Dr CK Das

AIIMS

Update in Lymphoma

Phase II Trial of R-CHOP Plus Bortezomib Induction Therapy Followed By Bortezomib

Maintenance for Previously Untreated Mantle Cell Lymphoma: SWOG 0601

Abstract :149

Back ground

• Mantle cell lymphoma (MCL) :no consensus for the optimal induction regimen.

• Bortezomib: mantle cell lymphoma who have received at least one prior therapy

• Bortezomib: combination with chemotherapy may be synergistic.

• maintenance rituximab after R-CHOP led to a survival benefit in MCL

Kluin-Nelemans et al N Engl J Med. 2012 Aug 9;367(6):520-31

N=68

stage III, IV, or bulky stage II

MCL

6# R-CHOP

bortezomib 1.3 mg/m2 on D1/D4

Bortezomib maintance

At least SD

SalvagePD• median age of 61

(range 36-85)

• 80% male

• 98% stage III-IV15% bulky disease,

• 37% elevated LDH

bortezomib maintenance therapy 1.3 mg/m2 days 1, 4, 8, and 11 every 3 months for 8 cycles

Results

• median follow-up time :5.9 years

• induction toxicities: 48% grade 4 hematologic toxicities,6% grade 4 non-hematologic

• maintenance therapy:13% grade 3 non-hematologic toxicities.

• Grade 3 PN 8% -induction 2% -maintenance bortezomib, and there was no grade 4 neuropathy.

Therapy 2-year PFS 2-year OS 5 years PFS 5 Year OS

VeR-CHOP 62%, 85%. 28% 66%.

R-CHOP 30%

MIPI Score low intermediate high

N 45% 43% 12%

2 yr PFS 72% 61% 25%

“Combination R-CHOP with bortezomib followed by maintenance bortezomib doubled the historical 2 year PFS rate, with nearly one third of patients achieving a PFS of 5 years or longer”

Abstract:148

Frontline Therapy with the RiBVD Regimen Elicits High Clinical and Molecular Response Rates and Long PFS in Elderly Patients Mantle Cell Lymphoma (MCL); Final Results of a Prospective Phase II Trial By the LYSA Group

Back ground

• RCHOP/21 cycles followed by Rituximab maintenance is considered the standard of care for first line therapy in elderly MCL

• complete clinical (CR) and molecular responses (MR) to therapy remain suboptimal(CR rate 30-35%, MR after 8 cycles 67 %).

• Regimen combining Rituximab and Bendamustine and more recently proteasome inhibitor Bortezomib (Velcade®) with CHOP regimen (VcR-CAP) demonstrated superior CR rates and PFS compared to R-CHOP

• prospective phase II trial

• The primary objective :improve the median PFS by 6 months over the current 18 months PFS obtained with RCHOP

• secondary objectives :prognostic impact of molecular and FDG-PET responses on survival

• inclusion criteria: patients aged 65 or older with a diagnosis of MCL : stage II-IV, PS < 3, no other neoplasm, no active HIV or HBV or HCV infections, no renal or cardiac dysfunction, no diabetes.

Results

PR/CR/CRu4#RiBVD

2#RiBVD

Salvage therapy

RQ-PCR IGH VDJ

FDG-PET Deauville

Score

>65 yr MCL

N =76

Median age 73 (64-83), sex ratio M/F = 2 (49/25), AAstage II/III-IV = 4/70, PS 0-1/2 = 63/11, MIPIscorelow/intermediate/high= 3/19/50

CR/CRu :74% (n=55) PR rate was 9% (n=7), 2 SD, 4 PD and 5 died .

MR rate>6 months on blood 83% (43/50) or bone marrow 74 % (32/43). At 24 months PFS was 69% and OS 80%.

Toxicities :grade 3 or 4 neutropenia 51% and thrombocytopenia 36% 3 or 4 fatigue (19%), neuropathy (14%), cardiac (7%) or febrile neutropenia (5%)

The MIPI score (high vs low/int) and blood MR after 6 cycles were the only two statistically prognostic factors for PFS and OS

The median follow-up is 21 months

“With 74% of CR/CRu, a 2 year PFS of 69% and 86% of patients achieving an MRD negative status in the blood after 6 cycles, the RiBVD regimen is identified as a highly effective, well tolerated, first line treatment for elderly MCL patients”

Brentuximab Vedotin in Combination with Bendamustine for Patients with Hodgkin Lymphoma who are Relapsed or Refractory after Frontline Therapy

• Abstract 293

Back ground

relapsed/refractory Hodgkin lymphoma salvage chemotherapy autologous stem cell transplantpts who CR with salvage chemotherapy prior to ASCT. Improved outcomes

standard salvage therapy(ICE/DHAP/MINE/mBEAM): Variable CR rates (19%-60%) and significant toxicities

BENDAMUSTINE in HL:Relapsed refractory setting(ORR 52% CR 33%)

BRENTUXIMAB :Post ASCT relapsed Hodgkin lymphoma and relapsed refractory HL(ORR 73% with a median duration of 6.7 months ,CR) rate 32 %)

58% female median age of 35 yrs

relapsed disease 58% and primary refractory disease42%

median of 13.1 m post diagnosis

Auto HSCT

N-24

BV 1.8 mg/kg on D 1

+bendamustine90 mg/m2 on

Days 1 and 2 of 3-week cycles

N=55

HL

median of 2 cycles(range, 1-6)

median number of CD34+ : 4.3 x106 median of 2 apheresis sessions (range, 1-5)

results

• CR rate : 82% (28/34 pts evaluable for response)

• overall objective response rate (CR and PR) 94% (32/34 pts).

• The majority of CRs (24/28 pts) were achieved after 2 cycles of combination therapy.

• Stem cell mobilization and collection was considered adequate in all 24 pts who underwent the procedure.

• The median number of CD34+ : 4.3 x106 (range, 1.7- 16.0 x106) median of 2 apheresis sessions (range, 1-5)

• 0 SAEs, 1 treatment discontinuation, and 2 Grade 3 toxicity

(dyspnea (13%), flushing (13%), and chills (11%).)

• brentuximab +bendamustine :manageable safety profile

• The very high CR rate with combination treatment compares favorably with historical data.

• “A promising approach for maximizing responses prior to ASCT in ptswith HL who are either relapsed or are refractory after frontline therapy”

371 Pediatric ALL-like Therapy in Adults with T-Cell Lymphoblastic Lymphoma: Results of the GRAALL-LYSA- LL03 Study

Back ground

• using paediatrics inspired protocols in Adult ALL yielded good results –GRALLL-2003 study

• disease-free survival of about 65%-75% and an overall survival rate of 60%.

N=155

N=121

N=5

N=30

Total RelapseN=34

Total death N=37

patients with high-risk disease (defined as need for a second-

induction salvage course and/or CNS

disease

131 T-LL patients

median age, 33 years; M/F ratio 4

95% mediastinalenlargement, 5% CNS involvement,

119 patients (91%) reached CR/CRu

30 patients needing a salvage course

34 relapsed.

46 Death(37 relapse; 5 induction; 3 TRM and 1 other)

Response evaluation was based on CT scan

5 years DFS 71% EFS 61% and OS 66%,

The lymphoma IPI-score had no prognostic value

increased serum LDH level associated with a significant decrease in EFS and OS

need for a salvage course was not associated with shorter DFS in CR/CRu patients.

4-gene risk classifier (NOTCH1, FBXW7, N/K-RAS and PTEN status)

high-risk genetic profile was predictive of shorter EFS (HR = 14.3 [1.9 – 107.8])

DFS (HR = 9.5 [1.2 – 74.3])

OS (HR = 11.5 [1.5 – 87.5])

• Good outcome in T-LL patients treated with a pediatric-inspired ALL strategy.

• The NOTCH1/FBXW7/RAS/PTEN T-ALL risk classification is a strong prognostic factor in these T-LL patients.

• Allogeneic SCT did not appear to significantly influence the outcome of selected T-LL patients