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favourably with these two large international reports: response rate to ATG+CsA at 6 months was 70% compared to 35% for patients receiving CsA alone, 22% for eltrom- bopag alone, and 21% for androgens alone (Figure 1). Overall response rates in patients receiving these different treatment options is outlined in Figure 1, which highlights a superior response rate with the ATG+CsA combination. Figure 1 also shows there was no difference in response for patients in this older patient population receiving horse (hATG) versus rabbit ATG (rATG), which is in keeping with two large recently published real-life studies.7,8 Also, sur- vival was comparable in patients receiving horse or rabbit ATG. The higher response rate of patients receiving ATG+CsA did not translate to a significantly improved sur- vival compared to other regimens, as already shown in an EBMT study;9 possibly due to second treatment or improved supportive care. Further support to long-term sur- vival also for non-responders comes from the rabbit ATG study; it showed that the 10-year survival of AA patients, classified at 6 months as non-responders to a first course of rATG+CsA, was comparable whether patients were then allografted (64% survival) or not (60% survival).8 Late responses, improved supportive care, and second treat- ments could possibly explain the outcome of non-allograft- ed patients.
In conclusion, ATG+CsA remains the treatment of choice for patients with AA, also for those over the age of 60; it should be preferred over the administration of CsA with or without androgens or eltrombopag, with or without CsA. Whether the addition of eltrombopag to ATG-CsA first line will further improve the outcome, as recently suggested,10 will be determined by an ongoing prospective randomized trial (RACE trial, EBMT). This study also confirms that in real-life analysis, horse or rabbit ATG produce almost iden- tical response rates and survival, also in older AA patients.
References
1. ContejeanA,Resche-RigonM,TamburiniJetal.Aplasticanemiainthe elderly: a nationwide survey on behalf of the French Reference Center for Aplastic Anemia. Haematologica, 2018;104 (2):256-262.
2. Shin SH, Jeon YW, Yoon JH, et al. Comparable outcomes between younger (⩽40 years) and older (>40 years) adult patients with severe aplastic anemia after HLA-matched sibling stem cell transplantation using fludarabine-based conditioning. Bone Marrow Transplant. 2016;51(11):1456-1463
3. Anderlini P, Wu J , Gersten I, et al. Cyclophosphamide conditioning in patients with severe aplastic anaemia given unrelated marrow trans- plantation: a phase 1–2 dose de-escalation study. Lancet Haematol. 2015;2(9):e367-75.
4. Giammarco S, Peffault de Latour R, Sica S, et al. European Group for Blood and Marrow Transplantation Severe Aplastic Anemia Working Party. Transplant outcome for patients with acquired aplastic anemia over the age of 40: has the outcome improved? Blood. 2018;131(17):1989-1992
5. Al Marki MM, Nathwani N, Yang D, et al. Melphalan based reduced intensity conditioning is associated with favorable disease control and acceptable toxicities in patients older than 70 years with hematologic malignancies, undergoing allogeneic stem cell transplantation. Biol Blood and Marrow Transpl. 2018;24(9):1828-1835
6. Tichelli G, Schrezenmeier H, Socie G, et al. A randomized controlled study in patients with newly diagnosed severe a aplastic anemia receiv- ing antithymocyte globulin (ATG), cyclosporine, with or without G- CSF: study of the SAA Working Party of the European Group for Blood and Marrow Transplantation. Blood. 2011;117(17):4434-4441
7. PeffaultdelaTourR,TabriziR,MarcaisA,etal.Nationwidesurveyon the use of horse antithymocyte globulins (ATGAM) in patients with acquired aplastic anemia: A report on behalf of the French Reference Center for Aplastic Anemia. Am J Hematol. 2018;93(5):1-8
8. Bacigalupo A, Oneto R, Schrezenmeier H, et al. First line treatment of aplastic anemia with thymoglobuline in Europe and Asia: Outcome of 955 patients treated 2001-2012. Am J Hematol. 2018;93(5):643-648
9. MarshJ,SchrezenmeierH,MarinP,etal.Prospectiverandomizedmul- ticenter study comparing cyclosporin alone versus the combination of antithymocyte globulin and cyclosporin for treatment of patients with nonsevere aplastic anemia: a report from the European Blood and Marrow Transplant (EBMT) Severe Aplastic Anaemia Working Party. Blood. 1999;93(7):2191-2195.
10. Townsley D, Scheinberg P, Winkle T, et al. Eltrombopag added to stan- dard immunosuppression for aplastic anemia. New Engl J Med. 2017; 376(16):1540-1545.
Milk and the “Grandmother Effect”– a new contribution to the legacy of Ray Owen
William J. Burlingham
University of Wisconsin, Madison, WI, USA E-mail: burlingham@surgery.wisc.edu
doi:10.3324/haematol.2018.207340
The article by Schonewille et al., in the September 2018 edition of Haematologica,1 tests the theory
2 originally proposed by Owen et al. [PNAS, 1954 ]
that a “Grandmother Effect” can protect the offspring from hemolytic disease of the fetus and newborn (HDFN) [see illustration, Figure 1]. This disease is caused by maternal antibodies formed against the baby’s red blood cells (rbc). One should note here that, thanks to the research of Owen and others in the 1950s, anti-Rhesus D (RhD) antibody (aka “Rhogam”) prophylaxis began to be practiced for all preg- nant women who are RhD- bearing an RhD+ fetus. The absence of such therapy prior to 1954 enabled Owen and colleagues to determine that, when the grandmother had RhD, the mother who was RhD- and had thereby already been “naturally” exposed to this antigen in utero and as a
newborn via breast-feeding, was rendered incapable (for the most part) of producing antibody to an RhD encoun- tered in her adult life as the mother of a child sired by her RhD+ husband. Subsequent to the routine application of Rhogam (anti-RhD prophylaxis) in the 1960’s, the incidence of hemolytic disease of the newborn was greatly decreased, although not completely eliminated. Briefly, Rh- mothers are given a bolus of Rhogam at 28 weeks of pregnancy. If the baby that is born is Rh+(a 50:50 chance, if her husband is RhD heterozyogous), she will receive a second dose, 72 hours after giving birth. This procedure has revolutionized obstetrics and made it possible for healthy Rh+ babies to be born from multiple pregnant Rh- women.
While a boon to Ob/Gyn medicine, this highly effective clinical practice made it nearly impossible for others to
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