Pediatric Hematology and Oncology

ISSN: 0888-0018 (Print) 1521-0669 (Online) Journal homepage: http://www.tandfonline.com/loi/ipho20

Lineage Switch in a Childhood T-Cell Acute Lymphoblastic Leukemia Rosamaria Mura, Paolo D'angelo, Carmelo Rizzari, Andrea Biondi, Giovanni Giudici, Lucia Crosti, Marina Castagni & Angelo Cantu'-Rajnoldi To cite this article: Rosamaria Mura, Paolo D'angelo, Carmelo Rizzari, Andrea Biondi, Giovanni Giudici, Lucia Crosti, Marina Castagni & Angelo Cantu'-Rajnoldi (1992) Lineage Switch in a Childhood T-Cell Acute Lymphoblastic Leukemia, Pediatric Hematology and Oncology, 9:3, 281-288, DOI: 10.3109/08880019209016598 To link to this article: http://dx.doi.org/10.3109/08880019209016598

Published online: 09 Jul 2009.

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Date: 16 March 2016, At: 20:52

Letter to the Editor

LINEAGE SWITCH IN A CHILDHOOD T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA Rosamaria Mura, MD, Paolo D’Angelo, MD, and Carmelo Rizzari, M D 0 Pediatric Hematology Department, University of Milan, San Gerardo Hospital, Monza (Milan), Italy

Andrea Biondi, MD, and Giovanni Giudici, Chemist

0 Pediatric Hematology Department, Laboratory of Cytogenetics and Molecular Biology, University of Milan, San Gerardo Hospital, Monza (Milan), Italy

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Lucia Crosti, MD

0

Department of Dermatology, University of Milan, Italy

Marina Castagni, MD, and Angelo Cantu’-Rajnoldi, M D

0

Laboratory of Clinical

Researches, Istituti Clinici di Perfezionamento, Milan, Italy

INTRODUCTION

Despite the fact that most leukemic patients present at relapse the original phenotype observed at diagnosis, a lineage conversion of blast cells has been reported.’.‘ Lineage switch is the term commonly used to define the conversion of the leukemic lineage (as assessed by morphology, cytochemistry, and immunology) from diagnosis to relapse. This rare event can now be studied more accurately, thanks to immunophenotype, karyotype, and molecular analysis at diagnosis and r e l a p ~ e These .~ studies can confirm or exclude the same clonal origin of blast cells at diagnosis and relapse. The finding, as in our case, of the identical rearrangement for T-cell receptor (TCR) genes, despite a clear switch from T-lymphoid to myeloid phenotype, demonstrates that the clone involved in the leukemic transformation preserves the possibility of a different lineage commitment. CASE REPORT

In November 1987, a 13-year-old boy was admitted to our hospital with a history of fever and fatigue. Physical examination revealed diffuse lymphThis work was supported by “Cornitato M. L. Verga per lo studio e la cura della leucernia del bambino,” by “Fondazione Tettamanti,” and by Minister0 della Pubblica Istruzione, 40%, Roma, Italy and by CNR (Consiglio Nazionale delle Ricerche), Progetto ACRO (Applicazioni Cliniche della Ricerca Oncologica). Pediatric Hmtolosy and Oncology, 9:281-288, 1992 Copy2ht @ 1992 by Hemisphere Publishing Corporation

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adenopathy as well as liver and spleen enlargement. Chest X ray showed a mediastinal enlargement and multiple nodular infiltrates in the lungs. The blood count showed hemoglobin 12.2 g/dL, white blood cells (WBC) 15,500/ pL (blasts IS%), platelets 127,OOO/pL. Bone marrow (BM) aspirate showed a complete infiltration with blasts, some with unusually large dimensions and irregular nuclear shape, L2 according to FAB classification (Figure 1).

FIGURE 1. Bone marrow picture at presentation (myeloperoxidase); a positive granulocyte is surrounded by negative lymphoid blasts ( X 1000).

LINEAGE SWITCH IN A CHILDHOOD T-CELL ALL

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TABLE 1 Bone Marrow Morphology and Cytochemistry at Diagnosis and Relapse Factor

Diagnosis

Blasts FAB classification MPO PAS AP ANAE NASDA NASDA NaF CAE

94 %

71 %

L2

M

Neg. 10% Neg. Neg. Not done Not done Not done

100% 90% Neg. 90 % +++I+

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+

--

Relapse

+

+/-

53 90

-

--

Abbrcuiations: FAB French-American-British; M P O myeloperoxidase; PAS periodic acid-Schiff; AP acid phosphatase; ANAE a-naphthyl-acetate esterase; NASDA naphthyl AS-D acetate esterase; NaF sodium fluoride; CAE chloracetate esterase.

-

-

BM morphology, cytochemistry, and immunophenotype are shown in Tables 1 and 2. No involvement of the central nervous system was documented. Chromosome preparations were obtained from 24-hour unstimulated bone marrow cell cultures and stained with quinacrine mustard (QFQ banding technique). Of the 46 metaphases analyzed at diagnosis, 31 revealed a hyperdiploid number (4n/8n) of chromosomes with no apparent abnormalities. Diagnosis of T-ALL was made and the patient underwent intensive TABLE 2 Bone Marrow Immunophenotype at Diagnosis and Relapse MoAb tested

Diagnosis

Relapse

HLA-DR TdT CDlO CD20 CD24 cyCD3 CD5 CD7 CD2 E-rosettes CD33 CD13 CD14w CDllb CD15 CD1 l c

58 % 80 % Neg. Neg. Neg. 90 % 60 % 60 % 48 % 41 7’0 Neg. Neg. Not done Neg. Neg. Neg.

34% Neg. Neg. Neg. 18% Neg. Neg. Neg. Neg. Neg. 65 % 39 % 18% 80 % 47 % 24%

Abbreuiation: MoAb

-

monoclonal antibodies.

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R. MURAET AL

antiblastic treatment according to protocol ALL-NHL BFM 86 for high-risk patients, achieving the complete hematological remission after the induction phase. During maintenance treatment, 9 months after diagnosis of T-ALL, the boy presented with pneumonitis and hematuria. Physical examination showed diffuse hemorrhagic diathesis as well as liver and spleen enlargement. Chest X ray revealed mediastinal enlargement. WBC count was 24,OOO/pL with 88% blasts, hemoglobin 7.1 g/dL, platelets 24,OOO/pL. Bone marrow aspirate showed an almost complete replacement with atypical large monocytoid blasts, half of them having many conspicuous azurophilic granules (Figure 2). BM morphology, cytochemistry, and immunophenotype are shown in Tables 1 and 2. Cytogenetic study on bone marrow cells revealed a hyperdiploid karyotype (4n/8n) with complex multiple rearrangements. The configuration of TCR-y and 6 chains was studied at diagnosis and at relapse, as previously described in more detail.4 Briefly, EcoRI and BamHI digests were probed with a 0.7-kb Hind 111-EcoRI genomic fragment containing the Jyl gene, which detects rearrangements at virtually all Jy segm e n t ~To . ~study the 6-chain gene configuration, a 5-kb EcoRI genomic fragment (MH6) mapping between JS, and JS,“ was used after digestion with BamHI and Bgl 11. Figure 3 shows the results of DNA configuration at the 6 locus at diagnosis and at relapse. Laboratory findings showed disseminated intravascular coagulation (DIC). Supportive therapy with fresh plasma, platelet, and blood transfusions was started; antineoplastic treatment consisted of Ara-C (100 mg/m2 daily on days 1-7 in continuous infusion) and of daunomycin (20 mg/m2 iv on day 4 and 40 mg/m* iv on day 5). DIC was well controlled but the patient died of multiorgan failure on day 7 of antineoplastic treatment. Autopsy was not performed.

DISCUSSlON The phenomenon of an acute leukemia recurring with phenotypic features different from those observed at presentation has been variously reIt should be noted that the ported as secondary leukemia or lineage term secondary leukemia implies that the second leukemia is an evenience clonally unrelated to the primary one, as for acute leukemia occurring after radio- or chemotherapy with alkylating agents in primary solid tumors and lymphomas. The availability of cytogenetic and molecular biology techniques may unequivocally demonstrate that a lineage switch occurred in the same clone and that in such cases the term “secondary leukemia’’ is inappropriate. 1-3 In our case, morphological, cytochemical, and immunological

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LINEAGE SWITCH IN A CHILDHOOD T-CELL ALL

FIGURE 2. Bone marrow picture at relapse showing large granulated myeloid blasts (MGG

X

1000).

characteristics at diagnosis showed a clear evidence of the T-cell nature of the leukemic lineage. Also to be noted, however, is the unusually large dimension of blast cells along with the negativity of AP and the positivity for DR antigen (Table 1, Figure 1). O n the contrary, blast cells at relapse showed a complete negativity for all T-lymphoid markers and a strong positivity of myeloid cytochemical and immunological patterns (Table 2, Figure

R. MURA ET A1

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FIGURE 3. Southern blot analysis of the TCR-6 chain gene at diagnosis and at relapse. D N A was digested with B o d I and Bgl I1 and probed with a JS, probe (MH6). Lane G shows the germ line control.

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2). As shown in Figure 3, the MH6 probe detects the same TCR-8 gene rearrangement of diagnosis and at relapse. A correlation between the T-lymphoid immunophenotype at diagnosis and a subsequent occurrence of acute myeloid leukemia was suggested by Pui et a1 in their large series of secondary leukemias.’ A lineage switch in the same leukemic clone was described in a case of T-ALL relapsed as AML with maintenance of the same cytogenetic marker.7 Moreover, of five patients described by Gagnon et al,3who had a valuable immunophenotype at presentation, two had T-ALL and of these one relapsed as AML 8 months later, maintaining the same cytogenetic abnormality, while in the second an AML subsequently occurred with the features of a true secondary leukemia. Interestingly, acute hybrid leukemia showing mixed T-lymphoid and myeloid features is relatively frequent in our experience,8 suggesting that a common progenitor capable of both lymphoid and myeloid differentiation could be a common target for leukemogenesis and its involvement as the basis of the association between myeloid lineage switch and T-immunophenotype at presentation. This hypothesis is further sustained by the observation, in secondary leukemias, of cytogenetic abnormalities involving the 11q23 region’ in multipotent progenitor cells,g capable of both myeloid and lymphoid differentiation. Finally, it should be considered that chemotherapy (higher doses of drugs usually assumed by “high-risk” T-ALL patients) may play a role in phenotypic leukemic conversion whether inducing a different commitment of a multipotent clone or as a cause of a true secondary leukemia or selecting a drug-resistant clone in case of multiclonal leukemia.’.1°

REFERENCES 1. Pui C H , Behm FC, Raimondi SC, et al. Secondary acute myeloid leukemia in children treated for acute lymphoid leukemia. N Engl J Mcd. 1989;321:136-142. 2. Stass S, Mirro J, Melvin S, Pui C H , Murphy SB, Williams D. Lineage switch in acute leukemia. Blood. 1984;64:70 1 - 706. 3. Gagnon GA, Childs CC, LeMaiste A, et al. Molecular heterogeneity in acute leukemia lineage switch. Blood. 1989;74:2088-2095. 4. Biondi A, Francia di Celle P, Rossi V, Casorati G, Matullo G, Giudici G, Foa R , Migone N. High prevalence of T-cell receptor V62-(D)-DS3 or D6112-Db3 rearrangements in B-precursor acute lymphoblastic leukemias. Blood. 1990;75: 1834-1840. 5. Lefranc MP, Rabbitts TH. Two tandemly organized human genes encoding the T-cell y constantregion sequences show multiple rearrangement in different T-cell types. Nafure. 1985;316:464-466. 6. Hara J, Benedict SH, Champagne E, Takihara Y, Mak TW, Minden M, Celfand EW. T-cell receptor 6 gene rearrangements in acute lymphoblastic leukemia. J Clin Invest. 1988;82:1974-1982. 7. Simpson EM, Mott MG. Hybrid leukaemia of T cell and myeloid lineages: cytogenetic distinction from second (induced) malignancy. BrJ Haematol. 1987;65:401-403. 8. Canth-Rajnoldi A, Schirb R, Rossi V, Biondi A, Masera G. Biphenotypic acute leukemias with myeloid and T-lymphoid features. XXII Congress of the International Society of Hematology, Milan, 1988; Abstract Book, p. 481.

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9. Katz F, Malcom S, Gibbons B, et al. Cellular and molecular studies on infant null acute lymphoblastic leukemia. Blood. 1988;71:1438-1447. 10. Hershfield MS, Kurtzberg J , Harden E, Moore JO, Whang-Pheng J , Haynes BF. Conversion of a stem cell leukemia from a T-lymphoid to a myeloid phenotype induced by the adenosine deaminase inhibitor 2'-deoxycoformycin. Roc Nut1 Acad Sci USA. 1984;81:253-257. Received October 7, 1991 Accepted November 28, 1991

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Address correspondence to Carmelo Rizzari