Risk of head and neck squamous cell cancer and death in patients with Fanconi anemia who did and did not receive transplants

Abstract

Hematopoietic stem cell transplant (SCT)is currently the only therapy that can restore normal hematopoiesis in patients with Fanconi anemia (FA). Patients with FA have a high baseline risk of squamous cell cancers (SCCs) of the head, neck, and esophagus, and SCT conditioning may increase SCC incidence. We evaluated the risks of SCC and death in 145 patients with FA in the North American Survey (NAS) cohort who did not receive transplants, and 117 patients with FA in the Hô pital Saint Louis (SLH) cohort who did receive transplants. The age-specific hazard of SCC was 4.4-fold higher in patients who received transplants than in those who did not (P ‫؍‬ .003), and SCCs occurred at significantly younger ages in the former (respective medians, 18 and 33 years, P ‫؍‬ .004). Survival after SCC was similarly poor in both cohorts (P ‫؍‬ .135, median, 13 months). The hazard of SCC increased at a greater than linear rate, to 4.4% per year by age 40 in NAS and 4.7% per year by 10 years after transplant in SLH. In SLH, the hazard of non-SCC death was biphasic, declining significantly (P ‫؍‬ .004) from 7.1% per month during the first 6 months after transplant to 0.13% per month (1.6% per year) after the first year. Acute and chronic graft-versushost diseases were significant SCC risk factors. Adverse event rates in these cohorts provide historical control rates to assess emerging therapies for FA. IntroductionFanconi Anemia (FA) is an autosomal recessive genomic instability syndrome 1 associated with congenital abnormalities, progressive pancytopenia, and a predisposition to cancer. 2 Acute myeloid leukemia (AML) is the most frequent cancer of FA, 3 but a number of specific solid tumors occur at remarkably high rates in patients with FA who survive to adulthood, notably squamous cell cancers (SCCs) of the head, neck, and esophagus, and vulvar and cervical cancer in women. 4,5 Hematopoietic stem cell transplant (SCT) is currently the only therapy that can restore normal hematopoiesis in FA. It has been difficult to optimize transplant protocols for patients with FA. Standard regimens are too toxic for patients with FA,6,7 but the graft will fail if the conditioning is too mild. Effective regimens have been developed. 8 However, in non-Fanconi patient populations, conditioning increases the incidence of certain tumors, 9-14 especially SCCs, that occur at high baseline rates in FA. The occurrence of these cancers in Fanconi patients following SCT has been an ongoing concern. [15][16][17][18][19][20] Two methodological issues affect risk assessment in patients with FA who receive transplants. First, SCT protocols for patients with FA are institution-specific, and when protocols are enhanced over time, a number of modifications may be made at once. However, secondary solid tumors and some transplant-related deaths occur years after transplant. Therefore, the ultimate assessment of any new protocol must compare adverse event rates that manifest over time to corresponding rates in the past, for instance, using historical controls. ...

National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Subsequent Neoplasms Working Group Report

“…76 In another study of 262 patients with FA, the 117 HCT recipients had a four-fold increased risk of developing SCC. 143 …”

Fanconi anaemia: new strategies

“…Approximately 40% of FA patients develop a malignancy within 15-20 years after HSCT, 19 but indeed head and neck squamous cell carcinomas may occur earlier after transplant at a median of 8.2 years from the graft in patients conditioned with lowdose CY þ TAI who had extensive GvHD. 15 Another recent study 16 demonstrated that transplanted FA patients have increased risk and earlier occurrence of head and neck squamous cell carcinomas compared with non-transplanted FA patients and confirmed the strong association between GvHD and late malignancies. Although transplant results have now importantly improved in terms of quality and duration of engraftment and reduction of toxicity, it looks clear, on the basis of these data, that strategies in FA patients should now aim to minimize GvHD in the view of reducing the risk of late post transplant malignancies.…”

“…11 Of note is that GvHD, in addition to negatively impacting on survival and quality of life, is one of the major risk factors for the development of late tumours. 15,16 Over the recent years, fludarabine (Flu)-containing reduced-intensity conditioning regimens have become more popular and are being successfully employed also in FA. In a recently published cohort of 11 patients, 14 actuarial overall survival was 82%, TRM was 9%, GvHD was negligible and toxicity, on the whole, low.…”

Successful SCT for Nijmegen breakage syndrome

“…Humoral immunity was impaired in five of six patients. Four of the patients developed lymphoid malignancy at a median age of 12 years (range [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. One patient experienced a second, different lymphoid malignancy 8 years after chemotherapy for his first malignancy.…”