Transplant and Cellular Therapy Unit (U2T)Department of HematologyCentre de Recherche en Cancérologie, Inserm U891Institut Paoli Calmettes

CIC de Biotherapie de MarseilleUniversité de la MéditerranéeMarseille, France

Didier Blaise, MDDidier Blaise, MD

ALLOGENEIC STEM CELL TRANSPLANTATION FOR ACUTE MYELOBLASTIC LEUKEMIAS

2

3

INTERMEDIATE RISK GROUP

POOR RISK GROUP

LOW RISK GROUP

Score: Cytogenetics+WBC+FAB+NB of Induction course

4

Allo SCT for CR1 AMLAllo SCT for CR1 AML

Cornelissen, Blood, 2007

Allo SCT

Donor• Match sibling

Stem Cell Source• Bone Marrow

Conditioning• Standard Myeloablative

• TBI• No TBI

GVHD prophylaxis• CSA• CSA + MTX

Dis. Status• CR1 • CRn• advanced

PatientDisease• Cytology

Allo SCT

Donor• Match sibling• Match unrelated / MM unrelated

• Typing resolution• 6/6 vs 10/10

• MM Sibling

Stem Cell Source• Bone Marrow• PBSC• Cord Blood

Conditioning• Standard Myeloablative

• TBI• No TBI

• Reinforced Myeloablative• Reduced intensity• Non Myeloablative

GVHD prophylaxis• CSA• CSA + MTX• others• Ex vivo T Cell depletion• ATG

Dis. Status• CR1 • CRn• advanced

Patient• Age• Comorbidities

Disease• Cytology• Gen Abnormality• Response to Trt

Allo SCT

Donor• Match sibling• Match unrelated / MM unrelated

• Typing resolution• 6/6 vs 10/10

• MM Sibling

Stem Cell Source• Bone Marrow• PBSC• Cord Blood

Conditioning• Standard Myeloablative

• TBI• No TBI

• Reinforced Myeloablative• Reduced intensity• Non Myeloablative

GVHD prophylaxis• CSA• CSA + MTX• others• Ex vivo T Cell depletion• ATG

Dis. Status• CR1 • CRn• advanced

Patient• Age• Comorbidities

Disease• Cytology• Gen Abnormality• Response to Trt

8

TBI

No TBI?

1999- ? ?

9

The ideal preparative regimen for marrow transplantation of patients with malignant diseases should

Be capable of eradicating malignancy Have tolerable morbidity without mortality Have sufficient immunosuppressive effect … to avoid

graft rejection The search for an ideal preparative regimen serving all

these purposes have been a major focus … over the past 20 years

No ideal preparative regimen currently existsFinn B. Petersen and Scott I. BearmanPreparative regimens and their toxicity

In Bone Marrow tranplantation by SJ Forman, KG Blume and E Donnall Thomas, 1994

CONDITIONING REGIMEN IS A MAJOR STEP OF ALLOGENEIC TRANSPLANT

10

Which myeloablative conditioning regimen:Which myeloablative conditioning regimen:TBI or BTBI or Busulfanusulfan based regimen?based regimen?

Main concern of early days = engraftment.Main concern of early days = engraftment.

Total Body Irradiation:Total Body Irradiation: Highly myeloHighly myelo--ablativeablative

Highly immunosuppressiveHighly immunosuppressive

Few chemical drugsFew chemical drugs

Total Body Irradiation fulfilled expectations:Total Body Irradiation fulfilled expectations: Animal modelsAnimal models Clinical situationClinical situation

11

Bucy

Blood, 15 December 2001- Volume 98, Number 13

12

High Leukemia controlHigh Leukemia control Long term disease controlLong term disease control Usually high LFSUsually high LFS Higher survival in selected populationHigher survival in selected population

How to achieve better results?How to achieve better results?Higher disease eradication Higher disease eradication

•• higher TRMhigher TRMAttempt to decrease GVHDAttempt to decrease GVHD

•• higher relapsehigher relapse

Myeloablative Allogeneic stem cell transplantationMyeloablative Allogeneic stem cell transplantation

13

To decrease TRM by optimizing Conditioning intensity ??

DonorT Cell

Donormononuclear cell

Host cells

Conditioning regimenDisease

Endotoxin

IL2IFN G

IL1TNF@

IL1TNF@

14

15

To decrease TRM by optimizing Conditioning intensity ??

DonorT Cell

Donormononuclear cell

Host cells

Conditioning regimenDisease

Endotoxin

IL2IFN G

IL1TNF@

IL1TNF@

Minimal Conditioning ?Minimal Conditioning ? Intermediate Myeloablation?Intermediate Myeloablation? Reduced toxicity approach ?Reduced toxicity approach ?

16

Achievements after RIC Allo SCT N=100 CR1-2 AL : 100% Age: 33 (14-49) CDT: MAC = 100%

5 year LFS: 53% (42-61)

N=100 Age: 50 (18-64) CDT: RIC = 100%

5 year LFS: 60% (48-70)

CR1-2 AL+ age < 50: 24%

5 year LFS: 69% (48-84)

17

IS A RIC ALLO-SCT BETTER THAN ANOTHER?

n= 122n= 122 Status: CR 74% (CR1: 42%)Status: CR 74% (CR1: 42%) Donor: MRD: 48%Donor: MRD: 48% Not Eligible for STD ASCTNot Eligible for STD ASCT AGE: 57 (17AGE: 57 (17--74)74) TBI 2 Gy +/TBI 2 Gy +/-- FLUDAFLUDA CSA + MMFCSA + MMF

NRD:NRD: 16% at 2 yrs16% at 2 yrs Relapse:Relapse: 39% at 2 yrs39% at 2 yrs OS:OS: 48% at 2 yrs48% at 2 yrs LFS:LFS: 44% at 2 yrs44% at 2 yrs

U. Hegenbart, R. Storb et al.; JCO, 2006

Treatment for Acute Myelogenous Leukemia by LowTreatment for Acute Myelogenous Leukemia by Low--dose, dose, TotalTotal--body, Irradiationbody, Irradiation--based conditioning and hematopoietic based conditioning and hematopoietic

cell transplantation from related and unrelated donorscell transplantation from related and unrelated donors

CR1

UN

RELATED

RELA

TED

19

FAI:FAI: FLUDA: 120 mg/mFLUDA: 120 mg/m²² CYTARABINE: 4 g/mCYTARABINE: 4 g/m²² IDARUBICINE: 36 mg/mIDARUBICINE: 36 mg/m²²

FMFM FLUDA: 100FLUDA: 100--150 mg/m150 mg/m²² MELPHALAN: 140 mg/mMELPHALAN: 140 mg/m²²

20

* HIDAC* HIDAC Dauno (60 mg/mDauno (60 mg/m²²) day 1 and 2; ARAC: 3 g/m) day 1 and 2; ARAC: 3 g/m²² x 2/d over 3 H for 4 daysx 2/d over 3 H for 4 days

or HIDAC + HDM:or HIDAC + HDM: Melphalan 140 mg/mMelphalan 140 mg/m²²

InductionInduction ConsolidationConsolidation Intensive consolidation*Intensive consolidation* RICRIC

FBA (High ATG)

- 12

- 11

- 10

- 9

- 8

- 7

- 6

- 5

- 4

- 3

- 2

- 1

Fludarabine 30 mg/m2 X X X X X X Busulfan4 mg/kg X X ATG * 2,5 mg/kg X X X (X)

*: THYMOGLOBULINE*: THYMOGLOBULINE

FBA (Low ATG) - 12

- 11

- 10

- 9

- 8

-7

- 6

- 5

- 4

- 3

- 2

- 1

Fludarabine 30 mg/m2 X X X X X X Busulfan 4 mg/kg X X ATG * 2,5 mg/kg X

•• Pre AHSCT chemotherapyPre AHSCT chemotherapy

•• Allogeneic transplantAllogeneic transplant

Is there an alternative Is there an alternative to the toxicityto the toxicity--efficacy dilemma for AMLs?efficacy dilemma for AMLs?

n= 37Patient Age 52 (26-60)Pts with poor leukemic risk

poor risk cytogen. 2 induction courses WBC ≥ 30 x 109/l M0-M6-M7 FAB Secondary leukemia

24 (65)13 (35)10 (27)5 (14)4 (11)1 (3)

Pts with high clinical risk• Age > 50• Serious comorbidities

26 (70) 22 (59)10 (30)

Follow-up: months 36 (16-70)

Non relapse deathsDays

8% (0-17)89,176,1067

RelapseDays

22% (9-35)143 (71-566)

4Y Overall Survival 67% (49-81)

2 Year LFS 68% (50-80)

RIC AML for patients with CR1 AMLRIC AML for patients with CR1 AML

Blaise et al, Cancer 2005, updated

No cGVHD

cGVHDP=.003

22

Donor

No Donor

No Donor

Donor

ARE FURTHER PROGRESSES ACHIEVABLES?

REDUCED TOXICITY CONDITIONING?

DiseaseProgression

OrganToxicity

THERAPEUTICTHERAPEUTICWINDOW WINDOW

MyeloablationMyeloablation

Drug exposure to busulfan

I.V.

Oral

Which benefits with a Busulfan I.V. form ?Which benefits with a Busulfan I.V. form ?D

istr

ibut

ion

freq

uenc

y

Courtesy from C Puozzo

61 patients61 patients Conditioning:Conditioning:

IV BU: 0.8 mg/Kg x 16IV BU: 0.8 mg/Kg x 16 CY: 60 mg/Kg x 2CY: 60 mg/Kg x 2

Age : 37 (20Age : 37 (20--63)63) HLA matchedHLA matched--sibsib AML (43%); CML (27%); AML (43%); CML (27%);

MDS (15%); NHL/HD (15%)MDS (15%); NHL/HD (15%) Active disease: 75%Active disease: 75%

86% with AUC: 80086% with AUC: 800--15001500

No Graft failureNo Graft failure

T to .5 ANC: 13T to .5 ANC: 13

Full D Chimerism: 100%Full D Chimerism: 100%

100d TRM: 6/61 (9.8%)100d TRM: 6/61 (9.8%)

Fatal VOD: 2 (1 sFatal VOD: 2 (1 sndnd SCT)SCT)

2 year OS: 67%2 year OS: 67%

2 year DFS: 42%2 year DFS: 42%

Andersson et al, BBMT, 8, 145-154, 2002

IV Busulfan and Cyclophosphamide (IV BuCy2)IV Busulfan and Cyclophosphamide (IV BuCy2)for hematologic malignancies prior to Allo HSCT: for hematologic malignancies prior to Allo HSCT:

a phase II studya phase II study

Patients aged 55Patients aged 55--70 years 70 years Busulfex: 0.8 mg/kg IV x 16 dosesBusulfex: 0.8 mg/kg IV x 16 doses

PK on first, 2PK on first, 2ndnd and 13and 13thth dosedose Target an average of Target an average of 650 ng/ul650 ng/ul

Cyclophosphamide 60 mg/kg x 2 dCyclophosphamide 60 mg/kg x 2 d HLAHLA--ID or 10/10 matched MUDID or 10/10 matched MUD

Targeted BU-CY Program Phase II 3/06

Salt Lake City Intermoutain Blood and Marrow Transplant Program, FB Petersen, MD

Intensive supportive care Palifermin pre- and post prep. regimen Prograf + MMF as GVHD prophylaxis Ursodiol and Enoxeparin for SOS prophylaxis Mould, Candida, gram-neg and CMV ID

prophylaxis Higher PRBC Transf. parameters (Hct 28-30%) TPN if needs <50% >3d when indicated PBSC’s used All protocol driven

Patient Characteristics 17 enrolled, 13with Fup > 3 months

HLA Ident Sib: 10 MUD: 3

Age : 59 (55-66) Diagnosis:

AML: 9 (CR1: 8/CR2: 1) /MDS: 2/ MM: 2 (after auto)

Outcome F/U: 13 (3-28) months TRM:

Day 100: 0 GVHD related: 1

Relapse : 4 Alive in CR: 8

*Busilvex= 3.2 mg/kg/d3.2 mg/kg/d

FLUDA: 40 mg/m²/d x 4

BUSILVEX: 130 mg/m²/d* x 4

THYMO: 0.5, 1, 2 mg/kg D- 3, -2, -1 if MUD

De Lima M. et al., Blood 2004

Once dialy Intravenous Busulfan and Once dialy Intravenous Busulfan and FludarabineFludarabine: clinical and : clinical and pharmacokinetic results of a myeloablative reduced toxicity pharmacokinetic results of a myeloablative reduced toxicity

conditioning regimen for Allo HSCT in AML and MDSconditioning regimen for Allo HSCT in AML and MDS

VOD = 0VOD = 0TRM = 1%TRM = 1%

Survival - patients in CR at transplant

0 10 20 30 40 50 60 70 80 90

Time in months

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

port

ion

Surv

ivin

g

P=0.01

BuFlu

BuCy2

Patients in CRPatients in CR--AMLAMLI.V. BuFlu (FB4) vs. I.V. BuCy2I.V. BuFlu (FB4) vs. I.V. BuCy2

de Lima M et al. ASH 2006

BuFlu n= 148 AML(69 CR) and MDS, 53% MRD, 30% bad riskBuCy2 n= 67 AML(32 CR) and MDS, 79% MRD, 30% bad risk

Significant survival benefit with I.V. BuFlu compared to BuCy2 Significant survival benefit with I.V. BuFlu compared to BuCy2 due to a significant reduction in TRM (7% due to a significant reduction in TRM (7% vsvs 18%)18%)

29

-6 -5 -4 -3 -2 -1Fludarabine 50 mg/m² X X X X XIV Busulfan 3.2 mg/kg X X X XATG 1.5 mg/kg X X XCSA + MTX (1,3,6,11)

Once-Daily Intravenous Busulfan/Fludarabine with Thymoglobulin for Allo SCT from Matched Siblings Using :

A Myeloablative Regimen with Low Nonrelapse Mortality in All But Older Patients with High-Risk Disease

Russel et al, BBMT, 2008

30

Conclusions Allo HSCT remains the standard treatment for intermediate/high rAllo HSCT remains the standard treatment for intermediate/high risk isk

AML patients.AML patients.

How to improve current results: better selection of patients basHow to improve current results: better selection of patients based on:ed on: Disease statusDisease status Cytogenetic risk groupCytogenetic risk group CoCo--morbid conditionsmorbid conditions Choice of conditioning regimens Choice of conditioning regimens

Is there a best conditioning regimen? Is there a best conditioning regimen? TBI = Still most commonly used conditioning regimenTBI = Still most commonly used conditioning regimenI.V. Busulfan = an appealing alternativeI.V. Busulfan = an appealing alternativeMyeloablative or reduced intensity?Myeloablative or reduced intensity?

Ongoing prospective trialsOngoing prospective trialsResponse might vary : diagnosis, donorResponse might vary : diagnosis, donorIV BU + Flu? IV BU + Flu? ““The good from Standard and the good from RIC?The good from Standard and the good from RIC?””

31

32

33

34

35

CONCLUSIONS Cure is usually offered only onceCure is usually offered only once Individual prognosis is still to be determinedIndividual prognosis is still to be determined Biomarkers for individual prognosisBiomarkers for individual prognosis Allo SCT affords long term remission and cureAllo SCT affords long term remission and cure Debate remains openDebate remains open Goal of RIC approach: SCT Goal of RIC approach: SCT ImmunotherapyImmunotherapy

Complete chemotherapy approachComplete chemotherapy approach Search for improvements:Search for improvements:

Early post Graft ImmunomodulationEarly post Graft Immunomodulation

75% patients have no sibling donor75% patients have no sibling donor RIC and MUD/CB: will NRD be decreased enough?RIC and MUD/CB: will NRD be decreased enough?

The real challenge is the elderly populationThe real challenge is the elderly population

SEER Crude Incidence Rates LeukemiaSEER 13 Registries for 1998-2002

37

Don’t Forget Most of the knowledge we have is based on Most of the knowledge we have is based on

Patients under 50Patients under 50 CR1CR1 Myeoablative conditioningMyeoablative conditioning Geno identical Geno identical Bone Marrow Bone Marrow

Do not translate results right away intoDo not translate results right away into Elderly patientsElderly patients Advanced DiseasesAdvanced Diseases Reduced intensity conditioningReduced intensity conditioning Non GenoNon Geno--identicalidentical PBSC and Cord BloodPBSC and Cord Blood

Science is facts.Just as houses are made of stones,

so is science made of facts; but a pile of stones is not a house

and a collection of stones is not necessarily science.

Henri Poincaré

Mohamad Mohty, MDCatherine Faucher, MD

Sabine Fürst, MD

M. MohtyB Gaugler N VeyC Chabannon

C Faucher