As public health safety measures implemented in response to coronavirus disease 2019 (COVID-19) continue, the 62nd American Society of Hematology (ASH) Annual Meeting & Exposition, originally scheduled to be held in San Diego, California, was conducted for the first time as an all-virtual event.
The ASH Annual Meeting & Exposition is the premier hematology event of the year and the largest hematology conference in the world. Approximately 3500 abstracts were presented in 2020, including 750 oral presentations (many potentially practice-changing) that covered the spectrum of malignant and nonmalignant hematologic disorders. A number of papers focused on acute myeloid leukemia (AML), a common form of leukemia seen primarily in older adults and characterized by historically poor outcomes.
The therapeutic landscape of AML has relied primarily on intensive induction and consolidation chemotherapy based on what is known as the 7+3 first-line induction regimen. This landscape has begun to change, however. Novel agents and formulations, including targeted therapies such as venetoclax, have come to market, and clinical trials are increasingly focused on subgroups of patients who are not candidates for standard intensive regimens.
The following presentations represent a sampling of research focused on AML and presented at this year’s meeting.
Outcomes of Therapy With Venetoclax Combined With Hypomethylating Agents in Favorable-Risk Acute Myeloid Leukemia (AML)1
Venetoclax combined with hypomethylating agents (Ven-HMA) has been associated with a high rate of complete remission (CR) or CR with incomplete recovery (CRi) among older and unfit patients with untreated AML. However, data regarding the activity of Ven in those with favorable-risk AML are limited. To fill this knowledge gap and identify patient variables associated with a favorable response, a multicenter retrospective analysis was conducted that included 46 patients treated with Ven-HMA, 26 of whom were newly diagnosed and 20 who had relapsed or refractory AML.
The CR/CRi rate was 80% (n=37), with no difference seen between patients with either newly diagnosed or relapsed or refractory AML. Prior HMA exposure was associated with a lower response rate (55%) than the response rate in HMA-naive patients (88%) (P =.025), and no difference in response was observed based on core genetic mutations. Although the analysis was limited by a relatively small sample and the retrospective nature of the study, this is the first study to assess Ven-HMA in favorable-risk patients and showed a highly promising CR/CRi rate with a durable response.
VEN-HMA was found to be associated with a promising CR/CRi rate with durable responses in patients with favorable-risk AML, and most responders who underwent measurable residual disease (MRD) assessment were found to have achieved MRD negativity.
Flotetuzumab as Salvage Therapy for Primary Induction Failure and Early Relapse Acute Myeloid Leukemia2
Approximately 40% of patients with newly diagnosed AML either fail to achieve CR after primary induction therapy or experience early relapse within 6 months. The probability of response in this patient subgroup is poor — approximately 12% — and median expected overall survival is approximately 3.5 months. However, there is no approved therapy for this specific population.
A first-in-human study of flotetuzumab (ClinicalTrials.gov Identifier: NCT02152956), an investigational CD123 x CD3 bispecific DART® molecule in clinical development for this subgroup of patients with AML, was conducted. The study comprised 38 patients with AML and primary induction failure or early relapse who underwent a median 2 lines of therapy; median baseline bone marrow blast percentage was 34%.
Median time to first response was 1 cycle (range, 1-3 cycles); 59% of patients had evidence of a reduction in blast count, with a median decrease of 81% in bone marrow blasts. The composite complete response was 31.8%, and more than one-half of patients who achieved complete response went on to undergo transplantation. Median duration of response was 8.13 months, and median overall survival was 10.7 months.
Flotetuzumab demonstrated encouraging activity in patients with newly diagnosed AML who either fail to achieve CR after primary induction therapy or experience early relapse within 6 months, especially because historical data show that CR to salvage therapy is only 5% to 12%.
Five-Year Final Results of a Phase 3 Study of CPX-351 Versus 7+3 in Older Adults With Newly Diagnosed High-Risk/Secondary Acute Myeloid Leukemia (AML): Outcomes By Age Subgroup and Among Responders3
A pivotal randomized phase 3 study (ClinicalTrials.gov Identifier: ) comprising 309 patients 60 to 75 years of age with newly diagnosed high-risk or secondary AML found that after induction that was followed by consolidation with CPX-351 (daunorubicin and cytarabine liposome for injection), median overall survival was significantly improved compared with conventional 7+3 therapy. The estimated survival rate was higher at 3 years and 5 years for CPX-351 (21% and 18%, respectively) than for 7+3 (9% and 8%, respectively). At 60.65-month follow-up, median overall survival favored CPX-351 over 7+3 (9.33 vs 5.95 months, respectively; hazard ratio [HR]=0.70; 95% CI, 0.55-0.91).
More patients in the CPX-351 arm vs the 7+3 arm went on to undergo transplantation (35% vs 25%, respectively); estimated survival rate from date of transplantation was higher at 3 years for CPX-351 than for 7+3 (56% vs 23%, respectively). Median overall survival was not reached for CPX-351 compared with 10.25 months for 7+3 (HR=0.51).
CPX-351 can potentially be used as a bridge to transplant in patients with newly diagnosed high-risk or secondary AML. These data support earlier evidence that CPX-351 has the ability to produce or contribute to long-term remission and survival in older patients with newly diagnosed high-risk or secondary AML.
Results of Venetoclax and Azacitidine Combination in Chemotherapy Ineligible Untreated Patients with Acute Myeloid Leukemia with IDH 1/2 Mutations4
Isocitrate dehydrogenase (IDH) mutations occur in approximately 20% of patients with AML. Studies suggest that patients with an IDH1 or IDH2 mutation who are treated with venetoclax plus azacitidine (Ven+Aza) achieve a high durable response rate and longer median overall survival. This study (ClinicalTrials.gov Identifier: NCT02993523) evaluated the efficacy and safety of Ven+Aza in a cohort of treatment-naive patients with AML (107 with an IDH1 or IDH2 mutation and 326 in whom IDH was not detected) who were considered unfit for intensive treatment because of comorbidity or age 75 years or older.
In patients with the IDH1 mutation, CR/CR with partial hematologic recovery (CRh) was 59% with Ven+Aza and 9% with placebo+Aza. Median time to first CR/CRh response was 2.3 months for Ven+Aza and 3.1 months for placebo+Aza. One-quarter of patients with an IDH1 mutation receiving Ven+Aza achieved CR/CRh by the initiation of cycle 2; no patients with an IDH1 mutation receiving placebo+Aza achieved CR/CRh by this time point.
Similar results were observed for patients with an IDH2 mutation. CR/CRh was 75% with Ven+Aza and 7% with placebo+Aza. Median time to first CR/CRh response was 1.0 month with Ven+Aza and 2.1 months with placebo+Aza. More than half (58%) of patients with an IDH2 mutation receiving Ven+Aza patients achieved CR/CRh by initiation of cycle 2; no patients with an IDH2 mutation receiving placebo+Aza achieved CR/CRh by this time point.
Patients with an IDH1 or IDH2 mutation achieved a higher CR/CRh rate with Ven+Aza (72%) than did patients in whom IDH was undetected (60%).
Ven+Aza might be an effective first-line option for patients with AML and an IDH1 or IDH2 mutation who are ineligible for intensive chemotherapy.
Outcomes of TP53-Mutant Acute Myeloid Leukemia With Venetoclax and Decitabine5
TP53 mutations in AML generally confer poor prognosis and are associated with a limited response to chemotherapy; however, a 10-day regimen of decitabine (DEC10) has shown high efficacy in this population. It is hypothesized that adding venetoclax to a DEC10 regimen (DEC10-Ven) could improve outcomes in patients with high-risk AML, although preclinical data suggest that TP53 mutations confer resistance to venetoclax in AML.
In this study (ClinicalTrials.gov Identifier: NCT03404193), 121 patients, 37 (31%) of whom harbored a TP53 mutation, received frontline therapy with DEC10-Ven. Patients with a TP53 mutation were more likely than patients with wild-type TP53 to have therapy-related AML (43% and 11%, respectively) and adverse European LeukemiaNet cytogenetic risk (92% and 27%).
The rate of CR/CRi was 69% for the entire cohort, with negative MRD in 42% of patients. Compared with those with wild-type TP53, those with a TP53 mutation had a lower CR rate (57% and 35%, respectively; P =.026), a lower CR/CRi rate (76% and 54%, respectively; P = .015), and a lower MRD rate (52% and 19%, respectively; P = .001). Sixty-day mortality was higher in patients with TP53 mutation vs those with wild-type TP53 (27% vs 2%, respectively); all deaths were associated with refractory disease in patients with TP53 mutation.
Despite reasonable response, survival was limited in patients with AML and the TP53 mutation receiving DEC10-Ven. Novel therapies are needed for this AML subgroup.
Molecular Characterization of Clinical Response and Relapse in Patients With IDH1-Mutant Newly Diagnosed Acute Myeloid Leukemia Treated with Ivosidenib and Azacitidine6
Acute myeloid leukemia is characterized by clonal expansion of abnormal myeloid progenitors and exhibits a dynamic mutational landscape over time, with somatic mutations in IDH1 reported in 6% to 10% of patients. Ivosidenib is a targeted inhibitor of the IDH1 mutation that has been approved by the US Food and Drug Administration to treat relapsed or refractory, or newly diagnosed AML in adults with the IDH1 mutation who are aged 75 years or older or with comorbidity. An ongoing phase 1b clinical trial (ClinicalTrials.gov Identifier: NCT02677922) involving 23 patients is evaluating the use of ivosidenib plus azacitidine in patients with newly diagnosed AML and has sought to characterize clonal evolution and resistance in this patient population.
Emerging mutations were observed in 9 (41%) patients, including 4 with multiple mutations; 3 (14%) patients had an emerging IDH2 mutation and a concurrent rise in plasma 2-hydroxyglutarate levels. Among patients with relapsed or progressive disease, emerging mutations were observed in 4 patients; however, emergence of an IDH1 second-site or receptor tyrosine kinase pathway (FLT3, KRAS, NRAS, and PTPN11) mutation was not seen. Further sequencing showed that 1 of 2 patients with relapsed AML had an emerging IDH2 mutation; 1 patient had a minor IDH2 clone present at baseline that expanded independently from IDH1 during therapy.
These findings emphasize the importance of mutational testing, especially during disease progression, to determine optimal salvage therapy in AML.
Clinical Benefit and Tolerability of Crenolanib in Children With Relapsed Acute Myeloid Leukemia Harboring Treatment Resistant FLT3 ITD and Variant FLT3 TKD Mutations Treated on Compassionate Access7
Pediatric AML associated with the FLT3 mutation, a biologically and clinically diverse disease, is associated with poor prognosis, and relapse after hematopoietic stem cell transplantation (HSCT) is a serious unmet need. Crenolanib is a pan-FLT3 inhibitor that has been safely and tolerably administered to more than 55 pediatric patients, 2 to 18 years of age, with diffuse intrinsic pontine glioma and high-grade glioma, as part of a compassionate use program. In this study, crenolanib was given to 5 patients, aged 4 to 12 years, for AML associated with the FLT3 mutation on a compassionate basis. All patients had undergone HSCT and experienced relapse. At the time of the compassionate use request, all standard and experimental therapies had been exhausted.
Four patients achieved clinical benefit with crenolanib; 2 remain alive and in remission. One of those patients with KMT2A-rearranged infant AML achieved molecular CR following treatment with daunorubicin-cytarabine liposome (Vyxeos®) plus crenolanib. This patient was successfully bridged to a second HSCT and remains in remission 1.5 years after crenolanib treatment. The other surviving patient — who had KMT2A fusion, a p53 mutation, and central nervous system (CNS) AML — also achieved CR with crenolanib plus sorafenib and was successfully bridged to a second HSCT. This patient received 1 year of post-transplant crenolanib maintenance and remains in remission 3.5 years later.
This series demonstrates that full doses of crenolanib can be safely combined with salvage chemotherapy in pediatric AML associated with the FLT3 mutation and that rapid remission can be achieved even in patients with concurrent KMT2A, 3q, and p53 mutations.
AGILE: Phase 3, Double-Blind, Randomized, Placebo-Controlled Study of Ivosidenib in Combination With Azacitidine in Adults with Newly Diagnosed Acute Myeloid Leukemia and an IDH1 Mutation8
An ongoing phase 1b trial (ClinicalTrials.gov Identifier: NCT02677922) showed that, in a cohort of 23 patients, ivosidenib (also known as AG-120) combined with azacitidine (IVO+Aza) conferred an overall response rate of 78.3% (n=18). Among patients who demonstrated response, 60.9% (n=14) achieved CR, with median time to response of 1.8 months and time to CR of 3.7 months. Median response duration has not been reached; overall 12-month survival probability is 82.0%.
An ongoing phase 3 study, the AGILE trial (ClinicalTrials.gov Identifier: NCT03173248), is evaluating IVO+Aza in adults with newly diagnosed AML and the IDH1 mutation who are not candidates for intensive treatment. Updates to key inclusion criteria and study design have now been reported.
In this multicenter trial that is currently enrolling patients, participants are randomly assigned 1:1 to receive IVO (500 mg) plus Aza (75 mg/m2) for 7 days in 28-day cycles or matched placebo+Aza. The key inclusion criterion is untreated AML associated with the IDH1 mutation in patients ineligible to receive standard intensive chemotherapy. Recently amended criteria further stipulate ineligibility as age 75 years and older, reduced performance (Eastern Cooperative Oncology Group performance status grade 2), or significant comorbidity.
The favorable safety profile from the phase 1b trial and the encouraging clinical activity that was observed warrant timely and accurate confirmation of the clinical benefit of IVO+Aza in this patient population that has proved difficult to treat.
Summary of Type, Patient Characteristics/Interventions, and Secondary Outcomes of Selected Studies
AML is a heterogeneous disease characterized by an array of molecular alterations that are providing potential targets for drug development. These abstracts offer a glimpse of ongoing research into new therapies and drug combinations, especially for patients whose disease type has a historically poor prognosis. Most of this research focuses on specific gene mutations: how they affect treatment response and how different regimens might be more effective depending on genetic makeup. Most new AML treatments target specific gene mutations or pivotal cell survival pathways, or both. The clinical trial landscape for AML appears to be robust, with no signs of slowing down.
Several study authors declared affiliations with the pharmaceutical industry. Please see the original references for a full list of authors’ disclosures.
- Arslan S, Zhang J, Dhakal P, et al. Outcomes of therapy with venetoclax combined with hypomethylating agents in favorable-risk acute myeloid leukemia (AML). Blood. 2020;136(Suppl 1):41-42. doi:10.1182/blood-2020-142780
- Aldoss I, Uy GL, Vey N, et al. Flotetuzumab as salvage therapy for primary induction failure and early relapse acute myeloid leukemia. Blood. 2020;136(Suppl 1):16-18. doi:10.1182/blood-2020-134576
- Lancet JE, Uy GL, Newell LF, et al. Five-year final results of a phase 3 study of CPX-351 versus 7+3 in older adults with newly diagnosed high-risk/secondary acute myeloid leukemia (AML): outcomes by age subgroup and among responders. Presented at: American Society of Hematology (ASH) 62nd Annual Meeting and Exposition; December 5-8, 2020. Abstract 635.
- Pollyea DA, Dinardo CD, Arellano ML, et al. Results of venetoclax and azacitidine combination in chemotherapy ineligible untreated patients with acute myeloid leukemia with IDH 1/2 mutations. Blood. 2020;136(Suppl 1):5-7. doi:10.1182/blood-2020-134736
- Kim K, Maiti A, Kadia TM, et al. Outcomes of TP53-mutant acute myeloid leukemia with venetoclax and decitabine. Blood. 2020;136(Suppl 1):33-36. doi:10.1182/blood-2020-140182
- Daigle SR, Choe S, DiNardo CD, et al. Molecular characterization of clinical response and relapse in patients with IDH1-mutant newly diagnosed acute myeloid leukemia treated with ivosidenib and azacitidine. Blood. 2020;136(Suppl 1):49-51. doi:10.1182/blood-2020-136922
- Tarlock K, Meshinchi S, Rubnitz JE, et al. Clinical benefit and tolerability of crenolanib in children with relapsed acute myeloid leukemia harboring treatment resistant FLT3 ITD and variant FLT3 TKD mutations treated on compassionate access. Blood. 2020;136(Suppl 1):23-24.
- Montesinos P, Recher C, Zarzycka E, et al. AGILE: phase 3, double-blind, randomized, placebo-controlled study of ivosidenib in combination with azacitidine in adults with newly diagnosed acute myeloid leukemia and an IDH1 mutation. Presented at: American Society of Hematology (ASH) 62nd Annual Meeting and Exposition; December 5-8, 2020. Abstract 2814.
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Reviewed December 2020