Cyclosporin A and short-term methotrexate versus cyclosporin A as graft versus host disease prophylaxis in patients with severe aplastic anemia given allogeneic bone marrow transplantation from an HLA-identical sibling: results of a GITMO/EBMT randomized trial

A randomized trial was carried out comparing cyclosporin A (CsA) and short-term methotrexate (MTX) versus CsA alone for graft versus host disease (GVHD) prophylaxis in patients with severe aplastic anemia (SAA) undergoing allogeneic bone marrow transplantation (BMT) from a compatible sibling. Seventy-one patients (median age, 19 years; range, 4-46 years) were randomized to receive either CsA and MTX or CsA alone for the first 3 weeks after BMT. Subsequently, both groups received CsA orally, with gradual drug reduction until discontinuation 8 to 12 months after BMT. Patients randomized in both arms had comparable characteristics and received the same preparative regimen (ie, cyclophosphamide 200 mg/kg over 4 days). The median time for neutrophil engraftment was 17 days (range, 11-31 days) and 12 days (range, 4-45 days) for patients in the CsA/MTX group and the CsA alone group, respectively (P =.01). No significant difference was observed in the probability of either grade 2, grade 3, or grade 4 acute GVHD or chronic GVHD developing in the 2 groups. The Kaplan-Meier estimates of 1-year transplantation-related mortality rates for patients given either CsA/MTX or CsA alone were 3% and 15%, respectively (P =.07). With a median follow-up of 48 months from BMT, the 5-year survival probability is 94% for patients in the CsA/MTX group and 78% for those in the CsA alone group (P =. 05). These data indicate that the use of CsA with MTX is associated with improved survival in patients with SAA who receive transplants from compatible siblings. (Blood. 2000;96:1690-1697)     

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.     

An increased risk of relapse in cyclosporin-treated compared with methotrexate-treated patients: long-term follow-up of a randomized trial

Patients with haematological malignancies and HLA-identical marrow donors were randomized to treatment with cyclosporin A (CSA, n = 30) or methotrexate (MTX, n = 29) with a follow-up ranging from 32 to 70 months. The two groups were comparable regarding disease status and age. Acute graft-versus-host disease (GVHD) was similar and the cumulative incidences of chronic GVHD was 42% in both groups. The overall incidence of cytomegalovirus (CMV) infection and other late infections were also the same in the two groups. Interstitial CMV pneumonitis occurred in 13% in the CSA group compared with 32% in the MTX group (ns). The probability of relapse was 42% after 4 years among the CSA patients and was significantly higher than the probability of relapse in the MTX patients which was found to be 10% (p = 0.03). The actuarial survival after 5 years was 53% for the CSA patients and 57% for the MTX patients (ns). The relapse-free survival was 41% and 59%, respectively (ns). There were no differences between the two groups in terms of renal or hepatic function, incidence of cataracts, blood cell counts, bone marrow cellularity or Karnofsky scores at 2 and 4 years after transplantation.     

Increased risk of chronic graft-versus-host disease, obstructive bronchiolitis, and alopecia with busulfan versus total body irradiation: long-term results of a randomized trial in allogeneic marrow recipients with leukemia. Nordic Bone Marrow Transplantation Group

Leukemic patients receiving marrow from HLA-identical sibling donors were randomized to treatment with either busulfan 16 mg/kg (n = 88) or total body irradiation ([TBI] n = 79) in addition to cyclophosphamide 120 mg/kg. The patients were observed for a period of 5 to 9 years. Busulfan-treated patients had an increased risk of veno-occlusive disease (VOD) of the liver (12% v 1%, P =.01) and hemorrhagic cystitis (32% v 10%, P =.003). Acute graft-versus-host disease (GVHD) was similar in the two groups, but the 7-year cumulative incidence of chronic GVHD was 59% in the busulfan-treated group versus 47% in the TBI group (P =.05). Death from GVHD was more common in the busulfan group (22% v 3%, P <.001). Obstructive bronchiolitis occurred in 26% of the busulfan patients but in only 5% of the TBI patients (P <.01). Complete alopecia developed in 8 busulfan patients and partial alopecia in 17, versus five with partial alopecia in the TBI group (P <.001). Cataracts occurred in 5 busulfan-treated patients and 16 TBI patients (P =.02). The incidence of relapse after 7 years was 29% in both groups. Seven-year transplant-related mortality (TRM) in patients with early disease was 21% in the busulfan group and 12% in the TBI group. In patients with more advanced disease, the corresponding figures were 64% and 22%, respectively (P =.004). Leukemia-free survival (LFS) in patients with early disease was 68% in busulfan-treated patients and 66% in TBI patients. However, 7-year LFS in patients with more advanced disease was 17% in the busulfan group versus 49% in the TBI group (P <.01). In patients with chronic myeloid leukemia (CML) in first chronic phase, 7-year LFS was 72% and 83% in the two groups, respectively.     

Impact of alemtuzumab as conditioning regimen component on transplantation outcomes in case of CMV-seropositive recipients and donors

We studied the incidence of cytomegalovirus (CMV) infection, clinical outcomes, and complications in 39 recipients of alemtuzumab-containing conditioning-stem cell transplantation, who were classified into two groups based on the median dose (35 mg) of alemtuzumab. All the recipients and donors were CMV-seropositive before transplantation. The median survival duration was 321 days (range, 46-1098 days) and the 2-year survival rate was 47.8%. The probability of nonrelapse mortality at 100 days and 2 years was 14.6% and 31.2%, respectively. The cumulative incidence of Grade II-IV acute graft-versus-host disease (GVHD) at Day 100 was 21.8%. The overall incidence of chronic GVHD (cGVHD) was 28.6%, including a 17.9% incidence of extensive cGVHD. The cumulative incidence of CMV antigenemia was 68.0%. There were no statistical differences in the engraftment, acute and cGVHD, relapse, CMV antigenemia, and overall survival (OS) between the two groups. Yet, the nonrelapse mortality (NRM) was significantly lower for the low-dose group (5.9% vs. 51.7%, P = 0.010). The present study showed that alemtuzumab was effective for GVHD prevention, yet caused a relatively high incidence of CMV antigenemia, regardless of the dose. Thus, a low dose of alemtuzumab (< or = 35 mg) would seem to be preferable in an allogeneic SCT setting when both the recipient and the donor are CMV seropositive.     

Intensive graft-versus-host disease prophylaxis is required after unrelated-donor nonmyeloablative stem cell transplantation

Nonmyeloablative stem cell transplantation (NST) harnesses the graft-versus-tumor effect while minimizing regimen-related toxicity, and can result in donor chimerism and remission. Acute graft-versus-host disease (GVHD) and infections are major complications after sibling NST. Toxicity of unrelated-donor (UD) NST and the most appropriate GVHD prophylaxis in this setting remain poorly defined. We describe 25 patients who received UD-NST conditioned with fludarabine and cyclophosphamide. The first six patients received cyclosporine (Cs) and mycophenolate mofetil (MMF) (n=5) or methotrexate (MTX) (n=1) as GVHD prophylaxis (group 1) and all developed grade III-IV acute GVHD. The next 19 patients received the same conditioning regimen with the addition of alemtuzumab, and all received Cs/MTX post-transplant. Engraftment and donor chimerism were achieved in all but one evaluable patient. In all, 15 patients died: five of six deaths in group 1 were attributable to acute GVHD, while deaths in group 2 were due to infection or progressive disease (P=0.05). The combination of Cs/MMF is inadequate GVHD prophylaxis for UD-NST. The use of Cs, MTX, and alemtuzumab eliminated severe acute GVHD; its impact on response merits further study.     

Graft-versus-host disease following marrow transplantation for aplastic anemia: different impact of two GVHD prevention strategies

Prevention of GVHD is one of the most desirable goals of BMT in aplastic anemia (AA). We reviewed the medical records of 24 consecutive patients treated with BMT for acquired AA using two different GVHD prevention strategies. Ten patients were given alemtuzumab-based GVHD prophylaxis (50-60 mg in three divided doses on days -8, -7 and -6), and 14 patients were given conventional GVHD prophylaxis with calcineurin inhibitors plus MTX before the introduction of the alemtuzumab-based protocols. The incidence of acute, chronic and 'serious GVHD' was significantly reduced in alemtuzumab-treated patients compared to conventionally treated patients [11 vs 64% (P=0.03), 0 vs 78% (P=0.002) and 0 vs 57% (P=0.007), respectively]. Engraftment time and rates of graft failure appeared similar in the two groups. A significantly higher proportion of alemtuzumab-treated patients developed CMV reactivation compared to control patients (83 vs 12%; P=0.03); none developed CMV disease. The rates of other infectious complications did not appear significantly different. Our data suggest that 50-60 mg of alemtuzumab given according to the current schedule significantly reduces the risk of GVHD without increasing the risk of graft failure or serious infections.     

Marked reduction in the incidence of hepatic veno-occlusive disease after allogeneic hematopoietic stem cell transplantation with CD34(+) positive selection.

Veno-occlusive disease of the liver (VOD) is a common and severe complication of allogeneic hematopoietic stem cell transplantation (HSCT). To determine the incidence of, and the risk factors for the development of VOD, we performed a retrospective analysis of a series of 178 patients, who underwent allogeneic HSCT at our institution between 1990 and 1999. Busulfan and cyclophosphamide constituted the conditioning regimen most frequently administered. Bone marrow was the source of stem cells in 129 patients (73%), and peripheral blood (PBSC) in 49 patients (27%). Thirty-one patients of the PBSC group received CD34(+) positively selected grafts. Most patients were given cyclosporin A and methotrexate (MTX) as graft-versus-host disease (GVHD) prophylaxis. Overall, 30 patients (17%) developed VOD. In univariate analyses, the incidence of VOD was significantly higher in recipients of unmanipulated grafts (20% vs 0%; P = 0.01), in patients with active malignant disease at transplantation (24% vs 9%; P = 0.03), in recipients of marrow from unrelated donors (33% vs 15%; P = 0.03), in patients grafted with bone marrow (21% vs 6%; P = 0.03), and in those receiving MTX as GVHD prophylaxis (21% vs 6%; P = 0.05). Under multivariate analysis, only CD34(+) positive selection (P = 0.0004) and the status of the disease at transplant (P = 0.03) were statistically significant variables for the development of VOD. We conclude that CD34(+) positively selected PBSC transplantation could result in a marked reduction in the incidence of VOD after allogeneic HSCT.     

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.     

Cyclosporin, methotrexate and prednisolone for graft-versus-host disease prophylaxis in allogeneic peripheral blood progenitor cell transplants

The utility of GVHD prophylaxis with cyclosporin, MTX and prednisolone (CSA/MTX/Pred) in allogeneic PBPC transplants is not well described although there are published data using this combination after bone marrow transplants. The effectiveness of this regimen on the prevention of GVHD was assessed in 107 consecutive sibling and less-than-ideal donor transplant recipients over a 5-year period and compared to that observed in 65 patients receiving standard CSA and short-course MTX without prednisolone. Oral prednisolone was commenced on day +14 at 0.5 mg/kg per day, increased to 1 mg/kg per day on day +21 to day +34 then gradually tapered and ceased by day +100. The cumulative incidence of acute GVHD (grades II-IV) to day 100 in those receiving prednisolone prophylaxis was lower (52 versus 76%, P<0.01). The onset of symptomatic GVHD requiring systemic treatment was delayed from a median of 41 days post transplant to 92 days. When assessment of the cumulative incidence of symptomatic GVHD continued to day +180 incidence became similar (74 versus 78%), there was no difference between the two groups in rates of relapse, transplant-related mortality, infections or chronic GVHD. We conclude that the addition of prednisolone to CSA/MTX delays the onset of early acute GVHD in PBPC recipients but has no impact on the overall incidence of GVHD.     

A randomized trial comparing use of cyclosporin and methotrexate for graft-versus-host disease prophylaxis in bone marrow transplant recipients with haematological malignancies

Patients with haematological malignancies with HLA-identical marrow donors were randomized to treatment with cyclosporin (CSA) or methotrexate (MTX). Two of the 29 patients randomized to MTX died before engraftment compared with none of the 30 treated with CSA. Engraftment by leucocytes (P less than 0.0001), granulocytes (P less than 0.02), and reticulocytes (P less than 0.01) was faster among the CSA patients. There were no significant differences between the two groups regarding transfusions, hospitalization and incidence of early septicaemia. Granulocyte transfusions were required in seven of 29 MTX and two of 30 CSA patients (not significant: NS). Overall (grade I-IV) acute graft-versus-host disease (GVHD) was more common (P = 0.001) in the CSA patients. Grade II-IV acute GVHD was seen in 40% of the CSA patients compared with 22% in the MTX patients (NS). In the adult patients grade II-IV GVHD was slightly more common (P less than 0.05) in those treated with CSA compared with MTX. Chronic GVHD appeared in 30 and 39% in the two groups respectively. Actuarial 3-year survival was 58% for the CSA patients and 69% for the MTX patients. There were no significant differences regarding the incidence of interstitial pneumonitis or relapses between the two groups. The side-effects of CSA treatment includes nephrotoxicity (83%), hepatotoxicity (20%), hirsutism (43%), hypertension (23%), tremor (27%) and gingival hyperplasia (27%). Serum creatinine values were increased at 3 and 6 months in the CSA group but were within the normal range after 6 months. A blind study on oral side-effects revealed that CSA patients more often had a normal mucosa (P = 0.025) and less frequently had mucositis (P = 0.01) compared with the MTX group.     

Ursodeoxycholic acid for the prevention of hepatic complications in allogeneic stem cell transplantation

The role of ursodeoxycholic acid (UDCA) in the prevention of hepatic complications after allogeneic stem cell transplantation was studied in a prospective randomized open-label multicenter trial. A total of 242 patients were allocated to receive (n = 123) or not to receive (n = 119) UDCA in the dose of 12 mg/kg/d orally from the day preceding the conditioning until day 90 after transplantation. In the UDCA-treated group a significantly smaller proportion of patients developed a serum bilirubin level exceeding 50 microM (18 of 123 versus 31 of 119, P =.04), and similarly a smaller proportion of patients exceeded the alanine aminotransferase level of 100 U/L. There was no difference in the incidence of veno-occlusive disease of the liver. Compared to the control group, in the UDCA-treated group there was a nonsignificant trend toward a lower overall incidence of acute graft-versus-host disease (GVHD) and a significantly lower incidence of grade III to IV acute GVHD (5 of 123 versus 17 of 119, P =.01), stage II to IV liver and intestinal GVHD, and stage III to IV skin GVHD. There was no difference in the incidence of chronic GVHD or in the relapse rate. Among the patients given UDCA, the survival at 1 year was significantly better, 71% versus 55% (P =.02), and the nonrelapse mortality rate was lower, 19% versus 34% (P =.01), than in the control group. There were significantly more deaths in GVHD in the control group. In conclusion, UDCA administration reduced hepatic problems and severe acute GVHD and improved survival. These results suggest a role for UDCA in the prevention of transplant-related complications in allogeneic transplantation.     

Risk factors for late cytomegalovirus infection after allogeneic stem cell transplantation using HLA-matched sibling donor: donor lymphocyte infusion and previous history of early CMV infection

An increased incidence of late cytomegalovirus (CMV) infection has been reported during the last decade since the introduction of ganciclovir (GCV) prophylaxis or GCV pre-emptive therapy. Given that a donor lymphocyte infusion (DLI) can induce more severe GVHD, this may predispose a patient to late CMV infection. In all, 64 patients (median age 36, M/F 38/26) underwent allogeneic stem cell transplantation (SCT) using a matched sibling donor with bone marrow (n=9) or peripheral blood stem cells (n=55). The overall incidence of CMV infection, early and late CMV infection was 46.9 (30/64), 42.2 (27/64), and 16.4% (9/55), respectively. Early CMV infection was treated with GCV pre-emptive therapy that produced a 92.6% success rate. Among the 20 patients who received 35 DLIs, late CMV infection developed in eight (42.1%) of 19 evaluable cases with a median onset at 127 days post transplant. Risk factors for late CMV infection in a logistic regression analysis included DLIs (P=0.001) and a previous history of CMV infection (P=0.006). In conclusion, late CMV infection was strongly associated with DLIs and a previous history of early CMV infection. Accordingly, extended surveillance of CMV antigenemia is recommended for patients receiving DLIs or who have a previous history of CMV infection.     

Infectious complications associated with alemtuzumab use for allogeneic hematopoietic stem cell transplantation: comparison with anti-thymocyte globulin

Objectives. To evaluate the incidence of infectious complications after receiving alemtuzumab as part of a conditioning regimen for allogeneic hematopoietic stem cell transplantation (HSCT) in Korean patients.
Methods. From November 2004 to January 2006, 12 patients who received alemtuzumab-based conditioning regimens for allogeneic HSCT were evaluated retrospectively until death or until the end of the follow-up in July 2007; they were compared with 18 patients who received rabbit anti-thymocyte globulin (ATG)-containing conditioning regimens from January 2002 to January 2006.
Results. Post-engraftment infections occurred more frequently in the alemtuzumab recipients than in the ATG recipients; the mean number of infections, excluding cytomegalovirus (CMV) infections, per patient during the follow-up period was 2.6±1.4 vs. 1.0±0.8 ( P =0.003), respectively. Although there was no statistical difference in the cumulative incidence of CMV  infection between the 2 groups (91.7% vs. 55.6%, P =0.381), the alemtuzumab recipients had a higher incidence of CMV  diseases (41.6% vs. 0%, P =0.0006) and a higher recurrence rate of CMV infection (90.0% vs. 27.3%, P =0.008) than did the ATG recipients, irrespective of the dose of alemtuzumab. Hemorrhagic cystitis (HC) (66.7% vs. 16.7%, P =0.009) and BK virus-associated HC (41.7% vs. 5.6%, P =0.026) developed more frequently in the alemtuzumab recipients. The all-cause mortality rate was not significantly different between the alemtuzumab and the ATG recipients (75% vs. 55.6%, P =0.28).
Conclusion. Alemtuzumab recipients had a high incidence of CMV disease as well as BK virus-associated HC compared with the ATG recipients. The dose of alemtuzumab should be tailored to patients' risk; in addition, the implementation of the appropriate prophylaxis for CMV and early detection strategies for BK virus are recommended.     

Cyclosporin A and mini short-term methotrexate vs cyclosporin A as graft-versus-host disease prophylaxis in patients with beta thalassemia major undergoing allogeneic blood and marrow transplantation

We compared the effects of cyclosporin A (CsA) alone as graft-versus-host disease (GVHD) prophylaxis vs cyclosporine with short-course methotrexate (MTX) in patients with thalassemia. In all, 140 patients were enrolled in this study. The first group, of 50 patients, received CsA alone at 3 mg/kg i.v. from day -2 to +5 followed by 12.5 mg/kg p.o., which was tapered according to the patient's condition. The other group, of 90 patients, received the combination of CsA+MTX in which CsA was used with the above-mentioned dose and MTX was on 10 mg/m(2) day +1 and 6 mg/m(2) on days +3 and +6. Incidence of acute GVHD grade II-IV in the CsA group was 78% and in the CsA+MTX group was 52.2%, which was statistically significant (P=<0.001). There were no significant differences in the incidence of chronic GVHD between the two groups. The mean neutrophil engraftment to 0.5 x 10(9)/l was 14 and 23 days for CsA group and CsA+MTX group, respectively (P=<0.001). There were no significant differences for platelet recovery between the two groups. Graft failure in the CsA and CsA+MTX groups was seven (14%) and nine (10%) patients, respectively (P=0.58). Overall survival in the CsA and CsA+MTX groups was 77 and 85%, respectively. Disease-free survival in the CsA and CsA+MTX groups were 58 and 80%, respectively.     

Antithymocyte globulin for graft-versus-host disease prophylaxis in transplants from unrelated donors: 2 randomized studies from Gruppo Italiano Trapianti Midollo Osseo (GITMO).

One hundred nine patients with hematologic malignancies, undergoing bone marrow transplants (BMT) from unrelated donors, were randomized in 2 consecutive trials to receive or not to receive antithymocyte globulin (ATG) in the conditioning regimen, as follows: (A) 54 patients (median age, 28 years; 39% with advanced disease) were randomized to no ATG (n = 25) versus 7.5 mg/kg rabbit ATG (Thymoglobulin; Sangstat, Lyon, France) (n = 29); (B) 55 patients (median age, 31 years, 71% with advanced disease) were randomized to no ATG (n = 28) versus 15 mg/kg rabbit ATG (n = 27). Grade III-IV graft-versus-host disease (GVHD) was diagnosed in 36% versus 41% (P =.8) in the first and in 50% versus 11% (P =.001) in the second trial. Transplant-related mortality (TRM), relapse, and actuarial 3-year survival rates were comparable in both trials. In fact, despite the reduction of GVHD in the second trial, a higher risk for lethal infections (30% vs 7%; P =.02) was seen in the arm given 15 mg/kg ATG. Extensive chronic GVHD developed overall more frequently in patients given no ATG (62% vs 39%; P =.04), as confirmed by multivariate analysis (P =.03). Time to 50 x 10(9)/L platelets was comparable in the first trial (21 vs 24 days; P =.3) and delayed in the ATG arm in the second trial (23 vs 38 days; P =.02). These trials suggest that (1) 15 mg/kg ATG before BMT significantly reduces the risk for grade III-IV acute GVHD, (2) this does not translate to a reduction in TRM because of the increased risk for infections, and (3) though survival is unchanged, extensive chronic GVHD is significantly reduced in patients receiving ATG.     

Paraproteinaemia after allo-SCT, association with alemtuzumab-based conditioning and CMV reactivation

Paraproteinaemia following allo-SCT is common. We analysed 91 consecutive patients undergoing allo-SCT; conditioning included alemtuzumab in 42% of the patients. Paraproteinaemia incidence at 2 years was 32%. In univariate analysis paraproteinaemia was associated with unrelated donor, age, recipient seropositivity for CMV and alemtuzumab conditioning (hazard ratio (HR) 3.93, P=0.0006). Paraproteinaemia was not associated with haematological diagnosis; disease status at transplant; varicella zoster, herpes simplex or EBV serology; reduced-intensity vs myeloablative conditioning or GVHD. CMV reactivation-more frequent in alemtuzumab recipients-was associated with paraproteinaemia (HR 7.52, P<0.0001). In multivariate analysis, only increasing age (HR 1.04 per year, P=0.048) and CMV reactivation (HR 5.74, P=0.001) were significantly associated with paraproteinaemia. Alemtuzumab without CMV reactivation, however, resulted in significantly more paraproteinaemia, suggesting an effect that is independent of CMV reactivation. OS was poorer in patients with paraproteinaemia (HR 2.54, P=0.04) and relapse increased (HR 2.38, P=0.087). Paraproteinaemia was not significantly independently associated with decreased survival on multivariate analysis. Post transplant paraproteinaemia is associated with CMV reactivation, is more frequent in alemtuzumab-conditioned transplants and is not associated with improved OS.     

Superior survival associated with transplantation of matched unrelated versus one-antigen-mismatched unrelated or highly human leukocyte antigen-disparate haploidentical family donor marrow grafts for the treatment of hematologic malignancies: establishing a treatment algorithm for recipients of alternative donor grafts.

The purpose of this study was to compare transplantation outcomes in patients with hematologic malignancies who received marrow grafts from either phenotypically matched unrelated, one-antigen-mismatched unrelated, or highly human leukocyte antigen (HLA)-disparate family donors. Between 1993 and 2000, 139 patients underwent transplantation from unrelated donors (81 matched and 58 mismatched) and 48 patients received marrow grafts from family donors that were mismatched at 2, 3, or 4 of 8 HLA loci. All patients received a standardized conditioning regimen and a graft-versus-host disease (GVHD) prophylaxis schedule with the exception of recipients of haploidentical marrow grafts, who received antithymocyte globulin after bone marrow transplantation as additional immunosuppression. There was no statistically significant difference in the rate of engraftment, or the cumulative incidences of acute and chronic GVHD between any of the 3 groups. The 2-year cumulative incidence of relapse was lower in matched unrelated patients (25%, P =.01) and mismatched unrelated patients (26%, P =.014) than in haploidentical patients (42%). Transplant-related mortality was significantly higher in recipients of mismatched unrelated grafts (45%, P =.01) and haploidentical grafts (42%, P =.001) compared with recipients of matched unrelated marrow grafts (23%). This resulted in a significantly higher probability of overall survival for matched unrelated patients (58%) versus either mismatched unrelated (34%, P =.01) or haploidentical (21%, P =.002) patients. There was no statistically significant difference in survival between patients who received mismatched unrelated grafts versus those who received haploidentical grafts. This study supports a donor selection algorithm whereby patients who lack a closely matched family donor be offered a phenotypically matched unrelated donor if available. There is no apparent advantage to using a mismatched unrelated versus a highly HLA-disparate family donor.     

Allogeneic bone marrow transplantation after high-dose busulfan and cyclophosphamide in patients with acute nonlymphocytic leukemia

Ninety-nine patients with acute nonlymphocytic leukemia (ANLL) received HLA-identical bone marrow transplants (BMTs) from sibling donors after preparation with high doses of busulfan and cyclophosphamide. Forty- nine patients were transplanted in first complete remission (CR), and 50 patients were transplanted in second and third CR and early relapse. Fifty-three received one of three regimens containing primarily low- dose cyclophosphamide (group I) for graft-v-host disease (GVHD) prophylaxis; since March 1983, 46 patients received intravenous (IV) cyclosporine (group II). After December 1983, only cytomegalovirus (CMV)-seronegative blood products were used in appropriate patients, and since April 1984 patients seropositive for herpes-simplex virus (HSV) and CMV received high-dose acyclovir prophylaxis. For patients transplanted in first CR, there was a significantly lower incidence of acute GVHD (P = .005) and deaths related to GVHD and interstitial pneumonitis (P = .001) in patients in group II. This was reflected in an improved Kaplan-Meier probability of disease-free survival (DFS) in the 22 patients transplanted in group II as compared with the 27 patients in group I (64% +/- 10% v 30% +/- 9%, P = .017). The probability of remaining in remission was slightly lower in group II (82% +/- 9% v 94% +/- 6%, P = .479). For patients transplanted in second and third CR and early relapse, the incidence of acute GVHD (P = .026) and deaths related to GVHD and interstitial pneumonitis was significantly lower in group II (P = .029); the probability of remaining in remission was also less (47% +/- 15% v 91% +/- 15%, P = .022). However, the probability of DFS was not significantly different between the two groups (26% +/- 10% v 35% +/- 18%, P = .957). We conclude that transplantation for patients in first CR who received IV cyclosporine therapy is effective treatment; patients with more refractory disease treated with the same cyclosporine regimen (group II) had a lower incidence of GVHD than those treated in group I, but survival did not improve because of an increase in the number of relapses and other nonleukemic complications.