Hematopoietic stem cell transplantation for sickle cell disease. Hazza Al-zahrani KFSHRC-Riyadh

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1 Hematopoietic stem cell transplantation for sickle cell disease Hazza Al-zahrani KFSHRC-Riyadh

2 SCD major Health Burden in KSA endemic in southern and eastern prevalence remains higher than that in other countries - Per 10,000 population East prov. 145 cases South 24 cases Western 12 cases central 6 cases Al-Qurashi Saudi Med J 2008 SCD trait carriers: 2 27% of the population of KSA Jastaniah Ann Saudi Med 2011

3 Challenges in Controlling SCD in Saudi Arabia consanguineous marriages (57.7%->80% ) How to overcome this issue? - Awareness programs: Education of people regarding the effects of consanguineous marriages - Premarital Screening Program and the Genetic Counseling Program mandatory for all couples free at all government facilities Results: Adult 4.2% carriers 0.26% of the population is affected by SCD reduced the number of voluntary cancelations of at-risk marriage proposals by 60% increased by 5-fold over 6 years Ann Saudi Med 2011 Memish Six-year outcome of the national premarital screening and genetic counseling program for sickle cell disease and b thalassemia in Saudi Arabia Ann Saudi Med (2011)

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6 Disability-Adjusted Life Year (DALY) One DALY one lost year of "healthy" life Sum: measurement of the gap between current health status and an ideal health situation where the entire population lives to an advanced age, free of disease and disability. Feb 2017 Journal of Epidemiology and Global Health M Alosaimi

7 Feb 2017 Journal of Epidemiology and Global Health M Alosaimi

8 KFSHRC Experience: Background-Challenges SCD adults have many comorbidities - Many are ineligible to full intensity Conditioning - Repeated transfusion + chr Inflam. Rejection risk Intensifying conditioning loose the patient Reducing conditioning loose the graft Anything in the middle medium size results

9 Hypothesis: SCD is a chronic inflammatory Hypothesis: SCD is a stem cell disease Needs Anti-inflammatory induction before BMT Needs MAC or close to MAC to prevent relapse Adults with Tx-dependent SCA may be alloimmunized Adults with high Risk SCA cannot tolerate MAC Pre-BMT Steroids ATG with conditioning Reduced Toxicity Condtioning RTC)

10 AIM OF THE STUDY: assess safety & efficacy of 1. Pre-conditioning: Steroids+ HU & HyperTransfusion 2. Reduced Toxicity Conditioning : FLA, iv-bu + LD-ATG Patient population : Adolescents and Adults (>14 years) Sickle Cell Anemia in young adults with Sickle Cell Anemia (SCA).

11 Indications for Transplantation 1. Recurrent severe VOC 2. Recurrent ACS 3. Stroke (none-debilitating) 4. AVN 5. Tx-dependence 6. Pulm. HTN (Mod)

12 Eligibility for Transplantation 1. The presence of matched Sib or EFdonor 2. Age > Performance: (KPS <=2 ; ECOG >70%) 4. NO Chr. active hepatitis due to HBV/HCV 5. NO HIV/AIDS 6. Consent

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14 SCD SCT at KFSHRC Patients Started cases of high risk SCD - 5 cases per year - Age: yrs - Median age 17 years - Comorbidities Non : 26% 1 patient had also smoldering Myeloma

15 Patients: Indications of HSCT Recurrent severe VOC (n:25; 100%) Acute chest syndrome (n: 10; 40% ) stroke or silent brain insult (8; 32% ) including Moya Moya (2; 8%) AVN (n; 8; 32%) Moderately severe (O2-dependent) pulmonary HTN in 1 patient

16 Donor and Recipient Sex 56% females and 44% males Sex distribution of the 39 patients Sex distribution of the 39 donors

17 ABO Compatibility Major Minor Compatible

18 Donors HLA-matching was 10/10 in all pairs (100%) 8 donors (32%) SCA trait Identical siblings (20 BM, 4 PB and 1 BM+PB) CD34+ cell dose x10 6 /kg ( ) for Marrow - 7 x10 6 /kg for the peripheral blood

19 Comorbidities Score 4 Score 3 Score 0 Score 2 Score 1 score 0 score 1 score 2 score 3 score 4

20 Comorbidities

21 SCD SCT at KFSHRC Conditioning - IVBU14/FLU/ATG - Gvhd PROPHYLAXIS : MTX +CSA Stem cell dose average 6.12 X10 6 /Kg X10 6 /Kg Jan 2011\till Jan required boost and 3 required DLI

22 Change of paradigm of Conditioning MAC HIT+RTC TRM TRT GVHD! RTC Less/No delay Less/No crisis Less TRT No TRM Less Rejection & Less GVHD Well Being!!!! Outpatient BMT? Fertility: Better? CSA H. I. T. CSA

23 Total WBC (x10^9/l) Total WBC during pre-conditioning phase week -6week -4week -2week

24 ALLOGENEIC PROGENITOR STEM CELL TRANSPLANT PROGRAM ADULT HEMATOLOGY/ BMT UNIT- KFSHRC, Riyadh, SA SICKLE CELL-BMT IV-BUSULFAN/FLUDARABINE and ATG o HEIGHT: cm WEIGHT: kg BSA: o ALLERGIES: o NOTE: This regimen is for the exclusive use for Sickle Cell Conditioning. DATE 1 Feb Feb Feb Feb Feb 2015 Days Mon Tue Wed Thurs Fri Sat Sun Mon Tue Wed Thurs BMT/PBSCT DAY FLUDARA x 160 x mg/m2 x x 40mg/m 2 IV- BUSULFAN 0.8 mg/kg q6hx 14 doses ATG Thymoglobulin; Genzyme 1.5 mg/kg 4 doses 4 doses 6 Feb Feb 2015 ALLOGENEIC PROGENITOR STEM CELL TRANSPLANT 4.5 mg/kg PROGRAM. 4 doses 2. Doses. ADULT HEMATOLOGY/ BMT UNIT 8 Feb Feb 2015 x x x PHENYTOIN X X X X X X Keppra Levetiracetam Rest Day HSCT 11.2 mg/kg x 10 Feb 2015 X 11 Feb 2015 X

25 Engreftment Granulocytes - Median day 19 Platelets - Median day 20

26 Neutrophil count/ul d0 d2 d+4 d+6 d+8 d+10 d+12 d+14 d+16 d+18 d+20 d+22 d+24 d+26 d+28 Figure 1A. Kinetics of Neutrophil drop and engraftment after RTC-conditioning for Allo-sib HSCT in adults with severe SCA.

27 Platelet count (x1000/ul) d0 d2 d+4 d+6 d+8 d+10 d+12 d+14 d+16 d+18 d+20 d22 d+24 d+26 d+28 d+30 Figure 1B. Kinetics of platelet drop and engraftment after RTC conditioning for Allo-sib HSCT adults with severe SCA (n=21)

28 Complications of SCT in SCD KFSHRC experience Fungal infections - 11% Varicella zoster Infection: % CMV pcr detection: - 70% pre-emptively treated - 0% CMV disease

29 Peri-transplant complications Mucositis - grade I in 6 (24)% - grade II in 2 (8) % - Grade III in 2( 8)%) one (4%) patient bled due to gastritis and possible pulmonary invasive fungal disease in one (4) New minor stroke with monoparesis in a patient with Moya Moya disease that recovered in a few days One patient developed severe hypertension PRESS in 2 patients, fits in 3 patients - one other patient developed PRES-like syndrome at Hb S of 32% treated and recovered after exchange transfusion. TMA in 1 patient treated with Fresh frozen plasma infusion, fits with change level of consciousness in one treated with Exchange transfusion and resolved within a few hours, Mohamed S.Y, 2017

30 Complications of SCT in SCD KFSHRC experience Mucositis: - 70% Hemorrhagic cystitis : - 1 patient 2.9% Veno-occlusive Disease of the liver 1 patient 2.9%

31 SCD SCT KFSHRC Acute GVHD 70% are grade I-II

32 SCD SCT KFSHRC Chronic GVHD

33 Graft Stability Boost 3 DLI 3

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35 N:1 8 Boost+DLI Boost+DLI Fig 2. Kinetics of Myeloid (M) and lymphoid (L) Chimerism after RTC conditioning for Allo-Sib HSCT in adults with severe SCA

36 Mo 2Mo 3Mo 4mo 6Mo 1Y 15 mo 18mo 21 mo 24mo 30 mo

37 120 Cyclosporine

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39 1980s-2007 SCA transplant experience Study US collaborati ve French Belgian CIBMTR n Median age (y) EFS GVHD Horan JT et al., 2005 Bernaudin F et al., 2007 Krishnamurti m et al.,2007 Angelucci E et al.,2009

40 Pre- HU & pre BMT fertility preservation HU naïve (pre HU) On HU & pre BMT Semen analysis (SA) optimal Suboptimal Suboptimal optimal Collect Transfuse or Exchange qmo SA Up to 3 mo Exchange Hold HU Qmo SA Up to 6moif if improving Collect Start HU Resume HU

41 1Death 16-year-old male SCD History of TB lymphadenitis and he completed ant tuberculous therapy June 2016 post neurosurgery for Moya-Moya Dec 2016 AlloSCT well for 4 months Secondary graft failure, S/P Stem cell boost on March 30th & 31st septic shock ARDS Medivac transfer - Severe sepsis, septic shock - Acute respiratory failure, ARDS - Bilateral pneumothoraces - CNS hemorrhage - HLH - Chronic hypernatremia

42 Af. Fi. 16 year old girl SCD Acute chest syndrome mechanical ventilator subglottic stenosis Laparoscopic cholecystectomy Tonsillectomy History of recurrent chest infection, community-acquired pneumonia hydroxyurea 6 tables History of pancytopenia secondary to hydroxyurea overdose Frequent admission History of AVN of Rt shoulder 11 January 2011 for allogenic sibling SCT The donor: 3-year-old sister ABO incomp. (A O) pre-implantation genetic diagnosis for selection

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47 Conclusion HSCT remains the only curative therapy for SCD HLA-identical sibling transplantation in patients with SCD offers excellent overall and disease free survival Risk of GVHD, infections, infertility, and other long-term transplant complications, limits widespread use of SCT but our results are relatively low toxicity allowing SCT in patients with significant morbidity Post SCT cyclophosphamide is being explored at our center graft failure rate was low and manageable with boost and DLI long-term follow up is needed

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