Cancer risk and gammopathies in 2123 adults with Gaucher disease type 1 in the International Gaucher Group Gaucher Registry

Abstract

There are numerous reports of cancers in Gaucher disease (GD) from mostly small single-center studies; however, precise risk estimates and cancer types involved have not been delineated. We conducted a study involving 2123 patients with GD type 1 (GD1) to assess the incidence of hematological malignancies, gammopathies, and solid tumors in an international observational study, the International Cooperative Gaucher Group Gaucher Registry (Clinicaltrials.gov: NCT00358943). Risk for cancer overall and for each type of malignancy was compared to the United States (US) population using the Surveillance, Epidemiology, and End Results database. Natural history of gammopathy was determined through assessing the progression from a diagnosis of monoclonal gammopathy of unknown significance (MGUS) to multiple myeloma (MM). Risk for hematological malignancies was more than four times higher than expected compared to the general population: non-Hodgkin lymphoma was approximately three times higher; MM was approximately nine times higher. Age-specific incidence rates of MGUS were unexpectedly high among younger patients. The 10-year cumulative incidence of MM after diagnosis of MGUS was 7.9%, comparable to the general population. Compared to the general US population, GD1 patients were at higher risk for solid malignancies of liver (2.9 times), kidney (2.8 times), melanoma (2.5 times), and breast (1.4 times). Colorectal, prostate, and lung cancer risks were lower than expected. These findings help advance care of patients with GD1 by supporting recommendations for individualized monitoring for malignancies and antecedents such as MGUS for MM and provoke important questions of the role of glucosylceramide and related sphingolipids in cancer biology.

Conflict of interest statement

Barry E. Rosenbloom: Was a principal investigator in the eliglustat ENCORE trial and has received honoraria and travel reimbursement from Sanofi. Maria Domenica Cappellini: Is a member of the advisory board for Sanofi, BMS, Vifor, Vertex, and Silence. Neal J. Weinreb: Has received honoraria for consultancy or participation on Advisory Boards for Sanofi, Pfizer and Shire and fees or honoraria from speaking at the invitation of Sanofi, Pfizer, and Shire. He has received grant support from Sanofi. Marta Dragosky: She was a Principal Investigator in the eliglustat Phase 2 and ENCORE clinical trials and has received speaker fees and travel support from Sanofi and Shire. Shoshana Revel‐Vilk: Has received research grants, speaker fees, and travel support from Pfizer, Sanofi and Takeda/Shire. Davorka Sekulic: Employee of Sanofi and owns stock and/or stock options in the company. Julie L. Batista: Employee of Sanofi and owns stock and/or stock options in the company. Pramod K. Mistry: Has received research grant, travel support from Sanofi. He was a principal investigator in the ENGAGE clinical trial.

© 2022 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.

Figures

FIGURE 1

Malignancy rates and comparison of risk for solid and hematologic malignancies of GD1 patients with the United States general population using the SEER data from 2015 are shown for those solid and hematological malignancies where a difference in rates was observed. Incidence rates are age‐adjusted to the 2000 US Census population for comparison. The log of the incidence rate ratios is graphed. Only females are included for breast cancer. Only males are included for prostate cancer. Disease type reported by physician. *n is the number of cases for each malignancy type in the ICGG Gaucher Registry. “All malignancies” include all malignancies except basal cell and squamous cell skin cancer, which are not reportable to the SEER database. CI, confidence interval; GD1, Gaucher disease type 1; ICGG, International Cooperative Gaucher Group; IRR, incidence rate ratio

FIGURE 2

Cumulative incidence curves for MGUS, for multiple myeloma for patients with MGUS diagnosis, and for polyclonal gammopathies. (A) Overall cumulative incidence curve for MGUS. (B) Cumulative incidence curves for MGUS with age as time scale by category of time from GD1 diagnosis to first treatment. (C) Cumulative incidence curve for MM among GD1 patients with MGUS diagnosis. One patient reported diagnosis of MGUS after MM and is not included in the analysis. Eleven of the 22 patients with MM had a “no” response to MGUS and are not included in this analysis. (D) Overall cumulative incidence curve for polyclonal gammopathy. (E) Cumulative incidence curves for polyclonal gammopathies with age as time scale by category of time from GD diagnosis to first treatment. Records with missing dates of diagnosis of the relevant malignancy for the analysis or date of birth are excluded. If a patient was diagnosed more than once with the relevant malignancy for the analysis, the earliest date for the type of event is used for the analysis. Disease type is as reported by physician. GD1, Gaucher disease type 1; MM, multiple myeloma; MGUS, monoclonal gammopathy of unknown significance [Color figure can be viewed at wileyonlinelibrary.com]