700 -

Original Study

Associated Cancers in WaldenströmMacroglobulinemia: Clues for Common Genetic

PredispositionEnrica Morra,1 Marzia Varettoni,2 Alessandra Tedeschi,1 Luca Arcaini,2

Francesca Ricci,1 Cristiana Pascutto,2 Sara Rattotti,2 Eleonora Vismara,1

Laura Paris,1 Mario Cazzola2

AbstractAn increased risk of second cancers has been reported in lymphoproliferative disorders (LPDs). We retro-spectively studied 230 patients with Waldenström macroglobulinemia (WM) and found that they are at higherrisk of diffuse large B-cell lymphoma (DLBCL), myelodysplastic syndrome/acute myeloid leukemia (MDS/AML),and brain malignancies compared with an age- and sex-matched population. The increased risk of secondcancers should be considered in the follow-up of patients with WM.Background: Several population-based and cohort studies have reported an increased risk of second cancers inlymphoproliferative disorders (LPDs). The cause of second cancers in LPDs is probably multifactorial, and the relativecontribution of treatments, genetic predisposition, and immune dysfunction typical of LPDs is still unclear. Patientsand Methods: We retrospectively studied 230 patients with Waldenström macroglobulinemia (WM) to assess thefrequency, characteristics, and predictive factors of second cancers and to evaluate whether patients with WM are athigher risk of second cancers compared with an age- and sex-matched control population. Results: In a competing-riskmodel, the cumulative incidence of solid cancers was 6% at 5 years, 11% at 10 years, and 17% at 15 years, whereas theincidence of hematologic malignancies was 4% at 5 years, 7% at 10 years, and 8% at 15 years. Compared with an age-and sex-matched population, the overall risk of second cancers was 1.7-fold higher than expected (95% confidenceinterval [CI], 1.22-2.38; P ¼ .002). Patients with WM were at increased risk for diffuse large B-cell lymphoma (DLBCL)(standardized incidence ratio [SIR], 8.64; 95% CI, 3.88-19.22; P < .0001), myelodysplastic syndrome/acute myeloidleukemia (MDS/AML) (SIR 9.5; 95% CI, 3.6-25.3; P < .0001), and brain cancer (SIR, 7.59; 95% CI, 1.9-30.4; P < .0001).The risk of a second hematologic malignancy was 5-fold higher in treated than in untreated patients (P ¼ .08).Conclusion: Patients with WM are at increased risk of DLBCL, MDS/AML, and brain cancers compared with the generalpopulation. Further studies are needed to clarify whether the increased incidence of second cancers is related totreatments, to the immunologic impairment associated with the disease, or to genetic predisposition.

Clinical Lymphoma, Myeloma & Leukemia, Vol. 13, No. 6, 700-3 ª 2013 Elsevier Inc. All rights reserved.Keywords: Hematologic malignancies, Second cancers, Solid tumors, Waldenström macroglobulinemia

IntroductionSeveral population-based and cohort studies have reported an

increased overall risk of second cancers in lymphoproliferative

1Division of Hematology, Niguarda Ca’ Granda Hospital, Milano, Italy2Department of Hematology Oncology, Fondazione Istituto di Ricerca e Cura aCarattere Scientifico Policlinico San Matteo, University of Pavia, Pavia, Italy

Submitted: Oct 25, 2012; Revised: May 7, 2013; Accepted: May 7, 2013; Epub:Sep 24, 2013

Address for correspondence: Marzia Varettoni, MD, Department of HematologyOncology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, ItalyE-mail contact: m.varettoni@smatteo.pv.it

Clinical Lymphoma, Myeloma & Leukemia December 2013

disorders (LPDs).1-8 Most of these studies showed an increased riskof myelodysplastic syndrome/acute myeloid leukemia (MDS/AML),associated with exposure to alkylating agents or nucleoside ana-logues (NAs).9-15 The development of second solid cancers inLPDs, however, is still a controversial issue and is an object ofspeculation.

The cause of second cancers in LPDs is probably multifactorial,and the relative contribution of treatments, genetic predisposi-tion,16,17 and immune dysfunction typical of LPDs18 is still to bedetermined.

We performed a retrospective study to assess the frequency, char-acteristics, and predictive factors of second cancers in Waldenström

2152-2650/$ - see frontmatter ª 2013 Elsevier Inc. All rights reserved.http://dx.doi.org/10.1016/j.clml.2013.05.008

Table 1 Characteristics of 230 Patients With WaldenströmMacroglobulinemia

Age (years) 61 (26-86)

M/F, n (%) 140/90 (61%/39%)

Previous history of cancer, n (%) 17 (7%)

Median follow-up after diagnosis,years (range)

5.6 (0.5-29.3)

Treatment, n (%) 143 (64%)

Watch and wait, n (%) 87 (36%)

Number of treatments, median(range)

2 (1-7)

Type of therapy, n (% treated)

Alkylating agents 139 of 143 (97%)

Nucleoside analogues 39 of 143 (27%)

Anti-CD20 monoclonal antibody 59 of 143 (41%)

Median follow-up after therapy,years (range)

Alkylating agents 5.4 (0.5-29.2)

Nucleoside analogues 3.9 (0.5-8.0)

Anti-CD20 monoclonal antibody 3.3 (0.5-9.0)

Figure 1 Cumulative Incidence of Hematologic Malignanciesand Solid Cancers

Figure 2 Incidence of Second Cancers During Follow-up.(CI [ Confidence Interval.)

0

2

4

6

8

10

12

14

16

18

20

0 5 10 15 20

Years since diagnosis

In

cid

en

ce

(X

1

00

p

yrs

)

incidence rat95% CI _low95% CI _high

macroglobulinemia (WM) and to evaluate whether patients withWMare at higher risk of second cancers compared with an age- and sex-matched control population of the same geographic region.

Patients and MethodsWe retrospectively evaluated 230 consecutive patients with WM

diagnosed and followed in 2 hematologic centers in northern Italy.The diagnosis of WM and IgM monoclonal gammopathy of unde-termined significance was made according to the consensus recom-mendations from the Second International Workshop on WM.19

Only second cancers occurring after the diagnosis of WM, exceptfor nonmelanoma skin cancers and in situ cervical cancer, wereconsidered in the analysis. The incidence of second cancers perperson-year in the study population was compared with the inci-dence of malignancies in the population of northern Italy, applyingthe sex- and age-specific incidence rates reported by AssociazioneItaliana Registri Tumori. The standardized incidence ratio (SIR)was calculated as the ratio between the observed and the expectednumber of cases; 95% confidence intervals (CI) were based on theassumption that the observed numbers of second cancers weredistributed as Poisson variables. The cumulative incidence of secondcancers was estimated in a competing-risk model, considering solidtumors, hematologic malignancies, and death from any cause ascompeting events. Cox proportional hazards regression was used toevaluate risk factors for second cancers. Therapy was analyzed as atime-dependent covariate. Statistical analyses were performed usingSTATISTICA, version 8 software (StatSoft, Tulsa, OK) andMicrosoft Excel 2000 (Microsoft Corp, Redmond, WA). A P valueof .05 was considered statistically significant.

ResultsA total of 230 patients with WM with a median follow-up after

diagnosis of 6.3 years (range, 1-29.3 years) were included in the

analysis. Their characteristics are reported in Table 1. Twenty-fourpatients (10.4%) had solid cancers and 11 (4.8%) patients hadsecond hematologic malignancies, with a median time from diag-nosis of 4.4 years (range, 0-16.7 years) and 4.1 years (range, 2-12years), respectively. Solid tumor sites were as follows: gastrointes-tinal tract (n ¼ 6), prostate (n ¼ 4), urinary tract (n ¼ 4), lung(n ¼ 4), breast (n ¼ 3), brain (n ¼ 2), and thyroid (n ¼ 1).Hematologic malignancies were represented by diffuse large B-celllymphoma (DLBCL) (n ¼ 6), MDS/AML (n ¼ 4), and chronicmyeloid leukemia (n ¼ 1). In a competing-risk model, thecumulative incidence of solid cancers was 6% at 5 years, 11% at10 years, and 17% at 15 years, whereas the incidence of hemato-logic malignancies was 4% at 5 years, 7% at 10 years, and 8% at15 years (Fig. 1). The incidence of second cancers during follow-upis shown in Figure 2.

Compared with an age- and sex-matched population, the overallrisk of second cancers was 1.7-fold higher than expected (95% CI,

Clinical Lymphoma, Myeloma & Leukemia December 2013 - 701

Table 2 Second Cancers and Cancer-Specific Standardized Incidence Ratios

Type of Cancer Cases Observed SIR 95% CI P Value

All cancers 35 1.70 1.22-2.38 .002

DLBCL 6 8.64 3.88-19.22 < .0001

Lung 4 1.37 0.51-3.65 .53

Gastrointestinal tract 6 1.07 0.48-2.38 .87

Urinary tract 4 2.15 0.81-5.72 .12

Prostate 4 1.28 0.48-3.41 .62

MDS/AML 4 9.5 3.6-25.3 < .0001

Breast 3 1.54 0.49-4.69 .47

Brain 2 7.59 1.9-30.4 .0007

Thyroid 1 4.84 0.68-34.3 .08

CML 1 NA NA NA

Abbreviations: CML ¼ chronic myeloid leukemia; DLBCL ¼ diffuse large B-cell lymphoma; MDS/AML ¼ myelodysplastic syndrome/acute myelogenous leukemia; NA ¼ not available;SIR ¼ standardized incidence ratio.

Associated Cancers in Waldenström Macroglobulinemia

702 -

1.22-2.38; P ¼ .002). Patients with WM were at increased risk forDLBCL (SIR, 8.64; 95% CI, 3.88-19.22; P < .0001), MDS/AML(SIR, 9.5; 95% CI, 3.6-25.3; P < .0001), and brain cancer (SIR,7.59; 95% CI, 1.9-30.4; P < .0001) (Table 2).

Most second cancers (23 of 35 [66%]) occurred after treatment.In particular, 5 of 6 patients with DLBCL had received alkylatingagents (4 cases) or alkylating agents plus NAs (1 case), and allpatients with MDS/AML had received alkylating agents (2 cases) oralkylating agents and NAs (2 cases). The 5-, 10-, and 15-yearcumulative incidence of all second cancers was 9%, 16%, and25% respectively, in patients previously treated and 10%, 16%, and21%, respectively, in untreated patients (hazard ratio, 1.2; P ¼ .6).The incidence of second hematologic malignancies was 5% at5 years, 9% at 10 years, and 11% at 15 years in patients previouslytreated. In untreated patients, the cumulative incidence of secondhematologic malignancies was 1.8% at 5 years, and no cases wereobserved later during follow-up. The risk of a second hematologicmalignancy was 5-fold higher in treated than in untreated patients(P ¼ .08). The 5-, 10-, and 15-year incidence of solid cancers was4%, 8%, and 15%, respectively, in patients previously treated,compared with 9%, 15%, and 20%, respectively, in untreatedpatients (hazard ratio, 0.7; P ¼ .46).

DiscussionInformation on the occurrence of second cancers is scanty in

WM and is limited to the risk of therapy-related MDS/AML andtransformation to DLBCL.

We retrospectively studied 230 patients with WM who werediagnosed and followed at 2 hematologic centers of northern Italy.The first important finding of the study is that patients with WMare at higher risk of second malignancies compared with an age- andsex-matched population living in the same geographic area. Theanalysis of cancer-specific SIR showed that this excess of tumorsresults from a higher incidence of DLBCL, MDS/AML, and brainmalignancies. However, in this series we observed only 2 cases ofbrain tumors, and therefore this finding needs validation in otherseries before drawing any conclusion.

The incidence of MDS/AML was nearly 2%, in keeping with2 previous studies including patients treated exclusively with

Clinical Lymphoma, Myeloma & Leukemia December 2013

alkylating agents.20,21 All cases of MDS/AML were observed inpatients previously treated only with alkylating agents or withalkylating agents and NAs. In recent years, some studies haveraised concerns about a possible role of NAs in the pathogenesis ofMDS/AML. In a retrospective study of 439 patients, the incidenceof MDS/AML was 1.6% in patients treated with NAs, whereas nocases were observed in patients treated with other regimens or inuntreated patients.15

We observed transformation to DLBCL in 2.6% of patients,most of them previously treated with alkylating agents alone or incombination with NAs. The incidence of transformation to DLBCL(Richter syndrome) reported in WM ranges from < 1% to 9% indifferent studies.12-15 Histologic transformation events have beenthought to occur within the original B-cell clone as a consequence ofthe acquisition of additional genetic events. However, histologictransformation events in WM can include clonally unrelated eventsthat probably result from an underlying immune deficiency asso-ciated with WM and its treatment. A high incidence of Richtertransformation has been observed in patients with WM exposed toNAs.12-15 In the largest study published so far, the incidence oftransformation was significantly higher in patients with WM treatedwith NAs than in those treated with other regimens (4.6% vs. 0.4%;P < .001).15 However, in a prospective randomized trial, theincidence of DLBCL was not statistically different in patientstreated with NAs compared with patients treated with alternativeregimens.12

Although not statistically significant, the risk of a second hema-tologic malignancy was 5-fold higher in treated than in untreatedpatients. The lack of statistical significance might by attributable tothe sample size and to the relatively short follow-up of patientstreated with NAs. Because of its retrospective design, this study isnot suited to evaluate if treatments (and which treatments) areresponsible for the increased incidence of second cancers, andprospective studies will better address this important issue. In arandomized trial of chlorambucil vs. fludarabine in indolent lym-phomas, including WM, a French and British group reporteda 6-year cumulative rate of second malignancies of 20.6% in thechlorambucil arm vs. 3.7% in the fludarabine arm, indicating apossible oncogenic role of alkylators.22

Enrica Morra et al

ConclusionIn conclusion, patients with WM are at increased risk of DLBCL,

MDS/AML, and brain cancers compared with the general population.Further studies are needed to clarify whether the increased incidenceof second cancers is related to treatments, to the immunologicimpairment associated with the disease, or to genetic predisposition.Regardless of the underlying pathogenicmechanisms, the increased riskof second cancers should be kept in mind in the follow-up of patientswith WM.

DisclosureThe authors have stated that they have no conflicts of interest.

References1. Travis LB, Curtis RE, Glimelius B, et al. Second cancers among long-term sur-

vivors of non-Hodgkin’s lymphoma. J Natl Cancer Inst 1993; 85:1932-7.2. Brennan P, Scelo G, Hemminki K, et al. Second primary cancers among 109,000

cases of non-Hodgkin lymphoma. Br J Cancer 2005; 93:159-66.3. Tward JD, Wendland MM, Shrieve DC, Szabo A, Gaffney DK. The risk of

secondary malignancies over 30 years after the treatment of non-Hodgkin lym-phoma. Cancer 2006; 107:108-15.

4. Mudie NY, Swerdlow AJ, Higgins CD, et al. Risk of second malignancy after non-Hodgkin’s lymphoma: a British cohort study. J Clin Oncol 2006; 24:1568-74.

5. Sacchi S,Marcheselli L, Bari A, et al. Secondary malignancies after treatment for indolentnon-Hodgkin’s lymphoma: a 16-year follow-up study.Haematologica 2008; 93:398-404.

6. Travis LB, Curtis RE, Hankey BF, et al. Second cancers in patients with chroniclymphocytic leukemia. J Natl Cancer Inst 1992; 84:1422-7.

7. Tsimberidou AM, Wen S, McLaughlin P, et al. Other malignancies in chroniclymphocytic leukemia/small lymphocytic lymphoma. J Clin Oncol 2009; 27:904-10.

8. Hisada M, Chen BE, Jaffe ES, Travis LB. Second cancer incidence and cause-specific mortality among 3104 patients with hairy cell leukemia: a population-based study. J Natl Cancer Inst 2007; 99:215-22.

9. Cheson BD, Vena DA, Barrett J, et al. Second malignancies as a consequence ofnucleoside analogs therapy for chronic lymphocytic leukemias. J Clin Oncol 1999;17:2454-60.

10. Thornton PD, Bellas C, Santon A, et al. Richter’s transformation of chroniclymphocytic leukemia: the possible role of fludarabine and the Epstein-Barr virusin its pathogenesis. Leuk Res 2005; 29:389-95.

11. LeBlond V, Ben-Othman T, Deconinck E, et al. Activity of fludarabine in pre-viously treated Waldenström’s macroglobulinemia: a report of 71 cases. GroupeCoopératif Macroglobulinémie. J Clin Oncol 1998; 16:2060-4.

12. Leblond V, Levy V, Maloisel F, et al. Multicenter, randomized comparative trial offludarabine and the combination of cyclophosphamide-doxorubicin-prednisone in92 patients with Waldenström macroglobulinemia in first relapse or with primaryrefractory disease. Blood 2001; 98:2640-4.

13. Tamburini J, Levy V, Chaleteix C, et al. Fludarabine plus cyclophosphamide inWaldenström’s macroglobulinemia: results in 49 patients. Leukemia 2005; 19:1831-4.

14. Treon SP, Branagan AR, Ioakimidis L, et al. Long-term outcomes to fludar-abine and rituximab in Waldenström macroglobulinemia. Blood 2009; 113:3673-8.

15. Leleu X, Soumerai J, Roccaro A, et al. Increased incidence of transformation andmyelodysplasia/acute leukemia in patients with Waldenström macroglobulinemiatreated with nucleoside analogs. J Clin Oncol 2009; 27:250-5.

16. Ojha RP, Hanzis CA, Hunter Z, et al. Family history of non-hematologic cancersamong Waldenstrom macroglobulinemia patients: a preliminary study. CancerEpidemiol 2012; 36:294-7.

17. Hanzis C, Ojha RP, Hunter Z, et al. Associated malignancies in patients withWaldenström’s macroglobulinemia and their kin. Clin Lymphoma Myeloma Leuk2011; 11:88-92.

18. Greene MH, Hoover RN, Fraumeni JF, Jr. Subsequent cancers in patients withchronic lymphocytic leukemia—a possible immunologic mechanism. J Natl CancerInst 1978; 61:337-40.

19. Owen RG, Treon SP, Al-Katib A, et al. Clinicopathological definition of Wal-denström’s macroglobulinemia: Consensus Panel recommendations from theSecond International Workshop on Waldenström’s macroglobulinemia. SeminOncol 2003; 30:110-5.

20. Garcia-Sanz R, Montoto S, Torrequebrada A, de Coca AG, et al. Spanish Groupfor the Study of Waldenström Macroglobulinaemia and PETHEMA (Programmefor the Study and Treatment of Haematological Malignancies). Waldenströmmacroglobulinaemia: presenting features and outcome in a series with 217 cases. BrJ Haematol 2001; 115:575-82.

21. Facon T, Brouillard M, Duhamel A, et al. Prognostic factors in Waldenström’smacroglobulinemia: a report of 167 cases. J Clin Oncol 1993; 11:1553-8.

22. Leblond V, Johnson S, Chevret S, et al. Results of a randomized trial of chlor-ambucil vs. fludarabine for patients with untreated Waldenström macroglobuli-nemia, marginal zone lymphoma, or lymphoplasmacytic lymphoma. J Clin Oncol2013; 31:301-7.

Clinical Lymphoma, Myeloma & Leukemia December 2013 - 703