1: Mangel J, Duncan A, Lachance S

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Auayporn Nademanee, Arturo Molina, Margaret R. O'Donnell, Andrew Dagis, David S. Snyder, Pablo Parker, Anthony Stein, Eileen Smith, Ina Planás, Ashwin Kashyap, Ricardo Spielberger, Henry Fung, K.K. Wong, George Somlo, Kim Margolin, Warren Chow, Irena Sniecinski, Nayana Vora, Karl G. Blume, Joyce Niland, and Stephen J. Forman

Results of High-Dose Therapy and Autologous Bone Marrow/Stem Cell Transplantation During Remission in Poor-Risk Intermediate- and High-Grade Lymphoma: International Index High and High-Intermediate Risk Group

Blood 90: 3844-3852.

Paul A Hamlin, Andrew D Zelenetz, Tarun Kewalramani, Jing Qin, Jaya M Satagopan, David Verbel, Ariela Noy, Carol S Portlock, David J Straus, Joachim Yahalom, Stephen D Nimer, and Craig H Moskowitz

The age-adjusted international prognostic index predicts autologous stem cell transplant (ASCT) outcome for patients with relapsed or primary refractory diffuse large B-cell lymphoma

Blood First Edition Paper, prepublished online April 3, 2003; DOI 10.1182/blood-2002-12-3837

Nicolas Mounier, Corinne Haioun, Bernard F. Cole, Christian Gisselbrecht, Catherine Sebban, Pierre Morel, Gerald Marit, Reda Bouabdallah, Christophe Ravoet, Gilles Salles, Felix Reyes, and Eric Lepage

Quality of life-adjusted survival analysis of high-dose therapy with autologous bone marrow transplantation versus sequential chemotherapy for patients with aggressive lymphoma in first complete remission

Blood 95: 3687-3692.

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Abstract 1 of 5 Blood, 1 October 2000, Vol. 96, No. 7, pp. 2399-2404

CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS

High-dose chemoradiotherapy and autologous stem cell transplantation for patients with primary refractory aggressive non-Hodgkin lymphoma: an intention-to-treat analysis

Tarun Kewalramani, Andrew D. Zelenetz, Eric E. Hedrick, Gerard B. Donnelly, Sonia Hunte, Anna C. Priovolos, Jing Qin, Nancy Coady Lyons, Joachim Yahalom, Stephen D. Nimer, and Craig H. Moskowitz

From the Memorial Sloan-Kettering Cancer Center, New York, NY.

High-dose chemoradiotherapy (HDT) with autologous stem cell transplantation (ASCT) is the treatment of choice for patients with relapsed aggressive non-Hodgkin lymphoma (NHL). However, its role in the treatment of patients with primary refractory disease is not well defined. The outcomes of 85 patients with primary refractory aggressive NHL who underwent second-line chemotherapy with ICE with the intent of administering HDT/ASCT to those patients with chemosensitive disease were reviewed. Patients were retrospectively classified as induction partial responders (IPR) if they attained a partial response to doxorubicin-based front-line therapy or as induction failures (IF) if they had less than partial response. Forty-three patients (50.6%) had ICE-chemosensitive disease; there was no difference in the response rate between the IPR and the IF groups. Intention-to-treat analysis revealed that 25% of the patients were alive and 21.9% were event-free at a median follow-up of 35 months. Among 42 patients who underwent transplantation, the 3-year overall and event-free survival rates were 52.5% and 44.2%, respectively, similar to the outcomes for patients with chemosensitive relapsed disease. No differences were observed between the IPR and IF groups, and there were no transplantation-related deaths. More than one extranodal site of disease and a second-line age-adjusted International Prognostic Index of 3 or 4 before ICE chemotherapy were predictive of poor survival. These results suggest that patients with primary refractory aggressive NHL should receive second-line chemotherapy, with the intent of administering HDT/ASCT to those with chemosensitive disease. Newer therapies are needed to improve the outcomes of patients with poor-risk primary refractory disease.

From the Department of Hematology and Bone Marrow Transplantation, City of Hope National Medical Center, Duarte, CA; and the Bone Marrow Transplant Program, Stanford University Medical Center, Stanford, CA

We have conducted a pilot study to investigate the role of high-dose therapy and autologous bone marrow/stem cell transplantation (ASCT) during first complete or partial remission in 52 patients with poor-risk aggressive lymphoma. There were 42 patients with intermediate-grade or immunoblastic lymphoma who were considered to be high (60%) and high-intermediate risk (40%) groups at diagnosis based on the age-adjusted International Prognostic Index (IPI) and 10 patients with high-grade, SNCCL (small non-cleaved cell, Burkitt's, and non-Burkitt's), who at presentation had poor-risk features defined as elevated serum lactate dehydrogenase level, stage IV, and bulky mass 10 cm. The median age was 34 years (range, 16 to 56 years). Thirty-nine were transplanted in first complete remission and 13 in first partial remission after conventional therapy. Conditioning regimens consisted of total body irradiation (TBI) administered as a single fraction 750 cGy in 3 patients and in fractionated doses for a total of 1,200 cGy in 44 patients, in combination with 60 mg/kg etoposide and 100 mg/kg cyclophosphamide. Five patients with prior radiotherapy received 450 mg/m2 carmustine instead of TBI. Stem cell sources were either bone marrow and/or peripheral blood. No in vitro purging was used. All patients engrafted. Two SNCCL patients died of venoocclusive disease at 25 days and acute leukemia at 27 months posttransplantation. There were six relapses at 1.5 to 12.8 months posttransplantation. At a median follow-up of 44 months (range, 1 to 113 months), the estimated 3-year overall survival (OS) and disease-free survival (DFS) for all patients was 84% (95% confidence interval [CI], 70% to 92%) and 82% (95% CI, 68% to 91%), respectively. In the subset of patients with intermediate-grade and immunoblastic lymphoma, the 3-year DFS was 89% (95% CI, 74% to 96%) for all patients, 87% (95% CI, 67% to 96%) for high-risk patients, and 92% (95 CI, 61% to 99%) for high-intermediate risk patients. The 3-year OS and DFS for SNCCL patients were identical at 60% (95% CI, 30% to 84%). These results suggest that high-dose therapy and ASCT during first remission may improve the survival and prognosis of patients with poor-risk intermediate- and high-grade lymphoma. A prospective randomized study comparing high-dose therapy and ASCT with conventional chemotherapy in IPI high-risk patients with aggressive non-Hodgkin's lymphoma should be undertaken.

Blood, Vol. 90 No. 10 (November 15), 1997: pp. 3844-3852

[Full Text of Nademanee et al.] [Reprint (PDF) Version of Nademanee et al.]

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Abstract 3 of 5

Primary Diffuse Large B-Cell Lymphoma of the Mediastinum: Outcome Following High-Dose Chemotherapy and Autologous Hematopoietic Cell Transplantation

Laurie H. Sehn, Joseph H. Antin, Lawrence N. Shulman, Peter Mauch, Anthony Elias, Marshall E. Kadin, and Catherine Wheeler

From the Hematology-Oncology Division, Brigham and Women's Hospital; Hematology-Oncology Division and Department of Pathology, Beth Israel Hospital; Joint Center for Radiation Therapy, Division of Medical Oncology, Dana-Farber Cancer Institute; and Harvard Medical School, Boston, MA.

We performed a retrospective analysis of 35 patients with primary diffuse large B-cell lymphoma of the mediastinum treated with high-dose cyclophosphamide, carmustine, and etoposide (CBV) plus autologous hematopoietic cell transplantation to determine outcome and prognostic features for progression-free survival (PFS). Thirty-five patients with primary diffuse large B-cell lymphoma of the mediastinum in first response (complete remission [CR] or partial remission [PR]) with poor prognostic features, with primarily refractory disease, or with relapsed disease following conventional chemotherapy, were treated with CBV and autologous hematopoietic cell transplantation. PFS and overall survival were assessed by the Kaplan-Meier method. Patient characteristics before transplantation were examined by univariate analysis using the log-rank test and by Cox's proportional hazards regression analysis to determine predictors of PFS. Estimated 5-year PFS varied significantly with patient disease status at transplantation. Patients transplanted in first response had an estimated 5-year PFS rate of 83%, compared with 58% and 27% for primarily refractory and relapsed patients, respectively (P = .02). The strongest predictor of PFS was chemotherapy responsiveness immediately before transplantation. Patients with chemotherapy-responsive disease had a significantly greater PFS rate than patients with chemotherapy-nonresponsive disease (risk ratio, 3.60; 95% confidence interval [CI], 1.14 to 11.4). No other factors were found to be significant on univariate or multivariate analysis. Patients with primary diffuse large B-cell lymphoma of the mediastinum can achieve prolonged PFS following high-dose chemotherapy and autologous hematopoietic cell transplantation. Outcomes are strongly correlated with disease status (first response v refractory v relapsed) at transplantation and chemotherapy responsiveness immediately before transplantation.

Blood, Vol. 91 No. 2 (January 15), 1998: pp. 717-723

[Full Text of Sehn et al.] [Reprint (PDF) Version of Sehn et al.]

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Abstract 4 of 5

Submitted December 19, 2002

Accepted March 20, 2003

The age-adjusted international prognostic index predicts autologous stem cell transplant (ASCT) outcome for patients with relapsed or primary refractory diffuse large B-cell lymphoma

Paul A Hamlin, Andrew D Zelenetz, Tarun Kewalramani, Jing Qin, Jaya M Satagopan, David Verbel, Ariela Noy, Carol S Portlock, David J Straus, Joachim Yahalom, Stephen D Nimer, and Craig H Moskowitz*

Department of Medicine - Lymphoma Service, Memorial Hospital, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; Department of Medicine - Hematology Service, Memorial Hospital, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

Department of Radiation Oncology, Memorial Hospital, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

Department of Biostatistics, Memorial Hospital, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

* Corresponding author; email: .

Second-line chemotherapy followed by high dose therapy (HDT) with autologous stem cell transplantation (ASCT) cures less than half of patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL). Prognostic models capable of predicting outcome are essential. In three sequential clinical trials, conducted from 1/93 to 8/00, we treated 150 patients with relapsed or primary refractory DLBCL with ifosfamide, carboplatin, and etoposide (ICE) chemotherapy followed by HDT/ASCT for patients with chemosensitive disease. We evaluated the age-adjusted international prognostic index at the initiation of second-line therapy (sAAIPI) as a predictor of progression free survival (PFS) and overall survival (OS). At a median followup of 4 years, the PFS and OS are 28% and 34% by intention to treat and 39% and 45% for only those patients with chemosensitive disease. Three risk groups with different PFS and OS were identified by the sAAIPI: low risk (0 factors) 70% and 74%; intermediate risk (1 factor) 39% and 49%; and high risk (2 or 3 factors) 16% and 18% (p<0.001 for both PFS and OS). The sAAIPI also predicts the PFS and OS for patients with ICE chemosensitive disease: low risk 69% and 83%; intermediate risk 46% and 55%; and high risk 25% and 26% (p<0.001 PFS and OS). The sAAIPI predicts outcome for patients with relapsed or primary refractory DLBCL in both intent-to-treat and chemosensitive populations. This powerful prognostic instrument should be used to evaluate new treatment approaches and to compare results of different regimens.

[Reprint (PDF) Version of Hamlin et al.]

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Abstract 5 of 5

Blood, Vol. 95 No. 12 (June 15), 2000: pp. 3687-3692

From the Département d'information hospitalier and Service d'hématologie clinique Hôpital Henri Mondor, AP-HP, Créteil, France; Dartmouth-Hitchcock Medical Center, Lebanon, NH; Institut d'hématologie, Hôpital Saint Louis, AP-HP, Paris, France; Service d'hématologie, Centre Léon Bérard, Lyon, France; Service d'hématologie, Centre Hospitalier du Dr Schaffner, Lens, France; Service d'hématologie, CHU de Bordeaux, Pessac, France; Service d'hématologie, Institut Paoli Calmette, Marseille, France; Service d'hématologie, Centre Jolimont, La Louvière, Belgium; and Service d'hématologie, Centre Hospitalier Lyon Sud, Pierre Bénite, France.

Evaluating high-dose therapy (HDT) with autologous stem cell transplantation (ASCT) in term of both duration and quality of life (QOL) presents major interests for patients with non-Hodgkin lymphoma. The quality-adjusted time without symptom and toxicity (Q-TWiST) methodology was applied to the LNH87-2 trial comparing HDT with ASCT versus sequential chemotherapy in 541 patients in first complete remission (CR). Overall survival (OS) and disease-free survival (DFS) curves were used to estimate duration of 4 health states: acute short-term toxicity (Tox1), secondary toxicity (Tox2), time without symptom and toxicity (TWiST), and relapse (Rel). Areas under survival curves (AUC) were retrospectively weighted according to QOL coefficients. HDT increased, but not significantly, TWiST (+2.4 months in AUC, P = .17) and decreased Rel (3 months, P < .01). Survival estimates did not differ between the 2 treatments (AUC 47.7 months for OS, 39.7 months for DFS). High-risk patients treated by HDT versus chemotherapy had a significant benefit in DFS (AUC 28.8 versus 24.9 months, P < .01) but not in OS (AUC 37.3 versus 36 months, P = .27). Sensitivity analysis, performed by varying QOL coefficients, demonstrated significant quality-adjusted survival gain in high-risk patients treated by HDT. In low-risk patients, a diagram provided an aid to clinical decision-making. This analysis supports the use of HDT in these patients with adverse prognostic factors in the first CR, even after adjusting for QOL using the Q-TWiST method.

[Full Text of Mounier et al.] [Reprint (PDF) Version of Mounier et al.]

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Tarun Kewalramani, Andrew D. Zelenetz, Eric E. Hedrick, Gerard B. Donnelly, Sonia Hunte, Anna C. Priovolos, Jing Qin, Nancy Coady Lyons, Joachim Yahalom, Stephen D. Nimer, and Craig H. Moskowitz

High-dose chemoradiotherapy and autologous stem cell transplantation for patients with primary refractory aggressive non-Hodgkin lymphoma: an intention-to-treat analysis

Blood 96: 2399-2404.