Update on Treatment for Lymphoma

Lymphoma Support Ireland MeetingLymphoma Support Ireland Meeting19-02-201119-02-2011

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 bodiesThey are carried through lymphatic system as well as the blood, so lymphoma can start both in lymph nodes and spread anywhere throughout the bodyLymphoma 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.

http://www.cancer.ie/index.php

Classification of Lymphoma

HistopathologicalNHL vs HLB vs T-cellCD20 +ve vs CD20 -vehigh grade vs low grade

Clinicalaggressive vs indolentstage I vs IV

Molecular c-myc gene translocation

Histopathological classification

Lymphoma

Non-Hodgkin Lymphoma85%

Hodgkin Lymphoma15%

B-cell NHL80%

T-cell NHL20%

New cases: 65,540Deaths: 20,210

Etiology

The exact etiology is unknown

Immune suppressioncongenital (Wiskott-Aldrich syndrome)organ transplant (immunosupressants)HIV infectionincreasing age

DNA repair defectsataxia telangiectasiaxeroderma pigmentosum

Etiology

Chronic inflammationHelicobacter pylori (gastric NHL)Chlamydia psittaci (ocular, adnexal NHL)

Viral causesEBV - Burkitt’s lymphomaHTLV-I - T cell leukemia-lymphomaHTLV-V - cutaneous T cell lymphomaHepatitis C

Diagnosis

Historyfatigueweight lossfeversnight sweatslump

Physical examinationlump(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- radiologyChemotherapy- combination CT- high dose CT + Bone marrow TxRadiotherapy

Follicular (indolent) lymphoma

Follicular lymphoma (FL)

10-15% in Stage I or IIpotentially curable

local radiotherapy

85-90% Stage III or IVincurable but treatable

treatment provides symptoms control

Management of FL

Observation – watch & waitLocal radiotherapySystemic chemotherapy

IV agents: CHOP, CVP, fludarabine, cladribine.oral agents: chlorambucil and prednisone

Monoclonal antibody against CD20RituximabBexxar, Zevalin

(Stem cell or bone marrow transplant) ?

Rituximab

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/m2 on Days 1 and 2 + Rituximab on Day 1 every 28 days

Parameter Bendamustine + Rituximab

R-CHOP P Value

CR, % 39.6 30.0 .0262

Median PFS, mos 54.9 34.8 .00012

Rummel M, et al. ASH 2009. Abstract 405.

Bendamustine + Rituximab vs R-CHOP in Indolent NHL: AEs

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

Rummel M, et al. ASH 2009. Abstract 405.

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

RANDOMIZED

Maintenance Rituximab 375 mg/m2 q2mo x 2 yrs

Observation

Available at: http://prima.gela.org.

Rituximab Maintenance for 2 Yrs: PRIMA Phase III Study

PFS 95% CI P Value

Rituximab, % 82 (2 yrs) 78-86 < .0001

Observation, % 66 (2 yrs) 61-70

Salles GA, et al. ASCO 2010. Abstract 8004.

At 2 yrs, rituximab arm had significant improvements in time to next antilymphoma treatment and RR

Grade 3/4 Adverse Events

RituximabOverall: 23%Neutropenia: 4%Infections: 4%

ObservationOverall: 16%Neutropenia: < 1%Infections: < 1%

clinicaloptions.com/oncologyLymphomas/Hodgkin Disease

Preliminary Analysis of Rituximab vsWatch and Wait in Asymptomatic FL Pts

Ardeshna K, et al. ASH 2010. Abstract 6.

Patients with FL grades 1, 2, 3a;

stage II, III, IV disease;

ECOG PS 0-1

Arm AW + W

Arm BR4

Arm CR4 + RM

RANDOMIZATION Progressive disease

requiring therapy stops protocol

treatment

Clinic visits

Continued follow-up

R x 4

R x 4 R R R R R R R R R R R R

1 3 5 7 9 11 13 15 17 19 21 23 25

CompulsoryCT scan

CT scan only if clinical CR

CompulsoryCT scan

Bone marrow for histology and MRD only if CT shows CR

Mos

Preliminary Analysis of Rituximab vs Watch and Wait in Asymptomatic FL Pts

Ardeshna K, et al. ASH 2010. Abstract 6.

Progression-free survival1.00.90.80.70.60.50.40.30.20.1

00 1 2 3 4 5

Pro

po

rtio

n o

f P

atie

nts

P

rog

ress

ion

Fre

e

Yrs From Randomization

3-Yr PFSW + W: 33%R4: 60%R4 + RM: 81%

W + WR4R4 + RM

Events1083333

Pts18183

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/m2 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/m2 Cycle 1: Days 1, 8, 15, 22

Cycles 2-5: Day 1 only

Rituximab + BortezomibRituximab 375 mg/m2

Cycle 1: Days 1, 8, 15, 22 Cycles 2-5: Day 1 only +Bortezomib 1.6 mg/m2

Cycle 1: Days 1, 8, 15, 22

25 Wks

Patients with relapsed, rituximab-naive or

-sensitive FL(N = 670)

Results

Response, n (%)

Bort + Ritux

(n = 315)

Ritux (n = 324)

PValue

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) --

Coiffier B, et al. ASH 2010. Abstract 857.

100

90

80

70

60

50

40

30

20

10

0480 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45

Pa

tie

nts

Wit

ho

ut

Ev

en

t (%

)

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 ToxicitiesAdverse 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)

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.

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.

Mos600 6 12 18 24 30 36 42 48 54

1.0

0.8

0.6

0.4

0.2

0

Pro

bab

ilit

y o

f P

FS

74%

32%

PET negativePET positive

HR = 3.5 (95% CI: 2.0-6.1)P < .0001

Diffuse Large B-Cell Lymphoma(DLBCL)

Management of DLBCL

Systemic chemotherapy

Stem cell or bone marrow transplant

Radiotherapy (palliative)

CHOP(R) Chemotherapy

Cyclophosphamide (Cytoxan)Hydroxydaunorubicin (Adriamycin)Oncovin (vincristine)PrednisoneRituximab

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

Su

rviv

al P

rob

abil

ity

0.8

0.6

0.4

0.2

00 12 24 36 48 60 72

Mos

P = .0015; HR: 0.482

R-ACVBPR-CHOP

3-Yr OS

1.0

Su

rviv

al P

rob

abil

ity

0.8

0.6

0.4

0.2

00 12 24 36 48 60 72

Mos

P = .0071; HR: 0.439

R-ACVBPR-CHOP

T-Cell Lymphoma

Romidepsin in Progressive or Relapsed PTCL: Phase II DataNovel, 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/m2 (4-hr IV) on Days 1, 8, and 15 of a 28-day cycle for 6 cycles

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)

Coiffier B, et al. ASH 2010. Abstract 114.

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

Systemic chemotherapy

Stem cell/bone marrow transplant

Adriamycin (doxorubicin)

Bleomycin

Vinblastine

Dacarbazine

E2496: ABVD vs Stanford V ± Radiation Therapy in Advanced Hodgkin Lymphoma

Gordon LI, et al. ASH 2010. Abstract 415.

ABVD6-8 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

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

Gordon LI, et al. ASH 2010. Abstract 415.

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 onoutpatient 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)

Response, % Inv. IRF

ORR 72 75

CR 33 34

PR 38 40

SD 27 22

PD 0 3

Not evaluable 1 1

Chen R, et al. ASH 2010. Abstract 283.

Wks

700 10 20 30 40 50 60

Pat

ien

ts F

ree

of

PD

or

Dea

th (

%)

100908070605040302010

0

OSPFS per investigatorPFS per IRF

Median, WksNot reached

39.125.1

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