Page 1374 - Hematology_ Basic Principles and Practice ( PDFDrive )

1220 Part VII Hematologic Malignancies

TABLE Standard Chemotherapy Regimens for the Treatment Furthermore, in one study comparing a modified hybrid of MOPP/
75.6 of Advanced Hodgkin Lymphoma ABV with ABVD alone, not only were similar OS rates seen (OS
ABVD 82% versus MOPP/ABV 81%), but pulmonary toxicity,
Regimen Drugs Route Schedule hematologic toxicity, treatment-related death, and secondary malig-
ABVD Adriamycin 25 mg/m 2 IV Day 1 and 15 nancies were also shown to be significantly less in the ABVD-alone
10
Bleomycin 10 mg/m 2 IV Day 1 and 15 arm. The conclusion was that ABVD was not only at least as
Vinblastine 6 mg/m 2 IV Day 1 and 15 effective as the standard of care at that time, but also easier to
Dacarbazine 375 mg/m 2 IV Day 1 and 15 administer and safer. These data subsequently led to the international
Every 28 days approval of six to eight cycles of ABVD as the new standard of care
for the frontline treatment of patients with newly diagnosed advanced
BEACOPP Bleomycin 10 mg/m 2 IV Day 8 HL (see Table 75.6).
(escalated) Etoposide 200 mg/m 2 IV Day 1–3 Although one of the main attractions of ABVD is its ability to
Adriamycin 35 mg/m 2 IV Day 1 maintain excellent OS without unnecessarily exposing the patient to
Cyclophosphamide 1250 mg/m 2 IV Day 1 the toxicity associated with alkylating agents, bleomycin-induced
Vincristine 1.4 mg/m 2 IV Day 8 pulmonary toxicity remains an important problem for some individu-
Procabazine 100 mg/m 2 PO Days 1–7 als. For this reason, alternative drug combinations utilizing agents
Prednisolone 40 mg/m 2 PO Days 1–14 that have previously shown promise in the setting of relapsed HL
G-CSF SC From day 8 have also been developed for the frontline treatment of patients with
Every 21 days advanced HL and of these, etoposide-based regimens have emerged
G-CSF, Granulocyte colony-stimulating factor. as acceptable substitutes.

ABVD BEACOPP

Despite the initial success of MOPP chemotherapy, failure to achieve The relationship between chemotherapy dose and tumor response is
initial remission continued to be a problem in up to 20% of patients well established. In 1992 the GHSG conducted a pilot study inves-
with advanced HL and of those patients who were successfully tigating whether treatment response and outcome could be improved
treated with MOPP, a third still relapsed. Furthermore, as a result of by dose intensification in patients with newly diagnosed advanced
prolonged exposure to alkylating agents, significant toxicities includ- HL. Dose intensification was achieved by reducing the duration over
ing secondary leukemias, myelodysplasia, and sterility had emerged which the same treatment was administered and adding etoposide.
with this regimen. As a result, the BEACOPP regimen (bleomycin, etoposide, doxoru-
In 1975, in an initial attempt to treat patients with relapsed HL, bicin, cyclophosphamide, vincristine, procarbazine, and predniso-
11
the ABVD drug combination was developed by Bonadonna and lone) was developed with encouraging results in preliminary studies.
6a
colleagues. An early randomized control study directly comparing The subsequent randomized HD9 trial, in 2009, comparing COPP/
MOPP with ABVD for patients with advanced HL showed compa- ABVD with standard-dose BEACOPP and escalated BEACOPP in
rable CR rates between the two groups (76% versus 75%) and patients aged 15−65 years with stage IIB, III, and IV HL, showed
crossover carried out for progressive disease or for relapse after initial significantly improved FFTF and OS rates with BEACOPP compared
remission successfully demonstrated an absence of cross-resistance with COPP/ABVD, with the best results observed with escalated
between the two regimens. As a result, ABVD was highlighted as an BEACOPP (OS 91% escalated BEACOPP vs. 88% standard
appropriate second-line option for those in whom initial MOPP BEACOPP vs. 83% COPP/ABVD, p < .002). The rate of early
therapy had failed. progression was also significantly lower in the escalated BEACOPP
In 1986, because of this success, the same group went on to arm (2% escalated BEACOPP vs. 8% standard BEACOPP vs. 10%
investigate the potential role for ABVD in the first-line setting by COPP/ABVD, p < .001). Because of the superior outcomes observed
comparing standard MOPP therapy with an alternating regimen of with both BEACOPP regimens, the COPP/ABVD arm in this study
MOPP and ABVD in patients with stage IV HL who were was closed at interim analysis. The improved outcome seen with
chemotherapy-naive. The alternating MOPP/ABVD regimen was escalated BEACOPP in the HD9 study was substantiated by long-
found to be superior to MOPP alone with regards to CR rate (88.9% term follow-up analysis at 10 years. 12
vs. 74.4%), FFP (64.6% vs. 35.9% at 8 years, p < .005), relapse-free Despite the success demonstrated by escalated BEACOPP in the
survival (72.6% vs. 45.1%), OS (83.9% vs. 63.9%, p < .06), and HD9 trial, longer-term complications including the development of
survival of complete responders (94.8% vs. 77.1%). Furthermore, in myelodysplastic syndrome and secondary acute myeloid leukemia
this landmark study there was no observed increase in associated (AML) occurred more frequently when compared with standard
major toxicity in the MOPP/ABVD arm. BEACOPP and COPP/ABVD. In addition, acute hematologic toxic-
A number of randomized trials were subsequently carried out to ity, including anemia and thrombocytopenia, was also greater in the
further investigate the role of ABVD for the upfront treatment of escalated BEACOPP arm, with blood product support being required
patients with advanced HL either by itself, or in combination with more frequently. The increased toxicity observed with escalated
MOPP. In 1992 results from a pivotal multicenter trial conducted by BEACOPP provided the rationale for the GHSG to investigate the
the Cancer and Leukemia Group (CALGB), comparing six to eight efficacy and toxicity of a time-intensified, rather than dose-intensified,
cycles of MOPP alone, six to eight cycles of ABVD alone, and 12 variant of BEACOPP for patients with advanced HL. In their pilot
alternating cycles of MOPP and ABVD, showed superior complete study, standard dose BEACOPP (i.e., nonescalated) was administered
response rates (MOPP 67%, ABVD 82%, MOPP/ABVD 83%, p = over a reduced cycle duration of 14 days, as opposed to 21 days, along
.006) and 5-year failure-free survival rates (MOPP 50%, ABVD with granulocyte colony-stimulating factor (G-CSF) support. Results
61%, MOPP/ABVD 65%, p = .02) in both the ABVD and ABVD/ showed that although acute leukopenia, thrombocytopenia, and
MOPP arms compared with MOPP alone. Although subsequent anemia were moderate with BEACOPP-14, the severity appeared to
analysis showed no significant difference between either of the be less than that observed previously with escalated BEACOPP, while
ABVD-containing regimens and MOPP with regards to OS, the efficacy was maintained. This led to a multicenter, noninferiority
ABVD-alone arm was consistently shown to be significantly less randomized study (HD15 trial) in which 2182 patients with newly
myelotoxic than either of the regimens containing MOPP. 7 diagnosed advanced HL, aged between 18 and 60 years, were assigned
Additional studies comparing hybrid regimens of MOPP and to receive either eight cycles of escalated BEACOPP, six cycles of
ABVD (given concurrently) with alternating cycles of MOPP and escalated BEACOPP, or eight cycles of BEACOPP-14, followed by
8,9
ABVD also demonstrated equivalent survival with either approach. PET-directed RT. The aim of the study was to establish the optimal