“La storia del trapianto allogenico: dal condizionamento a dosi convenzionali all’allo-RIC ed esperienza torinese ”

B Bruno

Divisione di Ematologia, Università di Torino, Italy

Orvieto, November 2009

Allogeneic transplants in MM patients from 1989 to 2009Allogeneic transplants in MM patients from 1989 to 2009

MUD

Pre 1989 221989 - 2008 1086

  Total MUD1989 71990 61991 151992 101993 151994 191995 211996 181997 281998 34 11999 34 22000 65 62001 81 82002 115 132003 128 102004 129 222005 103 252006 94 252007 94 302008 70 30

Myeloablative

Non-Myeloablative

New Drugs

Myeloablative conditionings

Timeline showing single Institutional reports:

Seattle1987 - 1999

Montreal1990 - 2000

Toronto1983 - 1995

Michigan1989 - 1995

Bologna1989 - 1992

Surrey1981 - 1998

Arkansas1992 - 1996

Boston1996 - 1999

Vancouver1988 - 1993

PatientsMedian age (range)

TRM CR (%)OS (%)months

Seattle(Bensinger - 2001)

136 <50(43-48)

48% day 10063% 1 year

34 22 (60)

Montreal(Le Blanc - 2001)

37 47(25 - 53)

22% 57 32 (40)

Toronto(Couban - 1997 )

22 43(25 – 53)

27% day 90 50 32 (36)

Michigan(Varterasian - 1997)

24 43(31 – 56)

25% 40 (36)

Bologna(Cavo - 1998)

19 43(36 - 50)

37% 42 21 (48)

Surrey(Gahrton - 2001)

33 38(30 – 53)

54% 37 36 (36)

Arkansas(Mehta - 1998)

42 45(29 – 59)

43% 41 29 (36)

Boston(Alyea - 2001)

24 46(36 – 54)

10% 55 (24)

Vancouver(Reece - 1995)

26 43(29 - 55)

19% day 100 62 47 (36)

Myeloablative conditioning

Myeloablative conditioningsSeattle experience:

• 136 patients (all < 60 y/o)• Treated between 1987 and 1999• Heavily pretreated pts

BU/CY TBI

Regimen

TRM Day 100 48%

Infections

GVHD

Day 365 63%

5 yr SURVIVAL 22%

Relapse-free SURVIVAL 14%

The reason for high TRM in MM patients remains unknown.

Detrimental myeloma effects on baseline organ functions

Increased risk of toxicity and infections given the severe immunodeficiency

Myeloablative conditionings

Impact of patient selection and better supportive care on outcome

Garthon G et al, Progress in haematopoietic stem cell transplantation for multiple myeloma, JIM, 2000

EBMT registry data:

690 MM patients

TRM

‘83-93 ‘94-98

6 mo 38% 21%

2 yr 46% 30%

of infections

Autologous SCT and Autologous SCT and Conventional Allogeneic CTConventional Allogeneic CT

Autograft versus Myeloablative allograftAutograft versus Myeloablative allograftSWOG 9321SWOG 9321

Barlogie et al. JCO 2006Barlogie et al. JCO 2006

Timeline showing advances in myeloma treatment

FDA approvation of Thalidomide

FDA approvation of Bortezomib in

refractory patients

FDA approvation of Bortezomib in patients who had recived at least one prior

therapy

FDA approvation of Bortezomib in first

line therapy

FDA approvation of Lenalidomide in patients

who had recived at least one prior therapy

Introduction of non-myeloablative

allogeneic SCT regimens in MM

(Maloney)

TBI-based non-myeloablative allogeneic

SCT in hematological malignancies (McSweeney)

Introduction of RIC-allogeneic SCT regimens in

MM(Kroger)

Standard-Allograft

Reduction of treatment related mortality from allogeneic SCT

High-dose conditioning

Autograft Allograft after reduced intensity

conditioning

Adoptive Immunotherapy

(DLI)

2 - 3Months

AllogeneicImmunotherapy

Kyle; Rajkumar, NEJM 2004

2. Dramatically reduced toxicity as compared to myeloablative regimens

1. Potentially Curative

Blood 2006;107:3474-3480

Garban, F. et al. Blood 2006;107:3474-3480Moreau, P. et al. Blood 2006;107:397-403

Busulphan 2 mg/kg/d x2 days,Fludarabine 25 mg/m2/d x5 days,ATG 2.5 mg/kg -5, -4, -3, -2, -1

Moreau P, Blood 2008

Long-term follow-up results of IFM99-03 and IFM99-04 trials comparing nonmyeloablative allotransplantation with autologous transplantation in high-risk de novo multiple myeloma.

Treatment Assignment *

PBSC mobilization

Autografting

Induction

(cyclophosphamide)

Autografting Low dose TBI (2Gy) and Allografting

(VAD - based regimens)

(Melphalan)

*Based on presence/abscence of an HLA matched sibling

“Pre” new drugs!!

60 enrolled in Auto - Allo

59 enrolled in Auto - Auto

199 with siblings

162 HLA-typed

58/60 (97%) completedProgram

46/59 (78%) completedProgram

245 Newly diagnosed patients<65y

No, n=82Yes, n=80 HLA-identical siblings

Intent-to-treat

46 no siblings

37 not HLA-typed:Refusal (n=9) Early death/ineligibility for high-dose chemotherapy (n=14)Ineligible donors (n=11)Unknown (n=3)

Refusal to allografting as first-line treatment (n=15)Iineligible donors (n=5)

Enrolled in intermediate-dose melphalan (n=20) Ineligible for high dose chemotherapy (n=3)

By Protocol

NEJM 2007

Intent-to-treat analysis (80 vs 82 pts) Median follow up: 6 yearsHLA-identical siblings vs no HLA-identical siblings

52 mo.29 mo.

35 mo.

“Pre” new drugs!!

Patients who completed protocols (58 vs 46 pts) Median follow up: 6 yearsAuto-Allo Vs Auto-Auto

64 mo.33 mo.

37 mo.

“Pre” new drugs!!

Estimates of cumulative incidence rates

Diagnosis

Induction treatment(VAD or equiv)

Response SD, PR or CRHLA-typing

Autologous stem cell harvest

HD-Melphalan + auto SCT

STUDY INCLUSION

HLA-id sibling No HLA-id sibling

RIC-allo transplant No treatment or 2nd HDM + auto SCT(optional)

CR

Continuous

No treatment

Relapse

PR

Treatment

DLI

Study design

BMT-CTN 0102: Schema

Melphalan 200 mg/m2

Auto HCT

Melphalan 200 mg/m2

Auto HCT

TBI 200 cGyMMF/CSPAllo HCT

MaintenanceThalidomide andDexamethasonefor 1 yr

Observation

Assigned based on HLA-ID sib

Randomized

Observation

age <70 At least 3 months of systemic

therapy 3-9 months from start of

therapy Autologous PBSC graft of

> 2 x 106 CD34 cells/kg per auto transplant

Maloney 2006

110 MM pts

Less than near CR after

autologous transplant

2° ABMT 85 pts

Allo-RIC 25 pts

Blade J, Blood, 2008Blade J, Blood, 2008

Figure 1A: progression-free survival from second transplant (median: 31months for 2nd ASCT and not reached for Allo-RIC, p=0.08).

Figure 1B: event-free survival (p=0.4)

Blade J, Blood, 2008Blade J, Blood, 2008

Blade J, Blood, 2008Blade J, Blood, 2008

Figure 1C: Panel C: overall survival from second transplant (median: 58 months for 2nd ASCT and not reached for Allo-RIC,p=0.9)

Blade J, Blood, 2008Blade J, Blood, 2008

Blood, 2009

A: Acute Graft vs Host Disease B: Transplant Related Mortality

Blood, 2009

A: Overall Survival B: Event Free Survival

Blood, 2009

A: OS by Kaplan-MeierB: EFS by KleinC: EFS by Kaplan-Meier

A

B

C

Blood, 2009

DLI with/without new drugs

Cox models for overall survival and event free survival

OVERALL SURVIVAL

Variable Univariate analyses Multivariate analyses

HR (95% CI) P value HR (95% CI) P value

Age* 1.07 (1.00-1.14) 0.056 2.01 (0.96-4.19) 0.063

Ig-G Myeloma 0.89 (0.39-2.04) 0.793 0.55 (0.20-1.52) 0.251

ISS 3 1.10 (0.76-1.58) 0.621 1.84 (0.56-6.01) 0.313

Disease in remission at allografting 0.44 (0.16-1.18) 0.104 0.46 (0.13-1.58) 0.216

HCT-Specific comorbidity Index > 1 0.58 (0.21-1.56) 0.277 0.49 (0.15-1.53) 0.218

EVENT FREE SURVIVAL

Variable Univariate analyses Multivariate analyses

HR (95% CI) P value HR (95% CI) P value

Age* 1.06 (1.01-1.10) 0.013 1.73 (1.12-2.68) 0.013

Ig-G Myeloma 0.95 (0.55-1.63) 0.846 0.52 (0.27-0.98) 0.043

ISS 3 1.23 (0.98-1.55) 0.076 2.15 (1.02-4.54) 0.044

Disease in remission at allografting 0.40 (0.21-0.75) 0.004 0.39 (0.18-0.82) 0.013

HCT-Specific comorbidity Index > 1 1.11 (0.63-1.96) 0.719 0.84 (0.44-1.60) 0.600

Blood, 2009

New drugs after allografting in myeloma

50%(20 mo)

NR66%NRLen (4)

Len+Dex (20)Relapse/

refractory59

(37-70)24

Lehmann et al

2008

NRNRNR§NRVel (7)Thal (9)

Vel+Thal (5)

No response to DLI

NR21/63Niels et al

2006

32% (36 mo) ^^^

17% (36 mo) ^^^

NR-Thal (NR)Vel (NR)Len (NR)

Relapse/ refractory ^^

56(44-64))

23/36Schmitt et al

2008

95%(7 mo) §

89%(7 mo) §

NR8 moVelSD, PR or

CR ^49

(32-68)18

Kroger et al2006

50%(13 mo)

50%(11 mo)

87%NRLen (8)

Len+Dex (8)Relapse/

refractory58

(43-67)16

Minnema et al

2008

90% vs. 62%***

(56 mo)

58% vs.35%***

(56 mo)

59%**NRThal (15) Vel (8) Len (2)

No CR after DLI *

50

(35-68)25/32

Kroger et al 2009

65% (18 mo)

NR73%20 moVel (11)

Vel+Dex (26)Relapse/ efractory

49 (27-64)

37El-Cheikh et

al 2008

NR50%

(6 mo)61%20 mo

Vel (9)Vel+Dex (14)

Relapse/ refractory

64 (48-

85)23

Bruno et al 2006

50%~ 15 mo §

NR 29%NRThalRelapse/

refractory54

(39-64)31

Mohty et al 2004

OS after salvage

treatment

PFS after salvage

treatment

OR(at least

PR)

Median time to salvage

DrugDisease status

Median age

Pts

NR: not reported; § see text; * DLI was administrated in 32 patients who achieved only partial remission after allogeneic SCT; ** percentage of CR obtained after DLI and treatment with new drugs; *** patient who achieved CR versus patients who did not achieve CR; ^ obtained after RIC allogeneic SCT; ^^ obtained before RIC allogeneic SCT; ^^^ calculated on all 36 patients.

A: Overall Survival B: Event Free Survival

del13q

No del13q

No del13q

del13q

13 pts.

26 pts.

13 pts.

26 pts.

Blood, 2009

Pros….

Depth of Response

Molecular Remissions

? Eradication

EBMT study:EBMT study: Pcr Neg Pcr Mixed Pcr posPatient number: 16 19 13Relapse at 5 years 0% 33% 100%

Corradini, Blood, 2003Corradini, Blood, 2003

Molecular Remissions after Myeloablative Transplants

Corradini, JCO, 1999Corradini, JCO, 1999

Allografting AutologousMolecular CR 50% 7%

Ladetto, JCO in pressLadetto, JCO in press

Autologous + Maintenance with Thal-Vel-DexMolecular CR 5/22 patients

0 3 6 9 12 15 18 21 24 months

Pt-3

Pt-5

Pt-4

Pt-7

Pt-1

Pt-2

Pt-6

40 MONTHS

60 MONTHS

Au t

o gra

ft

All

ogra

ft

Molecular Remissions after Auto-Allo Transplants

Pcr pos Pcr neg

M.W. Dgn +29 +29 +100 +100 +230 +230 +390 +390 +601 +601 Neg No M.W. BM PB BM PB BM PB BM PB BM PB BM Contr DNA

Graft vs. Myeloma Effects after Auto-Allo Transplants

Plasma Cell Infiltration > 90% (d +20) Graft-versus-Host Disease (d +50) Graft-versus-Myeloma (d +60)

Skin Biopsies (H&E)

Timing ….

Tandem AutoAllo in newly diagnosed patients

Allo at relapse

Need to reduce disease (pre-tx therapy/ more intense conditioning) Risk of higher toxicity and less response

- Higher rates of CR and less toxicity

Graft versus Hematological Malignancies

immunefailure

tumorescape

earlier phases

Donor immune-competent cells

later phases

Plasma cells

Siegel S et al J Immunol 2006

Stem Cell Harvesting

Mini-AlloAutoTx HLA

Typing Induction

“New drugs”

Velcade-thalidomide or lenalidomide

MEL 200 TBI2Gy

Tandem transplant phase

Post transplant phase

Maintenance

Lenalidomide (10 mg daily continuously)

Preliminary results

25 patients enrolled, 11 at least 1 month post allografting

Overall response rate 81% (9/11) at the time of allografting

After a median follow-up of 11 months (2-26), all patients are alive and the overall response rate was 91% (10/11).

Incidence of grade II-IV GVHD was 34% (4/11)

Chronic GVHD was observed in 40% (4/10) of patients with at least 3 months of follow-up.

Conclusions: Induction with lenalidomide, thalidomide or bortezomib does not impact feasibility and safety of tandem auto-allo.

Conclusions

Subgroup analyses are IMPERATIVE

30-35% in continuos CR (including molecular CR), median follow-up of 5-6 years

Only prospective clinical trials can establish their role in the setting of allografting

Most studies were designed before the introduction of new drugs

Allografting remains a treatment option for myeloma patients with a potential donor

New drugs are NOT mutually exclusive with an allograft, may decrease tumor burden and increase long term disease control post-transplant

Acknowledgments:

Divisions of Hematology

Alessandria (Dr Levis/Dr Allione)Candiolo (Prof Aglietta/Dr Carnevale-Schianca)Cuneo (Dr Gallamini/Dr Mordini)Bolzano (Prof Coser/Dr Casini)Pescara (Dr Di Bartolomeo/Dr.ssa Bavaro)Pisa (Prof Petrini/Dr.Benedetti)Udine (Prof Fanin/Dr.ssa Patriarca)Bergamo (Dr Rambaldi/Dr.ssa Barbui)Monza (Prof Pogliani/Dr Parma)MI-Osped. Maggiore (Prof Soligo)MI- Ist.Tumori (Prof Corradini/ Dr Montefusco)Rozzano- Humanitas (Dr Santoro/Dr. Castagna)Roma - Tor Vergata (Prof De Fabritiis)Roma -La Sapienza (Prof Foa, Dr.ssa Iori)Torino (Dr Vitolo/Dr Falda)Torino Universita (Prof Boccadoro/ Dr. B. Bruno )

FHCRC, SeattleR. Storb

D. MaloneyB. Sandmaier

Thank you

for

your attention !

IBMDR, GenovaS. Pollichieni

R. OnetoB. BrunoN. Sacchi