Toxicity Of Gemtuzumab Ozogamicin Research Articles

An open-label, multicenter phase 1 study to characterize safety, tolerability, preliminary antitumor activity, pharmacokinetics, and pharmacodynamics of VIP943 monotherapy in patients with advanced CD123+ hematologic malignancies.

TPS3167 Background: VIP943 is an anti-CD123 antibody-drug conjugate (ADC) with a unique linker cleaved only by legumain and a novel kinesin spindle protein inhibitor payload. The linker-payload was engineered to increase the therapeutic index thereby improving efficacy and reducing severe toxicities compared with current ADCs. In an in vivo MOLM-13 model, VIP943 had statistically significant (p <0.001) improvement in tumor growth inhibition compared with the only ADC approved for the treatment of acute myeloid leukemia (AML), gemtuzumab ozogamicin (GO). In a nonhuman primate (NHP) single dose toxicology study, VIP943 (20 mg/kg) showed no signs of toxicity as measured by hematology, serum chemistry and survival. In contrast, NHP treated with a single dose of GO (3 mg/kg) had significant toxicity including death and mandatory euthanasia. The single-dose toxicity of GO was ameliorated by substituting the VIP943 proprietary linker and payload on an anti-CD33 antibody (3 mg/kg) as measured by hematology, serum chemistry and survival. (1,2). Methods: This trial in progress (NCT06034275) is an open-label, multicenter, Phase 1, first-in-human (FIH), dose-escalation and dose-optimization study of VIP943 in subjects with relapsed or refractory CD123+ hematologic malignancies including AML, myelodysplastic syndrome, and B-cell acute lymphoblastic leukemia. A cycle of VIP943 treatment is 28 days of once weekly intravenous infusions with no pause between cycles. The dose-escalation portion of this study follows a standard 3+3 design. Dose escalation decisions will be made by the safety review committee, and decisions will be based on the incidence of dose-limiting toxicities (DLTs). Based on FDA guidance, a dose-optimization portion of this study will randomize subjects into ≥2 dose cohorts to derive a recommended dose range for Phase 2. The study will also characterize the pharmacokinetics of VIP943 and its components and explore potential biologic activity by assessing pharmacodynamic/exploratory biomarkers, and antitumor activity using standard response criteria. As this is a FIH study, only subjects with CD123+ hematologic malignancies who have exhausted all available therapies or are not fit for standard of care can be enrolled. The results from this study will form the basis for decisions for future studies. Enrollment for cohorts 1 (no DLTs) and 2 (safety review ongoing) has completed. 1. Stelte-Ludwig et al ASH 2022. 2. Stelte-Ludwig et al ASH 2023. Clinical trial information: NCT06034275 .

Clinical Benefits and Safety of Gemtuzumab Ozogamicin in Treating Acute Myeloid Leukemia in Various Subgroups: An Updated Systematic Review, Meta-Analysis, and Network Meta-Analysis.

BackgroundPrevious trials demonstrated evidence involving the total effects of gemtuzumab ozogamicin (GO), an anti-CD33 humanized antibody, on treating acute myeloid leukemia (AML). In this updated systematic review, meta-analysis, and network meta-analysis (NMA), we aimed to comprehensively explore the clinical benefits and safety of GO in various subtypes of AML.MethodsPubMed, Embase, Cochrane, and Chinese databases were filtered to search randomized controlled trials (RCTs) and retrospective cohort studies that compared clinical efficiency and toxicity of GO with non-GO groups in AML. Random-effects models were used to calculate pooled effect sizes and 95% confidence intervals (CIs). Relative risk (RR) was used for estimating complete remission (CR), early death, and toxicity. Hazard risk (HR) was accomplished to evaluate survival.ResultsFifteen RCTs and 15 retrospective cohort studies were identified (GO: 4,768; Control: 6,466). GO tended to improve CR (RR 0.95, p = 0.084), followed by significantly improved survival (overall survival: HR 0.86, p = 0.003; event-free survival: HR 0.86, p = 0.015; relapse-free survival: HR 0.83, p = 0.001; cumulative incidence of relapse: HR 0.82, p < 0.001). GO benefits of CR and survival were evident in favorable- and intermediate-risk karyotypes (p ≤ 0.023). GO advantages were also associated with nucleophosmin 1 mutations (p ≤ 0.04), wild-type FMS-like tyrosine kinase 3 internal tandem duplication gene (p ≤ 0.03), age of <70 years (p < 0.05), de novo AML (p ≤ 0.017), and CD33(+) (p ≤ 0.021). Both adding GO into induction therapy (p ≤ 0.011) and a lower (<6 mg/m2) dose of GO (p ≤ 0.03) enhanced survival. Prognosis of combined regimens with GO was heterogeneous in both meta-analysis and NMA, with several binding strategies showing improved prognosis. Additionally, GO was related to increased risk of early death at a higher dose (≥6 mg/m2) (RR 2.01, p = 0.005), hepatic-related adverse effects (RR 1.29, p = 0.02), and a tendency of higher risk for hepatic veno-occlusive disease or sinusoidal obstruction syndrome (RR 1.56, p = 0.072).ConclusionsThese data indicated therapeutic benefits and safety of GO in AML, especially in some subtypes, for which further head-to-head RCTs are warranted.Systematic Review Registration[PROSPERO: https://www.crd.york.ac.uk/prospero/], identifier [CRD42020158540].

Clinical outcomes of gemtuzumab ozogamicin for relapsed acute myeloid leukemia: single-institution experience.

We retrospectively evaluated the clinical efficacy and toxicity of gemtuzumab ozogamicin (GO) in patients with relapsed acute myeloid leukemia (AML). Nineteen patients (median 70years) received GO (9mg/m2, days 1 and 15) as salvage therapy in our institution between 2006 and 2017. The primary endpoint was the response rate. The secondary endpoint was the occurrence of adverse events. Thirteen patients had de novo AML, and 6 patients had secondary AML. Most of the patients had received salvage treatments more than once prior to GO. Six patients responded to the treatment (31.6%) with 3 complete remissions (15.8%). Five patients had stable disease, and 8 patients did not show any response. GO was more efficacious among the patients with fewer numbers of prior salvage treatments. CD33 positivity of leukemic cells was higher in responders than in nonresponders. Peripheral WT1 mRNA levels mostly decreased over time in the responders. The adverse event most commonly seen was febrile neutropenia (84%). No patient presented with veno-occlusive disease. Three patients died by day 30 (mortality rate 15.8%), one due to acute respiratory distress syndrome and the other two due to sepsis. GO remains an effective salvage treatment.

Gemtuzumab Ozogamicin Combined With Intensive Chemotherapy in Patients With Acute Myeloid Leukemia Relapsing After Allogenic Stem Cell Transplantation

BackgroundMore than one-third of patients with acute myeloid leukemia (AML) will relapse after allogenic hematopoietic cell transplant (allo-HCT). The main challenge is to overcome disease resistance to achieve a new complete remission while avoiding excessive toxicity. Gemtuzumab ozogamicin (GO), a conjugate of calicheamicin linked to the humanized monoclonal anti-CD33 antibody, has been used for refractory or relapsed AML with promising response rates, but liver toxicity of GO has long been considered a limiting factor. Patients and MethodsWe included 18 consecutive patients with AML relapsing after a first allo-HCT and treated with fractioned GO (fGO) and intensive chemotherapy. The median age was 40 years (range, 18-65). ResultsThe overall response rate was 72% (13/18), including 7 complete remissions. No death was attributed to treatment toxicity. The main liver toxicity was transient and consisted of transaminase level elevation and hyperbilirubinemia. No cases of veno-occlusive disease were observed after the GO treatment. From the time of salvage treatment initiation, 1- and 2-year OS rates were 54% (95% confidence interval, 28%-74%) and 42% (95% confidence interval, 19%-63%), respectively. ConclusionsOur study suggests the feasibility, efficacy, and safety of an fGO-based salvage regimen combined with intensive chemotherapy in patients with CD33+ AML in the case of early relapse after an allo-HCT.

Dose-related efficacy and toxicity of gemtuzumab ozogamicin in pediatric acute myeloid leukemia

ABSTRACTGemtuzumab ozogamicin, an anti-tumour antibiotic linked to an anti-CD33 antibody (Mylotarg®), has been well studied in AML in adults but to a lesser extent in children. No review has yet been published on the dose-related toxicity and efficacy of gemtuzumab ozogamicin in pediatric AML patients. Here we looked at 14 studies then scatterplots and linear regressions were used to estimate the relationship between the dose of gemtuzumab and its toxicity and efficacy. A non-significant increase in bilirubin level and in incidence of veno-occlusive disease was seen with higher doses of gemtuzumab ozogamicin when used as single-agent. In terms of efficacy, even a low dose of 3 mg/m2 of gemtuzumab ozogamicin can have antileukemic effect, but available data do not allow conclusions on its dose-dependency. Data indicate that higher doses of gemtuzumab ozogamicin account for more adverse events. The data do not show that a high dose is required for anti-leukemic efficacy of gemtuzumab ozogamicin. This study also indicates that there seems to be a role for gemtuzumab ozogamicin in the treatment of pediatric AML and further studies are required to assess its optimal dose, schedule and balance between efficacy and side-effects.

Efficacy and toxicity of gemtuzumab ozogamicin in patients with acute myeloid leukemia

Gemtuzumab ozogamicin (GO) is a recently developed antibody-targeted chemotherapeutic agent and has been expected to be less toxic than conventional chemotherapy. We retrospectively evaluated the use of GO in 38 patients. Patients with acute myeloid leukemia (AML) at diagnosis and relapsed AML were treated with 6 and 9 mg/m(2) GO. Efficacy and toxicity of GO were analyzed, as well as several prognostic factors. A complete response (CR) was observed in 12 of 38 patients, including five patients with CR plus incomplete regeneration of platelets. In one patient a partial remission was observed. Twenty-five patients showed no change or progressive disease. The overall response (OR) in patients with AML at diagnosis was 47%, with the best response in patients with primary AML (OR 60%, compared with 21% OR in non-primary AML, P = 0.045). The OR in patients with relapsed AML was 22%. Median white blood cell (WBC) before treatment, CD33 expression on leukemic blasts, and kinetics of response were analyzed as prognostic factors. Median WBC was significantly lower in patients who responded to GO, compared with non-responders (2.1 x 10(9)/L vs. 6.8 x 10(9)/L, P = 0.036). CD33 expression and kinetics of response was not correlated to clinical outcome. Median days to reach 500 x 10(6)/L neutrophils and 100 x 10(9)/L platelets were 36 and 39 d, respectively. Infections and bleedings occurred in 45% and 12%, respectively. This report shows that GO has potent clinical activity and that the OR rate was by far the best in untreated primary AML patients.

Up-Front Window Trial of Gemtuzumab Ozogamicin (GO) in Previously Untreated Elderly Patients with AML: An EORTC Leukemia Group Study.

Gemtuzumab ozogamicin, a conjugate of a humanized anti-CD33 monoclonal antibody linked to the cytotoxic antibiotic calicheamicin, has shown significant antileukemic activity in relapsed AML with a favorable toxicity profile. The EORTC-LG performed a phase II study to investigate the activity and toxicity of GO used alone and in combination with conventional chemotherapy for remission induction in medically fit elderly pts (age between 61 and 75 years; WHO PS 0-1) with untreated AML. GO was administered iv over 2 hrs at the FDA-approved dose of 9 mg/m2. A second dose was given on day 15 in the absence of progressive disease or excessive toxicity and response was assessed four weeks later. This was to be followed by a course of conventional chemotherapy with mitoxantrone, cytarabine and etoposide (MICE regimen) and no further treatment in complete responders. Between 09/00 and 10/01 64 pts were enrolled , 57 of whom were evaluable for response and toxicity. The median age was 68 yrs (range 61–73); 43 pts had primary AML; CD33 positivity (≥20% marrow blasts) was documented in 44 pts (85%). GO therapy was completed by 47 of the 57 pts (82%): primary reasons 10 pts did not receive the scheduled second dose were disease progression (4), early death (2), toxicity (2) and protocol violation (2). The rate of initial response to GO was 35.1% (95% CI, 22.9%–48.9%) with 13 pts achieving complete remission (CR) and 7 CRp (complete remission with incomplete platelet recovery); 6 additional pts entered partial remission (PR). There were 3 (5.3%) toxic deaths (1 ARDS, 1 VOD, 1 infection) and 28 pts had resistant disease. Severe myelosuppression was the primary toxicity to GO. Grade 3 or 4 non-hematologic toxicities in more than 5% of pts during GO therapy included febrile neutropenia (39%), infection (28%), elevations of bilirubin, SGPT and creatinine of 8%, 6% and 6%, respectively. A clinical picture compatible with hepatic VOD developed in 3 pts (5%) resulting in 2 deaths (1 early, 1 in CRp). No baseline characteristics predicted for response to GO, but pts expressing CD33 in >80% marrow blasts tended to respond more favourably to the immunoconjugate (CR+CRp 7/14, 50%). Altogether, 51 pts survived GO therapy and 38 of them (75%) went on to receive a course of MICE after a median interval of 49 days (range 12–77) from the first dose of GO. Excessive toxicity (11 pts), protocol violation (1 pt) and treatment refusal (1 pt) were the main reasons for not starting chemotherapy. The ultimate best response rate was 54.4% (31/57; CR 35.1% and CRp 19.3%) increasing up to 65.8% among the 38 pts who were able to complete the whole induction sequence. Five pts died of toxicity during the MICE segment (2 VOD, 1 infection, 1 heart failure, 1 multi-organ failure) for an overall treatment related mortality of 14.1% (8/57). With a median follow-up of 3 yrs, 2-year overall survival (OS) and disease-free survival (DFS) estimates were 11.0% (SE=4.1%) and 12.1% (SE=3.5%), respectively. We conclude that: 1) single agent, standard dose GO has significant activity in untreated AML of the elderly with an acceptable safety profile; 2) sequential combination with standard chemotherapy is feasible and may improve treatment outcome in this poor risk disease, but myelotoxicity and liver dysfunction are of concern. An ongoing randomized trial will determine the contribution of GO given at reduced dose (6 mg/m2) to the observed antileukemic effect and toxicity.

Phase I/II Study of Gemtuzumab Ozogamicin (GO), Fludarabine and Melphalan (FM) Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) in AML/MDS.

Outcomes of patients with active AML/MDS remain poor after HSCT. Treatment failure is in part a result of poor disease control with the preparative regimen. Here we report toxicity and efficacy of the immunoconjugate GO incorporated to a reduced intensity regimen.Methods: Objective: determine which dose of GO between doses 2 and 4mg/m2 has the lowest toxicity(tox) probability with the highest response probability when added to FM (statistical method of Thall, Estey, Sung (1999)). Tox was defined as grade 3–4 organ tox, engraftment failure or early death (first 30 days post HSCT). Response was defined as engraftment, no tox and remission (CR) on day +30. Trial was planned with dose levels 4, 6 and 9 mg/m2 but given tox observed at 4mg/m2, the other dose levels were not explored and dose 2mg/m2 was added. Eligibility: patients (pts) age 12–75 years, ineligible for high-dose regimens or with high-risk CD33+ AML/MDS. Donors: related or unrelated (MUD). Treatment plan: GO 2 or 4mg/m2 day -12, fludarabine 30mg/m2 (days -5 to -2), melphalan 140mg/m2 (day -2); HSCT day zero. ATG was added in MUD HSCT. Graft-versus-host disease (GVHD) prophylaxis: tacrolimus and mini-methotrexate (5mg/m2 day+1,+3,+6,+11). GO was given on day -12 to avoid delay in engraftment and to decrease the number of committed myeloid progenitors prior to FM. Here we also included pts. treated under a compassionate IND and performed a non-randomized comparison with historic pts. treated with FM140 mg/m2 without GO.Results: 29 pts. have been treated. Table shows baseline characteristics.GO dose0 (n=49)2 mg/m2 (n=21)4 mg/m2 (n=8)P valueRemission at BMT26%9%12%0.25MUD41%28%25%0.52Median age (years-range)54 (21–75)53 (13–72)30 (23–67)0.08Peripheral blood stem cell transplant47%86%100%0.0005High-risk cytogenetics43%33%37%0.83Median follow-up is 10 months (range 2.5–36) for GOFM alive patients (n=18). CR rate: GO 2mg/m2 =90%; GO 4 mg/m2= 71%; control=71%. There was only 1 case of moderate, reversible hepatic VOD (GO 2mg/m2). Grade III-IV tox and early death rates were: GO 2 mg/m2, 19% and 5% (n=1 due to pulmonary hemorrhage); GO 4mg/m2, 25% and 25% (n=2, due to pneumonia and multi-organ failure); control, 21% and 12% (n=6). Acute gd. II-IV GVHD rate was 44% for GO treated patients. All evaluable patients had engrafted by day +30; 8 pts have relapsed.Comparison with historic controls: active disease and high-risk cytogenetics were significantly associated with worse event-free (EFS) and overall survival (unadjusted log-rank test). Cox proportional hazards model: risk of death or relapse was increased with older age (RR 1.02; P=0.06), MUD vs related donor (RR 1.91; P=0.03), active disease vs CR (RR 0.23; P=0.001), and having GO 4 mg/m2 or zero vs 2 mg/m2 (RR 0.46, P=0.04).Figure shows survival. [Display omitted] Conclusions: The addition of GO at the 2 mg/m2 dose level is promising and merits evaluation in a larger, controlled trial.

Gemtuzumab ozogamicin (Mylotarg) monotherapy for relapsed AML after hematopoietic stem cell transplant: efficacy and incidence of hepatic veno-occlusive disease.

Gemtuzumab ozogamicin (GO) (Mylotarg, CMA-676) is a novel chemotherapeutic agent consisting of an anti-CD33 monoclonal antibody linked to calicheamicin, and is associated with a 30% response rate in patients with CD33-positive acute myeloid leukemia (AML) in first relapse. GO therapy has a 20% incidence of grade 3 or 4 hepatotoxicity, and has recently been associated with hepatic veno-occlusive disease (VOD). The efficacy and toxicity of GO in patients with AML who have relapsed after hematopoietic stem cell transplant (HSCT) is unknown, as this population was largely excluded from phase II studies. We reviewed the outcomes of eight consecutive patients with AML who received GO following relapse after HSCT. Two (25%) had responses to GO. One patient, who had had two previous HSCT and prior hyperbilirubinemia, developed severe VOD and died 14 days after GO therapy. The other seven patients did not meet diagnostic criteria for VOD. We conclude that GO can be safe and effective in patients who relapse following HSCT, but that caution is warranted in patients with multiple risk factors for VOD.