Low-dose interleukin-11 in patients with bone marrow failure: update of the M. D. Anderson Cancer Center experience

A.-M. Tsimberidou1, F. J. Giles1, I. Khouri2, C. Bueso-Ramos3, S. Pilat4, D. A. Thomas1, J. Cortes1 and R. Kurzrock4,*

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


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background: Recombinant interleukin (IL)-11 is a thrombopoietic growth factor. The purpose of this study was to assess the toxicity, safety and efficacy of low-dose recombinant IL-11 in patients with bone marrow failure (BMF).

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 5–85). 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 0.3–11). 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 1.4–34.5+). Amongst responders, the median increment in platelet count was 111 x 109/l (range 43–165). The most common side-effects were grade 1–2 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


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients with bone marrow failure (BMF)-associated thrombocytopenia develop mild to life-threatening bleeding episodes [1Go]. The therapeutic options are limited and platelet transfusions remain the most widely used standard therapy. However, many such individuals require multiple platelet transfusions, and 30% to 70% of them eventually develop refractoriness to platelets due to non-immune and immune causes [2Go]. Refractoriness due to human lymphocyte antigen alloimmunization can be present in up to 80% of patients with aplastic anemia (AA) and 25% to 30% of transfused patients with leukemia [2Go].

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 [3Go]. It stimulates directly the proliferation of hematopoietic stem cells and megakaryocyte progenitors, and induces megakaryocyte maturation resulting in increased platelet production [3Go, 4Go]. It also has biological activity in other tissues, including brain, spinal cord neurons, gut and testis [3Go]. 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 5–7 days post-chemotherapy, and is well tolerated [4Go, 5Go]. 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 25–50 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. [6Go].

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.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Study population
Eligibility criteria included BMF due to myelodysplastic syndrome (MDS), graft failure, chemotherapy or AA. Patients could not have received chemotherapy for a period of ≥2 months and could not have progressive disease. Patients with AA had to have been at least 3 months out from their anti-thymocyte globulin (ATG) treatment. All bone marrow aspirates and biopsies were reviewed by a hematopathologist at the M. D. Anderson Cancer Center. To be eligible, patients had 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. Patients were excluded if they had a performance status 3–4 (Zubrod scale), known allergies to Escherichia coli or known hypersensitivity to IL-11, history of papilledema, history of active chronic heart failure, known antibodies against HIV or hepatitis viruses, or if they were pregnant or breast feeding.

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 0–1 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 [7Go]. 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.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Thirty-six patients were enrolled and 33 patients were evaluable. Three patients were excluded for non-compliance or registration error (n=2), or concurrent treatment with thalidomide (n=1). This analysis includes an update on the previously reported 16 patients [6Go].

Patient characteristics
The clinical characteristics of the 33 patients are summarized in Table 1. Fifteen patients (45%) were ≥60 years.


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Table 1. Patients' characteristics in 33 patients with bone marrow failure treated with interleukin-11

 
Six patients with MDS and three patients with prolonged thrombocytopenia following stem cell transplantation or chemotherapy had received no prior therapy for their BMF (Table 2). The remaining patients had received a median of two prior therapies (range one to four).


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Table 2. Prior therapy in 33 patients with bone marrow failure treated with interleukin-11

 
Response
Nine patients (27%) responded to IL-11. Eight of these patients were receiving the 10 µg/kg/day dose and one patient had been escalated to 15 µg/kg/day during maintenance (Table 3). The diagnoses of the responders included refractory anemia with ringed sideroblasts (n=1), refractory anemia with excess blasts (RAEB) (n=4), chronic myelomonocytic leukemia (n=1) and AA (n=3). IL-11 was started in the three patients with AA at 3, 8 and 32 months after ATG therapy. Platelet counts in these three patients were between 1 and 3 x 109/l when IL-11 was initiated. Four of the responders had normal karyotype and four of those with a diagnosis of MDS had received no prior therapy. Amongst responders, the median maximum post-treatment platelet count was 137 x 109/l (range 46–213) and the median increment in platelet count above baseline was 111 x 109/l (range 43–165).


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Table 3. Characteristics of responders to interleukin-11

 
The median time to response was 0.9 months (range 0.3–11). The median response duration was 3 months (range 1.4–34.5+). The three responders with very low platelet counts (baseline platelets 1–3 x 109/l) took much longer to respond (5, 5.9 and 11 months) than the six responders with higher platelet counts (baseline platelets 22–48 x 109/l; time to response 0.3–1.5 months).

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 9–126). (In normal individuals, 20–30 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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Table 4. Response by pretreatment characteristics

 
Three patients, one with RAEB and two with AA, showed a multilineage response. The time interval between anti-thymocyte globulin and IL-11 in the two responders with AA was 8 and 32 months, respectively. Both multilineage responders with AA received concurrent G-CSF; erythropoietin was added in one of these patients after 6 months of IL-11 and G-CSF therapy. The patient with RAEB who showed a trilineage response received no additional growth factor and had a concomitant decrease in his bone marrow blasts from 17% to 3%. Loss of response was accompanied by an increase in blasts in this patient (but not in other responders in this study). Interestingly, the three AA responders (Table 3) had previously failed the following therapies: ATG and prednisone, cytarabine and topotecan, and erythropoietic and G-CSF (one patient); ATG and cyclosporine, stem cell factor and G-CSF (one patient); and ATG, cyclosporine and G-CSF (one patient).

Side-effects
IL-11 as administered in this study was generally well tolerated. Ten patients (30%) had no side-effects. Other patients manifested grade 1–2 peripheral edema, conjunctival injection, fatigue, arthralgias and myalgias (Table 5). In 10 patients, furosemide 20 mg orally daily was given.


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Table 5. Toxicity

 
Grade 3–4 toxicities included transient ischemic attack (n=1) and atrial fibrillation/supraventricular tachycardia (n=1). The patient who developed a transient ischemic attack did so after the completion of the second course of IL-11. This patient was a 77-year-old man with RAEB who had an extensive cardiac history including bilateral endarterectomy 15 years prior to oprelvekin therapy, hypertension, hypercholesterolemia, coronary artery disease and chronic obstructive pulmonary disease (COPD). He received low-molecular weight heparin and the neurological symptoms completely resolved. Two patients with neutropenia and/or COPD developed pneumonia while on treatment. The latter was believed to be unrelated to IL-11 treatment.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
In this study, the overall response rate of low-dose IL-11 in patients with severe thrombocytopenia due to BMF was 27%. 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 time to response was 0.9 months (range 0.3–11) and the median response duration was 3 months (range 1.4–34.5+). Of interest, patients with very low baseline platelet counts (<5 x 109/l) required several months to respond. A similar prolonged time to response for some patients with AA or MDS was previously observed in studies using stem cell factor (SCF) or a combination of IL-3 and granulocyte–macrophage colony-stimulating factor (GM-CSF) [8Go, 9Go]. The most common side-effects were grade 1 lower extremity edema, conjunctival injections and fatigue. This is in contrast to studies of prolonged use of higher doses (25–50 µg/kg/day), in which toxicity was substantial (R. Kurzrock, unpublished data) [10Go].

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 [11Go–15Go]. These growth factors have acceptable toxicity without significant stimulation of leukemic myelopoiesis or subsequent progression into acute myeloid leukemia, as demonstrated in controlled studies [11Go–13Go, 16Go]. 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 [17Go]. Erythropoietin induces response in ~20% of patients with MDS, mainly in those with preserved erythroid function and relatively low endogenous erythropoietin levels [18Go–22Go]. 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 [23Go]. A 1–5 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 [24Go]. IL-3 has limited thrombopoietic activity as a single agent in patients with AA or MDS [25Go], but multilineage responses have been reported in combination with GM-CSF [26Go]. SCF has also induced multilineage responses in some patients with AA [9Go]. IL-6 is a thrombopoietic factor in MDS, but has significant toxicity [27Go].

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 [28Go]. Another study showed that in this setting neutropenia is more likely to improve (50% of patients) than anemia (23%) or thrombocytopenia (34%) [29Go]. The demethylating agent decitabine induces responses in 30% to 50% of patients with advanced forms of MDS [30Go]. In addition, the hypomethylating agent 5-azacytidine showed responses in 60% of MDS patients and also demonstrated a survival advantage in a randomized study [31Go]. 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 [32Go].

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 [33Go–35Go]. 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 [36Go]. 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 [37Go]. In regression analyses, IL-11 therapy was independently predictive of remission [37Go]. 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 [38Go]. IL-11 may have other benefits as well, such as reduction in the frequency and load of bacteremia during chemotherapy for hematological malignancies [39Go].

The combination of G-CSF or GM-CSF with or without erythropoietin has shown some activity in patients with AA [40Go]. In addition, some AA patients may recover spontaneously [41Go, 42Go]. 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.


    Acknowledgements
 
This study was supported in part by Wyeth Pharmaceuticals.

Received for publication April 30, 2004. Revision received July 8, 2004. Accepted for publication July 28, 2004.


    References
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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