Methotrexate and Cyclosporine Compared with Cyclosporine Alone for Prophylaxis of Acute Graft versus Host Disease after Marrow Transplantation for Leukemia

Storb, Rainer; Deeg, H. Joachim; Whitehead, John; Appelbaum, Frederick R.; Beatty, Patrick G.; Bensinger, William I.; Cd, Buckner; Clift, Reginald A.; Doney, Kristine; Farewell, Vernon; Hansen, John A.; Hill, Roger; Lum, Lawrence G.; Martin, Paul J.; McGuffin, Robert W.; Sanders, Jean E.; Stewart, Patricia; Sullivan, Keith M.; Witherspoon, Robert P.; Yee, Gary C.; Ed, Thomas

doi:10.1056/nejm198603203141201

Cited by 1,338 publications

(618 citation statements)

References 35 publications

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“…In this study, recurrence was observed in 24%, resulting in an event free survival of 54%. While follow up for the CTR-V group is more limited, these results compare favorably with the survival reported in individuals receiving unfractionated grafts [35][36][37][38][39][40][41][42][43]. Such differences may also be related to variations in the case selection, the schedule of the post-remission chemotherapy or by the considerable heterogeneity in the preconditioning in all of these studies.…”

Section: Discussionsupporting

confidence: 52%

Increasing dose intensity of anthracycline antibiotics improves outcome in patients with acute myelogenous leukemia

et al. 2004

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To understand the effect of dose concentration in the overall survival of AML, we conducted a study on the efficacy and toxicity of a drug combination where the dose of daunorubicin was intensified. For this analysis, the outcome of patients entered into two consecutive prospective trials was compared. Inclusion criteria in both arms were identical and consisted of primary AML in adults. Treatment protocol for Cape Town Regimen 4 (CTR-IV) comprised of cytarabine infusion (100 mg/m 2 ) and etoposide (100 mg/m 2 ), injection daily for 7 days in combination with daunorubicin (45 mg/m 2 ) on days 1, 2, and 3. Patients achieving remission were given two further courses of the same chemotherapy and received allogeneic or autologous transplantation. CTR-V was a similar treatment program, except that daunorubicin was escalated on days 1, 2, and 3 to 75 mg/m 2 during induction and to 60 mg/m 2 during a single consolidation. Patients were also offered stem cell transplantation. Between 1990 and 1997, 78 patients (median age 33; range 13-67 years) fulfilled entry criteria and received CTR-IV. From 1998 onwards, 35 patients (median age 36; range 15-66 years) were prospectively enlisted into the CTR-V trial. The patient population in CTR-V had fewer Caucasian individuals (P = 0.02) and had significantly lower presentation hemoglobin (P = 0.0002). Following initiation of induction chemotherapy, 40 patients failed to respond. Among these, 10 patients demised before day 28. Another 30 (25/69 CTR-IV and 5/32 in CTR-V groups; P = 0.01) had leukemia that was resistant to chemotherapy, and all died. Remission was achieved in 59% of patients treated with CTR-IV and 77% of those receiving CTR-V (P = 0.03). CR occurred with a single course in 64% versus 88% (P = 0.02), respectively. There were no differences in the toxicity profile between these two combinations. Disease recurred in 50% and 28% (P = 0.07) of patients. For the 113 individuals, median follow up is 254 (range 19-4,451) and 304 (12-1,702; P = 0.03) days. Survival is 23% and 40%, respectively, favoring patients treated with CTR-V (log rank; P = 0.03). Cox regression analysis showed that treatment group (P < 0.001), FAB type, hemoglobin level, and platelet count were independent factors for response to chemotherapy. Older age and not undergoing myeloablative therapy were the only adverse factors for survival. We conclude that increase in the treatment dose of daunorubicin in patients with AML led to a higher remission rate, particularly with a single course of chemotherapy and had an equivalent toxicity profile. This therapeutic modification is also likely to result in substantial reduction in patient stay in hospital and in the overall expenditure. Am.

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Section: Discussionsupporting

confidence: 52%

Increasing dose intensity of anthracycline antibiotics improves outcome in patients with acute myelogenous leukemia

et al. 2004

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“…Clinical observations with allotransplanted patients support these findings. For example, a combination of MTX, CsA and prednisone was found to be more effective in preventing acute GVHD than the combination of CsA and prednisone alone [50][51][52], supporting the idea that MTX deletes activated T cells that have escaped from proliferation blockade by other ISD. Recent data from mice with lupus nephritis also indicate that a treatment, which combines the inhibition of T cell activation by CTLA4Ig and the induction of apoptosis in immune cells by CP, reduced renal disease and prolongs survival [53].…”

Section: Discussionmentioning

confidence: 88%

“…Fifty ml of supernatant was assayed for 51 Cr-release in a Microbeta Trilux Counter (Wallac, Germany). Maximum release was determined by incubation of target cells in 100 ml 10% SDS and spontaneous release was determined by addition of medium.…”

Section: Cytotoxicity Assaymentioning

confidence: 99%

Induction of apoptosis and modulation of activation and effector function in T cells by immunosuppressive drugs

Strauß

Osen

Debatin

2002

Clinical and Experimental Immunology

149

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SUMMARYImmunosuppressive drugs (ISD) are used for the prevention and treatment of graft rejection, graftversus-host-disease (GVHD) and autoimmune disorders. The precise mechanisms by which ISD interfere with T cell activation and effector function or delete antigen-specific T cells are defined only partially. We analysed commonly used ISD such as dexamethasone (DEX), mycophenolic acid (MPA), FK506, cyclosporin A (CsA), rapamycin (RAP), methotrexate (MTX) and cyclophosphamide (CP) for apoptosis-induction and modulation of activation and effector function in human peripheral T cells, cytotoxic T cell lines (CTL) and Jurkat T cells. Of all drugs tested only CP and MTX prevented antigenspecific proliferation of T cells and decreased cytotoxicity of alloantigen specific CTL lines by direct induction of apoptosis. MTX and CP also slightly increased activation-induced cell death (AICD) and CD95-sensitivity. In contrast, all other drugs tested did not induce T cell apoptosis, increase CD95-sensitivity or AICD. CsA and FK506 even prevented AICD by down-modulation of CD95L. DEX, MPA, CsA, FK506 and RAP inhibited activation of naive T cells, but were not able to block proliferation of activated T cells nor decrease cytotoxic capacity of CTL lines. These results show that ISD can be classified according to their action on apoptosis-induction and inhibition of proliferation and would favour a rational combination therapy to delete existing reactive T cells and prevent further T cell activation.

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“…Currently, the most common GVHD prophylaxis is based on a calcineurin inhibitor (cyclosporine [CSA] or tacrolimus [Tac]) and a short course of methotrexate (MTX, 15mg/m 2 IV on day 1, followed by 10mg/m 2 on day 3, 6, and 11). MTX, an antimetabolite and folate antagonist, has had a long history in the prevention of GVHD and in combination with a calcineurin inhibitor, is the current standard in GVHD prevention [2][3][4]. However, MTX has many associated toxicities, including severe mucositis, delayed engraftment, and renal/hepatic toxicities.…”

Section: Introductionmentioning

confidence: 99%

Cyclosporine in combination with mycophenolate mofetil versus methotrexate for graft versus host disease prevention in myeloablative HLA‐identical sibling donor allogeneic hematopoietic cell transplantation

et al. 2014

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Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality in allogeneic hematopoietic cell transplantation (HCT) despite current prophylaxis. Methotrexate (MTX) with a calcineurin inhibitor (CNI) is the current standard, however, has several toxicities. Mycophenolate mofetil (MMF) is frequently used in reduced-intensity HCT, but data in myeloablative transplants is limited. We thus retrospectively identified 241 patients who underwent myeloablative HCT from an HLA-identical sibling donor; 174 patients received cyclosporine (CSA) 1 MMF and 67 received CSA1MTX. Patients receiving MMF 1 CSA had rapid neutrophil (median 11 vs. 19 days with MTX1CSA), and platelet recovery (median 19 vs. 25 days), lower incidence of severe mucositis by OMAS (19% vs. 53%), and shorter length of hospital stay (median 25 vs. 36 days) (P < 0.001 for all comparisons). There were no significant differences in incidence of grade 2-4 (MMF1CSA 37% vs. MTX1CSA 39%) or 3-4 acute GVHD (17% vs. 12%), chronic GVHD (46% vs. 56%), relapse (28% vs. 27%), non-relapse mortality (20% vs. 27%), or overall survival (47% vs. 44%) (P 5 NS for all). However, in multivariable analysis, the use of MMF1CSA was associated with an increased risk of severe grade 3-4 acute GVHD (HR 2.92, 95% CI 1.2-7.15, P 5 0.019). There were no differences between the two regimens in multivariable analyses for other survival outcomes. This analysis demonstrates that the use of MMF in myeloablative sibling donor transplantation is well tolerated. However, there may be an increased risk of severe GVHD with MMF1CSA compared to MTX1CSA. Further studies evaluating optimal dosing strategies are needed.

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Methotrexate and Cyclosporine Compared with Cyclosporine Alone for Prophylaxis of Acute Graft versus Host Disease after Marrow Transplantation for Leukemia

Cited by 1,338 publications

References 35 publications

Increasing dose intensity of anthracycline antibiotics improves outcome in patients with acute myelogenous leukemia

Increasing dose intensity of anthracycline antibiotics improves outcome in patients with acute myelogenous leukemia

Induction of apoptosis and modulation of activation and effector function in T cells by immunosuppressive drugs

Cyclosporine in combination with mycophenolate mofetil versus methotrexate for graft versus host disease prevention in myeloablative HLA‐identical sibling donor allogeneic hematopoietic cell transplantation

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