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© 2001 American Society for Clinical Oncology Extramedullary Involvement at Relapse in Acute Promyelocytic Leukemia Patients Treated or Not With All-Trans Retinoic Acid: A Report by the Gruppo Italiano Malattie Ematologiche dell’AdultoByFrom the Department of Hematology, University of Bari, Bari; Dipartimento di Biotecnologie Cellulari ed Ematologia, Università "La Sapienza," and Ematologia, Università "Campus Bio-Medico," Rome; Divisione di Ematologia, Ospedale Ferrarotto, Catania; Divisione di Ematologia-Oncologia, Azienda Ospedale "Bianchi-Melacrino-Morelli," Reggio Calabria; and Divisione di Ematologia, Ospedale "A. Cardarelli," and Ematologia, "Università Federico II," Naples, Italy. Address reprint requests to G. Specchia, MD, Department of Hematology, University of Bari, Policlinico, Piazza G. Cesare 11, 70124 Bari, Italy; email: emadhba{at}cimedoc.uniba.it
PURPOSE: Recent reports of extramedullary disease (EMD) at recurrence in acute promyelocytic leukemia (APL) have raised increasing concern about a possible role of retinoic acid (RA) therapy. PATIENTS AND METHODS: We analyzed the risk of developing EMD localization at relapse in APL patients enrolled onto two consecutive studies of the Gruppo Italiano Malattie Ematologiche dell’Adulto. The studies investigated chemotherapy alone (LAP0389) versus RA plus chemotherapy (AIDA). RESULTS: When all relapse types were taken into account, 94 (51%) of 184 patients and 131 (18%) of 740 patients who attained hematologic remission underwent relapse in the LAP0389 and AIDA studies, respectively (P < .0001). EMD localization was documented in five (5%) of 94 and 16 (12%) of 131 patients (P = .08). Hematologic and/or molecular relapse was diagnosed concomitantly in all but two patients with EMD in the AIDA study. For patients in the LAP0389 and AIDA series, the probability of EMD localization of any type at relapse was 3% and 4.5%, respectively (P = .79), while the probability of CNS involvement was 0.6% and 2% (P = .28). No significant differences were found with regard to mean WBC count and promyelocytic leukemia/retinoic acid receptor-alpha junction type in comparisons of patients with EMD and hematologic relapse. CONCLUSION: APL patients receiving all-trans retinoic acid in addition to chemotherapy have no increased risk of developing EMD at relapse as compared with those treated with chemotherapy alone.
ACUTE PROMYELOCYTIC leukemia (APL) is a distinct subtype of acute myelogenous leukemia with specific clinical, morphologic, and genetic features.1-4 At the clinical level, the disease is characterized by frequent association with severe hemorrhagic diathesis and by a striking sensitivity to anthracyclines.5-7 In addition, APL cells show the unique property of undergoing terminal differentiation in vitro and in vivo under the action of retinoid derivatives such as all-trans retinoic acid (ATRA).1-3 As recently reported in several large multicenter studies, the front-line use of combined ATRA plus anthracycline chemotherapy results in long-term remission and potential cure in the majority of patients.8-14 However, despite this progress, treatment failure still occurs in approximately 30% of patients receiving such therapies, because of early death during induction or, more frequently, disease recurrence.15-17 The occurrence of extramedullary disease (EMD) at presentation or at relapse has long been considered a rare event in APL.18-21 Conversely, EMD localization is known to develop in a sizable proportion (3% to 8%) of acute myelogenous leukemias, being more frequently reported in patients with myelomonocytic and monocytic forms (M4 and M5 French-American-British subtypes).22,23 Following the advent of ATRA treatment, an increasing number of reports have been published on EMD localization in APL, particularly at the time of relapse,18,24-35 with the CNS and skin being described as the sites most frequently involved. While these findings may suggest a link between EMD and ATRA therapy, the real impact of this agent on EMD development in APL has remained unclear. In fact, only single cases or very small series were reported in the above publications, and to date no studies have been conducted addressing this issue in large, homogeneous series of patients treated with or without ATRA. In particular, it is not clear whether a true increment of EMD has occurred since the ATRA era or if, alternatively, more cases are being described as a consequence of an increased risk exposure, which in turn is due to prolonged survival of patients receiving modern ATRA-containing therapies. Finally, clinical and/or biologic factors potentially associated with EMD development in APL have not been investigated in detail. In the present study, we analyzed the frequency and clinicobiologic correlates of EMD involvement at relapse in APL. To investigate the possible role of ATRA, we compared the relapse pattern and estimated the risk of EMD localization at relapse in APL patients enrolled onto two consecutive studies of the Italian multicenter Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA). One study investigated chemotherapy alone (LAP0389 protocol, 267 patients), and the other studied ATRA plus chemotherapy (AIDA protocol, 790 patients).
APL Studies LAP0389 and AIDA-0493 Between March 1989 and December 1999, 1,057 newly diagnosed APL patients from 69 Italian institutions were treated according to the GIMEMA protocols LAP0389 (chemotherapy alone, n = 267) and LAP0493 or AIDA (ATRA plus chemotherapy, n = 790). For patients enrolled onto the LAP0389 study (from March 1989 to February 1993), the diagnosis was based on the morphocytochemical criteria established by the French-American-British group.36 In the successively adopted AIDA protocol (from April 1993 to December 1999), eligibility criteria for patient enrollment included mandatory cytogenetic or molecular demonstration (by reverse transcriptase [RT] polymerase chain reaction [PCR] of promyelocytic leukemia [PML]/retinoic acid receptor-alpha [RAR  ]) of the t(15,17) in leukemia cells. A flow chart detailing both protocol schedules is shown in Fig 1. Briefly, the LAP0389 study included an initial randomization for induction therapy comparing idarubicin versus idarubicin plus cytarabine and, after three polychemotherapy consolidation courses, a second randomization for maintenance, comparing low-dose chemotherapy versus observation.37 The AIDA protocol consisted of a single-arm induction with simultaneous ATRA and idarubicin, followed by the same three consolidation courses as in the LAP0389 and four randomization arms for maintenance (chemotherapy v ATRA v chemotherapy plus ATRA v observation), as previously reported.38 The main presenting features of patients enrolled onto both studies are listed in Table 1. Unlike LAP0389, the AIDA study also included pediatric patients, with 70 (9%) of 790 patients aged less than 15 years. At the time of the present analysis, the median potential follow-up was 2.7 years (range, 0 to 8.3 years) for patients enrolled onto LAP0389 and 1.7 years (range, 0 to 5.2 years) for patients enrolled onto the AIDA protocol.
Response Criteria Hematologic complete remission and hematologic relapse were defined according to the National Cancer Institute criteria.39 Molecular remission (assessed only in AIDA-0493) was defined as the absence on ethidium bromide–stained electrophoresis gel of the specific PML/RAR amplification band detected at diagnosis, in the presence of RNA integrity as evaluated by minigel visualization and successful amplification of the internal control. Molecular relapse (assessed only in AIDA-0493) was defined as conversion from PCR-negative to PCR-positive for PML/RAR at any time after consolidation, confirmed in two successive marrow samples collected 2 to 4 weeks apart. The RT-PCR protocol for PML/RAR amplification and the sensitivity of the assay have been reported in detail elsewhere.40
Diagnosis of EMD Localization at Relapse
Statistical Analysis
The results of treatment outcome in the two studies are reported in Table 2. Ninety-four (51%) of 184 and 131 (18%) of 740 assessable patients experienced disease recurrence (including all relapse types) in the LAP0389 and AIDA studies, respectively (P < .0001). For the AIDA study, the relapse group included 14 patients who received salvage therapy for molecular relapses as defined in a previous report.43 No patients in this latter group had EMD involvement at the time of molecular relapse. The majority of patients in the LAP0389 study were not regularly monitored by RT-PCR, and no molecular relapses are reported in the present analysis for this patient group.
The pattern of disease recurrence in the two studies is described in Table 3. For the vast majority of patients in both series, relapse was reported as being only hematologic. EMD involvement was reported in five (5%) of 94 relapses and 16 (12%) of 131 relapses in the LAP0389 and AIDA studies, respectively (P = .08), and the overall rate of recurrence with EMD localization was similar in the two studies (five of 184, or 2.7%, and 16 of 740, or 2.2%, respectively). The median time from the achievement of hematologic complete response to relapse of any type was 12.8 months in LAP0389 and 12.9 months in the AIDA study. The median time from hematologic complete response to relapse with EMD involvement was 19.5 months in LAP0389 and 12.1 months in the AIDA (P = .1).
The sites of EMD involvement in the two series are listed in Table 4. Of the five relapses with EMD localization in the LAP0389 study, one occurred in the CNS and four occurred in other sites (three in the skin and one in the middle ear). Of the 16 EMD relapses in the AIDA study, 10 involved the CNS and six involved other extramedullary sites (three in the skin, two in the middle ear, and one in the lung). The proportion of CNS disease at relapse was significantly higher in the AIDA (10 of 131, or 8%) than in the LAP0389 study (one of 94, or 1%, P = .02), while the proportion of EMD in sites other than the CNS was similar in the two studies (Table 3). The Kaplan and Meier estimated probability of relapse with EMD involvement (including all localization types) was 3% and 4.5% for patients in the LAP0389 and AIDA studies, respectively (P = .79, Fig 2). The estimated probability of relapse with CNS localization was 0.6% and 2% in the LAP0389 and AIDA studies, respectively (P = .28) .
Bone marrow involvement was documented at the morphologic level in the majority of cases (14 of 21) simultaneously with EMD localization. Seven patients had isolated EMD localization at relapse while in hematologic remission (no evidence of disease in the marrow at the morphologic level). Of these seven patients, five tested PCR-positive and two tested PCR-negative for PML/RAR in the marrow at the time of EMD recurrence. The mean WBC count at presentation was 20.5 x 109/L for patients undergoing hematologic relapse versus 28.5 x 109/L for patients who had EMD with or without hematologic relapse (P = .31).
The incidence of the ATRA syndrome and type of PML breakpoint were evaluated for patients in the AIDA study. ATRA syndrome was documented in 11 (8%) of 131 relapsed patients, all of whom had only hematologic involvement at relapse. No statistically significant association was found between the PML/RAR
Patients with EMD were treated with heterogeneous protocols in the distinct GIMEMA institutions. Nineteen (90%) of 21 achieved second remission. Overall survival in patients with EMD localization at relapse was comparable to that of patients who relapsed at the hematologic level only (data not shown).
This study shows that EMD localization at relapse is infrequently observed in APL and that patients receiving ATRA plus chemotherapy (AIDA protocol) have a similar risk of undergoing relapse with EMD involvement as compared with patients treated with chemotherapy alone. However, our data point to a different pattern of EMD localization in the two cohorts, with a higher prevalence of CNS involvement at relapse in patients receiving ATRA. CNS involvement in APL is usually suspected on the basis of clinical symptoms and signs which may (or may not) lead to a lumbar puncture and examination of CNS fluid. Thus, rather than being objectively assessed by routine lumbar puncture (a procedure commonly avoided in APL patients in view of the associated hemorrhagic diathesis), the identification of CNS localization depends largely on subjective clinical judgment. It is conceivable that, in recent years, improvements in the control of coagulopathy and increased awareness of the CNS as a potential site of disease localization may have contributed to more frequent diagnoses of CNS leukemia involvement. The CNS disease localization had also been reported to occur, although rarely, in the pre-ATRA era and may therefore represent a possible (although unusual) evolution in the natural history of the disease.18-20 With the advent of ATRA and following its introduction in modern combination schedules with chemotherapy, a substantially higher fraction of patients who achieve long-term remission are at risk of developing CNS relapse, as compared with patients who were treated in the past with chemotherapy alone. Therefore, here we estimated the probability of EMD and CNS relapse by censoring patients who developed other unrelated events, including relapse at the hematologic level only. The results showed no significantly increased risk of CNS involvement for patients in the AIDA group, who had received ATRA. We show here that EMD (including CNS involvement) is accompanied in the vast majority of cases by disease recurrence in the marrow (detected morphologically or by RT-PCR). These data indicate that EMD recurrence should be regarded and managed as a systemic disease. On the other hand, it may be hypothesized that at least some patients whose relapse is detected in the marrow only could simultaneously present other subclinical disease localizations, including CNS leukemia. Several authors have hypothesized that biologic mechanisms mediated by ATRA, such as increased expression of certain adhesion molecules (eg, CD11c, CD13 and CD56), may facilitate leukemic infiltration in the CNS.44-47 Unfortunately, in only a few cases of the present series were CD11c and CD56 included in the diagnostic immunophenotypic characterization panel, and appropriate studies are warranted to analyze whether any of the above markers are associated with development of CNS infiltration. Others have proposed a possible link between EMD localization and hemorrhages, including those caused by venous catheterism or marrow biopsy, which may lead to skin infiltration by leukemic cells and subsequent development of EMD.29 In our experience, this was not the case. None of the skin relapses was at the site of previous subcutaneous bleeding. As to the suggested association of CNS disease and ATRA syndrome,30 we did not find confirmation of this correlation in our series. In conclusion, our study indicates that APL patients receiving ATRA in addition to chemotherapy have no increased risk of developing EMD at relapse as compared with APL patients treated with chemotherapy alone. However, a more extensive initial characterization of leukemia cells seems required to identify features potentially associated with the infrequent EMD localization in APL.
Supported by a research grant from Ministero dell’Università e della Ricerca Scientifica e Technologica.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 or Fisher’s exact test was used to compare categories. Student’s t test was performed for comparison of means. The probability of relapse with EMD localization (measured from the date of hematologic remission to that of diagnosis of relapse with EMD involvement) was calculated according to the Kaplan-Meier method.
