More than one quarter of a million adults throughout the world are diagnosed annually with acute myeloid leukemia (AML). Few diseases other than acute myeloid leukemia (AML) engender so much personal and institutional passion regarding treatment strategies. The median age of AML is 72 years of age, as reported by the Swedish Acute Leukemia Registry, a model for collection of real world data.
Although some improvement during the last 4 decades is apparent among younger patients, still only approximately 35% of such patients entered on clinical trials are cured of their disease. However, little progress occurred among older patients and indeed only those with acute promyelocytic leukemia (APL) which is a rare subgroup enjoy the excellent outcome and likelihood of cure we all desire.
Management of AML in Adults
To some extent, the management of adults with AML appears to be standardized. However, much of the so-called conventional therapy has been established with a lack of data or without rigorous review of the existing evidence; and so, considerable uncertainty remains. Such uncertainty is reflected in the significant diversity in the management of patients with AML, both in induction of older patients and postremission therapy of all patients.
Generally, the management of AML can be divided into three parts including the induction therapy, the postremission therapy, and the hematological emergent management. The induction therapy regimen now is standarized. The choice of induction and postremission thearpy is primarily and solely determined and based on the cytogenetic and molecular determinants at diagnosis. However, possibly minimal residual disease (MRD) after induction therapy, as determined by refined molecular or immunophenotypic analyses, plays a role in deciding the choice of postremission therapy.
When a patient is newly diagnosed with AML, the first thing to do is to evaluate the cytogenetics and karyotype of the patient,since that the two is important in the determining of the risk status, the prognosis, and then the treatment strategy of AML. According to the cytogenetics and karyotype the risk status of AML can be divided into three categories consisting of better-risk (favorable), intermediate-risk, and poor-risk (unfavorable).
Table 1. Risk Status of AML Based on Cytogenetics and Molecular Abnormalities
Table 2. Standardized Reporting for Correlation of Cytogenetic and Molecular Genetic Data in AML with Clinical Data
Although in the early 1990s several randomized studies of induction therapy suggested that using idarubicin, mitoxantrone, aclarubicin, or amsacrine demonstrated superior results compared with daunorubicin, there is no evidence that these studies reflected a true biologic advantage rather than a lack of dose equivalence. So the standard induction therapy regimen remains the “3+7”. It has now been established that the traditional approved dose of daunorubicin (45 mg/m2 for 3 days) is no longer appropriate as induction therapy for AML. A recent randomized trial for younger patients under age 60 years reported a significantly higher complete remission (CR) rate for patients receiving 90 mg/m2 of daunorbuicin compared with 45 mg/m2. The overall survival was also improved with the higher dose of daunorubicin.
The E1900 trial, which was undertaken by the Eastern Cooperative Oncology Group (ECOG) in 657 younger patients, compared a daunorubicin dose of 90 mg/m2 versus 45 mg/m2 in a 3+7 schedule for the first induction course. The higher dose achieved a significantly higher overall remission rate, with more patiens in CR after the first course and a better overall survival (23.7 vs 15.7 months). However, a study by Dutch-Belgian Hemato-Oncology Cooperative Group showed that with the similar approach in older patients with AML the overall remission rate was similarly improved, but overall survival was not, except in the case of patients in the 60- to 65-year subgroup.
So the induction therapy regimen is 3+7 that daunorubicin 90 mg/m2 for 3 days together with cytarabine 100 mg/m2 for 7 days.
Once the patient get CR after induction therapy postremission therapy need consideration. The choice of postremission therapy could be allogeneic hematopoietic cell transplantation (allo-HSCT), autologous transplantation (auto-HSCT), and consolidation chemotherapy. The decision for postremission therapy should be based on cytogenetic and molecular determinants, regardless of other factors.
Allo-HCT provides the most potent antileukemic effect of any postremission strategy in AML, as demonstrated by the lowest rates of relapse in all clinical studies. The donor categories of allo-HCT consist of HLA-identical sibling donor, matched unrelated donor (MUD), genetically haploidentical donor, and umbilical cord donor. Probably the HLA-identical sibling donor is the first-line and preferred choice, because other three choices might have higher rates of mortality and morbidity associated with GVHD (graft-versus-host disease). Although there is a substantial transplantation-related mortality of 15% to 20% with allo-HCT, the reduction in the relapse rate significantly outweighs the transplantation-associated risk.
In AML patients, it is clear that fewer marrow blasts at the time of transplantation portend for a better outcome than if the transplantation is done in the presence of more fulminant disease. So to obtain CR before transplantation in AML is a rule (see post “The Management of Myelodysplastic Syndromes”). However, in relapsed AML, patients with CR1 less than 6 months have less than 20% of likelihood to achieve CR2, where we would elect to proceed to an transplantation in an untreated first relapse. But there is a expection, it is older individuals with relapsed AML, more than or equal to 60 to 65 years. In these patients a RIC often is the preferred conditioning regimen before transplantation, but the likelihood of a cure when transplantation a patient with elevated blasts with RIC is low, where our own preference in this case would be to administer one cycle of induction therapy in an attempt to obtain a better control of the disease before transplantaion.
However, not all patients with AML should undergo hematopoietic cell transplantation. Patients whose leukemia cells expressing more favorable mutations with normal karyotype at diagnosis such as mutation of NPM1 or CEBPA have a more favorable outcome and may not benefit from an allo-HCT. These patients should not undergo allo-HCT.
Table 3. Suggested indications for allo-HSCT
If there is no HLA-identical sibling donor, MUD donor, genetically haploidentical donor, or umbilical cord donor could be the alternative approach. But, a recent study showed that there was an increased replase rate in MUD transplantation for AML patients in CR1 and the leukemia-free survival was also significantly improved for patients receiving a sibling transplantation.
There was an increased relapse rate in MUD transplantations for AML patients in CR1 and the leukemia-free survival was also significantly improved for patients receiving a sibling transplantation. Although the presence of GVHD is associated with reduced relapse of AML, it dose not appear that such an effect is dependent on the degree of genetic disparity and the best donor remains the most closely matched donor.
If allo-HCT is chosen, a fully myeloablative conditioning regimen is appropriate and the reduced-intensity conditioning (RIC) regimen should be reserved for older patients or those with significant comorbidities. The transplantion should be underwent immediately after the CR1 without any consolidation chemotherapy. 2 retrospective analyses from large international registries suggest that there is no benefit to adding any consolidation therapy before an allo-HCT. Also the allo-HCT transplantation should not be delayed or reserved until the patient has a event of relapse. Delaying transplantation until after relapse is a misleading strategy.
In the majority of major prospective studies published over the past decade, a lower relapse rate was reported for patients undergoing an autologous transplantation compared with chemotherapy. If autologous transplantation is chosen, the patient should receive 2 cycles of consolidation therapy with high-dose cytarabine (3g/m2 given every 12 hours on days 1, 3, and 5) followed by the transplantation. The rationale for using an autologous transplantation is based on the fundamental concept that the optimal approach to postremission therapy is based on the regimens with the most potent antileukemic activity, provided this effect is not abrogated by unacceptably high mortality. Currently, the mortality rate associated with an autologous transplantation is less than 2%, which results from the technology that collecting hematopoietic cells from the peripheral blood. Of note, if the patient is in the poor-risk group, autologous transplantation should be avoided. I think the reason is associated the unfavorable cytogenetic mutations or karyotype.
One point must be emphasized that if the patient dosen’t achieve CR after the first induction course (i.e., the patient dosen’t clear his/her blasts in bone marrow by day 14 after the first induction therapy) but subsequently achieve CR after the second induction therapy, the prognosis is similar to those achieving CR with one cycle of induction. Thus, the postremission strategy should not be altered if the patient eventually responds successfully to the induction therapy.
Table 4. Response Criteria in AML
Patients with initial AML may experience hyperleukocytosis which could result in leukostasis (when the WBC > 200 × 109/L) and therefore potentially lethal central nervous system and pulmonary complications. The optimal emergent management is uncertain, and one approach is to initiate immediate induction thearpy. An alternative strategy consists of daily leukapheresis with the concurrent administration of hydroxyurea at doses of 2 to 6 g/day. Generally, some experts suggest this alternative approach and wait for the initiation of induction therapy until the WBC has fallen below 40 × 109/L to 50 × 109/L, they think that this approach would increase the likelihood of achieving CR with a single cycle of chemotherapy.
The issue of prophylaxis for the central nervous system is controversial in any patients with AML and is often considered in a patient who presents initially with a high WBC. The experts don’t recommend the prophylaxis routinely if in the absence of any symptoms related to the central nervous system.
Table 5. Outcome Measures in AML