Hematopoietic Growth Factors and Cytokines

EPO: Clinical Trials/Applications

EPO is most useful in those anemias in which there is an absolute or a relative deficiency in endogenous EPO levels, such as in renal failure and cancer, respectively (see Table 57-2 ). The quality of life for patients with anemia due to renal failure or cancer who respond to EPO is clearly improved. Although EPO has generally been used for patients with hemoglobin below 10 g/dL, the maximum improvement in the quality of life actually occurs in patients with higher hemoglobin levels (11 to 13 g/dL ). In the case of cancer, however, not all patients respond, and those with the highest levels of endogenous EPO are probably less likely to benefit. A recently discovered complicating factor to defining optimal EPO treatment has been the finding of decreased survival in some patients treated in randomized trials with “optimization” of hemoglobin.

Erythropoietin-stimulating agents (ESAs) have been shown in clinical trials to decrease the transfusion requirements and increase the hemoglobin in patients with chemotherapy-induced anemia. However, these trials have not shown that ESAs prolong survival or improve quality of life in these patients. Moreover, ESAs have been associated with a number of unwanted outcomes in cancer patients, including an increased risk of stroke and venous thromboembolism, worse cancer outcomes, and increased mortality. With these findings of worse outcomes in patients treated with ESAs, the U.S. Food and Drug Administration (FDA) issued warnings against the use of ESA. The 2010 ASH/ASCO (American Society of Hematology/American Society of Clinical Oncology) Guidelines recommend a thorough workup for other causes of anemia before initiation of ESAs as well as discussion of the potential benefits and harms of ESAs.

GM-CSF: Clinical Trials/Applications

GM-CSF is safe and effective in the treatment of patients with acute myelogenous leukemia (AML) who are undergoing induction therapy. GM-CSF decreases the neutropenic period and the rate of serious infections in the elderly. This molecule is also indicated for accelerating myeloid reconstitution after allogeneic bone marrow transplantation. It also increases survival in patients who have engraftment failure or delay after allogeneic or autologous transplantation, and it can be exploited to enhance stem cell mobilization for transplant.

G-CSF: Clinical Trials/Applications

G-CSF promotes a rapid increase in neutrophilic leukocytes, which lasts about 24 hours. Despite the multitude of patients who have received G-CSF, few side effects have been reported. Even very long-term G-CSF administration seems fairly innocuous; the most common toxicity is bone pain.

A summary of current American Society for Clinical Oncology (ASCO) guidelines suggests that CSF can be used for primary prophylaxis of febrile neutropenia after chemotherapy if the risk is about 20%. It is also recommended for patients at high risk, based on age, medical condition, disease characteristics, and myelotoxicity of chemotherapy. Prophylaxis is also recommended for diffuse aggressive lymphoma in patients older than 65 treated with curative therapy. Patients exposed to lethal radiotherapy should also receive CSF. In the transplantation setting, the administration of G-CSF reduces neutropenia and infection. G-CSF also mobilizes autologous peripheral blood progenitor cells; these cells are used to accelerate hematopoietic recovery in patients who have received myeloablative or myelosuppressive chemotherapy. Finally, in patients with acquired immunodeficiency syndrome (AIDS), G-CSF reverses and prevents zidovudine-induced neutropenia. Of interest, G-CSF may also be useful in enhancing the defenses of nonneutropenic patients with AIDS who have bacterial infections. However, studies have shown only modest benefit for G-CSF in the setting of nonneutropenic infection in normal individuals.

M-CSF: Clinical Trials/Applications

M-CSF given to patients with AML after consolidation chemotherapies shortened the periods of neutropenia and thrombocytopenia after chemotherapy and reduced the incidence and shortened the duration of febrile neutropenia. Similar salutary effects have been reported after chemotherapy or bone marrow transplantation. M-CSF can elevate neutrophil counts in children with chronic neutropenia.

SCF: Clinical Trials/Applications

SCF seems to be reasonably well tolerated by patients, with the predominant side effects being transient local erythema and long-lasting hyperpigmentation at injection sites. The most worrisome toxicity is a mast cell effect resulting in allergic-like reactions characterized by urticaria, with or without respiratory symptoms.

Of special interest is the role of mutations in the SCF receptor (kit) in gastrointestinal stromal tumors. These mutations activate the kinase enzymatic activity of kit. Kinase inhibitors targeted against kit (imatinib and sunitinib) have been found to be dramatically effective in these notoriously chemotherapy-resistant tumors.

TPO: Clinical Trials/Applications

Two forms of TPO have entered clinical trials : (1) TPO (the full-length polypeptide) and (2) polyethylene glycol (PEG)-conjugated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF). Because its biologic action is prolonged, parenteral administration of TPO for 7 to 10 days increases platelet production 6 to 16 days later. Results of clinical trials of PEG-rHuMGDF or recombinant human TPO in patients with cancer who were receiving chemotherapy, albeit with regimens that produce only moderate thrombocytopenia, suggest that platelet counts return to baseline significantly faster and that the nadir platelet counts are higher. However, the effectiveness of these molecules in accelerating platelet recovery after myeloablative therapy has not been impressive. Furthermore, in most patients with delayed platelet recovery after peripheral-blood stem-cell or bone marrow transplantation, recombinant human TPO did not significantly raise platelet counts. TPO can result in multilineage mobilization of peripheral blood progenitor cells. The kinetics of progenitor release differs from that after G-CSF. Following G-CSF, peripheral blood progenitors increase almost immediately, peak at day 5 to 6, and decrease with G-CSF cessation. In contrast, PEG-MGDF resulted in a late and sustained increase in progenitors, with levels first detected on day 8 and climbing on day 12, despite cytokine discontinuation. PEG-rHuMGDF has also been given to healthy subjects in a single dose of 3 mg/kg of body weight. Administration of this molecule increased the yield of platelets by a factor of nearly 4 and was associated with a quadrupling of platelet counts in the recipients of the apheresed platelets.

IL-1: Clinical Trials/Applications

IL-1α and IL-1β have also been administered in clinical trials, mainly involving cancer patients. In general, the acute toxicities of either isoform of IL-1 were greater after intravenous injection than after subcutaneous injection. Subcutaneous injection was associated with significant local pain, erythema, and swelling. Dose-related chills and fever were observed in nearly all patients, and even a 1-ng/kg dose was pyrogenic. Nearly all patients receiving intravenous IL-1 at doses of 100 ng/kg or greater experienced significant hypotension, probably because of induction of nitric oxide. IL-RA has been approved by the FDA for the treatment of rheumatoid arthritis. Its use in metastatic disease to reduce IL-1 activity, particularly IL-1β, in cancer is being actively discussed. The most compelling design could be to add an IL-1 blocking approach to anti-VEGF or antibodies to VEGF receptors in order to reduce toxic side effects by increasing the anti-angiogenic efficacy.

IL-2: Clinical Trials/Applications

Because of its potent ability to stimulate cytotoxic T cells and NK cells, IL-2 has been an attractive candidate for immunotherapy of metastatic cancer, such as melanoma and kidney cancer, although with relatively low response rates and at the cost of considerable toxicity. For instance, overall response rates of renal cell cancer to IL-2 are in the range of 15% to 25%, with a complete remission rate of 5% to 10%. Complete response rates and response duration seem to favor high-dose rather than low-dose regimens. In melanoma biochemotherapy, regimens combining IL-2 and interferon-α with, for instance, cisplatin, vinblastine, and dacarbazine produce response rates of up to 60%, but this has yet to be translated into a confirmed survival effect. IL-2 has also been given to leukemic patients in a variety of doses and schedules, with hints that it might be useful in remission maintenance. Development of second-generation IL-2 analogs that do not induce the same high levels of secondary cytokines provides promise for further reduction of toxicities, providing that the efficacy is not dependent on these secondary effects. Another approach to therapy has been to use IL-2 attached to a toxin to target and kill cancer cells bearing the IL-2 receptor. DAB389IL-2 is an IL-2 receptor (IL-2R)-specific fusion protein. It contains the enzymatic and translocation domains of the diphtheria toxin fused to human IL-2. This chimera is able to direct the cytocidal action of the diphtheria toxin enzymatic region only to cells that bear the IL-2R. DAB389IL-2 has been approved for the treatment of cutaneous T-cell lymphomas that are CD25 (IL-2 receptor) positive. Antitumor effects may also be seen in patients with other lymphoid diseases bearing the IL-2 receptor.

Recent advances for the use of low-dose IL-2 therapy is promising on chronic graft-versus-host disease (GVHD), which develops in some patients who have undergone allogeneic hematopoietic stem-cell transplantation for the treatment of lymphomas and leukemias. Chronic GVHD, a systemic inflammatory disorder with pleomorphic autoimmune features, is associated with considerable morbidity and mortality. In this setting, it has been shown that IL-2 promotes both effector and regulatory T-cell responses without impairing other immune functions in the patients.

About half of patients showed clinical improvement, even including an improvement in GVHD manifestations in some. These studies may provide a path for the effective use of IL-2 as a regulatory component of immunotherapy. However, the number of subjects in these trials needs to be expanded, and combinations of IL-2 with other directed immunotherapies, such as the infusion of ex vivo expanded Treg cells, could be considered as alternative approaches. However, the results of low-dose IL-2 regimens as an immunotherapy approach in cancer have been disappointing, presumably because of the combined effects of the expansion of the CD25 ⁺ Treg cell population and the poor stimulation of CD25 ⁻ antitumor T cells. In contrast, as a single agent or in combination with tumor vaccines, the use of high-dose IL-2 in patients with metastatic melanoma or metastatic renal cell carcinoma has led to significant therapeutic responses in up to 20% of cases and to long-term survival beyond 10 years in approximately 10% of cases. In a recent randomized, multicentral Phase III trial in advanced melanoma, the response rate was higher and progression-free survival longer with vaccine [gp100:209-217(210M) peptide vaccine] and interleukin-2 than with interleukin-2 alone.

IL-3: Clinical Trials/Applications

IL-3 has been studied in clinical trials of peripheral blood stem cell mobilization, as well as for postchemotherapy and posttransplantation cytopenias and for bone marrow failure states. Most studies have shown only modest effects of IL-3 by itself; in conjunction with other growth factors, however, significant benefits have been demonstrated. For instance, in patients with bone marrow failure treated with IL-3 followed by GM-CSF (IL-3 dosages greater than 1.2 μg/kg/d), 7 (44%) of 16 patients with severe pancytopenia had multilineage responses with normalization or near-normalization of blood counts. Although prolonged therapy was necessary to achieve maximal hematopoietic recovery, responses were durable for up to 4 years after discontinuation of treatment. Side effects of IL-3 include dose-dependent fever, rash, fatigue, diarrhea, rigor, musculoskeletal pain, chills, headache, conjunctivitis, edema, chest pain, dyspnea, decreases in platelet counts, increases in basophilic counts, marrow fibrosis, and pulmonary edema. The tolerance to IL-3 seems to be severalfold better in patients with bone marrow failure states compared with those treated after chemotherapy.