EMA, consisting of etoposide, mitoxantrone, and cytarabine, is a timed-sequential chemotherapy (TSC) regimen and an efficacious option for induction treatment of acute myelogenous leukemia (AML). Hematopoietic growth factors (HGFs) have been shown to recruit leukemic blasts into cell cycle. We postulated the addition of granulocyte colony-stimulating factor (G-CSF) to EMA (EMA-G) might enhance treatment efficacy. EMA-G consisted of mitoxantrone on days 1–3, cytarabine on days 1–3 and 8–10, etoposide on days 8–10, and G-CSF from day 4 until absolute neutrophil count (ANC) >500/μl. In total, 28 patients were enrolled. All patients had newly diagnosed de novo AML. The median age was 42 years. Of the 27 patients with cytogenetic analysis, six had favorable karyotype, 18 intermediate karyotype, and three unfavorable karyotype. The median follow-up was 37.5 months. The median time for both ANC recovery and last platelet transfusion was 26 days. The toxicities associated with this regimen were no more than those expected with the standard chemotherapy. In all, 24 (86%) patients achieved complete remission (CR), three (11%) patients had no response, and one patient died within 24 h of induction therapy before response could be evaluated. Of the 24 patients who achieved CR, 22 received high-dose cytosine arabinoside and two received allogeneic bone marrow transplant as initial postremission therapy. For the whole cohort, the estimated 3-year survival rate was 67%. The median relapse-free survival was 30.5 months. We conclude that EMA-G regimen is a safe regimen and administration of G-CSF during and after induction treatment is not associated with prolongation of marrow aplasia or acceleration of leukemia relapse. It is efficacious for induction therapy for newly diagnosed de novo AML. A high CR rate can be achieved with only one course of this chemotherapy.
The primary objective in treating patients with acute myelogenous leukemia (AML) is to induce remission and thereafter prevent relapse. For more than 30 years, cytosine arabinoside (Ara-C) and anthracyclines have been the mainstay of induction chemotherapy for AML. However, induction therapy with standard-dose Ara-C and anthracyclines fails to achieve complete remission (CR) in about 20–30% of patients who are 60 years of age or younger and in approximately 50% of older patients.1,2,3
It is generally accepted that resistance of quiescent malignant clonogenic cells to cytotoxic therapy might be an important mechanism for in vivo drug resistance since Ara-C and anthracyclines are preferentially cytotoxic to proliferating cells. A series of laboratory and clinical studies suggest that chemotherapy recruits quiescent leukemic blasts into cell cycle. Based on those findings, the concept of timed-sequential chemotherapy (TSC) was introduced.4,5,6 TSC utilizes a second sequence of cycle-active cytotoxic drugs at the time of presumed peak cell recruitment induced by the first sequence of chemotherapy. Several TSC regimens are effective as induction therapy in patients with newly diagnosed AML,7,8,9,10 and in patients who are resistant to or relapsed after con-ventional daunorubicin-cytarabine regimens.11 Archimbaud et al12,13,14 designed a TSC regimen consisting of etoposide, mitoxantrone, and cytarabine (EMA), and used it effectively for induction therapy in refractory or relapsed AML patients in several clinical trials.
Hematopoietic growth factors (HGFs), such as granulocyte colony-stimulating factor (G-CSF) and granulocyte–macrophage colony-stimulating factor (GM-CSF), may have a role in the treatment of AML. Several prospective randomized trials used G-CSF or GM-CSF after induction chemotherapy to improve remission and survival rates by reducing infectious deaths through accelerated hematopoietic recovery.15,16,17,18,19 In the aggregate experience, HGFs shorten the duration of neutropenia following induction chemotherapy. This benefit translates into fewer days of antimicrobial therapy and fewer days of hospitalization in some patients. Most studies failed to show a reduction in the rate of infections or infectious deaths in the patients receiving HGFs. Only one study reported an increase in the rate of initial response,15 and another study reported that survival was increased.18 Most importantly, the use of HGFs appears to be safe, with little or no risk of accelerating leukemic relapse.
The priming effect of HGFs on quiescent leukemic cells has also been explored extensively. AML blast cells generally express functional G-CSF and GM-CSF receptors on their surface.20 Recruitment of leukemia blasts into cell cycle with HGFs in vitro resulted in increased cytotoxicity to cytarabine and anthracyclines.21,22,23,24,25,26,27 Several pilot studies suggested a potential therapeutic benefit from administering HGFs before or during induction therapy, but recent randomized clinical trials have not demonstrated any significant advantages from this priming strategy.28,29,30,31,32
We suggested that the efficacy of EMA might be because of the administration of two courses of chemotherapy in addition to a possible recruitment effect of their timed, sequential schedule. We postulated that adding G-CSF to EMA (EMA-G) might enhance the recruiting effects of TSC, and therefore improve the efficacy of EMA. We have previously reported that EMA-G is a safe and efficacious regimen for induction therapy in patients with refractory, relapsed, or secondary AML.33 We have now extended our experience with EMA-G to induction therapy in patients with newly diagnosed, de novo AML. We demonstrate that EMA-G can be administered safely and is efficacious in this group of patients.
Materials and methods
The diagnosis of AML was made for all patients according to the standard French–American–British (FAB) cytologic and cytochemical criteria. 34 Eligibility for this clinical trial required a diagnosis of AML, no antecedent history of myelodysplasia or myeloproliferative syndrome, FAB M0–M7 excluding FAB M3 (acute promyelocytic leukemia), age >18 and <65 years, and no major comorbidity. All patients were previously untreated and had an Eastern Cooperative Oncology Group performance status of 0–2. Patients with leukemic meningitis were excluded, as were patients with severe organ failure, unless organ failure was related to the leukemia itself. Patients were considered to have good-risk cytogenetics if their karyotype included either t(8;21), inv(16), or t(16;16). Poor-risk cytogenetics included complex karyotypes, −5, −7, del5q, t(3:3), and 11q23 abnormalities. Intermediate-risk cytogenetics included normal cytogenetics and other miscellaneous single abnormalities. Signed informed consent was obtained from each patient according to the institutional guidelines and each patient was treated on a Cleveland Clinic Foundation Internal Review Board approved protocol.
The EMA regimen contains etoposide, mitoxantrone, and cytarabine administered in a timed-sequential fashion.12 We added G-CSF to the EMA-G.33 The treatment schema is provided in Figure 1. EMA-G consists of mitoxantrone 12 mg/m2/day intravenous (i.v.) bolus for 3 days (days 1–3) with cytarabine 500 mg/m2/day i.v. continuous infusion (CI) for 72 h (days 1–3). Etoposide 200 mg/m2/day IVCI for 72 hours and cytarabine 500 mg/m2/day IVCI for 72 h were administered on days 8–10. G-CSF 5 μg/kg/day subcutaneously was started on day 4 and continued until the absolute neutrophil count (ANC) rose above 0.5 × 109/l for two consecutive days. G-CSF was stopped when a bone marrow aspirate or biopsy obtained on or after day 14 contained 5% or more blast cells. Only one course of EMA-G induction was given.
All patients were treated in semiprivate rooms equipped with HEPA filters on a regular oncology unit. All patients received standard supportive care including blood component support for severe cytopenias as previously described.35 All patients had indwelling central venous catheters. Broad-spectrum antibiotics were used for the first febrile episode. Acyclovir 250 mg/m2/day IV or 400–600 mg PO BID, allopurinol 300 mg PO QD and fluconazole 400 mg PO QD were administered prophylactically.
Evaluation of therapy
Bone marrow aspirates and biopsies were obtained on day 8 of chemotherapy to monitor the achievement of aplasia or hypoplasia, and then at the discretion of the treating physicians. CR required normocellular bone marrow with less than 5% blasts as well as a peripheral blood neutrophil count greater than 1.5 × 109/l, hemoglobin more than 11 gm/dl, and platelet count greater than 1 × 1011/l for a minimum of 4 weeks. Nonresponse (NR) was defined as the absence of CR after one course of induction therapy. Relapse was defined by the appearance of circulating blasts or bone marrow blasts >5% in a patient previously in CR. Severity of treatment-related toxicity was graded according to the common toxicity criteria of Ajani et al.36
Patients who achieved complete response received chemotherapy, allogeneic bone marrow transplantation (BMT) or peripheral stem cell transplantation (PSCT) at the treating physician's discretion.
Survival duration was measured from the date of enrollment to the date of death owing to any cause or the date of most recent follow-up. Relapse-free survival (RFS) was measured from the data of enrollment to the date of death or relapse. The method of Kaplan and Meier37 was used to analyze overall survival (OS), RFS, time to neutrophil recovery, and time to last platelet transfusion. Exact 95% confidence intervals (CIs) based on the binomial distribution were calculated for proportions, such as complete response.
Between August 1995 and June 1999, 28 patients with newly diagnosed de novo AML were enrolled in this clinical trial. All patients were eligible for the study. The clinical characteristics of these 28 patients are detailed in Table 1. The median age of the cohort was 42 years (range 24–61 years). In all, 27 patients had cytogenetic studies of bone marrow aspirates. Most patients had either a favorable (n=6) or intermediate-risk (n=18) karyotype. A total of 26 patients received one complete course of EMA-G. Two patients received only part of EMA-G because of the development of severe toxicities. One patient stopped the protocol at day 9 and the other at day 12. Thus, all patients were evaluable for toxicity and survival.
Recovery of neutrophil and platelet count
All patients who achieved CR had full recovery of peripheral blood counts. In all, 26 patients received G-CSF until neutrophil recovery as dictated by the protocol. Two patients discontinued G-CSF before neutrophil recovery (on days 8 and 12, respectively) because of the development of severe toxicities that prohibited further chemotherapy. The median time to ANC recovery (exceeding 0.5 × 109/l) from the first day of chemotherapy was 26 days (range 20–43 days). The median time to last platelet transfusion from the first day of chemotherapy was also 26 days (range 13–67 days). There was no reappearance of leukemic blasts from either peripheral blood or bone marrow after the initiation of the second sequence of cytotoxic agents and G-CSF.
Major treatment-related toxicities are as listed in Table 2. All patients experienced neutropenic febrile episodes. In all, 10 patients had documented sepsis with positive blood cultures. Three other patients had localized infections (one with peritonsillar abscess with pre-existing periodontal infection, one with perineal abscess with pre-existing perilabial infection, and one with infectious colitis). The abscesses were managed with local evacuation in addition to systemic antibiotic therapy. Nonhematologic toxicity during induction therapy was not more than that expected from standard chemotherapeutic regimens. Grade 3 or 4 nausea and vomiting (22%), mucositis (18%), skin rash (18%), and diarrhea (11%) were entirely reversible. Grade 3 or 4 hyperbilirubinemia occurred in nine (32%) patients but was also reversible. Grades 1–2 transient renal insufficiency occurred in 13 (46%) patients and there was no grade 3 or 4 renal insufficiency. Complications in two patients necessitated discontinuation of the treatment protocol. One stopped the protocol treatment on day 9 because of necrotizing enterocolitis. The other stopped the protocol treatment on day 12 because of bronchiolitis obliterans organizing pneumonia, atrial fibrillation, and paralytic ileus. Other major complications included a minor stroke in one patient and excessive menstrual bleeding that was controlled with administration of estrogen and platelet transfusion in another patient.
Efficacy of therapy
Of the 28 patients, 24 (86%, 95% CI 67–96%) achieved CR and four (14%) failed to achieve CR. Of the 24 patients who achieved CR, 22 received at least one cycle of postremission high-dose cytarabine (HDAC) consolidation and two received postremission matched-related donor (MRD) allogeneic BMT. Following HDAC for consolidation, eight of 22 patients received transplants for relapsed disease (MRD allogeneic BMT=2, matched-unrelated donor (MUD) BMT=2, autologous PSCT=3 and MUD nonmyeloablative allogeneic PSCT=1). Overall, 10 patients received transplants following documentation of CR.
Of the four patients who did not achieve CR, one died within 24 h of initiation of induction therapy as a result of pre-existing leukostasis and septic shock, and thus could not be evaluated for response. Three patients achieved clearance of leukemic blasts from peripheral blood and bone marrow without full recovery of peripheral blood parameters, although only one of them still required transfusion support. All three NR patients received MRD allogeneic BMT as salvage treatment for primary refractory disease. Two patients did not respond to BMT and expired shortly after the transplant. One patient had a complete response to BMT and is still alive 3 years after the transplant.
Of the 24 patients with favorable or intermediate-risk cytogenetics, 22 (92%) achieved CR. Of the three patients with unfavorable cytogenetics, two (67%) achieved CR.
At the last follow-up, 16 (57%) patients were alive without disease. The median follow-up for these 16 patients was 48 months (range 15–71 months). For the whole cohort, the estimated 3-year OS rate is 67% (standard error, 9%). For the 24 patients who achieved CR, median relapse-free survival is 30.5 months (range 1–48 months).
Clinical trials demonstrate that adding HGF before starting chemotherapy is a failed strategy28,29,30,31,28 and may have a deleterious effect. 33,39 The use of HGF may compromise results either by stimulating the large, untreated leukemic burden or by the inevitable delay to institute cytotoxic chemotherapy (Rowe JM et al. Blood 1998; 92(Suppl): 313a; abstract). TSC offers the opportunity to start HGF after an initial cytoreductive course of chemotherapy, thus avoiding overstimulating a large burden of leukemic blasts while also recruiting residual quiescent blasts into proliferation. Archimbaud et al40 added HGF to the EMA regimen by starting GM-CSF after the first sequence of chemotherapy, but discontinuing it immediately after the second sequence. When given in this fashion, there was no advantage to EMA-GM compared to EMA alone for patients with relapsed and refractory AML in a randomized trial.41 We added G-CSF to EMA and, unlike EMA-GM, we continued the G-CSF until neutrophil recovery. We obtained results comparable to EMA and EMA-GM in patients with advanced AML.33 We have now extended our study of EMA-G to patients with untreated AML and obtained a CR rate of 86% and a 3-year survival rate of 67% with no more than expected toxicity.
Treatment-related toxicities associated with EMA-G were reversible and not more severe than those with the conventional induction regimens. The early death rate following therapy with EMA-G appears less than that reported for most other regimens (Table 3). Hematopoietic recovery is faster when compared with other TSC regimens. The median duration of 26 days for both neutrophil and platelet recovery in the current cohort compares favorably to that of 31–34 days and 30–33 days, respectively, for the TSC regimens administered with or without HGFs by other investigators.13,40,42
A CR rate of 86% was achieved in the current study in patients with newly diagnosed de novo AML comparing favorably to many different induction regimens for this population of patients (Table 3). Although different strategies of induction therapy have been tested, none has demonstrated consistently better results than the traditional daunorubicin and cytarabine combination (3+7). Several studies suggest that idarubicin may be superior to daunorubicin in standard induction regimens, but it is not clear that any improvement represents an inherent biological advantage rather than a biological dose advantage for idarubicin.43,44,45,46 Many studies also employ more intensive induction regimens as compared to the standard dosing regimen to improve results. These dose escalation strategies include more days of regularly dosed cytarabine and anthracyclines,47 high-dose cytarabine,48,49,50 or double induction regimens comprising the rapid sequence of two courses of identical or different cytotoxic regimens.51,52,53 There is also evidence that the addition of etoposide to the standard regimen may further increase remission rates.54,55,56 However, clinical trials demonstrate no consistent advantage for remission induction with more intensive approaches but do suggest a disease-free survival benefit (Table 3). Similarly, TSC regimens such as EMA appear to improve survival, if not CR rates, in both adult and pediatric patients with AML (Petersdorf S et al. Proc Am Soc Clin Oncol 1998; 17: 15a; abstract).42,57,58
The favorable outcome from EMA-G may be because of the more intensive nature of the cytotoxic agents employed with a higher dose of cytarabine (total dose, 3000 mg) and the addition of etoposide compared to the standard regimen of cytarabine (total dose, 1400 mg). Furthermore, EMA-G delivers two sequences of cytotoxic agents in a fashion mimicking a double induction regimen. This split course of intensive chemotherapy has the advantage of increased cytotoxic effect with no apparent increase in toxicity. Randomized trials have shown that HDAC does not improve CR rates in induction therapy when given over one sequence.48,49,50 The contribution of G-CSF to the favorable efficacy of EMA remains unconfirmed in our trials. Although cell cycle studies were planned in our trials, they could not be accomplished because of the difficulty of recovering a sufficient number of cells following the first sequence of the treatment. Nonetheless, the recruiting effect of HGFs on leukemic blast cells was clearly demonstrated in many in vitro models and clinical trials.41 Therefore, the question remains as to whether or not the recruitment effect of HGFs improves the overall efficacy of EMA.41
Cytogenetic abnormalities are used to define prognostic subgroups of AML with respect to achieving CR and remaining disease free. The group with favorable cytogenetics benefits more from cytarabine dose escalation in induction therapy (Burnett AK et al. Br J Haemtol 1996; 93(Suppl 2): 313; abstract)59,60,61 and from HDAC in consolidation therapy.62,63 Jahns et al64 reported the findings of cell-cycle studies of the blast cells from different cytogenetic risk groups.64 Blast cells from patients with a favorable karyotype had a high level of spontaneous proliferative activity and were not responsive to growth stimulatory cytokines, while blasts from most patients with an unfavorable karyotype had a low level of spontaneous proliferative activity and were sensitive to HGF growth stimulation. These data suggest that the patients with unfavorable karyotype may benefit more from priming strategies with HGF. In the present study, two out of three patients with unfavorable cytogenetics achieved CR with EMA-G induction. In our prior study, six of 17 (36%) previously treated patients with unfavorable cytogenetics achieved CR, while seven of 11 (64%) patients with either favorable or intermediate cytogenetics achieved CR. On-going, larger clinical trials were designed to examine the relation between cytogenetics and response to HGF priming.53 It is conceivable that the HGF priming strategy may be used only for patients with certain cytogenetic features that maximize recruitment effect. Lack of robust improvement of induction efficacy with recent strategies further underscores the notion that any significant advancement is more likely to be achieved through a better understanding of different biological or cytogenetic mechanisms and tailoring the treatment modalities accordingly.
Relapse is still a major problem for AML patients who achieve CR. In the current study, 20 of the 22 patients received HDAC as initial postremission therapy and the median relapse-free survival of 30.5 months is comparable to that achieved with similar postremission strategies.62,63 Nonetheless, 13 of those 20 patients relapsed and eight of the relapsed patients received transplants subsequently. Since CR rates are unlikely to improve further, future studies should concentrate on improving postremission strategies.
In all, 13 patients received transplants (three for NR after induction chemotherapy, two for consolidation after CR, and eight for relapse after CR). OS and RFS for transplant patients are worse than those for nontransplant patients (data not shown). Since 11 out of 13 patients in the transplant group received transplants for either refractory or relapsed diseases, their poorer outcome is most likely because of their disease status. Therefore, it is unlikely that the overall favorable outcome from the whole cohort is due to the use of transplants in 13 patients.
Overall, EMA-G is a rationally designed regimen that combines proven EMA with G-CSF to enhance their respective ability to recruit blasts into S-phase and, therefore, to increase their cytotoxic effect. Although our trials do not prove that the addition of G-CSF recruited leukemic blasts and may have no significant role in improving induction CR over EMA, its administration was not associated with prolongation of marrow aplasia or acceleration of leukemia relapse. This regimen produced a favorable CR rate in newly diagnosed primary AML in the present trial and a comparable CR rate in more advanced AML patients in a trial reported earlier. Although our trials are pilot studies with small numbers of patients, they are consistent with the encouraging result from an increasing number of other studies that support the concept of TSC and the potential benefits of HGF priming. We conclude that combination of TSC and HGF is a reasonable option for the induction therapy of AML patients and worthy of further study.
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We are indebted to the nurses and staff of H71 Nursing Station at the Cleveland Clinic Foundation. This study would not be possible without their support.
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He, X., Pohlman, B., Lichtin, A. et al. Timed-sequential chemotherapy with concomitant granulocyte colony-stimulating factor for newly diagnosed de novo acute myelogenous leukemia. Leukemia 17, 1078–1084 (2003) doi:10.1038/sj.leu.2402955
- acute myelogenous leukemia (AML)
- timed-sequential chemotherapy (TSC)
- EMA regimen
- EMA-G regimen
- granulocyte colony-stimulating factor (G-CSF)
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Timed-sequential chemotherapy as induction and/or consolidation regimen for younger adults with acute myelogenous leukemia
Homoharringtonine in combination with cytarabine and aclarubicin resulted in high complete remission rate after the first induction therapy in patients with de novo acute myeloid leukemia