Annals of Oncology Advance Access originally published online on September 28, 2007
Annals of Oncology 2008 19(1):128-134; doi:10.1093/annonc/mdm451
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hematologic malignancies |
Gemtuzumab ozogamicin, citosine arabinoside, G-CSF combination (G-AraMy) in the treatment of elderly patients with poor-prognosis acute myeloid leukemia
1 Istituto di Ematologia, Università Cattolica del Sacro Cuore, Roma
2 Dipartimento di Ematologia, Università di Firenze
3 Dipartimento di Ematologia, Università Cattolica S. Cuore, Campobasso, Italy
* Correspondence to: Dr. L. Fianchi, Istituto di Ematologia, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, I-00168 Roma, Italy. Tel: +39-063-0154180; Fax: +39-063-5503777; E-mail: luana.fianchi{at}rm.unicatt.it
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Abstract |
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Background: Gemtuzumab ozogamicin (GO) is effective as single agent in the treatment of acute myeloid leukemia (AML). We evaluated efficacy and safety of a chemotherapy including growth factors, cytarabine, and GO (G-AraMy) in the treatment of poor-prognosis AML in elderly patients.
Patients and methods: In three Italian hematology departments from September 2003 to September 2006, 53 elderly patients [median age 69 years (range 65–77)] with untreated or primary refractory/relapsed AML were enrolled on the combination G-AraMy administered according to two consecutive schedules (G-AraMy1 and G-AraMy2), with intensified consolidation in the second. Twenty-three of 53 patients had a secondary acute myeloid leukemia (sAML).
Results: The overall response rate was 57%. The most common adverse event was myelosuppression. Seven patients died in induction (13%). No differences for response rate and toxicity profile were observed between untreated and primary resistant/relapsed patients, de novo AML and sAML, and in the two treatment trials. Median disease-free survival and overall survival were 8 months (range 2–23+) and 9 months (range 2–24+).
Conclusions: G-AraMy therapy may be considered an useful treatment approach for poor-risk elderly AML patients, with a complete remission rate comparable to literature data with reduced side-effects, also in a poor-prognosis population.
Key words: Acute myeloid leukemia, elderly, gemtuzumab-ozogamicin
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introduction |
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Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Its incidence increases exponentially with age, which is considered an important pretreatment prognostic factor [1–2]. Older patients with AML are thought to have a poorer outcome than young patients due to biological differences in the disease and the inability of older patients to tolerate intensive antileukemic therapies [3–4]. Chronic comorbidity conditions, poor performance status (PS), and abnormal organ function, could contribute to the unfavorable prognosis of these patients. Newly diagnosed AML patients treated with combination chemotherapy show remission rates of 40%–60% [1, 4–7].
About 80% of patients who achieve a first complete remission (CR1) eventually relapse and <10% of all AML patients survive at 3 years [8–13].
Therefore, new therapies are needed to improve overall survival (OS) and to reduce therapy-related toxicity. Antibody-targeted chemotherapy is expected to be less toxic than conventional chemotherapy and has been developed for the treatment of CD33-positive AML. Gemtuzumab ozogamicin (GO) (formerly CMA-676; Wyeth Laboratories, Philadelphia, PA), a humanized anti-CD33 monoclonal antibody conjugated to calicheamicin, has shown efficacy in AML treatment and has been approved for the therapy for relapsed AML in the elderly [14–16]. GO as monotherapy or in combination with conventional chemotherapy has been reported [17–29].
Although nearly 80% of AML cells express the CD33 antigen, the intensity of expression is variable. Several data indicate that the CD33 antigen is significantly up-regulated on AML blasts exposed to recombinant human granulocyte colony-stimulating factor (rhG-CSF) and that CD33-positive AML cells are particularly sensitive to the growth-promoting effect of rhG-CSF [30–31]. Cytokines have been extensively used in AML before chemotherapy to sensitize leukemic blasts to the cytotoxic effects of S-phase-specific drugs, with good results in older patients treated with low-dose chemotherapy [30–34].
In a previous pilot study, we administered a sequential treatment with rhG-CSF and GO to relapsed elderly AML patients using rhG-CSF as priming. rhG-CSF increased, in vivo and in vitro, the proportion of CD33-positive blasts, with a high proliferative potential in vitro [33].
In this multicenter study, we treated 53 elderly patients with a sequential treatment with rhG-CSF, GO, and cytarabine as intravenous continuous perfusion (G-AraMy), to evaluate the efficacy and safety of this combination in the treatment of poor-prognosis untreated and relapsed/refractory AML patients.
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patients
Between September 2003 and September 2006, 53 consecutive patients from three hematological departments, responding to eligibility criteria, were enrolled in the G-AraMy protocol. Eligibility criteria included de novo or secondary acute myeloid leukemia (sAML, except for acute promyelocytic leukemia, treated according to the AIDA protocol); primary refractory or relapsed AML, age between 65 and 80 years, untreated patients older than 70 years or younger than 65 years not eligible for aggressive chemotherapy; adequate organ function [total bilirubin level, <2.0 mg/dl; aspartate aminotransferase, <100 U/l; creatinine level, <2.0 mg/dl; and cardiac ejection fraction, >45% by multigated blood pool scan); and PS lower than 3. Written, informed consent according to local regulations was obtained from each patient before participation.
treatment schedules
The study design (G-AraMy) was divided in two phases: G-AraMy1 protocol from September 2003 to December 2004 and G-AraMy2 from January 2005 to September 2006.
G-AraMy1
Induction treatment consisted of rhG-CSF 5 µg/kg s.c. on days 1–8; Ara-C 100 mg/m2 i.v. as continuous perfusion on days 4–8; and GO 6 mg/m2 i.v. for 2 h on day 9. Treatment was modified in patients with peripheral blast counts >5000 per µl, according to the following schedule: Ara-C 500 mg/m2 i.v. infused for 2 h daily, every 12 h for four doses on days 1–2; rhG-CSF 5 µg/kg s.c. on days 3–7; Ara-C 100 mg/m2 i.v. in continuous perfusion on days 3–7; GO 6 mg/m2 i.v. for 2 h on day 8.
Patients achieving complete response (CR), CR with incomplete platelet recovery (CRp), or partial response (PR) received one course of consolidation therapy consisting of rhG-CSF 5 µg/kg s.c. on days 1–6; cytarabine 100 mg/m2 i.v. as continuous perfusion on days 2–6; GO 6 mg/m2 i.v. for 2 h on day 7.
G-AraMy2
In this phase, induction schedule was modified substantially, increasing the duration of cytarabine perfusion from 5 to 7 days as follows: rhG-CSF 5 µg/kg s.c. on days 1–8; Ara-C 100 mg/m2 i.v. in continuous perfusion on days 2–8; GO 6 mg/m2 i.v. for 2 h on day 9. The consolidation was also intensified according to the following schedule: rhG-CSF 5 µg/kg s.c. on days 1–5; cytarabine 1000 mg/m2 i.v. for 3 h every 12 h on days 2–5; GO 6 mg/m2 i.v. for 2 h on day 6.
Maintenance therapy was carried out every 3 months with cytarabine 15 mg s.c. daily every 12 h on days 1–14 and GO 3 mg/m2 i.v. for 2 h on day 15. This schedule was similar in the two groups.
Treatment schedules are reported in Figure1.
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efficacy assessment
The primary efficacy end point of the study was the rate of CR. CR was defined as (i) absence of blasts in the peripheral blood; (ii) 5% or less blasts in the bone marrow, assessed by morphology; (iii) hemoglobin level of 9 g/dl or greater with RBC transfusion independence for at least 2 weeks; absolute neutrophil counts of 1500 per µl or higher; and platelet count of 100 000 per µl or higher with platelet transfusion independence for at least 1 week [14]. Patients with all CR criteria, with persistence of thrombocytopenia were defined as CRp. The overall remission rate was the sum of CR and CRp rates. Patients with persistence of up to 15% bone marrow blasts were considered in PR. Non-responders were all those patients who did no achieve CR, CRp, and PR.
statistical analysis
OS was measured from the first dose of granulocyte colony-stimulating factor (G-CSF) administration to death or last follow-up. Disease-free survival (DFS) was measured from the first documentation of CR or CRp to the date of relapse. All survival data were analyzed using Kaplan–Meier estimates, with comparisons on the basis of log-rank tests. Data were analyzed by descriptive statistical methods and differences between groups were calculated using 
2 test or Fisher's exact two-tailed test if appropriate. All P values were two-sided, with 0.05 or less denoting statistical significance. A comparison between the two treatment groups (G-AraMy1 and G-AraMy2), although not randomized, between untreated and resistant/relapsed patients, and between de novo and sAML patients was carried out. Data were analyzed using the Statistical Package EpiInfo6.
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patient characteristics
Of the 53 patients enrolled, 27 received G-AraMy1 and 26 G-AraMy2 protocols.
The clinical characteristics of all patients treated and a comparison between the two trial groups are summarized in Table 1. The two treatment groups were not randomized but there were no substantial differences in the clinical characteristics of patients enrolled in the two trials.
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Twenty-six (49%) patients were at first diagnosis, while 27 (51%) patients had previously received chemotherapy (at relapse: 15 patients; primary resistant: 12 patients). The median duration of CR1 in relapsed patients before G-AraMy treatment was 40 weeks (range 8–92). Notably, 23 of 53 patients (43%) had a sAML: 11 patients had a post-myelodysplastic syndromes AML and 12 patients had received chemotherapy for a prior malignancy (three Hodgkin's lymphoma, five breast, two thyroid, one bladder, one gut cancer).
Cytogenetic study was carried out in all patients; karyotype was ‘intermediate’ in 30 cases, ‘unfavorable’ in 12 cases, and ‘favourable’ in one patient. No metaphases were observed in 10 patients. Immunophenotypic analysis for the CD33 antigen was carried out for all patients at diagnosis, resulting in 90% (range 25%–95%) CD33-positive blasts (CD33 positivity was defined as >20% positive blast cells).
Median peripheral blood leukocyte counts before treatment were 7.9 x 109 per l (range 0.45–290). Twelve patients (five in G-AraMy1 and seven in G-AraMy2) (22%) had peripheral blood blast counts >5 x 109 per l. In two patients (one in G-AraMy1 and one in G-AraMy2) with leukocyte counts >100 x 109 per l, a therapeutic leukopheresis was carried out before treatment start.
treatment response
After induction treatment, 23 patients (43%) achieved CR and one patient (2%) CRp. Eleven patients (21%) had PR, 11 patients (21%) resulted refractory to treatment, and seven (13%) patients died during the aplasia following induction treatment. Among patients who met the criteria for CR or CRp, 15 were untreated, five were at first relapse, and three were primary resistant to previous treatments.
Consolidation therapy was administered to 30 of 35 patients who achieved CR, CRp, or PR. Consolidation therapy was not carried out due to sudden death in two cases (one patient died due to ictus cerebri and one due to relapse of bladder cancer) and due to veno-occlusive disease (VOD), developed during induction therapy, in one case. Two patients refused consolidation treatment.
Notably, six of 10 PR patients in whom consolidation treatment was carried out achieved CR, increasing the overall response rate to 57% (30 of 53 patients). Median DFS time for all patients achieving CR or CRp was 8 months (range 2–23+). Median OS of the whole population was 9 months (range 2–24+), with a 12-month OS rate of 28% (Figure 2A and B).
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No differences in CR rate were observed between untreated and relapsed/refractory patients (P = 0.66) and between de novo versus sAML patients (P = 0.78). Stratifying patients according to different CD33 expression levels, no differences emerged in term of CR rate. Comparing the two not-randomized trials (G-AraMy1 versus G-AraMy2), no significant differences were observed for CR rate (57.5% versus 57%, P = 0.9, Table 2). On the other hand, there was a difference in DFS for the two treatment groups, which did not reach significance (P = 0.07), with a longer DFS in the G-AraMy2 group (Figure 3A and B). A significantly longer OS was observed for the G-AraMy2 treatment group (10.7 versus 6.13 months, P = 0.017).
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toxicity
The incidence of treatment-emergent adverse events (TEAEs) was used to assess safety. The USA National Cancer Institute–Common Toxicity Criteria (version 2.0) were used to assess the severity of all TEAEs.
A grade 3 infusion-related allergic reaction during GO therapy was observed in three patients (5.5%). Myelosuppression was as expected: all patients had grade 3–4 neutropenia and thrombocytopenia, with complete responders requiring a median of 20 days (range 10–66) from the start of treatment to recover of neutrophil counts >0.5 x 109 per l, and a median of 18 days (range 8–39) to reach a platelet count >50 x 109 per l. Three patients (6%) experienced grade 4 bleeding consisting in intracranial hemorrhage in two cases and gastrointestinal bleeding in one case.
The most common grade 3 or 4 non-hematologic adverse events were infections which occurred in 19 patients (36%) and consisted of pulmonary aspergillosis in six cases and bacterial sepsis in 13 patients. Only one patient developed VOD with grade 3 transaminasis and severe hyperbilirubinemia, which resolved with defibrotide treatment. No patients experienced severe mucositis; diarrhea occurred in only one patient who previously had Crohn's disease.
Overall treatment-related mortality was 13%: seven patients died during aplasia following induction treatment, four due to infection and three due to hemorrhagic complications.
No differences in toxicity profile were observed between the two treatments groups (G-AraMy1 versus G-AraMy2).
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discussion |
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The largest proportion of AML cases are elderly individuals; in contrast to younger patients, the disease in the elderly is frequently resistant to chemotherapy and overall outcome remains extremely poor. CR is achieved in <60% of elderly AML patients treated with standard chemotherapy, but <15% of these patients survive free of leukemia at 3 years [1–3]. Patients with relapsed or refractory AML have less chance of obtaining remission than newly diagnosed AML. Besides the biologic characteristics associated with resistance to cytotoxic agents, elderly patients with AML are generally less tolerant to intensive chemotherapy [35]. Comorbidity has been identified as an independent predictor of CR in elderly patients receiving induction chemotherapy [36–37]. Several evidences indicate that novel therapeutic strategies rather than an increase in the intensity of chemotherapy may improve clinical outcome in this patient subset.
Most of the clinical experience with GO is in elderly patients with AML. Following preliminary studies showing feasibility and efficacy as monotherapy, with overall response rates ranging between 12.5% and 53%, the drug has been used in combination with conventional chemotherapy and the Food and Drug Administration approved its use for relapsed AML patients, older than 60 years [14–20]. The tolerability and the promising results led the use of the drug at first diagnosis.
Some trials evaluated the efficacy of GO in combination with other cytotoxic agents (i.e. daunorubicine, cytarabine, fludarabine, mitoxantrone, etoposide, interleukin-11, Bcl-2 antisense, etc.) both in refractory/relapsed patients and as frontline therapy [21–29]. In these studies, CR rates ranged from 36% to 91%, with median DFS and OS variable from 5 to 13 months and from 2 to 11 months, respectively. Recently, an in vitro study by Morris et al. [38] concluded that by combining GO with low-dose cytarabine or etoposide, the dose of GO could be reduced 10-folds to produce the same effects, indicating that low-dose GO in combination with cytarabine or etoposide also at low doses may offer an effective chemotherapy regimen for AML patients in vivo, especially for elderly patients, unfit to receive intensive chemotherapy.
Based on these data, we carried out the sequential treatment with rhG-CSF, GO, and cytarabine as continuous perfusion, to improve outcome and reduce toxicity in poor-prognosis untreated and relapsed/refractory AML patients.
The rationale for rhG-CSF use was supported by previous studies showing the efficacy of in vitro rhGM-CSF (recombinant human granulocyte–macrophage colony-stimulating factor) or rhG-CSF priming, to increase the susceptibility of leukemic cells to killing by chemotherapy, especially by the cell cycle-specific agent cytarabine [30–34]. In addition, in a multicenter randomized trial by the HOVON group, young and middle-aged patients with newly diagnosed AML were randomly assigned to receive cytarabine plus idarubicin (cycle 1) and cytarabine plus amsacrin (cycle 2), with or without G-CSF. In this study, G-CSF improved OS and DFS, demonstrating that the efficacy of a regimen including cytarabine was enhanced by G-CSF in vivo priming [31]. Furthermore, a recent experience of the Acute Leukemia French Association group demonstrated significantly better CR rates and a higher 3-year EFS in patients receiving GM-CSF. No impact on OS was observed in this study [34].
Comparing our data with those of previous studies including GO, we observed similar CR, DFS, and OS rates [20–28]. We obtained CR rates analogous to Buchner et al. [39], using aggressive chemotherapy in selected population aged 60 years or older. Different from the report by van der Heiden et al. [28], who observed higher CR rates in patients with untreated primary AML (60%), compared with secondary (20%) and relapsed AML, we did not find differences between untreated and relapsed or resistant patients and notably between de novo and sAML. The CR rate in sAML patients (61%) was even higher than that of de novo AML (53%). This confirms data reported by some authors emphasizing that sAML prognosis is similar to de novo AML, with corresponding cytogenetic risk [40–42].
Recently, a study by Kantarjian et al. reported the results of intensive chemotherapy in elderly patients with AML or high-risk myelodysplastic syndrome [37]. In this study only patients receiving regimens containing conventional or high-dose cytarabine or non-cytarabine-intensive regimens (including anthracyclines) were included. The CR rate was 45% and the median OS was 5.4 months (range 4.4–6.3). At multivariate analyses the miscellaneous cytarabine regimen was associated with higher mortality rate, while therapy type did not demonstrate any significant prognostic associations with survival. The 8-week mortality of this population was 33% (332 of 988 patients).
If compared with this data, our study, although including patients selected for poor prognosis, not eligible for aggressive chemotherapy, or primary refractory or relapsed patients, with 43% sAML, demonstrated a higher percentage of CR and a longer OS. Furthermore, it is remarkable that our results have been obtained without the use of anthracyclines, which represent the gold standard in the treatment of AML, but are associated to important toxicity, particularly in elderly patients [43]. Important differences can be observed also in 8-week mortality rate which resulted of 7.5% of our series versus of 33% of the Kantarjian et al. study, where notably cytarabine regimen was associated with higher mortality rate.
Protocol intensification from G-AraMy1 schedule to G-AraMy2 in our study did not significantly influence response rates, although DFS was longer in the G-araMy2 patients, without reaching significance. Interestingly, a significantly longer OS emerged for the G-AraMy2 treatment, including a more intensive consolidation approach with intermediate cytarabine doses.
A relevant observation was the good safety profile. In our experience, the association of GO at 6 mg/m2 and cytarabine had a low toxicity profile. Treatment was associated with grade 3–4 neutropenia and thrombocytopenia in all patients as expected, but polymorpho-nucleates >0.5 x 109 per l and platelet recovery (50 x 109 per l) occurred at a median time, less than half of that observed in pivotal studies. Three patients (6%) experienced severe bleeding, and infections occurred in 36% of cases.
One of the major concerns using GO was the risk of liver toxicity. In studies using a dose of 9 mg/m2 of GO, grade 3 or 4 liver function tests abnormalities were reported in up to 39% of the patients [14, 18–25, 31]. Our protocol at the dose of 6 mg/m2 GO had an acceptable hepatic toxicity profile. Only one patient developed significant hepatotoxicity (VOD), which resolved with defibrotide treatment. No differences in toxicity profiles were observed between the two schedules: the increased duration and dose of cytarabine in the second group did not result in increased toxicity.
On the basis of our results, the G-AraMy protocol, in particular G-AraMy2, might be an efficacious therapy with an encouraging safety profile for poor-prognosis elderly AML patients, showing overall response rates comparable to those of conventional protocols. Unfortunately, DFS and OS were not improved when compared with previous protocols, although an improvement could be observed combining GO with escalated doses of cytarabine, as indicated by G-AraMY2 results. The favorable safety profile encourages its use also in older AML patients unable to tolerate intensive antileukemic conventional therapies.
Received for publication July 16, 2007. Revision received August 9, 2007. Accepted for publication August 13, 2007.
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