Featured research from recent issues of Blood

PAPER SPOTLIGHT

In a first-in-human study of patients with CD33-positive acute myeloid leukemia ( AML ), treatment with single-agent vadastuximab talirine ( a CD33-targeted antibody-drug conjugate ) resulted in a complete remission ( CR ) and CR with incomplete blood count recovery ( CRi ) rate of 28 percent . Half of patients who responded also achieved minimal residual disease ( MRD ) negativity .

“ Responses were achieved across the spectrum of [ patients with ] AML , including those with traditionally poor disease risk factors , such as underlying myelodysplasia and adverse-risk cytogenetics ,” wrote Eytan M . Stein , MD , of the Memorial Sloan Kettering Cancer Center in New York , and co-authors of the findings , which were published in Blood .

This phase I , dose-escalation study enrolled 131 patients ( median age = 73 years ; range = 26-89 years ) with newly diagnosed or relapsed AML who were recruited from 14 U . S . centers between July 2013 and February 2016 . Individuals with central nervous system leukemia were excluded , and antileukemic treatment ( other than hydroxyurea ) was prohibited within 14 days of starting study treatment .

Half of patients had underlying myelodysplasia , and 58 ( 44 %) had disease that relapsed following a complete or partial response to the most recent therapy ; 44 ( 34 %) had refractory disease .

Using a standard 3 + 3 design , participants received doses ranging from 5 to 60 µ g / kg . During the evaluation period for dose-limiting toxicities ( DLTs ; the first treatment cycle ), there were no DLTs observed at the 30 µ g / kg dose or in the first three patients treated at the 40 µ g / kg dose . One DLT ( grade 4 hypocellular marrow ) was observed in 18 patients treated with the 40 µ g / kg dose in the doseescalation and -expansion phases . Given the increasing myelosuppression observed at higher doses , the researchers selected 40 µ g / kg for the dose-expansion phase , despite no identification of a formal maximum tolerated dose .

Across all cohorts , the 30- and 60- day mortality rates were 8 percent and 27 percent , respectively . Most deaths were considered related to underlying disease .

Among all treated individuals , the most common any-grade and grade

TABLE . Treatment-Emergent Adverse Events (> 25 %)

> 3 adverse events ( AEs ) included febrile neutropenia , anemia , and thrombocytopenia ( see TABLE ). Most patients ( 70 %) reported infections , with the most common grade ≥3 infections being lung infection ( 25 %), sepsis ( 16 %), and bacteremia ( 8 %).

Thirty-four people ( 26 %) discontinued treatment because of AEs , and , at the 40 µ g / kg dose , 30 percent of doses were delayed because of neutropenia , thrombocytopenia , and febrile neutropenia .

“ AEs were primarily related to on-target myelosuppression ,” the researchers observed , and nonhematologic DLTs primarily occurred in the cohort of patients whose disease relapsed post-allogeneic hematopoietic cell transplantation ( alloHCT ).

Among 27 older , treatment-naïve patients ( median age = 74 years ; range = 67-89 years ) who received vadastuximab talirine 40 µ g / kg , two experienced DLTs ( grade 3 decrease in diffusing capacity of the lungs for carbon monoxide and grade 3 hematuria ). The most common AEs were decreased appetite ( 52 %), diarrhea ( 48 %), fatigue ( 48 %), peripheral edema ( 48 %), thrombocytopenia ( 48 %), anemia ( 44 %), dizziness ( 41 %), and febrile neutropenia ( 41 %). No deaths were reported within 30 days of last dose .

Treatment with vadastuximab talirine as monotherapy appeared to have a better safety profile than seen in other trials combining vadastuximab talirine with hypomethylating agents . “ The optimal approach to incorporating vadastuximab talirine into a therapeutic strategy for patients with AML has not yet been determined ,” Dr . Stein noted . In June 2017 , Seattle Genetics , the manufacturer of vadastuximab talirine , suspended all ongoing trials involving the drug amid rising concerns about patient deaths in the phase III CASCADE trial of older patients with newly diagnosed AML .

The median treatment duration was six weeks ( range = 2-50 weeks ), and 20 patients ( 15 %) remain on vadastuximab talirine in the extension phase ; most are receiving vadastuximab talirine 5 µ g / kg , the authors reported .

Fourteen patients ( 11 %) went on to receive alloHCT after completing study treatment .

The CR rate ( defined as CR + CRi ) among all 69 patients in the dosefinding cohorts was 19 percent ( CR = 13 %; CRi = 6 %). At the recommended monotherapy dose of 40 µ g / kg , the CR rate among 18 efficacy-evaluable patients was 28 percent ( CR = 11 %; CRi = 17 %).

The median time to neutrophil count recovery was 6.4 weeks ( range = 3-9 weeks ), and the median time to platelet recovery was 10.6 weeks ( range = 4-25 weeks ). The researchers observed a trend toward increasing blast clearance with increasing dose level : 49 percent of patients cleared marrow blasts at higher dose levels ( ≥30 µ g / kg ), compared with 32 percent at lower dose levels ( p value not reported ). However , the occurrence of grade 3 mucositis and sepsis led researchers to recommend a single 40 µ g / kg dose .

When the investigators assessed CD33 expression in 90 bone marrow ( BM ) samples and 105 peripheral blood ( PB ) samples , they found that higher expression correlated with the likelihood of achieving blast clearance ( odds ratio [ OR ] for PB = 3.58 ; 95 % CI 1.10-12.6 ; p = 0.040 ; and OR for BM = 4.50 ; 95 % CI 1.31-17.0 ; p = 0.021 ), but not with complete remission or MRD negativity .

Inclusion of NPM1 mutation , however , decreased the significance . “ Taken together , these data suggest a possible increased potential for achieving blast clearance with higher levels of CD33 expression , but that this effect is closely linked to higher CD33 levels on blasts with NPM1 mutation , a known favorable prognostic marker ,” the authors noted .

The study is limited by its small patient population in each subgroup and lack of a comparator arm . Seattle Genetics funded the study . The authors report financial support from Seattle Genetics .

REFERENCE

Stein EM , Walter RB , Erba HP , et al . A phase 1 trial of vadastuximab talirine as monotherapy in patients with CD33 positive acute myeloid leukemia ( AML ). Blood . 2017 December 1 . [ Epub ahead of print ]

24 ASH Clinical News February 2018