Allogeneic HSCT in elderliesa chimera?

Didier Blaise, MDAUBOH 2015, Bangkok

August 28th, 2015

Epidemiology

70 %

Smith,JCO 2009

AML in elderlies…5-year relative survival rates with

respect to age in patients with AML1

0

10

20

30

40

50

%

Age, years <45 45–54 65+55–64

1. Howlader N, et al (eds). SEER Cancer Statistics Review, 1975-2008 (2010); available at http://seer.cancer.gov/csr/1975_2008/

2. Appelbaum FR et al, Hematology Am Soc Hematol Educ Program 2001:62–86

OS in patients aged >55 years (ECOG data from 1973–1997)2

4y à 48 %

4y à 37 %

4

Allogeneic HSCT in elderlies• Needs to address

– Specific approaches• Conditioning• Graft• Donor

– Patient selection

5

RIC=Reduced intensity conditioning14 patients (2001-2003)Age : 62RICSibling :13/MUD : 1

6

Long-term Outcome372 patients (98-08)Age : 64 [60-75]HLA identical 91 %NMAC : Flu5/TBI2HCT-CI>3:47%

Sorror, JAMA 2011

5y 27% 5y 41% 5y 35%

Results need improvement

Age ≠ Prognostic

7

Prospective phase II clinical trialRIC MRD Allo HSCT

over the Age of 55 Years

75 patients

Age :60 [55-70]

Hematologic Malignancies

HLA Ident Sib

RIC : Flu5-Bu2-ATG2

Blaise, Haematologica 2015

2y 36 %

1y 9 %

2y 67 %

2y 51 %

8

RIC MRD Allo HSCT over the Age of 55 Years

2y 36 %

1y 9 %

2y 67 %

2y 51 %

9

75 patients

Age :60 [55-70]

Hematologic Malignancies

HLA Ident Sib

RIC : Flu5-Bu2-ATG2N NRM P OS P

Age< 60≥ 60

3342

12 %17 %

0,650 61%45%

0,579

Karnofsky index90-100≤80

4819

7%26%

0,020 42%56%

0,146

HCT-CI0-2≥ 3

2647

20%13%

0,514 39%62%

0,094

Disease risk indexLowIntermediateHigh/Very High

85312

13% 9%25%

0,500 88%56%31%

0,041

10

Patients reporting an impaired EORTC score one year after HSCT

Pain

Fatigue

Social Functining

Cognitive Functioning

Emotional Functioning

Physical Functioning

Role Functioning

Global Quality of Life

-40% -20% 0% 20% 40% 60% 80% 100%

81.3%

70.6%

75.0%

71.4%

82.4%

81.2%

63.2%

75.0%

Situation impaired when compared to day -6 Situation equal or not impaired when compared to day-6

RIC MRD Allo HSCT over the Age of 55 Years

Blaise D, et al. Haematologica 2015

• Patients (n=516)– Period: 2008-2012 – Median age at allo-HSCT: 63 years (range: 60-74)– Disease: Myeloid disorders (65%), Lymphoid disorders (35%) – Donors: HLA matched unrelated donors (URD) (96%) – RIC regimen: Fludarabine-based (91%)]– Stem cells source: PBSC (92%)– Disease status at allo-HSCT: early (65%), advanced (35%)– EBMT score: 75% with score ≥ 2– GVHD prophylaxis: CSA + MMF (47%), CSA + methotrexate (20%)

• No statistical difference between the group of patients with age < 65 years (60-65), N=374 (72%) and patients with age ≥ 65 years, N=142 (28%).

Allogeneic HSCT after RIC for patients ≥ 60 years with hematological malignancies using unrelated donors

Progression-Free Survival

Allo-HSCT in elderly patients

• PFS at 2 years:– Group ≤ 65 years: 42% (37-47), median = 14.5 months – Group > 65 years: 47% (39-56), median = 16.6 months

p=0.60

≤ 65 years> 65 years

Allo HSCT beyond 60 years: Institut Paoli Calmettes

• 2005 to 2014 • 263 patients• Median Fup:34 months

13

Age (médiane, extrêmes)

63 (60-72)

60-65 190 (72%)

65-70 65 (25%)

>70 8 ( 3%)

Sexe Femme 111 (42%)

Homme 152 (58 %)

HCT-CI ≥3 120 (45 %)

Diagnosis

ACUTE LEUKEMIA 95 (36%)AML 84

ALL 8

MIXTE 3

CML 4

CLL 13

LPC 1

LYMPHOMA 53 (20 %)NHL 51

HD 2

MULTIPLE MYELOMA 37 (14 %)MDS 41 (15 %)MYELOFIBROSIS 11

MDS/PMS 8

Disease Risk Index (DRI)Low 51(19 %)Intermediate 160(61 %)High/Very High 52(20 %)

SourcePBSC 234 (89%)

BM 9 ( 3%)

Cord Blood 17 ( 6%)

PBSC+BM 3 ( 1%)

Compatibilité HLAHLA Id Sibling 106 (40%)

MUD 97 (37%)

MMUD 28 (10%)

Haplo 32 (12 %)

ConditionnementNMAC 70 (26 %)

RIC 177 (67 %)

RTC 16 ( 6 %)

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GVH aigue II-IV 31 %III-IV 15 %

GVH chronique

Limitée/extensive 27%

Extensive 18 %

GVHD

16

HLA identical HSCT in 205 patients

17

J100 9%

1 an 23%

3 ans 28%

0 1 2 3 4 5

0.0

0.2

0.4

0.6

0.8

1.0

20560

12727

9515

689

404

244

0 1 2 3 4 5

0.0

0.2

0.4

0.6

0.8

1.0

20560

11324

7615

518

323

223

0 1 2 3 4 5

0.0

0.2

0.4

0.6

0.8

1.0

20560

11324

7615

518

323

223

0 1 2 3 4 5

0.0

0.2

0.4

0.6

0.8

1.0

20560

11324

7615

518

323

223

No différence!

OS

PFS

RINRM

HLA id Non HLA id

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HLA id HSCT in 205 pts

HLA identical Donors in elderlies?

- elderly- Comorbidities: frequent contra-indication for donation- Clonal hematopoiesis?

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What about siblings?

%

Genovese, NEJM 2014 20

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Alternative Donors? Haplo-ID HSCT

Retrospective Study of 2 strategies• Patients– Age > 55 years– High risk hematologic malignancies

• Innovation: Haplo HSCT patients : N=31– 5 to 2 Ag MM– Negative DSA– Modifications according to learning process: Graft, CDT

• Standard: UD and MRD: N= 47+63– Same period– 9 or 10/10– RIC: F5-BX2-ATG2

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HaploN 31

Median age 62 (56-73)HCT-CI > 2 58%Myeloid Malignancies 48%Active Disease 39%High/Very High DRI 35%CDT NMAC RIC TT-RTCF5BX2S2

21 (68%)6 (19%)4 (12%)

PBSCT 87%

HLA sibN 47

UDN 63

62 (55-71) 64 (60-68)55% 49%46% 51%

40% 30%25% 27%

100% 100%

100% 95%

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HaploN 31

Graft Failure 13-4 aGVHD 10%Ext cGVHD 0%NRM 9%Relapse 28%2y OS 70%2y PFS 67%2y PFS w/o ext cGVHD 67%

HLA sibN 47

UDN 63

0 013% 25%11% 15%10% 36%28% 29%77% 51%64% 38%51% 31%

Comparison of 2 allo HSCT strategies for patients older than 55 years and lacking MRD

• Primary Question– One year DFS w/o ext cGVHD

• Starting time: – Day of no MRD

• Population– High risk hematologic malignancies

• Numbers: 54 patients per arm• Secondary questions

– other– QOL – Economic evaluation

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• Prospective Study– HAPLO

• F5Bx2• Thiothepa: 5mg• HD Cy post HSCT• CyA+MMF

– MUD 10/10 and 9/10• F5Bx2• ATGx2• CyA+MMF

• Graft– PBSC

Conclusion• Feasibility of allo HSCT in elderly• No more GVHD! • HLA id is not a prerequisite!

• Needs– Better antitumoral activity– Lower toxicity by tailoring approach

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• Eligibility• Age 55-65 or Cormorbidities• Poor prognosis AML/MDS• HLA identical RD or UD

• Primary endpoint : 2 year PFS• Sample size: 177 patients

• Quality of life study• Economics• Non interventional PK• BX Pharmacogenomics

National Prospective Trial on dose intensity of conditioning

NCT0198506

DonorConditioning

Patient

-3 -2 -1-4-6 -5 0

GVHD prophylaxis

Chimerism

Individualized Immunotherapy

• Cellular therapy: DLI, NK-DLI , Treg• Tumor Antigen vaccination: WT1…• Post graft drugs: Aza, Lenalidomide,

anti-NKG2A moab…• CAR-T? Checkpoint inhibitors?

Allo-HSCT

Disease

Relapse

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Importance of Geriatric assessment

Muffly,Haematologica;2014 28

Oncogeriatric evaluationSelection and care…

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• Since 2012• Patients > 65 years• With Geriatric MDs- Pre-HSCT, 3 m, 1 y

Therapeutic Education Program (TEP)

• Labelized TEP• To improve OS and QOL

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Conclusion• Allo HSCT in elderly is achievable• Better outcome to be achieved if needs and reality of this population

taken into account

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Collaborations– FB Petersen, Intermountain HC, SLC– M Mohty, St Antoine, Paris– B Andersson, MD Anderson, Houston– L Luznick, E Fuchs, Johns Hopkins, Baltimore