Autologous Stem Cell Transplantation with Thiotepa,

Busulfan, and Cyclophosphamide (TBC) Conditioning

in Patients with CNS Involvement by
Non-Hodgkin Lymphoma
Gregory M. Cote,1 Ephraim P. Hochberg,1 Alona Muzikansky,1 Fred H. Hochberg,1
Jan Drappatz,2 Steven L. McAfee,1 Tracy T. Batchelor,1 Ann S. LaCasce,2 David C. Fisher,2
Jeremy S. Abramson,1 Philippe Armand,2 Yi-Bin Chen1

Primary central nervous system non-Hodgkin lymphoma (PCNSL) carries a poor prognosis and, although it
responds to chemotherapy, fewer than 20% of patients are long-term disease-free survivors. Secondary CNS
non-Hodgkin lymphoma (SCNSL) has an even worse prognosis with a median survival of only months and
very few reported long-term survivors. For both of these groups of patients, there has been interest in using
high-dose chemotherapy with autologous stem cell transplantation (ASCT) following conditioning with thio-
tepa, busulfan, and cyclophosphamide (TBC). We performed a retrospective review (from 2006-2010) of 32
patients from the Dana-Farber Cancer Institute and Massachusetts General Hospital with PCNSL or SCNSL
who underwent ASCT with TBC conditioning. Of the 32 patients, 56% received TBC/ASCT after achieving
brain magnetic resonance imaging (MRI) and/or cerebrospinal fluid complete response in brain, and 44% of
patients were treated with TBC/ASCT in the setting of measurable CNS disease. The 100-day transplant-
related mortality rate was only 3%. The most common nonhematologic grade 3 or 4 toxicity was mucositis,
which occurred in 73% of patients. Notably, there was only 1 patient with prolonged significant neurologic
toxicity that manifested as ataxia and dysphagia. The 1-year OS estimate is 93% (95% confidence interval [CI]:
75%-98%), and the 1-year progression-free survival (PFS) estimate is 90% (95% CI: 72%-96%) from the date of
transplantation. Although these outcomes are encouraging, longer follow-up is required and comparison
with other traditional ASCT regimens used for patients with non-Hodgkin lymphoma (NHL) is warranted.
Biol Blood Marrow Transplant 18: 76-83 (2012) Ó 2012 American Society for Blood and Marrow Transplantation

KEY WORDS: Lymphoma, Autologous stem cell transplantation, Thiotepa, CNS lymphoma, PCNSL

INTRODUCTION cantly improved the response rates and prognosis in

Involvement of the central nervous system (CNS)
by non-Hodgkin lymphoma (NHL) has traditionally
carried a poor prognosis, with a median survival of
only 40 months following diagnosis [1-5]. Modern
therapies including chemotherapy-only regimens
with high levels of CNS penetration (typically using
a backbone of systemic high-dose methotrexate
[MTX]) and combined modality therapy have signifi-
From the 1MGH Cancer Center, Boston, Massachusetts; and 2Dana-
Farber Cancer Institute, Boston, MA.
Financial disclosure: See Acknowledgments on page 83.
Correspondence and reprint requests: Yi-Bin Chen, MD, MGH
Cancer Center, 100 Blossom Street, Cox-108, Boston, MA
02114-2617 (e-mail: ychen6@partners.org).
Received April 21, 2011; accepted July 6, 2011
Ó 2012 American Society for Blood and Marrow Transplantation
1083-8791/$36.00
doi:10.1016/j.bbmt.2011.07.006
these diseases. For example, in primary CNS lym-
phoma (PCNSL), chemotherapy-based phase II trials
(with or without consolidative radiotherapy) have re-
ported response rates of 70% to 90% and median
survivals of 3 to 5 years [1-5]. However, despite
these successes, relapse rates are high, with only 20%
to 30% of patients achieving a durable long-term re-
mission. Importantly, although the inclusion of whole
brain radiotherapy (WBRT) with to chemotherapy
can improve survival, this has been shown to carry an
unacceptable rate of neurotoxicity, particularly in pa-
tients over the age of 60 [1,3,6]. Secondary CNS
lymphoma (SCNSL), defined as CNS involvement in
addition to systemic disease or as an isolated
recurrence in a patient with a history of systemic
disease, is also a difficult therapeutic problem. In
several large retrospective studies, SCNSL has
a dismal median survival on the order of 2.5 to 4
months, with 1-year survival rates of only 25% [7-9].

76
Biol Blood Marrow Transplant 18:76-83, 2012
Given these historically poor outcomes, intensifi-
cation of treatment with high-dose chemotherapy and
autologous stem cell transplantation (HDT/ASCT)
in PCNSL and SCNSL has been explored [10-21].
Although early investigations of ASCT in CNS NHL
had outcomes similar to standard therapy, most of
these series reported intriguing number of patients
with long-term remissions, particularly among those
who had achieved a chemosensitive complete or partial
response before ASCT.
One high-dose chemotherapy regimen that has been
used for patients with CNS lymphoma is the combina-
tion of thiotepa, busulfan, and cyclophosphamide
(TBC) [19,20]. Extensive pharmacokinetic studies have
shown that all 3 agents have significant CNS
penetration, with thiotepa and busulfan achieving
CSF levels of over 80% of plasma concentrations
[19,20,22-27]. In theory, the volume of distribution of
these agents thus offers distinct advantages over
standard conditioning regimens such as BEAM
(Bis-chloroethylnitrosourea [BCNU], etoposide,
cytarabine, melphalan). In light of the promising
data for HDT/ASCT using TBC conditioning from
Soussain et al. [19,20], we adopted this regimen for
eligible patients with CNS involvement by NHL. In
this retrospective study, we reviewed the outcomes of
patients treated at 2 partner institutions with HDT/
ASCT using TBC conditioning for PCNSL and
SCNSL from 2006 through 2010.
PATIENTS AND METHODS
Patients
This study was approved by the institutional re-
view board at the Dana-Farber Harvard Cancer Cen-
ter. We searched the clinicopathologic databases and
bone marrow transplant databases at the Massachu-
setts General Hospital and Dana-Farber Cancer Insti-
tute for all patients 18 years or older who had CNS
involvement by NHL and received HDT/ASCT
with TBC conditioning from 2006 to 2010. A total
of 33 patients were identified from the database. We
excluded 1 patient for lack of confirmation of CNS re-
lapse. A retrospective review of electronic medical re-
cords was performed to assess the safety and efficacy of
the TBC regimen. All patients met institutional stan-
dard criteria for ASCT including Eastern Cooperative
Oncology Group performance status of 0 or 1, total
bilirubin \2.0 mg/dL, creatinine \2.0 mg/dL, a dif-
fusing capacity of lung for carbon monoxide
(DLCO) of .50% of predicted valued corrected for
hemoglobin, and a cardiac left ventricular ejection
fraction of .45%. The disease status at the time of
ASCT was identified by magnetic resonance imaging
(MRI) (or computed tomography angioagraphy
[CTA] for 1 patient) and/or cerebral spinal fluid
ASCT in patients with CNS lymphoma 77
(CSF) analysis (if applicable) at first or subsequent re-
mission and either partial (PR) or complete response
(CR). CR was defined as no evidence of tumor on im-
aging and negative CSF analysis when available. PR
was defined as a reduction in tumor burden by imaging
and negative CSF analysis when available. Formal
tumor-metrics were not performed on these patients;
when the imaging results were equivocal, the radiology
and clinical interpretation described in the medical re-
cord were used to guide response assessment. Post-
ASCT responses were determined by imaging (MRI
or CT), CSF analysis, or clinical findings (e.g., death)
when available.
Regimen
Beginning on day 29 through day 27, each patient
was treated with thiotepa (250 mg/m2 i.v. per day). On
days 26 to 24, patients received busulfan (0.67 or 0.8
mg/kg i.v. every 6 hours for 12 doses), and on days 23
and 22, cyclophosphamide (60 mg/kg i.v. per day) was
given with mesna (15 mg/kg 4 times per day) for uro-
protection. Filgrastim (5-10 mg/kg i.v. or s.c. once per
day) was started on day 11 until count recovery.
Busulfan-related seizure prophylaxis was given with ei-
ther levetiracetam or phenytoin on days 29 to 23. Pa-
tients also received institutional standard supportive
care including ursodiol (300 mg twice per day), infec-
tious prophylaxis (acyclovir or famciclovir, a quino-
lone, and fluconazole). Patients were discharged
from the hospital when engraftment had been
achieved, they were free of any evidence of infection,
and they were clinically stable.
Patient characteristics were reported descriptively.
Engraftment was defined as the first of 2 consecutive
days with an absolute neutrophil count greater than
500 cells per mm3. Platelet recovery was defined as
the first of 2 consecutive days with the platelet count
.50,000 per mm3. Infections were included if there
was positive culture data, radiographic evidence, or
a high-level of clinical suspicion. Febrile neutropenia
with negative culture data and no identified source
was not recorded as an infectious complication.
Statistical Methods
Progression-free survival (PFS) was calculated us-
ing the Kaplan-Meier method from the date of trans-
plant to the date of disease progression or death from
any cause. Overall survival (OS) was calculated using
the Kaplan-Meier method from the date of transplant
to death from any cause. One-hundred-day transplant-
related mortality (TRM) was derived from death of any
nonrelapse cause during the days from admission
through day 100 after ASCT. Patients who were alive
without relapse or progression were censored at the
time of the last clinical evaluation.
78 G. M. Cote et al. Biol Blood Marrow Transplant 18:76-83, 2012

Table 1. Clinical and Pathological Characteristics of the Study Patients

PCNSL (n 5 16) SCNSL (n 5 16)

Age at NHL diagnosis, median years (range) 49.5 (26-67) 45 (21-67)

Age at ASCT, median years (range) 52 (32-68) 56 (21-69)
Sex, male/female 5/11 10/6
Stage III or IV,* median (range) — 4 (1-4)
ECOG PS at diagnosis $2/<2 4/8 6/7
ECOG PS at transplantation $2/<2 0/16 0/16
LDH > upper limit of normal* (median, range) 4 (294, 162-512) 7 (285.5, 158-10703)
>1 extranodal site* — 9
RIPI,* median (range) — 3 (2-4)
High-risk extranodal sites*
Testicular (%) — 0 (0)
Hepatic (%) — 0 (0)
Extradural (%) — 0 (0)
Renal (%) — 0 (0)
Adrenal (%) — 1 (9)
Bone marrow (%) — 7 (63)
Retroperitoneal adenopathy (%) — 4 (36)
Histopathologic features
Diffuse large B cell lymphoma (%) 14 (88) 12 (75)
Mantle cell lymphoma (%) 0 (0) 1 (6)
Lymphoplasmacytic lymphoma (%) 0 (0) 1 (6)
Peripheral T cell lymphoma (%) 1 (6) 1 (6)
Other (%) 1 (6) 1 (6)
c-myc and bcl-2 (%) 0 (0) 1 (6)
c-myc (%) 0 (0) 0 (0)
Bcl-2 (%) 7 (44) 3 (19)
ki67, median (range) 82.5 (35-95) 80 (30-95)

RIPI indicates revised international prognostic index; ASCT, autologous stem cell transplantation; NHL, non-Hodgkin lymphoma; LDH, lactate dehydro-
genase, ECOG, Eastern Cooperative Oncology Group.
*DLBCL only.

RESULTS volvement at initial diagnosis. Of the SCNSL patients,

Patient Characteristics
Thirty-two patients (15 men, 17 women) were
identified who underwent HDT/ASCT with TBC
conditioning at Massachusetts General Hospital
(MGH) and Dana-Farber Cancer Institute (DFCI).
Sixteen patients had PCNSL and 16 had SCNSL.
The clinicopathologic characteristics for all patients
are reported in Table 1. The median age at diagnosis
for PCNSL and SCNSL was 49.5 (range: 26-67) and
45 years old (range: 21-67), respectively.
The majority of cases of PCNSL were diffuse large
B cell lymphoma (DLBCL, 14 cases, 88%). One pa-
tient had a B cell lymphoma not otherwise specified
(NOS), and 1 patient had a poorly characterized pe-
ripheral T cell lymphoma (PTCL).
Most patients with SCNSL were also of DLBCL
histology (12 cases, 75%). One of these was of the in-
travascular lymphoma subtype. There was 1 patient
with lymphoplasmacytic lymphoma, 1 with ALK-
positive anaplastic large cell lymphoma, and 1 with
a high-grade B cell lymphoma that was likely Burkitt’s
lymphoma (although c-myc analysis was not available).
The international prognostic index (IPI) scores and
high-risk sites are listed for the DLBCL patients
only. The median IPI at diagnosis was 3 with most hav-
ing .1 extranodal site of involvement. Seven of 11
(63%) SCNSL DLBCL patients had bone marrow in-
9 had CNS involvement with initial presentation or
within 6 months of diagnosis. Four patients developed
CNS relapse .6 months after their diagnosis. One pa-
tient relapsed in the CNS almost 8 years after primary
treatment. Two patients relapsed with simultaneous
involvement of systemic and CNS disease. The loca-
tion of CNS involvement was relatively similar be-
tween the groups. In patients with SCNSL, 6 had
parenchyma-only disease, 4 had leptomeningeal-only
disease, and 5 had multiple sites of CNS involvement
(eg, parenchyma and ocular). There was 1 SCNSL pa-
tient with direct invasion of a mass into the cauda
equina. Eight PCNSL patients had parenchyma-only
disease, and 8 had multiple sites of involvement includ-
ing parenchyma and either leptomeningeal lymphoma
or ocular lymphoma. There were no patients in either
group with ocular lymphoma as the sole site of CNS
disease.
Pretransplantation CNS-Directed Therapy
Therapy before TBC/ASCT for all 32 patients is
shown in Table 2. The treatment course for many of
the patients with PCNSL was complex, with a median
number of 3 regimens. At first diagnosis, all patients
received high-dose methotrexate-based therapy (de-
fined as .3 g/m2) with or without rituximab, temozo-
lomide, and/or intrathecal therapy. Only 2 of 16
patients with PCNSL underwent ASCT in CR1.
Biol Blood Marrow Transplant 18:76-83, 2012 ASCT in patients with CNS lymphoma 79

Table 2. Patient Treatments ASCT, and 1 of these received WBRT in this setting.
PCNSL SCNSL
There was 1 patient who went to ASCT with progres-
(n 5 16) (n 5 16) sive SCNSL. In all, 18 of the 32 patients (56%)
achieved a CNS CR before HDT/ASCT. Twelve
Systemic therapy before HDT/ASCT with TBC
CNS prophylaxis (%) — 2 (12.5) had a PR (37.5%). There was 1 patient (3%) with sta-
R-CHOP (%) — 11 (69) ble disease (SD) and 1 patient (3%) with progressive
CHOP (%) — 1 (6)
disease (PD) who still proceeded to ASCT.
R-EPOCH (%) — 1 (6)
Other (%) — 3 (19)
No. of systemic therapies, median — 1 (1-6) Transplantation Outcomes
(range)
CNS-directed therapies at first diagnosis* The median days to neutrophil engraftment and
Steroids (%) 10 (62.5) 3 (19)
platelet recovery were 9 (range: 8-16) and 13 (range:
Surgery (%) 0 (0) 3 (19)
Whole brain radiation therapy (%) 0 (0) 0 (0) 8-44), respectively. The median length of transplanta-
Other radiation therapy (%) 0 (0) 2 (12.5) tion hospitalization stay was 24 days (range: 20-38).
Intrathecal MTX (%) 1 (6) 4 (25)
The PFS and OS curves are shown in Figure 1. At
Intrathecal Ara-C/liposomal 1 (6) 3 (19)
cytarabine (%) this early follow-up period (median 379 days, range:
High-dose MTX (3-3.5 g/m2) (%) 5 (31) 6 (37.5) 43-1467 days from transplantation, or median 866
High-dose MTX (8 g/m2) (%) 11 (68) 8 (50)
days, range: 349-4516 from CNS diagnosis), 90%
Rituximab (CNS directed) (%) 6 (37.5) 5 (31)
Temozolomide (%) 6 (37.5) 2 (12.5) (29 of 32) of patients are alive and 78% (25 of 32) are
Other 6 (37.5) 0 (0) without disease progression. The 1-year OS estimate
CNS-directed therapies in relapse or progressive disease*
from the day of transplantation is 93% (95% confi-
Total no. of patients 13 2
Steroids (%) 3 (23) 0 (0) dence interval [CI]: 75%-98%) and 1-year PFS esti-
Whole brain radiation therapy (%) 2 (15) 1 (50) mate from the day of transplantation is 90% (95%
Other radiation therapy (%) 3 (23) 0 (0)
CI: 72%-96%).
Intrathecal MTX (%) 0 (0) 0 (0)
Intrathecal Ara-C/liposomal 0 (0) 1 (50) Of the patients who recurred, 1 patient relapsed
cytarabine (%) outside of the CNS and 3 patients relapsed in the
High-dose MTX (3-3.5 g/m2) (%) 1 (8) 0 (0)
CNS. Two of these have died from progressive lym-
High-dose MTX (8 g/m2) (%) 7 (54) 1 (50)
Rituximab (CNS-directed) (%) 11 (85) 1 (50) phoma (described below). One is alive after having re-
Temozolomide (%) 10 (77) 1 (50) ceived several salvage therapies, and the fourth patient
Other (%) 9 (69) 0 (0)
remains in CR after intrathecal liposomal cytarabine
No. of CNS-directed therapies, 3 (1-8) 1 (1-3)
median (range)† monotherapy now at day 1763 from ASCT. In our
CNS lymphoma clinical status before ASCT study cohort, 1 patient died of a transplant-related in-
Complete response 7 (44) 11 (69)
fection (described below under transplant-related tox-
Partial response 8 (50) 4 (25)
Stable or progressive disease 1 (6) 1 (6) icity) and 2 other patients died of recurrent disease.
The first patient had a systemic relapse approximately
R-CHOP indicates rituximab, cyclophosphamide, doxorubicin, vincris-
tine, prednisone; R-EPOCH, rituximab followed by infusional doxorubi- 2 months out from transplantation, which was refrac-
cin, etoposide, vincristine, and cyclophosphamide and prednisone; MTX, tory to salvage therapy. The second patient was found
methotrexate; ASCT, autologous stem cell transplantation; PCNSL, to have an asymptomatic CNS recurrence on 3-month
primary central nervous system non-Hodgkin lymphoma; SCNSL, interval scans. He underwent multiple rounds of intra-
secondary CNS non-Hodgkin lymphoma; TBC, thiotepa, busulfan, and
cyclophosphamide; HDT, high-dose chemotherapy. thecal/systemic chemotherapy and radiation therapy
*Totals >100%. to obtain a second CR. Ultimately, this patient under-
†Steroid monotherapy was not considered a separate regimen. went an allogeneic double umbilical cord blood trans-
plantation, but unfortunately he died from progressive
There was 1 other patient with a near-CR who went
disease.
directly to ASCT after high-dose methotrexate. The
remaining 13 patients had relapsed or progressive dis-
ease prior to ASCT and second-line therapies included Transplant-Related Toxicity
WBRT in 2 patients, reinduction with MTX in 8 pa- The transplant-related toxicity is shown in Table 3.
tients and agents including rituximab, temozolomide, Twenty-eight percent (9/32) of patients had a docu-
and pemetrexed among other treatments. Of the 16 mented infection during their ASCT course. Bacterial
patients with SCNSL, 14 received high-dose MTX- infections included 4 positive blood cultures from cen-
based therapy, with or without rituximab and temozo- tral or peripheral blood draws, 2 cases of Clostridium
lomide. Several patients received intrathecal therapy (4 difficile colitis, and 2 patients with pneumonia. There
with methotrexate and 3 with cytarabine or liposomal were 2 fungal infections, including Candida albicans cul-
cytarabine). No patients received WBRT initially. tured from a polymicrobial lung abscess (described in
Thirteen of 16 patients with SCNSL received HDT/ further detail below), and 1 case of an invasive skin can-
ASCT at first response, either CR or PR. Only 2 didiasis with positive serum biomarkers. There were
patients with SCNSL had second CNS relapses before no significant viral infections documented, although
80 G. M. Cote et al. Biol Blood Marrow Transplant 18:76-83, 2012

Figure 1. (A) Overall (OS) and progression-free survival (PFS). (B) OS and PFS by pretransplantation status. (A) The OS and PFS are shown by primary
or secondary CNS lymphoma from the day of transplantation. Median time points have not yet been reached. (B) The OS and PFS are shown by pre-
transplantation complete response (CR) or partial response (PR) from the day of transplantation. Two patients are not shown: 1 with either progressive
disease at transplantation (currently alive without disease recurrence) and 1 with stable disease at transplantation (relapsed within 3 months, currently
still alive in CR after salvage therapy).

3 patients developed uncomplicated BK virus–mediated
cystitis, all of which were successfully managed with
supportive care. One case of pneumonia progressed to
a large lung abscess and empyema, resulting in death
at day 98, and the rest of the infections resolved with ap-
propriate antimicrobial therapy.
There were no cases of hemorrhagic cystitis or he-
patic veno-occlusive disease (VOD). Seventy-two per-
cent (23 of 32) of patients developed grade 3-4
mucositis with 16% requiring total parenteral nutrition
(TPN). There was 1 incident of possible busulfan-
induced pulmonary toxicity. This patient was a 61-
year-old man who was found on routine day 100
follow-up pulmonary function testing to have devel-
oped an asymptomatic decrease in his DLCO from
118% of predicted to 72% of predicted. The DLCO
improved to 83% (normal) on the most recent set of
pulmonary function testing. The patient remained min-
imally symptomatic other than mild dyspnea, and he did
not require supplemental oxygen or systemic steroids.
There was 1 case of engraftment syndrome that
presented with persistent high fevers without an infec-
tious source on day 15. This was accompanied by
a rash during the early phase of count recovery. The
patient responded to empiric steroids and was slowly
tapered without event. One patient developed revers-
ible congestive heart failure felt to be from cyclophos-
phamide toxicity. This was diagnosed on day 12 by
transthoracic echocardiography, with a decrease in
ejection fraction from 66% to 35% in the setting of
a new oxygen requirement. She was treated with sup-
plemental oxygen, furosemide, lisinopril, and meto-
prolol. On day 116, repeat echocardiography
showed recovery, with an ejection fraction of 66%.
Although no formal neurologic assessments were
performed, with over 1 year of median follow-up, there
have been no cases of significant long-term cognitive
dysfunction or decline. There were 5 patients with
transient delirium suspected by the treating clinicians
to be related to supportive medications (e.g., narcotics
or benzodiazepines). There was 1 patient with a tran-
sient delirium at day 48 of unknown etiology. Addi-
tionally, there was 1 patient with significant
neurological toxicity that persisted after the transplan-
tation hospitalization discharge. This patient was
a 67-year-old man with a history of cerebrovascular
Biol Blood Marrow Transplant 18:76-83, 2012 ASCT in patients with CNS lymphoma 81

Table 3. ASCT Toxicity dose chemotherapy with autologous stem cell trans-
PCNSL SCNSL Combined
plantation in both first-line treatment and in relapse
has shown promise in selected patients [10-21]. Here,
Transplant-related toxicity
we report the largest experience to date of HDT/
Infections
Bacterial (%) 4 (25) 4 (25) 8 (25) ASCT with TBC conditioning for patients with CNS
Viral (%) 0 (0) 0 (0) 0 (0) involvement by NHL. Although the median PFS and
Fungal (%) 1 (6) 1 (6) 2 (3)
OS have not been reached, 90% of patients are alive
Veno-occlusive disease (%) 0 (0) 0 (0) 0 (0)
DAH/IPS (%) 0 (0) 0 (0) 0 (0) and 78% of patients are without disease progression
Engraftment syndrome (%) 0 (0) 1 (6) 1 (3) at over 1 year (median 379 days) of follow-up after
Cardiac toxicity (%) 0 (0) 1 (6) 1 (3)
ASCT. The posttransplantation 1-year OS estimate is
Hemorrhagic cystitis (%) 0 (0) 0 (0) 0 (0)
Mucositis, grade 3 and 4 (%) 13 (81) 10 (62.5) 23 (72) 93% (95% CI: 75%-98%) and the 1-year PFS estimate
Busulfan pulmonary toxicity (%) 0 (0) 1 (6) 1 (3) is 90% (95% CI: 72%-96%). Moreover, 100-day TRM
Seizures (%) 0 (0) 0 (0) 0 (0)
was only 3%. Although the period of follow-up after
Persistent neurotoxicity (%)* 0 (0) 1 (6) 1 (3)
Transient neurotoxicity (%)† 1 (6) 6 (33) 7 (22) ASCT is still early, these patients have now been fol-
Transplant-related mortality (%)‡ 0 (0) 1 (6) 1 (3) lowed for a median of 643 days for SCNSL and 1260
DAH/IPS indicates diffuse alveolar hemorrhage/idiopathic pulmonary days for PCNSL since initial diagnosis.
syndrome; PCNSL, primary central nervous system non-Hodgkin lym- There have been several reported retrospective and
phoma; SCNSL, secondary CNS non-Hodgkin lymphoma. prospective studies of ASCT in primary or secondary
*Any event persisting after discharge from the transplantation hospital-
CNS lymphoma (Table 4) [10-21]. Although most of
ization.
†Includes short-term events during or after hospitalization that resolved these series are relatively small, survival ranges from
in less than 7 days. 21% to 87% at 2 to 5 years, which is comparable to
‡Transplant-related mortality includes days 0-100. nontransplant combined modality regimens. Within
this heterogeneous experience, the use of agents
disease and PCNSL who was heavily treated with
with known CNS penetration including thiotepa,
4 separate chemotherapy regimens and 39 Gy of
carmustine, busulfan, and cyclophosphamide suggests
WBRT plus 10 Gy to the cerebellum before condi-
that improved outcomes can be achieved [10,16,18-21].
tioning and transplant. During the transplantation
The experience from Illerhaus et al. [16,18] included
hospitalization, he developed acute delirium accompa-
conditioning with carmustine and thiotepa with or
nied by ataxia, dysphagia, and weakness. The delirium
without WBRT consolidation. Impressively, OS for
resolved during the hospitalization; however, the dys-
patients with PCNSL in CR1 was 77% to 87% at 3 to
phagia did require temporary enteral tube feeding.
5 years. Similarly, Montemurro et al. [21] achieved
The ataxia gradually improved where by day 34 he
a 61% OS at 2 years, with a conditioning regimen
was ambulating with a walker without assistance. At
using busulfan and thiotepa with or without WBRT
the last follow-up, he was using a cane for balance
in 16 PCNSL patients in CR or PR following high-
and there was some mild subjective difficulty with
dose MTX.
short-term memory.
The pilot study for TBC/ASCT in CNS NHL
The 100-day transplant-related mortality rate was
from Soussain and colleagues [20] from France en-
3%, with 1 patient dying at day 198 from complica-
rolled 22 patients with relapsed/refractory PCNSL or
tions of a lung abscess and a significant cerebrovascular
intraocular lymphoma (IOL). Following salvage ther-
accident. The patient was a 69-year-old woman who
apy (including 12 with radiation therapy), 20 patients
likely had active SCNSL at the time of ASCT. She en-
underwent HDT/ASCT using TBC conditioning.
grafted well, but did have a bacterial pneumonia that
The event-free survival (EFS) was 53% and the OS
required prolonged intravenous antibiotics and a stay
was 60% for the patients who underwent ASCT. Tox-
at an inpatient rehabilitation facility for weakness
icities were somewhat high, however, including 19 of
and impaired mental status. After finishing a full
22 patients who had infectious complications. One pa-
course of antibiotics, she was noted to be febrile and
tient developed VOD that resolved without specific in-
short of breath, and chest CT showed a large 8- to 9-
tervention. Notably, 7 patients developed neurologic
cm cavitary lung abscess, for which she again received
toxicity and TRM was 5%. Investigators attributed
intravenous antibiotics as well as percutaneous drain-
the overall relatively high toxicity of their experience
age. However, she did not improve from these inter-
to the age of their patients (eg, 5 of 7 over the age of
ventions and eventually died of complications related
60 died from treatment complications) and the number
to the infection and a cerebrovascular accident.
of prior therapies including WBRT.
Based on this preliminary experience, a follow-up
DISCUSSION multicenter phase II study was performed, which
included 43 patients with relapsed/refractory
Primary and secondary CNS lymphomas are devas- PCNSL or IOL intended to be treated with CYVE
tating diseases with historically poor prognoses. High- (cytarabine/etoposide) salvage therapy followed by
82 G. M. Cote et al. Biol Blood Marrow Transplant 18:76-83, 2012

HDT/ASCT using TBC conditioning [19]. For the 27

TRM indicates transplant-related mortality; TBC, thiotepa, busulfan, cyclophosphamide; BEAM, carmustine, etoposide, cytarabine, melphalan; BCNU/T, carmustine, thiotepa; Bu/T, busulfan, thiotepa; PCNSL, primary
central nervous system non-Hodgkin lymphoma; SCNSL, secondary CNS non-Hodgkin lymphoma; ALL, acute lymphoblastic leukemia; AML, acute myelogenous leukemia; CML, chronic myloid leukemia; TBI, total
71% (at 5-42 months)
9-42% (5+ years)†,‡
patients who underwent HDT/ASCT, the 2-year PFS

23% (2 years)¶,**
PFS/EFS/DFS

77% (3 years)¶

90% (1 years)‡
46% (5 years)§
43% (3 years)§
66% (3 years)§

61% (2 years)§

53% (3 years)§

58% (2 years)§
was 58% and OS was 69%. The median PFS and OS
were 41.1 and 58.6 months, respectively. Toxicity
was similar to the prior study including neurotoxicity

N/A
(5 patients). A total of 27 patients died during the
36-month follow-up period (19 from progression of
CNS lymphoma, 3 from CYVE salvage therapy before

71% (at 5-42 months)

HDT/ASCT, and none from HDT/ASCT). Thirteen
patients eventually relapsed at a median time of 7.1
25% (2 years)**
64% (4 years)^
41% (5 years)
60% (3 years)

87% (5 years)

months after HDT/ASCT [19].

61% (2 years)
77% (3 years)

60% (3 years)

69% (2 years)
93% (1 year)
OS

In this current analysis, we report our institutional

experience of HDT/ASCT with TBC conditioning
N/A

for primary or secondary CNS lymphoma. Our patient

population had been heavily pretreated (median of 3
prior CNS regimens for the PCNSL patients), and
45%**

there were no cases of primary intraocular lymphoma.

TRM

N/A
7%
6%
0%
13%
0%

5%
14%
0%
3%
15%

Compared with prior series, our patients are relatively

young (median age in the 40s) with the majority in
body irridiation; OS, overall survival; PFS, progression-free survival; DFS, disease-free survival; EFS, event-free survival; CR, complete response.

a good state of disease response (30 of 32 patients

achieving a CR or PR) before ASCT.
Neurotoxicity

Interestingly, although formal prospective neuro-

40%**
39%^
N/A
33%
0%
13%
17%

0%

32%
0%
19%
3%

psychiatric assessments were not performed, there was

only 1 case of significant neurologic toxicity and there
have been no cases of late cognitive decline to date.
There were 5 other patients with transient delirium
that cleared by the time of discharge, and there was 1 pa-
Variable (BEAM 5 17, cy/TBI 5 15)

tient with delayed presentation well after hospitalization

BCNU/T (WBRT for non-CR)

that rapidly resolved. The event rate of neurologic tox-

icity in our study is comparable to other publications
Regimen

BEAM+WBRT± boost

of TBC in PCNSL and in non-TBC regimens without

BCNU/T+WBRT

consolidative WBRT. Given the low number of patients

TBC (+IT MTX)
CBV (1 pt TBI)

with neurotoxicity, analysis for risk factors associated

Bu/T+WBRT

with this adverse event was not performed. Retrospec-

Table 4. Comparison with Other Conditioning Regimens and Case Series

BEAM

tive data suggests that neurocognitive decline is highly

TBC
TBC
TBC
TBC

related to patient age and the use of WBRT

pre-ASCT [1,3,6]. Indeed, Illerhaus et al. [16,18]
described 17% late neurologic decline with mandatory
SCNSL 5 9 AML, ALL, CML 5 15

consolidative WBRT, but the absence of late

neurocognitive decline when WBRT was reserved for
PCNSL 5 16 SCNSL 5 16
PCNSL 5 2 SCNSL 5 13
PCNSL 5 13 SCNSL 5 1

patients who did not achieve a CR. Three patients in

No. ASCT

†PFS range of patients in non-CR to CR before transplant.

our study received WBRT before transplantation, and

all remain alive and disease-free at the time of this study.
Of note, however, 1 of these patients did experience
PCNSL 5 17
PCNSL 5 23
PCNSL 5 16
PCNSL 5 11

PCNSL 5 20

PCNSL 5 27
SCNSL 5 62

PCNSL 5 7

the acute neurotoxic event described previously.

Includes both ASCT and non-ASCT patients.
**Includes patients in CR before ASCT only.

In summary, in patients with either primary or sec-

ondary CNS lymphoma, who are eligible for ASCT,
TBC is a safe and efficacious conditioning regimen
with low rates of acute and chronic transplantation-
Montemurro et al. (2006) [21]

related toxicities. More follow-up is needed to deter-

Van Besien et al. (1996)* [12]
Colombat et al. (2006) [15]
Williams et al. (1994) [13]

mine if long-term PFS and OS and rates of neurotoxicity

Alvarnas et al. (1999) [11]

Soussain et al. (2001) [20]

Soussain et al. (2008) [19]

Illerhaus et al. (2006) [16]

Illerhaus et al. (2008) [18]

Cheng et al. (2003) [10]

Abrey et al. (2003) [14]

are comparable other regimens, specifically those using

Author

Cote et al. (2010)*

BCNU, in patients with CNS involvement. This is the

*Retrospective.

first description of this transplant regimen in SCNSL

in CR1, and it now is our standard therapy for eligible
patients with primary or secondary CNS involvement
¶DFS.
‡PFS.
§EFS.

with lymphoma.
^
Biol Blood Marrow Transplant 18:76-83, 2012
ACKNOWLEDGMENTS
Financial disclosure: Dr. Chen is a recipient of a
career development award in clinical research from
the Leukemia Lymphoma Society, and receives fund-
ing from Otsuka Pharmaceuticals, Inc. to conduct clin-
ical trials. The other authors have nothing to disclose.
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