Case study 8.1

A 45-year-old man with no past medical history presents with easy bruising and pancytopenia, and he is diagnosed with acute myeloid leukemia (AML). Further work-up, including cytogenetic analysis, reveals inv(16) karyotype in all metaphases. He would like to know first about his prognosis and then about goals of therapy.

1. What should you tell him?

He has an adverse prognosis. His disease is characterized by low response to front-line chemotherapy and frequent relapses; treatment will be composed of two cycles of palliative chemotherapy, followed by observation and comfort care
He has a relatively good prognosis. His treatment will consist of eight cycles of intense multiagent chemotherapy with a good response rate, followed by 2 years of maintenance therapy with oral chemotherapy
He has a relatively adverse prognosis with a low response to front-line therapy. His treatment will consist of a round of high-intensity chemotherapy followed immediately by allogeneic stem cell transplantation (SCT)
He has a relatively good prognosis with good response to front-line chemotherapy and very good potential for long-term benefit. His treatment will consist of a round of intense chemotherapy followed by three or four more cycles of high-dose chemotherapy

Several studies investigating variations of induction and consolidation approaches in core binding factor (CBF) AML have demonstrated complete remission (CR) rates of >90% and overall survival (OS) rates of about 70% at 5 years or longer. Three to four cycles of high-dose ara-C-based consolidation are an important part of treatment for CBF leukemias. The goal of therapy is to achieve a CR, followed by postremission consolidation to maintain remission and contribute to long-term OS. CR in AML is defined by a bone marrow blast count of <5%, and recovery of peripheral absolute neutrophil count to >1000 and platelets to >100,000. Given the excellent long-term prognosis associated with CBF leukemias, allogeneic bone marrow transplant is typically not considered for patients in first remission. Recent data suggest that it may be possible to identify patients with CBF leukemia who are destined not to do well perhaps by identification of those patients with an associated c-KIT mutation or those with persistent minimal residual disease after induction and consolidation. Identification of c-KIT mutants may also be important therapeutically as these leukemias may be susceptible to the effects of KIT kinase inhibitors.

Case study 8.2

A 62-year-old man is referred to you with pancytopenia and a new diagnosis of AML. His karyotype includes multiple chromosomal abnormalities, including −5, −7, +8, and 17p−. He has been told by his local oncologist that these portend an overall adverse prognosis with a lower rate of remission, high rate of relapse, and shortened OS using traditional regimens.

1. Is this true?

This patient’s AML is characterized by multiple (≥3) abnormalities, including the presence of multiple monosomies. Complex karyotype, defined variably as ≥3, ≥4, and ≥5 abnormalities, has long been regarded as conferring the most adverse prognosis in AML—characterized by low response rates, high relapse rates, and poor long-term outcome. Recently, this definition of adverse, complex karyotype has been further refined by the introduction of the “monosomal karyotype” (MK). MK is defined as a karyotype with ≥2 distinct autosomal chromosome monosomies OR a single autosomal monosomy in the presence of an additional chromosomal structural abnormality. By this definition, this patient has an MK. Multiple studies comparing MK to the previously defined “complex karyotype” demonstrate improved prognostication and the identification of a subgroup of AML with an extremely adverse outcome. For example, Haferlach et al. (2012) compared the significance of MK to complex karyotypes (defined as ≥3 or 4 abnormalities (abnl)). The found that the MK predicted for an even more adverse prognosis than a complex karyotype (≥3 abnl) without MK and added further negative prognosis to those with complex and ≥4 abnl. The incidence of an MK karyotype in newly diagnosed AML appears to increase with increasing age: it is present in 6–10% of patients under age 60, but in up to 20% of patients >60. The MK confers a very adverse prognosis at any age, however. CR rates range from 24% to 50% in patients <60 years and only 13–34% in those >60. Overall survival rates are equally poor: 17–40% at 4 years in patients ≤30 years, 3–4% at 4 years in patients <60 years, and 1% at 4 years in patients >60 years. Such poor outcomes with standard approaches to treatment argue for newer, innovative approaches and clinical trials for this population. Due to the poor outcomes with standard therapies, these patients should be considered for investigational clinical trials and for early allogeneic SCT in first remission in appropriate candidates.

Case study 8.3

A newly diagnosed 37-year-old man with AML is found to have a FLT3–ITD mutation and is clearly concerned about his prognosis with standard therapy.

1. Are there any ways to target FLT3 abnormalities in AML?

As mentioned in Case studies 8.1 and 8.2, mutated FLT3 leads to constitutive activation of this receptor tyrosine kinase, and several small-molecule tyrosine kinase inhibitors are currently in investigational development for the treatment of FLT3-mutated AML. In a phase I–II study of sorafenib in combination with idarubicin and cytarabine in patients with AML, Ravandi et al. (2010) demonstrated an overall CR rate of 75%. In patients with FLT3 mutations, the CR rate was 93%, with a 1-year OS rate of 74%. Correlative studies showed an on-target effect of sorafenib on FLT3, and the combination was well tolerated. Stone et al. (2012) studied the combination of midostaurin with daunorubicin and cytarabine in patients with AML. The CR rate was 80% in all patients overall, but 92% in those patients with FLT3-mutated AML. Importantly, the OS rates for FLT3-mutated patients at 1 and 2 years were 85% and 62%, respectively. These rates were similar to those with FLT3 wild type, suggesting that the addition of midostaurin may have negated the negative impact of the FLT3 mutation. Further studies to confirm these observations are ongoing. AC220 (quizartinib) is a new, potent FLT3 inhibitor that is currently in development. After positive results in a phase I trial, Cortes et al. (2012) recently presented the final results of a phase II trial of single-agent quizartinib in patients with relapsed and refractory AML regardless of their FLT3 mutation status. The composite CR, CR with incomplete platelet recovery (CRp), and CR with incomplete hematologic recovery (CRi) rate was 32% in patients without FLT3–ITD mutations and 54% in those with a FLT3–ITD mutation. The OS in those with FLT3–ITD(+) AML treated with quizartinib was 25 weeks. These high response rates with single-agent quizartinib in a relapsed population are encouraging and have led to several ongoing studies of this agent in frontline AML in combination with chemotherapy. Our approach to patients with FLT3-mutated AML involves risk stratification based on FLT3 mutation, allelic burden, and enrolling in an investigational trial implementing an FLT3 inhibitor when available. Newer studies involving inhibitors of FLT3–TKD mutations are also ongoing and may be an important breakthrough for that subset of patients.

Case study 8.4

A 34-year-old female with no past medical history and no siblings presents with a new diagnosis of AML. Her bone marrow reveals 78% blasts with a myeloid immunophenotype and no evidence of dysplasia. Cytogenetics are diploid. Mutational screening is negative for FLT3, NPM1, or CEBPA mutations. She comes to see you for treatment options. She would like to know about the “standard” treatment, the overall plan, and goals of treatment.

• What should you tell her?

The case presented is of a young woman with newly diagnosed AML with a normal karyotype and no known molecular aberrations. Overall, she has intermediate-risk disease with none of the known favorable (CBF cytogenetics, NPM1 mutation, and bi-allelic CEPBA mutation) or unfavorable (adverse karyotype, dysplasia, and FLT3 mutation) characteristics. Her question regarding standard therapy in AML is a challenging one. Despite advances in understanding the biology of AML, there have been few changes in the treatment strategies used for the majority of patients. Outside of academic centers, the “standard” induction therapy for AML has been described as a combination of 7 days of cytarabine (ara-C) at a dose of 100–200 mg/m²/d with an anthracycline (daunorubicin or idarubicin) during days 1–3; this is typically referred to as the 7+3 regimen. Following documentation of remission, the response is consolidated with four cycles of high-dose ara-C. Achieving a CR after induction chemotherapy is the most important factor predicting a favorable outcome and prolonged overall survival. Based on this approach, Mayer et al. (1994) reported a CR rate of 64%, and 4-year disease-free survival (DFS) and OS rates of 39% and 46%, respectively. The rates of CR, DFS, and OS were lower with increasing age. Multiple randomized trials have attempted to improve response rates and survival using newer agents and variations in doses. Important areas of investigation have included (i) dose of anthracycline, (ii) choice of anthracycline, (iii) dose of ara-C, and (iv) additional nucleoside analogs to implement three drug combinations.

• Is the dose of the anthracycline important? What is the optimal dose?

Intensifying the dose of daunorubicin above the “standard” 45 mg/m² has been suggested as means to achieve higher CR rates and prolong overall survival. Several single-arm studies have investigated higher doses ranging from 60 mg/m² to 90 mg/m², suggesting improved response rates. Investigators from ECOG conducted a study in newly diagnosed AML patients ≤60 years of age, randomizing them to therapy with daunorubicin 45 mg/m²/d × 3 days versus 90 mg/m²/d × 3 days, each in combination with ara-C 100 mg/m²/d × 7 days. 582 patients were evaluable with a median age of 48 years. The CR rate (57% vs. 71%; P < 0.001) and median OS (15.7 vs. 23.7 months; P = 0.003) were significantly better in the higher-dose daunorubicin arm. There were no differences in the rate of serious adverse events in the two arms, and the death rates were similar (4.5% (low-dose) vs. 5.5%; P = 0.6). The greatest benefit was seen in patients with intermediate-risk disease, while those with adverse cytogenetics or FLT3 mutation did not benefit. In a separate study based on these patient samples, Patel et al. (2012) performed an 18-gene mutational analysis to identify pretreatment genetic abnormalities that would predict for benefit from high-dose daunorubicin. They demonstrated that high-dose daunorubicin significantly improved outcomes in those patients whose AML had mutations in DNMT3A, NPM1, or translocations involving MLL.

In a study similar to the ECOG trial, the European Hemato-Oncology Cooperative Group and the Swiss Group for Clinical Cancer Research (HOVON/SAKK) cooperative group investigated the same question of 45 mg/m² versus 90 mg/m² of daunorubicin, but in patients above the age of 60. The treatment plan randomized patients to daunorubicin 45 mg/m²/d × 3 days versus 90 mg/m²/d × 3 days, each in combination with ara-C 200 mg/m²/d × 7 days. A total of 813 patients were evaluable, with a median age of 67. The CR rate was higher (65% vs. 54%; P = 0.002) in the higher-dose arm. However, there was no difference seen between the two groups with regard to event-free survival (EFS) (P = 0.12), DFS (P = 0.77), or OS (P = 0.16). The 30-day mortality rate was similar in the two groups (12% vs. 11% in the high-dose group). The 2-year cumulative incidence of relapse was 61% versus 54% (in the high-dose group). However, this was offset by the increased rate of death in CR in the higher-dose group (10% vs.16%). In a post-hoc subgroup analysis, patients between the ages of 60 and 65 may have had some significant benefit with the higher-dose daunorubicin, including a better rate of CR (51% vs. 73%), 2-year EFS (14% vs. 29%; P = 0.002), and 2-year OS (23% vs. 38%; P = 0.001). Based on these data, higher-dose daunorubicin appears to be superior to the 45 mg/m² dose in younger patients with intermediate- or low-risk disease. The question remains whether an intermediate dose of 60 mg/m² is sufficient to improve outcomes and avoid excess toxicity—especially in the older AML population. This remains the subject of future clinical trials.

• Is the choice of anthracycline for induction in AML important?

Following from the question of dose intensity of anthracycline during induction of AML comes the question of choice between daunorubicin and idarubicin. Several comparisons between idarubicin and daunorubicin have been conducted to resolve this debate, including a collaborative meta-analysis of five trials suggesting that treatment with idarubicin had higher rates of CR and overall survival. However, many of these studies have been fraught with dose inequalities when comparing 12 mg/m² of idarubicin to now “substandard” doses of daunorubicin. The Acute Leukemia French Association (ALFA) has conducted a number of studies to investigate this issue. In a randomized trial of 468 evaluable patients with AML and a median age of 60, Pautas et al. (2010) compared daunorubicin 80 mg/m²/d × 3 (DNR) versus idarubicin 12 mg/m²/d × 3 (IDA3) versus idarubicin 12 mg/m²/d × 4 (IDA4), each in combination with ara-C 200 mg/m²/d × 7. In this study, IDA3 was found to have a significantly superior CR rate compared to DNR (83% vs. 70%; P = 0.007). This superior response was also seen in patients with unfavorable karyotype. There were no significant differences in induction deaths or serious adverse events, except for slightly more mucositis with IDA. There was a trend for better 4-year EFS (12% vs. 21% for IDA3) and OS (23% vs. 32% for IDA3), but these did not reach statistical significance. In a more recent follow-up analysis of two large trials comparing idarubicin to daunorubicin, the ALFA group evaluated 727 patients who had received either DNR or IDA3. IDA3 was associated with a significantly higher CR rate (69% vs. 61%; P = 0.029). Although the OS was similar between the two groups, the investigators found a significantly higher cure rate associated with IDA3 compared to DNR (16.6% vs. 9.8%; P = 0.018). Based on the available data, treatment with idarubicin 12 mg/m²/d 3× may be at least as good as, if not better than, high-dose daunorubicin (90 mg/m²/d 3×). At the University of Texas MD Anderson Cancer Center, we favor the use of idarubicin over daunorubicin for induction therapy of younger patients with AML.

• Is the dose of cytarabine (ara-C) during induction of AML important? Is there an optimal dose?

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8: Induction Therapy in Acute Myeloid Leukemia

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