Anti-CD22 Immunoconjugate Inotuzumab Ozogamicin (CMC-544) + Rituximab In Relapsed DLBCL Patients Followed by Stem Cell Transplantation: Preliminary Safety and Efficacy

Inotuzumab ozogamicin (CMC-544) is a humanized anti-CD22 antibody conjugated to calicheamicin, a cytotoxic agent. CMC-544 targets CD22, which is expressed in the majority of B-cell non-Hodgkin lymphomas (NHL). CMC-544 alone and in combination with rituximab has demonstrated efficacy and tolerability in relapsed/refractory NHL patients including diffuse large B-cell lymphoma (DLBCL) patients who were ineligible for high-dose therapy and autologous stem cell transplant (HDT-aSCT). This trial is evaluating the safety and preliminary efficacy of CMC-544 plus rituximab (CMC-544+R) followed by HDT-aSCT.

Assess the safety and activity of CMC-544+R prior to HDT-aSCT in relapsed/refractory DLBCL patients using overall response rate (ORR), rate of successful peripheral blood stem cell (PBSC) collection, and aSCT rate as endpoints.

Patients: Patients are eligible for this ongoing trial if they have CD20+/CD22+ B-cell DLBCL, have received 1 or 2 therapies, have at least 2 adverse prognostic factors (prior rituximab exposure, early (<12 months) relapse [or persistent disease] with most recent prior therapy, and/or sIPI >1), and are judged eligible for HDT-aSCT. Rituximab (375 mg/m²) is given on day 1, then CMC-544 (1.8 mg/m²) on day 2 every 21 days for up to 6 cycles; PBSC mobilization with G-CSF (+/− plerixafor injection [Mozobil®]) begins no earlier than day 8 of cycle 2. Chemo-primed mobilization (with cyclophosphamide [C] or etoposide [E]) is allowed if insufficient PBSCs are collected by G-CSF and is initiated only after disease response is observed. Patients responding to CMC-544+R and with sufficient PBSCs (>2×10⁶ CD34+ cells/kg) proceed to HDT-aSCT.

To date, 34 patients have been treated with CMC-544+R. Median age is 62 y (range: 19–75); 74% male; 50% had 1 prior chemotherapy regimen, 38% had 2, and 9% had ≥ 3. Most common adverse events during CMC-544+R treatment were: thrombocytopenia (38%), neutropenia (21%), lymphopenia (21%), nausea (27%), fatigue (29%), and increased aspartate aminotransferase (21%). Three deaths have been reported: 2 due to disease progression at days 76 and 126 after last dose of CMC-544; and 1 after HDT-aSCT. There have been no reports of veno-occlusive disease. To date, 19 patients have postbaseline disease assessment(s), with adverse prognostic factors as follows: 100% prior treatment with rituximab; 79% with sIPI >1 (range, 2–4); 37% had no response to their most recent prior therapy, 53% responded but had early relapse or required initiation of new anti-cancer treatment (CMC-544+R) <12 months from the start of prior therapy, and only 11% had durable responses (>12 months). Additionally, all had prior treatment with both anthracyclines and alkylating agents. For these 19 patients (each with ≥ 2 adverse prognostic factors) and who received a median of 2 cycles, a best ORR of 21% was observed (2 complete and 2 partial responses); 26% showed stable disease, and 53% had disease progression. Of the 4 responders, 1 had no response to prior R-ICE, 1 had early relapse (~ 6 months) after prior R-CHOP, 1 relapsed 12 months after prior aSCT, and 1 had a complete response to R-DHAP 5 years prior to study treatment. To date, 7 patients have had PBSC collections: of these, 5 had successful collections (3 with G-CSF plus plerixafor, 1 with G-CSF alone, 1 with G-CSF plus chemo-priming); 2 patients, receiving G-CSF alone, did not have successful collections. Three patients have had both a response to CMC-544+R and sufficient PBSCs allowing HDT-aSCT: 1 patient had successful carmustine/E/cytarabine/C (BEAC)-aSCT (neutrophil, platelet recovery 11 and 29 days after aSCT, respectively); 1 patient did not have complete platelet recovery after busulfan/E/melphalan (M)-aSCT with 4.35×10⁶ CD34+ cells/kg (platelet levels were as low as 19,000/μL ~60 days after aSCT, and transfusions were required to sustain levels ≥20,000/μL); and 1 patient, a 74-y old male, expired 39 days after BEAM-aSCT from neutropenic sepsis with multiorgan failure.

In this patient population, CMC-544+R has a safety profile similar as previously reported. The preliminary ORR observed is notable given the poor prognosis of these patients. Current results suggest that successful PBSC mobilizations following CMC-544+R are possible. Additional data from this ongoing trial will be helpful to further assess the safety and efficacy of CMC-544+R prior to HDT-aSCT.

Goy:Allos Therapeutics: Consultancy, Honoraria; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Goh:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Ciliag: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sweetenham:Pfizer: Research Funding. Powell:Pfizer: Employment, Equity Ownership. Sullivan:Pfizer: Employment, Equity Ownership. Vandendries:Pfizer Inc.: Employment, Equity Ownership. Gisselbrecht:Allos Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.