Single Dose 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 .

Addition of single dose gemtuzumab ozogamicin to intensive induction chemotherapy in core-binding factor acute myeloid leukemia

In a meta-analysis of 5 trials, the addition of gemtuzumab ozogamicin (GO) to intensive induction chemotherapy led to a survival benefit in patients with core-binding factor (CBF) acute myeloid leukemia (AML). Given the heterogeneous incorporation of GO in clinical trials, the ideal dose and schedule remains unclear. We conducted a single-center retrospective analysis to compare outcomes of patients with CBF-AML treated with intensive induction chemotherapy, with or without a single dose of GO 3 mg/m2, during induction only. We included 87 patients (GO=32, control=55). The composite complete remission (cCR) rate was higher in the control group (93%) compared to the GO group (82%) (p<0.001). The rate of measurable residual disease (MRD) negative cCR, by flow cytometry, was similar between both groups. There were no significant differences between the two groups in terms of toxicity. The 3-year relapse-free survival (RFS) for both groups was similar (71% vs 68%, p=0.5). The 3-year overall survival (OS) for the GO group was 68%, compared to 66% for the control group (p=0.9).In multivariable analysis, age and MRD positive status were risk factors for inferior outcomes. We find that survival of patients with CBF-AML is favorable in the real-world setting. The addition of single-dose GO, during induction, did not lead to a higher remission rate or survival benefit, when compared to intensive chemotherapy without GO. Further investigation into the incorporation of GO in the treatment algorithm for CBF-AML is needed.

Addition of Single Dose Gemtuzumab Ozogamicin to Intensive Induction Chemotherapy in Core-Binding Factor Acute Myeloid Leukemia

Background: In a meta-analysis of 5 trials, the addition of gemtuzumab ozogamicin (GO) to intensive induction chemotherapy led to a survival benefit in patients with core-binding factor (CBF) acute myeloid leukemia (AML). The survival benefit was observed with a lower dose or fractionated schedule of GO. Given the heterogenous incorporation of GO in clinical trials, the ideal dose and schedule remains unclear. We report our outcomes of adding a single-dose of GO to intensive induction chemotherapy for patients with CBF-AML. Methods: We conducted a retrospective analysis to compare outcomes of patients with CBF-AML treated with intensive induction chemotherapy, with and without GO, at the University of Alabama at Birmingham (UAB) between January 2010 and April 2023. Single-dose GO was given at 3mg/m 2 during induction only. Results: There were 87 patients included in the analysis (GO=32, control=55). The baseline characteristics are shown in Table 1. The median age of the GO and control groups was 50y (19-68y) and 47y (21-74y), respectively. There was an overrepresentation of white patients in the control group. In the GO group, more patients had t(8;21) (53% vs. 31%, p=0.02), KIT (28% vs. 12%, p&amp;lt;0.01), FLT3-ITD (16% vs. 7%, p=0.03) and NRAS/KRAS mutations (40% vs. 20%, p&amp;lt;0.01) compared to the control group. Induction chemotherapy consisted of 7+3 in 88% of patients receiving GO and all patients in the control group. Patients &amp;lt;65y received idarubicin 12mg/m 2 while older patients received daunorubicin 45mg/m 2. The composite complete remission (cCR) rate was higher in the control group (93%) compared to the GO group (82%) (p&amp;lt;0.001). The rate of measurable residual disease (MRD) negative cCR, by flow cytometry, was similar between both groups (GO=62%, control=69%, p=0.5). There were no significant differences between the two groups in terms of time to neutrophil and platelet recovery, veno-occlusive disease, febrile neutropenia and length of hospital stay. GO was not administered during consolidation chemotherapy. The 3-year relapse-free survival (RFS) for both groups was similar (71% vs 68%, p=0.5). The 3-year overall survival (OS) for the GO group was 68%, compared to 66% for the control group (p=0.9) (Figure 1). Conclusion: In our report, we find that survival of patients with CBF-AML is favorable in the real-world setting. These outcomes are comparable to those reported in the meta-analysis leading to the approval of GO. The addition of single-dose GO did not lead to a higher remission rate or survival benefit, when compared to intensive chemotherapy without GO. However, the analysis is limited by differences in baseline characteristics between the two groups with more patients in the GO group harboring high-risk features such as the presence of t(8;21), KIT, FLT3-ITD and KRAS/NRAS mutations. Further investigation into the incorporation of GO in the treatment algorithm for CBF-AML is needed.

Trial-in-Progress: A Phase 2 Study of Mitoxantrone, Etoposide and Gemtuzumab Ozogamicin (MEGO) for Acute Myeloid Leukemia That Persisted after the 1st Induction Regimen

Background Acute myeloid leukemia (AML) is a disease characterized by a clonal proliferation of myeloid precursors with reduced capacity to differentiate into more mature cellular elements. The standard treatment for newly diagnosed AML has not changed appreciably over the last few decades and consists primarily of an anthracycline combined with a nucleoside analogue. Complete remission (CR) rates of 65-80% can be expected in younger patients but decrease with older age. There is no agreed standard of care for AML patients that do not respond to initial first line induction therapy. Although remission after second-line therapy may occur, the CR rate is lower. A few chemotherapy regimens have been used in patients with resistant disease with overall CR rates of 20-40%. Gemtuzumab ozogamicin (GO) is an antibody drug conjugate consisting of a recombinant humanized antibody to CD33 which is linked to calicheamicin. Although GO is currently approved for induction therapy in combination with "7+3", its benefit is mostly evident in favorable risk disease (Hills et al Lancet Onc 2014) and thus its use is mostly limited in this setting. Pre-clinical data suggest that GO is most effective when it saturates CD33 which happens in low-burden disease (Van der Velden et al Leukemia 2004). Thus, we decided to proceed with a trial that incorporates gemtuzumab ozogamicin on the 2nd induction regimen for patients that did not achieve complete remission with the first. Methods This is a phase II, singe-center clinical trial of GO in combination with mitoxantrone and etoposide in patients with AML that persisted after their 1st induction regimen. The patients are eligible if they have at least 10% of blasts in their day 14 bone marrow biopsy and CD33 expression in at least 30% of leukemic blasts in the bone marrow. Patients with repeat bone marrows after day 14 showing progression of AML (>5% blasts) were also eligible. Patients also need to have ECOG performance status 0-2, left ventricular ejection fraction (LVEF) >50%, GFR > 30 ml/min, AST/ALT < 2.5 x upper normal limits and total bilirubin <2 x upper normal limit. Patients that received CPX-531 for induction are excluded due to concerns for prolonged thrombocytopenia. The standard of care for our center for this patient population is 10mg/m2 of mitoxantrone on days 1-5 and 100mg/m2 of etoposide on days 1-5. Trial patients receive the same regimen and a single dose of GO 3mg/m2 (capped at 4.5mg) on day 6. The primary endpoint of the trial is complete remission rate (CR). The hypothesis is that addition of GO to mitoxantrone, and etoposide will increase our historical CR rate of 35% to 50%. The trial has a Simon's two-stage design, with an interim analysis planned after 16 evaluable patients have been enrolled. The trial plans to accrue 44 evaluable patients. This design has an alpha of 0.15 and 80% power. Secondary objectives include progression-free survival, overall survival, and treatment-related mortality. To-date we have enrolled 15 patients, 13 of them evaluable. 2 patients died from sepsis before the administration of GO. We have not recorded any episodes of VOD so far. Recruitment is continuing and this trial is registered on clinicaltrials.gov; NCT03839446.

United Arab Emirates Population-Based Acute Leukaemia Registry: Acute Myeloid Leukemia Real-World Data

Population-based registries may provide data useful for clinical decisions in patients' populations not well presented by clinical studies, which is essential to establish recommendations for the management of patients in the real world. The aim of the first Sheikh Shakhbout Medical City (SSMC) ongoing acute leukaemia registry is to obtain information about the demography, clinical presentation, genetic markers, risk stratification and disease response of patients with diverse ethnicities and backgrounds .The registry includes newly diagnosed adults with acute leukaemia, admitted to SSMC from June 2021 onward. SSMC acute leukaemia registry is an observational retrospective and prospective study. Electrical medical records were used to collect data, and coding was used for each variable based on the 2017 European leukaemia network (ELN) and the 2016 European society for medical oncology (ESMO) clinical practice guidelines. A total of 41 patients were registered between June 2021 and May 2022, 18 patients with acute myeloid leukaemia (AML), 3 acute promyelocytic leukaemia (APL) , and 1 blastic plasmacytoid dendritic cell neoplasm (BPDCN). Seventy three percent (n=16) of patients are males, and 27% (n=6) are females. Eighteen percent of patients (n=4) are older than 65 years of age, 2 of them with antecedent myelodysplastic syndrome. About 54% of patients are Arab, 32% are South Asian, and 14% are Southeast Asian (Table 1). Forty percent of patients with normal karyotype which is close to previously reported percentage in Grimwade D et al, MRC AML 10 Trial. Blood 1998. Though our patients median age is 47 years at time of diagnosis, according to the 2017 ELN molecular stratification, about 32% of our patient group have adverse prognosis, which is higher compared to other clinical trials including the ones with older patients population (Grimwade D et al, MRC AML11 trial. Blood 2001). Four patients are FLT3-ITD positive, accounts for 22% which is similar to the reported percentage in Papaemmanuil E et al, Genomic Classification and Prognosis in AML. N Engl J Med. 2016. Two patients are IDH1 positive, 1 patient is IDH2 positive, accounts for 5% compared to the reported 1% in Dohner H et al, Diagnosis and management of AML in adults. Blood. 2017 Jan. Seven patients have other abnormal Next generation sequencing (NGS) results, 2 patients have negative NGS and 6 patients have unknown cytogenetic risk group. Induction chemotherapy includes standard-dose cytarabine 100-200 mg/m2 continuous infusion x 7 days with idarubicin 12 mg/m2 x 3 days in 33% of patients with AML, single dose of gemtuzumab ozogamicin 3 mg/m2 in addition to standard-dose cytarabine 200 mg/m2 continuous infusion x 7 days with daunorubicin 60 mg/m2 x 3 days in 17% of patients, hypomethylating agents with or without venetoclax in 22% of patients, and 28% of patients were not treated for various reasons including death and refusal of treatment. The 3 patients with APL are low-risk (WBC count ≤10,000/mcL) as per Sanz MA et al, Management of APL. Blood. 2019 . All treated with all-trans retinoic acid (ATRA) 45 mg/m2 in two divided doses daily and arsenic trioxide (ATO) 0.15 mg/kg IV daily. The patient with BPDCN was treated with hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with high-dose methotrexate and cytarabine. About 43% of patients achieved complete response (CR) or CR with incomplete hematologic recovery (CRi) post-induction as per the 2017 ELN guidelines. SSMC is one of the leukaemia centres in Abu Dhabi, United Arab Emirates (UAE), where petroleum and natural gas are the main industry. UAE population consists of mixed ethnicities with different socioeconomic backgrounds where consanguinity is common and air pollution exposure at home countries is a big possibility. Despite the fact that our patient population is small, and statistically significant analysis might not be possible at this stage, we believe that our patient population demographics and genetic markers are not well-reflected in the standard guidelines. With longer observation and time the SSMC acute leukaemia registry promises to provide interesting data that may shed important input for better treatment algorithms. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

No Advantages of Fractionated Versus Single Dose(s) of Gemtuzumab Ozogamicin (GO) As Part of the Midam Salvage Regimen in Relapsed/Refractory Acute Myeloid Leukemia (AML) Patients

Background: Gemtuzumab Ozogamicin (GO) is a humanized anti-CD33 monoclonal antibody linked to calicheamicin. It was developed to treat relapsed CD33+ AML patients, first at the dose of 9 mg/m² administered twice at day +1 and +14, than combined with chemotherapy but with reduced dose to lower toxicity. In 2008, we reported a 63% (50% of complete remission (CR) + 13% of CR with incomplete platelets recovery (CRp), platelets Materials and Method: This was a single center retrospective study including all CD33+ relapsed/refractory AML patients who received the MIDAM regimen, from 2008 to March 2015. Between 2008 and July 2012, all patients received GO as a single dose at 9 mg/m² day +4 (s-MIDAM group) and after until March 2015 it was decided to fractionate the GO dose according to Castaigne9schedule at 3 mg/m²/day day +1 +4 and +7 (fra-MIDAM group). All patients were treated as part of a compassionate use program as GO is not available in France for routine use. The main objective was to compare the incidence of SOS and related-deaths between both groups (s-MIDAM vs fra-MIDAM). Secondary objectives were to compare ORR (CR+CRp), median time of neutrophils and platelets (>20 Giga/L, >50 Giga/L, >100 Giga/L) recovery and overall survival (OS). Results: 33 patients were included in the study, 15 in the fra-MIDAM group and 18 in the s-MIDAM group. Characteristics of patients were similar between the former and the latter in terms of age (median: 55 vs 52 years, p=NS), gender (male: 60% vs 66%, p=NS), cytogenetics risk (favorable 33% vs 28%, intermediate 60% vs 39%, high: 7% vs 33%, p=NS) or median CD33+ expression (99% vs 99.5%, p=NS).There were more refractory patients in the s-MIDAM group (39% vs 7%, p=0.04) but more patients for whom adapted lower dose of Ara-C (4 g/m² instead of 10 g/m² total dose, for one patient) or mitoxantrone (3 patients did not received any, and 1 received 2 days instead of 3 days) were prescribed in the fra-MIDAM group (27% vs 0%, p=0.04). Also, 20% and 28% of patients received a reduced dose of GO (6 mg/m², administered in 2 fractionated dose (3 mg/m² twice) or a single dose) in the fra-MIDAM and the s-MIDAM groups, respectively (p=NS). ORR was similar between both groups (fra-MIDAM: 53% vs s-MIDAM: 61%, p=NS) as well as the CR rate (33% vs 39%, p=NS) or the CRp rate (20% vs 22%, p=NS). Median time to neutrophils and platelets (>20 Giga/L, >50 Giga/L and >100 Giga/L) recovery were also similar (fra-MIDAM: 29 days vs s-MIDAM: 26 days, p=0.25; 24 vs 26 days, p=NS; 27 vs 34 days, p=0.13 and 38 vs 36.5 days, p=NS). Among patients in response, 40% vs 67% were allotransplanted after the fra-MIDAM and the s-MIDAM regimens, respectively, (p=NS). With a median follow-up of 139 days and 782 days for the fra-MIDAM and the s-MIDAM groups, respectively, median OS was 7.2 months for the former and 10.2 months for the latter (p=NS). Sixty percent of patients died in the fra-MIDAM group vs 72% in the s-MIDAM group (p=NS), with no significant differences in terms of causes of death. Regarding our primary objective, 2 and 3 cases developed SOS after the fra-MIDAM and the s-MIDAM regimen, respectively, and these 5 patients died of SOS. Conclusion: Use of fractionated GO doses compared to single GO dose as part of the MIDAM salvage regimen for relapsed/refractory AML patients showed no advantages in terms of outcomes or lower toxicity, especially regarding incidence of SOS or death due to SOS. Both schedules are equivalent and can be used. Disclosures Mohty:Janssen: Honoraria; Celgene: Honoraria. Moreau:Novartis: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity9s Board of Directors or advisory committees.

Reprise: Gemtuzumab Ozogamicin for Older Patients With Acute Myeloid Leukemia

Reprise: Gemtuzumab Ozogamicin for Older Patients With Acute Myeloid Leukemia

Autologous transplantation gives encouraging results for young adults with favorable-risk acute myeloid leukemia, but is not improved with gemtuzumab ozogamicin

AbstractWe report the results of a prospective, randomized phase 3 trial evaluating the use of gemtuzumab ozogamicin (GO) in an intensive consolidation approach in 657 patients 17-60 years of age. Patients in first complete remission (CR1) after cytarabine and standard- or high-dose daunorubicin induction received 2 cycles of consolidation with high-dose cytarabine followed by peripheral blood progenitor cell collection. The 352 patients who entered consolidation were randomized to receive GO (n = 132) or not (n = 138) and then proceeded to autologous hematopoietic cell transplantation (HCT). GO was given to 67 patients. Median follow-up was 50.9 months. Results of the intention-to-treat analysis demonstrated a 4-year disease-free survival (DFS) of 33.6% versus 35.9% (P = .54) and an overall survival (OS) of 41.3% versus 41.9% (P = .52) for those randomized to receive GO versus no GO, respectively. Patients with favorable- and intermediate-risk acute myeloid leukemia (AML) treated with high-dose daunorubicin and autologous HCT had 4-year DFS rates of 60% and 40% and OS rates of 80% and 49.3%, respectively. For younger AML patients in CR1, autologous HCT should be considered in favorable- and intermediate-cytogenetic risk patients who do not have an allogeneic donor. The addition of a single dose of GO in this setting did not improve outcomes. This trial is registered at http://www.clinicaltrials.gov as NCT00049517.

Identification of Patients With Acute Myeloblastic Leukemia Who Benefit From the Addition of Gemtuzumab Ozogamicin: Results of the MRC AML15 Trial

Antibody-directed chemotherapy for acute myeloid leukemia (AML) may permit more treatment to be administered without escalating toxicity. Gemtuzumab ozogamicin (GO) is an immunoconjugate between CD33 and calicheamicin that is internalized when binding to the epitope. We previously established that it is feasible to combine GO with conventional chemotherapy. We now report a large randomized trial testing the addition of GO to induction and/or consolidation chemotherapy in untreated younger patients. In this open-label trial, 1,113 patients, predominantly younger than age 60 years, were randomly assigned to receive a single dose of GO (3 mg/m(2)) on day 1 of induction course 1 with one of the following three induction schedules: daunorubicin and cytarabine; cytarabine, daunorubicin, and etoposide; or fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin. In remission, 948 patients were randomly assigned to GO in course 3 in combination with amsacrine, cytarabine, and etoposide or high-dose cytarabine. The primary end points were response rate and survival. The addition of GO was well tolerated with no significant increase in toxicity. There was no overall difference in response or survival in either induction of consolidation. However, a predefined analysis by cytogenetics showed highly significant interaction with induction GO (P = .001), with significant survival benefit for patients with favorable cytogenetics, no benefit for patients with poor-risk disease, and a trend for benefit in intermediate-risk patients. An internally validated prognostic index identified approximately 70% of patients with a predicted benefit of 10% in 5-year survival. A substantial proportion of younger patients with AML have improved survival with the addition of GO to induction chemotherapy with little additional toxicity.

High dose equals improved response

The current induction therapy for patients with acute myeloid leukemia (AML) is anthracycline plus cytarabine. Complete remission is achieved in 50–75% of patients and the addition of other drugs or dose intensification has not improved survival. Whether dose intensification for induction therapy in patients (<60 years of age) with AML might improve survival has not been addressed. In a randomized phase III trial by the Eastern Cooperative Group (ECOG), Fernandez and colleagues compared standard-dose and high-dose daunorubicin in young adults with AML. The researchers randomly assigned 582 patients with AML, who had not been treated, to receive three once-daily doses of daunorubicin at the standard dose (45 mg/m2) or a higher dose (90 mg/m2), combined with cytarabine. Allogeneic hematopoeitic stem-cell transplantation, with or without a single dose of gemtuzumab ozogamicin, was offered to patients who experienced complete remission. Overall survival was the primary end point of the study and the median follow-up time was 25.2 months. Patients treated with high-dose daunorubicin had a significantly higher rate of complete remission (70.6% versus 57.3%) and improved median overall survival (23.7 months versus 15.7 months) compared with patients who received standard-dose daunorubicin. Moreover, serious adverse events were similar in both groups, indicating that administration of high-dose daunorubicin has a similar safety profile as the standard-dose. The researchers conclude that intensifying induction therapy with high-dose daunorubicin in young patients with AML significantly improved the rate of complete remission and the duration of overall survival; therefore, this treatment strategy should be considered as a standard of care in these patients.

A randomized trial of anthracycline dose intensification during induction of younger patients with acute myeloid leukemia: Results of Eastern Cooperative Oncology Group study E1900

7003 Background: In younger adults with newly diagnosed acute myeloid leukemia (AML), anthracycline dose intensification during induction may improve complete remission (CR) rates; however, an improvement in overall survival (OS) in a randomized trial has not been demonstrated. This unresolved issue led the ECOG to compare standard dose (SDD) to high-dose daunorubicin (HDD) in induction. Methods: Adult patients with previously untreated AML were randomized to receive either SDD (45 mg/m2/d) or HDD (90 mg/m2/d) each for 3days combined with standard-dose cytarabine (100 mg/m2/d) for 7 days by continuous intravenous infusion. Those achieving a CR were allocated to allogeneic hematopoietic stem cell transplantation (HSCT) or high-dose cytarabine (with or without a single dose of gemtuzumab ozogamicin) prior to autologous HSCT. Intravenous busulfan and cyclophosphamide was the preparative regimen for both allogeneic and autologous HSCT. The primary end point of this study was OS from the time of induction randomization. Results: 633 patients, age 18 to 60 (median 48) years, were entered in this study. There were no differences in patient demographics or disease characteristics between the two groups at presentation. In an intention-to-treat analysis, HDD resulted in a significantly higher CR rate (63.3% vs. 47.7%, p = 0.0003) than SDD. Induction deaths were similar between the two groups (5.4 vs. 5.0%, p = ns). 334 (52.8%) patients entered the consolidation phase. 57.4% of HDD and 48.1% of the SDD patients, received consolidation therapy on study, and 28.7% and 23.1% proceeded to HSCT respectively. Median OS was superior for the HDD (23.7 months) over the SDD (15.1 months) group (p = 0.005). In subgroup analysis, patients with favorable or intermediate-risk cytogenetics or age &lt;55 years benefited from the HDD. Conclusions: We demonstrate for the first time in a prospective randomized trial that intensifying induction therapy through a higher daily anthracycline dose, in the setting of identical intensive consolidation therapy, results in a higher CR rate as well as prolonged OS. In younger AML patients a higher dose of anthracycline in induction should be considered the new standard of care. No significant financial relationships to disclose.

Ara-C, Topotecan, and Gemtuzumab Ozogamicin [ATGO] Is An Effective Induction Regimen for Advanced MDS and Secondary or Relapsed AML: Analysis of a Phase I/II Study

Advanced myelodysplastic syndrome and secondary or relapsed AML are difficult to treat, with CR rates following standard induction chemotherapy less favorable than those for de novo AML. We examined an induction approach using the anti-CD33-calicheamicin conjugate gemtuzumab ozogamicin (GO) in combination with conventional chemotherapy.Methods and Patient Population: We present data from a completed phase I/II study, demonstrating the activity and tolerability of the combination in patients with MDS and AML. 44 pts (19 pts from phase I, 25 from phase II) were assigned to receive cytarabine 2 g/m2 over 4 hours once daily, and topotecan 1.5 mg/m2 by continuous infusion daily on days 1–5. GO was given on day 6 at a dose of 3 mg/m2 (7 pts), 4.5 mg/m2 (28 pts), or 6 mg/m2 (7 pts); 2 additional pts did not receive the GO because of intercurrent toxicities. The MTD of GO was established at 4.5 mg/m2, which was used in phase II. The study population consisted of 15 pts with advanced MDS (IPSS 2–3), 23 pts with previously untreated secondary AML, and 6 pts with relapsed AML. Median age was 64 (34–77); 34 of 44 (77%) pts were over age 60.Results:ATGO was generally well tolerated. Infections, including 15 bacteremic episodes, were the most common non-hematologic complications. Two cases of reversible but unexplained grade 3 delirium were seen at 6 mg/m2 GO, meeting study criteria for dose-limiting toxicity. Only one case (3%) of clinical venoocclusive disease (VOD/SOS) occurred, in the single subject who received a second (half) dose of GO on day 16. Reversible and asymptomatic grade 3 hepatic transaminase elevations occurred in 8 pts (18%). There were 4 deaths (9%) prior to day 40: 2 infectious, 1 CNS bleed, and 1 sudden death. Based on intent to treat, 25 pts (56.8%) achieved complete morphologic remission, with or without full platelet recovery after one cycle of induction. The CR/CRp rate for pts over age 60 was similar to that for younger pts (59% vs 53%, respectively, p=NS). Similar proportions of pts with MDS, secondary AML, and relapsed AML achieved CR/CRp (60% vs 52% vs 67%, respectively, p=NS). Following ATGO induction, the majority of responders went on to receive post-remission therapy, including 11 pts who underwent allogeneic hematopoietic cell transplantation (HCT). Post-remission therapies, including HCT, were not associated with VOD/SOS or unusual toxicities. Median survival for all patients was 303 d (95% CI, 138–467 d), and the K-M estimated 2 year survival is 37%. As expected, achievement of CR after ATGO was associated with improved overall survival, and there was a trend toward improved survival in younger pts. Cytogenetic class, type of disease (MDS v. AML), and administration of prior chemotherapy were not significant predictors of either CR or OS. Ten pts (23%) are alive, with a median follow-up of 768 days (275–2001); 7 (16%) are currently in continuous CR, including 4 of the 11 pts who received allogeneic HCT.Conclusions: Our data show that ATGO is a well tolerated induction regimen, and is not associated with immediate or late VOD after a single dose of GO. The CR rate with this anthracycline-free induction regimen is promising across a range of ages and myeloid disease categories. Furthermore, the tolerability of ATGO is such that effective post-remission therapy including allogeneic HCT is feasible in responding pts. [Display omitted]

52: A Single Dose of Gemtuzumab-Ozogamicin (GO) in Consolidation Prior to Autologous Transplant for Younger Patients with Newly Diagnosed Acute Myeloid (AML) is Safe But Has No Effect on Disease Free Survival: Interim Results of Eastern Cooperative Oncology Group Study (E1900)

Gemtuzumab-Ozogamicin (GO), a CD33 directed monoclonal antibody linked to calicheamicin, was developed to provide targeted therapy for patients with AML. The addition of GO to standard induction therapy has had promising results, particularly in its ability to induce complete remission (CR). Its role in consolidation therapy in AML is not defined and therefore, the main objective of E1900 was to compare the disease-free survival (DFS) of adult patients with newly diagnosed AML, age 60 or less, between two consolidation regimens: Group A received high-dose cytarabine, 3 gm/m2 every 12 hours days 1, 3 and 5 for a total of 6 doses, for two cycles, collected autologous peripheral blood stem cells (PBSC), then proceeded to autologous transplant with high-dose intravenous busulfan and cyclophosphamide with PBSC support.

Clinical outcomes and rates of molecular remission with all-trans retinoic acid (ATRA) and arsenic trioxide (As2O3) combination therapy in newly diagnosed acute promyelocytic leukemia (APL)

6503 Background: ATRA and anthracyclines provide durable remissions in patients with untreated APL. As2O 3 has improved outcomes in untreated and relapsed/refractory APL. The aim of this study was to determine the rates of complete response (CR) and molecular remission with ATRA and As2O 3 combination therapy in untreated APL. Methods: From 2/02 to 1/06, 53 patients with untreated APL received ATRA 45 mg/m2 daily and As2O 3 0.15 mg/kg IV 1-hr infusion daily starting on day 10. Patients with WBC&gt;10×109/L also received gemtuzumab ozogamicin (GO) 9 mg/m2 on day 1 and/or idarubicin 12 mg/m2 on days 1–4. Patients in CR received As2O 3 0.15 mg/kg IV on days 1–5 weekly for 4 weeks on and 4 weeks off and ATRA 45 mg/m2 daily for 2 weeks on and 2 weeks off (for 28 weeks). Polymerase chain reaction (PCR) testing for PML-RARα (sensitivity level, 10−4) was performed every 3 months from CR for 2 years. Patients with molecular relapse received GO 9 mg/m2 once monthly for 3 months in addition to ATRA and As2O 3 as in postremission therapy. If PCR became negative, only the single dose of GO was given. Results: The median age was 46 years; and 20% of patients were Sanz low risk, 40% intermediate, and 40% high risk. The CR rate was 91% (low risk 91%, intermediate 95%, high risk 86%). The median follow-up in surviving patients was 1.6 years. Six patients died during induction, and 2 died in CR from other cancers. The 1-yr survival rate was 88%. Three patients relapsed (at 9, 9, and 16 months). The 1-yr failure-free survival (FFS) rate in responding patients was 94% (high risk 86%, other risk 100%). Molecular remission rates are shown in the Table . Grade 3–4 nonhematologic toxicities were infections (n=16), neurologic (n=4), cardiac arrhythmias (n=4), APL differentiation syndrome (n=4), and headache (n=2). Conclusions: ATRA plus As2O 3 results in high rates of CR, molecular remission, FFS, and survival and is an alternative to ATRA and idarubicin combination therapy in low-risk APL. [Table: see text] No significant financial relationships to disclose.

Gemtuzumab Ozogamicin Is an Acceptable Alternative to Anthracyclines in Combination with Standard Dose Infusional Cytarabine as Induction Therapy for Elderly Patients with Acute Myeloid Leukemia (AML).

Gemtuzumab ozogamicin (GO), a humanized IGG4 anti-CD33 antibody conjugated to calicheamicin, has demonstrated single agent efficacy in relapsed AML. Combination with other anti-leukemic drugs has required a significant dose reduction of GO to avoid excess liver toxicity. The maximally tolerated dose of GO in combination with cytarabine 100 mg/m2 by 24 hr infusion for 7 days, was established at 6 mg/m2 day 1 and 4 mg/m2 day 8 in a phase I trial involving relapsed patients as well as untreated adults with AML above the age of 60. From 7/03 to 7/05, 31 adults (M-17, F-14) with a median age of 70 (range 60–83) were treated with this regimen on a phase II trial. Patients with residual disease on day 14 were given cytarabine 100 mg/m2 by 24 hr infusion daily for 5 days without GO. Post remission therapy, generally included repetitive cycles of cytarabine 50 mg/m2 twice daily by subcutaneous injection in combination with rotating cycles of 6-thioguanine, cyclophosphamide, or daunorubicin. Patients with an antecedent hematological disorder (AHD) or secondary AML were not excluded, and prior treatment for myelodysplastic syndrome was allowed. An AHD was documented in 13/30 (43%) of patients and 3/30 (10%) had secondary AML. Unfavorable cytogenetics (−5, −7, 11q2,3 abnormalities and complex karyotypes) were present in 17/30 (56%) patients. Of the first 7 patients treated, 4 developed severe and fatal hyperbilirubinemia in conjunction with ascites, fluid retention and encephalopathy consistent with sinusoidal occlusion syndrome (SOS). Subsequent patients were treated with 6 mg/m2 of GO without the day 8 dose. Of these 24 patients, 4 developed grade 3 hyperbilirubinemia which was transient and not associated with SOS. Apart from this toxicity, other non-hematologic effects, including infusional reactions, mucositis, diarrhea, nausea, vomiting and anorexia were mild to moderate. No cardiac toxicity was observed in any patients including 3 patients with reduced left ventricular function documented prior to treatment. Overall 9/31 (29%) patients achieved a complete response (CR) and 1 achieved a CRp for an overall response rate of 32%. Of the 24 patients who received 1 dose of GO (6 mg/m2), the overall response rate was 9/24 (36%). The induction mortality rate in these 24 patients was 5/24 (21%). The median duration of response is 10.5 months (range 6 to 12 months) with 2 patients in ongoing CR at 12 months and 18 months respectively. This data demonstrates that GO administered on day 1 and day 8 leads to unacceptable liver toxicity in unselected patients with AML above the age of 60 yrs. However, in patients receiving a single dose of GO (6 mg/m2) in combination with cytarabine, the overall response rate and toxicity profile is comparable to a historical cohort of similarly unselected elderly AML patients treated with daunorubicin and cytarabine at our institution. We conclude that a single dose of GO (6mg/m2) is an equally safe and effective alternative to anthracycline in combination with standard doses of infusional cytarabine in adults with AML above the age of 60.

A Phase I Trial of Ara-C, Topotecan, and Gemtuzumab Ozogamicin (Mylotarg®) for Advanced MDS and Secondary or Relapsed AML.

The outlook for most pts with advanced MDS and secondary or relapsed AML is poor, given the limited efficacy of conventional chemotherapy. While allogeneic SCT is potentially curative, many pts are not candidates for myeloablative transplants, and newer reduced intensity conditioning approaches applicable to older pts are generally less effective unless pts are in remission. We designed a Phase I dose escalation study to examine the safety and efficacy of combining chemotherapy with the anti-CD33 mAb conjugate, Gemtuzumab Ozogamicin (GO) as induction therapy for high risk MDS and AML.Design and study population: Between 11/01 and 2/04, 19 pts were assigned to receive Ara-C 2 g/m2 over 4 hours daily, days 1–5; Topotecan 1.5 mg/m2 by continuous infusion daily, days 1–5; and GO on day 6 at a dose of 3, 4.5, or 6 mg/m2; the protocol included an option for a second dose of GO (at ½ of the day 6 dose) on the basis of results of the day 14 BM exam. Primary safety endpoints were Gr 4 or unexpected non-hematologic toxicities, or death within 30 days of treatment. The primary efficacy endpoint was CR, defined as complete morphologic, flow cytometric, and cytogenetic remission. The study population included 10 pts with advanced MDS (IPSS score ≥1.5), 6 with AML following MDS, and 3 with relapsed AML. All pts had blasts demonstrating CD33 expression. Median pt age was 64 yrs (37–77).Results: Table 1 summarizes results at each dose level. Assigned treatment was delivered in 17 of the 19 pts; 2 pts did not receive GO because of pneumonia (1pt), and elevated LFT's (1 pt). Infections accounted for the majority of non-hematologic complications, with 6 bacteremic episodes, 1 case of mild typhlitis, and 2 pneumonias. There was only one case of Gr 4 liver toxicity in the single pt who received a second dose of GO. There were two early deaths (10%), including a sudden death on day 20 in a pt who had an MI related to the GO infusion. At the 6 mg/m2 dose level, 3 of 6 pts treated with a single dose of GO experienced Gr IV–V non-hematologic toxicities (1 sudden death, 2 reversible but prolonged delirium). Based on intent to treat, 9 of the 19 pts (47%) achieved CR following therapy. With median follow-up of 311 d (161–889), 8 of the 19 pts were alive at last follow-up, 4 in CR. Five pts went on to allogeneic SCT; 3 are alive and disease-free 199, 219, and 713 days following treatment, and two died of transplant-related complications. None experienced VOD or other unexpected toxicities following SCT.Conclusions: These results compare favorably with those observed with standard induction therapy for MDS/secondary AML, and the safety data support the feasibility of combining GO with chemotherapy. Other combination studies have typically utilized a GO dose of 9 mg/m2 given prior to chemotherapy, and unacceptable toxicities have frequently been observed. In this study, GO doses of 3 and 4.5 mg/m2 administered after chemotherapy were well tolerated. At the 6 mg/m2 dose level, 4 of 7 pts experienced serious toxicities, meeting criteria for declaring the MTD to be a single dose of 4.5 mg/m2. A Phase II study at the 4.5 mg/m2 dose is planned to assess efficacy.ATGO: Outcomes by Dose LevelGO Dose (mg/m2)nCR (%)# DLT'sTRM (%)385 (62)11 (12.5)4.542 (50)00672 (28)4*1 (14)All pts199 (47)52 (10.5)* One pt received a 2nd dose of GO