Cancer Treatment Today » Graft versus Host Disease

Velcade for Graft Vesus Host Disease

M Levin, MD — Wed, 01 Jan 2014 18:10:42 +0000

Shen transplanted from an immunologically different person, graft cells can attack the host’s body. This is called Graft Versus Host Diseas*GVHD)e and remains a serious problem in transplantation. One trial by Koreth and others found that Velcade was beneficial in GVHD; but his was a phase II trial other phase II trials are ongoing. Koreth treated 45 patients; 89% of patients who were treated had 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 of CD8+ T cells and natural killer cells.
The editorial by Giralt that accompanied Koreth report, pointed out that there are four potential approaches to developing treatments for GVHD problem and that it may be necessary to perform a randomized phase II trial with a short primary end point to be able to rapidly pick a winner from among these competing approaches that could be compared with the current standard in a definitive trial.

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Graft versus host disease (GVHD) prophylaxis

M Levin, MD — Fri, 05 Oct 2012 16:28:40 +0000

GVHD is a serious complication of transplanting stem cells from a donor into a patient. These cells can attack the host. Calcineurin inhibitors, such as cyclosporine and tacrolimus, are commonly used in the prophylaxis of GvHD. 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.

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Thymogen (ATG) before stem cell transplant

M Levin, MD — Fri, 05 Oct 2012 12:32:27 +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 standas to reason that mores studies on relapse rates should be performed before wide scale adoption of the addition of thymogen to busulfan-fludarabine.

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Allogeneic transplantation in the elderly

M Levin, MD — Tue, 18 Sep 2012 20:22:32 +0000

The ability to escalate therapy and then salvage with stem cells from a donor has been a boon for patients with many types of cancer and hematologic malignancies, making possible a chance of cures in previously hopeless situations. In addition to the ability to markedly escalate the aggressiveness of chemotherapy that can be salvaged with transplanted stem cells, these outside donor cells, if properly managed, can provide an anticancer or anti- leukemia effect without provoking a full-scale debilitating graft versus host reaction. However, allogeneic transplantation remains a difficult, costly and toxic treatment. Taking into account toxicity and complications of high-dose chemotherapy and development of graft versus host disease, as well as infectious complications, unrelated donor transplantation can be deadly for the elderly. The recent (2011) controversy about heart transplantation for the 71-year-old former Vice-President of the United States Dick Cheney brought this issue (as well as the ethical quandaries of allocating scarce organs) to public attention. Elderly patients, even those without chronic medical problems have lower reserves to tolerate or surmount toxicity.

The maximum age for allogeneic transplantation has been increasing as methods of transplantation and supportive care have advanced. Most centers are now considering unrelated donor transplantation for patients at around seventy year mark. Unfortunately this remains an ongoing source of controversy because the literature is contradictory and confusing, owing primarily to the lack of phase 3 studies, which, however, would be very difficult to do. This remains a matter for discussion between patient and physician and an individualized decision between them. The age of around 75 years is now being routinely approached in major centers.

Conditioning for allogeneic transplantation in Aplastic Anemia

M Levin, MD — Fri, 24 Aug 2012 19:43:35 +0000

Stem cell Transplantation is the only curative therapy long term for Aplastic Anemia(AA). Before stem cells can be transfused, the marrow needs to be conditioned. In younger patients with Aplastic Anemia, the standard conditioning proposed by the Working Party(WPSAA) on AA is cyclophosphamide 50 mg/kg 32 × 4 + ATG. This regimen does not completely destroy the patient’s bone marrow and it is highly immunosuppressive in order prevent graft rejection and GVHD. Often ATG(Thymogen/ anti-thymocyte globulin)) for more immunosupression 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.

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