Pcnsl

doi:10.1182/blood-2011-03-321349Prepublished online May 25, 2011;2011 118: 510-522

Andrés J. M. Ferreri How I treat primary CNS lymphoma

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How I treat

How I treat primary CNS lymphomaAndres J. M. Ferreri1

1Unit of Lymphoid Malignancies, Department of Onco-Hematology, San Raffaele Scientific Institute, Milan, Italy

Primary CNS lymphoma (PCNSL) is a raremalignancy with peculiar clinical and bio-logic features, aggressive course, andunsatisfactory outcome. It represents achallenge for multidisciplinary cliniciansand scientists as therapeutic progress isinhibited by several issues. Molecular andbiologic knowledge is incomplete, limit-ing the identification of new therapeutictargets, and the particular microenviron-ment of this malignancy, and sanctuarysites where tumor cells grow undis-turbed, strongly affects treatment effi-

cacy. Moreover, active treatments areknown to be associated with disablingneurotoxicity, posing the dilemma ofwhether to intensify therapy to improvethe cure rate or to de-escalate treatmentto avoid sequels. The execution of pro-spective trials is also difficult because ofthe rarity of the tumor and the impairedgeneral condition and poor performancestatus of patients. Thus, level of evidenceis low, with consequent uncertainties intherapeutic decisions and lack of consen-sus on primary endpoints for future trials.

Despite this unfavorable background, lab-oratory and clinical researchers are coor-dinating efforts to develop new ideas,resulting in the recent publication of stud-ies on PCNSL’s biology and molecularmechanisms and of the first internationalrandomized trials. Herein, these impor-tant contributions are analyzed to providerecommendations for everyday practiceand the rationale for future trials. (Blood.2011;118(3):510-522)

Introduction

Primary CNS lymphoma (PCNSL) is an aggressive malignancyarising exclusively in the CNS, that is, the brain parenchyma,spinal cord, eyes, cranial nerves, and/or meninges.1 This lymphomarepresents 4% of intracranial neoplasms and 4%-6% of all extran-odal lymphomas but some registry studies suggest that its inci-dence in immunocompetent patients is progressively increasing.2

PCNSL exhibits peculiar clinical and biologic features and consti-tutes a diagnostic and therapeutic challenge for multidisciplinaryclinicians and scientists. Its outcome remains unsatisfactory ifcompared with that of patients with extra-CNS lymphomas of asimilar stage and histotype, and several factors prevent therapeuticprogress. First, molecular and biologic knowledge is insignificantcompared with other lymphomas, which limits the identification ofnew therapeutic targets. Second, patients with PCNSL usuallyexhibit impaired general condition and poor performance status(PS) more often than subjects with other lymphomas.1 This usuallyinterferes with the enrollment of patients in prospective trials. Infact, current therapeutic knowledge is only based on 3 randomizedtrials, some single-arm phase 2 trials, anecdotal meta-analyses, anda few multicenter retrospective studies. Thus, available level ofevidence is low, with consequent uncertainties in therapeutic decisionsand lack of consensus on primary endpoints for future trials.

In this manuscript, I discuss available clinical and biologic dataon PCNSL in immunocompetent patients and provide recommenda-tions for everyday practice and the rationale for future trials.

Clinical presentation and imaging

Which are the most common presentations?

In immunocompetent patients,3,4 the median age at diagnosis is60 years, with a male:female ratio of 1.2:1.7. The most commonsymptoms, which often span weeks to months, are focal deficits,

personality changes, and increased intracranial pressure (Figure 1).B symptoms are rare.3 Intraocular involvement is observed in10%-20% of patients. It can be the sole expression of lymphoma(primary intraocular lymphoma), or can be followed by the onset ofbrain lesions after weeks or months. Tumor cells can infiltrate thevitreous humor, the retina, the choroid, and optic nerve. Only halfof these patients experience visual complaints such as floaters,blurred vision, visual field defects, and diminished visual acuity.

PCNSL tends to infiltrate the subependymal tissues, disseminat-ing through the cerebrospinal fluid to the meninges. Concurrentmeningeal involvement, often asymptomatic, is detected by conven-tional cerebrospinal fluid cytology examination in 16% of pa-tients,3 while isolated leptomeningeal lymphoma represents � 5%of all PCNSL. Spinal cord lymphoma is the rarest manifestation ofPCNSL.3 This lymphoma often arises in the upper thoracic or lowercervical regions of the spinal cord and presenting symptomsdepend on the level of the spinal cord involved. Their prognosis ispoor mainly because of delayed diagnosis and the sparse literaturesuggests that they should be treated similarly to other PCNSL.Lymphomas arising in the spinal nerves and ganglia (“neurolympho-matosis”), cauda equina, and the sciatic nerve are extremely rare.5

Diagnosis is confirmed by nerve biopsy in 88% of cases, withpositive cerebrospinal fluid cytology in 40% of patients. Neurolym-phomatosis should be distinguished from neural infiltration by asystemic lymphoma.

Which is the best neuroimaging modality?

The above-mentioned symptoms usually lead to neuroimagingassessment. Contrast-enhanced cranial magnetic resonance imag-ing (MRI) is the best imaging modality for assessing PCNSLpatients. Lesions are often isointense to hypointense on T2-weightedMRI, with variable surrounding edema and a homogeneous and

Submitted March 7, 2011; accepted May 9, 2011. Prepublished online as BloodFirst Edition paper, May 25, 2011; DOI 10.1182/blood-2011-03-321349.

© 2011 by The American Society of Hematology

510 BLOOD, 21 JULY 2011 � VOLUME 118, NUMBER 3




strong pattern of enhancement (Figure 1-2).6 In cases of MRIcontraindications, contrast-enhanced cranial computed tomography (CT)scans are recommended. PCNSL presents as a solitary intracranial

mass lesion in 60%-70% of patients, mostly located in thehemispheres, basal ganglia, corpus callosum, and periventricularregions (Figure 1). Gliomas, metastases, toxoplasmosis, sarcoidosis, and

Figure 1. Flow chart of management of PCNSL from presentation to therapeutic decision in ordinary clinical practice. MRI indicates magnetic resonance imaging; CT,computerized tomography; CSF, cerebrospinal fluid; LDH, lactate dehydrogenase serum level; and ADC, average diffusion coefficient. Deep regions refers to basal ganglia,corpus callosum, periventricular areas, brain stem, and/or cerebellum. (1) Ocular examination should include slit-lamp examination, indirect ophthalmoscopy,and ophthalmicultrasonography. (2) Cerebrospinal fluid evaluation should include cell counts, protein and glucose levels, cytology, flow cytometry, and IgHV gene rearrangement studies.

HOW I TREAT PCNSL 511BLOOD, 21 JULY 2011 � VOLUME 118, NUMBER 3




progressive multifocal leukoencephalopathy are the main differen-tial diagnoses, requiring brain biopsy for definitive diagnosis.

Diagnosis

When is tumor resection indicated?

Stereotactic-guided biopsy is the chosen method to diagnosePCNSL. Its morbidity is very low and permits the rapid detection oftumor cells in intraoperative analysis; however, samples are smalland it could have a negative effect on diagnosis and biologicinvestigations. Patients with a radiologic suspicion of gliomas,metastasis, meningiomas, or other tumors are routinely referred forcomplete resection, sometimes resulting in an unexpected diagno-sis of lymphoma. Conversely, I advise strongly against gross tumorresection if PCNSL is suspected because it can induce neurologicdeficits and treatment delays and has not been associated withsurvival benefits according to a meta-analysis of 50 publishedprospective and retrospective series.7 In these patients, tumorresection should be reserved for the timely control of neurologicdeterioration because of brain herniation or ventricle dilation toprovide prompt treatment in “fit” patients.

Should steroids be interrupted before biopsy?

As with most patients who have been newly diagnosed with anintracranial mass, steroids are also routinely prescribed to PCNSLpatients to rapidly improve neurologic performance and to reducethe risk of complications. Mass shrinking is obtained throughantiedema and cytotoxic effects, causing radiographic regression in� 40% of patients (“vanishing tumor”), which is suggestive forPCNSL. As many others, I believe that detection of a “vanishingtumor” should not be considered as diagnostic of PCNSL becausesarcoidosis, multiple sclerosis, acute encephalomyelitis, and othermalignancies can also exhibit a dramatic response to steroids.8

Steroid effects can interfere with histopathologic diagnosis.Although some authors reported that PCNSL can be successfullydiagnosed without stopping steroids,9 there is consensus that thesedrugs should be withheld in patients with a presumptive diagnosisof PCNSL until tissue is obtained, limiting its use to cases ofosmotherapy inefficacy.10 In our institution, we interrupt steroidtherapy for at least 7-10 days before biopsy to improve diagnosticyield. However, this measure is not needed in patients whoexperience MRI-confirmed disease progression under steroids.

Steroid administration during antilymphoma therapy should bemodified according to clinical requirements. During chemotherapy,

Figure 2. Neuroimaging example of PCNSL. MRI of thebrain showing an expansive mass lesion in the right frontallobe, which is hypointense in noncontrasted T1 scans(A), isointense with respect to cortex in T2-weighted images(C), with reduced average diffusion coefficient (B), andhomogeneous contrast enhancement in contrasted T1 weightedscans (D arrows). Lesion is surrounded by modest edema(A arrows). CT and MRI findings are attributed to the high celldensity and scant cytoplasm. Enhancement along theVirchow-Robin spaces, although not constant, is a highlyspecific feature of PCNSL.

512 FERRERI BLOOD, 21 JULY 2011 � VOLUME 118, NUMBER 3




I recommend maintaining steroids until radiologic confirmation ofresponse, and then tapering them as soon as possible to reduce theirimmunosuppressive effect. I am against any superfluous use ofsteroids, which aims to reassure physicians rather than to controlsymptoms or prevent complications, even in prospective trials,where response to steroids can be erroneously attributed toinvestigational chemotherapy activity, generating important inter-pretation biases.

Which are the most important histopathologic and molecularfeatures?

Ninety-five percent of PCNSLs are diffuse large B-cell lymphomas(DLBCL). Neoplastic B lymphocytes usually grow forming perivas-cular cuffings (Figure 3), with an almost constant expression ofpan-B-cell markers and markers of germinal center and lategerminal center B cells, while are rarely positive for CD10(� 10%), and are negative for EBV.11 Proliferating index is usuallyhigh. Other lymphoma categories like Burkitt, lymphoblastic,marginal zone, and small lymphocytic lymphoma are uncommondifferential diagnoses. T-cell PCNSLs are � 2% of cases inWestern countries3 and, in my opinion, should be treated similarlyto standard PCNSL, with the obvious exclusion of anti-CD20agents, and expecting similar results.12 Neuroepithelial tumors,metastatic lesions, histiocytic lesions, and inflammatory disorderslike vasculitis and multiple sclerosis are the main nonlymphoma-tous differential diagnoses.

Molecular studies focused on PCNSL development showedsome interesting features, such as a high load of somatic mutations,frequent ongoing somatic hypermutation patterns and biased usageof VH gene segments (IGHV4-34 rearranged in 50%-80% ofcases), suggesting a role for antigen(s) triggering13,14; importantdifferences in IG and BCL6 translocations with respect to nodalDLBCL15; mutations in oncogene and tumor suppressor gene loci(CD95, CMYC13, PAX5, PIM1, PRDM114, and TTF)15; andderegulation of specific pathways (NF-�B, CARD11, MALT1, andp50).16,17 Moreover, studies of chemokines showed that CXCL9/CXCL12 coexpression is a strong chemoattractant stimulus forboth CXCR4�/CXCR3�/CD8� tumor-infiltrating lymphocytes andCXCR4�/CXCR3� malignant B cells in the perivascular microen-vironment.18 Gene expression profiling (GEP), array comparativegenomic hybridization, and single-nucleotide polymorphism (SNP)–chip analyses were used to characterize biologic mechanisms. SNPand GEP results appear consistent and suggest an improvedproliferation and harmed apoptosis in tumor cells; however, thecomprehensive interpretation of resulting data are far from beingestablished. GEP results on a CNS signature were conflicting,mostly because of the small size of investigated samples anddifferences in platforms and algorithms.19-21 Gene silencing be-cause of epigenetic phenomena like CpG islands promoter hyper-methylation could be related to lymphomagenesis and lymphocytemotility. Some of them, such as RFC and MGMT, may haveimportant therapeutic implications.22,23

Staging and pretreatment evaluations

Which staging procedures should be performed?

By definition, PCNSL is a stage I disease. The involvement ofdifferent CNS areas such as eyes, meninges, and/or cranial nerves,does not imply a more advanced stage with a worse prognosis.Pretreatment “staging” procedures have 2 main goals in PCNSL: to

define the extension of the disease in different CNS structures andto exclude concomitant systemic lymphoma. Conventional lym-phoma staging demonstrates the presence of extraneural disease in4%-12% of patients with presumptive diagnosis of PCNSL.24

Specific baseline evaluations and staging have been standardizedby The International PCNSL Collaborative Group (Figure 1).10

During staging, we pay particular attention to ophthalmic examina-tions, which allow the detection of asymptomatic ocular involve-ment in 5% of PCNSLs. The suspicion of ocular infiltration should

Figure 3. Classic histopathologic picture of PCNSL of diffuse large B-celllymphoma category. Tumor cells (filled arrows) usually grow forming classicperivascular cuffings, are CD20 positive, and express other pan-B-cell markers(CD19, CD20, CD22, CD79a), markers of germinal center B cells (bcl-6; 60%-80% ofcases), and markers of late germinal center B cells (MUM1; 90%), while are CD3negative. A reactive T-cell infiltrate (open arrows) constituted by a perivascular rim ofsmall lymphocytes interposed between vessel (VL) and neoplastic cells is observedin one-third of cases. These lymphocytes are smaller than neoplastic ones, and areCD20 negative and CD3 positive. The presence of this reactive infiltrate is associatedwith significantly better outcome in patients treated with modern approach.





be confirmed by vitrectomy for cytologic examination and flowcytometry, mostly in patients with primary intraocular lymphoma.IgHV gene rearrangements analyses and intravitreal levels of IL-10and IL-6 are, probably, adjuncts for intraocular lymphoma diagno-sis.25 Cerebrospinal fluid sampling should be performed in everypatient with suspected or confirmed PCNSL. Increases in the whiteblood cell count and protein concentrations are often present, whileglucose concentration is usually normal.3 Cytology and PCRshould be regarded as complementary methods because of the highrate of discordant results.26 A contrasted whole-spine MRI may beuseful if lumbar puncture is contraindicated. I recommend that atesticular ultrasound examination is performed in elderly patientsbecause of frequent CNS involvement in testicular lymphomas.The clinical relevance of positron emission tomography (PET) requiresprospective evaluation. In a retrospective study,27 18FDG-PETdisclosed concomitant systemic lymphoma in 7% of patients with apresumptive diagnosis of PCNSL, with detection of other malignan-cies in 5% of cases and false positives in 13%.

Are there reliable prognostic factors?

The identification of reliable prognostic factors is the first steptoward a risk-tailored treatment of PCNSL. Virtually all studiesconfirm the importance of age and PS, whereas the InternationalPrognostic Index does not discriminate among risk groups. Thecombination of 5 independent predictors of response and survival,that is, age, PS, serum lactate dehydrogenase level, cerebrospinalfluid protein concentration, and the involvement of deep structures(Figure 1), distinguishes 3 risk groups based on the presence of 0-1,2-3, or 4-5 unfavorable features (IELSG [International ExtranodalLymphoma Study Group] prognostic score).28 Currently, we in-clude the IELSG score as a stratification criterion in randomizedtrials, and I strongly recommend its use in choosing individualizedrisk-tailored treatment. Another scoring system that only uses ageand PS also distinguishes 3 risk groups.29 Several biochemical,histopathologic, and molecular variables were suggested as prognosticindicators. However, none of these observations were confirmed.

First-line treatment

For decades, radiotherapy was the exclusive treatment for patientswith PCNSL, while the addition of chemotherapy has significantlyimproved their outcome. Even though this was not confirmed in arandomized trial, there is consensus that combined chemoradiother-apy is superior to radiotherapy alone and this is the most commonlyused approach.1 With variable chemotherapy regimens and radia-tion doses, upfront chemoradiotherapy has been addressed inseveral trials, obtaining complete remission rates (CRR) of 30%-87% and 5-year overall survival (OS) rates of 30%-50% (Table 1).These strategies are often associated with severe neurotoxicity,especially among elderly patients. Therefore, the dilemma posedby PCNSL treatment is the choice between strategies designed tointensify therapy to improve cure rate and treatment de-escalationstrategies to avoid neurotoxicity.

Chemotherapy

Chemotherapy plays a central role in the management of PCNSL.Its efficacy is limited by several factors including the biology andmicroenvironment of this malignancy, which is protected by theblood-brain barrier (BBB). This results in the formation ofchemotherapy sanctuaries, such as cerebrospinal fluid, meninges,

and eyes, where tumor cells grow undisturbed. For this reason,I suggest taking into account the ability to cross the BBB andachieve therapeutic concentrations in the CNS as an important drugselection parameter for treating PCNSL patients. Most regimensinclude drugs able to cross the BBB at conventional doses (ie,steroids, some alkylating agents) and cytostatics with low tomoderate ability to cross the BBB that can be safely administered athigh doses to improve CNS bioavailability (ie, methotrexate,cytarabine). Conversely, drugs with poor BBB penetration thatcannot be administered at high doses because of dose-limitingtoxicity (ie, anthracyclines, vinca-alkaloids) are inefficient in PCNSL.

Does CHOP regimen play any role in PCNSL?

CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)regimen represents the backbone for treating extra-CNS DLBCLbut exhibits negligible activity in PCNSL; this has been confirmedin a randomized trial with incomplete accrual.30 In retrospectiveseries, the addition of CHOP to high-dose methotrexate (HD-MTX) resulted in higher toxicity without improved outcomecompared with HD-MTX alone.31 Most patients treated withCHOP have an immediate radiographic response followed by earlyprogression, probably because of the normalization of the disruptedBBB. This suggests that the bulky tumor not protected by the BBBresponds, while the microscopic tumor is not adequately treatedand progresses. In line with this evidence, we have abandonedCHOP chemotherapy in classic PCNSL. However, I prescribeCHOP-rituximab combined with good CNS bioavailability agentsto patients with neurolymphomatosis5 or intravascular large B-celllymphoma with CNS involvement32 as tumor cells of these lymphomasmostly grow in structures (nerves and blood vessels, respectively)variably, or not, protected by physiologic barriers (Figure 4).

Which is the backbone of upfront chemotherapy?

Antimetabolites such as MTX and cytarabine (ara-C) constitute thebackbone of most anti-PCNSL regimens with proven efficacy inprospective trials (Table 1). MTX doses up to 8 g/m2 are feasible inPCNSL patients; both dose and infusion rate are important forMTX delivery to the brain parenchyma and cerebrospinal fluid.33

MTX doses � 1 g/m2 result in tumoricidal levels in the brainparenchyma and doses � 3 g/m2 yield tumoricidal levels in thecerebrospinal fluid.34 Conversely, doses up to 8 g/m2 delivered in a24-hour continuous infusion do not achieve an adequate cerebrospi-nal fluid level.35 HD-MTX (8 g/m2) monochemotherapy yieldedactivity and efficacy similar to those recorded in trials assessingpolychemotherapy with a MTX dose of 3.5 g/m2, but it requiresmore frequent dose reductions because of impaired creatinineclearance.36 As many others, I believe tolerability and activity ofMTX 3.5 g/m2 suggest this may be a good compromise betweensafety and efficacy for combination regimens. In the future,individualized dosing of MTX using creatinine clearance orglomerular filtration rates may have the potential to improveoutcome in PCNSL patients.33,37,38

Noncomparative studies suggesting an improvement of survivalby adding HD–ara-C to HD-MTX3,39 were the background of thefirst randomized trial with completed accrual in PCNSL.40 In thistrial, named IELSG no. 20, 79 patients have been assigned to4 courses of MTX 3.5 g/m2, alone or combined with ara-C (4 dosesof 2 g/m2) in both arms followed by whole-brain irradiation(WBRT). The addition of ara-C has resulted in significantlyimproved response (CRR � 46% vs 18%; P � .006) and survivalrates (3-year OS: 46% vs 32%; P � .07) compared with HD-MTX





alone (Table 1), with manageable hematologic toxicity and uncom-mon nonhematologic side effects.40 A recent study highlighted theimportance of ara-C dose, suggesting that 4 doses of 2 g/m2 is anappropriate choice.41 Although it was not addressed in a phase3 trial, the MTX-ara-C combination is the current standardchemotherapeutic approach for de novo PCNSL as it is supportedby the highest level of evidence available (Figure 4).

Are there other active drugs?

Some active drugs have emerged from prospective studies and arebeing tested in ongoing trials of new first-line combinations.Temozolomide, an oral alkylating agent largely used in neuro-oncology, is the best example. It has been associated with excellenttolerability, 31% CRR and 1-year OS of 31% in patients withPCNSL relapsed or refractory to HD-MTX.42 As upfront mono-therapy, temozolomide was associated with 47% CRR, and medianOS of 21 months in elderly patients.23 The combination of temozo-lomide with HD-MTX was associated with encouraging results,even among elderly patients.43,44 Topotecan, a topoisomerase-Iinhibitor, is another example. It is active in relapsed PCNSL.However, I do not prescribe this drug as its responses areshort-lived (1-year PFS: 13%) and it is frequently associated withsevere leukopenia and neurologic deterioration.45

Is there a role for rituximab in the treatment of PCNSL?

Rituximab is used in PCNSL patients because of its positive effectin extra-CNS DLBCL patients. However, as a large protein, itshows poor CNS penetration and its ability to prevent CNSdissemination of DLBCL remains debatable. Promising effects ofrituximab were reported, both as salvage monotherapy46 (Table 4)and combined with HD-MTX47 (Table 1). Although the level ofevidence supporting rituximab for the treatment of PCNSL remainsvery low, its use is encouraged by several hematologists. I believerituximab should only be used in PCNSL patients in prospectivetrials, at least until its role is defined by the 2 large ongoingrandomized trials focused on this issue (NCT01011920; NTR2427).

Treatment of relapsed PCNSL with the anti-CD20 radio-immunoconjugate 90Y-ibritumomab-tiuxetan is feasible.48 Al-though capable of targeting brain lymphoma, this radio-immunocon-jugate cannot treat microscopic lesions with intact BBB adequately,resulting in high relapse rates.49

Is intrathecal chemotherapy needed?

Cerebrospinal fluid acts as a reservoir for PCNSL tumor cells; thepersistence of tumor cells in this chemotherapy sanctuary results inincreased risk of failure. Some authors advised including intrathecal/

Table 1. Published prospective trials in immunocompetent patients with PCNSL

No. TS*

Primary chemotherapy†

ORR, %‡ CRR, %§Median

follow-up, mo

OS, %Neurotoxicity,

%Drugs M dose it CHT 2 y 5 y

Chemotherapy alone

31 C M 8 g/m2/14 d — 100 NR 31 63 NR 0

25 C M 8 g/m2/14 d — 74 52 23 70 NR 5

65 C M V I C A 5 g/m2/28 d ivM/a 71 61 26 69 43 3

37 C M 8 g/m2/14 d — 35 30 56 51 25 20

46 C M R Te–a E 8 g/m2/14 d — NR 63 40 71 NR 0

HD-MTX plus RT

25 CR M 3.5 g/m2/21 d — 88-92 56-88 60 58 38 8

46 CR M 1 g/m2/7 d a¶ NR-95 NR-82 36 62 37 22�31 CRC M 1 g/m2/7 d M 64-87 NR-87 97 72 22 32

HD-MTX-containing

chemotherapy plus RT

25 CR A a C M O P 3 g/m2/21 d M/a/P 72-72 67-78 24 70 56 0

57 CRC aBnMO � CHOP 1.5-3 g/m2/14 d — 68-71 62-64 59 60 36 NS

56 CR Bn M N P 1.5 g/m2/28 d M 71-100 54-61 8 86 NS 29

31 CR A B C M O P 2 g/m2/15 d M/a/P¶ 89-67 24 48 36 7

52 CRC M N O 3.5 g/m2/7 d M 90-94 56-87 60 75 40 25

102 CR M N O 2.5 g/m2/14 d M 94-NR 58-NR 56 64 32 15

52 CR Bn M O P 3 g/m2/14 d M NR-81 33-69 27 69 NR 12

41 CR A I M T 3.5 g/m2/21 d — 76-83 44-56 49 50 41 NR

30 CRC M N O R 3.5 g/m2/14 d M¶ 93-NR 44-77 37 67 NR NR

99 CR AaCMO 3 g/m2/21 d M/P 70-68 33-49 83 55 34 32

Randomized trials

79

CR M 3.5 g/m2/21 d — 40-40 18-30 30 39 26 20

M a 3.5 g/m2/21 d — 69-74 46-64 56 46 6

551

C � R M 4 g/m2/14 d — 50 32

M I 3 g/m2/14 d — 65 42

Only trials on 25 patients or more and published as original articles are considered. Trials on high-dose chemotherapy supported by ASCT (Table 2) and focused on elderlypatients (Table 3) are excluded. Updated from 40.

No. indicates number of enrolled patients; NS, not specified; and NR, not reported.*Treatment sequence: C indicates chemotherapy alone; CR, chemotherapy followed by radiotherapy; and CRC, chemotherapy followed by radiotherapy and further

chemotherapy.†Primary chemotherapy: A or H, adriamycin; a, cytarabine; B, bleomycin; Bn, BCNU; C, cyclophosphamide; Cn, CCNU; E, etoposide; I, ifosfamide; M, methotrexate; N,

procarbazine; O, vincristine; P, prednisone or other corticoids; R, rituximab; T, Thiotepa; Te, temozolomide; and V, teniposide.‡ORR indicates overall response rate; in series treated with combined modality, response rate after chemotherapy and (—) after the entire planned treatment is reported.§CRR, Complete remission rate; in series treated with combined modality, response rate after chemotherapy and (—) after the entire planned treatment is reported.¶Series using intrathecal chemotherapy (it CHT) exclusively in patients with positive CSF cytology at diagnosis.�Five-year risk rate.





intraventricular drug delivery as part of primary chemotherapy toimprove disease control. However, this suggestion is questionableas systemic HD-MTX can clear the cerebrospinal fluid of neoplas-tic cells. Moreover, intrathecal/intraventricular chemotherapy hasnot been studied prospectively, only one phase 1 trial suggeststransient activity of intraventricular rituximab.50 Two large retro-spective studies have not demonstrated benefits from addingintrathecal drug delivery in patients treated with HD-MTX.3,51

Conversely, the comparison of 2 single-arm trials seems to suggestsome benefit from intraventricular chemotherapy.52,53 In the firsttrial,52 65 PCNSL patients were treated with MTX–ara-C–basedchemotherapy combined with intraventricular delivery of MTX,ara-C, and steroids, resulting in a median EFS of 21 months, with57% of young patients alive at a median follow-up of 100 months.In the second trial,53 18 patients received the same chemotherapywithout intraventricular treatment to reduce Ommaya reservoirinfections. Despite a similar response rate, more than half of theresponders relapsed within the first year, prompting prematuretermination of the trial, which was attributed to the omission ofintraventricular chemotherapy. Overall, there is no consensus on

cerebrospinal fluid prophylaxis and treatment but most recentlyreported or ongoing PCNSL trials do not use intrathecal/intraventricular chemotherapy. In our institution, we do not useintrathecal/intraventricular chemotherapy in PCNSL patients as itis based on a low level of evidence and is associated with additionalrisk of infective complications, neurotoxicity, and chemicalmeningitis.

How should intraocular lymphoma be treated?

The eye is another reservoir for PCNSL tumor cells. Chemotherapyefficacy depends on intraocular pharmacokinetics, which are notwell understood for most cytostatics. Systemic administration ofMTX and ara-C can yield therapeutic drug levels in the intraocularfluids and clinical responses have been documented; however, drugconcentrations in vitreous humor are unpredictable and intraocularrelapse is common.54 For these reasons, I treat patients withPCNSL and intraocular disease with HD-MTX–based chemo-therapy followed by WBRT and ocular irradiation, which results inbetter disease control.55 Some authors are investigating the role of

Figure 4. Flow chart of therapeutic management of PCNSL in everyday practice. (1) Mostly marginal zone B-cell lymphoma, small lymphocytic lymphoma, andlymphoplasmacytic lymphoma. (2) Mostly intravascular large B-cell lymphoma and neurolymphomatosis. (3) Conclusion from the IELSG no. 20 trial.40 (4) Several regimens areavailable (Table 3). (5) A higher amount of available evidence suggests WBRT. The discussion with selected patients about the pros and cons of the use of consolidation WBRTor HDC/ASCT is recommended. (6) Available literature suggesting that some elderly patients in CR after primary chemotherapy could be watchful waited withoutOS impairment is constituted by a few small retrospective series. However, to delay WBRT until relapse is an acceptable strategy considering the increased risk of disablingneurotoxicity in these patients. (7) Radiation field and dose should be chosen on the bases of response to primary chemotherapy. WBRT dose reduction to 23-30 Gy in patientsin CR after chemotherapy is recommended. DLBCL indicates diffuse large B-cell lymphoma; HD-MTX, high-dose methotrexate; ara-C, cytarabine; WBRT, whole-brainradiotherapy; CR, complete remission; PR, partial response; SD, stable disease; PD, progressive disease; and HDC/ASCT, high-dose chemotherapy supported by autologousstem cell transplantation.





direct intravitreal injection of cytostatics. Intravitreal MTX ishighly active (remission in 100% of treated eyes) but does notaffect OS and is associated with important side effects in 73% ofeyes and significant deterioration of visual acuity in 27% ofpatients.56,57 Among the other drugs examined, intravitreal ritux-imab appears safe and active.58

Is HDC/ASCT indicated?

Overall, high-dose chemotherapy with autologous stem cell trans-plantation (HDC/ASCT) is used as a dose intensification treatmentto overcome drug resistance. In PCNSL, HDC/ASCT shouldimprove CNS drug bioavailability and replace WBRT to reduceneurotoxicity. In patients with relapsed or refractory PCNSL (Table2), HDC/ASCT has been associated with 60% CRR, a 2-year OS of45%, with treatment-related mortality of 16% and severe neurotox-icity in 12% of cases.59 First-line HDC/ASCT was investigated in afew small phase 2 trials (Table 2), suggesting a curative effect inyoung patients.60 However, efficacy data are controversial becauseof different induction and conditioning combinations. Cumulativeresults suggest that HD-MTX–based polychemotherapy inductionis more active than monochemotherapy, while intensification withHD–ara-C, alone or in combination, was useful as mobilizingregimen but did not improve response rates. Among conditioningregimens, those containing thiotepa seem to be more effective butmore toxic, in particular, the busulfan-thiotepa combination.60

BEAM (carmustine, etoposide, cytarabine, and melphalan) regi-men, which was chosen because widely used for other aggressivelymphomas, was ineffective in PCNSL, with median EFS of9.3 months.61 I believe the discrepancies in effectiveness betweenBEAM and thiotepa-based regimens may be related to the different

capability of drugs to cross the BBB. In fact, busulfan, thiotepa,and carmustine (BCNU) exhibit excellent CNS penetration, withcerebrospinal fluid levels exceeding 50%-80% serum levels, whileCNS penetration rates of agents used in BEAM range from5%-22%.62 Interestingly, a small phase 2 study suggested thatHDC/ASCT could replace consolidation radiotherapy, with a3-year OS of 77% (Table 2, last line). However, the real impact ofHDC/ASCT on neurocognitive functions was not defined becausetreated patients were not prospectively assessed with adequateneuropsychologic tests. At our institution, we do not use HDC/ASCT as part of first-line therapy because it remains an experimen-tal approach; in routine practice, we use HDC/ASCT with aBCNU-thiotepa conditioning combination as part of salvage treat-ment for selected patients. I am convinced that the comparisonbetween WBRT and HDC/ASCT in 2 ongoing randomized trials(NCT01011920; NCT00863460) will establish the most effectiveand better-tolerated strategy to consolidate response to primarychemotherapy.

Which chemotherapy for elderly patients?

Age has a profound influence on prognosis and treatment choices inPCNSL.28,29 A large proportion of PCNSL patients is more than60 years old and is still treated with radiotherapy alone, withdisappointing results.63,64 The addition of HD-MTX–based chemo-therapy resulted in improved outcome in selected elderly patients(Table 3). As many others, I believe the interpretation of theseresults is biased because “the elderly patient” has not been clearlydefined in PCNSL. With a few exceptions (Table 3), studiesfocused on the “elderly” include patients with a median age� 70 years, with the lowest age oscillating between 54 and

Table 2. Prospective phase 2 trials on high-dose chemotherapy supported by autologous stem cell transplantation

Ref.No. of

patientsMedian age,

y (range)Treatment

lineTherapy,

induction3intensificationConditioning

regimen WBRTOutcome,

%Neurotoxicity,

%Median

follow-up, moTRM,

%

87 22 53 (27-64) Salvage araC � VP16 Bu/TT/Cy No 3-yOS:64 32 41 4

59 43 52 (23-65) Salvage araC � VP16 Bu/TT/Cy No 2-yOS:45 5 36 7

88 6 53 (30-66) First-line MBVP3IFO � araC BEAM Yes 2-yOS:40 33 41 0

89 25 52 (21-60) First-line MBVP3IFO � araC BEAM Yes 4-yOS:64 8 34 4

61 28 53 (25-71) First-line HD-MTX3araC BEAM No 2-yOS:55 0 28 4

90 23 55 (18-69) First-line HD-MTX3 Bu/TT Yes* 2-yOS:48 39 15 13

91 7 56 (41-64) First-line† HD-MTX3araC Bu/TT/Cy No 3-yOS:50 0 28 14

92 30 54 (27-64) First-line HD-MTX3araC � TT BCNU/TT Yes 5-yOS:69 17 63 3

78 13 54 (38-67) First-line HD-MTX3araC � TT BCNU/TT Yes* 3-yOS:77 0 23 0

araC indicates cytarabine; BCNU, carmustine; BEAM, carmustine, etoposide, cytarabine, and melphalan; Bu, busulfan; Cy, cyclophosphamide; IFO, ifosfamide; MBVP(regimen), methotrexate, carmustine, etoposide, and methylprednisolone; OS, overall survival; TRM, treatment-related mortality; TT, thiotepa; VP16, etoposide; and WBRT,whole-brain irradiation.

*Only for patients not achieving a complete remission.†One patient received the treatment as salvage therapy.

Table 3. Reported studies focused on elderly patients with PCNSL

Ref. N Median age, y (range) MTX, g/m2 Other drugs IT WBRT PFS, mo OS, mo Neurotoxicity

43 23 68 (60-79) 3 Te No No 8 35 0

66 10 73 (66-75) 8 — No No 18 36 0

79

22 70 (54-89) 3.5 O, P Yes No NR 33 5

12 67 (60-72) 3.5 O, P Yes Yes NR 32 83

93 13 76 (54-89) 1-3.5 A, O, P, T Yes No NR 31 0

94 50 72 (60-81) 1 CN, P, S Yes No 7 14 8

95 30 70 (57-79) 3 CN, P No No 6 15 7

96 17 67 (58-78) 1 MCN, P, S Yes No 20 36 0

MTX indicates methotrexate delivered dose; PCNSL, primary CNS lymphoma; IT, intrathecal chemotherapy; WBRT, whole-brain irradiation dose; —, not applicable;PFS, median progression-free survival; and OS, median overall survival.

Other drugs: A indicates cytarabine; CN, lomustine; MCN, ranimustine; O, vincristine; P, procarbazine; S, steroids; T, thiotepa; and Te, temozolomide.





60 years, which suggests important selection biases because of theinclusion of several “young” patients. In my opinion, the age upperlimit currently used for clinical trials (70-75 years old for conven-tional-dose combinations or 70 in HDC/ASCT trials) represents anacceptable cutoff point to define elderly patients.

I am for treating all elderly patients with primary chemotherapyand I choose a chemotherapy regimen on the basis of PS andcomorbidity. Despite common perception that HD-MTX is tootoxic for the elderly, some studies suggest that older patients cantolerate this therapy, provided their renal and liver functions arepreserved (Figure 4).65,66 MTX 1-3 g/m2 in combination withalkylating agents resulted in median survival ranging from 14 to36 months (Table 3), but median PFS was usually disappointing,often requiring salvage WBRT to prolong disease control.67,68

However, this approach is associated with severe neurocognitivedecline, which, added to the lack of safe and active salvagetherapies, strongly condition outcome in elderly patients.

Is there a role for BBB disruption and intra-arterialchemotherapy?

Reversible BBB disruption by intra-arterial infusion of mannitolfollowed by intra-arterial chemotherapy aims to increase drugconcentrations in the lymphoma-infiltrated brain, with particularvalue in the delivery of agents unlikely to traverse the BBB.69 Ininstitutions with adequate expertise, this strategy was associatedwith a 58% CRR, a 5-year PFS of 31% and acceptable morbidityand neurotoxicity.69 I do not expect that BBB disruption andintra-arterial chemotherapy will be used worldwide in the nextyears because its efficacy is similar to that of conventionaltreatments but it is a procedurally intensive treatment, requiringmonthly intravascular interventions under general anesthesia overthe course of 1 year.

Radiotherapy

PCNSL is a radiosensitive tumor and radiotherapy has been thestandard treatment for decades. In these patients, the whole brainshould be irradiated because of the diffuse infiltrative nature ofPCNSL and the inclusion of the eyes within the radiation volume issuggested.55 Focal brain radiotherapy attempts resulted in highrecurrence rates. Although microscopic cerebrospinal fluid dissemi-nation is common, craniospinal irradiation does not confer addi-tional survival benefit and is associated with significant morbidity.7

Most trials have used conventional photons font and standardfractionation. As an exception, a RTOG (Radiation TherapyOncology Group) trial failed to show a clear benefit whenhyperfractionated WBRT was used.70 WBRT and tumor bed dosesare variable in published trials, these parameters depending on theuse of radiotherapy as exclusive or complementary treatment.

Who are the best candidates for radiation therapy alone?

WBRT alone is rarely curative in PCNSL patients because responseis usually short-lived, with median survivals ranging from 10 to18 months.71 The optimal dose of WBRT is controversial, but adose of 40-50 Gy has been suggested, resulting in a 19% CRR.Doses � 50 Gy and the addition of a boost are associated withincreased risk of neurotoxicity without further efficacy.71 WBRT40-50 Gy appears advisable as exclusive treatment when chemo-therapy is contraindicated (Figure 4). Encouraging results wereobtained with steroid maintenance after primary WBRT,72 butconfirmatory studies are needed.

As exclusive treatment, radiotherapy plays a palliative role inpatients with cerebrospinal fluid dissemination. Conversely, it is acurative strategy in indolent lymphomas (13% of all PCNSLs3).Patients with marginal zone, small lymphocytic, or lymphoplasma-cytic lymphoma, mostly arising in the meninges, have excellentlong-term prognosis with local therapy alone (Figure 4) andconsolidation radiotherapy may be unnecessary after completeresection. Experience with HD-MTX suggests modest activity.73

Isolated CNS plasmacytoma and Hodgkin lymphoma are othersuitable candidates for radiotherapy alone. Plasmacytoma can besuccessfully managed with involved field irradiation with 50 Gy,preceded by chemotherapy in patients with large lesions.74 WBRT35-45 Gy followed by a 5-15 Gy boost was proposed for CNSHodgkin lymphoma, with a median OS from CNS involvement of44 months.75

Is consolidation radiotherapy really needed?

Consolidation after HD-MTX–based chemotherapy represents thebest role for radiotherapy in patients with PCNSL (Figure 4).However, this strategy is associated with disabling neurotoxicity,with a cumulative 25%-35% incidence at 5 years and related 30%mortality.76 Long-term impairment in the areas of attention,executive function, memory, and psychomotor speed are the mostcommonly reported. The mechanisms by which treatment producesCNS damage are unknown, but demyelination, necrosis, andmicrocavitary changes have been described. Neurotoxicity inPCNSL patients has not been clearly defined because it is usuallyassessed in small series and rarely in prospective trials. Impor-tantly, a panel of neuropsychologic tests to assess, quantify andfollow-up treatment-related neurologic deterioration in PCNSLpatients was recently established.77 I expect its wide use will allowbetter definition of this severe complication both in prospectivetrials and everyday practice.

To avoid postchemotherapy, WBRT was proposed as the mainstrategy to reduce neurotoxicity risk. Feasibility and impact of thisapproach should be analyzed separately in subgroups of patientsdivided according to response degree after chemotherapy. Comple-mentary WBRT in patients with residual disease after chemo-therapy is unavoidable in routine practice because of the lack ofvalid alternatives. The small group of available active drugs hasshown a significantly lower activity in PCNSL patients unrespon-sive to upfront chemotherapy; only HDC/ASCT has shown someactivity in these patients,78 but this remains an experimentalapproach. In my opinion, the use of any second-line chemotherapyin not irradiated patients should be confined to prospective trials. Ineveryday practice, I strongly recommend WBRT 40-45 Gy forpatients with residual disease after primary chemotherapy.

Recommendations on consolidation WBRT in patients in com-plete remission (CR) after chemotherapy are less clear. Some smallexperiences, mostly on elderly patients, suggest that avoidingconsolidation WBRT is feasible and results are similar to thoseobtained with chemoradiation combinations.79 A CALGB (Cancerand Leukemia Group B) phase 2 trial recently reported in abstractform,44 assessed a combination of HD-MTX, temozolomide, andrituximab followed by consolidation with HD-araC and HD-VP16without WBRT in 46 patients, with a 3-year PFS and OS of 50%and 67%, respectively, a single toxic death and no evidence forsignificant iatrogenic neurotoxicity. These encouraging results,suggesting that consolidation WBRT can be deferred until relapse,deserve to be assessed in future randomized trials. In a recentrandomized trial,80 551 patients treated with HD-MTX–basedchemotherapy were randomly allocated to receive WBRT 45 Gy





versus observation in the case of CR after chemotherapy or versusHD-araC in the case of partial or no response. The results indicatethat consolidation WBRT is associated with a significantly betterPFS (median � 18 vs 12 months), but does not change OS(median � 32 vs 37 months). Unfortunately, this trial is fraughtwith design and execution flaws resulting in important interpreta-tion biases and unreliable conclusions.81,82 In fact, this trial exhibitsmajor protocol violations in 30% of patients, biased analyses ofthese violations, evident unbalanced comparisons resulting fromrandomization caveats in � 20% of patients, inconsistent data oniatrogenic neurotoxicity, and 10% of patients lost to follow-up.Moreover, it has low statistical power (60%) and failed to prove theprimary hypothesis. As many others,81,82 I believe this trial does notprovide reliable conclusions on the role of consolidation WBRT. Inmy opinion, the optimization of radiation parameters is a validalternative to radiation withdrawal in PCNSL. Two recent studiessuggested that WBRT dose reduction to 23-30 Gy in patients in CRafter chemotherapy is associated with similar outcomes to receiv-ing higher radiation doses, with better neurotolerability.83,84 Theseobservations deserve to be addressed in multicenter prospectivetrials, with standardized neuropsychologic assessment.

In our institution, we discuss with selected patients the pros andcons of using consolidation WBRT or alternatives in everydaypractice (Figure 4). I strongly encourage the enrolment of patientsin prospective trials comparing consolidation WBRT with experi-mental approaches because these studies will furnish importantdata useful to minimize neurotoxicity. Hopefully, I expect thatfuture clinical, biologic, and technologic investigations will pro-vide relevant information on how to maintain neuropsychologicperformance in these patients.

Salvage treatment

A variety of salvage therapies was successfully used in selectedsubgroups of patients with recurrent or refractory PCNSL (Table4). Although these therapies may be used in routine practice, I amconvinced that patients with failed disease must be entered intophase 1/2 trials assessing new drugs and combinations. Althoughthe amount of trials assessing first-line treatments is increasing andfailure rates in those trials range between 40% and 70%, thenumber of reported studies on salvage therapy remains negligible.This is because of the hasty and aggressive course of relapsingPCNSL that produces a drastic PS impairment preventing physi-

cians from enrolling patients in prospective trials and, sometimes,from recommending any treatment.

In routine practice, salvage treatment should be chosen on thebasis of the patient’s age, PS, the site of relapse, prior therapy, andduration of previous response. At our institution, we give WBRT topatients who experienced failure after chemotherapy alone (Table4). This strategy is associated with a median survival after relapseof 16 months, but with increased risk of neurotoxicity.67,68 In a fewstudies, previously nonirradiated, relapsing patients have beentreated with salvage chemotherapy to improve disease controlwhile reducing neurotoxicity; reinduction with HD-MTX is anexample.85 In my opinion, salvage WBRT should be offered topreviously nonirradiated, relapsing patients considering that radio-therapy is more active than most salvage chemotherapies and thatthe majority of cytostatics used in these combinations were notpreviously addressed in ad hoc prospective trials.

Single drugs or chemotherapy combinations as well as HDC/ASCT have produced encouraging results in patients relapsingafter chemoradiation therapy (Table 4). Isolated systemic (extra-CNS) dissemination (3%-7% of failures3) seems to be associatedwith a significantly better outcome with respect to CNS relapses,in particular if treated with conventional antilymphomachemotherapy.86

Future perspectives

I expect that future therapeutic progress in PCNSL will be mainlybased on the expansion of molecular and biologic knowledge, theimprovement of diagnostic sensitivity and specificity, the conduc-tion of well-designed prospective trials, and the prevention ofiatrogenic neurotoxicity. All these goals will require multidisci-plinary and international efforts. Laboratory research will allow usto better understand important tumor mechanisms and to identifynew therapeutic targets. Molecular and biologic studies will requireadequate amounts of freshly stored biologic samples; neurosur-geons should be encouraged to consider investigational purposesother than diagnostic suitability and sequel risk when making adecision on sample size. The use of new, more expensive labora-tory techniques for research in this “orphan” malignancy willrequire additional funding from scientific institutions and societies.

Modern functional neuroimaging will help us to establish asuspicion of PCNSL earlier, resulting in timely treatment and lessCNS damage. Conducting well-designed trials is key to improve

Table 4. Salvage treatment for PCNSL

Treatment, Ref. Study No.Medianage, y

PriorRT, %

CR � PR,% PFS OS

1-y OS,%

Grade 3-4neutropenia, %

Grade 3-4thrombocytopenia, %

Othertoxicities, %

VP16 � Ifosfamide � Ara-C97 R 16 54 100 37 � 0 4.5 6.0 41 69 50 37

i. a. Carboplatin � VP16 �

CTX � RT98

R 37 57 24 24 � 11 3.0 6.8 25 22 19 � 30

Methotrexate85 R 22 58 14 73 � 19 26 26 70 5 5 36

Temozolomide � rituximab99 R 15 69 13 40 � 13 2.2 10.5 58 7 27 7

Topotecan45 P 27 51 52 19 � 14 2.0 8.4 39 26 15 11

Temozolomide42 P 36 60 86 25 � 6 2.8 4.0 31 6 3 3

Rituximab46 P 9 NR 9 11 � 22 3.7 NR NR 0 0 44*

Radiotherapy68 R 27 67 — 37 � 37 9.7 10.9 49 NR NR 15†

Radiotherapy100 R 20 NR — 60 � NR NR 19.0 NR NR NR 58†

Studies focused on HDC/ASCT are reported in Table 2.P indicates prospective; R, retrospective; RT, radiotherapy; PCNSL, primary CNS lymphoma; CR, complete response; PR, partial response; PFS, median progression-free

survival; OS, median overall survival; i.a., intra-arterial; VP16, etoposide; ara-C, high-dose cytarabine; —, not applicable; NR, not reported; and CTX, cyclophosphamide.*Allergic reaction, fatigue, anxiety, and pain.†Neurotoxicity.





therapeutic efficacy. IELSG no. 2040 and G-PCNSL-GS180 studiesopened the era of randomized trials in PCNSL and both randomizedtrials and phase 2 trials testing new drugs in relapsing patientsshould be encouraged. All these approaches should be associatedwith the development of strategies aimed to prevent iatrogenicneurotoxicity given the importance and fragility of organs wherethis lymphoma arises.

Acknowledgments

I am thankful to the Colleagues and Friends of the InternationalPCNSL Collaborative Group (IPCG). The continuous update anddiscussion with them led me to improve my own knowledge on thisdemanding malignancy. Our debates on new concepts and clinicaltrials, even if sometimes a little spicy, are the fertile background forfuture improvements in the management of PCNSL patients.

I appreciate the excellent support of scientists and cliniciansfrom the San Raffaele Scientific Institute (Milan, Italy), in particu-lar: Silvia Govi, Silvia Mappa, Marta Bruno Ventre and Emerenzi-

ana Marturano (Unit of Lymphoid Malignancies), Michele Reni(Medical Oncology Unit), Maurilio Ponzoni, Maria Rosa Terreniand Claudio Doglioni (Pathology Unit), Marco Foppoli andFederico Caligaris-Cappio (Internal Medicine Unit), Fabio Ciceri(BMT and Hematology Unit), Anna Chiara (Radiotherapy Unit),Alberto Franzin and Piero Picozzi (Neurosurgery Unit), LetterioPoliti and Andrea Falini (Neuroradiology Unit), Giulio Modorati(Ophthalmology Unit), Giulio Truci (Neurology Unit), andcoworkers.

Authorship

Contribution: A.J.M.F. wrote the entire manuscript.Conflict-of-interest disclosure: The author declares no compet-

ing financial interests.Correspondence: Andres J. M. Ferreri, MD, Unit of Lymphoid

Malignancies, Department of Onco-Hematology, San RaffaeleScientific Institute, Via Olgettina 60, 20132-Milan, Italy; e-mail:[email protected].

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