Donor-type aplasia after stem cell transplantation in aplastic anaemia: Current understanding and intervention
Former Director, National Institute of Immunohematology, 13 th fl, KEM Hospital Multistorey Building, Parel, Mumbai, Maharashtra, India
Former Director, National Institute of Immunohematology, 13 th fl, KEM Hospital Multistorey Building, Parel, Mumbai, Maharashtra
|How to cite this article:|
Ghosh K. Donor-type aplasia after stem cell transplantation in aplastic anaemia: Current understanding and intervention.J Postgrad Med 2021;67:196-197
|How to cite this URL:|
Ghosh K. Donor-type aplasia after stem cell transplantation in aplastic anaemia: Current understanding and intervention. J Postgrad Med [serial online] 2021 [cited 2022 Jul 5 ];67:196-197
Available from: https://www.jpgmonline.com/text.asp?2021/67/4/196/331276
In the current issue of this journal Majumder et al., have described a case of severe aplastic anaemia who died after successful allogenic stem cell transplantation due to donor-type aplasia (DTA). Secondary marrow aplasia following full donor cell chimerism after allogeneic transplantation in aplastic anaemia is extremely rare amongst Caucasians but reported frequently from southeast Asian countries in 5-18% cases. Data from stem cell transplantation centers in India is meagre. Therein lies the interest in this case report.
Severe aplastic anaemia can be treated preferably by allogeneic stem cell transplantation in young patients if matched sibling (family) donor (MSD) or even matched unrelated donor (MUD) is available. Following transplantation in aplastic anaemia, complications like relapse/refractoriness is an important challenge.
Initially this was described as primary and secondary and was related to immediate rejection of donor cells in primary refractoriness with dire consequences. Secondary refractoriness or relapse used to happen several months and years after transplantation and has been analyzed in great details with reference to donor cell chimerism. Full donor chimerism or stable mixed chimerism was associated with best results and continuous donor cell loss, secondary relapse and refractoriness complicate other types of chimerism.
Most interesting finding in some of the series of transplantation cases in severe aplastic anaemia was DTA. This is intriguing because in these cases more than 90% of marrow cells were still of donor origin though the patient had relapsed to marrow aplasia as described in the case report. Usual techniques like increasing immunosuppression, rituximab therapy and donor lymphocyte infusion do not work in such cases, except re-transplantation with the primary donors stem cells The phenomenon of DTA occurred 1 to 6 years after transplantation and proportion of such cases increased with increased use of fludarabine-based conditioning regimens where cyclophosphamide injection was reduced by 50%. Whether it happens for Indian patients with aplastic anaemia in some frequency is not known. Even in the multicentric study reported with fludarabine-based conditioning from the country at the end of 5 years 75% patients were well so what happened to other 25% patients? Ten years back, DTA was not considered as a serious challenge and hence it has not been studied. But in future it has to be considered seriously in our country.
What is the pathogenesis of DTA? This is not known with any degree of certainty but following conjectures have been made:
After transplantation, the donor stem cells continue to be destroyed over the years leading finally to haemopoietic stem cell deficiency but other cells of donor origin remain.A small lymphoid clone of recipient origin persists and destroys donor cells. Hence after second conditioning and transplantation this is destroyed and patient recovers.For DTA a second hit in terms of virus infection e.g., parvovirus, cytomegalovirus and Epstein-Barr virus is required. In some cases of DTA parvovirus infection has been documented.Finally a lot more is known about immune dysregulatory microenvironment in aplastic anaemia along with destruction of stem cell niche constituted by various types of mesenchymal cells in this condition. Destruction of these niche can lead to DTA.
Is there some predisposition for DTA? It seems more than 40 units of prior blood product transfusion, low number of infused CD34 + ve cells (<3 × 10 6 cells/kg), elderly patient >40 years, fludarabine-based conditioning regime with reduced dose of cyclophosphamide to be more often associated with DTA. There is a need to dissect each of these components operative for production of DTA through culture and co-culture experiments and see if there is loss of CD34 +ve donor cells or haemopoietic differentiation block in these cases.
In the present case DTA occurred after stoppage of cyclosporin. Probably with stoppage of cyclosporine, residual recipient anti-donor clones of lymphocytes proliferated and resulted in immune dysregulation causing DTA. There are reports of eltrombopag reversing DTA. This therapy can be tried in these patients while waiting for second transplantation, or CD34 cell boost from the donor with augmented immunosuppression.
|1||Majumder A, Misra S, Kumar V. Recurrent aplastic anaemia with donor type aplasia: A rare occurrence in the Indian subcontinent. J Postgrad Med 2021;67:235-7.|
|2||Eapen M, Davies SM, Ramsay NK. Late graft rejection and second infusion of bone marrow in children with aplastic anaemia. Br J Haematol 1999;104:186-8.|
|3||Yoshida N, Yagasaki H, Yabe H, Kikuchi A, Kobayashi R, Takahashi Y, et al. Donor type aplasia after bone marrow transplantation in children with aplastic anaemia: A nationwide retrospective study. Blood 2012;120:959.|
|4||George B, Mathews V, Lakshmi KM, Melinkeri S, Sharma A, Viswabandya A, et al. The use of fludarabine-based conditioning regimen in patients with severe aplastic anemia - A retrospective analysis from three Indian centres. Clin Transplant 2013;27:923-9.|
|5||Lawler M, McCann SR, Marsh JC, Ljungman P, Hows J, Vandenberghe E, et al. Serial chimerism analysis indicate that mixed haemopoietic chimerism influences the probability of graft rejection and disease recurrence following allogeneic stem cell transplantation (SCT) for severe aplastic anaemia (SAA): Indication for routine assessment of chimerism post SCT for SAA. Br J Haematol 2009;144:933-45.|
|6||Shaw A, Passweg JR, De La Fuente J, Bajwa R, Stein J, Al-Zaben A, et al. Relapse of aplastic anemia with majority donor chimerism (donor-type aplasia) occurring late after bone marrow transplantation. Biol Blood Marrow Transplant 2020;26:480-5.|
|7||Medinger M, Drexler B, Lengerke C, Passweg J. Pathogenesis of acquired aplastic anemia and the role of the bone marrow microenvironment. Front Oncol 2018;8:587.|