What is the efficacy of Uproleselan combined with chemotherapy in the treatment of relapsed and refractory acute myeloid leukemia?

Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy in which progenitor cells are clonally expanded in peripheral blood and bone marrow
.

Despite numerous advances in recent years, drug resistance and subsequent disease progression dominate the course of most AML patients
.

Patients with resistance to treatment or with a transient initial response have a poor prognosis, with a median overall survival (OS) of 3-7 months
.

Furthermore, despite recent advances, the management of newly diagnosed elderly patients with AML remains a challenge with poor prognosis due to the toxicity of induction chemotherapy and the short duration of remission
.

Uproleselan (GMI-1271) is a novel E-selectin antagonist that disrupts cell survival pathways, enhances chemotherapy response, improves survival in xenograft and allograft mouse models, and reduces chemotherapy toxicity in vivo
.

We conducted a Phase 1/2 study to evaluate the safety and tolerability of uproleselan in combination with induction chemotherapy in patients with relapsed/refractory (R/R) AML and in newly diagnosed elderly patients with AML
.

STUDY METHODS The study was a multicenter, open-label, phase 1/2 study (NCT02306291), conducted at 8 academic hospitals in the United States (6), Ireland (1), and Australia (1)
.

R/R AML patients were enrolled in the initial dose-escalation phase of the study to determine the safety, tolerability, and pharmacokinetics of uproleselan in combination with the MEC regimen (mitoxantrone, etoposide, and cytarabine).
(PK) and recommended phase 2 dose (RP2D); the expansion phase of the study evaluated uproleselan (RP2D) with salvage chemotherapy in the same R/R AML population, and uproleselan in combination with standard (7+3) first-line AML induction regimens Efficacy in a separate cohort of elderly (≥60 years of age) patients with newly diagnosed AML (Figure 1)
.

The primary endpoint of the study in Figure 1 was the frequency, severity, and correlation of treatment-emergent adverse events (TEAEs) in patients receiving uproleselan in combination with chemotherapy
.

In addition, patients were monitored for leukemia remission, duration of remission, subsequent therapy, transplantation, and survival
.

Study Results 1.
Patient Characteristics From May 14, 2015 to May 18, 2017, 91 patients were enrolled and received uproselan in combination with chemotherapy in all phases of the study
.

Sixty-six patients with R/R AML were enrolled, of which 19 were in the dose escalation phase and 47 were in the expansion phase
.

Including 7 patients who received 10 mg/kg uproleselan in the dose escalation phase, a total of 54 patients received RP2D uproleselan in combination with MEC
.

In the cohort of newly diagnosed AML patients, 25 patients received 7+3 in combination with RP2D uproselan
.

The pre-treatment characteristics of all patients enrolled in the study are shown in Table 1
.

Table 12.
Safety and Tolerability Dose Escalation Cohorts: Nineteen patients in the dose escalation phase were enrolled in 3 separate uproselan dose level groups, 5 (n=6), 10 (n=7), and 20 ( n=6) mg/kg
.

Uproleselan at 10 mg/kg twice daily was identified as RP2D and used as the dose in combination therapy with MEC during the dose expansion phase and with idarubicin and cytarabine in the newly diagnosed cohort
.

R/R AML Cohort: For the R/R AML cohort, the incidence of TEAEs (regardless of relationship to study drug) was similar across all uproselan dose levels
.

None of the 66 R/R AML patients discontinued treatment due to AEs
.

As expected, all patients in the R/R cohort had evidence of grade 4 myelosuppression (thrombocytopenia, neutropenia, or anemia) during the study period
.

For patients who achieved remission (complete remission [CR] or CR with incomplete count recovery [CRi]), the median time to count recovery (ANC ≥ 500/μL and platelets ≥ 50/μL) was 33.
0 days (90% CI, 31.
0-34.
0)
.

Table 2 shows the overall incidence of grade 3 or 4 TEAEs
.

Most of the TEAEs observed were attributed to chemotherapy and few TEAEs were attributed to uproleselan
.

Besides hematologic toxicity, the only grade 3 or 4 TEAE reported in ≥10% of patients was sepsis (12%)
.

Gastrointestinal toxicities, including nausea, vomiting, diarrhea, and colitis, were mild, with grade 3 events occurring in <5% of patients
.

Liver and kidney TEAEs were mostly grade 1 or 2, and grade 3 or 4 TEAEs occurred in 5% of patients
.

One patient (2%) died within 30 days of treatment initiation; 60-day mortality was 9% (n=6)
.

Grade 3 mucositis was reported in only 2% of patients
.

Other non-hematologic TEAEs were mild and generally considered unrelated to uproselan
.

Table 2 Newly diagnosed AML cohort: In the newly diagnosed cohort, the observed toxicities were only related to the effect of the underlying leukemia and chemotherapy regimen (Table 2)
.

As in patients with R/R disease, grade 4 myelosuppression is common
.

The median time to recovery of neutrophil and platelet counts in remission patients was 32.
0 days (90% CI, 28.
0-32.
0)
.

Grade 3 or 4 non-hematologic TEAEs that occurred in ≥10% of this cohort included pneumonia (16%), hypokalemia (16%), respiratory failure (16%), pulmonary edema (12%), and hypokalemia Phosphatemia (12%)
.

The 30-day and 60-day all-cause mortality rates were 8% and 12%, respectively
.

3.
Clinical Response and Survival R/R Cohort: The clinical results are detailed in Table 3
.

At the RP2D (n=54) dose, the CR/CRi rate was 41%, with the majority being CR (35%)
.

The CR/CRi rates in patients with primary refractory and relapsed disease were 29% and 46%, respectively
.

Patients with relapsed disease who received 1 induction regimen had a CR/CRi rate of 52%, and those who received ≥2 prior regimens had a CR/CRi rate of 36%
.

Table 3 shows response rates by duration of initial response and cytogenetic risk
.

Among relapsed patients, the CR/CRi rate was 28% (7/25) in patients with initial CR duration <12 months, while the response rate was 83% (10/12) in patients with initial CR duration ≥12 months
.

Overall, 51% (34/66) of patients had previously received high-dose cytarabine (≥1 g/m2) as prior induction and/or post-remission therapy; these patients had a CR/CRi rate 47%, similar to the entire R/R cohort
.

 Table 3 With a median follow-up of 9.
7 months, for patients treated with RP2D at 10 mg/kg, the median OS was 8.
8 months (95% CI, 5.
7-11.
4; Figure 2A), and at 1 year, the survival rate was 37.
0%
.

The median event-free survival was 1.
5 months (95% CI, 1.
3-2.
8; Figure 2B)
.

Figure 2 Newly Diagnosed Cohort: Table 3 summarizes clinical remission responses
.

18 patients (72%) achieved CR/CRi, most of them (13/18) were CR
.

11/18 (61%) responders achieved CR/CRi through 1 induction cycle
.

Nine (69%) patients with newly diagnosed secondary AML (n=13) achieved CR/CRi
.

Of the 7 patients who had been treated with HMA prior to the diagnosis of AML, 4 achieved CR/CRi
.

Eleven patients (61%) who achieved CR/CRi underwent allogeneic hematopoietic stem cell transplantation after induction therapy with uproselan and 7+3
.

Among 25 patients with newly diagnosed AML who received 10 mg/kg uproselan in combination with 7+3, the median OS was 12.
6 months (95% CI, 9.
9 to not applicable; Figure 2C)
.

At 12 months, the survival rate was 52.
0%
.

Event-free survival was 9.
2 months (95% CI, 3-12.
6; Figure 2D)
.

4.
E-selectin ligand expression and impact on clinical outcomes In patients with relapsed and primary refractory AML and in newly diagnosed high-risk cytogenetically elderly patients and patients with secondary AML, the expression of E-selectin on leukemic blasts E-selectin ligand expression was higher
.

In the R/R cohort, E-selectin expression >10% was associated with higher response rates and survival
.

Conclusions Chemotherapy combined with uproleselan is well tolerated, with high remission rate, low induced mortality and low incidence of mucositis, providing strong data for a phase 3 randomized confirmatory study
.

Reference source: Daniel J.
DeAngelo, Brian A.
Jonas, Jane L.
Liesveld, et al.
Phase 1/2 study of uproleselan added to chemotherapy in patients with relapsed or refractory acute myeloid leukemia.
Blood (2022) 139 (8): 1135–1146.
https://doi.
org/10.
1182/blood.
2021010721.
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