1. Several novel agents have shown efficacy against T cell lymphomas based on key clinical trials, including brentuximab vedotin, mogamulizumab, romidepsin, pralatrexate, lenalidomide, and bendamustine. 2. Brentuximab vedotin combined with chemotherapy resulted in high overall response rates of 85-100% in trials. Mogamulizumab demonstrated a 35% overall response rate for relapsed peripheral T cell lymphoma and cutaneous T cell lymphoma. 3. Romidepsin trials showed overall response rates of 25-38% in relapsed/refractory T cell lymphomas, with median durations

1. How do we best deploy novel agents
for T cell lymphoma – what have we
learned from key clinical trials: Should
they be employed upfront?
Yok-Lam Kwong
Department of Medicine
Queen Mary Hospital
Hong Kong

2. Disclosure
Nothing to disclose

3. 393 cases of lymphomas in 5
hospitals in Hong Kong in 2006

4. AsiaLymph project

5. Overview of the management of TCL
1. All TCL are not the same
2. Different subtypes of TCL may need different
treatment strategies
3. There may be intrinsic differences in some
types of TCL in different patient populations
4. Owing to relative rarity of these lymphomas,
large controlled trials have not been
conducted to evaluate the efficacy of different
treatment protocols

6. The three most common subtypes of
T-cell lymphomas
1. Peripheral T cell lymphoma, not
otherwise specified (PTCL-NOS)
2. Angioimmunoblastic T cell
lymphoma (AITL)
3. Anaplastic large cell lymphoma
(ALCL)

7. Problems of treatment of TCL
1. CHOP designed for conventional aggressive B-cell
lymphoma still used
2. Response is suboptimal, and remissions are
often short-lived
3. Dose dense or escalation on a CHOP backbone
has not been shown to be beneficial
4. Patient factors, including old age and poor
performance status, hinder effective treatment
5. High dose chemotherapy + autologous
hematopoietic stem cell transplantation (HSCT)
may improve outcome. However, many patients
do not actually make it to HSCT because of
disease progression

8. Novel drugs for T-cell lymphomas
Antibodies
Brentuximab vedotin (anti-CD30)
Mogamulizumab (anti-194)
Alemtuzumab (anti-CD52)
Small molecules targeting aberrations of molecules,
pathways or biological processes
Epigenetic: romidepsin
Anti-metabolite: pralatrexate
IMID: lenalidomide
Aurora kinase inhibitor: alisertib
Cytotoxic: bendamustine

9. Brentuximab vedotin

10. Design
Brentuximab vedotin 1.8 mg/kg (two cycles) + CHOP 21 (6 cycles)
or
- brentuximab vedotin 1.8 mg/kg plus CHP 21 (BV+CHP) (6 cycles)
- Responders: brentuximab vedotin (8 – 10 cycles)
- Primary objective: Safety
- Secondary end points: ORR, CR, PFS, and OS.
Result
B + CHOP: ORR: 85%; CR: 62%; 1-year PFS rate: 77%
No drop-out
BV+CHP: ORR: 100%, CR: 88%; 1-year PFS: 71% combination
treatment Drop-out rate: 12%
Conclusion
B + CHOP or
BV + CHP
Tolerable with good efficacy

11. Mogamulizumab

12. Mogamulizumab
Design
Mogamulizumab (1.0 mg/kg) weekly for 8 weeks
R/R CD194+ PTCL or CTCL
Primary end point: ORR
Secondary end point: safety, PFS, OS
Results
38 patients were enrolled, and 37 patients received
mogamulizumab
ORR: 35%; CR: 14%
PFS: 3.0 months
Adverse effects: hematologic, pyrexia
Conclusion
Mogamulizumab exhibited clinically meaningful antitumor
activity in patients with relapsed PTCL and CTCL

13. Mogamulizumab
experimental efficacy in NK/T-cell lymphoma
Kanazawa T et al Clin Cancer Res 2014

15. Design
Phase II study in R/R lymphoma
Alisertib: 50 mg twice daily for 7 days in 21-day cycles
Results
RESULTS:
Peripheral T-cell lymphoma; N=8
ORR: 50%, all CR

16. Lenalidomide

17. Lenalidomide
Design
Phase II single-agent lenalidomide
Refractory mycosis fungoides / Sézary syndrome
Results
32 patients with a median of 6 prior treatment regimens
ORR: 28%, all PR
Median survival: 43 months
Median PFS: 8 months
Median duration of response: 10 months
Transient flare reaction (TFR) appeared to correlate with clinical response
Decreased circulating CD25(+) T cells and CD4(+) T-cell numbers
Conclusion
Lenalidomide monotherapy demonstrated activity in refractory cutaneous
T-cell lymphomas, along with acceptable toxicity.

18. • Novel, potent, bi-cyclic class 1
selective histone deacetylase
inhibitor
• Approved in 2009 by US FDA for
patients with cutaneous T-cell
lymphoma who received at least
one prior systemic therapy and in
2011 for patients with PTCL who
received at least one prior
therapy
• Approval in PTCL was primarily
based on results from a phase 2,
single-arm, open-label study in
relapsed/refractory PTCL, GPI-06-
00021
18
Romidepsin

19. Romidepsin for PTCL – phase II
studies

20. Phase II Trial of Romidepsin in patients with T-Cell
Lymphomas
Piekarz et al.
Relapsed/refractory mature T-cell lymphoma
Romidepsin: 14 mg/m2 per day on days 1, 8 and 15 every 4
weeks.
Primary end point: overall response rate (ORR)
Secondary end points: duration of response (DOR),
toxicity profile

21. Results
45 patients; median age 59
Histology: PTCL-NOS (57%) and AITL (15%)
Stage IV: 72%
Median number of prior chemotherapies: 2 (1 – 6)
Prior HSCT: 38%
ORR: 38%
CR: 8 patients (18%)
PR: 9 patients (20%)
Overall median DoR: 8.9 months (2-27) [for CR pt – 29.7 months]
Most common non-haematological adverse effects
Nausea(51%); fatigue (40%)
Grade III/IV Haematological toxicities
Neutropenia:26%; thrombocytopenia: 15%
Infections:2%

22. Phase II Study of Romidepsin in Relapsed/Refractory
T-Cell Lymphomas
Coiffier et al.
Relapsed/refractory mature T-cell lymphoma that had
failed at least one standard regimen
Romidepsin: 14 mg/m2 per day on days 1, 8 and 15
every 4 weeks.
Primary end point: overall response rate (ORR)
Secondary end points: duration of response (DOR),
toxicity profile

23. Results
131 patients, 130 had histologically PTCL
Median number of prior therapies: 2 (1-8)
ORR: 25%, CR/Cru: 15%
Median DOR: 17 months
Grade ≥ 3 adverse events were
thrombocytopenia (24%), neutropenia (20%),
and infections (all types, 19%).

24. Phase II Study of Romidepsin in
Relapsed/Refractory T-Cell Lymphomas
Coiffier et al.

25. Phase II Study of Romidepsin in
Relapsed/Refractory T-Cell Lymphomas
Coiffier et al.

26. Conclusions
• Durable responses in patients with the more
common subtypes of relapsed/refractory PTCL
– Rate of CR/CRu similar across 3 subtypes
• 14% in PTCL-NOS to 19% in AITL and ALK-1 negative ALCL
– Nearly half (46%) of patients experienced disease
control
– Median DOR of 17 months, with responses ongoing up
to 34 months
• Thrombocytopenia (25%), neutropenia (18%), and
any infection (15%) were the most common ≥
grade 3 adverse events
– Only infections, thrombocytopenia, dyspnea, and
fatigue led treatment discontinuations in >1 patient.
FDA approval of Romidepsin in R/R T-cell lymphoma

28. Pralatrexate in Patients with Relapsed or Refractory
Peripheral T-Cell Lymphomas: PROPEL Study
O’Connor et al.
Relapsed/refractory mature T-cell lymphoma
Pralatrexate: 30 mg/m2 per week for 6 weeks in 7-week
cycle
Primary end point: overall response rate (ORR)
Secondary end points: duration of response (DOR),
toxicity profile

29. Results
111 patients; median age 58
Histology: PTCL-NOS (53%); ALK1-ve ALCL (15%); AITL (12%);
transformed MF (11%)
Median number of prior chemotherapies: 3 (1 – 12)
Prior HSCT: 16%
ORR: 29%
CR: 12 patients (11%)
PR: 20 patients (18%)
Overall median DoR: 10.1 months
Median PFS: 3.5 months
Median OS: 14.5 months
Most common non-haematological adverse effects
Mucositis(71%, Gr3/4:22%); fatigue (36%); oedema(34%)
Grade III/IV Haematological toxicities
Neutropenia:22%; thrombocytopenia: 33%
Sepsis:5%

30. Bendamustine

31. Results From a Prospective, Open-Label, Phase II Trial of
Bendamustine in Refractory or Relapsed T-Cell
Lymphomas: The BENTLY Trial
Damaj et al.
Histologically confirmed peripheral T-cell lymphoma
(PTCL) or cutaneous T-cell lymphoma
Disease progression afterone or more lines of prior
chemotherapy
Bendamustine: 120 mg/m2 per day on days 1, 2 every 3
weeks for six cycles.
Primary end point: overall response rate (ORR)
Secondary end points: duration of response (DOR),
progression-free-survival (PFS), and overall survival (OS).

32. Results
60 patients, 27 (45%) of whom were refractory to their last
prior chemotherapy
Histology: PTCL-NOS and AITL, advanced stage in 87% of
patients.
Median number of previous chemotherapy: 1 (1 – 3)
ORR: 50%
CR: 17 patients (28%)
PR: 13 patients (22%)
DoR: 3.5 months
PFS: 3.6 months
OS: 6.2 months
Grade III/IV adverse effects
Neutropenia:30%; thrombocytopenia: 24%;
Infections: 20%

33. First-line treatment of T-cell lymphoma
1. Novel chemotherapy regimens (gemcitabine,
platinum) that are applicable to older individuals
2. Targeted therapy involving either surface antigens
(CD30, CD194, CD52) or pathways shown to be
deranged
3. High dose chemotherapy and autologous HSCT
appears to be an attractive consolidation strategy
4. Small molecules with “30% response” (romidepsin,
pralatrexate, lenalidomide) are unlikely to be of major
impact in the first line management of patients

34. Case study
- 60+ year-old man
- Mycosis fungoides
(MF) for several
decades
- Civilian pilot
- Recent deterioration
with multiple bleeding
nodules
- Biopsy
- Large cell
transformation of MF

35. Case study
- Large cell transformation may herald a
poor outcome
- Could not continue with his job as a pilot
if under chemotherapy or radiotherapy
- Choices: romidepsin / alemtuzumab
- Romidepsin: 3 infusions in a month (D1, 8
and 15), with less monitoring needed
- Alemtuzumab: 3 times per week, requires
regular monitoring of CMV reactivation and
anti-infective prophylaxis

36. Case study
- Romidepsin given for 6 months: minimal
initial response, stable disease for 6
months followed by disease progression
- Alemtuzumab given
- Complete remission after 8 weeks of
treatment
- Alemtuzumab is actually remarkably safe
with appropriate anti-fungal, anti-bacterial
and anti-CMV prophylaxis

37. MF in LCT: CR with alemtuzumab

38. Acknowledgement
Patients
Haematology team, Queen Mary Hospital