Although high dose chemotherapy and AHCT is the most effective treatment for patients with recurrent or refractory HL, disease recurrence in nearly half of patients requires new approaches [1
]. We sought to reduce the toxicity of the conditioning regimen while maintaining efficacy to create an optimal platform for post-transplant therapeutics. In our previous experience, the pulmonary toxicity associated with augmented BCNU regimens (550 mg/m2
) prohibited the introduction of post-transplant therapy in the first 100 days [12
The present study was designed to evaluate the feasibility of a transplant regimen in which the combination of gemcitabine and vinorelbine allowed for a lowered dose of BCNU along with standard doses of etoposide and cyclophosphamide (GN-BVC). It was recognized that pretransplant GN-containing salvage regimens were being developed during this trial period with similar GN-dosing [7
]. Our toxicities and responses as a transplant regimen, compared to a pretransplant salvage approach with GN, however, might be expected to be different due to the administration close to BVC and thus, was a new experience.
The primary endpoint of the study was met in terms of demonstrating a reduced incidence of BCNU-related toxicity of 15% (CI 9% to 24%). A nominal rate of 35% was used as the historical control rate in the study design, which was a best estimate based on our own data and those of other studies using augmented BCNU dosing [10
], and served to establish the study size for high probability to detect a toxicity reduction. It should be noted that a more stringent pulmonary definition of BCNU-related toxicity (DLCO decrease ≥20%) was applied in prior Stanford studies [19
]. In fact, only two patients had a documented DLCO decrease of at least 20% in the current study, suggesting an even more favorable result. Reducing the dose of BCNU from 15 mg/kg to 10 mg/kg in this regimen likely contributed to the reduced toxicity. Better supportive care in the current era of autografting [23
], as well as earlier recognition and initiation of corticosteroid treatment for BCNU pneumonitis, has undoubtedly played a role in reducing BCNU-related toxicity and deaths. Our institution does not use prophylactic corticosteroids in the high dose BCNU regimens, however, this practice has allowed certain groups to decrease their incidence of interstitial pneumonitis while maintaining BCNU doses of 600 mg/m2
]. A specific pretransplant pulmonary function threshold that predicts for post-transplant pulmonary complications and mortality is not yet established [50
], and this remains the case for BCNU toxicity. A corrected DLCO of 55% was used for entry onto the current study, which is the lowest threshold for our institution's AHCT regimens, and thus allowed more compromised patients to move forward to AHCT with less toxicity result.
The anti-tumor efficacy of the conditioning regimen did not appear to be compromised in our cohort. With a median follow-up of 29 months, the 2-year FFP was 96%, 72%, 67%, and 14% for 0, 1, 2, and 3 risk factors, respectively. As a comparison, in our previous report [12
], the 3-year FFP were 85%, 57%, 41%, and <20% for 0, 1, 2, and 3 risk factors, respectively. Patients with 1 or 2 risk factors appear to benefit with this new regimen over our historical experience. The distribution of risk factors was similar in the earlier and current studies [12
]. When looking at more universal risk factor groups, such as duration of first remission, our study results showed 2-year FFP of 48% for primary IF, 90% for remission duration ≤ 1 year, and 80% for remission duration > 1 year. As a comparison, the conditioning approach utilizing high dose sequential therapy followed by BEAM-AHCT, reported in the phase 2 Cologne trial by the GHSG [8
], shows a freedom from second failure for risk groups having progressive disease versus early relapse (≤ 1 year) versus late relapse (> 1 year) of 41%, 62%, 65%, respectively, at a median follow-up of 30 months. The ongoing GHSG/EBMT randomized trial [9
] is investigating the efficacy of high dose sequential therapy and BEAM-AHCT with standard DHAP followed by BEAM-AHCT, and results are awaited, however, this is limited to chemosensitive patients and questions remain on outcomes for chemorefractory patients prior to AHCT.
Subsequently, FDG-PET imaging has become incorporated in HL response assessment [40
]. In the current study, pre-transplant PET status significantly correlated with FFP (P< 0.0001) and EFS (P= 0.003), and was of borderline significance with regard to OS (P= 0.07). Constitutional symptoms at relapse (P= 0.008) and induction failure (P= 0.0003) were also identified as significant adverse risk features. In multivariate analysis, PET-positive status and constitutional symptoms were independent risk factors for treatment failure. Further, we observed that the combination of constitutional symptoms and PET-positive status, representing 19% of patients with pre-transplant scans, conferred a very poor prognosis, with just 14% FFP at 2 years. In contrast, FFP at 2 years was >80% for patients with only 1 or neither risk factor. This observation should be viewed as hypothesis-generating and interpreted with caution given the small sample size.
In general, the literature is concordant regarding adverse risk factors prior to transplant for HL. B symptoms at relapse, extranodal disease, chemoresponsiveness before transplantation, and remission duration < 1 year [5
] have been reported as independent predictors of long-term disease-free survival in primary refractory and relapsed HL patients. More recently, there are several reports indicating the prognostic significance of PET pre-transplant. The retrospective study by Jabbour et al [54
] identified pretransplant PET status to be independently predictive for progression-free survival (PFS) and OS. In that study, 3-year PFS rates for PET positive and negative patients was 23% and 69%, respectively. Castagna et al [55
] further showed that early PET after two cycles was predictive of survival after AHCT with 2-year PFS of 10% for PET positive vs 93% for PET negative patients (P<0.001). Of note, patients who achieve normalization of PET prior to AHCT with additional non-cross resistant second-line therapy had improved EFS in single institution study [56
], but it is unclear if this strategy results in selection bias, meaningful tumor reduction for cure, or a combination of both.
In conclusion, the regimen of GN-BVC is associated with less pulmonary toxicity than the prior augmented BCNU-containing regimen with equal or greater efficacy. A prospective comparison of this new combination with other conditioning regimens using risk stratification is warranted. Whether using the previously established risk model or incorporating PET, about two-thirds of patients are alive and event-free at 2 years after transplant. A small group with multiple risk factors [12
] in our former model or both symptomatic and PET-positive, had a dismal outcome. Targeting these higher risk patients for novel therapies should be the objective for future studies. Tandem AHCT [57
] has been explored in a risk-adapted transplant strategy but requires further study. Other approaches could include antibody-drug conjugates, histone deacetylase inhibitors, immunomodulating agents and cell-based therapies which hold promise as peri-transplant therapeutics [58