Anti-CD22 Immunoconjugate Inotuzumab Ozogamicin + Rituximab Followed by Stem Cell Transplantation in Relapsed/Refractory DLBCL Patients: Safety and Efficacy

Inotuzumab ozogamicin (INO) is a humanized anti-CD22 antibody conjugated to cytotoxic calicheamicin. In a prior study, INO combined with rituximab (INO+R) had an overall response rate (ORR) of 78% in patients (pts) with relapsed diffuse large B-cell lymphoma (DLBCL) who were not candidates for high-dose therapy and autologous stem cell transplant (HDT-aSCT). An ORR of ∼20% was seen in pts with refractory aggressive lymphoma.

Safety and activity of INO+R followed by HDT-aSCT in relapsed/refractory DLBCL pts. Primary endpoint: ORR. Secondary endpoints: successful peripheral blood stem cell (PBSC) collection, aSCT rate, progression free survival (PFS), and overall survival (OS).

CD20+/CD22+ B cell DLBCL, HDT-aSCT eligible, ≥2 adverse prognostic factors (prior R exposure, early relapse/persistent disease with prior therapy, sIPI ≥2). R 375 mg/m² on day (d) 1, INO 1.8 mg/m² on d 2 every 21 d, up to 6 cycles; PBSC mobilization with G-CSF (+/− plerixafor injection) on d ≥8, cycle 2. Chemo-priming if insufficient PBSC collected by G-CSF and after response observed. INO+R responders with >2×10⁶ CD34+ cells/kg proceed to HDT-aSCT.

63 pts were enrolled; 61 received INO+R in this ongoing trial. Median age was 60 y (range 19–75 y); 46% had 1 prior therapy, 41% had 2, and 11% had ≥3. Pts had adverse prognostic factors: 100% prior R treatment; 78% sIPI ≥2 (range 0–4); 25% had no response to most recent prior therapy, 60% responded with early relapse/failure (<12 mo). Median time to treatment failure with most recent prior therapy was 5.9 mo. All previously treated with anthracyclines and alkylating agents. Pts received median of 3 INO+R cycles (range 1–6). For 54 evaluable pts, ORR after INO+R was 35% (24% complete response, 11% partial response), 13% stable disease, 50% progressive disease (PD). Response to most recent therapy was predictive of response: pts with responses >12 mo, early relapse/failure (<12 mo), or no response had ORR of 90% (n = 10), 30% (n = 30), and 8% (n = 12), respectively. To date, 16 pts collected >2×10⁶ CD34+PBSC/kg (range 2.1–7.1 ×10⁶/kg): 7 mobilized with G-CSF, 6 with G-CSF + plerixafor, 3 with G-CSF + chemo-priming (2 also received plerixafor). Five pts collected <2×10⁶ CD34+ PBSC/kg, including 1 with PD prior to collection attempt and 1 with insufficient counts to initiate apheresis (<5 CD34+ cells/mL): 3/5 pts had 2 prior regimens (1 also had prior aSCT); 2 had 1 prior regimen (1 with bone marrow involvement). For INO+R treated pts, 18 (30%) underwent HDT-aSCT. Consolidation treatment, most commonly BEAM, started 44.5 d (median) after INO+R (range 25–89 d). Of these 18 pts, 14 had successful engraftment. One pt had persistent thrombocytopenia ∼6 mo after HDT-aSCT (platelets 19000/mL), and 3 did not engraft before death: 1 due to neutropenic sepsis at d 23, 1 due to PD at d 25, 1 due to cytomegalovirus (CMV) complications at d 124. For INO+R treated pts, 6- and 12-mo PFS rates are 31% and 13%, respectively (median 2.6 mo, 20 pts censored); median OS is 10 mo (35 censored). PFS was independent of the number of prior regimens, but dependent on prior therapy response: pts with prior responses >12 mo had longer PFS than those with early relapse/failure or no response (median 12.8, 2.1, 2.7 mo, respectively). Pts who underwent HDT-aSCT had 6- and 12-mo PFS rates of 79% and 35%, respectively (median 10 mo); median OS not reached.

Common adverse events during INO+R treatment: thrombocytopenia (68%), nausea (46%), lymphopenia (41%), increased aspartate aminotransferase (38%), fatigue (38%), neutropenia (30%), pyrexia (29%), and vomiting (24%). Two pts had veno-occlusive disease, each occurred after HDT-aSCT: 1 recovered without intervention, the other did not recover, ultimately dying from CMV complications (above). In addition, 26 other deaths occurred: 22 due to PD, 2 due to infection after HDT-aSCT (1 neutropenic sepsis pre-engraftment, 1 sepsis post-engraftment), 1 due to neutropenic sepsis (death 77 d after last INO dose), and 1 attributed to complications of pre-existing chronic obstructive pulmonary disease (death 101 d after last INO dose).

In this selected high-risk population with relapsed/refractory DLBCL, INO+R shows activity and a 12-mo PFS rate of 35% after aSCT. The safety profile was most notable for some toxicities (hematologic, infectious, and hepatic) after aSCT. Further follow-up is required to assess long-term impact after aSCT.

Wagner-Johnston:Sanofi Aventis: Consultancy. Goy:Pfizer Inc: Honoraria, Research Funding. Rodriguez:Pfizer Inc: Research Funding; Genentech: Research Funding; Ortho-Biotech: Research Funding. Hamlin:Seattle Genetics: Consultancy, Honoraria, Research Funding; Calistoga: Consultancy; Spectrum: Consultancy; Pfizer Inc: Research Funding. Thieblemont:Assistance Publique - Hôpitaux de Paris: Employment; Institut National du Cancer - INCa [French National Cancer Institute]: Research Funding. Suh:Wyeth advisory member: Consultancy. Jiang:Pfizer Inc: Consultancy, Employment. Sullivan:Pfizer Inc: Employment. Vandendries:Pfizer Inc: Employment, Equity Ownership. Gisselbrecht:Pfizer Inc: Research Funding; Baxter: Consultancy, Honoraria; Allos: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding.