POS TRANSPLANT CYCLOPHOSPHAMIDE (PTCy) FOR PRIMARY IMMUNODEFICIENCIES (PID): CURITIBA

EXPERIENCE

Nichele S., Ribeiro L., Loth G., Kwahara C., Fabro A.L, Koliski A., Beltrame M., Bonfim C.

HEMO, 2016

Introduction• PID are medical emergencies and HSCT can be curative for the

majority of patients.

• In the absence of MRD or MUD, the use of T cell depleted haploidentical donors resulted in similar outcomes but it is limited by costs, slow immune recovery and high rate of infections.

• HSCT using alternative donors with post-transplantation cyclophosphamide (PT/Cy) for GVHD prophylaxis has been performed for hematologic malignancies with engraftment, GVHD, and TRM comparable to that seen with MRD.

• There are limited reports of HSCT in nonmalignant pediatric disorders using alternative donors and PT/Cy

Rebecca H. Buckley. Immunology Research, 2011Ephraim J. Fuchs. Hematology, 2012Heather J. Symons. Biol Blood Marrow Transplant, 2016

215 pts transplanted in BrazilDiagnosis, stem cell source and type of donor

2014 and 2015: 22 SCIDsCuritiba: 10 pts

Eisntein/Itaci: 7 pts

6570

24

14 146 5 3 3 3 2 2 1 1 1 1

PTCy for PID – Curitiba experience

• Objective: Describe our institutional experience treating 20 patients with primary immunodeficiency using alternative donor sources and post transplant cyclophosphamide for GVHD prophylaxis.

• Method: descriptive and retrospective.

Patients characteristics• 20 pts transplanted in

Curitba– HC/UFPR: n = 10– HIPP: n = 5– HNSG: n = 5

• fev/12 – dez/15

• Median age = 16 months (2,7m – 10 y)

• Male: 18 / Fem: 2

7

28

12

SWA

HLH

SCID

CH

DGC

Donor characteristicsUpfront 15

Source HLA match Donor Disease

BoneMarrowN = 20

5/10Mother: 6

Father: 5

WAS 3

SCID 4

HLH, DG, CH 4

9/10 Cousin: 1 SCID 1

10/10Father: 2

URD male: 1

SCID 3

Second transplant 5

5/10 Father: 3Mother:1

WAS 4

10/10 Sister CDG 1

No HLA antibody

father: 9mother: 7Sister: 2Aunt: 1

Unrelated: 1

Med CNT : 6,86 x 108/Kg (2,8 – 14,4 x 108/Kg)Med CD34: 4,38 x 106/Kg (1,8 -20,8 x 106/Kg)

CSA 2mg/Kg bid

John Hopkins- O’Donnel; Luznik; Fuchs

Post transplantation CY platform

N = 191 pt no TBI2 pt TBI 400cGy1 pt + ATG

N = 1 CGD pt

levo

Supportive care

• Levofloxacin • Bactrim while on IS or CD4+ > 200/μL.• Acyclovir until D+100.• Fluconazol or Micafungin until neutrophil

recovery.• IGIV replacement for SCIDs patients until

complete immune recovery• Single rooms with laminar airflows

Results

Upfront transplants

Upfront transplants: 15• 13 patients engrafted

– Median time to neutrophil recovery: 15 days.– Median time to platelet recovery: 18 days– All but two with mixed chimerism (20 – 89%)

• Primary graft failure: 2– 1 HLH ( died after 2nd haplo transplant)– 1 CGD ( waiting 2nd transplant).

• Secondary graft failure: 2 WAS – 1 alive after 2nd transplant– 1 died due to bacterial infection.

Upfront transplants: 15• Early Toxicity:

– hematological grade 4, with low transfusion requirement– VOD: 1 pt– Mucositis: mild

• GVHD– Acute GVHD: 2 SCIDs, grade 3 (skin and liver) responsive to steroids– Chronic GVHD (HLH): 1 pt on treatment, 1 pt died (GVHD + disease

progression)

• Infections– 2 SCIDs with BCGítis + mycobaterial infection, resolved after HSCT– Limited in the majority of patients– Virus infection: 11 (CMV = 10)

Survival

• 10 pts are alive with a median FU of 16 months.

• All but one have mixed chimerism (20 – 89%).• Incomplete immune reconstitution: 2 SCIDs• 2 SCIDs are still on IGIV replacement • One patient is on GVHD treatment.

Causes of death: 5• 1 - WAS: transplanted with active infection, died with full engraftment,

due to disseminated aspergilosis no D+41.

• 2 - WAS: early cmv infection, rejection, sepsis and death D+93.

• 3 - SCID: transplanted and discharged home under ventilatory support, with full donor chimerism, and died one year after transplant from congestive heart failure and unknown infection

• 4 - HLH: rejected the graft, received a second transplant, mixed chimerism, and died 2 years after HSCT due to disease progression + GVHD.

• 5 – SCID: died 1 year after transplant with severe cytopenia (unknown cause), fungal infection.

Second transplant using Haplo donors and PT/Cy

Cy29 + Flu150 + TBI 200 rads Cy 100mg/Kg + CSA + MMFAge, diagnose

Previoustransplant

Indication for 2nd

HSCT

Outcome/Chimerism

GVHD Infections

1y, WAS 6/6 CBU

Primary graft failure

Alive/100% no no

10m, WAS 5/6 CBU Alive/100% no no

1y, WAS 5/6 CBU Alive/100% no CMV retinitis

3y, WAS 9/10 URD Secondary graft failure

Alive/100% Chronic* no

11y, CGD MSD Alive/62% no CMV

• 1 Chronic GVHD, NIH moderate, off treatment• 1 WAS is still on IS

Conclusions and future directions• This is a small and retrospective study but it is the largest series

reported up until now for pts with PID transplanted using PTCy.

• 15/20 patients are alive and well.

• Low toxicity of the preparatory regimen and rapid engraftment with limited GVHD.

• Low morbidity due to viral reactivation, no PTLD reported.

• Promising approach to rapidly treat patients with life-threatening diseases who lack a MSD.

• Excellent strategy to rescue primary and secondary graft failures quickly.

Future perspectives• Feasible, safe and low cost procedure that may allow developing

countries to perform haplo-HSCT.

• Because of the near universal availability of haplo-donors, this strategy could permit to treat every patient facing life-threatening conditions and who lack a matched donor.

• The optimal preparatory regimen needs to be defined for each disease.

• Best selection of patients and donors can provide best results.

• Prospective studies are needed to identify the best approach for HSCT using alternative donors.

Acknowledgment

• Scientific committee for the opportunity to show this data.

• Patients and families for confidence, respect and affection.

• BMT and multidisciplinary team from those three hospitals in Curitiba who have been working hard taking care of patients.

• Laboratory team who is deeply committed doing a great job in this field.

• Specially to Dr. Carmem Bonfim for attention, support and encouragement for scientific growth.