Pierre Soubeyran

Phase III Trial of Consolidation Therapy With Yttrium-90–Ibritumomab Tiuxetan Compared With No Additional Therapy After First Remission in Advanced Follicular Lymphoma

PURPOSE We conducted an international, randomized, phase III trial to evaluate the efficacy and safety of consolidation with yttrium-90 ((90)Y)-ibritumomab tiuxetan in patients with advanced-stage follicular lymphoma in first remission. PATIENTS AND METHODS Patients with CD20(+) stage III or IV follicular lymphoma, who achieved a complete response (CR)/unconfirmed CR (CRu) or partial response (PR) after first-line induction treatment, were randomly assigned to receive (90)Y-ibritumomab tiuxetan (rituximab 250 mg/m(2) on day -7 and day 0 followed on day 0 by (90)Y-ibritumomab tiuxetan 14.8 MBq/kg; maximum of 1,184 MBq) or no further treatment (control). The primary end point was progression-free survival (PFS), which was calculated from the time of random assignment. RESULTS A total of 414 patients (consolidation, n = 208; control, n = 206) were enrolled at 77 centers. (90)Y-ibritumomab tiuxetan consolidation significantly prolonged median PFS (after a median observation time of 3.5 years) in all patients (36.5 v 13.3 months in control arm; hazard ratio [HR] = 0.465; P < .0001) and regardless of whether patients achieved PR (29.3 v 6.2 months in control arm; HR = 0.304; P < .0001) or CR/CRu (53.9 v 29.5 months in control arm; HR = 0.613; P = .0154) after induction treatment. Median PFS with consolidation was prolonged in all Follicular Lymphoma International Prognostic Index risk subgroups. After (90)Y-ibritumomab tiuxetan consolidation, 77% of patients in PR after induction converted to CR/CRu, resulting in a final CR rate of 87%. The most common toxicity with (90)Y-ibritumomab tiuxetan was hematologic, and grade 3 or 4 infections occurred in 8% of patients. CONCLUSION Consolidation of first remission with (90)Y-ibritumomab tiuxetan in advanced-stage follicular lymphoma is highly effective with no unexpected toxicities, prolonging PFS by 2 years and resulting in high PR-to-CR conversion rates regardless of type of first-line induction treatment.

Follicular Lymphoma International Prognostic Index 2: A New Prognostic Index for Follicular Lymphoma Developed by the International Follicular Lymphoma Prognostic Factor Project

PURPOSE The aim of the F2 study was to verify whether a prospective collection of data would enable the development of a more accurate prognostic index for follicular lymphoma (FL) by using parameters which could not be retrospectively studied before, and by choosing progression-free survival (PFS) as principal end point. PATIENTS AND METHODS Between January 2003 and May 2005, 1,093 patients with a newly diagnosed FL were registered and 942 individuals receiving antilymphoma therapy were selected as the study population. The variables we used for score definition were selected by means of bootstrap resampling procedures on 832 patients with complete data. Procedures to select the model that would minimize errors were also performed. RESULTS After a median follow-up of 38 months, 261 events for PFS evaluation were recorded. beta2-microglobulin higher than the upper limit of normal, longest diameter of the largest involved node longer than 6 cm, bone marrow involvement, hemoglobin level lower than 12 g/dL, and age older than 60 years were factors independently predictive for PFS. Using these variables, a prognostic model was devised to identify three groups at different levels of risk. The 3-year PFS rate was 91%, 69%, and 51% for patients at low, intermediate, and high risk, respectively (log-rank = 64.6; P < .00001). The 3-year survival rate was 99%, 96%, and 84% for patients at low, intermediate, and high risk, respectively (P < .0001). CONCLUSION Follicular Lymphoma International Prognostic Index 2 is a simple prognostic index based on easily available clinical data and may represent a promising new tool for the identification of patients with FL at different risk in the era of immunochemotherapy.

High-Dose Methotrexate-Based Chemotherapy Followed by Consolidating Radiotherapy in Non–AIDS-Related Primary Central Nervous System Lymphoma: European Organization for Research and Treatment of Cancer Lymphoma Group Phase II Trial 20962

PURPOSE To confirm the feasibility and estimate the efficacy of methotrexate (MTX), teniposide, carmustine, and methylprednisolone (MBVP) chemotherapy combined with radiotherapy (RT) for patients with non-AIDS-related primary CNS lymphoma (PCNSL) treated in a multicenter setting. PATIENTS AND METHODS Treatment consisted of two cycles of MBVP (MTX 3 g/m2 days 1 and 15, teniposide 100 mg/m2 days 2 and 3, carmustine 100 mg/m2 day 4, methylprednisolone 60 mg/m2 days 1 to 5, and two intrathecal injections of MTX 15 mg, cytarabine 40 mg, and hydrocortisone 25 mg) followed by 40 Gy of RT. Primary end points were response and safety of this regimen. RESULTS Twelve centers included 52 patients who were all analyzed on an intent-to-treat basis. Median follow-up of all patients was 27 months. One patient progressed and died before treatment, and five patients died during treatment. Four patients received RT after one cycle of chemotherapy, and 42 patients completed the entire treatment. Hematologic grade 3 and 4 toxicity was seen in 78% of patients for leukocytes and 24% of patients for platelets. The overall response rate of all 52 patients was 81%. Two patients who did not fulfill the criteria of objective response survived more than 1 year; one of them is still alive without disease. Eighteen patients died; 11 deaths were a result of tumor, five were probably treatment-related, one was caused by late leukoencephalopathy, and one was a result of intercurrent disease. Median estimated overall survival was 46 months. CONCLUSION MBVP followed by RT for PCNSL has a high response rate. However, the 10% toxic death rate during treatment in a multicenter setting underlines the need for highly specialized care.

Predictors of Early Death Risk in Older Patients Treated With First-Line Chemotherapy for Cancer

PURPOSE Objective factors for making choices about the treatment of elderly patients with cancer are lacking. This investigation aimed to help physicians select appropriate treatments through the identification of factors that predict early death (< 6 months) after initiation of chemotherapy treatment. PATIENTS AND METHODS Previously untreated patients greater than 70 years of age who were scheduled for first-line chemotherapy for various types of cancer were included. Baseline abbreviated comprehensive geriatric assessment (aCGA), including the Mini-Mental State Exam, Timed Get Up and Go (GUG), Activities of Daily Living (ADL), Instrumental Activities in Daily Living (IADL), Mini Nutritional Assessment (MNA), Geriatric Depression Scale (GDS15), and comorbidities index (Cumulative Index Rating Scale-Geriatric), was carried out. Prognostic factors of early death were sought from aCGA results and traditional oncology measures. RESULTS A total of 348 patients were included across 12 centers in Southwest France (median age, 77.45 years; ratio of men to women, 1.47; advanced disease, 65%). Abnormal aCGA scores were observed for 18.1% of patients on the ADL, 73.0% of patients on the IADL, 24.1% of patients on the GUG, 19.0% of patients on the MMS, 44.0% of patients on the GDS15, and 64.9% of patients on the MNA. Advanced disease (odds ratio [OR], 3.9; 95% CI, [1.58 to 9.73]), a low MNA score (OR 2.77; 95% CI, [1.24 to 6.18]), male sex (OR, 2.40; 95% CI, [1.2 to 4.82]), and long GUG (OR, 2.55; 95% CI, [1.32 to 4.94] were associated with higher risk of early death. CONCLUSION In patients greater than 70 years of age with cancer, advanced disease, a low MNA score, and poor mobility predicted early death. We recommend that the MNA and GUG, performed by a trained nurse, be maintained as part of routine pretreatment workup in these patients to identify at-risk patients and to inform the decision-making process for chemotherapy.

EORTC Cancer in the Elderly Task Force guidelines for the use of colony-stimulating factors in elderly patients with cancer.

Increasing age is not, in itself, a contraindication to cancer chemotherapy. Myelosuppression, however, a common adverse consequence of the administration of many standard-dose chemotherapy regimens to both young and elderly patients with cancer, increases with age. The risk of development of febrile neutropenia may contribute to a reluctance to administer chemotherapy in the elderly patient population. We conducted a detailed literature search (1992-2002) to derive evidence-based conclusions on the value of prophylactic colony-stimulating factor (CSF) administration in elderly patients receiving chemotherapy. Sufficient evidence allows us to affirm that prophylactic granulocyte colony-stimulating factor (G-CSF) reduces the incidence of chemotherapy-induced neutropenia, febrile neutropenia and infections in elderly patients receiving myelotoxic chemotherapy for non-Hodgkins lymphoma (NHL), small-cell lung cancer (SCLC) or urothelial tumours. Lack of available trial data does not allow similar conclusions to be drawn for other cancers studied, but it is likely that similar benefits would accrue from the use of prophylactic G-CSF. There is insufficient evidence to extend this recommendation to include the use of granulocyte-macrophage colony-stimulating factor (GM-CSF). There are insufficient data available to allow the evaluation of the impact of prophylactic CSF on the incidence of toxic deaths in elderly patients with cancer and this is a crucial question for geriatric oncology practice. There is no evidence in elderly patients that the delivery of standard-dose chemotherapy on schedule improves efficacy measures. The data show that febrile neutropenic events are more likely to occur during the first and second cycles of chemotherapy, thus prophylactic measures should be considered early in the course of treatment. Furthermore, since systematic dose reduction can impact on outcome, primary prophylactic use of G-CSF for all elderly patients receiving curative myelotoxic chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) or CHOP-like) is indicated and we suggest a risk-adapted strategy with primary prophylactic G-CSF administration in high-risk patients. Dose intensification, through dose interval reduction, facilitated by prophylactic G-CSF, improved survival in elderly patients with some specific diseases. There is a need for further well-designed studies to identify the elderly patients who will benefit most from prophylactic G-CSF. To achieve this, we strongly urge the design of and participation in further trials.

IGHV gene features and MYD88 L265P mutation separate the three marginal zone lymphoma entities and Waldenström macroglobulinemia/lymphoplasmacytic lymphomas

To clarify the relationships between marginal zone lymphomas (MZLs) and Waldenström macroglobulinemia/lymphoplasmacytic lymphomas (WM/LPLs), immunoglobulin heavy chain variable gene (IGHV) features were analyzed and the occurrence of MYD88 L265P mutations was identified in a series of 123 patients: 53 MZLs from the spleen (SMZLs), 11 from lymph nodes (NMZLs), 28 mucosa-associated lymphatic tissue (MALT) lymphomas and 31 WM/LPLs. SMZLs were characterized by overrepresentation of IGHV1–2 gene rearrangements with a canonical motif, without selection pressure and with long CDR3 segments. NMZLs had increased frequencies of IGHV3 genes. The IGHV gene was unmutated in most cases, often with long CDR3 segments. MALT lymphomas were usually associated with a mutated IGHV gene, but with the absence of selection pressure. WM/LPLs were associated with an IGHV3–23 overrepresentation and high IGHV mutation rate, with features of selection pressure and short CDR3 segments. MYD88 L265P mutations were almost restricted exclusively to WM/LPL patients. Taken all diagnoses together, all patients with MYD88 L265P mutations had an immunoglobulin M peak and almost all patients except one had bone marrow infiltration. These results demonstrate that the history of antigen exposure of the four entities studied was different and MYD88 L265P was specifically associated with WM/LPLs. WM/LPL may thus be functionally associated with constitutive nuclear factor-κB activation.

Recurrent Mutations of MYD88 and TBL1XR1 in Primary Central Nervous System Lymphomas

Purpose: Our objective was to identify the genetic changes involved in primary central nervous system lymphoma (PCNSL) oncogenesis and evaluate their clinical relevance. Experimental Design: We investigated a series of 29 newly diagnosed, HIV-negative, PCNSL patients using high-resolution single-nucleotide polymorphism (SNP) arrays (n = 29) and whole-exome sequencing (n = 4) approaches. Recurrent homozygous deletions and somatic gene mutations found were validated by quantitative real-time PCR and Sanger sequencing, respectively. Molecular results were correlated with prognosis. Results: All PCNSLs were diffuse large B-cell lymphomas, and the patients received chemotherapy without radiotherapy as initial treatment. The SNP analysis revealed recurrent large and focal chromosome imbalances that target candidate genes in PCNSL oncogenesis. The most frequent genomic abnormalities were (i) 6p21.32 loss (HLA locus), (ii) 6q loss, (iii) CDKN2A homozygous deletions, (iv) 12q12-q22, and (v) chromosome 7q21 and 7q31 gains. Homozygous deletions of PRMD1, TOX, and DOCK5 and the amplification of HDAC9 were also detected. Sequencing of matched tumor and blood DNA samples identified novel somatic mutations in MYD88 and TBL1XR1 in 38% and 14% of the cases, respectively. The correlation of genetic abnormalities with clinical outcomes using multivariate analysis showed that 6q22 loss (P = 0.006 and P = 0.01) and CDKN2A homozygous deletion (P = 0.02 and P = 0.01) were significantly associated with shorter progression-free survival and overall survival. Conclusions: Our study provides new insights into the molecular tumorigenesis of PCNSL and identifies novel genetic alterations in this disease, especially MYD88 and TBL1XR1 mutations activating the NF-κB signaling pathway, which may be promising targets for future therapeutic strategies. Clin Cancer Res; 18(19); 5203–11. ©2012 AACR.

Screening for Vulnerability in Older Cancer Patients: The ONCODAGE Prospective Multicenter Cohort Study

Background Geriatric Assessment is an appropriate method for identifying older cancer patients at risk of life-threatening events during therapy. Yet, it is underused in practice, mainly because it is time- and resource-consuming. This study aims to identify the best screening tool to identify older cancer patients requiring geriatric assessment by comparing the performance of two short assessment tools the G8 and the Vulnerable Elders Survey (VES-13). Patients and Methods The diagnostic accuracy of the G8 and the (VES-13) were evaluated in a prospective cohort study of 1674 cancer patients accrued before treatment in 23 health care facilities. 1435 were eligible and evaluable. Outcome measures were multidimensional geriatric assessment (MGA), sensitivity (primary), specificity, negative and positive predictive values and likelihood ratios of the G8 and VES-13, and predictive factors of 1-year survival rate. Results Patient median age was 78.2 years (70-98) with a majority of females (69.8%), various types of cancer including 53.9% breast, and 75.8% Performance Status 0-1. Impaired MGA, G8, and VES-13 were 80.2%, 68.4%, and 60.2%, respectively. Mean time to complete G8 or VES-13 was about five minutes. Reproducibility of the two questionnaires was good. G8 appeared more sensitive (76.5% versus 68.7%, P =  0.0046) whereas VES-13 was more specific (74.3% versus 64.4%, P<0.0001). Abnormal G8 score (HR = 2.72), advanced stage (HR = 3.30), male sex (HR = 2.69) and poor Performance Status (HR = 3.28) were independent prognostic factors of 1-year survival. Conclusion With good sensitivity and independent prognostic value on 1-year survival, the G8 questionnaire is currently one of the best screening tools available to identify older cancer patients requiring geriatric assessment, and we believe it should be implemented broadly in daily practice. Continuous research efforts should be pursued to refine the selection process of older cancer patients before potentially life-threatening therapy.

Impact of [18F]Fluorodeoxyglucose Positron Emission Tomography Response Evaluation in Patients With High–Tumor Burden Follicular Lymphoma Treated With Immunochemotherapy: A Prospective Study From the Groupe d'Etudes des Lymphomes de l'Adulte and GOELAMS

PURPOSE [(18)F]Fluorodeoxyglucose positron emission tomography (PET) is widely used for the staging and restaging of patients with aggressive lymphoma, but less is known about the utility of PET in patients with follicular lymphoma (FL). In a prospective study, we evaluated the prognostic value of PET performed during treatment and at the end of treatment in 121 patients with FL treated with first-line immunochemotherapy. PATIENTS AND METHODS Patients with previously untreated high-tumor burden FL were treated with six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) plus two cycles of rituximab, without rituximab maintenance. PET was performed before treatment, after four cycles of R-CHOP (interim PET), and at the end of treatment (final PET). PET scans were centrally reviewed. RESULTS The total number of patients included was 121. Median age was 57 years. After central review, interim PET (n = 111) was negative in 76% of patients, and final PET (n = 106) was negative in 78%. With a median follow-up of 23 months, 2-year progression-free survival rates were 86% for interim PET-negative versus 61% for interim PET-positive patients (P = .0046) and 87% for final PET-negative versus 51% for final PET-positive patients (P < .001), respectively. Two-year overall survival also significantly differed according to final PET results: 100% versus 88% (P = .0128). CONCLUSION PET performed either after four cycles of R-CHOP or at the end of therapy was strongly predictive of outcome in this prospective study. Therapeutic intervention based on PET results during or after inductive treatment should be evaluated.

90Yttrium-Ibritumomab Tiuxetan Consolidation of First Remission in Advanced-Stage Follicular Non-Hodgkin Lymphoma: Updated Results After a Median Follow-Up of 7.3 Years From the International, Randomized, Phase III First-Line Indolent Trial

PURPOSE Updated results are presented after a median follow-up of 7.3 years from the phase III First-Line Indolent Trial of yttrium-90 ((90)Y) -ibritumomab tiuxetan in advanced-stage follicular lymphoma (FL) in first remission. PATIENTS AND METHODS Patients with CD20(+) stage III or IV FL with complete response (CR), unconfirmed CR (CRu), or partial response (PR) after first-line induction treatment were randomly assigned to (90)Y-ibritumomab consolidation therapy (rituximab 250 mg/m(2) days -7 and 0, then (90)Y-ibritumomab 14.8 MBq/kg day 0; maximum 1,184 MBq) or no further treatment (control). Primary end point was progression-free survival (PFS) from date of random assignment. RESULTS For 409 patients available for analysis ((90)Y-ibritumomab, n = 207; control, n = 202), estimated 8-year overall PFS was 41% with (90)Y-ibritumomab versus 22% for control (hazard ratio [HR], 0.47; P < .001). For patients in CR/CRu after induction, 8-year PFS with (90)Y-ibritumomab was 48% versus 32% for control (HR, 0.61; P = .008), and for PR patients, it was 33% versus 10% (HR, 0.38; P < .001). For (90)Y-ibritumomab consolidation, median PFS was 4.1 years (v 1.1 years for control; P < .001). Median time to next treatment (TTNT) was 8.1 years for (90)Y-ibritumomab versus 3.0 years for control (P < .001) with approximately 80% response rates to second-line therapy in either arm, including autologous stem-cell transplantation. No unexpected toxicities emerged during long-term follow-up. Estimated between-group 8-year overall survival rates were similar. Annualized incidence rate of myelodysplastic syndrome/acute myeloblastic leukemia was 0.50% versus 0.07% in (90)Y-ibritumomab and control groups, respectively (P = .042). CONCLUSION (90)Y-ibritumomab consolidation after achieving PR or CR/CRu to induction confers 3-year benefit in median PFS with durable 19% PFS advantage at 8 years and improves TTNT by 5.1 years for patients with advanced FL.