Advances in the treatment of T cell lymphomas

Yok-Lam KwongDepartment of Medicine

Queen Mary Hospital

Mature T and NK cell malignancies

T-cell prolymphocytic leukaemiaT-cell large granular lymphocyte leukaemiaChonic lymphoproliferative disroder of NK cellsAggressive NK cell leukaemiasEpstein-Barr virus positive T-cell lymphoproliferative disease of childhoodAdult T-cell leukaemia/lymphomaExtranodal NK/T-cell lymphoma, nasal typeEnteropathy associated T-cell lymphomaHepatosplenic T-cell lymphomaSubcutaneous panniculitis like T-cell lymphomaMycosis fungoidesSezary syndromePrimary cutaneous CD30 positive T-cell lymphoproliferative disordersPrimary cutaneous peripheral T-cell lymphomasPeripheral T-cell lymphoma, NOSAngioimmunoblastic T-cell lymphomaAnaplastic large cell lymphoma, ALK positiveAnaplastic large cell lymphoma, ALK negative

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

Overview of the management of TCL

1. All TCL are not the same2. Different subtypes of TCL may need different

treatment strategies3. There may be intrinsic differences in some

types of TCL in different patient populations4. 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 / leukaemia2. Enteropathy associated T cell lymphoma3. Hepatosplenic T cell lymphoma4. Subcutaneous panniculitis-like T cell

lymphoma5. Mycosis fungoides6. Primary cutaneous T cell lymphomas

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)

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-CellLymphomas: The BENTLY TrialDamaj et al.

Histologically confirmed peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphomaDisease progression afterone or more lines of prior chemotherapyBendamustine: 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 chemotherapyHistology: 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 monthsPFS: 3.6 monthsOS: 6.2 months

Grade III/IV adverse effectsNeutropenia:30%; thrombocytopenia: 24%;Infections: 20%

Autologous HSCT

Schetelig et al Haematologica 2003;88:1272-1278

EBMT-based survey 29 patients with AITL in 16 transplant centersMedian age at HSCT: 53 years. Upfront: N=14 (48%)2nd / 3rd-line therapy: N=15 (52%) Conditioning regimens: BEAM: 16 patientsICE: 7 patientsOthers: 6 patientsTRM: 1 patientOutcomeCR increased from 45% before HSCT to 76% afterwardsMedian observation time: 5 years (range 2.5 to 10 years)14 patients have died (13 from progressive disease)15 patients are alive5-year overall survival: 44% (95% CI, 22% to 66%) 5-year event-free survival was 37% (95% CI, 17% to 57%)

AITL

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 alive51 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 yrProgressive free survival according to statusCR: 70% at 2 yr and 56% at 4 yrChemotherapy sensitive disease: 42% at 2 yr and 30% at 4 yrChemotherapy refractor disease: 23% at 2 yr and 23% at 4 yr1. HSCT offers the possibility of long-term disease-free

survival to patients with AITL. 2. Early transplantation is necessary to achieve optimal

results.

Yang et al Biol Blood Marrow Transplant 2009;15:118-25

Retrospective analysis of autologous HSCT64 patientsMedian age 44 years (range: 15-63 years)Risk categorizationa-IPI: 8 patients (12.5%) at high riskPIT: 16 patients (26.6%) at 2 – 3Median follow-up of 29.7 months3-year overall survival (OS): 53%3-year progression-free survival (PFS) 44.3% Risk factors on univariate analysis for OSpoor 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 OSNon-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 yearsMega-CHOP, responders received autologous HSCT28 patients (68%) received planned treatmentCR: 20 patients (50%), PR: 4 patients (10%)HSCT in 17 patients Median follow-up of 3.2 years for the whole cohort4 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

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 HSCTConditioning regimen: Cy – TBI83 patients were enrolled (PTCL-NOS: 32; AITL: 27)55 / 83 patients (66%) received autologous HSCT

progressive disease was the main reason for no HSCTOverall response rate after HSCT: 66% (56% CR and 8% PR). Median follow-up time of 33 months, 43 patients were alive3-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 HSCT2. Treatment needs to be improved so that more patients can

receive HSCT

PTCL-NOS , AITL

Reimer P et al. JCO 2009;27:106-113

Sieniawski et al Blood 2010;115:3664-3670

26 patients

EATL

5-year PFS: 52%5-year OS: 60%Significantly better than conventional CHOP treatment alone

Rodriguez et al Ann Oncol 2007;18:652-7

Retrospective analysis of T-cell lymphoma transplanted at CR174 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 months5-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 HSCT2. 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 lymphomaAITL: 11ALCL: 9NK/T: 7PTCL-NOS: 12Condition at HSCT: CR: 17; Non-CR: 12

Median follow up of 78 months5-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 patientsALCL: 18; PTCL-NOS: 17; AITL:9; NK/T: 7; Hepatosplenic: 2; ATLL: 1CR1 / PR1: 15CR2 / PR2+: 32Primary refractory: 11Median follow up: 5 years (range: 1.0 – 11.5 years)5-year progression free survival (PFS): 25%5-year overall survival: 48%

CR1/PR1 CR2/PR2+ Refractory5-yr PFS 51% 12% 0%5-yr OS 76% 40% 30%

T-cell lymphoma

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

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 categories34 patients had received ≥ 2 chemotherapies11 patients had failed a previous autologous HSCTMyeloablative conditioning: 25Reduced intensity conditioning: 20Sibling donors: 26None-sibling donors: 19Chemotherapy-sensitive disease: 27Chemotherapy-refractory: 18Non-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)

AITL

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 patientsConditioning: 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 months6 patients were alive and without evidence of lymphomaAllogeneic 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

EBMT60 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 disease40 patients had advanced disease

Sibling donor (N=45); MUD (N=15) Myeloablative: 16; Reduced intensity conditioning: 44T cell depletion: 25Overall 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 relapsesDLI might be effective in relapses

Mycosis fungoides and Sezary syndrome

Jacobsen et al Ann Oncol 2011;22:1608-13

Retrospective analysis52 patients Median age: 46 (24 – 72) yearsMyeloablative: 31, Reduced intensity conditioning: 21Nodal (AITL, PTCL-NOS, ALCL): 31Extranodal (NK/T, EATL, HSTCL, SPTCL, MF): 21Median follow-up of 49 monthsNon-relapse mortality: 27% (3 yr)Relapse: 43% (3 yr)3-year progression-free survival was 30%3-yr PFS: 45% for nodal3-yr PFS: 6% for extranodalOverall survival: 41% (3 year)

Allogeneic HSCT can produce long-term remissions in nodal T-cel;l lymphomas

T-cell 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

• 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

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Romidepsin

Romidepsin for PTCL – phase II studies

Phase II Trial of Romidepsin in patients with T-CellLymphomasPiekarz et al.

Relapsed/refractory mature T-cell lymphomaRomidepsin: 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 59Histology: 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 effectsNausea(51%); fatigue (40%) Grade III/IV Haematological toxicitiesNeutropenia:26%; thrombocytopenia: 15%Infections:2%

Phase II Study of Romidepsin in Relapsed/Refractory T-Cell LymphomasCoiffier et al.

Relapsed/refractory mature T-cell lymphomaRomidepsin: 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 61Histology: 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 monthsMedian PFS: 4 months [18 months for CR patients]

Most common non-haematological adverse effectsNausea(59%); fatigue (55%) Grade III/IV Haematological toxicitiesNeutropenia:18%; thrombocytopenia: 23%Infections:6%

• 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.

Conclusions

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 StudyO’Connor et al.

Relapsed/refractory mature T-cell lymphomaPralatrexate: 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 58Histology: 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 monthsMedian OS: 14.5 months

Most common non-haematological adverse effectsMucositis(71%, Gr3/4:22%); fatigue (36%); oedema(34%) Grade III/IV Haematological toxicitiesNeutropenia:22%; thrombocytopenia: 33%Sepsis:5%