Thomas Pabst

BACKGROUND: A complete remission is essential for prolonging survival in patients with acute myeloid leukemia (AML). Daunorubicin is a cornerstone of the induction regimen, but the optimal dose is unknown. In older patients, it is usual to give daunorubicin at a dose of 45 to 50 mg per square meter of body-surface area. METHODS: Patients in whom AML or high-risk refractory anemia had been newly diagnosed and who were 60 to 83 years of age (median, 67) were randomly assigned to receive cytarabine, at a dose of 200 mg per square meter by continuous infusion for 7 days, plus daunorubicin for 3 days, either at the conventional dose of 45 mg per square meter (411 patients) or at an escalated dose of 90 mg per square meter (402 patients); this treatment was followed by a second cycle of cytarabine at a dose of 1000 mg per square meter every 12 hours [DOSAGE ERROR CORRECTED] for 6 days. The primary end point was event-free survival. RESULTS: The complete remission rates were 64% in the group that received the escalated dose of daunorubicin and 54% in the group that received the conventional dose (P=0.002); the rates of remission after the first cycle of induction treatment were 52% and 35%, respectively (P<0.001). There was no significant difference between the two groups in the incidence of hematologic toxic effects, 30-day mortality (11% and 12% in the two groups, respectively), or the incidence of moderate, severe, or life-threatening adverse events (P=0.08). Survival end points in the two groups did not differ significantly overall, but patients in the escalated-treatment group who were 60 to 65 years of age, as compared with the patients in the same age group who received the conventional dose, had higher rates of complete remission (73% vs. 51%), event-free survival (29% vs. 14%), and overall survival (38% vs. 23%). CONCLUSIONS: In patients with AML who are older than 60 years of age, escalation of the dose of daunorubicin to twice the conventional dose, with the entire dose administered in the first induction cycle, effects a more rapid response and a higher response rate than does the conventional dose, without additional toxic effects. (Current Controlled Trials number, ISRCTN77039377; and Netherlands National Trial Register number, NTR212.)

BACKGROUND: Patients with acute myeloid leukemia (AML) often reach complete remission, but relapse rates remain high. Next-generation sequencing enables the detection of molecular minimal residual disease in virtually every patient, but its clinical value for the prediction of relapse has yet to be established. METHODS: We conducted a study involving patients 18 to 65 years of age who had newly diagnosed AML. Targeted next-generation sequencing was carried out at diagnosis and after induction therapy (during complete remission). End points were 4-year rates of relapse, relapse-free survival, and overall survival. RESULTS: At least one mutation was detected in 430 out of 482 patients (89.2%). Mutations persisted in 51.4% of those patients during complete remission and were present at various allele frequencies (range, 0.02 to 47%). The detection of persistent DTA mutations (i.e., mutations in DNMT3A, TET2, and ASXL1), which are often present in persons with age-related clonal hematopoiesis, was not correlated with an increased relapse rate. After the exclusion of persistent DTA mutations, the detection of molecular minimal residual disease was associated with a significantly higher relapse rate than no detection (55.4% vs. 31.9%; hazard ratio, 2.14; P<0.001), as well as with lower rates of relapse-free survival (36.6% vs. 58.1%; hazard ratio for relapse or death, 1.92; P<0.001) and overall survival (41.9% vs. 66.1%; hazard ratio for death, 2.06; P<0.001). Multivariate analysis confirmed that the persistence of non-DTA mutations during complete remission conferred significant independent prognostic value with respect to the rates of relapse (hazard ratio, 1.89; P<0.001), relapse-free survival (hazard ratio for relapse or death, 1.64; P=0.001), and overall survival (hazard ratio for death, 1.64; P=0.003). A comparison of sequencing with flow cytometry for the detection of residual disease showed that sequencing had significant additive prognostic value. CONCLUSIONS: Among patients with AML, the detection of molecular minimal residual disease during complete remission had significant independent prognostic value with respect to relapse and survival rates, but the detection of persistent mutations that are associated with clonal hematopoiesis did not have such prognostic value within a 4-year time frame. (Funded by the Queen Wilhelmina Fund Foundation of the Dutch Cancer Society and others.).

PURPOSE: Half the patients with acute myeloid leukemia (AML) who achieve complete remission (CR), ultimately relapse. Residual treatment-surviving leukemia is considered responsible for the outgrowth of AML. In many retrospective studies, detection of minimal residual disease (MRD) has been shown to enable identification of these poor-outcome patients by showing its independent prognostic impact. Most studies focus on molecular markers or analyze data in retrospect. This study establishes the value of immunophenotypically assessed MRD in the context of a multicenter clinical trial in adult AML with sample collection and analysis performed in a few specialized centers. PATIENTS AND METHODS: In adults (younger than age 60 years) with AML enrolled onto the Dutch-Belgian Hemato-Oncology Cooperative Group/Swiss Group for Clinical Cancer Research Acute Myeloid Leukemia 42A study, MRD was evaluated in bone marrow samples in CR (164 after induction cycle 1, 183 after cycle 2, 124 after consolidation therapy). RESULTS: After all courses of therapy, low MRD values distinguished patients with relatively favorable outcome from those with high relapse rate and adverse relapse-free and overall survival. In the whole patient group and in the subgroup with intermediate-risk cytogenetics, MRD was an independent prognostic factor. Multivariate analysis after cycle 2, when decisions about consolidation treatment have to be made, confirmed that high MRD values (> 0.1% of WBC) were associated with a higher risk of relapse after adjustment for consolidation treatment time-dependent covariate risk score and early or later CR. CONCLUSION: In future treatment studies, risk stratification should be based not only on risk estimation assessed at diagnosis but also on MRD as a therapy-dependent prognostic factor.

PURPOSE: Combined-modality treatment consisting of four to six cycles of chemotherapy followed by involved-field radiotherapy (IFRT) is the standard of care for patients with early unfavorable Hodgkin's lymphoma (HL). It is unclear whether treatment results can be improved with more intensive chemotherapy and which radiation dose needs to be applied. PATIENTS AND METHODS: Patients age 16 to 75 years with newly diagnosed early unfavorable HL were randomly assigned in a 2 × 2 factorial design to one of the following treatment arms: four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) + 30 Gy of IFRT; four cycles of ABVD + 20 Gy of IFRT; four cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP(baseline)) + 30 Gy of IFRT; or four cycles of BEACOPP(baseline) + 20 Gy of IFRT. RESULTS: With a total of 1,395 patients included, the freedom from treatment failure (FFTF) at 5 years was 85.0%, overall survival was 94.5%, and progression-free survival was 86.0%. BEACOPP(baseline) was more effective than ABVD when followed by 20 Gy of IFRT (5-year FFTF difference, 5.7%; 95% CI, 0.1% to 11.3%). However, there was no difference between BEACOPP(baseline) and ABVD when followed by 30 Gy of IFRT (5-year FFTF difference, 1.6%; 95% CI, -3.6% to 6.9%). Similar results were observed for the radiotherapy question; after four cycles of BEACOPP(baseline), 20 Gy was not inferior to 30 Gy (5-year FFTF difference, -0.8%; 95% CI, -5.8% to 4.2%), whereas inferiority of 20 Gy cannot be excluded after four cycles of ABVD (5-year FFTF difference, -4.7%; 95% CI, -10.3% to 0.8%). Treatment-related toxicity occurred more often in the arms with more intensive therapy. CONCLUSION: Moderate dose escalation using BEACOPP(baseline) did not significantly improve outcome in early unfavorable HL. Four cycles of ABVD should be followed by 30 Gy of IFRT.

BACKGROUND: Cytarabine (ara-C) is an important drug in the treatment of acute myeloid leukemia (AML). High-dose cytarabine (2000 to 3000 mg per square meter of body-surface area) is toxic but results in higher rates of relapse-free survival than does the conventional dose of 100 to 400 mg per square meter. Intermediate dose levels have not been thoroughly evaluated. METHODS: We compared two induction regimens in patients 18 to 60 years of age (median, 49) who had newly diagnosed AML. The intermediate-dose group, totaling 431 patients, received cytarabine at a dose of 200 mg per square meter given by continuous intravenous infusion for 24 hours during cycle 1 of induction therapy and 1000 mg per square meter by infusion for 3 hours twice daily during cycle 2 of induction therapy. The high-dose group, totaling 429 patients, received a dose-escalated regimen of 1000 mg of cytarabine per square meter every 12 hours in cycle 1 and 2000 mg per square meter twice daily in cycle 2. Patients with a complete response did not receive additional cytarabine but received consolidation therapy in a third cycle of chemotherapy (mitoxantrone-etoposide) or underwent autologous or allogeneic stem-cell transplantation. Complete remission rates, survival rates, and toxic effects were assessed for each treatment group. RESULTS: At a median follow-up of 5 years, no significant differences were noted between the intermediate-dose group and the high-dose group with respect to complete remission rates (80% and 82%, respectively), probability of relapse, event-free survival at 5 years (34% and 35%), or overall survival (40% and 42%). High-dose cytarabine provided no clear advantage in any prognostic subgroup. The high-dose treatment resulted in higher incidences of grade 3 and grade 4 toxic effects (in cycle 1), prolonged hospitalization, and delayed neutrophil recovery (in cycle 2) and platelet recovery (in cycles 2 and 3). CONCLUSIONS: Induction therapy with cytarabine at the lower dose already produced maximal antileukemic effects for all response end points, suggesting a plateau in the dose-response relationship above this dose level. High-dose cytarabine results in excessive toxic effects without therapeutic benefit. (Netherlands Trial Register number, NTR230.).