Original Article
Differentiation Therapy of Acute Promyelocytic Leukemia with Tretinoin (All-trans-Retinoic Acid)
N Engl J Med 1991; 324:1385-1393May 16, 1991
- Abstract
- Abstract
Background and Methods.
Patients with acute promyelocytic leukemia have a characteristic (15;17) translocation, with a breakpoint on chromosome 17 in the region of the retinoic acid receptor—alpha (RAR-α). Since this receptor has been shown to be involved with growth and differentiation of myeloid cells in vitro, and since recent clinical studies have reported that tretinoin (all-trans-retinoic acid) induces complete remission in patients with acute promyelocytic leukemia, we studied the effects of tretinoin on cellular maturation and molecular abnormalities in patients undergoing the induction of remission with this agent.
Results.
Eleven patients with acute promyelocytic leukemia were treated with tretinoin administered orally at a dose of 45 mg per square meter of body-surface area per day. Nine of the 11 patients entered complete remission. In two patients, complete remission was preceded by striking leukocytosis that then resolved despite continued drug treatment. Serial studies of cellular morphologic features, cell-surface immunophenotypic analysis, and fluorescence in situ hybridization with a chromosome 17 probe revealed that clinical response was associated with maturation of the leukemic clone. All patients who responded to treatment who were tested by Northern blot analysis had expression of aberrant RAR-α. As patients entered complete remission, the expression of the abnormal RAR-α message decreased markedly; however, it was still detectable in several patients after complete morphologic and cytogenetic remission had been achieved.
Conclusions.
Tretinoin is a safe and highly effective agent for inducing complete remission in patients with acute promyelocytic leukemia. Clinical response to this agent is associated with leukemic-cell differentiation and is linked to the expression of an aberrant RAR-α nuclear receptor. Molecular detection of the aberrant receptor may serve as a useful marker for residual leukemia in patients with this disease. (N Engl J Med 1991; 324:1385–93.)
Article Activity
- Article
ACUTE promyelocytic leukemia makes up approximately 15 percent of the adult acute nonlymphoblastic leukemias.1 The disease is associated with a specific cytogenetic abnormality, the translocation of a portion of the long arm of chromosome 17 onto the long arm of chromosome 15 — t(15;17)(q22;ql2–21).2 During the past year, the breakpoint region for the chromosome 17 translocation has been cloned,3 and molecular studies have revealed DNA rearrangements that clustered in the region of the first intron for the nuclear retinoic acid receptor—alpha (RAR-α).4 ' 5 This rearrangement resulted in the expression of abnormal messenger RNA (mRNA) transcripts for RAR-α.6 7 8 These findings were of special interest since RAR-α had previously been shown to be involved in the growth and differentiation of certain myeloid cells in vitro.9 Before these laboratory developments, investigators in China and France reported that treatment with tretinoin (all-trans-retinoic acid) induced complete remission in patients with acute promyelocytic leukemia.10 , 11 Together, these data suggested a possible molecular link between the pathogenesis of this malignant disease and its treatment.
To explore the nature of this clinical response further, we conducted a study using a new formulation of tretinoin in patients with acute promyelocytic leukemia. In this study, we confirmed that a high proportion of patients treated with tretinoin entered complete remission, that this beneficial effect was achieved with low morbidity, and that the clinical response to tretinoin was associated with the maturation of leukemic cells during the induction of remission. It did not appear that fully differentiated myeloid cells derived from the malignant clone persisted in patients who were in complete remission. Patients with acute promyelocytic leukemia who responded to tretinoin consistently expressed abnormal mRNA transcripts for RAR-α, suggesting that this rearranged receptor was a molecular target of the treatment. Although expression of the abnormal message decreased markedly after the clinical response, aberrant mRNA transcripts could still be detected in some patients who appeared to be in remission.
Methods
Clinical Protocol
Patients were eligible for this study if they fulfilled the morphologic diagnostic criteria for acute promyelocytic leukemia (M3 or M3-variant subtype) according to the classic French—American—British classification system.12 Karyotypes were determined on unstimulated cultures of bone marrow after 48 hours with the use of Giemsa- or quinacrine-banding techniques.13 Because of the preliminary evidence of the effectiveness of tretinoin,10 , 11 patients with either newly diagnosed disease or relapsed or resistant disease were deemed eligible. The patients were monitored by means of complete blood and platelet counts performed daily if they were hospitalized and twice weekly if they were treated as outpatients, until remission was achieved. Coagulation tests were performed daily until the results were normal. Heparin was not used to treat coagulopathy. Instead, patients with evidence of disseminated intravascular coagulation (thrombocytopenia with hypofibrinogenemia) were treated twice daily with transfusions of platelets and fresh-frozen plasma to maintain the platelet count at ≥50×109 per liter and the fibrinogen level at ≥1.0 g per liter. Liver-function tests were performed and serum cholesterol and triglycerides were measured twice a week. Bone marrow aspiration was performed approximately once a week during induction, until complete remission or failure was documented. Conventional response criteria were observed.14
Extrapolating from the study of Castaigne et al.,11 we treated the patients with tretinoin at a dose of 45 mg per square meter of body-surface area per day. In contrast to previous studies,10 , 11 in this study the drug was formulated in soft gelatin capsules similar to those used in the U.S. formulation of isotretinoin. Except on the first and seventh days, when the total dose was given once in the morning for pharmacokinetic studies, the drug was divided into two equal doses administered approximately six hours apart. In the patients who entered complete remission, subsequent therapy depended on their earlier treatment status. Patients with newly diagnosed disease received tretinoin for 30 days after entering complete remission, and they then received conventional consolidation chemotherapy or underwent bone marrow transplantation. If such treatment was deemed inappropriate (e.g., in elderly patients), a patient could receive continued treatment with tretinoin alone. Patients who had relapsed after previous chemotherapy received continued treatment with tretinoin unless they were eligible for bone marrow transplantation. Patients or their guardians gave written informed consent, and the study was reviewed and approved in advance by the center's institutional review board.
Cell-Surface—Antigen Immunophenotyping
Bone marrow mononuclear cells were separated by Ficoll–Hypaque density sedimentation, and peripheral-blood cells were analyzed as whole blood with the Q-Prep system (Coulter Immunology, Hialeah, Fla.). Using dual-color fluorescence of cells gated according to size and forward-scatter analyzed on an EPICS profile flow cytometer (Coulter),15 we determined the expression of a panel of antigens, including CD33 (early myeloid) and CD16 (late myeloid).16 All the cells in a sample were analyzed with up to three gated clusters (bitmaps) to allow simultaneous analysis of different cell populations in a single sample.
DNA Flow Cytometry
Bone marrow mononuclear cells were separated by density centrifugation and stained with acridine orange as previously described.17 Fluorescence of 10,000 cells was measured with a modified FacScan flow cytometer (Becton Dickinson, Mountainview, Calif.). Histograms were analyzed with CellFit software (Becton Dickinson).
Northern Blot Analysis for RAR-α Expression
Total cellular mRNA was purified from bone marrow mononuclear cells separated by Ficoll–Hypaque density centrifugation by an established technique.18 Northern blot analysis was performed on the RNA as previously described.6 The filters obtained were hybridized to a 600—base-pair PstI cut human complementary DNA for RAR-α19 and were washed stringently at 56°C.6
Southern Blot Analysis for Genomic Rearrangements of RAR-α
Genomic DNA was prepared as previously described.20 For Southern blotting, 10 μg of genomic DNA was completely digested for three hours with EcoRI or HindIII (2 to 3 U per microgram of DNA) (Boehringer–Mannheim, Indianapolis), size fractionated on a 0.8 percent agarose gel, denatured, renatured, neutralized, and blotted onto nitrocellulose filters.21 The filters were then hybridized to a 640–base-pair RI—SstI cut RAR-α complementary DNA19 and washed stringently at 55°C.20 Autoradiographs were obtained after exposure at —70°C to XAR film (Kodak, Rochester, N.Y.) with use of an intensifying screen.
Premature Chromosome Condensation and Fluorescence in Situ Hybridization
Peripheral blood was subjected to a two-step density centrifugation on a Ficoll–Hypaque gradient to separate cells into mononuclear and polymorphonuclear fractions.22 Cells from each fraction were fused with 5-bromodeoxyuridine—labeled mitotic Chinese-hamster—ovary cells to induce premature chromosome condensation in the blood-cell nuclei as previously described.23 , 24 In situ hybridization on these preparations with chromosome-specific probes was carried out with a modification of the technique described by Pinkel et al.25 The phage DNA library for human chromosome 17 (LN17NS03) was obtained from the American Type Culture Collection and amplified, and the DNA was isolated, nicktranslated, and labeled with biotin 16—deoxyuridine triphosphate. After in situ hybridization, the hybridized sequences were detected with fluorescein isothiocyanate–conjugated avidin. The preparations were counterstained with 0.5 μg of propidium iodide per milliliter and visualized with a fluorescence microscope.
Results
Patients
Eleven patients with acute promyelocytic leukemia were treated with tretinoin. Relevant clinical characteristics of these patients are shown in Table 1Table 1
Demographic and Clinical Characteristics of Patients with Acute Promyelocytic Leukemia and the Clinical Response to Tretinoin.*. Six of the patients had not received cytotoxic chemotherapy, whereas five had had a first or second relapse after previous treatment. Six patients had evidence of disseminated intravascular coagulopathy. Nine of the 11 patients had a characteristic karyotypic abnormality, t(15;17) (Table 1). Despite morphologic evidence of M3 leukemia, two patients were found on conventional cytogenetic testing not to have the translocation. Three patients (all of whom had previously received chemotherapy) had additional cytogenetic abnormalities.Clinical Response
Nine of the 11 patients entered complete remission. Seven of these nine were technically able to undergo cytogenetic analysis, and all seven had a normal karyotype during remission. The disappearance of coagulation abnormalities, manifested by an increased platelet count and plasma fibrinogen level, was generally the first sign of clinical response.
The median time to remission according to all criteria was 41 days (range, 24 to 53). Because the study was short, long-term remission could not be accurately assessed. Currently, the duration of complete remission ranges from 1 1/2 to more than 6 months. Four of the nine patients in complete remission (all previously untreated) have stopped taking tretinoin and have received consolidation chemotherapy. Two additional patients who entered complete remission when treated after a first relapse underwent bone marrow transplantation. Two patients continue to receive maintenance treatment with tretinoin after more than four and six months.
Despite continuous treatment with tretinoin, one patient (treated after a second relapse) relapsed after six weeks in remission. We could not reinduce a response in this patient despite increasing the dose to 90 mg per square meter per day for 12 days before switching to conventional chemotherapy. Two patients (one previously untreated and one in first relapse) were removed from the study because of increasing leukocytosis (described below), and their cases were considered clinical failures at that time. Both patients subsequently had complete remission with conventional chemotherapy.
Hyperleukocytosis Syndrome
A previous report suggested that a marked increase in the peripheral-blood leukocyte count was associated with a poor outcome.11 As shown in Figure 1Figure 1
Development and Course of Peripheral Leukocytosis in Four Patients with Acute Promyelocytic Leukemia during Treatment with Tretinoin., 4Figure 4
Northern Blot Analysis in Patients with Acute Promyelocytic Leukemia. of the 11 patients in this study had a leukocyte count higher than 35×109 per liter after treatment with tretinoin. The first two patients with these levels were removed from the study, although one had had partial morphologic maturation of her peripheral-blood leukocytes. The other two patients continued to receive treatment throughout the period of leukocytosis. As shown in Figure 1, the leukocyte count in one (Patient 9) peaked at 43 × 109 per liter in the first week and then receded. When the leukocyte count in the second patient (Patient 4) reached 77×109 per liter, repeated leukapheresis was undertaken to reduce the burden of leukemic cells. The leukocyte count in this patient remained above 50 × 109 per liter for three weeks before receding. Both patients subsequently entered complete remission with continued therapy and no alteration in the drug dosage. The S-phase component, as measured by flow cytometry, was generally unchanged or somewhat increased in the bone marrow or peripheral blood of most patients during the induction of remission (data not shown). As an example, the patient whose data are shown in Figure 1 who had the most extreme degree of leukocytosis also had a marked increase from 2 to 11 percent in the S-phase component of her peripheral blood coincident with the increase in her peripheral-blood leukocyte count. These data argue strongly that the maturing peripheral-blood leukocytes increased as a consequence of cellular proliferation rather than demargination.Morbidity and Adverse Effects
No patient died during treatment. Although this therapy did not eliminate the major complications of leukemia, in most patients they were less severe and more easily managed than expected. Seven patients required red-cell transfusions, and five received fresh frozen plasma for the treatment of hypofibrinogenemia. However, 5 of the 11 patients required no platelet transfusions. Nine of the 11 patients received systemic antibiotics for fever associated with neutropenia. Although two patients were discharged early from the hospital (on days 5 and 11), the median length of stay for all patients during the induction of remission (including failures) was 29 days.
Tretinoin was well tolerated. The most frequent reaction was headache that occurred several hours after drug ingestion and was relieved by mild analgesic agents. Intracranial hypertension (pseudotumor cerebri) was documented in two patients, however, manifested by severe headache, papilledema (in one case), and elevated opening pressure on lumbar puncture ranging from 2.65 to 5.39 kPa (27 to 55 cm of water). These patients continued to receive therapy and were treated with occasional lumbar puncture, dexamethasone, and analgesic agents. Additional side effects (all of mild intensity) included skin rash, nasal congestion, and hypertriglyceridemia. Unlike previous investigators,10 , 11 we did not observe bone pain or hepatic toxicity at the dose used in this study.
Immunophenotypic Studies
Cell-surface immunophenotyping showed progression from the expression of immature markers on the neoplastic cells at presentation toward the appearance of mature granulocytic markers during remission. In several cases, we observed morphologically maturing cells in the peripheral blood that simultaneously expressed mature and immature markers. Figure 2Figure 2
Results of Surface-Marker Studies of Peripheral-Blood Leukocytes from Patient 4 That Expressed Only Immature (CD33, Squares) or Only Mature (CD16, Triangles) Myeloid Surface Antigens. shows the results of serial studies of surface markers in a patient with newly diagnosed disease. Whole (unseparated) blood was used so that all populations of leukocytes in the peripheral blood could be analyzed separately as well as simultaneously. At the beginning of treatment, all gated cells stained for CD33 (an early myeloid surface antigen), and no cells expressed CD 16, a marker that appears at the band stage of myeloid maturation.16 With continued treatment, the neoplastic CD33+ cells also began to express CD16. Unexpectedly, these cells that expressed both early (CD33) and late (CD16) antigens (termed "intermediate cells") became predominant in the peripheral blood and peaked on day 25, making up 90 percent of the total leukocyte count. All cells that were CD33+ and CD16— (promyelocytes) had entirely disappeared by that time, and all remaining CD33+ cells were found only in this dual-staining intermediate population. After this peak, cells that were CD33 —and CD16+ (granulocytes) began to appear, coincidently with a decrease in the mean fluorescence intensity of CD33 expression on the intermediate cells (reflecting a reduction in the number of surface antigens in this maturing population). By day 40, no phenotypically intermediate cells remained. Morphologically, these marker findings were supported by the occasional observation of Auer rods in cells that appeared otherwise to be mature polymorphonuclear neutrophils, as shown in Figure 3Figure 3
Morphologic and Immunophenotypic Studies in a Patient with Acute Promyelocytic Leukemia. Panel A shows several Auer rods in a polymorphonuclear leukocyte surrounded by less mature myeloid cells containing vacuolated nuclei (cell centrifuge preparation from Patient 3 on day 16). Panel B shows the morphologic characteristics of a population of peripheral-blood cells drawn from the patient on day 21 that contained more than 95 percent polymorphonuclear leukocytes. Fluorescence in situ hybridization on prematurely condensed chromosomes showed that one third of these cells contained a chromosome 17 translocation, illustrated by the three bright areas of fluorescence in Panel C. The remaining two thirds of these cells were diploid without a chromosome 17 translocation, as shown by the normal appearance of two fluorescent areas in Panel D.A.Premature Chromosome Condensation and Fluorescence in Situ Hybridization Studies
The maturation results from the morphologic and immunophenotypic studies were confirmed by in situ demonstration of the t(15;17) abnormality on the same population of cells. Since the premature-chromosome-condensation technique allows a karyotypic evaluation of mature (nondividing) cells, granulocytes obtained from peripheral blood at various times during treatment were examined for the presence of this clonal abnormality. As an example, Figure 3B shows a Wright—Giemsa stain of the granulocyte population obtained after dual-density centrifugation of peripheral blood drawn on day 21 from Patient 3. Of 42 granulocyte-chromosome preparations analyzed by fluorescence in situ hybridization, 14 (33.3 percent) had evidence of a chromosome 17 translocation, shown as three bright areas of fluorescence in Figure 3C. The remaining granulocytes from this patient (66.7 percent) failed to reveal evidence of a chromosome 17 translocation, corresponding to the two normally fluorescent chromosomes in Figure 3D. After complete remission had been achieved, peripheral-blood granulocytes from four other patients (Patients 1, 2, 6, and 9) were studied, but no mature cells that exhibited a chromosome 17 translocation were found.
Together, the surface-marker and fluorescence in situ hybridization results indicate that a component of the leukemic clone was induced to form mature cells early in treatment with tretinoin. These cells, however, died after reaching maturation, and remission was associated with the preferential regrowth of normal myeloid elements. Within the limits of sensitivity of these techniques, we found no evidence that clonal
abnormalities persisted in the mature population of cells during complete remission.
Molecular Analysis of RAR-α
Nine patients could be evaluated by Northern blot analysis performed on total cellular RNA. (Because of insufficient yields of RNA, two early patients could not be evaluated by this technique.) Eight of these nine patients had aberrant mRNA expression of RAR-α (Table 1). All eight patients with the aberrant message for RAR-α on Northern blot analysis entered complete remission after treatment with tretinoin. Seven of these eight patients also had the characteristic t( 15; 17) karyotypic abnormality. However, one patient who had a normal karyotype on conventional cytogenetic analysis was shown to express an abnormal mRNA species for RAR-α on Northern blot analysis, and this patient also entered complete remission. Conversely, the single patient with morphologic M3 leukemia in whom treatment failed with no evidence of myeloid maturation had a normal karyotype by conventional cytogenetic analysis, a normal chromosome 17 on in situ hybridization, and normal RAR-α expression on Northern blot analysis.
Two predominant patterns of aberrant mRNA expression (one or two abnormal bands) were observed on Northern blot analysis (Fig. 4A). Furthermore, as patients entered complete remission, the expression of the abnormal RAR-α species markedly decreased (as illustrated in Fig. 4B by the serial Northern blot analyses in a representative patient), and disappeared in some patients. In several patients (including the patient who relapsed), however, the abnormal RAR-α message could be detected on Northern blot analysis despite the achievement of complete remission as defined by marrow morphologic features, peripheral-blood counts, and conventional cytogenetic analysis.
Southern blot analysis documented rearrangements of the RAR-α gene in several patients. A representative Southern blot analysis is shown in Figure 5Figure 5
Southern Blot Analysis to Determine RAR-α Genomic Rearrangements in Patients with Acute Promyelocytic Leukemia. Lane 1 represents DNA extracted from human placenta as a control, lane 2 DNA from HL-60 cells, lane 3 DNA from Patient 7, lane 4 DNA from Patient 6, and lane 5 DNA from Patient 9. The arrow in lane 3 indicates an RAR-α rearrangement. Values on the right are kilobases., with lane 3 showing the appearance of a rearranged genomic DNA band in Patient 7. Each of the patients with acute promyelocytic leukemia represented in Figure 5 expressed an abnormal RAR-α mRNA species on Northern blot analysis. In accord with other reports,5 , 8 DNA rearrangements were not detected on Southern blot analysis in HL-60 cells used as controls that are known to lack the (15; 17) translocation (Fig. 5, lane 2).Discussion
This clinical study confirms the effectiveness of tretinoin in patients with acute promyelocytic leukemia. On the basis of our results at least two plausible explanations can be offered for our observations and those of others.10 , 11 If the drug exerts a moderate antiproliferative effect on the leukemic clone, that effect might by itself be sufficient to reduce leukemia-derived inhibitory activity on normal cells. The regrowth of normal hematopoiesis could thus proceed, eventually overcoming (but not completely eradicating) the population of leukemic cells. Alternatively, tretinoin could induce immature leukemic cells to replicate, differentiate to form cells incapable of further division, undergo senescence, and eventually die. These explanations are not mutually exclusive; several lines of evidence from this study suggest, however, that a principal effect of tretinoin is the induction of leukemiccell differentiation.
First, even at the peak plasma concentrations of tretinoin achieved clinically (approximately 10–6 M),26 the viability of most leukemic cells was preserved in vitro, and these concentrations induced most cells to undergo division and morphologic maturation27 , 28 (and Jakubowski A: unpublished data). Second, clinical remission was achieved without evidence of bone marrow hypoplasia, but with clear evidence of increasing morphologic maturation of cells in bone marrow and peripheral blood. Unlike the profound reduction in the S-phase component of bone marrow cells, as measured by DNA flow cytometry, in patients taking cytotoxic drugs,29 cell-cycle analysis in the patients taking tretinoin commonly showed a stable or somewhat increased proportion of cells in the S phase during the induction of remission. Third, treatment with tretinoin resulted in the transient appearance of cells that were morphologically intermediate in maturation and that clearly coexpressed both primitive and mature myeloid surface antigens. Finally, we found occasional cells that were morphologically mature but that contained Auer rods as well as the characteristic (15; 17) translocation (Fig. 3). However, using the techniques described, we found no evidence that these clonally abnormal cells persisted for prolonged periods after the patients entered complete remission. Differentiation in this disease is not inconsistent with previous observations. With standard chemotherapy, some patients with acute promyelocytic leukemia have entered remission without severe bone marrow hypoplasia,30 with an unexpected persistence of abnormal promyelocytes during induction, or with delayed conversion of the abnormal karyotype.31 , 32
Using sophisticated cytogenetic techniques, some investigators have suggested that every patient with acute promyelocytic leukemia has the (15; 17) translocation.2 In this study, we found one patient with a normal karyotype who expressed the abnormal message for RAR-α, as well as several patients in whom expression of the aberrant message was detected after karyotypic normalization in remission. Patients who lack the typical (9;22) translocation of chronic myelogenous leukemia but who express the consequent bcr–abl fusion product are now well described.33 It thus seems likely that the presence of the aberrant RAR-α message in acute promyelocytic leukemia can also serve as a new molecular diagnostic marker that is both more sensitive and more specific than either light microscopy or conventional cytogenetic analysis.
Our study also suggests that the presence of the aberrant RAR-α receptor and the striking clinical responses seen after the pharmacologic provision of one of its ligands may be related. In this study, tretinoin was extremely effective when the abnormal transcript was expressed, and the drug was ineffective in the single patient who lacked this molecular abnormality. Moreover, minimal cytodifferentiating activity has been observed in liquid cultures of fresh non-M3 myeloid leukemic cells in vitro,27 and no activity has been described in preliminary clinical studies of other myeloblastic leukemias that lack the (15; 17) translocation.10 , 11 Several mechanistic explanations can be offered for this link. First, the abnormal RAR-α receptor may be partly functional but may bind the ligand less avidly. Pharmacologic provision of the ligand in excess might overcome the reduced binding affinity and could then activate the receptor. Alternatively, retinoid-mediated transcriptional events could result from the recruitment of a different retinoid-receptor pathway induced by high concentrations of tretinoin. We have observed mRNA expression of the newly described RXR-α receptor34 in several patients with acute promyelocytic leukemia.35 Finally, the altered receptor could function as a so-called dominant negative mutation36 — i.e., one that suppresses the function of a coexpressed normal RAR-α allele — similar to a retinoid-receptor mutation recently described in embryonal carcinoma cells.37 When the chimeric receptor protein in this disease has been fully characterized, DNA and ligand-binding studies should clarify its functional status, as well as possible structure—activity relations with other retinoids. For example, isotretinoin has occasionally been reported to induce complete remission in acute promyelocytic leukemia,38 39 40 41 42 but the effect has been inconsistent. Chomienne et al.27 , 28 have noted that tretinoin induced cytodifferentiation in fresh M3 leukemic cells at concentrations up to 10 times lower than those of isotretinoin.
On the basis of previous reports suggesting that the development of leukocytosis presaged a poor outcome,11 we withdrew two of our patients from treatment after their peripheral-leukocyte count increased to more than 35× 109 per liter. In at least one of the patients, that decision may have been in error. Two subsequent patients, both of whom had morphologic evidence of maturation in bone marrow and peripheral blood, continued to receive the drug despite gross elevations in their leukocyte counts. One of them was treated with leukapheresis to remove excess leukemic cells and minimize potential morbidity.43 Both of them subsequently entered complete remission with continued retinoid treatment. Moreover, the marked increase in the S-phase component that we observed in bone marrow cells from one of these patients indicated that this effect resulted from cell division rather than demargination. The development of extreme leukocytosis may thus indicate cellular proliferation and differentiation of an initially large burden of leukemic cells. The proper role of leukapheresis or cytotoxic therapy in the treatment of this complication requires further exploration.
Although it has not been previously reported, we found that headache, associated in two cases with intracranial hypertension, was the principal adverse effect of this dose of tretinoin. Other toxic reactions were extremely mild, consisting of chapped lips, nasal congestion, and hypertriglyceridemia. Although no dose–response correlation has yet emerged, complete remissions are clearly achieved at doses that are considerably lower than the maximally tolerable dose. Because of the relatively brief clinical experience, the durability of complete remission has not been reliably assessed, nor has the optimal role of tretinoin been clarified (i.e., its use in the induction of remission as compared with long-term maintenance). Nevertheless, given the extremely low morbidity, this agent should be considered in patients whose condition is resistant to conventional treatment.
Finally, we note an apparent paradox: a specific molecular genetic abnormality has resulted in the expression of an altered receptor, yet the presence of this abnormal receptor seems to confer exquisite therapeutic sensitivity on one of its ligands, causing cellular differentiation and complete clinical remission of leukemia. Since retinoids exert biologic effects in normal and malignant cells without known rearrangements of retinoid-receptor genes,44 45 46 47 48 further molecular and biochemical analysis is required to evaluate whether this aberrant receptor truly acts as a target of retinoid treatment. Whether this example in acute promyelocytic leukemia will serve as a paradigm for the treatment of other neoplastic states cannot yet be determined. Nonetheless, the striking success of this treatment may serve as a useful model for the exploration of agents that induce cellular differentiation in other malignant diseases.
Supported in part by grants from the Food and Drug Administration (FD-R-000674), the American Cancer Society (PDT–381 and IM–551), and the Markey Trust (88–23). Drs. Jakubowski and Dmitrovsky are recipients of Clinical Oncology Career Development Awards from the American Cancer Society. Dr. Miller is the recipient of a Young Investigator Award from the American Society of Clinical Oncology. Dr. Scheinberg is a Lucille P. Markey Scholar. Dr. Frankel is supported by the Mortimer J. Lacher Research Fund and is the recipient of a Cancer Chemotherapy Training Grant (CA–09207–14) from the National Cancer Institute.
We are indebted to Hoffmann—LaRoche for formulating and supplying tretinoin; to Dr. Laurent Degos, Hôpital St. Louis, Paris, for his advice in starting this study; to Dr. Pierre Chambon, Institute National de la Santé et de la Recherche Médicale, Strasbourg, France, for probes used for analysis of RAR-α; to Dr. Suresh Jhanwar for review of the cytogenetic karyotypes; to Teresa Snyder, R.N., Marianne Frisonne, R.N., Barbara Bosco, R.N., and Anna Eardley for expert clinical and data-management assistance; to Susan McKenzie, Ruth Rose, and Nikki Feirt for technical assistance; and to the physicians who referred patients to this study and who provided extended clinical follow-up and advice, including Drs. Timothy Gee, Ellin Berman, Paul Meyers, Norma Wollner, David Lovett, Mark Weiss, Philip Schulman, and Bayard D. Clarkson.
Source Information
From the Leukemia and Developmental Chemotherapy Services, Department of Medicine (R.P.W., S.R.F., L.M.I., M.A., A.T., M.S.G.), and the Laboratories of Molecular Medicine (W.H.M., E.D.), Hematopoietic Cancer Immunochemistry (D.A.S.), and Leukocyte Biology (A.J., J.G.), Memorial Sloan-Kettering Cancer Center, New York; and the Department of Medical Oncology, M.D. Anderson Cancer Center, Houston (W.N.H., R.V.). Address reprint requests to Dr. Warrell at the Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021.
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