Haematologica 2003 - Supplements

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P11.1.2
WHAT IS THE ROLE OF ALLOGENEIC
TRANSPLANTATION IN MM? BOLOGNA EXPERIENCE
Michele Cavo, Claudia Cellini, Francesca Bonifazi, Paola
Tacchetti, Elena Zamagni, Delia Cangini, Patrizia Tosi,
Giuseppe Bandini, Sante Tura, Michele Baccarani
Institute of Hematology and Medical Oncology “Seràgnoli;
University of Bologna, Italy
Clinical studies aimed at investigating the feasibility and toxicity
of allogeneic stem cell transplantation for the treatment of MM
were pionereed by our group (1) and other groups in the early
1980s. Initial studies mostly included heavily pretreated patients
with refractory disease and provided demonstration that
chemo(radio)therapy administered at myeloablative doses
overcame chemoresistance and induced complete remission (CR),
even in patients who failed on prior conventional chemotherapy.
The first patient who received an allotransplant at our centre for
relapsing MM is still in serological and molecular CR 19 years
after transplant. Following initial encouraging reports, interest in
the use of allotransplants has grown over the years and more than
2000 patients have been performed worlwide. In 1983, a registry
of allotransplants performed in Europe was opened; since then,
several updates of registry data were reported by the European
Group for Blood and Marrow Transplantation (EBMT) (2, 3).
Moreover, additional studies on single-centre experiences were
also published by other groups (4, 5). From the analysis of all
these studies it appears evident that the most crucial issue related
to the use of allogeneic stem cell transplantation for MM was the
high treatment related mortality (TRM) that exceeded 40% in
most series (4). In a retrospective case-matched study performed
by the EBMT group and aimed at comparing autologous and
allogeneic bone marrow transplants reported to the registry
between 1983 and 1994, TRM was significantly higher in the
allografted group (41% vs 13% for autotransplants) and did not
change appreciably over the time period analyzed (6). Based on
these observations, indications for the use of allogeneic stem cell
transplantation for MM patients have been for a long time the
matter of debate and controversies still exist. In an attempt to
investigate whether the outcome of allogeneic stem cell
transplantation was improved in more recent years, we
retrospectively analyzed a series of 84 consecutive patients
(median age, 43 years; stage III, 64%; refractory or progressive,
67%) who received allotransplants from HLA-identical sibling
donors (n=79) or HLA-matched unrelated donors (n=5) at our
centre between 1990 and 2002. Patients were divided into 3
groups according to the period in whom allotransplants were
performed (group 1, from 1990 to 1993; group 2, from 1994 to
1995; group 3, from 1996 to 2002). Notably, conditioning
regimens and treatments used to prevent graft-versus-host disease
(GVHD) were different over the periods of the study. More
specifically, patients in group 1 (n=20) received a combination of
busulfan (total dose, 16 mg/kg) and cyclophosphamide (CTX)
(total dose, 200 mg/kg), whereas patients in groups 2 (n=14) and
3 (n=50) were mostly treated with combined total body
irradiation (TBI), CTX and melphalan (MEL) (total dose, 100-
120 mg/m2). Cyclosporine + methotrexate (CsA + MTX) were
used to prevent GVHD in patients included in groups 1 and 3,
whereas patients in group 2 received a T-cell depleted marrow.
Bone marrow was the only source of repopulating hematopoietic
stem cells used from 1990 to 1995 (groups 1 and 2), while
approximately 75% of transplants performed after 1995 (group 3)
were performed with peripheral blood (PB) stem cells. TRM rate
at 1 year was significantly lower among patients included in
group 3 (16%), as compared with patients in group 2 (43%) and
in group 1 (30%) (P=0.0002). Notably, the decreased TRM
observed in recent years was not related to a more favorable
selection of the patients (stage III, 70%; refractory/progressive,
66%). At the opposite, comparison between the 3 groups showed
that patients in group 3 were transplanted earlier than the others
(median time interval from diagnosis to transplant: 13 months vs.
18 and 20 months for patients in groups 2 and 1, respectively).
Posttransplant mortality due to infections was 8% among patients
in group 3, as opposed to 36% for patients who received TBIincluding
regimens and a T-cell depleted marrow (group 2). As a
result of the lower TRM rate, overall survival for patients in
group 3 was significantly longer than that for the other groups
(66% projected at 4 years, as opposed to 35% for group 2 and
20% for group 1) (P=0.001). Similarly, the progression-free
survival for patients in group 3 was significantly longer than that
for the other groups (41% projected at 4 years, as opposed to 21%
and 15% for groups 2 and 1, respectively) (P=0.008). These
results compare favorably with those of a recent study carried out
by the EBMT registry demonstrating that TRM during the period
1994-1998 was significantly reduced in comparison with earlier
time periods (21% as opposed to 38% observed before 1994),
mainly as a result of a significant decrease in the frequency of
deaths due to interstitial pneumonia or bacterial and fungal
infections (7). As in the EBMT study, also in the present analysis
we were unable to demonstrate any improvement over time in the
response to transplant. On an intent-to-treat basis, the CR rate
was 38% in group 1, 43% in group 2 and 44% in group 3.
Overall, the 4-year and 7-year projected probabilities of relapse
were 33% and 46%, respectively. Due to several relapses
occurring as late as 9 and 10 years following transplantation,
there was no apparent plateau in the relapse-free survival curve.
This finding raises the issue of whether allotransplant has the
potential ability to cure MM. To address this poorly investigated
issue, we recently used a polymerase chain reaction-based (PCR)
strategy to retrospectively analyze the presence of residual
myeloma cells in serial posttransplant bone marrow samples
obtained from a series of patients in sustained CR following
allogeneic stem cell transplantation (8). For this purpose, patientspecific
primers were generated from complementarity
determining regions 2 and 3 of the rearranged IgH gene. It was
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