Pretargeted antibody-guided radioimmunotherapy in a child affected by resistant anaplastic large cell lymphoma

Pretargeted antibody-guided radioimmunotherapy in a childaffected by resistant anaplastic large cell lymphomaGiuseppe Palumbo1, Chiara M. Grana2, Francesca Cocca1, Rita De Santis3, Domenico Del Principe1,Silvia M. Baio2, Riccardo Mei2, Giovanni Paganelli2

1Department of Public Health and Cell Biology, Pediatrics, University of Rome ‘‘Tor Vergata’’ c ⁄ o Ospedale ‘‘S. Eugenio’’, Rome; 2Nuclear

Medicine Division, European Institute of Oncology, Milan; 3Sigma-Tau Industrie Farmaceutiche Riunite SpA, Pomezia, Rome, Italy

Anaplastic large cell lymphoma, (ALCL) is a high-grade

lymphoma, accounting for 10% of childhood lymphomas

(1). The most common translocation in ALCL is the

t(2;5) (p23;q35) chromosome translocation that causes

the anaplastic lymphoma kinase (ALK) gene on chromo-

some 2 to fuse with the NPM (nucleophosmin) gene on

chromosome 5. The NPM-ALK fusion gene encodes for

a chimeric protein that is thought to play a key role in

lymphomagenesis (2).

Different approaches have been adopted in the treat-

ment of ALCL in various cooperative trials, including

short high-dose intensive therapy and leukemia-like pro-

tocols (3). However, patients resistant to chemotherapy

or suffering from early relapse have a poor prognosis

and a poor chance of survival. The optimal therapeutic

strategy for this group of patients is still unclear. Alloge-

neic human stem cell transplantation (HSCT) has been

proposed as a therapeutic option in patients with relapse

of ALCL, but its role is still controversial (4).

More recently, radioimmunotherapy (RIT) has been

extensively studied in adult lymphoma patients (5–7)

with encouraging results.

Here we describe the case of ALCL in a child, who rela-

psed after cord blood stem cell transplantation (CBSCT),

treated with Pretargeted Antibody-Guided Radioimmuno-

Therapy (PAGRIT�) (8, 9), obtaining a complete remis-

sion, continuing after 10 months, without other therapies.

Case study

Patient

A 6-yr-old female was admitted to our hospital with a

1-month history of cough and fever, already treated with

Abstract

Anaplastic large cell lymphoma (ALCL) is characterized by preferential paracortical and intrasinusoidal

lymph node involvement by large anaplastic tumor cells expressing the CD30 antigen. Up to 80% of pedi-

atric patients with ALCL can be cured with multi-agent chemotherapeutic regimens. Patients resistant to

chemotherapy or suffering from early relapse have a poor prognosis and a poor chance of survival. In

these cases, the highly aggressive clinical course of ALCL, associated with systemic symptoms and

extranodal involvement, has been treated with different approaches in various cooperative trials, including

conventional chemotherapy and human stem cell transplantation (HSCT). However, the optimal treatment

has not yet been defined, in particular in cases of relapse. More recently, radioimmunotherapy has been

studied with encouraging results in cancer patients, including non-Hodgkin’s lymphoma. Here we describe

the case of a pediatric ALCL, relapsing after HSCT, treated with pretargeted antibody-guided radioimmuno-

therapy, obtaining a complete remission, with excellent quality of life over the past 10 months.

Key words radioimmunotherapy; anaplastic large cell lymphoma; pediatric non-Hodgkin’s lymphoma

Correspondence Giuseppe Palumbo, Department of Public Health and Cell Biology, Pediatrics, University of Rome ‘‘Tor Vergata’’

c ⁄ o Ospedale ‘‘S. Eugenio’’, P.zzale dell’Umanesimo, 10 – 00144 Rome, Italy. Tel: +390659290314; Fax: +39065917415; e-mail:

[email protected]

Accepted for publication 26 May 2007 doi:10.1111/j.1600-0609.2007.00910.x

CASE REPORT

European Journal of Haematology ISSN 0902-4441

258ª 2007 The Authors

Journal compilation 79 (258–262) ª 2007 Blackwell Munksgaard

antibiotics and corticosteroids, after the diagnosis of

pneumonia. Despite the therapy, the fever persisted, and

a CT scan revealed multiple bilateral lung lesions and

enlarged lymph nodes in the iliac region.

Physical examination revealed multiple non-ulcerated

cutaneous bullae.

Histologic examination and immunohistochemicalstaining

Histopathological diagnosis of the cutaneous lesions was

ALCL, ALK ⁄p80, CD30, EMA positive. The bone mar-

row examination was positive for t(2;5) (p23;q35).

Clinical stage

According to the St Jude classification, the patient had a

stage IV ALCL.

Treatments

Informed consent was obtained and the child was enrolled

in the European ALCL-99 high-risk study (Table 1).

Initial objective response was complete; molecular bone

marrow remission was demonstrated. One month after the

end of the maintenance protocol, she experienced cuta-

neous and bone marrow recurrence of the disease. The CT

scan revealed enlargement of mediastinic and inguinal

lymph nodes. Chemotherapy was changed to CC regimen,

repeated twice. After the first course, cutaneous and bone

marrow relapse was observed again. CVB regimen was

administered followed by CVCyt regimen, with no clinical

response. We changed chemotherapy to a maintenance ad

interim protocol (weekly vinblastin 6 mg ⁄m2).

As there was no sibling donor available, the patient

received unrelated CBSCT, which was performed

3 months after the last relapse. She had acute cutaneous

graft versus host disease (GVHD), grade III, developed

23 d after CBSCT, extended up to the 70% of the body

surface. Following therapy (methylprednisolone

1 mg ⁄kg ⁄die), cutaneous lesions regressed. No signs or

symptoms of chronic GVHD were observed. On day 57,

the patient developed cough, dyspnea and desaturation

and was referred to the intensive care unit. A broncho-

scopy revealed a mass occluding almost all (90%) the left

main bronchus; a biopsy demonstrated a relapse

(ALK ⁄p80, CD30, EMA positive). Prompt salvage the-

rapy was performed administering cyclophosphamide

(200 mg ⁄m2), with improvement of clinical conditions for

1 month.

In consideration of the poor prognosis, we started a

palliative therapy with weekly vinblastine (6 mg ⁄m2). In

the following 4 months she had two endobronchial relap-

ses, associated with bilateral lung nodules, that partially

regressed after cyclophosphamide administration. The

bone marrow examination demonstrated a complete

reconstitution and was 99% donor, with no t(2;5) (p23;

q35) expression.

Radioimmunotherapy

In consideration of the high toxicity of conventional

chemotherapy in this extensively treated patient,

Table 1 Chemotherapy treatments in this patient

(A) ALCL-99 protocol for patients with high risk ALCL

Pre-phase Dexamethason

10 mg ⁄ m2 ⁄ d (during 5 d)

Cyclophosphamide 400 mg ⁄ m2

Intrathecal medication

Course 1 Dexamethason


Methotrexate 3 g ⁄ m2

Cytarabin 600 mg ⁄ m2

Ifosfamide 4 g ⁄ m2

Etoposide 200 mg ⁄ m2

Course 2 (repeated three times) Dexamethason



Vinblastin 6 mg ⁄ m2

Cyclophosfamide 1 g ⁄ m2

Doxorubicin 50 mg ⁄ m2

Course 3 (repeated twice) Dexamethason




Ifosfamide 4 g ⁄ m2



Manteinance (weekly for 1 yr) Vinblastin 6 mg ⁄ m2

(B) CC regimen for patients with NHL

Dexamethason


Vindesin 3 mg ⁄ m2

Cytarabin 12 g ⁄ m2


Intrathecal medication

(C) CVB regimen for patients with NHL

Lomustin 100 mg ⁄ m2


Bleomicin 80 mg ⁄ m2

(D) CVCyt regimen for patients

with NHL

Lomustin 100 mg ⁄ m2



(E) Conditioning regimen for CBSCT

Fludarabine 150 mg ⁄ m2

Busulfan 9.6 mg ⁄ kg

Thiotepa 10 mg ⁄ kg

Palumbo et al. PAGRIT� in pediatric NHL

ª 2007 The Authors

Journal compilation 79 (258–262) ª 2007 Blackwell Munksgaard 259

after obtaining the consent of the Ethic Committee and

the parents, we discussed and planned a PAGRIT� in

order to achieve selective tumor uptake of the therape-

utic radionuclide, 90-Yttrium (electrons), with simulta-

neous reduction of non-target tissue background.

High tenascin expression in the neoplastic tissue at the

time of the relapse was detected, despite the fact that

such protein was not expressed at the time of diagnosis.

Therefore, the patient was proposed for PAGRIT� with

biotinylated ST2146 (TENATUMOMAB) anti-tenascin

monoclonal antibody (10). Clinical grade ST2146biot for

PAGRIT� applications was prepared by Tecnogen

SCpA, Piana di Monte Verna, Caserta, Italy.

We proposed PAGRIT� in order to achieve selective

high uptake of the therapeutic radionuclide, 90-Yttrium,

by the tumor with simultaneous reduction of non-target

tissue background. So, this young patient received 65 mg

of biotinylated anti-tenascin MoAbs, followed by the

administration of a molar excess of avidin

(50 + 150 mg) and by radioactive 90Y-biotinDOTA

(90Y-ST2210) (11) (3.5 GBq ⁄95 mCi), as essentially des-

cribed in previous studies in glioma patients (12).

Discussion

A 6-yr-old female affected by ALCL was extensively

treated with conventional therapies and CBSCT. After a

new relapse, she received PAGRIT�, with biotinylated

TENATUMOMAB anti-tenascin monoclonal antibody

and 90Y-biotinDOTA (90Y-ST2210), as a compassionate

therapy, obtaining a complete remission continuing after

10 months without other therapies (Fig. 1). She is going

to school again and enjoying a very good quality of life.

The PAGRIT� with the biotinylated ST2146 anti-tena-

scin monoclonal antibody was well tolerated, without

acute and subacute significant side effects. No hemato-

logical, liver and renal toxicities were observed, despite

the high dose of Y-90-biotin administered.

In the following 5 months she experienced two epi-

sodes of pneumonia, that completely remitted after

prompt endovenous antibiotic therapy.

Imaging studies (CT performed monthly four times

and then every 3 months) demonstrated the complete

remission of the disease.

Up to 80% of pediatric patients with ALCL can be

cured with multi-agent chemotherapeutic regimens.

Patients who suffer a relapse have an 85% chance of

achieving a second complete remission, but 40% of them

will have a second relapse. Patients resistant to chemo-

therapy or suffering from early relapse have a poor prog-

nosis and a poor chance of survival (13). There are

multiple chemotherapeutic options available in cases of

recurrence, but none have had a significant impact on

survival (14) .

This ALK+ ALCL child experienced lung relapse

after CBSCT, with full donor chimerism. Hence the need

for a different therapeutic approach, with few acute and

late side effects.

As already demonstrated in adult follicular CD20 po-

sitive lymphoma, radioimmunotherapy with 90Y-Ibritu-

momab Tiuxetan (Zevalin�, Bayer Schering Pharma,

Berlin, Germany, and Biogen Idec, San Diego, CA,

USA) combines the benefits of immunotherapy and radi-

oisotopes and has been shown to be an effective therapy,

in relapsed ⁄ refractory non-Hodgkin’s lymphoma patients

(6, 7).

There are many advantages to using RIT for the

treatment of lymphoma. Firstly, lymphoma cells are very

sensitive to radiation in a dose-dependent fashion. Sec-

ondly, in RIT radiation may destroy tumour cells not

directly targeted by MoAbs, with the so called ‘cross fire

effect’ (6).

However, in this particular case, the patient’s

lymphoma did not express CD20 antigen, but we found

the tenascin expression by immunohistochemistry.

A

B

Figure 1 Lung CT scan of the patient before (A) and 6 months after

(B) PAGRIT�.

PAGRIT� in pediatric NHL Palumbo et al.



Tenascin-C is an extracellular matrix protein, which is

abundant in the stroma of several solid tumors (15).

Recently, it has been demonstrated that tenascin expres-

sion is increased in sites involved with lymphoma, and

its expression varies over time, depending upon the state

of the disease (16). Radiolabelled anti-tenascin antibodies

have already been shown to have a clinical benefit in

some tumors although the radiation dose delivered to the

tumor is generally low (17).

The PAGRIT� method is based on the sequential

administration of a biotinylated antibody, avidin and Y-

90-labelled biotin. The main objective of pretargeting is

to maximize the accumulation of radioisotopes at the

tumour site while minimizing distribution at non-target

organs. Pre-clinical (18) and clinical (9, 17, 19–21) studies

showed that the multi-step avidin-biotin method results

in improved localisation of radionuclides to tumors com-

pared to the more conventional ‘one-step’ approach with

radiolabelled MoAbs. The good results obtained in this

young patient are certainly encouraging and warrant

further investigation.

We would emphasize that RIT should be used as part

of a combined modality approach at an early stage of

the disease. The smaller the tumor, the higher the dose

delivered to the target. Any tumor will respond if given a

sufficient dose. Unfortunately such doses are not achie-

vable because of high toxicity. Pre-targeting approach

and combined therapy may improve the outcomes (22).

We think that combined strategies should be employed

in hematological malignancies, which are particular radio-

sensitive, in children diseases too, where the life expec-

tancy is increasing, and we have the duty to maintain it,

without late side effects. The promise is that the combi-

nation of radiotherapy, chemotherapy and RIT may pro-

vide, at last, a way of increasing their life expectancy.

Acknowledgements

The Authors wish to thank Dr E. Palma, Dr M. Cani-

glia, Dr P. Pfizer and Dr M. Mottolese for their helpful

suggestions.

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Pretargeted antibody-guided radioimmunotherapy in a child affected by resistant anaplastic large cell lymphoma