Our place in the World

Transcription

1 Our place in the World Sickle cell disease is a public health problem that is not going to end or decrease over the years In 2050 Brazil will have the same number of newborns as in 2010 In other regions as in Africa this number will increase Piel et al. PLOS Meidicine; 2013

2 History of HSCT for Sickle Cell Disease in Ribeirão Preto 2 important references First case 2003 Profª Drª Belinda Simões BMT Unit Coordinator since 2012 Total cases until Prof Dr Júlio Voltarelli BMT Unit Founder and Coordinator from 1992 until 2012

3 Sickle Cell Disease Transplanted Patients in Clinical Hospital of Ribeirão Preto 6 transplants/year 30 ~1 transplant/year <1 transplant/year Number of HSCT

4 Patients Characteristics (N=41) Very homogeneous population if we look at gender and age Adults 49% Male 51% Children 51% < 16 years Female 49%

5 Patients Characteristics TOTAL (n=41) CHILDREN (n=21) ADULTS (n=20) Follow-up, months median (range) 42 (4-184) 37 (4-142) 50 (16-184) Age, years median (range) 15 (7-38) 12 (7-15) 27 (16-38) Gender, n(%) male female 21 (51,2) 20 (48,8) 10 (47,7) 11 (52,3) 11 (55) 9 (45)

6 Patients Characteristics - Indications 5% 2% 5% 2% 4% 22% stroke, neurological alteration that persists for more than 24 hours or alteration at imaging assessment 45% 15% increased vascular flow on transcranial Doppler Neurological alteration VOC (including ATS) Alloimmunization Leg ulcer Cerebrovascular disease Priapism Osteonecrosis Pulmonary hypertension

7 Patients Characteristics - Indications Children 42% 29% 58% - alterations related to CNS 29% Neurological alteration VOC (including ATS) Cerebrovascular disease

8 Patients Characteristics - Indications Other indications that were not seen in children Adults 10% 3% 3% 7% 16% 3% 10% 48% Neurological alteration VOC (including ATS) Alloimmunization Leg ulcer Cerebrovascular disease Priapism Osteonecrosis Pulmonary Hypertension

9 Transplantation Characteristics Source of HSC n(%) TOTAL (n=41) CHILDREN (n=21) ADULTS (n=20) BM 39 (95,1) 20 (95,2) 19 (95) PBSC 2 (4,9) 1 (4,8) # 1 (5) * * Urgency of engraftment -- Hyperhemolysis with no compatible blood products # Suspected of genetic donor disease wich can cause bone dysplasia

10 Transplantation Characteristics TOTAL (n=41) CHILDREN (n=21) ADULTS (n=20) Conditioning Regimen, n(%) MAC 39 (95.1) 20 (95.2) 19 (95) FLUBU 37 (90.2) 19 (90.5) 18 (90) BUCY 2 (4.9) 1 (4.7) 1 (5) RIC Moya Moya Syndrome Age 38 years old FLUCY 2 (4.9) 1 (4.8) 1 (5)

11 Transplantation Characteristics GVHD prophylaxis, n(%) TOTAL (n=41) CHILDREN (n=21) ADULTS (n=20) CSA+MTX 29 (70.8) 13 (62) 17 (85) CSA+MTX +MMF 1 (2.4) 1 (4.7) 0 CSA+MTX + Tacrolimus 6 (14,6) 3 (14.3) 3 (15) CSA + MTX + Rapamycin 5 (12,2) 4 (19) 1 (5) Some patients had to use alternative regimens due to toxicity or intolerance

12 Conditioning Regimen Fludarabine 120mg/m² (D-5 until D-2) Busulfan 3.2mg/kg/day (D-5 until D-2) Children dose based on weight

13 GVHD Prophylaxis CSA 3mg/kg/day IV D-1 (level ng/ml) Oral 7.5mg/kg/day (level ng/ml) Start reduction with 15 months Stop with 18 months MTX 15mg/m² D+1, 10mg/m² D+3, D+6 and D+11 ATG 4.5mg/kg IV D-5 until D-1

14 Concerns and Cautions HSCT for SCD has some peculiarities Maintain platelet levels > during conditioning regimen Not to raise Hb above 10g/dL during all the transplantation Maintain HbS<30% before conditioning regimen and procedures (ex: placement of central venous catheter)

15 Concerns and Cautions Hydroxyurea should be maintained until conditioning regimen Iron chelation before conditioning regimen Antiepileptic drug during the use of calcineurin inhibitors (Lamotrigine; option benzodiazepine) Care of leg ulcers before transplantation

16 Follow-Up Pre- HSCT D+28 D+60 D+90 D+120 D+180 D m 2 y 3 y 4 y 5 y Brain MRI X X X Chimerism (VNTR/STR) Lung function Sexual Hormones Fertility preservation (if possible) X X X X X X X X X X X X X X X X X X X X X X All patients were evaluated for a gynecological team for possible fertility preservation, wich is offered free of charge

17 Results Overall Survival Event Free Survival 89.4 % 79.4 % N=39 Months Months Unpublished data

18 Results TOTAL (n=41) CHILDREN (n=21) ADULTS (n=20) Acute GVHD, 14 (36.1) 7 (33.3) 7 (35) n(%) *# Chronic 6 (14,6) 5 (23,8) 1 (5) GVHD, n(%) * *No severe or extensive GVHD was observed Only skin was affected # 10 with skin, 3 with gastrointestinal (2 adults and 1 child) and 1 with probably liver GVHD (adult) Incidence of acute GVHD was similar among children and adults Incidence of chronic GVHD was higher in children

19 Results Graft failure, n(%) Primary TOTAL (n=41) 8 (19.5) 1 (2.4) CHILDREN (n=21) 5 (23.8) 1 (4.8) ADULTS (n=20) 3 (10) After RIC - second transplant with MAC 0 Secondary 7 (17.1) 4 (19) 3 (15) Autologous recovery without bone marrow aplasia 2 children 3 types of evolution Bone marrow aplasia followed by autologous recovery 1 adult and 2 children Bone marrow aplasia followed by death 2 adults Faster recovery without complications

20 Results TOTAL (n=41) CHILDREN (n=21) ADULTS (n=20) Death, n(%) 3 (7.3) 1 (4.7) *1 2 (10) *2,3 *1- Hemorrhagic stroke 18 months after second HSCT (Moya Moya before transplant) *2,3 Secondary graft failure with aplasia and infection

21 Chimerism STR Donor % * Results D+30 (1M) D+90 (3M) D+180 (6M) D+360 (12M) D+720 (24M) D+1080 (36M) D+1440 (48M) D+1800(60M) RP26 RP30 RP12 RP17 RP29 RP31 RP15 RP02 RP32 RP19 RP35 RP34 RP22 RP09 RP07 RP04 RP08 RP16 RP11 RP28 RP33 RP14 RP13 RP24 RP37 RP21 RP25 RP27 RP18 * Nucleated cells (myeloid and lymphoid) Data provided by Julia Teixeira and Kelen Malmegrin

22 Alloimmunization TOTAL (n=41) CHILDREN (n=21) ADULTS (n=20) 4 (9.7) 1 (4.7) 1 3 (15) 2,3,4 1 Anti-Dia 2 Anti-E + Anti-c + Anti-C + Autoantibody 3 Anti-E + Anti-Fy(a) + Anti-Jk(b) + Anti-S + Anti-K (Hyperhemolysis during erythrocytapheresis) Desensitization Protocol Anti-CD20 antibody Cyclophosphamide Plasmapheresis IVIG 4 Anti-E

23 Neurological alterations Can we improve them with HSCT? Would Moya Moya syndrome impact HSCT early outcomes?

24 Reduction of alterations related to brain vasculopathy after hematopoetic stem cell transplantation in a pediatric patient with sickle cell disease: case report Thalita Cristina de Mello Costa, Luiz Guilherme Darrigo Junior, Carlos Eduardo Setanni Grecco, Sara Reis Teixeira, Renato Luiz Guerino Cunha, Fabiano Pieroni, Joana Teresa Bisinella de Faria, Ana Beatriz Pereira Lima Stracieri, Maria Carolina Oliveira, Belinda Pinto Simões Hospital das Clinicas da Faculdade de Medicina de Ribeirão Preto da USP

25 11 years-old Indication for HSCT: cerebral vasculopathy with previous stroke (Moya-Moya pattern in MRI), acute thoracic syndrome and vaso-occlusive syndromes Before HSCT 1 year after HSCT Brain MRI: Reduction of internal carotid artery stenosis and reduction of arterial collateral circulation

26 Neurotoxicity Neurological complications due to calcineurin inhibitors in pediatric patients underwent to HSCT for SCD Laia Rigolin Fortunato 1, Carlos Eduardo Setanni Grecco 1, Luiz Guilherme Darrigo Junior 1, Thalita Cristina de Mello Costa 1, Nelson Hamerschlak 2, Ricardo Helman 2, Joana Tereza Bisinella de Faria 1, Ana Beatriz Pereira Lima Stracieri 1, Maria Carolina Oliveira 1, Belinda Pinto Simões 1 1 Faculdade de Medicina de Ribeirão Preto 2 Hospital Israelita Albert Einstein

27 Neurological complications due to calcineurin inhibitors in pediatric patients underwent to HSCT for SCD 22.58% neurological events Zero mortality All resolved after stopping CSA

28 Care of leg ulcer before HSCT Skin biopsy 6 weeks KC Fibroblasts Peripheral blood Fibrinogen Trombin SPRAY= Fibrinogen glue + cell Prof. Dr. Marco Andrey Cipriani Frade - Dermatology

29 30-year-old man Indication for HSCT: VOC, priapism, leg ulcer for years Almost complete resolution of his leg ulcer after transplantation (He also developed diabetes during the conditioning regimen)

30 35-year-old man Janeiro 2013 HSCT Indication: VOC and leg ulcer for 20 years January 2013 Complete resolution after 4 months Outubro 2013 October 2013

31 Quality of life Quality of life and sickle cell anemia: comparative study with HSCT patients and conventional treatment Érika Arantes de Oliveira Cardoso, Lucas dos Santos Lotério, Juliana Tomé Garcia, Ana Luisa Carvalho Guimarães, Karla Costa Pereira, Ana Beatriz Pereira Lima Stracieri, Fabiano Pieroni, Maria Carolina de Oliveira, Manoel Antônio dos Santos, Belinda Pinto Simões Faculdade de Medicina de Ribeirão Preto QL in transplanted patients is more preserved after 2 years of the procedure than in patients who received conventional treatment

32 Strategies to improve engraftment and reduce graft failure Change the conditioning regimen (more immunosuppression) Change GVHD prophylaxis (more immunomodulation)

33 Conditioning Regimen Fludarabine 150mg/m² (D-6 until D-2) Bussulfan 3.2mg/kg/day (D-5 until D-2)

34 GVHD Prophylaxis CSA 3mg/kg/day IV D-1 (level ng/ml) Oral 7.5mg/kg/day (level ng/ml) Sirolimus D+35/D+40 (level= 8-11ng/ml) Stop Sirolimus with 18 months MTX 15mg/m² D+1, 10mg/m² D+3, D+6 and D+11 ATG 8mg/kg IV D-5 until D-1 (0.5mg/kg D-5 and 1mg/kg D-4 until D-1)

35 In progress Continue to look for improvements to allogeneic HSCT for sickle cell disease in all aspects Immerse in Haploidentical HSCT (next step protocol with TBI collaboration Vanderbilt University) Continue to focus on improving engraftment, reducing GVHD and graft failure

36 In progress Researches Endothelial damage before and after HSCT (Thalita Costa and Belinda Simões) Thymic function (Luciana Jarduli and Antoine Toubert) Immune Recovery (Julia Teixeira, Kelen M. Farias, Olivier Hermine) Polymorphisms (Karina Tosetto, Eliane Gluckman, Ryad Tamouza, Barbara Cappelli)

37 Take Home Messages #1 1) HSCT for SCD goes beyond care with conditioning, GVHD prophylaxis and post-transplant care (social problems, treatment of chronic pain, use of opioids) 2) Sometimes the preparation of the patient is longer than the procedure itself (look for compatible blood products, treat leg ulcers, reduce HbS)

38 Take Home Messages #2 3) We need a very good Blood Transfusion Center 4) We need a broad medical team with different specialties (dermatologist, neurologist, psychiatris, radiologist) 5) We need a very good multidisciplinary team (nurse, psychologist, social worker, physiotherapist, nutritionist)

39 Acknowledgments

40 Acknowledgments

41 Bone Marrow Transplantation Unit from Clinical Hospital of Ribeirão Preto