Volume 15, Issue 4 , Pages 505-511, April 2009
First-Line Therapy for Chronic Graft-versus-Host Disease that Includes Low-Dose Methotrexate Is Associated with a High Response Rate
Article Outline
Abstract
We report the results of low-dose methotrexate (MTX) as first-line therapy mostly in combination with other immunosuppressive agents in patients with chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Between November 2001 and March 2008, 86 patients with cGVHD after allo-HSCT received low-dose MTX therapy until a complete or partial response (CR, PR) was achieved, or until treatment failure or intolerable side effects were found. The median time from HSCT to the start of MTX was 154 (range: 80-993) days. The median number of MTX administrations was 4 (range: 2-18). The overall response rate among all enrolled patients was 83% (71 of 86 patients). The response rate for GVHD involving various organs was 90% (45 of 50) in the skin, 75% (39 of 52) in the liver, 42% (5 of 12) in the mouth, 3 of 7 in the eye, and 2 of 2 in the gut. In addition, MTX treatment allowed for a significant reduction in the prednisone dosage (median 90%) from 20 (2.5-100) mg at the start of MTX administration to 5 (0-30) mg 1 month after MTX was last used. Multivariate analysis showed that the only significant factor related to higher CR rate was sole organ involvement (P = .007). Grade 3 toxicities occurred in only 3 patients presenting cytopenias or oral mucositis. From this analysis, MTX appears to be a well-tolerated, effective, and inexpensive agent when used as a first-line treatment in combination with other immunosuppressive agents for cGVHD, especially for skin or sole organ involvement without concomitant thrombocytopenia.
Key Words: Hematopoietic stem cell transplantation, Allogeneic, Methotrexate, Chronic graft-versus-host disease
Introduction
Chronic graft-versus-host disease (cGVHD) occurs in up to 60% of patients with HLA-identical sibling donors and in 70% of those with unrelated or an HLA-mismatched related donor after allogeneic hematopoietic stem cell transplantation (allo-HSCT) 1, 2, 3. Some patients fail conventional immunosuppressive therapy and succumb to depression of their immune system from GVHD and secondary infection 4, 5.
Methotrexate (MTX) has been widely used as an anti-inflammatory and immunomodulatory agent for the treatment of patients with rheumatoid arthritis and other inflammatory disorders by weekly low-dose (7.5-25 mg) administration, and its efficacy and safety have been documented in the literature 6, 7, 8, 9, 10. In addition, low-dose MTX has been employed for a long time as part of the prophylaxis for acute GVHD (aGVHD) after HSCT 11, 12, 13, 14. On the other hand, MTX has also been used as a part of a combined regimen for the treatment of aGVHD and cGVHD; however, there were a few published reports, most including <40 patients and only as salvage therapy, to evaluate the feasibility of MTX treatment for cGVHD 15, 16, 17. In our own previous report, MTX was used to treat 19 aGVHD and 21 cGVHD patients predominantly as salvage therapy with encouraging results [18].
Early initiation of drug therapy may be more effective than salvage therapy for the treatment of cGVHD. Furthermore, patients with cGVHD may benefit from early administration of MTX to lower the incidence of infectious complications and mortality related to the patients’ underlying immunocompromised state, as well as to the previous immunosuppressive agents, by shortening the period of immunosuppression. To date, there have been no other published reports evaluating the potential efficacy that this drug might have for treating cGVHD at an earlier stage of disease. Since 2001, we have employed low-dose MTX treatment for cGVHD. In this report, we show the data from 86 patients receiving low-dose MTX as a first line treatment for cGVHD.
Patients and Methods
Patients
The study was approved by the institutional review board of the Peking University Institute of Hematology. All patients gave written informed consent before participating in the study. Between November 2001 and March 2008, 86 consecutive patients with cGVHD given oral or parenteral low-dose MTX (10 or 15 mg, respectively) treatment as a first-line therapy were enrolled in this series. Data from 17 of these 86 patients were previously reported in 2005 [18], and these patients were further followed up in this study. In all cases, MTX was used as a first line therapy with or without other concomitant immunosuppressive treatments. Patients receiving MTX as a salvage therapy (where additional immunosuppressive agents other than MTX were given before MTX administration for treatment of newly diagnosed cGVHD) were not included in this series. Patients were informed about the risks, benefits, and uncertain outcomes associated with the use of MTX, and alternatives were explained. Characteristics of the 86 patients were summarized in Table 1.
Table 1. Patient Characteristics
| Characteristic | n |
|---|---|
| Total patients | 86 |
| Age (median) | 30 (range: 8-50) |
| Sex (male:female) | 53:33 |
| Onset of GVHD (median) (day) | 153 (range: 80-993) |
| Disease | |
 Acute myelogenous leukemia | 24 |
| Acute lymphoid leukemia | 27 |
| Chronic myelogenous leukemia | 28 |
| Myelodysplastic syndrome | 5 |
| Aplastic anemia | 1 |
| Multiple myeloma | 1 |
| Donor and HLA histocompatibility | |
| Related 6 of 6 identical | 39 |
| Mismatched related | 43 |
| Unrelated 6 of 6 identical | 1 |
| Mismatched unrelated | 3 |
| Stem cell source | |
| Bone marrow + peripheral blood cell | 54 |
| Peripheral blood cell | 32 |
| Preparative regimen | |
| Bu/Cy or Cy/TBI | 38 |
| Bu/Cy or Cy/TBI plus ATG | 46 |
| Cy/ATG | 2 |
| Onset of chronic graft-versus-host disease (cGVHD) | |
| De novo | 44 |
| Quiescent | 36 |
| Progressive | 6 |
| Type of cGVHD | |
| Limited | 38 |
| Extensive | 48 |
| Site of GVHD | |
| Skin | 50 |
| Liver | 52 |
| Mouth | 12 |
| Eye | 7 |
| Gut | 2 |
| Time to MTX start (days) median (range) | |
| From allo-HSCT | 154 (80-993) |
| From the day of diagnosis of GVHD | 1 (1-25) |
| Follow-up from onset of cGVHD (d) median (range) | 402 (36-2164) |
| Follow-up from HSCT (days) median (range) | 575 (146-2309) |
| Immunosuppressive agents before MTX administration | |
| CsA (50-200 mg orally in divided doses daily) | 38 |
| CsA + prednisone (2.5-75 mg daily) | 25 |
| Prednisone (2.5-15 mg daily) | 2 |
| CsA + prednisone + MMF | 10 |
| CsA + MMF | 5 |
| None | 6 |
Transplant Procedure
Details of the patients, conditioning regimen, infused cell counts, GVHD prophylaxis regimen, and supportive care measures were described in the previous study [18]. Patient-donor relationship and stem cell source are shown in Table 1.
Diagnosis and Grading of cGVHD
Prior to initiation of the treatment, patients underwent a thorough evaluation to ascertain the severity and extent of GVHD, including physical examination, laboratory evaluation, and consultation without tissue biopsy results. cGVHD was classified into several categories including: limited (localized skin involvement only or mildly increased transaminase level only) and extensive cGVHD (generalized skin, liver involvement with hyperbilirubinemia, multiple organ cGVHD) in accordance with the extent of the disease [19]; progressive cGVHD, whether it followed as a direct extension from aGVHD; quiescent cGVHD, if prior aGVHD had completely resolved; and de novo cGVHD, if there was no prior aGVHD at all. Onset forms and types of cGVHD among the 86 patients are described in Table 1. The most frequently involved organs were the skin and liver.
Involved Organ of cGVHD
Fifty patients had skin involvement manifesting as lichenoid papules (other skin manifestations such as sclerosis, lichen-sclerosis like, poikiloderma, or depigmentation were not encompassed in this group because of their long-standing and refractory nature), 52 with liver involvement had an elevation of enzymes (3 accompanied by an elevated bilirubin), 12 with oral involvement, 7 with eye involvement, and 5 patients presented with grade 2 or 3 thrombocytopenia.
Immunosuppressive Agents before Treatment with MTX
Details of immunosuppressive agents before treatment with MTX are described in Table 1.
Protocol of MTX Therapy
MTX was given i.v. at a dose of 10 mg or orally at a dose of 15 mg, repeated at day 3 or 4 and day 8 after the first dose and then at a weekly interval, until the patients showed a complete or partial response, treatment failure or intolerable side effects.
i.v. MTX was used in all in-patients and patients with gut GVHD because of concern that absorption might be limited by severe gut GVHD. Otherwise, it was determined at each physician's discretion. Drug dosage was adjusted according to the hemogram. MTX was administered at a dose of 5 mg i.v. or 10 mg orally if WBC <2 × 109/L or platelet <50 × 109/L. Leukovorin was not administered to all patients. Patients were scheduled to receive 3 doses (numbers of MTX administrations) for evaluation of the efficacy. If patients had improvement after 3 doses and were able to tolerate the toxicity, additional doses were given at each physician's discretion. In patients who had no response (progression or stable disease) after 3 doses, MTX administration was stopped and treatment was switched to other immunosuppressive agents.
For limited cGVHD, MTX was given with the original immunosuppressive regimen unchanged. Prednisone, cyclosporine A (CsA), and other immunosuppressive agents were gradually tapered off if cGVHD could be controlled with the sole addition of MTX. For extensive cGVHD, additional immunosuppressive agents other than the original ones can be administered in combination with MTX, which was determined by the severity and response after the initial 2 MTX doses. If patients who obtained a response flared up at least 2 weeks from the last dose of MTX, MTX can be given for retreatment with the original immunosuppressive regimen unchanged.
Evaluation of Response and Toxicity
Patients were evaluated 3 times per week after therapy. A complete response (CR) was classified as complete disappearance of all clinical manifestations of cGVHD. A partial response (PR) was defined as a change from extensive to limited stage or a more than 50% improvement in objective parameters of cGVHD manifestations including surface area of skin involvement, transaminase, or bilirubin level. A response in oral cGVHD was more difficult to quantitate objectively, but required symptomatic improvement as well as physician assessment of comparative improvement. Overall response (OR) included CR and PR. Patients were considered to have no response (NR) or treatment failure if GVHD progressed or failed to improve (stable disease) after 3 administrations of MTX. When there was no change in the extent or severity of the disease it was considered to be stable disease (SD), and in the event of worsening of the above-mentioned parameters it was termed progressive disease (PD). The common terminology criteria (CTC) for adverse events version 3.0 was used to grade the severity of side effects.
Statistical Methods
Data were collected on case report forms by medical record review. Laboratory values (complete blood counts, liver function tests, and renal function tests) were analyzed in reference to normal range and pretreatment baseline. The time elapsed between the onset of cGVHD and HSCT was defined as the time from HSCT to the onset of any grade of cGVHD. For comparison of group characteristics, Pearson chi-square test was applied for univariate analysis, and stepwise logistic regression was used for multivariate analysis. The probability of survival, the time course for cGVHD response, and subsequent recurrence were estimated using the method of Kaplan and Meier. The surviving patients were followed up, and the results of the follow-up examinations were analyzed on August 1, 2008. Unless otherwise specified, all the reported P values were based on 2-sided hypothesis tests. The SPSS software packages were used for data analyses.
Results
Drug Use
MTX was started at a median of 154 days (range: 80-993) after HSCT as first-line therapy with or without other concomitant immunosuppressive agents for treatment of cGVHD, which occurred at a median of 153 days (range: 80-993 days) after HSCT in 86 patients (Table 1). The drug was administered orally or intravenously in 25 and 61 patients, respectively. Fifty-four patients started MTX therapy with original immunosuppressive regimen unchanged including 3 patients receiving MTX alone with no original immunosuppressive agents, and additional immunosuppressive was given in combination with MTX in 32 patients with extensive cGVHD.
Responses
All 86 patients except 1 received at least 3 doses of MTX as scheduled. Only 1 patient received 2 doses of MTX because of severe cytopenia; however, the patient achieved CR after 2 doses of MTX. Therefore, all patients were eligible for efficacy and safety evaluation.
The OR and CR rates were 83% (71 of 86 patients) and 62% (53 of 86, respectively). MTX usage and immunosuppression taper results are shown in Table 2 and Table 3. The time course for cGVHD response is shown in Figure 1.
Table 2. The Usage of MTX in Patients Who Had a Response
| Number of doses or cumulative dose in mg | Median (range) |
|---|---|
| Doses to show improvement (<50% improvement, not reaching PR) | 2 (1-3) |
| Doses to achieve maximal response (CR or PR) | 4 (1-10) |
| cumulative dose to achieve a CR or PR | 35 (10-100) |
| Additional doses after the initial three doses | 2 (1-15) |
| cumulative dose of additional administrations | 20 (5-120) |
| Total number of doses of MTX administration | 4 (2-18) |
| Total cumulative dose | 40 (15-165) |
Table 3. Immunosuppression Taper 1 Month after MTX Last Used
| Other immunosuppressive agents tapering | Patient number and percentage |
|---|---|
| Initial prednisone dose median (range) | 43 patients∗ |
| 20 (2.5-100) mg | |
| Prednisone dose 1 month after MTX therapy | 23 patients discontinued |
| median (range) | 0 (0-25) mg |
| Percent of prednisone dose reduction | 100 (2.5-100)% |
| Sole tapering of CsA | 38 patients |
| Sole tapering of prednisone | 32 patients |
| Sole tapering of MMF | 3 patients |
| Simultaneous tapering of prednisone and MMF | 6 patients |
| Simultaneous tapering of CsA, prednisone and MMF | 4 patients |
| Simultaneous tapering of CsA and prednisone | 1 patient |
∗Prednisone was used in 43 patients either as a regularly reduced original use or as a concomitant additional use with MTX. |
Figure 1
Cumulative overall response rate after MTX therapy. Seventy-one of 86 patients achieved overall response with a median of 4 (1-10) MTX administrations.
Among the 71 patients who obtained a response, 25 (35.2%) flared up after a median of 50 days (range: 15-602 days) from the last MTX. Twenty-one of the 25 patients were given MTX again and 17 got a response with 12 CR and 5 PR. The other 46 of 71 patients who obtained a response after MTX administration did not flare up after a median of 339 days (range: 25-1851 days) from the end of the therapy. The time course for cGVHD recurrence was shown in Figure 2.
Figure 2
Cumulative cGVHD recurrence after MTX discontinued. Among the 71 patients who obtained a response, 25 flared up after a median of 50 days (range: 15-602 days) from the last MTX.
Subset analysis of responses was shown in Table 4. Overall response rates R and CR rates for skin involvement were significantly higher (80% and 90%) than those of other involved organs (P < .01); CR rate for single organ involvement was significantly higher than those for nonsingle ones: 71% versus 38%, P = .006; when accompanied by an elevated bilirubin or grade 2 thromocytopenia, CR rates were significantly lower than those without the factor: 0 of 3 versus 64%, P = .025 and 1 of 5 versus 64%, P = .049, respectively. R and CR rates in patients receiving MTX, in combination with additional immunosuppressive agents or receiving MTX on original immunosuppressive agents, including the 3 patients receiving MTX alone with no original immunosuppressive agents were: 88% versus 80% (P = .40) and 69% versus 57% (P = .36), respectively.
Table 4. Univariate Analysis of Overall Responses and Complete Responses
| Variable | Patients (n) | CR, n (%) | P∗ | OR, n (%) | P∗ |
|---|---|---|---|---|---|
| Onset forms of cGVHD | .21† | .01† | |||
| Quiescent | 44 | 26 (59%) | 31 (71%) | ||
| De novo | 36 | 25 (69%) | 34 (94%) | ||
| Progressive | 6 | 2/6 | 6/6 | ||
| Types of cGVHD | .48 | .72 | |||
| Limited | 38 | 25 (66%) | 32 (84%) | ||
| Extensive | 48 | 28 (53%) | 39 (82%) | ||
| Involved organ | <.01‡ | <.01‡ | |||
| Skin | 50 | 40 (80%) | 45(90%) | ||
| Liver | 52 | 27 (52%) | 39 (75%) | ||
| Mouth | 12 | 4 (33%) | 5 (42%) | ||
| Eye | 7 | 3 (29%) | 3 (29%) | ||
| Gut | 2 | 2/2 | 2/2 | ||
| Number of involved organs | .006 | .11 | |||
| Sole organ | 62 | 44 (71%) | 54 (87%) | ||
| Multiorgans | 24 | 9 (38%) | 17 (71%) | ||
| ≥Grade 2 thrombocytopenia | .049 | .58 | |||
| With | 5 | 1/5 | 5/5 | ||
| Without | 81 | 52 (64%) | 66 (82%) | ||
| Elevated bilirubin | .025 | .44 | |||
| With | 3 | 0/3 | 2/3 | ||
| Without | 83 | 53 (64%) | 69 (83%) | ||
| Treatment regimen | .37† | .06† | |||
| MTX + original IS | 51 | 30 (59%) | 42 (82%) | ||
| MTX + additional IS | 32 | 22 (69%) | 28 (88%) | ||
| MTX alone | 3 | 1/3 | 1/3 | ||
| Detailed combinations | .39‡ | .22‡ | |||
| CsA + MTX | 26 | 19 (73%) | 22 (85%) | ||
| CsA + pred + MTX | 35 | 18 (51%) | 27 (77%) | ||
| CsA + pred + MMF + MTX | 19 | 13 (68%) | 18 (95%) | ||
| CsA + MMF + MTX | 3 | 2/3 | 3/3 | ||
| MTX alone | 3 | 1/3 | 1/3 | ||
| MTX administration manner | .093 | .21 | |||
| Orally | 25 | 19 (76%) | 23 (92%) | ||
| Intravenously | 61 | 34 (56%) | 48 (79%) | ||
| Total | 86 | 53 (62%) | 71 (83%) |
∗For comparison of CR and OR rates within different variables, chi-square test was applied for univariate analysis. |
†Two degrees of freedom test. |
‡Fur degrees of freedom test. |
Factors Influencing CR Rate
In multivariate analysis, the following variables were considered as covariates: sole organ involvement or not, patient age, with or without concomitant thrombocytopenia, progressive onset or not, and MTX in combination with other immunosuppressive agents or not. Results showed that the only significant factor related to higher CR rate was sole organ involvement (P = .007).
Toxicity
CTC grade 2 and 3 cytopenia occurred in 3 and 2 patients. Two patients developed grade 3 thrombocytopenia and/or leukopenia after 2 and 8 doses with dosage of 20 and 40 mg, respectively. The platelet counts of these 2 patients were from 51 × 109/L to 36 × 109/L and from 74 × 109/L to 45 × 109/L from the start to the end of MTX administration, respectively. Neither of the patients required blood product transfusion or treatment with hematopoietic growth factors. One patient discontinued the medication after 2 doses because of cytopenia. No patient was withdrawn from the study because of hematologic side effects. Hematologic toxicity among patients receiving MTX in combination with additional immunosuppressive agents, remaining on the original immunosuppressive agents or receiving MTX alone was 9.4%, 3.9% and 0 of 3, respectively.
Seven patients aggravated from normal to grade 1, 2, or 3 oral mucositis after a median of 3 doses (range: 3-5 doses) and a median dose of 30 mg (range: 30-50 doses). Other nonhematologic toxicity or therapy-related infection or hemorrhage was not observed.
Long-Time Follow-up and Survival
Up to August 1, 2008, with a median follow-up of 402 days (range: 36-2164 days) from onset of cGVHD and 575 days (range: 146-2309 days) from HSCT, 10 patients relapsed of leukemia; among whom 4 died from leukemia relapse, 4 achieved complete remission after chemotherapy and donor lymphocyte infusion (DLI), 1 achieved complete remission after second transplantation, and another 1 remained alive with leukemia relapse status. In all, 8 patients died from interstitial pneumonia (n = 4) or leukemia relapse (n = 4), 78 patients remained alive and 77 remained disease-free, with a median survival of 424 days (range: 36-2164) from onset of cGVHD and 608 days (range: 146-2309) from HSCT. Mortality among patients receiving MTX in combination with additional immunosuppressive agents, receiving MTX alone or remaining on the original immunosuppressive regimen was 15.6%, 0 of 3, and 5.6% (P = .28), respectively. Estimated survival at 1 and 1.5 years were 96% and 90%. There was a difference in the estimated survival at 1.5 years between patients receiving MTX in combination with additional immunosuppressive agents and patients receiving MTX on the original immunosuppressive regimen including the 3 patients receiving MTX alone with no original immunosuppressive agents: 80 and 96%, (P = .053).
Discussion
Recent studies have suggested that a low dose of MTX, in addition to having antimitotic effects, can induce a sustained suppression of T cell activation, supporting its use in GVHD therapy [20]. Previous to this report, there were no other published reports that evaluated the potential efficacy that this drug might have for treatment of cGVHD as a first-line therapy. The current study was initiated to evaluate the safety and both the efficacy of MTX as a first-line treatment for cGVHD in a larger population and the factors influencing the response rate of MTX.
Early initiation of drug therapy may be more effective for the treatment of cGVHD. Vogelsang et al [21] reported that 7 of 21 patients with poor risk features had a CR using thalidomide as part of the first-line therapy in combination with prednisone (PSE)/CsA, whereas Parker et al [22] found that patients receiving thalidomide as a salvage treatment had a CR rate of 20%. Gaziev et al [23] found that patients receiving a 3-drug regimen with CsA, methylprednisolone (MP), and azathioprine (AZ) as first-line therapy had higher CR rates and fewer complications than did those receiving this combination as a salvage treatment.
To our knowledge, there have been 4 published reports to evaluate the feasibility of MTX in the treatment of cGVHD as a salvage therapy, using a variety of assessments and definitions of responses 15, 16, 17, 18. Response rates were reported to be 55% to 76% for cGVHD including 8-21 patients. Giaccone et al [15] reported with a median of 38 months after the diagnosis of cGVHD, 14 patients began low-dose MTX at a median dose of 10 mg weekly for a median of 25 weeks, where 5 of 9 closely watched patients experienced improvement or resolution of GVHD. Inagaki et al [16] reported a response rate of 58.8% with MTX at a dose of 10 mg/m2 weekly for a median of 18 months for the treatment of cGVHD in children. de Lavallade et al [17] found that 6 of 8 patients receiving MTX at a dose of 5 mg/m2 weekly for a median of 4 infusions as a salvage treatment had a response. These reports demonstrated the possible steroid-sparing effect of low-dose MTX for patients with long-standing cGVHD; however, it remained difficult to judge the potential efficacy that this drug might have for treatment of cGVHD at an earlier stage of the disease. In Inagaki et al's report, CR was achieved in 4 of 17 patients with cGVHD [16]. In these 4 CR patients, 3 began low-dose MTX soon after the diagnosis of cGVHD and the remaining patient began 25 days after the diagnosis. Our earlier study included a small number of successful cases with MTX as a first-line therapy for the treatment of cGVHD and achieved a response rate of 76% for cGVHD patients [18]. Our present study supports and confirms that larger scale use of MTX as a first-line therapy had better outcomes than when used as a salvage therapy.
It should be emphasized that most patients given MTX did receive other immunosuppressive agents such as CsA and MP (or prednisone), and the response rate might be increased when MTX is given in combination with other agents. Compared with patients receiving MTX in combination with other immunosuppressive agents, patients receiving MTX alone had a lower response rate. One prospective cohort study demonstrated that the response rate to combination therapy with steroid, CsA, and AZ was 61% [24]. Gaziev et al [23] used CsA, MP, and AZ as first-line therapy with a CR rate of 94%. Notably, that study population was small (18 patients) and young (median age of 11 years). In our present study, high response rates and minimal toxicity was demonstrated and most of the patients were able to either discontinue or reduce other immunosuppressive agents such as CsA, MP, or mycophenolate mofetil (MMF), which may be beneficial in the recovery of immune function. Randomized trials of comparing this regimen with other multidrug therapy for newly diagnosed cGVHD are needed to confirm its superiority.
The results were particularly good for patients with skin involvement. In fact, many other medications or complications after HSCT might influence the resolution process of liver disease. These results were in accordance with Inagaki et al's report [16]. GVHD-related symptoms in most patients improved within a few days and were controlled within 2-3 weeks after initiation of MTX. MTX was also effective on recurrent GVHD, which had previously responded to MTX.
Severe cytopenia seemed less than that of previous reports 15, 16, 17, maybe because of lower dose, shorter period of MTX administration, and MTX given beyond day 100 after transplantation in this series. Nevertheless, close monitoring of blood cells counts is necessary whenever MTX is administered. There were no episodes of severe infectious complications obviously related to MTX. No other well-described adverse events, such as gastrointestinal symptoms, immune-mediated pneumonitis, or renal impairment were seen even in the patients with long-term follow up. Low-dose use of MTX contributed to its safety. Therefore, these results confirmed that low-dose MTX might be safe and well tolerated in the larger population.
In summary, our results demonstrate that MTX appears to be a well-tolerated, effective, and inexpensive agent as a frontline therapy in combination with other immunosuppressive agents for treatment of cGVHD, especially for skin or sole organ involvement without concomitant thrombocytopenia. A prospective randomized trial is required to confirm the potential efficacy.
Acknowledgments
Financial disclosure: This work was supported by the National Outstanding Young Scientist's Foundation of China (Grant No. 30725038), Hi-tech Research and Development Program of China (Grant No. 2006AA02Z4A0), Program for Innovative Research Team in University (Grant No. IRT 0702), and Leading Program of Clinical Faculty accredited by the Ministry of Health of China. The authors thank American Journal Experts Team for critically reviewing this paper in English.
Authorship
Contribution: Xiao-Jun Huang, designed and performed research, analyzed data; Yu Wang, collected data, assisted with data analysis, and wrote the manuscript; Dai-Hong Liu, Lan-Ping Xu, Kai-Yan Liu Huan Chen, Yu-Hong Chen, and Wei Han provided patients’ information.
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Financial disclosure: See Acknowledgments on page 510.
PII: S1083-8791(08)01103-8
doi:10.1016/j.bbmt.2008.12.493
© 2009 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Volume 15, Issue 4 , Pages 505-511, April 2009
