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Blood, Vol. 92 No. 6 (September 15), 1998:
pp. 1933-1940
Treatment-Related Deaths and Second Cancer Risk After Autologous
Stem-Cell Transplantation for Hodgkin's Disease
By
Marc André,
Michel Henry-Amar,
Didier Blaise,
Philippe Colombat,
Joël Fleury,
Noël Milpied,
Jean-Yves Cahn,
José-Luis Pico,
Yves Bastion,
Mathieu Kuentz,
Gérard Nedellec,
Michel Attal,
Christophe Fermé, and
Christian Gisselbrecht for the Société Française de Greffe de
Moelle
From the Hematology Institute, Hôpital Saint-Louis, Paris,
France; Clinical Research Unit and INSERM CJF 96-03/GRECAN, Centre
Régional François Baclesse, Caen, France; Bone Marrow
Transplantation Unit, Institut Paoli-Calmette, Marseille, France;
Hematology Department, Hôpital Bretonneau, Tours, France; Bone
Marrow Transplantation Unit, Centre Jean Perrin, Clermont-Ferrand,
France; Hematology Department, C.H.U. Hôtel-Dieu, Nantes, France;
Hematology Department, Hôpital Jean Minjoz, Besançon,
France; Bone Marrow Transplantation Unit, Villejuif, France; Hematology
Department, Centre Hospitalier Lyon-Sud, Pierre-Bénite; Bone
Marrow Transplantation Unit, Hôpital Henri Mondor, Créteil,
France; Hematology Department, Hôpital Percy, Clamart, France;
Hematology Department, Hôpital Purpan, Toulouse, France.
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ABSTRACT |
Autologous stem-cell transplantation has become a widely used
therapy in Hodgkin's disease (HD). To appreciate the early and late
risks associated with this procedure, its lethal toxicity and effects
on the incidence of secondary cancers were studied. Data related to 467 French patients grafted from 1982 to 1995 for primary sensitive disease
(PSD, 22%), primary refractory disease (PRD, 18%), first relapse (R1,
45%), or subsequent relapses (R2, 15%) were analyzed. Grafted
patients (PSD, PRD, and R1; n = 393) were matched (3 controls for 1 case) on age, gender, clinical stage, B symptoms, and time at risk with
1179 conventionally treated patients issued from international
databases. The proportional hazards (Cox) model was used to assess
relative risks (RR). Among grafted patients, 8% died of toxicity
related to the procedure, and 18 secondary cancers occurred leading
to a 5-year cumulative incidence rate of 8.9%. In this series, risk
factors for second cancer were age  40 years (RR = 3.73, P
= .007) and the use of peripheral blood stem cells as source of graft
(RR = 3.10, P = .03). Among grafted and matched ungrafted
patients, risk factors for the development of secondary cancer were age
40 years (RR = 2.90, P < .001), relapse versus no
relapse (RR = 5.22, P = .006), PRD versus other patients
(RR = 3.86, P = .033), and grafted versus ungrafted
patients (RR = 2.04, P = .024). Solid tumors were more frequent in grafted than in ungrafted patients (RR = 5.19, P
= .001) although the incidence of myelodysplasia and acute
myeloid leukemia was similar in the two groups. We conclude that
high-dose chemotherapy administered as first-line treatment or after
relapse is associated with an acceptable toxic death rate. The risk of secondary myelodysplasia or acute myeloid leukemia is not
significantly increased after autologous stem-cell transplantation
for HD, whereas an increased risk of solid tumors exists. The
peripheral blood stem-cell-associated risk of secondary cancer
among grafted patients needs further investigations.
© 1998 by The American Society of Hematology.
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INTRODUCTION |
HODGKIN'S DISEASE (HD) is highly curable
by both radiotherapy and/or chemotherapy, but refractory
disease or early relapses are rarely cured by conventional salvage
therapy.1 Since the last decade, high-dose chemotherapy
(HDCT) and autologous stem-cell transplantation (ASCT) have been used
to treat such patients.2,3,4 Although a single randomized
study has been published showing a better event-free survival after
HDCT than after conventional salvage therapy with no survival
improvement,5 HDCT has become more widely used since the
availability of growth factors and the emergence of peripheral blood
stem cells (PBSC). ASCT has also been proposed to patients with poor
initial prognostic factors,6,7 such as age 40 years,
bulky mediastinal mass, extended stage, extranodal sites, serum lactate
dehydrogenase above normal value, bone marrow involvement, and anemia.
The clinical outcome of patients with three or more of these factors is
very poor, with a 5-year probability of survival after conventional
therapy not higher than 20.5%.8
Cohorts of patients with long survival after HDCT are now available and
secondary cancers have been reported after ASCT for non-Hodgkin's
lymphoma (NHL) and HD.9,10 At University of Nebraska, the
5-year cumulative incidence of secondary myelodysplasia and acute
myeloid leukemia (MDS/AML) was 4% in a series of 511 HD and NHL,
whereas at the Dana Farber Cancer Institute in Boston it was 18.6% in
a series of 206 NHLs.
In HD, the occurrence of MDS/AML and solid tumors after many years of
conventional treatment has been also well described.11 MDS/AML were generally related to age, the use and cumulative dose of
alkylating agents, and splenectomy, and the risk was limited to 10 to
15 years after treatment.12 Solid tumors were mostly ascribable to radiation therapy, and showed an incidence still increasing after 20 years.13 The incidence of secondary
cancers after ASCT for HD has not yet been assessed, and it is poorly understood whether such secondary cancers are due solely to prior conventional chemotherapy and radiotherapy, or whether HDCT also contributes to their development. Therefore, a series of 467 grafted HD
patients was studied to evaluate the HDCT-related toxicity and risk
factors associated with the development of secondary cancer. Patients
grafted either for primary sensitive disease (PSD), primary refractory
disease (PRD), or at first relapse (R1) were matched to 1179 patients
treated with conventional therapy to assess the contribution of HDCT
and ASCT to the risk of secondary cancer.
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PATIENTS AND METHODS |
Grafted patients.
Using the database of the Société Française de Greffe
de Moelle, French centers were identified in which more than 10 ASCT for lymphomas were regularly performed per year. Fourteen of them agreed to participate in the study and represented 481 (54%) of the
889 reported HD patients who underwent HDCT in France between 1982 and
1995. Files were reviewed and, by means of a standardized form, data on
initial patient characteristics, treatment type, the duration of each
treatment episode, response to initial and subsequent treatments,
conditioning regimen, source of stem cells, events after transplant,
patient status, and cause of death were collected.
Chemotherapy data included the type of regimen: MOPP (mechlorethamine,
vincristine, procarbazine, prednisone), Adriamycin containing mostly
ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine), MOP/ABV
hybrid, MOPP-ABVD alternating, or others and the number of cycles
given. For the analysis of survival and risk of second cancer, two
cycles of alternating MOPP-ABVD or hybrid MOP/ABV were considered to be
equivalent to one cycle of MOPP and, on this basis, the cumulative
chemotherapy was divided into four groups: 3 MOPP, <3 MOPP, an
Adriamycin-containing regimen, and others. All patients receiving
alternating- or hybrid-regimen chemotherapy are thus in the 3 or <3
MOPP groups. The MOPP-treated patients were divided into two groups
because of the dose-dependent relationship between alkylating agents
and the occurrence of secondary MDS/AML.14,15
Data relating to irradiation included the field (mantle, paraaortic,
spleen, pelvis, involved field, or others) and the dose delivered to
each field. Irradiation administered at different times during the
treatment (including total body irradiation [TBI], post-ASCT
irradiation, and irradiation for relapse) was pooled and classified as
follows. Mantle-field, inverted-Y, and involved-field irradiation were
considered as limited-field radiotherapy; other combinations were
considered as extended-field radiotherapy. All patients receiving TBI
as part of their high-dose therapy regimen were included in the
extended field group for the analysis.
After each treatment episode of chemotherapy and/or
radiotherapy, the disease status was evaluated as complete response
(CR; disappearance of all measurable lesions), partial response
(regression of at least 50% of the lesions), stable disease
(regression of fewer than 50% of the lesions), or progression
(progression of any lesion or new localization during treatment).
For the purposes of analysis, the whole population was divided into
four groups according to the indication for HDCT and ASCT. The PRD
group consisted of 86 patients who either progressed during initial
therapy (78 patients), or alternatively achieved an unstable partial
response lasting a median duration of 80 days (8 patients) before new
progression and then received HDCT as salvage therapy. Eighty of these
86 patients received a conventional-dose salvage chemotherapy before
undergoing HDCT. The PSD group consisted of 102 patients who responded
to initial therapy and then received HDCT and ASCT as consolidation
treatment. These patients presented with poor initial prognostic
features,7 achieved a partial (66%) or CR (34%), and did
not receive any additional treatment before undergoing ASCT. The other
two groups consisted of patients who underwent ASCT after R1 (210 patients) or subsequent (R2) relapse (69 patients). All these patients
achieved at least one CR and were treated with R1 or multiple R2
chemotherapy and/or irradiation before the stem-cell collection
and HDCT. In the R2 group, 56 patients received two second-line
treatments, whereas 10 received three and 5 received four. Fourteen
patients who received a second stem-cell transplantation were excluded
from the analysis.
After transplant, the 5-year overall survival rates of the 467 grafted
patients studied were 82% (95% confidence interval [CI], 72% to
89%) and 35% (95% CI, 23% to 49%), respectively, in the PSD and
PRD groups, and 44% (95% CI, 34% to 55%) and 52% (95% CI, 39% to
66%), respectively, in the R1 and R2 groups, with a median follow up
of 54 months from diagnosis and 23 months from autograft. The median
follow up from diagnosis of HD were 29, 47, 58, and 102 months for PRD,
PSD, R1, and R2 groups, respectively. These survival rates are similar
to those reported in the literature.5-8 After ASCT,
patients were monitored at each center in which the diagnosis of
secondary cancer was made. MDS/AML diagnosis was made after evaluation
of peripheral blood, bone marrow aspirate, and core biopsy, and was
based on the French-American-British (FAB) criteria. In five of eight
cases, cytogenetic analysis was performed using conventional methods
after short-term culture.
Ungrafted patients.
Ungrafted patients were identified through a search from the
computerized HD databases from the International Database of Hodgkin's
Disease (IDHD), European Organisation for Research and Treatment of
Cancer (EORTC), and Groupe d'Etude des Lymphomes de l'Adulte (GELA).
The 69 grafted patients from the R2 group were not included in this
analysis; they could not be matched because the date of the second or
subsequent relapse is not available in the IDHD, EORTC, and GELA
databases.
Three ungrafted patients were randomly matched with one grafted patient
on category (PSD, PRD, R1), age at HD diagnosis, gender, clinical stage
(I-II or III-IV), presence or absence of B symptoms, and follow up at
least as long as the interval between the end of first therapy and the
date of graft of the reference case. For few grafted patients, it was
difficult to find three controls. The difference accepted between
grafted patients and their controls was 3 years for age. If no
ungrafted patient satisfied this requirement, the patient who was the
closest was accepted as control. Age, gender, clinical stage, and B
symptoms were chosen because they were generally used to select
patients eligible for a given treatment. The year of HD diagnosis was
not considered for matching because most ungrafted patients were
diagnosed during the 1977 to 1990 period. Among grafted patients, five
could not be used for matching because one of the above matching
criteria was not available; these five patients belong to the PRD
(three patients) and the PSD (two patients) groups. Overall, 1179 ungrafted patients were matched with the 393 grafted cases, 258 (13 from the EORTC, 245 from the IDHD) in the PRD group, 300 (57 from the
EORTC, 44 from the GELA, 199 from the IDHD) in the PSD group and 621 (64 from the EORTC, 11 from the GELA, 546 from the IDHD) in the R1
group.
Statistical analysis.
Follow up began with the date of end of first HD treatment or the date
of ASCT (as appropriate) and ended at the date of death, date of second
cancer, or last examination, whichever came first. The cancers observed
were classified by site and histologic type in accordance with the
oncology section of the International Classification of
Diseases.16 Two approaches were used to analyze the
risk of secondary cancer after HDCT and ASCT. In the first approach, the cumulative incidence rate of secondary cancer since the end of last
treatment (initial treatment or that given for salvage) or graft was
calculated using Kaplan-Meier estimates.17 The Rothman
method was used to calculate the CI of the rates.
In the second method, the relationship between the occurrence of
secondary cancer and concomitant variables was calculated by means of
the Cox proportional-hazards model,18 using a backward, stepwise regression. This model was used twice, once among the grafted
population (internal comparison) and a second time when comparing
grafted patients to those treated with conventional therapy (external
comparison). Among the grafted patients, the variables tested were
gender, age at diagnosis (20-39, 40 v <20), clinical stage
(III-IV v I-II), B symptoms, splenectomy, type of initial
treatment (chemotherapy, combined modality therapy v
irradiation), type of initial chemotherapy (3 MOPP, <3 MOPP, Adriamycin-containing, others v no chemotherapy), type of
radiotherapy (limited field, extended field v no irradiation),
response to initial treatment (CR v no CR), age at ASCT (20-39, 40 v <20), type of all chemotherapy received before graft
chemotherapy (3 MOPP, <3 MOPP, Adriamycin-containing, others
v no chemotherapy), disease status before graft (CR v
no CR), interval between diagnosis and ASCT, conditioning regimen
(TBI-containing, BEAM [carmustine 300 mg/m2, etoposide
1,200 mg/m2, cytosine arabinoside 1,200 mg/m2,
melphalan 140 mg/m2], CBV [cyclophosphamide
6,000 mg/m2, carmustine 300 mg/m2, etoposide
1,200 mg/m2] v others), source of
stem cells (bone marrow or PBSC), platelet recovery (> 105/µL before or after 100-days postgraft), and
indication for ASCT (PRD, PSD, R1, or R2). Variables significantly
(P < .05 with logrank test) linked with second
cancer risk were included in the Cox model.
Among the overall series of grafted and ungrafted patients, the
variables tested were gender, age at last treatment or graft (40
v <40), clinical stage (III-IV v I-II), B symptoms,
splenectomy, type of overall chemotherapy administered (3 MOPP, <3
MOPP, Adriamycin-containing, others v no chemotherapy), type of
overall irradiation given (limited field, extended field v no
irradiation), and patient subgroup (PRD, PSD, or R1). Variables
significantly (P < .05 with logrank test) linked with second
cancer risk were included in the Cox model.
Data was updated as of June 1995, stored and analyzed at the Clinical
Research Unit of the Centre François Baclesse (Caen, France)
using a specific database management system.19 The STATA statistical package was used.20
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RESULTS |
Grafted patient characteristics.
The characteristics of patients and ASCT are listed in
Table 1. B symptoms were more often present
in the PRD and PSD groups (78% and 85%, respectively) than in the R1
and R2 groups (59% and 58%, respectively). Fifty-one percent of
stage-II patients exhibited B symptoms, compared with 69% of stage-III
patients and 92% of stage-IV patients. First-line chemotherapy
consisted in 3 MOPP (21%), <3 MOPP (51%), Adriamycin-containing
(23%), and others (5%). Forty-two percent had no initial
radiotherapy, 33% had limited-field radiotherapy, and 25% had
extended-field radiotherapy. Three percent received irradiation alone
and 55% combined-modality therapy. The median duration of initial
treatment was 7 (1 to 16), 6 (2 to 14), 8 (1 to 20), and 8 (1 to 17)
months in PRD, PSD, R1, and R2 groups, respectively. After this
first-line treatment, the patients of the PRD, R1, and R2 groups
received additional rescue treatments; cumulative treatments
(first-line and salvage) received by all patients before ASCT are
reported in Table 1. The median duration between the end of the
first-line treatment and ASCT was 13 months: 6.8 (0 to 34), 2.6 (0 to
30), 31 (4 to 146), and 76 (14 to 241) months for the PRD, PSD, R1, and
R2 groups, respectively.
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Table 1.
Characteristics of the 467 HD Patients Receiving
High-Dose Chemotherapy and Autologous Stem-Cell Transplantation
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Five percent of the patients received bone marrow and PBSC as the
source of stem cells, and were pooled for the analysis with patients
receiving PBSC alone. Indications for HDCT were equally distributed in
these two groups (Bone marrow: PSD 23%, PRD 19%, R1 41%, and R2
17%; PBSC: PSD 24%, PRD 17%, R1 49%, and R2 10%). Hematopoietic
growth factors (HGF) were commercially available in France since
January 1992; therefore, PBSC-containing grafts represented 16% of the
transplant procedure before 1992 and 68% after. In the PBSC-containing
group, 25% of the patients were grafted before 1992 and did not
receive HGF.
ASCT-related toxicity and causes of death.
Overall, 158 (34%) patients have died. HD was the main cause of death
in all patient groups, followed by toxicity related to the HDCT
(Table 2). Thirty-seven patients
died of complications related directly to the procedure, accounting for
23% of all causes of death. Thirty-two of these patients died within
the first 3 months after transplant and 5 (4 sepsis and 1 pneumopathy)
died more than 3 months after transplant. Infections (especially
pulmonary infections) and shock were the main causes of toxic death.
The etiology of the shock was seldom available, but was presumably septic in the most cases. One patient died of a renal tubular acidosis,
whereas 2 committed suicide just after the ASCT and were regarded as
toxic deaths related to the procedure. Toxic deaths were less frequent
in the PSD patients compared with other patients (3% v 9%,
P = .037). However, most PSD patients were grafted in 1989 or
later at a time in which hematological resuscitation has become
efficient.
One patient in the PSD group died of second cancer (myelodysplasia),
compared with five (myelodysplasia 1, acute nonlymphoblastic leukemia
1, NHL 1, solid tumor 2: lung and central nervous system) in the R1
group and one (acute nonlymphoblastic leukemia) in the R2 group.
Secondary cancers among grafted patients.
In the 467 patients, 18 secondary cancers occurred: 8 MDS/AML, 2 NHL,
and 8 solid tumors 51 months (10 to 134) since diagnosis and 21 months
(3 to 43) since graft. There were 4 refractory anemia with an excess of
blasts, 1 refractory anemia, 1 case of AML (M2 according to FAB
classification), 2 cases of unclassifiable AML, 3 lung cancers, 1 pleural carcinoma, 1 breast cancer, 1 pharyngeal cancer, 1 central
nervous system (CNS) carcinoma, and 1 vulva epithelioma. No second
cancer developed in the PRD group, 5 (3 MDS and 2 solid tumors)
developed in the PSD group, 10 (1 MDS, 2 AML, 1 NHL, and 6 solid
tumors) developed in the R1 group and 3 (1 MDS, 1 AML, and 1 NHL) in
the R2 group. Cytogenetic analysis performed in 5 of the 8 AML/MDS was
noninformative (ie, no mitosis) in 2 patients, and showed partial or
complete deletion of chromosome 7 in 3 patients; 11q23 rearrangement
was never observed. Two solid tumors (one pleural and one lung
carcinoma) developed within the radiation field, two (one breast and
one pharyngeal carcinoma) were borderline and four were outside the
field. The overall 5-year cumulative incidence of secondary cancer was
8.9% (95% CI, 5.4% to 14.3%). The 5-year cumulative incidence was
4.3% (95% CI, 1.9% to 9.3%) for MDS/AML and 3.7% (95% CI, 1.8%
to 7.3%) for solid tumors (Fig 1).
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| Fig 1.
Cumulative incidence of all second cancers (SC),
myelodysplasia/acute myeloid leukemia (MDS/AML) and solid tumors (ST)
after ASCT in 467 HD patients (PSD, PRD, R1, and R2 groups) with a
median follow up of 21 months since ASCT.
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Six of the seven patients who were grafted in 1992 or after (among 190 patients) and who developed a second cancer (1 MDS, 1 NHL, and 4 solid
tumors) have received hematopoietic growth factors at any time before
second cancer occurred.
Risk factors for secondary cancer in the grafted population.
The following variables were included in the Cox model: age at graft,
gender, B symptoms, stage (I-II v III-IV), splenectomy, radiotherapy, type of chemotherapy, high-dose chemotherapy, platelet recovery, source of graft, and time between diagnosis and graft. Taking
all the secondary cancers into account, two risk factors were
identified by multivariate analysis: age 40 years (RR = 3.73 with
95% CI, 1.43-9.67; P = .007) and the use of PBSC-containing graft (RR = 3.1 with 95% CI, 1.11-8.62; P = .03). There were
only 4% of the 467 grafted patients who received bone marrow and PBSC as a source of stem cells; for the purpose of this analysis, these patients were pooled with those who received PBSC only. The increased risk associated with PBSC was unchanged when the analysis was restricted to patients who received bone marrow or PBSC only. The
relative risk associated with splenectomy was 2.56 (95% CI, 0.89-7.36;
P = .08). An analysis restricted to MDS/AML showed that
splenectomy (RR = 3.86 with 95% CI, 0.91-16; P =
.067) and PBSC-containing graft (RR = 3.73 with 95% CI, 0.87-16;
P = .077) were at the limit of significance. No risk factor was
identified for solid tumors, and the analysis was not performed for NHL
because of the low number of cases.
Comparison with conventionally-treated HD patients.
The characteristics of the matched grafted and ungrafted patients are
described in Table 3. Most of the grafted
patients were diagnosed in the nineties (65%) whereas
conventionally-treated patients were mostly diagnosed in the seventies
(48%) and eighties (43%). This explains the differences between the
two groups for splenectomy (10% v 32%), type of chemotherapy
(Adriamycin containing: 18% v 1%), duration of follow up (21 months v 31 months), and increased death rate (33% v
44%; P < .001 for each). HDCT led to an increase
in toxic death (22% v 5%; P< .001) and deaths due to intercurrent disease were more frequent in the
conventionally-treated group because of the longer follow up. Frequent
irradiation after HDCT, either for consolidation or at relapse, was
responsible for the more extensive irradiation of the grafted patients
(extended field: 42% v 27%).
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Table 3.
Characteristics of the Matched Patients (PRD, PSD, and
R1) Included in the Risk-Factor Analysis for Second Cancer (External
Analysis)
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Six MDS/AML and 8 solid tumors occurred in the grafted group and 18 MDS/AML and 15 solid tumors occurred in the conventionally-treated group. The median duration after last treatment for occurrence of
second cancer was shorter (28 months v 50 months) in the
grafted group (Table 4). The 5-year
cumulative incidence of second cancer was 10.4% (95% CI, 5.8-18.5)
and 5.2% (95% CI, 3.4-7.7) for the grafted and ungrafted group,
respectively (Fig 2.).
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Table 4.
Secondary Cancers After Hodgkin's Disease in the
Matched Patients (PRD, PSD, and R1) Included in the Risk-Factor
Analysis (External Analysis)
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| Fig 2.
Cumulative incidence of second malignancies in the
matched 393 grafted and 1179 conventionally treated HD patients (PSD,
PRD, R1) since ASCT or last treatment.
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In multivariate analysis, four factors significantly correlated with an
increased risk of second cancer in this whole population of 393 grafted
and 1179 ungrafted patients (external analysis): age 40 (P < .001), relapse (P = .006), PRD (P = .033), HDCT (P = .024) (Table 5).
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Table 5.
Multivariate Analysis of Risk Factors in the 393 and
1,179 Matched Patients (PRD, PSD, and R1) Included in the Risk-Factor
Analysis (External Analysis)
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DISCUSSION |
Since the initial suggestion by Crosby11 in 1969 that acute
leukemia developing after the cure of HD could be related to the
therapy, MDS/AML and solid tumors secondary to conventional chemotherapy and irradiation have been recognized as a complication of
HD treatment. Alkylating agents,21 radiation
therapy,22 combined modality therapy,23 and
splenectomy24 have all been implicated in the development
of these poor-prognosis tumors. The risk of MDS/AML is limited to a
finite period of time and is at its maximum in the 5- to 9-year period
of follow up. For solid tumors, the period of risk is more prolonged,
even if it does seem to be a decrease in the relative risk in males
after 15 years.12,25
We reported in the IDHD study that after conventional treatment, age,
treatment, and gender were risk factors for all second cancer; for
MDS/AML, age and combination chemotherapy with or without radiotherapy
were risk factors; for NHL, age, gender, and relapse treatment were
risk factors; for solid tumors, age and extended radiotherapy were
risk factors.13
Myeloablative therapy with ASCT is increasingly used as part of the
treatment of HD in various clinical situations, eg, for induction
failure patients, after a first or subsequent relapse and also as part
of the initial treatment for high-risk patients.2,3,4,8 Two
recent series reported the occurrence of MDS/AML after ASCT for
lymphoid malignancies9,10 but, up to the present time, there has been little data available on the incidence, timing, and risk
factors for the development of MDS/AML and solid tumors after ASCT for
HD alone. Whether HDCT with stem-cell support is by itself responsible
for an increase in the incidence of secondary cancer after HD is
unknown.
Although the 467 grafted patients included in the study were drawn from
major French centers with expertise in HDCT, their characteristics and
survival are not different from those of patients from other
groups.5,26,27 The rather high proportion of B symptoms in
our series results from the large number of PSD (mostly stage IIIB-IVB)
and PRD patients (78% of B symptoms at diagnosis). The 4.3% 5-year
cumulative incidence rate of secondary MDS/AML in our series is similar
to the 4% reported by Darrington,9 but is somewhat lower
than the 18% ± 9% 6-year actuarial risk reported by Stone et
al.10 This latter study reported on NHL patients who were
all administered TBI, and the definition used for myelodysplasia
differed from that of the FAB classification used by
Darrington9 and our group. In most series, however, the
follow up of grafted patients has still only run for a short time and
it is likely that the peak incidence of MDS/AML (5-9 years) or solid
tumors (up to 15 years) has not been reached, suggesting that the
incidence could still increase. The presence of the groups of PRD and
PSD patients gave us an opportunity to analyze patients with short
treatment duration before ASCT and brief intervals between HD diagnosis
and ASCT, and to compare them with patients grafted after relapse.
The incidence of MDS/AML and solid tumors in the briefly treated group
of PSD patients is, so far, not different from that of the R1 patients
group. The reduction of the amount of mutagenic agents using up-front
transplant may not have been sufficient to significantly improve the
risk of secondary cancers.
No secondary cancer was observed in the PRD group, mainly a consequence
of the poor outcome of these patients (35% 5-year survival) and their
short follow up (29 months). Consequently, among the 467 grafted
patients (internal analysis), the disease status was not a significant
risk factor. However, when the matched 393 grafted and 1179 ungrafted
patients were analyzed (external analysis), the disease status (PRD)
with 3 second cancers in the ungrafted group emerged as a weak risk
factor (P = .033).
Age and splenectomy were found to be risk factors for the development
of secondary cancer after HDCT, after conventional chemotherapy, and
irradiation.28,29 The risk of secondary MDS/AML is related to the number of cycles of MOPP administered14 in
conventionally treated patients. This risk factor was not found to be
significant in our grafted group. The number of secondary MDS/AML is
small and may reflect our small median follow up that is far above the 10-year period of risk for secondary MDS/AML. Another hypothesis is
that the cumulative dose of mutagenic agents received by all patients
is high and may obliterate the role of MOPP exposure.
A major surprise was a higher incidence of secondary cancers observed
in patients receiving PBSC-containing graft. Bhatia et al30
recently reported a higher cumulative probability of MDS/AML in pooled
NHL and HD patients grafted with PBSC compared with bone marrow.
Traweek et al31 have also reported a trend towards a
decreased risk of cytogenetic abnormalities after HDCT with the use of
bone marrow alone or in combination with PBSC, compared with PBSC
alone. The reasons for such observations are still unclear. First,
indications for HDCT were similar in PBSC and bone marrow groups.
Therefore, the higher risk in patients who received PBSC does not
reflect a higher proportion of PSD patients with better survival and
prolonged exposure to the risk of developing a secondary cancer.
Second, HGF are commercially available in France since January 1992 and
their administration correlates with the increased use of PBSC. In our
series, 16% of the patients grafted before January 1992 received PBSC
compared with 68% after this date. It can be speculated that
widespread use of HGF, rather than PBSC, could be the risk factor
associated with a higher incidence of second cancer. However, only 6 of
the 18 patients who developed a second cancer have received HGF at any
time between the diagnosis of HD and the diagnosis of their second
cancer and among those 6, 4 developed a solid tumor that is unlikely to
be related to the use of HGF. Third, prolonged immune suppression is
associated with an increased risk of malignancy, because it is
observable after organ transplantation or in HIV-infected patients. The
difference between bone marrow and PBSC could therefore reflect a
difference in immune depression after HDCT. However, PBSC graft
contains more natural killer (NK) and T cells and leads to a faster
hematopoietic recovery than does bone marrow; the immune reconstitution
when studied is at least comparable.32
The small number of events and the, as yet, brief follow-up period mean
that we can assign only limited significance to this risk factor. The
evidence certainly does not entitle us to advocate discontinuation of
the use of PBSC as a source of stem cells in this situation. Recent
studies33,34,35 comparing PBSC and bone marrow in lymphoid
malignancies have shown numerous advantages for PBSC but did not report
an increase in second cancer. Further randomized trials comparing
primed and unprimed bone marrow may help to clarify this question but a
large number of patients will be necessary because of the low rate of
events and the long necessary follow up.
Most of the previous work on secondary malignancies after ASCT has
focused on MDS/AML, and the available evidence suggests that the
pretransplant therapy, rather than myeloablation, is the culprit. Time
from the initial therapy to the MDS/AML development, prolonged exposure
to chemotherapy (ie, alkylating agents), and the fact that MDS is only
rarely observed after allogenic BMT all support this hypothesis. The
results from this study comparing grafted to conventionally-treated
patients also suggest that chemotherapy-induced myeloablation does not,
by itself, increase the risk of MDS/AML. However, the more rapid onset
of solid tumors after HDCT does lead to an increased risk of second
cancer for the grafted population. Solid tumors, a complication known
to be associated with radiotherapy, are not due to more extensive
irradiation in the grafted group because this treatment modality is not
a significant risk factor in our multivariate analysis. Whether this
increased risk reflects differences in the immune status of grafted and
ungrafted patients or is merely a reflection of the smaller number of
events is unknown and merits further investigation through a careful
and prolonged follow up of these patients. However, a recent
retrospective study36 showed an early increased RR of solid
tumors after conventional chemotherapy for HD (1.4, 95% CI = 1.1  1.8). Chemotherapy was associated with an early increased risk
of cancers of the bones, joints, articular cartilage, and soft tissues
(RR = 6.0, 95% CI = 1.7 20), and cancers of the female genital
system (RR = 1.8, 95% CI = 1.1 3.2). A statistically
significant increase in the risk of respiratory and intrathoracic tumor
was also observed in the first 5 years after chemotherapy (RR=2.2; 95%
CI = 1.1-4.3).
Even in the absence of randomized trials, ASCT remains required for
some HD patients, and, because the procedure is safe and has minor
effects on the incidence of secondary malignancies, more data on the
incidence and etiology of these complications is required before it
would be reasonable to alter our current therapeutic approaches.
However, the occurrence of secondary malignancies after HDCT is now
well established and should be discussed with the patient as a
potential late complication when obtaining informed consent before
transplant.
| |
FOOTNOTES |
Submitted October 8, 1997;
accepted May 13, 1998.
M.A. was supported by the Collège de Médecine des
Hôpitaux de Paris and by the Centre Hospitalier Notre-Dame et
Reine Fabiola in Charleroi, Belgium. This study was also supported by a
grant from the Fondation Contre la Leucémie.
Address correspondence to Prof Christian Gisselbrecht, Hematology
Institute, Hôpital Saint-Louis, 1 Avenue C, Vellefaux, 75010 Paris, France.
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 indebted to Dr P. Biron, Dr H. Tilly, Dr A. Stamatoulas, Dr J.P.
Jouet, J. Beaune, T. Gargi, S. Cournier, H. Desmorat, M. Bataille, and
A-S. Woronoff for facilitating our access to the necessary data. We
thank Dr G. Socié for fruitful discussion and encouragement
during this work.
| |
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Abstract
Introduction
Abstract