Prognostic factors in follicular lymphoma: new tools to personalize risk

Abstract Follicular lymphoma (FL) is the most common indolent lymphoma, and it has a long median overall survival (OS). However, the recent discovery of clinical and biological prognostic biomarkers in FL is shedding light on FL heterogeneity and the need for a precise and risk-stratified individual approach at diagnosis and relapse. Many FL patients who are asymptomatic with indolent disease can be vulnerable to the toxicity, emotional distress, and financial burden of overtreatment. Yet a subset of FL patients develop chemoresistance to standard chemoimmunotherapy, experience transformation to aggressive lymphoma and rapid progression, and represent the population most in need of novel therapies and curative approaches. Novel biomarkers that incorporate both clinical and genetic determinants of poor risk are being developed with the hope of identifying high-risk patients at diagnosis in order to offer biologically rational targeted therapies.

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Majority of Transformed Lymphomas Have High SUVs on PET Scanning Similar to Diffuse Large B Cell Lymphoma (DLBCL).

Blood ◽

10.1182/blood.v110.11.2614.2614 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2614-2614

Author(s):

Ariela Noy ◽

Matthew Weissler ◽

Heiko Schoder ◽

Mithat Gonen ◽

Henry Yeung

Keyword(s):

Follicular Lymphoma ◽

Fdg Pet ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Lymphocytic Leukemia ◽

Pet Scan ◽

Aggressive Lymphoma ◽

Indolent Lymphoma ◽

Biopsy Site ◽

Pet Scans

Abstract Background: In our previous work, we correlated non-Hodgkins (NHL) histology with intensity of FDG uptake (SUVmax) on positron emission tomography in untreated patients: an SUVmax greater than 10 predicted an aggressive lymphoma with >80% certainty and an SUVmax greater than 13 predicted an aggressive lymphoma with >90% certainty. We sought to evaluate SUVmax in a series of patients with transformed lymphoma. Methods: All PET scans for lymphoma indications at our institution 1999-5/2007 were evaluated. Patients were included if they had biopsy proven transformation. FDG-PET scans were included if they were no more than sixty days prior to or 90 days after biopsy proven transformation. Patients had no therapy for sixty days prior to PET scan unless there was documented progression of disease after the last treatment. Results: Among the indolent diagnoses (n= 44), the following specific histologies were identified: 9 follicular lymphoma grade 1 (FL I), 9 FL grade 2 (FL 2), 7 small lymphocytic lymphoma / chronic lymphocytic leukemia (SLL/CLL), 11 marginal zone lymphoma (MZL) including one of mucosa associated lymphoid tumor (MALT) type, one mycoses fungoides, and one indolent lymphoma otherwise not specified. 5 FL 3 (FL 3), including one specified as grade 3a (FL 3a) were considered indolent if they preceded a diagnosis of DLBCL. Among the aggressive diagnoses (n= 28), the following specific histologies were identified: 37 DLBCL, one follicular lymphoma grade IIIa included as it was preceded by FLI, one large peripheral T-cell lymphoma, and 5 Large cell lymphoma(LCL), not otherwise characterized on account of biopsy size. Standard uptake values (SUV) were measured at the biopsy site when possible (n=38). In 6 patients the biopsy site was completely excised before the PET scan. The SUV of biopsy site ranged from 3-38, with a median of 10 and mean of 15. Among evaluable patients, 17/36 (47%) biopsies had an SUV above 10; and 12/36 (33%), above 13. The SUVmax for a transformed aggressive lymphoma ranged from 3.2–40, with a median of 12 and mean of 15. 27/44 (61%) patients had an SUVmax above 10; and 21/44 (48%), above 13. Conclusions: Similar to patients with de-novo aggressive lymphoma, the majority of patients with transformed lymphomas have high SUVmax for a given pre-treatment staging study. Therefore, transformation to aggressive lymphoma should be suspected in patients with indolent lymphoma found to have high SUVs on FDG PET, and biopsies should be directed to the site of greatest PET avidity whenever feasible.

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Majority of Transformed Lymphomas Have High SUVs on PET Scanning Similar To Diffuse Large B Cell Lymphoma (DLBCL).

Blood ◽

10.1182/blood.v108.11.2402.2402 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2402-2402

Author(s):

Matthew Weissler ◽

Ariela Noy ◽

Heiko Schöder ◽

Mithat Gönen ◽

Henry Yeung

Keyword(s):

Follicular Lymphoma ◽

Fdg Pet ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Lymphocytic Leukemia ◽

Pet Scan ◽

Aggressive Lymphoma ◽

Indolent Lymphoma ◽

Biopsy Site ◽

Pet Scans

Abstract Background: In our previous work, we correlated non-Hodgkin’s (NHL) histology with intensity of FDG uptake (SUVmax) on positron emission tomography in untreated patients: an SUVmax greater than 10 predicted an aggressive lymphoma with >80% certainty and an SUVmax greater than 13 predicted an aggressive lymphoma with >90% certainty. We sought to evaluate SUVmax in a series of patients with transformed lymphoma. Methods: All PET scans for lymphoma indications at our institution 1999–2005 were evaluated. Patients were included if they had biopsy proven transformation. FDG-PET scans were included if they were no more than sixty days prior to or 90 days after biopsy proven transformation. Patients had no therapy for sixty days prior to PET scan unless there was documented progression of disease after the last treatment. Results: Among the indolent diagnoses (n= 28), the following specific histologies were identified: 7 follicular lymphoma grade I (FL I), 5 follicular lymphoma grade II (FL II), 5 small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL), 6 marginal zone lymphoma (MZL) including one of mucosa associated lymphoid tumor (MALT) type, one mycoses fungoides, and one indolent lymphoma otherwise not specified. Three follicular lymphomas grade III (FL III), including one specified as grade IIIa (FL IIIa) were considered indolent if they preceded a diagnosis of DLBCL. Among the aggressive diagnoses (n= 28), the following specific histologies were identified: 22 DLBCL, one follicular lymphoma grade IIIa included as it was preceded by FLI, one large peripheral T-cell lymphoma, and 4 “Large cell lymphoma” (LCL), not otherwise characterized on account of biopsy size. Standard uptake values (SUV) were measured at the biopsy site when possible (n=25). In 3 patients the biopsy site was completely excised before the PET scan. The SUV of biopsy site ranged from 2.9–26.7, with a median of 9 and mean of 11. Excluding the three patients who had an excisional biopsy, 10/25 (40%) biopsies had an SUV above 10; and 8/25 (32%), above 13. The SUVmax for a transformed aggressive lymphoma ranged from 3.2–30.2, with a median of 10.8 and mean of 14. 16/28 (57%) patients had an SUVmax above 10; and 12/28 (43%), above 13. Conclusions: Similar to patients with de-novo aggressive lymphoma, the majority of patients with transformed lymphomas have high SUVmax for a given pre-treatment staging study. Therefore, transformation to aggressive lymphoma should be suspected in patients with indolent lymphoma found to have high SUVs on FDG PET, and biopsies should be directed to the site of greatest PET avidity whenever feasible.

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Follicular Lymphoma With a Burkitt Translocation—Predictor of an Aggressive Clinical Course: A Case Report and Review of the Literature

Archives of Pathology & Laboratory Medicine ◽

10.5858/2004-128-210-flwabt ◽

2004 ◽

Vol 128 (2) ◽

pp. 210-213 ◽

Cited By ~ 2

Author(s):

Peter M. Voorhees ◽

Kathryn A. Carder ◽

Scott V. Smith ◽

Lanier H. Ayscue ◽

Kathleen W. Rao ◽

...

Keyword(s):

Case Report ◽

Follicular Lymphoma ◽

Clinical Course ◽

Lymphoblastic Leukemia ◽

Initial Diagnosis ◽

Indolent Lymphoma ◽

Review Of The Literature ◽

Cell Type ◽

Aberrant Expression ◽

Aggressive Clinical Course

Abstract Follicular lymphoma is an indolent lymphoma characterized by the (14;18) translocation, which leads to aberrant expression of Bcl-2. Translocations involving 8q24 are most commonly associated with Burkitt lymphoma and result in c-Myc overexpression. We report a case of follicular lymphoma of predominant small cleaved-cell type (grade 1) associated with both a t(14;18)(q32;q21) and a t(8;22)(q24;q11). The 8q24 translocation predicted an aggressive clinical course, as the lymphoma transformed into acute lymphoblastic leukemia within a year of initial diagnosis. Routine cytogenetic analysis is recommended at initial diagnosis of follicular lymphoma to better identify abnormalities that may predict prognosis and influence therapy.

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Follicular lymphoma: are we ready for a risk-adapted approach?

Hematology ◽

10.1182/asheducation-2017.1.358 ◽

2017 ◽

Vol 2017 (1) ◽

pp. 358-364 ◽

Cited By ~ 10

Author(s):

Brad S. Kahl

Keyword(s):

High Risk ◽

Follicular Lymphoma ◽

Randomized Clinical Trials ◽

International Prognostic Index ◽

Prognostic Index ◽

Predictive Biomarkers ◽

Western Hemisphere ◽

Ongoing Research ◽

High Risk Patients ◽

Risk Patients

Abstract Follicular lymphoma is the most common indolent non-Hodgkin lymphoma in the Western hemisphere. The natural history of FL appears to have been favorably impacted by the introduction of rituximab after randomized clinical trials demonstrated that the addition of rituximab to standard chemotherapy induction has improved the overall survival. Yet, the disease is biologically and clinically heterogeneous with wide variations in outcomes for individual patients. The ability to accurately risk-stratify patients and then tailor therapy to the individual is an area of ongoing research. Historically, tumor grade, tumor burden, and the FL international prognostic index (version 1 and version 2) have been used to distinguish low-risk from high-risk patients. Biologic factors such as mutations in key genes can identify patients at high risk for poor outcomes to first-line therapy (mutational status of 7 genes [EZH2, ARID1A, MEF2B, EP300, FOX01, CREBBP, and CARD11] with Follicular Lymphoma International Prognostic Index). More recently, the quality of the response to initial therapy, as measured by either PET imaging or by remission duration, has been show to identify individuals at high risk. However, several unmet needs remain, including a better ability to identify high-risk patients at diagnosis, the development of predictive biomarkers for targeted agents, and strategies to reduce the risk of transformation.

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Multiple myeloma: VMCP/VBAP alternating combination chemotherapy is not superior to melphalan and prednisone even in high-risk patients.

Journal of Clinical Oncology ◽

10.1200/jco.1991.9.3.444 ◽

1991 ◽

Vol 9 (3) ◽

pp. 444-448 ◽

Cited By ~ 88

Author(s):

M Boccadoro ◽

F Marmont ◽

M Tribalto ◽

G Avvisati ◽

A Andriani ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Median Overall Survival ◽

Cell Labeling ◽

Induction Treatment ◽

Treatment Groups ◽

Significant Difference ◽

Risk Patients ◽

Beta 2 ◽

Beta 2 Microglobulin

The efficacy of alternating vincristine, melphalan (M), cyclophosphamide, prednisone/vincristine, carmustine, doxorubicin, and prednisone (VMCP/VBAP) polychemotherapy was compared with the M and prednisone (MP) regimen as induction treatment in multiple myeloma (MM). Three hundred four MM patients entered this study between March 1983 and July 1986; the analysis was performed in December 1989. The treatment groups did not show significant differences with respect to major prognostic factors. Median overall survival was 33.8 months. In the VMCP/VBAP and MP arms, after 12 induction chemotherapy cycles, 59.0% and 47.3% (P less than .068) of the patients achieved an M component reduction greater than 50%. No significant difference was observed in the two treatment arms in terms of remission duration (21.3 v 19.6 months, P less than .66) and survival (31.6 v 37.0 months, P less than .28). Patients younger than 65 years did not show any advantage from the alternating polychemotherapy. At diagnosis, the plasma cell labeling index (LI) and serum beta-2 microglobulin (beta 2-m) were evaluated in 173 and 183 patients, respectively. A significantly reduced survival was observed for patients with LI greater than or equal to 2% (16.4 months) or beta 2-m greater than or equal to 6 mg/L (20.4 months). Even in these poor-risk subgroups, VMCP/VBAP was not superior to MP.

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Evaluating upfront high-dose consolidation after R-CHOP for follicular lymphoma by clinical and genetic risk models

Blood Advances ◽

10.1182/bloodadvances.2020002546 ◽

2020 ◽

Vol 4 (18) ◽

pp. 4451-4462

Author(s):

Stefan Alig ◽

Vindi Jurinovic ◽

Mohammad Shahrokh Esfahani ◽

Sarah Haebe ◽

Verena Passerini ◽

...

Keyword(s):

High Risk ◽

Follicular Lymphoma ◽

Statistical Significance ◽

International Prognostic Index ◽

Prognostic Index ◽

Risk Scores ◽

High Dose ◽

Risk Models ◽

Progression Of Disease ◽

Risk Patients

Abstract High-dose therapy and autologous stem cell transplantation (HDT/ASCT) is an effective salvage treatment for eligible patients with follicular lymphoma (FL) and early progression of disease (POD). Since the introduction of rituximab, HDT/ASCT is no longer recommended in first remission. We here explored whether consolidative HDT/ASCT improved survival in defined subgroups of previously untreated patients. We report survival analyses of 431 patients who received frontline rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for advanced FL, and were randomized to receive consolidative HDT/ASCT. We performed targeted genotyping of 157 diagnostic biopsies, and calculated genotype-based risk scores. HDT/ASCT improved failure-free survival (FFS; hazard ratio [HR], 0.8, P = .07; as-treated: HR, 0.7, P = .04), but not overall survival (OS; HR, 1.3, P = .27; as-treated: HR, 1.4, P = .13). High-risk cohorts identified by FL International Prognostic Index (FLIPI), and the clinicogenetic risk models m7-FLIPI and POD within 24 months–prognostic index (POD24-PI) comprised 27%, 18%, and 22% of patients. HDT/ASCT did not significantly prolong FFS in high-risk patients as defined by FLIPI (HR, 0.9; P = .56), m7-FLIPI (HR, 0.9; P = .91), and POD24-PI (HR, 0.8; P = .60). Similarly, OS was not significantly improved. Finally, we used a machine-learning approach to predict benefit from HDT/ASCT by genotypes. Patients predicted to benefit from HDT/ASCT had longer FFS with HDT/ASCT (HR, 0.4; P = .03), but OS did not reach statistical significance. Thus, consolidative HDT/ASCT after frontline R-CHOP did not improve OS in unselected FL patients and subgroups selected by genotype-based risk models.

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MYC rearrangements in histologically progressed follicular lymphomas

Blood ◽

10.1182/blood.v80.3.758.758 ◽

1992 ◽

Vol 80 (3) ◽

pp. 758-767 ◽

Cited By ~ 171

Author(s):

T Yano ◽

ES Jaffe ◽

DL Longo ◽

M Raffeld

Keyword(s):

Follicular Lymphoma ◽

Molecular Organization ◽

Aggressive Lymphoma ◽

Chain Gene ◽

Low Grade ◽

Immunoglobulin Gene ◽

High Grade ◽

Light Chain Gene ◽

Myc Gene ◽

Follicular Lymphomas

Abstract Histologic transformation of low-grade follicular lymphoma to an aggressive-grade lymphoma occurs in 60% to 80% of patients during their clinical course. The events that drive the transformation process are poorly understood. Deregulation of the MYC gene has been implicated in a small number of cases. This observation led us to examine the molecular organization of the MYC oncogene in 38 cases of histologically transformed lymphomas that arose from follicular lymphomas, and in 18 of the initial pretransformation follicular lymphomas. In addition, we examined 58 “control” low-grade follicular lymphomas that had not yet shown evidence of histologic progression. Immunoglobulin heavy chain and light chain gene rearrangements were detected in all biopsies and rearrangements of the BCL-2 locus were seen in 36 of 38 of the transformed lymphomas (consistent with their origin from follicular lymphomas), in 18 of 18 of the pretransformation follicular lymphomas, and in 51 of 58 of the control follicular lymphomas. All 18 pretransformation follicular lymphoma specimens displayed at least one immunoglobulin gene and BCL-2 rearrangement in common with the corresponding histologically progressed lymphoma, indicating a clonal relationship between the original follicular lymphoma and the histologically transformed lymphoma. MYC rearrangements were detected in 3 of 38 (8%) transformed lymphomas and in 1 of 58 (2%) control follicular lymphomas. The latter MYC rearranged follicular lymphoma was clinically aggressive and transformed to a high- grade lymphoma that led to the death of the patient within 20 months. None of the 18 pretransformation follicular lymphomas showed MYC rearrangement, including two from patients who later demonstrated MYC rearrangement in the progressed aggressive lymphoma. PvuII mutational analysis failed to identify additional MYC gene abnormalities in the progressed lymphomas. Because the Epstein-Barr virus (EBV) is associated with a fraction of high-grade lymphomas and is known to upregulate BCL-2, we looked for a potential role for this agent in our progressed lymphomas. We did not detect viral sequences in any case indicating that EBV does not play a major role in progression. The presence of MYC rearrangements in a small fraction of progressed aggressive lymphomas, and not in the corresponding antecedent follicular lymphomas, suggests that acquisition of a MYC rearrangement is in some cases associated with the transformation event.

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High Resolution Screening of Genomic Aberrations in Follicular Lymphoma Using Microarray Based Comparative Genomic Hybridization (MATRIX-CGH).

Blood ◽

10.1182/blood.v104.11.2271.2271 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2271-2271

Author(s):

Carsten Schwaenen ◽

Swen Wessendorf ◽

Andreas Viardot ◽

Sandra Ruf ◽

Martina Enz ◽

...

Keyword(s):

Follicular Lymphoma ◽

Clinical Data ◽

Array Cgh ◽

Screening Method ◽

Comparative Genomic ◽

Rapid Progression ◽

Human Beings ◽

Data Set ◽

Term Survival ◽

Genomic Aberrations

Abstract Follicular Lymphoma (FL), one of the most frequent lymphoma entities in the western world, is characterized by a highly variable clinical course reaching from rapid progression with fatal outcome to cases with long term survival. In a recent study applying chromosomal comparative hybridization (CGH) to FL, in 70% of the cases genomic aberrations were detectable and a loss of genomic material on chromosomal bands 6q25-q27 was the strongest predictor for short overall survival. However, limitations of CGH as a screening method are a restricted genomic resolution to 3–10 Mbp and demanding non-automated evaluation procedures. Thus, high throughput analysis of genomic alterations for risk adapted patient stratification and monitoring within treatment trials should rely on efficient and automated diagnostic techniques. In this study, we used array CGH to a novel generation of DNA Chips containing 2800 genomic DNA probes. Target clones comprised i) contigs mapping to genomic regions of possible pathogenetic relevance in lymphoma (n=610 target clones mapping to e.g. 1p, 2p, 3q, 7q, 9p, 11q, 12q, 13q, 17p, 18q, X); ii) selected oncogenes and tumor suppressor genes (n=686) potentially relevant in hematologic neoplasms; and iii) a large genome-wide cluster of 1502 target DNA clones covering the genome at a distance of app. 2 Mbp (part of the golden path clone set). This chip represents a median genomic resolution of app. 1.5 Mbp. In total, DNAs from 70 FL samples were analyzed and results were compared to data from chromosomal CGH experiments and clinical data sets. The sensitivity of array CGH was considerably higher compared to chromosomal CGH (aberrations in 95% of cases vs 70% of cases). Most frequent aberrations were gain mapping to chromosome arms 2p (21%), 7p (24%), 7q (30%), 12p (17%), 12q (21%), 18p (21%) and 18q (34%) as well as losses mapping to chromosome arms 1p (19%), 6q (23%), 7p (20%), 11q (26%) and 17p (20%). In addition, several genomic aberrations were identified which have not been described before in FL. Currently, these aberrations are characterized in more detail and results will be correlated with the clinical data set. Moreover, three recurrent sites of genomic polymorphisms in human beings affecting chromosomes 5q, 14q and 15q were identified. In conclusion, these data underline the potential of array CGH for the sensitive detection of genomic imbalances in FL.

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Phase 2 study of suberoylanilide hydroxamic acid (SAHA) in relapsed or refractory indolent non-Hodgkin lymphoma: A California Cancer Consortium study

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.18515 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 18515-18515 ◽

Cited By ~ 6

Author(s):

M. Kirschbaum ◽

J. Zain ◽

L. Popplewell ◽

V. Pullarkat ◽

N. Obadike ◽

...

Keyword(s):

Follicular Lymphoma ◽

Hydroxamic Acid ◽

Marginal Zone ◽

Ct Scanning ◽

Complete Response ◽

Marginal Zone Lymphoma ◽

Clinical Activity ◽

Rapid Progression ◽

Non Hodgkin Lymphoma ◽

Mantle Cell

18515 Background: The indolent (follicular, marginal zone and mantle cell) lymphomas tend to recur with decreasing intervals of remission post standard chemotherapy. Vorinostat (SAHA, Zolinza), an orally administered hydroxamic acid histone deacetylase inhibitor with activity against class I and II deactylases, with preclinical and clinical activity against various forms of lymphoma, is being studied in patients with relapsed or refractory indolent lymphoma. Methods: Patients with relapsed or refractory follicular, marginal zone, or mantle cell lymphoma are eligible. Vorinostat is dosed at 200 mg po twice daily for 14 consecutive days on a 21 day cycle. CT scanning and marrow biopsy is performed after every three cycles. Patients may have received up to four prior chemotherapy regimens including Zevalin or Bexxar; previous transplant is allowed. Results: 15 patients (9 female, 6 male) have been enrolled thus far. Median age is 64 (40- 78) years One patient was found to have coexisting DLBCL and was removed from study. Four patients were taken off study due to progression, three stopped due to toxicity (fatigue in a 73 yo woman who had stable to improved marginal zone lymphoma after 10 cycles, fatigue and atrial fibrillation in a 65 yo man after 7 cycles, diarrhea in a 78 year old woman after 2 cycles). Complete Response (CR) in a patient with follicular lymphoma was attained after 9 cycles, this CR persists now for eight months at the time of abstract submission off therapy. A partial response (PR) was seen in a 40 yo man with lymphoma progression despite multiple rounds of therapy, with rapidly expanding masses just prior to starting vorinostat, the largest of which was 16x12.3 cm. This lesion currently measures 7.2x4.6 cm, with disappearance of many other sites; patient continues on vorinostat. Three of the patients with continued stable disease beyond 9 cycles have marginal zone lymphoma, while the two responders (CR or PR) have follicular lymphoma. A patient with PET resolution and decreases in two of the involved sites stopping after 10 cycles due to fatigue, developed rapid progression three months after stopping vorinostat. Conclusions: Vorinostat demonstrates preliminary activity against follicular and marginal zone lymphoma. No significant financial relationships to disclose.

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Maintenance Rituximab After Cyclophosphamide, Vincristine, and Prednisone Prolongs Progression-Free Survival in Advanced Indolent Lymphoma: Results of the Randomized Phase III ECOG1496 Study

Journal of Clinical Oncology ◽

10.1200/jco.2008.17.1561 ◽

2009 ◽

Vol 27 (10) ◽

pp. 1607-1614 ◽

Cited By ~ 202

Author(s):

Howard Hochster ◽

Edie Weller ◽

Randy D. Gascoyne ◽

Thomas M. Habermann ◽

Leo I. Gordon ◽

...

Keyword(s):

Follicular Lymphoma ◽

Residual Disease ◽

International Prognostic Index ◽

Prognostic Index ◽

Progression Free Survival ◽

Tumor Burden ◽

Phase Iii ◽

Indolent Lymphoma ◽

Free Survival ◽

Rank One

Purpose To determine if maintenance rituximab (MR) after standard chemotherapy improves progression-free survival (PFS) in advanced-stage indolent lymphoma. Patients and Methods Patients with stage III-IV indolent lymphoma with responding or stable disease after cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy were stratified by initial tumor burden, residual disease after CVP (minimal or gross), and histology, and randomly assigned to observation (OBS) or MR 375 mg/m2 once per week for 4 weeks every 6 months for 2 years. PFS was the primary end point. Results Three hundred eleven (282 with follicular lymphoma) evaluable patients who received CVP were randomly assigned to OBS (n = 158) or MR (n = 153). Best response improved in 22% MR versus 7% OBS patients (P = .00006). Toxicity was minimal in both study arms. Three-year PFS after random assignment was 68% MR versus 33% OBS (hazard ratio [HR] = 0.4; P = 4.4 × 10−10 [all patients]) and 64% MR v 33% OBS (HR = 0.4; P = 9.2 × 10−8 [patients with follicular lymphoma]). There was an advantage for MR regardless of Follicular Lymphoma International Prognostic Index score, tumor burden, residual disease, or histology. In multivariate analysis of MR patients, minimal disease after CVP was a favorable prognostic factor. OS at 3 years was 92% MR versus 86% OBS (HR = 0.6; log-rank one-sided P = .05) and, among patients with follicular lymphoma, OS was 91% MR versus 86% (HR = 0.6; log-rank one-sided P = .08). A trend favoring MR was observed among patients with high tumor burden (log-rank one-sided P = .03). Conclusion The E1496 study provides the first phase III data in untreated indolent lymphoma that MR after chemotherapy significantly prolongs PFS.

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