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Leukemia Research 31 (2007) 1445–1447

Case of the month

What is the best salvage therapy for treatment of isolated CNS relapsein elderly patients with imatinib-responsive Ph+ ALL?

Giuseppe Mele ∗, Salvatore Pinna, Angela Melpignano, Antonio Romano,Maurizio Claudio Brocca, Maria Rosaria Coppi, Giovanni Quarta

Clinical Division of Haematology and BMT Unit, “Antonio Perrino” Hospital, Brindisi, Italy

Received 12 December 2006; received in revised form 10 March 2007; accepted 12 March 2007Available online 25 April 2007

bstract

We report the case of an elderly patient affected by Philadelphia positive Acute Lymphoblastic Leukaemia (Ph+ ALL) who developedeningeal leukaemia during imatinib monotherapy, despite bone marrow molecular remission. Aggressive central nervous system (CNS)-

irected therapy in combination with continued imatinib treatment might be, at the moment, the most effective salvage therapy for imatinib-

esponsive elderly patients with isolated CNS relapse. In view of the inefficacy of imatinib at preventing meningeal leukaemia for its poorenetration into the CNS, CNS prophylactic therapy should always be an integral part of any imatinib-based treatment strategy for Ph+ ALL.

2007 Elsevier Ltd. All rights reserved.

eywords: Imatinib; Ph+ ALL; Elderly patients; Meningeal leukaemia

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. Introduction

Chemotherapic protocols in elderly patients with chromo-ome Philadelphia positive Acute Lymphoblastic LeukaemiaPh+ ALL) are associated with an exceptionally poor prog-osis due to a lower complete response rate, short remissionuration and high induction mortality [1]. Because of aignificant antileukaemic activity and a favourable toxicityrofile of imatinib, some international studies (GIMEMA andMALL) have explored the value of single-agent imatinib

nduction therapy without any other chemotherapeutic drugsncluding central nervous system (CNS)-directed prophylac-ic therapy in elderly patients with newly diagnosed Ph+ ALL2,3]. Unfortunately, imatinib does not cross the blood–brainarrier. So, Ph+ ALL are considered at high risk of meningealeukaemia during imatinib monotherapy [4–6].

∗ Corresponding author. Tel.: +39 0831 537506; fax: +39 0831 537613.E-mail address: giuseppemele@auslbr1.it (G. Mele).

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145-2126/$ – see front matter © 2007 Elsevier Ltd. All rights reserved.oi:10.1016/j.leukres.2007.03.018

. Case report

We report the case of a 64-year-old male patient affectedy Ph+ ALL who developed central nervous system involve-ent after 9 months of treatment with imatinib, despite

omplete molecular remission in the bone marrow. In July005, the patient entered ongoing GIMEMA LAL 0201 trial,tudy B, a study for newly diagnosed Ph+ ALL patients >aged0, and received induction therapy consisting of imatinib p.o.t the dosage of 400 mg × 2 daily “associated” to prednisone0 mg/m2/day for 30 days, without any other chemotherapeu-ic agents. At the time of the leukaemia diagnosis the physicalxam, instrumental tests (i.e. chest X-ray, electrocardiogram)nd laboratory parameters detected neither cardiovasculariseases, liver diseases, kidney diseases nor infection diseasesnd diabetes mellitus; the surveillance cultures periodi-ally performed from nasal, pharyngeal, rectal, urinary andkin swabs were negative. Our neutropenic patient received

ntibacterial prophylaxis with oral ciprofloxacin (500 mgwice a day) and antifungal prophylaxis with oral flucona-ole (100 mg once a day). During the induction phase theerum transaminases showed a progressive increase. Because

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446 G. Mele et al. / Leukemia

f persistent and progressive hepatic toxicity (grade 3) ima-inib was stopped 35 days after beginning the treatment. Afterweeks of interruption the liver function tests returned to nor-al; therapy with imatinib at dose 600 mg daily was started

gain. Bone marrow aspirate on the 45th day of inductionherapy (as performed by protocol), despite imatinib therapynterruption, showed haematological remission. At domicileur patient was given imatinib at the dosage of 600 mg dailyogether with allopurinol (300 mg once a day). By employingmatinib at 600 mg/day our patient did not show additionaloxicities related to drug administration.

In April 2006, during imatinib treatment, the patient devel-ped headache, vertigo, bilateral hypacusia; bone marrowspirate showed complete molecular remission; cytologi-al examination, molecular study and immunophenotypicnalysis of the cerebrospinal fluid revealed a relapse inhe CSF, showing 3.6 × 109 malignant cells/L (CD34,D10, CD19 positive, BCR/ABL positive); Cerebral Mag-etic Resonance Imaging (MRI) with and without contrastemonstrated nodular leptomeningeal enhancement in thearieto-occipital groove to the left and cerebellar to theight; widespread dural thickening was also present. Aggres-ive intrathecal chemotherapy with methotrexate 12 mg,ytosine-arabinoside 50 mg and hydrocortisone 10 mg forpplication together with craniospinal irradiation, accord-ng to GIMEMA LAL 0904 protocol, was commenced.onsidering the bone marrow molecular remission, duringNS-directed treatment (intrathecal chemotherapy and cran-

ospinal irradiation) imatinib therapy was not interrupted.fter complete treatment (seven lumbar punctures), cytologi-

al examination, immunophenotypic analysis and moleculartudy of the CSF revealed absolute absence of leukaemicells (0 × 109 cells/L). In August 2006, cerebral MRI did nothow the local and circumscribed pathological areas previ-usly described. At present, the patient is receiving therapyith imatinib p.o. at the dosage of 600 mg daily togetherith monthly prophylactic intracranial chemotherapy and is

n bone marrow molecular remission without signs of CNSnvolvement 8 months after the diagnosis of isolated CNSelapse.

. Discussion

Since Ph+ leukaemic cells are very sensitive to imatinib,nternational studies have explored the value of single-agentmatinib induction therapy without any other chemothera-eutic drugs including CNS prophylaxis in elderly patientsith newly diagnosed Ph+ ALL [2,3]. Unfortunately ima-

inib does not cross the blood–brain barrier. Several reportsemonstrate reduced distribution of imatinib into CNS asell as its difficulty of penetrating the brain [4–6]. Recently,

n vivo experimental studies conducted on mice reporthat limited distribution of imatinib in the brain might beaused by p-glycoprotein-mediated efflux [7]. Therefore,NS involvement limits the therapeutic value of this selective

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ch 31 (2007) 1445–1447

nhibitor of ABL tyrosine kinase in Ph+ ALL. Brooks hasecently described a case in which metastatic brain localiza-ions of gastrointestinal stromal tumours (GIST) respondedo oral therapy with imatinib [8]; the reasons why these

etastatic brain deposits disappeared are currently unknown;he metastases themselves probably disrupt blood–brain bar-ier supporting the transition of imatinib into CNS.

In our patient reduced distribution of imatinib into CNSnd absence of CNS prophylaxis, according to GIMEMAAL 0201 protocol, were responsible for meningeal

eukaemia.Attempts at improving transition of the drug across the

lood–brain barrier by dose increases are limited by systemicoxicity. A further possible alternative for overcoming theifficulty of penetrating the CNS might be intrathecal admin-stration of imatinib, although, at present the local irritantroperties of the available liquid formulation are forbiddingts use for parenteral applications [5]. Phase II studies ofwo novel second generation ABL tyrosine-kinase inhibitorsAMN107, BMS354825) are ongoing. Therefore, at theresent time, the best type of salvage treatment for isolatedNS relapse in elderly patients with imatinib-responsiveh+ ALL has not been established. Petzer for this sub-et of patients only suggests intrathecal chemotherapy withethotrexate, cytosine-arabinoside and dexamethasone [5];feifer suggests repeated intrathecal triple agent chemother-py and cranial irradiation together with continued imatinibherapy and additional low-dose IFN-� [6]. Both authors, but

ost of all Pfeifer, consider aggressive CNS-directed ther-py effective treatment for this subset of elderly patients.ur patient received intrathecal chemotherapy and cranial

rradiation according to GIMEMA LAL 0904 protocol inonjunction with continued imatinib therapy and demon-trates ongoing complete molecular remission without signsf CNS involvement 8 months after diagnosis of isolated CNSelapse. The relatively good survival of our patient togetherith prolonged molecular remission and Pfeifer’s clinical

esults indicate that aggressive CNS-directed therapy withontinued imatinib treatment might be a possible therapeu-ic alternative for imatinib-responsive elderly patients withsolated CNS relapse. For intrathecal treatment of meningealeukaemia encouraging results might also be achieved withepoCyte®, cytarabine at slow-release which reduces theecessity of submitting the patient to repeated and very closeumbar punctures [9]. Remission duration after CNS relapses very short; therefore, another question to face is the quan-ity and frequency of dressed lumbar punctures to administero a patient in order to maintain achieved remission.

. Conclusion

Our clinical experience extends the small number of pub-ished cases on isolated CNS relapse in elderly patients withmatinib-responsive Ph+ ALL. Aggressive CNS-directedherapy in combination with continued imatinib treatment

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release versus a standard formulation of cytarabine for the intrathecaltreatment of lymphomatous meningitis. J Clin Oncol 1999;17:

G. Mele et al. / Leukemia

ppears at present the most effective initial salvage therapy forhis subset of patients. In view of the inefficacy of imatinib atreventing meningeal leukaemia for its poor penetration intohe CNS, CNS-directed prophylactic therapy should alwayse an integral part of any imatinib-based treatment strategyor Ph+ ALL; the best type of prophylaxis – cranial irradiationnd/or intrathecal chemotherapy with conventional cytosine-rabinoside or new formulation of liposomal cytarabine –s well as the best scheduling, have not been establishedet. In addition, due to the brief interval between the begin-ing of imatinib-therapy and the appearance of meningealeukaemia, the CNS prophylaxis should be started at once10].

cknowledgements

This study was supported by the A.I.L.—Brindisi.iuseppe Mele, Salvatore Pinna, Angela Melpignano andntonio Romano: collection and interpretation of clinicalata. Maurizio Claudio Brocca and Maria Rosaria Coppi:nalysis of laboratory data. Giovanni Quarta: critical revision.n addition, we thank Mario Negro for technical assistance.

eferences

[1] Hoelzer D, Gokbuget N. Recent approaches in acute lymphoblasticleukaemia in adults. Crit Rev Oncol Hematol 2000;36:49–58.

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[2] Vignetti M, Fazi P, Meloni G, et al. Dramatic improvement in CR rateand CR duration with imatinib in adult and elderly Ph+ ALL patients:results of the GIMEMA prospective study LAL0201. Blood 2004;104[Abstract 2739].

[3] Ottmann OG, Wassmann B, Gokbuget N, et al. A randomized phaseII study comparing imatinib with chemotherapy as induction therapyin elderly patients with newly diagnosed Philadelphia-positive acutelymphoid leukemias. Hematol J 2004;5:S112.

[4] Takayama N, Sato N, O’Brien S, et al. Imatinib mesylate has limitedactivity against the central nervous system involvement of Philadel-phia chromosome-positive acute lymphoblastic leukaemia due topoor penetration into cerebrospinal fluid. Br J Haematol 2002;119:106–9.

[5] Petzer AL, Gunsilius E, Hayes M, et al. Low concentrations of STI571in the cerebrospinal fluid: a case report. Br J Haematol 2002;117:623–5.

[6] Pfeifer H, Wassmann B, Hofmann WK, et al. Risk and progno-sis of central nervous system leukemia in patients with philadelphiachromosome-positive acute leukemias treated with imatinib mesylate.Clin Cancer Res 2003;9:4647–81.

[7] Dai H, Marbach P, Lemaire M, et al. Distribution of STI571 to thebrain is limited by p-glycoprotein-mediated efflux. J Pharmacol ExpTher 2003;304:1085–92.

[8] Brooks J, Bani JC, Fletcher CDM, et al. Case 4 response of metastaticgastrointestinal stromal tumor including CNS involvement to imatinibmesylate (STI-571). J Clin Oncol 2002;20:870–2.

[9] Glantz MJ, LaFollette S, Jaeckle KA, et al. Randomized trial of a slow-

3110–6.10] Gokbuget N, Hoelzer D. Meningeosis leukaemia in adult acute lym-

phoblastic leukaemia. J Neuro-oncol 1998;38:167–80.