Waldenström’s macroglobulinemia (WM) is a rare type of B-cell non-Hodgkin lymphoma that is characterized by lymphoplasmacytic bone marrow infiltration and the production of monoclonal immunoglobulin M (IgM) paraprotein (1). WM accounts for 1-2% of all patients with hematological malignancies and the median overall survival is approximately 8 years (2,3). In rare cases, in 5-10% of patients with WM, the disease may undergo transformation into diffuse large B-cell lymphoma (DLBCL) and this can occur at any time in the course of the disease (4,5). DLBCL that arises from histological transformation (HT) of WM has worse prognosis compared with de novo DLBCL, with a median survival of less than 3 years (5-7).

In this case report, we present a woman with DLBCL which developed following WM who has remained disease-free over the past 10 years after completion of chemotherapy.

In February 2009, a 69-year-old woman (approval number 375/ 21-05-2019), with a history of anemia worsening over the previous 6 months, presented with a remarkably low hemoglobin level of 8 g/dl. The physical examination revealed paleness, enlargement of the spleen and absence of lymphadenopathy. Abdominal computed tomography confirmed these findings, while fundoscopy indicated lesions compatible with hyperviscosity syndrome. The laboratory examinations showed a remarkably level low of hemoglobin=7.3-8.9 g/dl, white blood cell count of 17.3×10³/μl (24% neutrophils, 60% lymphocytes), high IgM level of 9,110 mg/dl, abnormal high lactate dehydrogenase (LDH)=376 U/l and β2 microglobulin=3,500 μg/l. In addition, the bone marrow examination revealed 40-50% infiltration by monoclonal lympho-plasma cells and immunofixation was positive for IgM kappa monoclonal protein; thus, the diagnosis of WM was established.

The patient received a combination of dexamethasone at 20 mg on day 1, 375 mg/m² rituximab on day 1 and cyclophosphamide at 100 mg/m² twice daily for 5 days (DRC) every 21 days for 6 months. Erythropoietin and filgrastim were administered as supportive measures. The regimen was well tolerated, with no clinically significant major adverse events. Following eight cycles of chemoimmunotherapy, hematological partial response was achieved. The laboratory findings were improved as follows: hemoglobin=12.3 g/dl, white blood cell count of 5.2×10³/μl (63% neutrophils, 28% lymphocytes), IgM=2,620 mg/dl, LDH=137 U/l and β2 microglobulin=1,668 μg/l. The performance status of the patient was excellent and maintenance treatment with rituximab monotherapy was given every 2 months for 1 year. During a follow-up period of 3 years, the IgM level showed a constant decrease, and the laboratory findings were unremarkable.

However, during a routine follow-up visit in 2013, the physical examination revealed a gluteal mass and swelling of ipsilateral inguinal lymph nodes. A biopsy of the lymph node was performed, and immunohistochemistry demonstrated expression of CD20, CD30, paired box 5, CD79a, multiple myeloma oncogene-1, CIgM(ĸ) and p53, while there was no evidence of BCL2 apoptosis regulator (BCL2), BCL6 transcription repressor (BCL6), Epstein–Barr virus small RNA, syndecan and cyclin D1 expression; hence, the pathology report findings were suggestive of DLBCL. Staging with whole-body computed tomography did not reveal any other disease foci. The patient started treatment immediately with 660 mg rituximab, 1,300 mg cyclophosphamide, 80 mg doxorubicin, 2 mg vincristine and 100 mg prednisone (R-CHOP regimen) for six cycles. Importantly, the disease showed a rapid clinical response to treatment. At the beginning of the second cycle, the gluteal mass shrank at such an extent that it was no longer palpable during physical examination and the inguinal lymphadenopathy was significantly improved according to the imaging studies. After the third cycle, restaging was performed with computed tomography and showed complete response to treatment. The patient completed six cycles of treatment. She tolerated treatment well with no infusion-related reactions or other major toxicities to report. Diarrhea of grade one, grade one alopecia and a grade two thromboembolic event were reported, according to Common Terminology Criteria for Adverse Events. The laboratory hematological findings were unremarkable. Restaging after completion of therapy was also negative for residual disease. The patient has been followed up since then at regular time intervals with clinical, hematological, and imaging assessments. At 10 years after the completion of salvage chemotherapy for transformed DLBCL, there are no signs or symptoms of disease recurrence in terms of both DLBCL and WM.

Chronic lymphocytic leukemia/small lymphocytic lymphoma carry a risk for progression to DLBCL, which is known as Richter’s syndrome (4). WM can also undergo transformation into DLBCL. Since transformation of WM to a more aggressive type of lymphoma was described for the first time in the 1960s, similar cases have been recorded (8,9). Transformation into DLBCL is the most common type of high-grade lymphoma, while transformation into immunoblastic lymphoma, peripheral T-cell lymphoma, Hodgkin-type lymphoma and a plasma-type neoplasm have also been observed (10-13). In a retrospective study, Castillo et al. found that the risk of transformation of WM into DLBCL is 1% at 5 years, 2.4% at 10 years and 3.8% at 15 years (5).

When the disease involves transformation events that include mutations of MYC, BCL2 and/or BCL6, it is known as a ‘double hit’ or ‘triple hit’ lymphoma, according to the World Health Organization classification (14). When overexpression of MYC, BCL2 and BCL6 proteins is present without chromosomal translocation, it is called ‘double-expressor’ lymphoma. Moreover, these genes are considered as prognostic indicators (14). Hence, it is recommended that all patients with DLBCL should be tested for MYC, BCL2 and BCL6 rearrangements (14). Our patient was negative for Immunohistochemical expression of BCL2 and BCL6, while expression of MYC was not investigated.

Progression of WM to DLBCL is associated with poor prognosis. Lin et al. observed that eight out of nine (89%) patients died within 10 months of diagnosis of DLBCL, while one patient achieved complete response and remained alive after 8 months from the time of HT (4). The reported median survival was 5 months (4). In another study, Durot and colleagues found that among 77 patients with HT of WM to DLBCL the median progression-free survival and overall survival were 9 and 16 months, respectively (11). In another retrospective study, the median survival was 2.7 years after transformation to DLBCL(5). Taking all this into consideration, our patient had an outstanding clinical course and has remained alive for at least 10 years after the progression of WM to DLBCL with no evidence of disease recurrence.

The median time for WM transformation into DLBCL reportedly ranges from 4 to 6 years; HT is considered a complex and heterogeneous phenomenon and prognostic factors are still not well clarified (10,15). According to the literature, there is debate whether the transformation into DLBCL should be considered as being clonal-related or an independent second malignancy (16–18). Shiseki et al. found a complementarity-determining region 3 (CDR3) in the immunoglobulin heavy chain gene common to both DLBCL and WM cells, implying a probable clonal evolution as the etiological pathway of the transformation (16). In addition, a whole-exome sequencing study demonstrated recurrent mutations of Pim-1 proto-oncogene, serine/threonine kinase (PIM1), FRY-like transcription coactivator (FRYL) and hepatocyte nuclear factor-1-beta (HNF1B) genes present in transformed cells, indicating cooperation and interaction between the cell clones responsible for HT (19). The researchers also found a higher rate of mutations in the CD79B gene in patients with transformation into DLBCL, suggesting that it might be an indicator for HT (19). Concerning etiology unrelated to clonality, Epstein–Barr virus was described to have a critical role in the development of DLBCL in a patient with WM (20). However, other studies revealed that the majority of patients with transformed DLBLC were negative for Epstein–Barr virus, confirming the heterogeneity and complexity of DLBCL transformed from WM (4,5,11). An elevated LDH level, absence of response to treatment and time to progression of more than 5 years from WM diagnosis were also found to be negative prognostic factors (11). In our case, the patient had an LDH level of 691 U/l at the time of transformation, the progression occurred in less than 5 years from diagnosis of WM, and she had had a complete response to first-line salvage treatment. In order to make their prognostic model more accurate, Durot et al. developed a prognostic index for 2-year survival after WM transformation based on three unfavorable parameters: Platelet count <100×10⁹/l and previous treatment for WM, each scoring 1 point, and elevated LDH, scoring 2 points (21). Patients were classified as having a low transformation risk with zero or 1 point, intermediate risk with 2 or 3 points, and a high risk with 4 points, with 2-year survival rates being 81%, 47% and 21%, respectively (21). Our patient would be classified as having an intermediate risk (previously treated, 1 point; platelet count =287×10⁹/l, zero points; LDH=691 U/l, 1 point) with an expected 2-year survival of 47% according to this model. However, she unexpectedly exceeded these prognostic indications.

Previous exposure to nucleoside analogs has also been investigated as a risk factor for HT. Our patient received the DRC regimen for WM, including the alkylating agent cyclophosphamide. Some studies have found that there is an association between transformation following the administration of nucleoside analogs. Leleu et al. concluded that there were high rates of transformation events among patients pretreated with NA (12). Interestingly, Castillo et al. observed that HT occurred not only in patients with WM who were pretreated with nucleoside analogs, but also in those who were treatment-naïve. This suggested an inherent propensity for transformation (5). Similarly, in another study, prior use of purine analogues or alkylating agents was not statistically significant associated with the risk of HT (11). Hence, there is debate as to whether previous chemotherapy initiates or precipitates the genomic events leading to WM transformation.

Despite the fact that WM is a low-grade lymphoma with an indolent course, the rare event of transformation into DLBCL is characterized by a poor prognosis. Herein, we presented an exceptional case with long-term remission and survival, which underlines the need for large collaborative studies in order to discriminate patient subgroups with favorable prognosis.

The Authors declare no conflicts of interest in relation to this study.

Conceptualization: MAD; data curation: ES and INS; formal analysis: ES, MG; investigation: ES, INS, EK, ET, MAD and MG; methodology: MAD, MG; Project administration: EK and ET; supervision: MAD and MG; writing – original draft: ES and INS; writing–review and editing: all Authors. All Authors approved the final version of the article.