Hematologic Malignancies and Monoclonal Gammopathy of Undetermined Significance (MGUS) in Gaucher Disease Type 1 Patients in the International Cooperative Gaucher Group Gaucher Registry

Abstract (current character count: 3474; 3800 allowed excluding spaces; title, authors’ names, affiliations, figures, and tables are not included in the character count)

In Gaucher disease (GD), acid β-glucosidase deficiency causes immunoactive glucosylceramide and glucosylsphingosine to accumulate in tissue macrophages, leading to a multisystemic phenotype partly driven by metabolic inflammation. Large multi-center and global studies, including the International Collaborative Gaucher Group (ICGG) in 2005, reported increased prevalence of hematologic malignancies, especially multiple myeloma (MM) and lymphoma. Revisiting this topic 15 years later is important to refine recommendations for patient follow up, better understand long term effects of GD treatments, and provide clinical support for study of disease mechanisms. Here we report the frequency of the myeloma precursor, monoclonal gammopathy of undetermined significance (MGUS), and the incidence and relative risk for malignancies by organ site in the ICGG Gaucher Registry population.

The ICGG Gaucher Registry (NCT00358943/funded by Sanofi Genzyme) is a multicenter, international, longitudinal, observational, and voluntary program designed to track the natural history, treatment, and outcomes of patients with GD. The ICGG Gaucher Registry collects and analyzes clinical, biochemical, radiologic characteristics, and serial outcomes for GD patients.

We assessed MGUS frequency and progression to MM, and frequency of all malignancies in the GD1 population relative to United States (US) population-based rates from the Surveillance, Epidemiology, and End Results (SEER) Program. Patients diagnosed with low leukocyte acid β-glucosidase activity and/or biallelic mutations in GBA1 who had dates for assessment and malignancies were included. Study period was 1993-2019. Age-adjusted incidence was compared with SEER data.

We identified 1,998 eligible patients. Over half (53.5%) were female, with a mean [SD] age at GD1 diagnosis of 23.9 years [18.5]. The majority (89%) had received GD-specific therapy. Of 1,956 patients with data on gammopathy (yes/no), 218 reported a gammopathy (11.1%). MGUS was reported in 121 patients (6.2%). Mean age at MGUS diagnosis was 55.8 years (SD=14.9). Age-specific rates of MGUS per 100,000 person-years (number of MGUS diagnoses shown in parentheses; 1 MGUS patient excluded due to missing date of GD1 diagnosis):

<50 years (n=44) 89.5

50-59 years (n=23) 40.1

60-69 years (n=28) 55.7

70-79 years (n=21) 91.6

80+ years (n=4) 58.3

Only 12 of 22 MM patients (54.5%) reported a previous diagnosis of MGUS; the mean time interval between MGUS and MM diagnoses was 4.1 years (SD=4.5).

Among 1,995 patients with malignancy status information (yes/no), 245 patients (12.3%) had at least one malignancy diagnosed at ≥20 years of age; patients could report more than one malignancy. There were 61 hematologic malignancies of which the majority are non-Hodgkin’s lymphoma (NHL, 41.0%) and MM (34.4%). Mean age for NHL diagnosis: 55.6 years (SD=13.0); MM diagnosis, 62.0 years (SD=10.5). The average time from primary Gaucher treatment initiation to first hematologic malignancy diagnosis was 9.3 years. Of 193 non-hematological malignancies, 24.4% were basal or squamous cell skin cancers and 20.7% were breast. The age-adjusted rate comparisons with the SEER data show greater incidence rates for all malignancies combined, largely attributable to NHL, MM, liver, renal cell, and melanoma (Table 1). The reported incidence of lung and prostate cancer is unexpectedly low in the Registry population.

Our new findings show that despite common use of enzyme replacement therapy, the risk for MM and NHL in patients with GD1 continues elevated in all age groups compared to the general US population. Risk for liver cancer, renal cancer, and melanoma is also increased. The MGUS incidence rate in GD1 patients younger than 50 years old is also unexpectedly high and may indicate the need to monitor younger GD1 patients for MGUS. These findings underscore the relevance of cancer screening when following GD1 patients and the need for continued investigation of sphingolipid substrates and metabolites in carcinogenesis