Advances in the treatment of
T cell lymphomas
Yok-Lam Kwong
Department of Medicine
Queen Mary Hospital
Mature T and NK cell malignancies
T-cell prolymphocytic leukaemia
T-cell large granular lymphocyte leukaemia
Chonic lymphoproliferative disroder of NK cells
Aggressive NK cell leukaemias
Epstein-Barr virus positive T-cell lymphoproliferative disease of childhood
Adult T-cell leukaemia/lymphoma
Extranodal NK/T-cell lymphoma, nasal type
Enteropathy associated T-cell lymphoma
Hepatosplenic T-cell lymphoma
Subcutaneous panniculitis like T-cell lymphoma
Mycosis fungoides
Sezary syndrome
Primary cutaneous CD30 positive T-cell lymphoproliferative disorders
Primary cutaneous peripheral T-cell lymphomas
Peripheral T-cell lymphoma, NOS
Angioimmunoblastic T-cell lymphoma
Anaplastic large cell lymphoma, ALK positive
Anaplastic large cell lymphoma, ALK negative
393 cases of lymphomas in 5
hospitals in Hong Kong in 2006
0
1
2
3
4
5
6
7
8
9
10
11
99
HL
DLCL
FL
MZL/malt
MCL
LPC/LG
BL
CLL
NK/T
AILD
ALCL
PTLC
others
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
Specific subtypes of TCL that may require
different treatment strategies
1. Adult T cell lymphoma / leukaemia
2. Enteropathy associated T cell lymphoma
3. Hepatosplenic T cell lymphoma
4. Subcutaneous panniculitis-like T cell
lymphoma
5. Mycosis fungoides
6. Primary cutaneous T cell lymphomas
The three most common subtypes of Tcell lymphomas
1. Peripheral T cell lymphoma, not
otherwise specified (PTCL-NOS)
2. Angioimmunoblastic T cell
lymphoma (AITL)
3. Anaplastic large cell lymphoma
(ALCL)
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. 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
Bendamustine
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).
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%
Autologous HSCT
AITL
Schetelig et al Haematologica 2003;88:1272-1278
EBMT-based survey
29 patients with AITL in 16 transplant centers
Median age at HSCT: 53 years.
Upfront: N=14 (48%)
2nd / 3rd-line therapy: N=15 (52%)
Conditioning regimens:
BEAM: 16 patients
ICE: 7 patients
Others: 6 patients
TRM: 1 patient
Outcome
CR increased from 45% before HSCT to 76% afterwards
Median observation time: 5 years (range 2.5 to 10 years)
14 patients have died (13 from progressive disease)
15 patients are alive
5-year overall survival: 44% (95% CI, 22% to 66%)
5-year event-free survival was 37% (95% CI, 17% to 57%)
AITL
Kyriakou et al J Clin Oncol 2008;26:218-24.
Retrospective, EBMT multicenter study of 146 patients with
AITL undergoing autologous HSCT
PBHSC: 143 patients; BM: 3 patients
Conditioning: BEAM in most cases
Median follow-up of 31 months (range, 3 to 174 months)
95 patients (65%) remained alive
51 patients (35%) died (disease progression: 42, TRM: 9)
Non-relapse mortality at 1 yr: 5% and at 2 yr: 7%
Actuarial overall survival (OS): 67% at 2 yr and 59% at 4 yr
Cumulative incidence of relapse: 40% at 2 yr and 51% at 4 yr
Progressive free survival according to status
CR: 70% at 2 yr and 56% at 4 yr
Chemotherapy sensitive disease: 42% at 2 yr and 30% at 4 yr
Chemotherapy refractor disease: 23% at 2 yr and 23% at 4 yr
1. HSCT offers the possibility of long-term disease-free
survival to patients with AITL.
2. Early transplantation is necessary to achieve optimal
results.
PTCL-NOS
Yang et al Biol Blood Marrow Transplant 2009;15:118-25
Retrospective analysis of autologous HSCT
64 patients
Median age 44 years (range: 15-63 years)
Risk categorization
a-IPI: 8 patients (12.5%) at high risk
PIT: 16 patients (26.6%) at 2 – 3
Median follow-up of 29.7 months
3-year overall survival (OS): 53%
3-year progression-free survival (PFS) 44.3%
Risk factors on univariate analysis for OS
poor performance status, high lactate dehydrogenase (LDH) levels,
high a-IPI score, high PIT classes, failure to achieve complete
response (CR) at transplantation, and nonfrontline transplantation
Risk factors on multivariate analysis for OS
Non-CR at transplantation (hazard ratio [HR] 2.23; 95% CI 1.78-7.93)
2-3 PIT factors (HR 3.76; 95% CI 1.02-5.42)
PTCL-NOS
Mercadal et al Ann Oncol 2008;19:958-63.
Forty-one patients (men: 30; women: 11)
Median age: 47 years
Mega-CHOP, responders received autologous HSCT
28 patients (68%) received planned treatment
CR: 20 patients (50%), PR: 4 patients (10%)
HSCT in 17 patients
Median follow-up of 3.2 years for the whole cohort
4 yr progression free survival: 30%
4-yr overall survival: 39%
Prognostic factor: International Prognostic Index
Survivals were not different between patients receiving and not
receiving autologous HSCT
PTCL-NOS , AITL
Reimer et al J Clin Oncol 2009;27:106-13
Prospective multicenter study
CHOP (4–6 cycles)
CR and PR patients are eligible for autologous HSCT
Conditioning regimen: Cy – TBI
83 patients were enrolled (PTCL-NOS: 32; AITL: 27)
55 / 83 patients (66%) received autologous HSCT
progressive disease was the main reason for no HSCT
Overall response rate after HSCT: 66% (56% CR and 8% PR).
Median follow-up time of 33 months, 43 patients were alive
3-year overall survival for CR patients: 48%
3-year overall survival for HSCT patients: 71%
3-year overall survival for non-HSCT patients: 11%
1. Substantial impact on outcome for upfront autologous HSCT
2. Treatment needs to be improved so that more patients can
receive HSCT
Reimer P et al. JCO 2009;27:106-113
EATL
Sieniawski et al Blood 2010;115:3664-3670
26 patients
5-year PFS: 52%
5-year OS: 60%
Significantly better than conventional CHOP treatment alone
T-cell lymphoma
Rodriguez et al Ann Oncol 2007;18:652-7
Retrospective analysis of T-cell lymphoma transplanted at CR1
74 patients at a median age o f46 years.
Stage III / IV: 88%
B sympotms: 53%
Increased LDH: 52%
IPI (2–3 risk factors): 65%
PIT (> 2 risk factors): 14%
Median follow-up of 67 months
5-year overall survival (OS): 68%
5-year progression free survival (PFS): 63%.
Significant risk factor for OS and PFS on multivariate analysis
PIT > 2 risk factors
1. High risk patients benefited from autologous HSCT
2. Patients with unfavorable PIT scores did not appear to
benefit from autologous HSCT, and might be considered for
other innovative therapies
T-cell lymphoma
Numata et al Bone Marrow Tranplant 2010;45:311-316
Retrospective analysis
39 patients with T-cell lymphoma
AITL: 11
ALCL: 9
NK/T: 7
PTCL-NOS: 12
Condition at HSCT: CR: 17; Non-CR: 12
Median follow up of 78 months
5-year OS: 62.1%
CR patients - 5-year OS: 71.4%
Non-CR patients - 5-year OS: 27.3%
P=0.046
T-cell lymphoma
Chen et al Biol Blood Marrow Transplant 2006;14:741-7
Retrospective review
55 patients
ALCL: 18; PTCL-NOS: 17; AITL:9; NK/T: 7; Hepatosplenic: 2; ATLL: 1
CR1 / PR1: 15
CR2 / PR2+: 32
Primary refractory: 11
Median follow up: 5 years (range: 1.0 – 11.5 years)
5-year progression free survival (PFS): 25%
5-year overall survival: 48%
5-yr PFS
5-yr OS
CR1/PR1
51%
76%
CR2/PR2+
12%
40%
Refractory
0%
30%
Conclusions
1. Autologous HSCT improves outcome of patients with
T-cell lymphomas
2. The improvement, however, is seen mainly in patients
who attain a complete remission, or who have
chemotherapy sensitive disease in an up-front setting
3. The challenge therefore is to get the majority of
patients with T-cell lymphoma into a remission with
optimal chemotherapy
4. Patients with PIT of 2 or more risk factors do not
appear to benefit, and may be considered candidates
for experimental therapy
Allogeneic HSCT
AITL
Kyriakou et al J Clin Oncol 2009;27:3951-8
EBMT
45 patients undergoing allogeneic HSCT
Median age 48 years (range, 23 to 68 years)
Risk categories
34 patients had received ≥ 2 chemotherapies
11 patients had failed a previous autologous HSCT
Myeloablative conditioning: 25
Reduced intensity conditioning: 20
Sibling donors: 26
None-sibling donors: 19
Chemotherapy-sensitive disease: 27
Chemotherapy-refractory: 18
Non-relapse mortality (NRM): 18% (3m), 22% (6m), and 25% (12m)
NRM significantly correlated with poor performance status
Relapse rate: 16% (2 yr), 20% (3 yr)
Progressive free surival: 62% (1 yr), 53% (3 yr)
Overall survival: 66% (1 yr) and 64% (3 yr)
Mycosis fungoides and Sezary syndrome
Molina et al J Clin Oncol 2005;23:6163-71
8 patients
Failed a median of 7 (5 – 12) regimens
Marrow involvement confirmed by TCR rearrangement: 6 patients
Conditioning: Cy-TBI (N=3); BuCy (N=1); Flud/Mel (N=4)
Sibling donor (N=4); MUD (N=4)
CR: 8/8 (100%)
TRM: 2/8 (25%) (GVHD and RSV pneumonia)
Median follow up of 56 months
6 patients were alive and without evidence of lymphoma
Allogeneic HSCT may induce durable clinical, molecular, and
cytogenetic remissions in patients with advanced cutaneous T-cell
lymphoma refractory to standard therapies
Mycosis fungoides and Sezary syndrome
Duarte et al J Clin Oncol 2010;28:4492-9
EBMT
60 patients (men: 37, women: 23)
Median age: 46.5 years (range 22 – 66 years)
MF (n = 36); SS (n = 24)
Risk categories
44 had TMN stage IV disease
40 patients had advanced disease
Sibling donor (N=45); MUD (N=15)
Myeloablative: 16; Reduced intensity conditioning: 44
T cell depletion: 25
Overall survival: 66% (1 yr) and 54% (3 yr)
RIC gave higher OS
(RIC decreased NRM, without increaseing relapse)
Advanced-phase disease gave lower PFS and OS
(by increasing relapses)
Sibling better than MUD for PFS and OS
T-cell depletion increased relapses
DLI might be effective in relapses
T-cell lymphomas
Jacobsen et al Ann Oncol 2011;22:1608-13
Retrospective analysis
52 patients
Median age: 46 (24 – 72) years
Myeloablative: 31, Reduced intensity conditioning: 21
Nodal (AITL, PTCL-NOS, ALCL): 31
Extranodal (NK/T, EATL, HSTCL, SPTCL, MF): 21
Median follow-up of 49 months
Non-relapse mortality: 27% (3 yr)
Relapse: 43% (3 yr)
3-year progression-free survival was 30%
3-yr PFS: 45% for nodal
3-yr PFS: 6% for extranodal
Overall survival: 41% (3 year)
Allogeneic HSCT can produce long-term remissions in nodal T-cel;l
lymphomas
Conclusions
1. Allogeneic HSCT improves outcome of patients with
nodal T-cell lymphomas
2. Non relapse mortality is increased in patients with
poor performance status
3. In CTCL, HSCT from a sibling donor with reduced
intensity conditioning and performed early in the
disease cause leads to the best outcome
4. Efforts should continue for the definition of an optimal
primary chemotherapy
Romidepsin
• 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-0600021
29
Romidepsin for PTCL – phase II
studies
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
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%
Phase II Study of Romidepsin in Relapsed/Refractory TCell Lymphomas
Coiffier 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
Results
130 patients; median age 61
Histology: PTCL-NOS (53%); AITL (21%); ALK1-ve ALCL (16%)
Stage III/IV: 70%
Median number of prior chemotherapies: 2 (1 – 8)
Prior HSCT: 16%
ORR: 25%
CR: 19 patients (15%)
PR: 14 patients (11%)
Overall median DoR: 17 months
Median PFS: 4 months [18 months for CR patients]
Most common non-haematological adverse effects
Nausea(59%); fatigue (55%)
Grade III/IV Haematological toxicities
Neutropenia:18%; thrombocytopenia: 23%
Infections:6%
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
Pralatrexate
•
•
•
•
•
(RS)-10-propargyl-10-deazamminopterin
Anti-folate
Similar structure to methotrexate
Improved intracellular transport via reduced folate
carrier
Undergo greater polyglutamation, hence increased
intracelluar half-life of pralatrexate
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
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%