Departments of 1 Leukemia, 2 Bone Marrow Transplantation, 3 Hematopathology and 4 Bioimmunotherapy, University of Texas, M. D. Anderson Cancer Center, Houston, TX, USA
* Correspondence to: Dr R. Kurzrock, Division of Cancer Medicine, Unit 432, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Tel: +1-713-794-1226; Fax: +1-713-745-2374; Email: rkurzroc{at}mdanderson.org
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Abstract |
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Patients and methods: Patients with BMF due to myelodysplastic syndromes (MDS), graft failure, chemotherapy or aplastic anemia (AA) were treated. Patients were required to have a platelet count of <20 x 109/l, or a platelet count of <50 x 109/l with an absolute neutrophil count <1 x 109/l, or a hemoglobin value <10 g/dl. Treatment consisted of daily IL-11 at a dose of 10 µg/kg subcutaneously followed by a 2-week rest period. Two induction courses were given. Responders could receive maintenance therapy.
Results: Thirty-three patients (MDS, n=14; AA, n=16; prolonged thrombocytopenia following stem cell transplantation or chemotherapy, n=3) were evaluable. Their median age was 58 years (range 585). Three patients (9%) had poor risk cytogenetics. Nine patients (27%) responded to IL-11 (six MDS, three AA). Of these, three patients treated with IL-11 alone (n=1) or IL-11 together with other growth factors (n=2) showed multilineage recovery. The median time to response was 0.9 months (range 0.311). Factors associated with higher response rates in univariate analysis were age >50 years (P=0.008), diagnosis of MDS versus AA (P=0.025) and creatinine level >1 mg/dl (P=0.0004). The median response duration was 3 months (range 1.434.5+). Amongst responders, the median increment in platelet count was 111 x 109/l (range 43165). The most common side-effects were grade 12 lower extremity edema, conjunctival injections and fatigue. Grade 3 toxicities included arrhythmia (n=1) and transient ischemic attack (n=1). Ten patients (30%) had no side-effects.
Conclusions: Low-dose IL-11 has activity in patients with BMF and is generally well tolerated.
Key words: cytokine, growth factor, proliferation, thrombocytopenia
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Introduction |
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Recombinant human interleukin (IL)-11 (oprelvekin) is a novel therapeutic option for patients with severe thrombocytopenia. IL-11 is a cytokine with pleiotropic effects on multiple tissues [3]. It stimulates directly the proliferation of hematopoietic stem cells and megakaryocyte progenitors, and induces megakaryocyte maturation resulting in increased platelet production [3
, 4
]. It also has biological activity in other tissues, including brain, spinal cord neurons, gut and testis [3
]. Clinical trials in cancer patients have demonstrated that IL-11 attenuates post-chemotherapy thrombocytopenia at doses of 50 µg/kg/day subcutaneously (s.c.) for 57 days post-chemotherapy, and is well tolerated [4
, 5
]. The Food and Drug Administration (FDA) approved oprelvekin for the prevention of severe thrombocytopenia following myelosuppresssive chemotherapy in patients with non-myeloid malignancies at high risk for this toxicity.
Our initial experience with IL-11 in patients with BMF suggested that doses of 2550 µg/kg/day result in substantial peripheral and pulmonary edema, probably because prolonged therapy is required. Based on these observations, we initiated a pilot study of low-dose IL-11 (10 µg/kg/day) s.c. [6].
To date, we have treated 33 evaluable patients with BMF using this regimen. Our results indicate that low-dose IL-11 is well tolerated and has thrombopoietic activity in a subset of patients with chronic BMF states.
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Patients and methods |
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All patients signed informed consent, indicating that they were aware of the investigational nature of this study, in keeping with the M. D. Anderson Cancer Center policy. The Institutional Review Board at the M. D. Anderson Cancer Center approved the protocol.
Treatment plan
Patients received at least two courses of therapy. Each course consisted of 2 weeks of daily recombinant IL-11 (Neumega; Wyeth/Genetic Institute, Cambridge, MA, USA) at doses of 10 µg/kg s.c. followed by a 2-week rest period. Two induction courses were given (total 8 weeks).
Dose modifications. Patients with grade 01 toxicity related to IL-11 during a course could have a 5 µg/kg/day dose increase in subsequent courses. If grade 3 toxicity occurred, the dose of IL-11 was reduced by 50%. If grade 4 toxicity occurred, therapy was discontinued.
Maintenance therapy. During maintenance, patients could be treated with the same daily dose of IL-11 used in induction (10 µg/kg/day) given on alternate days or daily. Dosing could be increased by 5 µg/kg/day for patients with grade 3 toxicity. Patients could continue to receive IL-11 for as long as they showed hematological improvement without grade 3 or 4 toxicities.
Other growth factors. Patients with significant anemia (hemoglobin <10 g/dl) could receive erythropoietin (40 000 U s.c. weekly). Patients with significant neutropenia could receive granulocyte colony-stimulating factor (G-CSF) (300 µg s.c. three times per week).
End points and statistical methods
The response and end point assessments conformed to the published international working group response criteria for MDS with minor modifications, i.e. response duration for at least 1 month instead of 2 months, since this was a growth factor protocol [7]. Baseline counts were considered as the median of the untransfused counts in the 2 weeks before the initiation of IL-11. Adverse events were graded as per the National Cancer Institute Common Toxicity Criteria version 2.
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Results |
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Patient characteristics
The clinical characteristics of the 33 patients are summarized in Table 1. Fifteen patients (45%) were 60 years.
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Bone marrow aspirates and biopsies were re-reviewed in responders at three time points: prior to therapy, at the time of response and post-therapy (for patients who lost their response). The median cellularity prior to therapy was 30% (range 0% to 55%); and at the time of response, the median cellularity was 60% (range 25% to 90%). Mild improvement in degree of dysplasia was noted in two of nine patients. The median number of megakaryocytes per 10 high-power fields (x400 magnification) prior to therapy was 21 (range 0 to 75), and at the time of response it increased to 28 (range 9126). (In normal individuals, 2030 megakaryocytes are seen per 10 high-power fields.) There was no change in blasts, except for one patient, who showed a decrease from 17% (baseline) to 3%, which accompanied his multilineage response; blasts in this patient increased with loss of response.
Factors that were associated with a higher response rate in univariate analysis included age >50 years (P=0.008), diagnosis of MDS versus AA (P=0.025) and a creatinine level >1 mg/dl (P=0.0004) (Table 4). The presence of cytogenetic abnormalities, the severity of thrombocytopenia or anemia, the baseline white blood cell counts, the levels of lactate dehydrogenase and the cellularity or proportion of blasts in the bone marrow did not have a significant impact on response to IL-11.
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Side-effects
IL-11 as administered in this study was generally well tolerated. Ten patients (30%) had no side-effects. Other patients manifested grade 12 peripheral edema, conjunctival injection, fatigue, arthralgias and myalgias (Table 5). In 10 patients, furosemide 20 mg orally daily was given.
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Discussion |
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Bone marrow failure may be due to aplastic anemia, MDS, inherited syndromes, and chemotherapy or radiotherapy-induced prolonged pancytopenia. Several studies have demonstrated that G-CSF and GM-CSF enhance leukopoiesis in patients with MDS [1115
]. These growth factors have acceptable toxicity without significant stimulation of leukemic myelopoiesis or subsequent progression into acute myeloid leukemia, as demonstrated in controlled studies [11
13
, 16
]. In addition, anecdotal data suggest that some patients treated with these cytokines develop a malignant clone and eventually progress into acute leukemia. However, randomized studies, even in the setting of acute myeloid leukemia (AML), suggest that G-CSF does not negatively impact remission duration, and based on these studies, G-CSF is routinely used in AML studies [17
]. Erythropoietin induces response in
20% of patients with MDS, mainly in those with preserved erythroid function and relatively low endogenous erythropoietin levels [18
22
]. However, platelet responses to G-CSF, GM-CSF or erythropoietin therapy are rare.
The role of other molecules has also been investigated in BMF. Recombinant human thrombopoietin and its truncated, polyethylene glycol-conjugated form (PEG-rHuMGDF) can stimulate megakaryopoiesis. In vitro data suggest that PEG-rHuMGDF enhances megakaryocyte progenitor cells growth, and this effect can be augmented by IL-3 and SCF in bone marrow of patients with MDS and AML [23]. A 15 days per month schema of thrombopoietin administered to patients with graft failure showed no significant therapeutic benefit, but this may have been due to the small number of doses given [24
]. IL-3 has limited thrombopoietic activity as a single agent in patients with AA or MDS [25
], but multilineage responses have been reported in combination with GM-CSF [26
]. SCF has also induced multilineage responses in some patients with AA [9
]. IL-6 is a thrombopoietic factor in MDS, but has significant toxicity [27
].
Other agents have also shown activity in patients with MDS and cytopenias. The thiol compound amifostine can ameliorate cytopenias in some patients with MDS. In one study, single or multilineage responses were seen in 83% of patients with MDS and one or more refractory cytopenias [28]. Another study showed that in this setting neutropenia is more likely to improve (50% of patients) than anemia (23%) or thrombocytopenia (34%) [29
]. The demethylating agent decitabine induces responses in 30% to 50% of patients with advanced forms of MDS [30
]. In addition, the hypomethylating agent 5-azacytidine showed responses in 60% of MDS patients and also demonstrated a survival advantage in a randomized study [31
]. On this basis, 5'-azacytidine has recently been FDA-approved in the USA for the treatment of MDS. An immunomodulatory derivative of thalidomide, CC-5013, was shown to induce an erythroid response in 62% of MDS patients with symptomatic or transfusion-dependent anemia who completed at least 8 weeks of treatment [32
].
In our study, three patients achieved multilineage response. Two of these patients also received G-CSF and erythropoietin. G-CSF or GM-CSF and erythropoietin have also shown rare, but synergistic effects on trilineage recovery of patients with MDS or AA [3335
]. However, while these cytokines may have contributed to the response, they are unlikely to be solely responsible, since most patients had been treated with them prior to the use of IL-11 and had not demonstrated trilineage recovery. In vitro studies have previously shown that IL-11 alone or combined with G-CSF may stimulate progenitors of multiple lineages [36
]. One of our patients, however, showed a multilineage response accompanied by a decrease in bone marrow blasts on IL-11 given by itself. This raises the intriguing possibility that IL-11 induced an antitumor response. In this regard, in a study of gemtuzumab ozogamicin (GO) with or without IL-11 in patients with untreated AML or high-risk MDS, the arm with IL-11 demonstrated higher response rates than the arm with GO alone [37
]. In regression analyses, IL-11 therapy was independently predictive of remission [37
]. In contrast, IL-11 did not increase the response rates to idarubicin and cytarabine, and did not prolong survival or disease-free survival in a randomized study in previously untreated patients with AML who were >50 years old [38
]. IL-11 may have other benefits as well, such as reduction in the frequency and load of bacteremia during chemotherapy for hematological malignancies [39
].
The combination of G-CSF or GM-CSF with or without erythropoietin has shown some activity in patients with AA [40]. In addition, some AA patients may recover spontaneously [41
, 42
]. Interestingly, some of our responders, including all three AA responders, had previously failed G-CSF or GM-CSF and erythropoietin therapy, but responded to triple cytokine or combination therapy (IL-11, G-CSF and erythropoietin, or IL-11 and G-CSF). Therefore, the addition of IL-11, therapy to G-CSF or erythropoietin is likely to have contributed to the response of these patients. Additional well-designed studies of IL-11 with and without G-CSF and erythropoietin, are needed to determine the extent of synergy between these growth factors in BMF and to assess response rates accurately.
In conclusion, our data demonstrate that IL-11 has activity in a subgroup of patients with BMF. Future studies are needed to determine whether the loss of response without evidence of disease progression was due to antibody production and the relevance of the underlying pathological condition. Since some patients on maintenance therapy received, on average, a cumulative weekly dose of IL-11 ranging from 35 to 70 mg/kg, it might be possible to administer a single such dose once weekly. Finally, larger studies to assess response rates better in individual disease states, i.e. MDS versus AA, are underway, and investigations to determine whether biological factors, such as endogenous levels of hematopoietic cytokines, predict for response are planned.
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Acknowledgements |
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Received for publication April 30, 2004. Revision received July 8, 2004. Accepted for publication July 28, 2004.
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