Inotuzumab Ozogamicin versus Standard Therapy for Acute Lymphoblastic Leukemia.
BACKGROUND
The prognosis for adults with relapsed acute lymphoblastic leukemia is poor. We sought to determine whether inotuzumab ozogamicin, an anti-CD22 antibody conjugated to calicheamicin, results in better outcomes in patients with relapsed or refractory acute lymphoblastic leukemia than does standard therapy.


METHODS
In this phase 3 trial, we randomly assigned adults with relapsed or refractory acute lymphoblastic leukemia to receive either inotuzumab ozogamicin (inotuzumab ozogamicin group) or standard intensive chemotherapy (standard-therapy group). The primary end points were complete remission (including complete remission with incomplete hematologic recovery) and overall survival.


RESULTS
Of the 326 patients who underwent randomization, the first 218 (109 in each group) were included in the primary intention-to-treat analysis of complete remission. The rate of complete remission was significantly higher in the inotuzumab ozogamicin group than in the standard-therapy group (80.7% [95% confidence interval {CI}, 72.1 to 87.7] vs. 29.4% [95% CI, 21.0 to 38.8], P<0.001). Among the patients who had complete remission, a higher percentage in the inotuzumab ozogamicin group had results below the threshold for minimal residual disease (0.01% marrow blasts) (78.4% vs. 28.1%, P<0.001); the duration of remission was longer in the inotuzumab ozogamicin group (median, 4.6 months [95% CI, 3.9 to 5.4] vs. 3.1 months [95% CI, 1.4 to 4.9]; hazard ratio, 0.55 [95% CI, 0.31 to 0.96]; P=0.03). In the survival analysis, which included all 326 patients, progression-free survival was significantly longer in the inotuzumab ozogamicin group (median, 5.0 months [95% CI, 3.7 to 5.6] vs. 1.8 months [95% CI, 1.5 to 2.2]; hazard ratio, 0.45 [97.5% CI, 0.34 to 0.61]; P<0.001); the median overall survival was 7.7 months (95% CI, 6.0 to 9.2) versus 6.7 months (95% CI, 4.9 to 8.3), and the hazard ratio was 0.77 (97.5% CI, 0.58 to 1.03) (P=0.04). In the safety population, the most frequent grade 3 or higher nonhematologic adverse events with inotuzumab ozogamicin were liver-related. Veno-occlusive liver disease of any grade occurred in 15 patients (11%) who received inotuzumab ozogamicin and in 1 patient (1%) who received standard therapy.


CONCLUSIONS
The rate of complete remission was higher with inotuzumab ozogamicin than with standard therapy, and a higher percentage of patients in the inotuzumab ozogamicin group had results below the threshold for minimal residual disease. Both progression-free and overall survival were longer with inotuzumab ozogamicin. Veno-occlusive liver disease was a major adverse event associated with inotuzumab ozogamicin. (Funded by Pfizer; INO-VATE ALL ClinicalTrials.gov number, NCT01564784.).
From the University of Texas MD Anderson Cancer Center, Houston (H.M.K.); the Dana-Farber Cancer Institute, Boston (D.J.D.), and Pfizer, Cambridge (E.V.) - both in Massachusetts; Universitätsklinikum Münster, Münster (M.S.), and Goethe University, Frankfurt (N.G.) - both in Germany; Institute Seràgnoli, DIMES (Department of Experimental, Diagnostic and Specialty Medicine), University of Bologna, Bologna, Italy (G.M.); Stanford Cancer Institute, Stanford (M.L.), and the University of California, Irvine Medical Center, Orange (S.O.) - both in California; the University of Chicago, Chicago (W.S.); Pfizer, Pearl River, NY (K.W.); Pfizer, Groton, CT (T.W., M.L.P., B.S.); and Cleveland Clinic, Cleveland (A.S.A.).
Hagop M
HM
Kantarjian
From the University of Texas MD Anderson Cancer Center, Houston (H.M.K.); the Dana-Farber Cancer Institute, Boston (D.J.D.), and Pfizer, Cambridge (E.V.) - both in Massachusetts; Universitätsklinikum Münster, Münster (M.S.), and Goethe University, Frankfurt (N.G.) - both in Germany; Institute Seràgnoli, DIMES (Department of Experimental, Diagnostic and Specialty Medicine), University of Bologna, Bologna, Italy (G.M.); Stanford Cancer Institute, Stanford (M.L.), and the University of California, Irvine Medical Center, Orange (S.O.) - both in California; the University of Chicago, Chicago (W.S.); Pfizer, Pearl River, NY (K.W.); Pfizer, Groton, CT (T.W., M.L.P., B.S.); and Cleveland Clinic, Cleveland (A.S.A.).
Daniel J
DJ
DeAngelo
From the University of Texas MD Anderson Cancer Center, Houston (H.M.K.); the Dana-Farber Cancer Institute, Boston (D.J.D.), and Pfizer, Cambridge (E.V.) - both in Massachusetts; Universitätsklinikum Münster, Münster (M.S.), and Goethe University, Frankfurt (N.G.) - both in Germany; Institute Seràgnoli, DIMES (Department of Experimental, Diagnostic and Specialty Medicine), University of Bologna, Bologna, Italy (G.M.); Stanford Cancer Institute, Stanford (M.L.), and the University of California, Irvine Medical Center, Orange (S.O.) - both in California; the University of Chicago, Chicago (W.S.); Pfizer, Pearl River, NY (K.W.); Pfizer, Groton, CT (T.W., M.L.P., B.S.); and Cleveland Clinic, Cleveland (A.S.A.).
Matthias
M
Stelljes
From the University of Texas MD Anderson Cancer Center, Houston (H.M.K.); the Dana-Farber Cancer Institute, Boston (D.J.D.), and Pfizer, Cambridge (E.V.) - both in Massachusetts; Universitätsklinikum Münster, Münster (M.S.), and Goethe University, Frankfurt (N.G.) - both in Germany; Institute Seràgnoli, DIMES (Department of Experimental, Diagnostic and Specialty Medicine), University of Bologna, Bologna, Italy (G.M.); Stanford Cancer Institute, Stanford (M.L.), and the University of California, Irvine Medical Center, Orange (S.O.) - both in California; the University of Chicago, Chicago (W.S.); Pfizer, Pearl River, NY (K.W.); Pfizer, Groton, CT (T.W., M.L.P., B.S.); and Cleveland Clinic, Cleveland (A.S.A.).
Giovanni
G
Martinelli
From the University of Texas MD Anderson Cancer Center, Houston (H.M.K.); the Dana-Farber Cancer Institute, Boston (D.J.D.), and Pfizer, Cambridge (E.V.) - both in Massachusetts; Universitätsklinikum Münster, Münster (M.S.), and Goethe University, Frankfurt (N.G.) - both in Germany; Institute Seràgnoli, DIMES (Department of Experimental, Diagnostic and Specialty Medicine), University of Bologna, Bologna, Italy (G.M.); Stanford Cancer Institute, Stanford (M.L.), and the University of California, Irvine Medical Center, Orange (S.O.) - both in California; the University of Chicago, Chicago (W.S.); Pfizer, Pearl River, NY (K.W.); Pfizer, Groton, CT (T.W., M.L.P., B.S.); and Cleveland Clinic, Cleveland (A.S.A.).
Michaela
M
Liedtke
From the University of Texas MD Anderson Cancer Center, Houston (H.M.K.); the Dana-Farber Cancer Institute, Boston (D.J.D.), and Pfizer, Cambridge (E.V.) - both in Massachusetts; Universitätsklinikum Münster, Münster (M.S.), and Goethe University, Frankfurt (N.G.) - both in Germany; Institute Seràgnoli, DIMES (Department of Experimental, Diagnostic and Specialty Medicine), University of Bologna, Bologna, Italy (G.M.); Stanford Cancer Institute, Stanford (M.L.), and the University of California, Irvine Medical Center, Orange (S.O.) - both in California; the University of Chicago, Chicago (W.S.); Pfizer, Pearl River, NY (K.W.); Pfizer, Groton, CT (T.W., M.L.P., B.S.); and Cleveland Clinic, Cleveland (A.S.A.).
Wendy
W
Stock
From the University of Texas MD Anderson Cancer Center, Houston (H.M.K.); the Dana-Farber Cancer Institute, Boston (D.J.D.), and Pfizer, Cambridge (E.V.) - both in Massachusetts; Universitätsklinikum Münster, Münster (M.S.), and Goethe University, Frankfurt (N.G.) - both in Germany; Institute Seràgnoli, DIMES (Department of Experimental, Diagnostic and Specialty Medicine), University of Bologna, Bologna, Italy (G.M.); Stanford Cancer Institute, Stanford (M.L.), and the University of California, Irvine Medical Center, Orange (S.O.) - both in California; the University of Chicago, Chicago (W.S.); Pfizer, Pearl River, NY (K.W.); Pfizer, Groton, CT (T.W., M.L.P., B.S.); and Cleveland Clinic, Cleveland (A.S.A.).
Nicola
N
Gökbuget
From the University of Texas MD Anderson Cancer Center, Houston (H.M.K.); the Dana-Farber Cancer Institute, Boston (D.J.D.), and Pfizer, Cambridge (E.V.) - both in Massachusetts; Universitätsklinikum Münster, Münster (M.S.), and Goethe University, Frankfurt (N.G.) - both in Germany; Institute Seràgnoli, DIMES (Department of Experimental, Diagnostic and Specialty Medicine), University of Bologna, Bologna, Italy (G.M.); Stanford Cancer Institute, Stanford (M.L.), and the University of California, Irvine Medical Center, Orange (S.O.) - both in California; the University of Chicago, Chicago (W.S.); Pfizer, Pearl River, NY (K.W.); Pfizer, Groton, CT (T.W., M.L.P., B.S.); and Cleveland Clinic, Cleveland (A.S.A.).
Susan
S
O'Brien
From the University of Texas MD Anderson Cancer Center, Houston (H.M.K.); the Dana-Farber Cancer Institute, Boston (D.J.D.), and Pfizer, Cambridge (E.V.) - both in Massachusetts; Universitätsklinikum Münster, Münster (M.S.), and Goethe University, Frankfurt (N.G.) - both in Germany; Institute Seràgnoli, DIMES (Department of Experimental, Diagnostic and Specialty Medicine), University of Bologna, Bologna, Italy (G.M.); Stanford Cancer Institute, Stanford (M.L.), and the University of California, Irvine Medical Center, Orange (S.O.) - both in California; the University of Chicago, Chicago (W.S.); Pfizer, Pearl River, NY (K.W.); Pfizer, Groton, CT (T.W., M.L.P., B.S.); and Cleveland Clinic, Cleveland (A.S.A.).
Kongming
K
Wang
From the University of Texas MD Anderson Cancer Center, Houston (H.M.K.); the Dana-Farber Cancer Institute, Boston (D.J.D.), and Pfizer, Cambridge (E.V.) - both in Massachusetts; Universitätsklinikum Münster, Münster (M.S.), and Goethe University, Frankfurt (N.G.) - both in Germany; Institute Seràgnoli, DIMES (Department of Experimental, Diagnostic and Specialty Medicine), University of Bologna, Bologna, Italy (G.M.); Stanford Cancer Institute, Stanford (M.L.), and the University of California, Irvine Medical Center, Orange (S.O.) - both in California; the University of Chicago, Chicago (W.S.); Pfizer, Pearl River, NY (K.W.); Pfizer, Groton, CT (T.W., M.L.P., B.S.); and Cleveland Clinic, Cleveland (A.S.A.).
Tao
T
Wang
From the University of Texas MD Anderson Cancer Center, Houston (H.M.K.); the Dana-Farber Cancer Institute, Boston (D.J.D.), and Pfizer, Cambridge (E.V.) - both in Massachusetts; Universitätsklinikum Münster, Münster (M.S.), and Goethe University, Frankfurt (N.G.) - both in Germany; Institute Seràgnoli, DIMES (Department of Experimental, Diagnostic and Specialty Medicine), University of Bologna, Bologna, Italy (G.M.); Stanford Cancer Institute, Stanford (M.L.), and the University of California, Irvine Medical Center, Orange (S.O.) - both in California; the University of Chicago, Chicago (W.S.); Pfizer, Pearl River, NY (K.W.); Pfizer, Groton, CT (T.W., M.L.P., B.S.); and Cleveland Clinic, Cleveland (A.S.A.).
M Luisa
ML
Paccagnella
From the University of Texas MD Anderson Cancer Center, Houston (H.M.K.); the Dana-Farber Cancer Institute, Boston (D.J.D.), and Pfizer, Cambridge (E.V.) - both in Massachusetts; Universitätsklinikum Münster, Münster (M.S.), and Goethe University, Frankfurt (N.G.) - both in Germany; Institute Seràgnoli, DIMES (Department of Experimental, Diagnostic and Specialty Medicine), University of Bologna, Bologna, Italy (G.M.); Stanford Cancer Institute, Stanford (M.L.), and the University of California, Irvine Medical Center, Orange (S.O.) - both in California; the University of Chicago, Chicago (W.S.); Pfizer, Pearl River, NY (K.W.); Pfizer, Groton, CT (T.W., M.L.P., B.S.); and Cleveland Clinic, Cleveland (A.S.A.).
Barbara
B
Sleight
From the University of Texas MD Anderson Cancer Center, Houston (H.M.K.); the Dana-Farber Cancer Institute, Boston (D.J.D.), and Pfizer, Cambridge (E.V.) - both in Massachusetts; Universitätsklinikum Münster, Münster (M.S.), and Goethe University, Frankfurt (N.G.) - both in Germany; Institute Seràgnoli, DIMES (Department of Experimental, Diagnostic and Specialty Medicine), University of Bologna, Bologna, Italy (G.M.); Stanford Cancer Institute, Stanford (M.L.), and the University of California, Irvine Medical Center, Orange (S.O.) - both in California; the University of Chicago, Chicago (W.S.); Pfizer, Pearl River, NY (K.W.); Pfizer, Groton, CT (T.W., M.L.P., B.S.); and Cleveland Clinic, Cleveland (A.S.A.).
Erik
E
Vandendries
From the University of Texas MD Anderson Cancer Center, Houston (H.M.K.); the Dana-Farber Cancer Institute, Boston (D.J.D.), and Pfizer, Cambridge (E.V.) - both in Massachusetts; Universitätsklinikum Münster, Münster (M.S.), and Goethe University, Frankfurt (N.G.) - both in Germany; Institute Seràgnoli, DIMES (Department of Experimental, Diagnostic and Specialty Medicine), University of Bologna, Bologna, Italy (G.M.); Stanford Cancer Institute, Stanford (M.L.), and the University of California, Irvine Medical Center, Orange (S.O.) - both in California; the University of Chicago, Chicago (W.S.); Pfizer, Pearl River, NY (K.W.); Pfizer, Groton, CT (T.W., M.L.P., B.S.); and Cleveland Clinic, Cleveland (A.S.A.).
Anjali S
AS
Advani
D000293:Adolescent; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D000080045:Inotuzumab Ozogamicin; D057194:Intention to Treat Analysis; D008297:Male; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000401:mortality; D012074:Remission Induction; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000037:antagonists & inhibitors*; D016019:Survival Analysis; D055815:Young Adult
D061067:Antibodies, Monoclonal, Humanized; C497867:CD22 protein, human; D051918:Sialic Acid Binding Ig-like Lectin 2; D000080045:Inotuzumab Ozogamicin