Background
Allogeneic hematopoietic stem cell transplantation (allo‐HCT) is associated with improved outcomes for people with various hematologic diseases; however, the morbidity and mortality ...resulting from acute and subsequently chronic graft‐versus‐host disease (GVHD) pose a serious challenge to wider applicability of allo‐HCT. Intravenous methotrexate in combination with a calcineurin inhibitor, cyclosporine or tacrolimus, is a widely used regimen for the prophylaxis of acute GVHD, but the administration of methotrexate is associated with a number of adverse events. Mycophenolate mofetil, in combination with a calcineurin inhibitor, has been used extensively in people undergoing allo‐HCT. Conflicting results regarding various clinical outcomes following allo‐HCT have been observed when comparing mycophenolate mofetil‐based regimens against methotrexate‐based regimens for acute GVHD prophylaxis.
Objectives
Primary objective: to assess the effect of mycophenolate mofetil versus methotrexate for prevention of acute GVHD in people undergoing allo‐HCT.
Secondary objectives: to evaluate the effect of mycophenolate mofetil versus methotrexate for overall survival, prevention of chronic GVHD, incidence of relapse, treatment‐related harms, nonrelapse mortality, and quality of life.
Search methods
We searched Cochrane Central Register of Controlled Trials (CENTRAL) and MEDLINE from inception to March 2014. We handsearched conference s from the last two meetings (2011 and 2012) of relevant societies in the field. We searched ClinicalTrials.gov, Novartis clinical trials database (www.novctrd.com), Roche clinical trial protocol registry (www.roche‐trials.com), Australian New Zealand Clinical Trials Registry (ANZCTR), and the metaRegister of Controlled Trials for ongoing trials.
Selection criteria
Two review authors independently reviewed all titles/s and selected full‐text articles for inclusion. We included all references that reported results of randomized controlled trials (RCTs) of mycophenolate mofetil versus methotrexate for the prophylaxis of GVHD among people undergoing allo‐HCT in this review.
Data collection and analysis
Two review authors independently extracted data on outcomes from all studies and compared prior to data entry and analysis. We expressed results as risk ratios (RR) and 95% confidence intervals (CI) for dichotomous outcomes and hazard ratios (HR) and 95% CIs for time‐to‐event outcomes. We pooled the individual study effects using the random‐effects model. Estimates lower than one indicate that mycophenolate mofetil was favored over methotrexate.
Main results
We included three trials enrolling 177 participants (174 participants analyzed). All participants in the trials by Keihl et al. and Bolwell et al. received cyclosporine while all participants enrolled in the trial by Perkins et al. received tacrolimus. However, the results did not differ by the type of calcineurin inhibitor employed (cyclosporine versus tacrolimus). There was no evidence for a difference between mycophenolate mofetil versus methotrexate for the outcomes of incidence of acute GVHD (RR 1.25; 95% CI 0.75 to 2.09; P value = 0.39, very low quality evidence), overall survival (HR 0.73; 95% CI 0.45 to 1.17; P value = 0.19, low‐quality evidence), median days to neutrophil engraftment (HR 0.77; 95% CI 0.51 to 1.17; P value = 0.23, low‐quality evidence), incidence of relapse (RR 0.84; 95% CI 0.52 to 1.38; P value = 0.50, low‐quality evidence), non‐relapse mortality (RR 1.21; 95% CI 0.62 to 2.36; P value = 0.57, low‐quality evidence), and incidence of chronic GVHD (RR 0.92; 95% CI 0.65 to 1.30; P value = 0.62, low‐quality evidence). There was low‐quality evidence that mycophenolate mofetil compared with methotrexate improved platelet engraftment period (HR 0.87; 95% CI 0.81 to 0.93; P value < 0.0001, low‐quality evidence). There was low‐quality evidence that mycophenolate mofetil compared with methotrexate resulted in decreased incidence of severe mucositis (RR 0.48; 95% CI 0.32 to 0.73; P value = 0.0006, low‐quality evidence), use of parenteral nutrition (RR 0.48; 95% CI 0.26 to 0.91; P value = 0.02, low‐quality evidence), and medication for pain control (RR 0.76; 95% CI 0.63 to 0.91; P value = 0.002, low‐quality evidence). Overall heterogeneity was not detected in the analysis except for the outcome of neutrophil engraftment. None of the included studies reported any outcomes related to quality of life. Overall quality of evidence was low.
Authors' conclusions
The use of mycophenolate mofetil compared with methotrexate for primary prevention of GVHD seems to be associated with a more favorable toxicity profile, without an apparent compromise on disease relapse, transplant‐associated mortality, or overall survival. The effects on incidence of GVHD between people receiving mycophenolate mofetil compared with people receiving methotrexate were uncertain. There is a need for additional high‐quality RCTs to determine the optimal GVHD prevention strategy. Future studies should take into account a comprehensive view of clinical benefit, including measures of morbidity, symptom burden, and healthcare resource utilization associated with interventions.
Successful treatment with tacrolimus to prevent graft versus host disease (GVHD) and minimize tacrolimus-related toxicities among allogeneic hematopoietic cell transplantation (alloHCT) recipients is ...contingent upon quickly achieving and maintaining concentrations within a narrow therapeutic range. The primary objective was to investigate associations between
or
genotype and the proportion of patients that attained an initial tacrolimus goal concentration following initiation of intravenous (iv.) and conversion to oral administration.
We retrospectively evaluated 86 patients who underwent HLA-matched (8/8) related donor alloHCT and were prescribed a tacrolimus-based regimen for GVHD prophylaxis.
The findings of the present study suggests that
genotype may impact attainment of initial therapeutic tacrolimus concentrations with oral administration in alloHCT recipients.
To determine the maximum tolerated dose (MTD) of topotecan in combination with ifosfamide, mesna, and etoposide (TIME), followed by autologous hematopoietic cell transplant (HCT), in patients with ...chemotherapy-refractory malignancies.
Patients were treated with (in mg/m(2)/d) ifosfamide 3,333, mesna 3,333, and topotecan 3.3 to 28.3 during days -8 through -6 and etoposide 500 (days -5 through -3) followed by HCT on day 0. Once MTD was defined, we expanded this dosing cohort to include patients with high-risk lymphoma due to activity seen during dose escalation. Topotecan pharmacokinetic analyses were carried out, and topoisomerase I levels and activity were measured.
The topotecan MTD in this regimen was 64 mg/m(2) (21.3 mg/m(2)/d). Mucositis was dose limiting and correlated with topotecan dose level and area under the curve (AUC). Dose level was also correlated with length of hospitalization, number of days of parenteral nutrition, and neutrophil and platelet engraftment. Topotecan AUC was significantly correlated with time to platelet recovery. The baseline peripheral blood mononuclear cell topoisomerase I level was found to be a significant positive predictor for overall and progression-free survival. Topotecan AUC was positively correlated with dose level, with a trend toward decreasing clearance with increasing dose.
Topotecan can be a useful drug in the high-dose setting given its activity in some malignancies when given in standard dose. Pharmacokinetic monitoring may be a valuable tool for optimizing the use of topotecan and to avoid toxicity seen with high-systemic exposures. Baseline topoisomerase I levels may have an important role in predicting topotecan efficacy.
Systemic exposure to high-dose busulfan has been correlated with efficacy and toxicity after hematopoietic cell transplantation for malignancy. We used the area under the concentration-time curve ...(AUC) to prospectively determine the maximally tolerated systemic exposure to i.v. busulfan when given once daily after fludarabine administered at 40 mg/m2 for 4 days. Three target AUC levels were planned: 6,000, 7,500, and 9,000 μM-min. Included were patients 16 to 65 years old, with a hematologic malignancy, an HLA A, B, or C, DRB1 8/8 or 7/8 matched donor, Karnofsky performance status ≥70%, and adequate organ function. For level 1 patients, i.v. busulfan doses 1 and 2 were 170 mg/m2 /day, then doses 3 and 4 were adjusted based on first-dose pharmacokinetic modeling to achieve an average daily AUC of 6,000 μM-min. Doses 1 and 2 for the subsequent cohorts were based on the level 1 data: 180 mg/m2 /day for AUC 7,500 μM-min (level 2) and 220 mg/m2 /day for AUC 9,000 μM-min (level 3), with pharmacokinetic targeting for doses 3 and 4. Pharmacokinetic analysis after the last dose showed that 88% of the patients had been exposed to a mean AUC within 10% of the target. Forty patients were treated at level 1, 29 patients at level 2, and three patients at level 3. DLT was veno-occlusive disease of the liver, which occurred in none of 40 patients (0%) at level 1, two of 29 patients (7%) at level 2, and three of three patients (100%) at level 3. Dermatitis ( P < .01) and pulmonary toxicity ( P = .01) were also increased at higher AUC levels. Level 2 (7,500 μM-min × 4 days) was the maximally tolerated AUC. Within the confines of the trial’s small sample size, there was no suggestion that escalating busulfan AUC from 6,000 to 7,500 μM-min × 4 days increased nonrelapse mortality. Assessment of the higher busulfan AUC on relapse prevention requires trials in patients with a homogeneous risk of relapse.
The present study evaluates the clinical significance of detection of cytokeratin 19 (K19) in the bone marrow of patients with breast cancer undergoing high-dose chemotherapy (HDCT) and autologous ...bone marrow transplantation (ABMT).
We studied retrospectively cryopreserved bone marrow aspirates from 83 patients with high-risk stage II, III, and IV breast cancer obtained before bone marrow harvest but after induction chemotherapy. All samples were histologically negative for metastases. Polymerase chain reaction (PCR) for K19 was performed according to methods described previously and results were correlated with the probability of relapse following HDCT and ABMT.
The incidence of occult metastases as defined by PCR for K19 message was 52% for 19 stage II, 57% for 14 stage III, and 82% for 50 stage IV patients (two-tailed P = .0075, chi 2 test). The probability of relapse at 3 years after ABMT was 32% and 94% for K19-positive stage II/III and stage IV patients, respectively, versus 10% and 14% for K19-negative stage II/III and stage IV patients, respectively. The difference was significant for stage IV patients (two-tailed P = .0002).
It has been shown that PCR is a highly sensitive method to detect K19 message in the bone marrow. The incidence of K19 positivity in bone marrow increases significantly with advancing stage. In patients with breast cancer, especially metastatic breast cancer, undergoing HDCT and ABMT, the presence of K19 is associated with a poor prognosis.
A phase I dose-escalation study of ifosfamide, carboplatin, and etoposide (ICE) with autologous stem-cell rescue (ASCR) was conducted to determine the maximum-tolerated dose (MTD) of ICE given over 6 ...days.
One hundred fifty-four patients with a variety of poor-prognosis malignancies received escalating doses of ifosfamide 6,000 to 24,000 mg/m2, carboplatin 1,200 to 2,100 mg/m2, and etoposide 1,800 to 3,000 mg/m2 divided over 6 days. Mesna was administered in a dose equal to ifosfamide. ASCR was performed 48 hours after the completion of ICE. The source of stem cells was bone marrow (BM) in patients without BM micrometastases and peripheral-blood stem cells (PBSC) in patients with BM micrometastases. Patients were evaluated for hematologic and nonhematologic toxicities, as well as response to therapy.
The MTD of the ICE regimen is 20,100 mg/m2 of ifosfamide, 1,800 mg/m2 of carboplatin, and 3,000 mg/m2 of etoposide. The dose-limiting toxicities of ICE were CNS toxicity and acute renal failure. Additionally, reversible elevations of serum creatinine levels were noted in 29% of patients treated at the upper dose levels. Forty-six patients were treated at the MTD. Severe, reversible mucositis and enteritis were the major nonhematologic toxicities seen at the MTD (78% and 33%, respectively). The overall mortality rate was 8% for all dose levels (4% at the MTD). At the MTD, the median times to an absolute neutrophil count > or = 0.5 x 10(9)/L, to a platelet count > or = 20 x 10(9)/L, and to discharge were 18, 22, and 24 days, respectively. The overall response rate was 40% for 77 patients with assessable disease at the time of treatment.
ICE is well tolerated, with acceptable hematopoietic side effects and predictable organ toxicity.