CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: April 06, 2022
Expiration: April 05, 2023
B. Douglas Smith, MD:
The combination of venetoclax with HMAs is approved by the FDA for patients 75 years of age or older with newly diagnosed AML or those with comorbidities precluding intensive induction chemotherapy.7 However, this combination is associated with a high relapse rate and a low rate of survival beyond 2 years, and patients with TP53 mutations have particularly poor outcomes.3,8,9
Magrolimab is an anti-CD47 antibody with promising activity in combination with azacitidine for TP53 wild-type and mutated AML.10 CD47 is a cellular protein that protects the cell from being destroyed by the immune system. Blocking CD47 improves the host immune system’s ability to effectively kill the cancer cell. The present study by Daver and colleagues11 combines azacitidine, venetoclax, and magrolimab in patients with relapsed/refractory and newly diagnosed AML.
B. Douglas Smith, MD:
In the present analysis of this ongoing, open-label phase Ib/II trial, 25 patients were newly diagnosed with AML, 14 of whom had TP53-mutated disease.11 In addition, 23 patients had relapsed/refractory AML, 8 of whom were venetoclax naive.
Patients received 28-day cycles of therapy with azacitidine given over 7 days, venetoclax given over 21 days, and magrolimab given in 2, 4, or 6 doses in each cycle. Magrolimab was dose escalated to minimize AEs, particularly anemia. Patients continued on the study until receiving 12 cycles or disease progression.
The primary objectives of the phase Ib portion of the trial were to determine the maximum tolerated dose and recommended phase II dose. The primary objectives of the phase II portion include overall response rate (ORR), DoR, EFS, and OS.
Patients with newly diagnosed TP53-mutated AML had a much higher rate of adverse-risk cytogenetics by ELN compared with TP53 wild-type patients (86% vs 45%).11
Among patients with relapsed/refractory AML, the rate of adverse-risk cytogenetics was well matched between patients who were venetoclax naive (75%) and patients who had previously received venetoclax (73%).
B. Douglas Smith, MD:
The ORR was 86% (n = 12) in patients with newly diagnosed TP53-mutated AML and 100% (n = 11) in patients with TP53 wild-type AML.11 CR/CRi was achieved by 64% of patients with TP53 mutations and 91% of patients with TP53 wild type disease.
Six patients (75%) with relapsed/refractory disease who were venetoclax naive achieved a response vs only 3 patients (20%) who had previously received venetoclax.
The median time to first response was 0.7 months in all the newly diagnosed patients, as well as patients with relapsed/refractory AML who were venetoclax naive. Relapsed/refractory patients who received prior venetoclax had a median time to first response of 2.2 months.
B. Douglas Smith, MD:
This triplet therapy was well tolerated with no study discontinuations due to treatment-emergent AEs.11 However, 25 patients (52%) developed bilirubin increases, and 19 patients (39%) developed alanine aminotransferase increases.
Infections and infestations affected 7 patients (14%), and sepsis affected 3 patients (6%), both of which are comparable to what is expected with azacitidine plus venetoclax. So, I do not think the addition of magrolimab significantly impacted safety.
B. Douglas Smith, MD:
Preliminary data from this study show significant clinical activity with the addition of the anti-CD47 antibody magrolimab to azacitidine and venetoclax. I think this triplet really has some promise.
Dr. Wang, you know a lot about magrolimab. What are your thoughts about these results?
Eunice S. Wang, MD:
I agree with you. TP53-mutant AML remains a patient population of great need because outcomes with venetoclax plus HMA and intensive chemotherapy are poor. I think the way forward is novel agents such as magrolimab, and there is great interest in developing triplet approaches. Even though these are early data from a single center, this triplet therapy is promising, especially because magrolimab did not add significant toxicity.
I am very excited by magrolimab because it targets macrophages rather than T-cells, and T-cell–targeted checkpoint inhibitors seem to have limited efficacy. (Editor’s note: In January 2022, the FDA placed a partial hold on worldwide clinical trials of magrolimab in combination with azacitidine due to an apparent imbalance in investigator-reported unexpected serious AEs. Screening and new enrollment of patients on these trials will be paused, but current patients in the trials will be allowed to continue therapy.)
Eunice S. Wang, MD:
One of the most exciting abstracts in AML during the ASH 2021 meeting presented the results of the phase III AGILE study, which examined whether the combination approach of adding an IDH inhibitor to HMAs might be superior to HMAs alone in older patients with IDH1-mutant AML.
IDH1 mutations are found in a small subset of patients with AML and are associated with poor prognosis.12-15 Ivosidenib is a first-in-class oral IDH inhibitor that is approved by the FDA for older patients with IDH1-mutated AML considered unfit for intensive chemotherapy.16
A phase Ib study found that ivosidenib plus azacitidine is tolerable and results in high CR rates.17 The phase III AGILE trial built on this and compared ivosidenib plus azacitidine with azacitidine alone in patients with newly diagnosed IDH1-mutated AML. The results of AGILE were reported by Montesinos and colleagues18 at ASH 2021.
Eunice S. Wang, MD:
AGILE was a global, double-blind, randomized phase III trial enrolling 148 patients with previously untreated IDH1-mutated AML ineligible for intensive chemotherapy.18 Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) between 0 and 2 and were stratified based on region and disease history. Patients were randomized to receive ivosidenib plus azacitidine (n = 72) or placebo plus azacitidine (n = 74).
The primary endpoint was EFS with approximately 173 events (52 months), and secondary endpoints included CR rate, OS, and ORR.
The median age of patients at baseline was 76 years, and PS was largely 1 and 2.18 Three fourths of patients had de novo AML, and 60% to 67% of patients had intermediate cytogenetic risk.
Eunice S. Wang, MD:
Clinical outcomes were dramatically improved with added ivosidenib, including median EFS (HR: 0.33; P = .0011) and median OS (24.0 months vs 7.9 months; HR: 0.44; P = .0005).18
The EFS and OS benefits were consistent across patient subgroups based on de novo status, ECOG PS, and cytogenetic risk. Health-related quality of life also favored the addition of ivosidenib to azacitidine.
Eunice S. Wang, MD:
ORR was markedly higher with the addition of ivosidenib to azacitidine at 62.5% vs 18.9% (odds ratio: 7.2; P <.0001), with CR rates of 47.2% vs 14.9% (odds ratio: 4.8; P <.0001).18
The addition of ivosidenib also improved mutational IDH1 clearance, although the clinical significance of that is still unclear.
Eunice S. Wang, MD:
AEs were largely similar, but of interest, the rate of infections was higher among patients receiving placebo vs ivosidenib (49.3% vs 28.2%).18
Investigator-assessed grade ≥2 differentiation syndrome affected 14.1% of patients receiving ivosidenib plus azacitidine vs 8.2% of patients receiving placebo plus azacitidine. It is unclear why 8.2% of the patients receiving placebo plus azacitidine experienced differentiation syndrome, but it may be due to the investigator’s clinical assessment.
Eunice S. Wang, MD:
AGILE demonstrated the superiority of ivosidenib plus azacitidine over azacitidine alone for older, unfit patients with newly diagnosed IDH1-mutant AML. Every patient subgroup benefited from the addition of ivosidenib. However, many healthcare professionals treating older, unfit patients will administer venetoclax plus HMA without awaiting genomic testing results. For that reason, it is not clear to me whether ivosidenib plus azacitidine will become the new standard of care for these patients.
Dr. Smith, what are your thoughts? If a patient has the IDH1 mutation, would you consider ivosidenib plus azacitidine?
B. Douglas Smith, MD:
I find this an interesting challenge. I love the idea of a targeted approach, and these are promising data. But it is challenging to get mutational data quickly enough to start patients on therapy. So, we tend to reserve IDH inhibitors for relapsed disease. If we can get the mutational data faster, I would love to use ivosidenib plus azacitidine as frontline therapy.
Eunice S. Wang, MD:
Treatment options are currently limited for patients newly diagnosed with AML with FLT3 mutations ineligible for intensive induction chemotherapy.19-21 Gilteritinib is a second-generation FLT3 tyrosine kinase inhibitor and is approved by the FDA for FLT3-mutated relapsed/refractory AML.22
Preclinical studies have demonstrated that gilteritinib plus azacitidine hampers tumor growth and induces apoptosis.23 The LACEWING phase III study evaluated the efficacy and safety of the combination of gilteritinib plus azacitidine vs azacitidine alone in adults with newly diagnosed FLT3-mutated AML who are ineligible for intensive therapy.24 My colleagues and I presented results from this study at ASH 2021.
Eunice S. Wang, MD:
LACEWING was a randomized, open-label phase III study that enrolled 145 patients with newly diagnosed FLT3-mutated AML ineligible for intensive induction chemotherapy.24 Patients of all ages were eligible for the study, as were patients with comorbidities or an ECOG PS of ≥2. Patients were initially randomized 1:1:1 to receive gilteritinib alone, gilteritinib plus azacitidine, or azacitidine alone. However, investigator preference changed over the course of this study due to challenging accrual problems, so the decision was made to eliminate the gilteritinib monotherapy arm, and patients were then randomized 2:1 to receive gilteritinib plus azacitidine vs azacitidine alone.
As of August 2020, 123 patients were enrolled, with 74 receiving gilteritinib plus azacitidine and 49 receiving azacitidine alone. Patients had follow-up at 30 days and then every 3 months for up to 3 years. The primary endpoint of the study was OS, with secondary endpoints of EFS, response, and safety/tolerability and an exploratory endpoint of pharmacokinetics.
The median age of enrolled patients was approximately 76 years.24 Most patients in both arms had an FLT3-ITD mutation alone (78.4% to 81.6%) and an ECOG PS between 0 and 1. Patients with ECOG PS ≥2 made up slightly more of the combination arm (47.3% vs 35.7%).
Eunice S. Wang, MD:
A potential confounding factor in analysis for this trial is that patients who received azacitidine alone had a shorter median time to subsequent AML therapy (4.5 months vs 8.2 months).24 And although only 20.3% of the combination arm received any subsequent therapy, 44.9% the azacitidine monotherapy arm did. Patients in both arms went on to receive FLT3 inhibitor–containing regimens, with the majority receiving subsequent gilteritinib.
Eunice S. Wang, MD:
Median OS was 9.82 months (95% CI: 7.56-12.55) with combination therapy vs 8.87 months (95% CI: 4.34-14.03) with azacitidine alone (HR: 0.916; 95% CI: 0.529-1.585; P = .753).24
Patients with FLT3-ITD–mutated AML seemed to have the most OS benefit with combination therapy vs azacitidine monotherapy (11.5 months vs 8.1 months), particularly if their ITD allelic ratio was ≥0.5 (10.7 months vs 4.3 months).
Eunice S. Wang, MD:
Median EFS was 0.03 months in both arms (HR: 1.175; 95% CI: 0.764-1.807; P = .459), but when calculated based on composite CR (CRc), there was a slight trend toward improvement with gilteritinib plus azacitidine (4.73 months vs 2.07 months; HR: 0.896; 95% CI: 0.573-1.400; P = .668).24
ORR was achieved by 63.5% of patients receiving gilteritinib plus azacitidine vs 34.7% of patients receiving azacitidine alone. The rate of CRc was significantly improved with combination therapy (58.1% vs 26.5%; P <.001). CR rates were similar at 16.2% with combination therapy vs 14.3% with azacitidine alone; however, significantly more patients had CRi or CR with incomplete platelet recovery with gilteritinib plus azacitidine.
Eunice S. Wang, MD:
The rates of AEs were similar in both arms, with 100% of patients receiving gilteritinib plus azacitidine developing any AE vs 91.5% of patients receiving azacitidine alone; grade ≥3 AEs developed in 95.9% vs 89.4% of patients.24
Treatment-related AEs were more common in the gilteritinib plus azacitidine arm, occurring in ≥90% of patients vs 60% of patients in the azacitidine monotherapy arm. Grade 5 events and significant AEs were not markedly different.
Eunice S. Wang, MD:
Gilteritinib levels at steady state among patients with FLT3-mutated AML were twice the levels seen at steady state in relapsed/refractory patients enrolled in the ADMIRAL trial.24,25
No correlation was observed between gilteritinib trough levels at steady state and response rates or grade of thrombocytopenia or neutropenia. There also was no difference in the use of azacitidine on concomitant medications.
Eunice S. Wang, MD:
In the LACEWING trial, gilteritinib plus azacitidine did not improve OS in older patients with FLT3-mutated newly diagnosed AML. However, there were some potential confounding factors, including the large number of patients in the control group receiving subsequent FLT3 inhibitors, the lack of placebo in the azacitidine monotherapy arm, and the removal of the gilteritinib monotherapy arm. It is unknown which, if any, of these factors contributed to the negative results.
However, we can still conclude from this trial that gilteritinib plus azacitidine is an active and well-tolerated regimen that may improve ORR, particularly among patients with higher FLT3-ITD allelic ratios. These data could lay the groundwork for future studies evaluating gilteritinib and azacitidine in triplet regimens with venetoclax and other clinical disease settings.
B. Douglas Smith, MD:
These data are interesting to me because they show that improved CR and CRi do not necessarily always translate to an OS benefit when patients go on to receive alternative therapies.
Dr. Wang, what is your impression of gilteritinib as a single agent in this group of patients? We know it has good single‑agent clinical activity.
Eunice S. Wang, MD:
Only 22 patients were enrolled on the gilteritinib monotherapy arm, and responses were seen in that patient population. Because the study was altered to not look at this arm, it is uncertain what to do with those data. I agree with you that these are interesting data; people have interpreted these data as saying that they make the case for not using gilteritinib up-front but using sequential therapy. I think combinatorial therapy with FLT3 inhibitors, HMA, and venetoclax is probably in our future.
B. Douglas Smith, MD:
Agreed.
Eunice S. Wang, MD:
Prognosis is poor for patients with newly diagnosed and relapsed/refractory FLT3-mutated AML ineligible for intensive chemotherapy. For older and/or unfit newly diagnosed patients, median OS is 8-11 months with HMA plus venetoclax or with an FLT3 inhibitor.26,27
Quizartinib, like gilteritinib, is a potent second-generation FLT3 inhibitor, but it does not have activity against FLT3 TKD mutations. Quizartinib has been studied in the relapsed/refractory setting, where it led to improved ORR and OS vs the standard of care in patients with relapsed/refractory FLT3-mutated AML,28 garnering approval for the treatment of this patient population in Japan.
Preclinical studies demonstrated synergistic antitumor effects in combination with venetoclax, which led to this ongoing study evaluating the efficacy and safety of quizartinib in combination with venetoclax and decitabine. Yilmaz and colleagues29 presented this abstract at ASH 2021.
Eunice S. Wang, MD:
This is a single-center, open‑label phase I/II trial of patients with FLT3-mutated AML.29 The current analysis includes 23 patients in the relapsed/refractory setting and 5 in the newly diagnosed setting. All patients had FLT3-ITD mutations.
Induction therapy involved 28 days of quizartinib, 21 days of venetoclax, and 10 days of decitabine, all given together in one 28‑day cycle. This was followed by consolidation with 28 days of quizartinib, 14 days of venetoclax, and 5 days of decitabine.
The primary endpoint is the recommended phase II dose, with secondary endpoints looking at preliminary efficacy.
Patients in the newly diagnosed cohort had a median age of 69 years vs a median of 57 years in the relapsed/refractory cohort.29 In the newly diagnosed setting, 18 patients (78%) had de novo AML; the median number of prior therapies in the relapsed/refractory group was 3. Various mutations other than FLT3-ITD also were present in the patients.
Eunice S. Wang, MD:
Nine patients received the combination therapy during the dose-finding phase I portion, resulting in 7 instances of CR/CRi and 1 morphologic leukemia-free state.29 Hematologic dose-limiting toxicities occurred at the 40-mg dose, leading to the selection of 30 mg as the recommended phase II dose.
Eunice S. Wang, MD:
CRc was achieved by 18 patients (78%) in the relapsed/refractory setting and 5 patients (100%) in the newly diagnosed setting.29 There was no 30-day mortality, with only 1 patient (5%) dying within 60 days in the relapsed/refractory cohort. Eight patients (34%) in the relapsed/refractory setting were bridged to allogeneic stem cell transplant compared with 3 patients (60%) in the newly diagnosed setting.
CRc was achieved across most patient subgroups regardless of prior gilteritinib or prior HMA plus venetoclax.
Eunice S. Wang, MD:
Among 6 patients with durable remissions, all were RAS/MAPK wild type at baseline.29 Among 8 patients who responded and then relapsed, 3 patients (37%) relapsed with emerging RAS/MAPK mutations, 2 (25%) relapsed with emerging FLT3 F6911L mutation, and 2 (25%) relapsed with negative FLT3-ITD. No emergent FLT3 D835 was observed in any patients.
Eunice S. Wang, MD:
The major nonhematologic AE was QTcF prolongation (grade 1) that occurred in 3 patients (9%) receiving the triplet therapy.29 The most common nonhematologic TEAEs of grade ≥3 were pneumonia (42%), other infections (33%), febrile neutropenia (30%), and sepsis (9%).
Eunice S. Wang, MD:
Despite very small numbers of patients in each cohort, I think these data demonstrate that quizartinib plus venetoclax and decitabine is highly active. However, I do not think the data support the integration of this regimen into prime-time use. Many questions remain about safe administration outside of an academic medical center with inpatient monitoring. The tolerability of this regimen and the necessity of all 3 drugs in the induction and consolidation are still subject to question. Further studies optimizing triplet therapy—particularly in the older, unfit patients—are warranted.
Dr. Smith, what do you think?
B. Douglas Smith, MD:
I completely agree with you that this is exciting. It does exactly what we want to do: develop combination therapies that are selective and target mutations important in driving leukemias. However, when we add drugs, we also increase the risk of toxicity, and this is a perfect example. There is more work to do, but I believe if we refine the dosing, this should be a very effective therapy.
Eunice S. Wang, MD:
As we have noted, gilteritinib is a FLT3 tyrosine kinase inhibitor (TKI) that is FDA approved for the treatment of patients with relapsed/refractory AML harboring an FLT3 mutation,22 although effective, long-term efficacy is limited by the development of drug resistance.30 Combination therapy may enhance response and delay the development of drug resistance. A preclinical study also found that combination gilteritinib and venetoclax have synergistic antileukemic activity.31
The current abstract, presented by Daver and colleagues32 at ASH 2021, reports final response and survival data from a phase Ib study of gilteritinib plus venetoclax in patients with relapsed/refractory FLT3-mutated AML.
Eunice S. Wang, MD:
This was a multicenter, single-arm phase Ib trial enrolling 54 patients with relapsed/refractory AML with either FLT3 wild-type or mutated disease.32 Patients had received ≥1 prior line of therapy and had an ECOG PS of 0-2. All patients received 400 mg of venetoclax and either 80 mg or 120 mg (recommended phase II dose) of gilteritinib. Patients were followed monthly after treatment for up to 12 months after the last treatment dose.
The primary endpoint was modified CRc (mCRc), with secondary endpoints of CR plus CR with partial hematologic recovery and DoR of mCRc. Exploratory endpoints included OS in patients with FLT3 mutations and the allelic burden of FLT3 mutations.
Patients were older, with a median age of 64 years; 42 patients (78%) had de novo AML.32 In addition, 41 patients (76%) had received ≥2 prior therapies, 32 (59%) had received ≥1 FLT3 TKI, and 17 (31%) had prior allogenic stem cell transplant.
Eunice S. Wang, MD:
The 30-day mortality rate was 0%, and 60‑day mortality was 14%.32 Grade 3/4 cytopenia and anemia were AEs of special interest and affected 44 patients (81%) and 20 patients (37%), respectively. Grade 3/4 pneumonia affected 11 patients (20%), grade 3/4 sepsis affected 8 (15%), and grade 3/4 septic shock affected 1 (2%).
Eunice S. Wang, MD:
A best response of mCRc was achieved in 74.5% of all FLT3-mutated patients, but 37.3% of these responses were morphologic leukemia-free state, and only 19.6% were CR.32 So, although there was a high number of disease‑free states, there was not necessarily count recovery. The mCRc rate in this study was higher than single-agent gilteritinib in a previous trial (74.5% vs 54.3%).33
Eunice S. Wang, MD:
At a median follow up of 15.1 months, median OS in patients with FLT3-ITD–positive AML was 10 months (95% CI: 6.6-13.2) and appears higher than what has been observed with gilteritinib alone in the ADMIRAL trial.32 Encouragingly, 60% of patients achieved molecular clearance of FLT3 allelic burden.
Eunice S. Wang, MD:
Gilteritinib plus venetoclax appears highly active, so it is unclear whether HMA is really required to be the third drug in this type of regimen. Gilteritinib alone could definitely be improved in the relapsed/refractory setting, and this approach has promise to potentially supplant gilteritinib monotherapy.
Dr. Smith, are you using this in the relapsed/refractory setting?
B. Douglas Smith, MD:
We are, and I agree with you that these are very promising data. Just like what venetoclax did with HMA for older patients with poor‑risk AML, adding venetoclax to gilteritinib seems to increase efficacy in patients with FLT3 mutations. I am looking forward to future data on MRD status and DoR.
Eunice S. Wang, MD:
Yes, I am interested in knowing whether patients who achieve remission become MRD negative and whether that translates into better transplant outcomes.
B. Douglas Smith, MD:
I agree. That is an important question.
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