Use of Hematopoietic Hormones for Bone Marrow Defects in AIDS

Introduction

Hematopoietic hormones are being used increasingly in clinical practice, most often to maintain the dose intensity of conventional chemotherapy schedules, decrease the risk of neutropenic fever, and reduce the period of neutropenia or anemia following high-dose chemotherapy plus bone marrow transplantation and chemotherapy protocols for leukemia.[1] Hematopoietic growth factors are also frequently employed in the setting of active infections, including AIDS, either to ameliorate the myelosuppressive toxicities of various antibiotics and chemotherapy regimens or to augment the host immune response.[2,3] Clinicians use these drugs to control the number and function of host defense cells but are uncertain as to the specific settings in which they are most useful.[4,5]

This review briefly outlines the bone marrow defects that occur during various stages of HIV infection, as well as some pathophysiologic mechanisms that may contribute to alterations in hematopoiesis. The expanding literature on the use of hematopoietic growth factors in the treatment of AIDS is then discussed, with particular focus on the three colony-stimulating factors (CSFs) most commonly used clinically: recombinant human erythropoietin(Drug information on erythropoietin) (rHuEPO [Epogen, Procrit]), granulocyte-macrophage colony-stimulating factor (GM-CSF, sargramostim(Drug information on sargramostim) [Leukine, Prokine]), and granulocyte-colony stimulating factor (G-CSF, filgramostim [Neupogen]).

Bone Marrow Defects in HIV

The immunopathogenesis of HIV infection is extremely complex. A variety of viral and immune mechanisms contribute to the progressive deterioration of immunologic function and to the progression of HIV disease to AIDS.[6] By weakening the host’s immune system, the virus indirectly contributes to his or her likelihood of contracting opportunistic infections and malignancies, which are the clinical hallmarks of this devastating illness.

Cytopenias occur in 10% to 20% of individuals with early HIV disease and in 75% to 90% of those with advanced disease.[7] Ineffective hematopoiesis and premature destruction of circulating blood cells (due to autoimmunity and a menagerie of viral, bacterial, fungal, and protozoan infections) are additional contributing factors. Opportunistic malignancies and the myelosuppressive effects of antiviral, antimicrobial, and chemotherapeutic agents further compromise the host’s ability to maintain adequate blood counts. The precise mechanisms that result in ineffective hematopoiesis are poorly defined and usually multifactorial (Table 1).

Histologic Marrow Alterations With HIV Infection

In 50% to 60% of patients with AIDS, bone marrow is hypercellular, due to absolute hyperplasia in one or more of the nonlymphoid cell lines.[8,9] In general, the myeloid-to-erythroid ratio tends to be close to normal or shows a relative myeloid hyperplasia.[7] Lymphoid aggregates, plasmacytosis, and dysplasia are often noted, although their reported frequencies vary considerably in different reviews. This variation is due, in large part, to the failure of these retrospective studies to take into account such confounding clinical variables as the stage of HIV disease, coexisting infection, and drug therapies. Approximately 5% of patients have hypocellular bone marrow, typically in the setting of advanced HIV infection.

A dysplasia of at least one cell line occurs in approximately 70% of patients with AIDS.[10] The most common bone marrow features are dysplastic granulocytic maturation and vacuolization of granulocytic precursors. Roughly one-half of patients have erythrocytic dysplasia and one-third have megakaryocytic dysplasia.[11] Although the dysplasia is morphologically similar to that seen in primary myelodysplastic syndromes and is often associated with reticuloendothelial iron blockade and megaloblastic hematopoiesis, cytogenetic abnormalities and leukemic transformation rarely occur.[12] In general, the degree and frequency of dysplastic changes increase with concurrent opportunistic infections.[13]

Less certain is the relationship between peripheral blood cytopenias and the degree of marrow cellularity.[13,14] For example, the majority of patients with isolated thrombocytopenia have normal or increased marrow megakaryocytes with variable dysplastic features, as well as clinical findings suggestive of autoimmune idiopathic thrombocytopenia.[15] They may also have elevated levels of platelet-bound immunoglobulin and circulating immune complexes capable of binding platelets, and these abnormalities, more than a relative decrease in megakaryocyte production, contribute to the development of thrombocytopenia.[16]

Hematopoietic Alterations Due to Infection, Medications, or Tumor

Viral Infections—Several viruses may affect bone marrow function and diminish blood counts. The increased prevalence and pathogenicity of cytomegalovirus (CMV) infection in the immunocompromised host is particularly important. Like HIV, CMV may cause histiocytic erythrophagocytosis and autoimmune destruction of blood cells, but neither virus produces distinctive histopathologic changes in bone marrow.[17] Hematopoietic cells infected with CMV are less responsive to CSFs and may serve as reservoirs of latent viral infection.[18] Furthermore, CMV (and possibly HIV) can infect bone marrow stromal cells, potentially diminishing their ability to produce cytokines and growth factors.[19]

Parvovirus is a remediable cause of severe chronic anemia in patients with HIV infection.[20,21] Failure of erythrocyte production results from direct viral infection and lysis of erythroid progenitor cells. Although usually a self-limited illness, in the absence of an adequate antibody response, B19 parvovirus infection can persist. It may also rarely inhibit myeloid and megakaryocytic progenitors, resulting in neutropenia and thrombocytopenia.[22]

Pathognomonic histopathologic findings of parvovirus infection consist of giant pronormoblasts in the bone marrow together with an absence of erythroid progenitors.[20] The diagnosis can be confirmed by in situ hybridization, using sequence-specific parvovirus DNA probes.

Exposure to human herpesvirus-6 during infancy typically results in a mild, self-limited exanthem. The virus has a tropism for CD4+ lymphocytes and monocytes, where it may remain dormant for decades. With immunosuppression, it may reactivate and affect the ability of marrow precursor cells to respond to hematopoietic stimulants, resulting in further suppression of T-cell function.[23]

The various hepatitis viruses may also downregulate hematopoiesis, although the mechanism by which they do so is less well understood.

Other opportunistic infections that can involve the bone marrow include fungi and mycobacteria.[24] Cryptococcus neoformans, Histoplasma capsulatum, and Mycobacterium avium intracellulare (MAI) are the pathogens most likely to affect hematopoiesis.[7,8,12] In contrast, extrapulmonary pneumocystosis rarely involves bone marrow in the current era of effective systemic therapies to prevent Pneumocystis carinii pneumonia.[25,26]

Occasionally, the host marrow may reveal disseminated fungal or mycobacterial involvement long before other signs of infection are apparent. Histologic clues suggesting fungal or mycobacterial infection include a marrow diffusely infiltrated with lymphoid and plasma cells that have loose macrophage aggregates and clusters. Less frequently seen are pseudogranuloma cells and granulomata.[7,24]

Successful detection of these organisms requires the use of special stains, sensitive culture techniques, and patience. Weeks may pass before a fastidious pathogen is identified.

Examining the buffy coat may also demonstrate Histoplasma, Candida, or other phagocytized pathogens within the cytoplasm of neutrophils and monocytes. Many microbiology laboratories now employ lysis centrifugation techniques whereby white blood cells are lysed and intracellular pathogens are more rapidly released into culture media, reducing the time to obtain a positive culture.

Anti-infective Drugs—Drugs used to prevent and treat the infectious complications of AIDS are also hematotoxic. Of these, zidovudine (AZT [Retrovir]), cidofovir(Drug information on cidofovir), pentamidine, trimethoprim(Drug information on trimethoprim)-sulfamethoxazole, pyrimethamine (Daraprim), sulfadiazine(Drug information on sulfadiazine), dapsone(Drug information on dapsone) (Dapsone), amphotericin B(Drug information on amphotericin b), and, especially, ganciclovir(Drug information on ganciclovir) (Cytovene), are the most problematic.

Myelosuppression is the most common dose-limiting toxicity of ganciclovir therapy (both oral and intravenous forms) in immunocompromised hosts. Dose-limiting neutropenia (minimal absolute neutrophil count [ANC] less than 500 cells/mm³) occurred in 24% of AIDS patients receiving chronic oral ganciclovir for CMV retinitis, and anemia (minimal hemoglobin value less than 8.0 g/dL) developed in 15%; when ganciclovir was given intravenously, 37% of patients developed neutropenia and 24% became anemic.[27]

The hematologic side effects of many of these anti-infective drugs are amplified when they are used in varying combinations. Substituting less hematotoxic alternatives for the offending agent(s) can sometimes be accomplished without compromising treatment benefits.

Neoplasms are a common consequence of altered immunity. Non-Hodgkin’s lymphoma (NHL) will eventually develop in 10% to 15% of HIV-infected patients.[28] This percentage will likely increase as strategies to eliminate HIV viral replication and prevent and treat opportunistic infections improve. In this setting, lymphomatous bone marrow involvement is characterized by peripheral blood pancytopenia.[21] Obtaining a bone marrow aspirate and biopsy as part of the staging evaluation provides insight into the myeloid reserve, and possibly, the need for prophylactic intrathecal central nervous system therapy prior to beginning systemic chemotherapy.[29] Although not tested prospectively, retrospective studies suggest that patients at greatest risk for meningeal relapse are those with bone marrow involvement, sites of disease that are at close proximity to the meninges, or small noncleaved histology.[30]

Kaposi’s sarcoma has occurred in as many as 20% to 40% of HIV-infected adult homosexuals. However, the frequency of this complication in the United States is decreasing. Kaposi’s sarcoma rarely involves the bone marrow, although the drugs used to treat it are myelosuppressive. Interferon-alfa (Intron A, Roferon-A), vindesine(Drug information on vindesine) (Eldisine), doxorubicin(Drug information on doxorubicin), etoposide (VePesid), and paclitaxel(Drug information on paclitaxel) (Taxol) are associated with considerable hematologic toxicity, particularly if they are combined with other myelosuppressive drugs. Vincristine, bleomycin(Drug information on bleomycin) (Blenoxane),[31] and the newly available liposomal anthracyclines (Doxil and DaunoXome)[32,33] are generally less hematotoxic.