High rate of clinical and molecular remissions in follicular lymphoma patients receiving high-dose sequential chemotherapy and autografting at diagnosis: a multicenter, prospective study by the Gruppo Italiano Trapianto Midollo Osseo (GITMO)

Abstract

Single-center experiences have shown that intensified treatments with autologous transplantation are a promising therapeutic strategy for patients with high-risk follicle-center lymphoma (FCL) at diagnosis, whereas data from prospective multicenter trials are still lacking. This paper describes the results of a prospective multicenter study of an intensified purging-free high-dose sequential (i-HDS) chemotherapy schedule with peripheral blood progenitor cell (PBPC) autografting. The main feature of this program is harvesting stem cells after intensified chemotherapeutic debulking, with no ex vivo manipulation of PBPCs. Ninety-two previously untreated patients aged 60 or younger with advanced-stage FCL were enrolled by 20 Italian centers and evaluated on an intention-to-treat basis. i-HDS proved feasible with limited toxicity (87% patients completed the planned treatment schedule). i-HDS led to a complete remission rate of 88%. The projected overall survival and disease-free survival (DFS) were, respectively, 84% and 67% at 4 years. Centralized molecular analysis showed that polymerase chain reaction-negative harvests could be collected in 47% of cases. Following autograft, 65% of molecularly evaluable patients achieved clinical and molecular remission. The projected DFS at 4 years of this subgroup is 85%. This result emphasizes the importance of achieving maximal tumor reduction in these patients. In conclusion, our data show that highly effective intensified treatments can now be routinely offered to young patients with poor-risk FCL even at small institutions, with no need for sophisticated and expensive cell manipulation procedures. IntroductionSeveral studies have investigated the role of intensified chemotherapy followed by autologous transplantation in the management of relapsed follicle-center lymphoma (FCL). [1][2][3][4][5][6][7] Results were encouraging with high rates of complete remission (CR) and molecular remission. [1][2][3][4][5][6][7][8][9][10] The latest findings from the Dana Farber Cancer Institute show that molecular remission is associated with an extremely low relapse rate and a more than 80% projected freedom from relapse at 12 years. 7 Autologous transplantation may thus possess a curative potential in this otherwise incurable disease. 11,12 Similar approaches have been less frequently used at diagnosis. [13][14][15][16] In fact, a recent retrospective study from Stanford University showed that patients treated with autologous transplantation as first-line treatment have a better outcome compared to those treated with conventional chemotherapy. 16 Three important issues, however, still need to be addressed in evaluation of the real role of intensified approaches in FCL. First, there have been no multicenter prospective trials. A single-center trial carries the risk of overestimation of outcomes due to selection biases, and only highly qualified clinical teams may be able to achieve similar results with high-dose programs. Second, most autografting programs require ex vivo purging procedu...

Commercial LightCycler®-based quantitative real-time PCR compared to nested PCR for monitoring of Bcl-2/IgH rearrangement in patients with follicular lymphoma

“…If it would be possible to predict disease control after first-line therapy, these therapies could be selected for patients with a high likelihood of early relapse. With qualitative PCR, several studies were able to document a relationship between molecular response and time to relapse in patients treated with standard-dose chemotherapy [4,5,26], with high-dose chemotherapy [7,[27][28][29][30] and with rituximab-containing regimen [8,31,32]. Due to the low number of patients and the limited follow-up time of 6 months, we can only speculate on the role of molecular diagnostics for the prediction of relapsed disease.…”

Rituximab purging and maintenance combined with auto-SCT: long-term molecular remissions and prolonged hypogammaglobulinemia in relapsed follicular lymphoma

“…50 susceptibility to infections, although most studies of rituximab (including our own) have not reported an increased incidence of opportunistic infections, 30,46,47 with the exception of some reports of increased cytomegalovirus and herpes zoster. 51,52 Hypogammaglobulinemia may be expected to be even more profound in contemporary patient cohorts who have received rituximab combination or maintenance as part of both their initial and relapse therapies. Both graft contamination and resistance to high-dose therapy likely contribute to FL relapse after HDT/auto-SCT.…”

“…Thus, our results add to the growing body of literature, which suggests that molecular remission is an important predictor of long-term prognosis in FL. 32,33,51,59 We administered a single dose of rituximab to patients before stem cell collection as an in vivo purge. Belhadj et al 28 and Arcaini et al 29 used a similar strategy and achieved PCR-negative stem cell collections in 9 of 11, and 9 of 9 patients, respectively.…”

Vacuna idiotípica en el tratamiento del linfoma folicular: situación actual y perspectivas futuras

“…Por ello, se está realizando un gran esfuerzo con el fin de desarrollar técnicas lo suficientemente sensibles como para detectar la presencia de estas células que dan lugar a la denominada enfermedad mínima residual (EMR) 12 . La presencia de la translocación t (14;18) no posee valor pronóstico por sí misma pero hay estudios que han demostrado que la localización del reordenamiento bcl-2-JH puede correlacionarse con el desarrollo de la enfermedad 13,14 . Estos reordenamientos pueden ser analizados mediante técnicas de biología molecular, como la reacción en cadena de la polimerasa (PCR), para el diagnóstico de la EMR.…”