Stem Cells, Vol. 15, No. 5, 327-333,
September 1997
© 1997 AlphaMed Press
IL-3 in the Clinic
Matthias Eder,
Georg Geissler,
Arnold Ganser
Department of Hematology and Oncology, Hannover Medical School, Hannover, Germany
Key Words. Interleukin-3 • Clinical study • Therapy
Dr. Matthias Eder, Department of Hematology and Oncology, Hannover Medical School, D-30623 Hannover, Germany.
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Abstract
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Since the cloning of human interleukin 3 (IL-3) in 1986 [1] and the demonstration of its proliferative effects on multiple hematopoietic progenitor cells, IL-3 has been widely studied to treat different states of bone marrow failure or hematologic malignancies, to mobilize or expand hematopoietic progenitor cells for transplantation, and to support engraftment after bone marrow transplantation. However, no condition for the clinical use of IL-3 has been established so far despite its theoretical advantages as an early-acting cytokine and in contrast to erythropoietin (EPO), G-CSF, or GM-CSF all of which have already been approved for several clinical modalities. Here we shortly review our current knowledge about the effects of IL-3 on the molecular and cellular level, summarize recent clinical studies with IL-3, and discuss further perspectives for the use of this cytokine.
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Effects of IL-3 on IL-3-Responsive Cells
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Human interleukin 3 (IL-3) mediates its effects by binding to the human IL-3 receptor composed of an IL-3 binding 
-subunit (DUK-1, [2]) and a common ß-subunit also shared by the receptors for GM-CSF and IL-5 [3]. Binding of IL-3 induces the heterodimerization of the - and the ß-receptor subunit [4] that both belong to the cytokine receptor family and together form a high-affinity receptor. Upon ligand binding the tyrosine kinase JAK2 that associates with the ß-subunit [5] is believed to be activated by transphosphorylation [6], and the ß-subunit itself becomes phosphorylated on tyrosine residues providing docking sites for SH2- or PTB-domain containing proteins. A membrane proximal domain of the ß-subunit is linked to the activation of JAK-2, induction of c-myc and pim-1, whereas a more distal region is required for the activation of the ras-pathway. Tyrosine 577 of the ß-subunit mediates the binding of SHC to the ß-chain at least upon stimulation with GM-CSF [7, 8].
Since JAK2 is ubiquitiously expressed, responsiveness to IL-3 is believed to mainly depend on the expression of the receptor subunits [9]. Accordingly, both normal hematopoietic progenitor cells and blast cells in a subset of acute myelogeneous leukemia have been shown to express functional IL-3 receptors [10]. The multilineage response of normal hematopoietic progenitor cells to IL-3 has been demonstrated both in vitro and in vivo. In preclinical [11] and clinical trials (see below), the most prominent and consistent effect of IL-3 in vivo is a significant increase in the absolute neutrophil count (ANC). In vitro IL-3, in combination with other cytokines such as stem-cell factor, IL-6, IL-1, IL-11, G-CSF, GM-CSF, erythropoietin (EPO), or thrombopoietin (TPO) induces the proliferation of colony-forming units granulocyte-macrophage (CFU-GM), CFU-Eo, CFU-Baso, burst-forming units-erythroid (BFU-E), colony-forming units-megakaryocyte (CFU-MK) and colony-forming units-granulocyte/erythroid/macrophage/megakaryocyte (CFU-GEMM) in semisolid medium, and it stimulates the proliferation of purified CD34+ cells in suspension culture [12-16]. Therefore IL-3 is included in almost all protocols to culture hematopoietic stem and early progenitor cells. Such in vitro expanded cells are potential targets for gene transfer and are already being used to restore hematopoiesis after high dose chemotherapy. However, recent studies by Yonemura et al. [17] and Peters et al. [18] raise the possibility that the in vitro culture with IL-3 (and other cytokines) may compromise the reconstituting ability of stem cells at least when transplanted into irradiated mice.
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IL-3 in MDS
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The rationale for the clinical use of IL-3 in myelodysplastic syndromes (MDS) was the multilineage hematopoietic response with an increase of neutrophils, platelets and hematocrit in patients with normal hematopoiesis [19]. Table 1 shows the results of various IL-3 trials in MDS patients. The platelet counts increased in a quarter of the patients, while an increase in ANC was observed in nearly half of the patients. In addition, the basophilic granulocytes, monocytes and lymphocytes exhibited signs of activation. However, rising serum levels of tumor necrosis factor alpha (TNF-), a potent inhibitor of megakaryopoiesis, was associated with the lack of a platelet response or even a decrease in platelet counts during treatment with IL-3. The increase of blast cells by IL-3 treatment, described in a few patients, was not seen more often than in patients treated with G-CSF or GM-CSF. Furthermore, an increasing marrow fibrosis with consecutive thrombocytopenia was also observed.
The combination of IL-3 (0.75 to 10 ug/kg) and EPO was tested clinically because IL-3 stimulates erythroid progenitor cells which can mature under application of EPO. However, an erythroid response was found in 3 out of 22 patients only, while a striking decrease in platelet counts occured in 13 patients [26, 27]. When combined with GM-CSF in nine patients an increase in neutrophil and platelet counts was observed in seven of nine and three of nine patients, respectively, being of clinical relevance only in one patient [28].
Gerhartz et al. [29] compared: A) low-dose cytarabine (Ara-C) alone (2 x 10 mg/m2 day 1-14); B) low-dose Ara-C plus GM-CSF (0.15 mg s.c. day 8-21), and C) low-dose Ara-C plus IL-3 (0.15 mg s.c. day 8-21) in 130 patients with refractory anemia with excess blasts (RAEB) or refractory anemia with excess blasts in transformation (RAEB-T) with either ANC lower than 1,000/ul, thrombocytopenia lower than 50,000/ul, or RBC-transfusion requirement. There was no significant difference in the rate of complete response and the median survival (18 months) between the three treatment modalities. Infections and hemorrhage occurred in 30% (A); 37% (B); 36% (C); 46% (A); 39% (B), and 45% (C), respectively. Adjuvant therapy with GM-CSF and IL-3 appeared not to have a significant benefit under the conditions tested.
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IL-3 in AML
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G-CSF and GM-CSF have been studied in acute myelogenous leukemia (AML) to shorten the duration of neutropenia after chemotherapy and/or to sensitize leukemic cells to cytotoxic therapy [30]. Similarily, IL-3 has been shown to induce proliferation of AML blasts in vitro that may result in an increased cell kill by cytotoxic agents [31-33]. In a recent study by Wielenga et al. [34] 20 patients with AML in relapse received IL-3 by continous infusion starting 24 h before chemotherapy until day 28. Doses were 5 ug/kg/day (10 patients), 7.5 ug/kg/day (six patients), and 10 ug/kg/day (four patients), respectively. After the first cycle of chemotherapy with cytarabine and daunorubicin or mitoxantrone, 10 patients (50%) obtained complete remission (CR), eight entered partial remission, and two patients died from infectious complications. Neutrophils and platelets recovered to 0.5 x 109/l at day 25 (median) and to 50 x 109/l at day 32, respectively. Side effects during therapy included fluid retention, rash, bone pain, headache, fever, nausea, and arthritis, and IL-3 treatment had to be discontinued in two patients (10 ug/kg/day). The data demonstrate that IL-3 is tolerated with acceptable toxicity in patients with AML. It is not known at the moment whether IL-3 leads to an improvement in the rate or duration of CR or survival or whether it may have any advantages as compared with G-CSF and GM-CSF as adjunct to therapy in patients with AML. Ongoing studies with TPO should provide some information about the effects of thrombopoietic agents and will further define the role of cytokine treatment in AML.
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IL-3 in Aplastic Anemia
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In vitro data from supernatants of long-term bone marrow cultures suggest that marrow stromal cells may produce reduced levels of IL-3 in patients with aplastic anemia [35]. However, IL-3 failed to significantly increase the progenitor cell harvest and the colony-forming capacity from these long-term cultures in patients with severe-stage aplastic anemia [36]. In combination with GM-CSF, stem cell factor (SCF), and Flt-ligand (FL), IL-3 generated an increase in hematopoietic colonies in progenitor cell assays [36, 37].
Several clinical trials with IL-3 have been conducted in order to stimulate the bone marrow function in aplastic anemia [22, 23, 38-40]. However, apart from a mostly transient increase of peripheral blood leukocytes, only occasional trilineage reaction has been observed. In a phase I/II study for nine patients with refractory aplastic anemia and for four patients with relapsed aplastic anemia, Raghavachar et al. [41] used IL-3 in combination with anti-thymocyte globulin and cyclosporin A. IL-3 was administered s.c. at 250 ug/m2 beginning on day 1, 3, 6, or 9 after start of the immunosuppressive therapy. In two of 13 patients, an evidence for IL-3-induced CR was observed. Five patients had a partial remission, while two other patients developed AML 4 and 22 months after cessation of IL-3, respectively. A stem cell exhaustion was not observed. In summary, 30 of 60 patients enrolled in the six clinical trials mentioned had a response of polymorph nuclear cells, while reticulocytes and platelets increased in 15 and 12 patients, respectively.
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IL-3 in Diamond-Blackfan Anemia
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In a recent European multicenter study, 40 patients with Diamond-Blackfan anemia (9 adults, 31 children) were treated with IL-3 at a starting dose of 2.5 ug/kg, escalating at day 21 to 5 ug/kg and then to 10 ug/kg if there was no response, for up to 12 weeks [42]. Three children achieved sustained remission off all therapy up to three years in one case. At the time of entry, one was steroid-responsive and transfusion-independent, and two were transfusion-dependent. In addition, two adults had a transient reduction in transfusion requirements but could not tolerate the complete course of therapy because of infection in one case and fluid retention in the other. These data correspond to earlier studies by Gillio et al. with four of 18 patients responding to IL-3 [43], Dunbar et al. with sustained remission in two of six patients [44], and Olivieri et al. with no response to IL-3 in 13 patients with refractory Diamond-Blackfan anemia [45]. In all, nine responders to IL-3 treatment are reported so far out of a total of 77 patients (11.7%) with patients who have never achieved significant in vivo erythropoiesis in response to steroids or during a spontaneous remission being highly unlikely to respond to IL-3 [42].
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Use of IL-3 to Expand Progenitor Cells Ex vivo
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In combination with other cytokines, in particular SCF, IL-6, IL-1, FL, G-CSF, and/or EPO, IL-3 is included in almost all protocols to expand hematopoietic stem and progenitor cells in vitro. These cells can be used for both gene transfer studies and directly to reconstitute hematopoiesis after high-dose chemotherapy. Henschler et al. demonstrated that long-term culture initiating cells (LTCIC) can be preserved, but not amplified when CD34+ cells are expanded ex vivo with SCF, IL-3, IL-1, IL-6, and EPO in suspension culture [46]. Similarily, Shapiro et al. reported the expansion of myeloid and erythroid progenitors in the Delta-assay when CD34+ cells from patients with stage IV breast cancer were cultured with SCF, IL-3, IL-6, EPO, and G-CSF [47]. Based on these in vitro studies, Brugger et al. transplanted 10 patients with the progeny of 11 x 106 autologous CD34+ cells after a 12-day susupension culture with SCF, IL-3, IL-1ß, IL-6 and EPO [48]. No toxic effects were observed, and the cells prompted a rapid and sustained hematopoietic recovery with an identical kinetic as compared to a historic control transplanted with uncultured CD34+ or mononuclear cells. This approach is able to generate a sufficient number of progenitor cells for transplantation from a small number of CD34+ cells and can reduce the number of leukaphereses required to harvest sufficient numbers of CD34+ cells. In addition, it may reduce the number of contaminating tumor cells in the transplant. In a further study, Alcorn et al. transplanted 10 patients with both unmanipulated CD34+ and ex vivo expanded cells after an eight-day suspension culture with the same cytokine combination and observed no adverse effects immediately on cell infusion [49]. Again, the pattern of hematologic recovery was identical to that of historical controls.
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Use of IL-3 to Mobilize Circulating Progenitor Cells
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Transplantation of autologous or allogeneic circulating progenitor cells mobilized with G-CSF or GM-CSF is increasingly used to restore hematopoiesis after high-dose chemotherapy. However, it may be diffult to collect sufficient numbers of CD34+ cells after mobilization with G-CSF or GM-CSF if patients are pretreated with multiple rounds of intensive chemotherapy [50]. In a study by Vose et al. [51], IL-3 alone induced only a modest increase in circulating CFU-GM and inconsistent effects on BFU-E number in heavily pretreated patients. In contrast, the sequential application of IL-3 and GM-CSF after high-dose chemotherapy in patients with non-Hodgkin's lymphoma was reported to increase the number of collected CD34+ cells by up to 22-fold [52]. In a study by Geissler et al. [53], IL-3 was used in combination with G-CSF to potentiate the hematopoietic progenitor yield. After a first course of G-CSF (5 ug/kg/day s.c.) for five days, a second course was given after a treatment-free interval with IL-3 (5 ug/kg/d s.c.) for seven days followed by G-CSF (5 ug/kg/d) for another five days. Again, treatment with IL-3 did not mobilize by itself but significantly potentiated G-CSF-induced mobilization of all progenitor cell types. In two patients, leukapheresis after the IL-3/G-CSF combination obtained sufficient numbers of CD34+ cells; that was not the case after G-CSF treatment alone. Rosenfeld et al. [54] compared four cytokine regimens with IL-3 during steady-state hematopoiesis for mobilizing peripheral blood progenitor cells: IL-3 alone [1], IL-3 followed by G-CSF [2], IL-3 followed by GM-CSF [3], and IL-3 + G-CSF [4]. After PBSC infusion and treatment with GM-CSF, patients in arm 2 showed the fastest neutrophil recovery (ANC more than 500/ul after 13 days) whereas treatment 3 resulted in a significantly slower neutrophil reconstitution (day 22). The addition of GM-CSF to IL-3-containing mobilization regimens resulted in collection of PBSC that led to delayed engraftment.
To improve the bone marrow harvest for autologous BMT (ABMT), Sosman et al. [55] administered IL-3 s.c. for 10 days at dose levels from 2.5 to 15 ug/kg before bone marrow harvest, high-dose chemotherapy, and bone marrow rescue with GM-CSF in 19 patients with nonhematologic malignancies. The authors found only a modest increase in CFU-GM number and no consistent effect on CD34+ cell number within bone marrow. In addition, engraftment of neutrophils and platelets, transfusion rate for both platelets and packed RBCs, and discharge date were not different for the IL-3 doses tested and the authors found neither any enhancement of the stem cell pool nor faster engraftment.
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IL-3 to Improve the Engraftment After BMT
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In a phase I study, Nemunaitis et al. [56] compared the effects of IL-3 at doses of 1 to 10 ug/kg following high-dose chemotherapy and ABMT in 30 lymphoma patients with a GM-CSF-treated historic control. The authors found that it took almost identical periods of time to reach an ANC of 1,000/ul (24 and 26 days for IL-3 and GM-CSF, respectively) or to become independent of platelet substitution (27 and 26 days for IL-3 and GM-CSF, respectively). In contrast, when GM-CSF was administered after five or 10 days of IL-3 pretreatment in 20 patients with non-Hodgkin's lymphoma and 17 patients with Hodgkin's disease after high-dose chemotherapy and ABMT, the median time of neutrophil (ANC more than 1,000/ul) and platelet (more than 20,000/ul) recovery was 16 and 15 days, respectively [57]. The authors compare these results with published data from several studies and conclude that the combination of IL-3 and GM-CSF is more efficient to support the bone marrow engraftment than IL-3 or GM-CSF alone. The combination of IL-3 and GM-CSF was more efficient than G-CSF for supporting the platelet recovery but was of similar benefit for the reconstitution of myelopoiesis. In addition, fewer days of packed RBC transfusions were observed than in historic controls with no cytokines or GM-CSF. Suttorp et al. reported on a patient with juvenile chronic myeloid leukemia with graft failure after unrelated bone marrow transplantation who experienced complete recovery of autologous hematopoiesis and stable remission for 17 months after treatment with GM-CSF and IL-3 [58]. In addition, Vannucchi et al. [59] report on an effective sequential therapy with IL-3 and GM-CSF after an ineffective treatment with G-CSF for five days in a patient after allogeneic BMT with delayed graft failure. These data suggest that in rare cases, a therapy including IL-3 may be useful to be tested in the treatment of graft failures after allogeneic BMT.
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IL-3 After Chemotherapy
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When IL-3 was initially evaluated to decrease the duration of neutropenia and/or thrombocytopenia after chemotherapy, stimulatory effects on neutrophils, reticulocytes, and platelets were observed, and chemotherapy postponement due to insufficient bone marrow recovery was found less often when IL-3 was administered [60]. In a randomized phase Ib study with 28 patients with previously untreated small-cell lung cancer, IL-3 was given before and after chemotherapy with carboplatin, etoposide, and epirubicin at doses from 0.25 to 10 µg/kg by continous infusion for seven days [61]. Before chemotherapy, a dose-dependent increase in neutrophils and platelets was observed. Following the second cycle of chemotherapy, recovery of platelets was faster and postponement of therapy less frequent at higher (2.5 µg/kg and more) doses of IL-3. Similarly, IL-3 was found to enhance the neutrophil recovery at doses of 10-15 µg/kg after chemotherapy with ifosfamide, carboplatin, and etoposide in patients with non-small-cell lung cancer [62]. In this study, no significant effect on the recovery of platelets could be observed. In contrast, in a study by Speyer et al. [63] using IL-3 in patients with advanced-stage ovarian cancer treated with cyclophosphamide and carboplatin, a reduction of the median platelet nadir and the duration of thrombocytopenia (<50.000 /mm3) was found at doses of 250 µg and 500 µg of IL-3 without significant effects on the duration or degree of neutropenia.
When IL-3 (days 1-5) was combined with GM-CSF (days 6-15) after chemotherapy with ifosfamide, cisplatin, and etoposide for several advanced malignancies, IL-3 did not decrease the duration of neutropenia or thrombocytopenia as compared to patients treated with GM-CSF alone [64]. In a recent phase I study of 93 patients with advanced breast cancer treated with five cycles of 5-fluorouracil, leucovorin, doxorubicin, and cyclophosphamide followed by IL-3 and/or GM-CSF for 15 days, the sequential administration of IL-3 (9 days, 1 to 10 ug/kg) followed by GM-CSF (6 days, 5 ug/kg) was associated with higher platelets nadir, need for fewer platelet transfusions, and shorter duration of platelet counts lower than 50,000/ul than either cytokine alone or concurrent application of IL-3 and GM-CSF [65]. The duration of neutropenia was significantly worse with IL-3 alone than in each of the GM-CSF-containing regimens. In summary, IL-3 was found to attenuate the neutropenia and/or thrombocytopenia after chemotherapy in some but not all clinical studies. A significant benefit of IL-3 as compared with G-CSF or GM-CSF after chemotherapy has not yet been established.
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IL-3—Multiple Applications
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To test any antiproliferative effects of IL-3 on follicular small cleaved-cell lymphoma (FSCCL) cells, eight patients with relapsed FSCCL were treated with high-dose IL-3 (1 mg/m2) for 14 days followed by seven days without IL-3. [66]. One patient had a minor response after three courses, one patient with peripheral blood involvement had temporary growth arrest, and the other patients showed no therapeutic response.
IL-3 has also been tested to treat HIV-related cytopenia. In a study by Scadden et al. [67] IL-3 (0.5 to 5 uk/kg) was given s.c. with limited hematological effects on hemoglobin, platelets, and CD4- and CD8-counts. The white blood count and the ANC increased by 52% to 309% and 20% to 262%, respectively. Viral studies including serum HIV p24-antigen levels and competitive PCR of patient plasma did not demonstrate any consistent change in HIV-1 activity.
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Side Effects of IL-3 Therapy
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Fever, rash, fatigue, diarrhea, rigor, musculoskeletal pain, chills, headache, conjunctivitis, edema, chest pain, dyspnea, decrease in platelet counts, increase in basophilic counts, marrow fibrosis, and pulmonary edema have been observed in patients treated with IL-3 in a dose-dependent manner depending on the underlying disease. Usually, grade III toxicities develop only in very few patients receiving 1 or 2 ug/kg. In contrast, at a dose of 5 ug/kg or more, discontinuation of therapy for toxicity is not unusual. In addition, flu-like symptoms are quite often seen even at doses lower than 5 ug/kg. When combined with GM-CSF, the side effects may be even more pronounced. This is especialy the case in conditions when the monocyte-macrophage system or lymphocytes are activated and proinflammatory cytokines such as TNF- are produced. Furthermore, an acute arterial thrombosis in a patient with stage III adenocarcinoma of the breast after chemotherapy and IL-3 treatment has been reported [68]. In addition, Hurwitz et al. [69] reported on a fatal vascular leak syndrome with extensive hemorrhage, peripheral neuropathy, and reactive erythrophagocytosis in a 39-year-old patient with severe aplastic anemia upon treatment with IL-3.
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Conclusion
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Despite its broad range of action on hematopoietic progenitor cells in vitro, no condition for the use of IL-3 in vivo has been established thus far. In combination with G-CSF, GM-CSF, and EPO, it may be used in individual cases of insufficient mobilization of PBSC or of graft failure after BMT in experimental studies. In addition, experimental IL-3 therapy may be of benefit in some cases of aplastic anemia and Diamond-Blackfan anemia when established therapeutic regimens fail. At the moment IL-3 seems to have no significant benefit for the treatment of clonal hematologic malignancies such as MDS and AML.
In contrast to the in vivo application, the use of IL-3 in combination with other cytokines is well established to culture and expand hematopoietic progenitor cells in vitro. Such in vitro expanded hematopoietic progenitor cells are being used to restore hematopoiesis after high-dose chemotherapy for a variety of malignancies. In addition, such cells provide a potential target to correct inherited diseases of the lymphohematopoietic system and to mark or even treat some forms of malignancies by gene transfer.
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Acknowledgments
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Supported by Deutsche Forschungsgemeinschaft grant Ed 34/2-3 to M.E.
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accepted for publication May 29, 1997.
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Abstract
Effects of IL-3 on...
