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© 2000 American Society for Clinical Oncology CD56 Expression Is an Indicator of Poor Clinical Outcome in Patients With Acute Promyelocytic Leukemia Treated With Simultaneous All-Trans-Retinoic Acid and ChemotherapyFrom the Divisione di Ematologia, Sezione TERE, Servizio di Immunoematologia, Ospedale Cardarelli, Naples; Divisione di Ematologia e CTMO "A. Neri," Ospedale Bianchi-Malacrino-Morelli, Reggio Calabria; Divisione di Ematologia, Università di Bari, Bari; and Dipartimento di Biotecnologie Cellulari ed Ematologia, Università La Sapienza, Rome, Italy. Address reprint requests to Felicetto Ferrara, MD, Via Pigna 76 F/G, 80128 Napoli, Italy; email ferrara{at}itb.it
PURPOSE: Preliminary reports suggest that leukemic cell expression of CD56, a neural cell adhesion molecule, is associated with adverse clinical outcome in either acute myeloid leukemia with t(8;21) or acute promyelocytic leukemia (APL). We investigated the prognostic relevance of CD56 in a series of patients with APL who were treated homogeneously with all-trans-retinoic acid (ATRA) and chemotherapy. PATIENTS AND METHODS: Clinicobiologic presenting features and therapeutic results were analyzed in a series of 100 patients with genetically proven APL who were treated, according to the example of the Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto multicenter trial, with ATRA plus idarubicin (AIDA) and for whom data on CD56 expression were available at diagnosis. RESULTS: Fifteen patients (15%) showed expression of CD56 in greater than or equal to 20% blasts at diagnosis and were considered as CD56+. No differences were found regarding age, sex, WBC and platelet counts, incidence of coagulopathy, hemoglobin and fibrinogen levels, promyelocytic leukemia/retinoic acid receptor (PML/RAR) alpha fusion type, or complete remission (CR) rate in the comparison of the CD56+ and CD56- populations. Conversely, compared with patients who were CD56-, patients with CD56+ APL had shorter CR duration (P = .04) and overall survival (P = .002). In the multivariate analysis, CD56 positivity and initial WBC count greater than 10 x 109 cells/L retained statistical significance in overall survival (P = .04 and P = .02, respectively). CONCLUSION: The expression of CD56 is significantly associated with inferior CR duration and survival in patients with APL who were treated with modern frontline treatment that included ATRA and simultaneous chemotherapy. Combined with other well-established prognostic factors such as WBC count, CD56 expression at diagnosis might be used to build prognostic scores for risk-adapted therapy in APL.
ACUTE PROMYELOCYTIC leukemia (APL) is a particular subtype of acute myeloid leukemia (AML) that has distinctive biologic and clinical features. It includes a characteristic morphologic and surface marker phenotype and a unique chromosome translocation t(15;17), which results in the formation of a hybrid promyelocytic leukemia/retinoic acid receptor (PML/RAR) alpha fusion protein.1-3 At the clinical level, the disease is characterized by frequent association with a severe bleeding diathesis as well as by a striking response to differentiating therapy with all-trans retinoic acid (ATRA).4-6 In recent years, inclusion of this agent in frontline treatment has considerably improved the outcome of the disease, so that the majority of patients who received combined chemotherapy and ATRA regimens are reported to become long-term survivors. However, despite this improvement, treatment failure still occurs in approximately 30% of cases as a result of early hemorrhagic death or disease relapse.4-6 Prognostic factors that may predict for inferior outcome in APL have been investigated widely; yet, with the exception of older age and high initial WBC count, no features at diagnosis have been consistently associated with increased relapse risk in recently reported large multicenter studies.7-14 This field of investigation seems extremely relevant in light of the potential use, in the high risk category, of more aggressive postremission approaches such as bone marrow transplantation (BMT).15 Surface marker studies have shown that APL blasts disclose a consistently conserved profile that includes positive staining for CD33, CD13, and CD9 antigens, absence of HLA-DR, and low frequency of CD34, CD14, CD7, and CD11b expression.16,17 In addition, we and others have reported the expression in APL cells of certain adhesion molecules and their modulation by ATRA.18-23 Although this latter feature may be associated with the pathogenesis of ATRA syndrome,19-23 little is known about the impact of adhesion molecules expression on response to therapy and clinical outcome in APL. Recently, two preliminary reports have demonstrated that positive staining of leukemic blasts for CD56, a neural cell adhesion molecule,24 is associated with unfavorable clinical outcome in both AML with t(8;21) and APL.25,26 As for APL, however, the only clinical study reported to date was conducted in a small series of heterogeneously managed patients who, in the majority of cases, did not receive modern ATRA + chemotherapy treatments.26 Finally, other authors have reported the occurrence of rare CD56+ AML subsets, including the so-called myeloid/natural killer precursor acute leukemia, which are characterized by adverse prognosis.27,28 To gain further insights into the prognostic impact of CD56 expression in APL, we studied a series of 100 consecutive patients who were observed in Italy between 1993 and 1998 and who were uniformly treated with ATRA and idarubicin (AIDA) according to the example of the multicenter trial of the Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto.8
One hundred patients with genetically proven APL were included in this study. The series comprised all patients who were consecutively enrolled onto the AIDA study8 by five major participating institutions, which routinely included CD56 expression in the diagnostic characterization panel. Diagnosis was initially established by morphology according to the French-American-British criteria29 and was confirmed in all cases by cytogenetics and/or molecular biology. On light microscopy, 85 cases (85%) were classified as classical (or hypergranular) APL and 15 (15%) as variant (or microgranular) APL. Median age was 38 years (range, 2 to 77 years). Fifty patients (50%) were males and 50 (50%) were females. Ninety-five patients (95%) in this series were investigated at the molecular level for the detection of the PML/RAR alpha hybrid transcript as described elsewhere8: 62 (65%) had a 3' PML gene breakpoint (57 with breakpoint cluster region 1 [bcr1] and three with bcr2, hereafter combined as bcr1-2) and 33 (35%) had a 5' PML breakpoint (bcr3). In the remaining five patients for whom no molecular characterization data were available at presentation, APL diagnosis was confirmed at the genetic level by karyotypic demonstration of the t(15;17). Immunophenotyping was performed on freshly collected bone marrow samples, as previously described.22,23 A quality control program was applied to ensure comparability and reproducibility of data from the four different flow cytometry units. First, precalibrated microbeads were used to evaluate the instrument performances independently of cell preparation. Operators demonstrated that the blank bead was well resolved (with more than 80% of the distribution being moved out of the zero channel) and that the brightest bead did not go off-scale. Moreover, blood samples from healthy donors were characterized and results were collected to demonstrate that the detected expression levels of CD56 on normal cytotoxic lymphocytes, stained with the monoclonal antibody Leu19, were comparable among the various laboratories. Briefly, cells were isolated by Ficoll-Hypaque density gradient and analyzed by flow cytometry using Leu19 monoclonal antibody. An analytic gate was imposed on cell preparation to isolate the leukemic population. Samples were considered positive for CD56 when more than or equal to 20% of the cells stained above the negative control antibody. Data collected from patients with CD56+ and CD56- APL focused on pretreatment characteristics, including clinical features, common laboratory parameters, and molecular findings. A number of variables, including sex, age, morphologic APL type, WBC count at diagnosis, type of PML gene breakpoint, BMT (both autologous and allogeneic), and CD56 expression, were introduced in the prognostic evaluation either by univariate or multivariate analysis. Concerning WBC count, a cutoff point of 10 x 109 cells/L was established on the basis of recent results from the Medical Research Council cooperative study, which demonstrated that a WBC count of greater than 10 x 109 cells/L represents a key determinant of clinical outcome in APL.14 All patients were managed with the AIDA protocol, in which induction is based on the simultaneous combination of ATRA plus idarubicin (IDA).30 ATRA was given orally at 45 mg/m2 from day 1 until the achievement of hematologic complete remission (CR), whereas IDA was administered at a dose of 12 mg/m2/d intravenously on days 2, 4, 6, and 8. Consolidation included three additional courses of chemotherapy for all patients (IDA/cytarabine [ARA-C], mitoxantrone/etoposide, and IDA/ARA-C/thioguanine). Further details have been given elsewhere.8,30 Definition of CR and relapse were according to the criteria proposed by the National Cancer Institute–sponsored workshop for AML.31 Censoring was performed at the time of the last follow-up for patients alive and in CR. Overall survival was measured from the time of diagnosis to death or last observation, whereas disease-free survival (DFS) was measured from CR achievement to relapse or death while still in CR. Univariate analysis of categorical variables that compared CD56+ and CD56- APL subsets was performed by Fisher’s exact test. Continuous variables were compared by the Mann-Whitney test. All tests were two-sided.32 Survival curves were obtained by the Kaplan-Meier method33 and compared by the log-rank test. Finally, multivariate analysis was carried out by Cox regression model, using backward elimination.34
Fifteen patients (15%) showed expression of CD56 in greater than or equal to 20% blasts at diagnosis and were considered as CD56+. The range of positively staining cells was 22% to 86%. Clinical and hematologic characteristics according to CD56 expression are detailed in Table 1. There were no statistically significant differences between the two groups concerning age, sex, diagnosis of variant APL, WBC and platelet counts, hemoglobin level, incidence of diffuse intravascular coagulation, or fibrinogen and fibrinogen degradation products levels. The distribution of the PML/RAR alpha fusion type showed a higher incidence of the bcr3 isoform in the CD56+ group, but the difference with the CD56- group did not reach statistical significance (Table 1). No significant correlation was found between the expression of CD56 and that of the lymphoid markers CD2 and CD19 (not shown).
Overall, 93 (93%) of 100 patients achieved CR. Thirteen (87%) of 15 patients obtained CR in the CD56+ group, whereas the CR rate was 94% (80 of 85) in the CD56- cohort (P = .28). There were no refractory patients in either group, and treatment failures were only a result of early death in induction (which occurred in most cases because of cerebral hemorrhage). Salvage therapy included, in all cases, a reinduction protocol with ATRA followed by chemotherapy consolidation with ARA-C and mitoxantrone, as reported.35 Fourteen patients underwent BMT, nine for autologous and five for allogeneic in second CR. There was no difference in the proportion of patients who had undergone BMT to those who had not between CD56+ and CD56- groups (P = 1.00), as is listed in Table 1. Overall, nine extramedullary relapses occurred, which involved CNS (four cases), skin (three cases), middle ear (one case), and lung (one case). Patients with extramedullary relapse received ATRA plus consolidation therapy as reported above. In addition, those with CNS relapse were given intrathecal methotrexate and ARA-C. As detailed in Table 2, the incidence of extramedullary relapse did not differ between the two groups. Figure 1 shows the Kaplan-Meier estimates of overall survival according to CD56 expression. The median survival was not reached in either the CD56+ or CD56- group. However, survival was significantly inferior in the CD56+ cohort (P = .002). Similarly, DFS was significantly different between the two groups: median DFS was 22 months in the CD56+ group but was not reached in the CD56- group (P = .04) (Fig 2).
The study of the prognostic impact of five different variables on survival, as calculated by univariate analysis, is illustrated in Table 3. Only WBC count more than 10 x 109 cells/L and CD56 expression reached the level of statistical significance (P = .0001 and P = .002, respectively). In the multivariate analysis, CD56 expression retained the level of statistical significance after adjustment for WBC count (P = .02 and P = .04 for WBC count and CD56 expression, respectively).
The results of recently published multicenter trials indicate that the majority of newly diagnosed APL patients are now cured with modern regimens that include ATRA.8-14 In particular, the best results in terms of either CR or DFS were obtained by the use of simultaneous combinations of ATRA and anthracycline-containing chemotherapy in patients with genetically proven diagnoses.8-14 In addition, the Spanish Cooperative Group for the Study of Hematological Malignancies Treatment, Spanish Society of Hematology (PETHEMA), reported a high DFS rate when using a modified AIDA protocol in which, in contrast to the original Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto protocol,8 ARA-C was omitted from consolidation.13 The low toxicity that was reported in the latter study suggests that an increase in treatment intensity could be proposed for the small fraction of APL patients who present at diagnosis with high-risk features. A high initial WBC count has emerged in all recent studies as the most important risk factor in APL,7,11,13,14 whereas the impact of other diagnostic characteristics, such as platelet count, coagulopathy, additional karyotypic aberrations, PML/RAR alpha isoform, and expression of the reciprocal RAR alpha/PML hybrid gene, is still uncertain.2-6,8-14 Another feature that potentially could be associated with poorer outcome in APL is slow kinetics of molecular remission, as recently reported by the Medical Research Council group14; the analysis of such a variable, however, requires laborious molecular monitoring, the means of which are not widely available and the results of which were not available at the time of diagnosis. Considering the subset with high initial WBC count, it is not yet clear which type of treatment intensification should be adopted in such a patient category. In fact, it is important to consider that patients with hyperleukocytotic APL are also at increased risk of early hemorrhagic death,14 which discourages the use of more aggressive therapy during induction and suggests, rather, the intensification of the postinduction phase. The identification of diagnostic features other than WBC count that have potentially independent prognostic value would considerably contribute to better designed risk-adapted protocols in APL. In this study, we corroborate the preliminary findings reported by Murray et al26 on the prognostic significance of CD56 expression in APL. Moreover, with respect to the above study, we provide two novel observations that seem relevant in the clinical setting: (1) the value of this marker as an indicator of poorer outcome is demonstrated also in patients receiving modern state-of-the-art treatment including simultaneous ATRA and anthracycline-containing chemotherapy, and (2) the prognostic significance of CD56 expression is retained in the multivariate analysis that includes WBC count and is, therefore, independent of this latter variable. Unlike Murray et al,26 we were unable to find significant correlation between CD56 expression and diagnostic features, although a trend toward increased incidence of the bcr3 PML/RAR alpha isoform was detected in our study for patients with CD56+ APL. As for the prognostic impact of bcr3 PML/RAR alpha fusion, the results of recent large multicenter trials that used ATRA and chemotherapy combinations did not confirm initial reports of a supposedly inferior outcome for patients with this PML/RAR alpha isoform.8,13,14 In the present series, the bcr3 PML/RAR alpha type had no influence on survival prediction in the univariate analysis, which suggests that the prognostic relevance of CD56 expression was not related to its association with bcr3. In addition, unlike Murray et al, we found no association between CD56 expression and CR rate. Such discrepancy might be explained by taking into account the significantly higher CR rate and, consequently, the limited number of events that were observed in the AIDA study during and after induction. With respect to WBC count, it is worth noting that in our study the percentage of patients with WBC counts of greater than 10 x 109 cells/L did not differ between CD56+ and CD56-APL subgroups, which indicates that the adverse prognostic effect of CD56 expression was not related to a higher WBC count at diagnosis. This latter evidence is further supported in this study by the results of the multivariate analysis, which showed the independent value of CD56 expression on patient survival. When our multicenter AIDA study began, no centralized immunophenotypic studies were planned and preference was given to centralized molecular studies because diagnosis could be confirmed at the genetic level in all enrolled patients. In addition, the realization of the importance of CD56 expression in acute leukemia is relatively recent, and not all laboratories routinely include this marker in the diagnostic characterization panel. We believe that the results presented here, though preliminary, should foster accurate research of CD56 expression in APL at diagnosis, which would allow the analysis of its prognostic significance in larger cohorts. Such extended analyses are overdue, especially in light of the overall low number of events that we currently observe in APL patients who are treated with the simultaneous ATRA/chemotherapy combination, with DFS estimates of more than 80% in recent studies.8,9,13 To explain the worse prognosis of CD56+ acute leukemia, different hypotheses have been postulated, including a greater incidence in these patients of extramedullary involvement and a correlation between CD56 expression and drug resistance.25,36-39 In our series, the low number of extramedullary relapses and lack of multidrug resistance markers evaluation did not allow us to test these hypotheses. Nonetheless, the biologic relationship between the expression of CD56 and other adhesion molecules and adverse clinical outcome in APL and AML remains a fascinating area for investigation.
Supported, in part, by Consiglio Nazionale delle Ricerche Progetto Finalizzato Biotecnologie; Ministero dell’Università e della Ricerca Scientifica e Tecnologica; and Associazione Italiana per la Ricerca sul Cancro, Rome, Italy.
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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
