High Frequency of Pro-B Acute Lymphoblastic Leukemia in Adults

Home , Follicular lymphoma, Malignancy

Leukemia (2003) 17, 1091–1095 & 2003 Nature Publishing Group All rights reserved 0887-6924/03 $25.00 www.nature.com/leu High frequency of pro-B acute lymphoblastic leukemia in adults with secondary leukemia with 11q23 abnormalities S Ishizawa1,4, ML Slovak1, L Popplewell2, V Bedell1, JE Wrede1, NH Carter3, DS Snyder2 and DA Arber1

1Division of Pathology, City of Hope National Medical Center, Duarte, CA, USA; 2Hematology/Bone Marrow Transplantation, City of Hope National Medical Center, Duarte, CA, USA; and 3Biostatistics, City of Hope National Medical Center, Duarte, CA, USA

To evaluate the frequency and cytogenetic and immunopheno- balanced cytogenetic abnormalities that commonly involve typic features of therapy-related, precursor B-cell acute lym- chromosome region 11q23 (site of the MLL gene), and less phoblastic leukemia (ALL), 152 cases of immature B-cell ALL were reviewed. These were compared to the frequency of commonly 22q22 (site of the AML1 gene). The combined use of therapy-related acute myeloid leukemia (t-AML) during the chemotherapy and radiation therapy in bone marrow transplan- same time period. Eight ALL cases with a prior diagnosis of tation is reportedly associated with a 3–8% long-term risk of malignancy were identified, including six (4.0%) with prior developing a secondary solid tumor and a 1–3% long-term risk therapy considered to be therapy-related ALL (t-ALL). The t-ALL of developing AML or myelodysplasia.2 Clonal cytogenetic cases followed treatment for breast carcinoma (two cases), abnormalities, even in the absence of disease, occur in as many lung carcinoma (two cases), lymphocyte predominance Hodg- as 9% of patients after autologous bone marrow transplanta- kin’s disease and follicular lymphoma with a latency period of 6 13 months to 8 years. All t-ALL cases had a pro-B (CD10- tion. negative) immunophenotype with significantly higher expres- Therapy-related acute lymphoblastic leukemia (t-ALL) is sion of CD15 and CD65, compared to the de novo CD10-positive much less common than therapy-related AML and myelodsy- ALL cases. All six t-ALL cases had MLL abnormalities by plasia, with only a small number of total cases reported in the fluorescence in situ hybridization, and four showed literature.7–9 In one series, t-ALL represented 1.2% of ALL cases. t(4;11)(q21;q23). These represented half of all 11q23-positive adult ALL cases. During the same time period, 4.9% of all AML This rare leukemia type is associated with 11q23 abnormalities cases were considered t-AML. There was a 16.7% frequency of in most, but not all, reports. The current study was designed to 11q23 abnormalities in the t-AML group. Despite the similar determine the frequency of therapy-related precursor B-cell ALL frequency in therapy-related disease among ALL and AML in adult patients at a single institution, and to determine the cases, there were differences in the frequency of the diseases immunophenotypic and cytogenetic features of this disease. The and t-ALL represented 12% of all therapy-related leukemias. frequency of t-ALL was also compared to t-AML during the same However, t-ALL represented 46% of all 11q23-positive therapy- related leukemias. The immunogenetic features of t-ALL appear time period. distinct and may aid in identifying more cases of this disease type in the future. Leukemia (2003) 17, 1091–1095. doi:10.1038/sj.leu.2402918 Materials and methods Keywords: acute lymphoblastic leukemia; MLL; immunophenotyping; adult; therapy All cases of precursor B-cell ALL with immunophenotyping performed at the City of Hope National Medical Center between February 1989 and April of 2001 were reviewed. Of these, 152 Introduction cases were identified in patients 18 years of age or older, which included 82 newly diagnosed and 70 with relapsed ALL that The successful treatment of many malignancies with chemother- were originally diagnosed at 18 years of age or older. Of these, apy and radiation therapy has resulted in the long-term survival available immunophenotyping and genetic studies were re- and cure of many patients. However, this success has viewed for each case. Immunophenotyping studies were primarily performed by flow cytometry, as previously de- been accompanied by the realization that a subset of these 10 patients will ultimately develop a second malignancy. Second scribed. Flow cytometry immunophenotyping studies were malignancies after therapy include both solid tumors and compared between the pro-B and nonpro-B precursor B leukemias.1–4 Of the leukemias, therapy-related myelodysplasia (CD10+) ALL group. Blasts were considered positive if 20% or and acute myeloid leukemia (AML) are most often reported. more expressed an antigen. Blasts were initially gated for Differences in the treatment regimens used for the primary analysis by using forward vs side scatter, and since 1995, by tumors are now recognized to result in clinical and cytogenetic using CD45 antigen expression and right-angle light scatter. The differences in these therapy-related leukemias.5 Patients treated number of antibodies used varied, with fewer studies performed on the older cases. Some results were determined by immuno- with alkylating agents more commonly have a longer time 11 interval between the primary tumor and leukemia and are histochemistry, using previously described methods. A cutoff associated with unbalanced abnormalities of chromosomes 5 of 20% or greater for a positive interpretation was also used for and/or 7. In contrast, topoisomerase II inhibitor-related leukemia the immunohistochemical studies. is associated with a shorter latency period and more frequent Cytogenetic analysis was performed on peripheral blood or bone marrow specimens using standard techniques. GTG banding was used to identify the individual chromosomes. Correspondence: Dr DA Arber, Clinical Laboratories, Stanford University Medical Center, 300 Pasteur Drive, H1507, Stanford, CA When available, at least 20 metaphases were examined from 94305-5627 USA; Fax: +1 650 736 1473 each case. Cytogenetic nomenclature followed standard ISCN 12 4Visiting Scientist from Toyama Medical and Pharmacy Uni- 1995 criteria. versity Hospital, Toyama, Japan RNA was extracted from peripheral blood or bone marrow Received 28 June 2002; accepted 27 January 2003 aspirate cells and analyzed using the reverse transcriptase Therapy-related ALL S Ishizawa et al 1092 polymerase chain reaction (RT-PCR) technique designed to (4.0%) of them treated with chemotherapy and/or radiotherapy, detect both the p210 and p190 bcr/abl fusion transcripts of the consistent with therapy-related disease (t-ALL) (Table 1). The t- (9;22) translocation, as previously described.13 ALL cases showed a 2: 4 male-to-female ratio, with a median/ For fluorescence in situ hybridization (FISH) studies for BCR/ mean age of 59.5/53.7 years (range 25–69 years) (Table 2). The ABL and MLL rearrangements, chromosome spreads were remaining ALL cases had a median/mean age of 36/37.2 years prepared by standard methods. Slides were incubated in 2 Â SSC (range 18–81 years) and included 89 males and 57 females. The at 371C for 30 min, denatured in 70% formamide/2 Â SSC (pH t-ALL cases included two patients with prior breast carcinoma, 7.0) at 721C for 2 min. Slides were hybridized using MLL two with prior lung carcinoma, and one each with follicular breakapart and BCR/ABL single fusion probes (Vysis, Inc., lymphoma and recurrent lymphocyte predominance Hodgkin’s Downer’s Grove, IL, USA). A volume of 5 mL of probe was heat disease. The two other patients with prior tumors included one denatured at 721C for 5 min, applied to denatured slides and patient with malignant melanoma and one with a poorly defined covered with a 18 mm round coverslip sealed with rubber oral malignancy, and both were treated with wide local excision cement. Slides were incubated in a humidified chamber at 371C alone. Of the six patients with t-ALL, four received drugs that overnight. Nonspecific probe binding was removed by a cause topoisomerase II-dependent DNA cleavage, one was 0.4 Â SSC/0.3% Nonidet P40 (pH 7.0) posthybridization wash treated with only radiation therapy and details of the at 721C for 2 min, followed by 2 Â SSC/0.1% NP40 (pH7.0) at chemotherapy for one patient were not available. The latency room temperature for 1 min. Cells were counterstained with period could be determined for four of the cases and ranged 4060-diamino-2 phenyl indole dihydrochloride (Vysis, Inc.). from 13 to 96 months. Of the four patients with adequate Lymphocytes from a phenotypically normal female were used follow-up, two were dead of disease at 0.4 and 13.9 months and as a negative control. In all, 200 nuclei were scored for each two were alive with no evidence of disease at 21 and 54 probe combination and each patient. Using the single fusion months. BCR/ABL probe, in-house validation studies indicated that All t-ALL cases were CD10-negative (pro-B immunopheno- samples with greater than 6% positive cells had a BCR/ABL type), and these represented 35% (six of 17) of all pro-B ALLs in gene rearrangement [sensitivity 95.2% (95% confidence interval the study. Although a general cutoff of 20% was used for CD10 (CI) ¼ 76.2–99.9%) and specificity 100% (95% CI ¼ 82.4– expression, all cases of t-ALL had less than 5% CD10-positive 100%)]. Samples were considered positive for an MLL rearran- cells. These therapy-related pro-B ALL cases significantly gement if greater than 3% of the interphase nuclei scored were differed from the remaining CD10-positive ALL cases by their positive [sensitivity 100% (95% CI ¼ 80.5–100%) and specificity aberrant expression of CD15 (five of six cases) and CD65 (three 100% (95% CI ¼ 71.5–100%)] (Figure 1). of three cases) and by their decreased expression of CD34 (two w2 analysis was used for statistical comparison. A history of of six cases) (Table 3). No aberrant expression of CD13 or CD33 prior therapy was determined by chart reviews and Cancer was identified in this group. Similar differences in the expression Registry data, and such data were available for 150 ALL patients. of CD15, CD65 and CD34 were observed when all pro-B ALL The incidence of t-AML diagnosed during the same time period cases were compared to CD10-positive ALLs, but no significant at the City of Hope was also determined by a search of the City differences in the immunophenotype of t-ALL cases vs the other of Hope Cancer Registry and chart reviews. The City of Hope pro-B ALL cases was identified (data not shown). Institutional Review Board and Cancer Protocol Review & All six t-ALL cases had 11q23/MLL abnormalities with four Monitoring Committee (#95124) approved the study. showing t(4;11)(q21;q23) by karyotype analysis, one showing an unbalanced 11q23 abnormality and one with only FISH analysis (Table 4). Involvement of the MLL gene was confirmed by FISH Results in all cases. Six additional ALL cases with 11q23 abnormalities were present in the cohort, including three that had FISH studies Eight of the 150 adult precursor B-cell ALL patients with to confirm involvement of the MLL gene. These included five available data had a known history of prior malignancy with six cases with a pro-B ALL immunophenotype and one CD10-

a b

Figure 1 Representative signal patterns using the Vysis MLL dual color FISH. Panel A demonstrates the typical dual fusion signal pattern found in cases with normal intact MLL genes. In these cases, a fusion (red/green) signal is seen on each 11 chromosome (arrows). Panel B demonstrates the typical signal pattern obtained when the MLL gene is rearranged. In these cases, a fusion (red/green) signal represents an intact MLL gene, whereas separated red and green signals (arrows) represent an MLL rearrangement.

Leukemia Therapy-related ALL S Ishizawa et al 1093 Table 1 Details of original diagnosis, therapy and latency period for t-ALL patients

Case # Initial Original chemotherapy Original radiation Latency diagnosis (months)

1 Breast None Radiation therapy 13 to breast 2 Follicular lymphoma (F,N,D) Â 5 cycles None 13 3 Lymphocyte predominance (MOPPr/DOXBV) Â 6 cycles, (N, TT,CTX) Â 3 cycles Mantle ﬁeld 96 Hodgkin’s disease with bone marrow transplantation. (dose not known) 4 Breast (CTX,DOX,5-FU) Â 6 cycles, High-dose CTX, None 24 DOX and Taxol with bone marrow transplantation 5 Lung Carboplatin, VP16 Â 6 cycles 3400 cGy to lung ﬁeld Unknown 6 Lung Type unknown Unknown Unknown

F, ﬂudarabine; N, mitoxantrone; D, dexamethasone; TT-thiotepa; CTX, cyclophosphamide; DOX, doxorubicin; 5-FU, 5-ﬂourouracil; VP16, etoposide; I, idarubicin; M, mechlorethamine; O-vincristine; P, procarbazine; Pr, Prednisone; V, vinblastine; B, bleomycin; Da, Dacarbazine; Drug names in bold are dependent on topoisomerase II interaction or cause topoisomerase II-dependent DNA cleavage.

Table 2 Clinical features of t-ALL cases

Case # Age Sex WBC at diagnosis Follow-up Status last (years) ( Â 109/l) (months) contact

1 44 F 65 13.9 Dead of disease 2 65 F 22 2.6 Alive with disease, lost to follow-up 3 25 M 16.9 54.0 Alive with no evidence of disease 4 59 F 160 21.0 Alive with no evidence of disease 5 60 F 80 0.4 Dead of disease 6 69 M 74.4 NA NA

WBC, white blood cell count; NA, not available.

Table 3 Immunophenotypic comparisons of all t-ALLs and de novo CD10+ ALL (# positive/total tested)

Diagnosis CD11c CD13 CD15 CD20 CD22 CD33 CD34 CD36 CD45 CD65 t-ALLa 1/5 0/0 5/6 0/6 5/5 0/6 2/6 0/5 6/6 3/3 20% 0% 83% 0% 100% 0% 33% 0% 100% 100%

CD10+ALL 2/56 25/117 28/111 59/128 37/38 40/127 106/124 7/53 105/122 6/35 3.6% 21.4% 25.2% 46.1% 97.4% 31.5% 85.5% 13.2% 86.1% 17.1%

P-valueb 0.4489 0.6573 0.02 0.1761 0.9874 0.4398 0.01 0.8611 0.8100 0.01 aAll t-ALL cases were CD10 negative. bSigniﬁcant values are bold. Other antigens evaluated that showed no signiﬁcant difference between disease groups included CD2, CD3, CD4, CD5, CD7, CD8, CD14, CD19, CD56, CD61, CD117, glycophorin, HLA-DR and TdT.

positive ALL. The single CD10-positive, 11q23-positive case 35% of the total cases, including one of 15 pro-B cases and 45 of had over 90% CD10-positive cells. The presence of 11q23/MLL 115 CD10+cases. rearrangements was signiﬁcantly associated with a CD10- During the same time interval, 876 AML patients were negative, pro-B cell immunophenotype (Po0.0001). Cancer entered in the City of Hope Cancer registry. Of these, 68 had a Registry data, supplemented by a detailed chart review, failed to prior malignancy and 43 (4.9%) were treated with chemother- identify evidence of a history of prior malignancy or therapy in apy or radiation therapy and were considered therapy related. any of the other 11q23-positive cases or CD10-negative cases. Of these 16.7% (seven of 42 with data) were found to have There was no evidence of t(9;22) by karyotype, PCR or FISH in 11q23 abnormalities. No cytogenetic results were available for any of the t-ALL cases. This compared to 22.4% BCR/ABL one of the cases. Therefore, during this time period, 49 therapy- positivity in the remaining ALL cases, including two of 10 MLL- related acute leukemias occurred, representing 4.8% (49 of negative pro-B cell cases. A normal karyotype was identiﬁed in 1026) of all acute leukemias, and t-ALL composed 12% of all

Leukemia Therapy-related ALL S Ishizawa et al 1094 Table 4 Cytogenetic and molecular genetic features of t-ALL cases

Case # Karyotype MLL-FISH t(9,22), BCR/ABLa

1 46,XX,t(4;11)(q21;q23),i(7)(q10)[13] + À 2 46,XX,t(4;11)(q21;q23)[16]/ 46,XX [4] + À 3 46,Y,-X,t(2;15)(q?21;q15),der(11)t(11:?)(q23;?), + À del(13)(q14q34), inv(20)(p11.2q13.1), add(22)(q13),+mar [18]/46, idem,del(6)(q23q25)[2] 4 46,XX,t(4;11)(q21;q23)[8]/46,XX,add(5)(q33)[4]/46,XX [8] + À 5 46,XX,t(4;11)(q21;q23)[2] + À 6NA +NA

aEvidence of t(9;22) or BCR/ABL by FISH or PCR. NA=material not available for analysis.

therapy-related leukemias. Of the therapy-related leukemias, four showed t(4;11). The latency period for the development of 27% (13 of 48) had 11q23 abnormalities, of which 46% (six of t-ALL ranged from 13 months to 8 years. In contrast to most 13) were t-ALL. previous reports, one patient in the current study with a history of breast cancer did not receive chemotherapy and was only treated with radiation therapy to the breast. However, therapy- Discussion related leukemia with 11q23 abnormalities has been reported following radiation therapy alone, with five cases included in a Acute leukemia secondary to prior therapy may be of myeloid or recent report by Bloomfield et al.9 Not all reports of t-ALL, lymphoblastic lineage, but AML is most common. The current however, have such a prominent association with 11q23/MLL study, however, suggests that t-ALL is more common than rearrangements. In the GIMEMA study of t-ALL,7 karyotype previously thought, representing 12% of all therapy-related results were evaluable for 16 patients and only one had an leukemias in one institution. In a recent international study of 11q23 abnormality. 511 therapy-related acute leukemias and myelodysplastic The immunophenotypic features of precursor B-cell t-ALL also syndromes with balanced chromosome aberrations, only 20 appears to be unique when compared to other adult ALLs, and is (3.9%) cases were t-ALLs.5 The GIMEMA (Gruppo Italiano similar to MLL-positive infant ALL. All of the t-ALL cases in the Malattie Ematologiche Maligne dell’Adulto) Archive of Adult current study had a CD10-negative, pro-B immunophenotype Acute Leukemia retrospectively identified 21 cases of ALL in and there was significant aberrant coexpression of CD15 and patients with prior malignancy, representing 2.3% of all ALL CD65 in these cases. Prior studies have confirmed the cases.7 Of those cases, only 11 (1.2% of all cases) received prior correlation between lack of CD10 expression in ALL with chemotherapy or radiation therapy. The reason for the aberrant CD15 and CD65 expression and MLL rearrangements discrepancy in the incidence of t-ALL between these previous in both adults and infants.17–20 Other similarities between infant reports and the current study is not clear, but suggests that t-ALL pro-B ALL and therapy-related leukemia have also been may have been underrecognized in prior studies. Histories of described. Cimino et al21 analyzed the specific breakpoints in prior therapy may not be pursued as aggressively in patients with the MLL gene in infant leukemias, de novo leukemias and ALL as they are in AML because of lack of recognition of the topoisomerase II inhibitor-related leukemias, and found simila- possibility of therapy-related disease in ALL. The chart reviews rities in gene breakpoints between the infant and therapy-related of some of the t-ALL patients in the current study revealed that group that was not found in the de novo leukemia group. This the physician treating the patient for ALL did not appear to finding suggests a similar mechanism of leukemogenesis in the recognize a possible link between the patients’ prior malignancy two groups. and the later development of ALL. The current study also attempted to compare the frequency of It is now clear that many therapy-related leukemias have t-ALL to t-AML in a single institution. Although therapy-related rearrangements of the MLL gene and such rearrangements are disease represented 4.0 and 4.9% of all ALL and AML cases, highly associated with prior topoisomerase II inhibitor therapy. respectively, AML was much more common and t-AML The current study and others, however, suggest that MLL represented 88% of all therapy-related leukemia during the abnormalities are involved in a higher percentage of t-ALL time period of the study. In contrast, therapy-related 11q23 cases than t-AML cases, and t-ALL is usually associated with abnormalities were similar in the two groups with seven cases t(4;11).8,9,14–16 Andersen et al8 recently reported two cases of identified in the t-AML group and six in the t-ALL group. MLL-positive, t-ALL and identified 21 other cases in the Therefore, in the setting of therapy-related 11q23 abnormalities, literature. All of those previously reported cases had received there is a similar frequency in the development of ALL as AML. at least one topoisomerase II inhibitor. In an international While t-ALL remains a relatively uncommon disease, the current workshop focusing on 11q23 abnormalities,16 7.3% of patients findings suggest clues to the identification of such cases. Adult had secondary leukemia or myelodysplasia and 22.5% (nine of ALL with a pro-B cell immunophenotype and aberrant expres- 40) had ALL. Eight had t(4;11) and one showed t(1;11)(q21;q23). sion of CD15 or CD65 should warrant cytogenetic and possibly This study showed a latency period for developing 11q23- molecular genetic investigation for an 11q23 abnormality. associated t-ALL ranging from 12 months to 22 years with a Identification of such an 11q23 abnormality, especially t(4;11), median latency of 16 months. The six t-ALL cases in the current should raise suspicions for therapy-related disease. A relation study all demonstrated evidence of MLL rearrangements, and between prior therapy and ALL may have been unappreciated

Leukemia Therapy-related ALL S Ishizawa et al 1095 and significantly underestimated in prior studies. Recognition of 10 Khalidi HS, Chang KL, Medeiros LJ, Brynes RK, Slovak ML, Murata- this immunogenetic phenotype may result in an increased Collins J et al. Acute lymphoblastic leukemia. Survey of appreciation of t-ALL. immunophenotype, French–American–British classification, frequency of myeloid antigen expression, and karyotypic abnormalities in 210 pediatric and adult cases. Am J Clin Pathol 1999; 111: 467–476. Acknowledgements 11 Arber DA, Jenkins KA. Paraffin section immunophenotyping of acute leukemias in bone marrow specimens. Am J Clin Pathol This work was supported in part by NIH CA-33572 and CA- 1996; 106: 462–468. 30206. 12 ISCN (1995): In: Mitelman F (ed.), An International System for Human Cytogenetic Nomenclature. Basel: Karger, 1995. 13 Snyder DS, Rossi JJ, Wang J-J, Sniecinski IJ, Slovak ML, Wallace RB References et al. Persistence of bcr-abl gene expession following bone marrow transplantation for chronic myelogenous leukemia in chronic 1 Pui C-H, Behm FG, Raimondi SC, Dodge RK, George SL, Rivera phase. Transplantation 1991; 51: 1033–1040. GK et al. Secondary acute myeloid leukemia in children treated for 14 Pedersen-Bjergaard J. Acute lymphoid leukemia with t(4;11) acute lymphoid leukemia. N Engl J Med 1989; 321: 136–142. (q21;q23) following chemotherapy with cytostatic agents 2 Bhatia S, Ramsay NKC, Steinbuch M, Dusenbery KE, Shapiro RS, targeting at DNA-topoisomerase II. Leukemia Res 1992; 16: Weisdorf DJ et al. Malignant neoplasms following bone marrow 733–735. transplantation. Blood 1996; 87: 3633–3639. 15 Block AW, Carroll AJ, Hagemeijer A, Michaux L, van Lom K, 3 Pagano L, Pulsoni A, Tosti ME, Avvisati G, Mele L, Mele A et al. Olney HJ et al. Rare recurring balanced chromosome abnormal- Clinical and biological features of acute myeloid leukaemia ities in therapy-related myelodysplastic syndromes and acute occurring as second malignancy: GIMEMA archive of adult acute leukemia: report from an international workshop. Genes Chromo- leukaemia. Br J Haematol 2001; 112: 109–117. somes Cancer 2002; 33: 401–412. 4 Bhatia S, Louie AD, Bhatia R, O’Donnell MR, Fung H, Kashyap A 16 Secker-Walker LM, Moorman AV, Bain BJ, Mehta AB. Secondary et al. Solid cancers after bone marrow transplantation. J Clin Oncol acute leukemia and myelodysplastic syndrome with 11q23 2001; 19: 464–471. abnormalities. Leukemia 1998; 12: 840–844. 5 Rowley JD, Olney HJ. International workshop on the relationship 17 Pui CH, Rubnitz JE, Hancock ML, Downing JR, Raimondi SC, of prior therapy to balanced chromosome aberrations in therapy- Rivera GK et al.. Reappraisal of the clinical and biologic related myelodysplastic syndromes and acute leukemia: overview significance of myeloid- associated antigen expression in child- report. Genes Chromosomes Cancer 2002; 33: 331–345. hood acute lymphoblastic leukemia. J Clin Oncol 1998; 16: 3768– 6 Traweek ST, Slovak ML, Nademanee AP, Brynes RK, Niland JC, 3773. Forman SJ. Clonal karyotypic hematopoietic-cell abnormalities 18 Lenormand B, Bene MC, Lesesve JF, Bastard C, Tilly H, Lefranc occurring after autologous bone-marrow transplantation for MP et al. PreB1 (CD10À) acute lymphoblastic leukemia: Hodgkin’s-disease and non-Hodgkin’s-lymphoma. Blood 1994; immunophenotypic and genomic characteristics, clinical features 84: 957–963. and outcome in 38 adults and 26 children. The Groupe dEtude 7 Pagano L, Pulsoni A, Tosti ME, Annino L, Mele A, Camera A et al. Immunologique des Leucemies. Leukemia Lymphoma 1998; 28: Acute lymphoblastic leukaemia occurring as second malignancy: 329–342. report of the GIMEMA archive of adult acute leukaemia. Gruppo 19 Ludwig WD, Rieder H, Bartram CR, Heinze B, Schwartz S, Italiano Malattie Ematologiche Maligne dell’Adulto. Br J Haematol Gassmann W et al. Immunophenotypic and genotypic features, 1999; 106: 1037–1040. clinical characteristics, and treatment outcome of adult 8 Andersen MK, Christiansen DH, Jensen BA, Ernst P, Hauge G, pro-B acute lymphoblastic leukemia: results of the German Pedersen-Bjergaard J. Therapy-related acute lymphoblastic leu- multicenter trials GMALL 03/87 and 04/89. Blood 1998; 92: kaemia with MLL rearrangements following DNA topoisomerase II 1898–1909. inhibitors, an increasing problem: report on two new cases and 20 Borkhardt A, Wuchter C, Viehmann S, Pils S, Teigler-Schlegel A, review of the literature since 1992. Br J Haematol 2001; 114: Stanulla M et al. Infant acute lymphoblastic leukemia–combined 539–543. cytogenetic, immunophenotypical and molecular analysis of 77 9 Bloomfield CD, Archer KJ, Mrozek K, Lillington DM, Kaneko Y, cases. Leukemia 2002; 16: 1685–1690. Head DR et al. 11q23 balanced chromosome aberrations in 21 Cimino G, Rapanotti MC, Biondi A, Elia L, LoCoco F, Price C et al. treatment-related myelodysplastic syndromes and acute leukemia: Infant acute leukemias show the same biased distribution of ALL1 report from an international workshop. Genes Chromosomes gene breaks as topoisomerase II related secondary acute leuke- Cancer 2002; 33: 362–378. mias. Cancer Res 1997; 57: 2879–2883.

Leukemia