Patients with advanced MDS and secondary AML respond poorly to chemotherapy. Granulocyte–macrophage colony-stimulating factor (GM-CSF) can stimulate proliferation of leukemic blasts and sensitize these cells to the cytotoxic effects of S-phase-specific drugs. This is the first report of safety and efficacy of GM-CSF prior to and during cytarabine in a low-dose, intermittent regimen for elderly patients with poor risk acute myelogenous leukemia or myelodysplastic syndrome. Twenty patients, age 68 to 86 years, each received 250 μg/m2 of GM-CSF (Sargramostatin; Immunex, Seattle, WA, USA) subcutaneously (s.c.) or intravenously (i.v.) for 3 days followed by GM-CSF at the same dose and cytarabine 100 mg/m2 i.v. for 3 days. GM-CSF and cytarabine were both administered for 3 days during weeks 2 and 3 followed by a 3-week rest period. Rates of CR and PR were 20% and 40%, respectively. These included clinically significant resolution of cytopenias and transfusion requirements. Many of the responding patients had been heavily pretreated prior to enrollment. One- and 2-year survival estimates are 44% and 19%, respectively. Myelosuppression was the most significant toxicity. Our findings suggest that this novel combination of GM-CSF with sequential and concomitant low-dose cytarabine can benefit patients with poor risk myeloid malignancies.
Patients with myelodysplastic syndromes (MDS) associated with bone marrow blasts greater than 10%, and patients with acute myelogenous leukemia (AML) developing after prior chemotherapy or prior hematologic disorder have poor prognoses and low response to chemotherapy.1,2,3,4,5 Features responsible for these observations may include older age with poor tolerance to myelotoxic therapy,6 overexpression of P-glycoprotein,7 and resistance to cell cycle specific chemotherapy by leukemia cells which are not in S-phase at the time of drug exposure.8,9 Human granulocyte–macrophage colony-stimulating factor (GM-CSF) is a glycoprotein which supports proliferation and differentiation of a broad range of hematologic, especially myeloid, precursor cells.10 By stimulating proliferation of leukemic blasts, GM-CSF can sensitize these cells to the cytotoxic effects of S-phase-specific drugs, such as cytarabine. The use of growth factors to drive malignant cells into cell cycle and increase sensitivity to chemotherapy has been attempted in a variety of settings. Growth factors which have been studied both in the laboratory and in clinical trials include GM-CSF, granulocyte–colony stimulating factor (G-CSF), and interleukin-3 (IL-3). In vitro studies have generally confirmed the impact of growth factors on leukemic cell proliferation and sensitivity to chemotherapy.8,11,12 The proliferative effect has also been demonstrated during patient therapy although it has not usually correlated well with clinical outcome.13,14 Growth factor priming has most commonly been used with intensive chemotherapy, including intensive timed-sequential therapy, for remission induction. In this setting, time to neutrophil recovery is shortened by growth factor administration.15,16 Complete response (CR) rates and disease-free survival (DFS) rates have increased in some studies using growth factor priming.5,15,17 However, no trials have shown improved overall survival with growth factor priming for intensive induction chemotherapy. Much less is known about the utility of priming strategies when used with low-dose regimens, which may best suit elderly, high-risk patients. Published trials have used daily injections or continuous infusions of cytarabine for 14 to 21 days and the response rates in these settings have been encouraging.18,19 Intermittent dosing of growth factor with low-dose cytarabine may optimize S-phase recuitment and leukemia sensitivity without increasing toxicity. Based on these published data and on preliminary clinical experience at our own institution, we initiated a single arm study of an out-patient regimen using successive and concurrent GM-CSF with low-dose cytarabine in patients with very poor prognosis AML or MDS. To our knowledge, this is the first report of a clinical trial using growth factor priming with low-dose cytarabine in this fashion.
Materials and methods
Eligible patients had WHO performance status 0–2 and carried one of the following diagnoses: Myelodysplastic syndrome as defined by FAB criteria with a minimum of 10% bone marrow blasts, AML evolved from an antecedent MDS or myeloproliferative syndrome, AML secondary to prior chemotherapy, de novo AML in second relapse or refractory to a salvage chemotherapy regimen. Patients were not excluded if they had received prior therapy for MDS. Exclusion criteria included serum creatinine >2.0 mg/dl, active cardiac or respiratory failure, and hepatic disease unrelated to MDS or AML. All patients were treated after signing informed consent according to an institutional review board approved protocol.
Our treatment schema is shown in Figure 1. Patients with peripheral white blood cell counts (WBC) <25 000/μl were treated with recombinant GM-CSF (sargramostim, Immunex, Seattle, WA, USA) 250 μg/m2 by subcutaneous (s.c.) or intravenous (i.v.) injection on days 1–6 and with cytarabine 100 mg/m2 s.c. or i.v. on days 4–6. Patients with WBC greater than 25 000/μl were treated with concurrent GM-CSF and cytarabine at the above doses on days 1–3 only. Concurrent GM-CSF and cytarabine were administered for 3 days during weeks 2 and 3, followed by a 3-week rest interval to complete one cycle of therapy. Patients could receive a maximum of six cycles of therapy. Prophylactic antibiotic therapy was allowed. Need for transfusions was decided by the primary hematologist/oncologist. Indications for removal from treatment were bone marrow aplasia persisting 4 weeks after completing two cycles, intolerance to GM-CSF, life-threatening infections in the setting of neutropenia, or disease progression.
Bone marrow aspirate and biopsy were performed at the time of enrollment and prior to each cycle of therapy. Bone marrow was also examined in patients who had prolonged myelosuppression greater than 3 weeks’ duration. Complete blood counts (CBC) were followed at least weekly. Response criteria were similar to those of other investigators.17,20 Complete response (CR) was defined as achievement of all the following: reduction of bone marrow blasts and peripheral blasts to less than 5% and 1%, respectively; sustained neutrophil count >1000/mm3 for at least 4 weeks; sustained platelet count >100 000/mm3 for at least 4 weeks; reduction by >50% of red blood cell (RBC) transfusion requirements over a period of 4 weeks. Partial response (PR) was defined as achievement of any one of the following: a sustained (4 weeks) increase of neutrophils of at least 100% or more than 1000/mm3 in patients with pretreatment ANC of less than 1000/mm3, a sustained increase in platelet count of at least 100% or more than 50 000/mm3 in patients with pretreatment platelet count of less than 100 000/mm3, or a reduction of the bone marrow blasts by 50%. Other clinical endpoints were survival, neutropenia and infection.
Twenty-one patients were entered into the trial between February 1996 and February 2000. Of these, 20 patients were evaluable; one patient chose to receive donor lymphocyte infusion shortly after the first cycle of therapy and was removed from analysis. Patient characteristics at the time of trial entry, as well as clinical outcomes are shown in Table 1. The median age was 73 years (range 68 to 86 years). Two patients had WHO performance status (PS) of 2 at enrollment, the remainder had PS 0 or 1. Diagnoses at the time of entry were secondary AML (sAML: 14 patients, including 10 cases evolved from prior MDS, two cases secondary to chemotherapy, and one case evolved from a prior myeloproliferative disorder); refractory anemia with excess blasts (RAEB) (three patients), and relapsed or refractory de novo AML (three patients). Fifty percent of patients with sAML had received prior chemotherapy and all three patients with de novo AML had received two prior chemotherapy regimens (daunorubicin/cytarabine and mitoxantrone/etoposide). All patients were red cell and/or platelet transfusion dependent. The mean red cell transfusion requirement was 1.5 units of red blood cells per month. Cytogenetic studies were performed on all patients. There were seven normal karyotypes and 13 abnormal karyotypes, including one ‘favorable’ abnormality (−Y in patient 9).1 Only one patient had WBC greater than 25 000 at the time of enrollment. Of the three patients with MDS, two fit criteria for INT-2 risk and one for high-risk according to the international prognostic scoring system (IPSS) for MDS.1 An average of two cycles of chemotherapy were administered. Eight patients chose to end or change therapy in the absence of a protocol-defined reason for discontinuation; some went on to other experimental therapies as they became available. Other reasons for discontinuing protocol therapy included disease progression in seven patients and toxicity in four patients.
Overall, four patients (20%) achieved a CR and eight patients (40%) achieved a PR. Two of the PRs were based on reduction in blast %, while six were based on improvement in peripheral counts. Responses occurred in nine patients with sAML, two patients with MDS (including one secondary to prior chemotherapy), and one patient with refractory AML. Maximum response occurred after an average of two (range 1–4) cycles. Fifty percent of patients experienced an increase in WBC during GM-CSF priming. This was not associated with clinical responses (data not shown). Two of the complete responders had sAML and had CR confirmed after cycle 4 and cycle 1, respectively. Two other patients achieved complete response after one cycle and received no further protocol therapy. Patient 7 had secondary AML after prior chemotherapy at the time of enrollment. Shortly after achieving a CR from the AML diagnosis, he had resurgence of pre-existing multiple myeloma and died during aplasia from melphalan therapy. Patient 14 also had chemotherapy-related AML, which was recurrent and had received bryostatin and all-trans retinoic acid for this prior to enrolling in our trial. She developed prolonged neutropenia and grade 4 infection after one cycle of therapy. However, she was in complete remission at the time of bone marrow recovery and survived for nearly 1 year after enrollment. By life table analysis the estimated probability of survival for all patients at 1 and 2 years is 44% and 19%, respectively. Kaplan–Meier estimate of survival is shown in Figure 2. There was a non-significant trend toward higher 1 year survival rate among responders than non-responders (50% vs 25%, data not shown). Two (10%) of our patients survived for more than 2 years.
Table 2 summarizes the WHO-graded toxicities experienced by our patients at any time during therapy. Myelosuppression was the major toxicity occurring during treatment. Grade 4 neutropenia occurred in 14 patients and during 24 (59%) of treatment cycles. Grade 4 infections occurred in four (20%) patients. Four patients died within 2 months of beginning treatment. Patient 2 died of a myocardial infarction. Patient 1 died of progressive leukemia and patient 19 had acceleration of leukemia with extreme leukocytosis. Patient 17 died of sepsis due to Listeria monocytogenes. Other serious adverse events included another episode of extreme leukocytosis to 211 000/mm3, which resolved without obvious leukostasis, one case of hepatic candidiasis which required prolonged hospitalization, and one case of life-threatening ARDS which developed during the second week of therapy. Severe thrombocytopenia occurred in most patients; however, grade 3 hemorrhage occurred only once and there were no grade 4 hemorrhages. Two patients experienced chest pain during therapy without obvious cardiac etiology or complication. There were four episodes of mild bone pain. Six patients required hospitalization during the treatment period. The median length of hospital stay was 8 days.
The prognosis is very poor for patients with refractory AML, AML arising out of MDS, and advanced MDS1,4 Clinical trials using ‘induction’ doses of chemotherapy have reported CR rates of 30–65% for patients with these diagnoses; however, median survival is usually only 3 to 8 months.3,6,21 Therefore low-dose therapies have been sought as less toxic alternatives. To date prolonged survival has not been shown using these strategies.22 In this study, we treated patients with successive doses of priming GM-CSF and low-dose cytarabine. Our patients were at very high risk for resistance to chemotherapy and for death based upon their diagnoses, prior therapy and advanced age. The majority were >70 years old with secondary AML or refractory/relapsed AML. Many had received prior chemotherapy for their disease. Despite their unfavorable clinical characteristics, some patients had clinically significant responses and prolonged survival after treatment. The use of growth factor priming in a regimen of successive low doses of cytarabine may enhance leukemia response without increased toxicity.
Most clinical trials of growth factor priming have used intensive chemotherapy for remission induction of AML or high risk MDS. High CR rates were obtained in pilot studies of AML patients.14,23 Several randomized trials have used GM-CSF or G-CSF during and after induction chemotherapy for newly diagnosed AML in elderly patients.5,15,16,24 Using GM-CSF, studies by Lowenberg et al16 and Witz et al15 found no difference in complete response rates. However, Witz et al showed an improvement in disease-free survival (DFS) in GM-CSF-treated patients. There was a trend toward improved survival which was significant in patients younger than 64 years of age. Using G-CSF prior to chemotherapy, both Estey et al5 and Ohno et al24 found an improvement in complete response among treated patients, but no difference in event-free survival. None of these trials showed statistically significant differences in overall survival, although shortened time to neutrophil recovery was a consistent finding. G-CSF and GM-CSF have also been used in smaller randomized trials prior to and during intensive chemotherapy for high-risk MDS. In this setting they have been associated with trends toward improved response rates and survival which were not statistically significant.17,25 There is less published experience with growth factor priming before and during attenuated dosing regimens for AML or MDS. Furthermore, compared with low-dose cytarabine, intensive chemotherapy does not prolong survival in elderly AML patients due to an increased early death rate.26 A clinical benefit of growth factor priming may be found with low-dose therapy for high risk patients, even if such a benefit has not been proven in the intensive chemotherapy setting.
Our regimen produced a response rate (RR) of 60%, including 20% CR rate. This is comparable or better than results previously reported with low-dose therapies. Clinical trials using low-dose therapies without growth factor priming in elderly patients with advanced MDS have had mixed results. The average response rate from trials using low-dose cytarabine alone for AML or MDS has previously been calculated to be only 17%.27 In an important randomized trial by Miller et al,28 low-dose cytarabine used without growth factor priming was found to be more toxic, but no more effective than supportive therapy alone in the treatment of MDS. Among 53 patients randomized to treatment, there was 11% CR rate, 21% PR rate, and a median survival of 30 weeks. Another pyrimidine analog, 5-azacytidine has been used in a similar population with more promising results. Wijermans et al29 reported a response rate (RR) of 54% (28% CR); the median survival in that study was 46 weeks with 17% early deaths. A randomized comparison between 5-azacytidine and supportive care has been reported only in abstract form.30 In that report, quality of life was improved for the treated patients although there was no significant difference in survival. When GM-CSF has been used during or after treatment with low doses of cytarabine for patients with high risk MDS or elderly patients with AML (including secondary and relapsed AML), CR rates ranging from 14% to 37% and early death rates of 15% have been reported.18,19,31 Gerhartz et al19 using low-dose cytarabine daily for 14 days, found no difference in clinical outcomes between treatment using GM-CSF with simultaneous chemotherapy vs treatment with GM-CSF only after chemotherapy. However, none of the patients received growth factor as priming prior to chemotherapy. Frenette et al18 found that the addition of GM-CSF to a low-dose cytarabine and hydroxyurea regimen produced longer remission duration and longer survival among responding patients when compared with historical control patients who did not receive GM-CSF priming. Interestingly, although GM-CSF increased the percentage of CD33+ cells in S-phase among leukemic patients, this did not correlate with clinical outcome.18 More recently, topotecan has been used as single agent therapy for MDS or CMML, although typically using maximum tolerated doses. In a trial of 60 patients, 31% achieved a CR, with most of these occurring after the first cycle.32 Adverse effects were considerable, including 85% fever and neutropenia, 17% severe diarrhea, and 23% severe mucositis.
Although malignant cells of patients with sAML and MDS exhibit a high resistance to chemotherapy, our therapy demonstrated considerable anti-leukemic effect as measured by clearance of peripheral blood blasts and by a reduction of bone marrow blast by >50% among several patients. GM-CSF stimulates leukemic blasts to proceed through the cell cycle and the use of GM-CSF priming has enhanced the cytoreductive effect of cytarabine and has been correlated in vitro with the S-phase fraction of bone marrow blasts.8 Interestingly, in our study maximum clinical response was achieved after an average of two cycles of therapy. One patient had a complete response documented only after four cycles. This suggests that, although the regimen was not intensive, anti-leukemic effect persisted over time and subsequent cycles. We found a nonsignificant trend toward greater response, especially complete response, among patients with AML arising out of MDS (data not shown). These patients tended to have greater bone marrow cellularity than patients with other diagnoses at the time of enrollment and they were less heavily pretreated than relapsed/refractory de novo AML patients. It may be that the leukemic cells in this first group of patient are more likely to respond to growth factor stimulation and be sensitized to cytarabine. Alternatively, patients with hypocellular bone marrows prior to therapy may be less tolerant of myelosuppressive therapy. In vitro data suggest that the enhancement of cytarabine cytotoxicity by GM-CSF is more pronounced on cells from relapsed AML than those from de novo AML, although the effect of GM-CSF on in vivo blast proliferation in patients with relapsed or refractory AML has been variable.33,34 Our study enrolled three patients with relapsed or refractory AML. One had a good PR with long survival, while two had NR and short survivals. GM-CSF has not altered the outcome of relapsed/refractory AML after intensive therapy in published clinical trials.24,35 The specific impact of GM-CSF or other growth factor priming in the setting of low-dose therapies for high risk myeloid malignancies can only be determined by future randomized controlled trials.
Myelosuppression was the most common toxicity among our patients and our experience was similar to those reported from other trials using low-dose chemotherapy for AML and MDS.18,19,29 It is possible that growth factor stimulation can sensitize normal myeloid progenitors to chemotherapy. Randomized trials have not found increased myelosuppression in the treatment arms. However, as noted, most trials have continued growth factor after chemotherapy. GM-CSF may have contributed to leukocytosis and accelerated leukemia in two patients. Neither patient experienced leukostasis syndrome, but both had poor clinical outcomes. Other toxicities attributable to GM-CSF included chest pain and bone pain and were rare events. Overall, toxicities were acceptable given the high risk of our patient population. However, they may have significantly limited the number of treatment cycles that were delivered.
The dosing regimen of cytarabine in our trial differs from prior published regimens. This is the first reported trial using low-dose, single agent chemotherapy in successive, intermittent dosing for hematologic malignancies. It was given as a s.c. injection or i.v. bolus rather than by continuous infusion and was given on only 3 days per week for 3 consecutive weeks rather than the more typical daily dosing of low-dose cytarabine. Our goal was to exploit the known kinetics of leukemic cell proliferation after chemotherapy. Cell-cycle recruitment is maximal 7–10 days after initial cytoreduction.36 Another goal of this strategy was patient tolerance and convenience. We were able to use a non-intense regimen of cytarabine and offer it on a schedule which was feasible for outpatients. Unlike other investigators, we used GM-CSF only as a priming growth factor, prior to and during chemotherapy, but not to speed neutrophil recovery after chemotherapy. Overall, this schedule allowed high risk, elderly patients to stay at home during the period of therapy.
In summary, we used GM-CSF priming with low-dose, sequential and concomitant cytarabine as outpatient treatment for very high risk elderly patients with secondary AML, advanced MDS, or refractory/refractory AML. Although broad treatment recommendations should not be extrapolated from a small study, several of our patients treated in this fashion had clinically meaningful responses including improvement of cell counts, decreased need for transfusion, and survival longer than predicted by their diagnoses and risk factors.1,2,3 Toxicity of this regimen, like that of other low-dose regimens, is generally manageable, but can be severe and must be considered in view of the low likelihood of cure for these patients. In our next clinical trial we will attempt to further reduce toxicity with a lower dose of cytarabine. We will focus on patients with AML arising from a pre-existing MDS. This group seems to derive the greatest benefit from this strategy. Additionally, we will prospectively study GM-CSF receptor concentration and cell cycle response of leukemic blasts as a predictor of clinical outcomes.
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This work was supported by Immunex Corporation, 51 University Street, Seattle, Washington 98101, USA.
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Rossi, H., O'Donnell, J., Sarcinelli, F. et al. Granulocyte–macrophage colony-stimulating factor (GM-CSF) priming with successive concomitant low-dose Ara-C for elderly patients with secondary/refractory acute myeloid leukemia or advanced myelodysplastic syndrome. Leukemia 16, 310–315 (2002). https://doi.org/10.1038/sj.leu.2402368
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