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© 2000 American Society for Clinical Oncology Leukocytosis and the Retinoic Acid Syndrome in Patients With Acute Promyelocytic Leukemia Treated With Arsenic TrioxideFrom the Leukemia and Developmental Chemotherapy Services, Department of Medicine, and Department of Biostatistics, Memorial Sloan-Kettering Cancer Center; Joan and Sanford Weill Medical College of Cornell University; and PolaRx Biopharmaceuticals, Inc, New York, NY. Address correspondence to Raymond P. Warrell, Jr, MD, email warrell{at}genta.com
PURPOSE: Arsenic trioxide, like all-trans-retinoic acid (RA), induces differentiation of acute promyelocytic leukemia (APL) cells in vivo. Treatment of APL patients with all-trans RA is commonly associated with leukocytosis, and approximately 50% of patients develop the RA syndrome. We reviewed our clinical experience with arsenic trioxide to determine the incidence of these two phenomena. PATIENTS AND METHODS: Twenty-six patients with relapsed or refractory APL were treated with arsenic trioxide for remission induction at daily doses that ranged from 0.06 to 0.17 mg/kg. RESULTS: Twenty-three patients (88%) achieved complete remission. Leukocytosis was observed in 15 patients (58%). The median baseline leukocyte count for patients with leukocytosis was 3,900 cells/µL (range, 1,200 to 72,300 cells/µL), which was higher than that for patients who did not develop leukocytosis (2,100 cells/µL; range, 500 to 5,400 cells/µL; P = .01). No other cytotoxic therapy was administered, and the leukocytosis resolved in all cases. The RA syndrome was observed in eight patients (31%). Patients who developed leukocytosis were significantly more likely to develop the RA syndrome (P < .001), and no patient without a peak leukocyte count greater than 10,000 cells/µL developed the syndrome. Among the patients with leukocytosis, there was no observed relation between the leukocyte peak and the probability of developing the syndrome (P = .37). CONCLUSION: Induction therapy of APL with all-trans RA and arsenic trioxide is associated with leukocytosis and the RA syndrome. These clinical effects seem to be intrinsically related to the biologic responsiveness and the differentiation process induced by these new agents.
THE ADDITION OF all-trans-retinoic acid (RA) to standard treatment regimens for acute promyelocytic leukemia (APL) has more than doubled survival of patients compared with the use of cytotoxic chemotherapy alone.1-5 All-trans RA exerts its biologic effects, at least in part, by inducing terminal differentiation of leukemic cells.6-11 In vitro, this process has been associated with increased expression of integrins, cytokine release, and changes in cellular rheology.12-16 Possibly as a consequence of these or other pharmacologic alterations, 20% to 50% of APL patients treated with all-trans RA develop the RA syndrome,17-19 which is a loosely defined constellation of signs and symptoms that consist of fluid retention, hectic fever, pulmonary infiltrates, and pleural effusions. A number of deaths resulted from this problem before the use of corticosteroids was routinely introduced.17 Treatment with all-trans RA has also been associated with the development of leukocytosis in approximately one half of patients with APL.6-8,11,20 This phenomenon has prompted some investigators to administer low doses of cytotoxic drugs to reduce the elevated leukocyte count3,21 or, more commonly, to administer full doses of conventional drugs,1,4,10,11,22 similar to regimens that have been used for the past 25 years. Like all-trans RA, arsenic trioxide induces complete remission in a large proportion of patients with APL.23-27 Similar, albeit less striking, changes in the morphology and immunophenotype of leukemic cells have also been described.25,26,28,29 Preliminary clinical reports from China described leukocytosis in several patients, most of whom were then treated with cytotoxic chemotherapy.25 We recently completed pilot clinical studies with this drug and have found that this new agent induces both leukocytosis and the RA syndrome in substantial numbers of patients with APL. In this article, we describe this clinical experience and the clinical outcome of these events in our patients who received no additional cytotoxic drug therapy.
Patients Between October 1997 and April 1999, 26 patients with relapsed APL received induction therapy with arsenic trioxide at Memorial Sloan-Kettering Cancer Center. Patients were required to have a morphologic diagnosis of APL (ie, M3 by French-American-British classification), which was confirmed by reverse transcriptase polymerase chain reaction assay for promyelocytic leukemia and RA receptor alpha fusion transcripts.30 The initial cohort of 12 patients was previously characterized26; the additional 14 patients were accrued pursuant to a multicenter protocol.27
Treatment Program
Analysis
Treatment Efficacy Twenty-three (88%) of the 26 patients achieved complete remission. The median time to complete remission was 47 days (range, 15 to 83 days). One patient died on day 5 of CNS hemorrhage, one was removed from the study after the reverse transcriptase polymerase chain reaction was determined to be negative, and one proved resistant to arsenic therapy.
Incidence of Leukocytosis
Incidence of RA Syndrome Eight (31%) of 26 patients developed the RA syndrome during induction. The proportions of patients who developed the most common signs and symptoms are presented in Table 1. The mean time to diagnosis of the syndrome was 17 days (range, 7 to 24 days). The mean time from start of therapy to first dose of corticosteroids was 13 days (range, 5 to 19 days). Six (23%) of the 26 patients in the entire treatment group required temporary mechanical ventilation at some point; however, only four of these patients were considered to have had the RA syndrome as a potentially contributory cause of their respiratory failure. (Of the other two cases, one patient with intracranial hemorrhage sustained a respiratory arrest and the other developed pulmonary hemorrhage.) The RA syndrome was observed only during the induction course of arsenic trioxide therapy. Neither leukocytosis nor the RA syndrome were observed in any postremission course.
Relation Between RA Syndrome and Leukocytosis Data relevant to the interaction between the level of leukocyte counts and the development of the RA syndrome are presented in Table 2. The peak value of the leukocyte count was highly associated with the subsequent development of the RA syndrome (P < .001). In fact, no patient whose peak leukocyte count was less than 10,000 cells/µL developed the syndrome. The median daily leukocyte count in patients who did and did not develop the syndrome is shown in Fig 3. The median baseline level of the leukocyte count was higher in patients who developed the syndrome (P = .01). Although all patients who ultimately developed the syndrome also had leukocytosis, more than one half of all patients who manifested leukocytosis (53%) actually developed the syndrome. Moreover, among patients with a peak leukocyte count  10,000 cells/µL, there was no relation between the peak count and development of the syndrome. Among patients with leukocytosis, the median peak values of the leukocyte count in patients who did and those who did not develop the syndrome were 41,950 and 31,300 cells/µL, respectively (P = .37).
Like all-trans RA, arsenic trioxide induces complete remission in a large proportion of patients with APL.23-27 A common feature of both drugs is the induction of cellular differentiation, which has been associated with characteristic changes in morphology and immunophenotype.6-11,25-29 The RA syndrome was first described as a constellation of signs and symptoms that occurred only during induction therapy of APL using all-trans RA.17-19 Early signs of this problem are characterized by fluid retention, weight gain, hectic fever, and musculoskeletal pain. Later signs include progressive respiratory distress, pulmonary infiltrates, pleural effusions, renal insufficiency, skin infiltrates, hypotension, and death.17 The syndrome has not been observed in APL patients who receive retinoids during complete remission.17 However, signs identical to this syndrome have been described in patients with APL before initiation of RA treatment.31 Thus, the problem may in part be related to differentiation that spontaneously occurs at low levels in some patients, even in the absence of treatment. RA syndrome is highly responsive to treatment with corticosteroids when administered early in the course of the illness (ie, coincident with the earliest signs of fluid retention).17,32,33 However, corticosteroid therapy is considerably less useful once pulmonary symptoms have appeared. We have previously reported a poor response and increased early mortality using leukapheresis or low-dose chemotherapy (eg, hydroxyurea or cytosine arabinoside).33 Contrary to earlier expectations, others have noted that the use of high-dose chemotherapy may not reduce the incidence of this problem.1,3,34 Discontinuation of the drug also seems to have no material effect on the problem.3 The syndrome may recur in patients who have recovered from one (or more) treatment courses with corticosteroids17; however, corticosteroids do not seem to affect responsiveness to the differentiating effects of RA.35,36 Arsenic trioxide also induces differentiation of APL cells in vitro25-29 and in vivo26,28; however, the magnitude of the effect seems less than that observed after exposure to all-trans RA.26 Nonetheless, the similarity between this shared mechanism of action, combined with the large proportion of patients who developed leukocytosis and the RA syndrome, suggests a distinct link between these observations. We previously suggested that leukocytosis induced by all-trans RA may not represent an increase in leukemic cell proliferation, but rather a transient increase in the lifespan of leukemic cells, which would otherwise die at the promyelocyte stage without relief from the differentiation blockade that is associated with this disease. As with all-trans RA treatment,8,11,36,37 we observed leukocytosis in more than one half (58%) of APL patients who were treated with arsenic trioxide. In some cases, this response was extreme (ie, >200,000 cells/µL) (Fig 2); however, no specific treatment to reduce the peripheral leukocyte counts was required, and the leukocytosis resolved without sequelae in each case. RA induces a variety of effects in APL cells in vitro, including increased production of interleukin-1 beta (IL-1ß),13,38 IL-8,13 and receptors for granulocyte colony-stimulating factor39 and granulocyte-macrophage colony-stimulating factor.40 RA also increases the expression of cell-surface integrins.12,41-43 RA syndrome is characterized by several phenomena that seem to be related to these observations, in particular, fever, fluid retention, and the migration of differentiating myeloid cells into extravascular tissues.17 Extravascular migration of myeloid cells may be partly related to upregulated integrin expression, which could increase adhesion of these cells to vascular endothelium, thereby facilitating their extravasation.43-45 Fever and fluid retention have been associated with administration of exogenous cytokines,46 and both IL-1 and IL-8 have been associated with respiratory distress syndrome in other disorders.47,48 These mechanisms have not yet been identified in patients treated with arsenic trioxide. However, the clinical similarity of these phenomena, their responsiveness to corticosteroids, and the similar differentiating effects exerted by these agents on myeloid cells strongly suggest that pharmacologic induction of differentiation itself is a central feature of these processes. In further support of this hypothesis, we did not observe the development of signs and symptoms of the syndrome after a complete remission was achieved, when presumably almost all cells have completed differentiation. In summary, leukocytosis and the RA syndrome are commonly observed in patients treated with arsenic trioxide. Similar to our experience with all-trans RA,35 we have not found that the leukocytosis itself requires additional cytotoxic treatment, because it resolves with continuation of arsenic therapy. However, recognition of early signs or symptoms and prompt treatment with corticosteroids are required to avoid potentially fatal complications of the RA syndrome. Given the potency of this compound, we expect that both RA and arsenic will be increasingly used together. Further study is required to determine whether the severity of these two effects will be increased in such combinations.
Supported in part by grant no. CA-77136 from the National Cancer Institute, Bethesda, MD, and by grants from the Ruth Lane Charitable Foundation, the Lymphoma Foundation, and PolaRx Biopharmaceuticals, Inc.
Presented at the Forty-First Annual Meeting of American Society of Hematology, New Orleans, LA, December 6, 1999.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
/Pml proteins. Blood 88:1052-1061, 1996
