Phase III Randomized Multicenter Study of a Humanized Anti-CD33 Monoclonal Antibody, Lintuzumab, in Combination With Chemotherapy, Versus Ch
http://www.100md.com
《临床肿瘤学》
the Weill Medical College of Cornell University, New York, NY
Memorial Sloan-Kettering Cancer Center, New York, NY
Princess Margaret Hospital, Toronto, Ontario, Canada
Dana Farber Cancer Institute, Boston, MA
The Cleveland Clinic Foundation, Cleveland, OH
Duke University Medical Center, Durham, NC
Johns Hopkins Oncology Center, Baltimore
Greenebaum Cancer Center-University of Maryland, Baltimore, MD
Christie Hospital, Manchester, UK
Washington University, St Louis, MO
M.S. Hershey Medical Center, Hershey, PA
North Shore University Hospital, Manhasset, NY
Protein Design Laboratories, Fremont, CA
ABSTRACT
PURPOSE: Lintuzumab (HuM195) is an unconjugated humanized murine monoclonal antibody directed against the cell surface myelomonocytic differentiation antigen CD33. In this study, the efficacy of lintuzumab in combination with induction chemotherapy was compared with chemotherapy alone in adults with first relapsed or primary refractory acute myeloid leukemia (AML).
PATIENTS AND METHODS: Patients with relapsed or primary resistant AML (duration of first response, zero to 12 months) were randomly assigned to receive either mitoxantrone 8 mg/m2, etoposide 80 mg/m2, and cytarabine 1 g/m2 daily for 6 days (MEC) in combination with lintuzumab 12 mg/m2, or MEC alone. Overall response, defined as the rate of complete remission (CR) and CR with incomplete platelet recovery (CRp), was the primary end point of the study, with additional analyses of survival time and toxicity.
RESULTS: A total of 191 patients were randomly assigned from November 1999 to April 2001. The percent CR plus CRp with MEC plus lintuzumab was 36% v 28% in patients treated with MEC alone (P = .28). The overall median survival was 156 days and was not different in the two arms of the study. Apart from mild antibody infusion–related toxicities (fever, chills, and hypotension), no differences in chemotherapy-related adverse effects, including hepatic and cardiac dysfunction, were observed with the addition of lintuzumab to induction chemotherapy.
CONCLUSION: The addition of lintuzumab to salvage induction chemotherapy was safe, but did not result in a statistically significant improvement in response rate or survival in patients with refractory/relapsed AML.
INTRODUCTION
CD33 is a cell surface receptor, the presence of which is restricted to cells of myelomonocytic lineage.1,2 It has been shown to be a member of the sialic acid–binding immunoglobulin-like lectin family of receptors (Siglec) that contain cytoplasmic immune receptor–based tyrosine signaling motifs typically found in inhibitory receptors of the immune system.3,4 In vitro studies have demonstrated that engagement of the receptor with anti-CD33 antibodies results in a dose-dependent induction of apoptotic cell death in a manner similar to antibodies directed against other Siglec receptors such as CD22 in lymphoid malignancies.5,6 Because of its almost universal presence on acute myeloid leukemia (AML) blast cells (greater than 90%)7,8 and lack of expression on most, if not all, nonhematopoietic tissue, antibodies to CD33 have been developed to treat patients with AML.
The most successful anti-CD33 antibody-based drug to date has been gemtuzumab ozogamicin, composed of a humanized immunoglobulin G4 (IgG4) antibody conjugated to a powerful antitumor antibiotic, calicheamicin.9 When released into the leukemic cell, calicheamicin induces DNA damage and subsequent apoptotic cell death.10 In a series of three small phase II studies in adults with AML in first relapse, an overall 30% response rate (complete remission [CR] and CR with incomplete platelet recovery [CRp]) was achieved.11
An alternative approach directed toward CD33 has been the administration of an unconjugated antibody, lintuzumab (HuM195), a humanized monoclonal antibody consisting of a human IgG1 framework that contains human constant regions and murine complementarity–determining regions.12 In contrast to antibody-cytotoxic drug conjugates, unconjugated IgG1 antibodies have been shown to induce cell death by both complement and/or antibody-directed cellular cytotoxicity, or as a direct effect of the engagement of the CD33 receptor.12,13
The initial phase I studies with lintuzumab in AML primarily investigated the biodistribution, pharmacology, and immunogenicity of lintuzumab at doses ranging from 0.5 to 36 mg/m2. These studies demonstrated complete bone marrow targeting without blood pooling of radiolabeled lintuzumab after administration of 3 mg/m2 as well as complete and prolonged saturation of CD33, without evidence of a human antihuman antibody response at any dose. Of 23 patients enrolled onto two separate trials, lintuzumab, infused during 4 hours daily on days 1 to 4 and 15 to 18, resulted in clinical responses (reductions in peripheral and bone marrow blast counts) in five patients, including one CR in a patient who received 12 mg/m2. Toxicities were primarily related to the infusion period, and included fever, rigors, and transient hypotension.14,15
In a larger multicenter phase II investigation, lintuzumab was evaluated at two dose levels.16 Fifty adult patients (median age, 62 years) with AML refractory to or relapsed after chemotherapy were randomly assigned to receive lintuzumab at a dose of 12 or 36 mg/m2 by intravenous infusion during 4 hours on days 1 to 4 and 15 to 18. Of 49 assessable patients, two CRs and one partial remission (PR) were observed. All three responses were in patients treated at the 12 mg/m2 dose and all had baseline blast percentages less than 30%. Decreases in blast counts ranging from 30% to 74% were observed in nine additional patients. Toxicity was similar to that observed during the phase I trials. This phase II evaluation demonstrated that, as a single agent, lintuzumab had observable efficacy in patients with advanced AML; however, the antileukemic effects were confined to patients with low disease burden. This suggested that additional development of this agent would be best achieved by combining lintuzumab with chemotherapy, and that a phase III study of chemotherapy with or without lintuzumab would be optimal to assess the impact of this agent in relapsed or refractory AML.
PATIENTS AND METHODS
Patient Enrollment
Patients who were at least 18 years of age with AML (except acute promyelocytic leukemia [APL], French-American-British type M3) that was either resistant to initial induction, or that had relapsed within 1 year of first remission, were eligible for enrollment. Written informed consent, according to institutional guidelines, was obtained from all patients. Patients with treatment-related AML and those with pre-existing myelodysplastic syndrome or other antecedent hematologic disorders (other than chronic myeloid leukemia) were not excluded. Evidence of CD33 expression was not required to enter the study. A bone marrow blast count of at least 10% was required to confirm evidence of refractory or relapsed disease. Primary resistant patients were defined as patients with persistent leukemia after one to two cycles of a standard anthracycline/cytarabine induction regimen, and were excluded from the study if they had received a cumulative dose of cytarabine of 3 g/m2 or more during their initial induction therapy. This limitation on the prior dose of cytarabine received did not apply to patients with relapsed disease. In addition, patients were required to have serum levels of bilirubin and creatinine of less than 2 mg/dL, a normal left ventricular ejection fraction per institutional standard, and a Karnofsky performance status of at least 50%.
Treatment Plan
After baseline evaluations, all eligible patients received induction chemotherapy consisting of mitoxantrone 8 mg/m2, etoposide 80 mg/m2, and cytarabine 1 g/m2 daily each for 6 days (MEC). On day 5, patients were randomly assigned in a 1:1 ratio to continue to receive MEC alone (control group) or to receive lintuzumab in addition to MEC. This central randomization was stratified by age (50 years of age and older v younger than 50) and by duration of first CR (refractory or relapsed within 6 months [CR1, 0 to 6 months] v relapsed within > 6 to 12 months [CR1, > 6 to 12 months]). MEC was supplied by each institution, whereas lintuzumab was supplied by Protein Design Labs (Fremont, CA).
After induction chemotherapy was completed on day 6, patients in the lintuzumab arm received their first cycle of antibody, administered intravenously at a dose of 12 mg/m2 daily for 4 consecutive days, followed by a second cycle starting 10 to 12 days after completion of cycle 1. Before each infusion of lintuzumab throughout the study, patients received acetaminophen 650 mg and diphenhydramine 25 to 50 mg, with or without meperidine 25 to 50 mg, as premedication. Colony-stimulating factors were neither prohibited nor required during induction and consolidation periods. The use of these agents was at the discretion of the treating physician and no specific starting and stopping parameters were stipulated in the protocol.
Bone marrow aspirates and/or biopsies were obtained initially on days 29 to 36 and at subsequent intervals to assess remission status. CR was defined as the achievement of a cellular marrow with 5% myeloblasts or less, absence of circulating blasts, an absolute neutrophil count of 1.5 x 109/L, and a platelet count of more than 100 x 109/L for a duration of 4 weeks or longer. CRp was defined as achievement of all parameters of CR without full recovery of platelets to more than 100 x 109/L, but with platelet transfusion independence of at least 1 week. Control patients who did not achieve a CR were taken off study at the time of disease progression or when new therapy was started, and were observed subsequently for safety data until death. Lintuzumab patients without CR were allowed to continue with cycles of lintuzumab (up to 12 total) until disease progression or start of other therapy, at which time they also exited study and were observed for safety.
All patients who achieved CR received one consolidation chemotherapy cycle consisting of an attenuated MEC regimen given in the same doses as during induction for 4 days, with the exception of mitoxantrone, which was given for only 2 days or not at all if signs of cardiotoxicity (a reduction in left ventricular ejection fraction below normal and/or signs of clinical cardiotoxicity) had developed. As in the induction phase of the trial, patients in the control arm of the study received consolidation chemotherapy alone, whereas patients in the lintuzumab arm of the study received two additional cycles of antibody (cycles 3 and 4, separated by 10 to 12 days) after completion of consolidation chemotherapy.
A month after the start of consolidation therapy, responses were again assessed. Patients receiving the lintuzumab who remained in complete remission were eligible to receive additional 4-day cycles of maintenance therapy with lintuzumab monthly for up to eight more cycles (for a maximum total of 12 cycles), or until disease progression. Patients in the control arm of the study received no additional therapy.
Statistical Analysis
In this multicenter, randomized trial, the primary end point was rate of CR within 70 days of the start of induction therapy and before consolidation chemotherapy. The null hypothesis stated that the CR rates for each treatment were equal to 20%, which was the approximate expected rate of response to salvage therapy in this population. To detect an improvement in the CR rate from 20% to 40% with 80% power and a two-sided significance level of .05, 80 randomized patients per arm were required, leading to an enrollment goal of 200 patients to allow for dropouts and possible slight imprecision in estimating the control CR rate.
Secondary analyses included between-group comparisons of progression-free survival and of overall survival using Kaplan-Meier survival curves and log-rank test statistics. Multivariate Cox proportional hazards regression models were planned to relate time-to-event with treatment arm and prognostic variables, and would be used to test for significant between-group differences in durations. Initially, an additional secondary analysis was to compare CR plus PR rates between groups, in which a PR was defined as achievement of a bone marrow blast proportion of 5% or less and at least one of the other requirements for a CR was not achieved. During the trial, research involving an anti-CD33 immunoconjugate gemtuzumab ozogamicin led to the definition of a particular PR, termed CRp. Because CRp had been demonstrated to affect duration of survival,11 instead of performing a CR + PR analysis, an overall response (OR) was defined as CR + CRp any time before consolidation chemotherapy, and OR rates were compared between treatment groups of all randomized patients as the expanded primary analysis. Additional analyses included between-group comparisons of OR rate in subpopulations of interest split by age and duration of first CR.
A data safety monitoring board (DSMB) independent from the sponsor and the CRO periodically assessed safety data throughout the trial, and conducted the planned interim analysis after adequate data were available on at least 30 randomly assigned patients per arm. Prespecified stopping rules were serious safety concerns by the data safety monitoring board or a between-group CR rate in favor of the lintuzumab group at a two-sided significance level of .005 or less. In accordance with the O'Brien and Fleming methodology,17 a result significant at the final primary analysis would require a two-sided significance level of .048. The trial was not stopped on the basis of these rules, and continued to completion.
RESULTS
Patient Characteristics
November 12, 1999, to May 17, 2001, 191 adults with primary resistant AML or AML in untreated first relapse within 12 months of initial remission were entered onto the trial and randomly assigned to either chemotherapy with lintuzumab or chemotherapy alone. The baseline demographics for the patients entered are listed in Table 1. Overall, the two treatment groups were well matched with regard to patient age, performance status, and length of first response, and thus no statistically significant differences in baseline variables were observed between the arms of the study. Eighty-eight patients (46%) were older than age 60 years and more than 90% had an Eastern Cooperative Oncology Group performance status of 0 or 1. Sixty-nine percent of patients were either primary resistant to initial treatment (n = 86) or had experienced disease relapse within 6 months of achieving an initial remission (n = 46). There were more patients with a history of an antecedent hematologic disorder in the lintuzumab arm of the study compared with the control arm (29% v 21%), and more patients entered the study with a documented fever or infection in the lintuzumab arm compared with the control arm (26% v 22%). These differences were not statistically significant. Overall, 6% of patients had undergone a bone marrow transplantation during the first remission.
Induction Response and Toxicity
Of the 191 patients entered onto the trial, 94 were randomly assigned to receive chemotherapy in combination with lintuzumab and 97 received chemotherapy alone. Across both groups, 49 patients (26%) achieved a CR and 12 patients (6%) achieved CRp, for an OR rate of 32%. Patients who received lintuzumab had an OR rate of 36%, whereas patients receiving chemotherapy alone had an OR rate of 28% (Table 2). This difference in OR rate was not statistically significant (P = .28 by Fisher's exact test, two-sided). Induction-related mortality occurred in 15% of patients treated with chemotherapy in combination with lintuzumab, compared with 13% in patients treated with chemotherapy alone (P = not significant). OR rates for the patients with primary resistant AML or first remissions lasting 6 months or less were 22% for patients who received lintuzumab and 20% for control patients. OR rates for patients with first CR durations from more than 6 to 12 months were 64% for patients receiving lintuzumab versus 45% for patients receiving chemotherapy alone. However, these differences were not statistically significant.
Toxicity
All 191 patients except for one (in the lintuzumab group) completed the MEC induction regimen. Of the 94 patients randomly assigned to lintuzumab, only 12 did not complete the eight total infusions; thus, 87.2% received the prescribed dose. All patients experienced chemotherapy-related toxicities, whereas infusion-related events (primarily fever and chills), occurring on the day of lintuzumab administration, were the most common antibody-related adverse effects. Grade 3 fever and chills, attributed to administration of lintuzumab, occurred in 4% of 94 patients randomly assigned to lintuzumab (Table 3). Two patients developed a single episode of significant hypotension during administration of lintuzumab, in each case after having received several prior doses. In one patient, the hypotensive episode required temporary discontinuation of the antibody infusion and treatment with intravenous fluids. Both patients recovered from their hypotensive episodes and continued with subsequent cycles of lintuzumab. No specific studies, including measurement of anti-CD3 antibodies, were performed in patients developing infusion reactions.
Chemotherapy-related adverse effects included nausea/vomiting, oral mucositis, diarrhea, hepatotoxicity, and cardiac dysfunction (Table 3). Mucositis was the most common grade 3/4 toxicity observed, which occurred in 21% of patients overall. The incidence of grade 3 or greater mucositis was 19% in patients receiving lintuzumab versus 25% in patients treated with chemotherapy alone (P = not significant). Significant hepatic dysfunction was uncommon, occurring in 5% and 8% of patients with or without antibody, respectively. Significant cardiac dysfunction (defined as grades 3 or 4 tachycardia, arrhythmias, cardiomyopathy, pericarditis, pericardial effusion, myocardial infarction/ischemia, congestive heart failure, hypertension, and cardiovascular disorder) occurred in 13% of patients overall, with no increased incidence in patients treated with lintuzumab.
Survival
Survival from entry onto the study is shown in Figures 1 and 2. Overall median survival was 156 days and there was no significant difference in survival distributions between the two arms of the study (Fig 2). In addition, no significant difference in survival between the two arms of the study was seen in patients when analyzed by the duration of first CR, including patients with a first CR duration of 6 to 12 months. In that cohort, the median survival for lintuzumab-treated patients was 171.5 v 244 days for patients receiving chemotherapy alone (P = .37 by log-rank test). The median survival for all complete responders was 379 v 184 days for patients achieving CRp, with a P value of .04 by log-rank test applied to the survival distributions. Median survival for all nonresponders was 111 days (Fig 3).
DISCUSSION
Initial experiences with lintuzumab as a single agent in patients with relapsed/refractory AML demonstrated modest but observable antileukemic effects. Reductions in peripheral blood and bone marrow blast cells were seen in numerous patients, but achievement of CR occurred in less than 10% of patients and was confined to patients starting therapy with low-burden disease (blast percentage 5% to 30%).15,16 A similar pattern of lintuzumab effect that was limited to low-burden disease was also seen in patients with APL in CR with minimal disease documented by reverse transcriptase polymerase chain reaction evidence of PML/retinoic acid receptor (RAR)-alpha persisting in the marrow. In a study by Jurcic et al,18 11 of 22 patients with residual APL achieved a reverse transcriptase polymerase chain reaction–negative state after treatment with unconjugated lintuzumab. These studies demonstrated that the unconjugated antibody alone, which relies primarily on complement and/or antibody-directed cellular cytotoxicity, was relatively ineffective in patients with fully active AML, but might be of value if incorporated into current cytotoxic treatment regimens. The results of this randomized study have demonstrated that lintuzumab can be safely incorporated into an intensive induction regimen for AML, but that in the setting of poor-prognosis refractory or relapsed AML, the addition of lintuzumab does not result in a statistically significant improvement in remission rate or in survival duration when compared with patients treated with chemotherapy alone.
This trial represented the first clinical experience with the administration of an anti-CD33 antibody in combination with induction chemotherapy. The results have shown that an unconjugated anti-CD33 antibody can be added to an intensive induction chemotherapy regimen without worsening the toxicities associated with the cytotoxic agents. It was noteworthy that no increased hepatic or cardiac toxicities were observed in patients treated with chemotherapy and unattenuated doses of lintuzumab compared with patients treated with chemotherapy alone. Preliminary results reported from ongoing trials have demonstrated that the conjugated antibody, gemtuzumab ozogamicin, can also be safely combined with chemotherapy, but that the dose of the drug has to be reduced to avoid significant hepatotoxicity.19,20
Response rates to salvage therapy for patients with AML relapsing from, or refractory to, initial chemotherapy regimens depend significantly on the prognostic variables in the population treated, with age, duration of first response, bone marrow karyotype, and prior myelodysplastic syndrome being among the most important.21-24 Arguably, the cohort of patients enrolled onto this trial were among the most resistant of patients with AML undergoing salvage therapy; if the study were conducted in a group of patients with a more favorable prognosis, better results might have been achieved. More than two thirds of the patients entered had first response durations of less than 6 months, and of this group, 65% had not achieved an initial response. Patients older than age 60 represented a high percentage of those enrolled, and patients with prior myelodysplastic syndrome were not excluded. It is possible that these patients, who were relatively resistant to cytotoxic therapy, were unable to achieve sufficient cytoreduction of leukemic cells to a level where the addition of the unconjugated antibody might have resulted in a therapeutic advantage over chemotherapy alone. In less resistant patients enrolled onto the study (patients with first remissions lasting > 6 to 12 months) a higher response was seen in patients treated with antibody and chemotherapy compared with chemotherapy alone. These patients, however, represented a minority of patients in the study, and thus the difference in response rates was not statistically significant. It would require additional study in this less-resistant population of relapsed AML patients to determine if this apparent lintuzumab effect could be confirmed statistically.
In this trial, the degree of CD33 expression was not measured, and was not part of the eligibility criteria for entry. Although not conclusive, some studies have suggested a correlation between expression of CD33 and cytotoxicity induced by the conjugated anti-CD33 antibody, gemtuzumab ozogamicin.25 Although no observable correlation of CD33 expression and response has been demonstrated in the clinical trials, the phase II trials with gemtuzumab ozogamicin only included patients with a high degree of CD33 expression (> 80% of blasts with CD33 immunofluorescence staining four times above background).11 It is possible that anti-CD33 antibodies, and in particular, unconjugated antibodies such as lintuzumab, could have a reduced effect in patients with low or undetectable expression of CD33, and that entry of CD33-unselected patients into this randomized trial could have resulted in a dilution of the additive effects of lintuzumab.
The relatively large number of relapsed/refractory AML patients treated during this study allowed us to consider the merits of response definitions used in recent AML clinical trials. Until recently, for patients with AML, the only reliable surrogate end point for survival was CR, defined as the achievement of a post-treatment marrow with less than 5% myeloblasts and reconstitution of peripheral blood counts to adequate values. The clinical response designation CRp, indicating achievement of CR with incomplete platelet recovery, was first used to describe patients with AML treated with gemtuzumab ozogamicin in which fully half of the responding patients had incomplete platelet recovery.11 Because these patients appeared to have the same survival rates compared with patients achieving full CR, the lack of full platelet recovery was believed to be secondary to effects of anti-CD33 antibodies on normal hematopoiesis, rather than to represent evidence of residual leukemia. In our experience, 6% of patients treated with chemotherapy with or without lintuzumab achieved CRp. These patients, in contrast to patients achieving CRp in response to gemtuzumab ozogamicin, had rapid progression of leukemia and had a significantly worse survival compared with patients achieving a full CR. This may reflect the fact that many more patients achieving CRp treated with gemtuzumab ozogamicin underwent a subsequent hematopoietic stem-cell transplantation, whereas few patients in this study underwent a transplantation. For example, only one of 12 patients achieving CRp treated on this trial underwent a subsequent transplantation. In comparison, of the 142 patients reported by Sievers,11 seven of 19 patients achieving CRp underwent a transplantation. This would suggest that CRp might be a meaningful response only in that it allows patients to proceed to transplantation if this option is available to them. Although achievement of CRp results in better outcomes for those patients than for nonresponders, it should not be considered equivalent to CR as a reflection of the degree of leukemic cytoreduction.
Although additional studies with the unconjugated anti-CD33 antibody might demonstrate usefulness in a narrower segment of AML patients who have experienced disease relapse, the focus of development of lintuzumab has broadened to include the development of this antibody to deliver radioisotopes or toxins to leukemic cells. Several preliminary studies have demonstrated the safety and feasibility of anti-CD33 antibodies conjugated to beta particles such as iodine-131and yttrium-90.26,27 More recently, lintuzumab conjugated to alpha-emitting compounds such as bismuth has shown clinical activity in patients with refractory AML.28
Authors' Disclosures of Potential Conflicts of Interest
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Employment: Joseph C. Jurcic, Memorial Sloan-Kettering Cancer Center. Consultant/Advisory Role: Eric J. Feldman, Protein Design Labs; Richard Stone, Wyeth; Nancy Wedel, Protein Design Labs. Stock Ownership: Julie O'Connor, Protein Design Labs. Honoraria: Richard Stone, Wyeth; Raj Chopra, Amgen, Chingan, Pfizer. Research Funding: Joseph Brandwein, Protein Design Labs; Matt Kalaycio, Protein Design Labs; Joseph C Jurcic, Protein Design Labs; Philip Schulman, Protein Design Labs. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.
NOTES
Presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, May 18-21, 2002, Orlando, FL.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
Griffin JD, Linch D, Sabbath K, et al: A monoclonal antibody reactive with normal and leukemic myeloid progenitor cells. Leuk Res 8:521-534, 1984
Andrews RG, Torok-Storb B, Bernstein JD: Myeloid-associated differentiation antigens on stem cells and their progeny identified by monoclonal antibodies. Blood 62:124-132, 1983
Freeman SD, Kelm S, Barber EK, et al: Characterization of CD33 as a new member of the sialoadhesion family of cellular interaction molecules. Blood 85:2005-2012, 1995
Cornish AL, Freeman S, Forbes G, et al: Characterization of siglec-5, a novel glycoprotein expressed on myeloid cells related to CD33. Blood 92:2123-2132, 1998
Mingari MC, Vitale C, Romagnani C, et al: P75/AIRM1 and CD33, two sialoadhesion receptors that regulate the proliferation or the survival of normal and leukemic myeloid cells. Immunol Rev 181:260-268, 2001
Vitale C, Romagnani C, Puccetti A, et al: Surface expression and function of p75/AIRM-1 or CD33 in acute myeloid leukemias: Engagement of CD33 induces apoptosis of leukemic cells. Proc Natl Acad Sci U S A 98:5764-5769, 2001
Jilani I, Estey E, Huh Y, et al: Differences in CD33 intensity between various myeloid neoplasms. Am J Clin Pathol 118:560-566, 2002
Dinndorf PA, Andrews RG, Benjamin D, et al: Expression of normal myeloid-associated antigens by acute leukemia cells. Blood 67:1048-1053, 1986
Zein N, Poncin M, Nilakantan R, et al: Calicheamicin gamma II and DNA: Molecular recognition process responsible for site-specificity. Science 244:697-699, 1989
Prokop A, Wrasidlo W, Lode H, et al: Induction of apoptosis by enediyne antibiotic calicheamicin theta II proceeds through caspase-mediated mitochondrial amplification loop in an entirely Bax-dependent manner. Oncogene 22:9107-9120, 2003
Sievers EL, 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
Caron PC, Co MS, Bull MK, et al: Biological and immunological features of humanized M195 (anti-CD33) monoclonal antibodies. Cancer Res 52:6761-6767, 1992
Vitale C, Romagnani C, Falco M, et al: Engagement of p75/AIRM1 or CD33 inhibits the proliferation of normal or leukemic myeloid cells. Proc Natl Acad Sci U S A 96:5091-5096, 1999
Caron PC, Jurcic JG, Scott AM, et al: A phase IB trial of a humanized monoclonal antibody M195 (anti-CD33) in myeloid leukemia: Specific targeting without immunogenicity. Blood 83:1760-1768, 1994
Caron PC, Dumont L, Scheinberg DA: Supersaturating infusional humanized anti-CD33 monoclonal antibody HuM195 in myelogenous leukemia. Clin Cancer Res 4:1421-1428, 1998
Feldman E, Kalaycio M, Weiner G, et al: Treatment of relapsed or refractory acute myeloid leukemia with humanized anti-CD33 monoclonal antibody HuM195. Leukemia 17:314-318, 2003
O'Brien PC, Fleming TR: A multiple testing procedure for clinical trials. Biometrics 35:549-559, 1979
Jurcic JG, DeBlasio T, Dumont, et al: Molecular remission induction with retinoic acid and anti-CD33 monoclonal antibody HuM195 in acute promyelocytic leukemia. Clin Cancer Res 6:372-380, 2000
Cortes J, Tsimberidou AM, Alvarez R, et al: Mylotarg combined with topotecan and cytarabine in patients with refractory acute myelogenous leukemia. Cancer Chemother Pharmacol 50:497-500, 2002
Kell WJ, Burnett AK, Chopra R, et al: A feasibility study of simultaneous administration of gemtuzumab ozogamicin with intensive chemotherapy in induction and consolidation in younger patients with acute myeloid leukemia. Blood 102:4277-4283, 2003
Keating MJ, Kantarjian H, Smith TL, et al: Response to salvage therapy and survival after relapse in acute myelogenous leukemia. J Clin Oncol 7:1071-1080, 1989
Kantarjian H, Keating MJ, Walters RS, et al: The characteristics and outcome of patients with late relapse acute myelogenous leukemia. J Clin Oncol 6:232-238, 1988
Kern W, Schoch C, Haferlach T, et al: Multivariate analysis of prognostic factors in patients with refractory and relapsed acute myeloid leukemia undergoing sequential high-dose cytosine arabinoside and mitoxantrone (S-HAM) salvage therapy: Relevance of cytogenetic abnormalities. Leukemia 14:226-231, 2000
Estey E, Thall P, David C. Design and analysis of trial of salvage therapy in acute myelogenous leukemia. Cancer Chemother Pharmacol 40:S9-S12, 1997 (suppl)
Walter RB, Raden BW, Karnikura DM, et al: Influence of CD33 expression levels and ITIM-dependent internalization on gemtuzumab ozogamicin-induced cytotoxicity. Blood 105:1295-1302, 2005
Burke JM, Caron PC, Papadopoulos EB, et al: Cytoreduction with iodine-131-anti-CD33 antibodies before bone marrow transplantation for advanced myeloid leukemias. Bone Marrow Transplant 32:549-556, 2003
Mulford DA, Jurcic JG: Antibody-based treatment of acute myeloid leukemia. Expert Opin Biol Ther 4:95-105, 2004
Jurcic JG, Larson SM, Sgouros G, et al: Targeted alpha particle immunotherapy for myeloid leukemia. Blood 100:1233-1239, 2002(Eric J. Feldman, Joseph B)
Memorial Sloan-Kettering Cancer Center, New York, NY
Princess Margaret Hospital, Toronto, Ontario, Canada
Dana Farber Cancer Institute, Boston, MA
The Cleveland Clinic Foundation, Cleveland, OH
Duke University Medical Center, Durham, NC
Johns Hopkins Oncology Center, Baltimore
Greenebaum Cancer Center-University of Maryland, Baltimore, MD
Christie Hospital, Manchester, UK
Washington University, St Louis, MO
M.S. Hershey Medical Center, Hershey, PA
North Shore University Hospital, Manhasset, NY
Protein Design Laboratories, Fremont, CA
ABSTRACT
PURPOSE: Lintuzumab (HuM195) is an unconjugated humanized murine monoclonal antibody directed against the cell surface myelomonocytic differentiation antigen CD33. In this study, the efficacy of lintuzumab in combination with induction chemotherapy was compared with chemotherapy alone in adults with first relapsed or primary refractory acute myeloid leukemia (AML).
PATIENTS AND METHODS: Patients with relapsed or primary resistant AML (duration of first response, zero to 12 months) were randomly assigned to receive either mitoxantrone 8 mg/m2, etoposide 80 mg/m2, and cytarabine 1 g/m2 daily for 6 days (MEC) in combination with lintuzumab 12 mg/m2, or MEC alone. Overall response, defined as the rate of complete remission (CR) and CR with incomplete platelet recovery (CRp), was the primary end point of the study, with additional analyses of survival time and toxicity.
RESULTS: A total of 191 patients were randomly assigned from November 1999 to April 2001. The percent CR plus CRp with MEC plus lintuzumab was 36% v 28% in patients treated with MEC alone (P = .28). The overall median survival was 156 days and was not different in the two arms of the study. Apart from mild antibody infusion–related toxicities (fever, chills, and hypotension), no differences in chemotherapy-related adverse effects, including hepatic and cardiac dysfunction, were observed with the addition of lintuzumab to induction chemotherapy.
CONCLUSION: The addition of lintuzumab to salvage induction chemotherapy was safe, but did not result in a statistically significant improvement in response rate or survival in patients with refractory/relapsed AML.
INTRODUCTION
CD33 is a cell surface receptor, the presence of which is restricted to cells of myelomonocytic lineage.1,2 It has been shown to be a member of the sialic acid–binding immunoglobulin-like lectin family of receptors (Siglec) that contain cytoplasmic immune receptor–based tyrosine signaling motifs typically found in inhibitory receptors of the immune system.3,4 In vitro studies have demonstrated that engagement of the receptor with anti-CD33 antibodies results in a dose-dependent induction of apoptotic cell death in a manner similar to antibodies directed against other Siglec receptors such as CD22 in lymphoid malignancies.5,6 Because of its almost universal presence on acute myeloid leukemia (AML) blast cells (greater than 90%)7,8 and lack of expression on most, if not all, nonhematopoietic tissue, antibodies to CD33 have been developed to treat patients with AML.
The most successful anti-CD33 antibody-based drug to date has been gemtuzumab ozogamicin, composed of a humanized immunoglobulin G4 (IgG4) antibody conjugated to a powerful antitumor antibiotic, calicheamicin.9 When released into the leukemic cell, calicheamicin induces DNA damage and subsequent apoptotic cell death.10 In a series of three small phase II studies in adults with AML in first relapse, an overall 30% response rate (complete remission [CR] and CR with incomplete platelet recovery [CRp]) was achieved.11
An alternative approach directed toward CD33 has been the administration of an unconjugated antibody, lintuzumab (HuM195), a humanized monoclonal antibody consisting of a human IgG1 framework that contains human constant regions and murine complementarity–determining regions.12 In contrast to antibody-cytotoxic drug conjugates, unconjugated IgG1 antibodies have been shown to induce cell death by both complement and/or antibody-directed cellular cytotoxicity, or as a direct effect of the engagement of the CD33 receptor.12,13
The initial phase I studies with lintuzumab in AML primarily investigated the biodistribution, pharmacology, and immunogenicity of lintuzumab at doses ranging from 0.5 to 36 mg/m2. These studies demonstrated complete bone marrow targeting without blood pooling of radiolabeled lintuzumab after administration of 3 mg/m2 as well as complete and prolonged saturation of CD33, without evidence of a human antihuman antibody response at any dose. Of 23 patients enrolled onto two separate trials, lintuzumab, infused during 4 hours daily on days 1 to 4 and 15 to 18, resulted in clinical responses (reductions in peripheral and bone marrow blast counts) in five patients, including one CR in a patient who received 12 mg/m2. Toxicities were primarily related to the infusion period, and included fever, rigors, and transient hypotension.14,15
In a larger multicenter phase II investigation, lintuzumab was evaluated at two dose levels.16 Fifty adult patients (median age, 62 years) with AML refractory to or relapsed after chemotherapy were randomly assigned to receive lintuzumab at a dose of 12 or 36 mg/m2 by intravenous infusion during 4 hours on days 1 to 4 and 15 to 18. Of 49 assessable patients, two CRs and one partial remission (PR) were observed. All three responses were in patients treated at the 12 mg/m2 dose and all had baseline blast percentages less than 30%. Decreases in blast counts ranging from 30% to 74% were observed in nine additional patients. Toxicity was similar to that observed during the phase I trials. This phase II evaluation demonstrated that, as a single agent, lintuzumab had observable efficacy in patients with advanced AML; however, the antileukemic effects were confined to patients with low disease burden. This suggested that additional development of this agent would be best achieved by combining lintuzumab with chemotherapy, and that a phase III study of chemotherapy with or without lintuzumab would be optimal to assess the impact of this agent in relapsed or refractory AML.
PATIENTS AND METHODS
Patient Enrollment
Patients who were at least 18 years of age with AML (except acute promyelocytic leukemia [APL], French-American-British type M3) that was either resistant to initial induction, or that had relapsed within 1 year of first remission, were eligible for enrollment. Written informed consent, according to institutional guidelines, was obtained from all patients. Patients with treatment-related AML and those with pre-existing myelodysplastic syndrome or other antecedent hematologic disorders (other than chronic myeloid leukemia) were not excluded. Evidence of CD33 expression was not required to enter the study. A bone marrow blast count of at least 10% was required to confirm evidence of refractory or relapsed disease. Primary resistant patients were defined as patients with persistent leukemia after one to two cycles of a standard anthracycline/cytarabine induction regimen, and were excluded from the study if they had received a cumulative dose of cytarabine of 3 g/m2 or more during their initial induction therapy. This limitation on the prior dose of cytarabine received did not apply to patients with relapsed disease. In addition, patients were required to have serum levels of bilirubin and creatinine of less than 2 mg/dL, a normal left ventricular ejection fraction per institutional standard, and a Karnofsky performance status of at least 50%.
Treatment Plan
After baseline evaluations, all eligible patients received induction chemotherapy consisting of mitoxantrone 8 mg/m2, etoposide 80 mg/m2, and cytarabine 1 g/m2 daily each for 6 days (MEC). On day 5, patients were randomly assigned in a 1:1 ratio to continue to receive MEC alone (control group) or to receive lintuzumab in addition to MEC. This central randomization was stratified by age (50 years of age and older v younger than 50) and by duration of first CR (refractory or relapsed within 6 months [CR1, 0 to 6 months] v relapsed within > 6 to 12 months [CR1, > 6 to 12 months]). MEC was supplied by each institution, whereas lintuzumab was supplied by Protein Design Labs (Fremont, CA).
After induction chemotherapy was completed on day 6, patients in the lintuzumab arm received their first cycle of antibody, administered intravenously at a dose of 12 mg/m2 daily for 4 consecutive days, followed by a second cycle starting 10 to 12 days after completion of cycle 1. Before each infusion of lintuzumab throughout the study, patients received acetaminophen 650 mg and diphenhydramine 25 to 50 mg, with or without meperidine 25 to 50 mg, as premedication. Colony-stimulating factors were neither prohibited nor required during induction and consolidation periods. The use of these agents was at the discretion of the treating physician and no specific starting and stopping parameters were stipulated in the protocol.
Bone marrow aspirates and/or biopsies were obtained initially on days 29 to 36 and at subsequent intervals to assess remission status. CR was defined as the achievement of a cellular marrow with 5% myeloblasts or less, absence of circulating blasts, an absolute neutrophil count of 1.5 x 109/L, and a platelet count of more than 100 x 109/L for a duration of 4 weeks or longer. CRp was defined as achievement of all parameters of CR without full recovery of platelets to more than 100 x 109/L, but with platelet transfusion independence of at least 1 week. Control patients who did not achieve a CR were taken off study at the time of disease progression or when new therapy was started, and were observed subsequently for safety data until death. Lintuzumab patients without CR were allowed to continue with cycles of lintuzumab (up to 12 total) until disease progression or start of other therapy, at which time they also exited study and were observed for safety.
All patients who achieved CR received one consolidation chemotherapy cycle consisting of an attenuated MEC regimen given in the same doses as during induction for 4 days, with the exception of mitoxantrone, which was given for only 2 days or not at all if signs of cardiotoxicity (a reduction in left ventricular ejection fraction below normal and/or signs of clinical cardiotoxicity) had developed. As in the induction phase of the trial, patients in the control arm of the study received consolidation chemotherapy alone, whereas patients in the lintuzumab arm of the study received two additional cycles of antibody (cycles 3 and 4, separated by 10 to 12 days) after completion of consolidation chemotherapy.
A month after the start of consolidation therapy, responses were again assessed. Patients receiving the lintuzumab who remained in complete remission were eligible to receive additional 4-day cycles of maintenance therapy with lintuzumab monthly for up to eight more cycles (for a maximum total of 12 cycles), or until disease progression. Patients in the control arm of the study received no additional therapy.
Statistical Analysis
In this multicenter, randomized trial, the primary end point was rate of CR within 70 days of the start of induction therapy and before consolidation chemotherapy. The null hypothesis stated that the CR rates for each treatment were equal to 20%, which was the approximate expected rate of response to salvage therapy in this population. To detect an improvement in the CR rate from 20% to 40% with 80% power and a two-sided significance level of .05, 80 randomized patients per arm were required, leading to an enrollment goal of 200 patients to allow for dropouts and possible slight imprecision in estimating the control CR rate.
Secondary analyses included between-group comparisons of progression-free survival and of overall survival using Kaplan-Meier survival curves and log-rank test statistics. Multivariate Cox proportional hazards regression models were planned to relate time-to-event with treatment arm and prognostic variables, and would be used to test for significant between-group differences in durations. Initially, an additional secondary analysis was to compare CR plus PR rates between groups, in which a PR was defined as achievement of a bone marrow blast proportion of 5% or less and at least one of the other requirements for a CR was not achieved. During the trial, research involving an anti-CD33 immunoconjugate gemtuzumab ozogamicin led to the definition of a particular PR, termed CRp. Because CRp had been demonstrated to affect duration of survival,11 instead of performing a CR + PR analysis, an overall response (OR) was defined as CR + CRp any time before consolidation chemotherapy, and OR rates were compared between treatment groups of all randomized patients as the expanded primary analysis. Additional analyses included between-group comparisons of OR rate in subpopulations of interest split by age and duration of first CR.
A data safety monitoring board (DSMB) independent from the sponsor and the CRO periodically assessed safety data throughout the trial, and conducted the planned interim analysis after adequate data were available on at least 30 randomly assigned patients per arm. Prespecified stopping rules were serious safety concerns by the data safety monitoring board or a between-group CR rate in favor of the lintuzumab group at a two-sided significance level of .005 or less. In accordance with the O'Brien and Fleming methodology,17 a result significant at the final primary analysis would require a two-sided significance level of .048. The trial was not stopped on the basis of these rules, and continued to completion.
RESULTS
Patient Characteristics
November 12, 1999, to May 17, 2001, 191 adults with primary resistant AML or AML in untreated first relapse within 12 months of initial remission were entered onto the trial and randomly assigned to either chemotherapy with lintuzumab or chemotherapy alone. The baseline demographics for the patients entered are listed in Table 1. Overall, the two treatment groups were well matched with regard to patient age, performance status, and length of first response, and thus no statistically significant differences in baseline variables were observed between the arms of the study. Eighty-eight patients (46%) were older than age 60 years and more than 90% had an Eastern Cooperative Oncology Group performance status of 0 or 1. Sixty-nine percent of patients were either primary resistant to initial treatment (n = 86) or had experienced disease relapse within 6 months of achieving an initial remission (n = 46). There were more patients with a history of an antecedent hematologic disorder in the lintuzumab arm of the study compared with the control arm (29% v 21%), and more patients entered the study with a documented fever or infection in the lintuzumab arm compared with the control arm (26% v 22%). These differences were not statistically significant. Overall, 6% of patients had undergone a bone marrow transplantation during the first remission.
Induction Response and Toxicity
Of the 191 patients entered onto the trial, 94 were randomly assigned to receive chemotherapy in combination with lintuzumab and 97 received chemotherapy alone. Across both groups, 49 patients (26%) achieved a CR and 12 patients (6%) achieved CRp, for an OR rate of 32%. Patients who received lintuzumab had an OR rate of 36%, whereas patients receiving chemotherapy alone had an OR rate of 28% (Table 2). This difference in OR rate was not statistically significant (P = .28 by Fisher's exact test, two-sided). Induction-related mortality occurred in 15% of patients treated with chemotherapy in combination with lintuzumab, compared with 13% in patients treated with chemotherapy alone (P = not significant). OR rates for the patients with primary resistant AML or first remissions lasting 6 months or less were 22% for patients who received lintuzumab and 20% for control patients. OR rates for patients with first CR durations from more than 6 to 12 months were 64% for patients receiving lintuzumab versus 45% for patients receiving chemotherapy alone. However, these differences were not statistically significant.
Toxicity
All 191 patients except for one (in the lintuzumab group) completed the MEC induction regimen. Of the 94 patients randomly assigned to lintuzumab, only 12 did not complete the eight total infusions; thus, 87.2% received the prescribed dose. All patients experienced chemotherapy-related toxicities, whereas infusion-related events (primarily fever and chills), occurring on the day of lintuzumab administration, were the most common antibody-related adverse effects. Grade 3 fever and chills, attributed to administration of lintuzumab, occurred in 4% of 94 patients randomly assigned to lintuzumab (Table 3). Two patients developed a single episode of significant hypotension during administration of lintuzumab, in each case after having received several prior doses. In one patient, the hypotensive episode required temporary discontinuation of the antibody infusion and treatment with intravenous fluids. Both patients recovered from their hypotensive episodes and continued with subsequent cycles of lintuzumab. No specific studies, including measurement of anti-CD3 antibodies, were performed in patients developing infusion reactions.
Chemotherapy-related adverse effects included nausea/vomiting, oral mucositis, diarrhea, hepatotoxicity, and cardiac dysfunction (Table 3). Mucositis was the most common grade 3/4 toxicity observed, which occurred in 21% of patients overall. The incidence of grade 3 or greater mucositis was 19% in patients receiving lintuzumab versus 25% in patients treated with chemotherapy alone (P = not significant). Significant hepatic dysfunction was uncommon, occurring in 5% and 8% of patients with or without antibody, respectively. Significant cardiac dysfunction (defined as grades 3 or 4 tachycardia, arrhythmias, cardiomyopathy, pericarditis, pericardial effusion, myocardial infarction/ischemia, congestive heart failure, hypertension, and cardiovascular disorder) occurred in 13% of patients overall, with no increased incidence in patients treated with lintuzumab.
Survival
Survival from entry onto the study is shown in Figures 1 and 2. Overall median survival was 156 days and there was no significant difference in survival distributions between the two arms of the study (Fig 2). In addition, no significant difference in survival between the two arms of the study was seen in patients when analyzed by the duration of first CR, including patients with a first CR duration of 6 to 12 months. In that cohort, the median survival for lintuzumab-treated patients was 171.5 v 244 days for patients receiving chemotherapy alone (P = .37 by log-rank test). The median survival for all complete responders was 379 v 184 days for patients achieving CRp, with a P value of .04 by log-rank test applied to the survival distributions. Median survival for all nonresponders was 111 days (Fig 3).
DISCUSSION
Initial experiences with lintuzumab as a single agent in patients with relapsed/refractory AML demonstrated modest but observable antileukemic effects. Reductions in peripheral blood and bone marrow blast cells were seen in numerous patients, but achievement of CR occurred in less than 10% of patients and was confined to patients starting therapy with low-burden disease (blast percentage 5% to 30%).15,16 A similar pattern of lintuzumab effect that was limited to low-burden disease was also seen in patients with APL in CR with minimal disease documented by reverse transcriptase polymerase chain reaction evidence of PML/retinoic acid receptor (RAR)-alpha persisting in the marrow. In a study by Jurcic et al,18 11 of 22 patients with residual APL achieved a reverse transcriptase polymerase chain reaction–negative state after treatment with unconjugated lintuzumab. These studies demonstrated that the unconjugated antibody alone, which relies primarily on complement and/or antibody-directed cellular cytotoxicity, was relatively ineffective in patients with fully active AML, but might be of value if incorporated into current cytotoxic treatment regimens. The results of this randomized study have demonstrated that lintuzumab can be safely incorporated into an intensive induction regimen for AML, but that in the setting of poor-prognosis refractory or relapsed AML, the addition of lintuzumab does not result in a statistically significant improvement in remission rate or in survival duration when compared with patients treated with chemotherapy alone.
This trial represented the first clinical experience with the administration of an anti-CD33 antibody in combination with induction chemotherapy. The results have shown that an unconjugated anti-CD33 antibody can be added to an intensive induction chemotherapy regimen without worsening the toxicities associated with the cytotoxic agents. It was noteworthy that no increased hepatic or cardiac toxicities were observed in patients treated with chemotherapy and unattenuated doses of lintuzumab compared with patients treated with chemotherapy alone. Preliminary results reported from ongoing trials have demonstrated that the conjugated antibody, gemtuzumab ozogamicin, can also be safely combined with chemotherapy, but that the dose of the drug has to be reduced to avoid significant hepatotoxicity.19,20
Response rates to salvage therapy for patients with AML relapsing from, or refractory to, initial chemotherapy regimens depend significantly on the prognostic variables in the population treated, with age, duration of first response, bone marrow karyotype, and prior myelodysplastic syndrome being among the most important.21-24 Arguably, the cohort of patients enrolled onto this trial were among the most resistant of patients with AML undergoing salvage therapy; if the study were conducted in a group of patients with a more favorable prognosis, better results might have been achieved. More than two thirds of the patients entered had first response durations of less than 6 months, and of this group, 65% had not achieved an initial response. Patients older than age 60 represented a high percentage of those enrolled, and patients with prior myelodysplastic syndrome were not excluded. It is possible that these patients, who were relatively resistant to cytotoxic therapy, were unable to achieve sufficient cytoreduction of leukemic cells to a level where the addition of the unconjugated antibody might have resulted in a therapeutic advantage over chemotherapy alone. In less resistant patients enrolled onto the study (patients with first remissions lasting > 6 to 12 months) a higher response was seen in patients treated with antibody and chemotherapy compared with chemotherapy alone. These patients, however, represented a minority of patients in the study, and thus the difference in response rates was not statistically significant. It would require additional study in this less-resistant population of relapsed AML patients to determine if this apparent lintuzumab effect could be confirmed statistically.
In this trial, the degree of CD33 expression was not measured, and was not part of the eligibility criteria for entry. Although not conclusive, some studies have suggested a correlation between expression of CD33 and cytotoxicity induced by the conjugated anti-CD33 antibody, gemtuzumab ozogamicin.25 Although no observable correlation of CD33 expression and response has been demonstrated in the clinical trials, the phase II trials with gemtuzumab ozogamicin only included patients with a high degree of CD33 expression (> 80% of blasts with CD33 immunofluorescence staining four times above background).11 It is possible that anti-CD33 antibodies, and in particular, unconjugated antibodies such as lintuzumab, could have a reduced effect in patients with low or undetectable expression of CD33, and that entry of CD33-unselected patients into this randomized trial could have resulted in a dilution of the additive effects of lintuzumab.
The relatively large number of relapsed/refractory AML patients treated during this study allowed us to consider the merits of response definitions used in recent AML clinical trials. Until recently, for patients with AML, the only reliable surrogate end point for survival was CR, defined as the achievement of a post-treatment marrow with less than 5% myeloblasts and reconstitution of peripheral blood counts to adequate values. The clinical response designation CRp, indicating achievement of CR with incomplete platelet recovery, was first used to describe patients with AML treated with gemtuzumab ozogamicin in which fully half of the responding patients had incomplete platelet recovery.11 Because these patients appeared to have the same survival rates compared with patients achieving full CR, the lack of full platelet recovery was believed to be secondary to effects of anti-CD33 antibodies on normal hematopoiesis, rather than to represent evidence of residual leukemia. In our experience, 6% of patients treated with chemotherapy with or without lintuzumab achieved CRp. These patients, in contrast to patients achieving CRp in response to gemtuzumab ozogamicin, had rapid progression of leukemia and had a significantly worse survival compared with patients achieving a full CR. This may reflect the fact that many more patients achieving CRp treated with gemtuzumab ozogamicin underwent a subsequent hematopoietic stem-cell transplantation, whereas few patients in this study underwent a transplantation. For example, only one of 12 patients achieving CRp treated on this trial underwent a subsequent transplantation. In comparison, of the 142 patients reported by Sievers,11 seven of 19 patients achieving CRp underwent a transplantation. This would suggest that CRp might be a meaningful response only in that it allows patients to proceed to transplantation if this option is available to them. Although achievement of CRp results in better outcomes for those patients than for nonresponders, it should not be considered equivalent to CR as a reflection of the degree of leukemic cytoreduction.
Although additional studies with the unconjugated anti-CD33 antibody might demonstrate usefulness in a narrower segment of AML patients who have experienced disease relapse, the focus of development of lintuzumab has broadened to include the development of this antibody to deliver radioisotopes or toxins to leukemic cells. Several preliminary studies have demonstrated the safety and feasibility of anti-CD33 antibodies conjugated to beta particles such as iodine-131and yttrium-90.26,27 More recently, lintuzumab conjugated to alpha-emitting compounds such as bismuth has shown clinical activity in patients with refractory AML.28
Authors' Disclosures of Potential Conflicts of Interest
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Employment: Joseph C. Jurcic, Memorial Sloan-Kettering Cancer Center. Consultant/Advisory Role: Eric J. Feldman, Protein Design Labs; Richard Stone, Wyeth; Nancy Wedel, Protein Design Labs. Stock Ownership: Julie O'Connor, Protein Design Labs. Honoraria: Richard Stone, Wyeth; Raj Chopra, Amgen, Chingan, Pfizer. Research Funding: Joseph Brandwein, Protein Design Labs; Matt Kalaycio, Protein Design Labs; Joseph C Jurcic, Protein Design Labs; Philip Schulman, Protein Design Labs. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.
NOTES
Presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, May 18-21, 2002, Orlando, FL.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
Griffin JD, Linch D, Sabbath K, et al: A monoclonal antibody reactive with normal and leukemic myeloid progenitor cells. Leuk Res 8:521-534, 1984
Andrews RG, Torok-Storb B, Bernstein JD: Myeloid-associated differentiation antigens on stem cells and their progeny identified by monoclonal antibodies. Blood 62:124-132, 1983
Freeman SD, Kelm S, Barber EK, et al: Characterization of CD33 as a new member of the sialoadhesion family of cellular interaction molecules. Blood 85:2005-2012, 1995
Cornish AL, Freeman S, Forbes G, et al: Characterization of siglec-5, a novel glycoprotein expressed on myeloid cells related to CD33. Blood 92:2123-2132, 1998
Mingari MC, Vitale C, Romagnani C, et al: P75/AIRM1 and CD33, two sialoadhesion receptors that regulate the proliferation or the survival of normal and leukemic myeloid cells. Immunol Rev 181:260-268, 2001
Vitale C, Romagnani C, Puccetti A, et al: Surface expression and function of p75/AIRM-1 or CD33 in acute myeloid leukemias: Engagement of CD33 induces apoptosis of leukemic cells. Proc Natl Acad Sci U S A 98:5764-5769, 2001
Jilani I, Estey E, Huh Y, et al: Differences in CD33 intensity between various myeloid neoplasms. Am J Clin Pathol 118:560-566, 2002
Dinndorf PA, Andrews RG, Benjamin D, et al: Expression of normal myeloid-associated antigens by acute leukemia cells. Blood 67:1048-1053, 1986
Zein N, Poncin M, Nilakantan R, et al: Calicheamicin gamma II and DNA: Molecular recognition process responsible for site-specificity. Science 244:697-699, 1989
Prokop A, Wrasidlo W, Lode H, et al: Induction of apoptosis by enediyne antibiotic calicheamicin theta II proceeds through caspase-mediated mitochondrial amplification loop in an entirely Bax-dependent manner. Oncogene 22:9107-9120, 2003
Sievers EL, 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
Caron PC, Co MS, Bull MK, et al: Biological and immunological features of humanized M195 (anti-CD33) monoclonal antibodies. Cancer Res 52:6761-6767, 1992
Vitale C, Romagnani C, Falco M, et al: Engagement of p75/AIRM1 or CD33 inhibits the proliferation of normal or leukemic myeloid cells. Proc Natl Acad Sci U S A 96:5091-5096, 1999
Caron PC, Jurcic JG, Scott AM, et al: A phase IB trial of a humanized monoclonal antibody M195 (anti-CD33) in myeloid leukemia: Specific targeting without immunogenicity. Blood 83:1760-1768, 1994
Caron PC, Dumont L, Scheinberg DA: Supersaturating infusional humanized anti-CD33 monoclonal antibody HuM195 in myelogenous leukemia. Clin Cancer Res 4:1421-1428, 1998
Feldman E, Kalaycio M, Weiner G, et al: Treatment of relapsed or refractory acute myeloid leukemia with humanized anti-CD33 monoclonal antibody HuM195. Leukemia 17:314-318, 2003
O'Brien PC, Fleming TR: A multiple testing procedure for clinical trials. Biometrics 35:549-559, 1979
Jurcic JG, DeBlasio T, Dumont, et al: Molecular remission induction with retinoic acid and anti-CD33 monoclonal antibody HuM195 in acute promyelocytic leukemia. Clin Cancer Res 6:372-380, 2000
Cortes J, Tsimberidou AM, Alvarez R, et al: Mylotarg combined with topotecan and cytarabine in patients with refractory acute myelogenous leukemia. Cancer Chemother Pharmacol 50:497-500, 2002
Kell WJ, Burnett AK, Chopra R, et al: A feasibility study of simultaneous administration of gemtuzumab ozogamicin with intensive chemotherapy in induction and consolidation in younger patients with acute myeloid leukemia. Blood 102:4277-4283, 2003
Keating MJ, Kantarjian H, Smith TL, et al: Response to salvage therapy and survival after relapse in acute myelogenous leukemia. J Clin Oncol 7:1071-1080, 1989
Kantarjian H, Keating MJ, Walters RS, et al: The characteristics and outcome of patients with late relapse acute myelogenous leukemia. J Clin Oncol 6:232-238, 1988
Kern W, Schoch C, Haferlach T, et al: Multivariate analysis of prognostic factors in patients with refractory and relapsed acute myeloid leukemia undergoing sequential high-dose cytosine arabinoside and mitoxantrone (S-HAM) salvage therapy: Relevance of cytogenetic abnormalities. Leukemia 14:226-231, 2000
Estey E, Thall P, David C. Design and analysis of trial of salvage therapy in acute myelogenous leukemia. Cancer Chemother Pharmacol 40:S9-S12, 1997 (suppl)
Walter RB, Raden BW, Karnikura DM, et al: Influence of CD33 expression levels and ITIM-dependent internalization on gemtuzumab ozogamicin-induced cytotoxicity. Blood 105:1295-1302, 2005
Burke JM, Caron PC, Papadopoulos EB, et al: Cytoreduction with iodine-131-anti-CD33 antibodies before bone marrow transplantation for advanced myeloid leukemias. Bone Marrow Transplant 32:549-556, 2003
Mulford DA, Jurcic JG: Antibody-based treatment of acute myeloid leukemia. Expert Opin Biol Ther 4:95-105, 2004
Jurcic JG, Larson SM, Sgouros G, et al: Targeted alpha particle immunotherapy for myeloid leukemia. Blood 100:1233-1239, 2002(Eric J. Feldman, Joseph B)