Yesterday and today I read an literature by Gail J. Roboz in the Education Program Book by American Society of Hematology (ASH), which is named “Hematology” and published annually by the ASH in one volume per year. The name is “Novel Approaches to the Treatment of Acute Myeloid Leukemia”. In this article the author discussed several aspects of Acute Myeloid Leukemia (AML) including: the general, the chemotherapy regimen, the stem cell transplantation, and the prognostic of AML. Now let’s get into this article.
In the introduction section. Approximately 12,000 adults are diagnosed with acute myeloid leukemia (AML) in the United States annually, with a median age of 67 years. Despite advances in therapeutics and supportive care, the majority of patients with AML die from their disease. But among the subtypes acute promyelocytic leukemia (APL) is an important exception to the general statement of AML. In this subtype >75% of patients are cured with a combination of anthracycline-based chemotherapy, all-trans retinoic acid, and arsenic trioxide. For some APL patients, it is possible to eliminate cytotoxic chemotherapy altogether and to achieve cure with arsenic and all-trans retinoic acid alone. In this article we don’t discuss this subtype of AML in detail.
For all other subtypes of AML, the mainstay of initial treatment was developed nearly 40 years ago as a combination of cytosine arabinoside (ara-C) with an anthracycline, and this regimen remains the worldwide standard of care. Without stem cell transplantation, the age of patients is an in dependent major determinant indicator of the prognostic. For patients <60 years of age approximately 70%-80% of those will achieve complete remission, but most ultimately relapse and overall survival is only 40%-45% at 5 years. Among patients >60 years of age, 40%-50% of those with a good performance status can achieve complete remission, but cure rates are <10% and median survival is <1 year. Later in another section we will discuss the older AML patients in detail.
Advances in genomics technologies have identified AML as a genetically highly heterogeneous disease. As the technologies is well developed today, we are able to assign AML patients to many subgroups based on their molecular genetic defects. First we can assign AML patients to two subgroups which are cytogenetically normal and cytogenetically abnormal.
Cytogenetically normal patients comprise the largest subgroup of AML. This subgroup can now be further divided into a myriad of molecular subgroups too. Some subtypes of molecular genetic defects are know to have significant prognostic implications. For example, mutations in FLT3-ITD have been associated with an aggressive disease phenotype and poor outcomes. In contrast, patients with biallelic mutations in CEBPA and NPM1 without concomitant mutations in FLT3-ITD have significantly more favorable outcomes.
Also there is subgroup with abnormal cytogenetics. For example, mutations in KIT may negate the “favorable” classification previously associated with t(8;21).
Treatment of Acute Myeloid Leukemia
The treatment paradigm for AML generally includes remission induction, followed by consolidation with either 1-4 cycles of chemotherapy or stem cell transplantation.
The drugs for remission and consolidation have been variations on a theme of ara-C combined with an anthracycline or anthracenedione. In 1973 Yates et al first reported the result of a pilot trial of infusional cytarabine combined with daunorubicin in AML. The treatment was called “7&3 DNR 45” to indicate the dose of daunorubicin, 45 mg/m2. And there are many former studies to show the effects of the anthracyclines. There are five recommands for the treatment of AML.
- Cumulative anthracycline dose for induction should be at least 180 mg/m2 of daunorubicin or 36 mg/m2 of idarubicin and consider daunorubicin 270 mg/m2 (It’s called intensive therapy, we will discuss about it later) for patients up to 65 years of age with a good performance status and adequate cardiac function.
- Consider carefully if offering intensive consolidation to patients >60 years of age because this has not been shown to prolong survival and is associated with significant toxicity.
- Refer potential transplantation candidates immediately at time of diagnosis to allow adequate time for donor identification and transplantation planning.
- Age is not a major determinant of outcome after reduced intensity allogeneic transplantation; do not exclude patients on the basis of chronological age alone and refer older patients with good performance status early.
- Almost every patient with AML should be considered for a clinical trial, including those who are already in remission.
Although there are standard chemotherapy regimen (ara-C plus anthracycline). Many studies showed patients will benefit from the enhanced dose and/or prolonged duration of chemotherapy. First we discuss about the remission induction therapy and the two drugs – anthracycline (induction therapy) and ara-C (induction and consolidation therapy).
Trials from the Wouthwest Oncology Group, CALGB, and the Acute Leukemia French Association (ALFA) have shown high rates of complete remission with acceptable toxicity for intensified doses of daunorubicin 70-95 mg/m2 for 3 days. In a large randomized trial, the Eastern Cooperative Oncology Group (ECOG) demonstrated that doubling the daunorubicin dose from 45 to 90 mg/m2 for 3 days (cumulative dose, 270 mg/m2) resulted in both higher rates of complete remission and improved overall survival in patients with AML under the age of 60 years.
But there was no benefit with the higher dose in patients older than 50 years or in those with unfavorable cytogenetics. It can be concluded that dose intensification of daunorubicin to 90 mg/m2 for 3 days during induction should be strongly considered for AML patients <65 years of age with a good performance status and adequate baseline cardiac function.
The optimal dose of ara-C during AML induction and consolidation is controversial. Neither doubling the dose of ara-C from 100 mg/m2 to 200 mgm2 nor prolonging the infusion from 7 to 10 days resulted in additional benefit. Randomized trials of infusional ara-C 200 mg/m2 for 7 days versus 500 mg/m2 every 12 hours for 12 dose or 2 g/m2 every 12 hours for 12 doses did not result in improved overall survival, but a meta-analysis demonstrated the superiority of high-dose ara-C during induction, specifically with respect to long-term survival in patients <60 years of age. The National Comprehensive Cancer Network (NCCN) lists high-dose ara-C 2-3 g/m2 every 12 hours for 3 days in combination with daunorubicin or idarubicin as an alternative induction strategy, but recommends caution using this regimen outside of a clinical trial. Higher doses of ara-C (18 g/m2/cycle) have been standard for consolidation theray in younger patients since the early 1990s and are associated with a survival benefit in corebinding factor AML.
Prospective, randomized trials are still needed to clarify the timing, schedule, and total dose of ara-C for younger patients with AML not undergoing allogeneic transplantation.
Besides anthracycline and ara-C, other purine nucleoside analogs such as clofarabine, cladribine, and fludarabine have been used instead of and in addition to ara-C in a variety of induction regimens. But to date, none has proven to be superior to ara-C in AML induction or consolidation.
Treatment for Older AML Patients
Age ≥60 years has consistently been identified as an independent adverse prognostic factor in AML, and there are very few long-term survivors in this age group. Poor outcomes in elderly AML patients have been attributed to both host- and disease-related factors. Older patients with multiple poor-risk factors have a high probaility of early death and little chance of long-term disease-free survival with standard chemotherapy. In a retrospective analysis of 998 older patients treated with intensive induction at the M.D. Anderson Cancer Center, multivariate analysis identified age ≥75 years, unfavorable karyotype, poor performacne status, creatinine >1.3 mg/dL, duration of antecedent hematologic disorder >6 months, and treatment outside a laminar airflow room as adverse prognostic indicators. Patients with 3 or more of these factors had expected complete remission rates of <20%, 8-week mortality >50%, and 1-year survival <10%.
Despite the grim statistics, it is clear that selected older patients with AML will benefit from intensive therapy. For example, patients without adverse risk factors using the M.D. Anderson criteria have an expected complete remission rate of >60%, induction mortality of 10%, and a 1-year survival rate of >50%. Registry data from nearly 3000 unselected older patients in Sweden showed improved rates of eraly death and long-term survival in those treated with intensive therapy versus palliation. However standard chemotherapy using 3 days of 60 mg/m2 of daunorubicin or 12 mg/m2 of idarubicin with 100 mg/m2 of cytarabine for 7 days still carries the highest probability of complete remission and should be considered in older patients without multiple adverse-risk features who do not have the option of participating in a clinical trial.
Patients >60years of age, like younger patients, should be treated with the goal of achieving remission: complete remission is correlated with survival and quality of life after chemotherapy and also leads to better outcomes after allogeneic transplantation with reduced-intensity.
Remember that low-dose ara-C results in a complete remission rate of 18% and low-dose ara-C is almost never effective in patients with unfavorable cytogenetics.
Now there are no prospective, randomized trials confirming the benefit of postremission chemotherapy in older patients.
Allogeneic Stem Cell Transplantation
Allogeneic stem cell transplantation is probably still the most effective anti-AML therapy. With improvements in HLA matching, antimicrobial therapy, and management of GVHD, it is becoming increasingly feasible for more patients with AML to undergo the allogeneic stem cell transplantation. All AML patients with complex cytogenetics or monosomal karyotype who have a good performance status should be considered for allogeneic transplantation. However, posttransplantation quality of life data are very limited for patients >60 years of age.
MRD is short for Minimal Residual Disease. The current definition of complete remission in AML includes archievement of specific hematologic parameters and <5% BM myeloblasts by morphology. It has been clearly demonstrated that persistent cytogenetic and/or molecular abnormalities after induction chemotherapy are poor independent prognostic indicators in AML. For patients without baseline cytogenetic or molecular abnormalities, demonstration of MRD by multicolor flow cytometry is also correlated with inferior outcomes.
Why MRD exists? After treatment the leukemic cells are “left over” and eventually proliferate and cause disease relapse. This theory is supported by laboratory data. Now we can assume that these leukemic cells are, or arise from, so-called leukemia stem cells (LSCs). Whereas the exact characteristics of LSCs remain controversial, most agree that they are defined by their ability to recapitulate disease when transplanted into immunodeficient mice. Data suggest that AML is composed of biologically distinct leukemic stem, progenitor, and blast populations in which the LSCs comprise 0.1%-1% of the blasts and are largely quiescent but capable of endless self-renewal. A high frequency of LSCs at diagnosis is associated with a poor outcome in AML and, similarly, high expression of an LSC gene signature has also been independently associated with inferior survival. Funny the LSCs are well-hidden within the BM niche. LSCs have distinct characteristics, including aberrant surface, immunophenotype; dysregulated programs for survival, apoptosis, and differentiation; and complex interactions with their surrounding BM microenvironment, the LSC niche. All of these factors contribute to the incredible resilience of LSCs in surviving the harshest of antileukemic therapies, including allogeneic stem cell transplantation. Note that ara-C is ineffective against LSCs.
On the basis of this theory, if we could eliminate all LSCs, I believe the outcome of AML should be much better.
Finally, due to the heterogeneous pathogenesis and molecular genetics of AML, combination therayp may remain superior to any single agent and tailored, personalized treatment based on the specific biologic features of the leukemic cells should be the goal.