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Editorials
Table 1. Consideration for haploidentical versus unrelated donor transplants. Haploidentical transplants
• Most (but not all) patients have a haploidentical donor
• Transplants can be performed immediately after family typing
• Transplant center controls the donor and all aspects of the transplant co-ordinates
• Preparative regimens are generally intensified with TBI or thiotepa to prevent rejection
• There is a low rate of severe acute GvHD and chronic GvHD with post transplant cyclophosphamide based GvHD prophylaxis • Donor specific anti HLA antibodies may produce graft failure; must exclude patients with high titers
• Hemorrhagic cystitis and cardiac toxicity of cyclophosphamide may occur
• There is a longer time to hematologic recovery
HLA matched unrelated donor transplants
• HLA match can be identified for many patients, chance of success depends on race/ethnicity
• Established treatment modality; long track record
• Generally uses same preparative regimen and GvHD prophylaxis as matched related transplants
• Requires time for search process, coordination of the transplant with donor registries; patient s may deteriorate during this time; may need
to accommodate delays for intercurrent patient or donor problems
• One can often avoid donor specific anti HLA antibodies
GvHD: graft-versus-host disease; TBI: total body irradiation.
ately, without a need to wait for an unrelated donor search. The process for performing the unrelated donor search to identify the donor and deliver the transplant typically takes 2-4 months, although donor registries are working to develop procedures that would shorten this process. This study involved AML patients in first or sec- ond remission, which can generally accommodate the time needed to organize an unrelated donor transplant. In more urgent clinical situations, like advanced acute leukemia, precarious patients may progress, clinically deteriorate, or acquire serious infections during the unre- lated donor search and never receive a transplant. Often, the patient may develop medical complications that require the unrelated donor transplant to be rescheduled, which can be logistically challenging at short notice. If a prompt transplant is required and a matched unrelated donor is not immediately identified and available, it is appropriate to go forward with a haploHSCT.
Haploidentical transplants with post-transplant cyclophosphamide do have some special toxicities to consider. Hemorrhagic cystitis is a common complication and can be severe.21 Cyclophosphamide can produce car- diac toxicity, particularly in those with pre-existing car- diac disease. The patient must have adequate renal func- tion to safely tolerate post-transplant cyclophosphamide. Post-transplant cyclophosphamide does delay time to engraftment and hematologic recovery. Use of peripher- al blood stem cells for haploidentical transplants acceler- ates hematopoietic recovery, but with an increased risk of GvHD.22
There are patients who lack an acceptable haploidenti- cal donor, and an unrelated donor or cord blood is their only transplant option. These are typically older adults without healthy siblings or children. Cousins or other second-degree relatives who share a haplotype can be uti- lized for haploHSCT for these patients.
There are some advantages with unrelated donor trans- plants. It is a well established treatment modality with
over 30 years of experience. A general principle of trans- plantation is that better matching is associated with intrinsically less alloreactivity and better transplant out- comes. One problem with haploidentical transplants is graft failure due to donor specific anti-HLA antibodies (DSA), particularly if positive by the C1q assay.23,24 Diffuse sensitization can be induced by blood transfu- sions, with high titer anti-HLA antibodies against a broad range of HLA antigens, primarily in parous female recipi- ents. It is often impossible to identify a haploidentical donor without DSA for these individuals, and patients with high levels of DSA are appropriately excluded from trials of haploHSCT. Engraftment is not affected by anti- HLA antibodies that are not donor specific. Often, an HLA-matched or one antigen mismatched unrelated donor can be identified, avoiding donor specific antibod- ies, in broadly sensitized patients. Note, unrelated donor transplants matched for HLA A, B, C, DR and DQ are generally mismatched at DP, and anti-DP antibodies may be present which may lead to graft failure.25
In conclusion, the study by Perales et al.1 reports that matched unrelated donor transplants with donors younger than 40 years of age is preferred to haploHSCT for patients with AML in complete remission, with improved survival and lower risk of relapse. That may be true for this relatively stable patient population using the preparative and GvHD prophylaxis regimens employed, but this conclusion may not hold for other patient popu- lations where a prompt time to transplant is critical, or with alternative pre- and post-transplant treatment regi- mens. The ideal study would compare optimized ver- sions of both haploidentical and unrelated donor trans- plants, and use “intention-to-treat” analysis including all patients for whom a transplant is intended from the time of initial HLA typing. The study by Perales et al.1 should give pause for thought, however, for those considering jumping to haploidentical transplants as a preferred approach in general.
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