Treatment Options of Mature, Nodal T-Cell Lymphomas

  

    
Salvage    treatment 
    
ORR 
    
CR 
    
grade    3/4 toxicities 
    
comment 
  
  

    
pralatrexate    [20]
    
29%
    
11%
    
thrombocytopenia    33%
    
AITL    had fewer response
  
  

    
romidepsin    [21]
    
38%
    
18%
    

    

  
  

    
belinostat    [23,24]
    
26%
    
11%
    
thrombocytopenia    13%
    
AITL    had ORR 46%
  
  

    
brentuximab    vedotin [25]
    
86%
    
57%
    
neutropenia    21%
    

  
  

    
bendamustin    [28]
    
50%
    
28%
    
neutropenia    30%
    

  
  

    
mogamulizumab    [29]
    
50%
    
31%
    
lymphopenia    74%
    
only    CCR4+ TCL
  
  

    
mogamulizumab    [30]
    
35%
    
14%
    
lymphopenia    73%
    
only    CCR4+ TCL
  
  

    
zanolimumab    [31]
    
24%
    
10%
    
lymphopenia    10%
    
only    CD4+ TCL
  
  

    
lenalidomide    [32]
    
30%
    
0%
    
thrombocytopenia    42%
    

  
  

    
lenalidomide    [33]
    
22%
    
11%
    
thrombocytopenia    20%
    

  
  

    
alisertib    [35]
    
50%
    

    
neutropenia    63%
    

  
  

    
crizotinib    [37,38]
    
91%
    
27%
    

    
only    ALK+ ALCL
  
  

    
gemcitabin    [39]
    
55%
    
30%
    

    

  
  

    
bortezomib    [40]
    
67%
    
13%
    
neutropenia    13% (only grade3)
    

  
  

    
everolimus    [44]
    
44%
    
6%
    
anaemia    25%
    

  
  

    
duvelisib    [45]
    
47%
    
13%
    

    

  
  

    
nivolumab    [46]
    
17%
    

    

    
ORR: 40    % in PTCL patients
  
  

    
bortezomib-gemcitabin    [51]
    
36%
    
27%
    

    

  
  

    
gemcitabin-romidepsin    [52]
    
30%
    
15%
    
thrompocytopenia    60%
    

  
  

    
gemcitabin-dexamethason-cisplatin    [53]
    
72%
    
48%
    
neutropenia    16%
    

  
  

    
(ORR: overall response rate, CR: complete    response)
      
 
  

Table 2: New salvage treament options.

FDA approved new drugs

Pralatrexate: Pralatrexate, an antimetabolite drug, which selectively enters cells through reduced folate carrier type 1, FDA approved this drug for the treatment of patients with R/R PTCL in 2009. O’Connor, et al. conducted a dose/schedule finding study in R/R lymphomas [19]. ORRs were 10% and 54% in patients with B-cell and T-cell lymphomas respectively. All eight patients who achieved CR had T-cell lymphoma. PROPEL was the first international prospective study of novel therapeutic agents in patients with PTCL [20]. One hundred and nine heavily pretreated PTCL patients recevied the drug, ORR and CR/CRu (CR uncorfirmed) rates were 29% and 11%. Patients with AITL had fewer responses (1 out of 13 patients) than other subtypes. Patients who received only CHOP before pralatrexate, the ORR was 47% and the CR rate was 30%, suggesting that the response rate might be higher if pralatrexate is used earlier, not in heavily pretreated patients. Grade 3/4 adverse events (AEs) were thrombocytopenia (33%), mucositis (22%), neutropenia (22%) and anemia (18%) [20].

Romidepsin: Romidepsin is a new potent class I selective histone deacetylase (HDAC) inhibitor, which was was approved by the FDA in 2011 for the treatment of PTCL in patients who had received ≥ 1 prior therapies. A phase II trial used romidepsin in 47 PTCL patients with various histologic subtypes [21]. Among 45 evaluable patients in this study ORR was 38% and 18% had CR. The most common AEs were nausea (51%), thrombocytopenia (47%), leukopenia (47%), granulocytopenia (45%), fatigue (40%) and anemia (40%) [21]. One hundred and thirty patients were treated with romidepsin in another phase II trial. Most patients had PTCL-NOS (n = 69), AITL (n = 27), or ALK-negative ALCL (n = 21). The ORR was 25% and 15% had CR. The most common grade 3/4 AEs were thrombocytopenia (24%), neutropenia (20%) and infections (19%).

Single-arm, phase Ib/II study used CHOP plus romidepsin as first line treatment in 37 PTCL patients. Among 35 evaluable patients the ORR was 69% and CR was 51%. Three patients had early cardiac events, including two myocardial infarctions and one acute cardiac failure. The most frequent serious AEs were febrile neutropenia 14%, physical health deterioration and lung infection 11%. Grade 3/4 neutropenia were detected in 89% of patients and grade 3/4 thrombocytopenia in 78% [22].

Belinostat: Belinostat is a pan-HDAC inhibitor, which was investigated in R/R PTCL patients in the BELIEF trial. One hundred and twenty-nine patients received belinostat, among the 120 evaluable patients, the ORR was 26%, CR was 11%. ORR was the best, 46% in AITL. The most common grade 3/4 AEs were thrombocytopenia (13%), neutropenia (13%) and anemia (10%) [23,24]. Based on the results of this study FDA approval belinostat in 2014 for treatment of R/R PTCL patients.

Other new therapeutic options

Monotherapy: Brentuximab vedotin: Brentuximab vedotin (BV) is an immunoconjugate of an antitubulin agent and a CD30-specific immunoglobulin G1 monoclonal antibody. Fifty eight ALCL patients were treated with BV in a phase II study, ORR was 86% and CR was 57%. The most common AEs were peripheral sensory neuropathy (41%), nausea (40%), fatigue (38%) and pyrexia (34%). Based on the results of this study, the FDA and European Medicines Agency, in 2011 and 2012, approved the use of BV for patients with systemic ALCL after failure of ≥ 1 multi-agent chemotherapy regimen [25]. Another phase II trial of BV in 35 patients showed ORR of 41% and no correlation between CD30 expression per central review and response was observed [26]. Grade 3/4 adverse events were neutropenia (21%), thrombocytopenia (14%) and peripheral sensory neuropathy (12%) [27].

Bendamustine: Bendamustine is an alkylating agent with antimetabolite effect. In the BENTLY trial, 60 patients with CTCL and PTCL (mainly AITL and PTCL-NOS) were treated with bendamustine. The ORR was 50% and CR was 28%. The most frequent grade 3/4 AEs were neutropenia (30%), thrombocytopenia (24%) and infections (20%) [28].

Mogamulizumab: Mogamulizumab is an anti- CC chemokine receptor 4 (CCR4) monoclonal antibody. Mogamulizumab depletes CCR4-positive regulatory T cells and help to enhance antitumor activity. Twenty-seven relapsed agressive CCR4-positive T cell lymphoma patients received mogalizumab in a phase II study. ORR was 50% and CR was 31%. The most common grade 3/4 AEs were lymphopenia (74%), leukocytopenia (30%), thrombocytopenia (19%), neutropenia (19%) and rash (19%) [29]. Another phase II study of mogamulizumab at the same dose in 38 patients, of whom 37 were evaluable with relapsed CCR4-positive PTCL or CTCL, reported an ORR of 35%, including 14% with a CR. The most common grade 3/4 AEs were lymphopenia (73%) and neutropenia (19%) also [30].

Zanolimumab: Zanolimumab is an anti-CD4 monoclonal antibody. Twenty-one R/R CD4+ PTCL patients were treated with zanolimumab ORR was 24% and CR was 10%. Grade 3 AEs were lymphopenia (10%), infusion-related AEs (10%) and arthralgia (5%) [31].

Lenalidomide: Lenalidomide is an immunomodulatory drug which inhibits vascular endothelial growth factor (VEGF), activation of natural killer cells and T lymphocytes and modulates various cytokines such as tumor necrosis factor-α, interleukin-12 and interferon-γ. A phase II study used lenalidomid in 24 patients. Among the 23 evaluable patients, ORR was 30%, but there are no patients in CR. The most common grade 3/4 AEs were thrombocytopenia (42%), neutropenia (21%), dyspnea (17%), febrile neutropenia (17%), pain (17%) and pneumonitis (17%) [32]. EXPECT was an phase II study which included 54 patients with R/R PTCL. ORR was 22%, CR/CRu was 11%. Most common grade 3/4 AEs were thrombocytopenia (20%), gastrointestinal disorders (17%), neutropenia (15%) and infections (15%) [33].

Alisertib: Aurora A kinase (AAK) is a mitotic kinase which is upregulated in PTCL [34]. Alisertib is an oral selective AAK inhibitor, a phase II trial evaluated its efficacy in refractory T-cell and B-cell lymphomas. ORR was 50% in eight PTCL patients. Grade 3/4 AEs were neutropenia 63%, leukopenia 54%, anemia 35%, thrombocytopenia 33% and stomatitis 15% [35]. Thirty-seven R/R PTCL patients were treated in another phase II intergroup trial (SWOG 1108). Among ORR was 30% Grade 3/4 AEs were neutropenia (32%), anemia (30%), thrombocytopenia (24%), febrile neutropenia (14%), mucositis (11%) and rash (5%). Based on these results, a randomized phase III trial of alisertib versus the investigator’s choice (pralatrexate or gemcitabin monotherapy) was designed for patients with relapsed PTCL, but study was closed earlier due to alisertib was not more effective than other treatments [17,36].

Crizotinib: Crizotinib is an oral small-molecule tyrosine kinase inhibitor of ALK, which has been FDA approved for the treatment of lung cancer. Eleven refractory ALK+ lymphoma patients (9 ALCL) received crizotinib ORR was 91%, CR was 27%. There were no grade 3/4 toxicity [37,38]. A clinical trial is ongoing in ALK+ ALCL patients with use of crizotinib.

Gemcitabin: Gemcitabin is a nucleoside analog, which inhibits DNA replication and repair. Other nucleoside analogs are pentostatin, cladribine, fludarabine, clofarabine, forodesine and nelarabine. These agents are cytotoxic to both proliferating and non-proliferating cells. Gemcitabine, cladribine and fludarabine have shown efficacy in PTCL and gemcitabine is the most effective in PTCL. NCCN guidelines recommends as second-line therapy for patients with relapsed PTCL [5]. Twenty R/R PTCL-NOS patients were treated with gemcitabine [39]. ORR was 55% and CR was 30%. There was no grade 3/4 hematological toxicity.

Bortezomib: Bortezomib is a proteasome inhibitor. Fifteen relapsed CTCL or PTCL patients got in a phase II trial. ORR was 67% and CR was 13%. The most common grade 3 toxicities were neutropenia (13%), thrombocytopenia (13%) and sensory neuropathy (13%) and there was no grade 4 toxicity [40]. The NCCN has recommended bortezomib as a second-line therapy for patients without intention to proceed to transplantation [5].

AG-221: Isocitrate dehydrogenase 2 (IDH2) mutations have been identified in solid tumors and hematologic malignancies eg. glioblastoma, acute myeloid leukemia and myelodyplastic syndromes. AML and MDS patients reached 56% ORR with IDH2 inhibitor (AG- 221) in a phase I study [41]. IDH2 mutations are frequent in AITL (20-45%) so IDH2 inhibitor can be effective in this lymphoma type [42,43].

Everolimus: The mTOR pathway is responsible for TCL proliferation. Everolimus is a mTORC1 inhibitor. Sixteen relapsed TCL were treated with everolimus in a phase II study. The ORR was 44% and CR was 6%. Grade 3/4 AEs were anaemia (25%), leukopenia (19%) and thrombocytopenia 13%) [44].

Duvelisib: Duvelisib (IPI-145) is an oral phosphatidilinozitol 3-kinase inhibitor (PI3K). Sixteen PTCL patients received duvelisib. ORR was 47% and CR was 13% [45].

Nivolumab: Programmed death-1 (PD-1) immune checkpoint pathway help tumour cells to avoid immune surveillance. Nivolumab is a PD-1 inhibitor, which is approved by FDA in the treatment of Hodgkin lymphoma. The activity of nivolumab in other lymphoid malignancies also has been presented [46]. Responses also were seen in 23 patients with TCL, with superior response seen in patients with PTCL. The ORR for patients with TCL was 17%, there was no CR. The ORR in patients with PTCL was 40% and was 15% in those with cutaneous T cell lymphoma [46].

New combination therapy: Brentuximab vedotin-CHP: BV and CHP combination therapy was examined in a phase I open-label study as frontline treatment in patients with CD30-positive PTCL. Twenty-six patients were treated, all of them achieved an objective response and CR was 88%. Grade 3/4 AEs were febrile neutropenia (31%), neutropenia (23%), anemia (15%) and pulmonary embolism (12%) [47]. A randomized phase III trial is ongoing, comparing BV and CHP combination with CHOP alone.

Alemtuzumab-CHO(E)P: Alemtuzumab is an anti-CD52 monoclonal antibody that causes depletion of CD4 and CD8 T cells as well as B cells. Alemtuzumab combined with CHO(E)P was investigated 29 patients as consolidation therapy in a phase II trial, CR rate was 58.5%. Grade 3/4 toxicities were infections (14%) [48]. Another phase II study investigated combination of alemtuzumab, fludarabine, cyclophosphamide and doxorubicin in 27 PTCL patients’ first line treatment and 11 R/R PTCL patients. ORR was 61%, with a CR of 39%. The most frequent grade 3/4 toxicities were leukopenia (95%) and thrombocytopenia (58%). Cytomegalovirus (CMV) reactivation was detected in 12 patients, but only two had CMV disease. Treatment-related deaths occurred in six newly diagnosed and one R/R patient [49]. Alemtuzumab-based therapy was active in PTCL but was associated with significant toxicity.

Bortezomib-CHOP: Forty six patients were treated with bortezomib plus CHOP as firstline treatment. ORR was 76% and CR was 65%. Outcome was similar to CHOP alone. Grade 3/4 neutropenia was in 41% of patients, febrile neutropenia in 30% and thrombocytopenia in 11% [50].

Bortezomib-gemcitabin: Bortezomib with gemcitabin was used in 16 R/R PTCL patients in a phase I/II ORR was 36% and CR was 27% [51].

Gemcitabin-romidepsin: A phase II trial was conducted in R/R PTCL. Twenty patients were treated with combination of gemcitabine plus romidepsin (GEMRO regimen). The ORR was 30%, 3 patients had CR. Two-year OS was 50% and PFS 11.2%. Sixty percent of the patients had grade ≥3 thrombocytopenia, half of the patients had neutropenia. The majority of non-hematological toxicities were mild and transient. There was no treatment-related death or toxicity which led to treatment interruption [52].

Gemcitabin-dexamethason-cisplatin: CISL trial investigated GDP (gemcitabin-dexamethason-cisplatin) protocoll in 25 R/R PTCL patients. ORR was 72% and CR was 48%. Grade 3/4 neutropenia (16%) and thrombocytopenia (13%) was occurred [53].

Romidepsin-CHOP: Romidepsin plus CHOP was investigated in a phase Ib/II study in first line treatment of 14 PTCL patients. ORR was 78%, CR was 66% [54].

Everolimus-CHOP: A phase II study investigated the efficacy of everolimus plus CHOP therapy for first-line treatment in PTCL. Thirty patients were treated, ORR was 90%, CR was 57%. The CR rate was different among subtypes, all AITL patients had CR whereas PTCL-NOS and ALK-negative ALCL patients showed 63% and 29% CR. Eighty percent of patients suffered grade 3/4 neutropenia and 60% of patients had grade 3/4 thrombocytopenia [55].

Pirarubicin-COP: Pirarubicin is a derivative of doxorubicin, which is less cardiotoxici than the doxorubicin. A retrospective study analysed 56 patients with PTCL-NOS who had received pirarubicin plus COP or CHOP treatment. Twenty-nine patients received pirarubicin and COP and 27 received CHOP. CR was 52% in both groups and there were no significant differences in 3-year OS and PFS rates. Pirarubicin and COP led significantly better prognosis in low risk patients [56].

Alemtuzumab-CHOP: Phase I trial was conducted in 20 CD52- positive PTCL patients. ORR and CR were 68% and 37%. Grade 3/4 neutropenia were in 70% of the patients and thrombocytopenia 20% [57].

Pralatrexate-CEOP: First-line cyclophosphamide, etoposide, vincristine and prednisone (CEOP) alternated with pralatrexate treatment was used in a phase 2 study. Thirty-three PTCL patients were treated with this protocol. ORR was 70% and 52% of the patients had CR. The 2-year OS and PFS were 60% and 39%, so this new combination did not improve outcomes compared to historical data using CHOP. The most frequent grade 3/4 AEs were anaemia in 27% of patients and febrile neutropenia in 18% of patients [58].

Pixantrone-etoposid-bendamustin: Pixantrone is an analogue of mitoxantrone, but it has fewer cardiotoxic effect. A phase 1/2 study (pixantrone, etoposide and bendamustin) is ongoing in B- and T-cell lymphoma patients.

NCCN recommends in second-line therapy as single-agent treatment: clinical trials, belinostat, romidepsin, pralatrexat and brentuximab vedotin in CD30+ PTCL, or combination therapy (eg. DHAP, ESHAP, ICE). Other alternative regimens (eg. bendamustin, gemcitabin, lenalidomid) can also be used ( Figure 1)[5].

    

    

    Figure 1:  Treatment options (other than clinical trials) in mature, nodal T cell
lymphoma.