The "Retinoic Acid Syndrome" in Acute Promyelocytic Leukemia Stanley R. Frankel, MD; Anna Eardley, BS; Gregory Lauwers, MD; Mark Weiss, MD; and Raymond P. Warrell, Jr., MD
• Objective: To describe a novel complication of therapy with a\\-trans retinoic acid in patients with acute promyelocytic leukemia. • Design: Case series. • Setting: Comprehensive cancer center. • Patients: Consecutive patients with a morphologic diagnosis of acute promyelocytic leukemia who underwent remission induction treatment with a\\-trans retinoic acid, 45 mg/m2 body surface area per day. • Measurements and Results: Nine of 35 patients (26%; 95% CI, 9% to 52%) with acute promyelocytic leukemia who were treated with a\\-trans retinoic acid developed a syndrome consisting primarily of fever and respiratory distress. Additional prominent signs and symptoms included weight gain, lower-extremity edema, pleural or pericardial effusions, and episodic hypotension. The onset of this symptom complex occurred from 2 to 21 days after starting treatment. Three deaths occurred; post-mortem examinations in two patients showed pulmonary interstitial infiltration with maturing myeloid cells. Six other patients survived, each achieving complete remission (five patients with a\\-trans retinoic acid only; 1 patient with chemotherapy). In six of the nine cases, the onset of the syndrome was preceded by an increase in peripheral blood leukocytes to a level of at least 20 x 109 cells/L. Certain therapeutic interventions, including leukapheresis, temporary cessation of therapy with a\\-trans retinoic acid, and cytotoxic chemotherapy in moderate doses were not useful after respiratory distress was established. However, the administration of high-dose corticosteroid therapy (dexamethasone, 10 mg IV intravenously every 12 hours for 3 or more days) early in the course of the syndrome resulted in prompt symptomatic improvement and full recovery in three of four patients. • Conclusions: The use of a\\-trans retinoic acid to induce hematologic remission in patients with acute promyelocytic leukemia is associated in some patients with the development of a potentially lethal syndrome that is not uniformly accompanied by peripheral blood leukocytosis. Early recognition of the symptom complex of fever and dyspnea, combined with prompt corticosteroid treatment, may decrease morbidity and mortality associated with this syndrome.
Annals of Internal Medicine. 1992;117:292-296. From Memorial Sloan-Kettering Cancer Center and Cornell University Medical College, New York, New York. For current author addresses, see end of text. 292
An -trans retinoic acid (tretinoin) induces complete clinical remissions in a high proportion of patients with acute promyelocytic leukemia (1-3). Unlike conventional cytotoxic chemotherapy, 3\\-trans retinoic acid has initial biologic effects that are characterized by differentiation of the malignant cells into phenotypically mature myeloid cells (2, 3). Clinical response in many patients is accompanied by a transient rise in the peripheral leukocyte count (2-5) that is well tolerated by most patients. In one study, however, "hyperleukocytosis" was observed, and this event was associated with an unusually poor outcome, although the causes of death in that series varied widely (5). We recently completed a study using dXX-trans retinoic acid for remission induction in patients with acute promyelocytic leukemia. In that study, we observed a distinctive clinical syndrome characterized primarily by fever, dyspnea, weight gain, pleural or pericardial effusions, and episodic hypotension (6). Leukocytosis was frequently, although not invariably, associated with this symptom complex. In this article, we describe the clinical and post-mortem features of this syndrome and identify potential strategies for the management of patients who develop this complication. Methods Between July 1990 and September 1991, 35 consecutive patients with a morphologic diagnosis of acute promyelocytic leukemia (M3 by the French-American-British [FAB] classification [7]) were treated with dXX-trans retinoic acid (tretinoin) orally at a daily dose of 45 mg/m2 body surface area (3). Unlike in other studies (2), leukocytosis was managed by observation or leukapheresis and without the use of cytotoxic chemotherapy as a routine intervention. After an unusual respiratory distress syndrome was recognized as a distinctive complication of this treatment (6), subsequent patients were treated with corticosteroids (dexamethasone, 10 mg intravenously every 12 hours for at least 3 days). At the conclusion of the study, medical records on all 35 patients were reviewed. Results Between days 2 and 21 of treatment with dXX-trans retinoic acid, nine patients developed a distinctive symptom complex chiefly characterized by fever and dyspnea (Table 1). Radiographs of the chest showed interstitial infiltrates and pleural effusions in all cases. These symptoms were initially attributed to pneumonia or congestive heart failure; however, sputum cultures failed to reveal growth of pathogenic organisms and electrocardiograms showed nonspecific changes. Results of serial assays for serum creatine phosphokinase were not consistent with myocardial infarction. Peripheral edema, usually dependent but occasionally generalized,
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Table 1. Clinical Features of Patients with Acute Promyelocytic Leukemia and the Retinoic Acid Syndrome* Patient
Age
Sex
Relapses
Total Leukocyte Count Initial
n
y
At Onset (Day of Therapy)
Peak (Day of Therapy)
V If)911
c
Outcome
Treatment
>
1
61
F
0
0.8
16.2 (7)
31.8 (13)
2
51
F
0
4.4
10.2 (11)
36.4 (18)
3
65
M
1
3.2
1.2 (13)
10.6 (50)
4
61
F
1
12.7
17.5 (4)
41.3 (11)
5
28
M
4
1.4
45.0 (10)
70.5 (13)
6 7
52 25
M F
0 1
0.7 1.9
4.7 (21) 7.5 (19)
6.3 (27) 11.4 (27)
8 9
48 53
M M
1 0
8.1 18.1
22.2 (2) 82.3 (8)
Other Signs or Symptoms
53.1 (7) 82.3 (8)
Renal insufficiency; hypotension
Renal insufficiency; hyperbilirubinemia; leukemia cutis; hypotension Renal insufficiency; hyperbilirubinemia; hypotension Renal insufficiency; hyperbilirubinemia; leukemia cutis; hypotension Renal insufficiency Pericardial effusion; hypotension Renal insufficiency; hyperbilirubinemia
None
Died
M\-trans retinoic acid withdrawn; chemotherapyt None
Complete remission
Complete remission
None
Complete remission
Cytosine arabinoside; leukapharesis
Died
Corticosteroids Corticosteroids
Complete remission Complete remission
Corticosteroids Corticosteroids; leukapharesis
Complete remission Died
* All patients had fever, dyspnea, weight gain, pleural effusion, and pulmonary infiltrates on chest radiograph. t Subsequently shown not to have acute promyelocytic leukemia by molecular criteria (10, 12).
was also common. The median gain in body weight was 10.1 kg (range, 5.0 to 14.4 kg). Several patients also developed unexplained episodic hypotension, renal insufficiency, and hyperbilirubinemia, usually in a complex critical care setting associated with the administration of numerous other drugs. Echocardiography showed a pericardial effusion in one patient with chest pain typical of pericarditis.
Association of Symptoms with Leukocytosis Overall, 14 of 35 patients (40%; 95% CI, 23% to 57%) in our series developed leukocytosis (total peripheral blood leukocyte count > 20 x 109/L) during treatment with d\\-trans retinoic acid; however, only 6 of the 14 patients with leukocytosis developed the syndrome. Conversely, 3 of the remaining 21 patients with a peak leukocyte count of less than 20 x 109/L did develop the syndrome. In two of these 3 cases, symptoms of fever and respiratory distress were associated with a rising leukocyte count. Eight of the nine patients with this syndrome proved to have acute promyelocytic leukemia by conventional cytogenetic study [t(15;17)] (8, 9), and/or by Northern blot (10, 11) or by reverse-transcriptase polymerase chain reaction analysis (12, 13) for the newly described abnormality in the retinoic acid receptor-alpha (14-16) that is pathognomonic for this disease. However, one patient with morphologic characteristics of acute promyelocytic leukemia who developed leukocytosis (leukocyte count, 36.4 x 109/L) with this syndrome was subsequently shown not to have molecular evidence of the disease.
Management and Outcome Five of the nine patients required transfer to the intensive care unit and mechanical ventilation. Three of these five patients died of progressive pulmonary, renal, and hepatic failure; two recovered in complete remission. Of the six patients with leukocytosis, two underwent leukapheresis that yielded no discernable benefit. The patient who proved not to have acute promyelocytic leukemia was withdrawn from the study, received conventional chemotherapy, and achieved complete remission after a complicated course. Despite endotracheal intubation, attempts were made in this study to continue therapy with all-trans retinoic acid by administration of capsular contents via a nasogastric tube. After this syndrome was recognized as a distinctive complication of all-trans retinoic acid therapy in the first five patients, the next four patients were treated with dexamethasone (10 mg intravenously every 12 hours for at least 3 days). Three of these four patients experienced prompt resolution of their symptoms and subsequently achieved complete remission. After initial symptomatic improvement, the remaining patient developed pulmonary hemorrhage with progressive respiratory distress, sepsis, and intracranial bleeding that was ultimately fatal. Case Reports Two illustrative cases are described. A 28-year-old man (see Patient 5 in Table 1) presented after multiple relapses of acute promyelocytic leukemia, having been previously treated with daunomycin; conventional and high doses of cytosine arabinoside; idarubicin; mitox-
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antrone; and two syngeneic bone marrow transplantations after preconditionings with cyclophosphamide plus total body irradiation and busulfan plus etoposide, respectively. The initial leukocyte count was 1.4 x 109/L; a bone marrow aspirate showed 27% blasts and 54% promyelocytes with prominent Auer rods. During treatment with all-trans retinoic acid, he showed a progressive rise in peripheral blood leukocytes with clear evidence of myeloid maturation. Between days 10 and 14, he developed substernal discomfort, fever, dyspnea, unexplained hypotension, and weight gain (15 kg). A chest roentgenogram showed bilateral interstitial infiltrates and pleural effusions (Figure 1). His leukocyte count increased to 70.2 x 109/L on day 13; nodular subcutaneous masses consistent with leukemia cutis were observed. Therapy with all-trans retinoic acid was discontinued on day 15 after a bone marrow aspirate showed no blasts, 1% promyelocytes, numerous maturing myeloid cells with abnormal nuclear lobulation and Auer rods. Because of marked hypoxia, the patient underwent endotracheal intubation and mechanical ventilation with 100% Fi0 2 (fraction of inspired oxygen) and positive end-expiratory pressure. Despite leukapheresis, his leukocyte count remained greater than 50 x 109/L. He then received cytosine arabinoside 100 mg/m2 body surface area over a 24-hour period; however, this treatment provoked fulminant disseminated intravascular coagulation and pulmonary hemorrhage, followed by the development of acidosis, hypotension, and renal and hepatic failure (peak serum creatinine level, 345 /rniol/L [3.9 mg/dL]; serum bilirubin level, 385 /xmol/L [22.5 mg/dL]). He died on day 18. A 48-year-old man (see Patient 8 in Table 1) presented in first relapse with epistaxis and fever after having been treated with daunorubicin and cytosine arabinoside. The initial leukocyte count was 8.1 x 109/L; a bone marrow aspirate showed 78% blasts and 14% promyelocytes. On day 2 of therapy with all-trans retinoic acid, he developed chest discomfort, lower-extremity edema,* dyspnea, and leukocytosis (leukocyte count,
22.2 x 109/L). He was treated with dexamethasone, 10 mg intravenously every 12 hours for 6 doses, and his symptoms promptly abated. Therapy with all-trans retinoic acid was continued; his leukocyte count peaked at 53.1 x 109/L on day 7 of therapy. Subsequently, he was discharged from the hospital and achieved complete remission on day 44. Post-Mortem Studies Post-mortem studies of the two patients showed extensive organ infiltration by leukemic cells. One patient had leukemic infiltrates of lymph nodes, spleen, lung, liver, pleura, kidney, and pericardium. No infectious process was found in the lungs, although diffuse intraalveolar hemorrhage and edema were noted. The second patient had diffuse alveolar damage and terminally massive intra-alveolar hemorrhage. However, the interstitium of the lung was infiltrated with maturing myeloid cells in the absence of intra-alveolar infiltrates (Figure 2). The spleen, lymph nodes, and skin also had focal infiltrates of maturing myeloid cells. Discussion Most early deaths during remission induction therapy for acute promyelocytic leukemia have been caused by sudden intracranial or pulmonary hemorrhage in association with disseminated intravascular coagulation and thrombocytopenia. In the past, these events complicated induction chemotherapy in up to 40% of cases (17, 18). With aggressive supportive care, including hypertransfusion of blood products, the incidence of early fatal hemorrhage has been reduced to below 10% in several recent series (19-21). As in other types of acute leukemia, the major remaining cause of mortality has been sepsis related to neutropenia. Mi-trans retinoic acid may provide a superior therapeutic option for remission induction in this disease. The initial biologic response to all-trans retinoic acid
Figure 1. Chest radiographs taken before treatment with all-trans retinoic acid (left) and after development of the retinoic acid syndrome (right). The right panel shows bilateral interstitial infiltrates and pleural effusions. 294
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involves the "terminal differentiation" of leukemic cells (2, 3) that eventually enables repopulation of the bone marrow by normal hematopoietic elements. Unlike cytotoxic drugs, all-trans retinoic acid does not induce rapid cell lysis that initiates the typically florid disseminated intravascular coagulation; indeed it often improves within the first several days of starting treatment. Furthermore, such treatment does not induce bone marrow hypoplasia with its consequent pancytopenia and increased risk for infection. Despite these highly desirable features, treatment with this agent is not devoid of serious and potentially lethal complications. Castaigne and colleagues (5) reported several deaths associated with leukocytosis in patients with acute promyelocytic leukemia who received all-trans retinoic acid. This phenomenon appeared to be more common in newly diagnosed patients, and deaths were reportedly caused by hemorrhage or cardiovascular events. Because of this experience, Degos and associates (22, 23) have advocated early intervention with full doses of chemotherapy based on the absolute value of the leukocyte count or its rate of rise (that is, 5.0 x 109/L at 5 days, 10.0 x 109/L at 10 days, 15.0 x 109/L at 15 days, and so forth). In our series, however, almost half of the patients treated with all-trans retinoic acid developed leukocytosis, yet less than half of those patients developed important symptoms. Moreover, the onset of serious symptoms was not associated with leukocytosis in one third of our patients, and the initial leukocyte count at presentation (see Table 1) did not predict which patients were at risk. (Indeed, the aforementioned leukocyte count criteria would not have precluded development of this syndrome in three of the nine patients in this series.) Finally, the risk for this syndrome did not appear to be less for patients who had had multiple relapses than for patients who were newly diagnosed. One unusual feature was the development of leukocytosis with this syndrome in a patient who was subsequently shown to have no rearrangements in retinoic acid receptor-alpha; thus, the association of these symptoms is not diseasespecific to acute promyelocytic leukemia. The syndrome has not yet been observed in patients with nonhematologic cancers who have been treated with all-trans retinoic acid (Warrell, RP. Unpublished observations; Parkinson, D. Personal communication). The cause of this syndrome is speculative. Clinically, this symptom complex most closely resembles the "capillary leak" syndrome associated with administration of various cytokines, particularly interleukin-2 (24). Drug-induced release of vasoactive cytokines from differentiating leukemic cells would explain certain phenomena such as fever, generalized weight gain, and episodic hypotension. However, organ infiltration by leukemic cells was quite prominent in the two patients in whom post-mortem studies were done. An alternative explanation suggests that drug-induced maturation of previously undifferentiated leukemic cells, although still dysfunctional (25), could confer certain functional properties of mature neutrophils, including migratory capabilities. Migration of these cells into tissues such as lung and kidney could explain the respiratory distress and occasional renal impairment observed clinically. Finally, leukocyte adherence to capillary endothelial cells
Figure 2. Histologic findings in the lung. Marked interstitial infiltration is shown with maturing myeloid cells (top left) around an uninvolved alveolus (lower right). (Hematoxylin and eosin stain; original magnification, x250).
and extracellular matrix is mediated by integrins (leukocyte adhesion receptors) (26, 27), and genes that encode integrins were recently found to be up-regulated by retinoic acid (28). Conceivably, all-trans retinoic acid could increase integrin expression on the leukemic cell surface, which would enhance the cells' adherence to capillary endothelium and promote focal endothelial leakage. In our study, we found no histologic evidence for intraluminal capillary leukostasis, which would suggest impaired cellular rheology, a finding that has been reported secondary to leukocytosis in other types of leukemia (29, 30). Thus, mechanisms other than a simple increase in leukemic cell number are implicated in the pathogenesis of this syndrome. The potential utility of corticosteroids was suggested by an anecdotal report of benefit after empiric use (Bollag, W. Personal communication). In addition, the beneficial effects of dexamethasone in blocking the capillary-leak syndrome in patients who received interleukin-2 as cancer treatment have been reported (31, 32). Dexamethasone also inhibits generation of nitric oxide (33), a principal mediator of cytokine-induced vasodilatation (34-36). The response to early intervention with high doses of dexamethasone, immediately after the appearance of dyspnea, was dramatic in three of four patients who received this therapy. The optimal management of patients who develop leukocytosis remains to be clarified. Early intervention with full-dose cytotoxic chemotherapy may eliminate the stimulus that precipitates these symptoms. Preliminary results from the French cooperative study using this approach are encouraging (only one of nine patients with leukocytosis has died) (37); however, it is unclear whether any of these patients had significant symptoms. Such treatment is clearly not without risk; even a modest dose of cytosine arabinoside administered to one patient in this series provoked a fulminant coagulopathy that was fatal. Because less than half of patients who develop leukocytosis experience the syndrome we have described, treatment based solely on the leukocyte count may needlessly expose a high proportion of patients to the risks of conventional chemotherapy.
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All-trans retinoic acid is now being widely distributed for the treatment of acute promyelocyte leukemia. Based on our experience, early empiric treatment with high-dose dexamethasone appears to be indicated in the patients with fever, dyspnea, and pulmonary infiltrates who are undergoing induction therapy with all-tra/ts-retinoic acid, irrespective of the leukocyte count. Conversely, patients with uncomplicated leukocytosis can continue to receive therapy, but they must be observed closely. Given the potentially lethal nature of this syndrome, the benefits of early intervention with corticosteroids clearly outweigh theoretical risks associated with the occasionally inappropriate treatment of pneumonia or congestive heart failure. This article was presented in part at the 33rd Annual Meeting of the American Society of Hematology, December 1991. Acknowledgments: The authors thank Theresa Snyder and Marianne Campbell for expert assistance in patient care and Drs. Timothy Gee, Ellin Berman, and Ann Jakubowski for their expertise, advice, and patient management skills. Grant Support: In part by grant FD-R-000674 from the Orphan Product Division, Food and Drug Administration, and grant CA-09207-14 from the National Cancer Institute, Department of Health and Human Services; the Mortimer J. Lacher Research Fund; and the Coleman Leukemia Research Fund. Ml-trans retinoic acid was kindly supplied by Hoffmann LaRoche Inc., Nutley, New Jersey. Requests for Reprints: Raymond P. Warrell, Jr., MD, Memorial SloanKettering Cancer Center, 1275 York Avenue, New York, NY 10021. Current Author Addresses: Drs. Warrell, Lauwers, and Weiss, and Ms. Eardley: Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Dr. Frankel: Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. References 1. Huang ME, Ye YC, Chen SR, Chai JR, Lu JX, Zhoa L, et al. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood. 1988;72:567-72. 2. Castaigne S, Chomienne C, Daniel MT, Ballerini P, Berger R, Fenaux P, et al. All-trans retinoic acid as a differentiation therapy for acute promyelocyte leukemia. I. Clinical results. Blood. 1990;76:1704-9. 3. Warrell RP Jr, Frankel SR, Miller WH Jr, Scheinberg DA, Itri LM, Hittelman WN, et al. Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans retinoic acid). N Engl J Med. 1991:324:1385-93. 4. Chen ZX, Xue YQ, Zhang R, Tao RF, Xia XM, Li C, et al. A clinical and experimental study on a\l-trans retinoic acid-treated acute promyelocytic leukemia patients. Blood. 1991;78:1413-9. 5. Castaigne S, Chomienne C, Fenaux P, Daniel MT, Degos L. Hyperleukocytosis during all-trans retinoic acid for acute promyelocytic leukemia [Abstract]. Blood. 1990;76(Suppl):260a. 6. Frankel SR, Weiss M, Warrell RP J r . A "retinoic acid syndrome" in acute promyelocytic leukemia: reversal by corticosteroids. Blood. 1991;78(Suppl):380a. 7. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, et al. Proposed revised criteria for the classification of acute myeloid leukemia: a report of the French-American-British cooperative group. Ann Intern Med. 1985;103:620-5. 8. Golomb HM, Rowley J, Vardiman J, Baron J, Locker G, Krasnow S. Partial deletion of long arm of chromosome 17: a specific abnormality in acute promyelocytic leukemia? Arch Intern Med. 1976;136:825-8. 9. Larson RA, Kondo K, Vardiman JW, Butler AE, Golomb HM, Rowley JD. Evidence for a 15; 17 translocation in every patient with acute promyelocytic leukemia. Am J Med. 1984;76:827-41. 10. Miller WA Jr, Warrell RP Jr, Frankel SR, Jakubowski A, Gabrilove JL, Muindi J, et al. Novel retinoic acid receptor alpha transcripts in acute promyelocytic leukemia responsive to all trans-retinoic acid. J Natl Cancer Inst. 1990;82:1932-3. 11. Lo Coco F, Awisati G, Diverio D, Petti MC, Alcalay M, Pandolfi PP, et al. Molecular evaluation of response to all-trans retinoic acid therapy in patients with acute promyelocytic leukemia. Blood. 1991; 77:1657-9. 12. Miller WH Jr, Kakizuka A, Frankel SR, Warrell RP Jr, Deblasio A, Levine K, et al. Reverse transcriptase polymerase chain reaction for the rearranged retinoic acid receptor clarifies diagnosis and detects minimal residual disease in acute promyelocytic leukemia. Proc Natl Acad Sci (USA). 1992;89:2694-8.
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13. Chang KS, Lu J, Wang G, Trujillo JM, Estey E, Cork A, et al. The t(15;17) breakpoint in acute promyelocytic leukemia cluster within two different sites of the myl gene: targets for the detection of minimal residual disease by the polymerase chain reaction. Blood. 1992;79:554-8. 14. de The H, Chomienne C, Lanotte M, Degos L, Dejean A. The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus. Nature. 1990;347:558-651. 15. Alcalay M, Zangrilli D, Pandolfi PP, Longo L, Mencarelli A, Giacomucci A, et al. Translocation breakpoint of acute promyelocytic leukemia lies within retinoic acid receptor alpha locus. Proc Natl Acad Sci (USA). 1991;88:1977-1981. 16. Borrow J, Goddard AD, Sheer D, Solomon E. Molecular analysis of acute promyelocytic leukemia breakpoint cluster region on chromosome 17. Science. 1990;249:1577-80. 17. Humphries JE, Hess CE, Stewart FM. Acute promyelocytic leukemia: impact of hemorrhagic complications on response to induction chemotherapy and survival. South Med J. 1990;83:1157-61. 18. Jones ME, Saleem A. Acute promyelocytic leukemia. A review of the literature. Am J Med. 1978;65:673-7. 19. Rodeghiero F, Awisati G, Castaman G, Barbui T, Mandelli F. Early deaths and anti-hemorrhagic treatments in acute promyelocytic leukemia: A GIMEMA retrospective study in 268 consecutive patients. Blood. 1990;75:2112-7. 20. Feldman EJ, Arlin ZA, Ahmed T, Mittelman A, Ascensao JL, Puccio CA, et al. Acute promyelocytic leukemia: a 5-year experience with new antileukemic agents and a new approach to preventing fatal hemorrhage. Acta Haematol. 1989;82:117-21. 21. Tallman MS, Kwaan HC. Reassessing the hemostatic disorder associated with acute promyelocytic leukemia. Blood. 1992;79:543-53. 22. Fenaux P, Castaigne S, Dombrei H, et al. All-trans retinoic acid in newly diagnosed acute promyelocytic leukemia: a pilot study. Blood. 1991;78(Suppl):79a. 23. Fenaux P, Degos L. Treatment of acute promyelocytic leukemia with all-trans retinoic acid. Leuk Res. 1991;15:655-7. 24. Margolin KA, Raynor AA, Hawkins MJ, Atkins MB, Dutcher J P , Fisher RI, et al. Interleukin-2 and lymphokine-activated killer cell therapy of solid tumors: analysis of toxicity and management guidelines. J Clin Oncol. 1989;7:486-98. 25. zGordon M, Jakubowski A, Frankel S, Warrell RP Jr, Gabrilove J. Neutrophil function in patients with acute promyelocytic leukemia treated with all-trans retinoic acid. Proc Am Soc Clin Oncol. 1991;10:225. 26. Springer TA. Adhesion receptors of the immune system. Nature. 1990;346:425-34. 27. Doerschuk CM, Winn RK, Coxson HO, Harlan JM. CD18-dependent and -independent mechanisms of neutrophil migration in the pulmonary and systemic microcirculation of rabbits. J Immunol. 1990; 144: 2327-33. 28. Hickstein DD, Hickey MJ, Collins SJ. Transcriptional regulation of the leukocyte adherence protein beta subunit during human myeloid cell differentiation. J Biol Chem. 1988;263:13863-7. 29. Lester TJ, Johnson JW, Cuttner J. Pulmonary leukostasis as the single worst prognostic factor in patients with acute myelocytic leukemia and hyperleukocytosis. Am J Med. 1985;79:43-8. 30. Vernant JP, Brun B, Mannoni P, Dreyfus B. Respiratory distress of hyperleukocytic granulocytic leukemias. Cancer. 1979;44:264-8. 31. Vetto JT, Papa MZ, Lotze MT, Chang AE, Rosenberg SA. Reduction of toxicity of interleukin-2 and lymphokine-activated killer cells in humans by the administration of corticosteroids. J Clin Oncol. 1987;5:496-503. 32. Mier JW, Vachino G, Klempner MS, Aronson FR, Noring R, Smith S, et al. Inhibition of interleukin-2-induced tumor necrosis factor release by dexamethasone: prevention of an acquired neutrophil chemotaxis defect and differential suppression of interleukin-2-associated side effects. Blood. 1990;76:1933-40. 33. Rees DD, Cellek S, Palmer RM, Moncada S. Dexamethasone prevents the induction by endotoxin of a nitric oxide synthase and the associated effects on vascular tone: an insight into endotoxin shock. Biochem Biophys Res Commun. 1990;173:541-7. 34. Hibbs JR, Westenfelder C, Samlowski WE. Endogenous nitrate synthesis from a terminal guanidino nitrogen atom of L-arginine and physiology of nitrate excretion in patients receiving interleukin-2 therapy. In: Proceedings of Second International Conference Biology of Nitric Acid, London, October 1991. 35. Kilbourn RG, Gross SS, Jubran A, Adams J, Griffith OW, Levi R, et al. AfG-methyl-L-arginine inhibits tumor necrosis factor-induced hypotension: implications for the involvement of nitric oxide. Proc Natl Acad Sci (USA). 1990;87:3629-32. 36. Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev. 1991;43:109-42. 37. Fenaux P, Castaigne S, Dombrei H, et al. All-trans retinoic acid (ATRA) in newly diagnosed acute promyelocytic leukemia (APL): a pilot study [Abstract]. Blood. 1991;78(Suppl):79a.
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• Objective: To describe a novel complication of therapy with a\\-trans retinoic acid in patients with acute promyelocytic leukemia. • Design: Case series. • Setting: Comprehensive cancer center. • Patients: Consecutive patients with a morphologic diagnosis of acute promyelocytic leukemia who underwent remission induction treatment with a\\-trans retinoic acid, 45 mg/m2 body surface area per day. • Measurements and Results: Nine of 35 patients (26%; 95% CI, 9% to 52%) with acute promyelocytic leukemia who were treated with a\\-trans retinoic acid developed a syndrome consisting primarily of fever and respiratory distress. Additional prominent signs and symptoms included weight gain, lower-extremity edema, pleural or pericardial effusions, and episodic hypotension. The onset of this symptom complex occurred from 2 to 21 days after starting treatment. Three deaths occurred; post-mortem examinations in two patients showed pulmonary interstitial infiltration with maturing myeloid cells. Six other patients survived, each achieving complete remission (five patients with a\\-trans retinoic acid only; 1 patient with chemotherapy). In six of the nine cases, the onset of the syndrome was preceded by an increase in peripheral blood leukocytes to a level of at least 20 x 109 cells/L. Certain therapeutic interventions, including leukapheresis, temporary cessation of therapy with a\\-trans retinoic acid, and cytotoxic chemotherapy in moderate doses were not useful after respiratory distress was established. However, the administration of high-dose corticosteroid therapy (dexamethasone, 10 mg IV intravenously every 12 hours for 3 or more days) early in the course of the syndrome resulted in prompt symptomatic improvement and full recovery in three of four patients. • Conclusions: The use of a\\-trans retinoic acid to induce hematologic remission in patients with acute promyelocytic leukemia is associated in some patients with the development of a potentially lethal syndrome that is not uniformly accompanied by peripheral blood leukocytosis. Early recognition of the symptom complex of fever and dyspnea, combined with prompt corticosteroid treatment, may decrease morbidity and mortality associated with this syndrome.
Annals of Internal Medicine. 1992;117:292-296. From Memorial Sloan-Kettering Cancer Center and Cornell University Medical College, New York, New York. For current author addresses, see end of text. 292
An -trans retinoic acid (tretinoin) induces complete clinical remissions in a high proportion of patients with acute promyelocytic leukemia (1-3). Unlike conventional cytotoxic chemotherapy, 3\\-trans retinoic acid has initial biologic effects that are characterized by differentiation of the malignant cells into phenotypically mature myeloid cells (2, 3). Clinical response in many patients is accompanied by a transient rise in the peripheral leukocyte count (2-5) that is well tolerated by most patients. In one study, however, "hyperleukocytosis" was observed, and this event was associated with an unusually poor outcome, although the causes of death in that series varied widely (5). We recently completed a study using dXX-trans retinoic acid for remission induction in patients with acute promyelocytic leukemia. In that study, we observed a distinctive clinical syndrome characterized primarily by fever, dyspnea, weight gain, pleural or pericardial effusions, and episodic hypotension (6). Leukocytosis was frequently, although not invariably, associated with this symptom complex. In this article, we describe the clinical and post-mortem features of this syndrome and identify potential strategies for the management of patients who develop this complication. Methods Between July 1990 and September 1991, 35 consecutive patients with a morphologic diagnosis of acute promyelocytic leukemia (M3 by the French-American-British [FAB] classification [7]) were treated with dXX-trans retinoic acid (tretinoin) orally at a daily dose of 45 mg/m2 body surface area (3). Unlike in other studies (2), leukocytosis was managed by observation or leukapheresis and without the use of cytotoxic chemotherapy as a routine intervention. After an unusual respiratory distress syndrome was recognized as a distinctive complication of this treatment (6), subsequent patients were treated with corticosteroids (dexamethasone, 10 mg intravenously every 12 hours for at least 3 days). At the conclusion of the study, medical records on all 35 patients were reviewed. Results Between days 2 and 21 of treatment with dXX-trans retinoic acid, nine patients developed a distinctive symptom complex chiefly characterized by fever and dyspnea (Table 1). Radiographs of the chest showed interstitial infiltrates and pleural effusions in all cases. These symptoms were initially attributed to pneumonia or congestive heart failure; however, sputum cultures failed to reveal growth of pathogenic organisms and electrocardiograms showed nonspecific changes. Results of serial assays for serum creatine phosphokinase were not consistent with myocardial infarction. Peripheral edema, usually dependent but occasionally generalized,
© 1992 American College of Physicians
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Table 1. Clinical Features of Patients with Acute Promyelocytic Leukemia and the Retinoic Acid Syndrome* Patient
Age
Sex
Relapses
Total Leukocyte Count Initial
n
y
At Onset (Day of Therapy)
Peak (Day of Therapy)
V If)911
c
Outcome
Treatment
>
1
61
F
0
0.8
16.2 (7)
31.8 (13)
2
51
F
0
4.4
10.2 (11)
36.4 (18)
3
65
M
1
3.2
1.2 (13)
10.6 (50)
4
61
F
1
12.7
17.5 (4)
41.3 (11)
5
28
M
4
1.4
45.0 (10)
70.5 (13)
6 7
52 25
M F
0 1
0.7 1.9
4.7 (21) 7.5 (19)
6.3 (27) 11.4 (27)
8 9
48 53
M M
1 0
8.1 18.1
22.2 (2) 82.3 (8)
Other Signs or Symptoms
53.1 (7) 82.3 (8)
Renal insufficiency; hypotension
Renal insufficiency; hyperbilirubinemia; leukemia cutis; hypotension Renal insufficiency; hyperbilirubinemia; hypotension Renal insufficiency; hyperbilirubinemia; leukemia cutis; hypotension Renal insufficiency Pericardial effusion; hypotension Renal insufficiency; hyperbilirubinemia
None
Died
M\-trans retinoic acid withdrawn; chemotherapyt None
Complete remission
Complete remission
None
Complete remission
Cytosine arabinoside; leukapharesis
Died
Corticosteroids Corticosteroids
Complete remission Complete remission
Corticosteroids Corticosteroids; leukapharesis
Complete remission Died
* All patients had fever, dyspnea, weight gain, pleural effusion, and pulmonary infiltrates on chest radiograph. t Subsequently shown not to have acute promyelocytic leukemia by molecular criteria (10, 12).
was also common. The median gain in body weight was 10.1 kg (range, 5.0 to 14.4 kg). Several patients also developed unexplained episodic hypotension, renal insufficiency, and hyperbilirubinemia, usually in a complex critical care setting associated with the administration of numerous other drugs. Echocardiography showed a pericardial effusion in one patient with chest pain typical of pericarditis.
Association of Symptoms with Leukocytosis Overall, 14 of 35 patients (40%; 95% CI, 23% to 57%) in our series developed leukocytosis (total peripheral blood leukocyte count > 20 x 109/L) during treatment with d\\-trans retinoic acid; however, only 6 of the 14 patients with leukocytosis developed the syndrome. Conversely, 3 of the remaining 21 patients with a peak leukocyte count of less than 20 x 109/L did develop the syndrome. In two of these 3 cases, symptoms of fever and respiratory distress were associated with a rising leukocyte count. Eight of the nine patients with this syndrome proved to have acute promyelocytic leukemia by conventional cytogenetic study [t(15;17)] (8, 9), and/or by Northern blot (10, 11) or by reverse-transcriptase polymerase chain reaction analysis (12, 13) for the newly described abnormality in the retinoic acid receptor-alpha (14-16) that is pathognomonic for this disease. However, one patient with morphologic characteristics of acute promyelocytic leukemia who developed leukocytosis (leukocyte count, 36.4 x 109/L) with this syndrome was subsequently shown not to have molecular evidence of the disease.
Management and Outcome Five of the nine patients required transfer to the intensive care unit and mechanical ventilation. Three of these five patients died of progressive pulmonary, renal, and hepatic failure; two recovered in complete remission. Of the six patients with leukocytosis, two underwent leukapheresis that yielded no discernable benefit. The patient who proved not to have acute promyelocytic leukemia was withdrawn from the study, received conventional chemotherapy, and achieved complete remission after a complicated course. Despite endotracheal intubation, attempts were made in this study to continue therapy with all-trans retinoic acid by administration of capsular contents via a nasogastric tube. After this syndrome was recognized as a distinctive complication of all-trans retinoic acid therapy in the first five patients, the next four patients were treated with dexamethasone (10 mg intravenously every 12 hours for at least 3 days). Three of these four patients experienced prompt resolution of their symptoms and subsequently achieved complete remission. After initial symptomatic improvement, the remaining patient developed pulmonary hemorrhage with progressive respiratory distress, sepsis, and intracranial bleeding that was ultimately fatal. Case Reports Two illustrative cases are described. A 28-year-old man (see Patient 5 in Table 1) presented after multiple relapses of acute promyelocytic leukemia, having been previously treated with daunomycin; conventional and high doses of cytosine arabinoside; idarubicin; mitox-
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antrone; and two syngeneic bone marrow transplantations after preconditionings with cyclophosphamide plus total body irradiation and busulfan plus etoposide, respectively. The initial leukocyte count was 1.4 x 109/L; a bone marrow aspirate showed 27% blasts and 54% promyelocytes with prominent Auer rods. During treatment with all-trans retinoic acid, he showed a progressive rise in peripheral blood leukocytes with clear evidence of myeloid maturation. Between days 10 and 14, he developed substernal discomfort, fever, dyspnea, unexplained hypotension, and weight gain (15 kg). A chest roentgenogram showed bilateral interstitial infiltrates and pleural effusions (Figure 1). His leukocyte count increased to 70.2 x 109/L on day 13; nodular subcutaneous masses consistent with leukemia cutis were observed. Therapy with all-trans retinoic acid was discontinued on day 15 after a bone marrow aspirate showed no blasts, 1% promyelocytes, numerous maturing myeloid cells with abnormal nuclear lobulation and Auer rods. Because of marked hypoxia, the patient underwent endotracheal intubation and mechanical ventilation with 100% Fi0 2 (fraction of inspired oxygen) and positive end-expiratory pressure. Despite leukapheresis, his leukocyte count remained greater than 50 x 109/L. He then received cytosine arabinoside 100 mg/m2 body surface area over a 24-hour period; however, this treatment provoked fulminant disseminated intravascular coagulation and pulmonary hemorrhage, followed by the development of acidosis, hypotension, and renal and hepatic failure (peak serum creatinine level, 345 /rniol/L [3.9 mg/dL]; serum bilirubin level, 385 /xmol/L [22.5 mg/dL]). He died on day 18. A 48-year-old man (see Patient 8 in Table 1) presented in first relapse with epistaxis and fever after having been treated with daunorubicin and cytosine arabinoside. The initial leukocyte count was 8.1 x 109/L; a bone marrow aspirate showed 78% blasts and 14% promyelocytes. On day 2 of therapy with all-trans retinoic acid, he developed chest discomfort, lower-extremity edema,* dyspnea, and leukocytosis (leukocyte count,
22.2 x 109/L). He was treated with dexamethasone, 10 mg intravenously every 12 hours for 6 doses, and his symptoms promptly abated. Therapy with all-trans retinoic acid was continued; his leukocyte count peaked at 53.1 x 109/L on day 7 of therapy. Subsequently, he was discharged from the hospital and achieved complete remission on day 44. Post-Mortem Studies Post-mortem studies of the two patients showed extensive organ infiltration by leukemic cells. One patient had leukemic infiltrates of lymph nodes, spleen, lung, liver, pleura, kidney, and pericardium. No infectious process was found in the lungs, although diffuse intraalveolar hemorrhage and edema were noted. The second patient had diffuse alveolar damage and terminally massive intra-alveolar hemorrhage. However, the interstitium of the lung was infiltrated with maturing myeloid cells in the absence of intra-alveolar infiltrates (Figure 2). The spleen, lymph nodes, and skin also had focal infiltrates of maturing myeloid cells. Discussion Most early deaths during remission induction therapy for acute promyelocytic leukemia have been caused by sudden intracranial or pulmonary hemorrhage in association with disseminated intravascular coagulation and thrombocytopenia. In the past, these events complicated induction chemotherapy in up to 40% of cases (17, 18). With aggressive supportive care, including hypertransfusion of blood products, the incidence of early fatal hemorrhage has been reduced to below 10% in several recent series (19-21). As in other types of acute leukemia, the major remaining cause of mortality has been sepsis related to neutropenia. Mi-trans retinoic acid may provide a superior therapeutic option for remission induction in this disease. The initial biologic response to all-trans retinoic acid
Figure 1. Chest radiographs taken before treatment with all-trans retinoic acid (left) and after development of the retinoic acid syndrome (right). The right panel shows bilateral interstitial infiltrates and pleural effusions. 294
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involves the "terminal differentiation" of leukemic cells (2, 3) that eventually enables repopulation of the bone marrow by normal hematopoietic elements. Unlike cytotoxic drugs, all-trans retinoic acid does not induce rapid cell lysis that initiates the typically florid disseminated intravascular coagulation; indeed it often improves within the first several days of starting treatment. Furthermore, such treatment does not induce bone marrow hypoplasia with its consequent pancytopenia and increased risk for infection. Despite these highly desirable features, treatment with this agent is not devoid of serious and potentially lethal complications. Castaigne and colleagues (5) reported several deaths associated with leukocytosis in patients with acute promyelocytic leukemia who received all-trans retinoic acid. This phenomenon appeared to be more common in newly diagnosed patients, and deaths were reportedly caused by hemorrhage or cardiovascular events. Because of this experience, Degos and associates (22, 23) have advocated early intervention with full doses of chemotherapy based on the absolute value of the leukocyte count or its rate of rise (that is, 5.0 x 109/L at 5 days, 10.0 x 109/L at 10 days, 15.0 x 109/L at 15 days, and so forth). In our series, however, almost half of the patients treated with all-trans retinoic acid developed leukocytosis, yet less than half of those patients developed important symptoms. Moreover, the onset of serious symptoms was not associated with leukocytosis in one third of our patients, and the initial leukocyte count at presentation (see Table 1) did not predict which patients were at risk. (Indeed, the aforementioned leukocyte count criteria would not have precluded development of this syndrome in three of the nine patients in this series.) Finally, the risk for this syndrome did not appear to be less for patients who had had multiple relapses than for patients who were newly diagnosed. One unusual feature was the development of leukocytosis with this syndrome in a patient who was subsequently shown to have no rearrangements in retinoic acid receptor-alpha; thus, the association of these symptoms is not diseasespecific to acute promyelocytic leukemia. The syndrome has not yet been observed in patients with nonhematologic cancers who have been treated with all-trans retinoic acid (Warrell, RP. Unpublished observations; Parkinson, D. Personal communication). The cause of this syndrome is speculative. Clinically, this symptom complex most closely resembles the "capillary leak" syndrome associated with administration of various cytokines, particularly interleukin-2 (24). Drug-induced release of vasoactive cytokines from differentiating leukemic cells would explain certain phenomena such as fever, generalized weight gain, and episodic hypotension. However, organ infiltration by leukemic cells was quite prominent in the two patients in whom post-mortem studies were done. An alternative explanation suggests that drug-induced maturation of previously undifferentiated leukemic cells, although still dysfunctional (25), could confer certain functional properties of mature neutrophils, including migratory capabilities. Migration of these cells into tissues such as lung and kidney could explain the respiratory distress and occasional renal impairment observed clinically. Finally, leukocyte adherence to capillary endothelial cells
Figure 2. Histologic findings in the lung. Marked interstitial infiltration is shown with maturing myeloid cells (top left) around an uninvolved alveolus (lower right). (Hematoxylin and eosin stain; original magnification, x250).
and extracellular matrix is mediated by integrins (leukocyte adhesion receptors) (26, 27), and genes that encode integrins were recently found to be up-regulated by retinoic acid (28). Conceivably, all-trans retinoic acid could increase integrin expression on the leukemic cell surface, which would enhance the cells' adherence to capillary endothelium and promote focal endothelial leakage. In our study, we found no histologic evidence for intraluminal capillary leukostasis, which would suggest impaired cellular rheology, a finding that has been reported secondary to leukocytosis in other types of leukemia (29, 30). Thus, mechanisms other than a simple increase in leukemic cell number are implicated in the pathogenesis of this syndrome. The potential utility of corticosteroids was suggested by an anecdotal report of benefit after empiric use (Bollag, W. Personal communication). In addition, the beneficial effects of dexamethasone in blocking the capillary-leak syndrome in patients who received interleukin-2 as cancer treatment have been reported (31, 32). Dexamethasone also inhibits generation of nitric oxide (33), a principal mediator of cytokine-induced vasodilatation (34-36). The response to early intervention with high doses of dexamethasone, immediately after the appearance of dyspnea, was dramatic in three of four patients who received this therapy. The optimal management of patients who develop leukocytosis remains to be clarified. Early intervention with full-dose cytotoxic chemotherapy may eliminate the stimulus that precipitates these symptoms. Preliminary results from the French cooperative study using this approach are encouraging (only one of nine patients with leukocytosis has died) (37); however, it is unclear whether any of these patients had significant symptoms. Such treatment is clearly not without risk; even a modest dose of cytosine arabinoside administered to one patient in this series provoked a fulminant coagulopathy that was fatal. Because less than half of patients who develop leukocytosis experience the syndrome we have described, treatment based solely on the leukocyte count may needlessly expose a high proportion of patients to the risks of conventional chemotherapy.
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All-trans retinoic acid is now being widely distributed for the treatment of acute promyelocyte leukemia. Based on our experience, early empiric treatment with high-dose dexamethasone appears to be indicated in the patients with fever, dyspnea, and pulmonary infiltrates who are undergoing induction therapy with all-tra/ts-retinoic acid, irrespective of the leukocyte count. Conversely, patients with uncomplicated leukocytosis can continue to receive therapy, but they must be observed closely. Given the potentially lethal nature of this syndrome, the benefits of early intervention with corticosteroids clearly outweigh theoretical risks associated with the occasionally inappropriate treatment of pneumonia or congestive heart failure. This article was presented in part at the 33rd Annual Meeting of the American Society of Hematology, December 1991. Acknowledgments: The authors thank Theresa Snyder and Marianne Campbell for expert assistance in patient care and Drs. Timothy Gee, Ellin Berman, and Ann Jakubowski for their expertise, advice, and patient management skills. Grant Support: In part by grant FD-R-000674 from the Orphan Product Division, Food and Drug Administration, and grant CA-09207-14 from the National Cancer Institute, Department of Health and Human Services; the Mortimer J. Lacher Research Fund; and the Coleman Leukemia Research Fund. Ml-trans retinoic acid was kindly supplied by Hoffmann LaRoche Inc., Nutley, New Jersey. Requests for Reprints: Raymond P. Warrell, Jr., MD, Memorial SloanKettering Cancer Center, 1275 York Avenue, New York, NY 10021. Current Author Addresses: Drs. Warrell, Lauwers, and Weiss, and Ms. Eardley: Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Dr. Frankel: Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. References 1. Huang ME, Ye YC, Chen SR, Chai JR, Lu JX, Zhoa L, et al. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood. 1988;72:567-72. 2. Castaigne S, Chomienne C, Daniel MT, Ballerini P, Berger R, Fenaux P, et al. All-trans retinoic acid as a differentiation therapy for acute promyelocyte leukemia. I. Clinical results. Blood. 1990;76:1704-9. 3. Warrell RP Jr, Frankel SR, Miller WH Jr, Scheinberg DA, Itri LM, Hittelman WN, et al. Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans retinoic acid). N Engl J Med. 1991:324:1385-93. 4. Chen ZX, Xue YQ, Zhang R, Tao RF, Xia XM, Li C, et al. A clinical and experimental study on a\l-trans retinoic acid-treated acute promyelocytic leukemia patients. Blood. 1991;78:1413-9. 5. Castaigne S, Chomienne C, Fenaux P, Daniel MT, Degos L. Hyperleukocytosis during all-trans retinoic acid for acute promyelocytic leukemia [Abstract]. Blood. 1990;76(Suppl):260a. 6. Frankel SR, Weiss M, Warrell RP J r . A "retinoic acid syndrome" in acute promyelocytic leukemia: reversal by corticosteroids. Blood. 1991;78(Suppl):380a. 7. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, et al. Proposed revised criteria for the classification of acute myeloid leukemia: a report of the French-American-British cooperative group. Ann Intern Med. 1985;103:620-5. 8. Golomb HM, Rowley J, Vardiman J, Baron J, Locker G, Krasnow S. Partial deletion of long arm of chromosome 17: a specific abnormality in acute promyelocytic leukemia? Arch Intern Med. 1976;136:825-8. 9. Larson RA, Kondo K, Vardiman JW, Butler AE, Golomb HM, Rowley JD. Evidence for a 15; 17 translocation in every patient with acute promyelocytic leukemia. Am J Med. 1984;76:827-41. 10. Miller WA Jr, Warrell RP Jr, Frankel SR, Jakubowski A, Gabrilove JL, Muindi J, et al. Novel retinoic acid receptor alpha transcripts in acute promyelocytic leukemia responsive to all trans-retinoic acid. J Natl Cancer Inst. 1990;82:1932-3. 11. Lo Coco F, Awisati G, Diverio D, Petti MC, Alcalay M, Pandolfi PP, et al. Molecular evaluation of response to all-trans retinoic acid therapy in patients with acute promyelocytic leukemia. Blood. 1991; 77:1657-9. 12. Miller WH Jr, Kakizuka A, Frankel SR, Warrell RP Jr, Deblasio A, Levine K, et al. Reverse transcriptase polymerase chain reaction for the rearranged retinoic acid receptor clarifies diagnosis and detects minimal residual disease in acute promyelocytic leukemia. Proc Natl Acad Sci (USA). 1992;89:2694-8.
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