update on treatment for lymphoma, lymphoma support ireland meeting - feb 2011 - pc
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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.
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
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