Although the chemotherapeutic agents used in the initial therapy for AML have not changed much in the past 30 years, our knowledge of the biology of leukemia has increased. The identification of prognostic factors can provide more realistic expectations of response to standard treatment and can define the population for whom investigational therapy is appropriate early in the course of disease.
Cytogenetic abnormalities are the major predictors of remission and risk of relapse for patients with AML. Patients with translocation of genetic material involving core binding regions [t(15;17), t(8;21) inv(16), or t(16;16)] have a good prognosis, with remission rates of 88% and 5-year DFS rates of 55% to 80%, whereas patients with loss of genetic material from chromosome 5 or 7 (–5 or –5q, –7 or –7q) and complex karyotypic abnormalities (defined as more than five abnormalities) have lower rates of CR (30% to 40%) and DFS (5%) at 5 years. Another poor-risk karyotype is t(3;3)(q21;q23), which is correlated with ecotropic viral integration site 1 (EVI1) expression. EVI1 expression also occurs in about 4% of patients with a normal karyotype and about half of those with the MLL gene rearrangement. In patients with the EVI1 gene rearrangement, the median survival is 10.3 months with 0% 5-year relapse-free survival.
With more detailed genetic mapping of leukemia cells, new molecular markers are being identified, which may explain some of the initiation events in transforming cells from normal to leukemic. Internal duplication of FLT3 can be found in one-third of patients with normal cytogenetics or in patients with t(15;17) (APL) but is uncommon in either poor-risk karyotypes or non-APL translocations. This abnormality does not appear to have an impact on remission, but it is a predictor for relapse (74% relapse rate in patients with a normal karyotype with an isolated FLT3 mutation vs 46% for patients with wild-type FLT3). In patients with otherwise favorable cytogenetic abnormalities [t(8;21) or inv(16)], the presence of c-KIT mutation increases the risk of relapse.
Mutations of nucleophosmin (nucleolar phosphoprotein B23, numatrin; NPM1) which shuttles nucleic acids and proteins from the nucleus to the cytoplasm as well as binding TP53, are also a commonly reported abnormality, present in 47% of patients with a normal karyotype. Although there is frequent overlap with FLT3 mutations, patients with an isolated NPM1 mutation and a normal karyotype have a 60% DFS vs 40% for those with either wild-type or mutations of both FLT3 and NPM1 and 20% for those with an isolated FLT3 mutation. Other molecular mutations in patients with normal cytogenetics that have been reported to favorably impact relapse-free survival are CCAAT enhancer binding protein alpha (CEBPA) and neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS), while MLL partial tandem duplication and RUNX1 mutations carry unfavorable implications. Recently, an updated genetic risk classification has been reported by the European LeukemiaNet (ELN) using data from a large German cooperative group trial which included 847 patients ages 18-60 and 710 patients over age 60. The favorable group now includes patients with normal karyotye (NK) with a mutation of NPM1 but no mutation of FLT3 and NK with CEBPA mutation as well as inv(16) or t(8;21). The intermediate group was subdivided into intermediate I (which included NK AML with wild-type NPM1 NPM1-negative) and either mutated (FLT3-positive) or wild (FLT3-negative) or with mutations of both NMP1-positive and FLT3-positive. The ratio of FLT3-ITD mutation to the normal allele was also an important factor with significantly shorter survivals in patients with a ratio > 0.8. Intermediate II included t(9;11) (p22;q23) and other cytogenetic abnormalities not listed in either favorable or unfavorable. The unfavorable group included inv(3) (q21;26A) of t(3;3), t(6;9) (p23;q34) t(v;11)(v;q23) MLL rearrangements -5,del5q,-7,abn(17p) and complex karyotypes. Among patients under age 61, those in the intermediate I group had a higher rate of relapse and a lower relapse-free survival but similar overall survival compared to intermediate II. Among older patients there was no difference between intermediate I and II.
Poor-risk cytogenetics, antecedent MDS, and a high incidence of ATP-binding cassette, sub-family B (MDR/TAP), member 1 (ABCB1) protein are found more commonly in patients older than age 60, which has been used to explain the lower CR rates (30%–55%) seen in older individuals compared with their younger counterparts (60%–80%). Many older patients with preexisting MDS may clear marrow blasts with antileukemic treatment but may still have impaired hematopoiesis and persistent cytopenias, since they may have no residual normal stem cells to repopulate the marrow.
Ara-C and an anthracycline such as daunorubicin(Drug information on daunorubicin) or idarubicin(Drug information on idarubicin) have been the standard drugs used for AML induction chemotherapy for 30 years (Table 4). Depending on the prognostic groups, remission rates of 60% to 80% are seen in younger (< age 60) patients and of 35% to 55% in patients older than age 60. Recent studies have focused on optimizing anthracycline dosing. In 2009, the ECOG published results of a phase III trial comparing the prior standard dose of daunorubicin (45 mg/m2) with 90 mg/m2, both given on days 1 to 3 along with 7 days of infused cytarabine(Drug information on cytarabine) (100 mg/m2/d). CR rates were higher for the group using high-dose daunorubicin than for those using the standard dose (71% vs 53%, respectively), and median survival was also improved (23.7 vs 15.7 months) in patients up to 60 years of age. A large European consortium study by Lowenberg et al compared the same doses in patients over 60 years of age; after the first remission, an improved CR rate in the high-dose daunorubicin group (52%) when compared with the lower-dose group (35%) was reported. The 30-day mortality was 11% and 12%, respectively. Patients 60 to 65 years of age benefitted most and exhibited a higher event-free survival (29% vs 14%) and OS (38% vs 23%).
The French ALFA 9801 study compared 80 mg/m2 of daunorubicin for 3 days with 12 mg/m2 of idarubicin given for 3 or 4 days along with standard infusion of cytarabine in 468 AML patients between the ages of 50 and 70 years. After two consolidation courses based on intermediate cytarabine doses, patients in continuous remission were randomly assigned to receive or not receive maintenance therapy with recombinant interleukin (IL)-2 for 12 months. CR rates were 70% for those using daunorubicin, 83% for those using idarubicin for 3 days, and 78% for those using idarubicin for 4 days. There was no difference in relapse incidence, event-free survival, or OS. At 2 years, event-free survival was 23.5%, and OS was 38%. Neither intensification of anthracycline doses nor maintenance with recombinant IL-2 impacted the course of AML significantly. This implies that idarubicin at 12 mg/m2 for 3 days should produce response equivalent to 90 mg/m2 of daunorubicin for 3 days.
Previous attempts to improve outcomes in patients under age 60 focused on dose escalation of cytarabine in induction and/or consolidation. Both the ALSG and the SWOG compared standard Ara-C and daunorubicin (and etoposide(Drug information on etoposide) in the ALSG trial) with HDAC in patients < 50 years (Table 4). The CR rates were 71% and 74% for standard vs high-dose therapy in the ALSG study and 55% vs 58% in the SWOG trial. In both studies, there was a significantly higher DFS for the high-dose arm at 5 years (48% vs 25% for ALSG and 33% vs 22% for SWOG) but no difference in OS due to increased early toxicity.
Subgroups of patients may benefit from HDAC. In the SWOG trial, patients with CD34+ blasts had a low CR rate of 36% with standard Ara-C but an equivalent rate in those with CD34− blasts (58%) when treated with HDAC. There was a strong correlation between CD34 positivity and expression of ABCB1, the transporter protein associated with intracellular clearance of drugs in this cohort, leading to the inference that HDAC might help overcome drug resistance.
However, a 1,700-patient German trial showed no difference in DFS when 2 cycles of HDAC and mitoxantrone(Drug information on mitoxantrone) (HAM) were compared with 1 cycle of the standard Ara-C–containing regimen followed by HAM. The overall DFS was 40% for both arms in patients younger than age 60 and 29% for those older than age 60; 80% of young patients received both cycles, whereas only one-third of patients over 60 received cycle 2 irrespective of dose intensity of the initial cycle. Other agents such as mitoxantrone and etoposide also have antileukemic activity, but no significant increase in remission rates or relapse-free survival has been seen when mitoxantrone was substituted for an anthracycline or etoposide was added to infusional Ara-C and daunorubicin.
Gemtuzumab ozogamicin (Mylotarg), an anti-CD33 antibody conjugated to calicheamicin, was originally given accelerated approval by the FDA in 2000 for the treatment of relapsed AML in older patients after showing a 16% to 23% remission rate when used as a single agent. However, a large, randomized, phase III study conducted in the United States failed to show any improvement in remission rate when combined with cytarabine and daunorubicin in initial induction for patients under age 60. In addition, early mortality during induction was higher in the gemtuzumab arm (5.7%) than in the standard therapy arm (1.4%). The drug was withdrawn from the commercial market as of October 2010. It has shown benefit in treating relapsed APL and in initial therapy of high-risk APL in older patients when combined with arsenic trioxide(Drug information on arsenic trioxide) (Trisenox) and all-trans retinoic acid (ATRA, Tretinoin(Drug information on tretinoin), Vesanoid).
Therapy-related AML has a particularly poor prognosis. At best, only 50% of patients will achieve a remission, usually of brief duration (median, 5 months), despite the use of aggressive drug combinations. Allogeneic or unrelated-donor transplants appear to offer the only curative option in these patients, achieving a 3-year DFS rate of 25% in two studies of allogeneic transplantation.
Initial treatment of AML in older patients
The majority of AML patients are older than 60 years and constitute a group whose disease has a higher prevalence of unfavorable cytogenetics. Many also have poor marrow regenerative characteristics due to prior myelodysplasia. These patients are frequently burdened with comorbid conditions, which make them poor candidates for conventional Ara-C/anthracycline-based chemotherapy. Cytogenetics and performance status were the two most important predictive factors in this age group, followed by age in 5-year increments and secondary AML.
Mitoxantrone and etoposide were compared with Ara-C and daunorubicin as induction for patients older than age 55 in SWOG trials; CR rates were 44% for Ara-C and daunorubicin and 33% for mitoxantrone and etoposide, and median survival was 8 and 6 months, respectively. Older patients (> 65 years) with poor-risk cytogenetics have a CR rate of < 30% with standard induction chemotherapy, whereas those with a normal or favorable karyotype have a CR rate of 45% to 50%.
Thus, before initiating chemotherapy for older patients, it may be helpful to await the results of cytogenetic and molecular mutational profiles before choosing conventional chemotherapy in those "fit" for such therapy. Recent trials from the GLSG showed a benefit to chemotherapy in patients older than age 60 using Ara-C, idarubicin, and etoposide in those with either favorable cytogenetics or normal karyotypes with NPM1-positive/FLT3-negative mutational status, with a CR rate over 60% and a remission duration of 1,125 days. In other subgroups, the remission rates were 42%, with a remission duration of 440 days, and only 210 days for those who were FLT3-positive. Given these underwhelming outcomes combined with 30-day mortality in excess of 15% in many trials of Ara-C–based chemotherapy, new agents are being assessed as initial therapy for patients with abnormal karyotypes.
Given that 25% to 35% of older patients have a history of cytopenias or chemotherapy for a prior malignancy, trials of hypomethylation agents such as azacitidine (Vidaza) or decitabine (Dacogen) have been reasonable starting places. The original phase III trials of azacitidine for treatment of high-risk MDS included over 100 patients who would now be classified as having AML (20%–30% blasts in marrow). The 2-year OS for this group was 50% for those treated with azacitidine vs 16% for those treated with supportive care. Trials of decitabine (20 mg/m2 IV over 1 hour daily for 5 days) reported a CR rate of 26% when used alone or 49% when given at the same dose for 10 days combined with valproic acid. Clinical trials combining decitabine with a histone deacetylating agent, such as vorinostat (Zolinza), are now in progress.
Clofarabine is also being evaluated as a single agent for older patients with AML. In phase II trials using a dose of 30 mg/m2 IV for 5 days for induction therapy, CR was achieved in 38% of patients older than age 60 (median, 71 years). Patients achieving remission received a maximum of 6 cycles of consolidation therapy (at 20 mg/m2 for 5 days). The median DFS was 37 weeks, with a median survival of 59 weeks for those achieving CR or complete pathologic response. The 30-day mortality was 10% for those older than age 70. A British trial in a similar population also had a CR of 32% with an additional 16% CR with incomplete count recovery. Mortality at 30 days was higher (18%). The median OS was 19 weeks and 5 weeks for those not achieving CR. At the present time, the FDA has not approved the use of clofarabine for older AML patients pending the outcome of ongoing phase III comparative induction trials.
Once remission of AML is attained, consolidation chemotherapy is required to achieve a durable remission or cure. Standard consolidation regimens are listed in Table 4.
In a CALGB study, 596 patients in CR were assigned to receive 4 courses of postremission Ara-C in one of three dosages: 100 mg/m2 as a continuous infusion for 5 days, 400 mg/m2 as a continuous infusion for 5 days, or 3 g/m2 as a 3-hour infusion every 12 hours on days 1, 3, and 5. For patients ≤ 60 years old, the percentage of patients in CR at 4 years was significantly higher in the HDAC group (44%) than in either the 400-mg/m2 or 100-mg/m2 group (29% and 24%, respectively). For patients > 60 years old, consolidation dose intensity had no impact on DFS, with all groups plateauing at a rate of 16% by 2 years. However, more recent information suggests that for the small subset of patients with favorable cytogenetic or molecular markers, modified HDAC (1.5 to 2 g/m2) may improve outcomes in patients 60 to 70 years of age.
Other approaches to consolidation therapy include 1 to 3 cycles of consolidation followed by autologous or allogeneic hematopoietic stem cell transplantation (HSCT). Historically, both of these approaches also tend to be limited to patients < 60 years old and have produced long-term DFS rates of 45% to 60% in several studies. Long-term DFS is strongly influenced by cytogenetic and molecular abnormalities present at diagnosis. Transplant options should be considered for patients with high-risk features while in first remission, due to poor outcomes with conventional chemotherapy. However, patients with t(8;21), inv(16), or isolated NPM1 mutations can expect a 60% relapse-free survival following 3 to 4 cycles of HDAC. For these patients, HSCT should be reserved for relapse or CR2. Molecular mutations are being used to identify patients with normal karyotypes with a high risk (≥ 50%) of relapse for whom multiple cycles of HDAC consolidation therapy will not be sufficient to prevent relapse. For older patients, the data on the benefits of consolidation therapy are less clear. High-dose cytarabine with some dose modifications is a reasonable option for patients 60 to 65 years with favorable cytogenetic/molecular profiles, but for the majority of older patients there is little evidence that more than 1 cycle of standard-dose consolidation therapy is better than the more intensive regimens. In patients who recover with dysplastic marrows without frank leukemia, many practitioners will institute therapy using hypomethylating agents to forestall the subsequent evolution to AML. Trials assessing this strategy are in progress.
Reduced-intensity conditioning regimens are being employed as treatment options in older patients and in those with comorbidity that would otherwise preclude full-dose allogeneic transplantation. Preliminary results from several centers have shown 1- and 2-year DFS rates of 50% for patients aged 55 to 70 years receiving reduced-intensity allogeneic transplantation for consolidation of first remission.
CNS prophylaxis is not routinely recommended for adult patients with AML. Exceptions for which a screening lumbar puncture should be considered following remission induction therapy include those at high risk for CNS recurrence, ie, patients with a WBC count > 50,000/μL at presentation or those with myelomonocytic or monocytic AML (FAB M4 or M5). Patients receiving HDAC (≥ 2 g/m2) for induction or consolidation therapy achieve therapeutic drug levels in the cerebrospinal fluid, obviating the need for intrathecal therapy. Patients given conventional Ara-C doses may be treated with intrathecal (IT) methotrexate (12 mg IT) or Ara-C (30 mg IT). Both agents can be combined with hydrocortisone(Drug information on hydrocortisone) (30 mg IT) for patients with active CNS disease.
Treatment of Refractory or Relapsed AML
Patients who do not respond to initial therapy or who relapse within 6 months of attaining CR, as well as those with antecedent myelodysplasia or therapy-related AML, are considered to have relatively resistant disease.
Efforts to overcome drug resistance have focused on (1) HDAC-containing regimens, (2) new agents, and (3) targeted therapy using leukemia-specific monoclonal antibodies conjugated with radionuclides or toxins.
HDAC High doses of Ara-C (2–3 g/m2 for 8–12 doses) paired with mitoxantrone, etoposide, methotrexate(Drug information on methotrexate), or fludarabine have produced short-lived CRs in 40% to 60% of relapsed patients with AML (see Table 5 for dosage regimens). Response rates were higher in patients who had received standard-dose Ara-C for induction therapy and who had subsequently relapsed than in those in whom induction therapy had failed. The median duration of remission was 4 to 6 months.
Combinations of mitoxantrone and etoposide have been reported to produce a 40% to 50% CR rate in patients who had relapsed or for whom standard-dose Ara-C and anthracycline had failed, again with a median duration of remission of 4 to 6 months. Combinations of intermediate-dose Ara-C (1 g/m2/d for 6 days) with mitoxantrone and etoposide produced CR rates of 79% in relapsed patients and 46% in those who did not respond to induction therapy or had AML evolving from MDS, with a median CR duration of 8 months.
New agents Nucleoside analogs, such as cladribine(Drug information on cladribine) (2-CdA) and fludarabine, showed activity in pediatric AML. A British trial reported a 61% CR rate for a combination of fludarabine, Ara-C, G-CSF, and idarubicin, with a median CR duration of 7 months. Clofarabine showed a 16% remission rate in a phase I/II trial in patients with relapsed AML as a single agent and a 38% remission rate when combined with Ara-C (1 g/m2).
Targeted therapy Sorafenib(Drug information on sorafenib) (Nexavar), a small molecule kinase inhibitor, has shown activity in FLT3-positive AML. Sorafenib was combined with 1.5 g/m2 of cytarabine plus idarubicin in a phase I/II trial of relapsed refractory AML. CRs were achieved in 14 of 15 FLT3-positive patients and 24 of 36 unmutated patients with a 1-year OS of 74%, but 10 of 14 of the FLT3-positive had relapsed. Tosedostat, an oral aminopeptidase inhibitor was tested in a phase I/II trial in older patients with relapsed AML or in those who were "unfit " for standard induction therapy at a maximum total dose of 130 mg daily. Seven of 51 patients achieved clearing of marrow blasts and another seven had greater than 50% reduction in marrow blasts to between 5% and 15%. The majority of responders had marrow blasts less than 40% at the start of therapy with responses lasting 1 to 6 months. Synergy has been shown in vitro between this drug and agents such as ATRA, cytarabine, and bortezomib(Drug information on bortezomib).
Transplantation for relapsed disease Although none of the previous options currently offers more than a 10% to 15% chance of long-term DFS, they do provide temporary cytoreduction sufficient to permit further allogeneic HCT from sibling or unrelated donors. Allogeneic HCT achieves a 30% to 40% DFS rate at 5 years in patients transplanted during first relapse or second remission. Autologous bone marrow transplantation also has curative potential for patients beyond first CR, with most large series reporting DFS rates of 30% to 35% in selected patients (usually those with good-risk cytogenetics or initial CR duration longer than 1 year).
New methods of hematopoietic cell purging and post-transplant immune stimulation also are being explored to decrease relapse-related mortality.