Case study 9.1

A 49-year-old male with a new diagnosis of acute myeloid leukemia (AML) with t(8;21) as a single cytogenetic abnormality and no molecular mutations comes in for a second opinion. He presents to your clinic after undergoing standard chemotherapy with continuous infusion cytarabine at 100 mg/m² daily and 90 mg/m² daunorubicin. His induction course was complicated by Escherichia coli sepsis and intensive care unit admission, which resolved without long-term sequelae. After achieving complete remission, he is reluctant to receive further chemotherapy and asks, “Is further treatment worth it if I’m likely to die anyway?”

• Why is postremission therapy important in AML?

Although up to 80% of patients younger than 60 years of age will enter complete remission (CR) following a standard induction regimen, essentially all patients will relapse without further therapy. The Eastern Cooperative Oncology Group (ECOG) showed that 100% of patients in CR randomized to receive no further therapy relapsed at a median time of 4.1 months, with all patients relapsing by 17 months. These patients experienced significantly inferior remission durations compared to those randomized to maintenance, and these findings led to early termination of this trial. A subsequent ECOG trial demonstrated that two cycles of postremission chemotherapy followed by maintenance led to longer duration of remission and improved 2-year survival. Similarly, the German AML Cooperative Group (AMLCG) demonstrated no long-term survivors in patients not receiving consolidation therapy.

• How can risk-adapted strategies be used to select postremission therapy for younger adults with AML?

Although there is wide variation in consolidation regimens across different cooperative groups, current evidence supports the use of a risk-adapted strategy emphasizing the use of consolidation chemotherapy for patients with good-risk disease and allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with adverse-risk disease. (The treatment of acute promyelocytic leukemia has been revolutionized by the use of all-trans retinoic acid and arsenic trioxide; as it is now completely distinct, it will not be discussed further here.) Most of these data were generated from “genetic randomization” studies in which patients with matched allogeneic bone marrow donors undergo allo-HSCT, whereas those without a donor receive consolidation chemotherapy. These studies have consistently demonstrated that patients with favorable risk cytogenetics do not benefit from allo-HSCT in first CR (CR1) and should receive consecutive cycles of postremission chemotherapy. Conversely, a significant improvement in survival is noted in patients with adverse-risk disease following allo-HSCT. Patients with intermediate-risk features also appear to have a small, but significant, benefit with transplantation. The introduction of testing for molecular abnormalities in AML has further refined this classification by subdividing the normal-karyotype (intermediate-risk) patients into good-risk genotypes (NPM1-mutated and FLT3-wild-type, and bi-allelic CEBPA mutation) and poor-risk genotypes (the FLT3 ITD mutation and ASXL1 mutation). The impact of risk-adapted strategies on the outcome of molecularly characterized patients needs to be fully characterized, although some data suggest that NPM1-mutated, FLT3-wild-type patients should not undergo allo-HSCT in CR1, whereas all other molecular genotypes may benefit.

• Is there a standard postremission regimen for younger patients with AML in CR1 who are not candidates for allo-HSCT?

For favorable-risk patients with CBF–AML, postremission therapy with multiple cycles of high-dose cytarabine (HDAC) has been shown to significantly improve relapse-free and overall survival (OS) compared to either standard doses of cytarabine or multi-agent chemotherapy. Autologous transplant (auto-HSCT) after at least one cycle of HDAC appears to lead to equivalent outcomes in this patient population, although a direct comparison has not been performed. Patients with normal-karyotype AML that is positive for the NPM1 mutation and negative for the FLT3 ITD mutation also appear to benefit from intensive therapy with either multiple HDAC cycles or autologous transplant. The optimal postremission therapy for intermediate-risk patients not undergoing allo-HSCT remains controversial, with some studies showing little benefit of high-dose cytarabine therapy compared to a variety of intensive standard-dose regimens, and others demonstrating a small but significant benefit of multiple cycles of HDAC for intermediate-risk patients. For poor-risk patients, different chemotherapy regimens have consistently failed to improve disease-free survival (DFS) or OS rates; thus, allo-HSCT remains the gold standard for these patients. Adverse-risk patients who are unable or ineligible for allo-HSCT in CR1 may derive a small benefit from HDAC-based regimens (particularly patients with monosomal karyotype), although the benefit is minimal and may not be of clinical significance.

The most commonly used postremission regimen is HDAC, which consists of 3000 mg/m² Q12h of cytarabine given on days 1, 3, and 5 for three to four total cycles. There is, however, significant evidence that regimens utilizing lower cytarabine doses of 2000 mg/m² every 12 hours on days 1–5, or even 1000 mg/m² every 12 hours on days 1–6 may produce similar outcomes. Standard-dose postremission regimens use infusional cytarabine at doses between 100 mg/m² and 400 mg/m² for 5 days combined with two doses of anthracycline. Such regimens may be a reasonable option for patients with intermediate- or poor-risk disease who are ineligible for transplant and are deemed unable to tolerate HDAC therapy. Last, the addition of gemtuzumab ozogamicin (GO) to conventional regimens results in improved survival in patients with favorable- and intermediate-risk AML. GO does not appear to be effective in the setting of auto-HSCT.

There also remains significant debate regarding the optimal number of cycles of postremission therapy. The majority of trials to date have utilized a total of three cycles of therapy (either as a single induction followed by two consolidation cycles, or as a double induction followed by a single consolidation cycle). However, controversy still remains. Data from Cancer and Leukemia Group B (CALGB) studies suggest that three to four cycles of HDAC consolidation (after a single induction) are superior to one HDAC consolidation for favorable cytogenetic risk. The CALGB also retrospectively compared four total cycles to five total cycles (single induction plus three or four courses of HDAC) for patients with normal-karyotype AML and demonstrated a significant recurrence-free survival (RFS) benefit of the fourth HDAC cycle in this group. An alternative approach was taken by the Australasian Leukemia and Lymphoma Group, which utilized a highly dose-intense, HDAC-based induction (idarubicin, cytarabine, and etoposide) followed by randomization to either a second identical cycle or two cycles of standard-dose cytarabine consolidation therapy. Outcomes between the two groups were equivalent and similar to previously described results. The Finnish Leukemia Group compared four total cycles of therapy (double induction plus two HDAC consolidations) to eight total cycles (double induction plus six consolidations) and demonstrated no benefit to the additional consolidation cycles. However, this study included only a small number of patients with favorable-risk cytogenetics (6%). In summary, >4 cycles of therapy may be ideal for younger patients; however, fewer cycles may yield comparable outcomes if a sufficiently dose-intense HDAC regimen is used for induction.

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