High frequency of unrecognized indolent hematological ... - Nature

Bone Marrow Transplantation (2008) 42, 427–428 & 2008 Macmillan Publishers Limited All rights reserved 0268-3369/08 $32.00

www.nature.com/bmt

LETTER TO THE EDITOR

High frequency of unrecognized indolent hematological disorders among HLA-matched siblings of patients with lymphoproliferative malignancies eligible for allo-SCT Bone Marrow Transplantation (2008) 42, 427–428; doi:10.1038/bmt.2008.183; published online 30 June 2008 Since 2004, 19 patients with relapsed CLL and nonHodgkin’s lymphoma have been included in a phase II trial of allo-SCT from HLA-matched sibling donors. The donor screening includes all HLA-matched siblings in the sibship with a full-scale search by means of BM morphology, flow cytometry and clonality (Ig and TCR) testing to exclude subclinical malignant hematological diseases. An unexpectedly high frequency of malignant hematological diseases was detected: An otherwise healthy sibling was found to have a hematological disorder in 5 of the 19 families (26%; Figure 1). There were four cases of concordant lymphoproliferative disease (two large granular T-lymphocytic leukemia and two marginal zone lymphoma) and one case of myeloproliferative disease (JAK2 þ essential thrombocytosis). This remarkably high frequency is in accordance with the concept of clustered familial Family 1

P T-LGL-L fol NHL 67 41 Family 3

ET 24

P anapl NHL 19

Family 2

P CLL 62

T-LGL-L 57

Family 4

MZL 69

P fol NHL 65

Family 5

MZL 52

P MF 48

Figure 1 Sib concordance in five families with a patient (P) for transplantation. Numeric figures show the age at debut of disease. Circle ¼ female, square ¼ male, black ¼ lymphoproliferative disease, black and white ¼ myeloproliferative disease, white ¼ normal. anapl NHL ¼ analplastic large cell non-Hodgkin’s lymphoma; ET ¼ essential thrombocytosis; fol NHL ¼ follicular low-grade B non-Hodgkin’s lymphoma; T-LGL-L ¼ large granular T-lymphocytic leukemia; MF ¼ mycosis fungoides; MZL ¼ marginal zone lymphoma.

lymphoproliferative disease (LPD),1–4 and in keeping with a recent survey, which placed the myeloproliferative disease within this pleiotypic entity.5 There was a male– male sex concordance in three of the families (Figure 1; families 2, 3 and 4) and a sister–brother concordance in two families (Figure 1; families 1 and 5), but a marked male excess of affected siblings (eight males and two females). Transfer of hematological malignancies from donor to patient by an allograft has been reported in the past,6–8 but has been assumed to be rare. Niederwieser et al.9 reviewed the existing data on transmission of donor illness, including hematological disorders, taking into consideration the age of the donor. It was speculated that screening for occult hematological disease might be more important in older donors. However, routine BM aspiration was not found to be justified for screening related donors. It was recommended when blood tests were abnormal or there was a family history of malignancies. The donor screening performed at our institution included BM aspirates with flow cytometry and molecular investigations in case of abnormal findings. This probably explains the surprisingly high incidence of indolent hematological disorders observed. Although the clinical relevance is uncertain, we chose not to harvest the affected donors. LPD may be an innocent bystander as sometimes seen, for example, in stage A CLL, in some cases of lowgrade non-Hodgkin’s lymphoma, in monoclonal gammopathy of undetermined significance and in the CLL precursor B-lymphocytosis of undetermined significance. As inherited polysusceptibility genes to LPD are present lifelong, the increased risk of LPD in otherwise healthy members of such families is not related to old persons, and hence the donor screening in such families is not particularly crucial in old persons. Our small ‘look-back’ study will be a part of the more powerful prospective regression analysis where mathematic models are available.10 In the meantime, we speculate about the question of whether young and old donors are at an equal risk for transmitting malignant disease in general when a genetic mechanism and susceptibility genes are involved. In conclusion, our preliminary data raise the question of whether a more detailed screening of HLA-matched sibling donors should be considered in certain circumstances to detect occult hematological disease. A Kolstad1, G Tjnnfjord2 and V Jnsson3 1 Department of Oncology, Cancer Clinic, Rikshospitalet, Oslo, Norway;

Letter to the Editor

428 2

Department of Medicine, Rikshospitalet, Gaustad, Oslo, Norway and 3 Department of Haematology, Aker University Hospital, University of Oslo, Oslo, Norway E-mail: [email protected]

Acknowledgements We thank Torstein Egeland (Rikshospitalet) for his contribution to this work.

References 1 Houlston RS, Sellick G, Yuille M, Matutes E, Catovsky D. Causation of chronic lymphocytic leukaemia—insight from familial disease. Leuk Res 2003; 27: 871–876. 2 Goldin LR, Pfeiffer RM, Li X, Hemminki K. Familial risk of lymphoproliferative tumors in families of patients with chronic lymphocytic leukemia, results from the Swedish family cancer database. Blood 2004; 194: 1850–1854. 3 Daugherty SE, Pfeiffer RM, Mellemkjaer L, Hemminki K. No evidence for anticipation in lymphoproliferative tumors in population-based samples. Cancer Epidemiol Biomarkers Prev 2005; 14: 1245–1250.

Bone Marrow Transplantation

4 Wang SS, Slanger SL, Brennan P, Holly EA, De Sanjose S, Bernstein L et al. Family history of hematopoietic malignancies and risk of non-Hodgkin lymphoma (NHL), a pooled analysis of 10211 cases and 11905 controls from the International Lymphoma Epidemiology Consortium (InterLymph). Blood 2007; 109: 3479–3488. 5 Jnsson V, Tjnnfjord GE, Samuelsen SO, Johannesen TB, Ly B. Pleiotrophy in familial CLL. Leuk Lymphoma 2007; 48: S124. 6 Niederwieser D, Appelbaum FR, Gastl G, Gersdorf E, Meister B, Geissler D et al. Inadvertent transmission of a donors acute myeloid leukemia in bone marrow transplantation for chronic myelocytic leukemia. N Eng J Med 1990; 322: 1794–1796. 7 Berg KD, Brinster NK, Huhn KM, Goggins MG, Jones RJ, Makery A et al. Transmission of a T-cell lymphoma by allogeneic bone marrow transplantation. N Eng J Med 2001; 345: 1458–1463. 8 Baron F, Dresse M-F, Beguin Y. Transmission of chronic myelocytic leukemia through peripheral-blood stem cell transplantation. N Eng J Med 2003; 349: 913–914. 9 Niederwieser D, Gentilini C, Hegenbart U, Lange T, Moosmann P, Po¨nisch W et al. Transmission of donor illness by stem cell transplantation, should screening be different in older donors? Bone marrow transplant 2004; 34: 657–665. 10 Reilly M, Szulkin R. Statistical analysis of donor-transfusion data with complex correlation. Statist Med 2007; 26: 5572–5585.