Busulfan, fludarabine and thymogen (ATG) as conditioning for allogeneic stem cell transplantation – pro

M Levin, MD — Fri, 05 Oct 2012 12:30:23 +0000

The regimen of busulafan. fludarabine and thymogen has been very quickly adopted and now studies of it as a base for adding additonal drugs have been initiated. However, there is room for caution. Thymoglobulin added to busulfan and fludarabine to conditioning before an allogeneic stem cell transplant may reduce the incidence and severity of graft versus host disease, especially in matched unrelated graft, but it can potentially promote higher reapse rates. In a retrospective review, Bredeson found exactly such an outcome. A recent study(McCune et al) confirmed low GVHD rates for this conditioning regimen and concluded: “The low rates of GvHD, particularly in its chronic form, were encouraging, and further biomarker studies are warranted to optimize the fludarabine/Tbusulfan/rATG conditioning regimen.” It stands to reason that mores studies on relapse rates should be performed before wide scale adoption of the addition of thymogen to busulfan-fludarabine.

A 2012 guideline (Fischmann et al) says this: “Our systematic review suggests that the addition of ATG during allogeneic HSCT significantly reduces the incidence of severe grades (II to IV) of acute GvHD, whereas the incidence of overall acute GVHD (grades I to IV) was not significantly lowered. This indicates a reduction of the severity but not the incidence of acute GVHD. However, this effect did not lead to a significant improvement of overall survival, which may be due to the severe potential side effects of the consecutively increased immunosuppression.Furthermore, future research is needed to clarify the effect of ATG on the incidence and severity of chronic GVHD and consequently on all aspects of quality of life.From the currently available data, no recommendation on the general use of ATG in allogeneic HSCT can be supported.

Theurich S, Fischmann H, Shimabukuro-Vornhagen A, Chemnitz JM, Holtick U, Scheid C, Skoetz N, von Bergwelt-Baildon M. Polyclonal anti-thymocyte globulins for the prophylaxis of graft-versus-host disease after allogeneic stem cell or bone marrow transplantation in adults.Cochrane Database Syst Rev. 2012 Sep 12;9:CD009159.

Bredeson CN, Zhang MJ, Agovi MA, Bacigalupo A, Bahlis NJ, Ballen K, Brown C, Chaudhry MA, Horowitz MM, Kurian S, Quinlan D, Muehlenbien CE, Russell JA, Savoie L, Rizzo JD, Stewart DA. Outcomes following HSCT using fludarabine, busulfan, and thymoglobulin: a matched comparison to allogeneic transplants conditioned with busulfan and cyclophosphamide.Biol Blood Marrow Transplant. 2008 Sep;14(9):993-1003.

Jeannine S. McCune, Erica L. Woodahl, Terry Furlong, Barry Storer, Joanne Wang, Shelly Heimfeld, H. Joachim Deeg and Paul V. O’Donnell, A pilot pharmacologic biomarker study of busulfan and fludarabine in hematopoietic cell transplant recipients Cancer Chemotherapy and Pharmacology Volume 69, Number 1 (2012), 263-272

For Lay version see here

Conditioning for allogeneic transplantation in Aplastic Anemia – pro

M Levin, MD — Fri, 24 Aug 2012 19:42:30 +0000

In younger patients with Aplastic Anemia)AA), the standard conditioning proposed by the Working Party on SAA (WPSAA) is cyclophosphamide 50 mg/kg 32 × 4 + ATG. This regimen is nonmyeloablative and highly immunosuppressive to prevent graft rejection and GVHD. Often ATG(Thymogen) is also added. The benefit of adding ATG to cyclophosphamide is unclear, because a recently published prospective randomized clinical trial (RCT) from CIBMTR showed no significant benefit in terms of graft rejection, GVHD, and survival rates, compared with cyclophosphamide alone. Raw unadjusted data, from the EBMT database, however, show a slightly superior 10-year survival of 85% versus 75% when ATG is used as part of the conditioning regimen in sibling donor transplantation.

Patients older then 30 years of age, do less well with allogeneic transplantation because they tolerate GVHD less well. There is some support for using fludarabine, a more immunosupressive drug, for such patients. Fludarabine based conditioning regimen may reduce the negative impact of age in older patients receiving an HLA-identical sibling stem cell transplant Alemtuzumab is a new drug that has been studied and that may also decrease the risk of Graft versus Host Disease. A recent European retrospective review of the combination of Fludarabine, cyclophosphamide and antithymocyte globulin(FCA), with or without low dose total body irradiation, concluded that TBI might have a role. The overall survival was quite comparable for the two regimens, though significant differences were found following more detailed analysis of subgroups. FCA conditioning regimen seems suitable for very young patients with well-matched donors; in other settings the addition of TBI 2 Gy to the FCA regimen seems to offer a better chance of cure, in keeping with results of other recent studies

There is no comparative information for any specific conditioning regimen in young adults with Aplastic Anemia. FCA is as well supported as other alternatives. For that reason, since stem cell transplantation is well established for Aplastic Anemia and the conditioning regimens are a part of this established procedure, the FCA regimen should not be considered Experimental or Investigational and it is medically necessary. The evidence for TBI is weak for young patients and TBI is experimental and it is not medically necessary.

Jakob R. Passweg and Judith C.W. Marsh Aplastic Anemia: First-line Treatment by Immunosuppression and Sibling Marrow Transplantation
ASH Education Book December 4, 2010 vol. 2010 no. 1 36-42

Maury S, Bacigalupo A, Anderlini P, et al.(2009) Improved outcome of patients older than 30 years receiving HLA-identical sibling hematopoietic stem cell transplantation for severe acquired aplastic anemia using fludarabine-based conditioning: a comparison with conventional conditioning regimen. Haematologica 94:1312–1315.

Marsh, et al. Alemtuzumab with fludarabine and cyclophosphamide reduces chronic graft-versus-host disease after allogeneic stem cell transplantation for acquired aplastic anemia Blood 2011 118:2351-2357;

Andrea Bacigalupo et al, Fludarabine, cyclophosphamide, antithymocyte globulin, with or without low dose total body irradiation, for alternative donor transplants, in acquired severe aplastic anemia: a retrospective study from the EBMT-SAA working party haematol June 1, 2010 vol. 95 no. 6 976-982

Guideline] Killick SB, Bown N, Cavenagh J, Dokal I, Foukaneli T, Hill A, et al. Guidelines for the diagnosis and management of adult aplastic anaemia. Br J Haematol. 2016 Jan. 172 (2):187-207.
[Guideline] Barone A, Lucarelli A, Onofrillo D, Verzegnassi F, Bonanomi S, et al. Diagnosis and management of acquired aplastic anemia in childhood. Guidelines from the Marrow Failure Study Group of the Pediatric Haemato-Oncology Italian Association (AIEOP). Blood Cells Mol Dis. 2015 Jun. 55 (1):40-7.

Read the Layperson version here.

Cancer Treatment Today » Conditioning

Busulfan, fludarabine and thymogen (ATG) as conditioning for allogeneic stem cell transplantation – pro

Conditioning for allogeneic transplantation in Aplastic Anemia – pro