Acute Lymphoblastic LeukemiaAcute Lymphoblastic Leukemia

Minimal Residual Disease as a

Surrogate Response Endpoint

ASH/FDA WorkshopWashington DC

June 25, 2005

COG ALL Risk GroupsB-Precursor ALL

COG ALL Risk GroupsB-Precursor ALL

• NCI Risk Groups• CNS Disease• Trisomies 4, 10, & 17• TEL/AML 1• MLL• BCR-ABL• Chromosomes <44• Rapidity of Response• MRD - End of Induction

Low Risk

Standard Risk

High Risk

Very High Risk

Early ResponseEarly Response

• Takes into account host and tumor variables that influence sensitivity and resistance• Prednisone “prephase” (BFM)• Fall in peripheral blasts after one week of

multiagent induction (St. Jude)• Day 7 blast content in bone marrow (CCG)

Historical Control(HC) CCG-1800s/1922 series vs.Current CCG-1950/60s(1956s) series

EFS Outcome by Day 7 Marrow(Remission at End of Induction)

0.4

0.5

0.6

0.7

0.8

0.9

1

0 2 4 6 8 10 12 14

M1 HC (n=2026)

M2 HC (n=913)

M3 HC (n=969)

M1 1956s (n=1904)

M2 1956s (n=1119)

M3 1956s (n=1089)5 Year EFS:

HC Current

M1 80.4% 82.6%

M2 74.0% 74.6%

M3 67.9% 69.0%

Pro

bab

ility

Years Followed

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 1 2 3 4 5 6 7 8 9 10 11 12

CCG-1882: Augmented Therapy Improves EFS for Patients with an SER (M3 Marrow at day 7)

Pro

bab

ility

Years Followed (from Randomization)

8-Year EFS RHR

BFM 52.3%(s.d. 6.5%) 1.9

Augmented BFM 70.2%(s.d. 6.7%) Baseline

Augmented BFM (n=155)

BFM (n=156)

Log Rank p=.0006

Nachman et al., NEJM 338: 1663-1671, 1998

DATA UPDATED DEC 2004

Assessment of Early Response: Integration of MRD into Clinical Trials

Assessment of Early Response: Integration of MRD into Clinical Trials

• Morphologic assessment is a crude, but accurate and reproducible way to identify patients likely to have good or bad outcomes

• PCR or flow cytometric assessment of MRD• More sensitive and could be more accurate way to

identify groups for risk-adapted therapy• Results will vary based on:

• MRD timepoint analyzed• Therapy prior to MRD analysis• Sensitivity of MRD assay utilized

Major Techniques Used to Assess MRD in Leukemia

Major Techniques Used to Assess MRD in Leukemia

• Flow cytometry detection of leukemia associated phenotypes• Applicable in almost all cases• Fast, relatively inexpensive• Less sensitive than molecular methods

• Probably sensitive enough for identification of HR patients

• PCR amplification of antigen receptor loci (Ig or TCR)• Applicable to ~80% of cases• Laborious and expensive (10 x flow), but very sensitive

• Better for identification of LR patients??• PCR amplification of fusion transcripts only suitable for

defined molecular subgroups such as Ph+ ALL (40%)

Prognostic Significance of End Induction MRD: BFM-Austria

Prognostic Significance of End Induction MRD: BFM-Austria

• Many pilot studies show that MRD levels early in therapy are predictive of outcome

.01%-.1%<.01%

>0.1%

Dworzak et al. Blood 99: 1952, 2002

N=17

Early ResponseEarly Response• All studies show correlation between MRD and

outcome

End Induction MRD

Percent of Patients

EFS

(3 year)

No MRD 42% to 75% > 90%

< 10-3 20% to 42%

> 10-2 5% to 16% 26% to 28%

AEIOP ALL 2000/ALL-BFM 2000: Risk Stratification

AEIOP ALL 2000/ALL-BFM 2000: Risk Stratification

• Standard risk group (SR)• Prednisone good response + M1 day 33 AND• Negative MRD (<10-4) at day 33 and week 12 AND• No t(9;22) or t(4;11)

• Medium risk group (MR)• Prednisone good response + M1 day 33 AND• No t(9;22) or t(4;11) AND• Not SR or HR on MRD criteria

• High risk group (HR)• Prednisone poor response or not M1 day 33 OR• t(9;22) or t(4;11) OR• MRD >10-3 at week 12

MRD-SR .97, SE=.03 (N= 39, 1 event)MRD-MR .77, SE=.05 (N=160, 23 events)MRD-HR .38, SE=.06 (N=114, 57 events)

years

p: 1-2 .05 1-3 .0001 2-3 .0001

dsm

c040

5.ta

b 1

3AP

R05

P

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5

AIEOP + ALL-BFM 2000, EFS (4 years)

Risk Group HR 95 by MRD Risk Groups

Pts enrolledSep/Jul 00–Oct 04(Status April 05)

Data courtesy of Valentino Conter and Martin Schrappe

Reducing Disease Burden Pre-Transplant Improves OutcomesReducing Disease Burden Pre-Transplant Improves Outcomes

Uzunel et al. Blood 2001

TumorTumor

Dx

d29

POG ALinC17 to Date:> 2,000 samples

received95% compliance

MRD Sensitivity 1/1000 - 1/10,00024 hr turn around

28.6% of patients positive; Median .069%

Residual Disease Monitoring at End Induction: Flow Cytometry

Residual Disease Monitoring at End Induction: Flow Cytometry

0

20

40

60

80

100

120

140

160

180

End Induction Marrow 534/1937 (28%) of Cases Positive Overall

End Induction Marrow 534/1937 (28%) of Cases Positive Overall

No. ofcases +

<.01 .01-.1 .1-1.0 1.0-10 >10

Percent Leukemic CellsMichael Borowitz

Day 29 Flow MRD Correlates with NCI Risk Group

Day 29 Flow MRD Correlates with NCI Risk Group

0

5

10

15

20

25

30

>.01% >0.1%

std risk n=1046high risk n=546

% MRD +

MRD level

Median .043% LRMedian .14% HR

Michael Borowitz

Day 29 Flow MRD Correlates with Day 8 Morphologic Assessment of ResponseDay 29 Flow MRD Correlates with Day 8 Morphologic Assessment of Response

0

10

20

30

40

50

>0.01% >0.1%

<5%5-24%>25%

Day 8 MarrowBlasts

%MRD +(n=1879)

MRD level

p<.001

Michael Borowitz

Prognostic Significance of MRD - 9906Prognostic Significance of MRD - 9906

EVENT-FREE SURVIVAL

0

20

40

60

80

100

0 1 2 3 4 5

Years

Pro

bab

ility

(%

)

MRD>.01% MRD Negative

p-value=0.00304

n=79

n=156

0

20

40

60

80

100

0 1 2 3 4 5

Years

Pro

babi

lity

(%)

Negative

0.01-0.1

0.1-1.0

> 1.0 p-

Minimal Residual Disease 9906Minimal Residual Disease 9906

169

2133

24p=.0054

Challenges of Marrow RelapseChallenges of Marrow Relapse

• Despite the success in treating newly diagnosed ALL, outcomes following marrow relapse remain poor• Many relapses occur in favorable risk patients• It is difficult to predict response to retrieval

therapy• Attempts to further intensify therapy have

generally not led to improvements in outcome

Obstacles to Successful Treatment for Relapsed ALL

Obstacles to Successful Treatment for Relapsed ALL

• Remission re-induction failures

• Early second relapse

• Regimen-related toxicity

Remission Re-induction RatesRemission Re-induction Rates

Remission induction/re-induction rates

Newly diagnosed ALL

> 98%

Late marrow relapse

> 90%

Early marrow relapse

~ 75%

Obstacles to Successful Treatment for Relapsed ALL

Obstacles to Successful Treatment for Relapsed ALL

• Depth of second CR is shallow• 30-40% of patients who achieve a second

remission develop an early subsequent recurrence

• Significant regimen-related toxicity • Toxic death rates of 3-8% on average• Further intensification likely to be of limited

value

Higher Risk Relapse: Common Therapeutic Approaches

Higher Risk Relapse: Common Therapeutic Approaches

Early Marrow/T-cell Late Marrow/Early EM

Chemotherapy Alt Donor SCT

Matched Related Donor Transplant

Block 1 Block 2 Block 3

Early Marrow Late Marrow Early CNS Early Testicular

Common Re-induction

Introduction of New Agents in Patients with Very High Risk of Treatment FailureIntroduction of New Agents in Patients with Very High Risk of Treatment Failure

Re-induction

Block 1

Re-induction

Block 2

Reduction Phase

VCR, Pred, PEG, Adr

Re-induction

Block 3

ARA-C, ASPCTX, VP-16, MTX

VCR, Pred, PEG, Adr

ARA-C, ASPCTX, VP-16, MTX

MR

D

Time

MRD

MRDEpratuzumab

Pilot I

New Agent Pilot

Correlate with 4 month EFS

BLOCK 1 BLOCK 2 BLOCK 3

VCR days 1,8,15,22 CTX days 1-5 ARA-C days 1,2,8,9PRED days 1-29 VP-16 days 1-5 L-ASP days 2,9PEG days 2,8,15,22 IT MTX (ITT) days 1,22 DOXO day 1 *HD MTX day 22IT ARA-C day 1 (*count dependent)IT MTX days 15 ,29 (CNS -) ITT days 8,15,22,29 (CNS +)

* Imatinib is also given in combination with chemotherapy for Ph+ relapse

COG: AALL01P2COG: AALL01P2

AALL01P2 Study Design

Continuation Therapy

MRD

ARM A

MRD

MRD

Block 2

MRD

MRD

ARM B

Block 2

MRD

Block 1Block 1

Block 3

Block 3

On Study

Randomization

CNS + patients non-randomly assigned to ARM B

DNA Arrays DNA Arrays

MRD Detection During Treatment of Relapse: AALL01P2

MRD Detection During Treatment of Relapse: AALL01P2

Time

Point

MRD+ Median MRD level

1 66/101(65%) 0.73%

2 31/63 (49%) 0.19%

3 16/46 (35%) 0.34%

Slide courtesy of Mike Borowitz, MD, PhD

Correlation of MRD with Time of First Relapse: AALL01P2

Correlation of MRD with Time of First Relapse: AALL01P2

Time

Point

MRD+

Early Relapse

MRD+

Late

Relapse

p value

131/41 (76%)

14/29 (48%)

.018

218/22 (82%)

9/21

(43%).009

39/15

(60%)

3/19

(16%).01

Borowitz, et al. ASH 2004

Kinetics of MRD Response:Good Responders (34/46)Kinetics of MRD Response:Good Responders (34/46)

0.001

0.01

0.1

1

10

100

1 2 3

Time point

% M

RD

(n=15)

(n=8)

(n=11)

Epratuzumab: Mechanism of ActionEpratuzumab: Mechanism of Action

• Highly selective for CD22 positive B-precursor and B-Cells

• Alters lymphocyte adhesion & homing

• Reacts across B-cell lymphoma subtypes

• Minimal activity with normal non-lymphoid tissues

• Mechanisms of action:• Antibody-dependent cellular cytotoxicity• Complement-mediated lysis

6C-C

7C-C

2C-C

5C-C

3C-C

1C-C

4C-C

Leonard and LinkSeminars in Oncol 2002

CD22Epratuzumab

Carnahan et alClin CA Res 2003

Human IgG1

Murine CDRs

New Agent Initiatives: EpratuzumabADVL04P2 (Early Relapse)

New Agent Initiatives: EpratuzumabADVL04P2 (Early Relapse)

Block 1 Block 2 Block 3

MRD

Triple Induction

Phase 2

Block 1 Block 2 Block 3

Triple InductionReduction Phase

6 dose levels

Response

Phase 1

E-mab

MRD – Surrogate EndpointMRD – Surrogate Endpoint

• MRD Endpoints• MRD + vs. MRD-

• End Induction• Pre – BMT (after block 3)

• Median MRD Value• Slope of MRD Reduction

• R1, R2, R3

ConclusionsConclusions

• MRD is a Powerful Predictor of Outcome • MRD Measurements Can be Integrated into

Multi-institutional Trials• MRD Can Be Used To Track Response to New

Agents in the Context of Multiagent Re-induction• Data Indicates That MRD can Be Used as an

Endpoint to Assess Efficacy• Prioritize New Agents for Conventional Trials• Gain Accelerated Approval

Steve HungerNaomi Winick

Elizabeth RaetzMichael Borowitz

AcknowledgementsAcknowledgements