Rate of primary refractory disease in B and T-cell non-Hodgkin's lymphoma: correlation with long-term survival

Abstract

Background: 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.

Methods: 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.

Results: 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).

Conclusion: 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.

Figure 1. Raw Incidence of Primary Responsive vs Primary Refractory Patients Among Main B-Cell Lymphoma Subtypes, According to Rituximab Administration.

Blue = responsive, red = fully refractory, brown = early progression, grey = early death. No Rituximab = Chemotherapy without Rituximab; Rituximab = chemotherapy supplemented with Rituximab. DLB-CL: Diffuse Large B-Cell Lymphoma; FL: Follicular Lymphoma; MCL: Mantle-Cell Lymphoma; Miscellaneous B-cell NHL: marginal-zone, small lymphocytic, Burkitt’s and lymphoblastic lymphoma. Data on Rituximab administration were lacking on 21 out of 2,858 B-cell lymphoma patients. p values were calculated for responsive/refractory ratio in No Rituximab compared to Rituximab.

Figure 2. Overall Survival of 3,315 Non-Hodgkin’s Lymphoma (NHL) Patients following first line therapy.

At a median follow-up of 7.3 years., the median survival for the entire cohort was of 12.7 yrs. (range: 0–32.6yrs).

Figure 3. Overall Survival in Non-Hodgkin’s Lymphoma (NHL) Patients according to response to primary therapy.

A. Overall survival (OS) of 3,106 NHL patients diagnosed and managed during the period 1982–2012. The OS projections are of 82.8%, 69.5%, and 59.2%, for responsive patients, 31.5%, 21.6%, and 15.7% for early progression, 18.9%, 15.2%, and 14.2% for fully refractory patients, at 5, 10, and 15 years, respectively (responsive vs. refractory: p<0.001). Median follow-up for the whole series is 7.5 yrs (range, 0.6–31.2). B. OS of 1,231 NHL patients diagnosed and managed up to 1,999. The OS projections are of 81.4%, 68.1%, and 57.6%, for responsive patients, 26.7%, 17.7%, and 12.4% for early progression, 17.6%, 14.8%, and 13.8% for fully refractory patients, at 5, 10, and 15 years, respectively (responsive vs. refractory: p<0.001). Median follow-up for the whole series is 16 yrs (range, 0.6–31.2) C. OS of 1,875 NHL patients diagnosed and managed since 2,000. The OS projections are of 83.8% and 70.7%, for responsive patients, 39.1% and 28.4%, for early progression, 20.4% and 14.9%, for fully refractory patients, at 5 and 10 years, respectively (responsive vs. refractory: p<0.001). Median follow-up for the whole series is 5.1 yrs (range, 0.6–13.7).

Figure 4. OS in responsive lymphoma, according to T-cell vs. B-cell subtype.

The OS projections are of 78.9%, 62.5%, and 55.2%, for T-cell lymphoma patients (median follow up: 10.1 yrs, range, 0.9–26.7), and 83.1%, 69.9%, and 59.5%, for B-cell lymphoma patients (median follow up: 7.5 yrs, range, 0.6–31.2), at 5, 10, and 15 years, respectively (p = 0.326).

Figure 5. OS in Low-grade and Intermediate/High-grade NHL subtypes according to response to primary therapy.

A. OS of 842 Intermediate/High-grade NHL patients diagnosed and managed up to 1,999. The OS projections are of 78.9%, 65.6%, and 57.2%, for responsive patients, 18.5%, 13.2%, and 9.7% for early progression, 12.3%, 11.4%, and 10.4% for fully refractory patients, at 5, 10, and 15 years, respectively. Median follow-up for the whole series is 15.9 yrs (range, 0.6–28.9) B. OS of 1,301 Intermediate/High-grade NHL patients diagnosed and managed since 2,000. The OS projections are of 81.6% and 71.1%, for responsive patients, 30.7% and 25.2% for early progression, 14.3% and 14.3% for fully refractory patients, at 5 and 10 years, respectively. Median follow-up for the whole series is 5.0 yrs (range, 0.6–13.7) C. OS of 388 Low-grade NHL patients diagnosed and managed up to 1,999. The OS projections are of 78.0%, 64.0%, and 51.8%, for responsive patients, 51.1%, 31.1%, and 20.8% for early progression, 36.7%, 26.7%, and 26.7% for fully refractory patients, at 5, 10, and 15 years, respectively. Median follow-up for the whole series is 16.3 yrs (range, 1.7–31.2) D. OS of 574 Low-grade NHL patients diagnosed and managed since 2,000. The OS projections are of 83.5% and 64.2%, for responsive patients, 60.7% and 36.8% for early progression, 48.4% and 13.2% for fully refractory patients, at 5 and 10 years, respectively. Median follow-up for the whole series is 5.1 yrs (range, 0.5–13.7). (responsive vs. refractory: p<0.001, in all series).