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2514 High Prevalence of Constitutional Mismatch Repair Deficiency in a Pediatric T-Cell Lymphoblastic Lymphoma Cohort

Program: Oral and Poster Abstracts
Session: 627. Aggressive Lymphomas: Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
Clinical Research
Sunday, December 12, 2021, 6:00 PM-8:00 PM

Emma Kroeze1*, Dilys D Weijers1*, Melanie M Hagleitner, MD, PhD1*, Hester A. De Groot-Kruseman, PhD2*, Marjolijn C Jongmans, MD, PhD1,3*, Roland P Kuiper, PhD1,3, Rob Pieters, Prof, MD, PhD1, Jules PP Meijerink, PhD1 and Jan LC Loeffen, MD, PhD1*

1Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
2Pediatric Oncology, Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
3Department of Genetics, University Medical Center Utrecht, Utrecht, Netherlands

Introduction: Pediatric T-cell lymphoblastic lymphoma (T-LBL) is a subtype of non-Hodgkin lymphoma (NHL) that arises from the malignant transformation of immature T-cells, similar to T-cell acute lymphoblastic leukemia (T-ALL). T-LBL is characterized by massive infiltration of blasts in the mediastinum and lymph nodes without or occasionally with low percentages of blasts in the bone marrow (<25%). Even though T-LBL and T-ALL are thought to be closely related, extensive analyses have led to improved understanding of the biology of T-ALL, whereas similar efforts for T-LBL are still scarce. Nevertheless, recent studies have made progress in increasing the understanding of the biology of T-LBL. It has been reported that T-LBL seems to be associated with a high occurrence of second primary malignancies after treatment of non-Hodgkin lymphoma (NHL) (Attarbaschi, 2020). This study revealed a relatively high number of T-LBL patients in a selected cohort of NHL cases who developed second primary malignancies (69/189). In the current study, we describe a complete and unselected T-LBL cohort based on clinical presentation of disease, as well as second primary malignancies and comorbidities.

Methods: We present a retrospective pediatric T-LBL cohort (n=88) for patients diagnosed between January 2007 and September 2020 who were treated according to the EURO-LB02 protocol in one of the former pediatric oncology centers in the Netherlands.

Results: In total, 10.2% (9/88) of the T-LBL patients in this unselected cohort have been diagnosed with a cancer predisposition syndrome, almost exclusively constitutional mismatch repair deficiency (CMMRD) (8/88). All CMMRD patients in this cohort had mutations that affected PMS2 (5/8) or MSH6 (3/8) and most patients had compound heterozygous mutations. CMMRD diagnosis was expected and established based on the presence of multiple café-au-lait maculae in all patients and a history of previous or secondary cancers in various patients. Clinical and patient characteristics of CMMRD patients at time of T-LBL diagnosis were compared to sporadic T-LBL patients and summarized in Table 1. The most significant difference between CMMRD and sporadic T-LBL patients was the development of second primary malignant neoplasms (p<0.0001). Whereas clinical presentation of the CMMRD and sporadic T-LBL patients was comparable, the percentage of CMMRD patients who had one or multiple enlarged lymph nodes seemed lower than for sporadic patients albeit not significant (p=0.1179). None of the CMMRD patients presented with bone marrow involvement at T-LBL diagnosis in comparison to 25% of sporadic T-LBL patients who had >1% blasts in their bone marrow at time of diagnosis (and 8% having >5% blasts). Two sporadic patients presented with CNS3 and had 5 or more white blood cells/µl (WBC) in the cerebral spinal fluid (CSF) and nine patients had CNS2 (WBC in the CSF, but less than 5 WBC/µl CSF). In contrast, none of the CMMRD patients had evidence of blasts in the CSF, indicating that the T-LBL manifestation for CMMRD patients was more localized compared to sporadic T-LBL patients.

The treatment response of the CMMRD T-LBL patients was favorable, six out eight patients (75%) achieved complete remission (CR). In general, treatment was tolerated well in the CMMRD patients, without significant delay of chemotherapy. However, three out of eight CMMRD patients developed pulmonary aspergillosis infection during T-LBL treatment, which was fatal for one patient.

Conclusions: Currently, second primary malignancies during childhood are the main indicator for the presence of an underlying cancer predisposition syndrome. Additional CMMRD features, as proposed by the care for CMMRD consortium (Wimmer, 2014), are often missed. This shows that the diagnosis of a cancer predisposition syndrome is highly dependent on the alertness of the treating physician and is often missed at time of diagnosis of the first (childhood) malignancy, possibly causing an underestimation of the frequency of cancer predisposition syndromes among T-LBL patients at present. Therefore, we advocate for screening all pediatric T-LBL patients for the presence of germline mutations in mismatch repair genes.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH