ASH 2020 Highlights – Acute Myeloid Leukemia (AML)

ASH 2020 Highlights – Acute Myeloid Leukemia (AML)

Prescient looks at the critical data presented at the American Society of Hematology (ASH) Annual Meeting and how they might affect the treatment paradigm in AML.


Prescient Analytics

Shweta Srivastava, MBA, Therapeutic Area Group Manager; Syed Meheboob Ahmed, PhD, Research Manager; Ankita Shivhare, BPharm, Research Analyst; and Deepti Sharma, MTech, Research Analyst


Acute myeloid leukemia (AML) is the most common form of leukemia in adults. It has historically been associated with poor five-year overall survival (OS) rates (~25%) with treatment options limited to induction chemotherapy and, in some instances, allogeneic hematopoietic stem cell transplant; however, AML is now witnessing a paradigm shift from chemotherapy-based treatment toward targeted and combination therapies. The recent approvals of CPX-351, venetoclax, enasidenib, ivosidenib, gilteritinib and midostaurin have improved survival outcomes in AML patients, but there remains an unmet need for therapies that provide deeper and durable responses, especially in patients who are unfit and/or relapsed/refractory (R/R). Given the heterogeneity of AML, the treatment landscape is likely to continue to evolve with the approval of newer agents (and their combinations) for the treatment of molecularly defined patient segments, thereby warranting improved diagnostics for careful selection of the appropriate patient pool.

ABSTRACT #112 and #114

Efficacy Data from Biomarker-directed Phase II Trial of Tamibarotene (SY-1425), a RARα Agonist, in Patients with AML (NCT02807558)


The retinoic acid receptor alpha (RARα) transcription factor, encoded by the RARA gene, plays a critical role in myeloid cells, and is dysregulated in a subset of AML and myelodysplastic syndrome (MDS) tumors. Approximately 30% of newly diagnosed (ND) and R/R unfit AML patients are RARA+, with a majority (80%) of them associated with venetoclax resistance, thereby suggesting a poor-prognostic-risk group. Recent data demonstrated that selection of RARA+ ND or R/R AML using a novel blood-based test predicts sensitivity to tamibarotene (SY-1425), an oral and selective RARα agonist, evaluated in combination with azacitidine. Presented is an updated analysis with the combination of SY-1425 and azacitidine in the genomically defined subset of RARA+ ND or R/R AML.

Study Highlights

SY-1425 in combination with azacitidine demonstrates a high complete response (CR) rate, rapid onset of response and promising OS (among responders) in RARA+ ND unfit AML. The combination was also found to be well tolerated, with promising clinical efficacy observed in R/R AML population, majority of whom were previously treated with hypomethylating agents (HMA) and/or venetoclax.

ND unfit AML: A total of 51 ND treatment-naïve non-acute promyelocytic leukemia (APL) patients unfit for intensive chemotherapy were treated with tamibarotene (SY-1425) in combination with azacitidine. The populations selected in both the groups were elderly with intermediate- to poor-risk cytogenetics.

  • RARA+ patients (n=18) – ORR: 67%; CR/CRi: 61%; CR: 50%; MLFS: 6%
    • Deep CR with 8/9 (89%) CRm or CRc
    • Rapid onset of initial CR with median 1.2 months
    • Median duration of CR: 10.8 months
  • High proportion of RARA+ patients achieved or maintained transfusion independence
    • 67% (12/18) of patients were free of both RBC and platelet transfusions for a ≥8-week interval on treatment
    • 86% (6/7) of patients dependent on transfusions at baseline converted to transfusion independence during treatment
  • Median OS
    • RARA+ patients with CR/CRi (n=11): 18months
    • RARA+ patients without CR/CRi (n=11): 5.6 months
    • Total enrolled RARA+ patients (n=22): 8.4 months
  • RARA- patients (n=28) – ORR: 43%; CR/CRi: 32%; CR: 25%; MLFS: 4%
    • Response rates comparable to historical response rates with single agent azacitidine
    • Median time to initial CR delayed relative to that in RARA+ patients at 3 months
    • Median duration of CR: 10.3 months


  • The combination was well tolerated
  • Their myelosuppression rates were comparable to those of single agent azacitidine
  • Most non-hematologic AEs were of low grade and reversible
  • Grade ≥3 hematologic AEs included febrile neutropenia (33%), thrombocytopenia (24%), anemia (20%) and neutropenia (16%)
  • The most frequent SAEs included febrile neutropenia (27%), pyrexia (12%), pneumonia (12%) and sepsis (10%)
  • Two patients discontinued the treatment due to TRAEs, and one patient died

R/R unfit AML: A total of 28 elderly, heavily pre-treated patients, including 68% with prior HMA and/or venetoclax treatment, were treated with tamibarotene (SY-1425) in combination with azacitidine.

  • In n=21 evaluable patients, ORR: 19% (CR: 5%; CRc: 5%; CRi: 10%; MLFS: 5%)
    • Median time to response was 1.4 months
    • 30% (6/20) of patients were free of both RBC and platelet transfusion for ≥8-week interval on treatment
    • 27% (3/11) of patients dependent on transfusions at baseline converted to transfusion independence during treatment
  • Median OS (n=28): 5.9 months (95% CI: 3.8, NE)


  • The combination was well tolerated
  • Most non-hematologic AEs were of low grade and reversible
  • Grade ≥3 hematologic AEs included thrombocytopenia (18%), anemia (18%), febrile neutropenia (14%) and neutropenia (7%)
  • The most frequent SAEs included febrile neutropenia (25%) and sepsis (11%)
  • Four patients died

Insights & Implications

Data reported so far are likely to establish RARA as a biomarker to select ND AML patients; however, further development in this genomically defined subset of AML patients is warranted

  • SY-1425 in combination with azacitidine demonstrated high CR rates, rapid onset of action and a favorable tolerability profile in patients with RARA+ AML. The combination also demonstrated a high rate of transfusion independence and early evidence of durable responses
  • Based on the above data, the combination is likely to emerge as a treatment choice for RARA+ ND unfit patients

Additionally, ~80% of RARA+ ND unfit patients have monocytic phenotype associated with venetoclax resistance, which includes lower BCL2 and higher MCL1 expression. Patients who achieved CR/CRi with SY-1425 and azacitidine have this monocytic phenotype, suggesting the potential for this combination in mitigating venetoclax resistance

  • The early survival data demonstrated by the combination in R/R AML patients are encouraging, especially given most patients were previously treated with HMA and/or venetoclax. This augurs favorably for the combination of SY-1425 and azacitidine as a treatment option in patients who have progressed on or are resistant to venetoclax


Toxicity and poor responses to conventional salvage chemotherapy regimens preclude the use of allogenic hematopoietic stem cell transplant (allo-HSCT) in elderly AML patients with relapsed or refractory disease. To address these concerns, the ongoing Phase III SIERRA trial compares the efficacy of a targeted agent, Iomab-B (radioisotope iodine-131 conjugated CD45 antibody), against conventional care as a bone marrow conditioning therapy in elderly patients (age ≥55 years) with active R/R AML.

Study Highlights

The Phase III SIERRA trial demonstrated encouraging data with Iomab-B as pre-transplant conditioning therapy in elderly patients with R/R AML. Majority (88%) of the patients randomized to receive a therapeutic dose of Iomab-B underwent hematopoietic cell transplantation (HCT) compared to 16% patients receiving conventional care, indicating a higher failure rate to receive potentially curative HCT when treated with conventional agents in the salvage setting. Additionally, a 100% neutrophil and platelet engraftment rate were observed in patients treated with Iomab-B, despite a heavy leukemic burden prior to transplant. Detailed analysis of the data is included in the table below:

Insights & Implications

Allo-HSCT is a potential curative option for AML patients; however, achievement of complete remission is a pre-requisite for optimal outcomes. Elderly patients with R/R AML are not transplantable as they fail to achieve the required complete remission, owing to their inability to tolerate myeloablative conditioning and the higher rates of relapse associated with reduced-intensity conditioning therapy. This suggests a high unmet medical need for a tolerable conditioning regimen to improve survival outcomes in elderly R/R AML patients

Interim analysis of the Phase III trial reporting improvement in engraftment of the bone marrow after allo-HSCT in patients treated with Iomab-B compared to those treated with conventional therapy, despite a heavy leukemia burden prior to transplant, suggests the potential of Iomab-B in enabling transplant in elderly patients not in remission; however, more mature data demonstrating durable complete remission, improvement in overall survival and event free survival are required to support the approval of Iomab-B in this patient setting

Upon approval, the unique positioning of Iomab-B as the only targeted agent in clinical development as a conditioning therapy prior to allo-HSCT is expected to drive its adoption, not only for patients with AML but also for those with other hematological malignancies where HSCT is a potential curative option. This will subsequently boost the market potential of Iomab-B


AML has a higher incidence in older patients. Most elderly AML patients are unfit for intensive chemotherapy and their treatment remains a challenge. Treatment with standard chemotherapy results in frequent relapses, with a 5-year survival of approximately 20%. The recent approval of the venetoclax combination with azacitidine has considerably raised the benchmark; however, there is still a need for alternate therapy options for frontline AML patients unfit for standard intensive chemotherapy. Iadademstat, an lysine-specific demethylase 1 (LSD1) inhibitor, demonstrated promising single-agent activity and a good safety profile in a first-in-human Phase I trial in frontline unfit AML patients. To further validate the findings, an open-label, single-arm, Phase IIa (ALICE) trial was initiated to assess the safety and anti-leukemic activity of iadademstat + azacitidine in frontline unfit AML patients.

Study Highlights

The Phase IIa ALICE trial demonstrated a predictable and manageable safety profile restricted to hematological AEs with iadademstat + azacitidine in newly diagnosed unfit AML patients. The combination resulted in improved responses in patients compared to historical data with azacitidine alone, demonstrating a significant synergistic effect of iadademstat with hypomethylating agents (HMAs).

In n=14 evaluable frontline AML patients unfit to receive intensive chemotherapy, treatment with iadademstat + azacitidine resulted in:

  • ORR-per protocol population (n=11/14): 79%; ORR – ITT (n=11/19): 61%
    • Durable CR/CRi (>6 months): 86%
    • Durable ORR (>6 months): 73%
  • 60 µg/sqm/d was selected as the preferred dose
    • ORR: 85% (90 µg/sqm/d); 83% (60 µg/sqm/d)
  • PFS: 8.9 months
  • mOS: 8.9 months
  • mDoR: 10.3 months
  • mTTR: 1.1months
  • Transfusion independent patients >3 months of treatment: 44%
  • Current longest response (still ongoing): 22 months


  • Grade 3/4 AEs: Observed in two patients not related to hematological compartment (asthenia, dysgeusia and weight reduction)
  • SAEs: Differentiation syndrome and a fatal intracranial hemorrhage

Insights & Implications

  • LSD1 is associated with cancer stemness, and higher levels of LSD1 correlate with more aggressive phenotypes of cancer and poor prognosis among patients. Iadademstat, an LSD1 inhibitor, promotes differentiation of leukemic blasts, thereby reducing their stemness and proliferative potential
  • Preliminary data of iadademstat in combination with azacitidine are reporting a higher response rate (ORR: 79%) compared to historical responses of approximately 25% with azacitidine alone; this supports the therapeutic potential of LSD1 inhibitor as a pro-differentiating agent in unfit AML patients. However, to achieve competitive positioning in the patient setting against the approved SoC, the combination of iadademstat + azacitidine will have to demonstrate a significant improvement in OS (a gold standard in oncology) in a higher-phase trial
  • Oryzon plans to initiate a Phase IIb trial with the combination in H1 2021 and is currently pursuing an accelerated approval path for iadademstat in unfit AML patients. If approved, iadademstat, with a different MoA compared to pro-apoptotic Bcl2 inhibitor, will serve as an additional therapeutic option for frontline patients unfit to receive intensive chemotherapy and as an alternative for rescue treatment in refractory or intolerant patients treated with venetoclax in first line


Magrolimab (GS-4721) is a mAb against CD47 that is designed to interfere with the recognition of CD47 by the SIRPα receptor on macrophages, thus blocking the “don’t eat me” signal used by cancer cells to avoid being ingested by macrophages. Forty-Seven, Inc. developed magrolimab and was recently acquired by Gilead for $4.9 billion. Clinical investigation of magrolimab began in patients with myelodysplastic syndrome (MDS) and AML, and additional studies are now ongoing in non-Hodgkin lymphoma (NHL) and solid tumors. Based on the preliminary data, magrolimab has been granted Fast Track designation by the FDA for the treatment of MDS, AML, R/R diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma. Magrolimab has also been granted Orphan Drug designation by the FDA for the treatment of AML and MDS, and by the EMA for the treatment of AML.

Study Highlights

The combination of magrolimab with azacitidine demonstrated promising clinical activity resulting in improvements in mOS and DoR compared to the SoC in newly diagnosed unfit AML patients, including those who are TP-53 mutant and have other poor-risk cytogenetics.

All AML patients: n=43

  • ORR: 63% (42% CR, 12% CRi, 2% PR, 7% MLFS)
  • Median time to response: 1.95 months (range 0.95-5.6 months)
  • Patients with abnormal cytogenetics: 9/20 (45%) achieved a cytogenetic CR, and 8/23 (35%) with CR/CRi became minimal residual disease (MRD) negative
  • mDoR: 9.6 months (0.03+, 18.7)
  • Median follow-up for responders: 8.5 months (1.9, 25.1)

TP53-mutant AML patients: n=29

  • ORR: 69% (45% CR, 14% CRi, 3% PR, 7% MLFS)
  • mDoR: 7.6 months (0.03+, 15.1+)
  • Median follow-up for responders: 7.7 months (1.9, 16.9)
  • Patients with abnormal cytogenetics: 7/16 (44%) achieved a cytogenetic CR, and 5/17 (29%) with CR/CRi became MRD negative
  • mOS (TP53 wild type; n=16): 18.9 months at median follow-up of 12.5 months
  • mOS (TP53 mutant; n=47): 12.9 months at median follow-up of 4.7 months


  • Safety profile of the combination was comparable to azacitidine monotherapy and was tolerated
  • On-target anemia was generally transient and reversible with no observed Grade 4 or 5 AEs
  • No immune-related AEs were observed
  • Most common TRAEs were anemia (31%), fatigue (19%), blood bilirubin increase (19%), neutropenia (19%), thrombocytopenia (17%) and nausea (15%)
  • AEs leading to magrolimab dose reduction were 4.7%
  • Treatment discontinuations due to drug-related AEs were 4.7%

Insights & Implications

  • Early data with magrolimab and azacitidine reporting an improvement in mOS in TP53-mutant and wild-type AML patients compared to historical data with the SoC (venetoclax + azacitidine) suggests the potential of the combination as a therapeutic option as 1L therapy for AML patients who cannot tolerate intensive chemotherapy
  • Additionally, the promising response rates and durability of response with the combination, especially in the difficult-to-treat TP53-mutant AML, augurs in its favor. Given the high unmet medical need in this subgroup of patients due to lack of approved therapy, early encouraging data can be pursued further to file for an accelerated approval
  • A randomized Phase III trial comparing magrolimab + azacitidine to the SoC (venetoclax + azacitidine) in frontline TP53-mutant AML patients is planned for early 2021, positive outcomes of which will redefine treatment in the frontline AML setting


Mutations in FLT3 range from 20% to 30% in elderly AML patients and are associated with a high leukemic burden and frequent relapses. While the FLT3 inhibitor midostaurin is approved for newly diagnosed AML patients fit to receive intensive chemotherapy, the unmet need is high for FLT3-mutant unfit AML patients with no approved therapies. The pooled analysis of Phase III VIALE-A trial and Phase Ib (NCT02203773) trial was carried out to evaluate the efficacy and safety of venetoclax + azacitidine compared to azacitidine monotherapy in FLT3-mutant treatment-naïve AML patients who were unfit to receive intensive treatment.

Study Highlights

The pooled analysis reported a significant improvement in mOS and higher response rate with the combination of venetoclax + azacitidine compared to azacitidine alone in treatment-naïve FLT3-mutant AML patients unfit to receive intensive chemotherapy.

Detailed data were as follows: venetoclax + azacitidine (n=40) vs. azacitidine (n=22)

  • mOS: 13.3 months vs. 8.6 months
  • mOS (FLT3-TKD): 19.2 months (n=13) vs. 10.0 months (n=10)
  • mOS (FLT3-ITD): 11.5 months (n=28) vs. 8.5 months (n=13)
  • CR + CRh: 65% vs. 18%
  • CR + CRi: 70% vs. 36%
  • Median time to first CR/CRh response: 1.0 month vs. 3.2 months
  • Median time to first CR/CRi response: 1.2 months vs. 2.8 months
  • mDoR (CR/CRh): 18.3 months vs. 15.1 months
  • mDOR (CR/Cri): 17.3 months vs. 5.0 months
  • Grade 3/4 hematological AEs: 71% vs. 68%
  • Serious AEs: 78% vs. 68%

Insights & Implications

  • The promising clinical activity with venetoclax + azacitidine, showing higher response rates and an improvement in OS compared to azacitidine alone among treatment-naïve patients with FLT3 mut who are ineligible for intensive chemotherapy, suggests the therapeutic potential of the combination for the patient population; however, the data need validation in a larger patient population
  • With no currently approved therapy in the frontline setting of FLT3-mutant unfit AML, the promising data readout supports off-label use of the venetoclax + azacitidine combination for the patient pool. This in turn will strengthen the positioning of venetoclax in terms of market share in frontline unfit AML patients, where it is already approved in combination with azacitidine
  • However, with Astellas’ gilteritinib + azacitidine combination under evaluation in a pivotal trial for newly diagnosed FLT3-mutant AML, it will be interesting to keep a close watch on AbbVie-Roche’s clinical development strategy with venetoclax in order to maintain its dominance in the frontline setting of unfit AML across patient subgroups


Clinical studies in the past have demonstrated the clinical activity of venetoclax in combination with azacitidine in frontline IDH1/2-mutant AML patients who are unfit to receive intensive chemotherapy. To further validate the activity of venetoclax + azacitidine vs. azacitidine alone in the same patient population, a pooled analysis of the Phase III VIALE-A trial and Phase Ib (NCT02203773) trial is discussed below.

Study Highlights

The data from the pooled analysis reported a substantial improvement in mOS, higher response rates and longer duration of responses with the combination of venetoclax + azacitidine vs. azacitidine alone in treatment-naïve IDH1/2-mutant AML patients unfit to receive intensive chemotherapy.

Detailed data were as follows:

IDH1/2-mutant AML: Venetoclax + azacitidine (n=79) vs. placebo + azacitidine (n=28)

  • mOS: 24.5 months vs. 6.2 months
  • 2-year OS rate: 52.4% vs. 12.2%
  • CR + CRi: 78.5% vs. 10.7%
  • CR + CRh: 72.2% vs. 7.1%
  • Median time to first CR/CRi response: 1.1 months vs. 3.4 months
  • mDoR (CR + CRi): 29.5 months vs. 9.5 months
  • Median time to first CR/CRh response: 1.0 months vs. 2.6 months
  • mDoR (CR + CRh): 29.6 months vs. 15.5 months
  • SAEs: 82.3% vs. 82.1%

IDH1-mutant AML: Venetoclax + azacitidine (n=32) vs. placebo + azacitidine (n=11)

  • mOS: 17.5 months vs. 2.2 months
  • 2-year OS rate: 42.9% vs. NA
  • CR + CRi: 65.6% vs. 9.1%
  • CR + CRh: 59.4% vs. 9.1%
  • Median time to first CR/CRi response: 1.2 months vs. 3.4 months
  • mDoR (CR + CRi): 21.9 months vs. NR
  • Median time to first CR/CRh response: 2.3 months vs. 3.1 months
  • mDoR (CR + CRh): 29.6 months vs. NR

IDH2-mutant AML: venetoclax + azacitidine (n=49) vs. placebo + azacitidine (n=18)

  • mOS: NR vs. 13.0 months
  • 2-year OS rate: 58.6% vs. 19.0%
  • CR + CRi: 85.7% vs. 11.1%
  • CR + CRh: 79.6% vs. 5.6%
  • Median time to first CR/CRi response: 1.1 months vs. 4.6 months
  • mDoR (CR + CRi): NR vs. 9.5 months
  • Median time to first CR/CRh response: 1.0 months vs. 2.1 months
  • mDoR (CR + CRh): NR vs. 15.5 months

Insights & Implications

  • Mutations in IDH are present in approximately 20% of AML patients and are associated with poor prognosis. While the IDH1 inhibitor ivosidenib is approved for frontline IDH1-mutant AML patients unfit to receive intensive chemotherapy, there are no approved therapies in the frontline setting for IDH2-mutant unfit AML patients
  • Unlike approved IDH inhibitors, which are active in a sub-group of IDH mutants and have yet to demonstrate a survival advantage compared to azacitidine in a randomized trial, the promising clinical efficacy with venetoclax + azacitidine compared to single-agent azacitidine, demonstrating an improved OS (a gold standard for oncology drugs) in a broader pool of frontline IDH1- and IDH2-mutant unfit AML patients, competitively positions the combination against approved IDH inhibitors and bodes well for the combination to emerge as the SOC in the patient population; however, the data need validation in a larger patient pool
  • Approval of venetoclax + azacitidine for IDH mutants will lead to its label expansion and strengthen venetoclax’s foothold in the frontline setting, given its approval in combination with azacitidine for newly diagnosed unfit AML patients.


A majority of older adults or unfit AML patients are not offered intensive therapy, resulting in dismal long-term survival outcomes. This suggests a high unmet need for safer treatment options that can also improve survival in AML patients. Following the promising safety and clinical activity of aspacytarabine, a cytarabine prodrug, in a Phase I/IIa (NCT02544438) BSTPHASE1-01 trial in newly diagnosed or R/R AML patients, a Phase II (NCT03435848) ELPIS trial was initiated to further validate the single-agent activity of aspacytarabine in newly diagnosed AML patients.

Study Highlights

Treatment with aspacytarabine was well tolerated among newly diagnosed elderly and unfit AML patients with mainly “on target” toxicities and no cerebellar toxicity, mucositis, alopecia or renal failure. Additionally, single-agent aspacytarabine as induction and consolidation therapy resulted in durable responses with mOS greater than 1 year among responders.

In n=31 efficacy-evaluable newly diagnosed AML patients unfit for standard chemotherapy, treatment with aspacytarabine resulted in:

  • mOS: 6.8 months (NR for de novo AML and 6.8 months for secondary AML)
  • mOS (in patients with CR): NR at a follow-up of 24 months
  • mDoR (in patients with CR): NR at a follow-up of 12 months
  • CR: 32% (43% in n=14 de novo AML and 24% in n=17 secondary AML)
  • 57% CRs were MRD negative
  • Grade ≥3 TEAEs: Febrile neutropenia (48.6%), anemia (20%), thrombocytopenia (14.5%), pulmonary oedema (14.5%), WBC decreased (14.5%) and neutropenia (14.3%)

Insights & Implications

  • Cytarabine has been the backbone of treatment for AML patients for decades; however, its use is associated with severe toxicities (bone marrow suppression, cerebellar toxicity and infection), which precludes its use in elderly patients and those unfit for standard induction chemotherapy. Aspacytarabine is a prodrug of cytarabine which enables delivery of high doses of cytarabine with lower systemic exposure to the free drug, thereby minimizing toxicity
  • The promising clinical activity and safety profile of aspacytarabine as a frontline induction and consolidation therapy in AML patients unfit for standard intensive chemotherapy suggests its potential to emerge as the SoC; however, the data need validation in a larger patient pool. Recognizing its safety and efficacy, the FDA has granted Fast Track designation to aspacytarabine for treatment of unfit AML patients
  • If approved, aspacytarabine holds the potential to not only emerge as the new intensive therapy backbone for fit AML patients, but also allow unfit patients the benefit of intensive treatment for the first time
ABSTRACT #331 and #2001

A Phase I/II Trial Evaluating Investigational Agent Flotetuzumab (CD123 x CD3 DART) in AML Patients with Primary Induction Failure or Early Relapse (NCT02152956)


A substantial percentage of newly diagnosed AML patients fail to achieve complete remission with intensive induction therapy (primary induction failure (PIF)) or experience disease recurrence after a short remission lasting less than six months (early relapse (ER)). Mutation in TP53 and 17p deletions occur in 8-10% of de novo AML and 37-46% of AML cases with adverse-risk cytogenetics and are associated with PIF, ER and dismal prognosis. The potentially registrational Phase I/II trial was aimed at investigating the clinical activity of flotetuzumab (CD123 x CD3 DART) in AML patients with PIF or ER. Additionally, sub-group analysis evaluating the potential of flotetuzumab in TP53-mutant AML was carried out.

Study Highlights

Treatment with flotetuzumab resulted in promising clinical activity compared with historical data with salvage therapy in heavily pretreated AML patients who failed induction therapy or showed early relapse within 6 months of induction therapy. Flotetuzumab treatment also resulted in a manageable safety profile with majority of the patients experiencing low grade cytokine release syndrome (CRS) and infrequent, fully reversible neurological adverse events of short duration. The incidence of CRS progressively decreased during dosing allowing outpatient treatment after day 8. Additionally, sub-group analysis in R/R TP53 mutant AML patients demonstrated that, responses to flotetuzumab correlated with a higher inflammatory or IFN-γ gene signatures at baseline.

Detailed data readout were as follows:

In n=44 evaluable PIF/ER AML patients:

  • mOS: 10.7 months
  • CR/CRh: 25%
  • CR/CRh/Cri: 31.8%
  • MLFS: 6.8%
  • mDoR: 8.13 months
  • 57.1% patients received HSCT
  • Grade ≥3 TRAEs: Febrile neutropenia (13.6%), ALT increased (4.5%), nausea (4.5%), AST increased (2.3%), CRS (2.3%) and fatigue (2.3%)

In n=27 evaluable PIF AML patients:

  • mOS: 15.9 months
  • CR/CRh: 33.3%
  • CR/CRh/CRi: 37%
  • MLFS: 3.7%
  • mDoR: 15.2 months
  • 70% patients received HSCT

In n=17 evaluable ER AML patients:

  • mOS: 5.0 months
  • CR/CRh: 11.8%
  • CR/CRh/CRi: 23.5%
  • MLFS: 11.8%
  • mDoR: 2.4 months
  • 25% patients received HSCT

In n=15 evaluable R/R TP53-mutant AML patients:

  • ORR: 60%; CR: 47%
  • Reduction in bone marrow blasts: 51.2%
  • mOS (in responders): 10.3 months
  • Furthermore, the tumor inflammation signature (TIS), inflammatory chemokine, Treg and IFN-γ gene expression scores were significantly higher at baseline in patients with complete remission compared with those in non-responders

Insights & Implications

  • Leukemic stem cells (LSCs), which confer resistance to induction therapy with conventional chemotherapeutic agents and in turn perpetuate AML, are characterized by increased expression of CD123
  • Early data demonstrating a manageable safety profile and encouraging clinical activity with flotetuzumab (mOS: 10.7 months, CR/CRh: 25%) compared to historical data (mOS: 3.5 months, CR/CRh: ~5-12%), establishes the potential of CD123 targeted T-cell engaging bispecific in selective elimination of LSCs characterizing AML patients with PIF or ER
  • Additionally, subgroup analysis correlating responses to flotetuzumab in TP53 mutant AML patients with an inflamed tumor microenviroment, enriched in patients with chemotherapy resistance, warrant further exploration of the T-cell targeting immunotherapy in patients with higher expression of inflammatory gene signatures at baseline
  • Continued promising clinical activity with flotetuzumab in the ongoing registration enabling phase I/II trial will form the basis for the accelerated approval of the agent in PIF or ER AML patients given the high unmet need due to lack of approved therapies in these poor prognostic groups
ABSTRACT #1036, #111 and #692

Phase III QUAZAR AML-001 Trial – Maintenance Therapy with Oral Azacitidine (Onureg)


The Phase III, randomized, double-blind, placebo-controlled QUAZAR AML-001 trial was initiated to assess the safety and efficacy of maintenance therapy with oral azacitidine (Onureg) in older patients (aged ≥55 years) with AML who are in first CR or CR with incomplete recovery (CRi) following induction therapy with or without consolidation chemotherapy. A significant improvement in OS with Onureg as a maintenance therapy compared to placebo resulted in its recent approval in the US. Discussed are the sub-group analyses comparing Onureg with placebo in patients defined by number of consolidation courses, minimal residual disease (MRD) status and early relapse.

Study Highlights

Frontline maintenance therapy with Onureg resulted in improvements in OS and RFS in AML patients compared to placebo irrespective of the number of consolidation cycles received and MRD status at study entry. Additionally, in patients experiencing an early relapse on treatment with Onureg, a 21-day escalating dosing not only resulted in an improvement in OS, but also restored complete remission (CR/CRi) in approximately one-fourth of patients with no meaningful increase in AEs or deterioration in quality of health status.

Detailed data were as follows:

Assessment based on number of consolidation courses

  • No consolidation cohort: Onureg (n=52) vs. placebo (n=42)
    • mOS: 23.3 months vs. 10.9 months (HR: 0.55)
    • mRFS: 8.4 months vs. 3.9 months (HR: 0.55)
  • 1 consolidation cohort: Onureg (n=110) vs. placebo (n=102)
    • mOS: 21.0 months vs. 14.3 months (HR: 0.75)
    • mRFS: 10.0 months vs. 4.7 months (HR: 0.72)
  • ≥2 consolidation cohort: Onureg (n=76) vs. Placebo (n=90)
    • mOS: 28.6 months vs. 17.6 months (HR: 0.75)
    • mRFS: 13.0 months vs. 6.1 months (HR: 0.59)

Assessment based on MRD status at study entry

MRD-positive patients: Onureg (n=103) vs. placebo (n=116)

  • mOS: 14.6 months vs. 10.4 months (HR: 0.69)
  • mRFS: 7.1 months vs. 2.7 months (HR: 0.58)
  • MRD response (MRD-positive at baseline to MRD-negative): 37% vs. 19%

MRD-negative patients: Onureg (n=133) vs. placebo (n=111)

  • mOS: 30.1 months vs. 24.3 months (HR: 0.81)
  • mRFS: 13.4 months vs. 7.8 months (HR: 0.71)
  • Median duration of MRD negativity (MRD-negative at baseline and MRD responders): 11.0 months vs. 5.0 months (HR: 0.62)

Assessment in patients with early relapse: Onureg (n=51) vs. placebo (n=40)

  • mOS: 22.8 months vs. 14.6 months (HR: 0.66)
  • 1-year OS rate: 80.4% vs. 59.5%
  • CR 2 (CR/CRi) during dose escalation: 23% vs. 11%
  • Grade 3/4 AEs: Febrile neutropenia (24% vs. 3%), neutropenia (22% vs. 13%), thrombocytopenia (18% vs. 30%), anemia (16% vs. 18%) and fatigue (6% vs. 0%)
  • Treatment discontinuation rates: 8% vs. 3%

Insights & Implications

  • Treatment with standard intensive induction followed by consolidation chemotherapy for AML leads to complete remission in most patients; however, a large proportion of patients undergo relapse, suggesting a need for an effective treatment option that provides long-term remission
  • Sub-group analysis of the QUAZAR AML-001 trial demonstrates a significant improvement in OS and RFS with Onureg compared to placebo regardless of the number of consolidation cycles, MRD status and early relapse with ≤15% blasts (restoring complete remission in approximately one-fourth of patients with escalating doses). This suggests the robustness of frontline maintenance therapy with Onureg and further validates its recent approval in the US
  • The application for approval of Onureg as a frontline maintenance therapy has been accepted by the EMA, and a positive CHMP opinion will lead to Onureg’s market expansion to European geographies
  • However, although the fact that Onureg is an oral formulation of azacitidine aids patient compliance, Onureg cannot act as a substitute for IV or SC azacitidine due to substantial differences in PK/PD parameters and high-grade AEs such as myelosuppression and neutropenia)
The commentary included in this newsletter has been generated by the disease and market experts within Prescient’s dedicated Analytics function following analysis of publicly available sources of information.

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