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AML Rx Evolves With Growing List of Options
In acute myeloid leukemia (AML), newer options, such as a FLT3 inhibitor for relapsing-remitting disease and several therapies for patients who are ineligible for intensive chemotherapy, are pushing out old standards, according to data recently presented at the 2020 virtual annual meetings of the American Society of Clinical Oncology (ASCO) and European Hematology Association (EHA). After decades of little progress, the options in AML are evolving quickly.
ADMIRAL Trial: Long-Term Survivors
New data from the phase 3 ADMIRAL trial presented at ASCO show that in a subset of patients who achieved an overall survival (OS) of 18 months or longer after treatment with the FLT3 inhibitor gilteritinib (Xospata, Astellas), the median duration of complete response (CR) has not been reached (abstract 7514).
In the trial, 371 patients with FLT mutation–positive AML were randomly assigned to receive gilteritinib or standard therapy. When the trial results were published last year (N Engl J Med 2019;381[18]:1728-1740), gilteritinib had demonstrated an OS advantage (9.3 vs. 5.6 months; P<0.001), but the new data show very long periods of disease control, particularly in patients who continued to take gilteritinib.
The focus of this analysis was on the 63 patients who had survived at least 18 months, reported Alexander E. Perl, MD, an associate professor of medicine at the University of Pennsylvania, in Philadelphia. Of the 35 patients who underwent hematopoietic cell transplant (HCT), 25 (71%) remained on gilteritinib after transplant. Of the 28 patients who did not undergo HCT, 15 (54%) have received gilteritinib for at least 18 months, and some remain on this therapy.
Extended gilteritinib is feasible because it has been well tolerated despite substantial initial rates of cytopenias, Dr. Perl said, noting that the most common grade 3 or higher adverse events (AEs) occurring during the first 12 months of gilteritinib therapy were febrile neutropenia (45%), anemia (40%) and thrombocytopenia (23%). After 12 months, the incidences of these AEs decreased to 8%, 10% and 0%, respectively, he added.
When the ADMIRAL trial was published, Dr. Perl said the OS benefit coupled with the drug’s greater tolerability established gilteritinib as a standard for treatment of FLT3-positive relapsingremitting AML. These new data from ADMIRAL confirm a persistent mortality benefit at 24 months (20% vs. 14%). term survival with the ongoing remispatients receiving HCT and post-HCT administration of gilteritinib.
Two phase 3 studies have expanded the evidence that venetoclax (Venclexta, AbbVie/Genentech) can be combined with other well-tolerated agents to improve OS in older AML patients who are ineligible for more intensive chemotherapy regimens. One of the trials, called VIALE-A, was presented as a latebreaker at EHA (abstract LB2601). The other, VIALE-C, was presented at ASCO (abstract 7511).
In VIALE-A, investigators enrolled 433 treatment-naive AML patients who were not eligible for intensive chemotherapy based on an age greater than 75 years or the presence of comorbidities, such as heart failure, lung dysfunction or poor performance status. The patients were randomly assigned, in a 2:1 ratio, to receive azacitidine combined with either venetoclax or placebo. To improve tolerability, they used a ramp-up schedule of venetoclax in the first cycle.
Median OS, a co-primary end point with CR, was 14.7 months in the
Dr. Perl associated the improved longsions, improvement in the proportion of
Phase 3 Venetoclax Data Broaden Role in Older Patients With AML
In VIALE-A,
venetoclax arm versus 9.6 months in the placebo arm. Venetoclax reduced the risk for death by 34% (hazard ratio [HR], 0.66; P<0.001) reported Courtney DiNardo, MD, an associate professor in the Department of Leukemia at the University of Texas MD Anderson Cancer Center, in Houston.
The rate of CR or CR plus partial hematologic recovery (CRh) was 66.4% with venetoclax versus 28.3% without it (P<0.001). Venetoclax also was favored for the combined end point of CR plus CR with incomplete blood count recovery (CRi) in the FLT3-positive patients (72% vs. 36%; P=0.021) as well as in the IDH1/2-positive patients (75% vs. 11%; P<0.001).
Several grade 3 or higher cytopenias, including neutropenia (42% vs. 29%) and febrile neutropenia (42% vs. 19%) were more common in the group receiving venetoclax. Gastrointestinal events also were more common in patients receiving venetoclax, but most were grade 2 or lower, and no early deaths were associated with the combination. Tumor lysis syndrome (TLS), which has been associated with venetoclax in the past and is the reason that a rampup strategy is used when this drug is started, was not a significant issue in this study. Although there were three cases of minor TLS, no patient required a modified course of venetoclax.
An inhibitor of the B-cell lymphoma-2 (or BCL-2) protein, venetoclax is approved in combination with azacitidine or decitabine, another hypomethylating agent, for the types of patients enrolled in the VIALE-A trial. It also is approved in combination with low doses of cytarabine, which was the focus of VIALE-C.
In VIALE-C, 211 patients were randomly assigned in a 2:1 ratio to receive oral venetoclax plus a low dose of subcutaneous cytarabine or low-dose cytarabine alone. As in VIALE-A, venetoclax was initiated in a ramp-up strategy in the first cycle. In both groups, 20 mg/m 2 of cytarabine was administered on the first 10 days of each 28-day cycle.
For the primary end point of OS, venetoclax plus cytarabine was superior to cytarabine alone (8.4 vs. 4.1 months; HR, 0.70; P=0.04), according to investigator Andrew Wei, MBBS, PhD, an adjunct associate professor at the Australian Centre for Blood Diseases at Monash University, in Melbourne.
Several secondary end points also favored venetoclax in combination with low-dose cytarabine, including CR/CRh (48% vs. 15%) and CR/CRi (48% vs. 13%). The median event-free survival was nearly twice as long in the group receiving both venetoclax and cytarabine (4.9 vs. 2.1 months).
Grade 3 or higher neutropenia was twice as common with the combination (49% vs. 18%), but Dr. Wei called the safety profile of the combination “tolerable and manageable.”
He concluded that these data support this combination as an option for newly diagnosed AML patients who are unfit for intensive chemotherapy.
5-Year Data With CPX-351 Support Survival Benefit
Five-year data with CPX-351 ( Vyxeos, Jazz), a liposomal encapsulation of cytarabine and daunorubicin, confirm a long-time OS benefit in newly diagnosed patients with high-risk or secondary AML.
An OS benefit in this phase 3 trial of CPX-351 versus 7+3 chemotherapy was reported earlier (J Clin Oncol 2018;36:2684-2692), but these updated
results show the proportion of AML patients aged 60 to 75 years who are alive five years after randomization is twice as great in the group treated with CPX-351 compared with the group treated with 7+3 chemotherapy (18% vs. 8%).
The 7+3 regimen (seven days of cytarabine and three days of daunorubicin or another anthracycline) was a standard for AML for decades before the head-to-head comparison that established the superiority of CPX-351 led to its approval.
The updated results of that trial were presented at ASCO (abstract 7510). The median follow-up now exceeds 60 months. Ultimately, 53 of the 153 patients randomly assigned to receive CPX-351 (35%) and 39 of the 156 patients assigned to 7+3 (25%) received HCT. Even among these patients, survival at five years ears was longer for those randomized to to CPX-351 (52% vs. 23%).
“The study shows that CPX351 has the ability to produce or r contribute to long-term remission on and survival in these older patients,” reported investigator Jeffrey E. Lancet, MD, a senior member in the Department of Malignant Hematology at Moffitt Cancer Center, in Tampa, Fla.
Dr. Lancet and his co-investigators concluded that these long-term results strengthen the conclusion that CPX351 is a superior treatment for relatively fit patients.
Promising AML Strategy: Novel CD47-Targeted Therapy
Other new drugs are in the pipeline. A monoclonal antibody called magrolimab (Gilead) that targets CD47 on cancer cells also showed uncommon activity in newly diagnosed AML patients who were unable to receive intensive chemotherapy. The study included patients with highrisk myelodysplastic syndrome (MDS), who obtained similar benefits.
“The six-month overall survival estimate was 100% in MDS and 91% in TP53-mutation AML patients,” reported David A. Sallman, MD, an assistant professor in the Department of Malignant Hematology at Moffitt Cancer Center.
By blocking CD47, magrolimab acts as an immunotherapy. The CD47 protein on cancer cells generates a “do not eat me” signal to macrophages, but when CD47 is blocked, phagocytosis can proceed, according to Dr. Sallman.
In this phase 1b trial presented at For patients who are ineligible for intensive chemotherapy, ‘the treatment options really come down to side effects, treatment schedules and, ultimately, whether the characteristics of their disease might better match one study’s cohort of patients versus another.’ —Martina Fraga, PharmD
ASCO (abstract 7507), magrolimab was combined with azacitidine, which Dr. Sallman said has been shown to synergize with magrolimab. The median age of the 68 patients enrolled in this study was 72 years, and 68% had poor-risk cytogenetics.
The CR/CRi rate was 56% in the 25 evaluable AML patients. In the 12 patients with TP53-mutated AML, the CR/CRi rate was 75%, even though this is regarded as a treatment-refractory form. In the 39 MDS patients, the CR rate was 42%.
Although there was no control arm, the response rates are impressive, according to Dr. Sallman. He reported that the median response has not yet been reached for AML or MDS.
Importantly for this older patient population unfit for intensive chemotherapy, magrolimab was well tolerated. The types and severity of AEs were similar to those expected with azacitidine alone, Dr. Sallman reported.
A phase 3 trial is planned. Although the study will be limited to high-risk MDS patients, Gilead has reported that the FDA has granted fast track designation to this drug for other B-cell malignancies, such as non-Hodgkin lymphoma and diffuse large B-cell lymphoma, and that trials in these other malignancies are underway.
Progress in AML Means Challenging Choices
In AML patients, the expanding number of treatment options associated with improved OS relative to previous standards is good news, but it also creates challenges for clinicians. There are limited or no data comparing many of the newer treatments. Many factors, such as the mutational profile of the AML and the ability of AML patients to tolerate treatment, are important to consider.
“This is definitely an interesting time in the treatment of AML,” suggested Martina Fraga, PharmD, a pharmacy specialist in hematology/oncology at the University of Michigan in Ann Arbor. “Traditionally, the treatment decision revolved around whether the patient could tolerate intensive chemotherapy. That is definitely still part of the discussion, but the newer options have allowed clinicians to target specific disease characteristics, such as molecular and cytogenetic aberrations.”
For patients who are ineligible for intensive chemotherapy, “the treatment options really come down to side effects, treatment schedules and, ultimately, whether the characteristics of their disease might better match one study’s cohort of patients versus another,” Dr. Fraga added. “The presence of the FLT3 and IDH2 mutations and other targetable molecular characteristics can also help further guide therapy decisions.”
More head-to-head studies will facilitate these decisions, but Dr. Fraga said many choices could be made on the basis of disease characteristics and patient preference.
“As it stands right now, the newer agents all tend to be fairly tailored to be used within specific subtypes,” she said. When more than one choice is reasonable, “it comes down to weighing the different side effect profiles, drug interactions and
routes of administration to figure out which would be the best fit for for the lifestyle and goals of the patient.”
Dr. Fraga noted, however, that “as more drugs are approved and they start to be moved up in the treatment algorithms, these decisions are going to get more complex.” —Ted Bosworth
The sources reported the following fi nancial relationships: Dr. Perl: AbbVie, Actinium, Agios, Astellas, Daiichi Sankyo, Jazz, Newlink Genetics, Novartis, Takeda; Dr. DiNardo: AbbVie, Agios, Celgene, Daiichi Sankyo, Immune-Onc, Notable Labs, Novartis; Dr. Wei: AbbVie, Amgen, Celgene, Genentech, Janssen, Novartis, Pfi zer, Roche, Servier; Dr. Sallman: AbbVie, Agios, Argenx, Celgene, Celyad, Incyte, Novartis; Dr. Lancet: Agios, Daiichi Sankyo, Jazz, Pfi zer; Dr. Fraga: None.
