Haploidentical Stem Cell Transplantation with post transplantation Cyclophosphamide for the treatment of Fanconi Anemia

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1 Haploidentical Stem Cell Transplantation with post transplantation Cyclophosphamide for the treatment of Fanconi Anemia Carmem Bonfim Director Pediatric Blood and Marrow Transplantation Program HC Federal University of Parana and Hospital Nossa Senhora das Graças Coordinator Pediatric Blood and Marrow Program Hospital Pequeno Príncipe

2 What is Fanconi Anemia? Fanconi anemia(fa) is a rare inherited disorder characterized by congenital abnormalities, progressive bone marrow failure and cancer predisposition. Hallmarks are chromosome fragility and hypersensitivity to drugs that induce DNA interstrand cross-links DEB/Mytomicin Physiological and cellular abnormalities likely contribute to pathogenesis Bogliolo and Surrales Current Opinion in Genetics & Development 2015, 33:32 40

3 Fanconi Anemia HSCT is the only treatment able to cure the hematologic complications related to FA, and results are better when transplantation is performed early and with a matched unaffected sibling. If a MFD is not available, pts may be treated with androgens, but response is usually short-lived. Although the results of matched URD transplantation for FA have improved during the past decade, availability of a MUD as well as time to find a donor and the costs related to the acquisition of the graft are important limitations in countries with ethnical minorities and fewer resources.

4 Pilot study to identify what happened to 266 pts with FA who initiated the donor search process from 1993 to : 46 pts M: 276 days 41 pts OS 35% at 6 years 47 patients!!! Unrelated CBT: 41 pts Graft failure 40% TRM at one year : 60% Died during search process : 47 pts M: 317 days Kleina et al, Poster presented at the FARF meeting 2016; Poster -172

5 Haploidentical transplantation with PT-CY Luznik, Fuchs, O Donnel Johns Hopkins Hospital In 2012 we published the first 3 FA pts submitted to a haplo BMT with PT-CY (Thakar et al 2012). These studies were updated in 2016 and included patients transplanted in the USA (5 pts - Thakar et al 2017) and Curitiba ( 26 pts - Bonfim et al 2017)

6 Pediatric Haploidentical/AD HCT with PT-CY for non malignant diseases - Curitiba, Brazil to transplants in 119 pts in Curitiba (90% haplos) 8 pts received a second haplo BMT ( 3 FA; 2 DC; 1 WAS; 1 HLH, 1 DBA) First haplo transplants 2nd or 3rd haplo BMT after GF Other alternative donors Fanconi Anemia Dyskeratosis Congenita Other BMF including SAA SCID pts WAS CGD pts Other PID Inborn Errors of metabolism 5 (ADL) 2 (MPS) 0 89 pts 17 pts 13 pts Other alternative donor : Unrelated donors or mismatched family donors

7 The use of PT-CY for the treatment of FA pts 04/ /2018 N = 49 pts (52 transplants) Stem Cell Source: Bone Marrow Haploidentical donors 44 pts Mismatched unrelated 5 pts First transplant 40 pts Rescue transplants 4 pts Aplastic phase 4 pts SAA: 33 pts MDS: 3 pts AML: 4 pts PGF:2pts LGF:2pts MDS 1 pts + 3 second haplo transplants after primary or secondary graft failures Haploidentical donors ( 8/10 family donors)

8 Protocol evolution Haplo BMT (n=40) Cy 10mg/kg + FLU + TBI (n=4) PT-CY 50mg/kg + oral MMF + Csa+GCSF FLU + TBI (n=8) PT-CY 50mg/kg + oral/iv MMF + Csa FLU + TBI + r ATG 4-5mg/kg ( n=16) PT-CY 50mg/kg + IV MMF + Csa +/- steroids FLU + TBI + r ATG 4-5mg/kg (n=4) PT-CY 60mg/kg + IV MMF + Csa (Bacigalupo) + steroids FLU + TBI + r ATG 7.5 mg/kg (n=8) PT-CY 60mg/kg + IV MMF + Csa (JH) + steroids Haploidentical donors ( 8/10 family donors)

9 Haplo with PT-CY No r-atg D-8 D-7 Luznik, Fuchs, O Donnel Johns Hopkins Hospital ATG 7.5mg/kg total IV 45mg/kg/day Steroids 1mg/kg Cyclosporine CY 30mg/kg/d CY before transplant was eliminated IV MMF r-atg was added and then steroids introduced during engrafment PT-CY increased from 50mg/kg to 60mg/kg r-atg increased from 4.5mg/kg to 7.5mg/kg

10 Patients characteristics First Haplo BMT (n=40) Age: 4 to 31 ys (Median: 9 ) Gender: 77% were male 33 were in aplastic phase and all pts had failed androgen therapy Previous transfusions (n=38) : (Median: 12) CMV IgG positive: 92% EBV IgG positive: 87% Toxoplasmosis IgG positive: 70% Donor: Mother 18; father 13; siblings 9 Gender mismatch: M/F : 18 pts; F/M: 5 pts

11 Transplant TNC infused : 2,21 10,87 x 10*8/kg (M: 7.03) 4 pts with DSA; 3 received rituximab and plamapheresis and all engrafted Engraftment: 1 pt developed PGF and 1 pt had a SGF ( none were heavily transfused or had DSA). Both received a 2nd haplo BMT from a different donor and died. 1 pt : poor graft function after CMV infection, severe pancytopenia, 2nd BMT, died ANC > 500 : days ( M: 14) Platelets > : days (M: 17) Hemorragic cystits : 45% 37/40 at risk for CMV reactivation CMV reactivation occurred in 73%

12 Acute and Chronic GvHD No ATG: 12 pts 9/12 pts developed grade II-IV Acute GvHD Out of the 9 pts ; 5 died due to severe GvhD and 1 died from relapse + severe GvHD With ATG: 28 pts 14 out of 27 evaluable pts developed grade II-IV Acute GvhD; 3/14 pts died 13 out 23 evaluable pts developed Chronic GvHD; 1/13 pts died

13 Other transplants using PT-CY Age, gender Previous transplants Indication for 2nd/3rd BMT Protocol GVHD Alive chimeris m 6 yo female* UCBT 6/6 Primary graft failure No ATG Yes severe Yes 8 years, off IST 100% 11 yo female HLA MSD ( 2 transplants) Primary graft failure No ATG Yes mild chronic Yes 6 years, off IST 100% 7 yo female 9/10 URD DSA + Primary graft failure r-atg No Yes 3.6 years, off IST 100% 7yo male 10/12 (NP mis DP) Secondary graft failure r-atg Yes, mild chronic Yes 3.7 years, off IST 100% Unrelated donors: 2/5 pts are alive and well. Severe acute and chronic GvHD + poor graft function was the cause of death in 2 pts. One pt died in his home town due to bacterial pneumonia (??); no GvHD. All pts (n=3) who received a 2nd haplo after primary or secondary graft failure died from infection ( fungal or virus)

14 Overall Survival: 49 pts Haplo: 44 pts; OS 68% at 3 ys 32 pts alive, OS: 65% at 3 ys Median FU 36 months ( 3-100) URD: 5 pts ; OS 40 % at 3 ys p:ns 17 patients died at a median of 150 days after transplant ( range : ) GVHD was the major cause of death

15 Haploidentical BMT for FA: 44 pts FA pts all phases of disease FA pts in aplastic phase With r-atg: 30 pts, OS 77% With r-atg: OS 78% No r-atg: 14 pts, OS 50 % No r-atg: 40% p: NS p: NS 14 pts died 7/14 pts who did not receive ATG and 7/30 pts with ATG in the prep regimen GVHD was the major cause of death

16 Conclusions Haploidentical BMT using PT-CY is an option for children with Fanconi Anemia who need an immediate transplant but lack a matched related or unrelated donor CMV reactivation occurred in 73% of transplant recipients, independent of the use of ATG, but 92% pts were at risk. Hemorrhagic cystitis secondary to polyoma / adenovirus ocurred in 44% of pts, irrespective of ATG New approaches to GVHD prophylaxis as well as better control for viral reactivation are needed

17 Lessons learned PT-CY: There is a learning curve in regards to adopting the accepted strategy for malignant diseases for non malignant diseases In this study, r-atg was added with some success at limiting severe GVHD but clearly better strategies are needed to control this complication as it is related to the development of squamous cell carcinoma in FA patients The current protocol uses a higher dose of ATG ( 7.5mg/kg) ; PT- CY 60mg/kg and steroids during engraftment

18 Acknowledgments Prof Ricardo Pasquini Fanconi Anemia Lab Pediatric BMT team Patients and families Mary Eapen Medical College of Wisconsin Ephraim J Fuchs John Hopkins University