stephanie a. gregory, md, facp the elodia kehm chair of hematology professor of medicine rush...
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Stephanie A. Gregory, MD, FACPThe Elodia Kehm Chair of Hematology
Professor of Medicine
Rush University Medical Center/Rush UniversityChicago, Illinois, USA
Treatment Strategy of Indolent Treatment Strategy of Indolent Lymphoma and the Role of Lymphoma and the Role of
RadioimmunotherapyRadioimmunotherapy
ObjectivesObjectives
After completing this activity, participants should be able to:
•Assess options for first-line and subsequent lines of therapy for indolent B-cell NHL in order to select the optimal treatment for individual patients
•Explain the rationale for the use of radioimmunotherapy (RIT)
•Describe the efficacy and safety of RIT
•Formulate treatment strategies for relapsed and refractory indolent B-cell NHL using currently available options in order to optimize outcomes for individual patients
•To be knowledgeable regarding potential barriers of use of RIT in the community practice setting
Lecture OutlineLecture OutlineLecture OutlineLecture Outline
1. Overview of Indolent Non-Hodgkin Lymphoma (NHL) with a focus on follicular
lymphoma (FL)
2. Current approaches for initial therapy
3. Approaches for relapsed disease
4. Use of RIT after front-line therapy for indolent NHL and the role of RIT in relapsed disease
2012 Estimated US New Cancer Cases2012 Estimated US New Cancer Cases
Females
Prostate 241,740 29%
Lung & bronchus 116,470 14%
Colon & rectum 73,420 9%
Urinary bladder 55,600 7%
Melanoma of skin 44,250 5%
Kidney & renal pelvis 40,250 5%
Non-Hodgkin 38,160 4%Non-Hodgkin 38,160 4%
lymphomalymphoma
Oral cavity & pharynx 28,540 3%
Leukemia 26,830 3%
Pancreas 22,090 3%
ALL SITES 848,170 100%
Males
BreastBreast 226,870 29% 226,870 29%
Lung & bronchusLung & bronchus 109,690 14% 109,690 14%
Colon & rectumColon & rectum 70,040 9% 70,040 9%
Uterine corpusUterine corpus 47,130 6% 47,130 6%
ThyroidThyroid 43,210 5% 43,210 5%
Melanoma of skinMelanoma of skin 32,000 4% 32,000 4%
Non-Hodgkin Non-Hodgkin 31,970 4% 31,970 4%
lymphomalymphoma
Kidney & renal pelvis 24,520 3%Kidney & renal pelvis 24,520 3%
OvaryOvary 22,280 3% 22,280 3%
PancreasPancreas 21,830 3% 21,830 3%
ALL SITESALL SITES 790,740 100% 790,740 100%
CA: A Cancer Journal for Clinicians, Vol. 62, January/February 2012.
2012 Estimated US Cancer Deaths2012 Estimated US Cancer Deaths
Females
Lung & bronchus 87,750 29%
Prostate 28,170 9%
Colon & rectum 26,470 9%
Pancreas 18,850 6%
Liver & intrahepatic 13,980 5%
bile duct
Leukemia 13,500 4%
Esophagus 12,040 4%
Urinary bladder 10,510 3%
Non-Hodgkin Non-Hodgkin 10,320 3% 10,320 3%
lymphomalymphoma
Kidney & renal pelvis 8,650 3%
ALL SITES 301,820 100%
Males
Lungs & bronchusLungs & bronchus 72,590 26% 72,590 26%
BreastBreast 39,510 14% 39,510 14%
Colon & rectumColon & rectum 25,220 9% 25,220 9%
PancreasPancreas 18,540 7% 18,540 7%
OvaryOvary 15,500 6% 15,500 6%
LeukemiaLeukemia 10,040 4% 10,040 4%
Non-HodgkinNon-Hodgkin 8,620 3% 8,620 3%
lymphomalymphoma
Uterine corpusUterine corpus 8,010 3% 8,010 3%
Liver & intrahepatic 6,570 2%Liver & intrahepatic 6,570 2%
bile duct bile duct
Brain & other nervous 5,980 2%Brain & other nervous 5,980 2%
systemsystem
ALL SITES ALL SITES 275,370 100% 275,370 100%
CA: A Cancer Journal for Clinicians, Vol. 62, January/February 2012.
NHL SubtypesNHL SubtypesNHL SubtypesNHL Subtypes
Percentages of all NHLsMALT=mucosa-associated lymphoid tissue; NHL=non-Hodgkin’s lymphoma NK=natural killerLichtman MA. Williams Hematology. 7th ed. New York, NY: McGraw Hill. 2006;1408.
T and NK cell(12%)
Other subtypes(9%)
Burkitt(2.5%)
Mantle cell(6%)
Diffuse large B cell
(DLBCL)(30%)
Follicular(25%)
Small lymphocytic(7%)
MALT-type marginal-zone
B cell (7.5%)
Nodal-type marginal-zone
B cell (<2%)
Lymphoplasmacytic (<2%)
Follicular Lymphoma (FL)Follicular Lymphoma (FL)Follicular Lymphoma (FL)Follicular Lymphoma (FL)• Most common indolent NHL, accounts for ~22%-25% of
NHL in North America
• Variable presentation and prognosis, but typically advanced stage at presentation
• Often asymptomatic
• Advanced stage FL not curable with standard therapy
• Median survival was about 10 years, but has increased with the advent of rituximab and RIT
• Multiple therapies: no standard, how best to sequence
• Many novel therapies in development
• Reliable biomarkers needed
Modified from Skarin AT, Dorfman DM. CA Cancer J Clin. 1997;47:351-72.
Follicular Lymphoma
TransformationAccelerated Indolent10% to 15% 40% to 65% 20% to 60%
A View of the Natural History of A View of the Natural History of Follicular LymphomaFollicular Lymphoma
A View of the Natural History of A View of the Natural History of Follicular LymphomaFollicular Lymphoma
Horning SJ. Semin Oncol. 1993;20(suppl 5):75-88.
0
20
100
80
60
40
0
Pro
bab
ilit
y (%
)
5 10 15 20 25 30
Years
1987-1993 (n=668)
1976-1987 (n=513)
1960-1976 (n=195)
Prognoses in FL Correlated with Gene Expression Prognoses in FL Correlated with Gene Expression Patterns in Tumor-Infiltrating Patterns in Tumor-Infiltrating
Normal Immune CellsNormal Immune Cells
Prognoses in FL Correlated with Gene Expression Prognoses in FL Correlated with Gene Expression Patterns in Tumor-Infiltrating Patterns in Tumor-Infiltrating
Normal Immune CellsNormal Immune Cells
Dave SS, et al. N Engl J Med. 2004;351:2159-69.
Genes Associated with FAVORABLE PROGNOSIS
Genes Associated with POOR PROGNOSIS
NCCN Practice Guidelines forNCCN Practice Guidelines forRelapsed Follicular Lymphoma: 2012Relapsed Follicular Lymphoma: 2012
NCCN Practice Guidelines forNCCN Practice Guidelines forRelapsed Follicular Lymphoma: 2012Relapsed Follicular Lymphoma: 2012
Additional TherapyAdditional TherapyInitial Therapy
F OLLICULAR
LYMPHOMA
PROGRESSIVE
DISEASE
Stage I, IIStage I, II
Stage II Stage II StageStage III, IV III, IV
• Locoregional RT or • ImmunoRx ± Chemo Rx ± RT • Observe (if tx not indicated)
• Clinical trial or• Local RT• Chemotherapy followed by RIT•Observe (if tx not
indicated)
• Clinical trial or • Chemotherapy
Rituximab or • Rituximab maintenance or• RIT or• Stem Cell Transplant• Local RT• Observe (if tx not indicated)
Without transformation
Transformed to DLBCL
• Clinical trial or
• Rituximab
Chemotherapy ± Rituximab or
• Chemotherapy ± RT
NCCN Practice Guidelines in Oncology, v.2.2012.
Follicular Lymphoma: Factors to Follicular Lymphoma: Factors to Consider When Choosing TherapyConsider When Choosing TherapyFollicular Lymphoma: Factors to Follicular Lymphoma: Factors to
Consider When Choosing TherapyConsider When Choosing Therapy
• PATIENTPATIENT Characteristics
– Age
– Symptoms
– Short & long term goals
– Comorbidity
– Preserve future options • DISEASE DISEASE Characteristics
– Stage
– Grade
– Transformation
– Sites of involvement
Overall Survival According to FLIPI:Overall Survival According to FLIPI:Clinical Prognosis FactorsClinical Prognosis Factors
Overall Survival According to FLIPI:Overall Survival According to FLIPI:Clinical Prognosis FactorsClinical Prognosis Factors
Adapted from Solal-Celigny P, et al. Blood. 2004;104:1258-65.
Su
rviv
al p
rob
abil
ity
Low risk
Intermediate risk
High risk
0
0.2
0.4
0.6
0.8
1.0
Years0 1 2 3 4 5 6 7
No Nodal regions 4
L LDH increased
A Age ≥60
S Stage III/IV
H Hemoglobin <120 g/L
Risk Group No. of Factors % of Pts 5-y OS (%) 10-y OS (%)
Low 0-1 36 90.6 70.7
Intermediate 2 37 77.8 50.9
High 3-5 27 52.5 35.5
p<10-4
FLIPI-2: Risk AssessmentFLIPI-2: Risk AssessmentFLIPI-2: Risk AssessmentFLIPI-2: Risk Assessment
Federico M, et al. J Clin Oncol. 2009;27:4555-62.
• Updated version
• Accounts for immunochemotherapy as a widely used treatment option
• Future treatment guidelines will most likely be based on staging, genetic profiles, and immune response signatures
FLIPI 2Age >60 yrs
BM involvement
Anemia (Hgb <120 g/L)
Nodes >6 cm
β2m > ULN
PFS:
After Staging Evaluation
Advanced stage:low tumor burden
Advanced stage:high tumor burden
Observation Chemo-immuno-
therapyTherapy
RituximabClinical Trial
eg, RESORT Trial orW & W vs. Rituximab
Update on Treatment Options for Update on Treatment Options for Follicular LymphomaFollicular Lymphoma
Update on Treatment Options for Update on Treatment Options for Follicular LymphomaFollicular Lymphoma
Courtesy of Stephanie A. Gregory, MD.
Immunotherapy Targets on B CellsImmunotherapy Targets on B CellsImmunotherapy Targets on B CellsImmunotherapy Targets on B Cells
slg
DR
CD19 CD20
CD22
B lymphocyte
• Surface proteins targeted by immunotherapy– Naked monoclonal
antibodies (mAbs)– Conjugated mAbs
- Radioisotopes
- Drugs
- Toxins
Adapted from Press OW. Cancer J Sci Am. 1998;4(suppl 2):S19-S26.
Friedberg JW. J Clin Oncol.2009;27:1202-08.
Observation(Watch and Wait)
18%
Radiotherapy 6%
Rituximab Monotherapy14%
Chemotherapy +Rituximab
52%
Chemotherapy 3%
Clinical trial6%
Other 2%
Initial Treatment – All PatientsInitial Treatment – All PatientsInitial Treatment – All PatientsInitial Treatment – All Patients
Current Practice: the LymphoCare StudyCurrent Practice: the LymphoCare Study2004-2007 n=2728 at 265 US Sites: 80% Nonacademic, 20% Academic
Treatment Deferral vs. Initiation: Treatment Deferral vs. Initiation: GELF CriteriaGELF Criteria
Treatment Deferral vs. Initiation: Treatment Deferral vs. Initiation: GELF CriteriaGELF Criteria
All of the Following:
Maximum diameter of disease <7 cmFewer than 3 nodal sitesNo systemic symptomsSpleen <16 cm on computed tomography (CT)No significant effusionsNo risk of local compressive symptomsNo circulating lymphoma cells
Brice P, et al. J Clin Oncol. 1997;15:1110-1117.
GELF, Groupe pour l’Etude de Lymphome Folliculaire
Randomized Trials with the Watch-and-Wait Approach vs. Chemotherapy for
Asymptomatic Patients with Advanced FL
Randomized Trials with the Watch-and-Wait Approach vs. Chemotherapy for
Asymptomatic Patients with Advanced FL
Study NChemotherapy
RegimenOS With Chemotherapy
OS with Watch-and-Wait Approach
Ardeshna et al 309Chlorambucil (Leukeran®)
Median:5.9 y
Median: 6.7 y
Brice et al 193Prednimustine 5 y: 70%
5 y: 78%IFN- 5 y: 84%
Young et al 104 ProMACE-MOPP Median: NR Median: NR
Ardeshna KM, et al. Lancet. 2003:362:516-22; Brice P, et al. J Clin Oncol. 1997;15:1110-7; Young RC, et al. Semin Hematol. 1988;25:11-6.
IFN=interferon; MOPP=mechlorethamine, vincristine, procarbazine, prednisone; NR=not reached; ProMACE=prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide.
Rituximab (R) vs. a “Watch and Wait” Strategy in Rituximab (R) vs. a “Watch and Wait” Strategy in Patients with Stage II-IV Asymptomatic, Patients with Stage II-IV Asymptomatic,
Nonbulky FLNonbulky FL
Rituximab (R) vs. a “Watch and Wait” Strategy in Rituximab (R) vs. a “Watch and Wait” Strategy in Patients with Stage II-IV Asymptomatic, Patients with Stage II-IV Asymptomatic,
Nonbulky FLNonbulky FL
Intervention Observe R x 4 weeks R x 4 weeks
Maintenance --- --- R q 2 mos. x 2 years
Number 187 84 192
CR/PR (%) 2/3 43/30 54/33
3-year PFS 33% 60% 81%
Time to next treatment 33 months Not reached Not reached
• Patients had: stage II–IV, asymptomatic, non-bulky low-grade FL• Improved PFS in rituximab arms (p ≤0.001)• Time to initiation of new treatment in the rituximab arms
• 33 months vs. not reached at 4 years (p ≤0.001)• No difference in OS (p ≥0.5)• Quality of life no worse
Ardeshna KM, et al. ASH 2010. abstr 6 (oral, Plenary Session).
Observation vs. Single-Agent RituximabObservation vs. Single-Agent RituximabObservation vs. Single-Agent RituximabObservation vs. Single-Agent Rituximab
Watch and Wait = 52%Rituximab = 20%Rituximab and maintenance rituximab = 9%
0 1 2 3 4 5
Years from Randomization
Time to initiation of new therapy
Ardeshna K, et al. ASH 2010. abstr 6 (oral, Plenary Session).
Initial Therapy for Low Tumor Burden: Initial Therapy for Low Tumor Burden: Follicular LymphomaFollicular Lymphoma
Initial Therapy for Low Tumor Burden: Initial Therapy for Low Tumor Burden: Follicular LymphomaFollicular Lymphoma
• Rituximab as first-line therapy for indolent lymphoma
Regimen n ORR CR TTF/PFS (months)
Rituximab monotherapy(patients with low tumor burden)
Colombat P, et al. ASH. 2006, abstr 486.
49 74% 49% 24
Rituximab monotherapy
Witzig TE, et al. J Clin Oncol. 2005;23:1103-8.
37 72% 36% 26
Chemoimmunotherapy in Chemoimmunotherapy in Follicular NHL PatientsFollicular NHL Patients
Chemoimmunotherapy in Chemoimmunotherapy in Follicular NHL PatientsFollicular NHL Patients
• CHOPCHOP ++ RituximabRituximab
• BendamustineBendamustine + + RituximabRituximab (Treanda(Treanda®®))
• CVPCVP ++ RituximabRituximab
• FNDFND ++ RituximabRituximab
• BVRBVR ++ RituximabRituximab
• FCMFCM ++ RituximabRituximab
• FludarabineFludarabine ++ RituximabRituximab
NCCN Practice Guidelines in Oncology, v.2.2012.
0102030405060708090
100
CHOP-R FND-R Fludarabine-R
PR
CR
CHOP-RCHOP-R FN-R CVP-R
Chemo Rituximab Trials for Chemo Rituximab Trials for Initial Therapy Initial Therapy of Follicular NHLof Follicular NHL
Czuczman Zinzani 1 McLaughlin Czuczman
Hiddemann Zinzani 2 Marcus Rummel
Bendamustine-R
Fludarabine (Fludara®).Courtesy of Oliver W. Press, MD, PhD, and Stephanie A. Gregory, MD.
GELA PRIMA Phase III Study: GELA PRIMA Phase III Study: Rituximab Maintenance in FLRituximab Maintenance in FLGELA PRIMA Phase III Study: GELA PRIMA Phase III Study: Rituximab Maintenance in FLRituximab 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 I–III FL
(n = 1,200)
CR/CRu, PR
RANDOMIZED
Maintenance Rituximab 375 mg/m2 q2mos x 2 yrs
Observation
Salles GA, et al. Lancet. 2011;377:42-51.
• 1,217 patients in 223 centers– 43% FLIPI 3-5
– Median age 56 y
– 90% stage III-IV
PRIMA Study: ResultsPRIMA Study: ResultsPRIMA Study: ResultsPRIMA Study: Results
• The risk of progression was significantly reduced for the rituximab maintenance group (HR 0.55, 95% CI: 0.44–0.68)
74.9%
57.1%
Salles GA, et al. Lancet. 2011;377:42-51.
Parameter Rituximab Observation HR P value
3-yr PFS 78.6% 60.3% 0.55 <0.0001
Deaths 6% 5% 0.87
CR/CRu 75% 55% <0.0001
FDA approved rituximab for front-line maintenance therapy in advanced FL in January, 2011
BendamustineBendamustineBendamustineBendamustine• Alkylating agent
– Induces durable DNA damage resulting in apoptosis and mitotic catastrophe
• Lacks cross resistance with other agents (including alkylators)
Rummel MJ, et al. J Clin Oncol. 2005;23:3383-9; Friedberg JW, et al. Blood. 2005;106:abstr#229; Chovan JP, et al. Drug Metab Dispos. 2007;35:1744-53; Weide R. Ther Clin Risk Manag. 2008;4:727-32; Cheson BD, Rummel MJ. J Clin Oncol. 2009;27:1492-501.
O
O
C
N
N
N
Cl
Cl
Nitrogen mustard
Carboxylic acid
Untreated pts with
indolent and MCL
(n=513)
RANDOMIZE
BR (× 6 cycles)Bendamustine: 90 mg/m2:
day 1-2, q4w+
Rituximab: 375 mg/m2
day 1, q4w
R-CHOP (× 6 cycles)Rituximab: 375 mg/m2
day 1, q3w+
CHOP (standard)day 1, q3w
Primary objective: To prove a non-inferiority of BR vs R-CHOP in PFS (defined as a difference of less than 15% in PFS after 3 years)Secondary objectives: ORR, OS, relapse-free survival, and safety
n=260
n=253
Evaluable patients
Rummel MJ, et al. Blood. 2009;114:168-169;abstr #405.
Phase III Study of First-line Phase III Study of First-line Bendamustine/Rituximab (B-R) Versus R-CHOP Bendamustine/Rituximab (B-R) Versus R-CHOP
in Indolent NHL: Final Results in Indolent NHL: Final Results
Phase III Study of First-line Phase III Study of First-line Bendamustine/Rituximab (B-R) Versus R-CHOP Bendamustine/Rituximab (B-R) Versus R-CHOP
in Indolent NHL: Final Results in Indolent NHL: Final Results
Key Eligibility Criteria:
• CD20+ FL (grade 1/2), MCL, MZL, WM, SLL, other LPL
• Stage III/IV
• No prior therapy
• Age ≥18 years
Bendamustine/Rituximab Versus R-CHOP for the Bendamustine/Rituximab Versus R-CHOP for the Frontline Treatment of Follicular Lymphoma: PFSFrontline Treatment of Follicular Lymphoma: PFS
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Su
rviv
al P
rob
abili
ty
0 12 24 36 48 60 72
Bendamustine/Rituximab(N=260)
R-CHOP (n=253)
*p=0.0281HR=0.63 (95% CI, 0.42-0.95)
RegimenMedian PFS*
ORR CR
R-CHOP 46.7 mos 91.3% 30.0%
Bendamustine/Rituximab NR 92.7% 39.6%
P value NS 0.026
• Significantly less adverse events with bendamustine/rituximab: alopecia, paresthesias, stomatitis, erythema, allergic reactions, and infectious complications
Time (Months)
Rummel MJ, et al. Blood. 2009;114:168-169;abstr #405.
Phase III Study of First-line Bendamustine/Rituximab Phase III Study of First-line Bendamustine/Rituximab (B-R) Versus R-CHOP in Indolent NHL: Safety(B-R) Versus R-CHOP in Indolent NHL: Safety
Phase III Study of First-line Bendamustine/Rituximab Phase III Study of First-line Bendamustine/Rituximab (B-R) Versus R-CHOP in Indolent NHL: Safety(B-R) Versus R-CHOP in Indolent NHL: Safety
Will B+R replace R+CHOP/CVP???Await formal publication and closer analysis of Rummel trial… long-term F/U?
Rummel MJ, et al. Blood. 2009;114:168-169;abstr #405.
NCCN Practice Guidelines forNCCN Practice Guidelines forRelapsed Follicular Lymphoma: 2012Relapsed Follicular Lymphoma: 2012
NCCN Practice Guidelines forNCCN Practice Guidelines forRelapsed Follicular Lymphoma: 2012Relapsed Follicular Lymphoma: 2012
Additional TherapyAdditional TherapyInitial Therapy
F OLLICULAR
LYMPHOMA
PROGRESSIVE
DISEASE
Stage I, IIStage I, II
Stage II Stage II StageStage III, IV III, IV
• Locoregional RT or • ImmunoRx ± Chemo Rx ± RT • Observe (if tx not indicated)
• Clinical trial or• Local RT• Chemotherapy followed by RIT•Observe (if tx not
indicated)
• Clinical trial or • Chemotherapy
Rituximab or • Rituximab maintenance or• RIT or• Stem Cell Transplant• Local RT• Observe (if tx not indicated)
Without transformation
Transformed to DLBCL
• Clinical trial or
• Rituximab
Chemotherapy ± Rituximab or
• Chemotherapy ± RT
NCCN Practice Guidelines in Oncology, v.2.2012.
Recurrent Follicular Lymphoma: Recurrent Follicular Lymphoma: Recommended TreatmentRecommended Treatment
Recurrent Follicular Lymphoma: Recurrent Follicular Lymphoma: Recommended TreatmentRecommended Treatment
• Conventional strategies– Rituximab ± maintenance– Chemoimmunotherapy
± maintenance– Radioimmunotherapy– External-beam
radiotherapy– Autologous transplantation– Allogeneic transplantation
• Novel strategies– Novel monoclonal
antibodies– Bortezomib (Velcade®)– Bendamustine– Lenalidomide
(Revlimid®)– Others
• Clinical trial
NCCN. Available at: http://www.nccn.org.
FDA-Approved Agents (US) for FDA-Approved Agents (US) for Rituximab-Refractory* Indolent, Rituximab-Refractory* Indolent,
Follicular NHLFollicular NHL
FDA-Approved Agents (US) for FDA-Approved Agents (US) for Rituximab-Refractory* Indolent, Rituximab-Refractory* Indolent,
Follicular NHLFollicular NHL
• Chemotherapy: bendamustine
•Radioimmunotherapy: I-131 tositumomab (Bexxar®) & Y-90 ibritumomab tiuxetan (Zevalin®)
* Defined as: No response to last rituximab treatment or relapse within 6 months of last rituximab
Bendamustine MonotherapyBendamustine MonotherapyBendamustine MonotherapyBendamustine Monotherapy
• Single-arm, multicenter trial in patients with rituximab-refractory indolent NHL – Eligible patients were 18 years of age, had a
WHO PS 2, at least one lesion measuring 2 cm, and had received 1 to 3 previous chemotherapies
• Bendamustine 120 mg/m2 on days 1 and 2, q21 days x 6-8 cycles
Kahl BS, et al. Cancer 2010; 116:106-14.
Bendamustine Monotherapy ResultsBendamustine Monotherapy ResultsBendamustine Monotherapy ResultsBendamustine Monotherapy Results
Efficacy by NHL type ORR, % (CR/CRu)
Follicular (62%)
Small lymphocytic (21%)
Lymphoplasmacytic (1%)
LN marginal zone (9%)
Ex-LN marginal zone (7%)
Total (100%)
74 (15/5)
71 (5/0)
100 (0/0)
78 (11/0)
86 (43/0)
*75 (14/3)
ORR=overall response rate; CR=complete response; CRu=unconfirmed CR.
Kahl BS, et al. Cancer 2010;116:106-14.
*95% CI, 65% to 83%.
• N=101 patients– Median age, 60 years; 76% with advanced-stage disease; FL (n=63);
marginal zone lymphoma (n=16); SLL (n=21); lymphoplasmacytoid lymphoma (n=1)
– Median number of prior chemotherapy regimens = 2
Radioimmunotherapy (RIT)Radioimmunotherapy (RIT)Radioimmunotherapy (RIT)Radioimmunotherapy (RIT)
Radiolabeled Monoclonal Antibodies for Radiolabeled Monoclonal Antibodies for RadioimmunotherapyRadioimmunotherapy
Radiolabeled Monoclonal Antibodies for Radiolabeled Monoclonal Antibodies for RadioimmunotherapyRadioimmunotherapy
• Proliferating tumor cells are inherently sensitive to radiation
• Continuous rather than intermittent RT
• Crossfire effect—kill tumor cells a few mm from the bound antibody & antigen-negative tumor cells
Crossfire Enhances EfficacyCrossfire Enhances EfficacyCrossfire Enhances EfficacyCrossfire Enhances Efficacy
Unlabeled “Cold” Antibody Radiolabeled Antibody
Courtesy of Andrew D. Zelenetz, MD, PhD.
Radiolabeled Monoclonal AntibodiesRadiolabeled Monoclonal AntibodiesRadiolabeled Monoclonal AntibodiesRadiolabeled Monoclonal Antibodies
Monoclonal Monoclonal antibodyantibody
Bond or Bond or ChelatorChelator RadionuclideRadionuclide
RadiationRadiation
RIT Historical TimelineRIT Historical TimelineRIT Historical TimelineRIT Historical Timeline
1985 1990 1995 2000 2005 2010
Trials of RIT begin
Phase I/II trial of I-131 tositumomab begins at Michigan
Phase I/II trial of Y-90 ibritumomab begins
FDA approvals of both agents in 2002 & 2003
First reports of frontline RIT
Randomized trial of RIT consolidation reported
Frontline trial of 131I tositumomab begins (1996)
Chemo + RIT in frontline begins (2000)
Durable remissions from all previous studies continue
Courtesy of Mark S. Kaminski, MD.
Regulatory Status of Anti-CD20 RadioimmunotherapyRegulatory Status of Anti-CD20 RadioimmunotherapyRegulatory Status of Anti-CD20 RadioimmunotherapyRegulatory Status of Anti-CD20 Radioimmunotherapy
• Y-90 ibritumomab tiuxetan– 2002 FDA approval: relapsed or refractory, low grade or
follicular NHL – 2009 FDA approval: treatment of previously untreated
follicular NHL in patients who achieve a partial or complete response to first-line chemotherapy
• I-131 tositumomab– 2003 FDA approval: treatment of patients with CD20
antigen-expressing relapsed/refractory, low grade, follicular, or transformed NHL, including rituximab-refractory NHL
• Not indicated for first-line treatment of CD20+ NHL
I-131 Tositumomab & I-131 Tositumomab & Y-90 Ibritumomab Tiuxetan Y-90 Ibritumomab Tiuxetan
I-131 Tositumomab & I-131 Tositumomab & Y-90 Ibritumomab Tiuxetan Y-90 Ibritumomab Tiuxetan
• I-131 Tositumomab – Mouse anti CD20– Direct iodination of tyrosine
amino acids on the antibody, subject to dehalogenation
& 1 mm emission– 8.0 day half life– Thyroid uptake of free 131I – 50%-90% of 131I cleared in
urine within 48 hour – Scans needed to determine
residence time and rate of clearance
• Y-90 Ibritumomab tiuxetan– Mouse anti CD20– Indirect linkage via tiuxetan
linker chelated to 90Y and covalently linked to lysine and arginine amino acids
– 5 mm emission length– 2.7 day half-life– 5%-10% of 90Y-chelate
cleared in urine, some through bowel
– No scans needed
Clinical Criteria for Radioimmunotherapy Clinical Criteria for Radioimmunotherapy in Lymphomain Lymphoma
Clinical Criteria for Radioimmunotherapy Clinical Criteria for Radioimmunotherapy in Lymphomain Lymphoma
• Relapsed low-grade, follicular, and/or transformed low grade B-cell lymphoma
• Normocellular marrow
• Bone marrow involvement 25%
• ANC >1500/mm3
• Platelet count 150,000/mm3 (lower dose if 100k-149k)
• Peripheral blood lymphocytes <5000/mm3
• No human anti-mouse antibodies (HAMA)
• No prior radioimmunotherapy (preferred)
• No prior stem cell transplant (preferred)
Efficacy of RIT in Patients with Relapsed or Efficacy of RIT in Patients with Relapsed or Refractory CD20+ B-cell NHLRefractory CD20+ B-cell NHL
Efficacy of RIT in Patients with Relapsed or Efficacy of RIT in Patients with Relapsed or Refractory CD20+ B-cell NHLRefractory CD20+ B-cell NHL
Reference n Patient Characteristics
Median Number of Prior
Therapies
ResponseRate
ORR CRDisease Control
Median Duration of Response
I-131 tositumomab
Horning SJ, et al. J Clin Oncol 2005;23:712-9
40 CD20+ small cleaved or mixed lymphoma, de novo follicular large cell, or transformed lymphoma; relapsed or refractory after ≥ 1 course of standard rituximab
4 65% 38% Median PFS: 10.4 months (24.5 months for responders; NR for CR patients after median 39 months of follow-up)
NR in patients with grade 1 or 2 FL and tumor bulk ≤ 7 cm
Kaminski MS, et al. J Clin Oncol 2001;19:3918-28
60 Relapsed or refractory low-grade or transformed low-grade CD20+ B-cell NHL
4 65% 20% Median PFS: 8.4 months
6.5 months (NR for CR patients with >47 months of follow-up)
Witzig TE, et al. Leukemia Lymphoma. 2011;52:1188-99.
Efficacy of RIT in Patients with Relapsed/Refractory CD20+ B-cell NHLEfficacy of RIT in Patients with Relapsed/Refractory CD20+ B-cell NHL Efficacy of RIT in Patients with Relapsed/Refractory CD20+ B-cell NHLEfficacy of RIT in Patients with Relapsed/Refractory CD20+ B-cell NHL
Reference nPatient
Characteristics
Median Number of
Prior Therapies
Response Rate
ORR CRDisease Control
Median Duration of Response
Y-90 ibritumomab tiuxetan
Witzig TE, et al. J Clin Oncol 1999;17:3793-803
51 Relapsed or refractory low-grade or follicular NHL or intermediate-grade or mantle-cell NHL
2 67% 26% Median TTP: 12.9+ months
11.7+ months
Witzig TE, et al. J Clin Oncol 2002;20:2453-63
143 Relapsed or refractory low-grade, follicular, or transformed NHL
2 80% CR 30%; CRu 4%Rand Trial of Zevalin vs. Rituximab
Median TTP: 11.2 months
14.2 months
Wiseman GA, et al. Blood 2002;99:4336-42
30 Relapsed or refractory low-grade, follicular, or transformed CD20+ NHL and mild thrombocytopenia
2 83% CR: 37%; CRu: 6.7%
Median TTP: 9.4 months (12.6 months in responders)
11.7 months
Witzig, et al. J Clin Oncol 2002;20:3262-9
54 Rituximab-refractory follicular B-cell NHL
4 74% 15% Median TTP: 6.8 months (8.7 months in responders)
6.4 months
Gordon LI, et al. Blood 2004;103:4429-31
51 Relapsed or refractory low-grade or follicular B-cell NHL
2 73% CR: 29%; CRu: 22%
Median TTP: 9.3 months (12.6 months in responders)
11.7 months
Witzig TE, et al. Leukemia Lymphoma. 2011;52:1188-99.
I-131 Tositumomab and Y-90 Ibritumomab Tiuxetan I-131 Tositumomab and Y-90 Ibritumomab Tiuxetan Are Active in Patients with Follicular Lymphoma Who Are Active in Patients with Follicular Lymphoma Who
Are Refractory to Rituximab (No Response or Are Refractory to Rituximab (No Response or Duration <6 Months)Duration <6 Months)
I-131 Tositumomab and Y-90 Ibritumomab Tiuxetan I-131 Tositumomab and Y-90 Ibritumomab Tiuxetan Are Active in Patients with Follicular Lymphoma Who Are Active in Patients with Follicular Lymphoma Who
Are Refractory to Rituximab (No Response or Are Refractory to Rituximab (No Response or Duration <6 Months)Duration <6 Months)
• I-131 tositumomab – 40 patients (35 fit criteria)– Median age 57 y– 4 prior chemo median– 28% >7cm bulk– 32% BM involved– 68% response rate, 30% CR – 14.7 mos median duration of
response– >2 yrs CR durationHorning SJ, et al. J Clin Oncol
2005;23:712-9
• Y-90 ibritumomab tiuxetan– 54 patients– Median age 54 y– 4 prior chemo med– 44% >7cm bulk– 32% BM involved– 74% response rate, 15%
CR – 6.4 mos median duration
of response – 7.2 mos CR duration Witzig TE, et al. J Clin Oncol.
2002;20:3262-9
Responses Are Durable: PFS for Patients Treated Responses Are Durable: PFS for Patients Treated with I-131 Tositumomab Across Multiple Studieswith I-131 Tositumomab Across Multiple Studies
Fisher RI, et al. J Clin Oncol. 2005;23:7565-73.
PFS for Patients Treated with PFS for Patients Treated with Y-90 Y-90 Ibritumomab TiuxetanIbritumomab Tiuxetan
PFS for Patients Treated with PFS for Patients Treated with Y-90 Y-90 Ibritumomab TiuxetanIbritumomab Tiuxetan
Zevalin Package Insert. Spectrum Pharmaceuticals, Inc. 2011.
HR = 0.46 [95% CI: 0.35,0.60]; P <0.0001
Earlier Is Better: Higher Responses with Earlier Is Better: Higher Responses with Y-90 Ibritumomab Tiuxetan if Fewer Prior Y-90 Ibritumomab Tiuxetan if Fewer Prior
Chemotherapy Regimens Chemotherapy Regimens
Earlier Is Better: Higher Responses with Earlier Is Better: Higher Responses with Y-90 Ibritumomab Tiuxetan if Fewer Prior Y-90 Ibritumomab Tiuxetan if Fewer Prior
Chemotherapy Regimens Chemotherapy Regimens
1 prior (n=63)2 (n=148)
Com
plet
e R
espo
nder
s (%
)
CR Patients
Number of prior chemotherapy regimens
P<0.01
Emmanouilides C, et al. Leuk Lymphoma. 2006;47:629-36.
Number of prior regimens
Time to progression
1 12.6 mos
≥2 7.9 mos
P value <0.05
Efficacy by Treatment EncounterEfficacy by Treatment EncounterEfficacy by Treatment EncounterEfficacy by Treatment Encounter
I-131 Tositumomab Use by Treatment SequenceI-131 Tositumomab Use by Treatment Sequence
11stst Line Line(n=141)(n=141)
22ndnd Line Line(n=226)(n=226)
33rdrd Line Line (n=228)(n=228)
44thth+ Line + Line (n=540)(n=540)
Response rate, % Response rate, % 9595 7373 5858 4646
Median duration of Median duration of response, moresponse, mo NRNR 3535 1616 1212
Complete response (CR), Complete response (CR), % % 7878 4646 3232 2323
Median duration of CR, Median duration of CR, momo NRNR NRNR 3535 5959
PFS >1 year, % PFS >1 year, % 82 82 5959 4242 2727
All differences are statistically significant (p <0.001). All differences are statistically significant (p <0.001).
Gregory SA, et al. Proc Am Soc Clin Oncol. 2005;24:Abstr #6561.
Event-Free Survival for Event-Free Survival for I-131 Tositumomab by Line of TherapyI-131 Tositumomab by Line of Therapy
Event-Free Survival for Event-Free Survival for I-131 Tositumomab by Line of TherapyI-131 Tositumomab by Line of Therapy
0000
2020
4040
6060
8080
100100
11 22 33 44 55 66 77Time from treatment, yearsTime from treatment, years
Ev
ent-
fre
e s
urv
iva
l, %
pa
tie
nts
Ev
ent-
fre
e s
urv
iva
l, %
pa
tie
nts
11stst line (n = 141) line (n = 141)
22ndnd line (n = 291) line (n = 291)
33rdrd line (n = 260) line (n = 260)
≥ ≥ 44thth line (n = 484) line (n = 484)
Gregory SA, et al. Proc Am Soc Clin Oncol. 2005;24:Abstr #6561.
Low Incidence of Secondary Malignancies After RITLow Incidence of Secondary Malignancies After RITLow Incidence of Secondary Malignancies After RITLow Incidence of Secondary Malignancies After RIT
131I Tositumomab trials(n = 1071)
90Y IT registrational trials (n = 211)
Median follow-up, (range) 2.1 years3.2 years (1.2-75.5)
MDS/AML cases, n 35 7
Crude incidence of MDS/AML 3.3% 3.3%
Annualized incidence of MDS/AML
1.4% per year 0.70% per year
• MDS/AML with chemotherapy (no high-dose therapy)– Cumulative incidence 4% to 8%– Annualized incidence 1% to 1.5%
Bennett JM, et al. Blood. 2005;105:4576-82; Emmanoulides C, et al. Proc Am Soc Clin Oncol. 2004;23: Abstr #6696; Pedersen-Bjergaard, et al. Ann Intern Med. 1985;103:195-200; Greene MH, et al. Cancer Res. 1983;43:1891-8; Kantarjian HM, et al. Semin Oncol. 1987;14:435-43.
Subsequent Chemotherapy Regimens Are Subsequent Chemotherapy Regimens Are Well-Tolerated After RadioimmunotherapyWell-Tolerated After RadioimmunotherapySubsequent Chemotherapy Regimens Are Subsequent Chemotherapy Regimens Are Well-Tolerated After RadioimmunotherapyWell-Tolerated After Radioimmunotherapy
• 58 patients (Mayo Clinic) who had disease progression after previous treatment with Y-90 ibritumomab tiuxetan
– Median of 2 prior therapies before RIT: 54 CHOP, 35 CVP, 24 rituximab, 20 chlorambucil, 11 fludarabine
– 1-7 subsequent chemo regimens, median 2• Grade IV toxicity: 25% platelets, 33% ANC • 1/3 required CSF &/or hospitalized for febrile neutropenia and/or
bleeding• similar to contemporary cohort controls without RIT
– 8 had autologous stem cell transplants (7 PBSC)
Ansell SM, et al. J Clin Oncol. 2002;20:3885-90.
Chemotherapy, Radiation Therapy Chemotherapy, Radiation Therapy and Rituximab Can Be Effective and Rituximab Can Be Effective
After RadioimmunotherapyAfter Radioimmunotherapy
Chemotherapy, Radiation Therapy Chemotherapy, Radiation Therapy and Rituximab Can Be Effective and Rituximab Can Be Effective
After RadioimmunotherapyAfter Radioimmunotherapy
• 153/521 (29%) patients received other treatment after Y-90 ibritumomab tiuxetan
• Response data for 100/153 patients: first subsequent therapy after Y-90 ibritumomab tiuxetan 60/100 (60%) ORR
– 20/25 (80%) RR to focal radiation therapy– 25/49 (53%) RR to chemotherapy– 15/26 (58%) RR to rituximab
Schilder RJ [abstract #1064], Saleh F [abstract #30], ASCO 2002.
Algorithm for the Treatment of Relapsed or Algorithm for the Treatment of Relapsed or Refractory Follicular LymphomaRefractory Follicular Lymphoma
RIT
RITRIT
RIT
Witzig TE, et al. Leuk Lymphoma. 2011;52:1188-99.
Has the Natural History of Follicular NHL Changed?Has the Natural History of Follicular NHL Changed?
Reproduced with permission from Fisher RI, et al. J Clin Oncol. 2005;23:8447-52.
OS According to Treatment Program
Sur
viva
l (%
)
Time After Registration (Years)
OS by Treatment Program
CHOP + MoAb
ProMACE
CHOPPts Deaths
4-Year Estimate
179 18 91%
425 189 79%
356 226 69%
100
80
60
40
20
02 4 6 8 10
CHOP=cyclophosphamide, doxorubicin, vincristine, prednisone; MoAb=monoclonal antibody.
SummarySummarySummarySummary
• Many options of therapy exist for patients with follicular lymphoma
• There is no standard of care for both front-line and relapsed disease
• Radioimmunotherapy is an effective therapy for indolent B cell lymphoma
– One course of therapy is as effective as multiple courses of chemotherapy
– Patient selection is important to maximize benefit and minimize toxicity
– New approaches include frontline treatment with RIT and RIT consolidation after chemotherapy for frontline treatment of follicular lymphoma
Case StudyCase Study
• Walter: 59 year-old male diagnosed with stage 4, grade II follicular lymphoma 3 years ago
• At time of diagnosis, FLIPI score was low-risk
• Patient and his physician chose a watch and wait approach
• Patient has now developed progressive disease with multiple areas of lymphadenopathy but not systemic symptoms
What Would You Do Next?What Would You Do Next?
A. Continue to watch and wait
B. Single-agent rituximab
C. Rituximab + chemotherapy
D. Radioimmunotherapy
Case StudyCase Study
• Single-agent rituximab was prescribed because patient had a low tumor volume
• He had a good partial response to treatment, tolerated it well, and was left further untreated
• One year later he developed progressive disease with extensive lymphadenopathy (the largest mass measured 7 cm)
– 10% bone marrow involvement– Rebiopsy confirmed grade II follicular lymphoma
Now What?Now What?
A. Another course of single-agent rituximab
B. Rituximab + chemotherapy
C. Chemotherapy + radiation
D. Radioimmunotherapy
Case StudyCase Study
• Walter and his doctor decided to go with radioimmunotherapy
What Are Some Considerations When Choosing RIT?
What Are Some Considerations When Choosing RIT?
A. Percentage of bone marrow involvement
B. Platelet count
C. Absolute neutrophil count
D. Age of patient
E. Comorbidities of patient
If Walter Relapses After RIT, What Other Treatment Options
Available?
If Walter Relapses After RIT, What Other Treatment Options
Available?
A. Single-agent rituximab
B. Chemoimmunotherapy
C. Stem cell transplant
D. Repeat RIT
Questions?Questions?