Il trapianto allogeniconelle SMD ad alto rischio

Stella Santarone

Unità di Terapia Intensiva Ematologica per il Trapianto Emopoietico

Pescara

1) QUANTI pazienti con MDS vengono allotrapiantati?

1) QUANDO trapiantare la MDS?

2) QUALI sono i candidati per la tipizzazione HLA?

3) Esperienza di Pescara

4) Fattori prognostici post-trapianto – Studio GITMO

5) Terapia di condizionamento al TMO: Mieloablativo o non-mieloablativo?

6) Impatto prognostico della storia trasfusionale e del sovraccarico di ferro

7) Impatto prognostico del grado di fibrosi midollare

8) Impatto prognostico del disease tumor burden

9) CONCLUSIONI

AGENDA

La domanda

Perche’ si trapiantano più leucemie sel’incidenza delle MDS è la stessa se non

superiore?...

AML 188ALL 128

CML 108

MDS 36MM 36LYMPH 35

SAA 42

TM 132

OTHER 18

5%

HSCT in PESCARA 1976 – 2010 n = 723

26%

LeucemiaMieloideAcuta LeucemiaLinfa5caAcutaLeucemiaLinfa5caCronica LeucemiaMieloideCronicaMielMult/Plasmacell LinfomiTumoriSolidi MDS/MPSAnemiaAplas5ca ImmunodeficienzeTalassemia Errorigene5ciMalaDeAutoimmuni

AA:219

ID:144

Thal:329 IE:

52 AD:6

LMA:178526%

LLA:1186

LLC:147

LMC:548

MM/PCD:644

LY:880

ST:363

MDS/MPS:5668,2%

GITMO ALLOTRAPIANTI 2001-2005 n= 6869

Most common hematopoietic malignancy in the elderly

PEDIATRICS Annual incidence: ~ 1.8 per million <14 yrs

4 - 5% of all childhood leukemia

Myelodysplastic Syndromes

Age years Incidence (100.000 adults)

> 80 89

70-79 49

60-69 15

50-59 5,3

<50 0,6

Comorbid diseases significantly impact treatment option and outcome

Age at HSCT, by year

QUANDO trapiantare la MDS?

When to transplant ?

Intermediate 2/high-risk patients:immediate transplantation

Intermediate 1/low risk:delayed transplantation at progress

Characteristics of progression

clinically important cytopenia

increase of % marrow blasts or/and new chromosomalabnormality

QUALI sono i candidati per la tipizzazioneHLA?

Which patients are candidates for HLA typing ?

Patients under 55 years old: HLA typing of the patient andsiblings is recommended, irrispectively of the former’s riskclass or performance status

Patients more than 55 years old but less than 65 yearsold: HLA typing is recommended only for those with a goodperformance status (ECOG 1-2)

Evidence and consensus-based practice guidelines forthe therapy of primary MDS

A statement from the Italian Society of Hematology

Esperienza di Pescara

HSCT in MYELODISPLASTIC SYNDROMEPescara 1981 - 2010

N. of patients 36 (M 25 - F 11)

Median age, yr 50 (6 – 71)

Diagnosis – HSCT, mo 11 (5 – 105)

IPSS Low INT-1 INT-2 High AML-MDS

4118112

WPSS Low INT High Very High Unavailable

551745

15

21

DONORRELATED 28 HLA-id 23

1 ant. mm 2Haploid. 3

MUD 8 A,B,DR id 71 ant. mm 1

SOURCEBM 25PBSC 11

CONDITIONINGMAC 22 BU 16

TREO 5TBI 1

RIC 14 CTX 1TH+MEL± FLU 11TH+MEL+TBI 2

HSCT in MYELODISPLASTIC SYNDROMEPescara 1981 - 2010

All patients n = 36

Median follow-up mo 80 (12-230)

41%

DISEASE-FREE SURVIVAL @ 20 years

HSCT in MYELODISPLASTIC SYNDROMEPescara 1981 - 2010

<50 yr n=17 51%

>50 yr n=19 32%

Low/INT 1 n=15 47%

INT 2/High n=21 35%

Patient age IPSS

P=NS P=NS

HSCT in MYELODISPLASTIC SYNDROMEPescara 1981 - 2010

Conditioning Intensity

MAC n=22 48%

RIC n=14 36%

BM n=25 41%

PBSC n=11 39%

P=NS P=NS

Stem Cell Source

HSCT in MYELODISPLASTIC SYNDROMEPescara 1981 - 2010

Registro GITMO MDS Allo (1983-2006)

N= 783Median age 42 (0-71)

Source of HSC Conditioning

BM 396 Standard 331

PBSC 343 Reduced 174

BM+PBSCBM+CB

PBSC+CBCBUnk

1911212

Unk 2

Donor relation TBI Yes/No/Unk 219/531/1

Related 582 Alive Yes/No/Unk 364/412/7

Unrelated 195

Unk 6

Overall Survival: All patients

daysfromBMT

Overall Survival: Related vs Unrelated donor

daysfromBMT

Unrelated

Related

40%

32%

p=0.85

36%

Fattori prognostici post-trapiantoStudio GITMO

WHO CLASSIFICATION AND WPSS PREDICT POSTTRANSPLANTATION OUTCOMEIN PATIENTS WITH MDS: A STUDY FROM THE GITMO

Alessandrino EP et al. BLOOD 2008;112:895-902

MDS AML-MDSNo. of patients 238 127Median age, yr 48 (17-67) 47 (23-72)Time Dx-HCT,mo

9,5 (1-189) 8,3 (1-15)Type of donor Sibling MUD

166 (70%)72 (30%)

83 (65%)44 (35%)

Source of HCT PBSC / CB BM

139 (58%)99 (42%)

61 (48%)66 (52%)

Conditioning MA RIC

156 (66%)82 (34%)

89 (70%)38 (30%)

All patients (n=365) were classified according to:WHO – IPSS - WPSS

TRM

WHO category

IPSS category WPSS category

OverallSurvival

WHO category

IPSS category WPSS category

CONCLUSIONS

WHO classification and WPSS show a relavantprognostic value in posttransplantation outcome andmight help decision making in transplantation;

BIAS: retrospective study on a national transplantationregistry, patient selection, missing data, long period ofrecruitment, different types of transplantation;

A prospective validation of these results is needed

WHO CLASSIFICATION AND WPSS PREDICT POSTTRANSPLANTATIONOUTCOME IN PATIENTS WITH MDS: A STUDY FROM THE GITMO

Alessandrino EP et al. BLOOD 2008;112:895-902

Terapia di condizionamento al TMO:Mieloablativo o non-mieloablativo?

REDUCED-INTENSITY vs CONVENTIONAL CONDITIONING FOR ALLOSCT USING HLA-IDENTICAL DONORS IN MDS

Total number of patients 836 (IBMTR)

Conventional conditioning 621 median age 45 (18-67)Reduced intensity conditioning 215 median age 56 (27-72)

Martino R et al. Blood 2006;108:836-846

REDUCED-INTENSITY vs CONVENTIONAL CONDITIONING FOR ALLOSCT USING HLA-IDENTICAL DONORS IN MDS

NON RELAPSE MORTALITY and RELAPSE @ 36 months

REDUCED-INTENSITY vs CONVENTIONAL CONDITIONING FOR ALLOSCT USING HLA-IDENTICAL DONORS IN MDS

OVERALL SURVIVAL @ 36 months FROM A MULTIVARIATE COX MODEL

REDUCED-INTENSITY vs CONVENTIONAL CONDITIONING FOR ALLOSCT USING HLA-IDENTICAL DONORS IN MDS

CONCLUSIONS

The reduction in 3-year NRM after a heterogeneous group of

RIC indicates that the goal of reducing early NRM with RICs

has been accomplished, BUT at coast of a significantly

higher risk of relapse.

Thus, patients with no controindications for conventional

conditioning should NOT receive RIC outside of prospective

randomized trials.

CONVENTIONAL TRANSPLANT vs REDUCED INTENSITY CONDITIONING

THE OPTIMAL BALANCE OCCURS WHEN THE COMBINATION OF CT and GVL OUTWHEIGHS THE RISK OF RELAPSE, GVHD AND TRM

Porter DL Blood 2006;108:780-781

Impatto prognostico della storiatrasfusionale e del sovraccarico di ferro

TRANSFUSIONINDEPENDENT

TRANSFUSIONDEPENDENT

No. of patients 102 223Hemoglobin (g/dL) 9,7 (7,9-11,2) 8,6 (7,1-9,6)Platelets (x109/L) 64 (29-577) 46 (3-686)Ferritin (ng/ml) 426 (7-2260) 1326 (685-11800)

PROGNOSTIC IMPACT OF PRE-TRANSPLANTATION TRANSFUSION HISTORY ANDSECONDARY IRON OVERLOAD IN PATIENTS WITH MDS UNDERGOING ALLOGENIC SCT

Alessandrino EP et al. HAEMATOLOGICA 2010;95:476-484

ThecurveswereesNmatedfrommulNvariableCoxregressionanalysis

OverallSurvival Non-relapse Mortality

PROGNOSTIC IMPACT OF PRE-TRANSPLANTATION TRANSFUSION HISTORY ANDSECONDARY IRON OVERLOAD IN PATIENTS WITH MDS UNDERGOING ALLOGENIC SCT

Alessandrino EP et al. HAEMATOLOGICA 2010;95:476-484

ThecurveswereesNmatedfrommulNvariableCoxregressionanalysis

Overall Survival Non-relapse Mortality

PROGNOSTIC IMPACT OF PRE-TRANSPLANTATION TRANSFUSION HISTORY ANDSECONDARY IRON OVERLOAD IN PATIENTS WITH MDS UNDERGOING ALLOGENIC SCT

Alessandrino EP et al. HAEMATOLOGICA 2010;95:476-484

CONCLUSIONS

Pre-transplantation transfusion history and serum ferritinhave a significant prognostic value in MAC transplantsinducing a significant increase of TRM;

Patients with a long history of transfusion and evidenceof iron overload at time of transplantation might benefitfor a RIC regimen in order to reduce TRM;

The possible role of pre-transplant chelation therapy ismandatory in a prospective study.

PROGNOSTIC IMPACT OF PRE-TRANSPLANTATION TRANSFUSION HISTORY ANDSECONDARY IRON OVERLOAD IN PATIENTS WITH MDS UNDERGOING ALLOGENIC SCT

Alessandrino EP et al. HAEMATOLOGICA 2010;95:476-484

Impatto prognostico del grado di fibrosi midollare

Allogeneic stem cell transplantationfor myelodysplastic syndromes withbone marrow fibrosis

N. Kroger, Haematologica, 2011; 96 (2)291-297

CUMULATIVE INCIDENCEENGRAFTMENT TREATMENT‐RELATED

MORTALITY

RELAPSE

Allogeneic stem cell transplantation for myelodysplastic syndromes with bonemarrow fibrosis

N. Kroger, Haematologica, 2011; 96 (2), 291-297

P= 0.009

P= 0.04

P= 0.34

Disease-Free Survival Overall Survival

none none

mild/modmild/mod

severesevere

Months after SCTMonths after SCT

Allogeneic stem cell transplantation for myelodysplastic syndromes with bonemarrow fibrosis

N. Kroger, Haematologica, 2011; 96 (2), 291-297

Bone marrow fibrosis in MDS patients influences

engraftment after allogeneic SCT BUT ONLY

SEVERE bone marrow fibrosis affects survival

because of a higher risk of relapse, while MDS

patients with mild or moderate bone marrow

fibrosis have an outcome COMPARABLE to that of

MDS patients without bone marrow fibrosis.

CONCLUSION

Impatto prognostico deldisease tumor burden

Allogeneic stem cell transplantation for Adults with Myelodysplastic Syndromes:importance of Pretransplant disease Burden

Erica D. Warlick – Biol. Blood Marrow Transplant, 15: 30-38,2009

Cumulative incidence of RELAPSE @ 1 year<5% blasts versus 5-20% blasts

5-20% blasts= 35%

<5% blasts= 18%

p=.07

Cumulative incidence of RELAPSE @ 1 yearMAC conditioning versus NMA conditioning

MA= 16%

NMA= 35%

p=.07

Cumulative incidence of RELAPSE @ 1 yearCR or <5% blasts at HCT

MAC conditioning versus NMA conditioning

p=.04

NMA= 31%

MA= 9%

Disease-Free Survival@ 1 yearCR - <5% blasts - 5-20% blasts

CR= 80%

<5% blasts= 42%

5-20% blasts= 19%

p=.12

Erica D. Warlick – Biol. Blood Marrow Transplant, 15: 30-38,2009

CONCLUSIONS

Blast percentage <5% at HSCT is the major predictor of improved DFSand relapse and prior treatment to reach this disease status may havevalue in leading to improved DFS;

MA conditioning is associated with lower relapse risk, particularly inpatients with CR or <5% blasts, but is not able to overcome increaseddisease burden;

NMA conditioning yields equivalent TRM, DFS, and OS, and isreasonable in patients unsuited for MA conditioning;

The donor sources tested (PBSC, BM or CB) yielded similar outcomes.

Allogeneic stem cell transplantation for Adults with Myelodysplastic Syndromes:importance of Pretransplant disease Burden

CONCLUSIONSHSCTinMDS(1)

Allogeneic HSCT is a potentially curativetreatment for MDS

HSCT remains a high-risk treatment, however,and careful selection of patients is mandatory toensure that this treatment approach is justified

First choice therapy for patients < 55 yr with HLA-id sibling donor

MUD transplant feasible in patients whitout familydonor

CONCLUSIONSHSCTinMDS(2)

Relapse, GvHD and regimen-related toxicity stillremain problems, although a significant reduction ofTRM has been observed

Patients with INT-2 or HIGH RISK: HSCT as soonas possible

Patients with LOW or INT-1 RISK: HSCT may bepostponed

RIC transplant to be reserved to patients olderthan 55 yr or for patients with significativecomorbidities

CASO CLINICO

• Uomodi65anni• MDS–LMMoC:anemia–leucocitosi–piastrinopenia

• Idrossiurea,AzaciNdina,Trasfusioni(RBC20–PLT82)

• Altrapianto:IPSSIntermedio1–WPSSIntermedio

• Comorbidità(Sorror):5(obesità,fibrillazioneatriale,aspergillosipolmonare,FEV176%)

• NondonatorefamiliareHLAidenNco

• DonatoreMUDnonindicato(età>65anni)

• Unfiglio40anniAPLOIDENTICO(3/6)

• BlasNmidollarialtrapianto5%

• Splenomegalia18cm

• FerriNna983

• PazientefortementemoNvato

CASO CLINICO

Trapianto di midollo osseo non manipolato dadonatore familiare aploidentico

CONDIZIONAMENTOTBF-RIC

(Thiotepa 5 mg/Kg+Busilvex 6.4mg/Kg+Fludarabina 150 mg/sq)

PROFILASSI GvHD ATG-F, CSA, MTX, MMF, Basiliximab

CELLULE INFUSE MNC 0.69 x108/KgCD34 2,3 x106/KgCD3 33,7 x106/Kg

Trapianto di midollo osseo non manipolato dadonatore familiare aploidentico

RISULTATIATTECCHIMENTO PMN>500 g +27

PLT> 25.000 g +23

GvHD acuta e cronica ASSENTE

Follow-Up vivo in remissione completa +15 mesipost-TMO

Ultimo emocromo Hb 15, 7 – GB 8620 – PMN 4000PLT 153.000

TAKE HOME MESSAGE

TUTTI I PAZIENTI < 70 ANNI DOVREBBEROESSERE CONSIDERATI PER UNAPROCEDURA TRAPIANTOLOGICA…………