DISCUSSION
HGBCL with MYC and BCL2 and/or BCL6 rearrangements is an aggressive LPD.1 A definitive diagnosis requires collection of morphologic and immunophenotypic evaluations of suspicious tissue. Approximately 60% of patients with HGBCL have translocations in MYC and BCL2, 20% have MYC and BCL6 translocations, and the remaining 20% have MYC, BCL2 and BCL6 translocations (triple-hit disease).1
The MYC and BCL gene rearrangements are thought to synergistically drive tumorigenesis, leading to accelerated lymphoma progression and a lesser response to standard multiagent chemotherapy than seen in diffuse large B-cell lymphoma.1-3 Consequently, there have been several attempts to increase treatment efficacy with intense chemotherapy regimens, namely DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab), or by adding targeted agents, such as ibrutinib and venetoclax to a standard R-CHOP (rituximab with reduced cyclophosphamide, doxorubicin, vincristine, and prednisone) backbone.4-7 Though the standard choice of therapy for fit patients harboring HGBCL remains controversial, these aggressive regimens at standard doses are typically difficult to tolerate for patients aged > 80 years.
Patients with immunosuppression are at higher risk for developing LPDs, including aggressive B-cell non-Hodgkin lymphomas such as diffuse large B-cell lymphoma. These patients are frequently classified into 2 groups: those with underlying autoimmune conditions (RA-associated LPDs), or those who have undergone solid-organ or allogeneic hematopoietic stem-cell transplants, which drives the development of posttransplant LPDs (Table).8-11 Both types of LPDs are often EBER positive, indicating some association with Epstein-Barr virus infection driven by ongoing immunosuppression, with knowledge that this finding is not absolute and is less frequent among patients with autoimmune conditions than those with posttransplant LPD.8,12
For indolent and early-stage aggressive LPDs, reduction of immunosuppression is a reasonable frontline treatment. In fact, Tokuyama and colleagues reported a previous case in which an methotrexate-associated EBER-positive early-stage diffuse large B-cell lymphoma responded well to methotrexate withdrawal.13 For advanced, aggressive LPDs associated with immunosuppression, a combination strategy of reducing immunosuppression and initiating a standard multiagent systemic therapy such as with R-CHOP is more common. Reducing immunosuppression without adding systemic anticancer therapy can certainly be considered in patients with EBER-negative LPDs; however, there is less evidence supporting this approach in the literature.
A case series of patients with EBER-positive double-hit HGBCL has been described previously, and response rates were low despite aggressive treatment.14 The current case differs from that case series in 2 ways. First, our patient did not have EBER-positive disease despite having an HGBCL associated with RA and methotrexate use. Second, our patient had a very rapid and excellent partial response simply with methotrexate discontinuation. Aggressive treatment was considered initially; however, given the patient’s age and performance status, reduction of immunosuppression alone was considered the frontline approach.
This case indicates that methotrexate withdrawal may lead to remission in patients with double-hit lymphoma, even without clear signs of Epstein-Barr virus infection being present. We are not sure why our patient with EBER-negative HGBCL responded differently to methotrexate withdrawal than the patients in the aforementioned case series with EBER-positive disease; nevertheless, a short trial of methotrexate withdrawal with repeat imaging 4 to 8 weeks after discontinuation seems reasonable for patients who are older, frail, and seemingly not fit for more aggressive treatment.
CONCLUSIONS
For our older patient with RA and biopsy-proven, stage IV EBER-negative HGBCL bearing MYC and BCL6 rearrangements (double hit), discontinuation of methotrexate led to a rapid and sustained marked response. Reducing immunosuppression should be considered for patients with LPDs associated with autoimmune conditions or immunosuppressive medications, regardless of additional multiagent systemic therapy administration. In older patients who are frail with aggressive B-cell lymphomas, a short trial of methotrexate withdrawal with quick interval imaging is a reasonable frontline option, regardless of EBER status.
