Download Brentuximab Vedotin in CD30-Positive Lymphomas: A SIE, SIES

Review
Brentuximab Vedotin in CD30-Positive
Lymphomas: A SIE, SIES, and GITMO
Position Paper
Pier Luigi Zinzani,1 Paolo Corradini,2 Alessandro M. Gianni,3,4 Massimo Federico,5
Armando Santoro,6 Umberto Vitolo,7 Giovanni Barosi,8 Sante Tura9
Abstract
Brentuximab vedotin (BV) is approved for the treatment of patients with relapsed or refractory CD30-positive Hodgkin
lymphoma, and relapsed or refractory systemic anaplastic large-cell lymphoma. Several uncertainties remain
regarding the optimal use of the drug in its approved indications as well as outside them. This article reports recommendations on the use of BV issued during a consensus project, sponsored by the Italian Society of Hematology
(SIE) and its affiliate societies, Società Italiana di Ematologia Sperimentale (SIES) and Gruppo Italiano Trapianto di
Midollo Osseo (GITMO). Scientific evidence on BV was evaluated by a panel of experts, and consensus was developed by group discussion for key questions selected according to the clinical relevance. The following key issues
were addressed: testing CD30 positivity to assess eligibility to BV; assessing practice indications of BV in Hodgkin
lymphoma and systemic anaplastic large-cell lymphoma; providing pretreatment evaluation of patients candidates to
BV; monitoring the response to BV; managing patients treated with BV; and assessing the role of BV in other
CD30-positive lymphomas.
Clinical Lymphoma, Myeloma & Leukemia, Vol. 15, No. 9, 507-13 ª 2015 Elsevier Inc. All rights reserved.
Keywords: Brentuximab vedotin, Consensus project; Guidelines, Hodgkin lymphoma, Systemic anaplastic large-cell lymphoma
Introduction
Brentuximab vedotin (BV) is an antibodyedrug conjugate
comprising a human CD30-directed chimeric immunoglobulin G1
antibody covalently bonded to a microtubule-disrupting agent
(monomethyl auristatin E [MMAE]) by a protease-cleavable linker.1
Institute of Hematology “Seràgnoli”, University of Bologna, Bologna, Italy
Division of Hematology and Bone Marrow Transplantation, Fondazione IRCCS
Istituto Nazionale dei Tumori, University of Milano, Milan, Italy
3
Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori,
Milan, Italy
4
Department of Pathophysiology and Transplantation, University of Milan, Milan,
Italy
5
Department of Diagnostic, Clinical and Public Health Medicine, Modena Cancer
Center, Italy
6
Department of Medical Oncology and Hematology, IRCCS Humanitas Cancer
Center, Rozzano, Milano, Italy
7
Department of Oncology and Hematology, “Città della Salute e della Scienza”
University-Hospital, Torino, Italy
8
Center of the Study of Myelofibrosis Biotechnology Research Area, IRCCS Policlinico
S Matteo Foundation, Pavia, Italy
9
University of Bologna, Bologna, Italy
1
2
Submitted: Jan 12, 2015; Revised: Apr 3, 2015; Accepted: Jun 12, 2015; Epub:
Jun 19, 2015
Address for correspondence: Giovanni Barosi, MD, Centro per lo Studio della Mielofibrosi, Fondazione IRCCS Policlinico S, Matteo, Viale Golgi 19, 27100, Pavia, Italy
Fax: þ39-0382-503917; e-mail contact: [email protected]
2152-2650/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.clml.2015.06.008
BV is internalized after binding to CD30 surface receptors, and
MMAE is released, inducing apoptosis.1 The drug has exhibited
potent and specific cytotoxicity against CD30-positive cells in vitro
and in vivo.1
BV has been approved in the United States, Canada, and Europe
for the treatment of patients with Hodgkin lymphoma (HL) after
failure of either autologous stem-cell transplantation (ASCT) or 2 or
more previous multiagent chemotherapy regimens in patients who
are not candidates for ASCT.2 It is also approved for the treatment
of patients with systemic anaplastic large-cell lymphoma (sALCL)
after failure of 1 or more previous multiagent chemotherapy
regimens.2
BV has represented a major breakthrough in the treatment of
CD30-positive lymphoid malignancies; however, several uncertainties still remain on the optimal use of the drug in approved
indications. In addition, new questions are emerging on the use of
the drug in earlier stages of HL and sALCL, as well as its effectiveness as a consolidation therapy in HL. Moreover, its role in
other CD30-positive lymphoid malignancies remains to be
determined.
In order to support physicians in managing patients who are
candidates for BV, a consensus development conference project on
Clinical Lymphoma, Myeloma & Leukemia September 2015
- 507
Brentuximab Vedotin in CD30-Positive Lymphomas
BV was convened under the sponsorship of the Italian Society of
Hematology (SIE) and its affiliate societies, Società Italiana di
Ematologia Sperimentale (SIES) and Gruppo Italiano Trapianto di
Midollo Osseo (GITMO).
Design and Methods
Organization
Two chairmen (S.T. and G.B.) appointed an expert panel (EP) of
7 experts, selected for their expertise in research and clinical practice
of adult lymphoid malignancies. A clinician with expertise in clinical
epidemiology (G.B.) assured the methodologic correctness of the
process.
Framing the Domain of Recommendations
During an initial meeting, the EP agreed on the areas of major
concern in the use of BV by generating and rank ordering clinical
key questions using the criterion of clinical relevance—impact on
the management of patients and risk of inappropriateness—through
a Delphi process.3 The 11 candidate key questions that ranked
highest formed the set of questions addressed in this article.
Consensus Process
During the first of 3 meetings, the EP examined the current state
of knowledge regarding BV. Each panelist drafted statements that
addressed 1 or more of the preliminarily identified key questions.
Subsequently, each panelist scored his agreement with the statements made by other panelists and provided suggestions for
rephrasing. For exploiting this phase of the process, the EP was
convened, and 3 consensus conferences were held in Bologna, Italy.
The overall goals of the meetings were to reach a definite consensus
over question-specific statement for which there was disagreement
during the first-round postal phase. The nominal group technique
was used by which participants were first asked to comment in
round-robin fashion on their preliminary votes and then to propose
a new vote. If an at least 80% consensus on the statement was not
achieved, the choices were discussed and a second vote taken. If
an 80% consensus was still not attained, the issue was declared
undecidable, and no further attempt was made.
Results
Testing CD30 Positivity to Assess Eligibility to BV
508
-
In classical HL and sALCL, CD30 positivity is present in nearly
100% of the malignant cells.4 Consequently, the US Food and
Drug Administration (FDA) did not require a validated CD30
in vitro diagnostic test for the accelerated approval for BV in both
diseases. However, other lymphoid neoplasms are much more heterogeneous as to what CD30 positivity is concerned. For instance,
primary mediastinal B-cell lymphoma carries CD30 in about 85%
of cases at a moderate intensity; endemic Burkitt lymphoma
expresses CD30 in about 30% of patients; and diffuse large B-cell
lymphoma shows positivity for CD30 in only a small proportion of
cases.5,6 CD30 expression on a variety of T-cell lymphomas,
including angioimmunoblastic T-cell lymphoma and peripheral
T-cell lymphoma (PTCL) not otherwise specified, ranges from 0%
to 64%.5,6
Documentation that CD30 protein expression in noncutaneous
PTCLs was highly correlated to mRNA levels led to the conclusion
Clinical Lymphoma, Myeloma & Leukemia September 2015
that immunohistochemistry is a valuable tool in clinical practice
to assess CD30 expression in CD30-expressing lymphomas.7 In the
most recent clinical trials with BV in T-cell and B-cell lymphomas,
responses were reported among patients with all levels of CD30
expression in their tumor samples, including patients with
CD30 undetectable by immunohistochemistry.5 The EP claimed
immunohistochemistry for CD30 to be a useful tool to assess
this biomarker for the correlation between the target and the effect
of BV.
Recommendations.
Testing and grading CD30 reactivity in malignant tissues in
order to assess the eligibility for BV is not mandatory in the
drug’s approved indications (ie, refractory or relapsed HL and
refractory or relapsed sALCL).
Testing and reporting the CD30 reactivity in malignant tissues is
recommended in the experimental use of the drug. In these
circumstances, a standard immunostaining technique is advised.
Practice Indications of BV in HL
Refractory or Relapsed Disease. An estimated 15% to 30% of patients with HL experience either primary refractoriness or relapse
despite modern therapy.8 A second chance of cure can be achieved
using non-cross-resistant second-line therapy followed in responsive
patients by high-dose chemotherapy and ASCT, a strategy that is
curative in approximately half of those who undergo the procedure.8
However, patients whose disease does not respond to second-line
therapy usually are not offered ASCT and instead are offered subsequent treatments.
The initial phase 1 clinical trial with BV examined the safety and
efficacy of the drug in 45 heavily pretreated relapsed or refractory
CD30-positive hematologic cancers, primarily HL.9 In a subsequent
pivotal phase 2 study, in 102 patients with relapsed HL previously
treated with ASCT, BV induced an overall response rate (ORR) of
75%, with 34% of patients experiencing complete response (CR).10
On the basis of these impressive results, the FDA granted approval
to HL patients who had experienced relapse after ASCT.
After approval by FDA, further evidence on efficacy of BV in
heavily pretreated relapsed or refractory HL was derived from patients receiving the drug through a Named Patient Program (NPP).
Comparing the NPP experiences11-14 with the pivotal study,10 the
ORR and CR rates ranged from 60% to 72% and from 17% to
22%, respectively (Table 1).
Table 1 Results of NPP in Relapsed or Refractory Hodgkin
Lymphoma
Study
10
Pivotal
German NPP11
UK NPP12
Italian NPP13
French NPP14
No. of Patients
ORR (%)
CR (%)
102
45
18
65
241
75
60
72
70.7
58
34
22
17
21.5
32
Abbreviations: CR ¼ complete response; NPP ¼ Named Patient Program; ORR ¼ overall
response rate.
Pier Luigi Zinzani et al
Follow-up analysis of the pivotal phase 2 study documented a
durable remission and favorable long-term survival. Twenty-five
percent of patients with an objective response to BV remained in
remission after a median follow-up of approximately 3 years.15
The FDA extended the approved indication to include patients
who were ineligible for a transplant and refractory to 2 prior
combination chemotherapy regimens.2 This extended-label indication, however, was based on poor evidence. In the initial phase 1
trial of the 12 patients who had not received ASCT before BV, 3
(25%) responded to BV, with 2 CR and 1 partial response (PR).9
However, the efficacy of BV in patients before transplantation
was confirmed in a published retrospective analysis of 20 transplantnaive patients with HL treated with BV within two phase 1 trials: 4
of the 6 responding patients were not previously eligible for ASCT
because their disease was chemorefractory.16 Another report by
Sasse et al17 included 14 patients with primary progressive or
relapsed HL without prior ASCT; the overall response was 71% (10
of 14), with 5 CR and 5 PR. In addition, Garciaz et al18 reported an
ORR of 66.6% in patients treated with BV before ASCT. Finally,
in all NPP experiences, responses were reported (with several CRs)
in transplant-naive relapsed or refractory HL patients.11-14 These
results indicate that BV allowed proceeding to high-dose chemotherapy in some of those patients with chemotherapy-refractory HL
and might finally result in overcoming their dismal prognosis.
Consolidation Therapy. The benefit of consolidation therapy with
BV is the question addressed by the AETHERA trial, a randomized,
double-blind, placebo-controlled, phase 3 trial at 78 sites in North
America and Europe.19 Patients with unfavorable-risk relapsed or
primary refractory classic HL who had undergone autologous stemcell transplantation were randomly assigned to receive 16 cycles of
1.8 mg/kg BV (n ¼ 165) or placebo (n ¼ 164) intravenously every
3 weeks, starting 30 to 45 days after transplantation. Progressionfree survival (PFS) by independent review was significantly
improved in patients in the BV group compared to those in
the placebo group (hazard ratio, 0.57; 95% confidence interval,
0.40-0.81; P ¼ .0013). Median PFS by was 42.9 months for patients in the BV group compared to 24.1 months for those in the
placebo group. The most frequent adverse events in the BV group
compared to placebo were peripheral sensory neuropathy (56% vs.
16%) and neutropenia (35% vs. 12%).
BV in Combination. Several ongoing trials including HL patients
with multiple relapses are investigating BV in combination with
other novel drugs such as temsirolimus (NCT01902160) or ipilimumab (NCT01896999) and conventional chemotherapeutics
such as bendamustine (NCT01874054) or gemcitabine
(NCT01780662). In particular, LaCasce et al20 reported the preliminary data on a phase 1/2 single-arm study to evaluate the safety
and efficacy of BV in combination with bendamustine for patients
with HL in the first salvage setting. Among 13 available patients, 10
(77%) experienced a CR, and 2 (15%) experienced a PR with an
ORR of 92% after 2 cycles of bendamustine plus BV.
Therapy in Newly Diagnosed Patients. BV in newly diagnosed
HL has been proposed under the rationale that the rate of
therapy-related acute and long-term toxicity with BV might be
lower than with conventional chemotherapy, and that the cure rate
achieved with front-line BV containing chemotherapy regimens
may be improved. A phase 1/2 study showed an excellent response
rate of 95% for the combination of BV and ABVD (Adriamycin,
bleomycin, vinblastine, dacarbazine) in newly diagnosed HL
patients.21 However, the combination of BV and ABVD was
associated with an unacceptably high rate of serious pulmonary
events. Therefore, the protocol was modified, and patients subsequently received BV combined with AVD until accrual was
completed.21 Response rates appeared not to be compromised by
the omission of bleomycin, and no more pulmonary events occurred
after switching from ABVD to AVD. Of note, BV is provided at a
dose of 1.2 mg/kg every 2 weeks when combined with AVD. A
phase 3 trial (NCT01712490) randomly compared classical ABVD
with a combination of BV and AVD in patients with newly diagnosed advanced HL. In a different approach, the German Hodgkin
Lymphoma Study group is conducting a clinical trial incorporating
BV with modified escalated BEACOPP (bleomycin, etoposide,
doxorubicin, cyclophosphamide, vincristine, procarbazine [Matulane], prednisone) regimen (NCT01569202). At the same time,
Yasenchak et al22 reported the interim results of a phase 2 study of
single-agent BV for front-line treatment of HL in patients aged 60
years and older; among 19 efficacy-evaluable patients, the ORR was
89%, with 12 patients experiencing CR. In a preliminary report,
Federico et al23 reported that 2 cycles of BV induced a complete
metabolic response in 10 (83%) of 12 enrolled patients with previously untreated, limited-stage HL.
Recommendations.
According to the FDA and the European Medicines Agency
(EMA), BV is indicated for the treatment of patients with HL
after failure of ASCT or after failure of at least 2 prior multiagent
chemotherapy regimens in patients who are not ASCT
candidates.
The EP agreed that there is now evidence for recommending BV
also in HL patients with disease refractory to salvage chemotherapy who are ASCT candidates and as a consolidation strategy
after ASCT.
The use of BV in HL after relapse from alloestem-cell transplantation (SCT) or as first-line therapy is at present only
experimental.
Practice Indications of BV in Systemic Anaplastic LargeCell Lymphoma
After initial chemotherapy, sALCL has an expected recurrence
rate of 40 % to 60%, and only 25% to 30% of patients experience a
second CR with combination chemotherapy. The typical duration
of the second remission is less than 1 year.24
In the initial phase 1 trial with BV, only 2 out of 45 patients had
sALCL (ALK positive), and both experienced CR.9 The efficacy of
BV in relapsed or refractory sALCL was evaluated in an open-label,
single-arm, phase 2 trial involving 58 patients (72% ALK negative).25 The ORR was 86% and CR 57%, with a median response
duration of 13.0 months. Median PFS was 14.6 months, and
median overall survival was not reached at the time of publication.
ORR and CR rate, median PFS, and duration of response were not
different according to ALK status. In addition, the likelihood of
Clinical Lymphoma, Myeloma & Leukemia September 2015
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Brentuximab Vedotin in CD30-Positive Lymphomas
experiencing CR was not influenced by disease status (relapsed vs.
primary refractory disease), prior ASCT, or bone marrow
involvement.
After these positive results, BV was approved in August 2011 by
the FDA for the treatment of sALCL after failure of at least 1
chemotherapy regimen. Subsequently, the EMA licensed BV for
this indication.
New relevant questions on the use of BV outside the approved
indications include its use earlier in the disease course by combining
with first-line regimens like CHOP (cyclophosphamide, doxorubicin hydrochloride [hydroxydaunomycin], vincristine sulfate
[Oncovin], prednisone) or CHP (CHOP without vincristine). In a
recent phase 1 trial, patients with ALK-positive sALCL and International Prognostic Index 2 received 2 different schedules of BV
and CHOP chemotherapy.26 In arm 1, 13 patients (3 ALK-positive
anaplastic large-cell lymphoma, 10 ALK negative) received 2 cycles
of 3 weekly 1.8 mg/kg BV, then CHOP (CR 38% with BV
initially; after CHOP, CR 62%). After sequential treatment, 12 of
13 patients remained on treatment and received single-agent BV.
After a median observation of 23 months, 1-year PFS was 77%. In
the other group, 26 (19 sALCL) patients received combination BV
plus CHP. Twenty-three of 26 patients completed 6 cycles of BV
plus CHP, and 21 received subsequent single-agent BV. Response
assessment was performed at the end of BV þ CHP treatment (6
cycles). The ORR was 100% and CR 88%. The 1-year PFS rate was
71%.
A randomized phase 3 trial is currently underway to compare BV
plus CHP versus standard-of-care CHOP in CD30-positive mature
PTCL (NCT01777152).
Recommendations.
According to the FDA and EMA, BV is indicated for the
treatment of patients with sALCL with disease refractory to
previous therapy or patients who experienced relapse after firstline therapy, regardless of ALK status and number of prior
treatments. The EP agreed on recommending these as stringent
indications of use.
Other uses of BV, like that of BV in combination with first-line
regimens, are experimental.
Pretreatment Evaluation of BV Candidates
510
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The EP discussed the most appropriate way to evaluate the
disease burden before BV treatment in order to better assess the
response to treatment. According to the revised response criteria for
lymphomas, 18F-fludeoxyglucoseepositron emission tomography
(FDG-PET) is strongly recommended before treatment for patients
with FDG-avid lymphomas such as HL to better delineate the
extent of the disease.27
In clinical trials with BV provided as a single agent to treat HL or
sALCL, baseline evaluations included documentation of diseaserelated signs and symptoms, physical examination, bone marrow
biopsy, and radiographic studies, including computed tomography
(CT) of the neck, chest, abdomen, and pelvis, and PET scan. In
studies reporting patients treated with BV either in a NPP or in the
context of safety studies associated with the registration program of
the drug, different schedules of pretreatment evaluation were used.
Clinical Lymphoma, Myeloma & Leukemia September 2015
In the German study, CT but not PET was mandatory at initial
staging.11 In the Italian study, all patients underwent baseline
assessment including PET/CT studies.13
The results of an observational study with a small cohort of
patients indicate that FDG-PET/CT is able to monitor metabolic
treatment response in patients treated with BV and helps to identify
patients with improved clinical outcome early during treatment. This
evidence prompted the EP to suggest FDG-PET scan in all patients at
initial staging before therapy as a tool to better test response.28
Recommendation.
Patients who are candidates for BV should receive an accurate
staging of disease that includes PET and CT scan before starting
treatment. Bone marrow biopsy should be performed only when
clinically indicated.
Monitoring the Response to BV
The Biological License Application for BV was the first application submitted to the FDA using the 2007 revised response
criteria for lymphoma, which may include FDG-PET scans in the
response assessment. However, FDA or EMA approval did not
produce specific indications on the best schedule to assess response.
The intervals between periodic assessments of response and
surveillance varied among BV clinical trials. In the initial phase
1 study, response was assessed after every 2 cycles (every 6 weeks).9
In the phase 2 study in sALCL, response was assessed after every
2 cycles (every 8 weeks).24 In the pivotal study of BV in relapsed or
refractory HL, tumor response assessments were performed by CT
scans at cycles 2, 4, 7, 10, 13, and 16 and by PET scans at cycles
4 and 7.10 The study reported also a median time to objective
response of 5.7 weeks (approximate time of the first postbaseline
CT scan); the median time to CR was 12 weeks (approximate time
of the first postbaseline PET scan). The majority of responses
occurred early during the treatment, but 1 CR was documented
after approximately 1 year of therapy.
In nontrial reports, the monitoring strategy also varied. In the
German study, staging and restaging CT was mandatory; however,
the time point of the restaging CT scans was not defined.11 A total
of 34 patients also underwent PET to determine the metabolic
response. In the Italian study, response was assessed by PET/CT
scan after cycles 3 and 8 and at treatment discontinuation, as
reported in the pivotal study.13
The EP claimed that an early PET evaluation is advisable;
furthermore, as with other treatments, further evaluation of
response is advisable before SCT, if planned.
Recommendations.
Patients treated with BV for HL should be clinically monitored
at each cycle of therapy. A PET scan should be performed after
cycle 4.
A final response assessment at the end of therapy in HL should
include a complete evaluation of the patient, including PET and
CT scans.
Patients treated with BV for sALCL should be monitored for
response after 4 courses of therapy with CT scan.
Further evaluation of response should be done before SCT, if
planned, or after 8 cycles of therapy.
Pier Luigi Zinzani et al
A final response assessment at the end of therapy in sALCL
should include a complete evaluation of the patient and a CT
scan.
Management of Patients Treated With BV
Treatment Duration. The overall management of patients treated
with BV varied among clinical trials. In the initial phase 1 study,
patients with CR, PR, or stable disease with protocol-defined
clinical benefit (improved performance status, decreased analgesic
consumption, or decreased disease volume) could continue therapy.9 Study treatment was discontinued at confirmation of disease
progression. Data of the pivotal phase 2 trial in HL indicate that it
might take not more than 4 courses to achieve the best response to
BV, suggesting a decision about high-dose chemotherapy and ASCT
after the fourth course of BV.10
In nontrial reports, the treatment strategy varied. In the German
study, treatment was continued until disease progression.11 The
major result of the Italian study indicates that the best responses,
and thus further therapy decisions, should occur after 3 or 4 cycles
of therapy.13
Retreatment With BV. Appropriateness of retreatment with BV in
HL and sALCL was investigated in a prospective study of 29 patients (21 HL, 8 sALCL) who had experienced relapse after experiencing CR or PR with BV. Among the 20 HL patients who were
evaluable for efficacy, 12 (60%) experienced a response (6 CR, 6
PR). The median response duration among patients responding to
BV retreatment was 9.4 months. Side effects were similar to those
seen after initial treatment. However, the rate of peripheral neuropathy appeared to be higher than after initial BV treatment, so
extended BV exposure should be closely monitored for this adverse
effect.
Bartlett et al29 reported that retreatment with BV monotherapy
was associated with 68% relative risk (39% CR) in patients with
relapsed HL and sALCL.
Allogeneic Transplantation After BV. The role of allogenic SCT
(allo-SCT) as a salvage regimen after BV and the impact of BV on
allo-SCT were retrospectively examined in 3 studies.18,30,31
Although the study was of a small series of patients, all 3 studies
reported a very favorable outcome in relapsed or refractory HL in
patients who received allo-SCT after response to BV. Additionally,
BV before reduced-intensity alloeSCT does not appear to adversely
affect engraftment, graft versus host disease, or survival, and may
provide sufficient disease control to enable reduced-intensity alloSCT.30
Peripheral Sensory Neuropathy. BV was designed to deliver the
cytotoxic agent specifically to tumor cells, thereby resulting in an
improved safety profile. The most common treatment-related
emergent adverse event is peripheral sensory neuropathy, occurring after prolonged exposure to the drug. In the AETHERA study,
the median time to onset of peripheral neuropathy events was 13.7
weeks.19 Patients can experience numbness and tingling of the
fingers and toes. Resolution of the symptoms after dose modification or therapy discontinuation occurred in 85% of the cases.
Recommendations.
In the approved indications of BV treatment for HL and sALCL,
treatment evaluation must be performed after 4 courses, and the
subsequent treatment should be determined according to the
response.
In patients with HL who experience a CR, either an early
consolidation program including allo-SCT or BV therapy
continued up to 16 cycles are the approved indications of use.
The EP did not reach a consensus on which of the 2 strategies
was more appropriate. More clinical trials are needed.
In patients with HL who experience a partial response, early alloSCT should strongly be considered. Patients not eligible for a
transplant should be treated with BV up to a maximum of 16
cycles.
In patients with HL and a stable disease, the decision to continue
BV should rely on a patient-centered balance between clinical
benefits and risks.
In patients with HL and progressive disease, BV therapy should
be discontinued.
In patients with sALCL who experience a CR after a strategy not
including ASCT, ASCT is the preferred therapy. In patients who
experience a CR after a strategy including ASCT, either an early
consolidation program including allo-SCT or BV therapy up to
16 cycles is an approved indication of use. The EP agreed that
both of these strategies are clinically appropriate. More clinical
trials are needed.
In patients with sALCL who experience a partial response, an
early consolidation program including SCT is the recommended
strategy. ASCT or allo-SCT in patients who had a previous
strategy including ASCT were judged as the most appropriate
candidates for this therapy. Patients not eligible for a transplant
should be treated with BV up to a maximum of 16 cycles.
Patients with sALCL and stable or progressive disease should be
shifted to an alternative treatment.
Patients with either HL or sALCL who experience relapse after a
complete or partial remission with initial BV therapy may be
retreated with BV.
Patients should be monitored for symptoms of neuropathy, such
as paresthesia, neuropathic pain, and weakness. For grade 2 or
higher or worsening neuropathy, dosing should be delayed until
neuropathy improves to grade 1 or baseline. Then BV should be
considered to be restarted at 1.2 mg/kg. For grade 4 peripheral
neuropathy, BV should be discontinued.
Role of BV in Other CD30-Positive Lymphomas
Preliminary results have shown the efficacy of BV in other subtypes of non-HLs that have various levels of CD30-positive cells,
including diffuse large B-cell lymphoma and primary mediastinal
large B-cell lymphoma,32 PTCL not otherwise specified, angioimmunoblastic T-cell lymphoma,33 and cutaneous T-cell
lymphoma.34,35
Activity of BV has been demonstrated in individual cases with
enteropathy-associated T-cell lymphoma,36 plasmablastic lymphoma arising from a background of chronic lymphocytic leukemia,37 posttransplantation lymphoproliferative disorders,38 and
effusion lymphomas.39
Clinical Lymphoma, Myeloma & Leukemia September 2015
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Brentuximab Vedotin in CD30-Positive Lymphomas
Recommendations.
There are no data to recommend the use of BV outside clinical
trials for patients with PTCLs (but anaplastic large-cell lymphoma), cutaneous T-cell lymphoma, primary mediastinal large
B-cell lymphoma, and diffuse large B-cell lymphoma.
The documented major activity of this pleiotropic drug on
CD30/CD30L signaling should encourage the enrollment of
patients with incurable lymphomas into clinical trials using BV.
Discussion
Experts in lymphomas judged whether the body of evidence was
sufficient to provide recommendations regarding the use of BV in
an on-label or off-label use, and how to optimize the approved use
of the drug. The efficacy and safety of BV were well established in
relapsed or refractory HL and sALCL. Recent evidence showed that
the drug may be safely and effectively used before ASCT in HL, and
as retreatment in the approved indications of use. Thus, the EP
extended the recommendations of use to HL patients whose disease
had failed to respond to at least 2 prior chemotherapy regimens
regardless of their eligibility for ASCT and to facilitate consolidation
allo-SCT after BV treatment.
Recently updated National Comprehensive Cancer Network
(NCCN) guidelines were concordant in indicating that HL
patients with disease refractory to second-line chemotherapy
should not proceed to high-dose therapy and ASCT, and those
with progressive or relapsed disease whose disease is not chemosensitive after 2 chemotherapy regimens should be provided a trial
of BV before ASCT, even though they may be candidates for a
transplant.40 In line with approved indications of use and our
recommendations, NCCN guidelines recommended that sALCL
patients who are candidates for transplant would be treated with
second-line regimens, and BV was included among the suggested
treatments.
Acknowledgments
Funding of the project was provided by SIE, SIES, and GITMO
with an at-arm’s-length contribution from Takeda Italy provided to
SIE. The SIE administered all aspects of the meetings. The funding
sources had no role in identifying statements, abstracting data,
synthesizing results, or preparing the manuscript, or in the decision
to submit the manuscript for publication.
Disclosure
The authors have stated that they have no conflicts of interest.
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