Several options have emerged for patients with acute myeloid leukemia who are not candidates to receive chemotherapy, with venetoclax-based regimens chief among them.
Courtney DiNardo, MD, MSCE
Several standard factors can make patients with acute myeloid leukemia unfit to receive intensive chemotherapy, including advanced age (75 years or older), an ECOG performance score of 2 or higher, and underlying organ dysfunction, such as renal failure, liver disease, or cardiomyopathy. Luckily, several options have emerged for these patients in recent years, with venetoclax (Venclexta)-based regimens chief among them, according to Courtney DiNardo, MD, MSCE.
“There are other things that we need to start thinking about that don’t necessarily make [a patient] unfit, but less appropriate for standard intensive chemotherapy,” DiNardo, a clinical researcher in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, said during a presentation at the 25th Annual International Congress on Hematologic Malignancies.1 For example, if patients had previously treatment antecedent hematologic disorders or if they had unfavorable, or high-risk, karyotypes, they would be less suited for this approach, according to DiNardo.
The median age at diagnosis for patients with AML is 68 years and the rate of 5-year survival is just 28.3% for these patients.2 Although other factors must be considered beyond age, age alone does play a relevant role in terms of overall survival (OS) and the ability to treat and cure patients with AML, added DiNardo.
The phase 3 SWOG S1203 study looked at 968 patients who were treated with intensive chemotherapy. Results showed that the risk of 30-day early mortality for patients was highest for those 75 years of age or older who had a poor ECOG performance status.3 “This is really quite relevant, [because] the whole point of what we're doing is to put our patients into a remission and a hopeful durable one, and not invoke an early mortality,” DiNardo said.
Additionally, while a high percentage of younger patients are able to achieve a complete remission (CR) with intensive chemotherapy, the CR rate for those with higher-risk adverse cytogenetics is only 55%, which correlates to a lower 5-year OS rate of 11%.4 “The utility of intensive chemotherapy is absolutely there, but we have to recognize some of the limitations,” DiNardo added.
Since 2017, significant progress has been made in the AML treatment landscape, with therapies such as novel FLT3 inhibitors, IDH1 inhibitors, and small molecule inhibitors, among others, being brought into the fold.5 New options have allowed for more tailored approaches for patients, whether they are eligible or ineligible for intensive chemotherapy.
The phase 3 VIALE-A study (NCT02993523) examined the combination of azacitidine plus venetoclax vs azacitidine alone in patients with previously untreated AML who were ineligible for intensive chemotherapy.6 Results showed a significant OS benefit in those who received the combination, at a median of 14.7 months vs 9.6 with single-agent azacitidine (HR 0.66; 95% CI, 0.52-0.85; P <.001), at a median follow-up was 20.5 months. Complete remissions in the investigative and control arms were 36.7% and 17.9%, respectively (P <.001).
“These remissions were independent of genomics, and even the highest-risk patients are obtaining benefit with an improvement in remission with venetoclax plus azacitidine,” DiNardo noted.
However, genomics does play a key role in how long patients will stay in remission, according to Dinardo. A majority of patients who achieve and stay in remission for more than 1 year without transplant have NPM1 or IDH2 mutations, while those who achieve remission and then relapse, or who are primary refractory, tend to have an enrichment of complex cytogenetics, with TP53, FLT3-ITD, or NRAS/KRAS mutations.7
Even patients with AML deemed unfit for intensive chemotherapy, venetoclax-based regimens can provide a path to curative allogenic stem cell transplant.8 A total of 304 patients received treatment with a venetoclax-based regimen and 31 (10%) proceeded to transplant. Of those 31 patients, 26 achieved CR or CR with incomplete hematologic recovery. Additionally, 68% (n = 21/31) remained alive 12 months after transplant. Fifty-five percent of patients (n = 17/31) achieved a post-transplant remission of at least 12 months; 71% of those patients ( n= 12) remained in remission for 2 years or longer.
“Allogenic transplant for a cure is not only reserved for patients who receive intensive chemotherapy,” DiNardo explained. “If you have a patient who receives a hypomethylating agent/venetoclax regimen and is able to obtain a remission, or has some of these higher risk genomic features, we know they probably are not going to have a remission that's going to last for years. As such, the role of a transplant has been evaluated.”
Another important update in terms of low-intensity treatment combinations came in the phase 3 LACEWING study (NCT02752035) presented during the 2020 ASH Annual Meeting & Exposition. Here, investigators evaluated the use of the FLT3 inhibitor gilteritinib (Xospata) plus azacitidine or azacitidine alone in patients with newly diagnosed, FLT3-mutated AML who were ineligible for intensive induction chemotherapy.9 A third arm of the study, which had examined gilteritinib alone, was closed.
Initial results from the study showed the combination of azacitidine with gilteritinib was safe, and a CR rate of 67% (n = 10/15) was reported; this was similar to rates seen with other combinations, like venetoclax/azacitidine, noted DiNardo. Among patients who achieved a CR, the median duration of remission was 10.4 months. However, another update reported that the study failed to meet its primary end point and has since stopped enrollment.10
“[We saw] azacitidine and venetoclax and azacitidine with a FLT3 inhibitor, [so the question now is,] is there a role to put all 3 together?” questioned DiNardo. “This is something that we are exploring further in a clinical trial at MD Anderson11 and the responses [that we have seen] look impressive. However, we do see pretty significant myelosuppression…As such, it’s definitely not necessarily an automatic [answer of] add everything together and that’s the best thing to do.”
Patients with IDH1 and IDH2 mutations do very well with the combination of venetoclax and azacitidine, according to DiNardo. Updated data from the VIALE-A study on this patient subgroup showed composite response rates of 85.7% in those with IDH2 mutations and 65.6% in those with IDH1 mutations.12
Another appropriate strategy in this patient population is a combination of azacitidine with an IDH2 inhibitor. A recent, non-blinded phase 2 study (NCT02677922) of azacitidine in combination with enasidenib (Idhifa; n = 68) vs azacitidine alone (n = 33) showed overall response rates (ORRs) of 71% and 42%, respectively.13 Additionally, composite response rates were 53% and 12% in the investigative and control arms, respectively, while the median event free survival was 17.4 and 10.4 months, respectively, in this patient subset.
In terms of sequencing IDH inhibitors and venetoclax, optimal methods have not yet been established. “Do you start with 1 doublet and switch to another doublet, or do you consider putting all 3 together in a triplet regimen?” DiNardo questioned.
To address this question, an ongoing phase 1b/2 study (NCT03471260) will determine the safety and efficacy of using a shorter duration of venetoclax with the initiation of continuous treatment with the IDH1 inhibitor ivosidenib (Tibsovo) and 7-day courses of azacitidine.14 “There are small numbers, but the responses look good with this triplet strategy,” noted DiNardo.
Fifteen to 20% of older patients with AML who are unfit for intensive chemotherapy have tumors that harbor TP53 mutations, according to DiNardo. These mutations are especially prevalent in those who have had antecedent hematologic disorders or therapy-related AML, added DiNardo. For these patients, investigators set out to evaluate 10-day decitabine with venetoclax.15
“We were particularly hopeful that patients with TP53-mutated leukemias would respond well [to this approach], given that the data [thus far] with 10 day-decitabine [showed that it] was really effective, at least in the short term, at eradicating TP53, and leading to responses,” DiNardo explained.
The study enrolled a sizable cohort of patients with TP53-mutated disease. Most participants were 70 years of age or older who had therapy-related AML and were more likely to have adverse risk or complex karyotype. The overall response rates achieved with this approach in patients with TP53-mutated AML was 66%, with a composite remission rate of 57%. Notably, these results were similar to those seen in VIALE-A, according to DiNardo; however, this did not translate into an OS benefit.
“The responses tended to be rather superficial and short lived. Few patients were able to transition to a transplant in our analysis, and there was a lot of relatively early mortality. Also, a lot of patients did not obtain a remission, having experienced infections and progression of disease,” reported DiNardo. “One of the most important things we need to do is find an approved improvement of therapy for our [patients with] TP53-mutated patients since, unfortunately, venetoclax doesn't seem to be the curative strategy here.”
To this end, an ongoing phase 1b study (NCT03248479) is examining the anti-CD47 antibody magrolimab in combination with azacitidine in patients with newly diagnosed disease; notably, the majority of patients had tumors that harbored TP53 mutations, said DiNardo.
“It was purposeful because, initially, patients with TP53-mutated disease were found to respond to this therapy,” DiNardo noted. “As such, [investigators made the] decision to enroll a majority of [patients with] TP53-mutated [disease].”
Results of this study showed an ORR of 70%, with a composite remission rate of 60% in the TP53-mutated cohort.16 Additionally, the median OS with the approach was longer than 12 months, although follow-up is short, according to DiNardo.
“This is just one example that I am paying a lot of attention to and hoping that that this could be used as a doublet [regimen], or maybe in other combinations, for patients with TP53-mutated disease,” DiNardo said.
Although venetoclax combinations provide improved outcomes for patients with AML who are unfit for intensive chemotherapy, there is a learning curve with their use, and providers must ensure patients are being managed in an optimal way, according to DiNardo.
A summary of adverse effects (AEs) from VIALE-A showed that 72% of patients who received venetoclax plus azacitidine had a dose interruption while on treatment, primarily between the first and second cycles. These dose interruptions were commonly due to AEs such as neutropenia, febrile neutropenia, and thrombocytopenia. In these cases, treatment was held for 2 weeks before starting back up again, according to DiNardo.
“That is a really important management piece that I think is lost sometimes for the clinician, DiNardo said. “That really helps patients tolerate this combination regimen better.”
Additionally, there were very few incidences of tumor lysis syndrome (TLS), due to mitigation techniques. Of the 3 patients who experienced TLS, all were able to continue on the study, DiNardo noted. Moreover, a majority of patients on the azacitidine plus venetoclax combination reported 32 events of cytopenia.17 In those instances, patients had their venetoclax dose reduced from 28 days to 21 days in subsequent cycles, according to DiNardo.
Another important management factor in patients with AML on venetoclax regimens is anti-infectious prophylaxis. Instances where antifungal agents such as CYP3A4 inhibitors are being used, it is recommended to reduce venetoclax doses to between 70 mg 100 mg, DiNardo concluded.