Allogeneic hematopoietic stem cell transplantation and the risk for transmission of heritable malignancy

R E V I E W

Allogeneic hematopoietic stem cell transplantation andthe risk for transmission of heritable malignancy

Kenneth D. McMilin

The safety of allogeneic stem cell products avail-able for transplantation or under developmentis of central importance to patients, to theirphysicians, and to the providers of stem cells. It

is critical that stem cell transplantation not be the sourceof significant new disease inadvertently transmitted tothe patient. The risk for transmission of infectious diseaseis well recognized, and numerous effective preventivemeasures are available and in place. The risk for trans-mission of genetic disease is less widely recognized, andfewer preventive measures are in place.

Heritable cancer constitutes an important subset ofpotentially transmissible genetic disease. Along with theoverall risk, heritable cancer transmission through allo-geneic stem cell transplantation merits thorough investi-gation, leading toward implementation of policies thatprotect the well-being of patients.

Among those stem cells with potential therapeuticapplication, it is hematopoietic stem cells (HSCs) forwhich transplantation is relatively well developed. In-deed, HSCs are vital in the treatment of numerous inher-ited and acquired diseases. In the treatment of cancer,transplanted stem cells generate new marrow cells, a re-placement for patient marrow cells severely damaged bycytotoxic drugs. In the treatment of genetic disease, allo-geneic stem cells provide the essence of transplantationtherapy, generating healthy tissue as a substitute for in-herently diseased tissue of the patient.

Unfortunately, donor tissue itself may be diseased ormay become diseased. Both leukemia and lymphomahave arisen from cells of donor origin.1-3 Furthermore,

cancer arising from transplanted cells may be due to pre-disposing mutation of donor origin.4 Hence, whetherHSCs or other stem cell types are used in the treatment ofinherited or acquired disease, the genetic integrity oftransplanted allogeneic progenitor cells is vital to thewell-being of the patient.

HERITABLE PREDISPOSITION TOHEMATOPOIETIC MALIGNANCY

Cancer is, fundamentally, genetic disease.5,6 Most cancerappears to be sporadic, predominantly caused by ac-quired somatic mutations. However, some cancer is in-herited, predominantly because of germline mutation inspecific genes transmitting strong predisposition for can-cer development.7 Hence, heritable cancer syndromes of-ten are characterized by affected individuals with mul-tiple primary cancers, beginning at a rather young age.The spectrum of cancers that are typical for specificsyndromes may be relatively narrow, as with retinoblas-toma, or may be relatively broad, as with Li-Fraumenisyndrome. Characteristic of Li-Fraumeni syndrome is afamily pedigree showing individuals in consecutive gen-erations afflicted with any of numerous diverse malig-nancies, including breast carcinoma, soft tissue sarcoma,brain tumor, bone sarcoma, adrenocortical carcinoma,and leukemia.8 Characteristic of inherited retinoblastomais the presentation of an infant with bilateral occurrenceof this ocular cancer. Nonetheless, genetic mutations un-derlying cancer development are of sufficient generalitythat, even with inherited retinoblastoma, the patient ispredisposed also to develop additional types of cancer.9

Furthermore, many genetic mutations predisposing tocancer are of such broad impact that they also causenumerous nonmalignant abnormalities.10

HSC proliferation and differentiation are under ge-netic control (hence are subject to genetic mutation).11

Diverse genes regulate complex interacting pathwayscritical to hematopoiesis, and many of these genes arepleiotropic, acting on various nonhematopoietic tissues.Thus, genetic disorders affecting hematopoiesis exhibit abroad spectrum of syndromic features. Some of these di-

ABBREVIATION: HSC(s) = hematopoietic stem cell(s).

From the American Red Cross Blood Services, Alabama Re-

gion, Birmingham, Alabama.

Address reprint requests to: Kenneth McMilin, MD, PhD,

Chief Medical Officer, American Red Cross Blood Services, Ala-

bama Region, 1130 22nd Street South, Birmingham, AL 35205-

2814; e-mail: [email protected].

Received for publication July 12, 2001; revision received

November 14, 2001, and accepted November 30, 2001.

TRANSFUSION 2002;42:495-504.

Volume 42, April 2002 TRANSFUSION 495

verse genetic disorders cause hematopoietic malignancy(Table 1). Clearly, a wide array of mutant genes may poserisk to the recipient of allogeneic stem cell transplanta-tion.

QUESTIONS REGARDING RISKAND RESPONSE

Numerous questions confront efforts to prevent trans-mission of genetic disease through allogeneic stem celltransplantation, to which there are some partial answers.

What criteria guide the selection ofpotential donors?For the risk of infectious disease, guidelines have beenpublished by the CDC, with eligibility criteria for stemcell donors that reflect the analogous criteria for wholeblood donors.88 However, the guidelines for HSC trans-plantation are, ultimately, remarkably liberal, in recogni-tion of the potentially limited availability of HLA-matched donors for the treatment of life-threateningdisease. The CDC acknowledge that “the transplantphysician often has to accept a higher risk for transmis-sion of an infectious agent through HSC transplantationthan would be permitted for routine blood transfu-sion.”88 (p. 49) The guidelines assert that “no personshould be denied a potentially life-saving HSC transplan-tation procedure solely on the basis of the risk for aninfectious disease.”88 (p. 49)

The acceptance of an elevated risk for infectious dis-ease transmission might reasonably be translated to ac-ceptance of a comparable elevated risk for genetic dis-ease transmission. Although useful, this concept lacksspecificity. Furthermore, as compatible stem cell prod-ucts become more readily available, tolerance for infec-tious and for genetic disease transmission will likely di-minish. However, for genetic disease, the comprehensivedetermination of risk and appropriate response is espe-cially difficult. There is a wide variation in the prevalenceof those genetic diseases posing risk, a wide variation inthe potential for detecting affected donors, a wide varia-tion in the probability for progression in recipients tomalignancy (or other grave outcomes), and there is lim-ited information concerning these matters to support ra-tional decision making.

Nonetheless, consideration of the precautionaryprinciple argues for the development of donor eligibilitystandards that help to protect patients from the trans-plantation of genetic disease, despite scientific uncer-tainty.

How prevalent are the disorders that pose risk?Some of the genetic disorders associated with a predis-position to hematopoietic malignancy are relatively com-

mon, including Down syndrome and type I neurofibro-matosis. For Noonan syndrome, with recognition of milddisease, prevalence as high as one in 100 has been sug-gested.67 Other genetic disorders may be rare in the gen-eral population, but relatively common in specific sub-populations, such as cartilage-hair hypoplasia, which hasan incidence of one in 1000 among Old Order Amish.22

Yet other disorders, transmitted as autosomal recessives,are themselves rare; however, carriers of the germlinemutation are rather common, and these carriers mayhave an increased cancer risk. For example, one person in100 carries an ataxia-telangiectasia mutation and mayhave a predisposition to develop leukemia, specificallyB-cell chronic lymphocytic leukemia.12,13 Similarly, it hasbeen suggested that carriers of Fanconi anemia mutation(1 in 300) might be at increased risk for leukemia55,56 andthat carriers of a Werner syndrome mutation (one per-son in several hundred) have genetic instability thatmight increase vulnerability to genotoxic drugs and pre-dispose to hematopoietic malignancy.76 Finally, many ge-netic mutations thought to be rare prove to be signifi-cantly less rare as genetic testing is more widely applied.For example, Wiskott-Aldrich syndrome has been char-acterized clinically as a severe, life-threatening disease.However, following identification of the causative gene,mutation testing reveals a larger spectrum of the popu-lation to be affected, with markedly variable severitywithin single kindreds and with many affected individu-als manifesting the distinct disorder of X-linked throm-bocytopenia.79,80

Hence, potential stem cell donors harboring a germ-line mutation of concern may be remarkably prevalent,but for many mutations, the magnitude and character ofthe risk to recipients remain poorly defined.

How reliable is a donor’s negative family history?For individuals affected with autosomal (or X-linked) re-cessive disorders, the absence of a positive family historyis not unusual, even if the potential donor has siblings.Parents (and other asymptomatic heterozygous relatives)are frequently unaware of their status as carriers. Further-more, a sibling may be unaffected (with a 75% probabil-ity) or affected but unrecognized (due to mild manifes-tations or delayed appearance of manifestations).

For autosomal dominant disorders, the absence of apositive family history is not unusual. Unrecognized dis-ease in a family with mild manifestations is quite pos-sible, and sporadic disease from de novo mutation maybe quite frequent. For example, most cases of Diamond-Blackfan anemia appear to be sporadic, with only 10 to 20percent showing clear inheritance (most commonly au-tosomal dominant).31

For cytogenetic disorders, the absence of a positivefamily history is typical. (Furthermore, for the detection

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496 TRANSFUSION Volume 42, April 2002

TABLE 1. Selected genetic disorders associated with a predisposition to hematopoietic malignancy*Disorder Locus† Inheritance‡ Incidence§ Features References

Ataxia-telangiectasia 11q22-q23 AR 1:100,000 Onset in early childhood; progressiveneuromotor dysfunction;immunodeficiency; predisposition tolymphoma, leukemia, other cancers

12-14

Autoimmune lymphopro-liferative syndrome

10q24.1 AD Rare Highly variable expression; chroniclymphadenopathy; splenomegaly;autoimmunity; Hodgkin’s andnon-Hodgkin’s lymphoma

15-18

Bloom syndrome 15q26.1 AR Rare Short stature; immunodeficiency;sun-sensitive facial erythema; higherincidence in Ashkenazi Jews (1:50,000);predisposition to leukemia, lymphoma,various carcinomas

19-21

Cartilage-hair hypoplasia 9p21-p12 AR Rare Variable expression; short-limbed shortstature; sparse hair; impaired cellularimmunity; anemia; lymphoma

22, 23

Chediak-Higashi syndrome 1q42.1-q42.2 AR Rare Albinism; immunodeficiency; neurologicdysfunction; lymphoma-like acceleratedphase

24, 25

Common variableimmunodeficiency

1:100,000 Hypogammaglobulinemia; diagnosis inchildhood or adulthood; increasedlymphoma risk; related to IgA deficiency(which has a prevalence of 1 in 1000)

26, 27

Congenital neutropenia 19p13.3 A Rare Severe neutropenia; manifest during firstyear of life; responsive to G–CSF therapy;increased leukemia risk

28-30

Diamond-Blackfan anemia 8p23.3-p2219q13.2

AD 1:100,000 Hypoplastic anemia; manifest in infancy orearly childhood; genetic heterogeneity;often sporadic; clinical heterogeneityincludes mild expression; predisposition tohematopoietic malignancy

31-33

Down syndrome 21q22.2-q22.3 Cyt 1:1000 Trisomy 21; mental retardation; congenitalheart defect; transient myeloproliferativedisorder; acute myelogenous leukemia;acute lymphocytic leukemia

34-38

Dyskeratosis congenita Xq28 XR Rare Manifest in childhood; mucosal leukoplakia;bone marrow failure; predisposition tocancer, including hematopoietic cancer

39, 40

Familial hemophagocyticlymphohistiocytosis

9q21.3-q2210q21-q22

AR 1:100,000 Genetic heterogeneity; manifest in infancy orearly childhood; lymphohistiocyticinfiltration; hepatosplenomegaly; centralnervous system involvement

41-45

Familial leukemia AD Rare Both familial chronic lymphocytic leukemiaand familial acute myelogenous leukemiareported; anticipation (earlier age infollowing generation)

46-49

Familial multiple myeloma Rare Multiple myeloma 50, 51Familial platelet disorder

with associatedmyeloid malignancy

21q22.1-q22.3 AD Rare Qualitative and quantitative platelet defects;predisposition to acute myelogenousleukemia

4, 52, 53

Fanconi anemia 3p26-p25.36p22-p219p139q22.311p1516q24.3

AR Rare Genetic and clinical heterogeneity; congenitalskeletal anomalies; childhood-onsetprogressive marrow failure; predispositionto cancer, especially acute myelogenousleukemia

54-58

Griscelli syndrome 15q21 AR Rare Partial albinism; variable immunodeficiency;hepatosplenomegaly; accelerated phasefatal lymphocytic infiltration;[myelodysplastic syndrome]

59, 60

Hyper-IgM syndrome Xq26 XR Rare Low serum levels of IgG, IgA, IgE; normal orelevated IgM; neutropenia; recurrentinfection; lymphadenopathy; increasedcancer risk; [lymphoma]

61, 62

Li-Fraumeni syndrome 17p13.122q12.1

AD Rare Predisposition to breast cancer, soft tissuesarcoma, brain tumor, bone cancer,leukemia, [lymphoma]

8

HERITABLE MALIGNANCY TRANSMISSION RISK


TABLE 1. ContinuedDisorder Locus† Inheritance‡ Incidence§ Features References

Neurofibromatosis type I 17q11.2 AD 1:3000 Approximately half caused by a new mutation;varies from mild to severe; café-au-laitspots; Lisch nodules; neurofibromas;neurofibrosarcoma; childhood leukemia

63, 64

Nijmegen breakagesyndrome

8q21 AR Rare Microcephaly from infancy; short stature;immunodeficiency; cancer predisposition,especially lymphoma; [increased cancer risk inheterozygotes]

65, 66

Noonan syndrome 12q24 AD 1:2000 Frequently sporadic; phenotypic variability;congenital heart defect; craniofacialdysmorphism; short stature; [leukemia]

67

Omenn syndrome 11p13 AR Rare Variant combined immunodeficiency; failure tothrive; lymphocytic infiltration; erythroderma;hepatosplenomegaly; lymphadenopathy

68, 69

Retinoblastoma 13q14.1-q14.2 AD 1:20,000 Inherited germline or acquired somatic mutationin RB1; bilateral or unilateral retinoblastoma;primary or treatment-related bone cancer, softtissue sarcoma; [leukemia, lymphoma]

9, 70

Severe combinedimmunodeficiency

20q12-q13.11Xq13

ARXR

Rare Heterogeneous group of immunodeficiencies;opportunistic infections; fatal by earlychildhood if untreated; mutations in theresponsible genes also cause delayed onsetand mild disease; [lymphoma]

62, 71, 72

Shwachman syndrome D7S482-D7S499 AR Rare Exocrine pancreatic insufficiency, especially inearly life; short stature; marrow dysfunctionwith prominent neutropenia; leukemia

73-75

Werner syndrome 8p12-p11.2 AR Rare Normal appearance in childhood; subsequentprogeroid features; atherosclerosis; diabetes;scleroderma-like skin; diverse cancers,especially sarcomas; myeloid disorders;[leukemia in adults]

76-78

Wiskott-Aldrichsyndrome

Xp11.4-p11.21 XR Rare Thrombocytopenia; immunodeficiency;eczema; autoimmunity; predisposition tolymphoreticular malignancy; variableexpression; potential onset in neonate anddeath before adolescence

79-81

X-linked agamma-globulinemia

Xq21.3-q22 XR 1:200,000 Low serum immunoglobulin levels; earlychildhood onset recurrent bacterial infections;severe enteroviral infections; [lymphoreticularmalignancy slightly increased]

71, 82

X-linked lymphoprolifera-tive disease

Xq25-q26 XR Rare Fulminant infectious mononucleosis;lymphoma; dysgammaglobulinemia;fatal, often during childhood or youngadulthood

83-85

* Predisposition to develop hematopoietic malignancy is well established for many of these disorders. For others, the cancer predispositionis subjectively judged to be less certain, less characteristic, or less well defined, and it is designated within brackets. Despite past or cur-rent suggestion of association with hematopoietic malignancy, certain disorders are explicitly (also subjectively and tentatively) omittedfrom the table, some because the association is reportedly weak, some because evidence for the association is presently weak, andsome because the disorder is exceptionally rare. Omitted disorders include ataxia-pancytopenia syndrome, Barth syndrome, congenitaldyserythropoietic anemia, Dubowitz syndrome, familial Hodgkin’s disease, familial melanoma, familial polycythemia, incontinentia pig-menti, IVIC syndrome, Klinefelter syndrome, Lynch cancer family syndrome II, N syndrome, Pearson marrow–pancreas syndrome, poly-cystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, Seckel syndrome, selective IgA deficiency, WHIM syndrome,WT limb–blood syndrome, xeroderma pigmentosum, and XYY syndrome.

† The cytogenetic loci86,87 (along with the recently reported molecular locus for Shwachman syndrome)73 are representative, not all-inclusive, and the described features (including incidence and inheritance) refer to the named disorder, not necessarily the specificlocus. (For example, a predisposition to leukemia in Down syndrome likely derives from trisomy for a region of chromosome 21 outsidethat considered to be the critical region for many features).36

‡ Some disorders may occur with patterns of inheritance additional to the listed designations: A (autosomal), AD (autosomal dominant), AR(autosomal recessive), XR (X-linked recessive), or Cyt (cytogenetic). Sporadic occurrence is relatively frequent for certain disorders. (It isnoteworthy, for example, that common-variable immunodeficiency is frequently sporadic and may involve an autosomal dominant, autoso-mal recessive, or nonmendelian genetic defect.86 Congenital neutropenia commonly arises sporadically or by autosomal inheritance ofdominant-acting mutation, and also appears to have autosomal recessive inheritance.28,29 Hyper-IgM syndrome occurs not only asX-linked, but also as autosomal recessive disease.)86

§ The incidence entries (actually prevalence for a few disorders) are generally rounded to a single significant digit, recognizing the approxi-mate character of these data. (Even for Down syndrome, previous data may not accurately reflect the current incidence at birth, becauseof changing maternal age and ethnicity demographics, and changing patterns of obstetric intervention.)38 The designation “Rare” meansthat various authorities have so described the given disorder.

McMILIN


of Down syndrome, even maternal age is of limited help,with most affected births occurring in women less than35 years old.)35

Hence, a negative family history for genetic diseaseprovides little assurance as to the absence of a significantgermline mutation in the donor.

What is the potential for undiagnosed disease inthe donor?Genetic disease in the donor may remain undiagnosed ifthe donor is presymptomatic (disease onset occurring atan age older than that of the donor) or if the donor hasespecially mild manifestation (disease expression beingvariable).

Some genetic diseases typically do not manifest untiladulthood. For example, in familial chronic lymphocyticleukemia, the median onset age is 72 years old in theinitial generation (falling to 51 years old in the succeedinggeneration, presumably because of anticipation).46

Certain other genetic diseases manifest during child-hood, but typically following years of apparent normalcy.For example, Werner syndrome patients generally appearnormal throughout their first decade of life,77 and dys-keratosis congenita patients generally develop theirfirst clinical manifestations only after reaching 5 yearsold.39,40

Also important is the large variability in apparentonset age, associated with a large variability in severity ofexpression, typical for some genetic disorders, includingautoimmune lymphoproliferative syndrome,16-18 Chediak-Higashi syndrome,24 and Diamond-Blackfan anemia.31

Marked variability of disease manifestation and age atdiagnosis may even occur with a single family.42 Indi-viduals with mild manifestation may persist unrecog-nized for many years but appear to have a late-onsetdisease when overt manifestation subsequently develops.At the extreme, individuals with a mild manifestationmay remain unrecognized and undiagnosed throughouttheir lives.

Thus, the absence of clinical diagnosis does not as-sure absence of germline mutation, whatever the age ofthe donor, and this risk becomes especially importantwhen considering transplantation from a sibling, whomay share with the recipient unrecognized familial mu-tation predisposing to the disease being treated.4

If donor disease is mild, does that limit therecipient’s risk?It is noteworthy that stable dominant mutations, trans-mitted from parent to child, often have very differentmanifestations in the child, ranging from much less tomuch more severe than in the parent. It is plausible thatmutant cells, transplanted from donor to recipient, mighthave very different manifestations in the recipient, as

compared with the donor, including either a markedlydecreased or increased likelihood for progression to ma-lignancy. Furthermore, certain drugs (including geno-toxic and immunosuppressive drugs) used in the treat-ment of the recipient could increase the likelihood formalignancy to arise from genetically vulnerable trans-planted cells.

In any case, mild expression of features typically as-sociated with a genetic disorder does not assure that thepredisposition to malignancy will not become manifest.Indeed, cancer may be the presenting manifestation indisorders that generally are recognized by their nonma-lignant features, including ataxia-telangiectasia,14 Bloomsyndrome,21 Fanconi anemia,57 and type I neurofibroma-tosis.63

Hence, the transplantation of cells bearing muta-tions predisposing to malignancy warrants concern,whatever the manifestations (or lack thereof) in the do-nor.

If transplanted, which disorders pose the greatestthreat to recipients?Various disorders posing risk have a remarkably strongpredisposition to malignant outcome, exhibiting a spec-trum of proliferative monoclonal and polyclonal abnor-malities of grave threat to individuals harboring germlinemutation (Table 2). However, it is not entirely clear whichof these genetic disorders present a comparable risk iftransplanted into stem cell recipients. For some disor-ders, the presence of normal recipient tissue might pre-vent overt disease from arising in mutant donor cells,whereas for other disorders, disease expression mightproceed despite the presence of normal recipient tissue.

Because cancers generally arise as malignant cloneswithin otherwise normal tissue, it seems probable thatpredisposition to cancer should be transmissible bytransplantation. However, given the diversity of onco-genic mechanisms, exceptions are possible. Female car-riers of X-linked lymphoproliferative disease generallydo not have a markedly elevated lymphoma risk (in con-trast to their affected sons) despite mosaicism for af-fected cells (subsequent to X chromosome inactivation),suggesting that normal cells compensate for mutant cellsin this disorder.85 Furthermore, with familial hemo-phagocytic lymphohistiocytosis, evidence from chimericpatients, following partial stem cell engraftment, suggeststhat normal hematopoietic tissue may prevent the fatallymphoproliferative outcome that is typical of this disor-der.45

Thus, numerous complex interactions between do-nor and host tissue (with host tissue function dependenton the extent of myeloablation) could modify diseaseprocesses, potentially preventing, allowing, or enhancingthe expression of disease from transplanted mutantcells.



Do germline or acquired mutations present thegreater risk?The age of the donor can impact transplantation out-come generally89 and might impact the risk for transmis-sion of malignancy as well. On the one hand, the olderthe donor of stem cells, the more reliable is the donor’sabsence of symptoms for indicating absence of signifi-cant germline mutation. On the other hand, the older thedonor, the greater is the likelihood that donor cells haveaccumulated somatic mutations. Because most cancerapparently arises following prolonged asymptomaticclonal accumulation of mutations, there is with older do-nors a greater risk for transplantation of cells predisposedto cancer secondary to acquired mutations. At the ex-treme, there is risk for direct transmission of occult ma-lignancy from donor to recipient, as has occurred with

the transplantation of a donor’s undiagnosed acute my-elogenous leukemia.90

It is an open question whether stem cells from ap-parently healthy adults or those from cord blood of ap-parently healthy neonates present less inherent risk forprogression to malignancy in the recipient. It is worthnoting, however, that stem cells of healthy neonates (asopposed to embryonic stem cells) have necessarilypassed a stringent test of their genetic integrity by sup-porting normal embryonic and fetal development, andyet, gestation is sufficiently brief that there is limited riskfor accumulation of somatic mutations.

Laboratory testing presents further opportunity forgenetic evaluation. Testing for germline mutation,present in all cells, might prove more reliable than test-ing for acquired mutation, present in a single clone,

TABLE 2. Risk for malignant outcome in selected genetic disorders*Disorder Risk Reference

Ataxia-telangiectasia Malignancy in approximately 40 percent of patients during their shortened lives; approximately80 to 90 percent are leukemia or lymphoma

14

Autoimmune lymphopro-liferative syndrome

Hodgkin’s and non-Hodgkin’s lymphoma risk, respectively, more than 50 and 10 times greaterthan expected; the lymphoma often arises during youth

15

Bloom syndrome Cancer in about 40 percent of patients at an average of 21 years of age; more than 40 percentare lymphoma or leukemia

21

Chediak-Higashi syndrome Lymphoma-like polyclonal lymphoproliferation with multiorgan infiltration in about 80 to 90percent of patients; frequent cause of death in early decades of life

25

Common variableimmunodeficiency

Lymphoma in 22 (9%) of 248 patients; non-Hodgkin’s lymphoma in 19 of the 22, at 13 through77 years old

27

Congenital neutropenia Malignant myeloid transformation in more than 8 percent of patients being treated with G-CSF,at an average of 14 years old

30

Diamond-Blackfan anemia Acute myelogenous leukemia relative risk of 200 (95% CI, 55-512); diagnosis of hematopoieticmalignancy at an average of 19 years old

32, 33

Down syndrome Acute megakaryoblastic leukemia, during the first 4 years of life, approximately 500 times morecommon than normal

34

Familial hemophagocyticlymphohistiocytosis

Clonal T-cell expansion, invariably with multiorgan lymphohistiocytic infiltration; 5-year survival of10 percent in absence of marrow transplantation

41, 43

Familial platelet disorderwith associatedmyeloid malignancy

Leukemia risk increases with age; overall lifetime risk for leukemia of approximately 30 percent 53

Fanconi anemia Myelodysplastic syndrome or acute myelogenous leukemia in 40 percent of patients by 30 yearsof age (actuarial risk); malignancy detected at median of 13 years of age

58

Griscelli syndrome Accelerated phase lymphohistiocytic infiltration in most patients; fatal in the absence of marrowtransplantation

59, 60

Neurofibromatosistype I

Malignant myeloid disorders, especially juvenile myelomonocytic leukemia, in young children,approximately 200 to 500 times the normal risk

63, 64

Nijmegen breakagesyndrome

Malignancy in approximately 40 percent of patients, predominantly in childhood; about 70percent are lymphoma

65, 66

Omenn syndrome Oligoclonal expansion and multiorgan infiltration of activated T lymphocytes; often fatal duringinfancy, in the absence of marrow transplantation

68, 69

Shwachman syndrome Myelodysplastic syndrome or acute myelogenous leukemia in one third of patients, at median of13 years old

75

Wiskott–Aldrich syndrome Lymphoreticular malignancy in 10 to 20 percent of patients, at an average age of approximately10 years

79, 81

X-linked lymphopro-liferative disease

Lymphoma in 30 percent of patients, often intestinal extranodal non-Hodgkin’s lymphoma,arising in early childhood

83, 84

* Although reflecting the magnitude and character of increased risk for malignant neoplasm or lymphoproliferation, the data in this table areapproximate and subject to caveats. For example, with G–CSF therapy, additional cases of malignancy occur in patients with congenitalneutropenia. Although conceivable that G–CSF could be leukemogenic, it also is plausible that G–CSF therapy, while providing patientswith longer lives, provides more time during which the inherent predisposition to malignancy of the disease process may be expressed.For other disorders, the cumulative incidence of malignancy, due to inherent predisposition, may still be limited by the as yet uncontrolledother causes of premature death.

McMILIN


thereby giving advantage to the younger cells of youngerdonors.

Thus, with appropriate genetic characterization,cord blood stem cells of healthy neonates could offer thebenefits of youth while presenting acceptable geneticrisk.

FUTURE PROSPECTSCellular therapy, including stem cell transplantation, ap-pears to have remarkable potential, mostly still unreal-ized, for treating an increasingly diverse spectrum of dis-eases.

Unfortunately, new therapeutic developments mayalso create new risk for transmission of genetic disease. Ifstem cells are transplanted to recipients in utero,91 therecould be additional risk from mutation in genes uniquelyactive during embryonic or fetal life. If stem cell trans-plantation is augmented by the inclusion of facilitatingcells,92 there could be additional risk from mutation ingenes uniquely active in the facilitating cells. If hepatic,mesenchymal, neural, or other stem cell types are trans-planted, there could be risk for transmitting a diversearray of additional genetic disease, including the appli-cable spectrum of heritable cancer. If other stem cellshave plasticity comparable to marrow-derived cells, theapplicable spectrum of heritable cancer could be remark-ably broad.93 Clearly, each additional risk would requirean appropriate response.

Beyond direct transplantation of donor cells, if thera-peutic cell lines are maintained through ongoing prolif-eration, thereby providing cells for transplantation to nu-merous patients, genetic evaluation would need to beespecially rigorous, recognizing that each round of pro-liferation presents risk for new mutation and the genera-tion of clones with malignant transformation.

Although risk is inevitable, the future clearly presentsopportunity for both improved therapy and reduced risk.Experimentation in animal models and surveillance oftransplant recipients may help clarify the risk and guidethe response. Furthermore, laboratory testing, already in-valuable for preventing transfusion of blood-bornepathogens, may become central to the genetic evaluationof allogeneic stem cell products, helping us to fulfill ourcommitment to protect the well-being of our patients.

ACKNOWLEDGMENTS

I thank my colleagues for their constructive comments. I am

especially grateful to June Fletcher for her support and for her

creation of the institutional environment that made this work

both possible and pleasurable.

REFERENCES1. Cooley LD, Sears DA, Udden MM, et al. Donor cell leuke-

mia: report of a case occurring 11 years after allogeneic

bone marrow transplantation and review of the literature.

Am J Hematol 2000;63:46-53.

2. Saito Y, Uzuka Y, Sakai N, et al. A Philadelphia chromo-

some positive acute lymphoblastic leukemia of donor ori-

gin after allogeneic bone marrow transplantation for

chronic myelogenous leukemia in chronic phase. Bone

Marrow Transplant 2000;25:1209-11.

3. Meignin V, Devergie A, Brice P, et al. Hodgkin’s disease of

donor origin after allogeneic bone marrow transplanta-

tion for myelogeneous chronic leukemia. Transplantation

1998;65:595-7.

4. Buijs A, Poddighe P, van Wijk R, et al. A novel CBFA2

single-nucleotide mutation in familial platelet disorder

with propensity to develop myeloid malignancies. Blood

2001;98:2856-8.

5. Fearon ER. Human cancer syndromes: clues to the origin

and nature of cancer. Science 1997;278:1043-50.

6. Knudson AG. Hereditary predisposition to cancer. Ann NY

Acad Sci 1997;833:58-67.

7. Guilford P. The inherited susceptibility to cancer. Cell

Mol Life Sci 2000;57:589-603.

8. Nichols KE, Malkin D, Garber JE, et al. Germ-line p53

mutations predispose to a wide spectrum of early-onset

cancers. Cancer Epidemiol Biomarkers Prev 2001;10:83-7.

9. Moll AC, Imhof SM, Bouter LM, Tan KE. Second primary

tumors in patients with retinoblastoma: a review of the

literature. Ophthalmic Genet 1997;18:27-34.

10. Ben-Yosef T, Benvenisty N. Hereditary cancer and devel-

opmental abnormalities. Biol Neonate 2000;77:1-11.

11. Phillips RL, Ernst RE, Brunk B, et al. The genetic program

of hematopoietic stem cells. Science 2000;288:1635-40.

12. Bullrich F, Rasio D, Kitada S, et al. ATM mutations in B-

cell chronic lymphocytic leukemia. Cancer Res 1999;59:

24-7.

13. Stankovic T, Weber P, Stewart G, et al. Inactivation of

ataxia telangiectasia mutated gene in B-cell chronic lym-

phocytic leukaemia. Lancet 1999;353:26-9.

14. Gatti RA. Ataxia-telangiectasia. In: Vogelstein B, Kinzler

KW, eds. The genetic basis of human cancer. New York:

McGraw-Hill, 1998:275-300.

15. Straus SE, Jaffe ES, Puck JM, et al. The development of

lymphomas in families with autoimmune lymphoprolif-

erative syndrome with germline Fas mutations and defec-

tive lymphocyte apoptosis. Blood 2001;98:194-200.

16. Peters AM, Kohfink B, Martin H, et al. Defective apoptosis

due to a point mutation in the death domain of CD95

associated with autoimmune lymphoproliferative syn-

drome, T-cell lymphoma, and Hodgkin’s disease. Exp He-

matol 1999;27:868-74.

17. Vaishnaw AK, Toubi E, Ohsako S, et al. The spectrum of

apoptotic defects and clinical manifestations, including

systemic lupus erythematosus, in humans with CD95

(Fas/APO-1) mutations. Arthritis Rheumatol 1999;42:1833-

42.

18. Lim MS, Straus SE, Dale JK, et al. Pathological findings in



human autoimmune lymphoproliferative syndrome. Am J

Pathol 1998;153:1541-50.

19. Roa BB, Savino CV, Richards CS. Ashkenazi Jewish popu-

lation frequency of the Bloom syndrome gene 2281 delta

6ins7 mutation. Genet Test 1999;3:219-21.

20. Li L, Eng C, Desnick RJ, et al. Carrier frequency of the

Bloom syndrome blmAsh mutation in the Ashkenazi Jew-

ish population. Mol Genet Metab 1998;64:286-90.

21. German J. Bloom’s syndrome. XX. The first 100 cancers.

Cancer Genet Cytogenet 1997;93:100-6.

22. Ridanpaa M, van Eenennaam H, Pelin K, et al. Mutations

in the RNA component of RNase MRP cause a pleiotropic

human disease, cartilage-hair hypoplasia. Cell 2001;104:

195-203.

23. Makitie O, Pukkala E, Teppo L, Kaitila I. Increased inci-

dence of cancer in patients with cartilage-hair hypoplasia.

J Pediatr 1999;134:315-8.

24. Certain S, Barrat F, Pastural E, et al. Protein truncation

test of LYST reveals heterogenous mutations in patients

with Chediak-Higashi syndrome. Blood 2000;95:979-83.

25. Introne W, Boissy RE, Gahl WA. Clinical, molecular, and

cell biological aspects of Chediak-Higashi syndrome. Mol

Genet Metab 1999;68:283-303.

26. Strober W, Chua K. Common variable immunodeficiency.

Clin Rev Allergy Immunol 2000;19:157-81.

27. Cunningham-Rundles C, Bodian C. Common variable im-

munodeficiency: clinical and immunological features of

248 patients. Clin Immunol 1999;92:34-48.

28. Ancliff PJ, Gale RE, Liesner R, et al. Mutations in the ELA2

gene encoding neutrophil elastase are present in most

patients with sporadic severe congenital neutropenia but

only in some patients with the familial form of the dis-

ease. Blood 2001;98:2645-50.

29. Dale DC, Person RE, Bolyard AA, et al. Mutations in the

gene encoding neutrophil elastase in congenital and cy-

clic neutropenia. Blood 2000;96:2317-22.

30. Freedman MH, Bonilla MA, Fier C, et al. Myelodysplasia

syndrome and acute myeloid leukemia in patients with

congenital neutropenia receiving G-CSF therapy. Blood

2000;96:429-36.

31. Gazda H, Lipton JM, Willig TN, et al. Evidence for linkage

of familial Diamond-Blackfan anemia to chromosome

8p23.3-p22 and for non-19q non-8p disease. Blood 2001;

97:2145-50.

32. Lipton JM, Federman N, Khabbaze Y, et al. Osteogenic

sarcoma associated with Diamond-Blackfan anemia: a

report from the Diamond-Blackfan Anemia Registry. J Pe-

diatr Hematol Oncol 2001;23:39-44.

33. Janov AJ, Leong T, Nathan DG, Guinan EC. Diamond-

Blackfan anemia: natural history and sequelae of treat-

ment. Medicine (Baltimore) 1996;75:77-8.

34. Zipursky A, Brown EJ, Christensen H, Doyle J. Transient

myeloproliferative disorder (transient leukemia) and he-

matologic manifestations of Down syndrome. Clin Lab

Med 1999;19:157-67.

35. Stoll C, Alembik Y, Dott B, Roth MP. Study of Down syn-

drome in 238,942 consecutive births. Ann Genet 1998;41:

44-51.

36. Groet J, Ives JH, South AP, et al. Bacterial contig map of

the 21q11 region associated with Alzheimer’s disease and

abnormal myelopoiesis in Down syndrome. Genome Res

1998;8:385-98.

37. Avet-Loiseau H, Mechinaud F, Harousseau JL. Clonal he-

matologic disorders in Down syndrome: a review. J Pedi-

atr Hematol Oncol 1995;17:19-24.

38. Anonymous. Down syndrome prevalence at birth: United

States, 1983-1990. MMWR Morb Mortal Wkly Rep 1994;43:

617-22.

39. Dokal I. Dyskeratosis congenita in all its forms. Br J Hae-

matol 2000;110:768-79.

40. Knight S, Vulliamy T, Copplestone A, et al. Dyskeratosis

Congenita (DC) Registry: identification of new features of

DC. Br J Haematol 1998;103:990-6.

41. Goransdotter Ericson K, Fadeel B, Nilsson-Ardnor S, et al.

Spectrum of perforin gene mutations in familial hemo-

phagocytic lymphohistiocytosis. Am J Hum Genet 2001;

68:590-7.

42. Allen M, De Fusco C, Legrand F, et al. Familial hemo-

phagocytic lymphohistiocytosis: how late can the onset

be? Haematologica 2001;86:499-503.

43. Arico M, Janka G, Fischer A, et al. Hemophagocytic lym-

phohistiocytosis: report of 122 children from the Interna-

tional Registry: FHL Study Group of the Histiocyte Soci-

ety. Leukemia 1996;10:197-203.

44. Mache CJ, Slavc I, Schmid C, et al. Familial hemophago-

cytic lymphohistiocytosis associated with disseminated

T-cell lymphoma: a report of two siblings. Ann Hematol

1994;69:85-91.

45. Landman-Parker J, Le Deist F, Blaise A, et al. Partial en-

graftment of donor bone marrow cells associated with

long-term remission of haemophagocytic lymphohistiocy-

tosis. Br J Haematol 1993;85:37-41.

46. Wiernik PH, Ashwin M, Hu XP, et al. Anticipation in fa-

milial chronic lymphocytic leukaemia. Br J Haematol

2001;113:407-14.

47. Goldin LR, Sgambati M, Marti GE, et al. Anticipation in

familial chronic lymphocytic leukemia. Am J Hum Genet

1999;65:265-9.

48. Horwitz M. The genetics of familial leukemia. Leukemia

1997;11:1347-59.

49. Horwitz M, Goode EL, Jarvik GP. Anticipation in familial

leukemia. Am J Hum Genet 1996;59:990-8.

50. Lynch HT, Sanger WG, Pirruccello S, et al. Familial mul-

tiple myeloma: a family study and review of the literature.

J Natl Cancer Inst 2001;93:1479-83.

51. Grosbois B, Jego P, Attal M, et al. Familial multiple my-

eloma: report of fifteen families. Br J Haematol 1999;105:

768-70.

52. Song WJ, Sullivan MG, Legare RD, et al. Haploinsuffi-

ciency of CBFA2 causes familial thrombocytopenia with

McMILIN


propensity to develop acute myelogenous leukaemia. Nat

Genet 1999;23:166-75.

53. Arepally G, Rebbeck TR, Song W, et al. Evidence for ge-

netic homogeneity in a familial platelet disorder with pre-

disposition to acute myelogenous leukemia (FPD/AML).

Blood 1998;92:2600-2.

54. Faivre L, Guardiola P, Lewis C, et al. Association of

complementation group and mutation type with clinical

outcome in Fanconi anemi: European Fanconi Anemia

Research Group. Blood 2000;96:4064-70.

55. Rischewski JR, Clausen H, Leber V, et al. A heterozygous

frameshift mutation in the Fanconi anemia C gene in fa-

milial T-ALL and secondary malignancy. Klin Padiatr

2000;212:174-6.

56. Awan A, Malcolm Taylor G, Gokhale DA, et al. Increased

frequency of Fanconi anemia group C genetic variants in

children with sporadic acute myeloid leukemia. Blood

1998;91:4813-4.

57. Cavenagh JD, Richardson DS, Gibson RA, et al. Fanconi’s

anaemia presenting as acute myeloid leukaemia in adult-

hood. Br J Haematol 1996;94:126-8.

58. Butturini A, Gale RP, Verlander PC, et al. Hematologic

abnormalities in Fanconi anemia: an International Fan-

coni Anemia Registry study. Blood 1994;84:1650-5.

59. Menasche G, Pastural E, Feldmann J, et al. Mutations in

RAB27A cause Griscelli syndrome associated with haemo-

phagocytic syndrome. Nat Genet 2000;25:173-6.

60. Cetin M, Hicsonmez G, Gogus S. Myelodysplastic syn-

drome associated with Griscelli syndrome. Leuk Res 1998;

22:859-62.

61. Ramesh N, Geha RS, Notarangelo LD. CD40 ligand and

the hyper-IgM syndrome. In: Ochs HD, Smith CIE, Puck

JM, eds. Primary immunodeficiency diseases, a molecular

and genetic approach. Oxford: Oxford University Press,

1999:233-49.

62. Filipovich AH, Mathur A, Kamat D, Shapiro RS. Primary

immunodeficiencies: genetic risk factors for lymphoma.

Cancer Res 1992;52(Suppl):5465s-7s.

63. Side LE, Emanuel PD, Taylor B, et al. Mutations of the

NF1 gene in children with juvenile myelomonocytic leu-

kemia without clinical evidence of neurofibromatosis,

type 1. Blood 1998;92:267-72.

64. Side L, Taylor B, Cayouette M, et al. Homozygous inacti-

vation of the NF1 gene in bone marrow cells from chil-

dren with neurofibromatosis type 1 and malignant my-

eloid disorders. N Engl J Med 1997;336:1713-20.

65. Anonymous. Nijmegen breakage syndrome: The Interna-

tional Nijmegen Breakage Syndrome Study Group. Arch

Dis Child 2000;82:400-6.

66. Wegner RD, Chrzanowska KH, Sperling K, et al. Ataxia-

Telangiectasia variants (Nijmegen breakage syndrome).

In: Ochs HD, Smith CIE, Puck JM, eds. Primary immuno-

deficiency diseases, a molecular and genetic approach.

Oxford: Oxford University Press, 1999:324-34.

67. Choong K, Freedman MH, Chitayat D, et al. Juvenile my-

elomonocytic leukemia and Noonan syndrome. J Pediatr

Hematol Oncol 1999;21:523-7.

68. Corneo B, Moshous D, Gungor T, et al. Identical muta-

tions in RAG1 or RAG2 genes leading to defective V (D) J

recombinase activity can cause either T-B-severe com-

bined immune deficiency or Omenn syndrome. Blood

2001;97:2772-6.

69. Loechelt BJ, Shapiro RS, Jyonouchi H, Filipovich AH. Mis-

matched bone marrow transplantation for Omenn syn-

drome: a variant of severe combined immunodeficiency.

Bone Marrow Transplant 1995;16:381-5.

70. Newsham IF, Hadjistilianou T, Cavenee WK. Retinoblas-

toma. In: Vogelstein B, Kinzler KW, eds. The genetic basis

of human cancer. New York: McGraw-Hill, 1998:363-92.

71. Mueller BU, Pizzo PA. Cancer in children with primary or

secondary immunodeficiencies. J Pediatr 1995;126:1-10.

72. Shovlin CL, Simmonds HA, Fairbanks LD, et al. Adult on-

set immunodeficiency caused by inherited adenosine de-

aminase deficiency. J Immunol 1994;153:2331-9.

73. Goobie S, Popovic M, Morrison J, et al. Shwachman-

Diamond syndrome with exocrine pancreatic dysfunction

and bone marrow failure maps to the centromeric region

of chromosome 7. Am J Hum Genet 2001;68:1048-54.

74. Ginzberg H, Shin J, Ellis L, et al. Shwachman syndrome:

phenotypic manifestations of sibling sets and isolated

cases in a large patient cohort are similar. J Pediatr 1999;

135:81-8.

75. Smith OP, Hann IM, Chessells JM, et al. Haematological

abnormalities in Shwachman-Diamond syndrome. Br J

Haematol 1996;94:279-84.

76. Moser MJ, Bigbee WL, Grant SG, et al. Genetic instability

and hematologic disease risk in Werner syndrome pa-

tients and heterozygotes. Cancer Res 2000;60:2492-6.

77. Schellenberg GD, Miki T, Yu CE, Nakura J. Werner syn-

drome. In: Vogelstein B, Kinzler KW, eds. The genetic

basis of human cancer. New York: McGraw-Hill, 1998:

347-59.

78. Goto M, Miller RW, Ishikawa Y, Sugano H. Excess of rare

cancers in Werner syndrome (adult progeria). Cancer Epi-

demiol Biomarkers Prev 1996;5:239-46.

79. Sullivan KE, Mullen CA, Blaese RM, Winkelstein JA. A

multi-institutional survey of the Wiskott-Aldrich syn-

drome. J Pediatr 1994;125:876-85.

80. Somerville C, Forsyth KD. Wiskott Aldrich syndrome: an

immunodeficiency syndrome not rare in Western Austra-

lia. Pediatr Allergy Immunol 1993;4:65-72.

81. Cotelingam JD, Witebsky FG, Hsu SM, et al. Malignant

lymphoma in patients with the Wiskott-Aldrich syndrome.

Cancer Invest 1985;3:515-22.

82. Smith CIE, Witte ON. X-linked agammaglobulinemia: a

disease of Btk tyrosine kinase. In: Ochs HD, Smith CIE,

Puck JM, eds. Primary immunodeficiency diseases, a mo-

lecular and genetic approach. Oxford: Oxford University

Press, 1999:263-84.

83. Strahm B, Rittweiler K, Duffner U, et al. Recurrent B-cell



non-Hodgkin’s lymphoma in two brothers with X-linked

lymphoproliferative disease without evidence for Epstein-

Barr virus infection. Br J Haematol 2000;108:377-82.

84. Sumegi J, Huang D, Lanyi A, et al. Correlation of muta-

tions of the SH2D1A gene and Epstein-Barr virus infec-

tion with clinical phenotype and outcome in X-linked

lymphoproliferative disease. Blood 2000;96:3118-25.

85. Nichols KE, Harkin DP, Levitz S, et al. Inactivating muta-

tions in an SH2 domain-encoding gene in X-linked lym-

phoproliferative syndrome. Proc Natl Acad Sci U S A

1998;95:13765-70.

86. Online Mendelian Inheritance in Man OMIM (TM).

McKusick-Nathans Institute for Genetic Medicine, Johns

Hopkins University (Baltimore, MD) and National Center

for Biotechnology Information, National Library of Medi-

cine (Bethesda, MD), 2001. Available at: http://www

.ncbi.nlm.nih.gov/omim/.

87. Pruitt KD, Maglott DR. RefSeq and LocusLink: NCBI

gene-centered resources. Nucleic Acids Res 2001;29:137-

40.

88. Guidelines for preventing opportunistic infections among

hematopoietic stem cell transplant recipients. Recom-

mendations of Centers for Disease Control and Preven-

tion, the Infectious Disease Society of America, and the

American Society of Blood and Marrow Transplantation.

MMWR Morb Mortal Wkly Rep 2000;49:1-125.

89. Kollman C, Howe CW, Anasetti C, et al. Donor character-

istics as risk factors in recipients after transplantation of

bone marrow from unrelated donors: the effect of donor

age. Blood 2001;98:2043-51.

90. Niederwieser DW, Appelbaum FR, Gastl G, et al. Inadver-

tent transmission of a donor’s acute myeloid leukemia in

bone marrow transplantation for chronic myelocytic leu-

kemia. N Engl J Med 1990;322:1794-6.

91. Flake AW, Zanjani ED. In utero hematopoietic stem cell

transplantation: ontogenic opportunities and biologic bar-

riers. Blood 1999;94:2179-91.

92. Li XC, Strom TB. A rare find: cells that improve bone

marrow transplantation. Nat Med 2000;6:866-7.

93. Krause DS, Theise ND, Collector MI, et al. Multi-organ,

multi-lineage engraftment by a single bone marrow-

derived stem cell. Cell 2001;105:369-77.

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Allogeneic hematopoietic stem cell transplantation and the risk for transmission of heritable malignancy