Haploidentical stem cell transplantation is now a well-accepted transplant platform for an increasing proportion of patients without matched sibling or unrelated donors. Initial studies in the 1980s were associated with unacceptably high rates of graft rejection and acute graft-versus-host disease.rr However, in recent years, the development of newer platforms for haploidentical transplantation incorporating alternative conditioning regimens, in-vivo and ex-vivo T-cell depletion, KIR ligand mismatching, intensified immunosuppression and post-transplantation cyclophosphamide have revolutionised its utility.rrrrr
Post-transplant cyclophosphamide is the most widely used platform, first developed by the Johns Hopkins group.r Cyclophosphamide is not toxic to primitive haematopoietic stem cells, induces tolerance to minor histocompatibility antigens, selectively targets proliferating alloreactive T-cells, and permits immune reconstitution.rr Initial studies used conditioning comprised of fludarabine, cyclophosphamide and 2Gy TBI in association with Day +3 (+/-Day +4) dose of post-transplant cyclophosphamide (50 mg/kg), tacrolimus and mycophenolate. T-replete bone marrow was infused in all patients.r
Current evidence for this reduced intensity conditioning (RIC) protocol is based on the updated patient cohort from Johns Hopkins using bone marrow.r Two separate groups, including a multicentre collaboration from the UK, US and Australia, have shown equivalent results using peripheral blood stem cells (PBSC) as a stem cell source.rr
There have been 3 retrospective single-centre studies comparing haploidentical transplant to other donor sources showing similar outcomes.rrr In addition, a Center for International Blood and Marrow Transplant Research (CIBMTR) registry study has also demonstrated comparable results between haploidentical transplants and unrelated donors using both myeloablative and RIC regimens.r
Efficacy
Major efficacy results using this protocol with bone marrow or PBSCs graft source.
Author |
Patient (n) |
Stem cell source |
Relapse rate |
OS |
PFS/EFS |
Comments |
McCurdy et al., 2015r |
372 |
BM |
37% @ 1yr;
50% @ 3 yrs
|
68% @ 1 yr;
50% @ 3 yrs
|
52% @ 1 yr;
40% @ 3 yrs
(PFS)
|
Significant impact of DRI on outcome |
Raj et al., 2014r |
55 |
PBSC |
28 % @ 2 yrs |
78% @ 1 yr;
48% @ 2 yrs
|
66% @ 1 yr;
51% @ 2 yrs
(EFS)
|
Included 4 patients with SAA |
Castagna et al., 2014r |
69 |
BM = 46
PBSC = 23
|
20% @ 1 yr |
68% @ 2 yrs (est) |
68% @ 2 yrs (est) |
No significant difference between groups |
OS = overall survival; PFS = progression-free survival; EFS = event-free survival; BM = bone marrow; DRI = disease risk index; SAA = severe aplastic anaemia
The most significant concern is the increased relapsed rate reported using non-myelablative conditioning in the Johns Hopkins patient cohortr although others report that the relapse rate is similar to matched sibling donor transplants when matched for DRI. rr However additional measures may be considered in patients with a high DRI.
Fig 1: Overall survival in the CIBMTR retrospective cohorts by donor type and adjusted for age and DRI for: (A) Myeloablative or (B) Reduced intensity regimens.r
© Blood 2015
Results from a single centre retrospective analysis comparing reduced intensity and myeloablative T-replete haploidentical bone marrow transplants with other donor sources demonstrated similar outcomes to matched sibling allografts in terms of OS and relapse rate and less acute and chronic graft-versus-host disease (GVHD).r
Fig 2: Actuarial survival of patients stratified for donor type. Overall there is no statistically significant difference in survival.
© Biol Blood Marrow Transplant 2014
Toxicity
Author |
TRM |
Acute GVHD |
Chronic GVHD |
Rejection |
Infection |
McCurdy et al., 2015r |
8% @ D180;
11% @ 1 yr
|
Gd 2-4 = 32%;
Gd 3-4 = 4%
|
13% @ 2 yrs |
8.2% |
NR |
Raj et al., 2014r |
17% @ 1 yr;
23% @ 2 yrs
|
Gd 2-3 = 53%;
Gd 3 = 8%;
No Gd 4
|
16% @ 1 yr;
18% @ 2 yrs
|
4% |
No CMV / EBV / mould disease
|
Castagna et al., 2014r |
18% @ 2 yrs |
Gd 2-4 = 25% / 33% (BM / PB)
Gd 3-4 = 6% overall
|
13% @ 1 yr
BM & PB
|
NS |
No CMV disease |
TRM = treatment-related mortality; CMV = cytomegalovirus; EBV = Epstein–Barr virus; Gd = grade; NR = not reported; BM = bone marrow; PB = peripheral blood
Overall graft rejection rates are <10% with rates of severe Grade 3-4 acute GVHD also <10% regardless of graft source. Chronic GVHD also remains at acceptable levels of <20%.
Fig 3 (A) Cumulative incidence of aGVHD. The highest rate for was mismatched unrelated donors (mmUD), followed by siblings (SIB), matched unrelated (MUD), unrelated cord blood (UCB) and haploidentical family donors (HAPLO). The difference is significant (P < .001). (B) Cumulative incidence of cGVHD, showing a borderline higher risk for sibling donors. r
© Biol Blood Marrow Transplant 2014
Fig 4: (Left) Cumulative incidence of TRM. The UCB, mmUD, and MUD show higher TRM compared with SIB and HAPLO donors; overall the difference is not significant, however. (Right) Cumulative incidence of relapse. Slightly higher rates are seen for the SIB and HAPLO groups.
© Biol Blood Marrow Transplant 2014