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Regular Article
CLINICAL TRIALS AND OBSERVATIONS
R-MPV followed by high-dose chemotherapy with TBC and autologous
stem-cell transplant for newly diagnosed primary CNS lymphoma
Antonio Omuro,
1
Denise D. Correa,
1
Lisa M. DeAngelis,
1
Craig H. Moskowitz,
2
Matthew J. Matasar,
2
Thomas J. Kaley,
1
Igor T. Gavrilovic,
1
Craig Nolan,
1
Elena Pentsova,
1
Christian C. Grommes,
1
Katherine S. Panageas,
3
Raymond E. Baser,
3
Geraldine Faivre,
1
Lauren E. Abrey,
1
and Craig S. Sauter
2
1
Department of Neurology,
2
Department of Medicine, and
3
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center,
New York, NY
Key Points
• We conducted a phase-2
study in newly diagnosed
PCNSL utilizing R-MPV and
HDC with ASCT.
• Excellent disease control and
OS (2-year PFS: 79%) were
observed, with an acceptable
toxicity profile and minimal
neurotoxicity.
High-dose methotrexate-based chemotherapy is the mainstay of treatment of primary
central nervous system lymphoma (PCNSL), but relapses remain frequent. High-dose
chemotherapy (HDC) with autologous stem-cell transplant (ASCT) may provide an
alternative to address chemoresistance and overcome the blood-brainbarrier. In this
single-center phase-2 study, newly diagnosed PCNSL patients received 5 to 7 cycles
of chemotherapy with rituximab, methotrexate (3.5 g/m
2
), procarbazine, and vincristine
(R-MPV). Those with a complete or partial response proceeded with consolidation HDC
with thiotepa, cyclophosphamide, and busulfan, followed by ASCT and no radiotherapy.
Primary end point was 1-year progression-free survival (PFS), N 532. Median age was 57,
and median Karnofsky performance status 80. Following R-MPV, objective response rate
was 97%, and 26 (81%) patients proceeded with HDC-ASCT. Among all patients, median
PFS and overall survival (OS) were not reached (median follow-up: 45 months). Two-year
PFS was 79% (95% confidence interval [CI], 58-90), with no events observed beyond
2 years. Two-year OS was 81% (95% CI, 63-91). In transplanted patients, 2-year PFS and OS were 81%. There were 3 treatment-related
deaths. Prospective neuropsychological evaluations suggested relatively stable cognitive functions posttransplant. In conclusion,
this treatment was associated with excellent disease control and survival, an acceptable toxicity profile, and no evidence of
neurotoxicity thus far. This trial was registered at www.clinicaltrials.gov as NCT00596154. (Blood. 2015;125(9):1403-1410)
Introduction
More than 90% of patients with primary central nervous system
lymphoma (PCNSL) display a diffuse large B-cell lymphoma (DLBCL)
phenotypic subtype, but standard DLBCL regimens such as cyclo-
phosphamide, doxorubicin, vincristine and prednisone and variations
are ineffective in this disease.
1,2
This has been explained by poor
penetration of these agents across the blood-brain barrier (BBB), a
problem that has been partially addressed with the development of
high-dose methotrexate-based regimens (HD-MTX) that result in
therapeutic central nervous system (CNS) and cerebrospinal fluid
(CSF) levels after rapid infusions of 1.5 to 8 g/m
2
.
3-5
Such high
methotrexate doses are made possible with the concomitant use of
leucovorin, which prevents bone marrow and systemic organ damage,
while limiting rescue of lymphoma cells in the CNS because it has poor
BBB penetration. This clever strategy, used with or without whole-
brain radiotherapy (WBRT), has resulted in remarkable survival im-
provements, with recent studies reporting median overall survival (OS)
of 31 to 79 months,
6-13
as compared with 12 months observed with
WBRT alone.
14
In spite of these improvements, early and late relapses
remain frequent, and the majority of patients still die of disease.
15
High-dose chemotherapy (HDC) followed by autologous stem-
cell transplant (ASCT) has been proposed as an alternative con-
solidation therapy in PCNSL.
16
In addition to overcoming intrinsic
chemoresistance of lymphoma cells, HDC-ASCT may improve
disease control by affording higher CNS drug concentrations,
circumventing chemoresistance mediated by the BBB, a similar
“high-dose/ rescue”paradigm proved successful in the development
of HD-MTX. We previously conducted a phase-2 study in newly
diagnosed PCNSL testing an induction chemotherapy with HD-
MTX and cytarabine, followed by consolidation HDC-ASCT
utilizing carmustine (BCNU), etoposide, cytarabine, and melphalan
(BEAM).
17
Unfortunately, that treatment resulted in suboptimal
disease control, with an intent-to-treat (ITT) 3-year event-free sur-
vival (EFS) of only 25%, and a 3-yearOS of 60%. In the present study,
we sought to optimize this strategy by utilizing an enhanced induc-
tion regimen consisting of rituximab, methotrexate, procarba-
zine, and vincristine (R-MPV),
6
as well as a more aggressive, CNS
penetrant HDC regimen consisting of thiotepa, busulfan, and cyclo-
phosphamide (TBC).
16
Submitted October 9, 2014; accepted December 22, 2014. Prepublished
online as Blood First Edition paper, January 7, 2015; DOI 10.1182/blood-2014-
10-604561.
The online version of this article contains a data supplement.
There is an Inside Blood Commentary on this article in this issue.
The publication costs of this article were defrayed in part by page charge
payment. Therefore, and solely to indicate this fact, this article is hereby
marked “advertisement” in accordance with 18 USC section 1734.
©2015 by The American Society of Hematology
BLOOD, 26 FEBRUARY 2015 xVOLUME 125, NUMBER 9 1403
For personal use only.on November 4, 2015. by guest www.bloodjournal.orgFrom
Patients and methods
Patients
Immunocompetent adult patients with histologically confirmed newly diagnosed
PCNSL with brain involvement were enrolled in this prospective, single-arm,
phase-2 study between June 2005 and September 2011. The supplemental
Appendix (available on the Blood Web site) details inclusion/exclusion criteria
and baseline evaluations. Patients were eligible if they had non-Hodgkin lym-
phoma involving the brain, as demonstrated by magnetic resonance imaging
(MRI) and histologic confirmation by (1) positive CSF cytology for lym-
phoma ora monoclonal lymphocyte populationdefined by cell surfacemarkers;
(2) vitreous or uvea biopsydemonstratingnon-Hodgkinlymphoma; or (3) brain
biopsy. Other inclusion criteria consisted of age 18 to 72 years; negative HIV
testing; left ventricular ejection fraction $50%; absence of systemic lym-
phoma on the chest, abdomen, and pelvis CT and bone marrow biopsy;
leukocytes .3000/mm
3
; platelets .100 000/mm
3
; bilirubin ,2mg/dL;
serum creatinine,1.5 mg/dL; or creatinine clearance .50cc/min per 1.73 m
2
.
Exclusion criteria consisted of prior cranial irradiation or chemotherapy for
PCNSL, other active malignancy (exception: skin basal cell carcinoma and
cervical carcinoma in situ), or immunodeficiency. Patients were eligible
regardless of performance status. Pretreatment evaluations also included
CSF sampling, slit lamp exam, electrolytes, liver enzymes, Epstein-Barr virus,
cytomegalovirus, herpes simplex virus and hepatitis B/C serologies, urinalysis,
24-hour creatinine clearance, and chest radiograph.
The trial and informed consent were approved by the Institutional Review
Board (www.clinicaltrials.gov: NCT00596154). Written informed consent
was obtained from all patients or guardians in accordance with the Dec-
laration of Helsinki. Data were analyzed by the authors at Memorial Sloan
Kettering Cancer Center, and all authors had access to primary clinical trial
data.
Induction chemotherapy
Treatment started with an induction R-MPV chemotherapy
6
(1 cycle 514 days),
as follows: day 1, rituximab 500 mg/m
2
IV; day 2, methotrexate 3.5 mg/m
2
IV
(over 2 hours) and vincristine 1.4 mg/m
2
(capped at 2.8 mg). Procarbazine
100 mg/m
2
per day was given on days 2 to 8 during odd cycles. Standard
hydration and leucovorin rescue were given per institutional guidelines.
To prevent febrile neutropenia and toxic deaths previously observed with
R-MPV, prophylactic filgrastim was given to all patients.
An MRI of the brain was performed after 5 cycles. Patients with pro-
gressive disease (PD) were taken off-study. Patients with complete response
(CR) proceeded directly to HDC-ASCT. Patients in partial response (PR) or
stable disease (SD) received 2 additional cycles and proceeded with HDC-
ASCT if PR/CR was observed on a repeat MRI or were taken off-study if SD
or PD. After transplant, patients were followed radiographically, with no
WBRT or further treatments offered until progression. Responses were
assessed utilizing previously described criteria
18
; in addition to CR, PR, SD
and PD, those criteria also characterize unconfirmed CR (CRu), defined
by absence of contrast-enhancing disease in the setting of corticosteroids use,
or minimal enhancing abnormalities of uncertain significance, typically cor-
responding to postoperative changes following biopsy.
Harvesting and HDC-ASCT
Peripheral blood stem cell harvesting was performed after the first or second
R-MPV cycle, or at the discretion of treating physician, following insti-
tutional standard procedures. Cytapheresis was performed after bone marrow
recovery and repeated daily up to day 7 until .5310
6
CD34
1
cells were
collected (minimum acceptable total yield: 2 310
6
CD34
1
cells per kg).
Patients in CR/PR as described previously underwent pretransplant
evaluation (supplemental Appendix); those deemed clinically eligible pro-
ceeded with HDC-ASCT with thiotepa 250 mg/m
2
IV on days 29, 28, and 27;
busulfan 3.2 mg/kg IV on days 26, 25, and 24; and cyclophosphamide
60 mg/kg IV on days 23 and 22. Stem cell reinfusion occurred on day 0.
Supportive therapy followed institutional guidelines, including granulocyte
CSF, seizure and infection prophylaxis, hydration, antiemesis, vitamin K, and
irradiated blood products.
Response was assessed after R-MPV and prior to transplant, and every
3 months thereafter (first 2 years), then every 4 months (third and fourth years)
and every 6 months thereafter. Repeat CSF and/or ocular exam were done at
those time points if CSF or ocular involvement was present at diagnosis.
Exploratory neuropsychological testing, quality of life, and
radiographic evaluation of neurotoxicity
In addition to investigators’clinical assessment of neurotoxicity,
19
potential
neurotoxic effects of disease, R-MPV, and HDC-ASCT were further char-
acterized through prospective neuropsychological and quality of life (QoL)
evaluations, as well as radiographic assessment of white matter abnormal-
ities. Evaluations were conducted in progression-free patients at the following
time points: pretreatment (baseline), after induction chemotherapy (before
transplant), and at 6-month intervals following transplant. The present analy-
sis reports on evaluations up to 24 months after transplant.
Neuropsychological evaluations were performed in 60-minute sessions.
Raw test scores were compared with published normative values according to
age and education, and converted into zscores to characterize presence and
severity of cognitive difficulties. A zscore #21.5 represents impairment.
The following tests were performed: Trail Making Test (TMT) Part A and
TMT Part B; Brief Test of Attention; Controlled Oral Word Association Test;
Hopkins Verbal Learning Test-Revised (HVLT-R)–Total Learning, HVLT-
R–Delayed Recall, and HVLT-R–Discrimination Index; and Grooved
Pegboard Test (GPT)–Dominant Hand and GPT–Non-Dominant Hand.
Self-reported QoL and mood were evaluated utilizing the Functional
Assessment of Cancer Therapy–Brain Cancer (FACT-BR) and the Beck
Depression Inventory (BDI), respectively.
Fluid-attenuated inversion recovery (FLAIR) MRI sequences obtained at
the same time points were scored for white matter abnormalities utilizing the
modified Fazekas scale.
20
Statistics
The primary end point was 1-year progression-free survival (PFS) among
all patients, defined as time from registration to tumor relapse, progression, or
death of any cause, whichever comes first. For the purposes of PFS estimates,
patients who withdrew consent or were removed from study because of reasons
other than progression, toxicity, or death were censored at the date of last ra-
diographic assessment confirming a progression-free status. With a sample size
of 33 patients, an exact binomial test with a nominal 0.05 1-sided significance
level has 90% power to detect the difference between the null hypothesis
(0.5 observed in HD-MTX without radiotherapy
13
) and the alternative propor-
tion of 0.75. The study was to be stopped if more than 2 toxic deaths occurred
among the first15patients,or4toxicdeathsatanytime.Ifthetrueriskoftoxic
death is $16%, then the probability of seeing 4 toxic deaths (and stopping the
trial) was at least 80%. Secondary end points consisted of OS, acute and chronic
toxicities (CTCAEv3), and response rate after R-MPV and after HDC-ASCT.
Explorator y end points consiste d of evaluation of neuro psychological, QoL ,
and white matt er abnormalities, as described previously.
Kaplan-Meier methodology was used for analysis of OS and PFS. Neuropsy-
chological test scores were summarized using descriptive statistics, and longitu-
dinal trajectories evaluated using linear mixed models (LMMs) controlling for age
and estimated interquartile range (IQR). Exact follow-up assessment times from
baseline were calculated, and both linear and quadratic terms were estimated by
the LMMs. McNemar’sx
2
test was used to test for significant changes in MRI
white matter abnormality scores between assessments.
Results
Patient characteristics
A total of 33 patients were enrolled and 32 analyzed; 1 registered
patient was excluded because of presence of systemic lymphoma at
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diagnosis, discovered upon post hoc radiology review, deeming the
patient ineligible. The median age was 57 (range: 23-67) and median
Karnofsky performance status (KPS) was 80 (40-100). Table 1 shows
detailed patient characteristics.
Induction treatment
Induction R-MPV was well tolerated, with no treatment-related
deaths and no treatment discontinuation because of toxicity; grades
3 and 4 toxicities are summarized in Table 2. Following 5 R-MPV
cycles, 14 patients were in CR/CRu, 16 in PR, and 1 progressed
(Table 3 and patient flowchart [supplemental Appendix]). One ad-
ditional patient had undergone complete resection prior to enroll-
ment and had no measurable disease at baseline; that patient was
stable after 5 cycles of R-MPV. All patients in less than CR, in ad-
dition to 2 patients in CR/CRu with incomplete resolution of symp-
toms after 5 cycles, received 2 additional R-MPV cycles (N 519).
The objective response rate after R-MPV, defined as CR, CRu, or PR
after 5 or 7 cycles in eligible patients with measurable disease (N 531
evaluable) was 97% (95% confidence interval [CI], 83-100).
HDC-ASCT
Thirty-one (97%) patients were deemed eligible for transplant based on
response, which includes the completely resected patient who remained
stable following 7 R-MPV cycles. A total of N 526 (81%) patients
eventually received HDC-ASCT. The other 5 patients did not undergo
transplant because of refusal/consent withdrawal (N 52) or physician’s
decision (N 53) and were removed from study. There were no har-
vesting failures.
Table 4 summarizes toxicities observed with TBC and median times
to hematologic recovery. There was no venoocclusive disease. Two
patients died of transplant-related acute complications: a 57-year-old
patient developed a Stevens-Johnson syndrome, and a 59-year-old
patient developed septic shock. Another patient aged 61 developed
a fatal chronic colitis of undetermined etiology, potentially representing
graft-versus-host disease. In that patient, symptoms started 3 weeks
following transplant and responded poorly to corticosteroids. To date,
no patient has developed secondary malignancies.
PFS and OS
Among all patients (N 532), the median PFS has not been reached
(Figure 1A), and the 1-year PFS estimate is 82% (95% CI, 62-92).
There have been no events after 2 years, and the 2-year, 3-year, and
5-year PFS estimates are 79% (95% CI, 58-90). Aside from the toxic
deaths, there was no treatment discontinuation because of toxicities,
and EFS and PFS are identical. The events were toxic deaths (N 53),
progression during R-MPV (N 51), and progression after transplant
(N 52).
The median OS (Figure 1B) has not been reached, and the 1-year
OS is 88% (95% CI, 70-95). No deaths were observed beyond
2 years, with a 2-year, 3-year, and 5-year OS of 81% (95% CI,
63-91). The median follow-up of survivors is 45 months (range:
27-86).
Among the 26 transplanted patients, the 1-year PFS is 85%
(95% CI, 64-94), and the 2-year, 3-year, and 5-year PFS est imates are
81% (95% CI, 60-92); the median PFS was not reached (Figure 1C).
The 1-year OS is 88% (95% CI, 68-96), and the 2-year, 3-year, and
5-year OS estimates are 81% (60% to 92%); the median OS was
not reached (Figure 1C).
The effects of age were analyzed according the MSK RPA class
cutoff of 50.
21
Patients age #50 tended to achieve superior PFS
(P5.05, Figure 1D) and OS (P5.06), with no observed progression
or death of any cause.
The outcomes of patients removed from study in spite of being
eligible for transplant (N 55) were as follows: 2 patients chose to
receive high-dose cytarabine and no further treatment; 1 of those
relapsed and received salvage chemotherapy and HDC-ASCT with
TBC. The remainder 3 patients chose to receive WBRT (2 patients:
23.4 Gy; 1 patient: 45 Gy) and have never relapsed. All 5 patients
remain alive, but as described previously, they were censored at the
time of last on-study radiographic assessment for the purposes of
PFS calculation, and therefore the reported PFS end points do not
reflect these additional treatments.
Neuropsychological testing, QoL, and radiographic evaluation
of neurotoxicity
No clinical neurotoxicity, defined as neurologic deterioration in the
absence of disease progression, was reported by treating physicians.
In addition, 16 progression-free patients participated in the neuro-
psychological and QoL evaluations (Figure 2 and supplemental
Appendix).
Table 1. Patient characteristics (N 532)
Characteristic Value
Median age (range) 57 (23-67)
Age ,60 21 (66%)
Age ,50 11 (34%)
Median KPS (range) 80 (40-100)
KPS ,70 6 (19%)
KPS ,50 1 (3%)
Women 15 (47%)
Men 17 (53%)
MSK RPA
Class I 11 (34%)
Class II 15 (47%)
Class III 6 (19%)
DLBCL 32 (100%)
CSF cytology*
Positive 1 (3%)
Suspicious 2 (6%)
Not performed 1 (3%)
Ocular involvement 3 (9%)
Median product of tumor diameters (range) 6 cm
2
(0-20 cm
2
)
MSK RPA, Memorial Sloan-Kettering prognostic score determined by recursive
partitioning analysis (I, age ,50; II, age $50 and KPS $70; III, age $50 and
KPS ,70).
*Conventional cytology; flow cytometry not performed.
Table 2. Grades 3 and 4 toxicities reported during R-MPV (N 532)
Toxicity Grade 3 Grade 4
Hemoglobin 6 18%
Neutrophils 6 18% 1 3%
ALT and/or AST 14 42% 3 9%
Creatinine 5 15%
Infection 4 12%
Peripheral neuropathy 2 6%
Fatigue 2 6%
Thrombosis/embolism 1 3% 2 6%
Constipation 1 3%
Syncope 1 3%
Encephalopathy 1 3%
ALT, alanine aminotransferase; AST, aspartate aminotransferase.
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As shown in Figure 2A, at baseline, there was evidence of
impairment in several cognitive domains, characterizing baseline
disease burden. Results of LMM analysis showed significant posi-
tive linear time components (months since baseline) for the HVLT-
R–Delayed Recall and HVLT-R–Discrimination Index (P,.05),
indicating continuous improvement in scores from baseline over
time. Likewise, all of the other tests had significant positive linear
components up to 12 to 18 months posttransplant. However, a
significant (TMT Part A, TMT Part B, Brief Test of Attention,
HVLT-R–Total Learning; P,.05) or marginally significant (Con-
trolled Word Association Test, GPT–Dominant Hand, GPT–Non-
Dominant Hand; P,.10) quadratic time component was observed,
suggesting that the rate of cognitive improvement slowed by 12 to
18 months posttransplant.
Self-reported QoL largely mirrored the improvement of cognitive
function in the LMM analysis (Figure 2B). FACT-BR scores sig-
nificantly improved from baseline, with slowed improvement by 12
to 18 months posttransplant; BDI scores significantly and linearly
decreased over time.
Analysis of white matter abnormalities (Figure 2C) showed an im-
provement after R-MPV, with 81% of patients displaying scores
2 to 3 at baseline, compared with 19% after R-MPV (McNemar’sx
2
P5.002). Following transplant, there was an increase in white matter
abnormalities, with 44% of patients with scores 2 to 3 (McNemar’sx
2
P5.046), which then remained stable over time. No scores above
3wereseenatanytime.
Discussion
In this phase-2 study, patients with newly diagnosed PCNSL were
treated with R-MPV chemotherapy, followed by consolidation
HDC-ASCT with TBC in responding patients and no further treat-
ment until progression. Favorable disease control was observed
(2-year PFS, 75%; 2-year OS, 81%), far exceeding results of our
previous experience with HDC-ASCT in PCNSL utilizing HD-
MTX/cytarabine and BEAM.
17
Importantly, no clinically significant
neurotoxicity has developed to date, and QoL continuously improved
over time.
A number of factors contributed to the favorable results observed
in this trial, in comparison with our previous study (Table 5).
17
The
induction chemotherapy performed better, with a higher response
rate (97%) that increased the number of patients undergoing HDC-
ASCT (81%) and minimized disease burden prior to transplant (69%
transplanted in CR). This excellent performance confirms our pre-
vious experience with R-MPV,
6
which seems superior to results with
MPV, although it remains difficult to determine the contribution of
rituximab, currently being investigated in an ongoing randomized
trial. Moreover, the TBC regimen, although more toxic, resulted in
improved, durable disease control, likely reflecting higher CNS drug
levels in comparison with BEAM.
The TBC regimen was chosen based on favorable results ob-
served in recurrent PCNSL.
16,22-25
In a multicenter phase-2 study
(N 543),
16
TBC was used following a cytarabine/etoposide (CYVE)
salvage chemotherapy, achieving PFS of 12 months and OS of
18 months. Among transplanted patients (N 527), PFS was 41 months.
Three patients died of CYVE, but there were no transplant-related
deaths, which is in line with other studies on TBC in CNS lym-
phomas
24,25
and other malignancies,
26-28
all reporting transplant-
related mortality under 5%. In our study, treatment-related mortality
appeared higher, but it is difficult to determine if this could be
because of a higher susceptibility specific to PCNSL patients, or
if it could reflect a less selected patient population, as compared
with recurrent disease patients receiving TBC after surviving highly
toxic salvage chemotherapies, such as CYVE. Also of interest is
the fact that some patients in Soussain’s study
16
were transplanted
in spite of no response to CYVE and still survived longer (OS:
9 months) than CYVE-refractory patients who were not transplanted
(OS: 5 months). This raises the intriguing question of whether
the chemoresistance observed in recurrent CNS lymphoma after
induction chemotherapies can be at least in part a consequence of the
BBB reducing drug access, which could be overcome by the high
chemotherapy doses afforded by transplant-based strategies. This
question was not addressed in our study, given that only 1 patient
progressed on R-MPV, and as per protocol design, she did not
receive HDC-ASCT.
In addition to our previous study with BEAM, a number of trials
have examined the use of HDC-ASCT in newly diagnosed PCNSL
(Table 5). However, interpreting results is difficult because, unlike
our trials, a significant proportion of patients in those studies also
received WBRT, given either as adjuvant treatment post-ASCT to
all patients or to patients who did not achieve a CR to induction.
In a study of 30 patients, methotrexate, cytarabine, and thiotepa
induction was followed by HDC-ASCT with BCNU/thiotepa, and
hyperfractionated WBRT (45 Gy for CR and 50 Gy for PR).
29,30
The 3-year OS was 69% in all patients, and 87% in transplanted
patients. There was no neuropsychological evaluation, but 5 patients
developed clinically defined neurotoxicity. That same group
subsequently reported a small series (N 513) using a similar
Table 3. Response status after R-MPV and following transplant
CR/CRu PR SD PD
Response after 5 R-MPV cycles (N 532) 14 (44%) 16 (50%) 1* (3%) 1 (3%)
Best response to R-MPV induction
chemotherapy (5 or 7 cycles) (N 532)
21 (66%) 9 (28%) 1* (3%) 1 (3%)
Pretransplant response status in the
transplanted patients (N 526)
18 (69%) 7 (27%) 1* (4%) 0 (0)
Best response after transplant (N 526) 21 (81%) 3 (11%) 1* (4%) 1 (4%)
*This 1 patient had no measurable disease at start of R-MPV because of
complete resection, remained stable after 7 cycles of R-MPV and underwent
HDC-ASCT, and was considered nonevaluable for objective response rate
assessment.
Table 4. Number of patients experiencing grades 3 to 5 toxicities
from transplant, and time to hematologic recovery (N 526)
Nonhematologic Grade 3 Grade 4 Grade 5
Febrile neutropenia 11 42%
Infection 4 15% 2 8% 1 4%
Skin rash 1 4% 1 4% 1 4%
Chronic colitis 1 4%
Encephalopathy 1 4%
Dehydration 1 4%
Cardiac failure 1 4%
Weight loss 1 4%
Nausea 1 4%
Diarrhea 1 4%
Mucositis 1 4%
Engraftment
Median time to neutrophil recovery (.500/mm
3
): 9 d (range: 7-15)
Median time to platelet recovery (.25 000/mm
3
): 15 d (range: 10-124)
Median duration of hospital admission for HDC-ASCT: 26 d (range 20-90)
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strategy, but without WBRT if a CR was achieved, and the 3-year OS
was 77%
31
; that study has been expanded,
32
and final results are
awaited. In another phase-2 study (N 525), induction with MTX 3 g/m
2
,
BCNU, etoposide, and methylprednisolone followed by HDC-
ASCT (BEAM) and WBRT (30 Gy) achieved 3-year EFS of
58% and 3-year OS of 64%. There was no neuropsychological
follow-up, but at least 1 patient developed neurotoxicity.
33
A study in
28 patients used 2 doses of single-agent HD-MTX, followed by
HDC-ASCT (busulfan/thiotepa), and WBRT 45 Gy if less than CR.
Three of the 9 irradiated patients died of neurotoxicity, for a 2-year
OS of 48%.
34
Another study focusing on patients with primary and
secondary CNS lymphoma of various histologies and previous treat-
ments selected for transplant used rituximab combined with TBC as
myeloablative regimen and found a favorable toxicity profile, with
a 2-year PFS of 81%.
35
Additional retrospective studies have been
reported, adding to anecdotal experience with HDC-ASCT in CNS
lymphoma.
36-39
The lack of clinically detectable neurotoxicity is a favorable
aspect of our regimen, but comprehensive neuropsychological eval-
uations are essential to fully characterize neurotoxic effects that
may impair QoL in long-term survivors. In line with previous reports
of R-MPV in PCNSL,
6
results showed marked improvements in
cognitive function and QoL following induction MTX chemother-
apy, reflecting a decrease in disease burden. Following transplant,
neuropsychological test scores remained overall stable, with self-
reported QoL continuously improving. However, we found some
indications of acute neurotoxicity following TBC, as exemplified by
the increase in white matter abnormalities, and a mild, transient
decrease in some neurocognitive scores at the first posttransplant
evaluation (Figure 2A and supplemental Appendix). Moreover, the
rate of cognitive improvement slowed after 12 to 18 months, and
long-term follow-up is warranted to determine whether this could
represent a trend toward development of late-delayed neurotoxicity.
Our study has some limitations. Inclusion criteria allowed for
enrollment of patients regardless of performance status, and up to
72 years old, but our oldest patient was 67, and median age was 57,
which is younger than the typical PCNSL population enrolled in
non-ASCT trials; only 19% of patients had an MSK RPA class III.
Therefore, results must be compared against other PCNSL transplant
trials (Table 5), rather than nontransplant treatment strategies that are
inclusive of a wider population of patients. Moreover, the R-MPV
regimen has not been formally tested without a consolidation strat-
egy such as WBRT or HDC-ASCT. Therefore, it is difficult to assess
whether such patients with a more favorable prognosis
40
could have
achieved similar results with R-MPV alone and without any con-
solidation treatment.It is noteworthy that salvage treatments including
TBC-based HDC-ASCT
16,24
or even WBRT
41,42
are also effective in
this population and will require further investigation. Ongoing study
Radiation Therapy Oncology Group 1114 is investigating R-MPV
with and without reduced-dose WBRT and willprovide further dataon
the relevance of consolidation treatments innewly diagnosed PCNSL.
Finally, this was a single-institution trial, and even though we are
Figure 1. PFS and O S. (A) PFS, all pa tients (N 532). (B) OS, all patients (N 532). (C ) PFS and OS in transp lanted patients. (D) PFS accord ing to age (above 50 v s 50
and under). P5.05.
BLOOD, 26 FEBRUARY 2015 xVOLUME 125, NUMBER 9 R-MPV AND TRANSPLANT FOR PRIMARY CNS LYMPHOMA 1407
For personal use only.on November 4, 2015. by guest www.bloodjournal.orgFrom
reporting on the largest number of transplanted patients published to
date (Table 5), the sample size remains small, and results need veri-
fication in a multicenter, randomized environment.
In summary, we report a prospective trial of HDC-ASCT in
newly diagnosed PCNSL that was associated with excellent disease
control, reflecting an optimized induction chemotherapy and a more
Figure 2. Neuropsychol ogical testi ng, mood/QoL scor es, and evaluat ion of white matte r changes on MRI ove r time. Time points: 1, baseline; 2, after R-MPV and
before transplant; 3, 4, 5, and 6, every 6 months after transplant. (A) Neuropsychological testing (zscores) boxplot. BL, baseline; BTA, Brief Test of Attention; COWA,
Controlled Word Association Test; GPT-D, Grooved Pegboard Test–Dominant Hand; GPT-ND, Grooved Pegboard Test–Non-Dominant Hand; HVLT-R-DEL, Hopkins Verbal
Learning Test-Revised–Delayed Recall; HVLT-R-DI, Hopkins Verbal Learning Test-Revised–Discrimination Index; HVLT-R-TL, Hopkins Verbal Learning Test-Revised–Total
Learning; R-MPV, after induction chemotherapy; TMTA, Trail Making Test Part A; TMTB, Trail Making Test Part B. The zscores #1.5 represent impairment. The lower and
upper boundaries of each box represent the first and third quartiles (ie, the 25th and 75th percentiles), respectively, at the indicated time point, and the IQR is the distance
between the lower and upper boundaries. The error bars (“whiskers”) extend from the first and third quartiles to the lowest and highest scores that are within 1.5 3IQR of their
respective quartile. Any scores beyond the error bars are considered outliers and are represented as individual points. The asterisks represent the median scores. The lines
connecting the medians over time for each test have no statistical interpretation and are intended to serve as visual aids. (B) BDI and FACT-BR (raw scores) boxplot. See
panel A for boxplot explanation. (C) White matter abnormality scores (modified Fazekas scale) over time (N 516). Fazekas scores: 0, no white matter abnormality; 1, minimal
patchy white matter foci; 2, start of confluence of white matter disease; 3, large confluent areas; 4, confluence of white matter abnormalities with cortical and subcortical
involvement; 5, diffuse leukoencephalopathy. No patient developed white matter abnormality scores of 4 or 5.
1408 OMURO et al BLOOD, 26 FEBRUARY 2015 xVOLUME 125, NUMBER 9
For personal use only.on November 4, 2015. by guest www.bloodjournal.orgFrom
effective myeloablative regimen. However, acute toxicities, in-
cluding 3 toxic deaths, were observed, and longer neurocognitive
follow-up is warranted for evaluation of late-delayed neurotoxic-
ity. This treatment should still be considered experimental, and
enrollment in randomized trials
43
encouraged to establish the ulti-
mate role and optimal timing of HDC-ASCT in the care of PCNSL
patients.
Acknowledgments
The authors thank participants of the American Association for Cancer
Research (AACR)/American Society of Clinical Oncology (ASCO)
Vail Workshop on Methods in Clinical Cancer Research where the
protocol was developed. Presented at the ASCO Annual Meeting 2012
(platform presentation).
This work was an investigator-initiated clinical trial sponsored by
Memorial Sloan Kettering Cancer Center Department of Neurology
Research and Development Funds and was conducted with no
industry support. K.S.P. received research funding from National
Institutes of Health, National Cancer Institute (grant P30 CA008748).
Authorship
Contribution: A.O., C.H.M., D.D.C., K.S.P., and L.E.A. con-
ceived of and designed the trial; A.O. and G.F. performed
collection and assembling of data; all authors performed analysis
and interpretation of data; A.O. and G.F. wrote the manuscript;
and all authors performed final approval of the manuscript.
Conflict-of-interest disclosure: L.E.A. is currently an employee at
Roche. The remaining authors declare no competing financial interests.
The current affiliation for L.E.A. is Roche, Basel, Switzerland.
Correspondence: Antonio Omuro, Department of Neurology,
Memorial Sloan Kettering Cancer Center, 1275York Ave, New York,
NY 10065; e-mail: omuroa@mskcc.org.
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Table 5. Trials or case series (20 or more patients) reporting outcomes in newly diagnosed PCNSL patients treated with consolidation
HDC-ASCT after methotrexate-based initial treatment
Reference N
Induction
regimen
ORR to
induction
HDC-ASCT
regimen
Received
consolidation
HDC-ASCT
Received
consolidation
WBRT*
ORR to
HDC-
ASCT
Med F/u
(mo)
ITT 3-y
PFS
ITT 3-y
OS
Regimens including WBRT to all patients
29 30 MTX 8 g/m
2
, Ara-C, thiotepa 80% BCNU, thiotepa 1WBRT 23 (77%) 21 (70%) 100% 63 na 69%
33 25 MTX 3 g/m
2
, BCNU, VP16,
methylpred
84% BEAM 1WBRT 17 (68%) 24 (96%) 100% 34 58% 64%
Regimens with WBRT to patients achieving less than CR
34 28 MTX 8 g/m
2
61% Busulfan, thiotepa 1WBRT
if no CR
16 (70%) 8 (29%) 69% 15 45% 48% (2 y)
Regimens without WBRT
17 28 MTX 3.5 g/m
2
, Ara-C 57% BEAM 14 (50%) 0 77% 28 25% 60%
This study 32 MTX 3.5 g/m
2
, rituximab,
procarbazine, vincristine
97% Thiotepa, busulfan, CTX 26 (81%) 0 92% 45 79% 81%
*Number of patients who received WBRT as part of initial treatment, in the absence of tumor progression.
Ara-C, cytarabine; CTX, cyclophosphamide; Med F/u, median follow-up; methylpred, methylprednisolone; MTX, methotrexate; na, not available; ORR, objective response
rate; VP-16, etoposide.
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1410 OMURO et al BLOOD, 26 FEBRUARY 2015 xVOLUME 125, NUMBER 9
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online January 7, 2015 originally publisheddoi:10.1182/blood-2014-10-604561
2015 125: 1403-1410
S. Panageas, Raymond E. Baser, Geraldine Faivre, Lauren E. Abrey and Craig S. Sauter
Thomas J. Kaley, Igor T. Gavrilovic, Craig Nolan, Elena Pentsova, Christian C. Grommes, Katherine
Antonio Omuro, Denise D. Correa, Lisa M. DeAngelis, Craig H. Moskowitz, Matthew J. Matasar,
stem-cell transplant for newly diagnosed primary CNS lymphoma
R-MPV followed by high-dose chemotherapy with TBC and autologous
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