Department of Hematology, Catholic Blood and Marrow Transplantation Center, Leukemia Research Institute, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Standard remission induction chemotherapy consisting of anthracycline plus cytarabine (3+7) is administered for adult acute myeloid leukemia (AML). However, the effects of intensified regimen on complete remission (CR), relapse and overall survival (OS) remain unknown.
We analyzed 1195 patients treated with idarubicin plus cytarabine/BHAC (3+7) from 2002 to 2013. Among them, 731 received early intensification with 3-day cytarabine/BHAC (3+10, N=363) or 2-day idarubicin plus cytarabine/BHAC 3 days (5+10, N=368). The 3+10 and 5+10 strategies were applied to patients with bone marrow blast counts of 5?20% and >20% on day 7 of 3+7, respectively.
Early intensification correlated with a younger age (median: 40 vs. 45 yr) and higher t(8;21) frequency (20.4% vs. 7.1%), compared to 3+7. After early intensification, the early death rates were higher among the elderly (3+10 [15.7%], 5+10 [21.7%] vs. 3+7 [6.3%],
Early intensification correlated with higher CR and lower relapse rates, but not OS in young AML patients. In elderly patients, early intensification correlated with a higher early death rate and poorer OS.
The current standard remission induction chemotherapy strategy for adult patients younger than 60 years with acute myeloid leukemia (AML) consisting of a continuous standard doses of cytarabine infusion (100–200 mg/m2) for 7 days combined with either idarubicin (12 mg/m2 for 3 days) or daunorubicin (40–60 mg/m2 for 3 days) , has not changed considerably over the last 25 years. However, several previous trials have used novel agents or dose-escalation methods to intensify this induction regimen for improving the hematological complete remission (CR) rate and reducing the relapse rate, which would yield better survival outcomes.
Initially, different types or doses of anthracyclines were compared to evaluate possible improvements in clinical outcomes. A recent meta-analysis of 29 randomized controlled trials comparing the efficacies of idarubicin and daunorubicin at different dosing schedules revealed that idarubicin reduced the remission failure rate, as indicated by a risk ratio of 0.81 (95% confidence interval [CI]; 0.66–0.99,
The adult AML patients visiting our healthcare center were initially treated with a protocol comprising 3 days of idarubicin and 7 days of intermediate-dose cytarabine or N4-behenoyl-1-β-D-arabinofuranosyl cytosine (BHAC). And then, they were administered early intensified induction therapy according to the bone marrow (BM) blast counts on day 7 of the initial chemotherapy regimen. We tried to identify the treatment outcomes associated with early intensification compared to those of the standard 3+7 regimen in Korean AML patients, with the aim of demonstrating the effect of additional cytarabine or dose-escalated idarubicin therapy.
After excluding patients with acute promyelocytic leukemia, we retrospectively enrolled 1,195 adult AML patients who were initially treated with idarubicin-based intensive induction chemotherapy between 2002 and 2013. The diagnoses were established by morphological, cytochemical, immunophenotypic, and cytogenetic analyses of BM blast cells. For karyotyping, at least 20 metaphase cells were analyzed using the GTG banding method and the International System for Cytogenetic Nomenclature (ISCN) . For the molecular analysis, we screened 28 genetic aberrations by multiplex reverse transcriptase polymerase chain reaction (RT-PCR) using the HemaVision Kit (DNA Technology, Aarhus, Denmark). Unfortunately, molecular studies, including the detection of
Fig. 1 shows the treatment strategy for adult AML used at the Catholic Blood and Marrow Transplantation Center in Korea. All patients were initially treated with 3+7 induction chemotherapy, comprising idarubicin (12 mg/m2) for 3 days plus cytarabine (100 mg/m2) or BHAC (300 mg/m2) for 7 days . Of these patients, 731 (61.2%) additionally received continuous early intensification with cytarabine or BHAC for the following 3 days (3+10, N=363) or idarubicin for the following 2 days and cytarabine or BHAC for the following 3 days (5+10, N=368). Decisions for early intensification were based on the follow-up BM blast counts on day 7 of 3+7 induction chemotherapy; 3+10 intensification was administered for blast counts of 5–20% and 5+10 intensification was administered for blast counts >20% (early intensification group). The remaining 464 patients with blast counts <5% finished the 3+7 regimen without early intensification (standard group). For patients who achieved a hematological CR after induction, we applied our standard consolidation chemotherapy, which consisted of a 3+5 regimen comprising mitoxantrone (12 mg/m2) or idarubicin (12 mg/m2) for 3 days plus an intermediate dose of cytarabine (1.0 g/m2 every 12 hr) or BHAC (300 mg/m2) for 5 days; these were alternatively applied. For patients who did not achieve remission, we administered re-induction chemotherapy, which comprised 4 days of mitoxantrone (10 mg/m2) and intermediate-dose cytarabine (1.0 g/m2 every 12 hr), followed by 3 days of etoposide (100 mg/m2).
For patients in CR, we searched for available donors for allogeneic-hematopoietic cell transplantation (HCT) during the consolidation period, giving initial preference to human leukocyte antigen (HLA)-matched sibling donors (MSDs), followed by HLA well-matched unrelated donors (URDs). When conventional donors were not available, we searched for haploidentical familial mismatched donors; if a patient refused allogeneic-HCT, we performed autologous-HCT or completed three cycles of consolidation chemotherapy alone according to the patient's and physician's joint decision . If a patient was a candidate for autologous-HCT, CD34+ hematopoietic stem cells were collected for 3 days during consolidation chemotherapy after the neutrophil count had recovered. For donor mobilization, we administered granulocyte-colony stimulating factor subcutaneously at a dose of 10 µg/kg/day for 4 days. Patients who underwent HCT received either a myeloablative (MAC) or a reduced-intensity (RIC) conditioning regimen. Briefly, the MAC regimen comprised cyclophosphamide (120 mg/kg) combined with total body irradiation (TBI; 1320 cGy) or busulfan (12.8 mg/kg). The autologous MAC regimen comprised TBI (1200 cGy) plus ARA-C (9 g/body surface area) and melphalan (100 mg/body surface area) . For the RIC regimen, we administered busulfan (6.4 mg/kg) and fludarabine (150 mg/m2) with TBI (400 cGy) . Anti-thymocyte globulin (ATG) at a dose of 2.5 mg/kg (1.25 mg/kg each on days -3 and -2) was administered to patients receiving stem cells from an URD. For haploidentical transplantation, we administered fludarabine (150 mg/m2) and busulfan (6.4 mg/kg) with TBI (800 cGy) and ATG (5 mg/kg in 1.25 mg/kg doses on days -4 to -1) .
This study was conducted to assess clinical outcomes according to induction chemotherapy intensity, and focused on early death (within 8 weeks), early relapse during or after the consolidation period before HCT, long-term overall survival (OS) and the cumulative incidence of overall relapse (CIR). All categorical variables were compared using a chi-squared analysis and Fisher's exact test, and continuous variables were assessed using Student's
The baseline characteristics of the two subgroups according to the induction chemotherapy induction are shown in Table 1. The standard group (N=464) and the early intensification group (N=731) had median ages of 45 years (range, 17–75 yr) and 40 years (range, 17–69 yr), respectively (
We calculated the early death rate (up to 8 weeks after induction therapy), CR rate and early relapse rate before HCT according to the induction chemotherapy intensity (Table 2). The early death rate was 4.8% (N=47) and significantly higher in early intensification group, especially among patients older than 55 years (17.5% vs. 6.3%,
Overall, early intensification was associated with a superior 5-year OS (44.4% vs. 37.4%,
Our current study demonstrated that early intensification with additional cytarabine or BHAC for 3 days, with or without an additional 2 days of idarubicin therapy, was associated with a higher early death rate and inferior OS in elderly group, despite higher post-induction CR rate and lower early relapse rate before HCT. However, both univariate and multivariate analysis showed that early intensification was associated with lower overall relapse rate in young patient group. In addition, early-intensification had no effect on clinical outcome in adverse-risk group. Therefore, we suggest that early intensification may benefit young patients without an adverse-risk molecular cytogenetic profile. Among patients in the adverse-risk category, clinical trials should be first consider the use of several novel
We mainly selected BHAC, widely used in Japan due to lower incidence of toxicities such as nausea and vomiting, as initial chemotherapy regimen . Owing to its lower CR rate and poorer survival outcome compared to cytarabine , we attempted to intensify the induction regimen by adding 3 further days of BHAC with or without 2 days of idarubicin therapy, according to the BM blast count on the final chemotherapy infusion day during the initial 3+7 regimen. However, we mainly replaced BHAC with cytarabine within the same intensification strategy since 2009. We found that our current results were mainly affected by the outcomes of treatment with the intensification strategy comprising BHAC plus idarubicin, which was associated with a relatively lower early death rate (12.2% in 3+10 and 18.8% in 5+10) even in the elderly group (
Our data showed that AML patients with the t(8;21) mutation were more likely to receive early intensification as a result of high remnant BM blast counts on day 7 of the 3+7 chemotherapy regimen, suggesting their late blast clearance, although t(8;21) is considered a favorable-risk cytogenetic marker. However, all patients with favorable-risk cytogenetics had an optimal response (blast ≤5%) and completed induction therapy without double induction on day 14 of induction chemotherapy. Several previous reports showed correlations of an early BM blast clearance with a higher CR rate and better survival outcomes , and many guidelines suggest that a second induction is recommended for patients with high remnant BM blasts on day 14 of induction chemotherapy. Therefore, our BM blast evaluation on day 7 was too early to predict the clinical outcomes for some patients such as those with the t(8;21) mutation. Nevertheless, our current study revealed that the administration of early intensification based on this earlier BM blast evaluation might be an acceptable remission induction strategy for young patients with intermediate-to-favorable-risk molecular cytogenetics, particularly with regard to a higher CR rate and lower early relapse rate. Given our experiences with a very long neutropenic period and higher mortality associated with additional 3+7 chemotherapy according to the BM blast count on day 14, it seems that the well-known Western protocol might be very toxic for Asian (and specifically Korean) patients. Therefore, based on our current results, we are currently planning a well-designed prospective trial to prove the role of BM blast evaluation on day 7 and the usefulness of early intensification for selected groups of AML patients.
After the consolidation chemotherapy comprising intermediate-dose cytarabine or BHAC combined with idarubicin, the patients underwent allogeneic-HCT when a well matched donor was available. Otherwise, the patients underwent autologous-HCT followed by chemotherapy alone or haploidentical HCT. Although high-dose cytarabine was recommended a standard consolidation regimen for patients younger than 60 years with intermediate-to-favorable-risk cytogenetics , we used an intermediate dose of cytarabine due to the risks of neurologic toxicity and non-relapse mortality associated with high-dose cytarabine and previous reports that demonstrated similar treatment outcomes with intermediate-dose cytarabine .
Considering the effects of consolidation therapy on survival and many confounding parameters in HCT, it is difficult to properly evaluate the long-term survival outcomes of each induction regimens. However, we expect that the high post-induction CR rate and lower early death rate of early intensification in the young patient group might increase the likelihood for undergoing HCT leading to better disease-free survival. Unfortunately, however, early intensification did not significantly improve survival outcomes, although it significantly reduced the early relapse rate before HCT without increasing the early death rate.
Although this study was a retrospective analysis of data collected from a heterogeneous cohort over a long period, our observations were based on a consistent (i.e., largely unchanging over time) treatment strategy including consolidation chemotherapy, donor searching, pre-HCT conditioning regimens, immunosuppressive agents and supportive management. In conclusion, we suggest that early intensification may benefit young patients, especially those who have been treated with a BHAC-based regimen, and could result in a higher CR rate and lower relapse rate. However, this early intensification should not be applied to the elderly patients treated with a cytarabine-based regimen or patients with adverse-risk molecular cytogenetics.
Treatment strategy for adult patients with acute myeloid leukemia (AML) at the Catholic Blood and Marrow Transplantation Center in Korea. Abbreviations: BHAC, N4-behenoyl-1-β-D-arabinofburanosyl cytosine; CR, complete remission; D7BM, bone marrow blast evaluation on day 7 of chemotherapy; HCT, hematopoietic cell transplantation; MSD, matched sibling donor; MTZ, mitoxantrone; URD, unrelated donor.
Early treatment outcomes according to the intensity of induction chemotherapy.
Overall survival (OS) and overall relapse rates according to the intensity of induction chemotherapy.