Remission of Relapsed Leukæmia During a Graft-Versus-Host Reaction a "Graft-Versus-Leukæmia Reaction" in Man?

Summary:The majority of patients with relapsed or refractory Hodgkin's lymphoma (HL) will not be cured with standard therapy. Relapse rates remain high even after autologous stem cell transplantation (SCT), particularly for patients with high-risk disease. Allogeneic SCT offers several potential advantages for patients with HL. It is feasible when autologous stem cells are not available and stem cell grafts will be tumor free. Perhaps a more important advantage is the potential to generate a graftversus-Hodgkin's lymphoma (GVHL) effect. Unfortunately, although allogeneic SCT may cure some HL patients, treatment-related mortality has been unusually high, and superior survival, when compared to autologous SCT, has not been demonstrated. Nonmyeloablative conditioning and allogeneic SCT may induce a direct GVHL reaction with less conditioning regimen-related toxicity and ultimately may have the potential to improve cure rates and survival for advanced HL patients. The success of allogeneic SCT in many cases is related not just to the intensive conditioning regimen, but also to the antitumor properties of the donor graft. This graft-versustumor (GVT) effect is independent of the high-dose conditioning therapy, and is mediated, at least in part, by donor T cells contained in the stem cell graft. In fact, the rationale for some of the first clinical attempts at SCT was based on the potential of allogeneic bone marrow to provide 'adoptive immunotherapy' and destroy leukemia cells surviving radiation therapy. The contribution of a GVT response has been studied extensively and is clearly documented in animal models of SCT.2-5 Over the past decade, evidence has also accumulated for a potent GVT effect in human SCT. Initial evidence was based on several indirect although important clinical observations that included: (1) the abrupt withdrawal of immunosuppression (or a flare of acute graft-versus-hostdisease (GVHD)) re-established complete remission in some patients with relapsed acute leukemia; 6,7 (2) the risk of leukemic relapse was higher for recipients of syngeneic marrow grafts than for recipients of allogeneic grafts; 8,9 (3) GVHD after allogeneic bone marrow transplantation (BMT) was protective against relapse in some patient groups; 8,10 and (4) T-cell depletion of an allogeneic donor graft resulted in an increased relapse risk, especially for patients with chronic myelogenous leukemia (CML). 8,11 However, the use of donor leukocyte infusions (DLI) to treat relapse after allogeneic SCT provides the most direct evidence for a GVT reaction in humans. A total of 60-80% of patients with relapsed CML will achieve a complete molecular remission after infusion of unmanipulated donor leukocytes.12-17 The majority of DLI-induced remissions for CML are durable, and event-free survival rates are over 60-70%. 18-20GVT activity is disease specific Unfortunately, not all patients develop a GVT effect after DLI. Responses are disease specific and results from various studies are shown in Table 1. Response rates for patients with ...

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confidence: 99%

‘GVHD’: graft-versus-host disease or graft-versus-Hodgkin's disease? an old acronym with new meaning

Porter

Stadtmauer

Lazarus

2003

“…[6][7][8][9][10] Due to the lack of GVHD, there is no graft-versus-leukaemia effect. [11][12][13][14] ABMT also carries a risk of reinjecting residual leukaemic cells. 15 Therefore, ABMT is associated with a higher risk of relapse, compared to BMT.…”

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confidence: 99%

The dismal outcome in patients with acute leukaemia who relapse after an autograft is improved if a second autograft or a matched allograft is performed

Ringdén

Labopin

Gorin

et al. 2000

Summary:All patients receiving autografts for acute leukaemia in remission between 1 January 1981 and 31 December 1996 and reported to the European Group for Blood and Marrow Transplantation and had a relapse, were included. The patients underwent an allograft (n = 90, group A), were treated with chemotherapy (n = 2584, group B) or received a second autograft (n = 74, group C). The 2-year survival after relapse was 32 ؎ 5%, 11 ؎ 1% and 42 ؎ 6% in groups A, B and C, respectively. In group A, those with an HLA-A, -B and -DR compatible related or unrelated donor had a 2-year survival of 37 ؎ 7% compared to 13 ؎ 8% for those receiving a graft from an HLA mismatched donor (n = 20). The following factors were associated with better survival in multivariate analyses: an interval from first autograft to relapse Ͼ5 months (P Ͻ 0.00001), a first autograft performed later than 1991 (P Ͻ 0.00001), patient age below 26 years (median, P Ͻ 0.002), group B vs HLA mismatches from group A (P = 0.002), group C vs group B (P Ͻ 0.005), patients who were not treated with total body irradiation at first autograft (P Ͻ 0.02) and patients in first remission at first autograft (P = 0.02). To conclude, the poor outcome in these patients was improved if a second autograft was feasible (P Ͻ 0.005), or if an HLA-matched allograft was performed (NS). Bone Marrow Transplantation (2000) 25, 1053-1058.

“…Most case reports concerning CsA withdrawal have reported a similar response period of 45-67 days after withdrawal of CsA until remission was documented, although in one case response time was 220 days. [6][7][8][9] A remission-inducing effect of CsA withdrawal after post-transplant relapse is not only described in patients with CML, but also in patients with ANL and Burkitt's lymphoma. [6][7][8][9] For patients with early CML we calculated a probability of 84% for achieving and remaining in remission after 4 years following relapse post BMT, whereas patients with AML have only a probability of about 10% of achieving and remaining in remission after 3 years.…”

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confidence: 99%

“…[3][4][5] In single case studies it has also been reported that abrupt CsA withdrawal can induce complete remission in patients with malignant diseases who relapse after allogeneic BMT. [6][7][8][9] CsA withdrawal is generally used as first-line treatment in patients with leukemic relapse after allogeneic transplant. However, to our knowledge the effectiveness of CsA withdrawal has never been systematically studied.…”

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confidence: 99%

Induction of a graft-versus-leukemia reaction by cyclosporin A withdrawal as immunotherapy for leukemia relapsing after allogeneic bone marrow transplantation

Elmaagacli

Beelen

Trenn

et al. 1999

Summary:We studied the immunomodulating effect of withdrawal of immunosuppression with cyclosporin A (CsA) in 42 patients with leukemic relapse of chronic myelogenous leukemia (CML) (n ‫؍‬ 24), acute myeloid leukemia (AML) (n ‫؍‬ 13) and acute lymphoblastic leukemia (ALL) (n ‫؍‬ 5) after allogeneic unmanipulated bone marrow (BMT) or peripheral blood stem cell transplantation (PBSCT). Response to CsA withdrawal was monitored molecularly by the polymerase chain reaction for elimination of CML cells containing the bcr-abl messenger RNA (mRNA) transcript (n ‫؍‬ 24), or mll-af4 mRNA transcript characteristic of leukemic cells with a 11q23 chromosomal abnormality (n ‫؍‬ 1). Rapid tapering of CsA resulted in subsequent achievement of cytogenetic remission in 11 of 14 CML patients (79%) who relapsed in early disease phase (n ‫؍‬ 9 cytogenetic relapse, n ‫؍‬ 2 hematological relapse) after a median of 57 days. Three of 13 AML patients and one of five ALL patients achieved complete remission. CsA withdrawal was accompanied by the development of acute graft-versushost disease (GVHD) grade II in most of the 24 patients with CML. Two patients who achieved remission of AML or ALL died from severe GVHD grade III-IV. We calculated a probability of 84% for achieving and remaining in remission with early relapse of CML 4 years after relapse post BMT, whereas patients with AML have only a probability of about 10% of achieving and remaining in remission after 3 years. Patients with advanced CML and ALL had no chance of achieving and remaining in remission in the same time period.