Leukemia and Lymphoma, 2000, Vol. 38(5-6). pp. 621-625 Repnnts available directly from the publisher Photocopying permitted by license only

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Acute Myeloid Leukemia, Inversion 16, Occurring in a Patient with Chronic Lymphocytic Leukemia

GRACE M. BARRESIa, MAHER ALBITARb and SUSAN M. O!EiRIENa*

aFrom the Departments of Leukemia and bHematopathology, at The University of Texas M.D. Anderson Cancer Centec Department of Leukemia, 1515 Holcombe Boulevard, Box 61, Houston Texas 77030 USA

The occurrence of acute myeloid leukemia (AML) in patients previously diagnosed with chronic lymphocytic leukemia (CLL) is rare. In most cases, AML develops after treatment of CLL and is thought to be therapy related; unfavorable karyotypes are often evident. Herein, we report a patient with a long-standing history of CLL who developed AML with cytoge- netic analysis revealing inversion 16. In keeping with the favorable prognosis of this abnor- mality, the patient has achieved a complete remission, which has been maintained for 13 months.

Keywords: chronic lymphocytic leukemia {CLW, acute myeloid leukemia (AML), therapy related AML (tAML), inversion 16

INTRODUCTION

The incidence of acute myeloid leukemia (AML) in patients previously diagnosed with chronic lym- phocytic leukemia (CLL) is rare (less than l%).(') In the majority of reported cases, AML is diagnosed fol- lowing treatment of CLL and is thought to be a sec- ondary leukemia or therapy-related (tAML).(2) However, there are reports of AML arising in patients with previously untreated CLL, as well as infrequent cases of AML and CLL diagnosed simultane- o u ~ l y . ( ~ . ~ , ~ ) Presumed mechanisms for the develop- ment of AML in patients with CLL include an immunodeficiency state and/or the use of alkylating agent^.(^'^'^) When reported, karyotypic abnormalities within the AML blasts are usually unfavorable, sup- porting a secondary leukemia.(3)

In this article, we report a case of AML with a favorable karyotype (inversion 16), occurring in a previously treated patient with CLL.

Case Report

A 67-year-old man was referred to M.D. Anderson Cancer Center (MDACC) in November 1997 with Rai stage IV CLL. The diagnosis of CLL was made in 1972 when the patient developed axillary lymphadenopathy (2cm). A hematologic work-up was consistent with B-cell CLL, Rai stage I. His course was indolent and he was observed without therapy. In 1997, the patient developed recurrent upper respiratory infections, leu- kocytosis, and thrombocytopenia and was referred to MDACC. Physical examination disclosed 2 cm axil- lary lymph nodes and a 15 cm palpable spleen. Hema- tologic parameters were as follows: white blood cell

* Address correspondence to: Susan M. O'Brien MD Professor of Medicine Telephone (713) 792-7543 Fax (713) 794-4297

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622 GRACE M. BARRESI et al,

FIGURE 1 Representative hone marrow morphology showing chronic lymphocytic leukemia on biopsy (A) and aspirate smear (B) at the time of presentation. Panels C and D are taken at the time of acute leukemia. Panel C is a biopsy section showing infiltrate by blasts and abnormal eosinophils surrounding a lymphoid aggregate (lymphoid nodule in right corner). Panel D is the aspirate smear corresponding to the biopsy seen in C and shows blasts, abnormal eosinophils and rare lymphoid cells. B and D are IOOOX and A and C 200X (See Color Plate IX at the back of this issue)

(WBC) count 90.2 x 109L with 93% lymphocytes, platelet count 64 x 109L and hemoglobin 13.8 g/dl. The bone marrow (BM) aspiration revealed 72% lym- phocytes with the biopsy showing a cellularity of 65 %, diffuse infiltration with lymphocytes, and decreased megakaryocytes.(Figure 1 A,B) Immunophenotypic studies were consistent with B-cell CLL (95% CD23, 90% CDYCD 19 coexpression). Cytogenetic analysis revealed only diploid metaphases.

The patient was started on therapy with fludarabine 30mg/m2/ day iv x 3 days and cyclophosphamide 300 mg/m2/day iv x 3 days with granulocyte-macro- phage-colony stimulating factor (GM-CSF) adminis- tered starting on day 4. The patient responded to the

chemotherapy with decreasing adenopathy and nor- malization of his WBC count. However, splenomeg- aly and thrombocytopenia persisted and he underwent a splenectomy in March 1998 after three courses of chemotherapy. The surgery was without complica- tions and the platelet count normalized shortly there- after. In June 1998 he completed six courses of chemotherapy but his peripheral blood counts remained low (Table I). A bone marrow aspiration and biopsy showed 16% lymphocytes and rare lym- phoid aggregates; a small percentage of cells coex- pressing CDYCD19 were evident on immunophenotypic analysis, suggesting minimal residual disease.

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AIVIL, IN VCKblUlV 10, ANU LLL 623

TABLE I Hematologic Parameters ~~

11/97 06/98 11/98 07/99

Peripheral Blood

WBC (x109n) 90 2.0 2.0 6.9 Lymphocytes 93 38 63 25

Neutrophils 5 43 4 47

Hemoglobin g/dl 13.8 12.9 10.6 12.3

Platelets ( ~ 1 0 ~ ~ ) 64 31 42 107

BoneMarrow

Aspiration Blasts % 1 2 30 0

Lymphocytes % 72 16 27 11

Biopsy diffuse, interstitial multiple lymphoid rare lymphoid no evidence of CLL lymphocytosis 80% aggregates aggregates

Cytogenetics diploid N/D Inv 16, -7, +21 diploid

PCR N/D NiD Inv 16 negative

Immunophenotype

CDS/CD19+ % 90 5 6 6

CD13+ % N/D NiD 85 N/D

CD33+ % N/D N/D 69 N/D

Abbreviation; N/D: not done

In November 1998, worsening pancytopenia was noted (Table I). Bone marrow at that time showed 30% blasts, 27% lymphocytes, 13 % eosinophils and 16% monocytes.(Figure 1 C,D) The blasts were mye- loperoxidase positive and flow cytometric analysis showed myeloid markers (85% CD13, 69% CD33). Cytogenetic analysis revealed 4 normal metaphases; 15 of 19 metaphases had inversion 16. Additionally, trisomy 21 and loss of the long arm of chromosome 7 (7q-) were noted in 3 metaphases. Minimal CLL was evident in the bone marrow with rare lymphoid aggre- gates and 5% CD5ICD19 coexpression on the lym- phocytes.

The patient received induction chemotherapy with cyclophosphamide 300 mg/m2 iv every 12 hours x six doses on days 1-3, cytarabine 1 g d m 2 iv daily on days 2-6, topotecan 1.5 mg/m2 iv continuous infusion over 24 hours on days 2-5 and G-CSF 5 mcgkg daily starting on day 5 (CAT + G-CSF). A complete remis- sion was documented on day 45. After four courses of chemotherapy, cytogenetic analysis revealed normal diploid karyotype and polymerase chain reaction

(PCR) for inversion 16 was negative. The patient remains in remission for 13 months from diagnosis.

DISCUSSION

Development of AML following CLL is rare, even though patients with CLL often have long-term expo- sure to alkylating agents. In most cases, AML occurs after treatment of CLL and is thought to be therapy related because poor-prognosis karyotypes are often evident. There have also been reports of patients with untreated CLL who developed AML. Stem et a1(@ published the first case of a patient with previously untreated CLL terminating in AML. The simultane- ous presentation of CLL and AML has also been described. Lima et al(9) reported a patient who was diagnosed concomitantly with CLL and AML and had karyotypic abnormalities representative of both diseases (-7, +12, +21). Monosomy 7 and trisomy 21 have been described in both de novo and secondary AML; trisomy 12 is the most frequent karyotypic

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624 GRACE M. BARRESI et al.

abnormality in B-CLL, occurring in one-third of patients with chromosomal abnormalities. Bracey et al(3)described a patient with a concurrent diagnosis of CLL and MDS with unfavorable chromosomal abnor- malities (-7, +8) who developed AML shortly after treatment of CLL.

The unusual aspect of the case described in this report is the development of AML, inversion 16, in a patient with a long-standing history of CLL. To our knowledge, this is the first case of AML with inver- sion 16 reported in a patient with CLL. Interestingly, there have been no reports of AML with other favora- ble karyotypes such as t(8,21) or t(15,17) occurring in patients with CLL.

The question remains as to whether this AML was a secondary leukemia, possibly resulting from prior treatment with cyclophosphamide and fludarabine, or a de novo malignancy. The earliest reports of CLL ter- minating in AML were published between 1949 and 1966 and involved patients treated with radioactive phosphorus and/or external radiation therapy.(@ In the 1970's, alkylating agents such as chlorambucil and cyclophosphamide replaced radioactive phosphorus and became the mainstay of therapy.(6910)

Prior exposure to alkylating agents may cause sec- ondary leukemias by directly damaging DNA(1 '); both chlorambucil and cyclophosphamide have been implicated in this process.(12) Catovsky and Galton first described the leukemogenic potential of chlo- rambucil in patients with CLL. The incidence of ther- apy-related acute myeloid leukemia (tAML) after exposure to alkylating agents is lower when the agents are used intermittently as opposed to pro- longed, continuous exposure. Of the alkylating agents, cyclophosphamide appears to be less leuke- mogenic.(' 2 ,

Therapy-related AML (tAML) resulting from pro- longed exposure to alkylating agents usually develops after an interval of 3 to 6 years, is associated with poor prognosis karyotypes (ie., del 5, del 7) and is often preceded by a preleukemic phase. Conversely, 5 % to 10 % of tAML are associated with favorable karyotypes such as inv(l6), t(8;21), and t(15;17). These cases occur after a brief latent period and are not preceded by a preleukemic phase.(13>14)

Robertson et analyzed a cohort of more than 1000 patients with CLL treated with fludarabine and found no evidence of an increased risk of AML. More recently, Keating et al(15) analyzed the long-term fol- low up of 174 patients with CLL who received initial therapy with fludarabine. No cases of AML were identified. Currently, there is no clear evidence that fludarabine plays a role in leukemogenesis.(16) Never- theless, long term follow-up of these patients may provide further information.

In this case, the patient developed AML, inversion 16, approximately four months after receiving chemo- therapy for his CLL. The relatively short latent period and absence of a preleukemic phase argue against a tAML, as does the favorable karyotype. The inci- dence of tAML, inversion 16, has been reported to be approximately 5 %6(7) whereas de novo AML, inver- sion 16, has been reported to be between 4 % and 8 %(17); both have favorable outcomes and respond to chemotherapy with similar complete remission rates and disease free intervals.(18)

Some authors have postulated that decreased immune surveillance in patients with CLL may con- tribute to the emergence of aberrant myeloid clones.(") Patients with immunodeficiency diseases have a higher incidence of neoplasia when compared to the general population.(20) Interestingly, in this case the patient had a very long history of CLL (25 years) and the associated immunodeficiency states may have played a role in his subsequent develop- ment of AML.

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AML. INVERSION 16, AND CLL 625

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15) Keating M.J., OBrien S.M., Lerner S, (1998) Long-term Fol- low-up of patients with Chronic Lymphocytic Leukemia receiving Fludarabine regimens as Initial therapy. Blood, 92 (4), 1165-1171.

16) Coso D, Costello D, Cohen-Valensi R, Sainty D, Nezri M, Gastaut, Bouabdallah R. (1 999) Acute Myeloid Leukemia and Myelodysplasia in patients with Chronic Lymphocytic Leukemia receiving Fludarabine as initial therapy. Ann Oncology, 10 (3), 362-363.

7) Mitelman F. (1991) In Catalog of Chromosome Aberrations in Cancer. 4” Ed, pp. New York: Wiley-Liss.

8) Kantarjian H.M., Keating M.J., Walters R.S., Beran M, McLaughlin P, McCredie K.B., Freireich E.J. (1986) The Association of Specific “Favourable” Cytogenetic Abnor- malities with Secondary Leukemias. Cancer, 58,924-927.

9) Wallis J.P., Joyner M.V. (1986) Acute Myeloid Leukemia developing in a patient with longstanding untreated Chronic Lymphocytic Leukemia. Acta Hematology, 75, 229.

20) Waldman T.A., Strober W, Blaese R.M. (1972) Immunodefi- ciency and Maligancy: various immunologic deficiencies of man and the role of immune processes in the control of malignant diseases. Annals of Internal Medicine, 77, 605- 628.

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Color Plate IX (See page 622, Figure 1) Representative hone marrow morphology showing chronic lymphocytic leukemia on biopsy (A) and aspirate smear (B) at the time of presentation. Panels C and D are taken at the time of acute leukemia. Panel C is a biopsy section showing infiltrate by blasts and abnormal eosinophils surrounding a lymphoid aggregate (lymphoid nodule in right corner). Panel D is the aspirate smear corresponding to the biopsy seen in C and shows blasts, abnorma1,eosinophils and rare lymphoid cells. B and D are lOOOX and A and C 200x

Color Plate X (See page 628, Figure 1) A Jainshidi hone marrow biopsy from a patient with acute leukemia showing evidence of extensive bone marrow necrosis. The cells have indistinct cellular inargins and pyknotic nuclei in an amorphous eosinophilic hack- ground

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