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Blood and Marrow Transplantation in Relapsed or Refractory Non-Hodgkin’s Lymphoma

Blood and Marrow Transplantation in Relapsed or Refractory Non-Hodgkin’s Lymphoma

ABSTRACT: It was not until 1995 that a phase III randomized trial demonstrated that autologous stem cell transplants (ASCT) improve the progression-free and overall survival of patients with relapsed refractory diffuse aggressive non-Hodgkin’s lymphoma. Investigators are now focusing on improving the clinical benefit of transplants. The relative contributions made by more intensive preparative regimens, purging, concomitant immunotherapy, and the timing of transplants are under study. Also, as transplant trials shift from relapsed disease to initial therapy, anticipated benefits must be balanced against both short-term and long-term toxicities.[ONCOLOGY 12(Suppl 8):56-62, 1998]

Introduction

Trials exploring high-dose chemotherapy for non-Hodgkin’s
lymphoma first began in the mid-1970s. It was not until 1995,
however, that autologous stem-cell transplants (ASCT) were shown to
improve the progression-free survival and overall survival of
patients with relapsed/refractory diffuse aggressive
non-Hodgkin’s lymphoma in a phase III randomized trial.[1] The
benefits of transplant therapy may extend to selected patients with
indolent non-Hodgkin’s lymphoma, with recent reports suggesting
a role for transplants when incorporated into the initial therapy of
patients with poor prognosis lymphoma.[1A]

Building on this theory, investigators are now focusing on four
important areas of clinical research. They include: 1) improving
cytoreduction with more intensive or targeted preparative regimens,
2) investigating the role of ex vivo purging, 3) re-exploring the
benefit of allogeneic transplants, and 4) clearly defining the
incidence of and risk factors for late complications after
transplantation in myelodysplastic syndrome and acute nonlymphocytic
leukemia (MDS/ANLL).

These four areas will become more important as transplant trials
shift from relapsed disease to initial therapy, with anticipated
benefits balanced against both short-term and long-term toxicities.
This article focuses on these areas and reviews the current status of
transplantation for both relapsed, diffuse aggressive, and indolent
non-Hodgkin’s lymphoma.

Diffuse Lymphomas:Current Transplant Indications

For the initial management of advanced, diffuse aggressive
non-Hodgkin’s lymphoma, CHOP chemotherapy (cyclophosphamide
[Cytoxan], doxorubicin [Adriamycin], vincristine [Oncovin], and
prednisone) remains the best conventional regimen.[2] Despite a high
remission rate, however, the 3 to 5 year progression-free survival is
only 40% to 50%. For those who fail or relapse after a remission,
conventional salvage chemotherapy produces remissions in the 50% to
70% range, but long-term remissions are seen in £
10% of patients.[3,4]

In early trials, ASCT for patients who failed initial therapy
produced a 3 to 5 year survival rate of 15% to 50%, with outcome
primarily related to prognostic factors present at the time of the
transplant.[1,5-10] Among the most important prognostic factors was
chemosensitivity immediately prior to transplant. For patients in
this group failing induction therapy, 3 to 5 year survival was 0%
compared to those patients with minimal chemosensitive disease in
whom 3 to 5 year survival was 35% to 50%.[5] The major cause for
failure was relapse, with rates of 54% to 84%[1,5-7,9,10] and in
those with chemosensitive first relapse (the best subpopulation),
relapse rates were 35% to 54%.[8,11]

The PARMA Trial

To further define the benefit of transplant for patients with
chemosensitive relapse, an international randomized trial (PARMA) was
conducted.[11] Patients who relapsed after a complete remission (CR),
but who had no evidence of marrow involvement were randomized (if
they responded to two cycles of DHAP chemotherapy [decedron,
high-dose ara-C [Cytarabine], and cisplatinum]) to one of these two
treatment groups: 1) continue DHAP for another four cycles with
involved field radiotherapy for bulk disease, or 2) undergo
autologous transplant using high-dose BEAM (BCNU, etoposide
[Carmustine], ara-C, and melphalan [Chlorambucil]), plus involved
field radiotherapy for bulk disease.

Patients who were randomized to transplant had a significantly higher
response rate (84% vs 44%), and event-free (46% vs 12 %) and overall
(53% vs 32%) survivals at 5 years. Because those randomized to
chemotherapy had the opportunity to undergo a transplant after their
second relapse, the improvement in survival suggests that transplants
should be performed after first relapse to be maximally beneficial.

A recent update and analysis of outcome using the age-adjusted
international prognostic factor index (IPI), demonstrated that for
patients treated with chemotherapy alone, there is a progressive
decline in disease-free survival with increasing IPI stage. Patients
in risk group 0 had a 36% 8-year survival rate, whereas those in risk
groups > 0 had a survival rate of 20%.[12] In contrast, no
difference in survival based on IPI was seen in the transplant group;
patients in risk group 0 had an 8-year survival of 47% vs 49% in risk
groups > 0. The data also suggest that for the 0 risk group,
either transplant or chemotherapy is acceptable, although these data
should be considered preliminary because the number of patients in
the two groups is small.

Transplants in Chemotherapy-Resistant Disease

While it is clear that ASCTs are of value for those with
chemosensitive relapse, the percent of patients with
chemotherapy-resistant disease who survive long-term is only 10% to
20%. Outcomes for patients failing induction therapy have been
reported to be even worse with essentially no survivors beyond 1
year. However, with improved conventional second-line chemotherapy,
this appears not always to be the case.

In particular, we recently reported that a subgroup of patients
failing induction therapy may have a significant long-term survival
if they respond to first salvage therapy.[13] In this retrospective
analysis, responding patients transplanted with less than 1 cm of
residual disease had a 2-year survival of 86% vs 7% for those with
residual disease greater than 1 cm. Thus, it appears appropriate to
treat induction failures with aggressive chemotherapy at the time of
failure. If a significant response is seen, a transplant should be
offered; if not, investigational approaches should be tested.

For patients who relapse but do not respond to salvage chemotherapy
(resistant relapse), transplants may be of benefit to some.[1,5-7,9]
However, when treated with conventional preparative regimens, less
than 20% will survive long-term.[5,6,7,9] Low tumor bulk does not
appear to improve prognosis for these patients, and those with
aggressive disease, ie, those who respond then regrow tumors between
cycles of salvage chemotherapy, are unlikely to benefit. As discussed
further, more intensive preparative regimens may be of value for this
patient group.

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