CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: April 06, 2022
Expiration: April 05, 2023
B. Douglas Smith, MD:
Outcomes with AML therapy are inferior in patients with poor-risk cytogenetics and TP53 mutations. Although venetoclax plus azacitidine is now a backbone of AML therapy, outcomes with this regimen have not been established for treatment-naive patients with poor-risk cytogenetics who are TP53 wild type.
At ASH 2021, Pollyea and colleagues1 presented data pooled from 2 studies assessing venetoclax plus azacitidine vs azacitidine alone in patients with previously untreated AML and poor-risk cytogenetics with or without TP53 mutation.
B. Douglas Smith, MD:
This retrospective review pulled data from the phase III VIALE-A trial and a phase Ib trial of venetoclax plus azacitidine.1 In total, 353 patients received venetoclax plus azacitidine, and 145 patients received placebo plus azacitidine. All patients were treatment naive and ineligible for intensive induction chemotherapy due to age 75 years or older and/or comorbidities. Patients from each trial were broken into subgroups for analysis by cytogenetic risk and TP53 mutation status.
Endpoints of the study were CR plus CRi, duration of response (DoR), and OS.
B. Douglas Smith, MD:
Patients with TP53 mutations and poor-risk cytogenetics were much less likely to have FLT3 and IDH1 mutations than patients with wild-type TP53.1 The incidence of complex karyotypes del 5 or 7 and del 17 also was higher among patients with TP53-mutated disease.
Because patients with intermediate cytogenetics have a lower frequency of TP53 mutations, this analysis focused only on patients with wild-type TP53.
B. Douglas Smith, MD:
Among patients with poor-risk cytogenetics, combination venetoclax and azacitidine improved CR and CRi rates vs azacitidine alone. Although the difference was most pronounced for patients with TP53 wild-type disease, patients with TP53-mutated disease also benefited.1 Patients with intermediate-risk cytogenetics and TP53 wild type also had a substantial benefit in CR and CRi rates with combination therapy vs azacitidine alone.
B. Douglas Smith, MD:
Patients with poor-risk cytogenetics and wild-type TP53 had the best median DoR with combination therapy vs azacitidine monotherapy at 18.37 vs 8.51 months.1 Patients who received the combination and had TP53-mutated disease had a median DoR of only 6.54 months with the combination vs 6.70 months with azacitidine alone. The DoR was 21.91 months in patients with intermediate-risk cytogenetics who received combination therapy vs 13.47 months in patients who received azacitidine monotherapy.
B. Douglas Smith, MD:
Combination therapy also improved OS in patients with poor cytogenetics and TP53 wild-type AML (23.43 months vs 11.29 months), but OS was not substantially different in patients with TP53 mutations (5.17 months vs 4.90 months).1 Patients with intermediate-risk cytogenetics also benefited, with a median OS of 19.15 months with venetoclax plus azacitidine therapy vs 10.61 months with azacitidine monotherapy.
B. Douglas Smith, MD:
Combination therapy increased the incidence of febrile neutropenia, infectious complications, and cytopenia.1
B. Douglas Smith, MD:
This study shows that azacitidine plus venetoclax is better than single-agent azacitidine, particularly in patients who are TP53 wild type and have poor cytogenetic risk.
Eunice S. Wang, MD:
As we gain more experience with this standard of care combination, it is becoming clear that the categories of patients with poor or good prognosis are different following venetoclax/azacitidine than what we have previously seen with 7 + 3.
Although venetoclax/azacitidine does not appear to improve outcomes of patients with adverse cytogenetics and TP53 mutant AML, the outcomes of venetoclax/azacitidine in patients with adverse cytogenetics and TP53 wildtype AML appear to be better than 7+3 in these patients. Moving forward, the question is whether clinicians will act on these findings and use venetoclax/azacitidine upfront instead of 7 + 3 for patients with poor risk cytogenetics but TP53 wild type AML.
B. Douglas Smith, MD:
Standard cytarabine and anthracycline intensive induction therapy for fit patients with AML has changed little in decades. However, fit patients with European LeukemiaNet (ELN) adverse risk have a lower CR rate following intensive induction and may benefit from other treatment approaches.2 Venetoclax plus azacitidine demonstrated a significant efficacy benefit in older patients ineligible for intensive induction therapy in the VIALE-A trial, and it also may benefit younger fit patients who have poor prognostic features.3
The current study is evaluating venetoclax plus decitabine as induction therapy in young adults with newly diagnosed ELN adverse-risk AML. Chen and colleagues4 presented data from an interim analysis of the trial at ASH 2021.
B. Douglas Smith, MD:
Twenty-seven patients 18-59 years of age with newly diagnosed adverse-risk AML are currently enrolled in this prospective phase II trial (planned N = 42).4 Patients with TP53 mutation, ASXL1 or RUNX1 mutation, or adverse fusion gene received decitabine plus dose-escalated venetoclax. Patients with FLT3-ITD mutation received decitabine, dose-escalated venetoclax, and the FLT3 inhibitor sorafenib.
All patients had bone marrow assessment on Day 28; patients who responded to the first cycle of induction therapy went on to receive consolidation therapy followed by allogeneic hematopoietic stem cell transplant. Patients who did not respond repeated induction before receiving consolidation and hematopoietic stem cell transplant or went off the study.
The primary endpoint is composite CR rate, and secondary endpoints are measurable residual disease (MRD) response, event-free survival (EFS), OS, and AEs. Superiority is being measured vs historical controls. The data presented at ASH 2021 were preliminary results from an interim analysis.
The median age of patients in both groups is approximately 40 years, but patients enrolled on this study were more likely to be male than the historical controls (74% vs 57%).4 The frequency of patients with FLT3, RUNX1, and ASXL1 mutations is well matched across the groups, with approximately 20% to 30% of patients in each cohort having each mutation.
B. Douglas Smith, MD:
Patients who received venetoclax plus decitabine had a significantly higher composite CR rate than the historical controls, who received cytarabine plus idarubicin (76% vs 38.3%; P = .002).4
CR was achieved by 52% of patients who received venetoclax plus decitabine vs 27% of the historical controls.
B. Douglas Smith, MD:
Venetoclax plus decitabine appeared more efficacious than traditional cytarabine plus idarubicin induction across patient subgroups.4
B. Douglas Smith, MD:
At cycle 2, the composite CR of the historical controls was much higher than at cycle 1, but it was still inferior to the composite CR of patients who received venetoclax plus decitabine (73.6% vs 95.7%; P = .044).4 Of importance, MRD negativity was significantly higher among patients who received venetoclax plus decitabine vs the historical controls (73.9% vs 43.4%; P = .023).
Median follow-up is 4.3 months, so median PFS and OS have not been reached with venetoclax plus decitabine, but it is notable that 60-day mortality was 0% in the combination cohort.
B. Douglas Smith, MD:
Therapies combining HMAs with venetoclax cause infections, but traditional chemotherapy had higher rates of pneumonia, sepsis, and intestinal infections in this study (P = .01).4 The incidence of grade ≥4 anemia and thrombocytopenia also were both significantly reduced with venetoclax plus decitabine vs cytarabine plus idarubicin. Together, these data suggest that venetoclax plus decitabine is well tolerated.
B. Douglas Smith, MD:
Patients who have poor-risk features, even if they are younger, have worse outcomes with traditional chemotherapy. I think the preliminary data from this study support moving decitabine plus venetoclax into younger patients with poor cytogenic risk, particularly because it is less toxic.
Dr. Wang, does your team use this combination in younger patients with known poor-risk features?
Eunice S. Wang, MD:
Our center sticks very closely to FDA indications, so we are primarily using venetoclax plus HMA in older patients. Younger patients with adverse-risk AML without significant comorbidities such as cardiomyopathy still are being offered intensive therapy at our center. I know other centers are treating patients as young as 35-40 years of age with venetoclax plus HMA, but we are hesitant to do that until we see more data. I do think this trial opens the door for combination HMA plus venetoclax as a valid alternative, and phase III clinical trials are being designed to compare venetoclax plus azacitidine with intensive therapy.
Dr. Smith, does your center use HMAs plus venetoclax in younger patients? And in what situations do you use decitabine instead of azacitidine with venetoclax?
B. Douglas Smith, MD:
We use HMA plus venetoclax in some younger patients with known TP53 mutations because traditional chemotherapy does not work well, but that is the only group of younger patients in whom we use HMA plus venetoclax. And although both azacitidine and decitabine are effective, our center leans toward using azacitidine with venetoclax.
B. Douglas Smith, MD:
CPX-351 and venetoclax plus HMA are novel regimens with OS benefits for older patients with treatment-naive AML.3,5
Clinical outcomes with CPX-351 vs venetoclax plus HMA have not yet been compared. This abstract, presented by Grenet and colleagues6 at ASH 2021, reports results from a retrospective analysis of patients with AML who received either CPX-351 or HMA plus venetoclax in the frontline setting.
B. Douglas Smith, MD:
In this real-world retrospective study, researchers reviewed the charts of patients with AML at 4 US academic centers who received frontline CPX-351 (n = 211) or HMA plus venetoclax (n = 226).6
Analysis was done for the overall patient population, which ranged in age from 34-93 years, as well as for an older patient cohort aged 60-75 years. Subgroup analyses were done by TP53 status, adverse ELN risk, prior myeloid malignancy, and prior HMA therapy. The primary outcomes were response rate, relapse-free survival, and OS.
B. Douglas Smith, MD:
In the overall patient population, patients who received HMA plus venetoclax were slightly older (75.2 years vs 66.8 years; P <.001) and more likely to have adverse-risk factors by ELN criteria (71.7% vs 61.1%).6 Mutational status was well matched except for ASXL1 mutations, which were more common in patients receiving HMA plus venetoclax (27.1% vs 16.5%; P = .010). Patients receiving CPX-351 were more likely to have a history of prior myeloid disorder than patients receiving HMA plus venetoclax (54.0% vs 40.7%; P = .005)—which is understandable because this is an indication for CPX-351—and to have previously received an HMA (20.4% vs 9.7%; P = .001).
In the population of patients aged 60-75 years, the median age among patients receiving HMA plus venetoclax was older than among patients who received CPX-351 (70.3 years vs 68.5 years; P = .002). Patients who received HMA plus venetoclax also were more likely to have adverse ELN risk (77.0% vs 55.9%). The incidence of TP53, RUNX1, and ASXL1 mutations also was higher among patients receiving HMA plus venetoclax vs patients receiving CPX-351.
B. Douglas Smith, MD:
Combined CR/CRi rates were very similar between the arms, with 57.8% of patients receiving CPX-351 achieving CR/CRi vs 56.6% of patients receiving HMA plus venetoclax (P = .803).6 However, CR was significantly more common in patients receiving CPX-351 (46.6% vs 27.4%; P <.001), whereas CRi was more common among patients receiving HMA plus venetoclax (29.2% vs 11.4%; P <.001).
The combined CR/CRi rates were not different in any of the analyzed subgroups, but there were higher rates of CRi with HMA plus venetoclax in several subgroups.
B. Douglas Smith, MD:
In the overall population, there was a statistically meaningful improvement in median OS with CPX-351 vs HMA plus venetoclax (17.3 months vs 11.1 months; P = .007).6
Patients across all subgroups had improved OS with CPX-351, with the greatest benefit among patients who had TP53 mutations (HR: 0.406; 95% CI: 0.224-0.735; P = .003).
B. Douglas Smith, MD:
In patients 60-75 years of age, OS was very similar across both treatments.6 The rate of CR/CRi also was not significantly different, with 59.2% of patients who received CPX-351 achieving CR/CRi vs 54.0% of patients who received HMA plus venetoclax (P = .41).
Patients who received CPX-351 had more than double the transplant rate of patients who received HMA plus venetoclax (47.7% vs 19.0%; P <.001). However, there was no significant difference in posttransplant OS among responders.
B. Douglas Smith, MD:
These real-world data, although not from a head-to-head trial, suggest that CPX-351 benefits poor-risk patients regardless of age. CPX-351 also increases the transplantation rate among older patients, but this was not associated with a difference in OS or posttransplant OS.
Eunice S. Wang, MD:
This and 2 other real-world studies at ASH 2021 all demonstrated similar outcomes with CPX-351 and HMA plus venetoclax in this difficult-to-treat older patient population. But given the retrospective nature, the patient populations were not quite the same. As you pointed out earlier, patients who received HMA plus venetoclax were older, had slightly more molecular risk factors, and differed in other important characteristics.
B. Douglas Smith, MD:
Dr. Wang, how do you approach older patients with poor-risk features who are eligible for intensive chemotherapy regimens such as CPX-351? Do you use intensive regimens, or do you use HMA plus venetoclax?
Eunice S. Wang, MD:
In fit older individuals potentially going to transplant, we offer CPX-351. In older individuals with comorbidities who are transplant ineligible, we use venetoclax plus azacitidine.
Although I think this abstract substantiates the real-world use of both regimens, the data are still unclear. A few recent publications have shown remarkably good outcomes following venetoclax plus HMA therapy and transplant. So, it might be a route to transplant for patients who do not look great at the time of diagnosis.
B. Douglas Smith, MD:
Absolutely. I liked the abstracts that were just like the original CPX-351 trials. Even though transplant was not built into them, patients who went to transplant from CPX-351 induction and consolidation had nice outcomes. Again, it is a select population of patients who have a good response and are healthy enough to get to transplant.
Same thing goes for HMA plus venetoclax. If a patient is young or healthy enough and gets a deep response to HMA plus venetoclax and moves to transplant, outcomes are good. We use both CPX-351 and HMA plus venetoclax to give patients the opportunity to try to get to transplant. But, just like your practice, we favor CPX-351 in our younger patients or healthier, fitter patients, with the intent of getting the transplant when at all possible.
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