Thomas, D.L., Thio, C.L., Martin, M.P., Qi, Y., Ge,

D., O’Huigin, C., Kidd, J., Kidd, K., Khakoo, S.I.,

Alexander, G., Goedert, J.J., Kirk, G.D., Donfield,

S.M., Rosen, H.R., Tobler, L.H., Busch, M.P.,

McHutchison, J.G., Goldstein, D.B. & Carring-

ton, M. (2009) Genetic variation in IL28B and

spontaneous clearance of hepatitis C virus.

Nature Genetics, 461, 798–80123.

Thompson, A.J., Fellay, J. & McHutchison, J.G.

(2010) How the human genome can predict

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Long term risk of infections in Hodgkin lymphoma long-termsurvivors

This study illustrates an elevated risk of late infection

in Hodgkin lymphoma survivors which is associated with

splenectomy and hypothyroidism.

Late effects, such as second primary tumours and cardio-

vascular diseases, have repeatedly been reported following

treatment for Hodgkin lymphoma (HL) (Aleman et al, 2007;

Swerdlow et al, 2000). Between 1960 and 1990, splenectomy

was a standard procedure in the diagnostic work up of HL

(Mauch & Somers, 1992). The spleen is of a great importance

in cell-mediated immune defence, particularly against encap-

sulated bacterial organisms, such as streptococcus pneumonia.

Studies have shown an increased risk of infections in splenec-

tomized patients, and the development of overwhelming post-

splenectomy infection (OPSI) is the most serious infectious

complication after splenectomy (Lynch & Kapila, 1996).

The impact of splenectomy and other covariates such as

diabetes, hypothyroidism and history of chemotherapy, on the

risk of developing serious infections, was analysed in a prospec-

tive study conducted on HL long term survivors in Sweden.

Since 1958 all malignancies in Sweden are reported to the

Swedish Cancer Registry (SCR), at the National Board of

Health and Welfare. Between 1965 and 1995, 6946 individuals

diagnosed with HL in Sweden were identified through the

SCR. The infection diagnoses were selected from International

Classification of Diseases 7 (ICD7) codes and recoded through

ICD 8–10. By law, since 1987, all health care units in Sweden

are required to report all in-patient care to the Hospital

Discharge Registry, Sweden (HDR). The HL cohort for this

study comprised patients registered to the HDR with infection

as the first diagnosis code for in-patient care.

A primary diagnosis of sepsis was defined as a significant

event of infection. For each in-patient care event, the date and

diagnosis was registered. The first year after HL diagnosis was

omitted to exclude infections related to HL treatment.

Incidence files of the entire HDR were created using the 9Æ5million observed in-patient registrations, categorizing variables

for calendar year, sex and age. The expected number of

infection cases was calculated by multiplying the person years

for every calendar year, sex and 5-year age group by the

corresponding age-specific incidence rate created from the

HDR. The standardized incidence ratio (SIR) was estimated by

dividing the number of observed cases by the number of

expected cases. Currently surviving patients from three of the

six University hospitals in Sweden (Lund, Umea and Uppsala)

who received treatment for HL when aged £45 years, between

1965 and 1995 (n = 702), were invited to participate in a

prospective study, the Swedish Hodgkin Intervention Preven-

tion study (SHIP), which has previously been described

(Andersson et al, 2009). The study included patients with

relapsed disease. However no data was available in individual

treatment data to study the impact on risk for infection in the

retrospective study. Four hundred and fifty-three (64Æ5%)

patients accepted the invitation and returned a completed

questionnaire concerning their HL disease, general health and

family history. These patients were then invited to an out-

patient visit to an oncologist for a physical examination and

blood sampling. Binary logistic regression analysis was per-

formed on data from the questionnaires using the Statistical

Package for the Social Sciences (spss, IBM Corporation,

Somer, NY, USA) software.

In the retrospective study an elevated risk for infections

1–9 years after treatment was observed, SIR 6Æ03 [95%

confidence interval (CI) 4Æ53–7Æ86], and remained elevated

even at a follow-up of 20 years or longer, SIR 2Æ94 (95% CI

1Æ84–4Æ45; Table I). Among the individuals in the prospective

study 249/453 were men. The median age at follow up was

51Æ0 years (17–84) and median follow up time was 22Æ0 years

(11–43). One hundred and ninety-nine of 453 underwent

Table I. Risk for developing serious infection requiring admission to

hospital after Hodgkin lymphoma (HL) diagnosis. First year omitted

due to risk of treatment-related infections during this time.

Years after HL O E SIR CI (95%)

1–9 54 9Æ0 6Æ03 4Æ53–7Æ86

10–19 28 8Æ9 3Æ15 2Æ09–4Æ55

20–¥ 22 7Æ5 2Æ94 1Æ84–4Æ45

O, observed cases; E, expected cases; SIR, standard incidence ratio; CI,

confidence interval.

Correspondence

ª 2011 Blackwell Publishing Ltd, British Journal of Haematology, 154, 654–665 661

splenectomy during HL diagnostic work up. In the splenec-

tomized group 58/199 individuals reported infection that

required hospitalization, defined as severe infection, odds ratio

(OR) 2Æ13 (CI 95% 1Æ35–3Æ36). Forty-one of 254 in the non-

splenectomized group reported severe infection. Individuals

with hypothyroidism (169/453 patients) also showed an

elevated risk for severe infection, OR 2Æ59 (CI 95% 1Æ64–

4Æ08). In a multivariate analysis the elevated risk for infections

in the splenectomized group remained significantly elevated

when adjusting for hypothyroidism (Table II).

This study showed an increased risk for infections in HL

survivors, which seems to remain over time and is still

increased after 20 years of follow up. The risk is associated

with hypothyroidism and splenectomy. The underlying cause

of the elevated risk with hypothyroidism is still unknown.

One can speculate that patients who developed hypothyroid-

ism had received a larger biological radiation dose and

thereby become more sensitive for upper respiratory tract

infection due to damaged cilia. An earlier Norwegian study

did not find any significant difference in non-fatal infections

between 95 HL splenectomized patients compared with 94

non-splenectomized patients (Abrahamsen et al, 1990). The

incidence of infections was, however, significantly higher in

more advanced disease (Abrahamsen et al, 1990). In a study

of 84 patients, Keel et al (1983) suggested that aggressive

therapy was of greater importance than splenectomy for the

risk of infections. In the present study, conducted on 453

patients and with a median follow up of 22Æ0 years, chemo-

therapy did not affect the long-term risk for infections. No

significantly increased incidence of infections in more

advanced stage disease was shown in a subset of the regions

of Umea and Skane from the present prospective study

(n = 204), (P = 0Æ09), data not shown. It could be speculated

whether HL itself, as a disease that affects the immune system,

contributed to any of this elevated risk for infections in the

HL cohort (Merk et al, 1990). In our study we had no

information on the infection subtypes and bacterial species, or

the vaccination status. No prophylactic antibiotic treatment

was given. A previous study, which was not conducted on HL

survivors only, demonstrated a lifelong increased risk of

severe sepsis in splenectomized individuals (Waghorn, 2001).

Landgren et al (2004) showed a significant antibody response

to pneumococcal vaccination in 311 splenectomized individ-

uals and that this was beneficial for patients at risk for

infection, suggesting frequent revaccination every 1–5 years.

Individuals in the present prospective study have been

recommended to continue or commence pneumococcal

vaccination every 5 years, if this had not already been

adequately addressed. Hopefully, this will reduce the risk of

developing serious infections in this cohort in the future.

Acknowledgements

This study was supported by grants from Northern Sweden

Cancer Society and the Swedish Cancer Society. BM was

supported by a grant from the Acta Oncologica foundation

through the Royal Swedish Academy of Science.

Anne Andersson1

Gunilla Enblad2

Anita Gustavsson3

Martin Erlanson1

Hans Hagberg2

Daniel Molin2

Bjorn Tavelin4

Beatrice Melin1

1Department of Radiation Sciences, Oncology, Umea University, Umea,2Department of Oncology, Radiology and Clinical immunology, Section of

Oncology, Uppsala University, Uppsala, 3Department of Oncology, Skane

University Hospital, Lund University, Lund, and 4Oncologic Centre,

Umea University, Umea, Sweden.

E-mail: anne.andersson@onkologi.umu.se

Keywords: survivorship, Hodgkin lymphoma, late effects,

cohort, infection.

First published online 7 April 2011

doi: 10.1111/j.1365-2141.2011.08638.x

Table II. Univariate and multivariate binary logistic regression analysis of risk factors for severe infection after treatment for Hodgkin Lymphoma in

individuals with (n = 99) and without (n = 354) an episode of severe infection, (n total = 453).

Risk for infection

Univariate analysis

Risk for infection

Multivariate analysis

OR 95% CI P value OR 95% CI P-value

Splenectomized (n = 199) 2Æ13 1Æ35–3Æ36 0Æ001 1Æ98 1Æ23–3Æ18 0Æ005

Hypothyroidism (n = 166) 2Æ59 1Æ64–4Æ08 <0Æ001 2Æ33 1Æ46–3Æ72 <0Æ001

Chemotherapy (n = 309) 1Æ23 0Æ75–2Æ02 0Æ397 1Æ53 0Æ91–2Æ57 0Æ107

Ever smoker (n = 215) 1Æ36 0Æ87–2Æ14 0Æ172 1Æ37 0Æ86–2Æ17 0Æ184

Male sex (n = 249) 0Æ75 0Æ48–1Æ18 0Æ216 0Æ74 0Æ47–1Æ19 0Æ220

OR, odds ratio; CI, confidence interval.

Correspondence

662 ª 2011 Blackwell Publishing Ltd, British Journal of Haematology, 154, 654–665

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use of diagnostic staging laparotomy and

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& Holm, G. (1990) Immune deficiency in family

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Temozolomide may induce therapy-related acute lymphoblasticleukaemia

Temozolomide (TMZ) is a second-generation oral alkylating

agent that is approved for treatment of high-grade gliomas, such

as anaplastic astrocytoma and glioblastoma multiforme.

Administration of TMZ together with cranial radiotherapy

after surgical removal of the glioblastoma is sufficiently

tolerable and confers significant survival benefits, when

compared with adjuvant radiotherapy alone (Stupp et al,

2005). Although traditional chemotherapy comprising procar-

bazine, lomustine (CCNU) and vincristine (PCV regimen)

demonstrates comparable efficacy against high-grade gliomas

(Brada et al, 2010), it has been replaced by TMZ because this

drug has less myelotoxicity and is thus more applicable to the

outpatient setting. On the other hand, previous exposure to

alkylators is strongly associated with therapy-related myelodys-

plastic syndrome (t-MDS) and therapy-related acute myeloid

leukaemia (t-AML) harbouring whole or partial losses of

chromosomes 5 and 7, with frequent complex or hyperdiploid

karyotype (Mauritzson et al, 2002). Because TMZ is a relatively

new agent and because glioblastoma is an aggressive malignant

neoplasm with a poor prognosis, TMZ-related haematological

disorders have not yet been fully characterized. Herein we

describe a case of glioblastoma who developed acute lympho-

blastic leukaemia (ALL) after prolonged exposure to TMZ. In

contrast to many other alkylating agents that cause secondary

haematological neoplasms of the myeloid lineage, we found

that TMZ-related leukaemia is predisposed to lymphoblastic

phenotypes through a literature review.

A 49-year-old Japanese female with no remarkable medical

history was diagnosed with grade II astrocytoma of the right

temporal lobe and received surgical resection. Three years

later, a follow-up magnetic resonance imaging scan revealed

local recurrence. A craniotomy was performed and the

recurrent tumour was largely resected except for the portion

that infiltrated the insula. A re-craniotomy was performed due

to post-operative intratumoural haemorrhage, and the patient

subsequently developed left hemiparesis. A malignant trans-

formation to glioblastoma was pathologically confirmed.

Hence, the surgery was followed by cranial radiotherapy at a

total dose of 80 Gy in 40 fractions. Adjuvant chemotherapy

was commenced with TMZ for five consecutive days every

4 weeks. After the initial dose of 150 mg/m2/d, the dose was

increased to 200 mg/m2 from the second cycle. This treatment

was discontinued after 54 cycles due to leucopenia. Five

months later, the patient was referred to our department,

because leukaemic blasts had appeared in the peripheral blood.

Her haemoglobin level was 101 g/l, leucocyte count 0Æ8 · 109/l

with 40% blasts, and platelet count 135 · 109/l. The bone

marrow aspiration demonstrated hypercellular marrow with

88% myeloperoxidase-negative blasts, which were positive for

CD10, CD19 and CD34 by flow cytometric analysis and also

positive for nuclear terminal deoxynucleotidyl transferase

(TdT) by immunohistochemical staining. Cytogenetic study

showed normal karyotype in all 20 metaphases analysed. BCR-

ABL1 gene rearrangement was not detected by reverse

Correspondence

ª 2011 Blackwell Publishing Ltd, British Journal of Haematology, 154, 654–665 663