study

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

• 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

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 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

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

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

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 TKIspost-transplant maintenance remains to be determined

1. TKI in the treatment of ph+ ALL2. Dose of chemotherapy with TKI3. SCT with TKI: allo-SCT and pre/post-SCT TKI auto-SCT4. 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 Dexamethasone 10 mg/m2, i.v., days −5 to −1

Induction 1Vincristine 1 mg (fixed dose), i.v., days 1, 8, 14, 22Imatinib 400 mg/d, p.o.Dexamethasone 10 mg/m2, i.v., days 1, 2, 8, 9, 15, 16

MaintenanceMercaptopurine 50 mg/m2, p.o., dailyMethotrexate 20 mg/m2, i.m., weeklyImatinib 400 mg/d, p.o.

Reinduction cyclesDexamethasone 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 HaematologyVolume 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 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 HaematologyVolume 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