Follicle centre cell lymphoma: optimal use of therapeutic options
Ama Rohatiner
Department of Medical Oncology, St Bartholomew's Hospital, London, UK
Introduction
die of progressive, resistant, follicular lymphoma,
or following transformation to diffuse large B-cell
histology [13-17]. Thus, new approaches are clearly
needed.
Despite responsiveness to chemotherapy, irradiation
and to biological therapies, most patients with follicular lymphoma still die as a consequence of progressive disease (or its treatment), often following
transformation to diffuse large B-cell lymphoma.
This pattern of repeated remission and recurrence
affords the opportunity to evaluate new treatments at
different time points in the course of the illness.
Recently, several new strategies have been shown
to result in 'molecular remission'. The concept is
based on the finding that 85% of patients with follicular lymphoma have a reciprocal t(14;18) translocation [1]. PCR (polymerase chain reaction) analysis
[2] enables one abnormal bcl-2 rearrangement-containing cell to be identified amongst 105 normal cells.
If it is assumed that the presence or absence of such
cells can be used as a surrogate marker of disease
activity, (and that at present is only a hypothesis), the
relative efficacy of a treatment can be evaluated at
the molecular level using PCR analysis.
Four approaches which have been shown to result in 'molecular remission' will be described, but
in order to put these into perspective, outcome to
conventional therapy as used at St Bartholomew's
Hospital (SBH), London, is first reviewed. Follicular
lymphoma is unusual amongst malignancies in that
some patients with disseminated disease may not
require any treatment at the time of presentation and
may therefore be managed expectantly [3-5]. Traditionally, alkylating agents have formed the basis of
therapy. In Europe, chlorambucil (CB) and CVP (cyclophosphamide, vincristine and prednisolone) have
been favoured [6-10] whilst in the United States,
'CHOP' (cyclophosphamide, doxarubicin, vincristine
and prednisolone) has generally been used [11,12].
However, irrespective of which of these treatments
has been given, responses are usually incomplete and
hardly ever more than temporary [5-12].
With conventional therapy, the median survival is
between 9 and 10 years, and the situation has not
changed appreciably in the last 25 years. Patients
Fludarabine-containing regimens
Fludarabine when used alone results in a response
rate of 50% in patients with recurrent disease
[18-22], and approximately 70% in newly diagnosed
patients [21,23-25], with a 38% complete response
rate in the latter group [23]. When compared with
CVP in a phase DI study, (in newly diagnosed patients with Stage III or IV 'low-grade' lymphoma)
a significantly higher response rate and complete response rate was seen with fludarabine and a trend
towards longer time to progression [24]. A similar study from Canada [25] showed progression-free
survival to be longer for patients who received fludarabine but no difference in overall survival. A
third study from France compared fludarabine with a
doxorubicin-containing regimen given in conjunction
with interferon. Response rate, remission duration
and survival were actually all better with the latter
[26].
Fludarabine has since been combined with mitoxantrone and dexamethasone (FMD) in studies
predominantly conducted at the MD Anderson Cancer Center [27,28] with a 94% response rate and a
47% complete response rate in patients with recurrent or refractory follicular (or small lymphocytic
and mantle cell) lymphoma. Dexamethasone has also
been omitted without any obvious diminution in activity [29,30]. In a proportion of patients, 'molecular
remissions' have been achieved [31]. Fludarabine
has also been combined with cyclophosphamide with
an extremely high CR rate (89%) in patients with
'low-grade' lymphoma but with appreciable toxicity
[32].
It should be remembered that, as in chronic lymphocytic leukaemia, fludarabine in combination has
the same propensity to cause T-cell dysfunction as
in
112
A. Rohatiner
when used alone, and is therefore associated with an
increased risk of opportunistic infections, (in particular Pneumocystis carinii and Listeria) [33]. Prophylactic co-trimoxazole should be given. Also, there
may be difficulty in collecting sufficient numbers
of CD34+ve cells afterwards to support high-dose
treatment (HDT), if needed and there is concern
about a possible association with the development of
secondary myelodysplasia [34,35] in patients subsequently proceeding to HDT.
High-dose treatment (HDT) with autologous
haemopoietic progenitor cell support
A number of patients have now received HDT (usually cyclophosphamide + total body irradiation [TBI]
or BEAM [BCNU, etoposide, ara-C and melphalan])
and the results may be summarised as follows:. .
• The treatment related mortality is less than 5%.
• In terms of outcome, the results from SBH
[36-38] which are virtually superimposable upon
those from the Dana Farber Cancer Institute
(DFCI) show no plateau in disease-free survival
or overall survival.
• For patients receiving HDT as consolidation of
second remission at SBH, albeit in comparison
with an historical control group who received conventional therapy, there is a significant advantage
in remission duration in favour of HDT. There is
currently no survival advantage [37].
• Outcome following recurrence relates to the histology at the time, patients with transformation
to diffuse large B-cell histology having a significantly worse prognosis [38].
• Secondary myelodysplasia and secondary AML
are emerging as significant late complications (see
below) [39,40].
It is now clear that 10-15% of patients who have
received HDT supported by autologous bone marrow
or peripheral blood progenitor cells have developed
secondary MDS or AML, which is a cause for serious concern. Two recent studies have described
the cytogenetic findings in such patients: the majority have had complex karyotypes, with monosomy
5 / 5 q - , 7 / 7 q - , 18/18q- and 13/13q being the
most prevalent [35,39]. The results from SBH using
multiplex-FISH analysis suggest that therapy given
prior to the HDT contributes to the damage to stem
cells, resulting in cytogenetic abnormalities, which
are then exacerbated by HDT and by TBI-containing
regimens in particular [41].
The majority of patients with follicular lymphoma
have marrow involvement PCR analysis has revealed
involvement at the molecular level in all patients with
recurrent follicular lymphoma [42]. Various techniques have therefore been developed to remove such
morphologically undetectable tumour cells. At SBH
and the DFCI autologous bone marrow has been
treated in vitro with antibody (or antibodies) and
complement [37,43,44]. PCR analysis before and after the in vitro treatment at the DFCI has shown PCR
negativity of the reinfused cells to be the most significant prognostic factor for freedom from recurrence
[44]. This is not the case at SBH [37], the discrepancy probably relating to differences in sensitivity
of the PCR assay. Molecular monitoring has also
been used in follow-up: patients can be classified
into three prognostic groups on the basis of the PCR
results. Those in whom the PCR result is consistently
negative have the lowest likelihood of recurrence,
followed by those in whom there is a mixture of
positive and negative results. In contrast, patients
in whom the samples are consistently PCR-positive
have a very high likelihood of recurrence [37,44].
AUogeneic bone marrow transplantation has been
used infrequently because of appropriate concerns
over treatment-related morbidity and mortality in an
illness with a relatively long natural history. The
treatment-related mortality has been high (30%) but
the CR rate also high, with a low recurrence rate
[45,46].
Non-myeloablative stem cell transplantation is
currently being evaluated. The use of Fludarabine
combinations as the preparative regimens allows
mixed chimerism to develop and hence engraftment
to occur over a period of time. The results from
MD Anderson Cancer Center in a small number of
patients with short follow-up are encouraging [47].
Anti-CD20
The chimeric mouse/human monoclonal antibody
anti-CD20, has been shown to be active in patients
with recurrent follicular lymphoma. The antibody is
thought to act by three separate mechanisms: complement mediated cytotoxicity, antibody-dependent
cellular cytotoxicity as well as directly by causing
apoptosis. Given as four, consecutive, weekly doses
of 375 mg/m 2 to 166 patients with recurrent follicular lymphoma, the response rate was 48%, with
a median progression-free interval of nine months
[48]. The toxicity was generally associated with the
first infusion and was mostly limited to chills, fevers
and headache. In a study conducted in the UK, in
patients with recurrent/resistant lymphoma, a similar
response rate was observed [49].
Follicle centre cell lymphoma: optimal use of therapeutic options
A study was recently conducted in the United
States combining anti-CD20 with 'CHOP' chemotherapy in 40 newly diagnosed patients. The overall
response rate was 95%, with a 55% complete response rate. No additional toxicity was observed
[50]. A similar study will therefore soon be starting,
comparing CVP alone to the same chemotherapy
given in conjunction with anti-CD20.
Radio-labelled anti-CD20
The use of a radio-labelled antibody has several
attractions; the treatment is given only once, it is
associated with relatively little clinical toxicity and
cells which do not bind sufficient antibody to induce apoptosis can be killed by the radiation emitted by radioactive conjugate bound to neighbouring
cells. 131Iodine and ^yttrium have been used in
the main. The problem with the former is that the
treatment generally needs to be given as an inpatient. ^Yttrium is not associated with gamma ray
emission; the latter can therefore be given on an
out-patient basis.
Both conjugates have resulted in high response
rates and complete response rates in patients with follicular lymphoma [51-53]. Responses can take several months to develop. Between November 1998 and
November 1999, radio-labelled anti-CD20 (Bexxar)
was given to 40 patients at the Christie and St
Bartholomew's Hospitals; 33 patients with follicular lymphoma were treated at first or subsequent
recurrence. The preliminary results are encouraging
with an overall response rate of 64% in patients
who had received multiple previous regimens [54].
Radio-labelled anti-CD20 has also been used in
myeloablative doses in Seattle, resulting in a very
high complete response rate of 75% [55] with an
estimated progression-free survival at six years of
51%.
Thus, in summary, this is an exciting time. Several
new approaches for follicular lymphoma are being
evaluated. It remains to be established whether some
of these, perhaps in sequence, will be curative.
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