Treatment Updates: Acute Myeloid Leukemia

TON - May 2010 Vol 3, No 3 — June 2, 2010

Acute myeloid leukemia (AML) is a heterogeneous disease affec ting approximately 13,000 people in the United States each year.1 For younger adults (<60 years) standard induction treatment includes 7 days of cytarabine and 3 days of an anthracycline. Adults 60 years and older may also be treated with this regimen or a less intensive approach using outpatient chemotherapy or supportive care. The intensive chemotherapy regimens have been in use since the 1970s, with little improvement in complete re sponse (CR) rate or overall survival (OS). Many of the clinical trials that have been reported in the past year investigate the ability to improve the efficacy of these intensive chemotherapy regimens by increasing dose intensity or adding novel agents to induction therapy.

More intensive regimens

One significant update was an intensified induction approach in adults who were younger than 60 years. In the Eastern Cooperative Oncology Group E1900 phase 3 trial, investigators randomized patients to either intensified daunorubicin (90 mg/m2 intravenous [IV]  3 days) or standard daunorubicin (45 mg/m2 IV  3 days).2 All patients also received 7 days of cytarabine (100 mg/m2 continuous IV infusion).

End points were evaluated in a total of 547 patients. The median age was 48 years, with other demographics, cytogenetics, and characteristics well matched at baseline. Median OS was significantly increased in the intensified-daunorubicin arm at 23.7 months compared with 15.7 months in the standard arm (P <.003). The CR rate was also higher in the intensified-daunorubicin arm (71% vs 57%; P <.001). The combination of an increased CR rate and an OS advantage is important, especially considering that previous trials with more intensive induction regimens have shown an increased CR rate without a significant increase in OS, presumably because of the increased toxicity profiles of the more intensive regimens.

In the current trial, both regimens had similar overall toxicity. The death rate during the induction period was 5.5% for the intensified-daunorubicin group and 4.5% for the standard-dose group (P = .6). Cardiotoxicity with higher doses of daunorubicin was not significantly higher than with the standard dose. Symptomatic heart failure was seen in 7.9% in the intensifieddaunorubicin group and 7.2% in the standard-dose group (P = NS). The investigators concluded that an intensified induction regimen using >45 mg/m2 of daunorubicin for 3 days (along with cytarabine) should be the new standard treatment for adults with AML who are younger than 60 years. Because oncologists may be uncomfortable prescribing such a high dose, some oncology associations recommend giving at least 60 mg/m2 of daunorubicin for 3 days during AML induction for younger adults, which may be more acceptable to providers. It should be noted that it is unknown whether 60 mg/m2 of daunorubicin would provide the same benefit as the 90-mg/m2 dose used in this trial.

Novel regimens

Many of the updates in AML were presented at the 2009 annual meeting of the American Society of Hematology (ASH). In one trial (MRC-AML 15), the Medical Research Council investigated various induction and consolidation regimens (Figure).3 Patients were randomized to induction therapy with two courses of cytarabine/daunorubicin (DA), cytarabine/daunorubicin/etoposide (ADE), or fludarabine/cytarabine/ idarubicin/granulocyte colony-stimulating factor (FLAG-IDA). As consolidation therapy, patients were randomized to ams acrine/cytarabine/etoposide (MACE)/mitozantrone/cytarabine (MidAC) or two courses of high-dose cytarabine. There was also a randomization for an additional cycle of high-dose cytarabine.

All the groups were well matched at baseline. Eighty-four percent of patients were between 15 and 59 years of age at diagnosis, and 90% had de novo AML. The majority (70%) of cytogenetic profiles were intermediate prognostic. Although there was a statistically significant increase in CR rate for DA compared with ADE, the rates are clinically similar. OS was also similar in all induction arms (Table 1). When focusing on the consolidation data, no major difference in OS was noted between MACE/MidAC and high-dose cytarabine (52% vs 54%; P = .2). OS also did not differ whether the patient received four or five courses of therapy (58% vs 60%; P = .7). The most meaningful information from this trial may come from the comparison of cytarabine dosed at 1.5 g/m2  6 versus 3 g/m2  6. The 5-year OS was not significantly different between the two groups (54% vs 52%; P = .7).2 The negligible difference in clinical outcomes produced by these two different dosing regimens suggests that it may be in the best interest of the patient to forego the risks of cerebellar toxicity associated with higher doses of cytarabine, and instead treat patients with the 1.5-g/m2 consolidation regimen.

The preliminary results of the South-western Oncology Group S0106 trial also were presented at ASH. This trial randomized adults aged between 18 and 60 years with de novo AML to receive gemtuzumab ozogamicin in addition to standard 7+3 therapy (daunorubicin 60 mg/m2 IV days 1-3 and cytarabine 100 mg/m2/day continuous IV infusion days 1-7) with or without gemtuzumab ozogamicin for induction.4 Prior studies had shown that adding gemtuzumab to induction therapy may increase diseasefree survival (DFS) without increasing toxicity.5 In the current trial, the treatment arm received daunorubicin 45 mg/m2 IV on days 1 to 3, cytarabine 100 mg/m2 IV on days 1 to 7, and gemtuzumab 6 mg/m2 IV on day 4. Patients in the control arm received daunorubicin at 60 mg/m2 IV on days 1 to 3 and cytarabine 100 mg/m2 continuous IV infusion on days 1 to 7. Those who entered into CRafter induction were given three cycles of consolidation therapy with cytarabine 3 g/m2 IV  6 doses. There was an additional randomization to three doses of gemtuzumab 5 mg/m2 IV or observation.4

Both groups in this trial were well matched (Table 2). At the second interim analysis, 596 patients were available for evaluation. The addition of gemtuzumab to standard 7+3 therapy was found not to affect the CR rate. The CR rate was 66% in the gemtuzumab arm and 69% in patients receiving standard 7+3 therapy. There was also no statistically significant difference in DFS (hazard ratio [HR], 1.35; 95% confidence interval [CI], 0.85-2.14; P = .9) or OS (HR, 1.15; 95% CI, 0.86-1.35; P = .35). Despite no benefit in efficacy, more adverse events were seen in the gemtuzumab group. Grade 4 and 5 infections were more frequent (11% vs 6%) in the gemtuzumab group as were deaths during induction (9% vs 2%).4 Based on the lack of efficacy benefit (CR, DFS, and OS) along with an increase in adverse events, the study was stopped before full accrual. Although gemtuzumab is US Food and Drug Ad - ministration–approved for relapsed AML in older adults, it appears that for younger adults, adding it to induction therapy provides no benefit.

Lenalidomide is approved for low- or intermediate-1-risk myelodysplastic syndrome. It is not completely clear why lenalidomide is effective, but its efficacy is thought to be due to immunomodulatory and antiangiogenic effects. It is hypothesized that there are common features between myelodysplastic syndrome and AML. Based on this theory, lenalidomide was studied as initial therapy for adults 60 years and older in an open-label, phase 2 trial.6 Patients had to have untreated AML with a good performance status. In the induction phase, patients received 50 mg of lenalidomide daily for 28 days. Those patients not in CR underwent another 28-day induction cycle with the same dosing scheme. Afterward, nonprogressing patients received lenalidomide 10 mg daily for up to twelve 28-day cycles. Therapy was stopped for progressive disease or severe toxicity. Patients were allowed to receive transfusions and growth factors during the trial.

Thirty-three patients with a median age of 71 years (60-88 years) were enrolled. Seventy percent had de novo AML, and 36% had poor-risk cytogenetics. The CR rate was 30%, including three cytogenic CRs, two morphologic CRs, and five CRs with with incomplete blood count recovery. The 60-day mortality rate was 27%, with the majority of the deaths resulting from disease progression. The most common toxicities experienced were related to myelosuppression and infections.

One of the benefits of this proposed therapy is that it can be taken orally. The median time spent in the hospital was 6 days (range, 0-40 days) for the entire group. Those who achieved CR had a median hospitalization time of 3 days (range, 0-14 days). For patients who elect to receive intensive induction therapy, a typical hospital stay can last 4 to 6 weeks. The mortality rate of 27% seen with lenalidomide is consistent with that of intensive induction therapy. This high-dose lenalidomide regimen is promising for older patients with AML. Further studies are ongoing to delineate the mechanism of action of lenalidomide and to discover ways to enhance the CR duration for these patients. The benefit of this therapy is not only that it is an oral option to treat AML, but also that it may be a novel approach for older adults.

One area of interest in AML research has been the effect of different tyrosine kinases on cell proliferation and apoptosis. A recent focus has been FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) domain mutations. More than 20% of de novo AML is associated with an FLT3 ITD mutation.7 Recent trials show that this mutation is associated with worse OS and an increase in relapse rates. Because of the incidence and pathophysiology of the FLT3 mutation it has become a target for pharmacologic therapy.8 One agent that has shown to be synergistic following chemotherapy and may affect FLT3 is lestaurtinib.9

In a phase 2 study, patients (n = 224) with relapsed AML and mutated FLT3 status were randomized to receive mitoxantrone/ etoposide/cytarabine or highdose cyta rabine alone, or either chemotherapy regimen followed by lestaurtinib 80 mg twice daily starting on day 7 or 8. The median age at relapse was 55 years, and 88% of patients had an FLT3 ITD mutation. The CR rate was not significantly different between the two groups (26% vs 21%; P = .35). OS was also not significantly different (P = .92). Lestaurtinib was well tolerated, and the side effect profile for the lestaurtinib arm was similar to that of the control arm. One of the secondary end points of the study was the pharmacokinetic profile of lestaurtinib. The investigators noted that the level of FLT3 inhibition was low (58% adequately inhibited at day 15) and not sustained at this level (27% had adequate inhibition at days 15 and 42). Further investigation showed that achieving FLT3 inhibition may have correlated with CR rate. In patients who had ample FLT3 inhibition on day 15, the CR rate was 39% compared with 9% in patients who did not have FLT3 inhibition. This finding may have been due to the dosing used in this trial or the pharmacokinetics of the drug. Further trials are looking at other methods to achieve more adequate FLT3 inhibition and the affect this may have on AML outcomes. Summary Much of the information presented in 2009 focused on more intensive or novel chemotherapy regimens to treat AML. Some of the data (high-dose lenalidomide, FLT3 inhibitors) were positive, and although other data (gemtuzumab) showed that no extra benefit was achieved, all the trials provide valuable information about a vastly heterogeneous disease. The most exciting news from 2009 were the data pertaining to higher doses of daunorubicin used during AML induction for adults 60 years and younger. It remains unclear the precise dose of daunorubicin that provides the most benefit without undue side effects, but the increase in CR rate and OS were welcomed news for a difficult-to-treat disease. !

References

1. American Cancer Society. Cancer facts and figures 2009. www.cancer.org. Acessed April 21, 2010.

2. Fernandez HF, Sun Z, Litzow MR, et al. A randomized trial of anthracycline dose intensification during induction of younger patients with acute myeloid leukemia: results of Eastern Cooperative Oncology Group study E1900. J Clin Oncol. 2009;27(15S):Abstract 7003.

3. Burnett AK, Hills RK, Milligan D, et al; for the NCRI AML Working Group. Attempts to optimise induction and consolidation chemotherapy in patients with acute myeloid leukaemia: results of the MRC-AML15 trial. Blood (ASH Annual Meeting Abstracts). 2009;114:Abstract 484.

4. Petersdorf S, Kopecky K, Stuart RK, et al. Preliminary results of Southwest Oncology Group study S0106: an international intergroup phase 3 randomized trial comparing the addition of gemtuzumab ozogamicin to standard induction therapy versus standard induction therapy followed by a second randomization to post-consolidation gemtuzumab ozogamicin versus no additional therapy for previously untreated acute myeloid leukemia. Blood (ASH Annual Meeting Abstracts). 2009;114:Abstract 790.

5. Burnett AK, Kell WJ, Goldstone AH, et al. The addition of gemtuzumab ozogamicin to induction chemotherapy for AML improves disease free survival without extra toxicity: preliminary analysis of 1115 patients in the MRC AML15 trial. Blood (ASH Annual Meeting Abstracts). 2006;108: Abstract 13.

6. Vij R, Nelson A, Uy GL, et al. A phase II study of high dose lenalidomide as initial therapy for acute myeloid leukemia in patients > 60 years old. Blood (ASH Annual Meeting Abstracts). 2009;114: Abstract 842.

7. Applebaum F, Meshinchi S. Structural and functional alterations of FLT3 in acute myeloid leukemia. Clin Cancer Res. 2009;15:4263-4269.

8. El-Shami K, Stone R, Smith D. FLT3 inhibitors in acute myeloid leukemia. Expert Rev Hematol. 2008;1:153-160.

9. Levis M, Ravandi F, Wang ES, et al. Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for FLT3 mutant AML patients in first relapse. Blood (ASH Annual Meeting Abstracts). 2009;114:Abstract 788.

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