On Monday 5th December, at the 58th Annual Meeting & Exposition of the American Society of Hematology (ASH) in San Diego, CA, there was an enriching session focusing on “Acute Myeloid Leukemia: Clinical Studies: New Drugs for Older AML”
Despite advancements in chemotherapy in particular Hypomethylating Agents (HMA), there are still high relapse rates in elderly patients, which presents a challenge when treating these patients. Consequently, there is more interest in targeted therapy which can hopefully combat the issue of resistance and provide improved tolerability. Vadastuximab talirine (33A) is a CD33-directed antibody that has demonstrated an enhanced cytotoxic effect after HMA priming, through upregulated CD33 expression.
This was a phase 1 study (NCT01902329) designed to evaluate the safety, tolerability, pharmacokinetics, and antileukemic activity of 33A in combination with an HMA. Fifty-three Acute Myeloid Leukemia (AML) patients with a median age of 75 years were included into this study.
At the congress, the lead investigator shared the results of this study
The key highlights were:
- Grade 3 AEs were reported in ≥15% of patients; thrombocytopenia (55%), anemia (43%), febrile neutropenia (43%), neutropenia (38%), pneumonia (19%), and leukopenia (17%).
- No G4 or 5 bleeding events were observed.
- Of all responding patients, 17 of 36 (47%) achieved Minimal Residual Disease (MRD) negativity by flow cytometry.
- Thirty-six of the 49 efficacy evaluable patients (73%) achieved Complete Response (CR)
- The median relapse-free survival was 9.1 months (range, 0.1-16.5+)
- Median Overall Survival (OS) was 11.3 months
- OS continues to evolve with 28% patients alive with a median follow-up of 14.7 months
In summary, the authors reported that the CR+CRi rate of 73% in older AML patients with poor risk factors in the setting of low early mortality was encouraging. The combination of 33A+HMA was well tolerated with no identified pattern of off-target toxicity and demonstrated a marked improvement in HMA activity.
Treatment of AML among the elderly is challenging due to intolerance of intensive therapy and greater prevalence of therapy-resistant biology. Hypomethylating agents (HMAs) are commonly used in this setting, but yield suboptimal remission rates and modest survival (Dombret 2015, Kantarjian 2012). Vadastuximab talirine (33A) is a CD33-directed antibody conjugated to 2 molecules of a pyrrolobenzodiazepine (PBD) dimer. Upon binding, 33A is internalized and transported to the lysosomes where PBD dimer is released via proteolytic cleavage of the linker, crosslinking DNA, and leading to cell death. In preclinical studies, HMA priming followed by 33A resulted in upregulated CD33 expression, increased DNA incorporation of the PBD dimer, and enhanced cytotoxicity.
A combination cohort in a phase 1 study (NCT01902329) was designed to evaluate the safety, tolerability, pharmacokinetics, and antileukemic activity of 33A in combination with an HMA. Eligible patients (ECOG status 0-1) must have had previously untreated CD33-positive AML and had declined intensive therapy. A single dose level of 33A, 10 mcg/kg, was administered outpatient IV every 4 weeks on the last day of HMA (azacitidine or decitabine [5-day regimen], standard dosing). Investigator assessment of response was per IWG criteria; CRi required either platelet count of ≥100,000/µL or neutrophils of ≥1,000/µL (Cheson 2003).
Fifty-three patients (median age 75 years; range, 60-87) have been treated with 33A+HMA. All patients had adverse (38%) or intermediate (62%) cytogenetic risk by MRC criteria; 40 patients (75%) were considered unfit for intensive therapy and 13 patients (25%) declined intensive therapy. Of the patients with secondary AML (23/53, 43%), median age was 77 years (range 60-87) with most of the patients ≥75 years (70%). The median treatment duration is currently 19.3 weeks (range, 2-86) with 13 patients remaining on treatment; no DLTs or infusion reactions were reported. G3 or higher AEs reported in ≥15% of patients were thrombocytopenia (55%), anemia (43%), febrile neutropenia (43%), neutropenia (38%), pneumonia (19%), and leukopenia (17%); no G4 or 5 bleeding events were observed. Other non-hematologic treatment-emergent AEs regardless of relationship to study treatment and reported in ˃25% of patients were fatigue (58%), nausea (47%), constipation (43%), decreased appetite, peripheral edema (40% each), pyrexia (32%), dyspnea (28%), diarrhea (26%), and dizziness (25%). 30- and 60-day mortality rates were 2% and 8% with no treatment-related deaths reported. A total of 37% (90/246) of doses were delayed due to AEs primarily related to myelosuppression (neutropenia 16%, thrombocytopenia 6%, febrile neutropenia 4%).Thirty-six of the 49 efficacy evaluable patients (73%) achieved CR (21, 43%) or CRi (15, 31%); an additional 4 patients were not efficacy evaluable by protocol definition, due to death (n=2) or withdrawal of consent (n=2) before a response assessment marrow could be obtained. Remissions were achieved after a median of 2 cycles (range, 1-4) and were observed in most of the patients with adverse risk disease including antecedent myelodysplasia (16/22, 73%), adverse cytogenetics (15/18, 83%), FLT3/ITD (5/5, 100%), and patients ≥75 years (17/26, 65%). Seventeen of 22 efficacy-evaluable patients with secondary AML (77%) achieved CR (11, 50%) or CRi (6, 27%). Of all responding patients, 17 of 36 (47%) achieved MRD negativity by flow cytometry. The median relapse-free survival was 9.1 months (range, 0.1-16.5+) and OS continues to evolve with 22 patients (42%) alive with a median follow-up of 10 months.
The combination of 33A+HMA is well tolerated with no identified pattern of off-target toxicity. Activity with the combination appears markedly improved when compared to the historical experience of HMA monotherapy in this patient population (Table 1). The CR+CRi rate of 73% in older AML patients with poor risk factors in the setting of low early mortality is particularly encouraging. Activity was maintained even in the highest risk patient groups (adverse risk cytogenetics, underlying myelodysplasia, secondary AML, FLT3/ITD). Survival data are evolving and compare favorably to historical controls. CASCADE, a phase 3 trial investigating 33A+HMA v. HMA alone in older AML patients is now enrolling (NCT02785900).