Current status and progress of lymphoma management in China

Lymphoma is a diverse group of malignancies that originates from either B, T or NK cells. According to the cancer statistics in 2013, the incidence of lymphoma was 4.2 per 100,000 and the mortality was 2.2 per 100,000 in mainland China [1], making it the eleventh most common cancer and the tenth leading cause of cancer death [2]. There are some differences in the distribution of lymphoma subtypes between East Asia and Western countries. The mature T/NK cell neoplasms display higher rates on the Asian continent than others [3, 4]. In mainland China, diffuse large B cell lymphoma (DLBCL) is still the most common subtype of lymphoma. Extranodal NK/T cell lymphoma, nasal type (ENKTL) is a common subtype and makes up 11–15% of all lymphoma [3, 4]. The treatment modalities for lymphoma include chemotherapy, radiotherapy, or their combinations. High-dose chemotherapy combined with autologous stem cell transplantation (HDC/ASCT) is still an important treatment strategy for high-risk or relapsed patients. Furthermore, advances in genetic analysis will provide new approaches in molecular targeted therapy. These new developments will improve the outcome of lymphoma patients.

Hodgkin lymphoma (HL) accounts for 8.6–13% of all lymphoma in mainland China [3, 4]. Currently, more than 80% of patients with newly diagnosed HL are likely to be cured. Patients with early-stage HL commonly receive abbreviated courses of chemotherapy followed by involved-field radiation therapy (IFRT). In contrast, patients with advanced-stage HL commonly receive prolonged courses of combination chemotherapy, with radiation therapy used only in selected cases.

For relapsed or refractory (R/R) patients who are ineligible for HDC/ASCT or those in whom HDC/ASCT have failed, treatment with brentuximab vedotin and anti-programmed death 1 (PD-1) antibodies could be considered. The phase II studies of pembrolizumab and nivolumab achieved overall response rates (ORR) of 69.0 and 66.3% in patients with R/R HL, respectively [5, 6]. In Hong Kong China, Chan et al. [7] indicated low-dose pembrolizumab was highly efficacious with minimal toxicity in five patients with R/R classical HL. Pembrolizumab was given with a median dose of 100 mg every 3 weeks and the ORR was 100% [7]. Nivolumab used in a low dose might similarly be efficacious. A patient received nivolumab at a fixed dose of 40 mg (about 0.55 mg/kg) every 2 weeks [8]. Complete remission (CR) was achieved after a cumulative dose of only 2.2 mg/kg [8]. Several anti-PD-1 antibodies are also developed in mainland China, such as IBI308 (NCT03114683), SHR-1210 (NCT0315425) and BGB-A317 (NCT03209973). Patients with R/R classical HL could participate in clinical trials to receive these anti-PD-1 antibodies treatment. The results of these clinical trials are worthy of expectation.

FL is the most prevalent indolent NHL. The management of FL is mainly determined by histologic grading, clinical stage and tumor burden. For patients with stage I and II, the IFRT is recommended and usually results in long-lasting remission. While for patients with stage III and IV, systemic therapy could be taken into consideration. The watchful waiting is still an option for patients without symptoms or/and low tumor burden.

Hou et al. [28] compared the efficacy and safety of RFT (rituximab, fludarabine and pirarubicin) with RCTVP (rituximab, cyclophosphamide, pirarubicin, vindesine and prednisone) in 248 indolent B cell NHL patients in mainland China. There were no statistically significant differences in OS between treatment groups [28]. Compared with RCTVP regimen, RFT regimen was associated with superior PFS both in previously untreated and R/R patients [28]. But grades 3 and 4 hematological adverse events were more common in the RFT group [28]. The efficacy and safety of rituximab and bortezomib were evaluated in 60 Chinese patients with R/R indolent B cell NHL, including FL grades 1–2 (n = 35), CLL (n=16) and marginal zone lymphoma (n = 9) [29]. The ORR was 70.0%, with a CR/CRu rate of 31.7% [29]. The 2-year OS and PFS rates of all patients were 75.0 and 41.0%, respectively [29].

Mantle cell lymphoma (MCL) may have two different subtypes, which are indolent or aggressive. Asymptomatic indolent MCL patients with low tumor burden can be closely observed, deferring therapy to the time of disease progression. Currently, the recommended first-line treatment for young transplant eligible patients is cytarabine/rituximab-based combination chemotherapies followed by HDC/ASCT [30, 31]. The bendamustine and rituximab (BR) regimen is becoming an popular treatment option among the elderly population [31, 32].

Novel agents such as bortezomib, lenalidamide and ibrutinib are now available for the treatment of R/R disease. Bruton’s tyrosine kinase (BTK) has been defined as a major mediator on B cell-receptor signaling pathway. A phase II study to evaluate the efficacy and safety of BGB-3111, a BTK inhibitor developed in mainland China, in patients with R/R MCL is ongoing (NCT03206970). Another BTK inhibitor CT-1530 is in phase I study for patients with R/R B cell NHL, CLL or Waldenstrom’s macroglobulinemia (NCT02981745). Wu et al. [33] discovered a selective and potent BTK/mitogen-activated protein kinase interacting kinase (MNK) dual kinase inhibitor (QL-X-138) through a structure-based drug design approach. QL-X-138 exhibits covalent binding to BTK and non-covalent binding to MNK [33]. Compared to the BTK kinase inhibitor (PCI-32765) and the MNK kinase inhibitor (cercosporamide), QL-X-138 displays a stronger anti-proliferative effect against a variety of B cell cancer cell lines [33]. In Hong Kong China, Gill et al. [34] found oral arsenic trioxide-based regimen was effective with minimal toxicity for R/R MCL. Thirty-nine patients ineligible for HDC/ASCT were treated with arsenic trioxide, chlorambucil and ascorbic acid [34]. The ORR was 49% with a CR rate of 28% [34]. The median PFS and OS were 16 and 38 months, respectively [34].

Peripheral T cell lymphoma (PTCL) makes up 23–27% of all NHL cases in mainland China [3, 4], much higher than that in Western countries of 10–15% [35]. The most common subtype of PTCL in mainland China is ENKTL, followed by PTCL not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma (ALCL) and angioimmunoblastic T cell lymphoma (AITL) [3, 4]. PTCL represents a relatively rare group of heterogeneous NHL with a very poor prognosis. The anthracycline-based conventional chemotherapy remains standard treatment, but most patients are either refractory to initial therapy or eventually relapse. A systematic review and meta-analysis of front-line anthracycline-based chemotherapy for PTCL patients showed the CR rate ranged from 35.9% for enteropathy-type T cell lymphoma (ETTL) to 65.8% for ALCL [36]. The 5-year OS rate was 38.5% for all PTCL patients [36]. Frontline consolidation treatment with HDC/ASCT was associated with favourable outcomes in patients with PTCL [37, 38, 39, 40]. CR to induction chemotherapy was a prognostic factor for survival [37, 38, 39, 40].

In mainland China, some new regimens were explored as first-line therapy against PTCL. Li et al. [41] compared the efficacy and safety of GDPT (gemcitabine, cisplatin, prednisone and thalidomide) with standard CHOP regimen for patients with newly diagnosed PTCL. 103 patients were randomly allocated into the GDPT group or CHOP group [41]. Patients receiving GDPT chemotherapy achieved significant higher 2-year PFS rate (57 vs 35%, p = 0.0035) and OS rate (71 vs 50%, p = 0.0001) than those receiving CHOP chemotherapy [41]. The CR rate (52 vs 33%, p = 0.0001) and the ORR (67 vs. 49%, p = 0.046) in the GDPT group were higher than in the CHOP group [41]. Haemocytopenia was the predominant adverse effect [41]. Endostatin (endostar) is an endogenous inhibitor of angiogenesis. Zhang et al. [42] explored the efficacy and safety of recombinant human endostatin in combination with CHOP in 15 PTCL patients. The ORR was 80%; 53.3% of patients achieved CR [42]. The CR rate was 100% (3/3) in AITL patients compared to only 36.4% (4/11) in PTCL-NOS patients [42]. The 5-year PFS and OS rates were 53 and 60%, respectively [42]. Grade 3–4 neutropenia was 86.7% [42].

In recent years, a variety of interesting novel combinations are also emerging. Several studies have evaluated the addition of a novel agent to CHOP-(like) chemotherapy in the front-line therapy [51, 52, 53]. The clinical trials of Chidamide combined with CHOP chemotherapy for newly diagnosed PTCL (NCT02809573) and Chidamide combined with ICE chemotherapy for R/R PTCL (NCT02856997) are ongoing.

ENKTL is specific subtype of PTCL with higher prevalence in East Asia. It comprises approximately 50% of PTCL in mainland China and only accounts for 4.3–5.1% in north America and Europe [3, 4, 35]. The upper respiratory tract, especially the nasal region, is the most common site of invasion [54]. A multicenter study of 1383 Chinese patients with NKTCL showed 92% of patients presented with early-stage disease [55]. The 5-year OS rate was 60.3% for all patients [55]. Stage, age, Eastern Cooperative Oncology Group performance status, lactate dehydrogenase and primary tumor invasion were important prognostic factors [55]. Jiang et al. [56] found Chinese patients with DDX3X mutations presented a poor prognosis. DDX3X mutants exhibited loss of suppressive effects on cell-cycle progression in NK cells, transcriptional activation of NF-κB and MAPK pathways [56].

Standard treatment for ENKTL patients has not been established. For patients with localized ENKTL, radiotherapy is widely administered and could achieve CR rates of up to 70% [57, 58]. However, radiotherapy alone seems inadequate for high-risk patients and the optimal treatment is combined chemoradiotherapy for these patients. In mainland China, some “sandwich” protocols, with earlier RT after an initial 2–3 cycles of chemotherapy followed by further “consolidation” cycles of chemotherapy, achieved good efficacy. The frontline use of “sandwich” chemotherapy regimens included LVP (l-asparaginase, vincristine and prednisone), GELOX (gemcitabine, oxaliplatin and l-asparaginase), P-Gemox (pegaspargase, gemcitabine and oxaliplatin) and LVDP (l-asparaginase, cisplatin, etoposide and dexamethasone) [59, 60, 61, 62]. The ORR were 86.4–96.3%, and the CR rates were 74.1–86.8% [59, 60, 61, 62]. Other studies demonstrated the DICE-L (cisplatin, ifosfamide, etoposide, dexamisone and l-asparaginase) chemotherapy followed by IFRT and intensity-modulated radiation therapy followed by GDP (gemcitabine, dexamethasone and cisplatin) chemotherapy were both effective for the treatment of newly diagnosed stage I to II ENKTL [63, 64].