New developments in antibody therapy for acute myeloid leukemia

New Developments in Antibody Therapy for Acute Myeloid Leukemia Marcie R. Tomblyn and Martin S. Tallman In the past three decades, improvements in the treatment of acute myeloid leukemia (AML) have increased survival in patients younger than 55 years without significant survival impact in older individuals. Unfortunately, many patients, regardless of age at diagnosis, will eventually die from their disease. Advances in the development of targeted therapies have proven beneficial in chronic myeloid leukemia and lymphoma. Gemtuzumab ozogamicin (GO; Mylotarg, Wyeth-Ayerst, St Davids, PA), a monoclonal antibody conjugated to calicheamicin, targets the CD33 antigen found on the surface of more than 80% of AML leukemic blasts. GO is approved for relapsed disease in patients older than 60 years, but is being evaluated in combination with chemotherapy, in the setting of hematopoietic stem cell transplant, and in high-risk myelodysplasia. Semin Oncol 30:502-508. © 2003 Elsevier Inc. All rights reserved.

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CUTE MYELOID LEUKEMIA (AML) is a hematologic malignancy resulting from transformation of a multipotent hematopoietic progenitor and leading to the accumulation of immature cells in the bone marrow. The principal disease manifestations are related to the resultant cytopenias and include fatigue, increased risk of infections, and bleeding. The incidence of AML is approximately 2.4 per 100,000 persons in the United States, with a steady increase in incidence with age.1 The median age at diagnosis is 70 years. Current standard therapy consists of induction with cytotoxic chemotherapy including an anthracycline and cytarabine and consolidation with cyclic intensive chemotherapy, usually high doses of cytarabine.2 Over the past three decades, improvement in diagnosis and therapy has increased the survival rate from 15% to almost 40% for those patients younger than 55 years of age.1 This is probably due, in part, to identification of cytogenetically defined prognostic groups, as well as advances in supportive care including management of neutro-

From the Northwestern University Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center, Chicago, IL. Address reprint requests to Martin S. Tallman, MD, Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, 676 N St Clair St, Suite 850, Chicago, IL 60611. © 2003 Elsevier Inc. All rights reserved. 0093-7754/03/3004-0001$30.00/0 doi:10.1016/S0093-7754(03)00234-3 502

penic and profoundly thrombocytopenic patients. There has not been a similar increase in survival rate for those persons older than 55 years of age.3 Data from the Eastern Cooperative Oncology Group (ECOG) show nearly superimposable curves for the 5-year survival rate for all patients ⱖ55 years of age treated on clinical trials from 1973 to 1997 (Fig 1). Altered disease biology with increased expression of multidrug resistance markers and a higher incidence of adverse cytogenetics; comorbid illnesses; and secondary leukemia likely contribute to these unfavorable outcomes.4-6 Despite years of research and therapeutic advancements, nearly two thirds of patients diagnosed with AML will die of the disease or of complications of treatment. Consequently, new therapies are necessary to improve survival. Opportunities for major therapeutic advances have come from the identification of novel targets to which specific therapy can be directed, theoretically sparing normal tissues. The development of targeted therapy with monoclonal antibodies, specifically gemtuzumab ozogamicin (GO; Mylotarg, Wyeth-Ayerst, St Davids, PA), has provided the first such agent in the armamentarium of antileukemic agents. GEMTUZUMAB OZOGAMICIN

GO is currently approved for the treatment of patients who are 60 years of age or older with CD33⫹ AML in first relapse and who are not considered candidates for cytotoxic chemotherapy.7 The drug is a humanized murine monoclonal antibody that targets the CD33 antigen and is chemically linked to calicheamicin, an enediyene antitumor antibiotic that results in DNA cleavage and apoptosis.7-10 The CD33 molecule is a cell surface differentiation protein that is expressed on normal progenitor and myeloid cells, as well as on more than 80% of AML blasts, but is not expressed on immature hematopoietic stem cells or nonhematopoietic cells.8-10 More importantly, the CD33 antigen is rapidly internalized upon binding of GO, promptly bringing the highly toxic calicheamicin into the cell.8 Upon internalization of GO, hydrolysis of the linker molecule releases calicheamicin into the cell, which is then reduced Seminars in Oncology, Vol 30, No 4 (August), 2003: pp 502-508

ANTIBODY THERAPY FOR AML

Fig 1. The upper curves demonstrate the survival of patients < 55 years with newly diagnosed AML treated on ECOG protocols since 1973. Patients > 55 years with newly diagnosed AML treated on ECOG protocols since 1973 are shown in the lower survival curves. (From: Appelbaum F, Rowe JM, Radich J, et al. Acute myeloid leukemia. Hematology 2001:62-86. Copyright American Society of Hematology, used with permission.)

by glutathione, associates with DNA, and causes double-stranded DNA breaks.8 Due to varying concentrations of CD33 among patients, GO exhibits a wide spectrum in its pharmacokinetic properties.10 In general, the half-life of the drug is nearly 3 days, but the maximum concentrations and volumes of distribution vary significantly.10 However, the standard dose of 9 mg/m2 results in saturation of more than 80% of the CD33 antigens in the majority of patients.10,11 The drug appears to be excreted through the biliary system and the serum levels of free calicheamicin are virtually undetectable.7 INITIAL TRIALS

In a phase I dose escalation study, Sievers et al treated 40 patients with refractory or relapsed CD33⫹ AML with single-agent GO in doses ranging from 0.25 to 9 mg/m2.11 Patients were required

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to have a minimum Karnofsky performance status of 60%, a white blood cell count ⱕ 30 ⫻ 103/␮L, and adequate renal and liver function. Eighteen patients had prior stem cell transplant. All patients enrolled had morphologic bone marrow involvement and 31 (78%) had circulating blasts present. After one to three doses of GO, eight patients (20%) had a reduction in marrow blast counts to less than 5% based on morphology. Five of these eight patients had recovery of neutrophil counts to ⱖ1,500 cells/␮L, but only three achieved normal platelet recovery. Those patients who achieved a complete remission (CR) by conventional criteria, but without recovery of platelet counts to greater than 100,000/␮L, were considered to have achieved CRp. Toxicities were primarily infusion-related fevers and chills and myelosuppression. Based on these promising results, three openlabel, multicenter phase II trials at the 9-mg/m2 dose were initiated.12 The studies required that all patients have AML in untreated first relapse and evidence of CD33 immunofluorescence four times background staining on at least 80% of AML blasts. One hundred forty-two patients with a median age of 61 years were enrolled in these three studies. More than 90% had either intermediate (56%) or poor risk (39%) cytogenetics. Only five patients had prior stem cell transplant. The overall response rate, defined as CR ⫹ CRp, was 30% with a median time to remission of 60 days. The relapse-free survival (RFS) was not statistically different between the patients achieving CR and CRp (Fig 2). The data from these phase II studies has recently been updated.13,14 A total of 277 patients have been evaluated as of October 2001. The CR rate, defined as ⱕ5% blasts in the marrow, neutrophils ⱖ 1,500/␮L, and platelets ⱖ 100,000/␮L, was 13% as was the rate of CRp.13 This was not different between patients stratified for age less than or ⱖ60 years or for cytogenetic risk groups.13,14 The median RFS for all patients achieving a remission was 5.3 months. The primary toxicities were myelosuppression with National Cancer Institute (NCI) grade 3 or 4 neutropenia and thrombocytopenia in more than 95% of patients. Approximately one third of patients developed treatment-related infections and/or hyperbilirubinemia and transaminase elevations.13 Hepatic veno-occlusive disease (VOD) occurred in seven patients (3%) and was fatal in 1%.

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Fig 2. Relapse-free survival for patients with CR (F) and CRp (■) (log-rank test; P ⴝ .624). There were 23 CR patients (median, 7.2 months) and 19 CRp patients (median, 4.4 months). (From Sievers et al.12 Reprinted with permission from the American Society of Clinical Oncology.)

TOXICITIES

The goal of targeted therapy is to selectively kill tumor cells and, thus, minimize nonspecific systemic toxicity. Treatment with GO results in an infusion-related symptom complex that consists of primarily fever and chills, and rarely shortness of breath and hypotension, similar to other monoclonal antibody therapies.12,13,15 Based on data from the phase II studies, these infusion-related NCI grade 3 or 4 toxicities have an incidence of 4% to 11% overall, but were significantly decreased after the first infusion.12 Symptoms occurred despite premedication with antihistamines and acetaminophen. Preliminary data suggest that prophylactic steroids decreased the infusion reaction from 29% to 3%.16 Myelosuppression is a significant complication of GO therapy. In fact, in the final analysis of 277 patients in phase II studies, the reported incidences of NCI grade 3 or 4 neutropenia and thrombocytopenia were 98% and 99%, respectively.13 However, this is to be expected given that more differentiated hematopoietic progenitors express CD33.8-10 Despite significant myelosuppression, less than one third of patients experienced any grade 3 or 4 infections and only 15% of patients had an episode of grade 3 or 4 bleeding.12 According to updated data, the early mortality rate was 17% for patients 60 years of age and older, and 13% for persons younger than 60.13 Causes of

death included disease progression, sepsis, hemorrhage, and multi-organ failure.12 The most worrisome toxicity associated with GO therapy is hepatotoxicity and apparent VOD. Hepatic VOD, a clinical constellation of fluid retention, painful hepatomegaly and jaundice, is seen in up to 60% of persons undergoing hematopoietic stem cell transplant (HSCT).17 Recent data show that 106 of 277 (39%) patients treated with GO in the phase II studies experienced NCI grade 3 or 4 elevations in transaminases or bilirubin.18 Despite that the majority of these were transient, seven patients developed VOD that was ultimately fatal in four. Giles et al reviewed data from a cohort of 119 patients receiving GO, generally concurrently with other chemotherapy or biologic agents, but without HSCT.19 They found that 14 (12%) patients developed VOD. Of these, six had GO as their initial therapy. No clinical factors, including age, performance status, regimen or total dose of GO, or baseline bilirubin or transaminase levels, predicted development of VOD. To determine the risk of development of hepatotoxicity with GO and HSCT, Rajvanshi et al evaluated 23 patients treated with GO for AML that had relapsed after myeloablative chemotherapy and HSCT.20 The median time from HSCT to GO therapy was 131 days. Eleven (48%) of the 23 patients developed liver toxicity manifested by hepatomegaly, weight gain, ascites, hyperbilirubinemia, and/or elevated transaminases. Symptoms developed within 1 to 3 weeks of infusion and seven patients died of sustained liver disease. Multiple factors in the post-HSCT setting were evaluated, but none was found to be significantly associated with the development of VOD. However, there was a trend toward greater likelihood of VOD with a greater total dose of GO (9 mg/m2 v 6 mg/m2). In a smaller analysis by Cohen et al, only one of eight patients developed clinical VOD after treatment with GO post-HSCT at a median time from HSCT to GO treatment of 9 months.21 Furthermore, treatment with GO followed by a subsequent HSCT has been associated with an increased risk of VOD.22 Goldberg et al retrospectively reviewed 61 consecutive patients undergoing myeloablative allogeneic HSCT for AML.22 Nine of the 61 patients had previously been treated with GO. A total of 23 of the 61 patients developed VOD and eight (89%) of these had been exposed to GO. A multivariate logistic re-

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Table 1. Studies of Combinations of GO with Conventional Cytotoxic Chemotherapy First Author

N

GO Dose (mg/m2)

Chemotherapy

CR (%)

Grade III/IV Nonhematologic Toxicities

Kell33

19

633

DAT

NR

Kell34 De Angelo31 Amadori29 Baccarani30

55 18 57 12

3 6 9 on d 1, 15 6 on d 1, 4 on d 8

DAT, DA, FLAG-Ida DA MICE* A

85 83 54 57

Hepatotoxicity (21%); multi-organ failure (5%); pulmonary infiltrates with hemoptysis (5%) Hepatotoxicity (45%) Hepatotoxicity (16%); infection (32%) Hepatotoxicity (13%); infection (28%) Hepatotoxicity (8%)

*Chemotherapy followed GO sequentially. Abbreviations: DAT, daunorubicin, cytarabine (ara-C), thioguanine; DA, daunorubicin, ara-C; FLAG-Ida, fludarabine, ara-C, granulocyte colony-stimulating factor, idarubicin; MICE, mitoxantrone, cytarabine, etoposide; A, cytarabine.

gression analysis of all patients demonstrated that exposure to GO prior to transplant is an independent risk factor for the development of VOD. The mechanism of liver toxicity due to GO is uncertain. Histopathology studies reveal that the damage is primarily directed at the hepatic sinusoids, with resultant ischemia and hepatocyte necrosis.20 To differentiate this newly described hepatic toxicity from VOD associated with HSCT, the term “sinusoidal obstructive syndrome” (SOS) has been suggested. Postulated methods of damage include exposure to free calicheamicin, nonspecific uptake of GO by the Kupffer cells, receptor mediated uptake of GO by CD33-expressing cells in the liver, and the generation of free radicals in the setting of prophylactic acetaminophen and subsequent glutathione depletion.20,23 Recently, Jedema et al hypothesized that there may be CD33-independent phagocytosis of antibody complexes as evidenced by work with CD33⫺ cells lines that were able to incorporate GO when exposed to high concentrations.24 Ursodiol for prophylaxis against the development of GO-induced SOS has not been successful.25 MECHANISMS OF RESISTANCE TO GO

With a response rate of only 30% despite adequate CD33 expression and receptor saturation, it is not known why more patients do not respond. Clearly some patients have different disease biology. The multidrug resistance phenotype that correlates with the expression of P-glycoprotein (Pgp) is thought to play a role in the lack of response.26,27 Linenberger et al evaluated samples for evidence of Pgp function and compared the results between GO responders and nonresponders.26 Pa-

tients with overexpression of Pgp were less likely to have a clinical response. In vitro data by Matsui et al also suggest that the addition of multidrug resistance modifiers may result in a response to GO, further supporting this mechanism of resistance.27 FUTURE DIRECTIONS

GO in Combination With Conventional Cytotoxic Chemotherapy GO as a single agent clearly serves a role in the setting of relapsed AML. However, several groups are evaluating this targeted therapy in combination with cytotoxic chemotherapy as front-line therapy (Table 1).28-34 Kell et al initially reported the feasibility of combining GO with induction chemotherapy in patients younger than 60 years of age.33 A total of 19 patients were treated with GO (3 mg/m2 or 6 mg/m2) in combination with daunorubicin, cytarabine (ara-C), and thioguanine (DAT regimen). Both doses of GO were well tolerated, but transient liver toxicities resulted in a dose reduction to 3 mg/m2 in subsequent studies. The Medical Research Council (MRC) also combined GO (3 mg/m2) with DAT, daunorubicin, ara-C (DA), or fludarabine, ara-C, granulocyte colony-stimulating factor (G-CSF), and idarubicin (FLAG-Ida regimen).34 Of 55 patients treated, 41 achieved a CR with one cycle of induction therapy. There were no significant differences in time to median neutrophil and platelet recovery compared to historical controls. Primary nonhematologic toxicities were hepatic, with 23 patients experiencing grade 3/4 liver dysfunction, primarily in conjunction with thioguanine induction therapy.

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The overall survival at 12 months was 68%. An additional phase I/II study for patients with relapsed, refractory, or de novo AML evaluated the safety and efficacy of GO (6 mg/m2) in combination with daunorubicin (45 mg/m2 days 1 to 3) and ara-C (100 mg/m2/d days 1 to 7).31 Fifteen of 18 patients achieved a CR with the median duration not reached at a median follow-up of 193 days. Plans for a phase III comparative trial of this regimen versus daunorubicin 60 mg/m2 and ara-C 100 mg/m2/d are underway. GO has also been combined with all-trans retinoic acid (ATRA) for the treatment of acute promyelocytic leukemia.32 Nineteen patients were treated with ATRA until CR with the addition of GO (9 mg/m2) on day 5. Maintenance ATRA and GO were used after achievement of CR. Sixteen patients (84%) achieved a CR, with 14 in a molecular CR, suggesting a benefit of the addition of GO to ATRA compared to historical controls. The combination of cytotoxic chemotherapy and GO is also being studied in older patients. Amadori et al presented data using GO on days 1 and 15 followed by the combination of mitoxantrone, ara-C, and etoposide in a cohort of patients with either de novo or secondary AML.29 Initial treatment with GO resulted in an overall response rate (CR ⫹ CRp) of 35% that was further increased to 54.4% with remission induction with combination chemotherapy. However, 14% of patients died of toxicity and the estimated probability of survival at 1 year is only 30%. Another study evaluated the combination of continuous infusion ara-C and GO.30 Twelve patients with a median age of 68 years were treated with GO (6 mg/m2 on day 1 and 4 mg/m2 on day 8) in combination with ara-C (100 mg/m2/d days 1 to 7). Therapy was well tolerated with only one patient experiencing a transient grade 4 elevation of transaminases. Integration of GO With HSCT Strategies The integration of GO and HSCT in the setting of relapsed AML is being further evaluated. In the original phase II studies by Sievers et al, 71 of the 277 patients achieved a CR.35 Twenty-five of these patients subsequently underwent HSCT as consolidation therapy in second CR. An additional 25 patients received further chemotherapy, while 21 patients had no further treatment. For those patients undergoing HSCT for consolidation, the median overall survival was 15.6 months. As previously demonstrated, the use of GO in the

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post-HSCT setting increases the risk of SOS. Consequently, a phase II multicenter study is investigating the safety and tolerability of GO in patients who are at least 60 days post-transplant.36 To date, 23 patients have been treated. Based on these data, patients with prior allogeneic HSCT appear more susceptible to SOS than those with prior autologous HSCT. Doses of 2 mg/m2 are being investigated in allogeneic HSCT patients and 6 mg/m2 for autologous HSCT patients. Potential Role of GO in Secondary AML and HighRisk Myelodysplastic Syndrome Patients with secondary AML, often the result of an antecedent myelodysplastic syndrome (MDS) that has progressed, usually have resistant disease. The role of GO is being further evaluated in the treatment of patients with secondary AML and/or high-risk MDS.28,37-39 Raza et al conducted a study in 26 patients with high-risk MDS, defined as refractory anemia with excess blasts in transformation.39 Patients were randomized to treatment with single-agent GO either as a single infusion on day 1 or two infusions on days 1 and 15. No patient achieved a CR and toxicities included 11 patients with grade 3/4 infections and eight patients with grade 3/4 hepatotoxicity. Eight of the 13 patients randomized to two infusions did not receive the second infusion due to infection or persistent adverse events. Estey et al compared the use of GO with or without interleukin-11 (IL-11) in patients with newly diagnosed AML or highrisk MDS.38 Fifty-one patients ⱖ 65 years of age were treated with GO (9 mg/m2) on days 1 and 15 (n ⫽ 22) or days 1 and 8 (n ⫽ 29) with or without IL-11. Complete responses were seen in 8% of patients without IL-11 and in 36% with IL-11. However, when compared with historical controls treated with idarubicin and ara-C, the CR rate was not improved in these patients. Other studies have looked at the addition of cytotoxic agents to GO for the treatment of this patient population.28,37 An additional study compared the efficacy and toxicity of GO in combination with ara-C, mitoxantrone, and amifostine in 19 patients with either relapsed AML or AML with prior MDS.37 Three patients had prior HSCT and died due to progressive hepatotoxicity after treatment with this regimen. An additional five patients without prior HSCT had treatment-related liver toxicity. Eleven of the 19 patients treated on study died of sepsis, bleeding, multiorgan failure, or progressive disease.

ANTIBODY THERAPY FOR AML

Six patients, five of whom were ⱕ55 years old, are alive and free of disease at a median of 325 days. Another group has evaluated the combination of GO, topotecan, and ara-C in 18 patients with refractory/relapsed AML or high-risk MDS.28 Two patients achieved a CR and five patients died within 4 weeks of treatment. Four of these deaths were due to sepsis. Despite its indications in relapsed disease, the role of GO continues to evolve. The data presented here support the role of further consolidative therapy after achievement of CR with GO. The treatment of choice seems to be HSCT, but the potential complications of SOS remain concerning. Furthermore, the use of GO in MDS remains unclear. Given the apparent role of Pgp in resistance to GO, it is unlikely that GO alone will provide adequate treatment for secondary AML and high-risk MDS. Further studies need to be performed and adequate time for data to mature before determining the efficacy of GO in combination with cytotoxic chemotherapy. CONCLUSIONS

The role of targeted therapy for the treatment of malignancy is continuing to expand as new targets are identified and advances in the conjugation of radioactive molecules and toxins occur. Clearly, the best-known examples of targeted therapy include imatinib mesylate for chronic myelogenous leukemia and rituximab for B-cell lymphomas. While GO is approved for older patients with relapsed AML who are intolerant of cytotoxic chemotherapy, its potential roles in other settings are actively being studied. The initial studies with GO demonstrated activity in relapsed patients, with approximately 30% of patients achieving a remission.11,12 However, toxicities include pancytopenia with associated infectious complications and hepatotoxicity. The association of hepatic SOS with this immunoconjugate has also been well described. These toxicities do not appear to be significantly different when GO is used in conjunction with cytotoxic chemotherapy, but the risk of SOS does appear greater when standard dosing schedules are employed in the peritransplant setting. The optimal role of GO continues to be defined through well-designed studies. Ongoing research defining the mechanisms of hepatotoxicity and the ways to diminish these toxicities will permit the integration of GO in HSCT strategies.24,35,36,40

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Additionally, mechanisms to alter the expression of CD33 antigens on the surface of AML blasts may prove particularly useful.41 Finally, understanding the mechanisms of resistance to GO may provide alternative combination therapy using multidrug resistance modulators resulting in CR for a greater number of patients. Since nearly two thirds of patients diagnosed with AML will die of their disease, the development of new drugs and new combinations remains critical. REFERENCES 1. Lowenberg B, Downing JR, Burnett A: Acute myeloid leukemia. N Engl J Med 341:1051-1062, 1999 2. NCCN Practice Guidelines in Oncology: Acute Myelogenous Leukemia. Rockledge, PA, National Comprehensive Cancer Network, 2002 3. Appelbaum F, Rowe JM, Radich J, et al: Acute myeloid leukemia. Hematology 62-86, 2001 4. Cuneo A, Bigoni R, Cavazzini F, et al: Incidence and significance of cryptic chromosome aberrations detected by fluorescence in situ hybridization in acute myeloid leukemia with normal karyotype. Leukemia 16:1745-1751, 2002 5. Hiddemann W, Kern W, Schoch C, et al: Management of acute myeloid leukemia in elderly patients. J Clin Oncol 17:3569-3576, 1999 6. Leith C, Kopecky KJ, Godwin J, et al: Acute myeloid leukemia in the elderly: Assessment of multidrug resistance (MDR1) and cytogenetics distinguishes biologic subgroups with remarkably distinct responses to standard chemotherapy. A Southwest Oncology Group study. Blood 89:3323-3329, 1997 7. Bross P, Beitz J, Chen G, et al: Approval summary: Gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin Cancer Res 7:1490-1496, 2001 8. Hamann P, Hinman LM, Hollander I, et al: Gemtuzumab ozogamicin, a potent and selective anti-CD33 antibodycalicheamicin conjugate for treatment of acute myeloid leukemia. Bioconjug Chem 13:47-58, 2002 9. van der Velden V, te Marvelde JG, Hoogeveen PG, et al: Targeting of the CD33-calicheamicin immunoconjugate Mylotarg (CMA-676) in acute myeloid leukemia: In vivo and in vitro saturation and internalization by leukemic and normal myeloid cells. Blood 97:3197-3204, 2001 10. Treish I: Targeting leukemia cells with gemtuzumab ozogamicin. Cancer Pract 8:254-257, 2000 11. Sievers E, Appelbaum FR, Spielberger RT, et al: Selective ablation of acute myeloid leukemia using antibody-targeted chemotherapy: A phase I study of an anti-CD33 calicheamicin immunoconjugate. Blood 93:3678-3684, 1999 12. Sievers E, Larson RA, Stadtmauer EA, et al: Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol 19:3244-3254, 2001 13. Larson R, Sievers EL, Stadtmauer EA, et al: A final analysis of the efficacy and safety of gemtuzumab ozogamicin in 277 patients with acute myeloid leukemia in first relapse. Blood 100:338a, 2002 (suppl 1, abstr) 14. Stadtmauer E, Sievers E, Larson R, et al: Final report of the effect of cytogenetic risk group on outcome of patients with

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of the EORTC Leukemia Group and GIMEMA. Blood 100: 340a, 2002 (suppl 1, abstr) 30. Baccarani M, Durrant S, Linkesh W, et al: Preliminary report of a phase 2 study of the safety and efficacy of gemtuzumab ozogamicin (Mylotarg) given in combination with cytarabine in patients with acute myeloid leukemia. Blood 100: 341a, 2002 (suppl 1, abstr) 31. De Angelo D, Schiffer C, Stone R, et al: Interim analysis of a phase II study of the safety and efficacy of gemtuzumab ozogamicin (Mylotarg) given in combination with cytarabine and daunorubicin in patients ⬍ 60 years old with untreated acute myeloid leukemia. Blood 100:198-199a, 2002 (suppl 1, abstr) 32. Estey E, Giles FJ, Beran M, et al: Experience with gemtuzumab ozogamycin (“Mylotarg” and all-trans retinoic acid in untreated acute promyelocytic leukemia. Blood 99:42224224, 2002 33. Kell J, Burnett AK, Chopra R, et al: Effects of Mylotarg (gemtuzumab ozogamicin, GO) in combination with standard induction chemotherapy in the treatment of acute myeloid leukaemia (AML): A feasiblity study. Blood 98:123a, 2001 (suppl 1, abstr) 34. Kell J, Burnett AK, Chopra R, et al: Mylotarg (gemtuzumab ozogamycin: GO) given simultaneously with intensive induction and/or consolidation therapy for AML is feasible and may improve the response rate. Blood 100:199a, 2002 (suppl 1, abstr) 35. Sievers E, Larson R, Estey E, et al: Final report of prolonged disease-free survival in patients with acute myeloid leukemia in first relapse treated with gemtuzumab ozogamicin followed by hematopoietic stem cell transplantation. Blood 100:89a, 2002 (suppl 1, abstr) 36. Sievers E, Spielberger R, Brunvand MW, et al: Gemtuzumab ozogamicin (Mylotarg) as a single agent to evaluate safety and determine maximum tolerated dose (MTD) in post hemaopoietic stem cell transplant patients with relapsed, CD33⫹ acute myeloid leukemia (AML). Blood 100:336a, 2002 (suppl 1, abstr) 37. Venugopal P, Gregory SA, Raza A, et al: Phase II study of gemtuzumab ozogamycin (Mylotarg) combined with intensive inductions chemotherapy using high dose ara-C and mitoxantrone followed by amifostine in poor prognosis acute myeloid leukemia: Preliminary results. Blood 100:341a, 2002 (suppl 1, abstr) 38. Estey E, Thall PF, Giles FJ, et al: Gemtuzumab ozogamicin with or without interleukin 11 in patients 65 years of age or older with untreated acute myeloid leukemia and high-risk myelodysplastic syndrome: Comparison with idarubicin plus continuous-infusion, high dose cytosine arabinoside. Blood 99: 4343-4349, 2002 39. Raza A, Fenaux P, Erba H, et al: Preliminary analysis of a randomized phase 2 study of the safety and efficacy of 1 vs. 2 doses of gemtuzumab ozogamicin (Mylotarg) in patients with high risk myelodysplastic syndrome. Blood 100:795a, 2002 (suppl 1, abstr) 40. Castaigne S, Raffoux E, Bastie JN, et al: Fractionated low-dose Mylotarg in relapsed AML patients. A pilot study. Blood 100:767a, 2002 (suppl 1, abstr) 41. Sivaraman S, Manjali J, Gregory SA, et al: G-CSF and other cytokines modulate expression of CD33 antigen on the surface of myeloid cells. Blood 100:554a, 2002 (suppl 1, abstr)