Extramedullary blast crisis in chronic myeloid leukemia

Lrukmiu Rtxarch Vol. 20, tie. 11/l?, pp. 905-908. 1996. Copyright 0 1996 Fhevier Science Ud. All rights reserved Prided in Great Britain 014%2124m flS.00 + 0.00

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EXTRAMEDULLARY

BLAST CRISIS IN CHRONIC MYELOID LEUKEMIA

Giorgina Specchia, Gaetano Palumbo, Domenico Pastore, Donata Mininni, Anna Mestice and Vincenzo Liso Departmentof Hematology, University of Bari, Bari, Italy (Received 23 February 1996.Accepted 14 May 1996). Abstract-Among 235 patients with CML we reviewed 91 patients with BC diagnosed between 1980 and 1995; 15 of the 91 (18%) developed extramedullary disease (EMD). The sites involved were the lymph nodes (13/15), CNS (l/15) and suborbital mass (l/15). The appearance of EMD was associated with chronic phase (CP) features in the bone marrow in 3/15 cases, with accelerated phase (AP) in 3/15 and with BC in 905. 1 l/15 (73%) cases of EMD were classified as myeloid (My-EMD) and 4/15 as lymphoid-type (Ly-EMD): three B-phenotype and one Tphenotype. All Ly-EMD cases were treated with vincristine, daunorubicin and prednisone and obtained complete remission (CR). Cases of My-EMD were treated with daunorubicin and cytosine arabinoside, of which only l/l 1 achieved CR. We suggest that in EMD also, the type, lymphoid or myeloid, of BC has a bearing on treatment response and prognosis: Ly-EMD is more responsive to treatment and has longer survival than My-EMD. Copyright 0 1996 Elsevier Science Ltd Key words: Chronic

myeloid

leukemia,

blast crisis, extramedullary

disease.

poor prognosis in comparison with other types of BC. The present study reports a retrospective analysis of our series of 15 CML patients with EMD carried out to evaluate the outcome of CML-BC EMD in our institution.

Introduction Chronic myeloid leukemia (CML) is a clonal disorder of the pluripotent hematopoietic stem cell characterized by an initial chronic phase (CP), usually lasting between 2 and 5 years, followed by an accelerated phase (AP) and a blast crisis (BC) [l]. On the basis of morphological and immunological studies, the blasts of the majority of CMLBC are recognized as myeloid (My-BC), whereas 15-20% of CML-BC show lymphoid characteristics (Ly-BC) [2,3]. In some patients (less than lo%), the CML-BC presents as an extramedullary disease (EMD) as blast proliferation develops in other organs rather than the bone marrow [4]. Very few studies on the incidence, evolution and prognostic significance of EMD-BC have been made in a large series of CML patients [4-141; the results of these studies suggest that CML with EMD-BC has a

Materials and Methods We reviewed 91 patients with CML-BC from a total of 235 CML cases diagnosed between 1980 and 1995 in our institution (77 with My-BC and 14 with Ly-BC); the diagnosis of BC was based on the presence of one of the following criteria: blasts 2 30% in peripheral blood and/ or in bone marrow, proliferation of blasts in other organs: CNS, lymph nodes, skin, etc. (EMD-BC) [2]. Fifteen patients (16% of patients in BC) developed EMD-BC, diagnosed on the basis of biopsy of the involved organs with morphocytochemical and immunophenotypical investigation of the blast cells [15]. In addition to clinical and laboratory features, bone marrow and peripheral blood slides, both at diagnosis and at the time of development of EMD-BC, were available in all cases. Cytogenetic and BCR breakpoint analyses with RT-PCR were performed in lymph node samples from three patients and in cerebrospinal fluid (CSF) from one patient. Complete remission (CR) was defined as complete

Abbreviations: CML, chronic myeloid leukemia; EMD, extramedullary disease;BC, blast crisis; CP, chronic phase; AZ’, accelerated phase; My, myeloid; Ly, lymphoid; CR, complete remission. Correspndence to: Dr Giorgina Specehia, Department of Hematology, University of Bari, Policlinico, Piazza G. Cesare, 11, 70124 Bari, Italy. 905

G. Specchiaet al.

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Table 1. Clinical and hematological characteristicsof 15 CML patients with extramedullary disease(EMD) Age median (range) Sex (m/f) WBC x lO”/l median (range) Hh g/d1 median (range) Plt x lO”/l median (range) Therapy of CP conventional chemotherapy IFN BMT

44 (19-65) 916 105 (4-204) 9.2 (6.6-13.7) 276 (12-1975)

11 (9 HU-2 BU) 3

1

Bone marrow at time of EMD CP AP BC Median time (months) from diagnosis of CML to onset of EMD (range)

3 3 9 24 (l-105)

HU: hydroxyurea; BU: busulphan; IFN: interferon alfa-2b; BMT: allogeneic bone marrow transplantation; CP: chronic phase;AP: acceleratedphase; BC: blast crisis.

clearance of blasts from peripheral blood and restoration of CP (with less than 5% of blasts in the marrow), together with complete disappearance of extramedullary involvement [2].

Results The clinical and hematological data of the 15 CML patients at the time of EMD-BC are summarized in Table 1. The median age was 44 years (range 19-65 years) and 9/15 patients were male. Prior to EMD-BC, 11 patients had been treated with conventional chemotherapy (hydroxyurea or busulphan) and three with

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interferon cl-2b (IFN). Allogeneic bone marrow transplantation (BMT) had been performed in one patient 31 months before the diagnosis of EMD. The sites of EMD were: lymph nodes (13/15); CNS (l/15); and suborbital mass (l/15). The cytological features of the bone marrow indicated CP in 3115 cases, AP in 3/15 and BC in 9/15. The median time from CML diagnosis to observation of EMD was 24 months (range l-105 months). There were 11/15 (73%) cases of EMDBC classified as myeloid-type, based on the morphologica, cytochemical (perox+) and phenotypic (CD13+/ CD33+) features (My-EMD). In 4/15, extramedullary findings showed lymphoid blasts: three B-phenotype (CD19+/CDlO+); and one T-phenotype (CD3+/CD7+) (Ly-EMD) (Table 2). Cytogenetic and molecular analyses were performed on the bioptic specimens (lymph nodes) from three patients and CSF from one patient. These cell samples, characterized by more than 90% blasts, showed the same presence of the M-BCR rearrangement as was observed in the bone marrow (Fig. 1). Of the four patients with Ly-EMD-BC, simultaneous bone marrow and lymph node involvement was observed in two; in another there was CNS involvement together with the bone marrow and lymph nodes while the last, whose bone marrow was in CP at the onset of Ly-EMD, had lymph node involvement only. All patients were treated with vincristine, prednisone and daunorubicin and CR was achieved in 414 with median duration of 6 months (range 2-12 months) (Table 2). The 11 cases of My-EMD-BC were treated with daunorubicin and cytosine arabinoside and three of these also received radiotherapy to the involved sites: l/11 patients achieved CR with a duration of 22 months (Table 2).

6 7

1’ 2’ 3’ 4’ 5’ 6’

bJa2.-... b2:a2-

Fig. 1. PCR analysis for detection of BCR-ABL fusion mRNA from two patients with EMD-BC. Lane 1: positive ccantrol; lanes 2 and 3: bone marrow and CSF mRNAs of a patient with b2a2 rearrangement;lanes 4 and 5: bone marrow and lymph ncbdemRNAs of a patient with b3a2 rearrangement;lanes 6 and 7: negative controls; lanes l’- 5’: analysis of c-abl.

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Extramedullary blast crisis in CML Table 2. Treatment, response and survival of CML patients with EMD EMD-BC MY B-Ly T-Ly

type 11(73%) 3 (20%) 1(7%)

Treatment ARA-C/daunorubicin (My-BC) VCR/PRD/daunorubicin (Ly-BC) Response CR F

11(73%) 4 (27%) 5 (33%): 4 Ly-1 My 10 (67%): 10 My

CR duration median (range) Overall survival (range) Total Ly-EMD My-EMD

8 months (2-22) 8 months (1-31) 15 months (4-49+) 6 months (1-31)

EMD-BC: extramedullary disease blast crisis; My: myeloid; Ly: lymphoid; ARA-C: cytosine arabinoside; VCR: vincristine; PRD: prednisone; CR: complete response; F: failure.

Median survival was 15 months (range 4-49t) in the Ly group and 6 months (range 1-31) in the My group (Table 2). Discussion CML-BC constitutes the most malignant form of leukemia because, despite its ‘morphological’ similarity to de novo acute leukemia, it has a poor response to therapy [2, 13, 161. In the last 10 years some individual cases of EMD-BC have been. reported in the literature [17-271 and a few studies of series of CML ranging from 3 to 24 patients [4-141. In accordance with previous reports [ll, 121 the incidence of CML-EMD in our series was 6% (15/235), the most frequent site being the lymph nodes (13/15). Several studies have reported that, in most cases, at the time of the EMD, the bone marrow is still in CP and have stressed the difficulty in distinguishing whether this BC is due to CML or lymphoproliferative disease [17,23, 25,271. But cytogenetic and molecular investigations made in some of these cases confirm the similarity of the lymph node cell alterations with those in the bone marrow. Our study shows that EMD-BC developed into Ly-BC more often than into My-BC: 4/14 (28%) and 11/77 (14%) respectively. However, Ly-EMD-BC had a better prognosis than My-BC; 4/4 Ly-EMD-BC achieved CR and median survival was 15 months versus only 6 months in My-EMD-BC (Table 2). Our study confirms that EMD-BC is a rare event in the course of CML. The reported studies concerning the

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