lenalidomide maintenance in DLBCL

1. Lenalidomide Maintenance Compared With Placebo
in Responding Elderly Patients With Diffuse Large
B-Cell Lymphoma Treated With First-Line R-CHOP
(Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and
Prednisone)

2. Why this study ?
• The standard treatment of patients with diffuse large B-cell
lymphoma (DLBCL) is rituximab in combination with
cyclophosphamide, doxorubicin, vincristine, and prednisone
(R-CHOP).
• Lenalidomide, an immunomodulatory agent, has shown
activity in DLBCL. This randomized phase III trial compared
lenalidomide as maintenance therapy with placebo in elderly
patients with DLBCL who achieved a complete response (CR)
or partial response (PR) to R-CHOP induction.

3. Introduction
• Diffuse large B-cell lymphoma (DLBCL) is the
most common non-Hodgkin lymphoma,
accounting for 30% to 40% of all cases .
• Two major DLBCL molecular subtypes:
germinal center B-cell–like (GCB) and
activated B-cell–like (ABC),
Immunohistochemistry based classification
defines only GCB and non GCB subtypes.

4. • The R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin,
vincristine, and prednisone), administered with curative intent, is
currently considered the standard of care therapy for patients of all
ages with newly diagnosed DLBCL, regardless of molecular subtype.
However, 3-year progression-free survival (PFS) and overall survival
(OS) rates remain at 60% and 70%, respectively.
• Patients with ABC DLBCL have a significantly worse outcome than
patients with GCB DLBCL.
• Attempts to improve the efficacy of R-CHOP by either adding
cytotoxic drugs or administering dose-intensified R-CHOP, have not
improved outcomes, except in specific subsets of young patients.
• Some 30% to 40% of patients continue to experience disease
progression or relapse, mostly during the first 2 years, and the
majority will succumb to lymphoma.

5. • The introduction of new drugs to R-CHOP may be an
option to improve patient outcomes; treatments are
currently under evaluation either in combination with
R-CHOP (RX-CHOP, X for new drug) or after R-CHOP as
maintenance therapy (R-CHOP→X).
• Maintenance therapy corresponds to a treatment
continuously administered for a prolonged time period,
typically with a single agent. The goal is to better
control the disease after initial therapy by improving
the quality of response, delaying disease progression,
and increasing long-term survival. This approach is
difficult to apply with classic cytotoxic agents because
of amplified toxicities

6. • In the context of targeted therapies, such as
monoclonal antibodies, kinase inhibitors, and
demethylating agents, maintenance strategies
have been used in clinical trials in a broad
range of neoplasia22-25 and recently in
lymphoma.

7. • Lenalidomide, an oral immunomodulator with direct
antineoplastic activity and immunologic effects, has
shown significant activity in relapsed DLBCL alone or
with rituximab.
• Its mechanisms of action are distinct from both
traditional chemotherapy and rituximab, and
lenalidomide has shown proven efficacy and
tolerability when used in combination with R-CHOP in
phase II trials.
• This provides a strong rationale for the addition of
lenalidomide to first-line induction therapy in DLBCL or
in the form of maintenance therapy after R-CHOP

8. • The Lymphoma Study Association (LYSA), in close
collaboration with other academic research
groups in some participating countries
(Arbeitsgemeinschaft Medikamentose
Tumortherapie, Austral- ¨ asian Leukaemia and
Lymphoma Group, and Grupo Español de
Linfomas y Trasplantes de Medula ´ Osea
[GELTAMO]), un- ´ dertook a study to compare
lenalidomide maintenance with placebo in
elderly patients with DLBCL who responded to
firstline R-CHOP

9. Study Design and Procedures
The REMARC study is an international,
multicenter,
double-blind,
randomized,
placebo-controlled
phase III trial
that was sponsored in 2009 by the
Lymphoma Academic Research Organization
(LYSARC).

10. Patients
Eligibility criteria :
1. age 60 to 80 years,
2.ECOG PS- 0 to 2,
3.Ann Arbor stage II to IV at diagnosis,
4.age-adjusted IPI 1 at diagnosis
5. untreated, histologically proven CD20+ DLBCL according to 2008 WHO
criteria.
*Eligible DLBCL histologies included
-de novo transformed DLBCL from low-grade lymphoma (follicular or others),
-associated with small-cell infiltration in bone marrow,
-CD20+ B-cell lymphoma with intermediate features between DLBCL and
Burkitt’s lymphoma or with intermediate features between DLBCL and Hodgkin
lymphoma,
-follicular lymphoma grade 3B,
- and CD20+ aggressive B-cell lymphoma unclassifiable.

11. • All patients were required to have achieved a
partial response (PR) or complete response
(CR) after first-line treatment.
• Responding patients were randomly assigned
(1:1) to 24 months of maintenance with either
lenalidomide or placebo.
• Stratification was realized according to country
and the response to R-CHOP (PR and CR)

12. Treatment
R-CHOP induction-
All patients received six or eight cycles of
R-CHOP–14 or –21 at standard doses.
Two cycles of rituximab could be administered
after six cycles at the investigator’s discretion. CNS
prophylaxis was applied at the investigator’s
discretion. Patients were included in the trial
either before induction (registration 1) or after
induction (registration 2).

13. Maintenance.
Maintenance treatment started within 12 weeks
after the first day of the last R-CHOP cycle or last
rituximab alone.
Lenalidomide or placebo was administered at the
starting dose of 25 mg/d, days 1 to 21 of every 28-
day cycle for 24 months (maximum, 26 cycles) until
completion of maintenance treatment, disease
progression or relapse, unacceptable toxicity, or
patient refusal.
A dose-reduction schedule was applied according to
toxicity (patients with moderate renal insufficiency
(creatinine clearance, 30 to 60 mL/min), the starting
dose of lenalidomide was 10 mg/d.

15. Evaluation of Response
After R-CHOP induction, response assessment was
analyzed between 3 and 8 weeks after day 1 of the
last induction cycle with a positron emission
tomography–computerized tomography (PET) scan
before randomization.
Bone marrow examination was repeated at the
end of induction if positive at diagnosis.

16. During maintenance, tumor response
assessment was performed
clinically every three cycles
CECT at cycles 6, 12 and 21 (18 months), at the
end of maintenance or time of discontinuation
from treatment, then annually.
Repeat PET scan evaluation was requested in
responding patients who were PET positive at
randomization.

17. Evaluation of Toxicity
An AE was defined as any adverse change from
the patient’s baseline condition, whether it was
considered related to treatment or not.
Each AE was graded according to the National
Cancer Institute Common Terminology Criteria
grading system version 4.
The following AEs were recorded in additional
detail: grade 3 to 5 toxicities, grade 2 to 5
infections and neurologic toxicities, and any
toxicity (regardless of grade) resulting in dose
modification.

18. Pathology and Cell of Origin
Characterization
Histologic diagnoses were centrally reviewed by
expert pathologists.
Expression of CD10, BCL6, and MUM1 was
examined by immunohistochemistry to classify all
cases as GCB or non-GCB using the Hans
algorithm.
Cell of origin was also determined in a subset of
patients by molecular testing from formalin-fixed
paraffin-embedded tissue using NanoString gene
expression profiling technology.

20. STATISTICAL ANALYSIS
• The primary end point of the study was PFS
defined using European Medicines Agency
censoring rules as first documented disease
progression or relapse assessed by a
blinded independent response committee
or death from any cause, whichever
occurred first from random assignment.
• Secondary end points were safety, the
percentage of patients who converted from
PR to CR, event-free survival, event-free
survival at 24 months, and OS.

28. Maintenance Completion
Among patients randomly assigned to lenalidomide, 196 (61%) prematurely
discontinued treatment, 111 (34%) completed maintenance, and 16 (5%)
remained on maintenance at the time of primary analysis
Among those in the placebo arm, 134 (41%) prematurely discontinued
treatment, 169 (52%) completed maintenance, and 24 (7%) remained on
maintenance.

29. PFS
• With a median follow-up of 39 months (range, 0.0 to
74.1 months), median PFS was not reached in the
lenalidomide arm but was estimated at 58.9 months in
the placebo arm (HR favoring lenalidomide, 0.708; 95%
CI, 0.537 to 0.933; P = .0135; ).
• The 2-year PFS was improved from 75% (95% CI, 70%
to 80%) to 80% (95% CI, 75% to 84%) in the
lenalidomide group. The PFS benefit of lenalidomide
maintenance over placebo was seen in all analyzed
subgroups predefined in the protocol

31. Overall Survival
• At a longer median follow-up of 52 months, median OS
was not reached in either group. The 2-year OS was
estimated at 87% (95% CI, 82% to 90%) for
lenalidomide versus 89% (95% CI, 85% to 92%) for
placebo (log-rank test P = .2640; HR, 1.218; 95% CI,
0.861 to 1.721; Fig 3B).
• Lymphoma was the main cause of death, including 41
(59%) of 69 patients in the lenalidomide arm compared
with 37 (62%) of 60 patients in the placebo arm
(Appendix Table A2, online only). Other causes of
death included other cancers (six for lenalidomide and
seven for placebo) and concurrent illness (seven for
lenalidomide arm and two for placebo).

32. Cell of Origin
• Analysis of outcomes on the basis of cell of origin (COO) per Hans
criteria in patients with DLBCL only showed a statistically significant
difference in median PFS in favor of lenalidomide (60.9 months;
95% CI, 59.8 months to not reached) over placebo (52.7 months;
95% CI, 40.5 months to not reached) in patients with a GCB profile
(HR, 0.491; 95% CI, 0.245 to 0.985; P = .04).
• No significant difference was seen in patients with a non-GCB
profile (HR, 1.081; 95% CI, 0.670 to 1.746; P = .75).
• For OS, there was no difference in either the GCB (P = .92) or the
non-GCB (P = .07) groups.
• Per NanoString, there was no difference in PFS for patients with
GCB-like, ABC-like, or unclassified DLBCL (log-rank P = .15, P = .82,
and P = .31, respectively; ) and no difference in OS (log-rank P =
.73, P = .29, and P = .42, respectively).

33. • Conversion From PR to CR and Response Rate at
the End of Maintenance
• In the lenalidomide arm, 23 (33%) patients
converted from PR to CR during maintenance
compared with 24 (29%) patients in the placebo
group (P = .56; ).
• On the basis of central review, 18 (21%) patients
converted from PET-positive to PET-negative in
the lenalidomide arm versus 13 (14%) patients in
placebo arm (P = .20).
• The median time of conversion was
approximately 6 months and was similar in both
groups.

34. • Safety
• The safety population included a total of 645 patients who received
at least one dose of maintenance treatment. The median average
daily dose was 19.8 mg/d (range, 5.2 to 25.0 mg/d) in lenalidomide
arm and 25.0 mg/d for placebo.
• The median number of maintenance cycles received in lenalidomide
arm was 15 (range, 1 to 26) versus 25 (range, 1 to 26) in the placebo
arm. In the lenalidomide arm, 72% of patients had at least one dose
reduction compared with 42% in the placebo arm, and 36% stopped
because of the toxicities due to treatment versus 16%, respectively.
• From this safety set, 564 patients (87%) reported at least one
treatment-emergent adverse event (TEAE), 296 patients (92%) in
the lenalidomide arm and 268 patients (83%) in the placebo arm.
• At least one serious TEAE was reported in 99 patients (31%) in the
lenalidomide arm and 91 patients (28%) in the placebo arm. Details
of the most common observed grade 3 or 4 AEs are listed in TEAEs
leading to dose reductions were reported in 66% and 32% of
patients, respectively. Occurrence of second primary malignancies
observed during or after maintenance was similar in both arms: 32
(10%) versus 41 (13%).

35. DISCUSSION
• The REMARC study is the first phase III
trial evaluating a maintenance strategy in
DLBCL to show a benefit in PFS.
• None of the previously reported trials
adding a novel drug to R-CHOP, either in
combination during induction
(bevacizumab) or after R-CHOP as
maintenance (rituximab,enzastaurin,or
everolimus) have achieved such a benefit.

36. • The PFS benefit of lenalidomide maintenance was
equally important in patients who achieved a CR as in
those achieving a PR.
• Interestingly, patients with PR, particularly those with a
positive PET scan, converted to CR within 6 months in
both arms, which suggested that induction treatment
may be more responsible for this conversion than the
maintenance treatment.
• The PFS benefit was also observed based on subgroup
analysis of clinical characteristics at diagnosis (age, sex,
International Prognostic Index).

37. • Lenalidomide is an IMiD immunomodulatory agent with activity in
lymphoid malignancies occurring primarily through immune modulation.
The strategy in REMARC was to take advantage of this potential to repair
T-cell immune synapse dysfunction by lenalidomide, as reported in
follicular lymphoma and chronic lymphocytic leukemia, to eradicate
resting lymphoma cells after R-CHOP induction, avoiding both early and
late relapse. It has been shown that lenalidomide reduces T regulatory
cells, activates CD8+ T cells, and skews T-helper (TH) subsets with TH1.TH2
response. It is unlikely that, in a maintenance setting like REMARC, the
clinical benefit observed in the lenalidomide arm could be due to a direct
tumoricidal effect with upregulation of interferon-stimulated genes that
require cereblon expression, but rather an immunomodulatory
mechanism. This speculation has been made in at least one other
lenalidomide maintenance trial in chronic lymphocytic leukemia and is
supported by the observation that PR-to-CR conversion is similar between
the lenalidomide maintenance and placebo in this trial and in the second
lenalidomide maintenance trial.

38. • At the time of this analysis, we do not yet fully
understand the basis for lack of OS benefit
despite the positive PFS data, other than that
this is not due to excessive toxicity in the
experimental arm. We speculate the reason
may be differences in the outcomes after
progression or some other unrecognized
reason.

39. • Finally, although lenalidomide toxicities
were as expected, with more grade 3 and 4
neutropenia and cutaneous reactions
resulting in more premature
discontinuations, even for patients with
minimal exposure to the drug, the benefit
of lenalidomide on PFS was still present
(data not shown). Of note, the rate of
second primary malignancies was similar
in both arms.

40. conclusion
• REMARC achieved its primary end point of a
statistically significant and clinically meaningful
improvement in PFS for patients receiving
lenalidomide maintenance, with an anticipated
and manageable safety profile.
• To our knowledge, this is the first randomized
study showing that an immunomodulatory agent
as maintenance therapy prolongs PFS for patients
with DLBCL after responding to R-CHOP.