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Abstract
Background:
Cyclosporine (CSA) plus 4 doses of methotrexate (MTX) is the commonly used regimen for GVHD prophylaxis. It has been previously found that the omission of the day +11 dose of MTX was associated with an increased risk of acute GVHD in the allogeneic BMT setting. However, little is known about its impact in the PBSCT setting.
Methods:
Of the 68 patients, 30 patients (44%) received 4 doses of MTX (the MTX4 group), while 38 patients (56%) received less than 4 doses (the MTX3 group) because of their severe mucositis, hepatic dysfunction or renal failure.
Results:
The cumulative incidence of acute GVHD was 60% in the MTX4 and 86% in the MTX3 group (P=0.038), while that of grade III and IV acute GVHD was 7% in the MTX4 group and 39% in the MTX3 group (P=0.017). Of the 61 patients evaluated for chronic GVHD, the cumulative incidence of chronic GVHD was 54% in the MTX4 group and 97% in the MTX3 group (P=0.001), while that of extensive chronic GVHD was 26% in the MTX4 group and 63% in the MTX3 group (P=0.004). There were no differences in the overall survival and the incidence of relapse between the two groups. On multivariate analyses, MTX3 was a poor prognostic factor in terms of acute GVHD and extensive chronic GVHD.
Conclusion:
This study suggested that omitting day +11 MTX and the clinical situation of the MTX3 group seemed to be associated with an increased incidence of acute and chronic GVHD. Accordingly, administration of day +11 MTX accompanied by active treatment of mucositis may prevent GVHD in the allogeneic PBSCT setting, but we need to conduct a large scale prospective study.
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REFERENCES
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 | Fig. 1The cumulative incidence of acute and chronic GVHD after HLA-identical allogeneic PBSCT (n=68). The group with 4 doses of methotrexate showed significantly lower incidence of acute GVHD (A), grade III-IV acute GVHD (B), overall chronic GVHD (C), and extensive chronic GVHD (D). |
Table 1.
Patients’ characteristics and transplantation outcomes
Table 2.
Patients’ characteristics and transplantation outcomes according to the MTX dose
| MTX3, n (%) | MTX4, n (%) | P value | ||
|---|---|---|---|---|
| No. of patients | 38 (59) | 30 (41) | ||
| Sex | Male/female | 20/18 | 22/8 | 0.041 |
| Age | Median (range) | 36 years (17～54) | 37 years (16～58) | 0.828 |
| Diagnosis | Acute myelogenous leukemia | 24 (63.2) | 11 (36.7) | 0.030 |
| Acute lymphoblastic leukemia | 3 (7.9) | 3 (10.0) | 0.761 | |
| Aplastic anemia | 1 (2.6) | 9 (30.0) | 0.002 | |
| Chronic myelogenous leukemia | 2 (5.3) | 3 (10.0) | 0.457 | |
| Myelodysplastic syndrome | 2 (5.3) | 1 (3.3) | 0.700 | |
| Non-Hodgkin's lymphoma | 4 (10.5) | 2 (6.7) | 0.577 | |
| Multiple myeloma | 1 (2.6) | 0 (0) | 0.371 | |
| Others | 1∗ (2.6) | 1† (3.3) | － | |
| Disease risk | High risk | 20 (52.6) | 12 (40.0) | 0.300 |
| Conditioning | Myeloablative | 31 (81.6) | 19 (63.3) | 0.090 |
| Nonmyeloablative | 7 (18.4) | 11 (36.7) | ||
| LV rescue | Done | 7 (18.4) | 18 (60.0) | 0.001 |
| Not done | 31 (81.6) | 12 (40.0) | ||
| Stem cell source | Peripheral blood | 38 (100) | 30 (100) | 1.00 |
| Cell dose | MNC (×108/kg) | 8.65±0.52 | 10.13±0.86 | 0.131 |
| CD34+ (×106/kg) | 9.14±0.81 | 8.48±0.98 | 0.603 | |
| Engraftment | WBC, median (range) | 14 days (10～29) | 13.5 days (10～25) | 0.344 |
| Platelet, median (range) | 14 days (9～56) | 12.5 days (10～34) | 0.263 | |
| CMV reactivation | Yes | 15 (39.5) | 15 (50.0) | 0.385 |
| GVHD | Acute GVHD | 28 (85.6) | 16 (60.0) | 0.038 |
| Acute GVHD Gr III, IV | 11 (39.4) | 2 (6.8) | 0.017 | |
| Chronic GVHD | 30 (96.7), n=34 | 14 (54.2), n=27 | 0.001 | |
| Chronic GVHD, extensive | 17 (63.4), n=34 | 5 (25.6), n=27 | 0.004 | |
| Survival | Overall survival | 16 (42.1±0.49) | 18 (60.0±0.50) | 0.143 |
| Relapse | 12 (31.6) | 10 (33.3) | 0.878 | |
| Non-relapse mortality | 14 (36.8) | 6 (20.0) | 0.130 | |
| Cause of death | Disease progression | 8 (21.0) | 5 (16.7) | 0.648 |
| Infection | 9 (23.7) | 5 (16.7) | 0.477 | |
| GVHD | 4 (10.5) | 0 (0) | 0.067 | |
| Others | 1 (2.6) | 1 (3.3) | － |
Table 3.
Acute and chronic GVHD incidence according to leucovorin rescue
Table 4.
Multivariate survival analyses in terms of acute and chronic GVHD
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