Identification of potential surrogate end points in randomized clinical trials of aggressive and indolent non-Hodgkin's lymphoma: correlation of complete response, time-to-event and overall survival end points

PURPOSE: To evaluate a chemotherapy regimen that consisted of ifosfamide administered as an infusion with bolus carboplatin, and etoposide (ICE) supported by granuloctye colony-stimulating factor (G-CSF) for cytoreduction and stem-cell mobilization in transplant-eligible patients with primary refractory or relapsed non-Hodgkin's lymphoma (NHL).PATIENTS AND METHODS: One hundred sixty-three transplant-eligible patients with relapsed or primary refractory NHL were treated from October 1993 to December 1997 with ICE chemotherapy at Memorial Sloan-Kettering Cancer Center. Administration of three cycles of ICE chemotherapy was planned at 2-week intervals. Peripheral-blood progenitor cells were collected after cycle 3, and all patients who achieved a partial response (PR) or complete response (CR) to ICE chemotherapy were eligible to proceed to transplantation. Event-free and overall survival, ICE-related toxicity, and the number of CD34+cells collected after treatment with ICE and G-CSF were evaluated.RESULTS: All 163 patients were assessable for response, and there was no treatment-related mortality. A major response (CR/PR) was evident in 108 patients (66.3%); 89% of the responding patients underwent successful transplantation. Patient who underwent transplantation and achieved a CR to ICE had a superior overall survival to that of patients who achieved a PR (65% v 30%; P = .003). The median number of CD34+cells/kg collected was 8.4 × 106. The dose-limiting toxicity of ICE was hematologic, with 29.4% of patients developing grade 3/4 thrombocytopenia. There were minimal nonhematologic side effects.CONCLUSION: ICE chemotherapy, with ifosfamide administered as a 24-hour infusion to decrease CNS side effects, and the substitution of carboplatin for cisplatin to minimize nephrotoxicity, is a very effective cytoreduction and mobilization regimen in patients with NHL. Furthermore, the quality of the clinical response to ICE predicts for posttransplant outcome.

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Histologic conversion in the non-Hodgkin's lymphomas.

Journal of Clinical Oncology ◽

10.1200/jco.1983.1.1.11 ◽

1983 ◽

Vol 1 (1) ◽

pp. 11-16 ◽

Cited By ~ 145

Author(s):

B Acker ◽

R T Hoppe ◽

T V Colby ◽

R S Cox ◽

H S Kaplan ◽

...

Keyword(s):

Hodgkin’S Lymphoma ◽

Randomized Clinical Trials ◽

Complete Response ◽

Hodgkin's Lymphoma ◽

Whole Body ◽

Actuarial Survival ◽

Non Hodgkin’S Lymphoma ◽

Non Hodgkin's Lymphoma ◽

Actuarial Risk ◽

Hodgkin's Lymphomas

Between July 1, 1971 and December 31, 1978, 150 patients with favorable subtypes of non-Hodgkin's lymphoma [nodular poorly differentiated lymphocytic (NLPD), nodular mixed, or diffuse well differentiated lymphocytic] were entered into prospective randomized clinical trials at Stanford University. Treatments included involved field, total lymphoid, or whole body irradiation, single alkylating agent chemotherapy, combination chemotherapy with cyclophosphamide, vincristine and prednisone (CVP) or with cyclophosphamide, vincristine, procarbazine, and prednisone (C-MOPP), or various combinations of chemotherapy and irradiation. The initial complete response rate (CR) was 79%. Among patients who achieved a CR, 31% later relapsed. There were 78 patients who either failed to achieve a CR or achieved a CR and later relapsed. Histologic conversion (change from initially favorable to an unfavorable subtype of non-Hodgkin's lymphoma) was documented in 22/78 patients (28%). However, the actuarial risk for conversion was actually much greater (60% at 8 yr). The median time to documentation of conversion was 51 mo. The most common type of histologic conversion was from NLPD to diffuse histiocytic lymphoma. Documented histologic conversion was often associated with a more aggressive clinical behavior of the lymphoma, and the median survival after conversion was less than 1 yr. However, those patients who achieved a CR after conversion had a more favorable outcome (actuarial survival 75% at 5 yr). No specific risk factors predictive of histologic conversion could be identified.

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CHOP Compared With CHOP Plus Granulocyte Colony-Stimulating Factor in Elderly Patients With Aggressive Non-Hodgkin’s Lymphoma

Journal of Clinical Oncology ◽

10.1200/jco.2003.01.076 ◽

2003 ◽

Vol 21 (16) ◽

pp. 3041-3050 ◽

Cited By ~ 124

Author(s):

J.K. Doorduijn ◽

B. van der Holt ◽

G.W. van Imhoff ◽

K.G. van der Hem ◽

M.H.H. Kramer ◽

...

Keyword(s):

Overall Survival ◽

Elderly Patients ◽

Hodgkin’S Lymphoma ◽

Complete Response ◽

Hodgkin's Lymphoma ◽

Granulocyte Colony Stimulating Factor ◽

Colony Stimulating Factor ◽

Non Hodgkin’S Lymphoma ◽

Non Hodgkin's Lymphoma ◽

Stimulating Factor

Purpose: To investigate whether the relative dose-intensity of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy could be improved by prophylactic administration of granulocyte colony-stimulating factor (G-CSF) in elderly patients with aggressive non-Hodgkin’s lymphoma (NHL). Patients and Methods: Patients aged 65 to 90 years (median, 72 years) with stage II to IV aggressive NHL were randomly assigned to receive standard CHOP every 3 weeks or CHOP plus G-CSF every 3 weeks on days 2 to 11 of each cycle. Results: In 389 eligible patients, the relative dose intensities (RDIs) of cyclophosphamide (median, 96.3% v 93.9%; P = .01) and doxorubicin (median, 95.4% v 93.3%; P = .04) were higher in patients treated with CHOP plus G-CSF. The complete response rates were 55% and 52% for CHOP and CHOP plus G-CSF, respectively (P = .63). The actuarial overall survival at 5 years was 22% with CHOP alone, compared with 24% with CHOP plus G-CSF (P = .76), with a median follow-up of 33 months. Patients treated with CHOP plus G-CSF had an identical incidence of infections, with World Health Organization grade 3 to 4 (34 of 1,191 cycles v 36 of 1,195 cycles). Only the cumulative days with antibiotics were fewer with CHOP plus G-CSF (median, 0 v 6 days; P = .006) than with CHOP alone. The number of hospital admissions and the number of days in hospital were not different. Conclusion: In elderly patients, G-CSF improved the RDI of CHOP, but this did not lead to a higher complete response rate or better overall survival. G-CSF did not prevent serious infections.

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Prognostic significance of bcl-2 protein expression in aggressive non- Hodgkin's lymphoma. Groupe d'Etude des Lymphomes de l'Adulte (GELA)

Blood ◽

10.1182/blood.v87.1.265.265 ◽

1996 ◽

Vol 87 (1) ◽

pp. 265-272 ◽

Cited By ~ 332

Author(s):

O Hermine ◽

C Haioun ◽

E Lepage ◽

MF d'Agay ◽

J Briere ◽

...

Keyword(s):

Overall Survival ◽

Protein Expression ◽

B Cell ◽

Hodgkin’S Lymphoma ◽

Prognostic Significance ◽

Hodgkin's Lymphoma ◽

Independent Effect ◽

Non Hodgkin’S Lymphoma ◽

Non Hodgkin's Lymphoma ◽

Large B Cell

Abstract Little is known about the expression of bcl-2 protein in intermediate and high grade non-Hodgkin's lymphoma (NHL) and its clinical and prognostic significance. We performed immunohistochemical analysis of bcl-2 expression in tumoral tissue sections of 348 patients with high or intermediate grade NHL. These patients were uniformly treated with adriamycin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP) in the induction phase of the LNH87 protocol. Fifty eight cases were excluded due to inadequate staining. Of the 290 remaining patients, 131 (45%) disclosed homogeneous positivity (high bcl-2 expression) in virtually all tumor cells, whereas 65 (23%) were negative and 94 (32%) exhibited intermediate staining. High bcl-2 expression was more frequent in B-cell NHL (109 of 214, 51%) than in T- cell NHL (6 of 35, 17%) (P = .0004), and was heterogeneously distributed among the different histological subtypes. Further analysis was performed on the 151 patients with diffuse large B-cell lymphoma (centroblastic and immunoblastic) to assess the clinical significance and potential prognostic value of bcl-2 expression in the most frequent and homogeneous immunohistological subgroup. High bcl-2 expression, found in 44% of these patients (67 of 151), was more frequently associated with III-IV stage disease (P = .002). Reduced disease-free survival (DFS) (P < .01) and overall survival (P < .05) were demonstrated in the patients with high bcl-2 expression. Indeed, the 3-year estimates of DFS and overall survival were 60% and 61%, respectively (high bcl-2 expression) versus 82% and 78%, respectively (negative/intermediate bcl-2 expression). A multivariate regression analysis confirmed the independent effect of bcl-2 protein expression on DFS. Thus bcl-2 protein expression, as demonstrated in routinely paraffin-embedded tissue, appears to be predictive of poor DFS, in agreement with the role of bcl-2 in chemotherapy-induced apoptosis. It might be considered as a new independent biologic prognostic parameter, which, especially in diffuse large B-cell NHL, could aid in the identification of patient risk groups.

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Relationship between response rates and median progression-free survival in non-Hodgkin's lymphoma: A meta-analysis of published clinical trials

Hematological Oncology ◽

10.1002/hon.2463 ◽

2017 ◽

Vol 36 (1) ◽

pp. 37-43 ◽

Cited By ~ 6

Author(s):

Naveen Mangal ◽

Ahmed Hamed Salem ◽

Mengyao Li ◽

Rajeev Menon ◽

Kevin J. Freise

Keyword(s):

Clinical Trials ◽

Hodgkin’S Lymphoma ◽

Meta Analysis ◽

Progression Free Survival ◽

Response Rates ◽

Hodgkin's Lymphoma ◽

Free Survival ◽

Median Progression Free Survival ◽

Non Hodgkin’S Lymphoma ◽

Non Hodgkin's Lymphoma

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Prognostic significance of bcl-2 protein expression in aggressive non- Hodgkin's lymphoma. Groupe d'Etude des Lymphomes de l'Adulte (GELA)

Blood ◽

10.1182/blood.v87.1.265.bloodjournal871265 ◽

1996 ◽

Vol 87 (1) ◽

pp. 265-272 ◽

Cited By ~ 7

Author(s):

O Hermine ◽

C Haioun ◽

E Lepage ◽

MF d'Agay ◽

J Briere ◽

...

Keyword(s):

Overall Survival ◽

Protein Expression ◽

B Cell ◽

Hodgkin’S Lymphoma ◽

Prognostic Significance ◽

Hodgkin's Lymphoma ◽

Independent Effect ◽

Non Hodgkin’S Lymphoma ◽

Non Hodgkin's Lymphoma ◽

Large B Cell

Little is known about the expression of bcl-2 protein in intermediate and high grade non-Hodgkin's lymphoma (NHL) and its clinical and prognostic significance. We performed immunohistochemical analysis of bcl-2 expression in tumoral tissue sections of 348 patients with high or intermediate grade NHL. These patients were uniformly treated with adriamycin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP) in the induction phase of the LNH87 protocol. Fifty eight cases were excluded due to inadequate staining. Of the 290 remaining patients, 131 (45%) disclosed homogeneous positivity (high bcl-2 expression) in virtually all tumor cells, whereas 65 (23%) were negative and 94 (32%) exhibited intermediate staining. High bcl-2 expression was more frequent in B-cell NHL (109 of 214, 51%) than in T- cell NHL (6 of 35, 17%) (P = .0004), and was heterogeneously distributed among the different histological subtypes. Further analysis was performed on the 151 patients with diffuse large B-cell lymphoma (centroblastic and immunoblastic) to assess the clinical significance and potential prognostic value of bcl-2 expression in the most frequent and homogeneous immunohistological subgroup. High bcl-2 expression, found in 44% of these patients (67 of 151), was more frequently associated with III-IV stage disease (P = .002). Reduced disease-free survival (DFS) (P < .01) and overall survival (P < .05) were demonstrated in the patients with high bcl-2 expression. Indeed, the 3-year estimates of DFS and overall survival were 60% and 61%, respectively (high bcl-2 expression) versus 82% and 78%, respectively (negative/intermediate bcl-2 expression). A multivariate regression analysis confirmed the independent effect of bcl-2 protein expression on DFS. Thus bcl-2 protein expression, as demonstrated in routinely paraffin-embedded tissue, appears to be predictive of poor DFS, in agreement with the role of bcl-2 in chemotherapy-induced apoptosis. It might be considered as a new independent biologic prognostic parameter, which, especially in diffuse large B-cell NHL, could aid in the identification of patient risk groups.

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A phase III, multicentric, open-label, two-arm, parallel group, active-control, randomized, comparative clinical study to evaluate efficacy and safety of RituxiRel™ arm (rituximab) with reference arm (rituximab) in patients with non-Hodgkin's lymphoma

Asian Journal of Oncology ◽

10.4103/asjo.asjo_29_16 ◽

2017 ◽

Vol 03 (01) ◽

pp. 017-022 ◽

Cited By ~ 1

Author(s):

Prasad Apsangikar ◽

Sunil Chaudhry ◽

Manoj Naik ◽

Parvez Kozgi

Keyword(s):

Partial Response ◽

B Cell ◽

Hodgkin’S Lymphoma ◽

Lymphatic System ◽

Complete Response ◽

Safety Analysis ◽

Hodgkin's Lymphoma ◽

Efficacy And Safety ◽

Non Hodgkin’S Lymphoma ◽

Non Hodgkin's Lymphoma

Abstract Introduction: Non-Hodgkin's lymphoma (NHL) is the sixth most common hematological malignancy in adults, with B-cell lymphomas accounting for 85% of all NHLs. Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of NHL and follicular lymphoma (FL) is the second most common form of B-cell NHL. Materials and Methods: The primary objective of this study is to assess the efficacy of Rituxirel™ arm with reference arm, whereas the secondary objective is to evaluate safety of Rituxirel™ arm with the reference arm in patients diagnosed with NHL. Results: The first patient was enrolled on April 30, 2012 and the efficacy and safety analysis was performed at 24 weeks. The objective response rate (ORR) was observed to be 87.87% in Rituxirel™ arm. 45.45% patients showed complete response and 42.42% patients showed partial response in Rituxirel™ arm. The ORR was observed to be 86.66% in the reference arm. 33.33% patients showed complete response and 53.33% patients showed partial response in reference arm in the Rituxirel™ arm, the most commonly reported treatment-emergent adverse events (TEAEs) related to blood and lymphatic system disorders were 52.94%, whereas in the reference arm, the reported TEAEs related to blood and lymphatic system disorders were 70%. Conclusion: Based on the results from the efficacy and safety analysis at week 24, Rituxirel™ arm was found to be as effective and safe as the reference arm. Rituxirel™ arm can be a prudent option to the reference arm, in patients undergoing treatment for DLBCL or FL.

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Evaluation of Continuous Tumor-Size–Based End Points as Surrogates for Overall Survival in Randomized Clinical Trials in Metastatic Colorectal Cancer

JAMA Network Open ◽

10.1001/jamanetworkopen.2019.11750 ◽

2019 ◽

Vol 2 (9) ◽

pp. e1911750

Author(s):

Tomasz Burzykowski ◽

Elisabeth Coart ◽

Everardo D. Saad ◽

Qian Shi ◽

Dirkje W. Sommeijer ◽

...

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Clinical Trials ◽

Metastatic Colorectal Cancer ◽

Tumor Size ◽

Randomized Clinical Trials ◽

End Points

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CEPP(B): an effective and well-tolerated regimen in poor-risk, aggressive non-Hodgkin's lymphoma

Blood ◽

10.1182/blood.v76.7.1293.1293 ◽

1990 ◽

Vol 76 (7) ◽

pp. 1293-1298 ◽

Cited By ~ 41

Author(s):

NJ Chao ◽

SA Rosenberg ◽

SJ Horning

Keyword(s):

Hodgkin’S Lymphoma ◽

Medical Center ◽

Palliative Therapy ◽

Complete Response ◽

Hodgkin's Lymphoma ◽

First Line ◽

First Line Therapy ◽

Line Therapy ◽

Non Hodgkin’S Lymphoma ◽

Non Hodgkin's Lymphoma

Abstract Eighty-three patients with intermediate- or high-grade non-Hodgkin's lymphoma were treated with CEPP(B) (cyclophosphamide, etoposide [VP- 16], procarbazine, and prednisone with or without bleomycin) chemotherapy at Stanford University Medical Center (Stanford, CA) from January 1982 through June 1989. Sixty-nine received CEPP(B) as second- line or subsequent therapy after relapse from previous combination chemotherapy, and 14 patients received CEPP(B) as first-line therapy. Of 75 patients evaluable for response, 30 patients (40%) achieved a complete response (CR) and 24 patients (32%) achieved a partial response (PR), providing an overall response rate of 72%. Complete responses were recorded on 21 of 61 (34%) patients with recurrent disease and 9 of the 14 patients who received CEPP(B) as first line therapy (64%). Myelosuppression was the major side effect of treatment, resulting in eight neutropenic-febrile episodes from a total of 253 courses. A single fatal toxic event occurred on a patient who developed adult respiratory distress syndrome. Overall, CEPP(B) was well- tolerated and proved to be effective palliative therapy for patients with non-Hodgkin's lymphoma after relapse. As such, CEPP(B) may be considered for cytoreduction before ablative therapy and bone marrow transplantation. CEPP(B) may also be considered for initial therapy in selected patients who cannot tolerate doxorubicin-containing regimens.

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Multicenter Phase II Clinical Study of Iodine-131–Rituximab Radioimmunotherapy in Relapsed or Refractory Indolent Non-Hodgkin’s Lymphoma

Journal of Clinical Oncology ◽

10.1200/jco.2005.05.3470 ◽

2006 ◽

Vol 24 (27) ◽

pp. 4418-4425 ◽

Cited By ~ 53

Author(s):

Michael F. Leahy ◽

John F. Seymour ◽

Rodney J. Hicks ◽

J. Harvey Turner

Keyword(s):

Hodgkin’S Lymphoma ◽

Progression Free Survival ◽

Complete Response ◽

Hodgkin's Lymphoma ◽

Whole Body ◽

Actuarial Survival ◽

Entire Cohort ◽

Non Hodgkin’S Lymphoma ◽

Non Hodgkin's Lymphoma ◽

Iodine 131

Purpose To evaluate efficacy and safety of iodine-131 (131I) –rituximab chimeric anti-CD20 antibody radioimmunotherapy in patients with relapsed or refractory indolent non-Hodgkin's lymphoma (NHL). Patients and Methods After a standard loading dose of rituximab 375 mg/m2, individualized dosimetry was performed by whole-body gamma imaging of a tracer activity of 131I-rituximab followed by administration of a therapeutic activity of 131I-rituximab to deliver an estimated whole-body radiation absorbed dose of 0.75 Gy. Results Ninety-one patients were entered onto the trial: 78 patients (86%) had follicular lymphoma, six patients (7%) had mucosa-associated lymphoid tissue/marginal zone lymphoma, and seven patients (8%) had small lymphocytic lymphoma. The objective overall response rate (ORR) was 76%, with 53% attaining a complete response (CR) or CR unconfirmed (CRu). Median duration of response for patients achieving CR/CRu was 20 v 7 months for those with a partial response (P = .0121). Median progression-free survival for the entire cohort was 13 months, with 14% remaining relapse free beyond 4 years. Median follow-up was 23 months, with a 4-year actuarial survival rate of 59% ± 10%. Toxicity was principally hematologic; grade 4 thrombocytopenia occurred in 4% and neutropenia occurred in 16% of patients, with nadirs at 6 to 7 weeks after treatment. Conclusion 131I-rituximab radioimmunotherapy of relapsed or refractory indolent NHL achieves high ORR and CR rates with minimal toxicity.

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