The combination of doxorubicin, bleomycin, vinblastine and dacarbazine for treatment of advanced Hodgkin lymphoma was first reported by Bonadonna et al.r ABVD was shown to be superior to the previous standard regimen, MOPP, alonerrr and less toxic than the MOPP/ABVD combination, with minimal infertility and reduced rates of secondary malignancy compared with radiation therapy (RT) or MOPP.r
A Cochrane meta-analysis in 2017r concluded that based on “moderate- to high-quality evidence that adult patients between 16 and 60 years of age with early unfavourable and advanced stage HL benefit regarding OS and PFS from first-line chemotherapy including escalated BEACOPP. The proven benefit in OS for patients with advanced HL is a new finding of this updated review due to the inclusion of the results from the EORTC 20012 trial. Furthermore, there is only low-quality evidence of a difference in the total number of secondary malignancies, as the follow-up period might be too short to detect meaningful differences. Low-quality evidence also suggests that people treated with escalated BEACOPP may have a higher risk to develop secondary AML or MDS. Due to the availability of only very low-quality evidence available, we are unable to come to a conclusion in terms of infertility. This review does, for the first time suggest a survival benefit. However, it is clear from this review that escalated BEACOPP may be more toxic than ABVD, and very important long-term side effects of second malignancies and infertility have not been sufficiently analysed yet".
Of note that studies using PET directed therapy were not included in the Cochrane review. Two important studies were published recently. In the RATHL study, 1129 patients have underwent interim PET-CT after 2 cycles of ABVD chemotherapyr. PET negative patients were randomised to ABVD or AVD, while PET positive patients were treated with 4 cycles of either BEACOPP-14 or escBEACOPP. Updated results presented at ICL-14r conference in 2017 showed that following a negative PET2, 952 pts were randomised to continue ABVD or AVD. With a median follow‐up of 52 months, PFS at 3 years for ABVD was 85.4% and for AVD 84.0%. Among 172 pts with a positive PET2, 5 year PFS was 65.7% and 5 year OS 85.1%. The primary outcome measure was the PFS rate among patients who were randomly assigned to continue or stop bleomycin after negative findings on an interim PET-CT scan; the aim was to exclude a difference of 5 percentage points at 3 years. The observed upper boundary of the 95% confidence interval (5.3 percentage points) was just over this margin, and this is probably due to the lower-than-expected 3-year PFS rate of 85.7% in the ABVD group, which would require more events to exclude a 5-percentage-point difference. The inclusion of bleomycin in the first two cycles may still make a positive contribution to the control of disease, but its omission after negative findings on an interim PET-CT scan carries a minimal risk of treatment failure, estimated in our trial to be 1.6%, and there was no significant difference in survival between the randomised groups.
Evidence of the efficacy of ABVD in advanced stage Hodgkin lymphoma comes from several RCTs comparing ABVD with other regimens (see table). In these studies, complete remission (CR) rates range from 76-89% with 5 year overall survival (OS) 73-90%.
||Results for ABVD arm
||FFS @ 5yrs
||PFS @ 5yrs
||OS @ 5yrs
||6-8 x ABVD vs MOPP vs MOPP/ABVD; no RT
||6 x ABVD vs MEC vs Stanford V; ± RT
||8-10 x ABVD vs MOPP/ABV; no RT
||6-8 x ABVD vs multidrug regimens; ± RT
||6 x ABVD vs mod Stanford V vs MOPPEBVCAD; ± RT
||6 x ABVD vs BEACOPP vs CEC; ± RT
||6-8 x ABVD vs Stanford V; ± RT
* outcome percentages are at 3 years, not 5 years as the other studies summarised here
** overall response rate (CR + PR)
MOPP= mechlorethamine + vincristine + procarbazine + prednisone
Stanford V= doxorubicin + vinblastine + mechlorethamine + vincristine + bleomycin + etoposide + prednisone
MOPPEBVCAD= mechlorethamine + vincristine + procarbazine + prednisone + epidoxirubicin + bleomycin + vinblastine + lomustine + doxorubicin + vindesine
CEC (COPPEBVCAD)= cyclophosphamide + lomustine + vindesine + melphalan + prednisone + epidoxirubicin + vincristine + procarbazine + vinblastine + bleomycin
BEACOPP= bleomycin + etoposide + doxorubicin + cyclophosphamide + vincristine + procarbazine + prednisone
ABVD is one of the two main international standard treatments for advanced stage Hodgkin lymphoma, the other being escalated BEACOPP (see link).
ABVD causes Grade 3-4 neutropenia in 30-34% of patientsrr Despite this rates of significant infections are low (1-2% Grade 3-4).rr Evens et al demonstrated that G-CSF support is not required to maintain near 100% dose intensity during ABVD treatment.r In their study 58% of 658 ABVD treatments were administered with an ANC <1.0 x 109/L without an increase in infection (incidence rate, 0.44%) when compared with those given G-CSF (incidence rate, 0.78%). Other Grade 3-4 early toxicities include alopecia (24-30%),rr nausea and vomiting (6-13%)rr and pulmonary (6-10%).rr
Fertility is relatively preserved after ABVD. 30-54% of males experience transient oligo/azospermia however most fully recover.rr Transient amenorrhoea occurs in around one third of women of reproductive age (<45 years) but permanent amenorrhoea secondary to ABVD alone is uncommon.r Furthermore, female Hodgkin lymphoma survivors attempting pregnancy after ABVD had fertility comparable with case controls with a 12 month pregnancy rate of 70%.r
Although second malignancies occur in patients post-ABVD (6% at 6-10 years follow up) rates of secondary MDS/AML are very low and do not appear to be significantly increased.rrr Other long term toxicities include bleomycin-induced lung injury (link to Pulmonary toxicity associated with antineoplastic agents) and doxorubicin-related cardiac toxicity (link to Cardiac toxicity associated with anthracyclines).
In the most recent Cochrane reviewr, authors concluded that: “The risk of secondary acute myeloid leukaemia and myelodysplastic syndrome (AML/MDS) is increased but efficacy is improved among patients treated with intensified chemotherapy protocols. Treatment decisions must be tailored for individual patients. Consolidating radiotherapy is associated with an increased rate of secondary malignancies; therefore it appears important to define which patients can safely be treated without radiotherapy after chemotherapy, both for early and advanced stages. For early stages, treatment optimisation methods such as use of fewer chemotherapy cycles and reduced field or reduced-dose radiotherapy did not appear to markedly affect efficacy or secondary malignancy risk. Due to the limited amount of long-term follow-up in this meta-analysis, further long-term investigations of late events are needed, particularly with respect to secondary solid tumours. Since many older studies have been included, possible improvement of radiotherapy techniques must be considered when interpreting these results.