Cancer Treatment Today » Graft versus Host Disease

DLI for T cell leukemia and lymphoma – pro

M Levin, MD — Fri, 10 Jan 2014 16:27:04 +0000

Donor lymphocyte infusions are designed to awaken some degree of graft versus host reaction, which contains within it also the graft versus disease effect. It is a modality that can be used after allogeneic transplantation to treat relapse by “awakening” an immune response. . Almost all work on DLI was in B cell leukemias and lymphomas. How it affects T cell malignancies is not well studied and most of what is known was in Adult T-Cell leukami/Lymphoma. Many questions remain. For example, achieving hematologic remission with DLI is not an easy task, especially in patients with a high tumor burden and rapidly proliferating leukemic cells.. Cytoreductive therapy before DLI is thought to improve effectiveness of DLI. Unfortunately, which regimens to use for this cytoreduction has not been defined. How to induce and manage graft versus host reaction has not been defined. Even the very effectiveness of allogeneic transplantation in T-Cell Leukemias continues to be studied. To conclude, DLI remains experimental for T Cell malignancies due to lack of reliable information on how to do it and how effective it is.

Hidehiro Itonag et al, Treatment of relapsed adult T-cell leukemia/lymphoma after allogeneic hematopoietic stem cell transplantation: the Nagasaki Transplant Group experience Blood January 3, 2013 vol. 121 no. 1 219-225

Gabriel IH. Graft versus lymphoma effect after early relapse following reduced-intensity sibling allogeneic stem cell transplantation for relapsed cytotoxic variant of mycosis fungoides. Bone Marrow Transplant 2007;40(4):401-403.

Herbert KE, . Graft-versus-lymphoma effect in refractory cutaneous T-cell lymphoma after reduced-intensity HLA-matched sibling allogeneic stem cell transplantation. Bone Marrow Transplant 2004;34(6):521-525.

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Velcade for Graft Versus Host DIsease – pro

M Levin, MD — Wed, 16 Oct 2013 21:01:41 +0000

Koreth found that Velcade was beneficial in GVHD; but his was a phase II trial and other phase II trials are ongoing. He found that i the 45 patients who were treated in the study; 89% of patients were treated with a one-locus and 11% of patients were treated with a two-loci mismatch. With a median follow-up of 3 years, the 180-day cumulative incidence of grade 2 to 4 acute GVHD was 22%, and the 1-year cumulative incidence of chronic GVHD was 29%. The non-relapse mortality rate was only 11%, and the relapse rate was 38%. Results were comparable with patients who received HLA-matched transplants with the unexpected observation that bortezomib therapy enhanced immune reconstitution on the basis of measurements of CD8+ T cells and natural killer cells.
The editorial by Giralt that accompanied Koreth report, pointed out that there are four potential current approaches that all are at the same stage of development and that it may be necessary to perform a randomized phase III trial with a short primary end point to be able to rapidly pick a winner from among these competing approaches, one that could be compared with the current standard in a definitive trial.

Koreth J, Stevenson KE, Kim HT, McDonough SM, Bindra B, Armand P, Ho VT, Cutler C, Blazar BR, Antin JH, Soiffer RJ, Ritz J, Alyea EP 3rd. Bortezomib-based graft-versus-host disease prophylaxis in HLA-mismatched unrelated donor transplantation.J Clin Oncol. 2012 Sep 10;30(26):3202-8.

Teresa Caballero-VelázquezPhase II clinical trial for the evaluation of bortezomib within the reduced intensity conditioning regimen (RIC) and post-allogeneic transplantation for high-risk myeloma patients. Phase II clinical trial for the evaluation of bortezomib within the reduced intensity conditioning regimen (RIC) and post-allogeneic transplantation for high-risk myeloma patients, British Journal of Haematology, Volume 162, Issue 4, pages 474–482, August 2013

Koreth J, Stevenson KE, Kim HT, McDonough SM … Antin JH, Soiffer RJ, Ritz J, Alyea EPBortezomib-Based Graft-Versus-Host Disease Prophylaxis in HLA-Mismatched Unrelated Donor Transplantation. J Clin Oncol. 2012 Aug 6

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Graft versus host disease (GVHD) prophylaxis – pro

M Levin, MD — Fri, 05 Oct 2012 16:25:54 +0000

Calcineurin inhibitors, such as cyclosporine and tacrolimus, are commonly used in the prophylaxis of GvHD (BCH guideline). For full-intensity stem cell transplantation most centres use a combination of a calcineurin inhibitor, such as ciclosporin or tacrolimus, given in combination with methotrexate. Low-dose methotrexate was the first generally prescribed GVHD preventive regimen for use as a cell-cycle specific chemotherapeutic agent following transplant and was subsequently combined with a T cell activation inhibitor, such as cyclosporin and tacrolimus. Calcineurin inhibitor-based regimens are now the most common form of GVHD prophylaxis. The majority of clinical trials over the past decades have shown the superiority of combination of a calcineurin inhibitor and a short course of methotrexate over either agent alone in the reduction of GVHD incidence and improvement in survival. A meta-analysis of prophylaxis regimens for GVHD also supports the use of cyclosporin-methotrexate over cyclosporin alone.

Bhurani D, Schifter M, Kerridge I. Folinic acid administration following MTX as prophylaxis for GVHD in allogeneic HSCT centres in Australia and New Zealand.Bone Marrow Transplant. 2008 Oct;42(8):547-50.

Ross M, Schmidt GM, Niland JC, et al. Cyclosporine, methotrexate, and prednisone compared with cyclosporine and prednisone for prevention of acute graft-vs.-host disease: Effect on chronic graft-vs.-host disease and long-term survival. Biol Blood Marrow Transplant. 1999;5:285-291.

http://arjournals.annualreviews.org/doi/pdf/10.1146/annurev.med.54.101601.152456

http://www.bcshguidelines.com/documents/BCSH_Guideline_Acute_GVHD_diagnosis_and_management_v1.pdf

http://bestpractice.bmj.com/best-practice/monograph/946/treatment/step-by-step.html, 2012

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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

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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.

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