Article Figures & Data
Figures
- Figure 1.
A, immunoconjugate binding and internalization. B, immunoconjugate intracellular trafficking from endosome to lysosome, with linker cleavage. Acid-labile AcBut hydrazone linker is cleaved in the acid environment of lysosome. C, calicheamicin derivative is released intracellularly. The reduction to the active enediyne form requires glutathione. D, the active enediyne form binds to the minor groove in DNA and causes double-strand breaks, resulting in cell death. E, Pgp-mediated efflux may be a mechanism of drug resistance in leukemic cells. The immunoconjugate structure on the upper right is modified from Advani et al. (52). Reprinted with permission. © 2008 American Society of Clinical Oncology.
- Figure 2.
Pharmacodynamics, pharmacokinetics, and clinical activity of inotuzumab ozogamicin. A, mean (SD) molecular equivalents of soluble fluorophore expression of CD19+ lymphocytes that are CD22-phycoerythrin–positive before and after the first and second doses. These are derived from lymphocytes exhibiting ≥500 CD19+ events from flow cytometric analysis. B, concentration-time curves of intact ADC (CMC-544) and its components after the first dose of 1.8 mg/m2. C, Kaplan-Meier estimates of progression-free survival according to lymphoma type and sensitivity to previous therapy in the phase I–II study of inotuzumab ozogamicin plus rituximab (rituximab, 375 mg/m2; inotuzumab ozogamicin, 1.8 mg/m2) ITT population. Panels A and B courtesy of Joseph Boni. Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. Advani et al. (52). Panel C courtesy of Dr. Erik Vandendries.
Tables
- Table 1.
Relevant gemtuzumab ozogamicin single-agent studies in adult patients
Reference Sample size Median age (range) Dose and schedule AML status CR/CRp (%) Median RFS Sievers et al. (16) 142 61 (22–84) 9 mg/m2 D1 and D15 First relapse AML 16/13 6.8 mo Taksin et al. (62) 57 64 (22–80) 3 mg/m2 D1, 4, and 7 First relapse AML 26/7 11.0 mo Piccaluga et al. (63) 24 63 (20–75) 6 or 9 mg/m2 for 2–3 doses Relapsed, refractory AML 13/8 6.0 mob Lo-Coco et al. (38) 16 52 (17–77) 6 mg/m2 for 2–3 doses Molecularly relapsed APL 88/0 15 moc Amadori et al. (64) 56a 78 (62–86) Arm A: 3 mg/m2 D1, 3, and 5 Untreated AML 21/0 Not reported Arm B: 6 mg/m2 D1 and 8 18/4 Not reported Amadori et al. (65) 40 76 (61–89) 9 mg/m2 D1 and D15 Untreated AML 10/7 6.1 mod Nabhan et al. (66) 12 75 (66–79) 9 mg/m2 D1 and D15 Untreated AML 27/0 Not reported NOTE: This table includes published studies only. Phase II studies with heterogeneous diagnosis and/or mixed AML status were excluded.
Abbreviations: CRp, complete remission with incomplete platelet recovery; D, day; RFS, relapse-free survival.
-
↵aRandomized phase II study. Patients on arm C (n = 28) received best supportive care. The rate of disease nonprogression, the primary endpoint, was 38% in arm A vs. 63% in arm B; the D1+8 schedule met the statistical criteria for phase III comparison.
-
↵bMedian duration of response.
-
↵cSeven patients who remained in sustained molecular remission for a median of 15 months.
-
↵dPatients with CR.
-
- Table 2.
Relevant gemtuzumab ozogamicin studies of combination therapy in adult patients
Single-arm studies Reference Sample size (N) Median age (range) GO dose and schedule AML status Combined with CR/CRp (%) Stone et al. (67) 37 64 (55–70) 9 mg/m2 D7 Relapsed, refractory AML High dose Ara-C 32/3 Chevallier et al. (68) 62 56 (16–71) 9 mg/m2 D4 Relapsed, refractory AML Ara-C and mitoxantrone 50/13 Tsimberidou et al. (69) 32 53 (18–78) 6 mg/m2 D1 Relapsed, refractory AML Fludarabine, Ara-C, cyclosporine 28/6 Ravandi et al. (35) 25a 47 (14–81) 9 mg/m2 D1 Untreated high risk APL ATRA and ATO 81/0 Estey et al. (37) 15 45 (NR) 9 mg/m2 D1 Untreated high risk APL ATRA and ATO 73/0 Estey et al. (39) 19 50 (NR) 9 mg/m2 D1 or D5 Untreated APL ATRA 84/0 Candoni et al. (70) 30 53 (25–65) 3 mg/m2 D6 Untreated AML Fludarabine, Ara-C, idarubicin 90/0 Eom et al. (71) 37 64 (55–76) 6 mg/m2 D1 Untreated AML Idarubicin and BH-AC 76/3 Tsimberidou et al. (72) 59 57 (27–76) 6 mg/m2 D1 Untreated AMLb Fludarabine, Ara-C, cyclosporine 46/2 Kell et al. (73) 64 47 (17–59) 3 or 6 mg/m2 D1 Untreated AML Daunorubicin, Ara-C, 6-TG; or fludarabine, Ara-C, idarubicin 84 Amadori et al. (74) 57 68 (61–75) 9 mg/m2 D1 or D15 Untreated AML Mitoxantrone, Ara-C, etoposide 35/19 Clavio et al. (75) 46 66 (60–80) 3 mg/m2 at D4 Untreated AML Fludarabine, Ara-C, idarubicin 52/0 Randomized phase II studies Reference Sample size (N) Median age (range) GO dose and schedule AML status Treatment CR/CRp (%) Litzow et al. (76) 82 60 (27–75) 6 mg/m2 D5 Relapsed, refractory (>50%) AML Arm A: Ara-C + GO 8/4 52 (27–85) NA Arm B: Ara-C + L daunorubicin 7/0 53 (25–78) NA Arm C: CAT regimen 4/0 Randomized phase III studies Reference Sample size (N) Median age (range) GO dose and schedule AML status Combined with 5-year OS Burnett et al. (17) 1,113 49 (0–71) 3 mg/m2 D1 of induction Untreated AML Induction: with DA, ADE, or FLAG-Ida 43%c Control arm: no GO 41% Petersdorf et al. (41) 627 NR (18–60) 6 mg/m2 at D4 of induction Untreated AML Induction: with DA 31 mod Control arm: no GO 35 mo Löwenberg et al. (77) 232 67 (60–78) 6 mg/m2 × 3 doses after induction Untreated AML GO after induction therapy 28%c Control arm: no further therapy 21% Abbreviations: 6-TG, 6-Tioguanine; ADE, cytarabine, daunorubicin, and etoposide; Ara-C, cytarabine; ATO, arsenic trioxide; ATRA, all-trans-retinoic acid; BH-AC, N4-behenoyl-1-b-arabinofuranosyl cytosine; CAT, cyclophosphamide with mesna, cytarabine, topotecan; CRp, complete remission with incomplete platelet recovery; D, day; DA, daunorubicin and cytarabine; FLAG-Ida, fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin; L, liposomal; NA, not applicable; NR, not reported; OS, overall survival.
- Table 3.
Characteristics of CD22 that make it a good target for antibody-based therapy
•The normal function of CD22 is to regulate signal transduction of the surface immunoglobulin receptors on B cells. •CD22 is expressed on the cells of the majority of B-lymphocyte malignancies. •It is not expressed on hematopoietic stem cells or any other nonlymphoid hematopoietic or nonhematopoietic cells. •Memory B cells do not express CD22. •Based on in vitro testing of human cell lines, CD22 is one of the better internalizing molecules among several B-lymphoid lineage-specific surface antigens. •CD22 is not shed into the extracellular environment. - Table 4.
Inotuzumab ozogamicin studies
Phase Description Identifier Sample size Status III Randomized, in combination with rituximab, compared with rituximab plus bendamustine or rituximab plus gemcitabine, in patients with relapsed/refractory CD22+ aggressive NHL who are not candidates for high-dose chemotherapy NCT01232556 377 Recruiting III Randomized, in combination with rituximab, compared with defined investigator's choice therapy in patients with relapsed or refractory CD22+ FL NCT00562965 ∼978 Terminateda II Single-arm, single-agent, in patients with indolent NHL that is refractory to or has relapsed after rituximab and chemotherapy or radioimmunotherapy (56) NCT00868608 80 Recruiting II Single-arm, in combination with rituximab prior to HSCT, in patients with relapsed/refractory DLBCL (78) NCT00867087 60 Ongoing I–II In combination with rituximab in patients with B-cell NHL (57) NCT00299494 119 Ongoing I First-in-human study in patients with B-cell NHL (52) NCT00073749 79 Completed I Single-agent, in Japanese patients with FL (54) NCT00717925 13 Completed I In combination with R-CVP or R-GDP in patients with CD22+ NHL NCT01055496 ∼100 Recruiting I In combination with rituximab in Japanese patients with B-cell NHL (79) NCT00724971 10 Completed I Single-agent and in combination with rituximab in patients with ALL NCT01134575 ∼40 Recruiting Abbreviations: DLBCL, diffuse large B-cell Non-Hodgkin lymphoma; R-CVP, rituximab, cyclophosphamide, vincristine, and prednisone; R-GDP, rituximab, gemcitabine, cisplatinum, and dexamethasone.
-
↵aEnrollment was discontinued because of poor enrollment and because it was unlikely that the study would meet the estimated enrollment of ∼978 subjects. The decision was not prompted by the identification of any safety signals in this or other studies. Active treatment and follow-up of the already enrolled subjects were continued.
-
Volume 17, Issue 20
