Purpose:

Nijmegen breakage syndrome (NBS) is a DNA repair disorder with a high predisposition to hematologic malignancies.

Experimental Design:

We describe the natural history of NBS, including cancer incidence, risk of death, and the potential effectiveness of hematopoietic stem cell transplantation (HSCT) in preventing both pathologies: malignancy and immunodeficiency.

Results:

Among 241 patients with NBS enrolled in the study from 11 countries, 151 (63.0%) patients were diagnosed with cancer. Incidence rates for primary and secondary cancer, tumor characteristics, and risk factors affecting overall survival (OS) were estimated. The cumulative cancer incidence was 40.21% ± 3.5% and 77.78% ± 3.4% at 10 years and 20 years of follow-up, respectively. Most of the tumors n = 95 (62.9%) were non-Hodgkin lymphomas. Overall, 20 (13.2%) secondary malignancies occurred at a median age of 18 (interquartile range, 13.7–21.5) years. The probability of 20-year overall survival (OS) for the whole cohort was 44.6% ± 4.5%. Patients who developed cancer had a shorter 20-year OS than those without malignancy (29.6% vs. 86.2%; P < 10−5). A total of 49 patients with NBS underwent HSCT, including 14 patients transplanted before malignancy. Patients with NBS with diagnosed cancer who received HSCT had higher 20-year OS than those who did not (42.7% vs. 30.3%; P = 0.038, respectively). In the group of patients who underwent preemptive transplantation, only 1 patient developed cancer, which is 6.7 times lower as compared with nontransplanted patients [incidence rate ratio 0.149 (95% confidence interval, 0.138–0.162); P < 0.0001].

Conclusions:

There is a beneficial effect of HSCT on the long-term survival of patients with NBS transplanted in their first complete remission of cancer.

Translational Relevance

Nijmegen breakage syndrome (NBS) is a rare autosomal-recessive primary immunodeficiency and tumor predisposition syndrome caused by mutations of the NBN gene on chromosome 8q21. The majority of patients are of central and eastern European descent. In the study, we have collected exhaustive clinical and genetic data from 241 patients within three international cohorts: Inborn Errors Working Party of the European Society for Blood and Marrow Transplantation, the I-BFM Genetic Variation Task Force, and within the LEGEND of the EU COST action (CA16223) over a span of an up to 40-year-long observation period. The work shows accurate prognosis of patients with NBS in terms of overall survival, details a cancer incidence, shows hazard dynamics of developing cancer, and presents the predisposition to secondary cancers of survivors. The study is practice changing, as we conclusively show that allogeneic hematopoietic stem cell transplantation prolongs survival and reduces the risk of malignancies.

Nijmegen breakage syndrome (NBS; Online Mendelian Inheritance in Man, #251260) is a rare autosomal-recessive primary immunodeficiency and tumor predisposition syndrome caused by mutations of the NBN gene on chromosome 8q21 (1, 2). The NBN gene encodes the nibrin protein which is a crucial component of the Mre11-Rad50-Nbs1 complex involved in DNA double- and single-strand break repair and in the activation of cell-cycle checkpoints via ataxia telangiectasia mutated (ATM; ref. 3). The exact prevalence value of NBS is not given, but according to the European Society for Immunodeficiencies (ESID) database, which is the largest registry for primary immunodeficiencies, 195 patients have been diagnosed with this syndrome, including 110 patients of Polish origin. The majority of these patients are of central and eastern Europe descent and share the founder homozygous five base pair deletion within the NBN gene (c.657_661del5, p.Lys219Asnfs; ref. 1). This deletion probably occurred in the Middle Ages, resulting in a particularly high (1/177) mutation carrier frequency in the Slavic populations (Poland, Ukraine, Czech Republic; ref. 3).

The essential phenotypic features describing patients with NBS are microcephaly at birth, a distinct dysmorphic facial appearance (prominent midface, receding forehead, and mandible), growth retardation, combined immunodeficiency, radiosensitivity, and an increased risk of cancer, especially of hematologic origin (1, 4). According to data published so far, the incidence of malignancy is extremely high, reaching 40%, but the population-based occurrence in NBS remains unknown (5). In addition, patients with NBS are also prone to develop secondary malignancies, but data on this aspect are scarce.

In addition, patients with NBS with cancer have poorer outcomes than patients with cancer without underlying DNA repair defects. Disease progression, relapses, and secondary malignancies are the primary causes of death in most patients with NBS who developed leukemias or lymphomas and contribute to their shortened life expectancy (5–7). Moreover, inherited chromosomal instability with a combination of primary and secondary immune defects make patients with NBS prone to developing severe infectious and excessive, toxic treatment-related complications. Notably, the reduction in chemotherapy dosages was not associated with reduced rates of side effects but contributed to a higher risk of disease recurrence and poorer overall survival (8). There are currently no dedicated protocols of cancer treatment for patients with NBS or recommendations of chemotherapy reduction. Formulation of each one requires accurate, wide-ranging, and long-term data on the natural history of the disease, outcomes, and effectiveness of therapeutic interventions attempted in patients with NBS.

Allogeneic hematopoietic stem cell transplantation (HSCT) provides a chance to bring clinical benefit for both immunodeficiency and hematologic cancer in patients with NBS. However, no studies have investigated the impact of HSCT on the first complete remission of malignancy on the long-term survival of patients with NBS and long-term complications, especially the risk of malignancies after transplantation. Clearly, the failure of previous studies was due to small sample sizes and short follow-up time.

The aim of this study was to present comprehensive, complete, and long-term data on cancer incidence, mortality, tumor characteristics, and the role of HSCT as a therapeutic option for malignancy and as a preemptive approach in patients with NBS.

Patients and genotype

Data of patients with NBS diagnosed between 1993 and 2018 were collected as result of an international collaboration in a frame of the Inborn Errors Working Party of the European Society for Blood and Marrow Transplantation, the I-BFM Genetic Variation Task Force, and within the LEGEND COST (CA16223) action. Inclusion criteria of the study were defined as clinical (according to the diagnostic criteria for NBS developed by Clinical Working Party of ESID) and/or genetically confirmed NBS and available information about cancer incidence during the observation time. Detailed clinical and biological data were gathered in the university hospitals located in the following countries: Poland, Belarus, Russia, Czech Republic, Slovakia, Turkey, United Kingdom, Germany, Ukraine, Pakistan, United States of America, and Austria. In these centers, patients with NBS were clinically characterized according to the genotype, patient demographic, primary and secondary cancer incidence, histopathologic diagnosis of malignancies, treatment, immunodeficiency, transplantation, overall survival, and cause of death. The study was approved by the Bioethics Committee of Children’s Memorial Health Institute, Warsaw, Poland, and by the local institutional review boards of the participating centers. Epidemiologic data on the number of children in Poland throughout the study period were obtained from the Local Data Bank of Poland (https://bdl.stat.gov.pl/BDL/start, accessed December 14, 2018). An informed written consent was obtained from each subject or each subject’s guardian. The study was conducted in accordance with the Declaration of Helsinki.

Cancer characterization

Cancers were classified according to the national pathology reports. Acute leukemias were categorized according to the current World Health Organization criteria of hematologic malignancies, including lineage and immunophenotype specification. With respect to lymphomas, we distinguished between Hodgkin lymphoma and non-Hodgkin lymphoma (NHL). NHL was further classified according to immunophenotype as B-cell [diffuse large B-cell lymphoma (DLBCL), other B-cell], T-cell (peripheral T-NHL, other T-cell), and unknown. A central pathology review was available for 81 (53.6%) patients with NBS with cancer. The nonhematologic group of cancers was categorized according to their histologic diagnosis described in the pathology reports. The outcome of cancer was reported as complete remission, relapse, and progression. Second cancer was defined as a different type in comparison with the first diagnosis or the same cancer type, which occurred after more than 5 years from diagnosis of the first malignancy among patients who achieved complete remission.

HSCT

We collected the following data in patients who underwent HSCT: indication for transplantation, type and source of HSC, conditioning regimen, incidence and severity of acute and chronic GVHD, severe transplant-related complications, survival post-HSCT, and incidence of cancer after HSCT. Patients who underwent HSCT before developing cancer were considered transplanted beacause of preemptive indications, usually because of clinically relevant combined immunodeficiency (9). Patients transplanted because of malignancies were classified according to achievement of complete remission of cancer before HSCT. For the 26 patients who are included in this study, the results of HSCT with a shorter follow-up time have already been reported (Supplementary Table S1). We included them in this analysis because of significantly longer follow-up compared with previously published studies.

Outcome analysis

The incidence of cancer and death due to any cause was treated as a primary outcome measure in the study. Overall survival (OS) time was defined as the time elapsed from birth to the last follow-up. Patients still alive at the end of the study were treated as a censored observation. Individuals were considered lost to follow-up if the period between the last visit and the date of analysis (January 2019) exceeded 2 years. Secondary reported outcomes were time to developing cancer presented as a cumulative incidence and the probability of second cancer, evaluated using a competing risk approach, with death included in the competing incidence rates model as a competing factor. In addition, treatment-related mortality for the first-line therapy and transplant-related mortality was also calculated.

Statistical analysis

OS probabilities were compared using the log-rank test. Kaplan–Meier survival curves were used to represent probabilities of survival over time. Multivariate analysis of survival was performed using Cox proportional hazard regression models. Competing incidence rate models were used for secondary cancer development with death as an interfering outcome and for death as the primary outcome with secondary cancer as the interfering outcome. Analyses were performed in Statistica (Statsoft, TIBCO) and STATA (StataCorp LLC). P values < 0.05 were considered statistically significant.

NBS cohort for analysis of the natural history of cancer

The study flow chart illustrating the natural history of cancer in the NBS cohort and the inference of HSCT in the course of malignancies is presented in Fig. 1. A total of 241 patients with NBS were initially enrolled in the study. Because of the lack of information about cancer incidence, one individual was excluded, and eventually, 240 patients were included in the final study group. After the exclusion of patients transplanted before malignancy (n = 14), the final number of 226 patients was enrolled in the analysis of the natural history of cancer occurrence. The median follow-up time of the entire cohort was 12.63 [interquartile range (IQR), 7.9–17.45] years, accounting for 3,342 person-years. Overall, 14 (5.8%) patients were classified as lost to follow-up. The median age at NBS diagnosis was 5.0 (IQR, 1.73–10.25) years, and 4 patients were diagnosed postmortem. Genetic diagnosis of biallelic mutation within the NBN gene was confirmed in 229 (95.4%) patients. All but 3 Pakistani patients, who were homozygous carriers of the c.1089C>A (p.Tyr363Ter) mutation, harbored a homozygous deletion (c.657_661del5, p.Lys219Asnfs; NM_001024688, NP_002476.2) within exon 6 of the NBN gene. Detailed patient characteristics within the entire cohort and within the subgroups are presented in Table 1 and Fig. 1.

Figure 1.

Flow chart of the study group: number of patients with NBS in each study subgroups according to cancer incidence and treatment with HSCT. The median follow-up time in years was assessed and compared for each subgroup. *, P = 0.041; #, P = 0.0002.

Figure 1.

Flow chart of the study group: number of patients with NBS in each study subgroups according to cancer incidence and treatment with HSCT. The median follow-up time in years was assessed and compared for each subgroup. *, P = 0.041; #, P = 0.0002.

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Table 1.

Patients characteristics.

Entire cohortMalignanciesaNo malignanciesa
CharacteristicN = 241N = 151N = 75P value
Sex n (%) 
 Male 120 (49.8) 84 (55.6) 44 (58.7) 0.77 
 Female 121 (50.2) 67 (44.4) 31 (41.3)  
Year of birth median (IQR) 2000 (1991–2007) 1995 (1990–2003) 2007 (1995–2011) <10−5 
Age at cancer diagnosis (years) median (IQR) 9.1 (5.9–14.0) 9.1 (5.9–14.0) NA NA 
Status n (%) 
 Alive 131 (54.3) 49 (32.4) 67 (89.3) <10−5 
 Dead 110 (45.7) 101 (67.6) 8 (10.7)  
Age at death (years) median (IQR) 13.8 (9.0–17.3) 13.0 (8.9–17.2) 13.4 (11.8–25.1) 0.34 
Lost to follow-up n (%) 38 (15.8) 20 (13.2) 18 (24.0) 0.065 
Follow-up time (years) median (IQR) 12.6 (7.8–17.5) 13.6 (9.1–18.3) 10.5 (6.4–20.9) 0.01 
Number of person-years 3,315.2 2,165.9 1,149.2 NA 
Transplantation n (%) 49 (20.3) 35 (23.2) 14 (18.7) 0.55 
Age at transplantation (years) 9.0 (5.7–14.5) 11.0 (7.5–15.6) 4.9 (2.3–7.9) 0.0005 
Entire cohortMalignanciesaNo malignanciesa
CharacteristicN = 241N = 151N = 75P value
Sex n (%) 
 Male 120 (49.8) 84 (55.6) 44 (58.7) 0.77 
 Female 121 (50.2) 67 (44.4) 31 (41.3)  
Year of birth median (IQR) 2000 (1991–2007) 1995 (1990–2003) 2007 (1995–2011) <10−5 
Age at cancer diagnosis (years) median (IQR) 9.1 (5.9–14.0) 9.1 (5.9–14.0) NA NA 
Status n (%) 
 Alive 131 (54.3) 49 (32.4) 67 (89.3) <10−5 
 Dead 110 (45.7) 101 (67.6) 8 (10.7)  
Age at death (years) median (IQR) 13.8 (9.0–17.3) 13.0 (8.9–17.2) 13.4 (11.8–25.1) 0.34 
Lost to follow-up n (%) 38 (15.8) 20 (13.2) 18 (24.0) 0.065 
Follow-up time (years) median (IQR) 12.6 (7.8–17.5) 13.6 (9.1–18.3) 10.5 (6.4–20.9) 0.01 
Number of person-years 3,315.2 2,165.9 1,149.2 NA 
Transplantation n (%) 49 (20.3) 35 (23.2) 14 (18.7) 0.55 
Age at transplantation (years) 9.0 (5.7–14.5) 11.0 (7.5–15.6) 4.9 (2.3–7.9) 0.0005 

Abbreviations: IQR, interquartile range; NA, not applicable.

aPatients with no cancer status known (n = 1) and patients transplanted preemptively (n = 14) were excluded.

Primary malignancies in NBS

Cancer was diagnosed in 151 (63.0%) patients, which corresponded to 4,743 events per 100,000 patient-years, with a median age at presentation of 9.31 (IQR, 6.0–14) years (Table 1). In 27% of patients, NBS was diagnosed after the cancer developed. The median follow-up time of patients with NBS who developed malignancies was 13.6 (IQR, 9.1–17.51) years. The cumulative cancer incidence was 40.21% ± 3.5% and 77.78% ± 3.4% at 10 years and 20 years of follow-up, respectively (Fig. 2A).

Figure 2.

A, Cumulative incidence of primary cancer among patients with NBS. B, Cumulative incidence of different types of malignancies in patients with NBS (AL, acute leukemia; NHL, non-Hodgkin lymphoma; HL, Hodgkin lymphoma; other). C, Prevalence of NBS (orange line) in the Polish population ages 0–35 years (blue line) over the 1995–2017 period. D, Cumulative incidence of cancer in patients with NBS depending on the patients' origin (Polish vs. non-Polish).

Figure 2.

A, Cumulative incidence of primary cancer among patients with NBS. B, Cumulative incidence of different types of malignancies in patients with NBS (AL, acute leukemia; NHL, non-Hodgkin lymphoma; HL, Hodgkin lymphoma; other). C, Prevalence of NBS (orange line) in the Polish population ages 0–35 years (blue line) over the 1995–2017 period. D, Cumulative incidence of cancer in patients with NBS depending on the patients' origin (Polish vs. non-Polish).

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With respect to the tumor type, we observed n = 95 (62.9%) NHLs, n = 32 (21.2%) acute leukemias, n = 9 (6.0%) Hodgkin lymphomas, and n = 11 (7.2%) other types of solid malignancies (medulloblastoma n = 3, neuroblastoma n = 2, thyroid carcinoma n = 1, gastric carcinoma n = 1, low-grade glioma n = 1, rhabdomyosarcoma n = 1, unspecified liver tumor n = 1, and dysgerminoma n = 1). For 4 patients (2.6%), the type of malignancy was unknown (Fig. 3). Both carcinomas and gliomas were diagnosed in early adulthood before the age of 25 years. The cumulative cancer incidence depending on the type of malignancy is presented in Fig. 2B.

Figure 3.

The incidence of the specific subtypes of primary and secondary malignancies in patients with NBS (NHL, non-Hodgkin lymphoma; HL, Hodgkin lymphoma; AL, acute leukemias).

Figure 3.

The incidence of the specific subtypes of primary and secondary malignancies in patients with NBS (NHL, non-Hodgkin lymphoma; HL, Hodgkin lymphoma; AL, acute leukemias).

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Among patients with NBS diagnosed with NHL, there was a similar number of lymphoid tumors of B-cell origin n = 49 (51.5%), including n = 25 cases of DLBCL, and lymphomas developed from abnormal T cells n = 43 (45.2%). In 3 and 2 patients, peripheral T-NHL and anaplastic large cell lymphomas were identified, respectively. The phenotype of NHL was unclassified in 3 patients (3.2%). The median age at diagnosis of lymphoma in NBS was 9.35 (IQR, 6–13.6) years. Tumors of B-cell origin occurred earlier in a lifetime in comparison with T-NHL 8.2 (IQR, 5.1–11.9) versus 10.53 (IQR, 8–14.2) years, respectively (P = 0.041). Hodgkin lymphoma in patients with NBS developed at adolescence with a median age at diagnosis of 13 (IQR, 7.53–18) years.

Regarding leukemic cell origin, patients with NBS predominantly developed T-cell acute lymphoblastic leukemia (T-ALL), n = 23 (71.8%) at different maturation stages. Only three cases of B-cell precursor ALL and single patients diagnosed with acute myelogenous leukemia (AML) and acute bilineage leukemia were observed in the cohort. For 4 patients, the immunophenotype of leukemia was not specified. Similarly, acute leukemias occurred in patients with NBS on average at approximately 9 (IQR, 5.9–12.3) years of age.

Analysis of the nationally representative Polish NBS cohort

Because the results of our study could be biased by the lack of group representativeness for populations within the particular countries, we selected the Polish NBS cohort as possibly the most complete cohort for further separate analysis. Overall, 137 out of 241 (56.8%) patients with NBS were of Polish origin. Four patients in this group were transplanted before cancer was diagnosed. First, we aimed to assess whether this group is truly representative of the Polish population. Next, we verified whether significant associations that were observed in the entire study cohort reflect similar trends in Polish patients only. The prevalence of NBS apparently increased over the 1995–2017 period in the Polish population (r = 0.7401, P < 0.0001; Fig. 2C). This was, however, caused by a negative trend of the population ages 0–35 years in Poland (r = −0.9937, P < 0.0001). After adjusting for the current population, a negative but nonsignificant trend was noted (rpartial = −0.3527, P = 0.114). These observations confirmed our assumptions of the Polish registry completeness. Within the Polish cohort, 86 (out of 133) patients (64.7%) developed malignancies (4,254 events per 100,000 patient-years) with a median age at presentation of 9.2 (IQR, 6.8–14) years. The 20-year cumulative incidence of cancer was 71.64% ± 4.5% in Polish patients with NBS, which was nonsignificantly lower than the 87.9% ± 4.5% observed in the non-Polish cohort (Fig. 2D).

However, in both the Polish and international cohorts, a three-stage joint-point model of cancer incidence fit the data better than a two-stage or continuous model (P < 0.0001 in all instances; Supplementary Fig. S1). In both cohorts, an initial rapid increase phase was noted (β = 0.39 and β = 0.66, both P < 0.0001) and ended at 7 [95% confidence interval (CI), 5–8] and 4 (95% CI, 4–9) years in the Polish and non-Polish cohorts, respectively. This was followed by a second, linear increase phase lasting until 13 years (95% CI, 11–16) in both cases, with trend coefficients of 0.09 and 0.14, respectively (both P < 0.0001). Afterward, the incidence showed a miniscule increase per year: 0.03 and 0.02, confirming that after 13 years, the risk of developing cancer decreases dramatically and significantly against earlier periods (P < 0.0001 in both cohorts). Curiously, the dynamics of the initial years of observation resulted in a statistically significant difference between the two cohorts (P = 0.032), which may result from different diagnostic strategies, genetic counseling or varied familial clustering patterns in the Polish and foreign patients. In this group, we observed the following subtypes of cancer: n = 57 (66.3%) NHLs, n = 15 (17%) acute leukemias, n = 6 (7.0%) Hodgkin lymphomas, and n = 8 (9.3%) other types of solid tumors. There were 16 HSCTs performed in Polish patients with NBS, including four preemptive transplantations. The remaining 9 and 3 patients were transplanted because of primary and secondary malignancies, respectively.

Survival

Overall, 110 patients with NBS out of 240 (45.8%) without preemptive HSCT transplantation died, including 102 patients diagnosed with malignancies and 8 patients without cancer after a median follow-up of 13 (IQR, 8.94–17.2) years and 13.4 (IQR, 11.5–25.72) years, respectively (P < 10−5).

The probability of 20-year OS for the whole group was 44.6% ± 4.5% (Fig. 4A). Patients who developed cancer had a shorter 20-year OS than those without malignancy (29.6% vs. 86.2%; P < 10−5; Fig. 4B). This association also remained significant when we analyzed OS in patients treated because of malignancies before and after 2000 (Supplementary Fig. S2). In addition, 20-year OS was marginally higher in Polish patients with NBS versus non-Polish individuals (Fig. 4C). We also analyzed OS after cancer diagnosis in the deceased patients finding that the patients die within the median time of 1.23 (±0.36 − 3.03) year from the first presentation of the tumor (Supplementary Fig. S3).

Figure 4.

A, Overall survival of the entire NBS study cohort. B, Overall survival of patients with NBS according to cancer incidence. C, Overall survival of patients with NBS depending on their origin (Polish vs. non-Polish). D, Cause of death reported in whole NBS cohort with subdivision of infectious basis.

Figure 4.

A, Overall survival of the entire NBS study cohort. B, Overall survival of patients with NBS according to cancer incidence. C, Overall survival of patients with NBS depending on their origin (Polish vs. non-Polish). D, Cause of death reported in whole NBS cohort with subdivision of infectious basis.

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Information about the cause of death was recorded for 99 (90%) patients with NBS. The main cause of death was cancer progression (61%) and infections (34%; Fig. 4D). Treatment-related mortality in the first line of anticancer therapy was 9.2%, which was mostly associated with infectious complications (85%). Transplant-related mortality was 18.3%, with an infection as the most frequent cause of death (67%).

HSCT in NBS

Between 2000 and 2018, 49 patients with NBS underwent HSCT in 17 BMT centers in nine countries (Supplementary Table S1). The transplantation procedure was performed twice due to rejection of the first graft in 2 patients. The median age at the time of HSCT was 9.0 (IQR, 5.7–14.5) years. In the transplanted group, 14 patients were transplanted before malignancy, 30 after the primary cancer diagnosis, and the remaining 5 after secondary tumors. A clinically relevant immunodeficiency with severe or chronic infections or immune dysregulation was the indication for HSCT in patients transplanted preemptively. The majority of patients with NBS (n = 31) obtained hematopoietic stem cells from matched donors [n = 30 and matched family donors (MFD) n = 1], 11 from matched sibling donors (MSD) and 2 from mismatched family donors (MMFD). For 5 patients, the information about the donor was unknown. Most patients received reduced conditioning regimens, adopted from protocols used in patients with Fanconi anemia. Detailed data on the HSCT procedure are presented in the Supplementary Materials (Supplementary Table S1).

In total, 13 patients died after HSCT, including 6 patients who developed fatal infections and 4 patients with cancer progression. In 3 additional cases, toxic complications of HSCT (GVHD with microangiopathy and bleeding, GVHD of gut followed by fatal respiratory infection and venooclussive disease with cooccurred infection) were the primary causes of death. Three relapses of malignancies occurred in transplanted patients, two of the primary lymphomas and one of the secondary T-NHL. Both patients who developed relapse of primary lymphoma were in partial remission of cancer at the time of transplantation.

In the entire cohort, 20-year OS in transplanted patients did not significantly differ from the one observed in the nontransplanted group (45.1% vs. 44.2%; P = 0.172; Fig. 5A). However, patients with NBS with diagnosed cancer who received HSCT had significantly higher 20-year OS than those who did not (42.7% vs. 30.3%; P = 0.038, respectively; Fig. 5B). Moreover, the difference in OS remained significant when we analyzed the cancer group depending on treatment before and after 2000 (Supplementary Fig. S2). Interestingly, in the group of patients who underwent preemptive transplantation, only 1 patient (1 per 14) developed kidney carcinoma with fatal outcomes, which corresponded to 708 (95% CI, 658–763) events per 100,000 patient-years. This is 6.7 times lower than in the group of patients who were not transplanted [incidence rate ratio 0.149 (95% CI, 0.138–0.162), P < 0.0001; Fig. 5C].

Figure 5.

A, Overall survival in the entire NBS cohort according to transplantation. B, Cancer incidence in patients with or without preemptive bone marrow transplantation. C, Overall survival in patients with NBS with cancer depending on transplantation. D, Cumulative risk of death with the occurrence of secondary malignancy as a competing event in patients with NBS with cancer according to transplantation status.

Figure 5.

A, Overall survival in the entire NBS cohort according to transplantation. B, Cancer incidence in patients with or without preemptive bone marrow transplantation. C, Overall survival in patients with NBS with cancer depending on transplantation. D, Cumulative risk of death with the occurrence of secondary malignancy as a competing event in patients with NBS with cancer according to transplantation status.

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Secondary malignancies in NBS

Overall, 20 (13.2%) patients with NBS developed secondary malignancies at a median age of 18 (IQR, 13.7–21.5) years. The most frequent subsequent cancer occurred in those patients whose primary diagnosis was B-cell leukemia/lymphoma (n = 12). Secondary malignancies were rarely diagnosed in patients with primary T-NHL/ALL (n = 3), Hodgkin lymphoma (n = 3), AML (n = 1), and ALL with an unspecified immunophenotype (n = 1). T-cell leukemia/lymphoma were confirmed as half of secondary tumors (n = 9), and the remaining types of cancer were DLBCL, Burkitt lymphoma, large cell anaplastic lymphoma, AML, meningioma, and ganglioglioma diagnosed in 5, 2, 1, 1, 1, and 1 cases, respectively (Fig. 3). All but 5 patients who developed secondary malignancies died of tumor progression or infectious complications during chemotherapy. Among the 5 patients who were still alive, 2 patients were observed for a relatively short time period (<6 months) after HSCT, and 1 who developed secondary T-NHL after transplantation had just started chemotherapy treatment. Two others were successfully transplanted from MSD or MMFD, and they remained in the remission of cancer for more than 5 years. Analysis of the impact of HSCT on the cumulative risk of death in the presence of secondary malignancy as a competing event showed that the risk for death was reduced 2-fold in transplanted patients compared with nontransplanted individuals [sub-distribution hazard ratio (SHR) = 0.42, 95% CI (0.21–0.85), P = 0.016; Fig. 5D].

This report describes, on an unprecedented scale, the natural history of NBS; details on cancer incidence, risk of death, and secondary cancer; and the potential effectiveness of HSCT in preventing either death or cancer. The 20-year cumulative incidence of cancer in NBS was considerably higher than reported in previous studies (1). Interestingly, this figure is almost three times more than the 20-year cumulative incidence of cancer described in ataxia telangiectasia and it is similar to the one reported for constitutional mismatch repair deficiency (CMMRD; refs. 10–13). However, in contrast to CMMRD, patients with NBS develop almost exclusively malignancies of hematologic origin (90%). The median age at diagnosis of most neoplasms is 9 years, which is similar to the age observed in ataxia telangiectasia. However, temporal differences in the cumulative incidences of the various cancers that were reported in ataxia telangiectasia differ from the ones we could identify in NBS (10). Apart from carcinomas, all malignancies occurred up to 25 years of age in patients with NBS. In addition, half of the patients with NBS (51%) developed first cancer before 10 years of age. Nevertheless, genetic heterogeneity of ATM mutation types in patients with ataxia telangiectasia affect the risk and spectrum of malignancies (14).

Consistent with previous smaller studies, most tumors diagnosed in NBS (62.5%) were NHLs with similar frequencies of B-cell lymphomas and tumors of abnormal T-cell origin (15). Inefficient elimination of damaged cells in patients with NBS and the fact that nibrin is involved in class switch recombination and alternative end joining DNA repair pathways contribute to the specific targeting of B cells by genomic instability (4). In addition, an increased chromosomal instability is also mediated by the extreme telomere attrition observed among homozygous carriers of NBN mutation (16). Telomere shortening was previously identified in patients with Fanconi anemia in whom the extent of telomere shortening correlated with the degree of bone marrow failure, but not with the presence of clonal abnormalities (17). There is a significant variation of telomere length dynamics in particular T-cell and B-cell lymphomas depending on the histologic subtype, the presence of specific translocation (e.g., involving TERT, BCL6), and germinal centre experience in case of B cells (18). Therefore, lymphoproliferative disorders with telomere dependent pattern of carcinogenesis may be more easily promoted in NBS. Because genomic data from tumors in NBS have not been published yet, we speculate that both telomere attrition together with hypermutability facilitate clonal selection of abnormal cells leading to early-onset malignancy.

Interestingly, among T-NHL’s three cases of lymphomas of peripheral T-cell origin, tumors rarely diagnosed in the nonsyndromic pediatric population were identified (19). T-cell ALL was the second most common malignancy diagnosed in patients with NBS (10). Recently published data showed a high frequency of chromothriptic events in ALL in ataxia telangiectasia individuals, but to our knowledge, chromothripsis has not been identified in T-ALL and in any other tumors in patients with NBS (20).

Although HSCT can correct both essential characteristics in NBS, immunodeficiency and susceptibility to hematologic malignancies, it has not been traditionally attempted in patients with NBS. The first encouraging results of HSCT among patients with NBS have already been provided by small case series (5, 21). Moreover, a recent study performed on a large group of patients with DNA repair syndromes who underwent HSCT demonstrated that HSCT can improve the survival of these patients, particularly when reduced intensity conditioning is applied (9). In contrast to the lack of beneficial effects of HSCT reported for patients with ataxia telangiectasia, transplantation improved OS in NBS individuals diagnosed with cancer. Moreover, preemptive HSCT performed in 14 individuals resulted in a more than 6-fold reduction in cancer incidence compared with patients with NBS selected for natural history of cancer incidence. There were no transplant-related deaths in the group of patients transplanted preemptively. In future, probably other alternative treatment strategies counteracting malignant transformation in NBS should be investigated. The example are substances which restore telomerase activity already successfully used in patients with telomere diseases such as dyskeratosis congenita (22).

In our study cohort, 13.2% of patients with NBS developed subsequent cancer. This frequency places NBS in the middle of the scale of risk for second tumors in DNA repair disorders (12, 23). An exposure to intensive chemotherapy was traditionally perceived to be a major factor contributing to the development of second tumors (24). However, in our cohort, half of subsequent cancers occurred in patients with NBS who obtained upfront reduced treatment, which should theoretically result in a lower rate of second cancers.

With respect to the recurrence of malignancy or the incidence of secondary cancer after transplantation, three NHL relapses, one subsequent lymphoma, and one case of renal carcinoma after preemptive transplantation were observed. A year after HSCT, only 1 patient out of 49 (2.0%) developed posttransplant lymphoproliferative disorder (PLTD). PLTDs are the most serious complication of HSCT resulting from iatrogenically impaired immune surveillance and Epstein–Barr virus primary infection/reactivation. On the basis of our results, the overall incidence of PLTD among patients with NBS seems to be similar as compared with nonsyndromic recipients of HSCT, for which it was estimated to be 3.2% (25). In addition, in contrast to patients with Fanconi anemia, patients with NBS are probably less prone to developing secondary nonhematologic tumors after HSCT (26). Only one primary solid tumor was detected in patients with NBS 17 years after preemptive transplantation. Although the median time of the follow-up after HSCT was relatively short in our cohort, the probability of cancer is not high after transplantation.

One of the main limitations of our study is an ascertainment bias resulting from the selection of NBS cases that were enrolled in the study group from particular countries, including Germany, Czech Republic, Slovakia, Serbia, Turkey, and Austria. To avoid possible misinterpretation, we decided to analyze the Polish NBS cohort separately as a possible representative group in which we investigated the same associations as we could previously identify in the entire cohort. Eventually, we managed to confirm both our assumptions of the Polish registry completeness and concordance of results between Polish and entire NBS cohorts, which all together increased the reliability of our observations. Finally, the selection of patients for HSCT may have been affected by center-specific factors and preferences with potential temporal bias. Patients who underwent transplantation did so mostly after 2000, which may have affected the quality of supportive and immunologic care provided. Nevertheless, the impact of transplantation persisted even if the year of diagnosis was factored in the analysis, supporting our claim that HSCT will contribute to longer OS without increasing the risk of secondary cancers.

In summary, our results strongly support the notion of a beneficial effect of HSCT in the first complete remission of cancer on the long-term survival of patients with NBS. Although there are very promising results after preemptive HSCT, there is still not enough data to estimate its positive influence on long-term patient survival. Despite the above, preemptive transplantation should be considered individually in every patient considering the clinical severity of immune defects and other comorbidities.

A. Pastorczak reports grants and personal fees from National Science Centre and grants from COST Action - CA16223 during the conduct of the study. K.-W. Sykora reports grants and other from Medac GmbH outside the submitted work. M. Eapen reports grants from NIH during the conduct of the study. M.G. Seidel reports personal fees from Jazz Pharmaceuticals, Novartis, and Amgen, as well as nonfinancial support from Shire outside the submitted work. No disclosures were reported by the other authors.

B. Wolska-Kusnierz: Conceptualization, resources, supervision, investigation, writing-original draft. A. Pastorczak: Conceptualization, resources, data curation, formal analysis, investigation, writing-original draft. W. Fendler: Formal analysis, investigation, methodology, writing-review and editing. A. Wakulinska: Resources, writing-review and editing. B. Dembowska-Baginska: Conceptualization, resources, writing-review and editing. E. Heropolitanska-Pliszka: Resources, writing-review and editing. B. Piatosa: Resources, writing-review and editing. B. Pietrucha: Resources, writing-review and editing. K. Kalwak: Resources, writing-review and editing. M. Ussowicz: Conceptualization, resources, writing-review and editing. A. Pieczonka: Resources, writing-review and editing. K. Drabko: Resources, writing-review and editing. M. Lejman: Resources, writing-review and editing. S. Koltan: Resources, writing-review and editing. J. Gozdzik: Resources, writing-review and editing. J. Styczynski: Resources, writing-review and editing. A. Fedorova: Resources, writing-review and editing. N. Miakova: Resources, writing-review and editing. E. Deripapa: Resources, writing-review and editing. L. Kostyuchenko: Resources, writing-review and editing. Z. Krenova: Resources, writing-review and editing. E. Hlavackova: Resources, writing-review and editing. A.R. Gennery: Data curation, writing-review and editing. K.-W. Sykora: Resources, writing-review and editing. S. Ghosh: Resources, writing-review and editing. M.H. Albert: Resources, writing-review and editing. D. Balashov: Resources, writing-review and editing. M. Eapen: Resources, writing-original draft. P. Svec: Resources, writing-review and editing. M.G. Seidel: Resources, writing-review and editing. S.S. Kilic: Resources, writing-review and editing. A. Tomaszewska: Resources, writing-review and editing. E. Wiesik-Szewczyk: Resources, writing-review and editing. A. Kreins: Resources, writing-review and editing. J. Greil: Resources, writing-review and editing. J. Buechner: Resources, writing-review and editing. B. Lund: Resources, writing-review and editing. H. Gregorek: Resources, writing-review and editing. K. Chrzanowska: Conceptualization, resources, data curation, writing-original draft. W. Mlynarski: Conceptualization, resources, data curation, supervision, writing-original draft.

This project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under ERA-NET Cofund action N643578 and was supported by the National Centre for Research and Development (No. ERA-NET-E-Rare-3/I/EuroCID/04/2016). A. Pastorczak was supported by the National Science Centre grant no. 2017/26/D/NZ5/00811. W. Mlynarski and A. Pastorczak were supported by the LEukemia GENe Discovery (LEGEND) by data sharing, mining, and collaboration (COST Action - CA16223) 2017–2021.

Data on number of registered patients with NBS were obtained from the ESID online database (www.esid.org).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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