Modified Dosing of Pegaspargase Proposed for ALL Induction
In the treatment of adults with newly diagnosed acute lymphoblastic leukemia (ALL), a pharmacokinetic-based intravenous dosing of pegaspargase, rationally synchronized with other chemotherapy drugs in a pediatric-inspired regimen, provides a safer induction with no detriment to clinical outcomes, compared with standard dosing.
The results of the multicenter study were reported by Dan Douer, MD, of Memorial Sloan-Kettering Cancer Center, New York, at the ASH annual meeting.
“Prolonged asparaginase (ASP) use is standard in all pediatric ALL regimens. In adults, ASP is either not used or is given for much shorter duration. Recently, several adult ALL protocols adopted pediatric regimens, with long duration of ASP, with better outcomes than historically reported. However, the optimal implementation of pediatric regimens to adults, especially ASP dosing, has not been studied, considering its potentially higher toxicity,” Douer noted.
He and his colleagues adopted the augmented Berlin-Frankfurt-Munster pediatric protocol, replacing the native E coli ASP with 6 doses of long-acting pegaspargase (PEG-ASP). While pediatric and most pediatric-inspired adult protocols use 2500 IU/m2 PEG-ASP at 2-week intervals, the researchers reduced the dose to 2000 IU/m2 at intervals no shorter than 4 weeks.
They also synchronized the PEG-ASP doses with the timing of myelosuppressive drugs to avoid “coinciding toxicities,” he said. In addition, they replaced the escalated methotrexate dosing plus E coli ASP with 4 fixed high doses of methotrexate, timing PEG-ASP to avoid its overlapping long enzymatic activity with methotrexate activity. Hydrocortisone premedication and steroids were administered for 7 to 14 days after each dose.
Outcomes for the 51 patients included a 96% complete response rate (98% at 4 weeks), 7-year overall survival of 51%, and disease-free survival of 58%. Median days to absolute neutrophil count >500/dL as well as platelets >50,000/dL were 17, and 83% of patients achieved these landmarks by day 21.
Fifty percent of patients received all 6 PEG-ASP doses. All toxicities were manageable and reversible, only 19% discontinued treatment due to toxicity, and there were no deaths at 30 days.
“Our study implies that the standard PEG-ASP adult dose can be 2000 IU/m2, which is lower than the FDA-approved dose, at intervals no less than 4 weeks, without impairing overall outcomes,” Douer said. “This is safer induction. Low blood counts do not coincide with ASP toxicity.”
Douer D, Aldoss I, Lunning MA, et al. Pharmacokinetics-based modification of intravenous pegylated asparaginase dosing in the context of “pediatric-inspired” protocol in adults with newly diagnosed acute lymphoblastic leukemia (ALL). Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 1495.
Eliminating Chemotherapy in Acute Promyelocytic Leukemia
At the ASH plenary session, investigators showed that acute promyelocytic leukemia (APL), traditionally one of the deadliest hematologic malignancies, can be treated without chemotherapy. Outcomes in the APL0406 study were just as good with a combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), compounds that have long been used in traditional Chinese medicine. The 2-year event-free survival was 97% in the ATRA/ATO arm versus 86.7% in the ATRA/chemotherapy arm, while overall survival was 98.7% and 91.1%, respectively.
The phase 3 trial, conducted in Italy and Germany, involved 162 patients with newly diagnosed APL. Patients received the noncytotoxic regimen of ATO plus ATRA daily until a complete response was achieved, then ATO for 5 days a week for 4 weeks on, 4 weeks off (4 courses), and ATRA 2 weeks on, 2 weeks off (7 courses). Patients in the control arm received standard ATRA plus idarubicin in- duction, followed by 3 cycles of an- thracycline-based chemotherapy plus ATRA consolidation, followed by ATRA and low-dose chemotherapy for maintenance.
Lo-Coco F, Avvisati G, Orlando SM, et al. ATRA and arsenic trioxide (ATO) versus ATRA and idarubicin (AIDA) for newly diagnosed, non high-risk acute promyelocytic leukemia (APL): results of the phase III prospective, randomized, intergroup APL0406 study by the Italian-German Cooperative Groups Gimema-SAL-AMLSG. Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 6.
Rivaroxaban Comparable to Enoxaparin for Anticoagulation
A pooled analysis of the EIN-STEIN-DVT and EINSTEIN-PE studies showed rivaroxaban to be as effective in preventing recurrences of venous thromboembolism as enoxaparin followed by a vitamin-K antagonist, with perhaps less risk for bleeding. Subgroup analyses found the drug to be safe and effective in specific high-risk populations, such as elderly fragile patients and patients with cancer or large clots. The studies had noninferiority designs and compared oral rivaroxaban (15 mg twice daily for 3 weeks, then 20 mg once daily for up to 12 months) with enoxaparin for 5 to 10 days followed by an oral vitamin-K antagonist.
Among the 8282 patients enrolled in the 2 trials, thromboembolism recurred in 2.1% receiving rivaroxaban and 2.3% receiving enoxaparin/vitamin-K antagonist; major or nonmajor clinically relevant bleeding was observed in 9.4% and 10.0%, and major bleeding in 1.0% and 1.7%, respectively. In patients with cancer, recurrence was observed in 2.6% and 4.0%, and major bleeding in 2.6% and 4.1%, respectively.
Buller HR. Oral rivaroxaban for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN DVT and EINSTEIN PE studies. Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 20.
Meta-Analysis Examines Adverse Effects of Rituximab Maintenance in Lymphoma
Rituximab has improved outcomes of patients with follicular lymphoma and mantle cell lymphoma. Treatment schedules have varied between a single infusion given every 2 or 3 months to 4 weekly infusions every 6 months, all given for a total of 2 years. This systematic review and meta-analysis analyzed prospective clinical trials of maintenance therapy to determine rates of grade 3 and 4 toxicities.
The study found that maintenance rituximab given every 6 months as 4 weekly infusions for 2 years was associated with fewer grade 3 or 4 toxicities compared with a single infusion every 2 months: 10% versus 28% (P = .035). The study was not able to compare the 3-month infusion schedule to other schedules, owing to the limited number of studies. Toxicities in patients receiving treatment in the frontline setting appeared lower than those treated for relapsed disease, but the difference was not statistically significant. Toxicities were lower when rituximab was given alone compared with chemotherapy in the induction program: 12% versus 35% (P = .031).
Nabhan C, Villines MA, Chiu B C-H, et al. Meta analysis of grade 3 and/or 4 toxicities in follicular (FL) and mantle cell (MCL) non-Hodgkin lymphoma (NHL) patients receiving maintenance rituximab (MR): impact of schedule, histology, and induction regimen. Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 3654.
Cyclophosphamide Reduces Risk of GVHD After Transplant
Investigators from the MD Anderson Cancer Center advised against using pulse doses of cyclophosphamide on days +3 and +4 after hematopoietic stem cell transplant as sole prophylaxis for graft-versus-host disease (GVHD). They previously reported that this practice was associated with lower rates of chronic GVHD than were traditional prophylaxis regimens in bone marrow transplant recipients undergoing ablative conditioning regimens. Using a matched-control design, the researchers assessed 37 patients to determine whether posttransplant cyclophosphamide would also be effective after a reduced-intensity conditioning regimen, compared with tacrolimus and minidose methotrexate (conventional regimen).
The incidence of acute GVHD grades 2 to 4 was 51% with cyclophosphamide as sole prophylaxis compared with 19% with the conventional regimen, for a hazard ratio of 3.2 (P = .009) favoring tacrolimus/methotrexate. Grades 3 and 4 acute GVHD occurred in 14% for cyclophosphamide and 0% for the conventional regimen (P = .02), but no significant differences were seen in chronic GVHD, 14% and 21%, respectively (P = .8). The experimental regimen was also associated with a trend toward higher nonrelapse mortality.
Alousi AM, Saliba RN, Chen J, et al. A matched controlled analysis of post-transplant cyclophosphamide (CY) versus tacrolimus and mini-dose methotrexate in matched sibling and unrelated donor transplant recipients receiving reduced-intensity conditioning: post-transplant CY is associated with higher rates of acute Gvhd. Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 4200.
VRE Bacteremia in AML Signals Worse Survival
Bacteremia caused by vancomycin resistant enterococcus (VRE) is an independent risk factor for worse overall survival (OS) in patients undergoing induction chemotherapy for acute myeloid leukemia (AML), Cleveland Clinic investigators reported at ASH.
“Patients with AML are more susceptible to VRE than other hospitalized patients, but the impact of VRE bacteremia on outcomes after induction chemotherapy has not been established,” said Moshe Ornstein, MD, MA, of the Taussig Cancer Institute, Cleveland, Ohio.
The retrospective study of 350 patients with AML who received cytarabine-based induction chemotherapy between 2000 and 2008 determined VRE rates and their effect on complete remission and OS. The overall complete remission rate was 73%, including 70% in patients who had VRE and 73% in patients who did not. At a median follow-up of 72 months, the unadjusted median OS was 12.8 months overall, including 7.1 months for patients who developed VRE and 13.1 months for the others, a numerical but not statistically significant difference (P = .13).
In a multivariable analysis that adjusted for important factors including VRE infection as a time-varying covariate, patients who had VRE infections during induction had significantly worse OS than did patients without infection. VRE infection was associated with a 77% increase in mortality (P = .022), Ornstein reported. “Consideration should therefore be given to escalating VRE-appropriate antibiotics in these patients sooner and in the postremission setting,” he said.
Ornstein M, Mukherjee S, King MK, et al. Vancomycin-resistant enterococcus (VRE) bacteremia during acute myeloid leukemia (AML) induction therapy is an independent predictor of poor outcome. Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 1487.
Should NCI Toxicity Criteria in AML Be Revisited?
The common toxicity criteria established by the National Cancer Institute (NCI) is not necessarily an accurate treatment guide for acute myeloid leukemia (AML), according to a study from the University of Washington and the Fred Hutchinson Cancer Research Center, Seattle, presented by Joshua R. Veatch, MD, PhD, at the ASH annual meeting.
“Our data suggest that if the principal purpose of toxicity grading is to guide subsequent dose reduction to prevent death, the NCI toxicity criteria should be revisited,” Veatch proposed.
NCI grade 3 toxicity leads to changes in disease management, but it is not known how these toxicity criteria relate to treatment-associated mortality. To provide a more empiric basis for decisions, the researchers analyzed the relationship between mortality and grades of NCI toxicity for bilirubin, creatinine, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) after chemotherapy for AML.
They examined 714 courses of chemotherapy in 509 patients with newly diagnosed or relapsed/refractory AML. At 28 days, the mortality rate was 5.6% for treatments and 7.7% for patients.
Maximum laboratory values for creatinine were strongly related to mortality. Grade 0 had a 1.0% mortality rate, and each increasing grade was associated with a significant increase over the preceding toxicity level: 5.1% for grade 1, 23% for grade 2, and 50% for grade 3 or 4. Relative to grade 0, bilirubin was significantly associated with mortality at grade 2 (11%) and grade 3 or 4 (17%), as was AST at grade 2 (10.2%) and grade 3 or 4 (15.6%). ALT, on the other hand, was not correlated with mortality, even at grade 3 or 4 (9.8% vs 5.6% at grade 0), Veatch reported.
“Creatinine was more highly correlated to mortality than liver function tests, and ALT did not significantly correlate,” he noted. “These correlations certainly do not imply causation, but suggest the common toxicity criteria be revised.”
Veatch JR, Sandhu RK, Shannon-Dorcy K, et al. NCI common toxicity criteria and mortality after chemotherapy for acute myeloid leukemia (AML). Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 1479.