Acute Lymphoblastic Leukemia

Early studies of acute lymphoblastic leukemia (ALL) treated with prednisone alone showed that 50% of the affected children responded with prompt clinical improvement and remission.⁸⁶ However, remission was short (1 year), and relapse, often coinciding with the appearance of steroid resistance, was inevitable. For these reasons, multiple drug therapy was initiated, which involves combining prednisone with other cytotoxic agents. With the advent of regimens that contain vincristine and prednisone or prednisolone, more than 90% of children^87,88 and 60 to 80% of adults^89–92 achieve remission. The inclusion of agents such as daunorubicin, l-asparaginase, cytosine arabinoside, doxorubicin, and cyclophosphamide appears to prolong remission, but whether it increases the rate of remission is unclear. More recent studies suggest that dexamethasone may be a more potent antileukemic agent than prednisone at conventional equivalent doses. Immunophenotyping to identify lineage in childhood ALL and prephase low-dose intrathecal methotrexate treatment of identified B-lineage ALL may result in higher percentages of treatment responders.⁹³ In one study, prednisone pretreatment before initiation of combination therapy improved the rate of complete remission in adult patients.⁹⁴

After remission is achieved, a 2- to 3-year program of maintenance therapy follows that involves regular intensive chemotherapy sessions that include glucocorticoids.^88,90,95 Prophylactic treatment to prevent relapse in the central nervous system is often administered; the treatment consists of cranial radiotherapy and intrathecal treatment with prednisone, methotrexate, and cytosine arabinoside.^96,97 With this approach, more than 50% of children appear to be cured (no relapse within 5 years). The success rate is considerably lower in adults; only 15 to 30% of adults appear to be cured.

In refractory cases, or in cases of relapse, which occurs in approximately 20% of children with acute lymphoblastic leukemia, re-induction involves more aggressive combination chemotherapy, again including a glucocorticoid.⁹⁸ Treatment with high doses of methylprednisolone (1 g/m² for 5 to 8 days) is also used and may be more effective than conventional-dose prednisolone, with little toxicity.^99,100 However, overall survival rates after relapse remain fairly low, averaging 35 to 65% in children^96,97 and less in adults.

Acute Myeloid Leukemia

Glucocorticoids appear to have little value in the treatment of acute myeloid leukemia. While they have been included in some combination chemotherapies, their importance in such regimens is unclear.¹⁰¹

Chronic Lymphocytic Leukemia

Recent trends in the treatment of chronic lymphocytic leukemia (CLL) have focused on inclusion of newer agents, such as purine analogs and monoclonal antibodies (such as Campath-1H and Rituximab), in conventional chemotherapeutic regimens.¹⁰² Typical B-cell chronic lymphocytic leukemia in the early stage of progression responds well to combination chemotherapy including an alkylating agent (such as chlorambucil) plus or minus prednisolone.^103,104 Advanced stages of the disease often require the addition of an anthracycline and a vinca alkaloid for successful therapy. One commonly used combination is cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP).¹⁰⁶ Fludarabine appears to be effective in both untreated and refractory cases of chronic lymphocytic leukemia.^106–108 Corticosteroids are particularly useful if the neoplasm is associated with autoimmune hemolytic anemia, neutropenia, and thrombocytopenia with hemorrhagic complications.¹⁰⁹ Glucocorticoids alleviate the lymphadenopathy and hepatosplenomegaly that are often associated with this condition.

Chronic Myeloid Leukemia

Chronic myeloid leukemia (CML) in the chronic phase presents no indication for corticosteroids. Blast transformation is characterized by increased splenomegaly, bone pain, and deposits of leukemia outside the lymphohematopoietic system. Between 20 and 30% of CML cases show blast cells that resemble those of acute lymphoblastic leukemia; the remainder are primarily myeloblastic, although a proportion have phenotypic features of both types.

Transformed lymphoblastic cells generally respond to the same treatments used in acute lymphoblastic leukemia. Some patients enter complete remission, but most return to the chronic phase. This chronic phase is brief; blastic transformation reappears and becomes increasingly difficult to treat due to the development of resistant cell types. Very recent studies suggest promise for tyrosine kinase inhibitors in the treatment of CML.¹¹⁰

Hodgkin Lymphoma

Hodgkin lymphoma is a solid tumor that is now considered curable by chemotherapy. Consequently, considerations in the choice of current treatment options revolve around selecting therapy that preserves fertility and minimizes toxicity and therapy-induced secondary malignancies. Corticosteroids alone can achieve worthwhile objective results in 66% of Hodgkin lymphoma patients resistant to alkylating agents. Combination therapy with mustine, oncovin (vincristine), procarbazine, prednisone (MOPP), developed in 1964, was the first treatment to effectively cause complete remission, and probably cures, in a majority of patients. Subsequent regimens, most of which employ a glucocorticoid, are as effective as MOPP. Adriamycin (doxorubicin), bleomycin, vinblastine, and dacarbazine (ABVD), a nonglucocorticoid regimen, has a favorable toxicity profile similar to that of MOPP and is now considered a superior first-line therapy.¹¹¹

Recent studies show that treatment of early stage Hodgkin lymphoma with a combination of radiotherapy and chemotherapy may be most effective. The NOVP (Novantrone [mitoxantrone], Oncovin [vincristine], vinblastine, prednisone) treatment regimen in combination with radiotherapy shows promise as an effective yet minimally toxic treatment for early Hodgkin disease, with all patients in a preliminary study achieving complete remission and 5-year overall survival rates of 95%.¹¹² Advanced stage disease treated with MOPP, ABVD, or other similar combinations exhibits a complete response rate of 55 to 75%.^113–115 Aggressive salvage therapies for relapsed or refractory Hodgkin disease that contain a glucocorticoid have a complete response rate around 30 to 50%.^116–118 It should be noted that targeted immunotherapy (Rituximab) also shows preliminary promise as a therapy because of its apparent combination of efficacy with minimal toxicity.

Non-Hodgkin Lymphoma

Corticosteroids used as single-agent therapy produce temporary responses in patients with non-Hodgkin lymphoma; they are therefore included in virtually every complex regimen used for the treatment of non-Hodgkin lymphoma. Regimens differ according to lymphoma histologic subtype and stage. Patients with disseminated lymphomas treated with recent generations of drug combinations have 3- to 4-year survival rates of 30 to 70%.¹¹⁹ Recent studies indicate that an intensified CHOP regimen (1.8 times the standard dosage) is a feasible and effective treatment for patients with histologically aggressive non-Hodgkin lymphoma.¹²⁰ One study indicates that the use of interferon-α2b in combination with a typical glucocorticoid-containing drug regimen produces good results (85% overall response rate and 86% 3-year survival rate).¹²¹ For tumors within the central nervous system, dexamethasone is preferred instead of prednisone to decrease tumor swelling.

Multiple Myeloma

The standard therapy for multiple myeloma, melphalan and prednisone, results in a 50% response rate.¹²² Complete remission is rare, however, and the median survival is only 24 to 30 months. A combination of vincristine, Adriamycin, and dexamethasone (VAD) is also effective, especially in refractory disease.^123–125 A recent study indicates that treatment of multiple myeloma with intermittent dexamethasone administration leads to an overall response rate of 43%,¹²⁶ a lower response than with VAD therapy, but with a much lower incidence of serious complications. Very high doses of glucocorticoids alone may be temporarily useful, albeit toxic, in cases of progressive or resistant disease, or if bone marrow reserve is limited. These doses can be as high as 1 g/m²/d for prednisone and 40 mg/m²/d for dexamethasone. High-dose melphalan plus methylprednisolone with autologous bone marrow transplantation as consolidation after conventional chemotherapy has resulted in a 75% complete remission rate and an estimated 54-month survival rate of 63%.¹²⁷ Interferon-α has been used as a single agent and in combination with other treatments with some success. The use of interferon-α along with a glucocorticoid for maintenance therapy appears to prolong remission duration.^128,129 Thalidomide produces a response in about 30% of patients with refractory disease, and is being investigated in combination with dexamethasone as initial therapy.¹³⁰

Breast Cancer

The highly malignant nature of breast cancers dictates aggressive therapeutic regimens, often including multiple drug chemotherapy. Although never used as the sole treatment for breast cancer, glucocorticoids are included in various combination chemotherapies. Cyclophosphamide, meth- otrexate, and 5-fluorouracil (CMF)-type regimens, with and without prednisone, result in tumor regression in 50 to 80% of patients and complete response in 15 to 20%.^131,132 Although palliation of symptoms occurs in a majority of patients, only a small percentage benefit by prolonged survival. The role of prednisone in the effectiveness of the CMF and prednisone (CMFP) regimen is unclear. Some trials comparing CMF and CMFP found that the response to CMFP in premenopausal, node-positive women was not different from the response to CMF, whereas another trial found that the inclusion of prednisone resulted in a longer time to treatment failure and a longer survival time¹³³; however, this may be a result of the higher average dose of CMF in the CMFP patients. A trial of radiation treatment plus or minus prednisone indicated that inclusion of prednisone improved disease-free and overall survival in premenopausal women older than age 45 years. A trial of high-dose 11-drug combination chemotherapy including prednisone resulted in a very high response rate (overall response, 92%; complete response, 73%), but median survival time was not markedly increased from other studies.¹³⁴ An 8-drug combination with autologous bone marrow transplantation and locoregional radiotherapy tested on patients with at least 5 involved lymph nodes resulted in a 5-year disease-free survival rate of 84%.¹³⁵ The efficacy of the glucocorticoids in such regimens may be due, at least in part, to the improved tolerance of cytotoxic drugs. For metastatic breast cancer patients who do not consent to aggressive cytotoxic chemotherapy, the alternative combination of mitoxantrone, leucovorin, 5-fluorouracil, and prednisone induced tumor regression in 67% of patients with a complete response in 25%.¹³⁶

Other Uses

Hydrocortisone replacement (approximately 40 mg/d) is indicated after surgical or medical (via steroid synthesis inhibitors) adrenalectomy. Such adrenalectomy eliminates circulating steroids in cases of breast cancer, prostate cancer, and ectopic ACTH excess.^137,138 Hemangiomas in infants are often treated with injections of glucocorticoids.¹³⁹ Thymomas are often treated with glucocorticoids either alone or in combination with cytotoxic drugs.^140,141 Other tumors that have been treated with combination chemotherapy involving a glucocorticoid include medulloblastoma, primitive neuroectodermal tumors, and ependymomas.^142,143

Palliative Care

Glucocorticoid treatment produces rapid symptomatic improvements in critically ill patients, including relief of fever, sweats, lethargy, weakness, and other nonspecific effects of cancer. Glucocorticoids also cause mild euphoria, a general feeling of well being, and a stimulation of appetite.^144,145 These effects are transient, and only short-term treatment is possible due to side effects of the high doses. In addition, glucocorticoid withdrawal can result in adrenocortical insufficiency. For these reasons, corticosteroid treatment is appropriate only for patients whose life expectancy is brief (a few weeks or less). Although doses of 25 mg/d prednisolone can be used, with a decrease to 7.5 to 15 mg/d for maintenance of effects, other options for pain management in terminally ill patients makes the use of glucocorticoids in this context relatively rare.

Hypercalcemia

Hypercalcemia, a common complication of many malignancies,¹⁴⁶ is often caused by increased bone resorption and renal calcium reabsorption. This effect is thought to be a consequence of factors secreted by tumors, particularly tumors of lymphoid origin. Although glucocorticoids do not lower normal calcium levels, high-dose glucocorticoid has efficacy in the treatment of hypercalcemia (100 mg/d prednisolone, 400 mg/d hydrocortisone). The mechanisms of glucocorticoid action in reduction of serum calcium are thought to be cytolytic effects on lymphoid cells, decreased lymphokine secretion, and inhibition of vitamin D action on calcium metabolism. Glucocorticoids are most effective on hypercalcemia that is secondary to high vitamin D levels, and least effective in patients with solid tumors. Results in treatment of multiple myeloma patients are inconsistent. Therefore, glucocorticoids are a poor treatment modality except in cases of vitamin D-mediated hypercalcemia.

Central Nervous System Tumors

Neurologic symptoms from primary and metastatic brain and spinal cord tumors are partially caused by peritumoral edema.¹⁴⁷ Glucocorticoids can ameliorate these symptoms in approximately 70 to 80% of cases after several days of treatment,¹⁴⁸ likely by inducing both decreased edema production and increased edema reabsorption. Dexamethasone is the recommended steroid for this treatment because it contains no mineralocorticoid activity and is highly potent. A dose of 16 mg/d is used with an increase to 100 mg/d if no response occurs. This dose is continued until the maximum response is obtained, then decreased gradually and maintained at the lowest effective dose. Recent findings suggest that currently used doses may be excessive, however, because 2 to 4 mg of dexamethasone per day is sufficient for controlling edema during radiotherapy for brain metastases.^149–151 Glucocorticoid effects on the brain and spinal cord are short-lived and only increase survival time slightly unless other measures, such as radiotherapy and surgery, are taken. Glucocorticoids are often administered during these therapies to alleviate the edema that is normally induced by these treatments. It has been observed that glucocorticoids can decrease the amount of a cytotoxic drug that gets to a tumor, possibly by decreasing capillary permeability. For this reason, a recent pilot study eliminated dexamethasone from the standard high-dose methotrexate protocol for children with brain tumors. The results indicated that dexamethasone could be eliminated from such treatment protocols without serious brain edema or increased toxicity, and with a reduction in the incidence of liver toxicity.¹⁵²

Antiemetic Action

Glucocorticoids decrease the severity of chemotherapy-induced emesis.¹⁵³ Both dexamethasone (8 to 20 mg) and methylprednisolone (125 to 250 mg) are employed for this indication, with vomiting episodes reduced by as much as 74%.

Glucocorticoids are most effective when used at low doses to enhance the antiemetic efficacy of other drugs. Recent findings suggest that the combination of glucocorticoids with serotonin receptor antagonists (eg, ondansetron, granisetron, tropisetron) is extremely effective.^154–156 The mechanism of glucocorticoid-mediated antiemesis is unknown. The effect may be associated with decreases in prostaglandin synthesis, or glucocorticoids may act directly on the chemoreceptor trigger zone by modifying capillary permeability or stabilizing lysosomal membranes.

Dyspnea Caused by Lymphangitic Carcinomatosis

Dyspnea in lymphangitic carcinomatosis may be a result of tumor edema, and is effectively relieved in most cases, at least temporarily, by glucocorticoid treatment.¹⁵⁷ Prednisone is given at a dose of 60 to 100 mg/d, and then reduced rapidly to the minimum level that maintains a response. If the primary tumor is chemosensitive, then cytotoxic agents are also given.

Other Uses of Glucocorticoids

Acute upper airway obstruction can result from direct tumor growth or by compression from thyroid, lung, and esophageal cancers. This obstruction can be reduced by glucocorticoid treatment, either alone or in combination with radiotherapy.^158,159 Other cancer-related obstructions and mass effects, including superior vena cava syndrome; lymphedema; liver metastases; masses in the pelvis, mediastinum, or retroperitoneum; and blockages of the large bowel or ureter,¹⁶⁰ can be partially controlled by glucocorticoids. Therapeutic effects are a result of a reduction in peritumoral inflammation and edema. Pain from bone metastases or metastatic arthralgia from solid tumors often responds to glucocorticoid treatment.¹⁶¹ Several chemotherapeutic agents (mitomycin, bleomycin, busulfan, carmustine), as well as radiotherapy, are associated with pulmonary toxicity. Preventive glucocorticoid administration during chemotherapy, for example, dexamethasone administration during mitomycin chemotherapy for nonsmall-cell lung cancer,¹⁶² can prevent lung injury. However, decreased antineoplastic effects of mitomycin in such a context suggests that further study of this application is warranted. Loss of vision associated with pseudotumor cerebri can be treated with glucocorticoids.¹⁶³

Mechanism of Glucocorticoid Action

The majority of the biologic effects of steroid hormones are mediated by intracellular receptors specific for each class of steroid. The glucocorticoid receptor (GR), a 98-kilodalton cytoplasmic protein, is present in all tissues that are targets of glucocorticoid action.¹⁶⁴ Mice with a disrupted GR gene lack a functional receptor and die shortly after birth, indicating that a functional glucocorticoid signaling pathway is essential for life.¹⁶⁵ Glucocorticoid receptors are generally required for glucocorticoid-induced changes to occur, but hormonal sensitivity is not guaranteed by the presence of receptors. While a good correlation between cellular concentration of glucocorticoid receptors and sensitivity to glucocorticoids exists, other factors (including nonfunctional or modified receptors and other cellular factors that modify receptor function) modulate glucocorticoid sensitivity.

The current model for glucocorticoid action is described in Figure 62-2. Free glucocorticoids are thought to diffuse into the cell, and then bind noncovalently and with high affinity to the cytoplasmic GR. GR, held in a ligand-binding competent conformation by its association with regulatory proteins including heat shock protein 90, becomes activated upon ligand binding. Activation is not completely understood, but is known to involve a conformational change in GR, increased phosphorylation of the receptor, and release of associated regulatory proteins. Activated steroid-receptor complex translocates to the nucleus, binds as a homodimer to specific DNA sequences called glucocorticoid-responsive elements (GREs), and alters the transcription rate of specific genes associated with the GRE. Figure 62-3 depicts a classical glucocorticoid-responsive gene. The GRE, shown with the consensus DNA sequence, is located in the 5′-regulatory region of the gene. GR dimer bound to this GRE can interact with transcriptional cofactors, as well as with DNA-binding transcription factors that bind to other regulatory elements located in the 5′ region, such as the TATA and CAAT boxes. By this mechanism, glucocorticoids acting via the GR can increase the transcription rate of a positive GRE-containing gene, or decrease the transcription rate of a negative GRE-containing gene. Alterations in the transcription rate lead to changes in the amount of messenger RNA and, ultimately, the level of protein that is synthesized from these genes, and thus alter cellular functions. GRs also negatively regulate the transcription of genes indirectly by interfering with the activity of other transcriptional activators, such as AP-1 and NFκB. These repressive actions are thought to be the result of protein-protein, rather than protein-DNA, interactions. GR interacts, either directly or via associated factors, with AP-1 heterodimers of fos and jun, thereby inhibiting the transcriptional activity of AP-1. Via this mechanism, GR modulates transcription of genes that lack a GRE but are AP-1 responsive. GR exhibits similar negative interactions with the transcription factor NFκB. In this case, the p65 subunit of NFκB interacts with GR. This interaction changes interactions with transcriptional cofactors which bind to both NFκB and GR, and probably with the transcriptional machinery.

Figure 62-2

Mechanism of action for the glucocorticoid signaling pathway. AP-1 = AP-1 responsive element; GR = glucocorticoid receptor; GRE = glucocorticoid responsive element; GTM = general transcriptional machinery; HSP = heat shock protein; NFκB = NFκB (more...)

Figure 62-3

Structural characteristics of a classical glucocorticoid-responsive gene. GRE = glucocorticoid-responsive element; N = unspecified nucleoside.

An important aspect of receptor regulation that is especially relevant to glucocorticoid therapy is glucocorticoid-induced downregulation of the GR. The ability of glucocorticoid to downregulate its own receptor is mediated by the receptor itself.¹⁶⁶ A maximal 50 to 75% decrease in receptor protein, mediated by a decrease in receptor messenger RNA, occurs within 24 h of treatment. Long-term administration of glucocorticoids, associated with downregulation of the glucocorticoid receptor, decreases function of many glucocorticoid-sensitive genes,¹⁶⁷ suggesting that continuous glucocorticoid treatment can have widespread deleterious effects on cell function. This may explain why alternate day glucocorticoid therapy presents less risk of unwanted side effects¹⁶⁸ and suggests that it may be important to administer therapeutic doses of glucocorticoids in a manner that simulates the natural diurnal rhythm of glucocorticoid secretion to maximize efficacy and safety.

Anticorticosteroids

Steroid receptor antagonists have been synthesized that inhibit the action of receptor ligands. Most of these antagonists are modified steroids that are competitive inhibitors of the receptor. The antagonist forms a complex with the receptor and then interferes with one or more of the normal functions of a ligand-bound receptor (nuclear translocation, association with GREs, interaction with transcriptional cofactors, transcriptional modulation). Selective GR antagonists are a currently active area of investigation, but one of the best-characterized antiglucocorticoids is the antiprogestin mifepristone (RU-486).¹⁶⁹ The antiprogestin effects of RU-486 are used clinically for the induction of abortions. Because of its antiglucocorticoid effects, RU-486 is sometimes used as a treatment for hypercorticism. RU-486 is under investigation as an antineoplastic agent for meningioma, breast cancer, prostate cancer, and hepatoma. Spironolactone, a commonly used antimineralocorticoid, has demonstrated great success in reducing mortality in severe heart failure and has lead to the examination of new, more selective aldosterone receptor antagonists (SARAs), such as eplerenone, in the management of hypertension.¹⁷⁰

Corticosteroid Resistance

Glucocorticoids have a specific cytolytic effect on human leukemic and lymphomatous tissue. However, not all leukemia patients respond to glucocorticoid treatment, and some patients cease to respond during therapy. These observations prompted investigators to try to identify a relationship between glucocorticoid receptor concentration and clinical responsiveness. Various human and mouse lymphoid cell lines have been studied to determine how these cells become resistant to glucocorticoids. In nearly all cases of resistance in mouse cells, the cause is a defective glucocorticoid receptor or a large decrease in receptor number.¹⁷¹ However, resistant human leukemia cell lines were not initially found to contain major defects in the glucocorticoid receptor, such as those described in mouse lymphoma cell lines. With the advent of molecular analysis of the glucocorticoid receptor gene, resistant variants of the human T-cell-derived CEM cell line, which is by far the most extensively studied human leukemia cell line, were found to contain mutations in the glucocorticoid receptor.^172,173 These mutations are often subtle, in some cases involving a single nucleotide base pair change. No consistent relationship has been found between glucocorticoid receptor number and sensitivity to lymphocytolysis (apoptosis). The correlation is strongest for acute lymphocytic leukemia and non-Hodgkin lymphoma,¹⁷⁴ yet acute myeloid leukemia shows no correlation. For chronic lymphocytic leukemia, the results are inconsistent.^175,176 The lack of a consistent relationship between receptor number and sensitivity to glucocorticoid therapy suggests that some factor(s) other than the presence of glucocorticoid receptors may mediate the susceptibility of lymphoid cells to glucocorticoid-induced apoptosis.

One topic of current research that may provide a better understanding of the mechanisms of corticosteroid resistance and help clarify the relationship between glucocorticoid receptor number and steroid sensitivity is the variant human glucocorticoid receptor hGRβ. hGRβ is identical to the classical human GR (hGRα) through the first 727 amino acids, but diverges at the carboxy terminus. This variant of GR, like hGRα, is widely expressed. However, unlike hGRα, hGRβ does not bind hormone, is localized to the cell nucleus independent of hormone status, and does not activate glucocorticoid-responsive genes. In vitro studies suggest that hGRβ functions as a dominant negative repressor of hGRα-mediated transactivation. Cell-type-specific expression patterns for hGRα and hGRβ may be a key modulator of glucocorticoid sensitivity—the ratio of hGRα:hGRβ may be a more important determinant of hormone responsiveness than the absolute number of glucocorticoid receptors.¹⁶⁶

Glucocorticoid-Induced Apoptosis

For many years it has been known that glucocorticoids induce massive lymphocytolysis in rats and mice, resulting in significant reductions in the size of the thymus, spleen, and lymph nodes. This widely studied phenomenon was characterized in rodent thymus, where immature thymocytes are available in high numbers and die rapidly after glucocorticoid treatment by a specific process of cell death known as apoptosis, or programmed cell death.¹⁷⁷ Apoptosis is associated with many physiologic processes, including embryogenesis, morphogenesis, normal tissue turnover, and cell-mediated immunity, and is induced by many different signals in these various systems. Morphologic characteristics of apoptosis include cellular condensation and internucleosomal chromatin degradation, followed by fragmentation into apoptotic bodies that are phagocytosed by neighboring cells or circulating macrophages.

Glucocorticoid-induced apoptosis occurs primarily in lymphocytes and is mediated by the GR.¹⁷⁸ However, not all lymphocytes are sensitive. Immature T cells and some B cells are very sensitive to apoptosis, whereas mature T cells are not. In rodents, responsive cell populations start to die within 8 h of glucocorticoid treatment in vivo. Nearly all immature thymocytes are dead within 48 h of treatment.

The sensitivity of human lymphocytes to glucocorticoid-induced apoptosis appears to differ. Although human lymphocytes respond to glucocorticoids, they do not die with the same kinetics as rodent cells. The marked lymphocytopenia observed after glucocorticoid treatment is mostly due to redistribution of lymphocytes into other tissues and is returned to normal within 24 h. Although human lymphocytes are generally more resistant to apoptosis, certain subpopulations do die in response to glucocorticoids. These include cortical and medullary thymocytes, mature Th cells, natural killer cells and cytotoxic T lymphocytes, and immature B cells.⁷⁴ More importantly, several malignant hematopoietic cells are sensitive to glucocorticoid-induced apoptosis. These include multiple myeloma,¹⁷⁹ acute lymphoblastic leukemia,¹⁸⁰ and chronic lymphocytic leukemia.¹⁸¹ Several investigators have demonstrated that some human leukemic cells, notably acute and chronic lymphocytic leukemia, show morphologic and biochemical signs of apoptosis upon death.¹⁸¹ The difference between normal and malignant human lymphocytes that causes the increased susceptibility of malignant cells to apoptosis is unknown. Targeted apoptosis is developing into an important tool in the repertoire of cancer therapy techniques. Much study remains to be done on the phenomenon of apoptosis to determine the mechanism and specificity of this therapeutically useful process.