In this report, we describe the efficacy of AHCT in patients with de novo DLBCL who failed to achieve a CR to front-line conventional chemotherapy. With a lengthy follow-up, we show an OS of 69% and an EFS of 59%, which compares favorably with earlier published reports of the outcomes of patients with induction failure, provided chemosensitivity is established.
The landmark Parma trial established the role of AHCT in patients with chemosensitive, relapsed disease, but the value of AHCT for patients with aggressive NHL who failed induction chemotherapy is less well defined.5
Previous studies have shown a poor prognosis for this particular population, with salvage therapy yielding an EFS of only <15% and a median OS of <15 months.4,5
In a randomized study, a prospective Italian multicenter study attempted to establish the optimal regimen for NHL patients who were induction failures.8
Patients were restaged after receiving four of six planned cycles of front-line therapy. Those who achieved a PR were randomized to receive salvage chemotherapy (n
=27) or AHCT (n
=22). The 3-year OS was 59% for the salvage group vs 73% for the AHCT group, with the corresponding PFS being 52 and 73%. Owing to the small sample size and lack of power, these differences were not statistically significant.
In an analysis from the Autologous Blood and Marrow Transplant Registry, Vose et al.11
identified 184 patients with diffuse aggressive NHL who never achieved a CR with conventional chemotherapy. A total of 96% of patients received subsequent salvage chemotherapy, with 60% being deemed chemosensitive and 28% being chemotherapy resistant before AHCT. A total of 12% were not assessable. For all patients, the 5-year OS and PFS were 37% and 41%, respectively, but patients who were chemoresistant at the time of AHCT had a 2.44-fold higher relative risk of death from relapse than chemosensitive patients (P
= <0.0001), thus confirming the unequivocal prognosticator of chemosensitivity. Response after transplantation also affected survival, as OS was 61% for patients who obtained a CR after AHCT compared with only 11% for PR patients and non-responders. These data are similar to a report from the GEL-TAMO (Grupo de Espanol de Linformas/Trasplante Autologo de Medula Osea) registry of 114 DLBCL patients who did not achieve a CR after induction.18
The 5-year OS was 43% for all patients. For patients who were truly chemoresistant and who did not respond to salvage therapy, OS and EFS were 10 and 0%, respectively, compared with 61 and 71%, respectively, for PR patients. Unlike our analyses, both of these registry studies included chemoresistant patients, which may explain our superior survival incidences.
In a single institution retrospective analysis, the Memorial Sloan Kettering group reported the outcome of 85 patients with aggressive NHL who achieved less than a CR after front-line chemotherapy.4
All patients subsequently received ICE (ifosfamide–carboplatin–etoposide) salvage chemotherapy. In an intent-to-treat analysis, the 3-year OS and EFS were 25 and 22%, respectively, but when the patients who actually proceeded to AHCT (n
=42) were analyzed separately, the 3-year OS and EFS were 52 and 44%, respectively. The patients who did not proceed to AHCT had a median OS of only 3.7 months. Thus, these results also validate the role of AHCT for this challenging patient population. The investigators note that the outcomes of their chemosensitive patients who proceeded to AHCT were similar to the Parma results, which confirm that once chemosensitivity is established, there is no significant difference in outcome after AHCT in patients who were induction failures or who had relapsed disease.
As previously mentioned, our results compare favorably with the above mentioned studies and show the long-term success of this treatment approach. In contrast to those reports, our study was limited to patients with histologically confirmed DLBCL. Previous similar studies included diverse NHL subtypes, including transformed indolent disease, high-grade disease or T-cell histologies.4,8,11
Another distinct feature of our study is the lengthy follow-up of 7.3 years as other similar published studies only reach a follow-up duration of up to 4 years. Despite the long follow-up duration, our favorable outcomes have remained durable over time.
All of our patients received ex vivo
purged autografts, which is another distinct feature of our study and also may have contributed to our notable outcomes. Our method of purging with a panel of MoAbs and complement has been shown to reduce the lymphoma tumor burden from peripheral blood autografts.17
Purging had no impact on the time to neutrophil and plt engraftment. A comparison of this with subsequent protocols at our institution using unpurged autografts showed comparable times to engraftment.
The impact of purging on survival after AHCT for NHL is controversial.19
Randomized trials that aimed at assessing the value of in vitro
purging have shown no benefit, although some of these studies were limited by the inclusion of diverse lymphoma histologies and a variety of purging techniques.19
Of patients with DLBCL in CR mobilized with chemotherapy and G-CSF, approximately 50% will have apheresis products that show a PCR evidence of contamination with tumor cells.20
Vose et al
also reported that patients with DLBCL who received unpurged BM with PCR evidence of contamination by lymphoma had an inferior EFS compared with patients whose grafts were PCR negative for tumor cells. There are no randomized studies evaluating the impact of B-cell purging of autografts in DLBCL, and it is unlikely that such studies will ever be conducted given the labor and cost of producing clinical-grade antibodies, as well as the increasing use of rituximab for the purposes of in vivo
In addition, with rare exception, DLBCL patients are currently treated with rituximab as part of front-line therapy, salvage therapy or both. Rituximab has also been used for purposes of in vivo
purging and has yielded PCR-negative grafts primarily in patients with follicular and mantle cell NHL.22–24
Thus, the advent of rituximab has nearly eliminated the need or interest in pursuing ex vivo
purging with MoAbs or immunomagnetic columns, both of which are quite labor intensive. Only seven patients in our cohort received rituximab before AHCT, and thus the impact of rituximab in our cohort cannot be accurately assessed. A recent publication by Alousi et al
has shown that patients with metabolically active disease and who receive rituximab as a component of the mobilization regimen have a 5-year PFS of 46%. In contrast, similar patients who did not receive rituximab had a 5-year PFS of 10%.
Another possible explanation for our notable results is that our patients were assessed by CT and not by metabolic imaging with [18
F] fluorodeoxyglucose PET scanning, which may have led to an underestimation of a true CR rate. CT scanning is unable to distinguish viable tumor from fibrotic or necrotic tissue, and is therefore likely to overestimate the presence of viable tumor. Juweid et al
compared the response assessment by CT with PET–CT in 54 patients with aggressive NHL, including 47 with DLBCL. A total of 31% of patients evaluated with CT achieved a CR, whereas restaging with PET–CT increased the CR rate to 65%. PET–CT eliminated the category of Cru
(complete response, unconfirmed) and also reduced the percentage of PR from 35 to 22%. The 3-year PFS was significantly lower in patients scored as PR by CT–PET compared with those scored as PR by CT alone. Thus, it is possible that a percentage of our patients were actually in a CR after front-line therapy and thus were already in a favorable prognostic group.
In summary, we conclude that for de novo DLBCL patients, failure to achieve a CR to upfront combination chemotherapy does not necessarily confer a poor prognosis. Our favorable outcomes may partially be attributed to our homogenous population of DLBCL patients and to the use of B-cell purging. Our results showed that over half of such patients can be cured with AHCT, provided chemosensitivity is established either with induction and/or with salvage chemotherapy. The impact of our B-cell purging technique cannot be definitively assessed as this was not a randomized trial, but the current widespread use of rituximab during induction, salvage and/or mobilization is most likely to reduce risk of tumor cell contamination in mobilized autografts and may ultimately improve outcomes of this patient population. Thus, our results show the long-term benefit of this treatment strategy for patients with DLBCL who do not achieve a CR with induction chemotherapy.