Salvage Chemotherapy with ABVD in MOPP-Resistant Hodgkin's Disease
ARMANDO SANTORO, M.D.; VALERIA BONFANTE, M.D.; and GIANNI BONADONNA, M.D.; Milan, Italy
Fifty-five consecutive patients with advanced recurrent
Hodgkin's disease resistant to MOPP chemotherapy
(mechlorethamine, vincristine, procarbazine, and
prednisone) were given ABVD chemotherapy
(doxorubicin, bleomycin, vinblastine, and dacarbazine). In
54 patients evaluable for response, complete remission
after pathologic restaging was seen in 5 9 % and partial
remission in 13%. Fifteen of 29 patients ( 5 2 % ) showing
disease progression during primary MOPP treatment
achieved complete remission after ABVD. The median
time to complete response was 3 months. The median
duration for complete remission was 17 months, and 3 8 %
of patients who attained complete remission have
remained alive and continuously disease free at 5 years
from start of ABVD treatment. The median survival of
complete responders was more than 60 months. Toxic
manifestations were moderate, aside from pronounced
vomiting in more than half of patients. These results
indicate that ABVD is an effective salvage regimen for
MOPP-resistant Hodgkin's disease.
T H E PROGNOSIS of Hodgkin's disease has been dramati-
cally improved since M O P P chemotherapy (mechlor-
ethamine, vincristine, procarbazine, and prednisone) was
introduced into clinical practice. This combination can
induce complete remission in 7 0 % to 8 0 % of patients
previously untreated (1) or those having relapse after
primary irradiation ( 2 ) . Recently De Vita and colleagues
(3, 4) have reported that for complete responders at risk
10 years the relapse-free survival was 63.4% and the total
survival, 7 3 % . The findings indicate that most patients
who attain a complete remission are indeed cured. Fur-
thermore, in patients who have relapse retreatment with
M O P P yielded a second complete remission in 5 9 % , and
the likelihood of a second long remission was significant-
ly affected by the duration of the first complete response
(3, 5). This clinical observation suggests a wide variation
in the fraction and absolute number of drug-resistant
Hodgkin's stem cells in individual patients at the time
initial treatment was begun and during and after cessa-
tion of M O P P treatment ( 6 ) .
In 1973 A B V D chemotherapy (doxorubicin, bleomy-
cin, vinblastine, and dacarbazine) was designed (7) spe-
cifically to treat MOPP-resistant patients, as the regimen
• From the Istituto Nazionale Tumori; Milan, Italy.
Annals of Internal Medicine. 1 9 8 2 ; 9 6 : 1 3 9 - 1 4 3 .
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includes drugs effective in Hodgkin's disease and not in-
dividually cross-resistant to the M O P P components ( 8 ) .
Whereas initial reports (7, 9, 10) have indicated the ef-
fectiveness of A B V D after crossover design in MOPP-re-
sistant Hodgkin's disease, the present report confirms in a
larger series of patients the usefulness of this second-line
regimen to improve the 5-year results in patients refracto-
ry to M O P P treatment.
Patients and Methods
Between January 1974 and May 1980, 55 consecutive pa-
tients with advanced recurrent Hodgkin's disease resistant to
MOPP combination chemotherapy were treated with the
ABVD regimen. Patients considered resistant to MOPP had
either progressive disease during primary MOPP administered
at full or nearly full doses or relapse within the first 12 months
after achievement of pathologic complete remission. Of the 55
treated patients, 54 were evaluable for response to ABVD; one
patient died of pneumonia after only one cycle of therapy. The
median age was 32 years (range, 18 to 65 years). Nodular scle-
rosis represented the single most frequent histologic subgroup
and accounted for 35 of 54 patients (65%). Of the remaining
19 patients, four had lymphocyte predominance; five, mixed
cellularity; and 10, lymphocyte-depleted histologic findings.
Other characteristics of the patient population are reported in
Table 1. At the start of ABVD chemotherapy, performance
status according to the Karnofsky scale was 60 or greater, and
the median follow-up time from the first course of ABVD was
12.5 months (range, 5 to 79 months). Extent of disease was
ascertained in all patients by chest roentgenogram, lymphogra-
phy, and two needle bone marrow core biopsies from posterior
iliac crests in addition to physical examination. Restaging with
laparoscopy and three to six liver biopsies were done in 17 pa-
tients.
In the ABVD regimen all four drugs were injected intrave-
nously every 15 days, and each treatment cycle consisted of two
drug courses (Table 2). As reported previously (7, 9), a sliding
dose scale was used with leukocyte counts less than 4000/mm 3
or platelet counts less than 130 000/mm 3 , ascertained on the
day of drug injection. The duration of induction treatment was
flexible and related to the achievement of complete response.
Treatment was continued at the maximum tolerated doses until
clinical complete remission was obtained. At this point, addi-
tional cycles were administered to all patients but two. Of the
32 patients who achieved complete remission, nine received
fewer than six cycles and six, more than six cycles (maximum,
10). Fewer than six cycles were given when patients refused
further chemotherapy once they became aware that complete
remission was obtained with the first three to five cycles of
ABVD. In 11 patients (seven with nodal and four with nodal
© 1 9 8 2 American College of Physicians
139
 Table 1. Response to Doxorubicin, Bleomycin, Vinblastine, and achieved complete remission ( 5 9 % ) . Table 1 summarizes
Dacarbazine Related to Patient Characteristics response rates according to the main patient characteris-
Patients Complete Partial
tics. The likelihood of complete remission in MOPP-re-
Resp onse Response sistant patients was significantly influenced by absence of
extranodal disease ( 7 4 % versus 4 4 % , p = 0.03) and of
n n % n systemic symptoms ( 8 2 % versus 4 9 % , p = 0.02). Five of
Age
nine patients with lung involvement and five of six with
< 40 years 42 23 5
> 40 years 12 9 75 2 bone marrow infiltration attained complete remission
Sex compared to two of six patients with metastases to other
Male 25 16 5 extranodal sites (bone, skin). Of six patients with multi-
Female 29 16 2 ple organ involvement only three were partial responders.
Disease extent
Nodal 27 20 74* 3 There was no statistical evidence that age, sex, histologic
Extranodal + nodal 27 12 44* 4 characteristics, prior radiotherapy, or type and duration
Histologic subtype of response to primary M O P P chemotherapy affected the
Nodular sclerosis 35 20 5 probability of attaining complete remission with ABVD.
Other subgroups 19 12 2 Fifteen of 29 patients ( 5 2 % ) showing disease progression
Systemic symptoms
Absent 17 14 82t 0 during primary M O P P achieved complete remission after
Present 37 18 4 9 t 7 ABVD. The median time to clinical complete remission
Prior radiotherapy was 3 months (range, 1 to 8 months). In all patients but
Yes 34 21 4 one complete remission was achieved within six cycles of
No 20 11 3
Response to primary M O P P therapy.
Progression 29 15 5 In Figure la the remission duration is graphed as a
Partial response 3 2 2 function of the magnitude of response. The median dura-
Complete response 22 15 0 tion of complete response was 17 months, and 3 8 % of
Duration of complete
those attaining complete remission remained alive and
response after primary
MOPP continuously disease free at 5 years from start of ABVD.
< 6 months 17 11 1 We have seen more relapses in patients with nodular scle-
7 to 12 months 5 4 1 rosis (nine of 20, or 4 5 % ) than in those with disease of
Totals 54 32 59 7 other histologic subtypes (four of 12, or 3 3 % ) . There
* p = 0.03. was also a trend toward a decreased fraction of complete
+ p = 0.02.
responders at 5 years in the presence of systemic symp-
toms ( 2 5 % ) compared to the absence of systemic symp-
and extranodal extent) radiotherapy (25 to 35 Gy) was admin- toms ( 4 4 % ) . In contrast, the median duration of com-
istered as consolidation therapy. No maintenance treatment plete remission was not significantly related to the num-
was administered in complete responders. Treatment at relapse
consisted of retreatment with ABVD if the duration of com- ber of cycles administered (fewer than six cycles, 15
plete response was longer than 6 months. Patients whose com- months; six or more cycles, 20 months) or to whether
plete remission was less than 6 months and those who failed to consolidation therapy was done with radiotherapy (ra-
respond to ABVD therapy were treated with lomustine (l-[2 diotherapy, 14.5 months; no radiotherapy, 24 months).
chloroethyl]-3-cyclohexyl-l nitrosourea) with or without fur-
ther vinblastine treatment. The survival of patients from start of A B V D therapy is
Patients were restaged 1 month after they had achieved com- shown in Figure lb. The median survival for the entire
plete remission or 1 month after the last cycle of chemotherapy series was 27 months: That for complete responders has
needed to consolidate the complete remission. In complete clini- not been reached, whereas partial responders and those
cal responders, restaging was done by repeating all tests of
which findings had been positive at the start of therapy, includ- who fail to respond had a median survival of 12 and 9
ing rebiopsy of both liver and bone marrow if these organs had months, respectively. The survival curve for the complete
been previously involved by Hodgkin's disease. A patient was responders differs significantly from the curve for pa-
considered to be in complete remission when all signs and tients showing less response or progression (p= 10 — 6 ).
symptoms of disease had disappeared for at least 1 month. Par-
tial remission was defined as 50% or greater reduction in the
Table 2. Outline of ABVD Chemotheraf >y (One Cycle)*
product of the longest perpendicular diameters of all sites of
measurable disease. Patients with tumor regression of less than Rest
Drugs Dose t Day of
50% were designated as nonresponders. Administration Period,
Degree of statistical significance on fractions of complete re- Day
sponders versus nonresponders was calculated by the chi-
squared test. Remission duration and overall survival were mg/m2
computed from the day treatment was started according to the body
life-table method. Degree of statistical significance of observed surface area
difference in various subgroups was assessed with the log-rank Doxorubicin 25 1, 15 16 to 28
test (11). Percentage of patients in remission or surviving are Bleomycin 10 1, 15 16 to 28
reported in the text for one time point whereas the p values Vinblastine 6 1, 15 16 to 28
represent comparison of the entire plots. Dacarbazine 375 1, 15 16 to 28

Results * A dose attenuation schedule should be app]lied in the presence o;f myelosup-
pression ( 7 ) .
Thirty-two of 54 patients evaluable for response t All drugs were giveii intravenously.

140 February 1982 • Annals of Internal Medicine • Volume 96 • Number 2

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 Figure l a . Remission duration re-
lated to magnitude of response to
ABVD. b. Total survival in complete
versus noncomplete responders.
CR = c o m p l e t e r e s p o n s e ; PR =
partial response.
Toxic manifestations can be summarized as follows.
Virtually all 55 patients complained of nausea and vomit-
ing within a few hours after each drug exposure. The
symptoms that were caused primarily by the high single
dose of dacarbazine were severe in more than half of pa-
tients, and nine complete responders became reluctant to
receive further chemotherapy. Myelosuppression was in
general moderate. A decrease in leukocyte count of less
than 2 5 0 0 / m m 3 occurred in 4 0 % of patients and in
platelet count of less than lOOOOO/mm3 in 2 5 % of pa-
tients, respectively. Loss of hair was seen in 5 6 % of pa-
tients. However, overt or almost complete alopecia oc-
curred in slightly fewer than 10% of cases. Moderate
skin hyperpigmentation induced by bleomycin was
detected in 19% of patients, particularly at the level of
fingers and elbows. Paresthesias ( 2 4 % ) induced by vin-
blastine were mild and rapidly reversible. Two patients
complained of reversible adynamic ileum. No patient
showed clinical or radiologic signs of cardiomyopathy in-
duced by doxorubicin or pulmonary fibrosis secondary to
bleomycin. One patient died unexpectedly because of ful-
minant bronchopneumonia after about 4 weeks from the
first dose of ABVD. His blood count was not depressed
by chemotherapy, and the cause of infection could not be
ascertained.
Discussion
About 5 0 % of patients with advanced Hodgkin's dis-
ease need alternative chemotherapy because they either
fail to achieve complete remission with primary M O P P
or because they have relapse within 12 months from the
achievement of complete response. In these patients the
relative insensitivity to M O P P chemotherapy is probably
due to multidrug-resistant phenotypes at the start of
chemotherapy, a necessary consequence of the mutation
theory (6, 12).
Since our initial reports with A B V D (7, 9, 10), other
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investigators have attempted to treat patients failing to
respond to M O P P by using several forms of chemothera-
py including most drugs effective in Hodgkin's disease
and not present in the classical M O P P regimen. In gener-
al the response rate has been high; the frequency of com-
plete responses has been in part due to the limited num-
ber of study patients and to disease characteristics includ-
ing the actual fraction of truly resistant patients over the
total number of M O P P failures (Table 3). Our experi-
ence with ABVD has indicated that the likelihood of
achieving complete remission was significantly influenced
by certain prognostic variables, namely nodal versus ex-
tranodal extent and absence versus presence of systemic
symptoms. The difference could be due in part to the
fraction of specifically and permanently drug-resistant
cells, which is a function of tumor cell burden (6, 12), as
in patients with extranodal involvement. In fact, when
neoplastic cells resistant to one drug treatment (for ex-
ample, M O P P ) reach some number (for example, multi-
ple organ involvement), the probability is high that they
will mutate to a state of resistance to other drugs (for
example, A B V D ) (6, 8).
The fraction of patients continuously free of disease
and the total survival are important variables for treat-
ment evaluation. With the A B V D regimen, 9 2 % of re-
lapses occurred within 2 years after discontinuation of
treatment, and more than one third of complete respond-
ers remain in their first remission at 5 years. That the
median survival for the entire series of patients treated
with A B V D was 27 months and for complete responders
more than 60 months makes us confident that a substan-
tial improvement has been achieved with this treatment
regimen, considering that the median survival of those
who have failed to respond to M O P P is only about 12
months (3, 4 ) .
The opposite sequence—that is, the administration of
M O P P in 16 ABVD-resistant patients—yielded complete
Santoro et a/. • ABVD in Hodgkin's Disease 141
 Table 3. Most Important Combination Regimens Effective in MOPP Failures

Regimen* Acronym Cases Response Rate Median Duration Median Survival References
Overall Complete of Complete of Complete
Response Responses Responders

n % m os
C C N U , VLB, BLM CVB 39 84.5 26 4.5 + 4.5 + 13
BLM, VLB, A D M , STZ BVDS 10 50 30 7 26 + 14
BLM, C C N U , A D M , VLB B-CAVe 22 77 50 35 + 24 15
STZ, C C N U , A D M , BLM SCAB 17 59 35 8 + 16 + 16
BLM, D T I C , VCR, P R D , A D M B-DOPA 15 80 60 14 + ? 17
A D M , D T I C , BLM, C C N U , P R D ABDIC 29 82.5 34.5 28 + 28 + 18
A D M , BLM, VLB, D T I C ABVD 54 72 59 17 60 + Present series

* C C N U = lomustine; V L B = vinblastine; B L M = bleomycin; A D M = doxorubicin; D T I C = imidazole-carboxamide; S T Z = streptozocin; P R D = prednisone;

V C R = vincristine.

response in only 2 5 % and partial response in 1 3 % . The
median duration of complete remission was 6.5 months,
and the median survival of complete responders, which
has not been reached, will be greater than 20 months.
Thus, according to available clinical data A B V D appears
to be superior to M O P P as salvage therapy. Secondary
treatment with ABVD, compared to secondary treatment
with M O P P , probably kills a higher fraction of specifical-
ly and permanently MOPP-resistant neoplastic cells.
The optimal duration of second-line therapy remains
to be further delineated. Since the experience reported
with M O P P ( 1 , 3 ) , however, we have applied the con-
cept of individual consideration to establish the duration
of induction therapy. Once complete remission was evi-
dent, we administered one to five additional cycles in all
our patients but two. Probably because of the prompt
remission induction and because pathologic restaging was
done in all patients, the remission duration was not af-
fected by the total number of cycles administered.
Toxicity related to A B V D administration consisted
primarily of pronounced nausea and vomiting. Severe
myelosuppression, even in patients previously treated
with extensive irradiation, was limited, both leukopenia
and thrombocytopenia recovering within 3 weeks. N o pa-
tient in our series needed leukocyte or platelet transfu-
sions. Also, no patient showed evidence of cardiac and
pulmonary abnormalities owing to doxorubicin and bleo-
mycin, regardless of age and previous irradiation to the
mediastinum. On the contrary, most M O P P salvage pro-
grams (Table 3) often involved severe and even fatal tox-
icity due to prolonged myelosuppression (13, 14, 16),
renal tubular disfunction secondary to streptozocin (16,
19), and doxorubicin cardiomyopathy ( 1 5 ) . This last
side effect was reported in two patients treated with B-
CAVe (bleomycin, lomustine, doxorubicin, and vinblas-
tine), probably because of the high single dose of doxoru-
bicin (60 m g / m 2 of body surface area). Therefore, some
of these drug regimens cannot always be recommended
for general use.
We conclude that A B V D chemotherapy is an effective
salvage regimen to be used as first treatment in M O P P -
resistant patients. Besides inducing a prompt high fre-
quency of complete remission followed by improved 5-
year survival, ABVD can probably cure one third of
complete responders and therefore about 2 0 % of all
MOPP-resistant patients. Present results fit well with the
principles of somatic mutation theory (6, 12) and pro-
vide a logical explanation for the superiority of cyclic
delivery of M O P P plus A B V D compared to M O P P alone
(20). Thus, the peculiar pharmacologic characteristics of
the ABVD combination, which appear to include absence
of carcinogenesis in humans (21, 22) and very low preva-
lence of sterility ( 2 3 ) , fully justify its administration
when alternated monthly with M O P P as first-line treat-
ment of advanced Hodgkin's disease.
ACKNOWLEDGMENTS: The authors thank the many clinical associates
of the division of medical oncology for contributions in patient care and
Pinuccia Valagussa for the statistical evaluation.
• Requests for reprints should be addressed to Gianni Bonadonna, M.D.;
Istituto Nazionale Tumori, Via Venezian, 1; Milan 20133, Italy.
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© 1 9 8 2 American College of Physicians 143