Intensive Therapy With Peripheral Blood Progenitor Cell

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Intensive Therapy With Peripheral Blood Progenitor Cell Transplantation in
60 Patients With Poor-Prognosis Follicular Lymphoma
By Y. Bastion, P. Brice, C. Haioun, A. Sonet, G. Salles, J.P. Marolleau,
and B. Coiffier
D. Espinouse, F. Reyes, C. Gisselbrecht,
Intensivetherapy, mainly with purged autologous bone marrow transplantation (ABMT), has been proposed in recent
years as consolidation treatment in young patients with follicular lymphoma. Reported experience
with transplantation
of peripheral blood progenitor cells (PBPC) is,so far, limited.
The feasibilii and the therapeutic efficacy of intensive therapy followed by unpurged autologous PBPC reinfusion were
evaluated in 60 patients with poor-prognosis follicular
lymphoma. Twelve patients were in first partial remission
(PR), 34 were in second partial or complete remission (CR),
and 14 were in subsequent progression.At the timeof the
procedure, 39 patients (65%) had persistent bone marrow
involvement, 49 patients (82%) were in PR, and 16 patients
had presented with a histologic transformation (HT). PBPC
were collected after chemotherapy followed by granulocyte
(G) colony-stimulating factor (CSF) or granulocyte-rnacrophage (GM)-CSF in 50 patients. Conditioning regimens included high-dose chemotherapy alone (14 patients);
mainly
regithe BCNU, etoposide,aracytine,melphalan[BEAM]
men), or cyclophosphamide with or without etoposide plus
total body irradiation (46 patients).The median time t o reach
a neutrophil count greater than 0.5 x 109/L was 13days.
There were five treatment-related deaths, with four being
associated with a delayed engraftment and all occurring in
patients in third or subsequent progression. At a median
follow-up of 21 months, 48 patients were still alive, 18 relapsed, and sevendied of lymphoma progression. Estimated
%year overall survival (OS) and failure-free survival (FFS)
rates were 86% and 53%, respectively, without a plateau.
Patients treated in PR1 or PR2/CR2 had asignificantly longer
rate of OS and FFS than those treated in subsequent progression (P= .002 and P = .001, respectively), whereasage,
response to salvage treatment, presence or absence
of residual bone marrow involvement, orconditioning regimen had
no influence on outcome. Patients with HT tended t o have
a worse FFS rate ( P = .04) without an OS difference. Along
with an unusual rate of engrafment failure, the poor FFS
observed in heavily pretreated patients suggests that intensive therapy should be performed early in the course of the
disease. Given the highpercentage ofpatients intensified in
PR with residual bonemarrow involvement, our results are
comparable with those achieved with ABMT published t o
date. Prospectivetrials are warranted t o compare this strategy with standard therapy in patients with relapsing or PR
follicular lymphoma.
0 1995 by The American Society of Hematology.
A
have theoretical advantages compared with bone marrow
cells. First, hematologic recovery is more rapid with PBPC
than with bone marrow cells.I4Second, peripheral blood may
be less contaminated by tumor cells, although this has not
been proven.” Third, this strategy remains feasible in heavily
pretreated patients, especially in those who have received
previous pelvic radiotherapy.“j The reported experience with
high-dose therapy followed by PBPC reinfusion is, so far,
very limited in patients with follicular 1ymph0ma.l~~~~
We present here the results obtained in 60 patients with
follicular lymphoma treated with high-dose therapy and
PBPC support in three French centers. The vast majority of
these patients were in the second or a subsequent phase of
their disease and had persistent bone marrow involvement
at the time of the procedure.
LTHOUGH FOLLICULAR lymphomas are characterized by a relatively indolent course, they remain an
incurable disease in spite of various therapeutic approaches.
Median survival ranges from 6 to 10 years in recent studi e ~ with
” ~ a constant annual rate of relapse and death. In
recent years, prognostic factors have been better defined,’
and the notion that a complete clinical remission is associated
with a longer outcome has e~nerged.~.~
Recently, the use
of intensive therapy supported by autologous bone marrow
transplantation (ABMT) has been investigated in these patients, especially for those aged less than 60 years with recurrent d i ~ e a s e . ~In” the
~ experience of St Bartholomew’s Hospital (London, UK), this strategy seems to be able to prolong
remission duration.’ However, this longer time-to-progression survival and the possible impact on overall survival
have not been proven in randomized controlled trials. Furthermore, the optimal modalities of this therapeutic approach
and, particularly, the influence of in vitro treatment of the
bone marrow on disease recurrence remain unknown. In the
experience of the Dana-Farber Cancer Institute (Boston,
MA), antibody-mediated purging eliminated lymphoma cells
detectable by polymerase chain reaction (PCR) in hematopoietic stem cell harvests in about half of the patients who
had a breakpoint involving the bcl-2 translocation, and disappearance of bcl-2-rearranged cells after in vitro treatment
was the single most important prognostic factor for freedom
from recurrence.” On the other hand, disappearance of bcl2-rearranged cells has rarely been achieved in the experience of the St Bartholomew’s Hospital, and the impact of
successful purging on further outcome is not clear.” Furthermore, the overall survival rates from the two centers are the
same.I3
The use of peripheral blood progenitor cells (PBPC) may
Blood, Vol 86, No 8 (October 15). 1995:pp 3257-3262
Fromthe Service d’Himatologie, Centre Hospitalier Lyon-Sud,
Pierre-Bdnite; the Service d’Himatologie, Hbpital Saint-Louis,
Paris; and the Service d’Himatologie, Hbpital Henri Mondor, Criteil, France.
Submitted February 2, 1995; accepted June 22, 1995.
Supported in part by the Ligue Contre le Cancer du Rhone et de
la Saone et Loire and by the Projet Hospitalier de Recherche Clinique (HCL PHRC-004).
Address reprint request to Y. Bastion, MD, Service d’Himatologie,
Centre Hospitalier Lyon-Sud, 69495 Pierre-Bdnite Cedex, France.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
“advertisement” in accordance with 18 U.S.C. section 1734 solely to
indicate this fact.
0 1995 by The American Society of Hematology.
0006-4971/95/8608-06$3.00/0
3257
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3258
BASTION ET AL
PATIENTS AND METHODS
Sixty patients, aged 20 to 58 years (median age, 47
years), treated between August 1990 and April 1994 in Lyon-Sud (34
patients), Paris-St-Louis (18 patients), and Crkteil (eight patients),
France, form the basis of this analysis. The clinical characteristics
of these patients are listed in Table 1. Patients were considered to
have a large tumor burden if they had at least one of the following
criteria, as determined by an analysis of the literature and a previous
study”: any nodal or extranodal tumor mass with a diameter larger
than 7 cm; involvement of at least three nodal sites, each of which
had a diameter larger than 3 cm; systemic symptoms; substantial
splenic enlargement; serous effusion; orbital or epidural involvement
or ureteral compression; andor leukemic presentation. In a previous
study, patients with such characteristics at diagnosis and treated with
a CHOP (cyclophosphamide, adziblastine, vinezistine, and prednisone)-like chemotherapy regimen with or without interferon experienced a median event-free survival of 28 months and an estimated
median overall survival of about 60 months.’”
Twelve patients were in first partial remission. In all cases but
one, intensive therapy was used because of the presence of at least
one of the following parameters: presence at diagnosis of a composite histology with coexistence of a more aggressive diffuse
lymphoma (three patients), presence of at least one adverse prognostic factor as defined above (10 patients), failure of a CHOP-like
chemotherapy regimen used as first-line treatment (1 1 patients).
Thirty-four patients were in second partial or complete remission.
Patients.
Table 1. Characteristics of the 60 Patients With Follicular
Lymphoma Treated With Intensive Therapy and PBPC Support
Characteristic
All
Patients
No.
Median age (yr)
Initial subtype
Small cell
Mixed
2
Large cell
HT
Initial stage
I II
111
1V
Bone marrow involvement 22
High tumor burden at
diagnosis*
Median no. of previous
regimens
Anthracyclin-containing
33
regimen
Previous CR
Status at time of intensive
therapy
CR
PR
Stable disease
Median mos from
diagnosis to intensive
therapy
Residual bone marrow
involvement at time of
intensive therapy
N
Y
11
Residual tumor mass at
time of intensive
therapy
N
<2 cm
2 2 cm
+
60
41
Patients
in PR1
14
Patients in
CR2/PR2
Patients in
r 3 r d Phase
12
46
34
44
21
32
7
16
1
8
3
3
14
5
-
3
8
23
2
1
11
9
23
5
9
46
42
38
12
11
10
2
1
58
25
11
10
2
49
18
6
6
2
3
3.5
14
9
-
16
-
8
25
1
2
12
10
49
1
12
33.5
11.5
33.5
63.5
21
39
1
14
20
6
8
24
13
23
4
5
3
14
12
8
6
6
2
Criteria of the GELF-86 protocol?’
-
-
Adverse prognostic factors as defined above were present at diagnosis in 23 of them (68%). Ten patients had presented with a histologic
transformation (HT) as second progression of their disease. Fourteen
patients were in subsequent progression.
Initial treatment was chlorambucil or prednimustine in seven patients (12%), CHVP regimen (cyclophosphamide 600 mg/m’, doxorubicin 25 mg/m2, teniposide 60 mg/m2, prednisone 40 mg/mz/d x
5 days) with (1 1 patients) or without (six patients) interferon-a2;’
in 17 patients (28%), standard-dose or high-dose CHOP’’in23
patients (38%), multidrug regimens without anthracyclin in six patients (IO%), fludarabine monophosphate in four patients (7%), interferon-azbin two patients (3%), and radiotherapy in one patient (2%).
At the time of intensive therapy, all patients except two hadreceived
at least one anthracyclin-containing regimen. Seven patients had
received localized radiotherapy.
Sixteen patients (27%)had experienced HT in the course of their
disease. Forty-nine patients (82%) had a history of previous bone
marrow involvement, and 38 patients had persistent marrow involvement at the time of stem cell harvest (63%). Twenty-five patients
(42%) had reacheda complete remission in the course of their disease
before intensive therapy.
Pretransplunt status. All patients except one responded to salvage treatment, but only 10 patients were in complete remission
(CR). Forty-nine patients were in partial remission (PR), 37 with a
minimal disease defined as reduction of the tumor masses to 2 cm
or
Fourteen of themhad residual bonemarrow involvement
as the only site of residual disease.
PBPC collection. At the time of PBPC collection, none of the
patients had cytologic evidence of blood involvement by lymphoma
cells. In those patients with previous blood involvement, immunologic studies were performed to search for a monoclonal B-cell
fraction andwere negative. Peripheral mononuclear cells (MNC)
were collected after a cycle of cytotoxic chemotherapy followed in
50 cases by granulocyte (G) colony-stimulating factor (CSF; 28
patients) or granulocyte-macrophage (GM)-CSF (22 patients). The
chemotherapy regimen used for PBPC mobilization was high-dose
cyclophosphamide in 30 patients, a CHOP or CHOP-like regimen
in 15 patients, high-dose cyclophosphamide plus etoposide in eight
patients, and another cytotoxic regimen in seven patients (with mitoxantrone in five patients; without anthracyclin or mitoxantrone in
two patients). The collections were performed daily to obtain at least
2 X lo8 MNC per kilogram in 1990 and 1991 and at least 4 X IOR
MNC per kilogram in the following period, with at least 2 X lo4
colony-forming units/granulocyte-macrophage (CFU-GM) per kdogram in both cases in Lyon-Sud, France. The minimum requirements
for CFU-GM were, respectively, 2 X lo4 and 4 X IO4 CFL-GM per
kilogram in Pari-St-Louis and Creteil, France.
A median MNC number of 4.25 X 10*/kg(range, 0.85 X IO8 to
16 x 10’) and a median CFU-GM number of 9.95 X 104/kg were
collected after a median number of 3.5 aphereses (range, one to
nine). The MNC were then cryopreserved without any in vitro manipulation in the patient’s serum with 10% dimethyl sulfoxide
(DMSO) in the vaporphase of liquid nitrogen. In two patients (LyonSud), the number of MNC and CFU-GM collected were below the
planned thresholds; considering the poor prognosis of their disease
(both patients had experienced HT, andonehad been previously
treated with ABMT), intensification was performed.
Conditioning regimen. Conditioning regimens are shown in Table 2. Forty-six patients received cyclophosphamide plus etoposide
(43 patients) and total body irradiation (TBI) as conditioning regimen. Because of extensive previous therapy, one patient inthird
progression of his disease received TB1 as a single dose of 8 Gy;
in other patients, TB1 was administered at a dose of 10 or 12 Gy,
whether fractionated or unfractionated according to each center’s
policy. However, because of previous radiotherapy or extensive pre-
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3259
INTENSIVETHERAPY WITH PBPCT IN FCL PATIENTS
vious chemotherapy, 14 patients received a pretransplant regimen
consisting of high-dose chemotherapy only. Median time from PBPC
collection to intensive therapy was 43 days (range, 9 to 376 days).
Thirty-three patients received no further treatment between PBPC
collection and high-dose therapy, and 27 patients received at least
one course of chemotherapy (median, one; range, one to six) during
this interval. Fifty-two patients received a hematopoietic growth
factor after PBPC reinfusion (GM-CSF, 30 patients; G-CSF, 22
patients) until neutrophil recovery.
Response criteria. Engraftment failure was defined as the absence of persistant recovery of neutrophil count greater than 0.500
x 1 0 9 L CR was defined as the disappearance of all sites of disease
including bone marrow. PR was defined as a reduction of more than
50% in the largest diameter of each measurable site of disease, or
as the persistence of bone marrow infiltration as the only residual site
of disease. Otherwise, the patient was considered as nonresponding.
Response was assessed 3 months after high-dose therapy with clinical examination, computed tomography (CT) scan, bone marrow
aspirate, and biopsy.
Statistical methods. Overall survival (OS) was defined as the
time from reinfusion of PBPC to death or date of last visit. Failurefree survival (FFS) was defined as the time from reinfusion of PBPC
to the time of disease progression, last follow-up, or death from any
cause. Survival distributions were estimated using the product-limit
method of Ka~lan-Meier.'~ Thestatistical significance of observed
differences in the distributions of OS and FFS were assessed using
the log-rank test.
RESULTS
Clinical toxicity and hematopoietic recovery. There
were five treatment-related deaths (8%):intraalveolar hemorrhage (one patient), failure to engraftment (four patients).
These four patients reached an absolute neutrophil count of
greater than 0.5 X 109/L between 15 and 24 days posttransplant, but neutropenia thereafter relapsed. They then died of
infectious complications between day 64 and 168, with an
absolute neutrophil count of less than 0.5 X 109/L and were
considered as engrafment failures. They were all in third or
subsequent phase of their disease, and they were older than
45 years. The number of MNC collected in these four patients ranged from 2.06 x 108/kg to 3.35 x 108/kg,and the
number of CFU-GM from 2 X 104/kg to 5.6 X 104/kg.No
other major adverse event was observed. The median time
to reach a neutrophil count of greater than 0.5 X 109/Lwas
13 days (range, 9 to 32 days). A platelet count of greater
1.0
0.8
g
-1
0.4
Oa2
0.0
11
I
0
,
,
6
.
.
,
12
,
.
18
, . ,
24
.
,
,
I
42
36
30
9
,
.
I
64
Months
48
Fig 1. OS and FFS in the 60 patienta with follicularlymphoma
treated with intensive therapywith PBPC support.
than 50 X 109/L was reached after amedian time of 19
days (range, 9 to 1,163+ days). One patient developed a
myelodysplastic syndrome 25 months after the procedure:
he had been extensively treated with a firsthigh-dose therapy
with TB1 and bone marrow stem cell support 3 years earlier.
Assessment of response afrer high-dose therapy. Fiftysix patients were assessable for response. CR was obtained
in 46 patients (77%), PR in nine patients (15%), and one
patient had a rapidly progressive disease.
OS and FFS. At the time of analysis, median follow up
after intensive therapy was 21 months. Forty-eight patients
were still alive. Apart from the five procedure-related deaths,
seven patients died of recurrent lymphoma. Eighteen patients
have had a lymphoma recurrence after a median time of 14
months (range, 2 to 31 months). Estimated 2-year OS and
FFS rates were 86% (95% confidence interval [CI], 76% to
96%) and 53% (95% CI, 37% to 69%), respectively (Fig 1).
No plateau was observed.
Prognostic factors forOS and FFS. There was no corre-
l.o
0.8
Table 2. Conditioning Regimens in the 60 Patients With Follicular
Lymphoma TreatedWith Intensive Therapy WithPBPC Support
1
U
Conditioning Regimen
Gy
Patients in
CRWR2
Patients in
~ 3 r Phase
d
+
Cyclophosphamide
etoposide TB1
10 Gy fractionated
12 Gy fractionated
10
nonfractionated
8 Gy nonfractionated
Cyclophosphamide TBI: 10
Gy nonfractionated
BEAM
Other
+
All
Patients
Patients PR1
in
+
43
24
13
5
1
3
12
2
11
8
2
1
22
13
6
3
-
-
1
-
3
7
2
10
3
5
1
1
-
C
P)
0.4
!i
n
0.2
0.0
i
BM +
1
I
0
t
6
12
l8
24
30
36
42
a
Months
4
-
Cyclophosphamide was given at the dose of 60 mglkg x 2, etoposide at 300
mg/mz/d x 3.
Abbreviation: BEAM: BCNU, etoposide, aracytine, and melphalan.
Fig 2. FFS of the 60 patients according to bone marrow involvement at the time of harvesting peripheralblood stem calk (log-rank
test: P = not aignificant). Bone marrow (BM) involved
(BM+), n = 38;
BM not involved (BM-), n = 22.
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3260
BASTION ET AL
lation between OS and FFS and anyof the following parameters: age, response to salvage treatment (CR v PR), presence
of a residual bone marrow involvement (Fig 2), previous CR
at any time, time from diagnosis to intensive therapy (less
or more than 30 months), or conditioning regimen with or
without TBI. The results are similar when the analysis is
confined to the subgroup of patients intensified after relapse.
There was no significant difference in OS or FFS between
patients intensified in PR2/CR2 and in PR1, but this latter
group comprises only 12 patients. However, patients who
received intensive treatment at a later stage of the disease,
ie, in third or subsequent progression, have clearly a poorer
OS and FFS (log-rank tests: P = .002 and P = .001, respectively; Fig 3). Patients with histologic transformation did not
have a statistically different OS but did have a significantly
shorter FFS (log-rank test: P = .04; see Fig 4). FFS was
shorter for patients with a tumor mass of 2 2 cm at time
of intensification compared with those with no detectable
residual disease or a tumor mass of less than 2 cm, but this
difference was not statistically significant.
Patients with previous HT. Sixteen patients received intensive therapy after they had experienced an HT. Two died
of treatment-related toxicity. Among the remaining 14 patients, eight have relapsed after a median time of 14 months;
two had an aggressive histology at that time, whereas six
had returned to a follicular histology. Among these last six
patients, four are still alive and on therapy at 2, 15, 25, and
34 months after relapse.
DISCUSSION
Although follow up is still short, this study is the largest
reported so far on intensive therapy with PBPC support in
patients with follicular lymphoma. As in patients with aggressive l y m p h ~ m a ? this
~ . ~approach is feasible even in patients with advanced disease andor with residual bone marrow involvement. The use of mobilized PBPC allows a more
1.0 I
I""
0.0
!
0
I
*
,
,
6
,
12
,
,
l8
,
,
24
.
S
,
30
,
l
36
,
,
42
,
48
Months
Fig 3. FFS of the 60 patients by diaease atatus at time of intensive
R
,
lfirst partlal m i u l o n ; PR2, second partial remission;
therapy: P
Cm, secondc0mpI.t. rerniaaion. Log-rank taat PR1VMUC PWCR2,
not aignificant; PR1 PR2/CR2 versus groater than second progression, P = .W1.
+
..
:"-L
0.2
0.0
""
-
8
, . ,
0
6
.
,
12
,
,
18
.
,
. ,
24
30
_ _ _ _ _ _HT
___
_ _ _ _ _ I
.
,
36
.
,
42
J
,
,
48
Months
Fig 4. FFS of the 60 patients by the presence or not of HT (logrank test: P = .04L HT present, n = 16; HT not preaent, n = 44.
rapid hematologic recovery than bone marrow stem cells,
with a 13-day median time to reach a neutrophil count of
20.5 X lo9&. However, our treatment-related death rate is
8%, which is higher than reported in most studies with PBPC
transplantation, although a comparable or even higher toxicity has been reported in heavily pretreated patient^.'^ This
toxicity is largely due to engrafment failures (6.5%): all of
them occured in patients who were at least in third progression of their disease with extensive previous treatments. A
major concern is the fact that in these four patients, the
amount of MNC and C m - G M collected seemed to be in
keeping with our usual thresholds. Therefore, these two parameters do not appear to be useful in selecting candidates
for high-dose therapy with PBPC support, at least not in
heavily pretreated patients. Other parameters such as the
count of CD34+ cells, which has not been performed systematically in this study, may help in selecting candidates
for this treatment among heavily pretreated patients. Along
with toxicity, the shorter FFS observed in heavily pretreated
patients suggests that intensive therapy should be performed
early in the course of the disease.
It is difficult to compare our results with those published
to date on intensive treatment followed by ABMT. In the
original report from the Dana Farber Cancer Institute, 3-year
disease-free survival after myeloablative treatment followed
by purged ABMT was approximately 50% for low-grade
lymphoma patient^.^ In this series, 30 patients of 69 had
residual bone marrow involvement at the time of the proced ~ r eIn. ~the report from St. Bartholomew's Hospital, which
only included follicular lymphoma patients in relapse, 3year freedom-from-recurrence survival was approximately
50%, with a median follow-up of 3.5 years. Only 30 of the
64 patients were in PR at time of intensive therapy, and only
seven had residual bone marrow involvement, which is a
much lower proportion than in our report for both parameters. Given the high proportion of patients in PR andor with
residual marrow involvement in our study, our results seem
comparable with those reported in these two series. Furthermore, in the present study, FFS did not differ for patients
receiving high-dose therapy while in PR or in CR, and the
presence of residual bone marrow involvement had no influ-
From www.bloodjournal.org by guest on December 29, 2014. For personal use only.
INTENSIVE THERAPY WITH PBPCT IN FCL PATIENTS
ence on outcome. This contrasts with data obtained after
purged ABMT” and may suggest a specific interest forintensive therapy with PBPC support in this subset of patients.
Indeed, this must be confirmed with a longer follow up.
Another important point is that patients treated after HT
have a relatively good outcome, with the same OS as patients
who retained a low-grade histology. This point is largely
controversial. In a report from the Nebraska Medical Center,
patients receiving transplants after HT had a very poor outcome.’ This poor outcome was also confirmed in a small
group of patients from the European Bone Marrow Transplant Group Registry.26This contrasts with the Dana-Farber
Cancer Institute experience, in which there was no difference
in the disease-free survival between patients with low-grade
and patients with a transformed lymphoma.’ Patients with
follicular lymphoma and HT have a very poor outcome with
standard chemotherapy: in our experience, median survival
was 7 months for all patients and 20 months for patients
who could be treated with a CHOP-like regimen.3 These
results suggest thatthe adverse prognosis associated with HT
may be modified by intensive therapy with PBPC support.
Notably, the majority of patients intensified after HT who
subsequently relapsed returned to a low-grade histology.
In recent years, our policy has been to propose intensive
therapy for young patients with recurrent disease or in first
partial remission if adverse prognostic factors were present
at diagnosis, but many questions remain unresolved. A study
of minimal residual disease in patients bearing a polymerase
chainreaction-amplifiablebreakpointafter
PBPC transplantation and during follow upis in progress in our institution~.~’
A prospective randomized study comparing standard
chemotherapy and a CHOP regimen followed by intensive
therapy with TB1 as consolidation has been initiated by our
group. In young patients with recurrent disease,
the comparison with historical control groups may suggest an improved
relapse-free survival.8 It remains unclear, however, whether
this treatment is able to prolongOS. If this intensive therapy
is to be considered for patients with HT who respond to
salvage chemotherapy, furtherexperience with a longer follow up is needed for relapsing patients or for first-line patients.
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1995 86: 3257-3262
Intensive therapy with peripheral blood progenitor cell
transplantation in 60 patients with poor-prognosis follicular
lymphoma
Y Bastion, P Brice, C Haioun, A Sonet, G Salles, JP Marolleau, D Espinouse, F Reyes, C
Gisselbrecht and B Coiffier
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