Modified conditioning regimen with chidamide and high‐dose rituximab for triple‐hit lymphoma

Abstract Triple‐hit lymphoma (THL), which is classified into high‐grade B‐cell lymphoma with rearrangements of MYC, BCL2 and BCL6, presents aggressive biological behaviour. High‐dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto‐HSCT) is considered to be one of the recommended treatment options. Here, we reported 3 THL patients received carmustine, etoposide, cytarabine and cyclophosphamide (BEAC) combined with chidamide and high‐dose rituximab conditioning regimen and found that this conditioning showed good efficacy and tolerance without increase of adverse events.

Modified BEAC conditioning regimen added with chidamide 10 mg/d, −14d~−2 d and rituximab 500 mg/m 2 , −1d, +8d was given to her followed with auto-HSCT. The time to neutrophil and platelets engraftment showed no extension. No severe adverse events (AEs) were observed. She is still in CR state till now without relapse.
The duration of remission time for her is over 5 years.
FISH showed Bcl-2, Bcl-6 and c-MYC rearrangements. A diagnosis of DLBCL, GCB subtype, triple-hit lymphoma was made. Then, she received six cycles of R-DAEPOCH and achieved CR.
Modified BEAC conditioning regimen with chidamide 10 mg/d, −15d~−3d and rituximab 500 mg/m 2 , −1d, +8d was given to her followed by auto-HSCT. Neutrophil and platelet engraftment restored on +14d and +18d. There was no complication in the aplastic period except neutropenic fever. She is still in CR state till now without relapse. The duration of remission time for her is four and a half years.

| C A S E 3
A 56-year-old male with multiple flat masses in his skin of right limb, chest, abdomen and back was administered in our hospital in A systematic meta-analysis revealed that first-line treatment with R-EPOCH significantly reduced the risk of progression compared with R-CHOP; however, OS was not significantly different across treatment approaches. 3 It was reported that DHL/THL patients who did not achieve CR had significantly prolonged overall survival (OS) after HSCT consolidation therapy, suggesting that THL patients may benefit from HSCT. 4 Landsburg et al revealed that consolidative auto-HSCT was not associated with improved 3year OS. 5 A phase III randomized study (SWOG S9704) found that there was a trend favouring outcomes after consolidative auto-HSCT in double protein-expressing lymphoma (DPL) and MYC protein overexpressing patients, whereas all DHL patients have died irrespective of HSCT. 6 A Japanese study compared auto-HSCT and allogeneic hematopoietic stem cell transplantation (allo-SCT) in DHL patients and found that auto-HSCT may be effective for chemosensitive and relapsed or refractory DHL patients. Since F I G U R E 1 CT scan showed a mass in ampullary and head of pancreas most patients received allo-HSCT not in CR, the outcome of allo-HSCT was unsatisfactory due to high non-relapse mortality (NRM) and early relapse. 7 It is reported that HDAC inhibitors can overcome congenital and acquired rituximab resistance in patients with B-cell lymphoma and augment the cytotoxic activity of rituximab by upregulating the expression of CD20 in lymphoma cells. Chidamide, a new HDAC inhibitor, could be a potent therapeutic agent to treat DLBCL by inducing the DLBCL cell apoptosis by inhibiting the HDACs/STAT3/ Bcl-2 pathway. 8 Hu et al reported that chidamide combined with lenalidomide could achieved excellent outcomes in heavily pretreated aggressive DLBCL patients. 9 Rituximab revolutionized the treatment landscape of B-NHL.
However, whether B-NHL patients could benefit from rituximabbased conditioning regimen are still unknown. Jagadeesh et al reported that the addition of high-dose rituximab (>375 mg/m 2 ) to the BEAM conditioning regimen had no impact on transplantation outcomes. 10 However, Shi et al demonstrated that high-dose rituximab followed with auto-HSCT is a feasible and promising treatment for relapsed or refractory DLBCL. 11 Chen et al reported that primary central nervous system (CNS) DLBCL patients gained perfect efficacy receiving high-dose rituximab (1000 mg/m 2 ) followed with auto-HSCT. 12 Laport et al revealed that high-dose rituximab conditioning conferred high CR rates, low relapse/progression incidence and excellent survival probabilities in heavily pretreated patients. 13 BEAC was one of the most commonly used conditioning regimens before auto-HSCT, given its optimal efficacy and tolerability. However, more tolerated and efficacious modified conditioning regimens aiming to obtain a higher anti-lymphoma activity are still indispensable, especially for DHL/THL. In our study, 2 patients showed good response to chemotherapy and achieved CR before auto-HSCT. BEAC combined with chidamide and high-dose rituximab conditioning regimen did not extend the time to completed haematopoietic engraftment. No other significant extrahaematological toxicities emerged, suggesting good tolerance. Both of them are still in CR state. However, the third patient died after auto-HSCT, suggesting that patients who were insensitive to chemotherapy had poor prognosis.

CO N FLI C T O F I NTE R E S T
The authors declare that they have no conflicts of interest.

CO N S E NT FO R PU B LI C ATI O N
Not applicable.

E TH I C S A PPROVA L A N D CO N S E NT TO PA RTI CI PATE
This study was subject to approval by the Research Ethics Committee of Tianjin Medical University Cancer Institute and Hospital.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data sets used and/or analysed during the current study are available from the corresponding author on reasonable request.