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Chapter 75 Hodgkin Lymphoma 1223

receiving brentuximab plus ABVD and 96% of those receiving disease-free survival in these patients is often bleak, particularly for
brentuximab plus AVD. Although a manageable toxicity profile was those with unfavorable prognostic factors.
observed with brentuximab and AVD, an unacceptable level of pul- The treatment of choice for the majority of patients with relapsed
monary toxicity was associated with brentuximab and ABVD, HL, or with refractory disease that has not responded to initial
exceeding that of ABVD alone, and, as a result, this combination was chemotherapy, is cytoreduction with salvage chemotherapy followed
contraindicated. In contrast, no toxic pulmonary effects were observed by high-dose salvage chemotherapy (HDCT) and ASCT. With
16
with the brentuximab and AVD regimen. A randomized phase III modern-day transplant techniques and improved peritransplant
trial comparing BV and AVD with standard ABVD alone is currently management, the rate of early transplant-related mortality with
ongoing (ECHELON-1). Similar studies investigating the combina- ASCT has fallen from as high as 20% previously to <5% and, as such,
tion of BV with BEACOPP-like regimens are also underway. Fur- ASCT is considered a safer and more accessible treatment option for
thermore, the incorporation of other novel agents including rituximab a wider group of patients. As described later, favorable remissions and
and lenalidomide into frontline chemotherapy for patients with improved outcomes have been observed with HDCT followed by
advanced HL is also being explored. ASCT, compared with conventional salvage strategies and, as a result,
In summary, the current standard of care for the upfront treatment this approach remains the standard of care for the initial treatment
of patients with advanced HL includes initial chemotherapy, gener- of patients with relapsed or refractory HL.
ally with ABVD or escalated BEACOPP. A clear role for consolidative
RT has not been established. The future standard of care for patients
with advanced HL is likely to be shaped by both PET-directed Salvage Chemotherapy and HDCT Before ASCT
therapy, in which treatment is modified according to risk, and the
incorporation of novel targeted agents into frontline chemotherapy The goal of cytoreduction with salvage chemotherapy and preparative
regimens, with the overall aim of achieving cure while limiting HDCT conditioning before ASCT is to achieve high response rates
exposure to unnecessary treatment-related toxicity. As a result, it is and a minimal disease state, while maintaining an acceptable toxicity
anticipated that the overall outcome for patients with advanced HL profile, without compromising subsequent stem cell mobilization. A
will continue to improve. number of second-line salvage chemotherapy combinations are cur-
rently in use, but because of a lack of randomized data comparing
these regimens, there is no consensus as to which is optimal. Common
RELAPSED AND REFRACTORY HODGKIN LYMPHOMA regimens include DHAP (dexamethasone, cisplatin, cytarabine), ICE
(ifosfamide, carboplatin, etoposide), GVD (gemcitabine, vinorelbine,
Although the vast majority of patients with newly diagnosed HL liposomal doxorubicin), ESHAP (etoposide, methylprednisolone,
achieve a remission after first-line therapy, around 10% will have cytarabine, cisplatin), mini-BEAM (carmustine, etoposide, cytara-
refractory disease (defined as progression or nonresponse during bine, melphalan) and dexa-BEAM (dexamethasone, carmustine,
initial treatment or within 90 days of completing treatment). In etoposide, cytarabine, melphalan), with patients typically receiving
addition, of those achieving initial cure, approximately 30% will two to three cycles of therapy before proceeding to ASCT. Of these
relapse. Further remissions can be achieved for these patients with regimens, the greatest experience has been reported with DHAP,
salvage therapy, for which the optimal choice depends on a combina- mini-BEAM, and dexa-BEAM in the context of randomized control
tion of factors including the patient’s stage of disease at relapse, their trials assessing ASCT, with similarly high response rates being
prior therapies, and their risk factor profile. observed with each combination. 19–21 Although there is no evidence
to suggest superiority of one salvage regimen over another with
Prognostic Factors in Relapsed or Refractory regards to efficacy, greater toxicity and impaired peripheral blood
stem cell mobilization have been reported with melphalan-containing
Hodgkin Lymphoma combinations.
A number of risk factors for refractory disease or relapse following
initial therapy have been identified for patients with HL. In two large HDCT and ASCT
retrospective analyses conducted by the GHSG, poor performance
score at the time of progression, age greater than 50 years, and failure The advantage of HDCT followed by ASCT over standard chemo-
to achieve a temporary remission on first-line treatment were high- therapy alone has been demonstrated in a number of studies. In 1997
lighted as significant predictors of adverse outcome for patients with Yuen and colleagues compared the outcome of patients receiving
primary refractory HL: in addition, time to first relapse, clinical stage high-dose etoposide, cyclophosphamide, and total body irradiation
III or IV disease at relapse, and anemia (hemoglobin <12 g/L males (TBI) or carmustine followed by ASCT, with a matched conventional
or <10.5 females) were considered significant predictors of adverse salvage group who received chemotherapy alone. At 4 years of
outcome for patients with relapsed HL. 17,18 Of these prognostic follow-up a clear improvement was seen in those who underwent
factors, performance status at relapse, advanced stage at relapse, and transplant with regards to OS, EFS, and FFP over chemotherapy
time to relapse appear to be consistently associated with poor risk alone (OS 54% vs. 47%, p = .25; EFS 53% vs. 27%, p < .01, FFP
across studies, but prospective confirmation of these is still needed. 62% vs. 32%, p < .01).
Two key randomized control trials (RCTs) have supported the
Treatment of Relapsed or Refractory superior role of HDCT followed by ASCT over conventional salvage
therapy and have been integral to establishing this approach as the
Hodgkin Lymphoma standard of care for patients with relapsed or refractory HL: In a
comparison of high-dose BEAM chemotherapy plus autologous
For a select group of patients with favorable criteria who experience transplant versus standard-dose mini-BEAM chemotherapy alone,
localized relapse at previously nonirradiated sites, treatment with the British National Lymphoma Investigation (BNLI) group demon-
salvage RT alone may be effective. More commonly, however, the role strated significant differences in EFS and PFS in favor of BEAM
19
for radiation in the management of relapsed HL is limited to the followed by autologous transplant (53% vs. 10%). In a larger trial
treatment of either localized residual disease following salvage che- conducted by the GHSG/EBMT, 161 patients with relapsed or
motherapy or localized late recurrence (>12 months) as part of refractory HL were randomized to receive either four cycles of dexa-
planned consolidation. For a subset of other patients who relapse after BEAM or two cycles of dexa-BEAM followed by two further cycles
primary chemotherapy, salvage chemotherapy alone with various, of high-dose BEAM and ASCT. In chemosensitive patients, FFTF at
more intensive, second-line regimens can achieve further responses, 3 years was significantly better for those proceeding to HDCT and
although these responses are often suboptimal and the long-term ASCT (55%) compared with standard chemotherapy alone (34%,