Reduced-Intensity Conditioning Allogeneic Transplantation from Unrelated Donors: Evaluation of Mycophenolate Mofetil Plus Cyclosporin A as Graft-versus-Host Disease Prophylaxis

Article Outline

• Abstract
• Introduction
• Patients and Methods
  • Patients Characteristics and Trial Desing
  • Conditioning Regimen and GVHD Prophylaxis
  • MMF Monitoring
  • Statistical Analysis
• Results
  • Regimen-Related Toxicity and GVHD
  • Chimerism and Drug Monitoring
  • Disease Response and Outcome
• Discussion
• Acknowledgments
• References
• Copyright

Abstract 

In the current study, we have analyzed the efficacy of cyclosporine A (CSA) plus mycophenolate mofetil (MMF) as graft-versus-host disease (GVHD) prophylaxis in the fludarabine plus melphalan or busulfan reduced intensity regimen (RIC) setting in a series of 44 patients receiving allogeneic transplantation from an unrelated donor. Only 23% were in the first complete remission at the time of transplant. Cumulative incidence of grades II-IV and III-IV acute GVHD (aGVHD) was 53% and 23%, respectively. Fifty-six percent had equal to or greater than grade 2 gut involvement. Cumulative incidence of overall and extensive chronic GVHD (cGVHD) was 93% and 63%, respectively. Ninety-two percent of patients who were evaluable +100 days after transplant were in complete remission. Relapse rate was 25% at 2 years. Event free (EFS) and overall survival (OS) at 2 years were 52%. Pharmacokinetic assays of mycophenolic acid (MPA) showed a therapeutic area under the curve (AUC) at the dosage of 3 g daily, although a large inter- and intraindividual variations of MPA plasma levels were found. In conclusion, the combination of CSA plus MMF in the fludarabine plus melphalan or busulfan RIC setting is feasible. Regarding GVHD, this combination allowed to control aGVHD but lead to a high incidence of cGVHD, so that newer strategies are required, especially in trying to decrease gastrointestinal involvement.

Key Words: Unrelated donor, Allogeneic transplantation, Reduced-intensity conditioning, Mycophenolate mofetil, Graft-versus-host disease

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Introduction 

Allogeneic transplantation is the most effective approach for the treatment of many patients diagnosed with hematologic malignancies 1, 2. The number of donors available from international registries allows to find an appropriate unrelated donor for a high percentage of patients [3], and results of unrelated donor transplantation have improved through the last years 4, 5, which is because of a better patient and donor selection 3, 6, a better prophylaxis against infectious episodes 7, 8, and a better management of graft-versus-host disease (GVHD) 9, 10, resulting in outcomes similar to those reported among patients receiving hematopoietic transplantation from related donors 11, 12, 13. Nevertheless, results in the long term are still hampered by a high transplant-related toxicity 14, 15, and this is especially true for older patients, those who have received a prior transplant, or those with a history of fungal infection or other comorbid conditions 15, 16, 17. In an attempt to reduce treatment-related mortality (TRM) in this subset of patients, many studies have been reported using nonmyeloablative or reduced-intensity conditioning (RIC) allogeneic transplantation. Unfortunately, no prospective studies have been conducted comparing the outcome of patients receiving myeloablative versus RIC. Moreover, within the nonmyeloblative or RIC setting, different conditioning regimens have been developed, ranging from truly nonmyeloablative, usually based on low dose total body irradiation (TBI), to more intense conditionings based on combinations of fludarabine plus melphalan or busulfan 18, 19, 20, 21, 22, 23, 24, 25, 26. In addition, GVHD prophylaxis greatly varies in different trials so that, currently, there is no RIC or GVHD prophylaxis, which can be considered as standard or optimal. Interestingly, cyclosporine A (CSA) plus methotrexate (MTX) in combination or not with anti-T monoclonal antibodies (mAb) have mostly been used in the RIC setting, whereas CSA plus mycophenolate mofetil (MMF) have been mainly used in the context of nonmyeloablative/low-dose TBI-based regimens 18, 19, 20, 21, 22, 23, 24, 25, 26. The latter GVHD prophylaxis was developed to induce a higher immunosupression that allowed the hematopoietic engraftment after truly nonmyeloablative conditionings. The only study prospectively comparing CSA plus MTX versus CSA plus MMF showed a faster engraftment and lower toxicity using MMF, with no significant differences in terms of GVHD [27], although this study did not include a large number of patients. In addition, MMF has been used as an effective approach for the treatment of GVHD.

With this background, we performed a clinical trial using RIC based on fludarabine plus melphalan or busulfan and CSA plus MMF as GVHD prophylaxis instead of our standard approach in the RIC setting based on CSA plus MTX, in a series of 44 patients receiving allogeneic transplantation from an unrelated donor.

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Patients and Methods 

Patients Characteristics and Trial Desing 

Forty-four patients from 5 different institutions in Spain were included in the trial TNE-ANM 2001 for the Grupo Español de Trasplante (GETH). Patients' characteristics are specified in Table 1, the most common diagnosis being acute myelogenous leukemia (AML) in 13 patients, non-Hodgkin lymphoma (NHL) in 8 patients, and myelodysplastic syndromes (MDS) in 7 patients. Fitfy-two percent of the patients were not in complete remission (CR) at the time of transplant, and only 23% were in first CR. Among patients younger than 40 years the reason to undergo RIC was: relapse to a prior autograft (n = 8), severe pneumopathy (n = 1), poor performance status (n = 1), active infection (n = 1), and heavily pretreated (n = 1).

Table 1. Patients Characteristics

Characteristics	N = 44 (%)
Diagnosis
Acute myelogenous leukemia	13
Acute lymphoblastic leukemia	5
Myelodysplastic syndrome	7
Chronic lymphocytic leukemia/prolymphocytic leukemia	3
Chronic myelogenous leukemia	2
Non-Hodgkin lymphoma	8
Multiple myeloma/Waldenström	4
Myelofibrosis	2
Disease status at transplant
First complete remission	10 (23%)
>First complete remission	11 (25%)
First partial response	2 (5%)
>First partial response	4 (9%)
Active disease	9 (20%)
Progressive disease	4 (9%)
Others (aplasia post chemotherapy)	4 (9%)
Age: median (range)	48 (17-60)
Sex:
Male∗	29 (66%)
Female	15 (34%)
Previous transplantation	19 (43%)

The aim of this phase II trial was to analyze event-free survival (EFS), GVHD, and TRM of the fludarabine plus busulfan or melphalan conditioning regimen using CSA plus MMF instead of our conventional approach for GVHD prophylaxis in the RIC setting based on CSA plus MTX. Stopping rules included: TRM of 3 of the first 5 or 6 of the first 10 patients, acute GVHD (aGVHD) grade III or higher in 3 of 5 or 6 of 10 patients, graft failure in 2 of 5 or 3 of 10 patients, and patients recruitment lower than 10 patients in the first 18 months after protocol approval.

Initially it was planned to recruit 30 patients in 36 months, although the recruitment period was increased and 44 patients were finally included.

Conditioning Regimen and GVHD Prophylaxis 

Two RIC regimens were used: 1 recommended for lymphoid malignancies, and 1 for myelogenous malignancies. The lymphoid RIC regimen consisted of fludarabine 30 mg/m² administered intravenously on days −9 to −5, followed by melphalan 70 mg/m² intravenously on days −3 and −2. The myeloid regimen consisted of the same doses of fludarabine together with busulfan 1 mg/kg for 10 doses (days −6 to −4, total 10 mg/kg), with phenytoin given as anticonvulsant prophylaxis.

Hematopoietic stem cells from an unrelated donor were infused on day 0. A single HLA mismatched of 10 was allowed at the allele level. Of the 44 patients, 14 received hematopoietic stem cells from mismatched donors, 13 had a single allele mismatched at HLA class I, and 1 at HLA class II level.

Stem cell source was bone marrow in 53% and peripheral blood in 47% of the patients.

GVHD prophylaxis consisted of CSA plus MMF for all patients. CSA was given at a dose of 1 mg/kg per day intravenously from days −7 to −2, and then 3 mg/kg/day intravenously or orally from day −1. Levels were maintained in the therapeutic range until tapering. MMF was given at a dose of 1 g every 12 hours for the first 10 patients and 1 g every 8 hours thereafter. In the case that patients did not tolerate oral medications, intravenous MMF was used at a dose of 15 mg/kg either every 12 hours or every 8 hours. The dose was planned to be tapered starting on day +56 and stopped on day +100, although it varied depending on the chimerism status or the development of GVHD.

aGVHD and chronic GVHD (cGVHD) were graded by established criteria 28, 29.

MMF Monitoring 

Drug concentration-time data were used to determine mycophenolic acid (MPA) pharmacokinetics from 8 patients included in 1 of the participating centers. At least 1 complete pharmacokinetic profile was obtained from each patient. For this purpose 8 to 9 blood samples were collected just prior to as well as 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after MMF administration. Five milliliters of blood anticoagulated with EDTA were centrifuged at 2000 rpm for 10 minutes, and the plasma was removed. The enzyme multiplied immunoassay technique (EMIT) for the determination of total MPA was performed on a Viva-E analyzer (Dade Behring, Germany). There was no adjustment of MMF dose based upon MPA plasma concentrations. All assays were performed in the same laboratory.

Statistical Analysis 

Events analyzed were calculated from the time of transplantation using Kaplan-Meier product-limit estimates. TRM was defined as death because of causes unrelated to the underlying disease, and relapsing patients were censored at the time of relapse. EFS was calculated from transplant until disease progression or death and those patients who did not reach disease response (complete or partial remission) any time after transplant were considered events on day 100, because that was the first date for complete disease evaluation. Overall survival (OS) was calculated from transplant until death. Kaplan-Maier estimates were used to analyze the impact on EFS and OS of sex, sex mismatch, age, diagnosis, disease status at transplant, source of progenitor cells, aGVHD and cGVHD.

Patients who had evidence of engraftment were evaluable for aGVHD, whereas patients who engrafted and survived more than 100 days were evaluable for cGVHD. The day of aGVHD was calculated from transplant until diagnosis of aGVHD among evaluable patients and the same for cGVHD. Cumulative incidence estimates for GVHD was performed taking into account death as competing risk. GVHD-related mortality was defined as death because of causes directly related to GVHD, and those deaths attributed to immunosupression in patients requiring treatment for GVHD were also considered as GVHD related mortality.

Noncompartmental analysis was used for calculation of pharmacokinetic parameters. The area under the curve (AUC) for the dosing interval was calculated by the log-trapezoidal rule using a proprietary computer program.

Data were analyzed by statistical software SPSS version 13.0 (SPSS Inc., Chicago, IL). Differences were considered to be statistically significant when P-values were <.05 and a 2-sided test was used.

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Results 

Regimen-Related Toxicity and GVHD 

Regimen was well tolerated. Extrahematologic toxicity was mild, with only 9% of patients developing grade 3 mucositis, 3% grade 3 nausea or vomiting, and 5% grade 3 liver toxicity. The median number of days with neutrophil counts <1000/mm³ was 9 days, and with platelet counts <20,000/mm³ was 7 days. Patients reached >1000/mm³ granulocytes and >20,000 platelets/mm³ at 18 and 12 days after transplant, respectively. No significant differences were observed in terms of extra-hematologic toxicity or engraftment between both preparative regimens.

aGVHD flared at a median of 25 days (range: 10-103 days) after transplant. Cumulative incidence of grades II-IV and III-IV aGVHD was 53% and 23%, respectively (Figure 1A). Out of the 29 patients who developed aGVHD, 17 (58%) had greater than or equal to grade 2 skin involvement, 16 (56%) had greater than or equal to grade 2 gut involvement, and 6 (21%) had greater than or equal to grade 2 liver involvement. Fifty-six percent of patients reached complete remission of aGVHD after first line treatment.

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• Figure 1. 

  Cumulative incidence of acute and chronic GVHD.

cGVHD flared at a median of 118 days (range: 97-1057 days) after transplant. Cumulative incidence of overall and extensive cGVHD was 93% and 63%, respectively (Figure 1B). Among the most frequently involved organs, there were mucosal involvement in 63% of cases, skin was affected in 53%, gut in 41%, and liver in 31% of patients with cGVHD. After first line treatment 21% of patients obtained complete remission and 47% of patients reached partial response.

A univariate analysis for grades II-IV aGVHD and extensive cGVHD was performed including the following variables: age, sex, diagnosis, sex mismatched, CD34 cell count, HLA disparity, use of melphalan or busulfan in the conditioning regimen, and source of progenitor cells (plus prior aGVHD in univariate analysis for the risk of extensive cGVHD). Use of busulfan or melphalan influenced the risk of GVHD with 46% versus 62% incidence of grades II-IV aGVHD among patients receiving the prior or the latter, respectively, P = .055. One or the other drug was used depending on patients diagnosis, the same values were obtained upon comparing patients diagnosed with myeloid versus lymphoid malignancies, respectively. Finally, patients sex marginally influenced on the incidence of aGVHD (cumulative incidence of 66% versus 47% grades II-IV aGVHD for male versus female recipients, respectively, P = .09).

Only prior aGVHD significantly influenced on the incidence of cGVHD in univariate analysis, with a cumulative incidence of extensive cGVHD of 87% versus 67% among patients with prior grades II-IV aGVHD or not, respectively, P = .01.

Chimerism and Drug Monitoring 

Chimerism assays showed complete chimerism in bone marrow in 80%, 90%, and 82% of patients analyzed on days +21, +50, and +100 after transplant, respectively. In peripheral blood these figures were 57%, 72%, and 82% in lymphocytes and 75%, 90%, and 86% in granulocytes.

The pharmacokinetic parameters for each patient as well as mean (and SD) values are shown in Table 2. A therapeutic AUC_0-24h, according to the recommended range for renal transplants (70-140 μg^∗h/mL), was observed in 9 of 12 pharmacokinetic profiles at the dosage of 3 g daily. Coefficient of variation for total MPA trough concentrations was higher than that obtained for AUC, 55.46% versus 34.12%, respectively. Large inter- and intraindividual variations of MPA plasma levels were found, as shown in Figure 2. By contrast, no significant differences were observed in pharmacokinetic parameters depending on the route of administration, because no evidence for enterohepatic circulation was observed in the AUC.

Table 2. Mycophenolic Acid Pharmacokinetic Parameters

C_min indicates trough concentration; AUC_0-tau, area under the curve for the dosing interval; AUC_0-24h, area under the curve for 24 hours; SD, standard deviation; AUC_0-tau, 38.81 μg^∗h/mL for oral versus 34.66 μg^∗h/mL for intravenous administration, P = .21

AUC_0-24h, 110.41 μg^∗h/mL for oral versus 103.9 μg^∗h/mL for intravenous administration, P = .33.

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• Figure 2. 

  Concentration versus time profile of mycophenolic acid in 8 patients after oral or intravenous MMF administration. Patients 2, 3, and 6 are highlighted to show the high intraindividual variation of MPA pharmacokinetics.

Route of administration or AUC did not significantly influenced on the risk of aGVHD or cGVHD. These data are summarized in Table 2.

Disease Response and Outcome 

Ninety-two percent of patients who were evaluable +100 days after transplant were in complete remission. Relapse rate was 25% at 2 years. Of the 8 patients who relapsed after transplant, 3 had active disease at the time of transplant and 3 had already relapsed to a prior autograft.

Overall TRM was 42% (Figure 3). Causes of death are summarized in Table 3. In univariate analysis only patients sex significantly influenced in TRM (68% versus 32% for males versus females, respectively; P = .007). EFS and OS at 2 years was 52% (Figure 4A and B). None of the variables analyzed significantly influenced on overall survival (OS).

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• Figure 3. 

  Transplant related mortality.

Table 3. Characteristics of Patients Who Died because of TRM

GVHD indicates graft-versus-host disease; NHL, non-Hodgkin lymphoma; AML, acute myelogenous leukemia; MDS, myelodisplastic syndrome; RAEB, refractory anemia with excess of blasts; ICU, intensive care unit.

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• Figure 4. 

  Event free and overall survival.

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Discussion 

MMF is being commonly used in the GVHD prophylaxis within the nonmyeloablative transplant setting. Nevertheless, in the fludarabine/melphalan-based RIC setting information regarding the use of CSA plus MMF is scanty. In this setting, Rodriguez et al. [30] have previously reported similar results to those shown in the current trial, with 32% TRM at 1 year, 63% incidence of grades II-IV aGVHD, and 73% cGVHD. In our study we found that, although the incidence of aGVHD was not higher than expected, cGVHD flared in 93% of patients, and most of them developed extensive forms of cGVHD. Interestingly, the gut was affected in 51% of patients who developed aGVHD and 41% of those with cGVHD, suggesting that GVHD prophylaxis was suboptimal at the gastrointestinal level. On the contrary, the liver was only involved in 21% of cases, which indicates that the efficacy of this type of GVHD prophylaxis varied depending on the targeted organ. Compared to the incidence of GVHD reported in the truly nonmyeloablative setting using the same prophylaxis, Maris et al. [31] have reported 52% incidence of grades II-IV aGVHD and 37% cGVHD, which is significantly lower compared to that reported using RIC, both by Rodriguez et al. [30] and in the current study. Interestingly, it has been shown that myeloablative conditioning increases the risk of aGVHD compared to RIC [32] or nonmyeloablative [33] allogeneic transplantation. According to the current results, even within the nonmyeloablative versus RIC setting, the dose of chemotherapy may be important to determine the risk of GVHD. In this regard, and considering the efficacy of the procedure to obtain disease control, we found an OS and EFS of 52% at 2 years, similar to that reported by Rodriguez et al. [30], and also similar to the results described by Kalh et al. [34] using nonmyeloablative conditioning. Of note, in the latter study, OS was 26% at 3 years among patients diagnosed with Hodgkin disease, RAEB, or acute leukemia, with disease status more advanced than CR, which was because of a high relapse rate of 57% at 3 years. In the current study, we did not find a higher relapse rate in this subset of patients, suggesting again that, also for disease control, the dose of chemotherapy does matter in the nonmyeloablative versus RIC setting, as previously suggested by de Lima et al. [35]. Compared to other studies using RIC, in the current study we found a higher incidence of cGVHD compared to that reported using CAMPATH-1H [25] or rapamycin [36], although, as previously shown, the development of cGVHD may influence on disease control after transplantation 18, 37, 38. In our own experience 18, 32, 37, 38, the incidence of both aGVHD and cGVHD was also higher with the current protocol compared to previous studies using CSA plus MTX. Nevertheless, contrary to the current trial, only matched related donors (MRD) were used. Using fludarabine plus melphalan and GVHD prophylaxis with CSA plus MTX, de Lima et al. [35] reported 39% grades II-IV and 19% grades III-IV aGVHD, whereas 53% of patients developed cGVHD. Again, these figures compare favorably with those observed in the current study using CSA plus MMF, but 40% of patients received allogeneic transplantation from MRD in the de Lima study. Among patients receiving allogeneic transplantation from 10/10 matched unrelated donors, the French Society of BMT and Cellular Therapy [39] reported 60% and 29% incidence of grades 2-4 and 3-4 aGVHD using CSA plus MTX in the myeloablative setting. This incidence is similar to that reported in the current study with an older patients population.

Finally, regarding drug monitoring, a therapeutic window for MPA has not been accurately established, either for AUC or for predose concentration. In our pharmacokinetic study, we found that most patients reached a therapeutic AUC_0-24h, according to the recommended range for renal transplants (70-140 μg^∗h/mL) [40], at dosage of 1 g every 8 hours, which suggests that the administration of MMF every 12 hours, as recommended among patients receiving solid organ transplantation, may lead to suboptimal levels in the hematopoietic transplant setting. These results are in accordance to those reported by Giaccone et al. [41], and could be attributed to a poorer absorption rate, because of mucositis or intestinal GVHD. Moreover, a higher clearance has been observed among patients undergoing hematopoietic stem cell transplantation. Similar to previous reports, we found an extensive inter- and intraindividual variability of MPA pharmacokinetics 42, 43, 44. Coefficient of variation for total MPA trough concentrations was higher than that observed for AUC (55.46% versus 34.12%, respectively). Accordingly, the AUC could be a more reliable pharmacokinetic parameter for MPA drug monitoring in clinical practice.

In the current study neither route of administration nor the AUC significantly influenced on the risk of aGVHD or cGVHD, although the low number of cases precluded to draw any conclusion in this regard.

In conclusion, the combination of CSA plus MMF in the fludarabine plus melphalan or busulfan RIC setting is feasible. The regimen allows to obtain disease control in a high-risk population of patients. Regarding GVHD, this combination allowed control of aGVHD but lead to a high incidence of cGVHD, so that newer strategies are required, especially trying to decrease gastrointestinal involvement.

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Acknowledgments 

The authors thank Nuria Pajuelo for the statistical review and Ruth Martin for her support and external monitoring.

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