anemias: the current situation

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1 Bone Marrow transplantation in rare anemias: the current situation Dr. Daria Pagliara, MD Pediatric Onco Haematology Department Ospedale Pediatrico Bambino Gesù, Rome 4th European Symposium on Rare Anaemias Sofia, 20th November 2011

2 Good Blood Good Chelator(s) Good Doctors Morbidity and Mortality Overall Survival Median age of Italian Thalassemic patients Pt referred to specialized centers (IC) vs non specialized Forni et al Am J Hematol

3 Palliative therapeuthic approaches: limitations transfusion and iron chelation therapy iron accumulation in different organs Serious causes of both morbidity and death viral infections transmitted with blood transfusions Cost of the treatment are relevant per patient/year in UK Chelation therapy (57%) Transfusions (36%) Surgical procedures (4%) Laboratory tests (3%) Is it possible a curative approache? Indications to ALLO HSCT - Acute lymphoblastic leukemia - Hemoglobinopathies - Acute myeloid leukemia - Severe combined immunedeficiencies (SCID) - Chronic myeloid leukemia - Wiskott-Aldrich Syndrome - Myelodysplastic syndromes - Hemophagocytic lymphohistiocytosis - Lymphomas/myeloma - Chédiak-Higashi Syndrome - Congenital aplasia (Fanconi anemia, congenital dyskeratosis) - Diamond-Blackfan anemia - Severe aplastic anemia - Chronic granulomatous disease - Infantile malignant osteopetrosis - Immune-deficiency with hyper- IgM - Congenital errors of metabolism (Hurler, Maroteaux-Lamy, adrenoleukodystrophy, metachromatic leukodystrophy) Β Thalassemia Sickle cell Disease

4 Seattle Dec 2, HLA identical transplants Adult and pediatric patients (aged 1 through 35 years) 1 Dec. 17, 1981 June 17, THALASSEMIA FREE SURVIVAL Probability % YEARS Pesaro, June 2001

5 What did we learned from HSCT in Thalassemic patients? Risk factors for HSCT Criteria for stratifying patients Chelation Hepatomegaly Hepatic Fibrosis Regular vs Irregular Absent vs Present Absent vs Present Lucarelli G, et al. N Engl J Med 1990; 322: Class I No hepatomegaly No portal fibrosis History of regular chelation Class II One or two of the risk factors Class III Hepatomegaly (>2 cm below costal margin) Portal fibrosis History of irregular chelation

6 109Adult Thalassemia Busulfan 14 mg/kg Cyclophosphamide mg /kg 1 Probability SURVIVAL THALASSEMIA FREE SURVIVAL NON REJECTION MORTALITY 66% 62% 36% REJECTION 4% YEARS The challanges for HSCT in patients with thalassemia Do we have alternative strategies to reduce the risk of TRM?

7 Sources of hematopoietic stem cells Bone Marrow (Since 1968) Cord Blood (Since 1988) HSC Peripheral Blood (after mobilization with G-CSF, since 1989) Cord blood stem cells transplantation Pros Immediate availability No need of surgery procedure for the donor Low risk of acute/chronic GvHD Cons Recipient body weight/number of infused cells Slower immunological reconstitution No infusion of memory cells Rocha V et al. N Engl J Med 2000;342:

8 EUROCORD Related Cord Blood Transplant in Patients with Thalassemia and Sickle Cell disease F. Locatelli, V. Rocha, W. Reed, F. Bernaudin, M Ertem, S Grafakos, B Brichard, X Li, G. Giorgiani, A Nagler, N. Tannoia, Lubin BH, Gluckman E. on behalf of Eurocord Cord Blood Transplant Group Eurocord Registry Locatelli F, et al. Blood 2003; 101: EUROCORD Overall survival probability 100 Survival probability = 100% 80 Probability (%) Months after CBT Locatelli F, et al. Blood 2003; 101:

9 The challanges for HSCT in patients with thalassemia Do we have alternative strategies to reduce the risk of TRM? How can we increase the number of How can we increase the number of patients treated with HSCT?

10 1% Family donor 25% HLA compatible 1 HLA locus disparate 70 75% Need alternative donors WORLD > Unrelated Bone Marrow Donors registered worldwide in ~ 40 registries ~ UBMT performed EUROPE ~

11 Probability of locating a suitable unrelated donor Positive result of donor search ranged from: 51% for BMT Centers in Sardinia to 32% for the other BMTC Centers, mainly dealing with patients belonging to mixed ethnical groups. MUD transplantation vs sibling Conclusions from 90 report: Higher incidence of acute/chronic GvHD Increased percentege of rejection Higher transplant related mortality (TRM)

12 How to lead in terms of outcome the results obtained from familiar donor comparable to those obtained with unrelated donor? Reducing the risks of immune complications, namely GvHD and rejection, through selection of donors identical at extended HLA loci using high resolution molecular typing. 132 MUD transplanted Thalassemia Patients median age 14 (1 35) Overall survival = 85,5% 5% Thalassaemia-free survival = 77,4% Probability Mortality = 14,5% Rejection = 10,7% Months after transplantation

13 81 Class 1and 2 MUD transplanted Thalassemia patients median age 7 (1 25) 51 Class 3/Adult MUD transplanted Thalassemia patients median age 19.5 (6 35) Risk Class 1,2 - Overall survival = 93,4% Risk Class 1,2 - Thalassaemia-free survival = 84,2% Risk Class 3 - Overall survival = 72,9% robability Pr obability Pro Risk Class 3 - Thalassaemia-free survival = 66,7% Risk Class 3 - Mortality = 27,1% Risk Class 1,2 - Rejection = 12,2% Risk Class 3 - Rejection = 8,5% Risk Class 1,2 - Mortality = 6,6% Months after transplantation Months after transplantation PROBABILITY (95% CI) Thalassemia-free survival by donor 1.0 MFD: 92% (80 100) )MUD: 87% (73 100) MFD: N = 28; E = 2 MUD: N = 29; E = 3 P = N.S YEARS AFTER BMT Pediatric Hematology / Oncology Policlinico San Matteo University of Pavia, Italy.

14 How to reduce the toxicity related to the conditioning regimen? Thalassemia and conditioning regimen Busulfan: Inhable to completely prevent a primary or secondary graft failure Associated to relevant life threatening complications (VOD, TTP) Treosulfan: Myelosuppressive (killing of immature and committed hematopoietic progenitors) e myeloablative (immunosoppressive action against B and T lymphocite) Well tolerated, even in children younger 2 years; Limited toxicity; Linear pharmacocynetic; Not interfere with fertility

15 Eligibility criteria for HSCT in patients with SCD Previous history of stroke Frequent episodes (more than 3 per year) of vaso occlusive crises and/or acute chest syndrome Multiple osteonecrosis RBC alloimmunization Abnormal velocity of arterial flow at transcranial Doppler Bernaudin et al. BLOOD 2007

16 Bone marrow transplantation from HLA identical sibling in SCD patients Bernaudin et al. BLOOD 2007 DBA and HSCT (1) who undergoes HSCT? Transfusion dependent patients Availability of a matched related donor (CB or BM) Availability of a MUD (BM) When performing HSCT? < 10 years (better between 2 and 5 years) bacause on iron overload indipendent prognostic factor British Journal of Haematology, 2008, 142:

17 DBA e HSCT (2) HSCT is at the moment the only curative therapy Few and controversial data in litterature The experience in our Centre: No differences between MFD e MUD in terms of outcome No differences between BM stem cells and CB stem cells from a sibling donor in terms of outcome Few and controversial data about CB stem cell transplantation from unrelated donor Haematologica 2011;96(01): Patient characteristics Number of patients 122 (100%) Gender ratio (M/F) 71 / 51 (58% / 42%) HCMV serology (donor/recipient) Positive/positive 42 (34%) Positive/negative 26 (21%) Negative/positive 28 (23%) Negative/negative 15 (12%) Missing/unknown 1 (9%) Pesaro risk class at HSCT Class 1 39 (32%) Class 2 41 (34%) Class 3 16 (13%) Class AD 26 (21%) HCV (P/N) 13 / 97 (12% / 88%)

18 Transplant procedure Age at BMT (years) 10.5 (1.5 31) Stem cell donor: Unmatched donor 122 (100%) Stem cell source: Bone marrow 122 (100%) Conditioning regimen Bu + CPN 13 (11%) Bu +Flu +TT 33 (27%) Treo + Flu + TT 35 (29%) Bu + Cy + TT 41 (34%) Number of BM cells infused (x 10 9 /Kg) 5 (1.4-15) AGVHD II/IV and III/IV Probability (95% CI) AGVHD II/IV: N = 34 AGVHD III/IV: N = 16 AGVHD II/IV = 26% (19 34) AGVHD III/IV = 12% (7 18) Years after HSCT

19 CGVHD Limited and Exstensive lative Incidence (95% CI) Cumu Lim cgvhd N=8 Exst cgvhd N=6 Exst cgvhd 4% (2 9) Lim cgvhd 6% (3 11) Years after HSCT TRM and REJECT tive Incidence (95% CI) Cumula TRM: N=122 E = 20 REJ: N=122 E = 16 TRM = 17% (11 27) REJ = 10% (6 16) Years after HSCT

20 OS, TFS and REJECT 1.00 OS = 84% (76 90) robability (95% CI) Pr TFS = 75% (66 81) TFS: N = 122 E = 33 OS: N = 122 E = 20 REJ: N = 122 E = 16 REJ = 10% (6 16) Years after HSCT TFS by Pesaro risk class 1.00 CLASS 1 = 87% (71 94) Probability (95% CI) CLASS 2 = 78% (62 88) CLASS 3 = 46% (20 68) Class 1: N = 39; E = 5 Class 2: N = 41; E = 9 Class 3: N = 16; E = 8 Class AD: N = 26; E = 8 CLASS AD = 68% (46 83) P = Years after HSCT

21 TFS by CGVHD 1.00 CGVHD no = 85% (76 91) Probability (95% CI) CGVHD yes = 64% (30 85) P = N.S. CGVHD yes: N = 14; E = 7 CGVHD no: N = 96; E = Years after HSCT TFS by age group 1.00 CHILDREN = 75% (64 83) Probability (95% CI) ADULTS = 73% (55 85) P = N.S. CHILDREN: N = 86; E = 21 ADULTS (>17 y): N = 36; E= Years after HSCT

22 Causes of death after HSCT Acute GvHD 6 patients Chronic GVHD 4 patients Toxicity 7 patients Infections 3 patients ACKNOWLEDGMENTS Ped Hematology/ Oncology Ospedale Pediatrico bambino Gesù, Roma Director: Prof Franco Locatelli Alice Bertaina Angela Mastronuzzi Luciana Vinti Giuseppe Palumbo Ippolita Rana Rita Maria Pinto Maurizio io Caniglia Mariaester Bernardo Francesca Rossi Lidia Russo Alessandra Lombardi Maria Deborah De Pasquale Roberta Caruso Matteo Luciani Sergio Rutella Valentina Coletti Barbarella Lucarelli Maria Antonietta De Joris Alessandro Jenkner Luigi De Sio Raffaele Cozza Annalisa Serra Francesco Zinno

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24 Treosulfan as conditioning regimen Thalassemia free survival by Donor 1.00 Matched Family Donor = 100% PROBABILITY (95% CI) Matched Unrelated Donor = 78% (63 94) MFD: N = 8; E = 0 MUD: N = 31; E = 6 Log rank P = N.S MONTHS AFTER HSCT Updated March 2009 DFS for cord blood transplants recipients with Thalassemia according to Pesaro Classification Class I 92±5% Class II III 53±12% P= months

25 TFS by AGVHD 1.00 AGVHD no = 79% (67 87) Probability (95% CI) AGVHD yes = 74% (59 84) P = N. S. AGVHD yes: N = 50; E = 12 AGVHD no: N = 68; E = Years after HSCT TFS by AGVHD II/IV III/IV 1.00 AGVHD II/IV = 88% (70 95) Probability (95% CI) AGVHD III/IV = 44% (18 67) AGVHD II/IV: N = 34; E = 4 P = AGVHD III/IV: N = 16; E = Years after HSCT