Concurrent Waldenstrom’s Macroglobulinemia and Myelodysplastic Syndrome with a Sequent t(10;13)(p13;q22) Translocation

Myelodysplastic syndromes (MDS) and Waldenstrom’s macroglobulinemia (WM) are rarely synchronous. Ineffective myelopoiesis/hematopoiesis with clonal unilineage or multilineage dysplasia and cytopenias characterize MDS. Despite a myeloid origin, MDS can sometimes lead to decreased production, abnormal apoptosis or dysmaturation of B cells, and the development of lymphoma. WM includes bone marrow involvement by lymphoplasmacytic lymphoma (LPL) secreting monoclonal immunoglobulin M (IgM) with somatic mutation (L265P) of myeloid differentiation primary response 88 gene (MYD88) in 80–90%, or various mutations of C-terminal domain of the C-X-C chemokine receptor type 4 (CXCR4) gene in 20–40% of cases. A unique, progressive case of concurrent MDS and WM with several somatic mutations (some unreported before) and a novel balanced reciprocal translocation between chromosomes 10 and 13 is presented below.


Introduction
Myelodysplastic syndromes (MDS) and Waldenstrom's macroglobulinemia (WM) are rarely synchronous. MDS is characterized by an ineffective myelopoiesis/hematopoiesis with clonal unilineage or multilineage dysplasia and cytopenias. WM includes bone marrow involvement by lymphoplasmacytic lymphoma (LPL) secreting monoclonal immunoglobulin M (IgM) with somatic mutation (L265P) of myeloid differentiation primary response 88 gene (MYD88) in 80-90%. We present a case of concurrent MDS and WM, with a unique translocation and somatic mutations.
Lenalidomide (10 mg for 21/28 days) was started per patient's request to avoid parenteral hypomethylating agents, and transfusion independence was achieved for 1 year (until April 2015). Afterward, pancytopenia (WBC = 2.7 × 10 3 /µL, Hgb = 7 g/dL, MCV = 75 fL, Plt = 32 × 10 9 /L) and WM (M spike = 0.53 g/dL and IgM = 1500 mg) recurred. The pa-tient received supportive treatment with blood product transfusions and eltrombopag prior to being scheduled for a BM transplant and receiving azacytidine for pre-transplant cytoreduction. A repeat BM biopsy (August 2015) showed residual LPL with normal cytogenetics. Hemolytic workup was negative, and also demonstrated hyperproteneimia (total protein = 8.6 g/dL) with an M-spike of 1.5 g/dL and total IgM of 2.86 g/dL indicating progression of WM. Cytogenetic analysis demonstrated a normal 46XY karyotype. PCR was negative for JAK-2 (V617F and exons 12/13), MPL (W515 AND S505), CAL-R, MYD88, CXCR-4 and BCR/ABL mutations. Fluorescent in situ hybridization analysis was negative for deletions of 5q, 7q and 20q, monosomies of chromosomes 5 and 7, trisomy of chromosome 8, and for common aberrations associated with chronic lymphocytic leukemia or multiple myeloma. Therefore, the diagnoses of low-grade B cell lymphoproliferative disorder with plasmacytic differentiation, consistent with lymphoplasmacytic lymphoma (LPL) and a concomitant myeloid neoplasm compatible with low grade MDS were made.
Lenalidomide (10 mg for 21/28 days) was started per patient's request to avoid parenteral hypomethylating agents, and transfusion independence was achieved for 1 year (until April 2015). Afterward, pancytopenia (WBC = 2.7 × 10 3 /µL, Hgb = 7 g/dL, MCV = 75 fL, Plt = 32 × 10 9 /L) and WM (M spike = 0.53 g/dL and IgM = 1500 mg) recurred. The patient received supportive treatment with blood product transfusions and eltrombopag prior to being scheduled for a BM transplant and receiving azacytidine for pre-transplant cytoreduction. A repeat BM biopsy (August 2015) showed residual LPL with normal cytogenetics. Hemolytic workup was negative, and also demonstrated hyperproteneimia (total protein = 8.6 g/dL) with an M-spike of 1.5 g/dL and total IgM of 2.86 g/dL indicating progression of WM.
Azacytidine was stopped after 2 cycles given the development of pancytopenia secondary to WM progression in the setting of treatment with 2 doses of IVIG and 4 cycles of rituximab. The patient received maintenance rituximab therapy from 2015 to 2018 before being transitioned to ibrutinib and obinotuzumab in August, 2018, due to disease progression. This treatment regimen achieved IgM normalization prior to being discontinued in March 2019 due to persistent pancytopenia and an M spike surge.
In August 2019, one cycle of dose-reduced bendamustine (30 mg/m2) and rituximab was administered, achieving improvement in blood transfusion requirements and undetectable M component. Figure 3 provides an outline of the patient's treatment. However, severe pancytopenia (WBC = 0.5, Hgb = 8 and Pts = 20) persisted. A pre-BMT BM biopsy (November 2019) showed decreased cellularity (50%) mostly composed of reactive T cells, stable moderate reticulin fibrosis and no residual lymphoma. Corresponding cytogenetics showed a novel t(10;13)(p13;q22) translocation. In January of 2020, the patient was hospitalized in preparation for an allogeneic BMT. However, severe pancytopenia persisted (despite 60 units of pRBCs and 20 units of Plts) and the patient developed respiratory failure requiring intubation. A transtracheal aspirate culture revealed methicillin-resistant staphylococcus aureus and he ultimately expired. The autopsy showed marked multisystemic hemosiderosis involving liver, spleen, pancreas, adrenal glands, thyroid and lymph nodes. Post mortem BM biopsy showed marked aplasia without myelofibrosis or residual LPL. The cause of death was sepsis and iron overload.

Discussion
Herein, we presented a complicated case of simultaneous MDS and WM in a 71-yearold African American male, which required multiple therapies during a 6-year prolonged course. LPL and MDS were refractory to initial lenalidomide treatment. Diverse therapeutic strategies, including ibrutinib and obinotuzumab finally achieved WM remission; however, refractory MDS persisted and a 20(q11.2q13.1) deletion was detected 4 years after treatment. The deletion of the long arm of chromosome 20, or del(20q), is a common cytogenetic abnormality in various myeloid disorders, such as primary MDS (and less frequently secondary MDS) [1][2][3], but is less common in lymphoid neoplasms, including WM [4][5][6][7][8]. Therefore, the observed del(20q) may represent primary de novo MDS and/or LPL, or a secondary therapy-related malignancy.
NGS revealed many mutations potentially representing novel therapeutic targets involving various signaling cascades: NFkB-related cell proliferation/survival (CXCR4, TBL1XR1 and TLL2); PI3K/AKT/mTOR-induced protein synthesis/cell growth (CXCR4,  CSF1R, EGFR, ERBB4, FGF23, FOXP1, LRP1B,   In January of 2020, the patient was hospitalized in preparation for an allogeneic BMT. However, severe pancytopenia persisted (despite 60 units of pRBCs and 20 units of Plts) and the patient developed respiratory failure requiring intubation. A transtracheal aspirate culture revealed methicillin-resistant staphylococcus aureus and he ultimately expired. The autopsy showed marked multisystemic hemosiderosis involving liver, spleen, pancreas, adrenal glands, thyroid and lymph nodes. Post mortem BM biopsy showed marked aplasia without myelofibrosis or residual LPL. The cause of death was sepsis and iron overload.

Discussion
Herein, we presented a complicated case of simultaneous MDS and WM in a 71-yearold African American male, which required multiple therapies during a 6-year prolonged course. LPL and MDS were refractory to initial lenalidomide treatment. Diverse therapeutic strategies, including ibrutinib and obinotuzumab finally achieved WM remission; however, refractory MDS persisted and a 20(q11.2q13.1) deletion was detected 4 years after treatment. The deletion of the long arm of chromosome 20, or del(20q), is a common cytogenetic abnormality in various myeloid disorders, such as primary MDS (and less frequently secondary MDS) [1][2][3], but is less common in lymphoid neoplasms, including WM [4][5][6][7][8]. Therefore, the observed del(20q) may represent primary de novo MDS and/or LPL, or a secondary therapy-related malignancy.
Mutations in many of these genes have been shown to be pathogenic either in WM (B2M, CXCR4, EP300, Well-known druggable oncogenic targets were PTEN, CXCR4, MLL2 and BRCA2 [1,3,14,16]. However, further studies are necessary to fully understand the significance of these alterations and precision medicine was not attempted since the patient expired.
PTEN loss has been found in 3% of diffuse large B cell lymphomas but has not been reported in WM [17,18]. Although the PTEN G132D point mutation seen in our patient has not been functionally characterized, it has been reported in the context of PTEN hamartoma tumor syndrome [19].
CXCR4 mutation is a frequent event in WM (30%) and is associated with survivalindependent aggressive MYD88 L256P mutated LPL [14]. However, the role of CXCR4 in the context of wild-type MYD88, such as in our patient, is unknown. CXCR4 truncation in WM has been linked with resistance to ibrutinib, but we detected CXCR4-Q318* after ibrutinib treatment [14].
Approximately 5 years after diagnosis, we detected a novel balanced reciprocal translocation, t(10;13)(p13;q22) of uncertain significance. This translocation could represent novel gene fusions that may disrupt/dysregulate critical genes at the break points, or represent a chemotherapeutic induced passenger mutation. Interestingly, the closest reported translocation, t(10;13)(q21;q14) involving CDK1 and DGKH, is believed to be pathogenic in acute lymphoblastic leukemia/lymphoblastic lymphoma [20][21][22][23]. The new translocation we found, was detected in unstimulated cultures, which suggests a secondary myeloid related change, or less likely, a transient post-treatment hit without significant clinical impact.

Conclusions
The development of cancer therapeutics targeting patient-specific mutational profiles remains an active area of research. We presented a unique case of synchronous WM and LPL with novel mutations in common driver genes [24] and a unique translocation, which may inform the pathogenesis or therapeutic strategies for complex cases in the future.  Institutional Review Board Statement: Ethical review and approval were waived for this study due to the fact that this was a case report and the patient granted permission.
Informed Consent Statement: Informed consent was obtained from all subjects involved in the study. Ethical review and approval were waived for this study due to the nature of the publication.

Data Availability Statement:
The data presented in this study are available on request from the corresponding author.

Conflicts of Interest:
The authors declare no conflict of interest.