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…………