Medical and Pediatric Oncology 20:48-52 (1992)

Acute Nonlymphoblastic Leukemia in Children Treated for Acute Lymphoblastic Leukemia With an Intensive Regimen Including Teniposide Arnparo Verdeguer, MD, Jose Gabriel Ruiz, MD, Josep Ferris, MD, Carlos Esquernbre, MD, Maria Jesus Tasso, MD, Jose Maria Fernandez, MD, Felix Prieto, MD, and Victoria Castel, MD ~

Some cases of conversion from acute lymphoblastic leukemia (ALL) to acute nonlymphoblastic leukemia (ANLL) at relapse have been reported recently. We report three cases initially diagnosed as having ALL and showing morphological, cytochemical, and immunophenotypic features of ANLL at relapse (lineage switch). Conversion was observed among 14 patients who developed bone marrow relapse while undergoing intensive treatment with our ALL protocol, which includes teniposide, and that had

been administered to 62 patients. The three cases converted at first relapse, with a mean time of 20 months (13-29 months). Clinical and immunologic characteristics of T-cell leukemia were present in one patient. Changes documented in cytogenetic studies are discussed. The underlying mechanisms for the lineage switch remain unclear as does its relation with mixed lineage leukemias, but we believe that drugs employed in our therapy protocol could have had an influence on this conversion.

Key words: acute lymphoblastic leukemia, switch lineage, acute mixed lineage leukemia, secondary acute nonlymphoblastic leukemia

INTRODUCTION

MATERIAL AND METHODS

Survival rate of acute lymphoblastic leukemia (ALL) in childhood has been gradually increased during the last few years. Aggressive chemotherapy schedules have led to a decrease in relapse rates. Nevertheless, some cases of conversion of cell phenotype at relapse have been reported recently. The combination of morphological, cytochemical, and immunological changes has been defined as “lineage switch’ [ 1-31. The factors responsible for the lineage switch remain unclear, but the wider use of intensive chemotherapy seems to have a possible influence on the increasing presence of this phenomenon. Chemotherapy would either erradicate a dominant clone at diagnosis or modify the original leukemia clone. On the other hand, the existence of hybrid or acute mixed lineage leukemias has been recognized and their relation with lineage switch is not clear [1,2,4-71. Patients showing a lineage switch possibly had a progenitor cell capable of differentiation along either a myeloid or a lymphoid pathway at diagnosis that was not identified because of the limited studies performed. We report three cases of conversion of cell phenotype observed among 14 cases of bone marrow relapse in 62 patients treated at our oncology unit. 0 1992 Wiley-Liss, Inc.

From December 1985 to December 1988, 62 children newly diagnosed as having ALL were admitted to our oncology unit. Bone marrow samples were obtained in order to perform morphological, cytochemical, immunophenotype, and cytogenetic studies. Bone marrow morphology was examined on May-Griinwald-Giemsastained smears, leukemias being subtyped according to F. A.B. classification [8]. Cytochemical studies included periodic acid-Schiff (PAS), Sudan black B (SBB), myeloperoxidase (MPO), nonspecific esterase (NSE), acid phosphatase (AP), and chloracetate esterase (CAE), and were carried out by standard methods [9]. Terminal deoxynucleotidyltransferase (TdT) was identified by use of indirect immunofluorescence [ 101. To practice immunophenotype, bone marrow or blood slides were immunostained with a panel of monoclonal antibodies directed

From the Pediatric Oncology Unit (A.V., J.G.R., J.F., C.E., M.J.T., J.M.F., V.C.) and the Genetic Unit (F.P.), Hospital Infantil L a Fe, Valencia, Spain. Received December 2, 1990; accepted May 23, 1991 Address reprint requests to Dr. Amparo Verdeguer, Oncologia Pediatrica, Hospital Infantil La Fe, Avia. Campanar 21, 46009 Valencia, Spain.

Lineage Switch in ALL

49

CONTINUATION THERAPY

INDUCTION PHASE (ALL RISK)

HIGH-RISK

ttt t t t

PRED

Ill1 I q I I I I

AA

I - - - - -

I

VM-261 ARA-C III

1111

1111 AA

AA

1

1

1

1

3

6

1

7

1

1

1

1

1

1

0

11

19

15

17

19 21

1

1

'

29 W

STANDARD-RISK

VCR

A

A

A

A

A

A

ttt

11111111

L-ASP

AAA

I

1

I

8

I

I

I

16

22

29

1

1

1

38 43 5 0

1

MyS

Fig. 1. LLA-V-85 therapy protocol. VM-26, 165 rng/m2; ARA-C, 300 rng/rn2; vincristine, 1.5 rng/m2; L-asparaginase, 10,000 U/m2, iv; prednisone, 60 rng/rn2, oral.

t

b

4

I

1

1

1

1

3

6

7

I 1 Q

111 AAA

I

1-

O

I

t

tlll b b t t

b I

1

1

11

13

16

1

17

I

t b 1

19 21

1

23

I

W

Fig. 2. LLA-V-85 therapy protocol. (Upright arrow), Intermediate dose iv methotrexate (1 g/m2 standard risk and 2 g/m2 high-risk patients) plus intrathecal triple chemotherapy. (Upright rectangle), VM-26 (165 rng/m2) plus ARA-C (300 rng/rn2). Pulses every 10 weeks (S.R.) and every 6 weeks (H.R.), during 2 years maintenance. ( A )Vincristine: I .5 mg/m2. Cranial irradiation (18 Gy). Rectangle, Oral rnercaptopurine; ( 4 )oral rnethotrexate; Filled-in rectangle, oral prednisone (40 mg/m2).

(m)

against cell differentiation antigens: HLA-DR, CD- 10 (J 5), CD-19 (B 4), CD-7 (3A1), CD-3 (OKT3), CD-13 MY^), CD-33 MY^), CD-llb (Mol), CD-14 (My14), and OK-M5 (11). Cytogenetic studies were performed using a direct bone marrow technique and a 48-hr culture to obtain G-banding [ 121. Leukemia patients were considered at high risk (HR) when at least one of the following parameters was present: WBC > 50 X 10g/liter, age 50. Twenty-four of 62 children were considered as HR-LLA. Therapy in standard and high-risk (SR and HR) group patients included the combination of teniposide (VM-26) and cytosine-arabinoside (ARA-C) besides 5 additional drugs (Figs. 1 and 2). Of 60 patients in which complete remission was attained, 39 are alive and in continuous complete remission with a mean follow up time of 35 months (19-56 months) and 14 have suffered a bone marrow relapse. At relapse, morphological, cytochemical, immunophenotyping, and cytogenetic studies were again performed by using the same methods as those employed at diagnosis. For statistical analysis, chi-square test was applied to analyze the possible influence of epipodophyllotoxins in the development of ANLL in our groups of patients [ 131. RESULTS

ANLL developed in 3 of 60 patients (5%), accounting for 21% (3 of 14) of the initial hematologic relapses. The

mean time from diagnosis to phenotypic conversion was 20 months (range 13-29 months). Clinical features of these three patients are listed in Table I. Patients 1 and 3 were initially considered to be standard risk and patient No. 2 high risk. The three patients were receiving chemotherapy with our ALL protocol when conversion occurred. At this time, the treatment was changed to ANLL therapy: VAPA protocol or high-dose ARA-C plus nitoxantrone [ 14-16]. The only complete remission was achieved in patient No. 1 following a course of HD-ARAC plus mitoxantrone. At initial diagnosis, the three patients appeared morphologically to be ALL. Acid phosphatase was positive and cytochemical evidence of myeloid or monocytic features was absent in two of the three cases (Table 11). Clinical characteristics and immunologic phenotype of T-cell leukemia (pre-T) were present only in patient No. 2. At relapse, leukemic cells were clearly nonlymphoid, showing positive reactivity to nonlymphoid-associated cytochemical tests (SBB, MPO, and NSE). Immunophenotype was consistent with findings in ANLL, although patient 2 also showed positive reactivity to CD-7, CD-3, CD-5, CD-4, and CD-8, CD-1 being negative. Cytogenetic features are shown in Table 111. Initially, in patient 2, 12 metaphases were studied, one showing an hyperdiploidy and the other 11 a normal karyotype. At

~

50

Verdeguer et a].

TABLE 1. Clinical Characteristics of Patients Patient no. Sex Age at diagnosis WBC (X 109/liter) Mediastinal mass Initial therapy Time to conversion from Dx (mo) No. relapse at conversion Therapy at conversion Achieved second remission

1

2

3

F 3yr 12

F 18mo 42

M 3yr 3

ALLa 23 First ANLL Yes

ALLb 17 First ANLL No

ALLa 29 First ANLL No

-

++

-

aStandard-risk LLA-V-85 protocol. bHigh-risk LLA-V-85 protocol.

relapse only the normal karyotype was found. Both patients 1 and 3 showed trisomy 8 and some anomaly of chromosome 11 (region 11 q23) when conversion to ANLL was undergone.

DISCUSSlON Some cases of ANLL as a second appearance of a malignancy have been reported in the last decade, in children with ALL [ 17-20]. The existence of a second malignancy has been attributed to constitutional factors interacting with direct carcinogenic effects of radiation and/or chemotherapy, which can lead to genetic mutations. Nevertheless, the classical criteria for secondary leukemia in the adult population does not seem to be applicable to the recently reported cases in children, nor in the three cases reported here. Conversions from lymphoid to myeloid lineage, taking place in a short period of time, have been defined as “lineage switch” [ 1-31. The underlying mechanisms for the lineage switch remain unclear, but it is thought the intensive chemotherapy schedules now employed may influence this conversion [2]. At our oncology unit an intensive therapeutic regimen is being used that includes teniposide (VM-26) associated with ARA-C not only in the induction remission phase but also in repeated pulses during continuation therapy. This treatment is effective because with a mean follow-up time of 36 months, only 14 of 60 patients (high and standard risk) have suffered an hematologic relapse, but three cases of conversion of cell phenotype (ALL to ANLL) were found among these 14 cases. Between 1981 and 1984, 45 children with standard-risk non-T ALL were treated at our Institution with a regimen that did not include VM-26 and ARA-C [21] and no cases of ANLL were observed at relapse. By using the chi-square test no significant difference regarding phenotype conversion

was found in our two groups. Although we cannot demonstrate the influence of VM-26 plus ARA-C in the development of this conversion, this possibility should be taken into account considering that a higher incidence of ANLL in children being treated for ALL has been reported from St. Jude Children’s Research Hospital, most of their patients having undergone chemotherapy including VM-26 plus ARA-C [ 1,221 and, on the other hand, ANLL has not been observed in other important groups of ALL patients where this combination of drugs was not included in the therapeutic regimen [23]. It is also difficult to establish the difference between lineage switch and a mixed lineage leukemia. Several studies have presented evidence for coexpression of lymphoid and myeloid characteristics and different terminology (lineage infidelity, biphenotypic leukemia, acute mixed lineage leukemia, etc.) has been used to define this finding [2,4,5,24-271. The development of leukemia research has demonstrated that leukemias expressing both lymphoid and myeloid-associated antigens appear with unexpectedly high frequency. It is possible that patients with lineage switch had an acute mixed lineage leukemia (AMLL) at diagnosis which was not identified because of insufficient studies. Myeloidmarker cell tests had not been performed at initial diagnosis in any of the three cases reported here, thus, it cannot be discounted that some of our patients initially had a mixed leukemia. Lineage switch has been observed more frequently in patients showing T-cell-associated characteristics. In the same way, cases of ANLL with positive T-cell markers have been reported, suggesting that there may exist a pluripotent stem cell capable of both T lymphoblast and myeloblastic differentiation [ I ,2,4,28]. Only one of our patients had clinical signs and the immunophenotype of pre T-cell leukemia at initial diagnosis. This case, at relapse, showed morphological, cytochemical, and immunological criteria of nonlymphoid leukemia (M-5) and also showed antigen expression of ‘‘late’’ thymocyte, uncommon in ALL, while at initial diagnosis the blasts were classified as prothymocyte [29,3O]. Myeloid monoclonal tests were not performed at diagnosis. We believe this case could be an AMLL. Chromosomal alterations usually observed in secondary therapy-related ANLL were not documented in these three patients. Two children had structural abnormalities involving chromosome 11 (region 1 lq23). These rearrangements of band llq23 have been observed in other cases of ANLL developed in patients previously treated with intensive regimens, most of which included epipodophyllotoxin [3,20,22,31-331. On the other hand, abnormalities of band 1lq23 are frequently observed in the novo acute myelomonocytic (M 4) and monocytic (M 5 ) leukemias, in acute mixed lineage leukemias but

Lineage Switch in ALL

51

TABLE 11. Laboratory Studies at Initial Diagnosis (DX) and Lineage Switch (IS)* Patient no. 2

1 Blast in BM (%) FAB subtype SBB MPO NSE AP Immunologic markers HLA-DR CD 7 CD 3 CD 10 CD 19 CD l l b CD 13 CD 33 CD 14 OKM5 TdT

3

DX

LS

DX

LS

DX

LS

81 L1

94 M4 80 20 64 ND

88 L1

85 M5b 100 81 100 1OOb

29 L1 ND ND ND -

88 M5 a 100 100 100 ND

-

11 75

96 64 40 ND 94

ND ND ND ND ND ND ND ND ND ND ND

12 4

36 (b)

ND ND ND ND ND ND ND ND ND ND 42

56 30

-

ND -

2 63a

-

10

ND ND ND ND -

8 58 68 ND 70

5 43 68 ND

*BM, bone marrow; SBB, Sudan black; MPO, myeloperoxidase; NSE, nonspecific esterase; AP, acid phosphatase; ND, not done; (-), negative; (+), positive. aCentrosomic pattern. bDiffuse pattern.

TABLE 111. Cytogenetic Studies Patient

Initial diagnosis

1

46,XX

2 3

46,XX/XO,XX Not evaluable

(ma (7) (' 2,

Lineage switch 47,XX,+S,t(3;17)(pl l;q25) t(4;ll) (q21;q23) 46,XX 47 ,XY,+8 ,- 15,del( 11)(q23) +der( 15)t( 15;7)(pl1;7)

(ma (53) (12) (12)

aNumber of metaphases studied.

rarely in primary ALL [7,22,31].It has been suggested that the llq23 band is preferentially involved in the malignant transformation of a pluripotential stem cell. Conversion from ALL to ANLL is a clinical problem that is being currently observed coinciding with a decreasing incidence of hematologic relapses. Clinical and laboratory characteristics of these ANLL differ from the classical secondary leukemias. The pathogenesis of this conversion remains unclear and will probably prove to be heterogeneous, but cannot be confirmed until further studies are carried out.

ACKNOWLEDGMENTS

The authors wish to thank Mike Harrison for his help in the preparation of this paper.

REFERENCES 1. Stass S, Mirro J, Melvin S, Pui CH, Murphy SB, Williams D: Lineage switch in acute leukemia. Blood 64:701-706, 1984. 2. Stass S, Mirro J: Unexpected heterogeneity in acute leukemia: Mixed lineages and lineage switch. Hum Pathol 16:864866, 1985. 3. Van Lierde S , Mecucci C, Van Daele MC, Van den Berghe H: Lineage switch and translocation t(9;ll) in acute leukemia. Am J Pediatr Hematol Oncol 11:2&22, 1989. 4. Mirro I, Zipf TF, Pui CH, Kitchingman G , Williams D, Melvin S, Murphy SB, Stass S: Acute mixed lineage leukemia: Clinicopathologic correlations and prognostic significance. Blood 66: 1115-1 123, 1985. 5 . Gale RP, Bassat IB: Hybrid acute leukemia. Br J Haematol 65:261-264, 1987. 6. Neame PB, Soamboonsmp P, Browman G , Barr RD, Saeed N, Chan B, Pai M, Benger A , Wilson EC, Walker IR, McBride JA: Simultaneous or sequential expression of lymphoid and myeloid phenotypes in acute leukemia. Blood 65:142-148, 1985.

52

Verdeguer et al.

7. Mirro J, Kitchingman G, Williams D, Lauzon GJ, Lin CC, Callihan T, Zipf TF: Clinical and laboratory characteristics of acute leukemia with the 4;ll translocation. Blood 67:689497, 1986. 8. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralnick HR, Sultan C: Proposals for the classifications of the acute leukemias. Br J Haematol 33:451458, 1976. 9. Hayhoe FGJ, Quaglino D: Haematological Cytochemistry . New York: Churchill-Livingston, 1980. 10. Bollum FJ: Terminal deoxynucleotidyl transferase as a hematopoietic cell marker. Blood 54:1203-1212, 1979. 11. Melvin SL: Immunological definition of leukemic cell surface phenotype. Cancer Res 41:4790-4793, 1981. 12. Seabright M: A rapid banding technique for human chromosomes. Lancet ii:971-972, 1971. 13. Colton Th: Estadistica en medicina (Sp version of Statistics in Medicine) Salvat Ed. Barcelona (Spain), 1979. 14. Weinstein HJ, Mayer RJ, Rosenthal DS, Coral FS, Camitta BM, Gelber RD: Chemotherapy for acute myelogenous leukemia in children and adults: VAPA update. Blood 62:3 15-319, 1983. 15. Hiddemann W, Kreutzman H, Straif K, Ludwig WD, Mertelsmann R, Donhuijsen-Ant R, Lengfelder E, Arlin Z, Buchner T: High-dose cytosine-arabinoside and mitoxantrone: A highly effective regimen in refractory acute myeloid leukemia. Blood 69:744-749, 1987. 16. Sanz MA, Martinez J , Borrego D, Martin-Aragones G, Lorenzo I, Sanz G, Sayas MJ, Jarque I, Pastor E, Rafecas J: High-dose cytosine-arabinoside and mitoxantrone in high-risk acute nonlymphoblastic leukemia. Sem Oncol 14:18-20, 1987. 17. Zarrabi H, Rosner F, Griinwald HW: Second neoplasms in acute lymphoblastic leukemia. Cancer 52: 1712-1719, 1983. 18. Mosijczuk AD, Ruymann FB: Second malignancy in acute lymphocytic leukemia. Am J Dis Child 135:313-316, 1981. 19. Weh HJ, Kabisch H, Landbeck G, Hossfeld DK: Translocation (9;l l)(p21;q23) in a child with acute monoblastic leukemia following 2Y2 years after successful chemotherapy for neuroblastoma. J Clin Oncol 4:1518-1520, 1986. 20. Orazi A, Sozzi G, Delia D, Morandi F, Rottoli L, Cattoretti G: Acute monoblastic leukemia as a second malignancy following chemotherapy for osteogenic sarcoma: A case report. Pediatr Hematol Oncol 5:3946, 1988. 21. Verdeguer A, Castel V, Fems J , Esquembre C: Leucemia

22.

23.

24.

25.

26.

27.

28.

29. 30. 31.

32.

33.

linfoblastica aguda de riesgo estandar: Resultados preliminares del protocolo LL-IV-81. An Esp Pediatr 27:325-330, 1987. Pui CH, Behm FG, Raimondi SC, Dodge RK, George SL, Rivera GK, Mirro J, Kalwinsky DK, Dahl GV, Murphy SB, Crist WM, Williams DL: Secondary acute myeloid leukemia in children treated for acute lymphoid leukemia. N Engl J Med 321: 136-142, 1989. Meadows AT, Robinson LL, Neglia JP, Sather H, Hammond D: Potential long-term toxic effects in children treated for acute Lymphoblastic leukemia. N Engl J Med 321:1830, 1989. Smith LJ, Curtis JE, Messner HA, Senn JS, Furthrnayr H, McCulloch EA: Lineage infidelity in acute leukemia. Blood 61:1138-1145, 1983. Greaves MF, Chan LC, Furley AJW, Watt SM, Molgaard HV: Lineage promiscuity in hemopoietic differentiation and leukemia. Blood 67: 1-1 1, 1986. Pui CH, Dahl GV, Melvin S, Williams D, Peiper S , Mirro J, Murphy SB, Stass S : Acute leukemia with mixed lymphoid and myeloid phenotype. Br J Haematol 56:121-130, 1984. Altman AJ: Clinical features and biological implications of acute mixed lineage (Hybrid) leukemias. Am J Pediatr Hematol Oncol 12:123-133, 1990. Cross AH, Goorha RM, Nuss R, Behm FG, Murphy SB, Kalwinsky DK, Raimondi S , Kitchingman GR, Mirro J: Acute myeloid leukemia with T-lymphoid features: A distinct biologic and clinical entity. Blood 72:579-587, 1988. Amylon MD: Treatment of T-lineage acute lymphoblastic leukemia. HematoliOncol Clin N Am 4:937-949, 1990. Cabrera ME: Immunologic classification of acute lymphoblastic leukemia. Am J Ped HematoliOncol 12:283-291, 1990. Prieto F, Palau F, Badia L, Beneyto M, Perez-Sirvent ML, Orts A, Castel V: 1 lq23 abnormalities in children with acute nonlymphocytic leukemia (M4 M5). Association with previous chemotherapy. Cancer Genet Cytogenet 45:l-11, 1990. Ratain MJ, Kaminer LS, Bitrain JD: Acute nonlymphocytic leukemia following etoposide and cisplatin combination chemotherapy for advanced non-small-cell carcinoma of the lung. Blood 70:1412-1417, 1987. Pui CH, Hancock ML, Raimondi SC, Head DR, Thompson E, Wilimas J, Kun LE, Bowman LC, Crist WM, Pratt CB: Myeloid neoplasia in children treated for solid tumours. Lancet 336:417421, 1990.

Acute nonlymphoblastic leukemia in children treated for acute lymphoblastic leukemia with an intensive regimen including teniposide.

Some cases of conversion from acute lymphoblastic leukemia (ALL) to acute nonlymphoblastic leukemia (ANLL) at relapse have been reported recently. We ...
440KB Sizes 0 Downloads 0 Views