Mylotarg (Gemtuzumab Ozogamicini) - Description and Clinical Pharmacology

CLINICAL PHARMACOLOGY

General

Gemtuzumab ozogamicin binds to the CD33 antigen. This antigen is expressed on the surface of leukemic blasts in more than 80% of patients with acute myeloid leukemia (AML). CD33 is also expressed on normal and leukemic myeloid colony-forming cells, including leukemic clonogenic precursors, but it is not expressed on pluripotent hematopoietic stem cells or on nonhematopoietic cells.

Mechanism of Action: Mylotarg is directed against the CD33 antigen expressed by hematopoietic cells. Binding of the anti-CD33 antibody portion of Mylotarg with the CD33 antigen results in the formation of a complex that is internalized. Upon internalization, the calicheamicin derivative is released inside the lysosomes of the myeloid cell. The released calicheamicin derivative binds to DNA in the minor groove resulting in DNA double strand breaks and cell death.

Gemtuzumab ozogamicin is cytotoxic to the CD33 positive HL-60 human leukemia cell line. Gemtuzumab ozogamicin produces significant inhibition of colony formation in cultures of adult leukemic bone marrow cells. The cytotoxic effect on normal myeloid precursors leads to substantial myelosuppression, but this is reversible because pluripotent hematopoietic stem cells are spared. In preclinical animal studies, gemtuzumab ozogamicin demonstrates antitumor effects in the HL-60 human promyelocytic leukemia xenograft tumor in athymic mice.

Human Pharmacokinetics

After administration of the first recommended 9 mg/m² dose of gemtuzumab ozogamicin, given as a 2 hour infusion, the elimination half lives of total and unconjugated calicheamicin were about 41 and 143 hours, respectively. After the second 9 mg/m² dose, the half life of total calicheamicin was increased to about 64 hours and the area under the concentration-time curve (AUC) was about twice that in the first dose period. The AUC for the unconjugated calicheamicin increased 30% after the second dose. Age, gender, body surface area (BSA), and weight did not affect the pharmacokinetics of Mylotarg.

Patients, especially patients previously treated with HSCT, have an underlying risk of VOD. The AUC of total calicheamicin was correlated with additional risk of hepatomegaly and the risk of veno-occlusive disease (VOD). There is no evidence that reducing Mylotarg dose will reduce the underlying risk of VOD. Metabolic studies indicate hydrolytic release of the calicheamicin derivative from gemtuzumab ozogamicin. Many metabolites of this derivative were found after in vitro incubation of gemtuzumab ozogamicin in human liver microsomes and cytosol, and in HL-60 promyelocytic leukemia cells. Metabolic studies characterizing the possible isozymes involved in the metabolic pathway of Mylotarg have not been performed.

CLINICAL STUDIES

The efficacy and safety of Mylotarg as a single agent have been evaluated in 277 patients in three single arm open-label studies in patients with CD33 positive AML in first relapse. The studies included 84, 95, and 98 patients. In studies 1 and 2 patients were≥ 18 years of age with a first remission duration of at least 6 months. In study 3, only patients ≥ 60 were enrolled and their first remission had to have lasted for at least 3 months. Patients with secondary leukemia or white blood cell (WBC) counts ≥ 30,000/μL were excluded. Some patients were leukoreduced with hydroxyurea or leukapheresis to lower WBC counts below 30,000/μL in order to minimize the risk of tumor lysis syndrome. The treatment course included two 9 mg/m² doses separated by 14 days and a 28-day follow-up after the last dose. Although smaller doses had elicited responses in earlier studies, the 9 mg/m² was chosen because it would be expected to saturate all CD33 sites regardless of leukemic burden. A total of 157 patients were≥ 60 years of age and older. The primary endpoint of the three clinical studies was the rate of complete remission (CR), which was defined as

1. leukemic blasts absent from the peripheral blood;
2. ≤ 5% blasts in the bone marrow, as measured by morphology studies;
3. hemoglobin (Hgb) ≥ 9 g/dL, platelets ≥ 100,000/μL, absolute neutrophil count (ANC) ≥ 1500/μL; and
4. red cell and platelet-transfusion independence (no red cell transfusions for 2 weeks; no platelet transfusions for 1 week).

In addition to CR, a second response category, CRp, was defined as patients satisfying the definition of CR, including platelet transfusion independence, with the exception of platelet recovery ≥100,000/μL. Remission status was determined at approximately 28 days after the last dose of Mylotarg. This category was added because Mylotarg appears to delay platelet recovery in some patients. Clinical equivalence between CR and CRp responses has not been established. Median time to recovery of platelet counts in patients who achieved a CR or a CRp is summarized in TABLE 4 (see ADVERSE REACTIONS section).

All patients were pre-medicated with acetaminophen 650-1000 mg and diphenhydramine 50 mg to decrease acute infusion-related symptoms. Growth factors and cytokines were not permitted. Use of prophylactic antibiotics was not specified.

Response Rate

The overall response (OR) rate for the three pooled monotherapy studies was 26% (71/277) consisting of 13% (35/277) of patients with CR and 13% (36/277) of patients with CRp. The median time to blast clearance in both CR and CRp patients was 28 days from the first dose of Mylotarg. The median time to remission was 60 days for both CR and CRp. Remission rates are shown in Table 1. Of the 157 patients who were ≥ 60 years old, the overall remission rate (OR = CR + CRp) was 24%. For the patients < 60 years old and all 277 patients the OR rates were 28% and 26%, respectively. Two of the most important determinants of response following relapse are age and duration of first remission. Remission rates by prognostic category are outlined in Table 1.

TABLE 1: PERCENTAGE OF PATIENTS BY REMISSION CATEGORY AND PROGNOSTIC GROUP

	Age < 60 years	Age ≥ 60 years	First Remission < 6 months	First Remission 6 – 12 months	First Remission ≥ 12 months
Type of Remission	n = 120	n = 157	n = 37	n = 124	n = 116
CR (95% CI)	13 8, 21	12 7, 18	5 1, 18	10 5, 16	18 12, 26
CRp (95% CI)	14 8, 22	12 7, 18	5 1, 18	12 7, 19	16 10, 24
OR (CR + CRp) (95% CI)	28 20, 36	24 18, 32	11 3, 25	22 15, 30	35 26, 44

The overall response rates were similar for females and males: 27% of females and 25% of males achieved remission.

In the studies, 95% of the patients were white and 5% of the patients were non-white.

Survival

Overall survival was measured from date of first dose of gemtuzumab ozogamicin to date of death or data cut-off date (Table 2). Relapse-free survival (duration of remission) for patients in remission was defined as the time period from date of first documentation of maximum response (CR or CRp) to the first date of documentation of relapse (pathology report or complete blood count showing leukemic blast recurrence in peripheral blood or bone marrow), or death, or data cut-off date.

TABLE 2: SUMMARY OF RELAPSE FREE^a and OVERALL SURVIVAL FOR PATIENTS WITH CR AND CRp

Remission Group	N	Relapse-Free Median months	Overall Survival Median monthsc
a: Number of months after achieving CR or CRp. b: Sixteen OR patients (6 CR and 10 CRp; 16/277; 5.7%) had a relapse-free survival at 12 months. 14/16 had stem cell transplants. 1/14 had a stem cell transplant prior to Mylotarg. The remaining 13 patients had stem cell transplants after Mylotarg. Six OR patients (3 CR and 3 CRp) had a relapse-free survival > 36 months. All 6 of these patients had subsequent stem cell transplants, representing 2.2% (6/277) of all patients. c: The median overall survival was 3.3 months for NR patients; in all 277 patients it was 4.9 months.
CR	35	6.4	12.0
CRp	36	4.5	12.7
ORb	71	5.2	12.4
Patients who responded to Mylotarg and received no further therapy
CR	17	3.7	11.5
CRp	18	2.4	10.7
OR	35	2.4	11.1

Rates of Remission by Cytogenetic Risk

Patients in all three cytogenetic risk classification groups (poor, intermediate, favorable) responded to gemtuzumab ozogamicin.

Post-Remission Therapy

Twenty-five (25/71, 35%) OR patients (11 CR and 14 CRp patients) went on to hematopoietic stem cell transplantation (HSCT). Fourteen (14) received allogeneic HSCT and 11 received autologous HSCT.

Thirty-five (35/71, 49%) OR patients (17 CR and 18 CRp patients) who responded to treatment with Mylotarg received no additional therapy.

Repeat Courses

Twenty (20) patients have received more than 1 course of Mylotarg in clinical trials. These patients were initially treated with Mylotarg, achieved remission, then subsequently relapsed and then received additional doses of Mylotarg.

Overview of Clinical Data

Available single arm trial data do not provide valid comparisons with various cytotoxic regimens that have been used in relapsed acute myeloid leukemia. Response rates are in the range of rates reported with such regimens only if the CRp responses are included. Nevertheless, treatment with Mylotarg can provide responses, including some of reasonable duration. The data support its use in patients for whom aggressive cytotoxic regimens would be considered unsuitable, such as many patients 60 years of age or older.

INDICATIONS AND USAGE

Mylotarg is indicated for the treatment of patients with CD33 positive acute myeloid leukemia in first relapse who are 60 years of age or older and who are not considered candidates for other cytotoxic chemotherapy. The safety and efficacy of Mylotarg in patients with poor performance status and organ dysfunction has not been established.

The effectiveness of Mylotarg is based on OR rates (see CLINICAL STUDIES section). There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival, compared to any other treatment.