Single Agent Inotuzumab Ozogamicin Research Articles

Inotuzumab ozogamicin for relapse prevention in a boy with Down syndrome and relapsed acute lymphoblastic leukemia.

Inotuzumab ozogamicin (InO), a CD22-directed antibody conjugated to calicheamicin, has demonstrated excellent efficacy in B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). It has been used for patients with relapsed or refractory BCP-ALL as a bridge to allo-HCT. Children with Down syndrome (DS) have an increased risk of BCP-ALL and higher rates of relapse and toxicity, including treatment-related mortality. Although allo-HCT is potentially curative for relapsed or refractory ALL, post-transplant leukemic relapse rates and transplant-related mortality are dismal in patients with DS-ALL, which results in less frequent use of allo-HCT in this group than in the non-DS population. Therefore, novel and less toxic therapeutic strategies are required to improve outcomes. Here we report the case of a child with DS who was diagnosed with a second relapse of BCP-ALL and has maintained complete remission through regular single-agent InO therapy. Single-agent maintenance using InO can be a good option to avoid subsequent relapse in patients with relapsed or refractory BCP-ALL who cannot proceed to allo-HCT and require less-toxic treatments.

Combining Inotuzumab Ozogamicin (IO) with PARP Inhibitors, Olaparib and Talazoparib, Exerts Synergistic Cytotoxicity By Inhibiting the Repair of IO-Induced DNA Strand Breaks in IO-Resistant ALL Cells

[Introduction]Inotuzumab ozogamicin (IO) is highly effective in the treatment of relapsed/refractory CD22-positive B-acute lymphoblastic leukemia (B-ALL). IO exerts the antileukemic effect via DNA single- and double-strand breaks induced by calicheamicin. Although IO has been reported to show more than 80% response rate, the duration of remission is only 4.6 months, suggesting the early acquisition of drug resistance. Thus, it is crucial to elucidate the mechanism of resistance to IO and overcome it. Polyadenosine diphosphate-ribose polymerase (PARP) inhibitors, such as olaparib and talazoparib, show the antitumor effect by inhibiting DNA repair. This study was conducted to enhance the antitumor effect of IO by inhibiting IO-induced DNA damage repair using PARP inhibitors. The study attempted to overcome the resistance of B-ALL cell lines developed to be IO-resistant. [Methods]Ph-negative, CD22-positive B-ALL Reh cell line was used to determine the cytotoxicity of IO and PARP inhibitors. Inotuzumab ozogamicin was kindly provided by Pfizer. Six IO-resistant cell lines were newly established by long-term exposure of Reh cells to IO, followed by the limiting dilution. FACS analysis evaluated CD22 expression. WTS assay and Annexin-V positivity were used to determine the antileukemic effects. The Comet assay assessed the DNA repair function. The DNA microarray compared gene expression between Reh and IO-resistant Reh clones. [Results] The growth inhibition effect of IO was significantly augmented by the addition of the minimally toxic concentration of olaparib or talazoparib in Reh cells. The combination index values were 0.19 and 0.42, respectively, demonstrating a strong synergism. Combining IO with olaparib or talazoparib increased IO-induced apoptosis compared to single-agent IO. The apoptosis rates induced by 20 ng/mL IO with minimally toxic concentrations of olaparib or talazoparib were 51.7% and 66.1%, respectively, showing significantly higher apoptosis rates than IO alone (23.5%). Assessment of DNA strand breaks using the Comet assay showed that the recovery of IO-induced DNA damage was inhibited in the presence of PARP inhibitors, and DNA strand breaks persisted. Next, six IO-resistant Reh (Reh-IO-R) cell lines were established as described above. The expressions of CD22 were more than 60%. All 6 cell lines had more than 60-fold resistance to IO with the 50%-inhibitory concentration (IC 50) values 474.3～782.3 ng/mL, compared with that of Reh cells (2.1 ng/mL). The IC 50 values of olaparib or talazoparib were similar to Reh and Reh-IO-R cell lines. When IO was combined with olaparib or talazoparib, the growth of Reh-IO-R cells was inhibited, with median IC 50 values were 359.4[290.3-406.2] and 179.1[59.3-240.5] ng/mL, respectively. This combination also remarkably increased apoptosis induction in Reh-IO-R cells. The apoptosis rate of Reh cells at 100 ng/mL IO alone was 77%, whereas the apoptosis rate of 6 Reh-IO-R cell lines averaged 5.9% [5.7-6.6%]. The median percentage of apoptosis in Reh-IO-R cell lines was 12.0% by IO + olaparib and 17.1% by IO + talazoparib. Furthermore, synergism was obtained in Reh-IO-R cell lines with the combination of 1,000 ng/mL IO with olaparib or talazoparib. The median percentage of apoptotic cell death was 24.2% by IO 1,000 ng/mL alone and 45.3% by the IO+olaparib, and 56.8% by the IO+talazoparib. These results suggest that the potentiating effect of PARP inhibitors would be attributed to more DNA cleavage occurring. The expression of genes ( ATM, ATR, DNA-PK, CHK1/2, PARP, RAD, ERCC1, BRCA1/2 Ku70/80) related to DNA repair was similar between Reh and Reh-IO-R cells. Of note, ABCB1 (p-gp) was overexpressed in Reh-IO-R cells. These results suggest that the expression of p-gp was one of the mechanisms of the resistance to IO, and the combination of IO and PARP inhibitors was effective to a certain extent in the Reh-IO-R cells expressing p-gp. This would be because the PARP inhibitors were still effective in inhibiting the DNA repair in Reh-IO-R cells where the DNA repair function was not augmented. [Conclusion]The combination of IO with PARP inhibitors synergized the antileukemic effect of IO by inhibiting DNA strand break repair in CD22-positive ALL cell lines and IO-resistant ALL cells, suggesting that these results may contribute to overcoming the IO resistance mechanisms.

Sequential Combination of Inotuzumab Ozogamicin (InO) with Low-Intensity Chemotherapy (mini-hyper-CVD) with or without Blinatumomab (Blina) As Salvage Therapy for Patients (Pts) with Acute Lymphoblastic Leukemia (ALL) in First Relapse

Sequential Combination of Inotuzumab Ozogamicin (InO) with Low-Intensity Chemotherapy (mini-hyper-CVD) with or without Blinatumomab (Blina) As Salvage Therapy for Patients (Pts) with Acute Lymphoblastic Leukemia (ALL) in First Relapse

A Retrospective Study on Inotuzumab Ozogamicin in Infants and Young Children with Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL)

A Retrospective Study on Inotuzumab Ozogamicin in Infants and Young Children with Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL)

Sequential Combination of Inotuzumab Ozogamicin (InO) with Low-Intensity Chemotherapy (Mini-hyper-CVD) with or without Blinatumomab Is Highly Effective in Patients (pts) with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia (ALL) in First Relapse

Sequential Combination of Inotuzumab Ozogamicin (InO) with Low-Intensity Chemotherapy (Mini-hyper-CVD) with or without Blinatumomab Is Highly Effective in Patients (pts) with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia (ALL) in First Relapse

A Phase I Study of Single-Agent Inotuzumab Ozogamicin in Pediatric CD22-Positive Relapsed/Refractory Acute Lymphoblastic Leukemia: Preliminary Results of the ITCC-059 Study

A Phase I Study of Single-Agent Inotuzumab Ozogamicin in Pediatric CD22-Positive Relapsed/Refractory Acute Lymphoblastic Leukemia: Preliminary Results of the ITCC-059 Study

PS950 EFFICACY AND SAFETY OF INOTUZUMAB OZOGAMICIN IN PATIENTS WITH RELAPSED/REFRACTORY B‐CELL ACUTE LYMPHOBLASTIC LEUKEMIA TREATED IN THE INO‐VATE TRIAL: OUTCOMES BY SALVAGE‐TREATMENT PHASE

Background:Inotuzumab ozogamicin (InO) is a humanized anti‐CD22 antibody conjugated to calicheamicin. Upon binding to CD22 on acute lymphoblastic leukemia (ALL) cells, InO is internalized and calicheamicin is released, resulting in DNA double‐strand cleavage and apoptosis. Single agent InO is highly effective in relapsed/refractory (R/R) ALL, having shown clinical activity in a Phase II study. In a Phase III randomized study (INO‐VATE), InO induced a higher response rate and better overall survival than standard of care (SoC).Aims:To assess outcomes by salvage line, for patients (pts) receiving InO vs SoC in the INO‐VATE study.Methods:In this global, open‐label, randomized trial, pts aged ≥18 years with R/R, CD22‐positive, and Philadelphia chromosome (Ph)+ or Ph‐ B‐cell ALL due to receive first (S1) or second salvage (S2) therapy were eligible for enrolment. Pts were randomized 1:1 to receive InO or the investigator's choice of SoC. Pts enrolled were stratified by age (<55 years vs ≥55 years), salvage‐treatment phase (S1 vs S2), and duration of first remission (<12 months vs ≥12 months). A total of 326 pts (InO: 164; SoC: 162) were randomized (intention‐to‐treat population). As per the case report form, pts received either S1 (InO: 111 pts; SoC: 102 pts) or S2 (InO: 51 pts; SoC: 59 pts) treatment. Data as of January 4, 2017 are presented.Results:Baseline characteristics were well balanced between InO and SoC (for both S1 and S2), with some exceptions for S2: compared with InO, a higher proportion of SoC pts were Ph+(17.6% vs 25.4%) and a lower proportion of SoC pts had complex cytogenetics (33.3% vs 16.9%). Responses stratified by S1 vs S2 are presented (Table). Rates of complete remission (CR)/CR with incomplete hematologic recovery (CRi) and rates of MRD negativity (among pts with CR/CRi) were significantly higher for InO compared with SoC, for both S1 and S2 (all P < 0.02). The difference in rates of CR/CRi and MRD negativity between InO and SoC tended to be larger for S1 but these differences were not statistically significant. PFS was significantly longer for InO compared with SoC, for both S1 and S2 (both P < 0.001). OS was longer for InO compared with SoC for S1 and S2; this difference was statistically significant for S1 (P = 0.035) but not S2 (P = 0.353). The proportion of patients proceeding to allogeneic stem cell transplantation (SCT) was significantly higher for InO compared with SoC, for both S1 and S2 (both P < 0.005). In each treatment arm, the proportion of patients proceeding to SCT was higher for S1 than for S2; the differences between S1 and S2 were not statistically significant in either treatment arm.The incidences of several classes of AEs were similar for S1 vs S2, for both InO and SoC; these included grade ≥3 AEs (InO: 91.0% vs 90.2%; SoC: 95.7% vs 98.0%), grade ≥3 thrombocytopenias (InO: 41.4% vs 39.2%; SoC: 60.2% vs 57.1%), and grade ≥3 febrile neutropenias (InO:24.3% vs 29.4%; SoC: 57.0% vs 49.0%). Hepatobiliary disorders (grade ≥3) were less common in S1 vs S2, for both the InO (12.6% vs 25.5%) and SoC (7.5% vs 10.2%) arms. Veno‐occlusive disease (VOD) was less common in S1 than S2 for the InO (9.9% vs 15.7%) arm but not for the SoC arm (2.2% vs 2.0%).Summary/Conclusion:InO is highly effective and provides significant clinical benefit compared with SoC in patients with R/R ALL. Analysis by salvage status indicates that InO provided higher efficacy and better outcomes when utilized as first salvage therapy. Hepatotoxicity was more common in S2 than S1 for both InO and SoC.image

Population pharmacokinetics of inotuzumab ozogamicin in relapsed/refractory acute lymphoblastic leukemia and non-Hodgkin lymphoma

This population pharmacokinetics analysis evaluated the target-mediated drug disposition of inotuzumab ozogamicin (InO) through an empirical time-dependent clearance (CLt) term and identified potential covariates that may be important predictors of variability in InO distribution and elimination. This analysis was conducted by pooling data from 2 studies of single-agent InO in patients with relapsed or refractory (R/R) B cell acute lymphoblastic leukemia (ALL), 3 studies of single-agent InO, 5 studies of InO plus rituximab (R-InO), and 1 study of R-InO plus chemotherapy in patients with R/R B-cell non-Hodgkin lymphoma (NHL). Pharmacokinetic data included 8361 InO concentration–time observations that were modeled using nonlinear mixed-effects analysis. Covariate relations were identified using generalized additive modeling on base model parameters and then tested in a stepwise manner via covariate modeling. InO concentration was described with a 2-compartment model with linear and time-dependent clearance components. Based on the final model, baseline body surface area was a covariate of the linear and time-dependent clearance components and volume of distribution in the central compartment; baseline percentage of blasts in the peripheral blood was a covariate of the decay coefficient of the time-dependent clearance term (CLt); and concomitant rituximab treatment was a covariate of the linear clearance component (CL1). The magnitude of change of each pharmacokinetic parameter due to these covariates was not considered clinically relevant. Therefore, no dose adjustment of InO for the treatment of patients with R/R B-cell ALL or NHL is needed on the basis of selected covariates.

Inotuzumab ozogamicin in pediatric patients with relapsed/refractory acute lymphoblastic leukemia (R/R ALL).

10512 Background: Inotuzumab ozogamicin (InO), a CD22-targeting antibody linked to calicheamicin demonstrated exceptional activity in R/R ALL in adults. InO has been available to pediatric patients with R/R ALL via a compassionate access program. Methods: Participating international pediatric oncology centers received IRB approval to submit retrospective demographic, outcome and toxicity data on pediatric patients who received at least one dose of InO. Results: Thirty-four patients, age 2.3-21.4 yrs (median 11.7) received 1-4 cycles (3 weekly doses) of InO. Patients were heavily pretreated in 1st-5threlapse; 28 were refractory to their preceding regimen. Thirteen patients had prior hematopoietic stem cell transplant (HSCT), 27 received prior CD19 and 8 prior CD22-directed therapy. Pre-InO disease was M3 ( > 25% blasts) in 26 patients, M2 (5-25%) in 3, and MRD only in 5 (1 with extramedullary disease). Of 29 patients with M2/M3 disease at baseline, 18 (62%) achieved a complete remission (CR), 13 of whom were MRD negative. Post-InO, 15 patients proceeded to HSCT and 5 to CAR T-cell therapy. Alterations in CD22 expression at subsequent relapse were noted in two patients with available blasts samples. No deaths were attributed to InO during therapy. The incidence of grade 3/4 infections was 38% and were of the expected types. Grade 1-4 hepatic toxicity was noted in 11/34 (32%) patients, primarily asymptomatic elevations in transaminases/bilirubin. There was no sinusoidal obstruction syndrome (SOS) during InO therapy but 8/15 patients who received HSCT post-InO developed SOS. One patient died from SOS, but the others recovered. The incidence of SOS was higher in patients who had undergone prior HSCT (6/8) versus no prior HSCT (2/7). SIRS (1), neurotoxicity (2) and hemorrhage (3) were infrequent. Three patients had musculoskeletal pain associated with edema. Conclusions: Single agent InO had a CR rate of 62% in heavily pretreated pediatric patients. Toxicities were similar to adults with hepatic and infectious toxicity being the most common. Overall InO was well tolerated, but the incidence of SOS was high in patients who underwent HSCT post-InO, particularly in those who had undergone a prior HSCT.

Phase II Study of the Salvage Mini-Hyper-CVD in Combination with Inotuzumab Ozogamicin (INO) for Adult Patients with Relapsed/Refractory (R/R) Acute Lymphoblastic Leukemia (ALL)

Background: Outcome of patients with R/R ALL is poor. INO is a CD22 monoclonal antibody bound to a calecheamicin, and has shown single-agent activity in R/R ALL with a response rate of 58% and median survival of 6.3 months. The addition of targeted therapy to effective low-intensity chemotherapy might further improve clinical outcome. The aims of this study are to evaluate response rate, progression-free survival (PFS), overall survival (OS), and to assess the safety of this regimen.Methods: Patients ≥18 years with R/R ALL were eligible. The chemotherapy was lower intensity than conventional hyper-CVAD and referred to as mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 x 4 doses). Rituximab and intrathecal chemotherapy were given for first 4 courses. INO was given on Day 3 of each of the first 4 courses. Patients received INO at 1.8 mg/m2 for cycle 1 followed by 1.3 mg/m2 for subsequent cycles. After the occurrence of veno-occlusive disease (VOD), the dose of INO was modified to 1.3 mg/m2 for Cycle 1 followed by 1.0 mg/m2 for subsequent cycles starting at the Patient #48.Results: Fifty-seven patients (29 men, 28 women) have been enrolled. Patient characteristics and outcome are summarized in Table 1. Median age is 34 years (range 9-87). Median follow-up is 15 months (range, 2-34). The overall response rate was 45 (79%): 31 (53%) CR, 13 (23%) CR without platelet recovery (CRp), and 1 (2%) CR with incomplete count recovery (CRi). Grade 3/4 toxicities included infections during induction (52%), infections during consolidation (73%), prolonged thrombocytopenia (79%), hyperglycemia (50%), hypokalemia (35%), hyperbilirubinemia (24%), elevated AST/ALT (21%), hemorrhage (18%), and VOD (11%; n=6). Of 6 patients who developed VOD, all 6 had allogeneic stem cell transplantation (allo-SCT) prior to or post INO therapy; three had prior allo-SCT (conditioning regimen; 2 fludarabine/clofarabine; 1 cyclophosphamide/total body irradiation); 4 had allo-SCT after INO therapy (conditioning regimen; 2 fludarabine/busulfan/clofarabine; 1 fludarabine/melphalan; 1 fludarabine/busulfan); 1 had chimeric antigen receptor T-cell therapy. Twenty-seven (47%) patients proceeded to receive allo-SCT. At the last follow-up, 25 (44%) patients are alive. Thirty-two (56%) patients died: 7 early death; 5 refractory disease; 7 post relapse after subsequent salvage, 3 in CR/CRp (1 sepsis; 2 unknown), 10 post allo-SCT (1 VOD; 3 transplant complications; 5 relapse; and 1 unknown). The 2-year PFS and OS rates were 52% and 34%, respectively (Figure 1). Median OS for patients with S1 was not reached with 2-year OS of 53%; patients with S2, 6 months with 2-year OS of 0%; patients with ≥S3, 5.6 months with 2-year OS of 0% (p=0.005). Patients who were treated with mini-hyper-CVD plus INO plus/minus rituximab had a tendency of higher PFS rates, and improved OS compared to a historical cohort with single-agent INO in R/R ALL (2-year PFS; 52% vs. 36%; p=0.20: 2-year OS; 44% vs. 25%; p=0.01).Conclusions: The combination of INO with low-intensity mini-hyper-CVD chemotherapy is effective and shows encouraging results in patients with R/R ALL. The risk of VOD should be considered carefully for patients with previous liver damage and transplant candidate. Lower dose schedule of INO are being explored. [Display omitted] [Display omitted] DisclosuresJabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. O'Brien:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Burger:Pharmacyclics: Research Funding. Jain:Pharmacyclics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Abbvie: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Seattle Genetics: Research Funding; Genentech: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; BMS: Research Funding; Servier: Consultancy, Honoraria; Infinity: Research Funding; Celgene: Research Funding; Novimmune: Consultancy, Honoraria. Konopleva:Calithera: Research Funding; Cellectis: Research Funding. DiNardo:Celgene: Research Funding; Agios: Other: advisory board, Research Funding; Abbvie: Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

A Phase II Study of Weekly Inotuzumab Ozogamicin (InO) in Adult Patients with CD22-Positive Acute Lymphoblastic Leukemia (ALL) in Second or Later Salvage

▪Background: InO is a humanized anti-CD22 antibody conjugated to calicheamicin. CD22 is expressed on the majority of cells derived from patients (pts) with B-cell ALL. An initial study suggested InO efficacy and tolerability in ALL (Kantarjian, et al. Cancer. 2013;119(15):2728-36).Aims: This ongoing study was preceded by phase 1 dose-escalation and expansion cohorts to select the recommended phase 2 dose (RP2D), determined as 1.8 mg/m2/cycle (0.8 mg/m2 on day 1 and 0.5 mg/m2 on days 8 and 15) as an initial starting dose followed by a dose reduction to 1.6 mg/m2/cycle upon achievement of complete response (CR) or CR without absolute neutrophil count (ANC) or platelet recovery (CRi). One dose-limiting toxicity (elevated lipase) was reported at this starting dose; however, dose delays and reductions were subsequently required in 5 patients for AEs (mostly owing to increased aspartate aminotransferase [AST]). Here we report the results of the phase 2 portion of the study which further evaluates the safety and efficacy of this regimen in patients with CD22+ relapsed/refractory ALL in the second and later salvage settings.Methods: Pts aged ≥18 y with CD22+ ALL in second or later salvage and no known central nervous system disease were enrolled. InO was administered in 28-d cycles up to 6 cycles. Adverse event (AE) severity was assessed per Common Terminology Criteria for Adverse Events (CTCAE) v3. CR was defined as <5% bone marrow blasts without peripheral blasts, ANC ≥1,000/µL, platelets >100,000/µL and no extramedullary disease. Blood samples were collected for pharmacokinetic analyses.Results: We report data for 35 pts: median age was 34 y (range, 20–79y); 77% were men; 6 (17%) pts were in salvage 5 or greater; 15 (43%) pts had prior allogeneic stem cell transplant (SCT). CD22 was expressed on a median of 99% blasts (range, 78%–100%); median peripheral blast count was 317.6/µL (range, 0–41,099/µL) and 28 (80%) pts presented with ≥50% bone marrow blasts. Aberrant baseline cytogenetics were reported in 27 (77%) pts including 9 (26%) with Ph+, 9 (26%) with complex cytogenetics (5 aberrations) and 9 (26%) with other aberrations. Three pts had normal cytogenetics at baseline and 5 had insufficient yield/unknown. Median follow-up in surviving pts was 4.4 (range, 0.7–11) months. Thirty-four pts discontinued InO: 17 owing to progressive disease (PD)/relapse or resistant disease; 7 proceeded to SCT (1 relapsed before SCT); 5 owing to AEs (grade [gr] 4 respiratory failure, gr 2 ascites in the setting of global deterioration, gr 2 increased alkaline phosphatase, gr 2 elevated AST and gr 2 increased transaminases); 2 died due to PD; 1 completed 6 cycles of InO and proceeded to maintenance therapy; 1 refused further treatment and 1 proceeded to DLI. InO-related gr ≥3 AEs (≥10% of pts) were thrombocytopenia (31%), neutropenia (26%) and febrile neutropenia (20%). Other gr ≥3 hepatic AEs included increased ALT/ increased transaminases (6%). Venoocclusive disease/sinusoidal obstruction syndrome occurred in 3 pts during the follow-up period: 2 (salvage 2 and 5) post-SCT and 1 (salvage 4) after the start of subsequent therapy. Prestudy SCT was not reported for these 3 pts. Nineteen deaths were reported: leukemia (n=14), hepatic failure/SOS (n=1), pneumonia (n=1), septic shock and graft versus host disease (n=1), subdural hematoma (n=1), and leukemia/liver failure (n=1).The remission rate (CR+CRi) was 65.7% (95% CI, 47.8, 80.9); 18/23 (78%) patients with CR/CRi achieved MRD negativity. Overall, the median time to remission and MRD negativity was 25 d (range, 15–86 d) and 25.5 d (range, 21–80 d), respectively. Six (67%) Ph+ pts and all 13 pts (100%) without peripheral blood blasts at baseline achieved CR/CRi. The median overall survival for the study population was 7.4 months (95% CI, 4.3–9.9).Summary/Conclusion: InO had a tolerable safety profile primarily characterized by hematologic, gastrointestinal and hepatic AEs. Single-agent InO demonstrated encouraging clinical activity in this multiply relapsed/refractory population. Further exploration in CD22+ ALL is ongoing.Table 1Median (range) InO cycles initiated, n3 (1–6)CR + CRi rate, n (%) [95% CI]23 (65.7) [47.8, 80.9]CR11 (31.4)CRi12 (34.3)MRD negative rate in pts with CR/CRi, n (%)18 (78.2)CR (n=11)8 (73)CRi (n=12)10 (83)OS (95% CI) at 12 mo, %26 (10, 50)Median (95% CI) OS, mo7.4 (4.3, 9.9) DisclosuresAdvani:Pfizer Inc: Research Funding. Kantarjian:Pfizer Inc: Research Funding. DeAngelo:Pfizer Inc: Advisory Board Other. Ananthakrishnan:Pfizer Inc: Employment. Liau:Pfizer Inc.: Employment. Vandendries:Pfizer Inc.: Employment. Stock:Amgen: Consultancy; Sigma Tau: Consultancy; Jazz: Consultancy; Seattle Genetics: Consultancy; UpToDate: Honoraria; American Board of Internal Medicine: Honoraria.

Inotuzumab ozogamicin (CMC-544) compared to chemotherapy in patients (pts) with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL): A retrospective comparison.

7095 Background: Modern multi-agent chemotherapy (CT) regimens result in complete remission (CR) rates of 80-90% and long-term survival rates of 40% in pts with ALL. The most common reason for treatment failure is relapse of the disease. Post-relapse therapies lead to second CR in 30-40% of pts with a 5-year survival of &lt;10%. CD22 expression occurs in &gt;90% of pts with ALL. Inotuzumab ozogamicin (IO) is a CD22 monoclonal antibody bound to a toxin, calecheamicin. We reported overall response rate of 57% with single-agent IO in R/R ALL (Kantarjian, Lancet Oncology 2012). Methods: We analyzed the outcomes of patients with R/R ALL treated with single-agent IO (n=90) vs. historical controls (n=292) treated with combination CT at our institution from 1990-2008. IO was dosed at 1.8 mg/m2 every 3-4 weeks (first 41 pts), and later weekly dosing (0.8 mg/m2 day 1, 0.5 mg/m2 on days 8 and 15, every 3-4 weeks). Fifty-percent of historical controls were treated with hyper-CVAD CT (n=147). Results: The median age in the IO cohort was 39.5 years (yrs) (range 4-84) and in the CT cohort was 37 yrs (range 14-81). Overall CR/CRp rate was 49% with IO vs. 29% with CT. In salvage 1, CR/CRp rate was significantly better with IO [66% vs. 40% with CT (p=0.007)]. When only hyper-CVAD-based regimens were included, the CR/CRp was not statistically different (66% with IO vs. 56% with hyper-CVAD, p=0.332). In salvage 1, the median overall survival (OS) was 9.2 months (mos) with IO vs. 6.2 mos with CT (p=0.06 compared with IO) vs. 7.9 mos with hyper-CVAD (p=0.48 compared with IO). In salvage 2, CR/CRp rate was better with IO vs. CT (44% vs. 16%, p=&lt;0.001); OS was not different (4.3 mos vs. 2.5 mos, p=0.74). In salvage 3, CR/CRp rate was better with IO vs. CT (46% vs. 19%, p=0.03); OS was also better with IO vs. CT (6.6 mos vs. 2.6 mos, p=0.01). In salvage 4, CR/CRp rate was better with IO vs. CT (27% vs. 9%, p=0.01); OS was not statistically different (7.4 mos vs. 1.9 mos, p=0.09). Conclusions: In pts with R/R ALL, outcomes after single-agent IO are better than pts treated with CT alone. In addition, IO has fewer side effects than CT. IO has the potential to replace multi-agent CT as standard of care for treatment of pts with R/R ALL.

Weekly Inotuzumab Ozogamicin in Adult Patients with Relapsed or Refractory CD22-Positive Acute Lymphoblastic Leukemia.

AbstractAbstract 2612▪▪This icon denotes a clinically relevant abstract Background:Inotuzumab ozogamicin (INO) is a humanized anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic antitumor agent. CD22 is expressed on a majority of B-cell acute lymphoblastic leukemia (ALL). An initial study suggested INO efficacy and tolerability in ALL (Lancet Oncol 2012;13:403-11). Objectives:The current phase 1, multicenter, dose-escalation study was performed to optimize the INO dose and schedule (weekly dosing) based on safety, efficacy, and pharmacokinetic data in CD22+ relapsed or refractory ALL. The safety and efficacy of INO at the recommended dose and schedule will subsequently be further evaluated in a 12-patient (pt) expanded cohort. Methods:Eligible pts were aged ≥18 y with CD22+ ALL (defined as ≥20% blasts CD22+ by flow cytometry) refractory to initial induction or in relapse (≥first relapse), with no evidence of central nervous system disease. INO was administered in 28-d cycles (see Table), with a maximum of 6 cycles. The final dose was to be determined based on both toxicity (ie, rate of dose-limiting toxicities [DLT] at each dose level) and evidence of efficacy using the EffTox V2.10 software (Biometrics 2004;60:684–693). Adverse event (AE) severity was assessed per CTCAE V3 with DLTs defined as any of the following INO-related events during Cycle 1: grade ≥4 non-hematologic toxicity; prolonged myelosuppression (absolute neutrophil count [ANC] <500/μL or platelets <25,000/μL in bone marrow) with no evidence of leukemia persisting >45 d from last dose; grade 3 non-hematologic toxicity persisting >7 d from the last dose; grade ≥3 elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), or bilirubin persisting >7 d; or any toxicity resulting in permanent INO discontinuation. Weekly teleconferences with investigators were used to assess toxicity. Complete response (CR) was defined as <5% bone marrow blasts with absence of peripheral blasts, ANC ≥1,000/μL, platelets >100,000/μL, and no extramedullary disease; incomplete CR (CRi) was similar but permitted ANC <1,000/μL and/or platelets ≤100,000/μL. Results:We report preliminary data for 13 pts (see Table), with a median duration of follow-up of 147 d (range, 30–188 d). Median age was 56 y (range, 23–65 y), and 69% of pts were male. Five (39%) pts were in salvage 1, 2 (15%) were in salvage 2, and 4 (31%) were in salvage ≥3. Two pts had prior allogeneic stem cell transplant. Three (23%) pts were Ph+ and 7 (54%) pts had circulating blasts at baseline; median baseline WBC was 2.01×103/mm3 (range, 0.5–29.11×103/mm3).The single DLT observed to date was transient grade 4 elevated lipase occurring at INO dose level 3. The most frequent (≥10% of pts) treatment-related AEs were thrombocytopenia (31%, all grade 3/4), neutropenia (15%), and elevated ALT (15%). Treatment-related elevated AST and alkaline phosphatase were each reported for 8% of pts. Reported dose delays were due to thrombocytopenia (n = 3), neutropenia (n = 2), elevated LFT (n = 2), bacteremia, increased blood creatinine, periorbital cellulitis, and QTc prolongation (n = 1 each). Fourteen serious AEs were reported for 9 pts, including 2 cases each of febrile neutropenia and septic shock.Responses were observed across all INO doses explored to date (see Table). The preliminary response rate was 82% (9/11 evaluable pts), including 36% of pts with a CR and 45% with a CRi. Median time to response was 43 d (range, 28–56 d). Six of 9 (67%) pts who achieved CR/CRi also achieved minimal residual disease (<1 blast out of 104 mononuclear cells by flow cytometry).Seven pts discontinued treatment, including 1 each due to disease progression and an AE (acute renal failure, not treatment related), and 5 pts who proceeded to transplant. Four deaths were reported, including 1 due to disease progression and 3 due to sepsis occurring within 30 d after stem cell transplantation. Conclusions:INO had a safety profile consistent with prior reports, characterized by hematologic, gastrointestinal, and hepatic events and infection. The remarkable response rate of 82% for single-agent INO in this relapsed/refractory population warrants further exploration in CD22+ ALL. Updated results will be presented at the meeting.INO dose levelnDay 1 (mg/m2)Day 8 (mg/m2)Day 15 (mg/m2)Day 28Total dose (mg/m2)/cycleDLTsCR/CRi rate, n (%)130.800.4Bone marrow and disease assessments1.202/3 (67)260.80.40.41.605/6 (83)340.80.50.51.812/2 (100)401.00.50.52.0–– Disclosures:Stock:Tau for work done through the CALGB/ALLIANCE: Research Funding. Wang:Pfizer Inc: Employment, Equity Ownership. Volkert:Pfizer Inc: Employment, Equity Ownership. Vandendries:Pfizer Inc: Employment, Equity Ownership. Advani:Pfizer Inc: Consultancy, Honoraria, Research Funding.

Inotuzumab Ozogamicin (IO) Is An Effective Salvage Therapy That Allows for Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) in Remission in Patients with Advanced Acute Lymphoblastic Leukemia (ALL)

Abstract 3102No highly effective salvage therapy exists for patients with relapsed acute lymphoblastic leukemia (ALL). Inotuzumab ozogamicin (IO) is a CD22 monoclonal antibody attached to calicheamycin and targets B lymphocytes in early stages of development. A 56% overall response rate was noted in a Phase I study of single agent IO in patients with refractory ALL (Jabbour ASCO 2011), enabling subsequent transplant in remission in a relatively large number of patients. Of note, in the year prior to the availability of IO, we consulted on 13 patients will ALL beyond second remission and transplanted 5 (38%), and after the availability of IO, we consulted on 41 patients and transplanted 27 (67%). Methods: We describe our findings in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT) following treatment with IO between June 2010 and May 2011. IO was administered at 1.8 mg/m2 IV every 3 weeks. Results: 19 patients with median age 32 years (range 5–60) received an allogeneic matched sibling (n=6), matched unrelated donor (n=8), mismatched unrelated donor (n=4), or cord blood HSCT (n=1) in complete remission (CR) (n=2), CR without platelet recovery (n=14), and active disease (n=3); 10 patients were MRD negative at time of HSCT as determined by multiparameter flow cytometry. Patients had received 2 (n=3), 3 (n=9), 4 (n=4), 5 (n=2), or 6 (n=1) lines of salvage therapy prior to HSCT, including 3 patients who had received a prior allogeneic HSCT; IO was the last agent in 17 patients (2 patients refractory to IO received other therapy prior to HSCT). Patients received 1 (n=1), 2 (n=9), 3 (n=6), 4 (n=2), or 5 (n=1) courses of IO a median of 35 days (range 18–69) prior to transplant conditioning with busulfan (Bu) and colafarabine (Clo) (n=8), BuClo+ thiotepa (TT) (n=4), fludarabine (Flu) and melphalan (Mel) (n=1), FluMelTT (n=3), or etoposide and total body irradiation (TBI) (n=3); GVHD prophylaxis was tacrolimus-based for all patients, with post-HSCT cyclophosphamide added for patients receiving mismatched unrelated donors. With a median follow-up of 3 months among surviving patients (0.6–8.2), overall and progression-free survival is 59% at 3 months. There were 11 deaths, 6 from relapse, 4 from multi-organ failure involving VOD, and 1 from pneumonia. Transient liver enzyme elevations were noted in all of the patients, with 26% (n=5) patients developing VOD. The development of VOD was associated with greater lines of prior therapy prior to HSCT (3–5 lines prior salvage therapy, including 2 patients who had a prior allo-HSCT) and more intense transplant conditioning regimens (4 of the 5 patients received BuCloTT or FluMelTT). Conclusions: IO is an effective salvage therapy in patients with advanced ALL, allowing more patients to receive HSCT with encouraging response rates. Longer follow-up is needed to more completely assess disease control. Using reduced intensity HSCT conditioning regimens and avoiding multiple lines of prior therapies may result in less hepatic toxicity. Disclosures:O'Brien:Pfizer: Consultancy. Kantarjian:Pfizer: Research Funding.