Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors

After the transplantation of unmodified marrow from human leukocyte antigen-matched unrelated donors receiving cyclosporine (CSP) and methotrexate (MTX), the incidence of acute graft-versus-host disease (GVHD) is greater than 75%. Tacrolimus is a macrolide compound that, in previous preclinical and clinical studies, was effective in combination with MTX for the prevention of acute GVHD. Between March 1995 and September 1996, 180 patients were randomized in a phase 3, open-label, multicenter study to determine whether tacrolimus combined with a short course of MTX (n = 90), more than CSP and a short course of MTX (n = 90), would reduce the incidence of acute GVHD after marrow transplantation from unrelated donors. There was a significant trend toward decreased severity of acute GVHD across all grades (P =.005). Based on the Kaplan-Meier estimate, the probability of grade II-IV acute GVHD in the tacrolimus group (56%) was significantly lower than in the CSP group (74%; P =.0002). Use of glucocorticoids for the management of GVHD was significantly lower with tacrolimus than with CSP (65% vs 81%, respectively; P =. 019). The number of patients requiring dialysis in the first 100 days was similar (tacrolimus, 9; CSP, 8). Overall and relapse-free survival rates for the tacrolimus and CSP arms at 2 years was 54% versus 50% (P =.46) and 47% versus 42% (P =.58), respectively. The combination of tacrolimus and MTX after unrelated donor marrow transplantation significantly decreased the risk for acute GVHD than did the combination of CSP and MTX, with no significant increase in toxicity, infections, or leukemia relapse.     

Combination of cyclosporin and methotrexate for prophylaxis of acute graft-versus-host disease after allogeneic bone marrow transplantation for leukemia

From May 1985 to July 1989, 76 patients with leukemia (30 acute myelogenous leukemia, 24 acute lymphoblastic leukemia and 22 chronic myeloid leukemia) were randomized to receive either cyclosporin (CSP) alone (n = 39) or CSP combined with methotrexate (CSP + MTX, n = 37) for graft-versus-host disease (GVHD) prophylaxis. Patients were conditioned with total body radiation and cyclophosphamide followed by bone marrow infusion from an HLA-identical sibling. Engraftment of the transplanted bone marrow was similar in both groups. The incidence of moderate to severe acute GVHD was significantly higher in the CSP group compared with the CSP + MTX group (20 (51%) versus 9 (25%), chi 2 = 4.76, p less than 0.02). There was no significant difference in the incidence of chronic GVHD. Survival was significantly better for the CSP + MTX group (63 +/- 16%) compared to CSP alone (42 +/- 18%). Leukemia-free survival tended to be better for the CSP + MTX group (55 +/- 17% versus 32 +/- 16%).     

Acute graft-versus-host disease: analysis of risk factors after allogeneic marrow transplantation and prophylaxis with cyclosporine and methotrexate.

Previous studies of risk factors for acute graft-versus-host disease (GVHD) involved patients receiving predominantly single-agent prophylaxis. Therefore, a retrospective analysis was performed on 446 patients, from a single institution, who received transplants of marrow from HLA-identical siblings and the combination of cyclosporine (CSP) and methotrexate (MTX) to determine risk factors for acute GVHD associated with this more effective form of GVHD prophylaxis. The incidences of Grades II-IV and Grades III-IV (severe) acute GVHD were 35% and 16%, respectively. Increased clinical grades of acute GVHD in patients without advanced malignant disease were associated with a decreased survival. In a multivariate Cox regression analysis, risk factors associated with the onset of Grades II-IV acute GVHD were sex mismatch and donor parity (P = .001), increased dose of total body irradiation (TBI) (P = .001), and reduction to less than 80% of the scheduled dose of MTX (P = .02) or CSP (P = .02). The multivariate analysis indicated a relative risk of 1.37 for acute GVHD in a group defined as having advanced malignant disease at transplant; however, this difference failed to reach conventional levels of statistical significance (P = .07). Reduction of MTX and CSP occurred in up to 36% and 44% of patients, respectively, primarily because of renal or hepatic dysfunction. The periods of increased risk for the onset of acute GVHD were up to 1 week after a reduction of MTX and 2 weeks after a reduction in CSP. When only patients who developed Grades II-IV acute GVHD were considered, the more severe acute GVHD of Grades III-IV was associated with increased patient age of 40 years or greater (P = .05) and dose reductions of CSP (P = .008). Serologic status of patient and donor for cytomegalovirus (CMV), HLA antigens in the A and B loci, and isolation in a laminar air flow room during marrow transplantation, all previously identified as risk factors for acute GVHD, were not confirmed as risk factors in this study population. The toxicity of MTX and CSP and the development of acute GVHD from inadequate immunosuppression because of dose reduction warrants further trials with potentially less toxic immunosuppressive agents. Risk factors for acute GVHD should be considered in clinical management and in the design of clinical trials.     

Low-Dose Cyclosporin A with Short-Term Methotrexate for Graft-versus-Host Disease Prophylaxis in Allogeneic Bone Marrow Transplantation from Human Leukocyte Antigen—Identical Siblings: A Prospective Phase II Study in Japanese Patients

We hypothesized that reducing the dosage of prophylaxis for graft-versus-host disease (GVHD) would reduce the risk of relapse and toxicity after bone marrow transplantation (BMT) from human leukocyte antigen (HLA)-identical siblings. In a prospective phase II trial, 21 patients with leukemia and myelodysplastic syndrome underwent BMT from HLA-identical siblings and received GVHD prophylaxis consisting of low-dose (1.5 mg/kg per day) cyclosporin A (CSP) with short-term methotrexate (MTX) treatment. This low-dose group was compared with a group of retrospective control patients (n = 22) who received a standard CSP dosage (3.0 mg/kg per day) and MTX. One patient died of transplantation-related causes within 100 days. The regimen-related toxicity was quite tolerable. Although acute GVHD of grades II to III was more frequent in the low-dose group (47.6%) than in the control group (22.7%), the increase in acute GVHD did not significantly contribute to morbidity or mortality. There were no differences between the groups in the incidence and severity of chronic GVHD. The probabilities of relapse and survival of the groups were similar according to the risk for relapse at the time of transplantation. A prospective randomized study is required to determine whether low-dose or standard-dose CSP in combination with MTX is optimal for Japanese patients who undergo allogeneic BMT from HLA-identical siblings.     

Marrow transplantation for chronic myelocytic leukemia: a controlled trial of cyclosporine versus methotrexate for prophylaxis of graft- versus-host disease

Forty-eight patients with chronic myelocytic leukemia, aged 11 to 47, were treated with high-dose cyclophosphamide and fractionated total body irradiation, followed by infusion of marrow from HLA-identical siblings. They were randomized to receive either methotrexate (MTX) (n = 23) or cyclosporine (CSP) (n = 25) as postgrafting prophylaxis for graft-v-host disease (GVHD). All patients had evidence of sustained hematopoietic engraftment. Seventeen of the 25 patients receiving CSP and 17 of the 23 patients receiving MTX are alive between one and almost four (median, 1.7) years, with an actuarial survival rate at three years of 62% and 66%, respectively (P = .60). Also, with respect to most other parameters studied, the two drugs were identical. The probability of acute GVHD was .42 and .46, respectively (P = .70), that of chronic GVHD, .50 and .63 (P = .44), and that of death from transplant-related causes, .30 and .24 (P = .51). There were no differences in the speed of granulocyte and platelet engraftment (P = .82 and .94, respectively), and the duration of hospitalization was comparable (P = .58). Patients receiving MTX required red cell transfusions for a shorter period of time (P = .02), but had a slightly increased morbidity from early oral mucositis. The leukemia recurrence rates were comparable (P = .60). With the regimens used in this study, we conclude that CSP failed to reduce the incidence of GVHD and improve the survival of patients with chronic myelocytic leukemia when compared to results with standard MTX.     

Conditioning-related toxicity and acute graft-versus-host disease in patients given methotrexate/cyclosporine prophylaxis

Intensive chemoradiotherapy conditioning regimens and acute graft-versus-host disease (GVHD) are both associated with significant morbidity and mortality after bone marrow transplantation. In this study, we investigated whether the conditioning regimen affected the development of acute GVHD. Thirty-four patients, four with severe aplastic anemia and 30 with a lymphohemopoietic malignancy, were prepared for transplantation either with cyclophosphamide (CY) alone, with CY combined with total body irradiation (TBI) or CY combined with etoposide and either TBI or busulfan. GVHD prophylaxis included methotrexate (MTX 10 mg/m2) given on days 1, 3 and 6, and daily cyclosporine (CSP) on days--1 through 180. The overall incidence of acute GVHD was 36% (15% for HLA identical, 87% for HLA non-identical recipients). However, when assessed by the severity of conditioning regimen-related toxicity, the incidence of GVHD grades II-IV (HLA identical; HLA non-identical) was 0% (0%; 0%), 37% (20%; 67%) and 50% (22%; 100%) for patients with mild, moderate and severe toxicity, respectively. Compliance with GVHD prophylaxis declined with increasing intensity and toxicity of the conditioning regimen. These data suggest that a regimen of three doses of MTX and daily CSP is as effective as four doses of MTX/CSP for GVHD prophylaxis in patients given HLA identical marrow grafts. However, GVHD regimen compliance and efficacy of GVHD prevention are inversely related to the intensity of the conditioning regimen.     

A prospective randomized trial comparing cyclosporine and short course methotrexate with cyclosporine and mycophenolate mofetil for GVHD prophylaxis in myeloablative allogeneic bone marrow transplantation

Cyclosporine (CSP) and short course methotrexate (MTX) have been the gold standard for GVHD prophylaxis for decades. Problems associated with MTX include increased time to hematopoietic engraftment, mucositis, and other organ toxicities. The combination of CSP with mycophenolate mofetil (MMF) has been used successfully for the prevention of graft rejection and GVHD in nonmyeloablative transplantation. We performed a prospective randomized trial comparing CSP and MTX with CSP and MMF in myeloablative (busulfan based) allogeneic 6/6 matched sibling bone marrow transplantation (BMT). The group receiving MMF (n = 21) had significantly less severe mucositis than did the group receiving MTX (n = 19) (21 vs 65%, P = 0.008). Median time to neutrophil engraftment was more rapid in the MMF group (11 vs 18 days, P < 0.001). The incidence of acute GVHD, as well as 100 day survival, was similar for both groups. The reduced toxicity of the CSP and MMF arm resulted in premature study closure. We conclude that a GVHD prophylaxis regimen of CSP and MMF after a myeloablative allogeneic preparative regimen is associated with faster hematopoietic engraftment, decreased incidence of mucositis, similar incidence of aGVHD, and comparable survival as compared to CSP and MTX.     

Low incidence of acute graft-versus-host disease by the administration of methotrexate and cyclosporine in Japanese leukemia patients after bone marrow transplantation from human leukocyte antigen compatible siblings; possible role of genetic homogeneity. The Nagoya Bone Marrow Transplantation Group

Japanese patients with leukemia who received bone marrow from human leukocyte antigen (HLA)-compatible siblings had a low incidence of acute graft-versus-host disease (GVHD). Twenty-five (21%) of 120 patients developed moderate (grade II) to severe (grades III to IV) acute GVHD. Severe GVHD was only seen in patients older than 20 years of age. It is also notable that only 2 (5%) of 39 patients who received the combination of methotrexate and cyclosporine (MTX/CSP) for the prevention of GVHD developed grade II acute GVHD, and none developed grades III to IV acute GVHD. Thirteen (30%) of 44 patients receiving MTX alone and 10 (27%) of 37 patients receiving CSP alone developed grades II to IV acute GVHD. Multivariate life-table analysis indicated that the prophylaxis by MTX/CSP was the risk factor for the low incidence of grades II to IV acute GVHD. Compared with the reported incidence of acute GVHD in the patients of the United States, lower incidence of acute GVHD in Japanese BMT patients might be attributable to a lesser degree of genetic diversity in histocompatibility antigens among Japanese.     

Acute graft-versus-host disease prophylaxis with methotrexate and cyclosporine after busulfan and cyclophosphamide in patients with hematologic malignancies

The combination of two powerful immunosuppressive agents, methotrexate (MTX) and cyclosporine (CSP), has resulted in a significant decrease in the morbidity and mortality after allogeneic bone marrow transplantation (BMT). However, the additive toxicities from ablative preparative regimens may lead to suboptimal use of this combined immunoprophylaxis. We evaluated the efficacy and feasibility of administering MTX/CSP with busulfan (4 mg/kg/d for 4 days) and cyclophosphamide (50 mg/kg/d for 4 days) (BuCy4) in 101 consecutive patients with hematologic malignancies categorized into high- and low- risk groups receiving HLA-matched marrow grafts. Postgrafting immunosuppression consisted of MTX short course (15 mg/m2 on day 1 and 10 mg/m2 on days 3, 6, and 11) and intravenous CSP (1.5 mg/kg every 12 hours). Eighty-three patients (82.1%) received 100% of MTX calculated dose and 87 (86.1%) achieved a CSP therapeutic level (250 to 600 ng/mL) within a median of 16 days. Seventy-three patients (72.2%) received optimal immunosuppressive therapy comprising a full MTX course and achieving CSP therapeutic concentrations. The Kaplan-Meier estimated incidence of grade II to IV acute graft-versus-host disease (GVHD) was 9.2% for all patients and 5.5% in patients receiving optimal GVHD prophylaxis. Eighty-nine patients (88.2%) survived > or = 100 days posttransplant and 43 (48.3%) developed chronic GVHD, the majority of which were de novo (31 of 43). The estimated incidence of relapse was 28.9% for all patients and 14.8% in the low-risk group, with a median follow-up of 24.5 months. High-risk features and the absence of chronic GVHD were significantly associated with relapse (P = .002 and .036, respectively) in multivariate analyses. Projected disease-free survival at 2 years was 52.3% for all patients and 65.2% in low-risk patients. Disease-free survival was significantly improved in optimally treated patients (P = .03) due to a lower incidence of early deaths from acute GVHD and infectious episodes. In conclusion, optimal delivery of MTX/CSP in association with BuCy4 resulted in a near complete abrogation of acute GVHD in HLA-matched transplants and a significantly improved disease-free survival.     

Cyclosporine A and mycophenolate mofetil vs cyclosporine A and methotrexate for graft-versus-host disease prophylaxis after stem cell transplantation from HLA-identical siblings

The combination of Cyclosporin A (CSA) and Methotrexate (MTX) is considered to be the standard regimen for the prevention of graft-versus-host disease (GVHD) after stem cell transplantation (SCT) from HLA-identical siblings. Mycophenolate Mofetil (MMF) has been widely used for GVHD prophylaxis after nonmyeloablative SCT, but experience following myeloablative therapy is still limited. We retrospectively compared CSA/MTX and CSA/MMF in 93 patients (median age 35 years, range 17-59 years, male subjects 48, female subjects 45) with acute myeloid leukemia (n=33), myelodysplastic syndrome (MDS) (n=3), acute lymphoblastic leukemia (ALL) (n=20) or chronic myeloid leukemia (n=37) who received CSA/MMF (n=26) or CSA/MTX (n=67) as GVHD prophylaxis following high-dose therapy and allogeneic SCT from HLA-identical siblings. No statistically significant differences were found in overall survival, relapse rate, treatment-related mortality and acute or chronic GVHD. Time to myeloid recovery was significantly shorter in patients who received CSA/MMF. We conclude that the combination of CSA/MMF appears equivalent to CSA/MTX for GVHD prophylaxis in patients receiving conventional-intensity SCT from HLA-identical siblings.     

非血缘关系异基因骨髓移植19例临床分析

目的 探讨非血缘关系异基因骨髓移植（URD－BMT）的疗效和相关合并症。方法 我所1998年8月－2001年2月行19例URD－BMT。预处理方案：2例以全身照射（TBI）为主的方案,其余均用化疗方案。移植物抗宿主症（GVHD）的预防：所有患者均接受环孢素A和短程甲氨蝶呤方案。其中7例用霉酚酸酯（MMF）,1例用CD3＋CD25,9例用抗胸腺细胞球蛋白（ATG）,其中1例骨髓经免疫毒素体外去除T淋巴细胞。骨髓回输：18例经股动脉插管输入。结果 19例中2例因观察期尚短不能评价,其余17例均植活。超急性GVHD发生7例;急性GVHDⅡ-Ⅳ度为9／17例,累积发生率为53.0%。采用单因素分析表明,HLA配型不合、未用ATG、MMF、输入细胞数枵植活时间,对Ⅱ-Ⅳ度急性GVHD的发生率均无显著影响。感染情况：移植后5周内发热的患者为11／17例。在随访期内,10例发生巨细胞病毒感染。存活情况：19例中死亡6例。18个月无病存活58.3%。结论 URD－BMT作为治疗恶性血液病的方法,因移植相关病死率较高,尚不能大规模开展。当高危急性白血病、慢性髓细胞白血病的患者没有合适的亲缘供者时,URD－BMT不失为治疗的措施之一。     

FK506 in combination with methotrexate for the prevention of graft- versus-host disease after marrow transplantation from matched unrelated donors

The safety and potential efficacy of FK506 in combination with a short course of methotrexate (MTX) for the prevention of acute graft-versus- host disease (GVHD) after marrow transplantation from HLA-matched unrelated donors was evaluated in a single-arm Phase II study conducted at two centers. Forty-three patients, 15 to 54 (median 41) years of age, were transplanted for hematologic malignancies. Thirty-seven of 43 evaluable patients had evidence of sustained marrow engraftment. Five patients died before day 17 after transplantation. The median time to an absolute neutrophil count of > 0.5 x 10(5)/L was 21 (range, 14 to 30) days. Nephrotoxicity (serum creatinine concentration > 2 mg/dL or doubling of baseline) occurred in 32 patients (74% cumulative incidence during the first 100 days after transplant). Other adverse effects included hypertension (n = 27), hyperglycemia (n = 27), neurotoxicity (n = 9) and thrombotic thrombocytopenic purpura (n = 2). Severe veno- occlusive disease of the liver occurred in 9 (21%) of the 43 patients. Eighteen patients (42%) developed grades II to IV acute GVHD and five (12%) developed grades III to IV acute GVHD. Twelve of 25 evaluable patients developed extensive chronic GVHD within 1 year of marrow transplantation resulting in an estimate of the probability of developing this complication of 48%. The cumulative incidence of transplant-related mortality during the first 100 days was 37%. Kaplan- Meier estimates of disease-free survival at 2 years for good-risk, poor- risk, and all patients were 65%, 4%, and 32%, respectively. FK506 in combination with a short course of MTX appears active in preventing acute GVHD after marrow transplantation from unrelated donors. Further studies comparing the combination of FK506 and MTX with cyclosporine and MTX for the prevention of acute GVHD are warranted.     

Influence of post-methotrexate folinic acid rescue on regimen-related toxicity and graft-versus-host disease after allogeneic bone marrow transplantation.

Thirty-two patients undergoing related-donor bone marrow transplantation (BMT) received cyclosporine (CSP) and methotrexate (MTX) with folinic acid rescue (FAR) as graft-versus-host disease (GVHD) prophylaxis. Fifty consecutive related-donor BMT patients given the CSP/MTX combination without FAR were utilized as historical controls. Patients receiving FAR experienced earlier engraftment, with absolute neutrophil count greater than 0.5 x 10(9)/l at a median of 17 days (vs 21 days in controls, p = 0.002). The day of last platelet transfusion was earlier in the FAR group (median of 14 days vs 17 days in controls, p = 0.01). Compared with the control group, patients receiving FAR had a lower incidence of grade II-IV stomatic (53% vs 78%, p = 0.04) and hepatic (25% vs 56%, p = 0.01) regimen-related toxicity. In the FAR group, 70% required total parenteral nutrition vs 92% of controls (p = 0.02). Broad-spectrum antibiotics were given to FAR patients for a median of 21 days (vs 23 days in controls, p = 0.09). The incidence of grade II-IV acute GVHD was similar in the FAR and control populations (45% and 35%, respectively, p = NS) as was the incidence of chronic GVHD (62% vs 55%, respectively, p = NS). Estimated event-free survival is 59% for FAR patients (median follow-up 64 weeks) and 58% for controls (median follow-up 109 weeks, p = NS). FAR reduces regimen-related toxicity in patients receiving CSP/MTX acute GVHD prophylaxis without significantly influencing GVHD incidence or event-free survival.     

No significant association between HA-1 incompatibility and incidence of acute graft-versus-host disease after HLA-identical sibling bone marrow transplantation in Japanese patients

We retrospectively examined HA-1 typing with polymerase chain reaction using sequence-specific primers in 120 samples from 60 HLA-A2-positive Japanese bone marrow transplantation recipients who received short-term methotrexate and cyclosporin A for graft-versus-host disease (GVHD) prophylaxis and their HLA-identical sibling donors. HA-1-incompatible pairs were observed in 22% of the samples. The probability of developing acute GVHD (grade II to IV) in HA-1-incompatible and -compatible patients was 0% and 19%, respectively (P = .10). In a comparison between HA-1-incompatible and -compatible patients with standard-risk leukemia, in whom age, patient/donor sex, and use of a total body irradiation-containing regimen were equivalent, the probability of developing acute GVHD (grade II to IV) was 0% and 10%, respectively (P = .38). No evidence of recurrent leukemia was observed in the HA-1-incompatible patients with standard-risk leukemia, compared with 37% in HA-1-compatible patients (P = .11). In conclusion, HA-1 incompatibility may not be a risk factor for grade II to IV acute GVHD in Japanese patients who receive methotrexate and cyclosporin A and undergo bone marrow transplantation from HLA-identical sibling donors.     

Incidence of acute graft-versus-host disease with and without methotrexate prophylaxis in allogeneic bone marrow transplant patients

Methotrexate has been used as the mainstay therapy to prevent or ameliorate graft-versus-host disease (GVHD) in allogeneic bone marrow transplantation. We began a nonrandomized study in which methotrexate was not given routinely. Fifty-five patients underwent transplant for acute leukemia (44 patients), aplastic anemia (6 patients), and other malignancies (5 patients). Methotrexate was given to 34 patients (MTX +) and was withheld in 21 patients (MTX -). Median (range) age of patients was 12 (0.8-43) years in the MTX + group, and 16 (3-45) years in the MTX- group. Mean days (+/- SEM) to engraftment (neutrophils greater than 500/microL, and platelets greater than 20,000/microL untransfused) occurred earlier in the MTX- patients (19.6 +/- 1.4 v 24.9 +/- 1.8 days for granulocytes, and 19.3 +/- 1.5 v 27.4 +/- 2.8 days for platelets, P less than .05). There were no statistically significant differences between the patient groups for the incidence or severity of GVHD (10/34 in the MTX + group had grade O-l GVHD compared to 9/21 in the MTX- group). The interstitial pneumonitis occurred at a significantly increased rate in patients who received methotrexate (15/34) compared to those patients who did not (3/21) (P = .02). However, there was also a significant relationship between the interstitial pneumonitis and the preparative regimen: if the preparative regimen contained 1,000 rad single fraction total body irradiation, 8/14 patients were affected compared to 5/22 patients affected when 1,200 rad fractionated total body irradiation was used (P = .03). Because methotrexate significantly retards hematopoietic reconstitution, randomized trials for GVHD prevention are recommended.     

Prophylaxis with FK-506 for graft-versus-host disease after transplantation of bone marrow from unrelated donors

Forty-eight patients who underwent bone marrow transplantation (BMT) from serologically HLA-matched unrelated donors received tacrolimus (FK506) alone or with methotrexate (MTX) and/or methylprednisolone (mPSL) to prevent graft-versus-host disease (GVHD). We analyzed retrospectively the efficacy of FK506 for GVHD prophylaxis, and its toxicity, by comparing three groups of patients: those given FK506 alone, those given FK506 + mPSL, and those given FK506 + MTX + mPSL. Grade III and IV acute GVHD occurred in five of 10 patients given FK506 alone and in 11 of 30 patients given FK506 + mPSL. In these groups, severe acute GVHD was commonly seen in the patients who discontinued FK506 administration early after BMT and in those who received bone marrow from genotypically HLA-mismatched donors. Early withdrawal of FK506 was due mainly to severe nephrotoxicity. The incidence of nephrotoxicity was very high in patients who received high-dose FK506 as well as melphalan-containing preconditioning (80% and 50%). None of eight patients who received FK506 + mPSL + MTX developed grade III-IV acute GVHD even though five of them received bone marrow from genotypically HLA-mismatched donors. In patients receiving bone marrow from unrelated donors, adjustment of the initial dose of FK506 seems essential in order to avoid severe nephrotoxicity, and combination of MTX and FK506 is useful for preventing severe acute GVHD.     

A PROSPECTIVE RANDOMISED TRIAL OF CYCLOSPORIN VERSUS METHOTREXATE AFTER HLA-IDENTICAL SIBLING MARROW TRANSPLANTATION FOR PATIENTS WITH ACUTE LEUKEMIA IN FIRST REMISSION: ANALYSIS 2.5 YEARS AFTER LAST PATIENT ENTRY

:The results of a prospective randomised trial comparing cyclosporin (CSP) with methotrexate (MTX) as immunosuppressive therapy after HLA-identical sibling marrow transplantation for patients with acute leukemia in first remission were analysed 2.5 years after entry of the last patient into the trial. Patients given cyclosporin showed a faster rate of marrow engraftment, less oro-pharyngeal mucositis, more azotemia and more diastolic hypertension than those receiving methotrexate. Actuarial four-year survival was 69% for patients receiving MTX and 43% for those receiving cyclosporin (not significant). Actuarial four-year survival in continuous complete remission from the time of transplant was 69% and 38% respectively (not significant, p = 0.09). While there was no difference in the incidence or severity of acute or chronic graft-versus-host disease, the actuarial rate of leukemic recurrence was 0% in the MTX and 36% in the CSP group (p = 0.02). This finding emphasises the importance of long-term follow up for the full assessment of new therapeutic protocols of marrow transplantation in the treatment of hematological malignancy.     

Benefits of mycophenolate mofetil for refractory graft-versus-host disease

We retrospectively evaluated the efficacy of mycophenolate mofetil (MMF) in the treatment of steroid-resistant acute and chronic graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation. Thirteen patients, ten men and three women, consisted of 5 cases of acute myelogenous leukemia, 2 of acute lymphoblastic leukemia, 2 of chronic myelogenous leukemia, 2 of lymphoblastic lymphoma, and 1 case each of adult T-cell leukemia and peripheral T-cell lymphoma. The transfusions consisted of 5 peripheral blood, 7 bone marrow and 1 cord blood from 3 mothers, 4 siblings and 6 unrelated donors with conditioning treatments, including 8 total-body irradiation-based regimens, and 2 busulfan plus cyclophosphamide and 2 reduced-intensity regimens. GVHD prophylaxis included FK506 plus methotrexate (MTX) and/or antithymocyte globulin for 9 patients, and cyclosporine and MTX for 4 patients. All patients were treated with second-line MMF for steroid-refractory acute and/or chronic GVHD, and 11 patients improved. The adverse events were tolerable except for one patient in whom grade 3 neutropenia forced discontinuation of treatment. No case of non-relapse mortality occurred. We consider that MMF is beneficial and well tolerated for treatment of steroid-refractory GVHD.     

Marrow transplantation for patients with acute lymphoblastic leukemia in first marrow remission

Forty-six patients with acute lymphoblastic leukemia (ALL) in first marrow remission underwent allogeneic marrow transplantation between August 1976 and June 1985. Thirty-four patients had no extramedullary disease after remission induction and 12 had extramedullary relapses prior to or at the time of marrow grafting. The conditioning regimen included cyclophosphamide followed by total body irradiation, 9.2-15.75 Gy, administered as a single dose or in six or seven daily fractions. Marrow donors were genotypically HLA-identical siblings. Methotrexate was given as prophylaxis for graft-versus-host disease (GVHD). Forty-four patients had marrow engraftment. The incidence of grades II-IV acute GVHD was 52%. Clinical chronic GVHD occurred in 21 patients. Eighteen patients are alive 1-9 years (median = 4.2 years) after marrow grafting, 15 of whom are in continuous complete remission. The estimated probability of relapse within 2 years (+/- standard error) is 41 +/- 9% and the probability of relapse-free survival at 5 years is 28 +/- 7%. Major causes of death were recurrent leukemia, acute GVHD and interstitial pneumonia. Actuarial probabilities of survival, relapse and disease-free survival were not significantly different between those patients who did and those who did not have extramedullary disease after attaining first marrow remission.     

Cyclosporine alone vs cyclosporine plus methotrexate for post-transplant immunosuppression after HLA-identical sibling bone marrow transplantation: a randomized prospective study

The role of methotrexate (MTX), given with cyclosporine (CS), after HLA-identical sibling bone marrow transplantation needs to be defined. In all, 80 patients with hematologic malignancies were enrolled in a prospective randomized trial. All were given BuCy conditioning. The 40 patients in the CS arm received CS 3 mg/kg/day intravenously, with subsequent oral dosing. Patients in the CS + MTX arm received, in addition to CS, MTX intravenously, 15 mg/m2 on day 1, and 10 mg/m2 on days 3, 6, and 11. Transplantation-related mortality was low in both groups of patients (13 vs 11% for CS vs CS + MTX groups, P = 0.94). The CS group had a significantly higher frequency of chronic graft-versus-host disease (56 vs 32%, P = 0.05). After a median follow-up of 22.1 months (5.1-47.8 months), three of 30 vs 10 of 28 patients with acute leukemia/myelodysplastic syndrome (MDS) in CS group vs CS + MTX group relapsed (P = 0.01) yielding better overall survival for patients with acute leukemia/MDS treated with CS (P = 0.02). After HLA-identical sibling bone marrow transplantation, immunosuppression with CS, with or without MTX, resulted in similarly low transplantation-related mortality. In acute leukemia/MDS, decreased relapse with patient survival prolongation was observed in the CS group.