Tarella Corrado, Gueli Angela, Delaini Federica, Rossi Andrea, Barbui Anna Maria, Gritti Giuseppe, Boschini Cristina, Caracciolo Daniele, Bruna Riccardo, Ruella Marco, Gottardi Daniela, Passera Roberto, Rambaldi Alessandro
Department of Biotechnology and Life Sciences, University of Torino, Torino, Italy; Hematology and Cell Therapy Division, Mauriziano Hospital, Torino, Italy.
Hematology and Bone Marrow Transplant Units, A. O. Papa Giovanni XXIII, Bergamo, Italy.
PLoS One. 2014 Sep 25;9(9):e106745. doi: 10.1371/journal.pone.0106745. eCollection 2014.
Primary refractory disease is a main challenge in the management of non-Hodgkin's Lymphoma (NHL). This survey was performed to define the rate of refractory disease to first-line therapy in B and T-cell NHL subtypes and the long-term survival of primary refractory compared to primary responsive patients.
Medical records were reviewed of 3,106 patients who had undergone primary treatment for NHL between 1982 and 2012, at the Hematology Centers of Torino and Bergamo, Italy. Primary treatment included CHOP or CHOP-like regimens (63.2%), intensive therapy with autograft (16.9%), or other therapies (19.9%). Among B-cell NHL, 1,356 (47.8%) received first-line chemotherapy with rituximab. Refractory disease was defined as stable/progressive disease, or transient response with disease progression within six months.
Overall, 690 (22.2%) patients showed primary refractory disease, with a higher incidence amongst T-cell compared to B-cell NHL (41.9% vs. 20.5%, respectively, p<0.001). Several other clinico-pathological factors at presentation were variably associated with refractory disease, including histological aggressive disease, unfavorable clinical presentation, Bone Marrow involvement, low lymphocyte/monocyte ration and male gender. Amongst B-cell NHL, the addition of rituximab was associated with a marked reduction of refractory disease (13.6% vs. 26.7% for non-supplemented chemotherapy, p<0.001). Overall, primary responsive patients had a median survival of 19.8 years, compared to 1.3 yr. for refractory patients. A prolonged survival was consistently observed in all primary responsive patients regardless of the histology. The long life expectancy of primary responsive patients was documented in both series managed before and after 2.000. Response to first line therapy resulted by far the most predictive factor for long-term outcome (HR for primary refractory disease: 16.52, p<0.001).
Chemosensitivity to primary treatment is crucial for the long-term survival in NHL. This supports the necessity of studies aimed to early identify refractory disease and to develop different treatment strategies for responsive and refractory patients.
原发性难治性疾病是非霍奇金淋巴瘤（NHL）治疗中的主要挑战。本调查旨在确定B细胞和T细胞NHL亚型中一线治疗难治性疾病的发生率，以及原发性难治性患者与原发性反应性患者的长期生存率。
回顾了1982年至2012年间在意大利都灵和贝加莫血液学中心接受NHL原发性治疗的3106例患者的病历。原发性治疗包括CHOP或类似CHOP方案（63.2%）、自体移植强化治疗（16.9%）或其他治疗（19.9%）。在B细胞NHL中，1356例（47.8%）接受了含利妥昔单抗的一线化疗。难治性疾病定义为病情稳定/进展，或在6个月内出现疾病进展的短暂反应。
总体而言，690例（22.2%）患者表现为原发性难治性疾病，T细胞NHL的发生率高于B细胞NHL（分别为41.9%和20.5%，p<0.001）。其他几个初诊时的临床病理因素与难治性疾病存在不同程度的关联，包括组织学侵袭性疾病、不良临床表现、骨髓受累、低淋巴细胞/单核细胞比值和男性。在B细胞NHL中，添加利妥昔单抗与难治性疾病的显著减少相关（未添加化疗的患者为26.7%，添加后为13.6%，p<0.001）。总体而言，原发性反应性患者的中位生存期为19.8年，而难治性患者为1.3年。无论组织学类型如何，所有原发性反应性患者均观察到生存期延长。在2000年之前和之后管理的两个系列中均记录了原发性反应性患者的长预期寿命。对一线治疗的反应是迄今为止长期预后最具预测性的因素（原发性难治性疾病的风险比：16.52，p<0.001）。
对原发性治疗的化疗敏感性对NHL的长期生存至关重要。这支持了旨在早期识别难治性疾病并为反应性和难治性患者制定不同治疗策略的研究的必要性。
