NON-HODGKIN LYMPHOMA I: CHANGING THERAPEUTIC STRATEGIES IN AGGRESSIVE LYMPHOMAS
Is there any role for transplantation in the rituximab era for
diffuse large B-cell lymphoma?
Christian Gisselbrecht1
1Hospital
Saint Louis, Paris Diderot University, Paris, France
Salvage chemotherapy followed by high-dose therapy and autologous stem cell transplantation is the standard of
treatment for chemosensitive relapses in diffuse large B-cell lymphoma. The addition of rituximab to chemotherapy
has improved the response rate and failure-free survival after first-line treatment and relapses. Fewer relapses are
expected, although there is no consensus on the best salvage regimen. The intergroup Collaborative Trial in Relapsed
Aggressive Lymphoma (CORAL) set the limits for this standard of treatment after first comparing 2 salvage regimens:
rituximab, ifosfamide, etoposide, and carboplatin (R-ICE) and rituximab, dexamethasone, aracytine, and cisplatin
(R-DHAP). There was no difference in response rates or survivals between these salvage regimens. Several factors
affected survival: prior treatment with rituximab, early relapse (⬍ 12 months), and a secondary International Prognostic
Index score of 2-3. For patients with 2 factors, the response rate to salvage was only 46%, which identified easily a
group with poor outcome. Moreover, patients with an ABC subtype or c-MYC translocation responded poorly to
treatment. More than 70% of patients will not benefit from standard salvage therapy, and continued progress is needed.
Studies evaluating immunotherapy after transplantation, including allotransplantation, new conditioning regimens with
radioimmunotherapy and other combinations of chemotherapy based on diffuse large B-cell lymphoma subtype, are
discussed herein. Early relapses and/or patients refractory to upfront rituximab-based chemotherapy have a poor
response rate and prognosis. A better biological understanding of these patients and new approaches are warranted.
Introduction
The development of rituximab, a chimeric anti-CD20 Ab, represented a revolutionary advance in the therapy of hematologic
malignancies. The combination of rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) has produced significant survival benefits in elderly patients with untreated
diffuse large B-cell lymphoma (DLCBL) compared with CHOP
alone.1 The same immunochemotherapy regimen has resulted in an
improved outcome in young, low-risk patients as defined by the
age-adjusted International Prognostic Index (aaIPI).2 Despite these
major advances, some patients will experience early treatment
failure, a partial response, or a relapse after the initial chemotherapy. In this context, treatment is a major challenge. The initial
approach to relapsed DLBCL management is to determine whether
a patient is a candidate for high-dose therapy (HDT) and autologous
stem cell transplantation (ASCT). In 1995, the PARMA trial
evaluated salvage chemotherapy with a platinum- and cytarabinebased (DHAP) regimen alone or in combination with ASCT.3 Both
the event-free survival (EFS) and overall survival (OS) were
superior in the transplantation group compared with patients
receiving chemotherapy alone. Based on these results, HDT/ASCT
has become the standard of care in younger patients with chemosensitive relapsed or primary refractory aggressive lymphoma. However, in the rituximab era, the impact of chemotherapy on the final
therapeutic results must be determined along with other prognostic
factors. For example, how many patients require salvage treatments
and is salvage with ASCT an efficient treatment?
What is the rate of relapse or failure according to
aaIPI after first-line treatment?
In young patients (⬍ 60 years) with no adverse prognostic factors,
the expected relapse rate after first-line treatment for DLBCL is
410
10%.2 In the case of only one IPI factor, the rate of relapse varies
from 20%-30% depending on whether the patient has received
treatment with dose-intensive R-ACVBP (Adriamycin, cyclophosphamide, vindesine, and prednisone) or R-CHOP.4 Fewer data are
available for patients with 2 or 3 aaIPI factors, but the relapse rate is
estimated at between 25% and 35% after generally intensive
treatment and ASCT.5,6 Finally, in patients between 60 and 70 years
of age, the relapse rate was 40% in the R-CHOP study. Despite
major progress, the number of patients eligible for salvage treatment
and ASCT remains significant.
What are the results of salvage regimens before
HDT/ASCT?
Only patients identified with a disease responsive to salvage
regimens are eligible for HDT/ASCT. The addition of rituximab
was expected to improve the complete remission and partial
remission (CR/PR) rates and allow more patients to access HDT/
ASCT. The initial studies incorporating rituximab in salvage
regimens, mostly in rituximab-naive patients, were encouraging
(Table 1).7-10
A clear demonstration of the impact of rituximab is provided by a
prospective randomized trial exploring the potential benefits associated with the addition of rituximab to platinum-based salvage
regimens. In a study conducted by the Dutch-Belgian HematoOncology Cooperative Group (HOVON) group, 239 patients with
relapsed or refractory DLBCL received a salvage regimen consisting of DHAP-VIM-DHAP with or without rituximab followed by
ASCT.9 The analysis of the 225 evaluable patients showed that after
2 courses of chemotherapy, CR/PR was obtained in 54% of the
patients in the DHAP arm and 75% in the R-DHAP arm (P ⱕ .01).
Posttransplantation PR and CR were obtained in 50% and 73% of
American Society of Hematology
Table 1. Rituximab-based salvage therapy in relapsing/refractory DLBCL
Study
n
DLBCL
Therapy
Conditioning regimen
PFS/EFS
P
OS
P
36
147
19
19
113
100%
Plus RIT†
2 y: 54%
2 y: 43%
2 y: 57%
2 y: 18%
2 y: 52%
NS
2 y: 67%
2 y: 56%
2 y: 77%
2 y: 37%
2 y: 59%
NS
80.5%
112
78.6%
Martin10
163
100%
R-ICE
ICE
R-DHAP*
DHAP*
R-DHAP
VIM
DHAP*
DHAP
VIM
DHAP*
R-ESHAP
Gisselbrecht11
202
194
100%
100%
R-ICE
R-DHAP
Kewalramani7
Sieniawski8
Vellenga9
80%
BEAM
BEAM
BEAM
Various
BEAM
.0051
.002
2 y: 31%
2 y: 52%
5 y: 38%
5 y: 50%
2 y: 31%
2 y: 42%
NS
2 y: 47%
2 y: 51%
.0051
NS
NS
NS indicates not significant.
*Plus RIT at bulky disease.
†The choice of conditioning regimen depended on physician decision and the clinical trial.
the patients, respectively (P ⫽ .003). A marked difference in favor
of the R–DHAP arm was observed at 24 months for failure-free
survival, at 50% compared with 24% (P ⬍ .001), respectively, but
not for OS, at 52% compared with 59% (P ⫽ .15), respectively. A
Cox regression analysis demonstrated a significant effect of rituximab treatment on failure-free survival and OS when adjusted for
time since upfront treatment, age, performance status, and secondary aaIPI. However, ⬍ 5% of the patients had been exposed to
rituximab previously.
Is there an optimal salvage chemotherapy regimen?
The Collaborative Trial in Relapsed Aggressive Lymphoma
(CORAL) intergroup trial compared a combination therapy consisting of rituximab, ifosfamide, etoposide, and carboplatin (R-ICE)
with rituximab, dexamethasone, aracytine, and cisplatin (R-DHAP).
Patients who were DLBCL CD20⫹ at the time of the first relapse
and patients remaining refractory after first-line therapy were
randomized between the R-DHAP and R-ICE groups. Responding
patients received BEAM and ASCT and were randomized between
observation and rituximab maintenance for 1 year. An analysis was
conducted on the first 396 randomized patients (R-ICE, n ⫽ 202;
R-DHAP, n ⫽ 194).11 The median age was 55 years. In 225 patients,
a relapse after ⬎ 12 months was observed after initial CR. In
166 cases, patients did not achieve initial CR (ie, were refractory) or
had early relapses at ⬍ 12 months. A group of 244 patients (63%)
received immunochemotherapy with rituximab as the first-line
treatment. At the time of relapse, 226 patients had a secondary aaIPI
score of 0-1 and 149 patients had an aaIPI of 2-3. The overall
response rate was 63%; 38% of patients achieved CR. There was no
difference between the response rates in the R-ICE (63.5%; 95%
confidence interval, 56%-70%) and R-DHAP (62.8%; 95% confidence interval, 55%-69%) groups or in the mobilization-adjusted
response rates (52% vs 54%, respectively). The factors that affected
the response significantly (P ⬍ .0001) were as follows: refractory/
relapse at ⬍ 12 months, with response rates of 46% versus 88%,
secondary aaIPI ⬎ 1 (52% vs 71%), and prior exposure to rituximab
(51% vs 83%). There were no statistically significant differences
between the patients achieving CR/PR just before ASCT. Patients
with prior exposure to rituximab had more refractory disease and
adverse prognostic factors.
Based on this first randomized study on relapses, there is no
difference in the response rates and the ability to mobilize stem cells
Hematology 2012
between the 2 commonly used regimens. A similar study under the
National Cancer Information Center (NCIC) sponsorship comparing R-GDP (gemcitabine, dexamethasone, and platinum) with
R-DHAP has been completed and results are awaited. There is
obviously a need to incorporate new agents to improve the response
rates of salvage regimens. Several phase 1/2 clinical trials are
currently under way. For example, one trial has combined inotuzumab ozogamicin, a humanized anti-CD22 Ab conjugated to
cytotoxic calicheamicin, with rituximab, gemcitabine, and oxaliplatin (R-Gem-Ox)12 and another trial has added lenalidomide to
various regimens such as R-DHAP.
What are the clinical characteristics of patients failing
salvage treatment?
Only 206 ASCTs were performed in the CORAL study, which had
an dropout rate of 50% mainly due to tumor progression.11 Despite
salvage therapy, only approximately half of patients actually
proceed to transplantation, a figure that identifies one of the key
limitations to current salvage practice. There was no significant
difference between the R-ICE and R-DHAP groups with respect to
3-year EFS (26% vs 35%, respectively; P ⫽ .6) or OS (47% vs 51%,
respectively; P ⫽ .5). The 3-year EFS was affected by the following
factors: prior treatment with rituximab (21%) versus none (47%;
P ⬍ .0001), early relapse at ⬍ 12 months (20%) versus ⬎ 12 months
(45%; P ⬍ .0001), and secondary aaIPI 2-3 (18%) versus 0-1 (40%;
P ⫽ .0001). In the Cox model, all of these parameters were
significant (P ⬍ .0001) for EFS, progression-free survival (PFS),
and OS, but not the treatment arm. Because early relapse (⬍ 12
months) was the main prognostic factor, we more closely examined
the population with a relapse at ⬎ 12 months to determine whether
prior exposure to rituximab affected the outcome. There was no
difference in EFS or OS between the 2 subgroups with or without
rituximab exposure. At the other end of the spectrum, the population
of relapsed patients with prior rituximab exposure and relapse
at ⬍ 12 months had a 46% response rate, with a 3-year PFS rate of
23% and a median PFS of 5 months (Figure 1). The same negative
impact of rituximab was found in other nonrandomized studies.10
Due to the introduction to the armamentarium of a very efficient
mAb for first-line treatment, we are now observing patients with
early relapse who are more refractory to any available treatment.
Currently, salvage therapy using HDT/ASCT is inefficient and
requires improvement. One may even question whether it is helpful,
411
Figure 1. PFS according to failure from diagnosis by prior rituximab therapy in DLBCL (CORAL study). Failure from diagnosis was ⬍ 12 months.
because no randomized study has been modeled after the PARMA
trial. In the European Group for Blood and Marrow Transplantation
(EBMT) registry, we found 470 relapsed DLBCL patients, but only
those in CR after salvage and pre-ASCT were evaluated.13 The
median duration of the first remission was ⬍ 12 months in 49% of
the patients; 119 patients received rituximab in the first-line
treatment and 351 did not. The 5-year OS was 63% and the 5-year
PFS was 48%. The duration of post-ASCT PFS was longer than that
before ASCT in 289 patients. When each patient was used as his/her
own control, PFS after ASCT was longer than PFS before ASCT
(P ⬍ .001). This difference in favor of post-ASCT remission was
significant for patients with or without rituximab exposure. In
patients responding to a salvage regimen, even those in good PR,
HDT/ASCT remains the best choice of treatment.14
Is determining the biological characteristics of
patients helpful for adapting treatment?
Among the 394 patients included in the CORAL study, histological
material was available for a total of 249 patients at the time of
diagnosis (n ⫽ 189 cases) and/or relapse (n ⫽ 147 cases). The
samples were analyzed by immunohistochemistry to establish cell
of origin using CD10, BCL6, MUM1, FOXP1, and BCL2 expression and by FISH for BCL2, BCL6, and c-MYC break points.15 One
interesting finding was the similar biological characteristics between diagnosis and relapse biopsies in 87 pair-matched patients.
When treatment interaction was tested, the GCB-like DLBCL based
on the Hans algorithm was significantly associated with a better PFS
in the R-DHAP arm.16 In a multivariate analysis, independent
prognostic relevance was found for the interaction between GCB/
non-GCB Hans phenotype and treatment (P ⫽ .04), prior rituximab
exposure (P ⫽ .0052), secondary aaIPI (P ⫽ .039), and FoxP1
expression (P ⫽ .047). Confirmation was obtained by geneexpression profiling in a subset of 39 patients (Figure 2). In a
univariate analysis, the presence of c-MYC gene rearrangement was
the only parameter significantly correlated with both a worse PFS
(P ⫽ .02) and a worse OS (P ⫽ .04). Of the 161 patients analyzed,
28 (17%) presented with a MYC⫹ DLBCL, targeted as either a
simple hit (25%) or complex hits (n ⫽ 75%), including MYC/BCL2,
412
MYC/BCL6, and MYC/BCL2/BCL6.17 The outcomes of patients
with MYC⫹ DLBCL were significantly worse than those with MYC⫺
DLBCL, with the 4-year PFS rate at 18% versus 42% (P ⫽ .0322),
respectively, and the 4-year OS rate at 29% versus 62% (P ⫽ .0113),
respectively. The type of treatment (RDHAP or RICE) had no
impact on survival, with the 4-year PFS rate at 17% versus 19%,
respectively, and the 4-year OS rate at 26% versus 31%, respectively. These findings underline the need to study the effects of new
treatments according to DLBCL subtypes.
Rituximab for posttransplantation
maintenance/consolidation
After transplantation, the rate of progression in the CORAL study
was 39% at 3 years. The focus should now be on preventing
relapses. Post-ASCT rituximab maintenance has been evaluated as a
means to reduce minimal residual disease. Two institutions have
independently reported improvements in disease-free survival and
OS rates with the use of rituximab after ASCT. In the first study,18
concurrent administration of rituximab was introduced at a dose of
1000 mg/m2 before the collection of peripheral blood stem cells for
a purging effect and after transplantation on days 1 and 8. The
disease-free survival rate after a median follow-up of 20 months was
67% (compared with 43% in a historical control group). The 2-year
OS rate was 80%, an improvement compared with the 53% in
historical controls who underwent ASCT without rituximab. In
another study,19 rituximab was given once weekly at weeks 4-8
after salvage ASCT (and repeated if needed over 4 weeks at month
6) to 21 patients with relapsed or refractory large-cell lymphoma.
After a median follow-up of 30 months, the EFS rate was 81% and
the OS rate was 85%. It should be noted that there was an increased
risk of prolonged neutropenia complicated by infection and
hypogammaglobulinemia.
The second question addressed in the CORAL study was whether
additional therapy with rituximab improves PFS. Patients were
randomized after transplantation to observation or rituximab given
at a dose of 375 mg/m2 every 2 months for 1 year.20 The 4-year
post-ASCT EFS rates were 52% and 53% for the 122 patients with
American Society of Hematology
Figure 2. OS and PFS according to the treatment and GC/ABC classified by the gene predictor based on gene signatures.34 Gray lines
indicate patients with a GCB profile (n ⫽ 19, 51%). Red lines indicate patients with an ABC profile (n ⫽ 18, 49%). Patients with GCB-like DLBCL
treated with R-DHAP had a significantly better PFS and OS than patients with ABC-like DLBCL treated with R-DHAP. Patients treated with R-ICE had
poor survival regardless of the molecular subtype. Adapted by Catherine Thieblemont from Thieblemont et al.15
rituximab and the 120 patients in the observation group, respectively (P ⫽ .7). Several factors affected in univariate analysis EFS
posttransplantation (P ⬍ .05), including relapsed disease within
12 months (46% vs 56%, respectively), secondary aaIPI ⬎ 1 (37%
vs 61%, respectively), and prior treatment with rituximab (47% vs
59%, respectively) (Figure 3). However, the Cox model revealed
Figure 3. OS according to the aaIPI at the time of relapse in DLBCL after transplantation.
Hematology 2012
413
that only a secondary aaIPI of 2-3 remained significant (P ⬍ .001)
for EFS, PFS, and OS. The relapse rate posttransplantation remains
over 40% despite adjuvant treatment with anti-CD20. The introduction of other immunomodulatory agents constitutes an alternative
that remains to be established in a randomized study.
Improving the conditioning regimen
A further attempt to develop a more effective therapeutic strategy
for relapsed DLBCL patients consists of the combination of
radioimmunotherapy (RIT) with standard chemotherapy regimens.
After an initial report of the use of high-dose iodine-131 and
ASCT,21 several studies have used myeloablative RIT with promising results. The development of radiolabeled immunotherapies such
as 90Y-ibritumomab tiuxetan has capitalized on the targeting ability
of Abs to deliver therapeutic doses of radiation to disseminated
tumor sites with limited radioprotection. In a phase 2 study,
90Y-ibritumomab tiuxetan combined with BEAM was superior to a
historical control in the salvage of patients with high aaIPI scores.22
To further increase the therapeutic potential of RIT, a dose
escalation study for 90Y-ibritumomab tiuxetan with BEAM and
ASCT has been performed.23 The delivered RIT dose could safely
reach 70 mCi, twice the standard dose, in 44 patients. Careful
dosimetry was required to avoid toxicity rather than weight-based
dose escalation. More recently, a randomized study compared
90Y-ibritumomab tiuxetan and BEAM chemotherapy versus BEAM
alone in 22 and 21 patients, respectively, followed by ASCT. The
2-year OS rates were 91% and 62% after the Z-BEAM and BEAM
treatments, respectively (P ⫽ .05).24 The investigators concluded
that Z-BEAM was safe and possibly more effective than BEAM
alone in the era of rituximab. Almost simultaneously, the results of
the randomized comparison between 2 conditioning regimens were
reported: rituximab BEAM versus iodine-131/tositumomab BEAM
followed by ASCT.25 For the 113 patients treated with RituxanBEAM, the 2-year PFS rate was 49%, which was similar to the
2-year PFS rate (48%) of the 111 patients treated with 131-iodine/
tositumomab BEAM. One of the principles of a conditioning
regimen with ASCT is to use drugs such as alkylating agents at the
maximum tolerated dose for nonhematologic toxicities. It should be
noted that the RIT dose used in the RIT-BEAM treatment was a
standard dose with limited myelosuppression, which might explain
its lack of superiority. If new developments are to be made in this
field, a regimen with a higher RIT dose or with other noncompeting
antigens such as CD22 should be implemented.
Is there a place for reduced-intensity allografts?
Unlike ASCT, allogeneic SCT (alloSCT) generates an allogeneic
GVL effect that reduces the likelihood of disease relapse after
transplantation. It needs to be pointed out that previous studies,
including the large Center for International Blood and Marrow
Transplant Research (CIBMTR) report,26 suggested a very modest
GVL effect (if any) in aggressive histology lymphomas. Standard
myeloablative conditioning regimens were associated to unacceptable treatment related deaths and age limitations. The advent of
reduced-intensity conditioning (RIC) regimens has renewed interest
in alloSCT, which reduces nonrelapse mortality while maintaining a
GVL effect and therefore allows the treatment of elderly patients
and/or patients with comorbidities. Currently, the major role of RIC
allogeneic transplantation (RIC-allo) is in the treatment of patients
who have failed an autograft or in whom an autograft is not possible.
Although RIC-allo has only been used for a few DLBCL patients,
the results suggest that it may be beneficial. In previously published
studies of RIC-allo, the rates of relapse at 2 or 3 years ranged from
414
33%-79%27; the stringency of patient selection is likely to be a
major reason for such discrepancies. The use of RIC-allo in
48 consecutive patients with DLBCL (18 transformed from follicular lymphoma), 69% of whom had failed a previous autograft, was
also reported,28 with an OS rate of 47% at 4 years. The French
Society of Marrow Transplantation and Cellular Therapy reported
68 patients29 who had received a median of 2 regimens of therapy
before RIC-allo, and 54 (79%) had previously undergone ASCT.
Before allotransplantation, 32 patients (47%) were in CR. With a
median follow-up of 49 months, the estimated 2-year OS, PFS, and
cumulative incidence of relapse rates were 49%, 44%, and 41%,
respectively. The 1-year cumulative incidence of nonrelapse mortality was 23%. Given the poor prognosis of this subset of patients
when treated with conventional therapy, these results suggest that
RIC-allo is an attractive therapeutic option for patients with
high-risk DLBCL. An exciting finding of this BM transplantation
study is that a history of anti-CD20 therapy before allogeneic
transplantation did not affect the incidence of disease progression or
relapse significantly (2-year PFS, 40% vs 48%, P ⫽ .59). The
results of all of these studies can be considered encouraging and are
confirmed by EBMT registry data.30 In a study of 101 patients who
had relapsed after ASCT, the 3-year PFS and OS rates after
transplantation were 41% and 52%, respectively. A comparison of
RIC and myeloablative conditioning regimens before alloSCT
revealed no significant differences in PFS or OS. However, there
was a trend of lower unrelated mortality with RIC-allo. The 2 main
factors affecting outcome were relapses ⬍ 12 months after ASCT
and the quality of response before the transplantation. Improvement
of the response remains the key issue.31 The introduction of RIT in a
nonmyeloablative conditioning regimen has been proposed in phase
2 studies32,33 to improve the antitumor effect without increasing
toxicity significantly.
With a better definition of the prognostic factors and the poor results
obtained with HDT/ASCT in early relapse, high secondary aaIPI,
and the ABC subtype, we can now discuss whether, in the case of a
response, these patients should be transplanted directly with RICallo or ASCT or treated with a tandem approach of ASCT followed
by RIC-allo. Nevertheless, it should be pointed out again that
RIC-allo should not be proposed to refractory patients. The
evaluation of such an approach remains an unsolved challenge.
Conclusions
If the introduction of rituximab represents major progress in the
treatment of B-cell lymphoma, patients failing to respond early to
rituximab combination chemotherapy generally have a poor prognosis and may be candidates for more experimental and innovative
treatments or trials testing significant improvements of the existing
tools. In total, only 30% of relapsed patients will benefit from
HDT/ASCT. Identifying an efficient second-line treatment for
DLBCL remains a key issue. Most regimens yield the same
response rate and there are no differences between the 2 most
widely used salvage treatments, R-ICE and R-DHAP. Based on the
main prognostic factors, 2 prognostic groups can be identified. A
good-prognosis group, with an 80% response rate and a 60% PFS
rate, remains accessible to standard salvage HDT/ASCT. In the
second group, patients with poor prognoses, with a 40% response
rate and a 25% PFS rate, are candidates for alternative approaches.
Any progress can be detected readily in a poor-prognosis patient.
Improvements in salvage therapy will require the introduction of
new drug combinations targeting the pathways involved in the
biology of the different subtypes of DLCBL. Improvements in the
American Society of Hematology
existing situation may be directed toward the prevention of postASCT relapses using new immunomodulators or RIC-allo, which
remains experimental. Enrollment in large, randomized studies will
be more problematic in the absence of significant progress in
response rates.
Disclosures
Conflict-of-interest disclosure: The author has received research
funding from Baxter and Roche and has consulted for Roche.
Off-label drug use: Rituximab after transplantation.
Correspondence:
11.
12.
13.
Christian Gisselbrecht, Professor of Hematology, Hospital Saint
Louis, Paris Diderot University, Paris, France; Phone: ⫹33-1-40-0546-96; Fax: ⫹33-1-34-29-54-93; e-mail: christian.gisselbrecht@
gmail.com.
14.
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American Society of Hematology