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Blood, Vol. 92 No. 3 (August 1), 1998:
pp. 790-794
Anaplastic Large Cell Lymphoma Hodgkin's-Like: A Randomized
Trial of ABVD Versus MACOP-B With and Without Radiation Therapy
By
Pier Luigi Zinzani,
Maurizio Martelli,
Massimo Magagnoli,
Alfonso Zaccaria,
Fioravante Ronconi,
Maria Cantonetti,
Monica Bocchia,
Roberto Marra,
Marco Gobbi,
Brunangelo Falini,
Filippo Gherlinzoni,
Luciano Moretti,
Amalia De Renzo,
Patrizio Mazza,
Enzo Pavone,
Elena Sabattini,
Angela Amendola,
Maurizio Bendandi,
Stefano A. Pileri,
Franco Mandelli, and
Sante Tura
From the Institute of Hematology and Medical Oncology
"Seràgnoli," University of Bologna, Bologna; the Department
of Hematology, "La Sapienza" University, Rome; the Department of
Hematology, Ravenna Hospital, Ravenna; the Department of Hematology,
Avellino Hospital, Avellino; the Department of Hematology, "Tor
Vergata" University, Rome; the Department of Hematology, Siena
Hospital, Siena; the Department of Hematology, "Cattolica"
University, Rome; the Department of Hematology, D.I.M.I. University of
Genova, Genova; the Department of Hematology, University of Perugia,
Perugia; Hematology Division, Pesaro Hospital, Pesaro; the Department
of Hematology, University of Napoli, Napoli; the Division of
Hematology, Taranto Hospital, Taranto; and the Department of
Hematology, University of Bari, Bari, Italy.
 |
ABSTRACT |
During the last few years, morphological, immunohistochemical, and
genetic findings have placed anaplastic large cell lymphoma (ALCL) as a
distinct clinicopathologic entity, and several reports have focused on
the existence of different subtypes of the tumor. Particular attention
has been paid to the ALCL-Hodgkin's-like (HL) subtype, which seems to
be on the border between Hodgkin's disease (HD) and high-grade
non-Hodgkin's lymphoma (HG-NHL). From September 1994 to July 1997, during the course of an Italian multicentric trial, 40 ALCL-HLs were
randomized to receive as front-line chemotherapy MACOP-B (methotrexate
with leucovorin, doxorubicin, cyclophosphamide, vincristine,
prednisone, and bleomycin a third-generation HG-NHL regimen) or ABVD
(doxorubicin, bleomycin, vinblastine, and dacarbazinea scheme
specific for HD). All patients with bulky disease in the mediastinum at
diagnosis underwent local radiotherapy after the chemotherapeutic
program. Complete response (CR) was achieved in 17 of the 19 (90%)
patients who were treated with MACOP-B, and in 19 of the 21 (91%)
patients who were administered ABVD. The probability of relapse-free
survival, projected at 32 months, was 94% for the MACOP-B subset and
91% for the ABVD subset. The majority of patients with mediastinal
bulky disease obtained CR (evaluated with 67Ga single
photon emission computed tomography [SPECT]) after their radiotherapy. The present study suggests that ALCL-HL, in line with its
borderline status, responds in an equivalent way to third-generation chemotherapy for HG-NHL and to conventional HD treatment in terms of
both CR and relapse-free survival rates. However, as to the latter, a
longer follow-up period may be needed before stating the absolute
equivalence of the two regimens used.
© 1998 by The American Society of Hematology.
| |
INTRODUCTION |
IN 1985, STEIN ET AL1 first
reported the expression of the lymphoid activation antigen CD30/Ki-1 in
a group of large-cell neoplasms characterized by subtotal effacement
of the lymph node structure, prominent sinusal diffusion with
spread to the adjacent paracortical areas, and bizarre/anaplastic
morphology. These neoplasms turned out to represent a distinct entity,
which has been designated as Ki-1/CD30+ anaplastic large cell lymphoma
(ALCL), in line with their Ki-1/CD30 expression,2-4
morphological features, and lymphoid origin. Although the
tumor has also been referred to in other ways, the initial term ALCL is
the most appropriate one. The neoplasm was incorporated into the
Updated Kiel classification in 1988; subsequently, four
histological subtypes were detected in the course of two
international workshops: common type (ALCL-CT), Hodgkin's-related
(ALCL-HR), giant cell-rich, and lymphohistiocytic.5-8 The
ALC-HR subtype has recently been recognized by the Revised European-American Lymphoma (REAL) classification as
provisional with just one semantic change: the term
Hodgkin's-related was replaced by Hodgkin's-like
(ALCL-HL).9
The HL subtype is the most controversial of the varieties, as implied
by its inclusion in the REAL classification as a provisional entity.
The findings of our previous reports10,11 showed that ALCL-HL has distinctive clinical features slightly different from those
of the common type. In particular, our ALCL-HL patients were young
adults who most often presented in stage II and had a mediastinal mass,
with frequent bulky disease. At present, there is increasing evidence
that some cases of Hodgkin's disease (HD) previously diagnosed within
the spectrum of the nodular sclerosing and/or lymphocyte
depletion variants might represent examples of ALCL-HL.
As regards treatment, our previous data10,11 and those
reported by others12-21 have confirmed that ALCL responds
to third-generation chemotherapy regimens in a way similar to other
aggressive high-grade non-Hodgkin's lymphomas (HG-NHL) in
terms of both complete response (CR) and relapse-free survival rates.
It is noteworthy that patients with ALCL-HL tended to maintain CR more
easily than those with ALCL-CT.11
Despite these encouraging findings, there is no general agreement as to
the optimal treatment of the ALCL-HL, and studies are needed to compare
the effectiveness of third-generation chemotherapy regimens for HG-NHL
with standard protocols for HD. To the best of our knowledge, herein we
report on the first randomized, prospective trial comparing the
activity of the MACOP-B protocol (methotrexate with leucovorin,
doxorubicin, cyclophosphamide, vincristine, prednisone, and
bleomycinspecific for conventional HG-NHL) versus ABVD regimen (doxorubicin, bleomycin, vinblastine, and dacarbazinestandard polychemotherapy for HD) in untreated patients with ALCL-HL in terms of
CR rate.
| |
MATERIALS AND METHODS |
From September 1994 through July 1997, 40 consecutive, unselected adult
patients with previously untreated primary ALCL-HL were randomly (ratio
1:1) assigned to receive combination chemotherapy with either MACOP-B
or ABVD at 13 Italian institutions. Diagnosis was performed on
pathological specimens according to the REAL classification.9 The criteria for eligibility included a
confirmed histological diagnosis of ALCL-HL stage II to IV disease
according to the Ann Arbor system,22 or stage I with bulky
mediastinal tumor, age between 15 and 60 years, an Eastern Cooperative
Oncology Group23 performance status less than 3, and human
immunodeficiency virus negativity. Informed consent was obtained from
all patients in accordance with the ethical policy of the institutes.
Staging evaluation in all cases included bone marrow biopsy and
hematologic and chemical survey, in addition to chest radiograms,
abdominal ultrasonography, and computerized tomography (CT) of the
chest and abdomen. The characteristics of all patients are listed in Table 1.
Histopathology.
In all cases, the diagnosis was based on the detection of a series of
morphological and immunohistochemical findings, as previously described.11 In particular, on morphological grounds the
normal nodal structure was effaced by a neoplastic growth, consisting of large cells with variably shaped nuclei (kidney-shaped, round, or
oval), prominent nucleoli, and a wide rim of cytoplasm, which usually
stained grayish-violet with Giemsa. Tumoral elements showed intrasinusoidal diffusion and tended to give rise to nodular aggregates partially or completely surrounded by sclerotic bands.
Immunohistochemistry showed that the cases of the present series were
all characterized by T-cell or null phenotype. Tumors with the
expression of B-cell markers were excluded, according to the criteria
of the REAL Classification, which restricts the term "anaplastic
large cell lymphoma" to T-cell or null neoplasms.9 The
histological and immunohistologic evaluation was performed by three
independent observers (B.F., E.S., and S.A.P.); all interpersonal and
intrapersonal differences were recorded. In 15 cases with sufficient
pathological material available, the search for the NPM-ALK chimeric
fusion protein was performed according to previously reported
criteria.24
Chemotherapeutic regimens.
After stratification according to age, stage, performance status, and
presence of a mediastinal mass, the patients were randomly assigned to
one of two chemotherapy programs: MACOP-B or ABVD. The MACOP-B scheme
was administered as originally described by Klimo and
Connors.25 The ABVD regimen was administered according to
the scheme of the Milan Cancer Institute26; this scheme was
repeated every 28 days for a total of six cycles. Patients who
presented with mediastinal bulky disease received radiation therapy to
the mediastinum at a tumor dose of 36 Gy, after the chemotherapy
program. The definition of tumor bulk was represented by a
mass/thoracic ratio of greater than 0.33 between the largest transverse
diameter of the thorax at the level of T5 or T6 on a standing
posteroanterior chest radiograph.
Criteria for response.
Patients were restaged after completion of chemotherapy; clinical and
pathological evaluations were made by repeating radiographic investigations and bone marrow biopsy if previous results were positive. In all patients who presented a CT residual mediastinal mass
after chemotherapy phase, the radiologic clinical restage included CT
and 67Ga single photon emission computed
tomography (SPECT). CR was defined as a total
disappearance of signs and lymphoma-associated symptoms that was
maintained for at least 6 weeks. When a remarkable reduction
(>80%) but not complete disappearance of the original bulky mass was observed (a lesion  2 cm in diameter as detectable at
the CT), when repeated CT scans showed stable residual abnormalities, and 67Ga SPECT had been recorded as negative, the patient
was considered to be in CR. Partial response (PR) was defined as the
reduction of at least 50% of known disease with disappearance of the
systemic manifestations. No response was defined as anything less than a PR. The survival curve was measured from entry into the protocol until death; the relapse-free interval was calculated from the date of
response until relapse or death. Survival and relapse-free survival
curves were calculated according to the method of Kaplan and
Meier.27
| |
RESULTS |
All the cases were regarded as examples of ALCL-HL by the three
observers, who independently reviewed the histological and immunohistological preparations. In line with the previous reports by
Pileri et al10 and Zinzani et al,11 the
clinical picture of ALCL-HL turned out to be associated with stage I-II
disease (26 of 40; 68%), mediastinal masses (34 of 40; 85%), and
bulky disease (19 of 49; 48%). Among the 40 evaluable cases, 19 were treated with MACOP-B regimen and 21 with the ABVD scheme. Nineteen patients who presented bulky disease (17 on the mediastinum, 1 on the
left axilla, and 1 on the left inguinal lymph node) after the
chemotherapy program received radiotherapy on the site of bulky disease
at diagnosis.
Responses to therapy are listed in Table 2.
In particular, 36 of 40 (90%) patients obtained a CR and 1 of 40 (3%)
a PR, with a major response (CR plus PR) rate of 92.5%. No significant
differences were observed between patients of the MACOP-B arm and ABVD
arm, because 17 of 19 (90%) and 19 of 21 (91%) obtained a CR,
respectively. The remaining 3 patients (8%) were resistant to
first-line therapy (2 in the ABVD and 1 in MACOP-B arm). It is
noteworthy that 16 of 19 (84%) of the patients with mediastinal bulky
disease (8 in the ABVD subset and 8 in the MACOP-B group) obtained only
a PR after the chemotherapy. All these 16 patients subsequently achieved a CR with radiotherapy (when repeated CT scans showed stable
residual abnormalities, and 67Ga SPECT was recorded as
negative).
The two chemotherapeutic subsets did not show differences in terms of
relapse rate. In fact, 1 of 21 (5%) of the patients treated with ABVD
relapsed after 15 months, whereas 1 of 19 (6%) in the MACOP-B group
relapsed after 6 months. The overall actuarial risk of relapse of the
36 patients who obtained a CR was 7% at 32 months (median follow-up of
25 months [range, 7 to 37] for ABVD subset and median follow-up of 22 months [range, 5 to 36] for MACOP-B subset, respectively). Both
patients who relapsed presented without mediastinal bulky disease at
the time of diagnosis. The first-line ABVD patient has obtained a
second CR after MACOP-B regimen and is still alive with a second
relapse-free survival of 6 months. On the other hand, the patient who
relapsed after the MACOP-B CR did not respond completely to the
second-line treatment, obtaining only a PR. The overall survival rate
(Fig 1) at 37 months was 95% for the
MACOP-B patients and 90% for ABVD patients; the median follow-up time
for all patients was 24 months. The probability of relapse-free
survival (Fig 2), projected at 32 months
(median, 18; range, 6 to 32), was 94% and 91% for the MACOP-B and
ABVD patients, respectively. As to the search for the NPM-ALK chimeric fusion protein, only 2 of 15 (13%) cases tested turned out to be
positive.
| |
DISCUSSION |
The close morphological and phenotypical similarities2-4
between the neoplastic cells of ALCL and those of HD have recently raised two crucial questions involving possible pathogenetic
relationships between the two entities and the histological criteria
that would permit a precise differential diagnosis. At present, the
borders between grade II nodular sclerosis HD, syncytial nodular
sclerosis HD, and ALCL-HL seem to be rather vaguely
defined.5,10 It might be that this situation is largely due
to the application of subjective criteria for the distinction of the
two diseases and will be overcome by the systematic introduction of
more refined tools, such as the search for the t(2;5) or the NPM/ALK
product, which seem to exclusively occur in ALCL.24 In this
respect, the observation of the NPM/ALK hybrid gene product in 2 of 15 cases tested is of interest and supports the need of maintaining ALCL-HL as a provisional entity: further clinicopathologic studies are
required before any definitive conclusions can be drawn as to whether
it should be included among NHL or in the context of HD. The limited
number of cases with sufficient material available for further
immunohistochemical studies does not allow us to speculate on the
clinical relevance of the ALK protein in the present
series.28
To our knowledge, this report involves the largest series of ALCL-HL
patients yet studied. In line with the findings collected during our
previous trial,11 in the present study the ALCL-HL subtype
showed distinctive clinical features that differed slightly from those
of the common type. In particular, our ALCL-HL patients were young
adults (mean age, 29 years) who most often presented in stage I-II
(68%), mostly with a mediastinal mass (85%), and frequently with
bulky disease (48%). These data on a large series of patients confirm
the clinical identikit of ALCL-HL patients. In this light,
it is obvious that certain cases diagnosed as nodular sclerosing grade
II29 and most if not all examples of syncytial nodular
sclerosis HD30 could also easily be assigned to the
category of ALCL-HL.
Our previous study11 confirmed that third-generation HG-NHL
chemotherapy regimens are effective in the treatment of ALCL cases. The
present study is, to our knowledge, the first to assess the
effectiveness of a standard protocol for HD versus a third-generation chemotherapy regimen designed for the treatment of HG-NHL (with the
addition, when necessary, of local radiotherapy on the bulky site at
diagnosis). Despite the relatively short follow-up and limited number
of patients, it is interesting to note how the two chemotherapeutic
approaches have achieved remarkably similar degrees of success. In
particular, the CR rates showed similarly high levels of success in
both the chemotherapeutic subsets: 90% in MACOP-B patients versus 91%
in ABVD patients. Furthermore, on the basis of our limited follow-up
data, the MACOP-B and ABVD groups seem to show equivalent relapse rates
after CR induction: 1 of 17 (6%) patients successfully treated with
MACOP-B relapsed, as compared with 1 of 19 (5%) in the ABVD subgroup.
One of the relapsed patients has obtained a second CR after a crossover
to the MACOP-B regimen after first-line treatment with ABVD. At 32 months, with a median follow-up time of 18 months, the rates of relapse-free survival were 94% and 91% for patients with MACOP-B and
ABVD, respectively. It should be noted that in terms of CR rate, our
ALCL-HL patients fared better with respect to those of other HG-NHL
subtypes studied with the same MACOP-B regimen.31 However,
it must be remembered that according to the criteria of the
International Prognostic Factor Index,32 the majority of
our patients belonged to low or low-intermediate prognostic subgroups.
Concerning the role of autologous bone marrow transplantation as
consolidation phase described by Fanin et al,19 on the
basis of our data a sequential intensive treatment could be avoided for
the treatment of ALCL-HL patients.
Another significant finding was that ALCL-HL patients with bulky
disease in the mediastinum often had apparent minimal residual disease,
as shown by CT scan. The serial use of SPECT showed that in 16 of 17 (8 MACOP-B and 8 ABVD) patients residual active disease was present after
the chemotherapy phase. However, all these patients obtained a CR with
SPECT negativity after the additional radiation therapy as by protocol.
These data suggest a probable useful contribution played by
radiotherapy in obtaining the eradication of this lymphoma when there
is bulky disease involvement in the mediastinum.
In summary, these preliminary data suggest three considerations: (1)
third-generation chemotherapy for HG-NHL (MACOP-B) and conventional HD treatment (ABVD) have so far shown equivalent levels of
success in terms of CR and relapse-free survival rates (the latter data
being extremely preliminary due to the short follow-up time) in the
frontline treatment of ALCL-HL; (2) the probable use of radiation
therapy in the bulky mediastinum and the consequent role that nuclear
imaging techniques such as SPECT and positron emission
tomography are needed for evaluating the real CR in
patients with residual mediastinal abnormalities; and (3) on
therapeutic grounds, ALCL-HL again seems to reflect its hypothesized
statusas revealed by histological9 and
serological33 studiesof borderline entity lying midway
between HG-NHL and HD.
| |
FOOTNOTES |
Submitted October 23, 1997;
accepted March 26, 1998.
Supported in part by "TRENTA ORE PER LA VITA 1996."
Address reprint requests to Pier Luigi Zinzani, MD, Istituto di
Ematologia "L. e A. Seràgnoli," Policlinico S. Orsola, Via Massarenti 9, I-40138 Bologna, Italy.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
We are grateful to Robin M.T. Cooke for his helpful suggestions
regarding the manuscript.
| |
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Abstract
Introduction
Abstract
