Ann Hematol (1992) 65:143-146
Hematology 9 Springer-Verlag 1992
Secondary acute lymphoblastic leukemia with t (4; 11): Report o n two cases and review o f the literature E. Auxenfants, P. Morel, J.L. Lai, C~ Sartiaux, L. Detourmignies, F. Bauters, and P. Fenaux Service des Maladies du Sang and Service de Cytog6n6tique, C.H.U. 59037 Lille, France Received April 10, 1992/Accepted July 7, 1992
Summary. We report two cases of secondary acute lymphoblastic leukemia (ALL) with t (4; 11) (q21; q23) translocation occurring after chemotherapy and radiotherapy for a prior cancer. Seven previously published cases of secondary A L L with t (4; 11) (q21; q23) are also reviewed. Most patients had received a combination of topoisomerase II inhibitors (anthracyclines, mitoxantrone, or the epipodophillotoxin derivatives VP 16 or VM 26) and cyclophosphamide, which have also been implicated in the pathogenesis of secondary acute myeloid leukemia (AML) with 11 q23 rearrangements. These observations give further support to the existence o f a subgroup of secondary acute leukemias with cytogenetic findings "specific" for de novo A L L and AML, especially those with translocations involving the 11 q23 region. Key words: Acute lymphoblastic leukemia - Chromosomal abnormalities - Secondary leukemia
Introduction Most cases o f secondary leukemias (occurring after chemo- or radiotherapy for a prior cancer) are acute myeloid leukemias (AML). They are often preceded by a myelodysplastic phase and are associated with rearrangements of chromosomes 5 and/or 7 [18,24]. Recently, Pedersen Bjergaard et al. [23, 25] and other groups [1, 9, 10, 14, 27, 33] showed that a small subset of secondary A M L had a karyotype "specific" for de novo AML. In this subset, although some cases with t (8;21) t (15; 17), or inv (16) were found [9, 19, 14], the majority of patients had balanced translocations between the 11 q23 region and another chromosome. Those patients had generally received topoisomerase II-directed agents (i.e., the epipodophillotoxins VP 16 or VM 26 and, to a lesser extent,
Correspondence to: P. Fenaux, Service des Maladies du Sang, C.H.U. 1, Place de Verdun, Lille 59037, France
anthracyclines or derivatives) for a previous cancer [1, 23, 25, 27, 33]. Acute lymphoblastic leukemia (ALL) generally occurs without any known etiological agent, and cases of A L L occurring after exposure to chemotherapy or radiotherapy are very rare, accounting for only about 6~ of all cases of secondary acute leukemias . Among ALL, cases associated with t (4; 11) (q21; q23) translocation are usually characterized by their occurrence in infancy or early childhood, by organomegaly, a high white blood cell (WBC) count at diagnosis, and poor prognosis . Approximately 150 cases o f A L L with t (4; 11) have been reported so far . Nine of them occurred in patients previously exposed to carcinogens, including seven patients who had received therapy for a prior cancer and two patients who had a history of occupational exposure to carcinogens [2, 3, 8, 15, 17, 21, 30, 32]. From 1982 to 1991, cytogenetic analysis was performed at diagnosis at our institution in 297 cases of ALL. Ten o f them (3.3070) had t (4; 11) (q21; q23) translocation, including two patients who had previously received chemo- and radiotherapy for a prior cancer. We report those two cases and review previously reported cases of A L L with t (4, 11) occurring after chemo- and/or radiotherapy for a prior cancer.
Case reports Case 1
A 56-year-old woman was admitted to our department in August 1990. Nine months before, bilateral breast carcinoma had been diagnosed, and the patient underwent bilateral mastectomy followed by chemotherapy with cyclophosphamide, mitoxantrone, and 5 fluorouracil (5 FU) for 5 months. Cumulative doses (c.d.) were 2900 mg/m 2, 43 mg/m z, and 2900 mg/m 2, respectively. Adjuvant radiotherapy (40 Gy on the right breast; 48 Gy on the right nodal areas; 12 Gy on the left breast; 13 Gy on the left nodal areas) was administered. Upon admission, clinical examination was normal. The WBC count was 59.5 • 109/1 (77~ blasts), hemoglobin concentration was 10.4 g/100 ml, and the platelet count was 43 x 109/1. Disseminated intravascular coagulation was present. Bone marrow
144 smears showed 95% blasts wkh cytological features of lymphoblasts (L 1 according to FAB criteria) , which were peroxidase negative. The patient received antileukemic chemotherapy with mitoxantrone, cytosine arabinoside, prednisolone, and vincristine. Complete remission was achieved 1 month later. Intensive consolidation with prednisolone, cytosine arabinoside, mitoxantrone, and etoposide was administered in October 1990, but the patient died of sepsis during the following phase of aplasia, in November 1990.
Case 2 A 60-year-old man was admitted to our department in December 1990. He had a history of small cell carcinoma of the lung (T1 N1 M~), diagnosed in March 1989 and treated with chemotherapy: adriamycin (c.d. 200 mg/mZ), cyclophosphamide(c.d. 4000 rag/m2), vincristine (c.d. 0.9 mg/m2), VP16 (c.d. 2900 mg/m2) and C.C.N.U. (c.d. 460 mg/m2), followed by chest and lumbar radiotherapy (60 Gy and 39 Gy, respectively). Treatment was stopped in July 1990. Upon admission, clinical examination was normal. The WBC count was 64.4• (85% blasts), hemoglobin concentration 10.6 g/100 ml, and the platelet count was 72• 109/1. Bone marrow smears showed 90% blasts with cytological features of lymphoblasts (L2), which were peroxidase negative. The patient received induction chemotherapy with rubidazone, cyclophosphamide, vincristine, asparaginase, and prednisolone, but he died in aplasia, of sepsis, on day 19 of treatment.
Immunologic study Bone marrow cells were obtained at the time of diagnosis of A L L and prepared by Ficoll/Hypaque density gradient centrifugation. I m m u n o p h e n o t y p n g was performed using flow cytometric analysis of fresh cells in suspension. Monoclonal antibodies used for immunofluorescent stainings are listed in Table 1 . Cell surface antigens were considered positive if they were expressed in 25% or more of the blast cells.
Cytogenetic study Bone marrow cells were analyzed after a 24-h unstimulated culture, using R and G banding. Chromosomes were classified according to the International System for Cytogenetic Nomenclature .
Immunological studies are summarized in Table 1. Blasts were of B-lineage in both cases, as shown by the expression of CD 19, while CD 10 was not expressed. Myeloid antigens were also expressed in case 1. Karyotypic findings at diagnosis are shown in Table 2. A t (4; 11) (q21;q23) translocation was present in both cases. An isochromosome of the long arm of chromosome 7 (i (7q)) was also present in case 2.
Seven cases of A L L with t (4; 11) (q21; q23) occurring after chemo- or radiotherapy for a prior cancer have previously
Table 1. Immunologic studies
CD 2 CD 4 CD 5 CD 7 CD 8 CD 10 (CALLA) CD llB CD 13 CD 14 CD 15 CD 19 CD 24 CD 34 HLA DR
18 ND 14 11 ND 17 32 87 13 57 53 16 23 85
2 1 1 2 1 6 13 13 7 45 72 2 4 92
Table 2. Cytogenetic findings
Case 1 Case 2
No. of mitoses
16 8 16
46,XX, t (4; 11) (q21;q23) 46,XY,t (4;11) (q21;q23), i (7q) 46, XY
been reported [2, 3, 8, 15, 17, 21, 30], and their characteristics are summarized in Table 3. Two cases of A L L with t (4; 11) (q21;q23) occurring after occupational exposure to benzene  and X-rays , respectively, have also been reported. The incidence of carcinogen-related cases in A L L with t (4;11) thus appears to be low, as approximately 150 cases of A L L with t (4; 11) have been reported . In our series of A L L with t (4; 11), secondary cases accounted for two of ten cases. If one adds our patients to previously reported cases of A L L with t (4; 11) occurring after radio or chemotherapy, the prior cancer was a solid tumor in six patients and Hodgkin's disease in the three remaining cases (Table 3). Six of the nine patients were adults aged more than 30 years, as opposed to de novo cases of A L L with t (4; 11), which occur in young children or infants in 80% of cases [28, 29]. Eight of the nine patients had received adriamycin (or mitoxantrone), five had received cyclophosphamide (or ifosfamide) - always discontinuously for relatively short periods of time - five had received a vinca alkaloid, four had received an epipodophyllotoxin (VP 16 or VM26), three had received 5 FU, and three had received methotrexate, while other drugs had been used in only one or two cases. Most patients had received a combination of at least three drugs and six had also received radiotherapy. Cyclophosphamide, at least when used alone, discontinuously, and for short periods, seems to have limited leukemogenic potential . This potential is probably less important than that of other alkylating agents, es-
145 Table 3. Cases of secondary ALL with t (4; 11) reported in the literature and in the present series
1 2 3
F/56 M/60 F/7
Breast carcinoma Small cell carcinoma Neuroblastoma
5 6 7
F/51 F/43 M/33
Breast carcinoma Breast carcinoma Hodgkin's disease
Yes (40 Gy) Cy, 5FU, MTZ Yes (60 Gy) DOX, Cy, VCR, VP 16, CCNU None VCR, Cy, DOX, Cisplatin, VM 26 None MTX, VCR, DOX, IFOS, VP 16, Carboplatin Yes (45 Gy) DOX,MTX,5 FU Yes (50 Gy) DOX, Cy, 5 FU Yes MOPP, DOX, Bleomycin, VLB, Dacarbazine Yes (35 Gy) MOPP, CLB, VP 16,CCNU, MTX None MOPP, DOX, Bleomycin, VLB, Dacarbazine
0.75 1.75 4.5
No Yes NA
3 0.6 2
Present report Present report 
1.5 2 12
NA No No
13 8 1
[2, 3]  
NA, not available; VM 26, teniposide; VP 16, etoposide; Cy, cyclophosphamide; DOX, doxorubicin; VCR, vincristine; IFOS, ifosfamide; MTX, methotrexate, VLB, vinblastine; CLB, chlorambucil; 5 FU, fluorouracil; MTZ, mitoxantrone; MOPP: mechlorethamine, vincristine, procarbazin, prednisone
pecially nitrogen mustard, melphalan, or chlorambucil, often associated with the development of more classical secondary leukemias (AML with deletions of chromosomes 5 and/or 7) . These latter drugs had been used in only three of the nine patients analyzed in Table 3 . On the other hand, cyclophosphamide, when combined with topoisomerase II inhibitors (and often with radiotherapy), may be involved in the development of secondary A M L with translocations involving 11 q23 [1, 23, 25, 27, 33]. Our findings and previously reported cases suggest that the same type o f combination o f antineoplastic drugs may also cause A L L with t (4; 11) (q21; q23). Recent molecular findings have shown that breakpoints, in translocations involving 11q23, occur in a cluster region of less than 5.8 kb in 11 q23, both in A M L with t (9, ll) or variants and in A L L with t (4; 11). This locus has been referred to as ALL-I or M L L [26, 27]. O f note was the short interval (2 years or less) between treatment for the first cancer and diagnosis of A L L with t (4; 11) in six of the nine secondary cases reported in Table 3. Because this interval was shorter than in most cases o f therapy-related acute leukemias, this might suggest that ALL, at least in some cases, was not related to prior chemo- and radiotherapy, but was a coincidental event. However, short intervals between prior tumor and acute leukemia had also been reported in secondary A M L with rearrangements "specific" for de novo A M L (translocations involving 11 q23, t (8;21), inv (16) or t (15; 17)) [1, 9, 10, 14, 18, 23, 25, 27, 33]. Our two patients and previously published cases of secondary A L L with t (4, 11), had - except for the age of onset - most o f the characteristics of de novo A L L with
t (4; 11): high leukocyte counts, early B (CALLA negative) or mixed lymphoid-myeloid phenotype, and poor response to chemotherapy. An isochromosome i (7q) was found in one of our patients, in addition to t (4; 11). More than ten cases of A L L with t (4, 11) and associated i (7q) have been reported so far [5, 11, 16, 19,20,22,31], suggesting that i (7q) is a nonrandom secondary change in A L L with t (4;11). However, i (7 q) was seen in only one of 40  and one of 37  newly diagnosed cases of A L L with t (4,11), whereas it was observed in one third of relapsing A L L cases with isolated t (4; 11) at diagnosis . Thus, i (7q), in A L L with t (4; 11), is usually seen only in relapse. Contrary to our patient 2, previously reported cases of A L L with t (4; 11) and i (7q) were not secondary to chemo-, radiotherapy, or occupational exposure to carcinogens. Our findings and data from the literature suggest that secondary A L L with t (4; 11) (q21; q23) may be a rare but well-characterized entity, occurring mainly after chemotherapy with a combination of drugs including topoisomerase II inhibitors and cyclophosphamide, often in association with radiotherapy. The same drugs are also associated with the pathogenesis of secondary A M L with 11q23 rearrangements, with chromosomal breakpoints apparently occurring at the same gene locus. These findings provide additional support for the existence of a specific subgroup of secondary acute leukemias with 11 q23 rearrangements. The recent cloning of the breakpoint cluster region in 11q23 will probably stimulate studies analyzing the relationship between this locus and the action of chemotherapeutic agents, especially epipodophyllotoxins.
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