Cancer Genetics and Cytogenetics 182 (2008) 46e49

Short communication

A case of acute basophilic leukemia arising from chronicmyelogenous leukemia with development of t(7;8)(q32;q13)

Joseph Pidala*, Javier Pinilla-Ibarz, Hernani D. CualingH. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, MCC-GME, Tampa, Florida 33612-9416

Received 29 October 2007; received in revised form 5 December 2007; accepted 10 December 2007

Abstract Acute basophilic leukemia (ABL) is an uncommon form of acute myelogenous leukemia recentlyrecognized as a distinct entity in the World Health Organization classification of myeloid malignan-cies. A case is presented of ABL arising from chronic myelogenous leukemia with development oft(7;8)(q32;q13). Discussion includes a literature review. � 2008 Elsevier Inc. All rights reserved.

1. Introduction

Acute basophilic leukemia (ABL) is an uncommon formof acute myelogenous leukemia (AML). This has beenrecently recognized as a distinct entity in the World HealthOrganization (WHO) classification of myeloid malignancies[1]. It is characterized by blasts with basophilic granules,characteristic metachromatic toluidine blue positivity uponcytochemical staining, characteristic immunophenotypeupon flow cytometry with expression of myeloid markerssuch as CD13, CD33, CD34, and HLA-DR, and a diversegroup of cytogenetic abnormalities. The bulk of the litera-ture regarding ABL consists of case reports and case series.Despite progress since the initial description of basophilicleukemia nearly 100 years ago, considerable uncertaintyremains regarding optimal classification and management.

Here we report a case of ABL as blastic phase of chronicmyelogenous leukemia, with a previously unreportedcytogenetic abnormality t(7;8)(q32;q13). Also provided isa review of the available literature.

2. Case report

A 65-year-old man with a history of chronic myelogenousleukemia (CML) in accelerated phase was admitted to ourhospital with fever and cough in July 2007. The initial diag-nosis of CML had been made at an outside institution inJune, 2004. By report, bone marrow aspirate and biopsywere consistent with this diagnosis, and likewise the cytoge-netic karyotype, 46,XY,t(9;22)(q34;q11.2). He was treatedwith imatinib at 600 mg daily, which ultimately was reducedin dose and then discontinued because of neuropsychiatric

* Corresponding author. Tel.: (813) 745-2069; fax: (813) 745-4064.

E-mail address: Joseph.Pidala@moffitt.org (J. Pidala).

0165-4608/08/$ e see front matter � 2008 Elsevier Inc. All rights reserved.

doi:10.1016/j.cancergencyto.2007.12.009

side effects. The patient was first evaluated at our institutionin July 2005, to consider enrollment in a clinical study ofAMN-107 (nilotinib). At that time, bone marrow aspirateand biopsy confirmed CML in chronic phase. Cytogeneticanalysis of GTG-banded metaphases revealed t(9;22) in 19of 20 metaphases analyzed, and fluorescence in situ hybrid-ization (FISH) analysis, using a BCR/ABL single fusionprobe, was notable for 90.5% of marrow cells containinga single BCR/ABL fusion. On treatment with the investiga-tional agent AMN-107, the patient’s symptoms of fatigueand painful splenomegaly improved. Repeat bone marrowaspirate and biopsy in September 2005 revealed 48% of cellspositive for BCR/ABL fusion by FISH. He continued onAMN-107 and maintained a minor cytogenetic response,with serial FISH analyses revealing 37e72% of cells posi-tive for BCR/ABL fusion. The dose of AMN-107 was succes-sively decreased, because of limiting neutropenia.

In March, 2007, bone marrow biopsy revealed a hyper-cellular marrow with 7% blasts; peripheral blood exhibited29% basophilia, with the case thereby meeting WHO crite-ria for accelerated phase CML. Cytogenetics were notablefor t(9;22) in all 20 metaphases analyzed, and FISH analy-sis confirmed 80% of cells positive for BCR/ABL genefusion. Additionally, kinase domain mutational analysis re-vealed the presence of Q252H, E255K, and T315I muta-tions, the last of which confers resistance to the studydrug AMN-107, as well as to dasatinib. The patient wastherefore treated in a clinical trial with an investigationalagent, homoharringtonine (HHT) (CGX-635). He achievedno significant benefit, however, and developed transfusion-dependent anemia and thrombocytopenia.

The patient returned to the hospital with fever and respi-ratory complaints. He was empirically treated with broad-spectrum antimicrobial coverage. Because of rising white

47J. Pidala et al. / Cancer Genetics and Cytogenetics 182 (2008) 46e49

blood cell count and increased number of circulating blasts,he underwent bone marrow aspiration and biopsy, which re-vealed transformation to acute myeloid leukemia with 40%blasts. Peripheral blood analysis revealed 31% circulatingbasophilic blasts. Morphologically, the blasts displayedbasophilic granules, and were accompanied by basophilicpromyelocytes and myelocytes (Fig. 1). Flow cytometryfindings were CD34þ, HLA-DRþ, CD117�, CD13þ,CD33þ. The histochemistry analysis was notable for meta-chromatic staining with MayeGrunwald stain (Fig. 2) andperiodic acideSchiff positivity, but negativity for myeloper-oxidase and neuron-specific enolase. FISH analysis revealed86% of cells with BCR/ABL fusion signals. Cytogeneticanalysis now revealed t(7;8)(q32;q13) and t(9;22)(q34;q11.2) translocations in all metaphases (Fig. 3).

The patient experienced a progressive clinical decline,with respiratory failure necessitating intubation and me-chanical ventilation. Given his very poor clinical status,he was deemed not eligible for leukemia induction therapy.His blast count was controlled with hydroxyurea. Ulti-mately, all but palliative care was withdrawn, and he diedin the intensive care unit.

3. Discussion

Acute basophilic leukemia, a rare form of acute leuke-mia, was recognized as a distinct entity by the most recentWHO classification of myeloid malignancies [1]. Histori-cally, the term basophilic leukemia has been used to de-scribe a heterogeneous group of disorders, with the firstaccount published in 1906 by Joachim [2]. Since then, therehave been reports of basophilic blast crisis rising fromchronic granulocytic leukemia [3,4], as well as of de novoacute basophilic leukemia [5e16]. Overall, acute baso-philic leukemia has been characterized by a predilectionfor extramedullary involvement with cutaneous disease, or-ganomegaly, lytic bone lesions, and symptoms of hyperhis-taminemia [5]. Upon review, Seth et al. [9] reported that 9out of 29 cases evaluated of acute basophilic leukemia hadsymptoms of hyperhistaminemia, including, among others,urticaria, peptic ulceration, and anaphylactoid shock.

Fig. 1. Cluster of basophilic blasts evident on bone marrow aspirate.

WrighteGiemsa stain; 1,000�.

Basophilic blasts are typically characterized by a highnucleus-to-cytoplasm ratio, round to indented nuclei withopen chromatin pattern, and abundant basophilic granules.Variations have been reported in cases of acute basophilicleukemia. Upon cytochemical staining, there has beena unique pattern with myeloperoxidase negative, nonspe-cific esterase negative, metachromatic positivity with tolu-idine blue or Giemsa, acid phosphatase positivity, and insome cases periodic acideSchiff positivity [5]. There isno consensus agreement regarding the number of baso-philic blasts required for diagnosis of acute basophilic leu-kemia, with a vast reported range from 0 to 70% [5,7,9,13].Several authors have stressed the importance of correlativeimmunophenotypic studies, cytogenetics, and further char-acterization of granules with electron microscopy. Cases ofundifferentiated AML designated M0 have been demon-strated to have granules with basophilic or mast cell fea-tures upon electron microscopy [13]. Basophilic blastshave been described as expressing myeloid markers, in-cluding CD13, CD33, CD34, and HLA-DR. Additionally,distinctive patterns have been described, including dualpositivity for CD34 and CD25 [10], as well as negativityfor CD117 and cytoplasmic positivity for CD203 [11].

Although two cytogenetic abnormalities characteristi-cally seen in cases of AML with increased basophils, 12pand t(6;9), are not seen in cases of acute basophilic leuke-mia, there are many reports of other cytogenetic abnormal-ities. These include the following: a normal karyotype ort(2;6)(q23?4;p22?3) and del(12)(p11), as well as a normalkaryotype [6]; translocation t(X;6)(p11;q23) [7]; simulta-neous translocations t(8;21) and t(9;22) [8]; t(8;21) [9];monosomy 7 [12,16]; del(5)(q31q35) in the setting of con-version from myelodysplastic syndrome [14]; t(9;22) in denovo acute basophilic leukemia [15]; and trisomy 8 [16].

Here we have reported a newly identified abnormality,t(7;8)(q32;q13), in the setting of blastic transformationfrom accelerated phase CML. Previously, the patient’s

Fig. 2. Basophilic blasts on bone marrow aspirate exhibit metachromatic

staining. MayeGrunwald stain; 1,000�.

48 J. Pidala et al. / Cancer Genetics and Cytogenetics 182 (2008) 46e49

Fig. 3. The karyogram 46,XY,t(7;8)(q32;q13),t(9;22)(q34;q11.2)[20] from GTG banding.

cytogenetic analysis was notable only for t(9;22) on serialevaluations.

The exact significance of the t(7;8) translocation event isnot known. The TRIM24 gene (previously TIF1) is knownto localize at 7q32~q34. This transcription factor has beenimplicated in the setting of t(7;8)(q34;p11) in acute mye-logenous leukemia, as well as in the 8p11 myeloprolifera-tive syndrome. Additionally, the NCOA2 gene (aliasTIF2), which is thought to mediate transcriptional activa-tion by a mechanism involving chromatin remodeling, isknown to localize at 8q13 [17e22]. These are intriguingcandidates, but further sequencing would be needed toidentify the genes involved in this translocation event.

Induction therapy was not possible in the present case,because of the patient’s poor clinical status. Several au-thors, however, have reported results of various inductionregimens in the management of acute basophilic leukemia.These have included regimens typically used for inductiontherapy for AML and for acute lymphoblastic leukemia.Overall, the results have been disappointing, with low ratesof attainment of complete remission, and those reported tohave achieved complete remission had short-lived remis-sions, with relapse generally within months. Nonetheless,there is a great deal of variation among these results, rang-ing failure to achieve complete remission resulting in deathwithin months (range, 47 days to 11 months) to completeremission followed by relapse and death (range, 6e42months) [6,15,23e26].

There are no prospective randomized trials comparingmanagement strategies for acute basophilic leukemia. Ad-ditionally, there is no firm consensus regarding standardsfor defining complete remission. Seth et al. [9] proposed

criteria including a normocellular bone marrow with!5% blasts and !2% basophils, as well as peripheralblood with no blasts and !2% basophils. Further studiesare needed to better characterize this rare condition, inves-tigate prognostic factors, and define optimal management.

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