Update on treatment for lymphoma, Lymphoma Support Ireland meeting - feb 2011 - pc

Update on Treatment for Lymphoma Lymphoma Support Ireland Meeting 19-02-2011 Dr. Greg Korpanty Medical Oncology Registrar Beaumont Hospital

What is Lymphoma ?
Lymphoma is a malignant transformation of lymphocytes (white blood cells)
Lymphocytes (B-cell and T-cell)
involved in immune response to infection, transplanted organs or foreign bodies
They are carried through lymphatic system as well as the blood, so lymphoma can start both in lymph nodes and spread anywhere throughout the body
Lymphoma can also start in ANY solid organ of the body
- GI tract
- skin
- lung
- heart
- CNS
- bones

CLP, common lymphoid precursor; BLB, pre-B lymphoblast; DN, CD4/CD8 double-negative pro-T cell; DP, CD4/CD8 double-positive pre-T cell; GC, germinal-center B cell; MC, mantle B cell; MZ, marginal zone B cell; NBC, naive B cell; PTC, peripheral T cell.

Classification of Lymphoma
Histopathological
NHL vs HL
B vs T-cell
CD20 +ve vs CD20 -ve
high grade vs low grade
Clinical
aggressive vs indolent
stage I vs IV
Molecular
c-myc gene translocation

Histopathological classification Lymphoma Non-Hodgkin Lymphoma 85% Hodgkin Lymphoma 15% B-cell NHL 80% T-cell NHL 20%

New cases: 65,540 Deaths: 20,210

Etiology
The exact etiology is unknown
Immune suppression
congenital (Wiskott-Aldrich syndrome)
organ transplant (immunosupressants)
HIV infection
increasing age
DNA repair defects
ataxia telangiectasia
xeroderma pigmentosum

Etiology
Chronic inflammation
Helicobacter pylori (gastric NHL)
Chlamydia psittaci (ocular, adnexal NHL)
Viral causes
EBV - Burkitt’s lymphoma
HTLV-I - T cell leukemia-lymphoma
HTLV-V - cutaneous T cell lymphoma
Hepatitis C

Diagnosis
History
fatigue
weight loss
fevers
night sweats
lump
Physical examination
lump(s)
enlarged liver, spleen
pale skin; bruises

Diagnosis
Blood tests
- FBC, R/L
- LDH , uric acid
Bone marrow biopsy
Imaging
- CXR
- CT N/T/A/P
- PET/CT scan

Treatment
Multidisciplinary approach:
- pathology
- medical oncology
- haematology
- radiation oncology
- radiology
Chemotherapy
- combination CT
- high dose CT + Bone marrow Tx
Radiotherapy

Follicular (indolent) lymphoma

Follicular lymphoma (FL)
10-15% in Stage I or II
potentially curable
local radiotherapy
85-90% Stage III or IV
incurable but treatable
treatment provides symptoms control

Management of FL
Observation – watch & wait
Local radiotherapy
Systemic chemotherapy
IV agents: CHOP, CVP, fludarabine, cladribine.
oral agents: chlorambucil and prednisone
Monoclonal antibody against CD20
Rituximab
Bexxar, Zevalin
(Stem cell or bone marrow transplant) ?

Rituximab

Bexxar, Zevalin

When we treat FL
Symptoms
- fatigue
- pain
Organ dysfunction
Cosmetic considerations
Low Hgb, Plts, WBC

Bendamustine + Rituximab vs R-CHOP in Indolent NHL
Regimen: bendamustine 90 mg/m 2 on Days 1 and 2 + Rituximab on Day 1 every 28 days
Rummel M, et al. ASH 2009. Abstract 405. Parameter Bendamustine + Rituximab R-CHOP P Value CR, % 39.6 30.0 .0262 Median PFS, mos 54.9 34.8 .00012

Bendamustine + Rituximab vs R-CHOP in Indolent NHL: AEs Rummel M, et al. ASH 2009. Abstract 405. Parameter Bendamustine + Rituximab R-CHOP P Value Grade 3/4 neutropenia, 10.7 46.5 < .0001 Grade 3/4 leukocytopenia, 12.1 38.2 < .0001 G-CSF use 4 20 < .0001 Infections, n 96 127 .0025 Erythema, n 42 23 .0122 Allergic skin reaction, n 40 15 .0003 Paresthesias, n 18 73 < .0001 Stomatitis 16 47 < .0001

GELA PRIMA Phase III Study: Rituximab Maintenance in FL CHOP x 6 + Rituximab x 8 CVP x 8 + Rituximab x 8 FCM x 6 + Rituximab x 8 Patients with previously untreated grade 1-3 FL (N = 1200) CR, PR RANDOMI ZED Maintenance Rituximab 375 mg/m 2 q2mo x 2 yrs Observation Available at: http://prima.gela.org.

Rituximab Maintenance for 2 Yrs: PRIMA Phase III Study Salles GA, et al. ASCO 2010. Abstract 8004. At 2 yrs, rituximab arm had significant improvements in time to next antilymphoma treatment and RR PFS 95% CI P Value Rituximab, % 82 (2 yrs) 78-86 < .0001 Observation, % 66 (2 yrs) 61-70 Grade 3/4 Adverse Events Rituximab Overall: 23% Neutropenia: 4% Infections: 4% Observation Overall: 16% Neutropenia: < 1% Infections: < 1%

Preliminary Analysis of Rituximab vs Watch and Wait in Asymptomatic FL Pts Ardeshna K, et al. ASH 2010. Abstract 6. Progression-free survival 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 1 2 3 4 5 Proportion of Patients Progression Free Yrs From Randomization 3-Yr PFS W + W: 33% R4: 60% R4 + RM: 81% W + W R4 R4 + RM Events 108 33 33 Pts 181 83 189

Bendamustine in Rituximab-Refractory NHL (Phase III Single-Arm Study)
Pivotal evaluation of bendamustine for treatment of rituximab-refractory, indolent, B-cell NHL
Bendamustine 120 mg/m 2 given on Days 1 and 2 every 21 days
Kahl BS, et al. Cancer. 2010;116:106-114.

ORR
Patients with ≥ 1 dose of bendamustine (n = 100): 75%
Patients with ≥ PR to last regimen (n = 51): 88%
Patients with no response to last regimen (n = 36): 64%
Response rates did not significantly differ by
histology
Median PFS: 9.3 mos
Bendamustine in Rituximab-Refractory NHL: Phase III Results Kahl BS, et al. Cancer. 2010;116:106-114.

Rituximab ± Bortezomib in Relapsed, Rituximab-Naive or -Sensitive FL Coiffier B, et al. ASH 2010. Abstract 857. Rituximab 375 mg/m 2 Cycle 1: Days 1, 8, 15, 22 Cycles 2-5: Day 1 only Rituximab + Bortezomib Rituximab 375 mg/m 2 Cycle 1: Days 1, 8, 15, 22 Cycles 2-5: Day 1 only + Bortezomib 1.6 mg/m 2 Cycle 1: Days 1, 8, 15, 22 25 Wks Patients with relapsed, rituximab-naive or -sensitive FL (N = 670)

Results Coiffier B, et al. ASH 2010. Abstract 857. Response, n (%) Bort + Ritux (n = 315) Ritux (n = 324) P Value ORR 199 (63) 160 (49) < .001 CR 79 (25) 59 (18) .035 SD 78 (25) 120 (37) -- PD 38 (12) 44 (14) -- Overall durable response rate 159 (50) 124 (38) .002 Durable CR 76 (24) 54 (17) -- 100 90 80 70 60 50 40 30 20 10 0 48 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 Patients Without Event (%) Mos Median PFS (95% CI) 11.0 mos (9.1-12.0) 12.8 mos (11.5-15.0) Rituximab: Bortezomib-rituximab : HR: 0.822 (0.681-0.991; P = .039)

Grade ≥ 3 Toxicities
Peripheral neuropathy
Overall: 16% vs 1% in bortezomib + rituximab and rituximab pts, respectively
Most PN events were reversible in bortezomib pts
Coiffier B, et al. ASH 2010. Abstract 857. Adverse Event, n (%) Bortezomib + Rituximab (n = 334) Rituximab (n = 339) Constipation 1 (< 1) 0 Diarrhea 25 (7) 0 Fatigue 5 (1) 0 Nausea/Vomiting 10 (3) 2 (1) Neutropenia 37 (11) 15 (4) Febrile neutropenia 5 (1) 3 (1) Infections 36 (11) 15 (4) Herpes zoster 12 (4) 1 (< 1) Peripheral sensory neuropathy 9 (3) 0 Thrombocytopenia 10 (3) 2 (1)

Post-Treatment FDG PET-CT as Predictor of PFS in FL: PRIMA Analysis
PRIMA database reviewed to identify PET-CT scans at staging and assessment for response post induction
277 scans (160 patients of total PRIMA population [N = 1217])
Posttreatment PET shown to an independent predictor and stronger than other prognostic factors
Trotman J, et al. ASH 2010. Abstract 855. Mos 60 0 6 12 18 24 30 36 42 48 54 1.0 0.8 0.6 0.4 0.2 0 Probability of PFS 74% 32% PET negative PET positive HR = 3.5 (95% CI: 2.0-6.1) P < .0001

Diffuse Large B-Cell Lymphoma (DLBCL)

Management of DLBCL
Stem cell or bone marrow transplant
Radiotherapy (palliative)

CHOP(R) Chemotherapy C yclophosphamide (Cytoxan) H ydroxydaunorubicin (Adriamycin) O ncovin (vincristine) P rednisone R ituximab

LNH 03-2B: R-ACVBP vs R-CHOP in Treatment-Naive Pts With CD20+ DLBCL
Patients aged 18-59 yrs
No radiotherapy in either treatment arm
Récher C, et al. ASH 2010. Abstract 109.

LNH 03-2B Study: Results Récher C, et al. ASH 2010. Abstract 109. 3-Yr PFS 1.0 Survival Probability 0.8 0.6 0.4 0.2 0 0 12 24 36 48 60 72 Mos P = .0015; HR: 0.482 R-ACVBP R-CHOP 3-Yr OS 1.0 Survival Probability 0.8 0.6 0.4 0.2 0 0 12 24 36 48 60 72 Mos P = .0071; HR: 0.439 R-ACVBP R-CHOP

T-Cell Lymphoma

Romidepsin in Progressive or Relapsed PTCL: Phase II Data
Novel, bicyclic histone deacetylase inhibitor approved for cutaneous
T-cell lymphoma
Current trial: single-arm, international, open-label phase II study (N = 131)
Romidepsin given at 14 mg/m 2 (4-hr IV) on Days 1, 8, and 15 of a 28-day cycle for 6 cycles
Coiffier B, et al. ASH 2010. Abstract 114. Response, n (%) IRC (N = 130) Investigators (N = 130) Objective response 34 (26) 38 (29) Complete response 17 (13) 21 (16) SD 32 (25) 22 (17) PD 64 (49) 70 (54)

Hodgkin’s Lymphoma

1798 - 1866 Thomas Hodgkin

HL
One-seventh as common as NHL
Highly treatable and curable, even when disseminated
Presence of Reed-Sternberg cell is mandatory for diagnosis.

Management of HL
Radiotherapy
Stem cell/bone marrow transplant

A driamycin (doxorubicin)
B leomycin
V inblastine
D acarbazine

E2496: ABVD vs Stanford V ± Radiation Therapy in Advanced Hodgkin Lymphoma Gordon LI, et al. ASH 2010. Abstract 415. ABVD 6-8 cycles modified IFRT 36 Gy only in patients with massive mediastinal disease (n = 404) Stanford V - MOPPEBVCAD 12 wks’ chemotherapy, modified IFRT 36 Gy to sites > 5 cm in max transverse dimension (n = 408) *Defined as mass ≥ 1/3 maximum intrathoracic diameter on standing PA chest x-ray. Previously untreated patients with histologically proven HL, advanced or locally extensive disease, massive mediastinal adenopathy* (N = 812)

E2496: Results
ABVD remains standard of care
5-yr FFS: higher for ABVD
Similar rates of toxicity between treatment arms
Higher rates of grade 3 lymphopenia sensory neuropathy with Stanford V
Gordon LI, et al. ASH 2010. Abstract 415. Measure, % ABVD Stanford V Response* CR + CCR 72.0 69.0 PR 7.7 7.4 SD 7.9 10.3 PD < 1.0 2.0 5-yr FFS* 73.0 71.0 5-yr OS* 88.0 87.0

Brentuximab Vedotin (SGN-35) in Relapsed/ Refractory Hodgkin’s Lymphoma
Brentuximab vedotin anti-CD30 monoclonal antibody
Primary endpoint: overall objective response rate (CR + PR) by independent review facility
Secondary endpoints: OS and PFS
Chen R, et al. ASH 2010. Abstract 283. Brentuximab vedotin 1.8 mg/kg Administered every 21 days on outpatient basis over 30 min for a max of 16 cycles until at least SD achieved; patients restaged at cycles 2, 4, 7, 10, 13, 16 Follow-up every 12 wks Patients with relapsed/ refractory CD30+ disease, 12 yrs of age or older, measurable disease ≥ 1.5 cm, ECOG PS 0-1, previous ASCT (N = 102)

Brentuximab Vedotin (SGN-35) in Relapsed/Refractory HL: Results
94% of patients achieved tumor reduction
Median treatment cycles: 9 (range: 1-16)
Chen R, et al. ASH 2010. Abstract 283. Wks 70 0 10 20 30 40 50 60 Patients Free of PD or Death (%) 100 90 80 70 60 50 40 30 20 10 0 OS PFS per investigator PFS per IRF Median, Wks Not reached 39.1 25.1 Response, % Inv. IRF ORR 72 75 CR 33 34 PR 38 40 SD 27 22 PD 0 3 Not evaluable 1 1

Novel Therapies Under Investigation in Lymphomas

CAL-101
CAL-101: isoform-selective inhibitor of PI3K [1]
Dosed at 50 mg BID up to 350 mg BID at 50-mg increments in a phase I trial in 55 patients with relapsed/refractory NHL
Partial responses seen at all doses
Grade ≥ 3 adverse events included neutropenia, lymphopenia, and thrombocytopenia
1. Kahl BS, et al. ASH 2010. Abstract 1777.

KW-0761
KW-0761: anti-CCXR4 monoclonal antibody
Given at 1.0 mg/kg for 8 weekly infusions to 27 patients with relapsed T-cell lymphoma in a phase II trial
ORR: 14 patients (7 CR, 7 PR)
Ishida T, et al. ASH 2010. Abstract 285.

Conclusions
1. Selected group of DLBCL patients may benefit from more aggressive treatment than standard R-CHOP chemotherapy
2. New agents are being evaluated for relapsed disease (conjugated monoclonal Abs and small molecule oral drugs) with promising results in early phase clinical trials

Thank You

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Update on treatment for lymphoma, Lymphoma Support Ireland meeting - feb 2011 - pc

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