Volume 12, Issue 2 , Pages 217-225, February 2006
Tacrolimus and Mycophenolate Mofetil after Nonmyeloablative Matched-Sibling Donor Allogeneic Stem-Cell Transplantations Conditioned with Fludarabine and Low-Dose Total Body Irradiation
Article Outline
Abstract
We evaluated tacrolimus/mycophenolate mofetil (MMF) for graft-versus-host disease (GVHD) prophylaxis after a nonmyeloablative stem cell transplantation (NST) from a matched sibling donor (MSD). Thirty-two patients (median age, 57 years) with advanced hematologic malignancies, who were poor candidates for a conventional myeloablative transplantation, received fludarabine (30 mg/m2, day −4 to day −2), total-body irradiation (TBI) (200 cGy, day 0), infusion of donor peripheral blood progenitor cells (day 0), oral tacrolimus 0.06 mg/kg twice daily (from day 3), and oral MMF at 15 mg/kg twice daily (days 0-+27). Tacrolimus was tapered from day +100 to day +180 in those patients with indolent malignancies (n = 25), and from day +35 to day +56 in those with aggressive tumors (n = 7). Regimen toxicities and myelosuppression were mild, allowing 75% of patients to have entirely outpatient transplantations. One patient (3%) experienced a nonfatal graft rejection. Rates of grades II-IV and III-IV acute GVHD were 15.6% and 3%, respectively. Acute GVHD was diagnosed at median day +78 (range, days +31-+84). Extensive chronic GVHD was observed in 10 of 24 evaluable patients (41.6%) at a median onset of day +198 (range, days +128-+277), either spontaneously (n = 5) or elicited after tumor progression (n = 5). Five patients experienced transplantation-related mortality (TRM) (15.6%) from either acute GVHD-related multiorgan failure (MOF) (n = 3) or infectious complications (n = 2). At median follow-up of 19 months (range, 2-41 months), the overall survival, progression-free survival, and disease-free survival rates are 62.5%, 50%, and 40%, respectively. In conclusion, the use of tacrolimus/MMF after MSD NST is associated with encouraging rates of GVHD control.
Key words: Tacrolimus , Mycophenolate mofetil , Graft-versus-host disease , Nonmyeloablative transplantation , Matched sibling donor
Introduction
Nonmyeloablative allogeneic stem cell transplantation (NST) has emerged as a less-toxic alternative to fully myeloablative allogeneic stem cell transplantation (SCT). NST derives its antitumor effect largely from the induction of an immune graft-versus-tumor (GVT) effect. The use of lower doses of chemotherapy and radiotherapy has substantially decreased TRM, allowing the inclusion of poor candidates for myeloablative SCT, such as patients with advanced age, major comorbidities, or previous myeloablative SCT.
Several groups have developed different NST approaches with varying intensities [1, 2, 3, 4, 5, 6, 7]. Low-dose total body irradiation (TBI) (200 cGy) is at the lowest end of the intensity spectrum among NST conditioning regimens. Investigators at Seattle tested this approach in 45 patients who received a NST from a matched sibling donor (MSD) and reported rates of 47% stage II-IV acute GVHD, 70% chronic GVHD, 20% graft rejection, and 7% TRM, using cyclosporine/MMF as posttransplantation immunosuppression [7]. In a subsequent study in MUD NST recipients, the addition of fludarabine (30 mg/m2 × 3 days) to TBI as part of the conditioning regimen, appeared to decrease graft rejection [8].
This NST approach has decreased TRM both for MSD [9] and MUD [10] recipients, due largely to a major decrease in regimen-related direct organ damage. In contrast, age-matched comparisons with myeloablative SCT have shown little change in the incidence of GVHD after NST using cyclosporine/MMF [11].
In recent years, tacrolimus has emerged as an alternative to cyclosporine for GVHD prevention after myeloablative SCT. Both drugs are calcineurin blockers, and tacrolimus exerts an in vitro immunosuppressive effect that is 100 times more potent than that of cyclosporine [12]. Randomized trials have shown that posttransplantation tacrolimus/methotrexate is associated with decreased acute GVHD compared with cyclosporine/methotrexate in patients receiving a MSD [13] or matched unrelated donor (MUD) SCT [14]. We hypothesized that tacrolimus/MMF would provide superior GVHD protection after NST than cyclosporine/MMF. Both tacrolimus and MMF are synergistic in preclinical models [15]. In addition, tacrolimus does not appear to interact adversely with the metabolism of MMF, whereas cyclosporine causes a decrease in the trough levels of its active metabolite, mycophenolic acid [16, 17, 18].
Here we report the results of a prospective pilot trial evaluating the use of tacrolimus/MMF as GVHD prevention after fludarabine/TBI conditioning and a MSD NST in patients with hematologic malignancies who were ineligible for a conventional myeloablative allograft. The goal was to obtain preliminary data on the effect of substituting tacrolimus for cyclosporine within the framework of the NST approach developed by the Seattle investigators. Other components of this transplantation method remained intact, including the pretransplantation conditioning and collection of donor PBSC, and durations of postgrafting immunosuppression were consistent with those being tested by the Seattle group.
Patients and methods
Study Design
This prospective study was designed to test the safety and feasibility of tacrolimus and MMF as posttransplantation immunosuppression in patients with hematologic malignancies receiving a MSD NST after fludarabine/TBI. The study protocol was approved by the University of Colorado Cancer Center Protocol Review Committee and Institutional Review Board, and the Ethic Committees at Christchurch and Auckland Hospitals (New Zealand). The endpoints of the study were to determine whether stable allogeneic hematopoietic engraftment could be safely established in these patients, and to evaluate the incidence of grade II-IV GVHD associated with this treatment.
The inclusion criteria were the following: (1) availability of a donor, either an HLA-identical sibling or a phenotypically matched family member, and (2) patients with hematologic malignancies not eligible for a myeloablative allogeneic or autologous transplantation on the following grounds: (a) age >50 with AML or ALL, in ≥ second complete remission (CR2) or with <10% blasts in bone marrow; (b) age >50 with high-grade MDS; (c) age >50 with CML after failure of imatinib; (d) age >50 years with HD, NHL, or myeloma, after failure of chemotherapy and not candidates for an autologous transplantation; (e) any age with the foregoing malignancies, after failure of a previous autologous SCT; or (f) any age with major medical or psychiatric comorbidities considered ineligible for a myeloablative SCT. Patients with CLL and low-grade NHL were required to have failed at least treatment with a purine analogue and anti-CD20 monoclonal antibody rituximab.
Specific exclusion criteria were (1) myeloma, NHL, or HD eligible for an autologous SCT; (2) age ≤50 eligible for myeloablative allogeneic SCT; (3) rapidly progressive aggressive NHL; (4) active uncontrolled CNS involvement with malignancy; (5) fertile men or women unwilling to use contraceptive techniques during and for 12 months after treatment; (6) pregnancy; (7) HIV positivity; or (8) severe organ dysfunction, indicated by (a) left ventricle ejection fraction <35%, (b) carbon monoxide diffusion capacity (DLCO) <35% of predicted or receiving supplementary continuous oxygen; (c) total bilirubin >2 × the upper limit of normal and/or transaminases >4 × the upper limit of normal; (d) Karnofsky score <50 for patients <65 years, or <70 for patients age >65; or (e) hypertension poorly controlled on antihypertensive therapy. Patients with renal failure were considered eligible, although those with serum creatinine >2 mg/dL were informed that they could possibly require hemodialysis during the course of the study.
Study Therapy
Treatment was initiated on an outpatient basis, with patients only admitted as medically necessary for control of transplantation complications. Patients were conditioned with fludarabine (30 mg/m2/day on days −4 to −2) and TBI at 200 cGy on day 0, at 6-7 cGy/min from a linear accelerator, followed by stem cell infusion on day 0. The source of stem cells was donor peripheral blood progenitor cells (PBPC) mobilized with granulocyte colony-stimulating factor (G-CSF) at 16 μg/kg/day for 5 days, with apheresis products collected on the fifth day. Oral tacrolimus was started on day −3 at 0.06 mg/kg twice daily, and oral MMF was initiated at 15 mg/kg twice daily from day 0 (afternoon dose only).
Therapeutic monitoring of tacrolimus, with measurement of whole blood trough levels at least once a week, targeted 10-20 ng/mL. Holding of tacrolimus dosing and/or 25% dose reductions were made in the presence of tacrolimus toxicity, or with levels >20 ng/mL in the absence of toxicity. Blood pressure, renal function tests, electrolytes, and magnesium were monitored at least 3 times per week while receiving tacrolimus at full dose, and then at least once weekly until discontinuation of tacrolimus.
Dose adjustments of MMF for gastrointestinal toxicity deemed related to this drug mandated a 20% dose reduction, with a further 20% reduction in the absence of improvement. Severe MMF-related gastrointestinal toxicity required discontinuation of this drug. Dose adjustments were not contemplated for hematopoietic toxicity, except for severe and persistent (<100 neutrophils/mm3 for >5 days) or late (after day +21) neutropenia.
In the event of nausea and/or vomiting preventing oral intake at any time during tacrolimus or MMF treatment, these drugs were administered through an intravenous (IV) route, using IV-to-oral conversion ratios of 1 to 4 and 1 to 1, respectively.
MMF was discontinued without tapering after the second dose on day +27. Patients received tacrolimus according to 2 immunosuppressive schedules. Those with indolent diseases (cohort A) initiated tacrolimus tapering, in the absence of GVHD, on day +100 by approximately 10% per week through day +180. Cohort A included patients with CML in first chronic phase, CLL, low-grade NHL, myeloma, and MDS with <5% marrow blasts. Those patients with aggressive malignancies (cohort B) initiated tacrolimus tapering, in the absence of GVHD, on day +35 by approximately 33% per week, to be stopped by day +56. Cohort B included intermediate- and high-grade NHL, HD, AML, ALL, CML beyond the first chronic phase, and refractory anemia with excess of blasts (RAEB).
GVHD Grading and Treatment
Diagnosis and clinical grading of acute and chronic GVHD were made based on established criteria [19, 20]. Treatment decisions were based on each attending physician’s assessment of the severity of acute GVHD and usually included initially 6-methyl-prednisolone or prednisone at 1-2 mg/kg/day, with tapering after 14 days. Extensive chronic GVHD was usually treated with prednisolone and tacrolimus. Cases of serious acute or chronic GVHD were retrospectively identified following the criteria recently defined by Flowers et al.[21]: (1) death related to GVHD or its treatment, (2) severe disability due to GVHD or its treatment, (3) 3 or more major infections (eg, sepsis, pneumonia, mold infections, central nervous system infections) within 1 year because of GVHD, (4) hospitalization for >60 days in a single year because of GVHD, or (5) suicide or hospitalization because of GVHD or its treatment.
Evaluation of Chimerism
Chimerism studies, using short-tandem repeat or fluorescent in situ hybridization analyses for sex-matched and sex-mismatched transplantations, respectively, were to be performed at 1, 2, 3, and 12 months posttransplantation in the blood CD3 compartment and bone marrow. Mixed chimerism was defined as the detection of donor T cells at between 1% and 95% of the total T-cell population; donor chimerism was defined as detection of donor T cells at >95% of the total T cells. Failure of engraftment was defined as the absence of detectable donor cells in the marrow and peripheral blood on day +56.
Donor Lymphocyte Infusions
On discontinuation of immunosuppression, donor lymphocyte infusions (DLIs) were considered for those patients without GVHD who presented with persistent disease and/or stable mixed chimerism. Patients without detectable donor engraftment were not offered DLI. If rapid disease progression occurred early posttransplantation, then the patient was considered a study treatment failure and offered alternative treatments failure at the discretion of the treating physician, with or without DLI off protocol.
The first DLI consisted of 1 × 106 unirradiated donor T cells/kg. In the event of no GVHD, persistent disease, and failure to either achieve full donor chimerism or to exhibit an increase in donor T-cell chimerism ≥20% after the first DLI, each patient could receive up to 4 DLIs at increasing (1/2 log) cell doses, administered more than 28 days apart (if PD) or 65 days apart (if SD). Patients who developed ≥ grade 2 GVHD after a DLI were excluded from receiving further DLI on this protocol.
Supportive Care
Posttransplantation growth factors were not given unless severe neutropenia (ANC <100) developed or persisted past day +27. Patients with active uncontrolled bacterial or fungal infections could receive G-CSF for neutropenia <500/μL.
Patients received prophylaxis for Pneumocystis carinii, Herpes, Candida, and cytomegalovirus (CMV) following common guidelines [22]. Specifically, oral fluconazole was administered from day 0 to day +75 at 400 mg/day for creatinine clearance (CrCl) >50 mL/min, at 200 mg/day for CrCl 11-50 mL/min, or 200 mg 3 times weekly for CrCl <11 mL/min. CMV monitoring, with preemptive treatment if necessary, was performed in cases of seropositive donor and/or recipient, using a DNA hybrid capture assay, commencing on day +14 and repeated weekly until day +100.
Routine antibacterial prophylaxis was not used unless neutropenia (ANC <500/μL) developed, in which case levofloxacin therapy was administered until neutropenia resolved. Neutropenic fevers were treated with standard antibiotics, avoiding aminoglycosides.
Statistical Analysis
The minimum target enrollment was established at 30 patients. A 2- or 3-stage stopping rule was instituted for excessive transplantation-related mortality (TRM) within the first 100 days. Fifteen patients were to be enrolled in the first stage of the trial. If 4 or more patients experienced TRM, then the trial would be stopped, concluding that early TRM exceeded 5%. If 3 or fewer patients experienced TRM, then 15 additional patients were to be enrolled.
The 95% confidence interval (CI) of the incidence of GVHD was estimated using the exact binomial distribution. Survival analyses used the Kaplan-Meier method [23]. Progression-free survival (PFS) was defined as the time from study entry to a documented relapse or progression, or death without relapse or progression. Overall survival (OS) was defined as the time from study entry to death from any cause. The statistical analyses were performed using the Number Cruncher Statistical System (2001, NCSS, Kaysville, UT).
Results
Patient Characteristics
A total of 32 patients with hematologic malignancies were prospectively enrolled in this study at the University of Colorado (n = 17), Christchurch Hospital (n = 12), and Auckland Hospital (n = 3) between 2001 and 2004 (Table 1). The median patient age was 57 years (range, 36-68 years). The patients had undergone extensive previous treatments (a median of 3 courses of previous therapy), including previous autologous transplantation in 16 patients. Two patients had previously untreated disease (MDS), 7 patients underwent transplantation with progressive disease (3 NHL, 2 MDS, 1 AML, 1 HD, 1 myeloma), and 23 patients had tumors either stable or in response to previous treatments.
Table 1. Patient Demographics (n = 32)
| Age, median (range) (years) | 57 (36-68) |
| Sex, no. (%) | |
| Male | 21(66) |
| Female | 11(34) |
| Indication of nonmyeloablative transplantation, no. (%) | |
| Age >50 years | 26(81) |
| Substantial comorbidities | 8(25) |
| Previous myeloablative transplant | 16(50) |
| Diagnosis, no. (%) | |
| Non-Hodgkin’s lymphoma | 12(37) |
| Follicular lymphoma | 7(22) |
| Transformed follicular lymphoma | 2(6) |
| Diffuse large-cell lymphoma | 1(3) |
| Mantle-cell lymphoma | 1(3) |
| NK lymphoma | 1(3) |
| Myeloma | 12(37) |
| Myelodysplastic syndrome | 5(16) |
| Acute myeloblastic leukemia, CR ≥2 | 2(6) |
| Hodgkin’s disease | 1(3) |
| Disease status at transplant, no.(%) | |
| CR 1 | 2(6) |
| CR ≥2 | 6(19) |
| Partial remission ≥2 | 5(16) |
| Plateau phase(MM) | 9(28) |
| Stable disease | 1(3) |
| Progressive disease | 7(22) |
| Untreated | 2(6) |
| Number of previous lines of treatment, median (range) | 3(1-7) |
| Donor, no. (%) | |
| 6/6 HLA-matched sibling | 31(97) |
| 6/6 HLA-matched son | 1(3) |
| Donor sex, no. (%) | |
| Male | 15(47) |
| Female | 17(53) |
| Graft, no. (%) | |
| Peripheral blood | 31(97) |
| Bone marrow | 1(3) |
| CMV serologic status, no. (%) | |
| Donor, recipient, or both seropositive | 27(84) |
| Donor and recipient seronegative | 5(16) |
Twenty-five patients with indolent malignancies were allocated to cohort A (long tacrolimus taper), and 7 patients with aggressive disease were enrolled in cohort B (short tacrolimus taper).
Survival and Outcome
At median follow-up of 19 months (range, 2-41 months), 20 patients (62.5%) were alive. Of these patients, 16 (50%) were free of progression, and 13 (40.6%) were in CR. Four patients were alive with PD post-NST. Median EFS was 23 months; median OS was not reached (Fig. 1).
Figure 1.
Overall survival (OS) and event-free survival (EFS) curves.
TRM occurred in 5 patients (15.6%) (Fig. 2). Three patients died from multiorgan failure related to GVHD (on days +105, +343, and +354), and 2 died from infectious complications probably related to GVHD treatment (on days +141 and +625). Six patients died from tumor progression. One additional patient died (on day +981) from aspiration pneumonia related to mediastinal radiotherapy for a second primary adenocarcinoma of the lung, while in CR of his original transformed NHL.
Figure 2.
Nonrelapse mortality and mortality from disease progression.
GVHD
Four patients had grade II acute GHVD, and 1 patient had grade IV acute GVHD. The incidence of grade II-IV acute GHVD was 15.6% and that of grade III-IV acute GVHD was 3%, involving the skin (n = 5), gut (n = 2), and liver (n = 1), and presenting at median day +71 (range, days +31-+84) (Fig. 3). Only 2 patients (6.25%) presented with acute GVHD (both grade II) while still receiving tacrolimus therapy. The incidence of grade II-IV acute GVHD was 12% in cohort A and 28% in cohort B 28% (P = not significant [NS]). One other patient had grade I GVHD of the skin.
Figure 3.
Cumulative incidence of acute GVHD.
Three patients experienced resolution of GVHD and are currently alive and free of disease. The other 3 patients died, 1 from acute GVHD-associated multiorgan failure (MOF), 1 from invasive pulmonary aspergillosis after steroid therapy, and 1 from PD after resolution of GVHD.
Extensive chronic GVHD was observed in 10 of 24 evaluable patients (41.6%), appearing spontaneously in 5 of these (20.8%) at median day +240 (range, day +151-+277), or elicited after PD by immunosuppression withdrawal (n = 4) or DLI (n = 1) (Fig. 4). It involved the skin in 7 patients, gut in 7, liver in 6, lungs in 1, mouth in 2, and eyes in 1. There was 1 additional case of limited GVHD of the mouth.
Figure 4.
Cumulative incidence of chronic GVHD.
Five of these patients experienced resolution of their GVHD and were tapered off immunosuppressants, whereas 1 patient was still receiving treatment on day +399. Five patients died, 1 from PD, 1 from overwhelming sepsis while on immunosuppression, 2 from GVHD-related MOF, and 1 from complications of treatment for a second primary tumor after resolution of his chronic GVHD (described earlier). The incidence of extensive chronic GVHD among evaluable patients was 41% in cohort A and 20% in cohort B (P = NS).
In 3 cases, the picture of chronic GVHD was nonfibrotic changes consistent with the recently described syndrome of “late-onset acute GVHD” [10]. One of these patients had involvement of the skin and gut starting spontaneously on day +220; 1 had GVHD of the skin, gut, and liver on day +220 that was elicited by immunosuppression withdrawal; and 1 had involvement of the skin and liver on day +323 after DLI.
Seven cases of “serious GVHD” (21.8%), as defined recently [18], were identified. Five of these patients died from complications of GVHD (n = 3) or its treatment (n = 2), 1 patient experienced disability and 1 patient had prolonged hospitalization caused by extensive chronic GVHD.
Tacrolimus-Related Toxicity
Other toxicities related to tacrolimus included renal failure, which was grade 1 in 1 patient, grade 2 in 3 patients, grade 3 in 4 patients, and grade 4 requiring transient hemodyalisis in 1 patient. Seven patients complained of mild to moderate headache, 2 patients complained of mild tremors, and 2 patients had grade 1 hemolysis. Two patients experienced acute pancreatitis that resolved; in 1 case it was attributed to tacrolimus, whereas in the other case the picture appeared weeks after tacrolimus discontinuation and appeared to be related to alcohol. One patient experienced grade 1 peripheral neuropathy.
Overall, 24 patients experienced some degree of nausea or emesis in the first few weeks of tacrolimus therapy. Nausea was grade 1 in 19 patients (with no vomiting in 14), grade 2 in 4 patients (with some vomiting in 3), and grade 3 with vomiting in 1 patient.
In addition, 3 patients experienced grade 3 hyperglycemia caused by steroids prescribed for GVHD. Two patients had steroid-induced mental status changes, grade 2 in one and grade 4 with severe confusion in the other.
Infectious Complications
Fourteen patients (44%) presented with at least 1 infectious episode. Two patients experienced fatal infections while receiving treatment for GVHD: mixed bacterial (methicillin-resistant Staphylococcus aureus) and Aspergillus pneumonia in 1 case and overwhelming sepsis caused by an unidentified microorganism in 1 case. In addition, the following infections were observed, which resolved: CMV colitis (n = 3), herpes zoster (n = 2), gastrointestinal herpes simplex virus (HSV) (n = 1), genital HSV (n = 1), bacterial otitis media (n = 2), hepatitis B reactivation (n = 1), and West Nile virus (n = 1). CMV viremia without end-organ disease was detected in 3 patients.
Chimerism Analyses
One patient, with previously untreated RAEB, experienced graft rejection. She died from PD on day +185 (Table 2). The remaining 31 patients had sustained allografts, with full donor chimerisms by 1 year post-NST in 80% of them.
Table 2. Chimerism Analyses
| 1 Month | 2 Months | 3 Months | 12 Months | |
|---|---|---|---|---|
| Median % (range) of donor cells | ||||
| T cells | 88(30-97.5) | 74(52-100) | 75(33-100) | 93(86-100) |
| Bone marrow | 95(14-100) | 96.5(11-100) | 95(19-100) | 98.5(97-100) |
| Chimerism | ||||
| Percentage of patients with mixed chimerism | 77% | 77% | 86% | 20% |
| Percentage of patients with donor chimerism | 23% | 23% | 14% | 80% |
Immunosuppression Withdrawal and Donor Lymphocyte Infusions
Thirteen patients underwent immunosuppression withdrawal for PD. Five patients subsequently developed extensive chronic GVHD; 3 of them (with transformed NHL, NK NHL, and RAEB, respectively) experienced a CR, whereas the other 2, both with myeloma, did not respond. Of the 8 patients who did not develop GVHD, there was 1 CR in a myeloma case, whereas none of the remaining 7 patients responded.
Six patients received 1 (n = 3), 3 (n = 1), or 4 (n = 2) doses of DLI with no preceding salvage chemotherapy. All 6 of these patients had full donor chimerism before DLI. One of them, who initially experienced a PR of his transformed NHL, subsequently developed severe GVHD and died from MOF. None of the other 5 patients receiving DLI (1 with follicular NHL, 2 with myeloma, and 2 with advanced MDS) responded.
One patient received a second NST from a different donor for progressive RAEB and is currently in CR 4 months after the second transplantation.
Discussion
Fludarabine/low-dose TBI has emerged as an important relatively nontoxic preparative regimen for allogeneic transplantation, suitable for older patients and those with relative contraindications to conventional allografting. In trials reported by the Seattle-based multicenter consortium, prevention of GVHD and graft rejection has relied on cyclosporin/MMF, an approach that represents a translation of canine preclinical studies.
Because the major morbidity and treatment mortality with NST is related to GVHD, improved GVHD prevention could further enhance the safety of this treatment. Furthermore, recent analyses suggest that acute GVHD, particularly early-onset GVHD, is associated with increased TRM [24] but not with improved disease control, for which chronic GVHD appears more important [25].
This pilot phase II trial was performed to provide preliminary data on the effect of substituting tacrolimus/MMF for cyclosporin/MMF in patients receiving a MSD NST after fludarabine/TBI. Only 2 patients experienced grade 4 toxicities attributable to tacrolimus, both of which reverted: renal failure and acute pancreatitis, the latter a rare complication of this drug [26]. Most patients experienced only mild nausea, which allowed good compliance with oral therapy and achievement of therapeutic tacrolimus levels and ultimately resulted in outpatient transplantation for most patients. The incidence of CMV reactivation (16%) and fungal infection (3%) observed in this trial are consistent with previously reported data in this setting [27, 28].
Our preliminary observations suggest encouraging rates of acute and chronic GVHD control and low TRM resulting from this approach. We observed a 15.6% rate of grade II-IV acute GVHD starting on median day +71. These observations may compare favorably with previous results using cyclosporine/MMF reported by McSweeney et al. [7], who reported a 47% incidence of acute grade II-IV GVHD, starting at median day +40. The control of acute GVHD provided by tacrolimus/MMF in our trial appears encouraging, with very few patients developing acute GVHD while receiving full doses of tacrolimus. This resulted in elimination of early deaths within the first 100 days of transplantation. The single early death on day +105 occurred in a patient in the high-risk cohort for whom GVHD was induced to treat persistent disease. The ability to largely eliminate early acute GVHD with tacrolimus/MMF after fludarabine/low-dose TBI has potential implications for nonmyeloablative allografting of nonmalignant disease, in which GVHD is especially counterproductive.
There was a 42% incidence of extensive chronic GVHD, half of which was purposefully elicited as treatment for PD. In all but 1 case, chronic GVHD presented after discontinuation of tacrolimus. Three of these patients presented with nonfibrotic changes in skin, liver, and/or gut, compatible with the recently described picture of “late-onset acute GVHD” [10]. Whether extended GVHD prophylaxis with tacrolimus can reduce the later onset of GVHD seen during or after tacrolimus tapering is an important question to answer. Previous retrospective data from cyclosporine studies [29] may not be predictive for this question. While designing this study, we decided to adjust the length of immunosuppression to the estimated individual relapse risk, establishing a shorter (through day +56) tacrolimus taper for patients with rapidly proliferating disease and a longer (through day +180) tacrolimus taper for those with indolent disease. The small size of the 2 cohorts does not allow for meaningful comparisons of the respective incidences of acute and chronic GVHD. It is noteworthy that the incidence of GVHD in both cohorts appears to compare favorably with previous results using cyclosporine/MMF [7]. Although our study was not designed to formally test a risk-adjusted strategy of length of immunosuppression, this concept may merit further evaluation.
Our early experience with this immunosuppressive regimen needs to be confirmed in larger trials. We recently reported excellent rates of early GVHD protection with this immunosuppressive combination after MSD [30] myeloablative SCT, suggesting that this combination may have broader application for MSD transplantations. In conclusion, our pilot trial of tacrolimus/MMF in patients receiving NST from an MSD shows that this treatment is safe, permits outpatient transplantations in most cases, and is associated with encouraging rates of acute and chronic GVHD control and excellent early survival.
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- Risks and outcomes of invasive fungal infections in recipients of allogeneic hematopoietic stem cell transplants after nonmyeloablative conditioning . Blood . 2003;102:827–833
- Extending postgrafting cyclosporine does not decrease the risk of graft-versus-host disease after nonmyeloablative hematopoietic cell transplantation . [abstract] Blood . 2003;102a
- Favorable early transplant outcomes using tacrolimus and mycophenolate mofetil for GVHD prevention after matched sibling allografting . [abstract] Blood . 2003;102:714a
PII: S1083-8791(05)00682-8
doi:10.1016/j.bbmt.2005.10.012
© 2006 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Volume 12, Issue 2 , Pages 217-225, February 2006
