Gemtuzumab ozogamicin improves OS in older patients with AML

Issue: May 10, 2016

First-line monotherapy with gemtuzumab ozogamicin appeared to significantly extend OS in older patients with acute myeloid leukemia who were unable to receive intensive chemotherapy, according to the results of a randomized phase 3 trial.

Perspective from Andrew Artz, MD; Rebecca L. Olin, MD

Further, gemtuzumab ozogamicin (Mylotarg, Pfizer) appeared safe, with a manageable toxicity profile and no unexpected adverse events.

“Treatment of AML in older patients remains challenging,” Sergio Amadori, MD, professor of hematology at Vergata University Hospital in Rome, and colleagues wrote. “In this age group, the benefit associated with intensive chemotherapy is marginal and the chance for cure continues to be less than 10%.”

Amadori and colleagues compared gemtuzumab ozogamicin with best supportive care (BSC) — including hydroxyurea or low-dose cytarabine — in 237 patients aged older than 61 years (median age, 77 years; range, 62-88) with AML who were deemed unsuitable for intensive chemotherapy.

They randomly assigned patients to a single induction course of gemtuzumab ozogamicin (6 mg/m² on day 1; 3 mg/m² on day 8; n = 118) or BSC (n = 119).

Patients who did not progress after gemtuzumab ozogamicin induction could receive up to eight monthly infusions at 2 mg/m²per month.

OS served as the primary endpoint.

At data cutoff, 228 patients had died, with similar death rates in both groups (gemtuzumab ozogamicin, n = 113; BSC, n = 115).

Although gemtuzumab ozogamicin was only associated with a 1.3-month median OS improvement (4.9 months vs. 3.6 months), this difference met statistical significance (HR = 0.69; 95% CI, 0.53-0.9).

Further, more patients assigned gemtuzumab ozogamicin remained alive after 1 year (24.3% vs. 9.7%).

The OS benefits of gemtuzumab ozogamicin persisted across nearly all subgroups, with particular benefit observed in women (P = .05), patients with favorable or intermediate cytogenetic risk profiles, and among those with high CD33 expression (P = .05). Gemtuzumab ozogamicin significantly improved OS in patients with more than 80% CD33-positive blasts (HR = 0.49; 95% CI, 0.32-0.76).

Thirty patients assigned gemtuzumab ozogamicin (27%) achieved a complete remission or a complete remission with incomplete recovery of peripheral blood counts.

All patients experienced pancytopenia during gemtuzumab ozogamicin induction. However, rates of severe nonhematologic adverse events were similar in both study arms (any grade, 87.3% vs. 90.4%; grade 3, 61.2% vs. 67.5%).

Gemtuzumab ozogamicin did not appear associated with increased incidence of organ failure, bleeding or neutropenia.

“These findings suggest that single-agent gemtuzumab ozogamicin could represent a new option for this patient group,” Amadori and colleagues wrote. “These results, which add to the mounting evidence that withdrawal of gemtuzumab ozogamicin from the market in 2010 (due to lack of benefit and increased toxicity in a phase 3 trial) was premature, support further investigations of gemtuzumab ozogamicin in combination with other novel agents in this patient population of high unmet need.” – by Cameron Kelsall

Reference:

Amadori S, et al. J Clin Oncol. 2016;doi:10.1200/JCO.2015.64.0060.

Disclosure: Amadori reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.

Perspective

Andrew Artz, MD

The median age at acute myeloid leukemia diagnosis is 67 years, and older adults have a considerably worse prognosis. The options for older patients range from chemotherapy induction and consideration of an allogeneic transplant to best supportive care alone.
In this study conducted in Europe, Amadori and colleagues randomly assigned 237 newly diagnosed older patients deemed unfit for intensive chemotherapy to gemtuzumab ozogamicin (Mylotarg, Pfizer) or best supportive care alone. The median age was 77 years and 31% had secondary AML.
Patients assigned gemtuzumab monotherapy achieved an overall best response rate of 27%, which included complete remission and complete remission with incomplete recovery of peripheral blood counts. Further, patients assigned gemtuzumab achieved a median OS of 4.9 months vs. 3.6 months with best supportive care (P = .005), and 1-year OS was 24.3% vs. 9.7%.
Exploratory analysis suggested subgroups harboring high CD33 expression on blasts and favorable/intermediate karyotype derived the greatest benefit.
Gemtuzumab ozogamicin has been studied extensively over the past decade. The drug was previously withdrawn from the United States market in 2010 due to concerns of safety and lack of benefit, although clinical trials have continued using lower doses. A consistent story is emerging from this study and others showing the greatest benefit in response and outcome for AML harboring favorable and/or intermediate cytogenetics. Further, initial safety concerns of veno-occlusive disease have been mitigated using lower gemtuzumab doses. As with all studies of older patients with AML, the dilemma persists of defining the appropriate standard of care for a trial and in practice. Gemtuzumab is not readily available today, but the larger question is how gemtuzumab would compare with low-dose cytarabine or hypomethylating therapy. With many novel drugs now being tested in AML, we expect treatment options should be available for most patients with AML, irrespective of age, with reasonable performance status.

Andrew Artz, MD

The University of Chicago Medicine

Disclosures: Artz reports no relevant financial disclosures.

Perspective

Rebecca L. Olin, MD

In this study, Amadori and colleagues report that gemtuzumab ozogamicin (Mylotarg, Pfizer), at a reduced dose and fractionated schedule, is not only tolerable in older patients with acute myeloid leukemia, but is associated with an OS benefit compared with best supportive care.
This is noteworthy for two reasons.
First, this is yet another study demonstrating clinical benefit from gemtuzumab ozogamicin in AML. Gemtuzumab ozogamicin was withdrawn from the U.S. market in 2010 after the SWOG S0106 study failed to demonstrate additional benefit when it was added to “7+3” chemotherapy; the drug also was associated with increased toxicity. However, multiple subsequent randomized studies and meta-analyses have demonstrated the value of gemtuzumab ozogamicin in specific patient subsets, in particular for favorable- or intermediate-risk disease. We can only hope that the FDA reconsiders its position on gemtuzumab ozogamicin in the future.
Second, this study offers another option for treatment of older patients with AML, an area of significant unmet need. All patients on this study were aged least 61 years; many were aged older than 75 years. Although not detailed in the paper, they likely had significant comorbidities. Such patients are truly challenging to treat. Today, a reasonable standard in this setting would be treatment with a hypomethylating agent (azacitidine, decitabine).
A randomized study of gemtuzumab ozogamicin, a hypomethylating agent or the combination would have the potential to be practice changing.

Rebecca L. Olin, MD

University of California, San Francisco

Disclosures: Olin reports no relevant financial disclosures.