Blood and Marrow Transplantation for Haemoglobinopathies. Dr Josu de la Fuente St. Mary s Hospital London

Transcription

1 Blood and Marrow Transplantation for Haemoglobinopathies Dr Josu de la Fuente St. Mary s Hospital London

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3 Aim: Stem Cell Transplanta.on 1. Eradicate of disease = achieve myeloabla8on 2. Avoid rejec8on of the new bone marrow = avoid gra> failure 3. Avoid the body been aaacked by the immune system derived from the new bone marrow = avoid Gra> versus Host Disease How is it achieved? 1. HLA matching 2. Myeloabla8on 3. Immunosuppression

4 SCT in Haemoglobinopathies CCLG BMT Group Disease Allogeneic matched related Allogeneic unrelated Haploidentical related Autologous blood or marrow 10/10 sibling 10/10 adult Donor specifics other 10/10 related 9-10/10 adult <9/10 related 9/10 related 4-6/6 cord Stem Cell Source BM/PBPCs/cord BM/PBPCs/cord PBPCs/BM PBPCs/BM Thalassaemia S CO CO N/A Sickle cell disease S * CO CO N/A

5 1. VOC despite hydroxycarbamide: four or more episodes a year requiring hospitalisa8on or impac8ng in schooling despite hydroxycarbamide treatment 2. Recurrence of acute chest syndrome despite hydroxycarbamide 3. CNS disease: a. Stroke b. Abnormal TCD and silent infarct or abnormal psychometric tests/poor school performance formally assessed c. Silent infarcts with cogni8ve deficiency d. Significant abnormali8es in MRA despite transfusions e. Abnormal TCD and genera8on of red cell alloan8bodies f. CNS disease requiring transfusions leading to significant iron overload despite best aaempt at adequate management 4. Subop8mal medical care Is there a role for stem cell transplanta.on in pa.ents who do not fulfil this criteria during childhood and have progressed through puberty sufficiently to allow sperm cryopreserva.on or oocyte vitrifica.on?

6 DFS = 94.5% agvhd II-IV: 10.8% Limited cgvhd: 2.7% Extensive cgvhd: 1.4% n = to 2010

7 Chimerism β thalassaemia Day +28 Day +60 Day +90 Day +120 Day +150 Day +180 Day +360 >95% to 100% >90% to 95% >80% to 90% >50% to 80% >30% to 50% >20% to 30% <20% Total % 16.30% 16.30% 5.40% 3.60% 1.80% Sickle cell disease 12 pa8ents donor chimerism <90%, all before day +90 Day +28 Day +60 Day +90 Day +120 Day +150 Day +180 Day +360 >95% to 100% >90% to 95% >80% to 90% >50% to 80% >30% to 50% >20% to 30% <20% total % 33.30% 6.60% 6.60% 1 pa8ents donor chimerism <90% before +120

8 Quality of Life Caocci, BBMT 2011

9 No significant sickle related neurological events occurred during BMT. All 18 pa8ents with long- term engra>ment achieved radiological stabiliza8on of the underlying cerebrovascular disease. Imaging performed at least 12 months post SCT showed no further changes from pre- transplant images, except in one case with stroke where there was significant improvement. There were no clinical neurological events a>er SCT.

10 FSIQ Score Pre Post Pre Post Pre Post No Disease Stroke Silent Infarct PSI Score Pre Post Pre Post Pre Post No Disease Stroke Silent Infarct

11 Limita.ons of SCT Lack of donors Length of Treatment: 2 months as an inpa8ent 4 months as outpa8ent Transplant Related Mortality Long Term Effects: Infer8lity Pubertal failure Chronic GvHD Organ toxicity Secondary malignancies

12 Mul.center Study: growth Eggleston, Bri J Haem 2007; 136:

13 Availability of donors Related donors: Using broad criteria of Collabora8ve Study: 38% of SCD pa8ents qualify Only 18% of pa8ents have an HLA- matched sibling donor who is not affected Thus, as few as 1-2% of the total popula8on of children with sickle cell anaemia ul8mately qualify for bone marrow transplanta8on Mentzer, Am J Pediatr Hematol Oncol 1994 Unelated donors: HLA- A,B,DRB1 matched donor projected increase in NMDP: 27% to 34% for Black Americans 45% to 54% for Asian Kollman, Transplanta.on 2004

14 Reasons for not proceeding to HLA- typing or BMT Hansbury, 2012

15 EUROCORD STUDY Locatelli, Blood 2003 Needs and rights of donors to be considered Cost and logis8cal difficul8es to maintain quality and comply with different requirements. Who should be collected from? Thalassaemia: all siblings of affected pa8ents SCD: if on transfusions or HU Pre- implanta8on gene8c diagnosis and HLA typing with embryo selec8on Ethical considera8ons, psychological cost to the parents and financial cost

16 La Nasa, Blood 2002 Bernardo, Brit J Haem 2008 Unrelated allografts for β thalassaemia Grade II- IV agvhd: 11 (41%) cgvhd: 6 (25%) BU14- TT10- CY120 Grade II- IV agvhd: 15% cgvhd: 7% TT8- TREO42- FLU160

17 Availability of cord blood units Adamkiewicz, J Pediatr Hematol Oncol 2006

18 Haploiden.cal Transplanta.on Pa8ent Age at HPCT (yrs) CD34+ cells/kg CD3+ cells/kg DLI (CD3+ cells/kg) x x 10 6 Yes x 10 6 d +107 Max Grade agvhd Chronic GVHD Outcome SCA status None None Alive No SCA 4 years Follow- up dura8on x x 10 6 No Grade I None Alive No SCA 3.8 years x x 10 6 No None N/A Alive Recurrent SCA 3 years x x 10 6 No Grade II Limited (Skin) Alive No SCA 1.8 years x x 10 6 No Grade I Extensive (BOOP, skin) x x 10 6 Yes x 10 6 d x x 10 6 Yes x 10 6 d +51 Grade II Deceased No SCA 11 months Extensive (Skin/Gut) Alive No SCA 12 months None N/A Alive Recurrent SCA 12 months x x 10 6 No Grade III N/A Alive Recurrent SCA 2 months Personal communica.on Rupert Handgre.nger, Tubingen

19 Reduced Intensity Condi.oning for Sickle Cell Disease Less risk of morbidity and mortality from condi8oning- related toxicity: Infer8lity Neurodevelopmental effects Impaired growth Iannone BBMT 2003: Endocrine dysfunc8on Flu/ATG/200 cgy TBI BMT/PBSCT Secondary malignancy n = 7 Problems: Intact immune func8on Expanded haemopoie8c compartment Red cell alloimmunisa8on GvHD completely undesirable complica8on Hesieh, NEJM 2009

20 Conclusion BMT is feasible & able to offer long- term cure The challenge is to extend the number of pa8ents who may benefit Long- term aim is to deliver and enable gene correc8on Time is ready for alterna8ve sources of stem cells Understanding of the morbidity and end- organ damage Iden8fica8on of appropriate pa8ents who may benefit Par8cipa8on of pa8ents