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CD56 Expression in Acute Promyelocytic Leukemia: A Possible Indicator of Poor Treatment Outcome?

From Walter Reed Army Medical Center, Washington, DC; The University of Texas M.D. Anderson Cancer Center, Houston, TX; Montefiore/Albert Einstein Cancer Center, Bronx, NY; Eastern Cooperative Oncology Group, Brookline, MA; and Duke University Medical Center, Durham, NC.

Address reprint requests to John C. Byrd, MD, Hematology-Oncology Service, Ward 78, Walter Reed Army Medical Center, Washington, DC 20307; Email john_c.byrd{at}wrammaa.chcs .amedd.army.mil

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: Blast expression of CD56 is frequent in patients with t(8;21)(q22;q22) acute myeloid leukemia and is associated with an inferior outcome. The expression of CD56 has rarely been reported in acute promyelocytic leukemia (APL) and has not been clinically characterized. Therefore, we examined the prognostic significance of CD56 expression in APL.

PATIENTS AND METHODS: We identified all reported cases of CD56⁺ APL in the medical literature and collected clinical, biologic, and therapeutic details.

RESULTS: Data were obtained for 12 patients with CD56⁺ APL (> 20% blast expression of CD56), including four cases from a single institution with a total of 42 APL patients. All of the CD56⁺ APL patients had documented cytogenetic presence of t(15;17), and of the nine reported isotypes, eight (89%) were S-isoform. Only six CD56⁺ patients (50%) attained complete remission (CR); the other six individuals died within 35 days of presentation. Of the six patients who attained a CR, three (50%) relapsed at 111, 121, and 155 weeks, whereas three remained in continuous CR at 19, 90, and 109 weeks. Comparison of the control CD56^- to CD56⁺ APL patients demonstrated that the latter group had a significantly lower fibrinogen level (P = .007), and among patients for whom data were available, there was a higher frequency of the S-isoform (P = .006). Additionally, the CR rate (50% v 84%, P = .025) and overall median survival (5 v 232 weeks; P = .019) were significantly inferior for CD56⁺ APL patients.

CONCLUSION: CD56⁺ acute promyelocytic leukemia is infrequent, seems to occur more frequently with the S-isoform subtype, and may be associated with a lower CR rate and inferior overall survival.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
ACUTE PROMYELOCYTIC LEUKEMIA (APL) is a form of leukemia that is highly curable with molecularly targeted therapy.^1,2 Acute promyelocytic leukemia exhibits the translocation of the retinoic acid receptor alpha (RARa) gene on chromosome 17 with the promyelocytic leukemia (PML) gene on chromosome 15.^3-6 Approximately 65% to 80% of patients with APL have a complete remission (CR) after treatment with a combination of standard chemotherapy and/or all-trans-retinoic acid (ATRA).^7-9 However, early mortality and treatment failures do occur, and salvage therapy is currently inadequate.^1,7 Furthermore, approximately 10% to 20% of patients with APL die either before or during induction therapy as a result of bleeding disorders from disease-related disseminated intravascular coagulation.^7,10

Currently identified risk factors for poor prognosis in patients with APL include initial laboratory abnormalities, such as concurrent high peripheral leukocyte count and low platelet count.¹¹ In addition, the S-isoform (also known as the bcr3, "short," or type "A" isoform of the PML-RARa transcript) has been found to be associated with an increased incidence of early death or relapse and a shortened disease-free survival duration in some, but not all, series.^12-17 Furthermore, it is important to acknowledge that prognostic factors identified before the introduction of ATRA may no longer be of clinical significance. Identifying pretreatment features that predict outcome in patients with APL might allow for treatment stratification based upon risk factors.

The immunophenotype of APL is considered to be highly specific for blast expression of CD9⁺, CD33⁺, and CD13⁺ and absence of HLA-DR^-, CD34^-, CD11b^-, and CD15^-.^1,18,19 Blast expression of CD56, a neural-cell adhesion molecule, has been reported only rarely in APL.^20-27 CD56 has been described in plasma cell malignancies and acute leukemias, including acute myeloid leukemia and a myeloid/natural-killer cell acute leukemia.^28-32 Although CD56 has been reported to be associated with multidrug resistance and inferior outcomes in patients with t(8;21)(q22;q22) acute myeloid leukemia (AML),³³ its significance in APL is uncertain.

Given the rarity of CD56 expression with APL and its association with poorer outcomes in other favorable groups of AMLs, we investigated the impact of CD56 expression on treatment outcomes in patients with APL. Our retrospective findings suggest that CD56 expression may be an important pretreatment variable in APL patients. However, these results are preliminary and mandate confirmation in large prospective studies.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients
Using the MEDLINE database, we reviewed the reports on CD56⁺ APL patients in the medical literature published between January 1990 and September 1997. We contacted the authors for details on their institution's CD56⁺ APL patients. We obtained information on 12 cases: one from Walter Reed Army Medical Center, four from the University of Texas M.D. Anderson Cancer Center,²⁰ one from Duke University Medical Center,²¹ and six from Montefiore/Albert Einstein Cancer Center²² and the Eastern Cooperative Oncology Group. The University of Texas M.D. Anderson Cancer Center's experience with APL, dating back to 1990, provided the control cohort. During this time period, CD56 expression was examined in all APL patients.

Data Collection
Data collected for CD56⁺ and CD56^- APL patients included pretherapy clinical features, laboratory parameters, molecular features, and treatment outcome. Pretherapy clinical features included age, sex, race, evidence of bleeding, extramedullary leukemia, infection, and fever. Molecular features noted before therapy included the percentage of blasts and promyelocytic cells expressing CD56, cytogenetics, and PML isoform type. Pretherapy laboratory parameters included initial leukocyte and platelet counts and initial fibrinogen level. Data related to treatment included type of induction, consolidation, and relapse therapy. For deceased patients, the cause of death was obtained, when available.

Criteria for Response and Definition of Relapse
Definitions of CR and relapse were consistent with the criteria of the National Cancer Institute–sponsored workshop on AML.³⁴ Complete remission duration was measured from the date of attainment of CR to the date of either relapse or death while still in CR. Censoring was performed at the time of last follow-up for patients alive and in CR. Survival was measured from the date of enrollment in treatment to the date of death. Censoring was performed at the time of last follow-up for patients who were still alive.

Statistical Analysis
Univariate analysis of categorical variables comparing CD56^- and CD56⁺ APL patients was performed with the use of Fisher's exact test.³⁵ Continuous variables were compared with the Wilcoxon rank sum test. Time-to-event analyses were performed using Kaplan-Meier curves and the log-rank test.³⁶ The level of significance was .05 for all analyses, and all tests were two-sided. The small number of events precluded adjustment for other factors that might be associated with outcomes.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Literature Review
Several articles described the association of CD56⁺ immunophenotype and AML-M3, yielding a total of 12 CD56⁺ APL patients.^20-27 Twelve cases were obtained for analysis after discussion with the authors: one from Walter Reed Army Medical Center, four from the University of Texas M.D. Anderson Cancer Center,²⁰ one from Duke University Medical Center,²¹ and six from Montefiore/Albert Einstein Cancer Center²² and the Eastern Cooperative Oncology Group. In addition, the University of Texas M.D. Anderson Cancer Center provided their institutional experience since 1990 with APL, which included a total of 42 APL patients (38 CD56^- and four CD56⁺).

Clinical Features
The clinical features of the CD56⁺ and CD56^- APL patients included in this study are listed in Table 1. The median age of the 12 CD56⁺ APL patients was 39 years (range, 23 to 80 years). Seventy-five percent of the patients were women. Seven patients (58%) were white, three (25%) were black, and two (17%) were Hispanic. Two patients (17%) had documented infections, one with sepsis and the other with pneumonia. Four patients (33%) presented with fever, and eight (67%) had clinically significant bleeding.

Pretherapy laboratory parameters of the CD56⁺ APL patients included a median leukocyte count of 4.6 (range, 1 to 136) x 10⁹/L, with five patients having WBC of more than 50 x 10⁹/L, a median platelet count of 32 (range, 12 to 159) x 10⁹/L, and a median fibrinogen level of 119 (range, 65 to 300) mg/dL.

Molecular features noted before therapy included blast and promyelocytic expression of CD56 that varied from 24% to 100% (median, 54%). All of the CD56⁺ APL patients had documented cytogenetic presence of t(15;17). Of the nine patients (75%) for whom isoforms were reported, eight (89%) had the S-isoform. The other patient had the L-isoform.

Therapy varied considerably among the patients but included standard AML chemotherapy (n = 2), ATRA combined with AML chemotherapy (n = 5), or ATRA alone (n = 3) during induction or consolidation. Two patients died before the initiation of chemotherapy or ATRA. The results of initial induction therapy for CD56⁺ APL patients were unsatisfactory, with only six patients (50%) attaining a CR. Of the six patients not attaining a CR, all died within 35 days of presentation as a consequence of intracerebral hemorrhage (n = 3), stroke (n = 1), cardiac arrest (n = 1), or pulmonary hemorrhage (n = 1). Three of the patients not attaining a CR had received ATRA, and in no case was there evidence of resistant disease. Of the six patients who attained a CR, three (50%) relapsed at 111, 121, and 155 weeks. Of the patients relapsing, two had received therapy that included ATRA. Three patients with CD56⁺ APL remained in continuous CR at 19, 90, and 109 weeks.

To assess whether CD56⁺ APL had distinct clinical, molecular, or therapeutic outcomes, we compared the 12 CD56⁺ APL patients to a cohort of CD56^- APL patients identified from the 38 cases of CD56^- APL provided by the University of Texas M.D. Anderson Cancer Center. Table 1 lists the total number of patients evaluated and total number of missing data points. The data demonstrated a statistically lower pretherapy fibrinogen level (P = .007). There was also an increased association with the S-isoform in the CD56⁺ APL patients (P = .006). Six (50%) of the 12 CD56⁺ APL patients, in comparison to 32 (84%) of the 38 CD56^- APL patients, attained a CR (P = .025). As demonstrated in Fig 1, overall survival time was significantly shorter (P = .019) in the CD56⁺ APL patients, with a median survival time of 5 weeks, as compared with a median of 232 weeks in the CD56^- APL patients.

View larger version (12K): [in this window] [in a new window]   Fig 1. Survival duration for APL patients with (n = 12) and without (n = 38) expression of CD56.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
APL is characterized by PML-RARa molecular aberrance and often is effectively treated with ATRA and chemotherapy.^1,7-9,37-39 Despite the recent success observed with the combination of ATRA therapy and standard chemotherapy, 10% to 20% of patients experience early death, and 10% to 20% have a relapse.^7,10 To our knowledge, we are the first investigators to describe the clinical significance of CD56⁺ as a possible indicator of adverse outcome in APL. The data suggest that blast and promyelocytic expression of CD56⁺ in APL patients is associated with initially lower fibrinogen levels and the S-isoform. In our study, clinical outcomes included a lower CR rate and inferior overall survival duration.

Pretreatment characteristics that have been reported in previous studies to predict poor outcomes in APL include initially elevated leukocyte count, low platelet count, and S-isoform.^11-17 In our study, we were unable to delineate CD56⁺ expression and its association with adverse outcome with adjustments for WBC and platelets, owing to the small sample size. Therefore, our data should be viewed as preliminary. It has also been proposed in some series, but not all,^12-17 that the S-isoform PML-RARa transcript is associated with an increased incidence of early death, relapse, and a shortened duration of disease-free survival in APL patients. In two studies of APL patients, 20 (36%) of 56 patients and 17 (33%) of 52 patients with PML-RARa had the S-isoform.^12,14 Even though information on the isoform was not available for our entire control cohort, only two of 11 CD56^- APL patients (18%) had the S-isoform. In contrast, 89% of CD56⁺ APL patients had the S-isoform. The difference between the CD56^- and CD56⁺ APL patients was statistically significant, suggesting a possible association between CD56 and the S-isoform. If our data are confirmed, variable expression of CD56 in the different studies of S-isoforms might account for the differences in outcome observed.^12-17

CD56 expression is a rare phenomenon in lymphoid malignancies. It is generally associated with monocytic morphology and the cytogenetic abnormalities t(8;21)(q22;q22) or trisomy 8.³³ In patients with CD56⁺ t(8;21)(q22;q22) AML, CR duration and overall survival have been noted to be significantly shorter than in CD56^- patients. CD56 expression has also been associated with a myeloid/natural-killer cell form of acute leukemia in 20 patients with a morphology similar to that of APL, especially the M3 microgranular variant.³¹ The myeloid/natural-killer cell leukemia presents with bleeding diatheses similar to those occurring in APL; however, cytogenetic evidence of t(15;17) is absent, and response to ATRA does not occur.³¹ Another CD7⁺CD56⁺ myeloid/natural-killer cell precursor acute leukemia has been described.³² Initial response to standard chemotherapy was favorable; however, all seven patients died within 41 months of presentation.³² CD56 appears to be a marker for poor clinical outcome in certain acute leukemias and may have an impact on stratification of patients' responses to therapy.

Limitations of this study include the selection bias of obtaining patients from numerous institutions with varying approaches to reporting, treating, and managing the side effects associated with AML therapy. In addition, the S-isoform data were available for only 11 of the 38 CD56^- APL patients. Our data also did not report whether our patients had the microgranular variant of APL, which may have a worse prognosis; this aspect should also be evaluated in future prospective studies.¹ The data were obtained in a retrospective manner with certain biases associated with data collection. Given the rarity of CD56⁺ and the size of our sample, conclusions from this article should be interpreted as preliminary.

Given the risk of early mortality and the rate of relapse of APL, prognostic indicators would be beneficial for stratifying patients on the basis of risk factors. Our data suggest CD56 as one such indicator in APL. Examination of CD56 in the recently completed intergroup study⁷ and in future APL studies may further clarify the frequency and clinical significance of this cell surface adhesion antigen in APL.

	NOTES

 
The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the US Army or Department of Defense.

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Submitted February 23, 1998; accepted September 21, 1998.

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