Acute promyelocytic leukemia

OBJECTIVES: The objectives of this review paper are to:

Compare acute leukemia with chronic leukemia and other forms of cancer.

Review the pathophysiology and discuss the clinical and diagnostic features of M3.

Describe the variant of M3 (M3m or M3v).

Compare conventional chemotherapy with all-trans retinoic acid differentiation therapy (ATRA) in the treatment of M3. Discuss the future direction of differentiation therapy.

DATA SOURCES: Current literature.

DATA SYNTHESIS: Until the late 1970s, the methods of diag

nosis and treatment of AML-M3 were similar to the other forms of acute myelocytic leukemia. One notable difference between M3 and other acute myelocytic leukemias involved the common occurrence of life-threatening consumptive coagulopathies in M3 patients that dramatically affected patient outcomes. In 1977 the method of diagnosis confirmation was altered by the identification of a consistent chromosomal translocation involving the long arms of chromosomes 15 and 17. Reports in the 1970s and 1980s indicated that certain types of active metabolites of vitamin A, collectively termed retinoids, could induce differentiation in a variety of cancer derived cell lines, in vitro. It was shown in the early 1980s that 13-cis-retinoic acid (l3cRA) could stimulate differentiation in bone marrow cells collected from patients with various acute leukemias, including M3. The first clinical trial of a retinoid, given as a remission induction therapeutic regimen, involved all-traps retinoic acid (ATRA) administered to M3 patients in 1988. Since then, ATRA therapy has been shown to reduce tumor burden by stimulating differentiation of the leukemic cells, induce long-term clinical remission when administered in conjunction

with chemotherapy and lower the incidence of consumptive coagulopathies in patients with AML-M3.

CONCLUSION: The diagnosis and treatment of AML-M3 has

improved dramatically in the past decade, which has greatly enhanced the prognosis of patients with this disease. First remission rates have increased to greater than 85% world wide, the incidence of disseminated intravascular coagulation (DIC) has declined dramatically, and 60% to 70% of patients with AML-M3 have achieved long term survival and are potentially cured.

ABBREVIATIONS: AML = acute myelocytic leukemia; APL =

acute promyelocytic leukemia; aPTT = activated partial thromboplastin time; ATRA = all-trans retinoic acid; CML = chronic myelocytic leukemia; DIC = disseminated intravascular coagulation; FAB = French- American-British; FDP = fibrin degradation products; G^sub 0^ = resting phase of the cell cycle; M1 = acute myelocytic leukemia without maturation; M2 = acute myelocytic leukemia with maturation; M3 = acute promyelocytic leukemia; M4 = acute myelomonocytic leukemia; MS = acute monocytic leukemia; PT = prothrombin time; WBC = white blood cell

INDEX TERMS: acute myelocytic leukemia; acute promyelocytic

leukemia; all-trans retinoic acid (ATRA); AML-M3; t(15;17)

Clin Lab Sci 2000;13(2):98

LEARNING OBJECTIVES

1. Compare the basic mechanisms of, and pathophysiology resuiting from, carcinogenesis and leukemogenesis.

2. Compare the pathophysiology of acute and chronic leukemias.

3. Compare the proposed etiologic mechanisms of leukemogenesis in AML-M3 with the multi-step model of colorectal car

cinogenesis.

4. Describe the pathophysiology and clinical features of classical AML-M3.

5. Discuss the laboratory findings commonly seen in classical AML-M3.

6. Describe the variant of AML-M3 referred to as AML-M3m or M3v.

7. Discuss the conventional chemotherapeutic approach to the treatment of AML-M3 and the expected outcome.

8. Compare the mechanism of action of conventional chemotherapy with differentiation therapy in the treatment of leukemias.

9. Compare outcomes and sequelae between conventional chemotherapy and all-trans retinoic acid (ATRA) therapy.

10. Discuss retinoic acid syndrome.

INTRODUCTION

AML-M3 is an acute myelocytic leukemia commonly known as acute promyelocytic or progranulocytic leukemia. It has been given the French-American-British, or FAB, designation M3. The disease is initiated by a malignant transformation of an immature myeloid cell that produces a block in differentiation at the promyelocyte stage. This results in a dramatic increase in promyelocytes, and to a lesser degree blasts, in bone marrow and peripheral blood. This review will discuss M3 from a clinical and laboratory perspective; compare M3 to other cancers and leukemias; describe the t(15;17) translocation associated with M3; and discuss a form of treatment unique to AML-M3.

ETIOLOGY OF CANCER AND LEUKEMIA

Generally speaking, leukemia, and nearly all forms of cancer, represents malignant transformation of a single cell resulting from a series of mutations in the DNA of the transformed cell. Each mutation was either acquired by the cell at some time during the life of the patient, or it was present at conception as a congenitally acquired or inherited, cancer predisposing mutation. These mutations are additive and at some point the cell loses its ability to respond to signals that control growth and maturation. The resulting cells are unresponsive to physical and chemical regulators designed to shut down growth by triggering cells to move into the Go phase of the cell cycle. In addition, they lose their ability to respond to signals that stimulate differentiation and maturation. Control of cell growth is a multiple protein process, with synergistic protein requirements, that relies on complicated signal transduction pathways to initiate changes. Therefore, the mutation of a single protein in the system is usually insufficient to produce a full malignancy. The initial mutations may set the journey to malignancy in motion, as well as produce a dysplastic morphologic appearance. In general, dysplastic morphology could be described as a change in cellular appearance intermediate between normal and malignant. Many dysplastic conditions may represent a pre-malignant state, though dysplastic conditions do not indicate that cancer is inevitable. The dysplastic cells must still receive the remainder of the mutations necessary for full cancer transformation.

Colorectal cancer is the model system for the multi-step process of tumorigenesis, in that patients with the benign hyperproliferative condition known as familial adenomatous polyposis (numerous polyps in the intestine) have a much higher risk of colorectal cancer than those without the condition. The morphologic sequence of events begins with a normal colonic epithelium, that progresses to a hyperproliferative epithelium, then to an adenoma that terminates in carcinoma. Although there is not a defined sequence of mutations necessary for full carcinomatous transformation, the early mutations predominately activate oncogenes like ras, neu, myc, myb, and trc while the later mutations inactivate tumor suppressor genes like p53 and DCC. Evidence suggests that leukemias may behave in the same manner, such that some myeloproliferative and myelodysplastic disorders may represent a pre-malignant stage in the transformation process.1

The unregulated transformed cells now grow autonomously, initially as a mass. If left untreated, some cells will inevitably break from the mass, drain into the lymphatics and be delivered into the general circulation. Once this occurs the cancer is described as metastatic. Malignant cells deposit in distant tissues, establish residence, and grow. When a critical mass is reached, the functioning of normal cells is affected and the tissue or organ gradually shuts down. Death of normal cells is accomplished by virtue of cancer cells depriving the normal cells of space, nutrients, and cell regulatory signals.

In the case of leukemias, mutations occur in the DNA of immature blood forming precursor cells, located in the bone marrow, that block differentiation and/or promote unregulated growth. These could be stem cells, blast cells, or even cells intermediate in the maturation sequence. The more immature the transformed cells are, the more likely they will remain in the bone marrow. In contrast, the closer to maturity an immature transformed cell is, the more likely it will exit the bone marrow and enter circulation. Presumably, immature cells possess cell surface markers that promote retention of these cells in the bone marrow, that are lost as the cells mature. Thus the bone marrow is more dramatically of fected in acute leukemias, where blasts dominate, than in chronic leukemias characterized by cells intermediate in the maturation sequence. In acute leukemias the blasts that are retained in the bone marrow gradually diminish erythrocyte and platelet production causing anemia and thrombocytopenia, respectively. Blasts are eventually observed in the peripheral blood when the bone marrow becomes unable to house the massive overabundance of blasts that have accumulated. In chronic leukemias, erythrocyte and platelet counts are often normal or only slightly decreased, because the more mature transformed cells are more readily released from the bone marrow. Metastasis is a much faster process in leukemia than in other cancers because the release of transformed cells into circulation is a natural process for blood cells and it does not require the lymphatic intermediate to gain access to the blood stream. Regardless of the degree of immaturity of the transformed cells, they are unable to function properly so patients exhibit symptoms of white blood cell (WBC) malfunction even in cases with extremely elevated WBC counts.

Etiology of M3

In AML-M3 the block in maturation occurs at the promyelocyte, only one stage of development beyond the blast in the myelocyte maturation sequence. The DNA of the promyelocytes and blasts in nearly every case possess a balanced, reciprocal translocation involving the long arms of chromosomes 15 and 17 that is often the only cytogenetic abnormality present (Figure 1 ) 2-4 Some authors report the incidence of the t(15;17) translocation in M3 as ranging from 50% to 80%.5,6 Lower incidence rates are the result of data generated only by karyotype analysis, which falsely lowers the true incidence for two reasons. First, the technical difficulty inherent in the karyotype analysis prevents the resolution of all translocations that are present. Second, some translocations involve segments of DNA too small to be visualized by karyotype analysis, yet detectable by molecular techniques.6 A few patients with M3 have expressed a t(5;17) or a t(11;17) translocation. Therefore, it appears that chromosome 17 may possess the necessary gene that, when mutated, will initiate the leukemogenic process.8-10

Epidemiology of M3

The incidence of M3 is between 5 and 15% of all AML cases. It occurs in a slightly younger population than MI or M2 acute myelocytic leukemia, with a mean age of 39 years. M3 affects men at a slightly higher rate than women but each experience a mean survival of 18 months with conventional chemotherapy.5,6,11-13

Pathophysiology and Clinical Features of M3

Since the transformed promyelocytes are retained in the bone marrow, M3 behaves like, and is classified as, an acute leukemia.

These promyelocytes, and to a lesser extent myeloblasts, accumulate in the bone marrow, inhibit normal bone marrow function, and eventually spill over into general circulation. Patients present with weakness from the anemia, bleeding from the thrombocytopenia, and infections resulting from the malfunctioning WBCs.

Many of the clinical features of M3 are similar to other acute leukemias by virtue of the common pathophysiology. Bone marrow suppression produces anemia and thrombocytopenia resulting in symptoms of weakness, fatigue, dyspnea, pallor, bleeding, and bruising. However, M3 produces thrombotic and hemorrhagic manifestations that are life threatening and somewhat unique to this form of acute leukemia. The most severe coagulopathies result from the initiation of disseminated intravascular coagulation (DIC). DIC is a thrombotic disorder initiated by overwhelming stimulation of the clotting system. In acute DIC, coagulation is stimulated within the blood vessels at multiple locations throughout the body, simultaneously. This produces clot formation in various vessels and potentially in vital organs. Massive clotting consumes coagulation proteins and platelets, placing patients at risk for spontaneous or trauma induced hemorrhaging. Clot formation stimulates the fibrinolytic system, which begins the process of dot dissolution. Therefore, patients may exhibit concomitant symptoms of thrombosis, hemorrhaging, and fibrinolysis. The symptoms vary in severity proportional to the degree of clot activation, such that some patients with M3 induced DIC remain asymptomatic, while many others die from DIC. The most common presenting symptoms include petechiae, small ecchymoses, hematuria, and bleeding from venipuncture and bone marrow aspiration sites." Often, these are the symptoms that prompt the patient to seek medical attention. The mechanism of DIC induction in patients with AML-M3 appears to involve the primary granules of the transformed promyelocytes. These primary granules contain a thromboplastin-like substance capable of activating the extrinsic system of coagulation as well as cancer procoagulant, a factor X activator.5,6,15-- 17 The release of these substances sets the abnormal clotting phenomenon in motion such that the greater the release of primary granules, the greater the clotting, and the more severe the symptoms, M3 produces increased numbers of promyelocytes, which results in a large degree of cell death and the release of massive amounts of granule contents. The system is exacerbated by conventional chemotherapy, which is designed to induce massive cell death amongst the cell populations actively engaged in division.

Other investigators have suggested that the reason for the abnormal clotting tests may not be initiation of DIC, but rather excessive fibrinolysis. Leukemic promyelocytes have been shown to release plasminogen activators that inactivate (alpha^sub 2^,-plasmin inhibitor. Plasma levels of plasminogen and alpha^sub 2^,-plasmin inhibitor are consistently increased in M3 patients. In addition, enzymes such as human leukocyte elastase, cathepsin G, and proteinase 3 released from neutrophils, have been shown to cleave von Willebrand factor and fibrinogen, thus contributing to fibrinolysis.18-25

LABORATORY FINDINGS

The laboratory functions in the process of diagnosing and monitoring of patients with M3 and in the identification and monitoring of secondary coagulopathies. The complete blood count (CBC) will usually reveal a slight to moderate increase in the WBC count with a slight to moderate decrease in RBC count, hemoglobin, hematocrit, and platelet count. The evidence most diagnostic of M3 is the presence of numerous promyelocytes on the peripheral blood smear and bone marrow, often accompanied by a few blasts as illustrated in Figure 2. These promyelocytes are usually large and heavily granulated. In many promyelocytes, the granules may actually obscure the nucleus, making nuclear morphologic analysis impossible. In promyelocytes with a visible nucleus, the chromatin pattern is reasonably delicate with a reniform or bilobed nuclear structure. Since Auer rods are considered the product of the fusion of primary granules, many Auer rods are often observed in cases of M3. Promyelocytes may contain bundles of Auer rods in stacks or rosette configurations referred to as "fagot cells".

The monitoring of the hemostatic status of patients with M3 is of utmost importance. Test selection focuses on the process of platelet and clotting factor consumption resulting from the increased activation of the clotting system. The degree of consumption is directly proportional to the degree of abnormality seen in the coagulation assays. Other tests are performed to evaluate the degree of clot dissolution by the fibrinolytic system. A prolonged activated partial thromboplastin time (aPTT) and thrombin time with elevated fibrin degradation products (FDPs) and a decrease in fibrinogen and platelets, are the most consistent abnormalities present .21 In addition, the prothrombin time (PT) may be prolonged and schistocytes may be observed in the peripheral blood in more serious cases of DIC. As in other cases of DIC, anticoagulant therapy with heparin may be indicated and is often risky. Pabents with a stronger thrombotic than bleeding tendency tend to improve with heparin therapy.25,26 Clinicians must be alerted to the risk of initiating uncontrolled hemorrhages in DIC patients by placing them on heparin therapy.8

M3m (microgranular) or M3v (variant)

An uncommon morphologic variant of M3 has been described and referred to as M3m, for microgranular, or M3v, for variant. A representative microgranular promyelocyte is pictured in Figure 3. In this version of M3, the granules of the promyelocytes are difficult to see, if not invisible, under brightfield microscopy. However, granules are present and clearly observable under a transmission electron microscope. The granules that are visible under brightfield are smaller, fewer in number, and more dust-like in appearance as compared to normal promyelocytes or those seen in classic hypergranular M3. The morphology of microgranular promyelocytes closely resembles monoblasts in that both possess a folded, reniform nucleus with delicate chromatin and a softly granular cytoplasm. Therefore, care must be exercised to avoid misdiagnosing an M3m as an M4, acute monomyelocytic leukemia, or an M5, acute monocytic leukemia (Table 1 ). A thorough inspection of the Wright's stained peripheral blood smear will almost always reveal at least a few heavily granulated promyelocytes with Auer rods in M3m patients. Compared to M4 or M5, patients with M3m generally have a less dramatic degree of leukocytosis (usually

CYTOCHEMICAL RESULTS

Although cytochemical staining is seldom necessary to diagnose a classical hypergranular M3, it is one of the best ways to distinguish an M3m from an M4 or an M5. Regardless of whether the patient has an M3 or an M3m, the promyelocytes will stain intensely with cytochemical stains that target components of primary granules. The myeloperoxidase and Sudan black B stains are consistently positive while the nonspecific esterase is usually negative.sv In contrast, all three stains are positive in M4, while only the nonspecific esterase is positive in M5. An example of a Sudan black B stain is shown in Figure 4. Table 1 illustrates a comparison of the morphologic, cytochemical, and CBC related results of M3m verses the M4 and MS forms of acute myelocytic leukemia.

CONVENTIONAL THERAPY

Conventional therapy for any acute leukemia has traditionally involved multiple rounds of chemotherapy, while in some cases total body radiation and bone marrow transplant have been used. The goal of chemotherapy is to kill the malignant cells while preserving normal cells. However, chemotherapeutic drugs cannot differentiate cancer cells from normal cells. The general mechanism of action for most chemotherapeutic agents is to induce cell death by interfering with DNA synthesis. This requires that the cell be engaged in division for the interference to occur. Therefore, one can state that most chemotherapeutic drugs attack cells in the process of division. Cell types that have a larger population of cells engaged in active division, or those cell lines that remain in cell division for longer periods, will suffer a greater death toll than those that are quiescent. There are several normal tissues that maintain a relatively rapid cell production rate such as bone marrow, hair follicles, and the lining of the gastrointestinal tract. The normal cells within these tissues suffer a significant cell loss, along with the malignant cells, during chemotherapy treatments. The weakness, fatigue, pallor, and lethargy experienced by chemotherapy patients are the direct result of erythroid depletion. Likewise, bruising and bleeding is often the result of chemotherapy induced thrombocytopenia, at least in those M3 patients that have not developed DIC. Nausea and vomiting reflect the death of mucosal cells in the GI tract. Hair loss is attributable to follicle cell death. Although large numbers of normal cells engaged in division may die, sufficient numbers remain to reestablish the tissue following traditional chemotherapy regimens. It is possible to ablate the bone marrow with very high doses of chemotherapeutic drugs and local radiation. Total destruction of the bone marrow is actually the goal in preparing patients for bone marrow transplants.

PROGNOSIS WITH CONVENTIONAL THERAPY

The prognosis of all acute myelocytic leukemias is poor relative to other farms of cancer, and M3 is no exception. For M3, the rate of first remission with conventional antileukemic induction chemotherapy is approximately 70% while the 5-year disease-free survival rate is between 35 and 45%.27,32 Between 10 and 20% of M3 patients die from DIC either before or during therapy.15,16,23,33 However, death from therapy induced DIC seems to be falling, and remission rates are improving with the advent of differentiation therapy using all-traps-retinoic acid, also known as ATRA.34-43

ALL-TRANS RETINOIC ACID (ATRA) THERAPY Reports from the 1970s and 1980s indicated that several active metabolites of vitamin A, collectively known as retinoids, could induce differentiation, in vitro, in a variety of human cancer cell lines. The most successful combination of a retinoid and a malignant cell line was ATRA and M3 promyelocytes. Malignant promyelocytes that were unable to differentiate beyond the promyelocyte stage have been induced to do so in the presence of ATRA.11

Morphologic assessment of malignant promyelocytes in M3 patients undergoing ATRA therapy has been performed using brightfield and electron microscopy. After one week of ATRA therapy, leukemic cells in the bone marrow began to express morphologic evidence of maturation. Condensation of chromatin, nuclear lobe formation, and a reduction in the number of primary granules were all appreciated under both brightfield and electron microscopy. Auer rods were noted in a few myeloid cells, reaffirming their malignant origin. Two to three weeks of ATRA therapy produced mostly mature appearing neutrophils with subtle nuclear abnormalities. However, electron microscopy revealed an abundance of myeloperoxidase positive primary granules in the majority of cells, with very few myeloperoxidase negative secondary granules in the differentiating malignant clone. A few cells continued to express Auer rods but, only rarely were myeloid cells observed that possessed both primary and secondary granules. In addition, large spherical lipid droplets were noted on electron micrographs of differentiating neutrophils, indicating residual abnormalities in fat metabolism.44

Complete remission was achieved by the fifth week of ATRA therapy. At this time bone marrow cells appeared normal under brightfield microscopy with only a few cells retaining irregularities in nuclear shape. The promyelocytes in the peripheral blood appear normal and only occasional Auer rods could be observed. Neutrophils that were devoid of secondary granules became increasingly rare.44 Although maturation of promyelocytes is known to occur in M3 patients undergoing ATRA therapy, careful morphologic assessment confirms that differentiation follows a nearly normal course.

The effectiveness of ATRA therapy in improving the complete remission rate in M3 patients is without question. Complete remission rates of 75% to 80% with chemotherapy alone17,45-46 improved to 90% with ATRA alone.36,37,40,41 However, remissions with ATRA alone are often short lived, lasting between one and 19 months with a mean duration of 3.5 months. Intense antileukemic consolidation chemotherapy is required to prolong remissions.11,34,42 Even though ATRA may induce differentiation in most of the malignant promyelocytes present, the mutation or mutations that originally produced the malignant tranformation still remain. Mutant cells will eventually repopulate the bone marrow, resulting in relapse. Once the threat of DIC from the overabundance of promyelocytes is lessened through differentiation therapy, chemotherapy can then be used to kill the malignant progenitor cells. Remission rates of 96% are achieved with a combination of chemotherapy and ATRA.37 These remission rates only apply to M3 patients that present with the typical t(15;17) translocation. Promyelocytes from M3 patients that express the rare t(11;17) or t(5;17) translocation do not differentiate with ATRA therapy. In addition, the relapse rate of M3 patients after bone marrow transplant (28%) is higher than the rate following ATRA and chemotherapy treatments.8

ATRA has been used to rescue patients that have relapsed following a treatment regimen involving chemotherapy alone. Patients who relapse after completing the required rounds of chemotherapy become resistant to additional courses of chemotherapy. Complete remission rates of 85% to 90% have been achieved with ATRA therapy following first relapse, but almost all experience a subsequent relapse within a year.8

Another important benefit of ATRA is that differentiation therapy, unlike antileukemic induction chemotherapy, does not destroy cells. Not only does this abrogate many of the common symptoms of chemotherapy like nausea, vomiting, hair loss and fatigue, but it also reduces the incidence of therapy induced DIC. Many reports have also shown that ATRA therapy can even promote rapid resolution of an existing DIC within four days of initial administration.11

The two major drawbacks to ATRA differentiation therapy, when used alone, are drug induced leukocytosis and drug resistance. ATRA is effective at pushing the abundant immature myeloid cells toward complete maturation. About one third to one half of patients receiving ATRA alone developed a rapid increase in leukocytes shortly after therapy." Another problem with ATRA therapy is drug resistance. ATRA resistance is rare (

PROGNOSIS

The prognosis of M3 continues to improve. First remission rates using a combination of ATRA and chemotherapy are greater than 90% in the USA and the complicating effects of DIC are reduced. When ATRA is administered prior to chemotherapy, the abundant promyelocytes differentiate to the mature neutrophil forms. This dramatically reduces the threat of DIC, but the transformed cells retain the mutation and therefore the potential for relapse. When ATRA therapy is followed by chemotherapy, long-term remission can be achieved because the cytotoxic drugs destroy the rapidly dividing myeloid precursors that express the mutation. Between 60% and 70% of ATRA/chemotherapy treated patients with AML-M3 achieve long term disease free survival and are potentially cured. Bone marrow transplant is therefore unnecessary in the initial stages of therapy and is reserved for patients in relapse. As a result, AML-M3 has achieved the highest treatment success rate of all the acute myelocytic leukemias.42

RETINOIC ACID SYNDROME

Many side effects have been directly associated with ATRA therapy. These side effects are generally divided into two categories based on severity. The predominant, but less severe, side effects include dryness of skin and mucus membranes, red/cracked lips, headache, hypertriglyceridemia, bone pain, and intracranial hypertension, especially in pediatric patients.11

The second and more severe side effect is known as the retinoic acid syndrome. This syndrome is characterized by fever, respiratory distress, weight gain, lower extremity edema, pleural or pericardial effusions, hypotension, and sometimes renal failure.46 The incidence of retinoic acid syndrome is relatively low with the highest reported incidence of 23% 7,43 In most cases, retinoic acid syndrome is preceded or accompanied by leukocytosis. Two possible pathophysiologic reasons have been suggested. First, ATRA may stimulate the synthesis and release of cytokines by M3 promyelocytes, which would promote WBC production.47,48 An_ other explanation for leukocytosis may be the rapid release of M3 promyelocytes from the bone marrow due to a change in deformability from ATRA therapy.49 Although treatment protocols with retinoic acid are difficult to manage, there have been two successful approaches to the prevention of retinoic acid syndrome. Since patients with a high WBC count at diagnosis are more likely to develop retinoic acid syndrome, administering chemotherapy with ATRA to these patients will lower the incidence of retinoic acid syndrome by reducing the WBC count. Another approach is to administer high dose intravenous corticosteroids, like dexamethazone, at the first sign of symptoms.7,46,49

FUTURE DIRECTION

The future of differentiation therapy in other forms of cancer looks promising. Retinoic acid therapy has been shown to inhibit the conversion of oral leukoplakia to oral cancer, to reduce some cutaneous malignancies and to treat cervical dysplasias. Differentiation therapy using ATRA is being tested on other forms of AML and on T cell lymphoma. Although most patients respond to the combination of chemotherapy and ATRA therapy, overall effectiveness is still less than expected. Retinoic acid syndrome has become a serious complication, therefore alternative interventions to reduce or eliminate this syndrome is an area of intense investigation.11,50

REFERENCES

1. Fearon ER, Vogelstein BA. Genetic model for colorectal tumorigenesis. Cell 1990;61:759.

2. Golomb HM, Rowley J, Vardiman J, and others. Partial deletion of the long arm of chromosome 17: a specific abnormality in acute promyelocytic leukemia. Arch Intern Med 1976;136:825.

3. Rowley JD, Golomb HM, Dougherty C. 15/117 translocation: a consistent chromosomal change in acute promyelocytic leukemia. Lancet 1977;1:549.

4. Lavau C, Dejean A. The t(15;17) translocation in acute promyelocytic leukemia. Leukemia 1994;8:(suppl 2) S-9.

5. McKenzie SL. Textbook of Hematology. 2nd ed. Baltimore: Williams and Wilkins; 1996: p 385-7.

6. Evans VJ. In: Sciene-Martin EA, Lotspeich-Steininger CA, Koepke JA, editors. Clinical hematology; principles, procedures and correlations. 2nd ed. Philadelphia: Lippincott-Raven; 1988: p 444-8.

7. Lafage-Pochitaloff M, Alcalay M, Brunel V, and others. Acute promyelocytic leukemia cases with nonreciprocal PML/RARa or RARa/PML fusion genes. Blood 1995;85:1169.

8. Fenaux P, Chomienne C, Degos L. Acute promyelocytic leukemia: biology and treatment. Sem in Oncol 1997;24(1):92.

9. Early E and Dmitrovsky E. Acute Promyelocytic Leukemia: Retinoic Acid Response and Resistance. J Invest Med 1995;43(4):337.

10. Collins SJ. Acute promyelocytic leukemia: Relieving repression induced remission. Blood 1998;91(8):2631.

11. Tallman MS. All-trans-retinoic acid in acute promyelocytic leukemia and its potential in other hematologic malignancies. Seminars in Hematology 1994;31(4) Suppl 5:38.

12. Gralnick HR, Sultan C. Acute promyelocytic leukemia: haemorrhagic manifestations and morphologic criteria. Br J Haematol 1975;29:373.

13. Groopman J, Ellman L. Acute promyelocytic leukemia. Am J Hematol 1979;7:395.

14. Perkins ML, Odell JM, Braziel RM. In: Harmening DM. Clinical hematology and fundamentals of hemostasis. 3rd ed. Philadelphia: FA Davis; 1997: p 300-1.

15. Gouault-Heilmann M, Chardon E, Sultan C, and others. The procoagulant factor of leukemic promyelocytes: demonstration of immunologic cross reactivity with human brain tissue factor. Br J Haematol 1975;30:151.

16. Bauer KA, Rosenberg RD. Thrombin generation in acute promyelocytic leukemia. Blood 1984;64:791-G.

17. Rodighiero F, Avvisati G, Castman G, and others. Early deaths and anti-hemorrhagic treatments in acute promyelocytic leukemia: a GIME mA retrospective study of 268 consecutive patients. Blood 1990;11:2112.

18. Chan TK, Chan GT, Chan V Hypofibrinogenemia due to increased fibrinolysis in two patients with acute promyelocytic leukemia. Aust NZ J Med 1984;14:245.

19. Kahle LH, Avvisati G, Lampling RJ, and others. Turnover of alpha-2antiplasmin in patients with acute promyelocytic leukemia. Scand J Clin Lab Invest 1985 (suppl);178:75.

20. Ogston D, McAndrew GM, Ogston CM. Fibrinolysis in leukemia. J Clin Pathol 1968;21:136.

21. Schwartz BS, Williams EC, Conlan MG, and others. Epsilon-aminocaproic acid in the treatment of patients with acute promyelocytic leukemia and acquired alpha-2-plasmin inhibitor deficiency Ann Intern Med 1986;105:873.

22. Velasco F, Torres A, Andres P, and others. Changes in plasma levels of protease and fibrinolytic inhibitors induced by treatment of acute myeloid leukemia. Thromb Haemost 1984;52:81.

23. Gralnick HR, Abrell E. Studies of the procoagulant and fibrinolytic activity of promyelocytes in acute promyelocytic leukemia. Br J Haematol 1973;24:89.

24. Rand JJ, Moloney VUD, Sise HS. Coagulation defects in acute promyelocytic leukemia. Arch Inter Med 1969;123:39.

25. Hoyle C, Swirsky D, Freedman L, and others. Beneficial effects of heparin in the management of patients with APL. Br J Haematol 1988;68:283.

26. Goldberg MA, Ginsburg D, Mayer RJ, and others. Is heparin administration necessary during inductive chemotherapy in patients with acute promyelocytic leukemia? Blood 1987;69:187.

27. Fenaux P, Pollet JP, Vandenbossche - Simon L, and others. Treatment of acute promyelocytic leukemia: a report of 70 cases. Leuk Lymph 1991;4:239.

28. Kingsley EC, Durie BG, Garewal HS. Acute promyelocytic leukemia. West J Med 1987;146:322.

29. Arlin Z, Kempin S, Mertelsmann R, and others. Primary therapy of acute promyelocytic Leukemia: results of amacrine and daunorubicin based therapy. Blood 1984;63:211.

30. Kantarjian H, Keating MJ, Walters RS, and others. Acute promyelocytic leukemia: M.D. Anderson Experience. Am J Med 1986;80:789.

31. Stone RM, Maguire M, Goldberg MA, and others. Complete remission in acute promyelocytic leukemia despite persistence of abnormal bone marrow promyelocytes during induction therapy: experience in 34 patients. Blood 1988;71:690.

32. Cunningham I, Gee TS, Reich LM, and others. Acute promyelocytic leukemia: treatment results during a decade at Memorial Hospital. Blood 1989;73:1116.

33. Sultan C, Heilmann-Gouault M, Tulliez M. Relationship between blast cell morphology and occurrence of a syndrome of disseminated intravascular coagulation. Br J Haematol 1973;24:255.

34. Fenaux P, Ledely MC, Castaigne S, and others. Effect of all-cans retinoic acid in newly diagnosed acute promyelocytic leukemia: results of a multicenter randomized trial. Blood 1993;82:3241.

35. Dombret H, Scrobohaci ML, Ghorra P, and others. Coagulation disorders associated with acute promyelocytic leukemia: corrective effect of all-trans retinoic acid treatment. Leukemia 1993;7:2.

36. Huang ME, Ye YC, Chen SR, and others. Use of all-trans retinoic acid in the treatment of promyelocytic leukemia. Blood 1988;72:567

37. Castaigne S, Chomienne C, Daniel MT, and others. All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemias. I. Clinical results. Blood 1990;76:1704.

38. Muindi JRF, Frankel ST, Huseltion C, and others. Clinical pharmacology of oral all-trans retinoic acid in patients with acute promyelocytic leukemia. Cancer Res 1992;52:2138.

39. Comic M, Delva L, Guidez F, and others. Induction of retinoic acid-binding protein in normal and malignant myeloid cells by retinoic acid in acute promyelocytic leukemia patients. Cancer Res 1992;52:3329.

40. Degos L, Chomienne C, Daniel MT, and others. Treatment of first relapse in acute promyelocytic leukemia with all-trans retinoic acid. Lancet 1990;2:1440.

41. Fenaux PI Tertian G, Castaigne S. A randomized trial of amsacrine and rubidazone in 39 patients with acute promyelocytic leukemia. J Clin Oncol 1991;9:1556.

42. Warrell RP, Maslak P, Eardley A, and others. Treatment of acute promyelocytic leukemia with all-trans retinoic acid: an update of the New York experience. Leukemia 1994;8:926.

43. Degos L. Differentiation therapy in acute promyelocytic leukemia: European experience. J Cell Physiol 1997;173:285.

44. Miyauchi J, Ohyashiki K, Inatomi Y, and others. Neutrophil secondary-granule deficiency as a hallmark of all-trans retinoic acid-induced differentiation of acute promyelocytic leukemia cells. Blood 1997;90(2):803.

45. Degos L, Dombret H, Chomienne C, and others. All-trans retinoic acid as a differentiating agent in the treatment of acute promyelocytic leukemia. Blood 1995;85(10):2643.

46. Frankel SR, Eardley A, Lauwers G, and others. The "retinoic acid syndrome" in acute promyelocytic leukemia. Ann Intern Med 1992;117:292.

47. Dubois C, Schlageter MH, DeGentile A, and others. Hematopoietic growth factor expression and ATRA sensitivity in acute promyelocytic blast cells. Blood 1994;83:3264.

48. Dubois C, Schlegeter MH, De Gentile A, and others. Modulation of IL-G and IL-13 and G-CSF secretion by all-trans retinoic acid in acute promyelocytic leukemia. Leukemia 1994;8:1750.

49. Geiger S, Dombret H, Merle Beral H, and others. Study of microrheological properties of acute promyelocytic leukemia cells during all-trans retinoic acid therapy Br J Haematol 1994 (abstr, suppl 1);87:9.

50. Frankel SR, Eardley A, Heller G, and others. All-trans retinoic acid for acute promyelocytic leukemia: results of a New York study. Ann Intern Med 1994;120:279.

Tim R Randolph MS is an assistant professor in the Department of Clinical Laboratory Science, School of Allied Health Professions, Saint Louis University Health Sciences Center, St. Louis, MO.

Addressfor correspondence. Tim R Randolph, Department of Clinical Laboratory Science, School ofAllied Health Professions, Saint Louis University Health Sciences Center, 3437 Caroline St., St Louis MO. 63104-1111. (314) 577-8518, (314) 577-8503 (fax). Randoltr@ slu.edu

Copyright American Society for Clinical Laboratory Science Spring 2000
Provided by ProQuest Information and Learning Company. All rights Reserved