Folinic Acid a Good Adjunct to Methotrexate for GVHD Prophylaxis

TOP - May 2015, Vol 8, No 2 - Conference Correspondent

San Diego, CA—At the American Society for Blood and Marrow Transplantation’s (ASBMT) 2015 BMT Tandem Meetings, 4 studies were named the “Best Pharmacy Abstracts,” and are summarized here for our readers.

Investigators from the Mayo Clinic described their guidelines for using folinic acid rescue following methotrexate as prophylaxis for graft-versus-host disease (GVHD). Folinic acid may reduce the occurrence of mucositis and improve the probability of day +11 methotrexate dosing.

“In an effort to reduce the incidence of mucositis to improve the likelihood of administering day +11 methotrexate, and to provide a consistent treatment guideline, the Hemato­poietic Cell Transplant (HCT) program director enlisted the help of the HCT pharmacist to review the data and recommend guidelines,” explained Jeffrey Betcher, BSPharm, Clinical Pharmacy Specialist and Cancer Center Pharmacy Supervisor, Mayo Clinic, Phoenix, AZ.

The investigators reviewed the literature for post-methotrexate folinic acid use and developed recommendations for dosing, time of initiation, and schedule and number of doses. The recommendations call for giving folinic acid 10 mg/m2 intravenously every 6 hours for 3 doses, starting 12 hours after each methotrexate dose (days +1, +3, +6, and +11). Patients also received myeloablative conditioning (MAC) regimens and tacrolimus.

The study compared data from 27 patients treated in 2013 according to the guidelines with data from 31 patients receiving methotrexate regimens prior to the folinic acid guidelines, and observed a number of improved outcomes after the guidelines were initiated. Patients treated according to the guidelines were: (1) more likely to receive full-dose day +11 methotrexate, compared with controls (85.2% vs 48.4%; P = .0025), which has been reported to be important in reducing the risk of acute GVHD, and (2) less likely to require patient-controlled analgesia for mucositis (63.0% vs 87.1%; P = .03).

There were no significant differences in rates of total parenteral nutrition, development of grade II-IV acute GVHD at day 100 or chronic GVHD, cumulative incidence of relapse, transplant-related mortality at 1 year, and overall survival at 1 year, with a median follow-up of 465 days for the folinic acid group and 670 days for the controls.

“[These] end points trended in a favorable direction, but did not reach statistical significance,” discussed Mr Betcher.

“The development and utilization of the program [guidelines] improved consistency of care, improved staff satisfaction, and decreased patient discomfort,” he said. “HCT pharmacists play an important role in the review of literature and development of program guidelines.”

Antithymocyte Globulin Increases Risk of Infection

Mixed results have been reported for the incorporation of antithymocyte globulin (ATG) into allogeneic stem-cell transplant conditioning regimens as a means of preventing acute GVHD. A study from the University of North Carolina Hospitals and Clinics, Chapel Hill evaluated the impact of ATG on infection, occurrence of GVHD, incidence of relapse, and mortality rates in adult patients.

The investigators retrospectively reviewed charts of 250 patients treated between 2006 and 2013. The cohort included 125 unrelated/mismatched donor recipients who received ATG and 125 matched related donors who did not.

In the analysis, ATG use actually increased the rate of infection, with a greater impact on patients receiving reduced-intensity conditioning (RIC), compared with MAC, reported lead author Katie Kaminski, PharmD.

Patients receiving ATG had a median of 3 infections, versus 2 for those not receiving ATG (P = .0003). This increase was more pronounced in the RIC group, which had a median of 3 infections if they received ATG, versus 1 without ATG. Less difference was observed among patients receiving MAC.

In both the RIC and MAC groups, the use of ATG was associated with increased numbers of infections with cytomegalovirus (112 vs 61), human herpesvirus 6 (47 vs 13), and herpes simplex virus (32 vs 8). The relative increase in these infections was much greater among RIC than MAC recipients.

The ATG and non-ATG groups had similar rates of severe acute GVHD through day 180, indicating a potential protective effect of ATG in unrelated/mismatched transplants. Rates of death and relapse were not different between ATG groups, nor was mean time to relapse. At 180 days, survival rates were 71.4% for patients receiving ATG and 83.2% for the non-ATG group (P = .0426).

“Although relapse rates were similar between groups, the 180 day mortality for [patients receiving] ATG was significantly greater than [without] ATG, suggesting that infectious complications may impact mortality associated with ATG,” Dr Kaminski said.

Support Shown for CBV Regimen Over Busulfan/Cyclophosphamide

Two preparative regimens for patients with lymphoma receiving autologous hematopoietic stem-cell transplantations (HSCTs) were compared by pharmacists at Wake Forest University Baptist Medical Center, Winston-Salem, NC, who reported trends favoring the use of carmustine/etoposide/cyclophosphamide (CBV) in older patients.

“Current literature supports the use of HSCT over salvage chemotherapy for patients with lymphoma who have recurrent disease or are at high risk of relapse,” noted the study’s lead author, LeAnne Kennedy, PharmD. “Few studies have been published directly comparing preparative regimens, thus, most institutions select regimens based on associated toxicities.”

At their institution, she said, busulfan/cyclophosphamide (Bu-Cy) was historically used as the preparative regimen for patients with lymphoma, but clinicians transitioned toward use of the “theoretically less toxic” CBV regimen in older patients in 2009. This study retrospectively compared CBV to Bu-Cy in terms of tolerability and efficacy in patients aged ≥60 years receiving autologous HSCT.

Of 75 patients, 23 received Bu-Cy and 52 received CBV. Patients who received Bu-Cy experienced an average of 1.6 severe or life-threatening toxicities per person, compared with 1.7 in patients who received CBV, Dr Kennedy and colleagues reported.

At 60 days, there was no difference in progression-free survival (86% with Bu-Cy vs 95% with CBV), or overall survival (96% with Bu-Cy vs 94% with CBV). A trend was observed, however, toward increased progression-free survival with CBV at 3 years (31% with Bu-Cy vs 68% with CBV; P = .44), and this trend was supported by the significantly increased time to relapse (22.7 months with Bu-Cy vs 61.2 months with CBV; P = .0498).

“This review demonstrates no difference in terms of tolerability or efficacy between Bu-Cy and CBV; however, there is a trend towards improved relapse-free survival with CBV,” Dr Kennedy indicated. “Future studies are needed to compare other utilized preparative regimens.”

Stick with Standard-Dose G-CSF After Autotransplant

Different doses of granulocyte colony-stimulating factors (G-CSFs) have not been directly compared in terms of their effects on engraftment in autologous HSCT, thus, the optimal G-CSF dose remains unknown. Investigators at Northwestern Memorial Hospital, Chicago, IL, developed a clinical initiative of dose-escalated G-CSF to determine whether the duration of neutropenia can be reduced by using a higher G-CSF dose.

At the San Diego meeting, Steven Trifilio, BSPharm, presented the results of an observational study comparing standard-dose to dose-escalated G-CSF for the resolution of neutropenia following autologous HSCT. The study included patients who had received a single daily dose of filgrastim (5 mcg/kg) and others treated with twice-daily doses of filgrastim (total daily dose 10 mcg/kg). All patients started G-CSF 5 days after stem-cell infusion.

The analysis included 172 single-dose and 162 twice-daily dose recipients. The groups were balanced except for more CD34-positive stem cells infused in the twice-daily cohort.

Mr Trifilio reported that time to engraftment was 12 days with the single dose and 11 days with twice-daily dosing, while length of stay was 16 days per arm. In-hospital deaths occurred in 3 and 4 patients, respectively.

“In this study, a single 5 mcg/kg G-CSF dose was as effective as twice-daily 5 mcg/kg G-CSF doses for accelerating stem cell engraftment,” he said.—CH

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Last modified: May 22, 2015