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range exposure is unclear as studies have yielded conflict-ng results [8]. It cannot be determined whether the com-ination of Agent Orange exposure and RT will increasehe risk of leukemia, but given the large number of indi-iduals likely to receive radiation in the future we thoughtt would be of interest to call attention to this possiblenteraction.

cknowledgements

Contributions. Ehab Atallah, reviewed the literature androte the letter; Charles A. Schiffer, reviewed the letter andade corrections.

eferences

1] Frumkin H. Agent Orange and cancer: an overview for clinicians. CACancer J Clin 2003;53:245–55.

2] Beaumont M, Sanz M, Carli PM, et al. Therapy-related acute promye-locytic leukemia. J Clin Oncol 2003;21:2123–37.

3] Brenner DJ, Curtis RE, Hall EJ, Ron E. Second malignancies in prostatecarcinoma patients after radiotherapy compared with surgery. Cancer2000;88:398–406.

4] Schmidt CK, Hoegberg P, Fletcher N, et al. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters the endogenous metabolism of all-trans-retinoicacid in the rat. Arch Toxicol 2003;77:371–83.

5] Schwarz M, Appel KE. Carcinogenic risks of dioxin: mechanistic con-siderations. Regul Toxicol Pharmacol 2005;43:19–34.

6] Whitlock Jr JP. Induction of cytochrome P4501A1. Annu Rev PharmacolToxicol 1999;39:103–25.

7] Bock KW, Kohle C. Ah receptor: dioxin-mediated toxic responsesas hints to deregulated physiologic functions. Biochem Pharmacol2006.

8] Giri VN, Cassidy AE, Beebe-Dimmer J, et al. Association betweenAgent Orange and prostate cancer: a pilot case-control study. Urology2004;63:757–60.

Ehab Atallah ∗Charles A. Schiffer

Karmanos Cancer Institute, Wayne State University,Hematology, Oncology, 4100 John R, 4-HWCRC Detroit,

MI 48201, United States

∗ Corresponding author. Tel.: +1 313 576 8720E-mail address: atallahe@karmanos.org (E. Atallah)

4 June 2006Available online 7 September 2006

oi: 10.1016/j.leukres.2006.06.025

nefficacy of bortezomib therapy for CNS involvement ofefractory multiple myeloma

Although neurologic manifestations often complicate the

ourse of patients with multiple myeloma (MM), directentral nervous system (CNS) invasion is very rare. Weould recall the attention to the recent experiences about

he efficacy of bortezomib for treatment of extramedullary

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search 31 (2007) 719–726 721

elapses of MM including CNS involvement after autol-gous and allogeneic transplantation [1,2]. We report thease of a 57-year-old male patient affected by refrac-ory stage IIIA light-chain MM without any evidence ofxtramedullary disease at initiation of bortezomib ther-py, who developed CNS involvements after fourth cyclef treatment, despite good haematological response andignificant decrease of the original urinary monoclonalaraprotein.

In May 2001, our patient received treatment accord-ng to VAD-like protocol and radiotherapy to the right

andible for extramedullary disease confirmed by biopsy;hereafter, because of stable disease the patient was treatedith cyclophosphamide 1500 mg/m2 once daily i.v. on daysand 3 and dexamethasone 40 mg once daily i.v. for 4 con-

ecutive days, every 28 days (total four cycles). In November001, he underwent local radiotherapy on the pelvis for oneass involving the right wing of the ilium, despite bonearrow biopsy demonstrated haematological remission and

mmunofixation revealed the absence of the original uri-ary monoclonal paraprotein. In April and August 2002, theatient received double autologous peripheral blood stem cellransplantation, after conditioning regimen with 200 mg/m2

elphalan. In November 2003, the patient relapsed withxtensive skeletal disease and an increase of monoclonalaraprotein without extramedullary disease; bone marrowiopsy revealed 50% plasma cell involvement; therapy withhalidomide and dexamethasone was started. In April 2004,otal body computed tomography (CT), performed for tho-acic pain, showed one thoracic mass 10 cm × 10 cm aris-ng from fifth ring, despite bone marrow plasma cell rateas <10%; cerebral CT excluded all possibilities of CNS

nvolvement; local radiotherapy was performed after stop-ing thalidomide and dexamethasone treatment. In Octo-er 2004, because of a new haematological relapse (bonearrow malignant plasma cell rate = 45%) treatment with

ortezomib at the dose of 1.3 mg/m2 once daily i.v. onays 1, 4, 8 and 11, every 21 days, was started. In Jan-ary 2005, after fourth cycle of treatment with bortezomib,he patient was hospitalizated for fever superior to 38 ◦Cithout other clinically significant features. Absolute neu-

rophil count was constantly superior to 1.5 × 109 L−1; theaemoglobin level and platelet count were within normalimits. During hospitalization, the patient suddenly devel-ped cerebral findings: difficulty in speaking, convulsion andoss of consciousness. Cerebral magnetic resonance imagingith and without contrast in the cingulum groove showedhypointense collection in T1 and hyperintense collection

n T2 with strong enhancement after i.v. contrast injection;ocal and circumscribed dural thickening was also presentver the cerebral convexity into parietal site to the right,hich might have been misinterpreted as meningioma but

n the meantime intense and abnormal enhancement after i.v.ontrast injection and laboratory tests of the cerebrospinaluid helped identify the precise malignant nature of theffusion. Cytological examination, immunophenotypic anal-

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22 Letters to the Editor / Leuke

sis and microbiological assessments of the cerebrospinaluid were essential for differential diagnosis with intra-ranial haemorrhage and infectious meningitis, which haveeen cautiously and promptly ruled out. Cerebrospinal fluidevealed pleocytosis with more than 10 white blood cells pericroliter: the morphological examination evidenced atyp-

cal plasma cells and immunophenotypic analysis showedo-expression of CD38 and CD138; microbiological cul-ures and specific virological studies of cerebrospinal fluidere negative. Bone marrow biopsy showed a good haema-

ological response. Aggressive treatment with systemicigh-dose of dexamethasone, intrathecal administration oforticosteroids and cytosine-arabinoside and craniospinalrradiation was ineffective and the patient died 27 daysater.

Bortezomib is the first proteasome inhibitor with docu-ented activity against a broad range of human neoplastic

ells [3]. Bortezomib has been recently approved for thereatment of patients with MM who have received at leastne prior therapy and are not eligible for bone marrow trans-lantation. Unfortunately, it does not cross the blood–brainarrier. Clinical data about its difficulty of overcoming thelood–brain barrier mainly come from studies conducted inatients with solid malignancies [4,5], while very small ishe number of published experiences examining the role ofortezomib in CNS involvement of MM [1]. In our patient,erebral involvement occurs under bortezomib therapy with-ut any increase in bone marrow plasma cells and increasen the M-protein size. Our clinical experience extends theery small number of published cases on efficacy of borte-omib therapy for extramedullary disease progression ofM [1,2].In vivo experimental studies conducted in rats by i.v.

dministration of radiolabeled [14C]PS341 show reduced dis-ribution of bortezomib in some organs and tissues (skeletal

uscle and skin) as well as its difficulty of penetrating therain, spinal cord, testes and eye [6,7]. In adult patientsith solid malignancies, bortezomib rapidly spreads over all

issues, after giving a single dose with an initial plasma dis-ribution half-life of less than 10 min, but not in the CNS4,5]. Kropff experiences only a “bone marrow restrictedctivity of bortezomib” [8]. Contrarily, Patriarca, in completeisagreement with experimental data of pharmacokineticsublished by Adams and with clinical experiences conductedn patients with solid malignancies, reports the efficacy ofortezomib for extramedullary relapses of MM includingNS involvements after autologous and allogeneic transplan-

ation [1]. Although pharmacokinetics studies of bortezomibn patients with MM are not completely characterized, in vivoxperimental data and all additional clinical trials demon-trate lack of activity and efficacy of bortezomib in patientsith cerebral involvements; the absence of response of borte-

omib in this subset of patients is due to its difficulty ofenetrating the brain. Further biological bases and molec-lar principles of resistance to bortezomib are not known athe moment. Patriarca, in his singular clinical experience,

search 31 (2007) 719–726

uggests that the efficacy of bortezomib therapy could beue to an improbable immunological graft-versus-myelomaffect.

A possible alternative for overcoming the difficulty ofortezomib to penetrate the CNS might be its combinationith other anticancer drugs; in fact, bortezomib increases

he sensitivity of multiple myeloma cells to conventionalhemotherapy because of a potential synergic effect with anti-ancer agents.

cknowledgements

This study was supported by the A.I.L. (Associazionetaliana contro Leucemie-Linfomi e Mieloma)—Brindisi.iuseppe Mele and Salvatore Pinna: Collection and interpre-

ation of clinical data. Emilia Alloro: Analysis of radiologicalata. Maria Rosaria Coppi and Maurizio Brocca: Analysisnd interpretation of laboratory data. Giovanni Quarta: Crit-cal revision of the manuscript. In addition, we thank Marioegro for technical assistance.

eferences

1] Patriarca F, Prosdocimo S, Tomadini V, et al. Efficacy of borte-zomib therapy for extramedullary relapse of myeloma after autologousand non-myeloablative allogeneic transplantation. Haematol/Hematol J2005;90(2):278–9.

2] Krauth MT, Bankier A, Valent P, et al. Sustained remission includingmarked regression of a paravertebral plasmacytoma in a patient withheavily pretreated, relapsed multiple myeloma after treatment with borte-zomib. Leuk Res 2005;29:1473–7.

3] Adams J, Palombella VJ, Elliott PJ. Proteasome inhibition: anew strategy in cancer treatment. Investig New Drugs 2000;18:109–21.

4] Supko JG, Eder JP, Lynch TJ, et al. Pharmacokinetics of irinote-can and the proteasome inhibitor bortezomib in adult patients withsolid malignancies. Proc Am Soc Clin Oncol 2003;22:136 [Abs544].

5] Schwartz R, Davidson T. Pharmacology, pharmacokinetics and practi-cal applications of bortezomib. Oncology (Williston Park) 2004;18(14Suppl. 11):14–21.

6] Adams J, Palombella VJ, Sausville EA, et al. Proteasome inhibitors:a novel class of potent and effective antitumor agents. Cancer Res1999;59:2615–22.

7] Adams J, Kauffman M. Development of the proteasome inhibitor velcade(bortezomib). Cancer Invest 2004;22:304–11.

8] Kropff MH, Bisping G, Wenning D, et al. Bortezomib in combi-nation with dexamethasone for relapsed multiple myeloma. Blood2004;104(11):4923 [Abs].

Giuseppe Mele ∗Salvatore Pinna

Clinical Division of Haematology andBMT Unit, Antonio Perrino Hospital, SS 7,

72100 Brindisi, Italy

Emilia AlloroDivision of Neuroradiology, Antonio

Perrino Hospital, Brindisi, Italy

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Letters to the Editor / Leuke

Maurizio Claudio BroccaMaria Rosaria Coppi

Giovanni QuartaClinical Division of Haematology and BMT Unit,

Antonio Perrino Hospital, SS 7, 72100 Brindisi, Italy

∗ Tel.: +39 0831 537506; fax: +39 0831 537513.E-mail address: giuseppemele67@tiscali.it (G. Mele)

10 June 2006Available online 4 August 2006

oi: 10.1016/j.leukres.2006.06.019

eletion of chromosome 13: A rare form of cytogeneticvolution in blast phase of chronic myelogenous leukemias there an association with favorable outcome?

A 69-year-old man was referred to our facility with leu-ocytosis and splenomegaly. He stated that he had recentlyad recurrent fever (38–38.5 ◦C), fatigue, loss of appetitend weight loss. He was asymptomatic until 6 weeks beforedmission in our facility. On physical examination, the patientas afebrile. The head, neck, lungs, arms and legs were nor-al, and the results of a neurologic examination showed

o abnormalities. Blood levels of aminotransferases (ASTnd ALT), alkaline phosphatase, gamma-glutamyl transpep-idase, bilirubin, blood urea nitrogen, creatinine, glucosend serum LDH were normal. The white-cell count was8,500 mm−3. Granulocytes at all stages of developmentere present in the blood and were generally normal in

ppearance. The blast prevalence was 3%. Hemoglobinevel was 9.5 g/dL and platelet count was 501,000 mm−3.he bone marrow aspirate was reported to show a hyper-ellular marrow with granulocytes at all stages of devel-pment and 34% blast cells with high nuclear/cytoplasmatio, basophilic cytoplasm with the presence of Auer Rodsnd non-condensed nuclear chromatin. On a peroxidasetain the blasts showed granular positivity (51%); peri-dic acid-Schiff positivity was observed in 2% of thelasts. Immunophenotyping of a bone marrow aspirate byow cytometry revealed one immunologically distinct blastell subset expressing myeloid markers (CD13+, CD33+,yeloperoxidase+). Cytogenetic studies performed from

one marrow in short-term unstimulated culture evidenced6,XYt(99;22)(q34.1;q11.2)del(13)(q12)[20]. RT-PCR forCR-ABL transcripts was positive. These findings defined

he diagnosis of chronic myelogenous leukemia in blast phaseCML-BP) of myeloid phenotype. Patient received 400 mgf imatinib mesylate per day in association with cytarabine0 mg/m2 for 10 days each month; 3 months later cytarabineas discontinuated. The patient has been seen as an outpa-

ient at this facility (Table 1).Chronic myelogenous leukemia is a stem cell disorder

hich progresses from a chronic phase to an acceleratedhase and/or a blast phase of myeloid or lymphoid phe-

ccrp

search 31 (2007) 719–726 723

otype. This progression is frequently preceded or accom-anied by recurring secondary chromosomal abnormalitieshich are believed to play a role in the transformation and

linical outcomes [1]. We searched MedLine, Scielo andilacs from 1980 to the fourth quarter of 2005 to identifyapers dealing with chromosomal abnormalities identifiedy conventional cytogenetics in CML-BP. In this setting,erzianu et al. [2] described five patients with CML-BP inhich t(9;22) and inv(16)(p13q22) were identified by con-entional cytogenetics. The clinical course of these patientsas similar to patients with CML-BP without evidence of

nv(16)(p13;q22). On the other hand, unlike de novo acuteyelogenous leukemia (AML), inv(16)(p13;q22) in CML-P was not associated with a favorable prognosis. Patel et al.

3] describe two patients with CML-BP with clonal evolu-ion affecting 16q22 t(16;16)(p13;q22) and inv(16)(p13;q22),bnormalities of core binding factor, usually found in de novoML. The authors, based on a literature search focused onatients with CML-BP and additional chromosome changesore typical of AML, revealed that the morphology of the

lasts correlated with the finding typical of the underly-ng AML cytogenetic abnormality and an overall very poorlinical outcome, even in the groups with favorable AMLype translocations. In addition, Yin et al. [4] identified the(8;21)(q22;q22) by conventional cytogenetics and fluores-ence in situ hybridization in two patients with CML-BP,hich typically is associated with a distinct subtype of deovo AML, and discussed that the pathologic features ofML-BP with the t(8;21) resemble those of de novo AMLith the t(8;21). Finally, Storlazzi et al. [5] described recentlyne patient with CML-BP in which the malignant clone devel-ped a new additional cytogenetic abnormality consisting ofdeletion of chromosome 21.

Chromosomal analysis consisting of a deletion of chro-osome 13 (del(13)) restricted to patients with CML-BP has

ot been currently demonstrated. Among the myeloprolifer-tive diseases an association exists only for del(13)(q12;q14)nd chronic idiophatic myelofibrosis [6]. Besides, del(13) hasot been demonstrated in patients with acute leukemias [7].o the best of our knowledge, this is the first case of del(13)eported in literature associated with CML-BP; consequently,he clinical correlation or the descriptions of risk groups basedn del(13) alone or associated with other factors have noteen demonstrated in these patients. CML-BP, generally, is areatment-refractory and morbid state that is fatal in weeks to

onths. Patients with myeloid blast crisis have a median sur-ival of about 2 months, and patients rarely survive beyondmonths. On the other hand, the advent of imatinib has

mproved the progression-free survival in patients with CML-P [8]. However, little is known so far about the influence ofel(13) on the quality of responses to imatinib mesylate inhese patients. As demonstrated, the good response to three

ourses of lower dose cytarabine induction-therapy in asso-iation with the demonstration of cytogenetic and molecularesponses after 18 months of imatinib mesilate therapy in aatient with CML-BP who remained alive after a 24 months