1. Jointly sponsored by the Annenberg Center for Health Sciences at Eisenhower and Clinical Care Options, LLC
Workshop With the Experts: Overcoming Barriers to Optimal Treatment of Non-Hodgkin’s Lymphoma
Welcome to this program entitled, “Workshop With the Experts: Overcoming Barriers to Optimal Treatment of Non-Hodgkin’s Lymphoma.”
This program is supported by educational grants from
Image: Dr. Gopal Murti/Copyright©2010 Phototake. All Rights Reserved.

2. Evolving Treatment Paradigms in DLBCL
DLBCL, diffuse large B-cell lymphoma.
This presentation will be focused on evolving treatment paradigms in diffuse large B-cell lymphoma (DLBCL).

3. About These Slides
Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent
These slides may not be published or posted online without permission from Clinical Care Options (
Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

4. Program Faculty Program Director Faculty
Richard I. Fisher, MD Samuel E. Durand Professor of Medicine Director, James P. Wilmot Cancer Center Senior Associate Dean for Clinical Affairs School of Medicine and Dentistry Vice President, University of Rochester Rochester, New York
Faculty
Julie M. Vose, MD Neumann M. and Mildred E. Harris Professor Chief, Section of Hematology/Oncology Professor of Medicine University of Nebraska Medical Center Omaha, Nebraska
This slide lists the faculty who were involved in the production of these slides.

5. Faculty Disclosures
Richard I. Fisher, MD, has disclosed that he has received consulting fees from Millennium, Pfizer, and Roche. Julie M. Vose, MD, has disclosed that she has received research grants from Allos Therapeutics, AstraZeneca, Celgene, Exelixis, Genentech, Genzyme, GlaxoSmithKline, Millennium, Novartis, Pharmacyclics, and US Biotest.
This slide lists the disclosure information of the faculty involved in the development of these slides.

6. Overview of DLBCL DLBCL, diffuse large B-cell lymphoma.
We will begin with an overview of DLBCL.

7. Diffuse Large B-Cell Lymphoma
Most common NHL: 31%
Peak incidence in 6th decade
Clinical outcomes and molecular features highly heterogeneous
Large cells with loss of follicular architecture of node
30% to 40% present with rapidly enlarging, symptomatic mass with B symptoms
May present as extranodal disease (stomach, CNS, testis, skin)
Curable in 50% or more of cases
Median survival: wks to mos if not treated
CNS, central nervous system; NHL, non-Hodgkin’s lymphoma.
Diffuse large B‑cell lymphoma is the most common type of non‑Hodgkin’s lymphoma, representing about 30% of all non‑Hodgkin’s lymphoma. The average age at presentation is usually in the late 60s. The clinical outcomes are quite heterogeneous with respect to genetic subtypes and prognostic factors. Typically, the disease is curable in 50% or more of patients with modern therapy.
Michallet AS, et al. Blood Rev. 2009;23:11-23.

8. Essential Diagnostic Assessments for DLBCL
Hematopathology review of slides with ≥ 1 paraffin block representing tumor[1]
Excisional or incisional lymph node biopsy[1]
Core needle biopsy may be acceptable in combination with ancillary techniques (eg, flow cytometry) when lymph node cannot be readily accessed
DLBCL immunotype[1] is typically CD20+, CD45+, CD3-
CD20, CD3, CD4, CD10, CD45, BCL2, BCL6, Ki-67, IRF-4/MUM1 by immunohistochemistry of paraffin section or
CD45, CD3, CD5, CD19, CD10, CD20, kappa/lambda by flow cytometry
DLBCL subtypes[2]
GCB: CD10+ alone; CD10+ and bcl-6+; or bcl-6+, CD10-, and MUM1-
ABC: CD10- and bcl-6-; or bcl-6+, CD10-, and MUM1+
ABC, activated B cell; DLBCL, diffuse large B-cell lymphoma; GCB, germinal center B cell.
The essential diagnostic assessments for DLBCL are as follows:
Hematopathology review with paraffin sections or tumor blocks available for special studies.
An excisional or incisional lymph node biopsy. Core biopsies are not adequate for initial diagnosis. They may be adequate at the time of relapse in some types of lymphomas but are typically considered inadequate for diagnostic purposes.
DLBCL typically has a CD20-positive immunophenotype, but some subtypes have a different immunophenotype; some are CD20 negative.
The 2 most common genotypes are germinal center B‑cell lymphoma, which typically has the immunophenotype as shown on this slide, or activated B‑cell type, which is MUM1 positive. Patients with activated B‑cell–type DLBCL typically have a worse outcome with the cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) and rituximab (R)-CHOP regimens.
1. NCCN clinical practice guidelines in oncology: non-Hodgkin’s lymphomas. v Hans CP, et al. Blood. 2004;103:

9. DLBCL: Prognostic Factors IPI
Adverse risk factors correlated with response to chemotherapy and survival
Older than 60 yrs of age
LDH > normal
PS ≥ 2
Ann Arbor stage III/IV
Extranodal involvement > 1 site*
Risk Group
Risk Factors, n
CR, %
5-Yr OS, %
Patients (all ages)
Low
0-1 87 73
Low intermediate 2 67 51
High intermediate 3 55 43
High
4-5 44 26
CR, complete response; DLBCL, diffuse large B-cell lymphoma; IPI, International Prognostic Index; LDH, lactate dehydrogenase; OS, overall survival; PS, performance status.
The International Prognostic Index (IPI) has been used for patients receiving CHOP or R‑CHOP.
Adverse prognostic factors include:
Older than 60 years
Lactate dehydrogenase (LDH) level above the upper limits of normal
Performance status of 2 or greater
Advanced disease (stage III/IV)
More than 1 extranodal site of disease
The number of risk factors is correlated with the potential outcome. These data represent patients from the original publication, which used an anthracycline‑based regimen without R.
*Prognostic for patients older than 60 yrs of age only.
International NHL Prognosis Factors Project. N Engl J Med. 1993;329: 9

10. OS According to Revised IPI
1.0
0.9
0.8
0.7
0.6
Percent Survival
0.5
Legend
Revised IPI Risk Group
IPI Factors, n
Very good
Good
1, 2
Poor
3, 4, 5
0.4
IPI, International Prognostic Index; OS, overall survival.
This survival curve shows the results of applying the revised IPI to patients who received R‑CHOP chemotherapy. In the poor‑risk group, patients with 3-5 risk factors have an approximately 50% chance of disease‑free survival at 4 years.
0.3
0.2
0.1
P < .001 1 2 3 4 5
Yrs
Sehn LH, et al. Blood. 2007;109:

11. Diffuse Large B-Cell Lymphoma
Gene Expression Defines Molecularly and Clinically Distinct Subgroups in DLBCL
Diffuse Large B-Cell Lymphoma
DLBCL, diffuse large B-cell lymphoma.
The 2 most common types of DLBCL are activated B‑cell like and germinal center B-cell like; they have very different gene expression profiles. A third DLBCL classification is primary mediastinal B‑cell lymphoma. Gene expression as predictive factors helps examine both infiltrating cells as well as malignant cells.
Dave SS, et al. N Engl J Med. 2006;354: Graphic reproduced with permission.

12. Survival by Subgroups in DLBCL
Diffuse Large B-Cell Lymphoma
1.0
DLBCL Subgroup
5-Yr OS, %
PMBL 64
GCB DLBCL 59
ABC DLBCL 30
0.8
0.6 OS
ABC, activated B-cell; DLBCL, diffuse large B-cell lymphoma; GCB, germinal center B-cell; OS, overall survival; PMBL, primary mediastinal B-cell lymphoma.
In the original study, gene expression profiling was correlated with survival in patients with DLBCL who were receiving CHOP without R. In this study, only 30% of patients with the activated B‑cell subtype remained alive at 5 years.
0.4
0.2 2 4 6 8 10
Yrs
Rosenwald A, et al. J Exp Med. 2003;198:

13. Cytogenetic Changes Associated With Subgroups in DLBCL
GCB DLBCL
ABC DLBCL
PMBL
c-Rel amplification 16 25
Bcl-2 translocation 45 18
Gain of 3q 24 5
Gain/amplification of 9p24 6 43
Constitutive NF-κB activation No
Yes
ABC, activated B-cell; DLBCL, diffuse large B-cell lymphoma; GCB, germinal center B-cell; PMBL, primary mediastinal B-cell lymphoma.
Gene expression defines molecularly and clinically distinct groups of patients with DLBCL. Approximately 25% of patients with the activated B‑cell subtype appear to have a gain of 3q. A gain or amplification of 9p24 is seen in almost half of patients with primary mediastinal B‑cell lymphoma. In addition, constitutive activation of the NF‑kappa B pathway is present in patients with activated B‑cell or the primary mediastinal B‑cell lymphoma. This pathway may be a therapeutic target in the future.
Bea S, et al. Blood. 2005;106:

14. Molecular Changes Associated With DLBCL
Prevalence of genetic abnormalities
Recurring chromosomal translocations: ~ 50%
DNA imbalances: up to 67%
Gene(s) Affected/Disregulated
Frequency, %
Predominant Causal Genetic Abnormality
Multiple 45
Aberrant SHM
Bcl-6
35-40
3q27 translocations
Bcl-2
13/24
t(14;18)/amplification
Fas(CD95) 20
10q24 mutations
p53 16
17p mutations/deletions
c-Myc 15
t(8;14) deregulation
Potentially c-Rel 14
2p13 amplification
DLBCL, diffuse large B-cell lymphoma; SHM, somatic hypermutation.
Specific molecular changes and different genetic abnormalities are associated with DLBCL. Recurrent chromosomal translocations occur in about 50% of cases; one of the most common genes involved is Bcl‑6, which is abnormal in about 40% of cases, typically due to 3q27 translocations. Bcl‑2 with t(14;18) is present in approximately 20% of patients with DLBCL. Abnormalities in p53 are associated with the 17p mutation or deletion and represent a very poor prognosis in DLBCL. Likewise, the c‑Myc 8;14 translocation is present in about 15% of patients and typically represents a poor prognosis.
Abramson JS, et al. Blood. 2005;106:

15. DLBCL Subtype Retains Prognostic Value With R-CHOP Therapy
CHOP-Rituximab OS
CHOP-Rituximab PFS
CHOP OS
1.0
1.0
1.0
0.8
0.8
0.8
0.6
0.6
0.6
Probability
0.4
0.4
0.4
0.2
0.2
0.2
P < .001
P < .001
P = 8 x 10-6
ABC, activated B-cell; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; DLBCL, diffuse large B-cell lymphoma; GCB, germinal center B-cell; OS, overall survival; PFS, progression-free survival; R-CHOP, rituximab plus CHOP.
More recently, gene expression profiling was evaluated in patients treated with R-CHOP and again demonstrated that the patients with activated B‑cell subtype have a worse outcome, and patients with germinal center B‑cell type have an improved outcome. However, both subgroups experienced improved survival compared with previous data for CHOP. 1 2 3 4 5 6 1 2 3 4 5 6 1 2 3 4 5 6
Yrs
Yrs
Yrs
GCB DLBCL
ABC DLBCL
Lenz G, et al. N Engl J Med. 2008;359:

16. Advanced-Stage DLBCL DLBCL, diffuse large B-cell lymphoma.
We will now review data on advanced-stage DLBCL.

17. CHOP ± Rituximab in DLBCL: GELA LNH-98.5 Phase III Study
Assessment
Stratified by risk factors (0-1 vs 2-3)
R-CHOP every 3 wks for 8 cycles (n = 202)
Untreated elderly patients with stage II-IV DLBCL
(N = 399)
CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; DLBCL, diffuse large B-cell lymphoma; EFS, event-free survival; OS, overall survival; R-CHOP, rituximab plus CHOP; RR, response rate.
The modern era began with this GELA study, in which 399 patients older than 60 years were randomized to receive either CHOP or R‑CHOP chemotherapy for 8 cycles. The primary endpoint was event‑free survival.
CHOP every 3 wks for 8 cycles (n = 197)
Primary endpoint: EFS
Secondary endpoints: OS, RR
Coiffier B, et al. N Engl J Med. 2002;346: Feugier P, et al. J Clin Oncol. 2005;23:
Coiffier et al. N Engl J Med. 2002;346:235
Feugier et al. J Clin Oncol. 2005;23:4117. 17

18. Survival Distribution Function
CHOP ± Rituximab in DLBCL: 10-Yr Survival Results (GELA LNH-98.5 Study)
OS (N = 399)[1]
Parameter, %[2]
Low Risk
High Risk
Age, < 70 vs ≥ 70 yrs
58.0
49.0
LDH, NI vs > NI
69.0
45.0*
Stage, I/II vs III/IV
67.0
50.0
Bone marrow, yes vs no
60.0
34.5*
Tumor size, < 10 vs ≥ 10 cm
36.5
β2-microglobulin, NI vs > NI
64.5
39.0*
Serum albumin, ≥ 35 vs < 35 g/L
40.0
1.00
CHOP
R-CHOP
0.75
Survival Distribution Function
0.50
0.25
P < .0001
0.00
CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; DLBCL, diffuse large B-cell lymphoma; LDH, lactate dehydrogenase; OS, overall survival; R-CHOP, rituximab plus CHOP.
Over time, data from this trial continued to show improved survival in patients who received R-CHOP. Identified risk factors for a poor prognosis included age of more than 70 years, high LDH level, bone marrow involvement, and other prognostic signs. 2 4 6 8 10 12
OS (Yrs)
*P < .05 (multivariate analysis).
Median OS: 3.5 yrs with CHOP vs 8.4 yrs with R-CHOP
1. Coiffier B, et al. Blood. 2010;116: Coiffier B, et al. ASCO Abstract 8009.

19. CHOP ± Rituximab x 8 Cycles vs CHOP ± Rituximab x 6 Cycles Plus ASCT
Stratified by high-intermediate vs high IPI
CHOP ± Rituximab for 1 cycle + ASCT*
(n = 125)
Patients with ≥ PR after induction with CHOP ± rituximab for 5 cycles
(N = 253)
ASCT, autologous stem cell transplantation; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; IPI, International Prognostic Index; PR, partial response.
This recent trial evaluated high‑dose chemotherapy and autologous stem cell transplantation as part of initial therapy for patients with DLBCL and a high- or high-intermediate–risk IPI score. The patients received CHOP or R‑CHOP induction therapy and were then randomized to receive either 3 additional cycles of R‑CHOP or CHOP, or 1 cycle of high‑dose therapy and autologous stem cell transplantation.
For more information, go online to
CHOP ± Rituximab for 3 Cycles
(n = 128)
*Allowed ASCT regimens: - SWOG total body irradiation (12 Gy/8 fractions) or - Carmustine 150 mg/m2 x 3 days + etoposide 60 mg/kg + cyclophosphamide 100 mg/kg For patients older than 60 yrs of age, carmustine was only ASCT regimen allowed
Stiff PJ, et al. ASCO Abstract 8001.

20. ASCT After CHOP ± Rituximab Improves PFS in Advanced High-Risk Diffuse NHL
ASCT significantly prolonged PFS in patients with advanced high- intermediate or high-IPI diffuse NHL who responded to induction therapy with 5 cycles of CHOP ± rituximab
Outcome, %
CHOP ± R for 1 Cycle + ASCT
(n = 125)
CHOP ± R for 3 Cycles
(n = 128)
HR (95% CI)
P Value
2-yr PFS 69 56
1.72 ( )
.005
High-intermediate IPI pts
60 (n = 81)
63 (n = 84)
High IPI pts
75 (n = 44)
47 (n = 44)
.02
2-yr OS 74 71
1.24 ( )
.16
70 (n = 81)
75 (n = 84)
82 (n = 44)
64 (n = 44)
.01
ASCT, autologous stem cell transplantation; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; IPI, International Prognostic Index; NHL, non-Hodgkin’s lymphoma; OS, overall survival; PFS, progression-free survival.
The progression‑free survival data showed an improvement for high‑risk patients who received consolidation with high‑dose chemotherapy followed by autologous stem cell transplantation. Patients with a high IPI score experienced the most benefit. Of note, overall survival for all patients was not different between arms. However, patients in the high IPI category did have an improvement with consolidation therapy (ie, chemotherapy and autologous stem cell transplantation) at first complete remission. There was an expected increased incidence of toxicity in the patients who underwent transplantation.
For more information, go online to
Higher incidence of grade 3/4 adverse events observed with ASCT
Stiff PJ, et al. ASCO Abstract 8001.

21. R-CHOP-14 vs R-CHOP-21 in Newly Diagnosed DLBCL (Phase III Study)
Stratified by IPI score and age
R-CHOP-14 x 6 cycles +
Rituximab x 8 cycles +
Lenograstim on Days 4-12
(n = 540)
Newly diagnosed CD20+ DLBCL
patients
(N = 1080)
R-CHOP-21 x 8 cycles +
Rituximab x 8 cycles
(n = 540)
CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; DLBCL, diffuse large B-cell lymphoma; FFS, failure-free survival; IPI, international prognostic index; OS, overall survival; R-CHOP, rituximab plus CHOP.
In this phase III trial, patients with newly diagnosed DLBCL were randomized to receive either R‑CHOP-14 or R‑CHOP-21; they were stratified by IPI score and age. Patients in the R-CHOP-14 arm received growth-factor support with each cycle of therapy. Patients in the R‑CHOP-21 arm received growth factors only as clinically appropriate. The primary endpoint was overall survival.
Primary endpoint: OS
Secondary endpoint: FFS, toxicity, response rates
Cunningham D, et al. ASCO Abstract 8000.

22. R-CHOP-14 vs R-CHOP-21 in Newly Diagnosed DLBCL: Final Results
Response (Based on End of Treatment Scan), %
CR/CRu (P = .15) 63 58
CR/CRu/PR (P = .11) 88 90 CR 49 41
CRu 14 17 PR 25 32 SD 6 5
PD/relapse 4
Survival results, %
FFS (P = .94) 75
OS (P = .70) 81 83
CR, complete response; CRu, unconfirmed complete response; DLBCL, diffuse large B-cell lymphoma; FFS, failure-free survival; OS, overall survival; PD, progressive disease; PR, partial response; R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone; SD, stable disease.
Both the complete response rate and the overall response rate showed no difference between arms. Failure‑free survival was identical, with 75% in each arm remaining alive at 5 years; likewise, overall survival was not significantly different between arms, at 81% with R-CHOP-21 vs 83% with R-CHOP-14.
Cunningham D, et al. ASCO Abstract 8000.

23. LNH03-6B GELA: R-CHOP-14 vs R-CHOP-21 in Elderly DLBCL Patients
R-CHOP every 14 days for 8 cycles + IT MTX for 4 cycles (n = 103)
Prophylactic Darbepoetin alfa
Conventional treatment for chemotherapy- induced anemia
DLBCL patients yrs of age
(N = 202)
R-CHOP every 21 days for 8 cycles + IT MTX for 4 cycles (n = 98)
Prophylactic Darbepoetin alfa
Conventional treatment for chemotherapy- induced anemia
CR, complete response, CRu, unconfirmed complete response; DFS, disease-free survival; DLBCL, diffuse large B-cell lymphoma; EFS, event-free survival; IT, intrathecal; MTX, methotrexate; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone.
The LNH03-6B study randomized patients aged years to 8 cycles of either R‑CHOP-14 or R‑CHOP-21, both with intrathecal methotrexate for 4 cycles. The patients had a second randomization to receive prophylactic darbepoetin or conventional treatment for anemia. The primary endpoint in this trial was event‑free survival.
For more information, go online to
Primary endpoint: EFS
Secondary endpoints: CR or CRu , ORR, PFS , DFS, OS, dose intensity, toxicity
Delarue R, et al. ASH Abstract 406.

24. LNH03-6B GELA Trial: Results
Outcome
R-CHOP-21 (n = 98)
R-CHOP-14 (n = 103)
P Value
2-yr EFS, % 61 48
.11
Median EFS, mos
Not reached 22 --
2-yr PFS, % 63 49
.12
Median PFS, mos 23
2-yr DFS, % 70 57
.40
Median 2-yr OS, % 67
.37
End of treatment response rates
CR + CRu 75 NS PR 9 14
ORR 84 81
CR, complete response; CRu, unconfirmed complete response; DFS, disease-free survival; EFS, event-free survival; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone.
Results showed no difference in the 2‑year event‑free survival rate between patients randomized to R‑CHOP-21 vs R‑CHOP-14. Likewise, no difference was seen between arms in overall survival at 2 years: 70% vs 67%, respectively. Complete response and overall response rates were also nearly identical. Further follow‑up data from this trial should be available in the near future.
For more information, go online to
Delarue R, et al. ASH Abstract 406.

25. LNH03-6B GELA Trial: Toxicities
Hematologic toxicities greater for R-CHOP-14
Patients on R-CHOP-14 had higher rates of febrile neutropenia, hospitalization, and death due to toxicity
100 83 83
R-CHOP-14 80 73
R-CHOP-21 69 60 50
Patients (%) 40 36 26 22 21 22 20 15
RBC, red blood cells; R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone.
The toxicity data demonstrated that patients receiving the R‑CHOP-14 did have more hematologic toxicity and a slightly increased risk of needing transfusion.
For more information, go online to 11
Grade 3/4 Leukocytes
Grade 3/4 Neutrophils
Grade 3/4 Hemoglobin
RBC Transfusion
Grade 3/4 Platelets
Platelet Transfusion
Delarue R, et al. ASH Abstract 406.

26. R-EPOCH Regimen Given every 21 days for 4-6 cycles
Dose-adjusted regimen consisting of
Rituximab 375 mg/m2 on Day 1
Etoposide 65 mg/m2 continuous IV on Days 2-4
Prednisone 60 mg/m2 PO on Days 1-14
Vincristine 0.5 mg continuous IV on Days 2-4
Cyclophosphamide 750 mg/m2 IV on Day 5
Doxorubicin 15 mg/m2 continuous IV on Days 2-4
R-EPOCH, rituximab plus etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin.
Rituximab plus etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (R-EPOCH) is a slightly different regimen for induction therapy that is given every 21 days. It is a dose‑adjusted regimen, which includes a switch to the drugs in R‑CHOP, the addition of etoposide, and administration using continuous infusion for some of the agents.
Wilson WH, et al. J Clin Oncol. 2008;26:

27. Phase II Study of Dose-Adjusted EPOCH-R in DLBCL (CALGB 50103): PFS by IPI Score
5-yr PFS: 79%
Low risk IPI: 91%
Low-int risk IPI: 90%
High-int risk IPI: 67%
High risk IPI: 47%
IPI score significantly associated with PFS (P = .007)
100 80 60
PFS (%) 40
Low risk Low-intermediate risk High-intermediate risk High risk 20 1 2 3 4 5 6 7 8
DLBCL, diffuse large B-cell lymphoma; IPI, International Prognostic Index; PFS, progression-free survival; R-EPOCH, rituximab plus etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin.
Results from the CALGB study of R‑EPOCH showed a 5‑year progression‑free survival rate of 79% for all patients. The rate in patients with a high-risk IPI score was 47% vs 90% in low‑risk patients.
Yrs on Study
Median potential follow-up: 54 mos
Wilson WH, et al. J Clin Oncol. 2008;26:

28. CALGB 50303: R-CHOP vs R-EPOCH in Newly Diagnosed DLBCL
R-CHOP every 3 wks for 6 cycles
Untreated patients with newly diagnosed
DLBCL
(N = 478)
R-EPOCH Doxorubicin, etoposide, vincristine Days 1-4 +
Cyclophosphamide Day 5 +
Prednisone Days 1-5
DLBCL, diffuse large B-cell lymphoma; EFS, event-free survival; FDG-PET, fluorine-18 fluorodeoxyglucose positron emission tomography; OS, overall survival; PR, partial response; R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone; R-EPOCH, rituximab plus etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin; RR, relapse rate.
The current CALGB study will randomize newly diagnosed patients with DLBCL to R‑CHOP or R‑EPOCH. In addition, specimens from the patients will be looked at with respect to the genotype. Primary endpoints are event‑free survival and molecular predictors of outcome. Positron emission tomography scanning will be conducted to prospectively validate results.
Primary endpoints: EFS, molecular predictors of outcome for each regimen
Secondary endpoints: RR, OS, toxicity, use of molecular profiling for pathological diagnosis, prospective validation of FDG-PET
ClinicalTrials.gov. NCT

29. Relapsed DLBCL DLBCL, diffuse large B-cell lymphoma.
We will now review data on relapsed DLBCL.

30. Guideline Recommendations for Treatment of Relapsed DLBCL
Second-line therapy in candidates for high-dose therapy + ASCT
DHAP ± rituximab
ESHAP ± rituximab
GDP ± rituximab
GemOx ± rituximab
ICE ± rituximab
miniBEAM ± rituximab
MINE ± rituximab
Second-line therapy for patients who are not candidates for high- dose therapy
Clinical trial
Rituximab
CEPP ± rituximab
PEPC
EPOCH ± rituximab
ASCT, autologous stem cell transplantation; CEPP, cyclophosphamide, etoposide, procarbazine, prednisone; DHAP, dexamethasone, cisplatin, high-dose cytarabine; DLBCL, diffuse large B-cell lymphoma; EPOCH, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin; ESHAP, etoposide, methylprednisolone, cytarabine, cisplatin; GDP, gemcitabine, cisplatinum, dexamethasone; GemOx, gemcitabine, oxaliplatin; ICE, ifosfamide, carboplatin, etoposide; MINE, mesna, ifosfamide, mitoxantrone, etoposide; miniBEAM, carmustine, etoposide, cytarabine, melphalan; PEPC, prednisone, etoposide, procarbazine, cyclophosphamide.
More aggressive treatments, such as regimens containing cytarabine or gemcitabine, are appropriate for patients with relapsed DLBCL who are transplant candidates. Second‑line treatment for those not physically able to undergo high‑dose therapy and autologous stem cell transplantation (ie, the standard of care) include less toxic regimens such as cyclophosphamide, etoposide, procarbazine, and prednisone; and prednisone, etoposide, procarbazine, and cyclophosphamide. Clinical trials are also suggested for this patient population.
NCCN clinical practice guidelines in oncology: non-Hodgkin’s lymphomas. v

31. PARMA Study: Bone Marrow Transplantation vs Salvage Chemotherapy
100
100
Conventional treatment 80 80 60 60
EFS (%)
OS (%) 40 40 20 20
P = .001
P = .038
EFS, event-free survival; OS, overall survival.
The standard of care for patients with relapsed DLBCL who are transplant candidates is based on the PARMA study, which showed that patients receiving autologous stem cell transplantation had improved outcomes compared to patients receiving conventional dexamethasone, cisplatin, high-dose cytarabine (DHAP) chemotherapy. 15 30 45 60 75 90 15 30 45 60 75 90
Mos After Randomization
Mos After Randomization
Philip T, et al. N Engl J Med. 1995;333:

32. CORAL Trial of R-ICE vs R-DHAP
Which salvage regimen is the best? R A N D O M I Z E
R-ICE x 3
SD/PD → Off A S C T
CD20+ DLBCL
Relapsed/Refractory R A N D O M I Z E
R x 6
N = 400
R-DHAP x 3
PR/CR → →
ASCT, autologous stem cell transplantation; CR, complete response; DLBCL, diffuse large B-cell lymphoma; Obs, observation; PD, progressive disease; PR, partial response; R-DHAP, rituximab plus dexamethasone, cisplatin, high-dose cytarabine; R-ICE, rituximab plus ifosfamide, carboplatin, etoposide; SD, stable disease.
More recently, the CORAL trial compared 2 different induction salvage chemotherapy regimens for patients going on to transplantation. In this trial, patients with relapsed DLBCL were randomized to receive 3 cycles of either R plus ifosfamide, carboplatin, etoposide (R‑ICE) or R‑DHAP. Patients then went on to transplantation if they achieved a complete or partial remission. There was a secondary randomization to receive R posttransplant or observation.
Obs
Place of immunotherapy posttransplantation?
Gisselbrecht C, et al. J Clin Oncol. 2010;28:

33. CORAL Trial: OS and EFS OS According to Treatment Arm (Induction ITT)
EFS According to Treatment Arm (Induction ITT)
R-ICE R-DHAP
R-ICE R-DHAP
1.0
1.0
0.8
0.8
0.6
0.6
Survival Probability
Survival Probability
0.4
0.4
EFS, event-free survival; ITT, intent-to-treat; OS, overall survival; R-DHAP, rituximab plus dexamethasone, cisplatin, high-dose cytarabine; R-ICE, rituximab plus ifosfamide, carboplatin, etoposide.
The initial analysis showed no overall survival difference between patients randomized to salvage chemotherapy with R‑ICE or R‑DHAP; event‑free survival was also identical.
0.2
0.2
P = .4899
P = .2672 12 24 36 48 60 72 12 24 36 48 60 72
OS (Mos)
EFS (Mos)
Gisselbrecht C, et al. ASCO Abstract 8004.

34. CORAL Trial: Toxicity Event R-ICE R-DHAP
Infection with neutropenia: grade 3/4, n (%)
33 (17)
31 (16)
Infection without neutropenia: grade 3/4, n (%)
11 (6)
15 (8)
Renal: grade 3/4, n (%)
2 (1)
Platelet transfusions, % 35 57
Toxic deaths, n 1 3
R-DHAP, rituximab plus dexamethasone, cisplatin, high-dose cytarabine; R-ICE, rituximab plus ifosfamide, carboplatin, etoposide.
There were slight, but nonsignificant, differences in toxicity between the 2 regimens in terms of infectious complications.
Gisselbrecht C, et al. J Clin Oncol. 2010;28:

35. CORAL Trial: Rituximab Maintenance Therapy Not Superior to Observation
EFS at 4 yrs comparable between rituximab or no additional therapy (P = .7435)
No significant difference observed between maintenance arms in PFS (P = .8314) or OS (P = .7547)
Median time to OS not yet reached for rituximab maintenance
4-Yr Survival After Maintenance Therapy
Maintenance Rituximab
(n = 122)
No Additional Therapy
(n = 120)
EFS, % 55 53
Median EFS, mos
57.6
58.2
PFS, % 57
Median PFS, mos
OS, % 64 67
Median OS, mos
Not reached
62.9
EFS, event-free survival; OS, overall survival; PFS, progression-free survival.
Following secondary randomization to R maintenance or observation, the 4-year event-free survival rate was comparable between arms. Overall survival was also nearly identical. Of note, female patients tended to have a slightly improved outcome with R maintenance vs male patients.
For more information, go online to
Gisselbrecht C, et al. ASCO Abstract 8004.

36. Novel Approaches and Ongoing Clinical Trials
We will now discuss some novel approaches to the treatment of DLBCL and ongoing clinical trials.

37. Investigational Therapies for DLBCL
Bortezomib—proteasome inhibitor
Enzastaurin—PKCβ-selective inhibitor
PCI-32765—Btk Inhibitor
Epratuzumab—recombinant, humanized, monoclonal CD22 antibody
Everolimus—mTOR inhibitor
Bendamustine
Lenalidomide—immunomodulator, antiangiogenic
Radioimmunotherapy
Tamatinib—specific inhibitor of Syk in B-cell signaling pathway
DLBCL, diffuse large B-cell lymphoma; mTOR, mammalian target of rapamycin; PKC, protein kinase C.
Many investigational agents are in development for the treatment of DLBCL and target different pathways, such as the NF‑kappa B pathway and the B‑cell pathway. Agents include mammalian target of rapamycin inhibitors, Syk inhibitors, and Btk inhibitors. In addition, there are other new therapies such as bendamustine or use of immunomodulation or antiangiogenesis agents, such as lenalidomide.

38. Btk Inhibitor: PCI-32765 (Phase I Results)
Btk, a downstream mediator of B-cell receptor signaling
PCI a potent, irreversible, oral Btk inhibitor
Phase I study
Enrolled 47 patients with various relapsed/refractory B-cell malignancies (8 DLBCL)
ORR: 43%, including 3 CRs and 17 PRs
Of 14 patients on study ≥ 6 mos, 8 achieved ≥ PR and 6 SD
Grade ≥ 3 toxicities in 9 pts (19%)
5 pts discontinued due to AEs, but no Tx-related deaths
AE, adverse event; CR, complete response; DLBCL, diffuse large B-cell lymphoma; ORR, overall response rate; PR, partial response; R-EPOCH, rituximab plus etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin; SD, stable disease; Tx, treatment.
Some of the new therapies currently in clinical trials for patients who may not be transplant candidates, or who relapse, include inhibitors of B‑cell pathways. For example, PCI-32765, a Btk inhibitor. This phase I study enrolled 47 patients with different subtypes of B‑cell lymphomas, including 8 patients with DLBCL. The overall response rate was 43% and included 3 complete responses. Some patients had very prolonged treatment with good durability of remission. Toxicity was fairly minimal.
Fowler N, et al. ASH Abstract 964.

39. Epratuzumab + R-CHOP in First-line DLBCL (Phase II Study)
N = 78 eligible patients
85% EFS at 12 mos (n = 34) compared with 67% to 79% EFS and PFS at 12 mos in R-CHOP trials
95% ORR
62% CR/CRu
33% PR
ER-CHOP similar toxicity profile as R-CHOP
Results provide rationale for development of randomized phase III trial to compare ER-CHOP with R-CHOP
CR, complete response; CRu, unconfirmed complete response; DLBCL, diffuse large B-cell lymphoma; EFS, event-free survival; ER-CHOP, epratuzumab plus R-CHOP; ORR, overall response rate; PFS, progression-free survival; PR, partial response; R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone.
A phase II study of R‑CHOP plus epratuzumab (N = 78) showed a 12-month event-free survival rate of 85% and a high overall response rate of 95%. Adding epratuzumab to the R‑CHOP regimen did not appear to increase toxicity. A planned phase III randomized trial will compare R‑CHOP plus epratuzumab to standard R‑CHOP.
For more information, go online to
Micallef IN, et al. ASCO Abstract 8500. 39

40. Lenalidomide Lenalidomide: oral immunomodulatory agent
Antiangiogenic, less-toxic derivative of thalidomide
Recommended by NCCN as second-line regimen for MCL[1]
Phase II study (N = 49) in relapsed/ refractory aggressive NHL[2]
ORR: 35%, including 12% CR/CRu
Responses seen in DLBCL, FL, MCL, transformed lymphomas
Primary grade 3/4 toxicity: myelosuppression
Phase I/II trial of first-line lenalidomide plus R-CHOP in DLBCL or FL[3]
100
PFS 75
Patients (%) 50
CR, complete response; CRu, unconfirmed complete response; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; MCL, mantle cell lymphoma; NCCN, National Comprehensive Cancer Network; NHL, non-Hodgkin’s lymphoma; ORR, overall response rate; PFS, progression-free survival, R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone.
Lenalidomide is an oral immunomodulatory agent that also has antiangiogenic properties. It is recommended, although not US Food and Drug Administration approved, as a second‑line treatment for mantle cell lymphoma. Clinical trials of lenalidomide for DLBCL are ongoing. A phase II study with this agent showed an overall response rate of approximately 35%, including 12% complete responses. However, the duration of remission was short, and the median progression‑free survival was only 4 months. The primary toxicity of lenalidomide is myelosuppression, which often necessitates dose decreases. Studies are currently evaluating the addition of lenalidomide to R‑CHOP in frontline therapy. 25
Median PFS: 4 mos 5 10 15
Mos
1. NCCN Practice Guidelines in Oncology: Non-Hodgkin’s Lymphomas Wiernik PH, et al. J Clin Oncol. 2008;26: ClinicalTrials.gov. NCT 40

41. Bortezomib + R-CHOP as Frontline Therapy in DLBCL
Median follow-up: 21 mos (range: 9-35)
ORR results
ITT (n = 40): 90% (CR/CRu: 68%)
Evaluable (n = 36): 100% (CR/CRu: 75%)
Estimated 2-yr PFS: 72%
Treatment generally well tolerated
4 deaths prior to first response assessment
Phase I/II
N = 40 patients with previously untreated DLBCL
CHOP-21 + rituximab mg/m2 each cycle
Bortezomib given at 3 different doses
Arm 0 (n = 4): 0.7 mg/m2
Arm 1 (n = 8): 1.0 mg/m2
Arm 2 (n = 28): 1.3 mg/m2
CR, complete response; CRu, unconfirmed complete response; DLBCL, diffuse large B-cell lymphoma; ITT, intent to treat; ORR, overall response rate; PFS, progression-free survival; R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone.
Two studies are evaluating the addition of bortezomib to R‑CHOP chemotherapy as frontline therapy for DLBCL. In this phase I/II study, 40 patients received bortezomib with R‑CHOP at several different dosage levels. The overall response rate in the intent-to-treat population was 90%, and the 2‑year progression-free survival rate was 72%. The combination was well-tolerated, and bortezomib did not add any toxicity other than mild neuropathy.
Ruan J, et al. J Clin Oncol. 2011;29:

42. Everolimus: Ongoing Phase II and III Studies in DLBCL
Everolimus plus rituximab in relapsed/refractory DLBCL[1]
Everolimus, panobinostat, or both in relapsed/refractory DLBCL[2]
Everolimus in relapsed/refractory lymphoma[3]
Phase III
Everolimus as adjuvant therapy following CR to first-line rituximab-chemotherapy in patients with poor-risk DLBCL[4]
CR, complete response; DLBCL, diffuse large B-cell lymphoma.
Ongoing phase II and phase III studies are looking at everolimus in DLBCL. In the relapsed/refractory setting, agents under evaluation include everolimus with or without panobinostat and the combination of everolimus plus R. The addition of everolimus to upfront therapy also may be studied in the future.
1. ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT

43. Bendamustine + Rituximab
Bendamustine + Rituximab for Relapsed/ Refractory DLBCL: Phase II Study
Patients with relapsed/refractory
DLBCL,
failed at least 1 previous therapy
(N = 25, ITT)
Bendamustine + Rituximab
28-day cycles for 6 cycles
Day 1: bendamustine 120 mg/m2, rituximab 375 mg/m2
Day 2: bendamustine 120 mg/m2
ORR of 60% required by study design
DLBCL, diffuse large B-cell lymphoma; ITT, intent to treat; ORR, overall response rate.
Preliminary phase II data are available on bendamustine plus R for DLBCL. Bendamustine was given at the higher dose of 120 mg/m2. The overall response rate required for significance was 60%.
Vacirca JL, et al. ASCO Abstract 8041.

44. Bendamustine + Rituximab for Rel/Ref DLBCL: Preliminary Phase II Results
Response, %
(Median: 3 Cycles)
N = 25, ITT
N = 23, modified ITT
ORR 53 CR PR SD PD 12 41 18 29
AEs, adverse events; CR, complete response; DLBCL, diffuse large B-cell lymphoma; ITT, intent to treat; ORR, overall response rate; PD, progressive disease; PR, partial response; Rel/Ref, relapsed/refractory; SD, stable disease.
Preliminary results from this phase II study showed an overall response rate of 53%. As expected, hematologic toxicity was noted with this combination.
Grade 3/4 AEs, n
Neutropenia
Hematologic events
1 (grade 4)
9 (grade 3)
Vacirca JL, et al. ASCO Abstract 8041.

45. DLBCL Treatment
R CHOP the standard of care for the upfront therapy of DLBCL according to current NCCN guidelines
For patients with higher risk IPI score, a clinical trial may be appropriate
At the time of relapse, patients can be considered for stem cell transplantation
If they are transplant candidates, they should receive salvage therapy and then transplantation or, potentially, a clinical trial
For patients who are not candidates for transplantation, enrollment in a clinical trial would be appropriate.
DLBCL, diffuse large B-cell lymphoma; IPI, International Prognostic Index; NCCN, National Comprehensive Cancer Network; R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone.
Current National Comprehensive Cancer Network guidelines for the upfront therapy of DLBCL recommend R‑CHOP as the standard of care. For patients with a higher‑risk IPI score, a clinical trial may be appropriate. At the time of relapse, patients can be considered for stem cell transplantation. If they are transplant candidates, they should receive salvage therapy and then transplantation or, potentially, a clinical trial. For patients who are not candidates for transplantation, enrollment in a clinical trial would be appropriate. Recently, the data presented by Stiff and colleagues mentioned earlier at the 2011 American Society of Clinical Oncology meeting suggest that upfront chemotherapy with high‑dose chemotherapy and stem cell transplantation may be considered for patients with high‑risk disease.
NCCN. Clinical practice guidelines in oncology: non-Hodgkin’s lymphomas. v 45

46. Case Presentations
We will now review some case presentations to help illustrate the data we have just discussed.

47. Case Presentation 1
64-yr-old male diagnosed with stage IIIA DLBCL 3 yrs ago when he presented with diffuse lymphadenopathy, IPI 2/5
He was treated with R-CHOP x 6 and achieved a CR. He relapsed 1 yr later and underwent high-dose chemotherapy and autologous PSCT; he again had a CR
2 yrs after his transplantation and 3 yrs from his original diagnosis, he has relapsed again with diffuse lymphadenopathy but no other symptoms  
CR, complete response; DLBCL, diffuse large B-cell lymphoma; IPI, International Prognostic Index; PSCT, peripheral stem cell transplantation; R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone.
A 64‑year‑old male was diagnosed with stage IIIa DLBCL about 3 years ago. He presented at that time with diffuse lymphadenopathy and an IPI score of 2/5. He received R‑CHOP for 6 cycles and had a complete remission. He relapsed 1 year later and then underwent high‑dose chemotherapy and autologous stem cell transplantation, after which time he again attained a complete remission. At 2 years after transplantation (3 years from his original diagnosis) he relapsed again with diffuse lymphadenopathy but was asymptomatic.

48. Case Presentation 1 His options for therapy are: R-ICE R-ESHAP R-EPOCH
R-GemOx
Mini-allogeneic PBSCT
Clinical trial
PBSCT, peripheral blood stem cell transplantation; R-EPOCH, rituximab plus etoposide, prednisone, vincristine, cyclophosphamide; R-ESHAP, rituximab plus etoposide, methylprednisolone, cytarabine, cisplatin; R-GemOx, rituximab plus gemcitabine, oxaliplatin; R-ICE, rituximab plus ifosfamide, carboplatin, etoposide.
This patient’s options for therapy at this time include several different standard-of-care salvage regimens, such as R‑ICE, R plus etoposide, methylprednisolone, cytarabine, and cisplatin, R‑EPOCH, or R plus gemcitabine and oxaliplatin. Because the patient has already relapsed after transplantation, he may or may not be curable. If a patient wants aggressive treatment and is potentially curable, then any of the first 4 options would be adequate.
Option 5 is a mini-allogeneic transplantation, which is suitable for transplantation candidates. However, this patient is 64 years old and may be at high risk; the risks of a mini-allogeneic transplantation would have to be discussed with him.
Option 6 is a clinical trial. For a patient who has relapsed after transplantation and is not a candidate for mini-allogeneic transplantation, a clinical trial with some of these promising agents would be appropriate.

49. Case Presentation 2
73-yr-old man with stage IIIB DLBCL presents with diffuse lymphadenopathy, weight loss of 20 lbs, and drenching night sweats
LDH: 1257 U/L (upper limits of normal 618)
PS: 2
History of an MI 1 yr ago
Cardiac ejection fraction: 45%
DLBCL, diffuse large B-cell lymphoma; LDH, lactate dehydrogenase; MI, myocardial infarction; PS, performance status.
A 73‑year‑old man with stage IIIb DLBCL presents with diffuse lymphadenopathy, weight loss, and drenching night sweats. His LDH is twice the upper limit of normal at 1257 U/L. He has a performance status of 2, indicating that he is very affected by the lymphoma. He also had a myocardial infarction about a year earlier and has a slightly reduced cardiac ejection fraction.

50. Case Presentation 2 His options for therapy are: R-CHOP 14 R-CHOP 21
R-EPOCH
R-CEOP
R-CEOP, rituximab plus cyclophosphamide, epirubicin, vincristine, prednisolone; R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone; R-EPOCH, rituximab plus etoposide, prednisone, vincristine, cyclophosphamide.
This patient’s potential options for upfront therapy include R‑CHOP-14, R‑CHOP-21, or R‑EPOCH, which are anthracycline‑containing regimens. Because his ejection fraction is 45%, these are viable options. At this time, they all appear to be fairly equivalent with respect to outcome and any would be appropriate for this patient.
Option 4, R plus cyclophosphamide, epirubicin, vincristine, and prednisolone, is a non–anthracycline‑containing regimen; a Canadian study showed that this regimen used in elderly patients with very high‑risk disease and a history of heart problems performs almost as well anthracycline-based regimens. Therefore, for a patient who should not receive an anthracycline, this regimen would be an appropriate choice.

51. Case Presentation 3
34-yr-old female with stage IVA DLBCL presents to you for treatment
LDH: 800 U/L (upper limits of normal 618)
2 extra nodal sites: kidneys and lungs
Diffuse lymphadenopathy
PS: 1
DLBCL, diffuse large B-cell lymphoma; LDH, lactate dehydrogenase; PS, performance status.
Case 3 is a 34‑year‑old female with stage IVa DLBCL who presents for treatment. She has a slightly elevated LDH at 800 U/L (ULN: 618 U/L), 2 extranodal sites in the kidneys and lungs, diffuse lymphadenopathy, and a performance score of 1.

52. Case Presentation 3 Her options for therapy are: R-CHOP 14 R-CHOP 21
R-EPOCH
R-CHOP 14 or 21 with auto PBSCT
PBSCT, peripheral blood stem cell transplantation; R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone; R-EPOCH, rituximab plus etoposide, prednisone, vincristine, cyclophosphamide.
Her options for treatment at this time include R‑CHOP 14, R‑CHOP 21, and R‑EPOCH. All have performed similarly in clinical trials, and any would be an option for this patient.
She could also receive either R‑CHOP-14 or R-CHOP-21 with autologous stem cell transplantation. This would be based upon a study presented at the 2011 American Society of Clinical Oncology meeting in which patients with high‑risk IPI scores had better event‑free and overall survival if they received high‑dose chemotherapy and autologous stem cell transplantation as part of their initial management.

53. Now Take the Test . . .
To earn CME credit for this activity, please close this window and click the “Test” tab in the CME module underneath
Thank you for your attention. To earn CME credit for this activity, please close this window and click the “Test” tab in the CME module underneath.

54. Go Online for More on Overcoming Barriers to Optimal Treatment of Non-Hodgkin’s Lymphoma!
CME-certified slidesets: Current Treatment Options in Waldenström’s Macroglobulinemia Mantle Cell Lymphoma: Standard and Future Therapies Current and Emerging Treatment Options for Follicular Lymphoma
clinicaloptions.com/NHLworkshops