Marc André

Treatment of Older Patients with Mantle-Cell Lymphoma

BACKGROUND The long-term prognosis for older patients with mantle-cell lymphoma is poor. Chemoimmunotherapy results in low rates of complete remission, and most patients have a relapse. We investigated whether a fludarabine-containing induction regimen improved the complete-remission rate and whether maintenance therapy with rituximab prolonged remission. METHODS We randomly assigned patients 60 years of age or older with mantle-cell lymphoma, stage II to IV, who were not eligible for high-dose therapy to six cycles of rituximab, fludarabine, and cyclophosphamide (R-FC) every 28 days or to eight cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) every 21 days. Patients who had a response underwent a second randomization to maintenance therapy with rituximab or interferon alfa, each given until progression. RESULTS Of the 560 patients enrolled, 532 were included in the intention-to-treat analysis for response, and 485 in the primary analysis for response. The median age was 70 years. Although complete-remission rates were similar with R-FC and R-CHOP (40% and 34%, respectively; P=0.10), progressive disease was more frequent with R-FC (14%, vs. 5% with R-CHOP). Overall survival was significantly shorter with R-FC than with R-CHOP (4-year survival rate, 47% vs. 62%; P=0.005), and more patients in the R-FC group died during the first remission (10% vs. 4%). Hematologic toxic effects occurred more frequently in the R-FC group than in the R-CHOP group, but the frequency of grade 3 or 4 infections was balanced (17% and 14%, respectively). In 274 of the 316 patients who were randomly assigned to maintenance therapy, rituximab reduced the risk of progression or death by 45% (in remission after 4 years, 58%, vs. 29% with interferon alfa; hazard ratio for progression or death, 0.55; 95% confidence interval, 0.36 to 0.87; P=0.01). Among patients who had a response to R-CHOP, maintenance therapy with rituximab significantly improved overall survival (4-year survival rate, 87%, vs. 63% with interferon alfa; P=0.005). CONCLUSIONS R-CHOP induction followed by maintenance therapy with rituximab is effective for older patients with mantle-cell lymphoma. (Funded by the European Commission and others; ClinicalTrials.gov number, NCT00209209.).

Omitting Radiotherapy in Early Positron Emission Tomography–Negative Stage I/II Hodgkin Lymphoma Is Associated With an Increased Risk of Early Relapse: Clinical Results of the Preplanned Interim Analysis of the Randomized EORTC/LYSA/FIL H10 Trial

PURPOSE Combined-modality treatment is standard treatment for patients with clinical stage I/II Hodgkin lymphoma (HL). We hypothesized that an early positron emission tomography (PET) scan could be used to adapt treatment. Therefore, we started the randomized EORTC/LYSA/FIL Intergroup H10 trial evaluating whether involved-node radiotherapy (IN-RT) could be omitted without compromising progression-free survival in patients attaining a negative early PET scan after two cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) as compared with standard combined-modality treatment. PATIENTS AND METHODS Patients age 15 to 70 years with untreated clinical stage I/II HL were eligible. Here we report the clinical outcome of the preplanned interim futility analysis scheduled to occur after documentation of 34 events in the early PET-negative group. Because testing for futility in this noninferiority trial corresponds to testing the hypothesis of no difference, a one-sided superiority test was conducted. RESULTS The analysis included 1,137 patients. In the favorable subgroup, 85.8% had a negative early PET scan (standard arm, one event v experimental arm, nine events). In the unfavorable subgroup, 74.8% had a negative early PET scan (standard arm, seven events v experimental arm, 16 events). The independent data monitoring committee concluded it was unlikely that we would show noninferiority in the final results for the experimental arm and advised stopping random assignment for early PET-negative patients. CONCLUSION On the basis of this analysis, combined-modality treatment resulted in fewer early progressions in clinical stage I/II HL, although early outcome was excellent in both arms. The final analysis will reveal whether this finding is maintained over time.

Cytogenetic responses in high-risk myelodysplastic syndrome following low-dose treatment with the DNA methylation inhibitor 5-aza-2 '-deoxycytidine

Decitabine (5‐aza‐2′‐deoxycytidine) acts as a powerful demethylating agent in vitro. Clinically, low‐dose decitabine ameliorates cytopenias including induction of trilineage responses in ≈50% of patients with high‐risk myelodysplastic syndrome (MDS). We examined the incidence and kinetics of cytogenetic responses to decitabine in these patients. Of 115 successfully karyotyped patients, 61 (53%) had clonal chromosomal abnormalities prior to treatment. Major cytogenetic responses were observed in 19 patients (31% of those with abnormal cytogenetics, 17% of all patients by intention‐to‐treat) after a median of three courses (range, 2–6) until best cytogenetic response. Progressive decrease of the abnormal clone over time was also determined using fluorescence in situ hybridization (FISH) analysis in two patients. Median duration of cytogenetic responses was 7·5 months (range, 3–15). Analysis of response by the International Prognostic Scoring System (IPSS) cytogenetic risk groups revealed three out of five cytogenetic responses (60%) in the IPSS ‘low‐risk’ group, 6 out of 30 with ‘intermediate risk’ (20%) and 10 out of 26 in the ‘high‐risk’ group (38%). Median survival in these cytogenetic subgroups was 30, 8 and 13 months respectively. The relative risk of death in patients achieving a major cytogenetic response was 0·38 (95% confidence interval 0·17–0·88) compared with patients in whom the cytogenetically abnormal clone persisted (P = 0·0213). In conclusion, repeated courses of low‐dose decitabine induce cytogenetic remissions in a substantial number of elderly MDS patients with pre‐existing chromosomal abnormalites; these are associated with improved survival compared with patients in whom the cytogenetically abnormal clone persists. Patients with ‘high‐risk’ chromosomal abnormalities may particularly benefit from this treatment.

Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

H. Tilly1, M. Gomes da Silva2, U. Vitolo3, A. Jack4, M. Meignan5, A. Lopez-Guillermo6, J. Walewski7, M. Andre8, P. W. Johnson9, M. Pfreundschuh10 & M. Ladetto11, on behalf of the ESMO Guidelines Committee* Centre Henri-Becquerel, Universite de Rouen, Rouen, France; Portuguese Institute of Oncology, Lisbon, Portugal; A.O. Citta della Salute e della Scienza di Torino, Turin, Italy; St James’s University Hospital, Leeds, UK; Henri Mondor University Hospital, Creteil, France; Hospital Clinic, Barcelona, Spain; Maria Sklodowska-Curie Memorial Institute and Oncology Centre, Warsaw, Poland; CHU Dinant-Godinne, UCL Namur, Yvoir, Belgium; Cancer Research UK, University of Southampton, Southampton, UK; Innere Medizin I, Universitat des Saarlandes, Hamburg, Germany; Divisione di Ematologia, Azienda Ospedaliera Santi Antonio e Biagio e Cesare Arrigo, Alessandria, Italy

Prognostic factors for survival after high-dose therapy and autologous stem cell transplantation for patients with relapsing Hodgkin’s disease: analysis of 280 patients from the French registry

High-dose therapy with autologous stem cell transplantation (ASCT) has been widely proposed for patients with relapsed Hodgkin’s disease (HD). From 1982 to 1993, we selected (from the French registry for bone marrow transplantation) 280 patients, who underwent ASCT for relapsed HD after initial treatment including chemotherapy. Patient characteristics at diagnosis were: sex ratio (M/F): 1.5; median age: 30 years (5–59 years), stage I, II: 43%; III, IV: 57%; 32% had chemotherapy, 68% chemo+ radiotherapy. All patients achieved complete remission after first-line therapy and subsequently relapsed. The median interval between diagnosis and high-dose therapy was 34 months. First relapse occurred in 78% of the patients at a median end-of-treatment to relapse time of 18 months. All patients received salvage chemotherapy before high-dose therapy, and the median time between relapse and high-dose therapy was 5 months. After this regimen, 84% of the patients were considered to have chemosensitive relapse. Conditioning regimens were: BEAM: 60%; CBV/BEAC: 26%. Transplant-related mortality was 6%. With a median follow-up of 3 years after high-dose therapy, overall and progression-free survivals at 4 years were, 66 and 60%, respectively. Neither the conditioning regimen nor the stem cell source affected survival. Good prognostic factors for survival were: chemosensitivity of relapse (P < 0.001) and first relapse vs further relapse (P < 0.05). for 214 patients in first relapse, other significant factors for survival were: end-of-treatment to relapse interval <12 months (P < 0.05) and nodal vs extranodal relapse (P < 0.001). these two prognostic factors were used to validate a prognostic model with three significantly different subgroups: 0 (n = 59), 1 (n = 125), or 2 factors (n = 30) with 4-year survival, respectively, at 93, 59 and 43% (P < 0.001). salvage therapy can be tailored in patients with relapsing hd: conventional treatment in the good prognosis group (0 factor), high-dose therapy after response to second line regimen (1 factor) and more intensive treatments for the bad prognosis group (2 factors).

Comparison of High-Dose Therapy and Autologous Stem-Cell Transplantation With Conventional Therapy for Hodgkin's Disease Induction Failure: A Case-Control Study

PURPOSE To determine the prognostic factors and outcome of first-line induction failure Hodgkins disease patients who were treated with a salvage regimen of high-dose chemotherapy and autologous stem-cell transplantation, and to compare them with matched, conventionally treated patients. PATIENTS AND METHODS We retrospectively analyzed data relating to 86 Hodgkins disease patients who underwent autologous stem-cell transplantation after failure of the first chemotherapy regimen, either because they did not enter a complete remission and experienced progression of disease less than 3 months after the end of their first-line treatment or because they showed evidence of disease progression during first-line therapy. Graft patients were matched with 258 conventionally treated patients (three controls per case) for age, sex, clinical stage, B symptoms, and time at risk; patient data were obtained from international databases. RESULTS Among the 86 graft patients, the median age at diagnosis was 29 years (range, 14 to 57 years). Thirty-nine percent of patients had stage II disease, 23% had stage III disease, and 38% had stage IV disease. Seventy percent of the patients received chemotherapy and 30% received combined modality therapy; 60% of the patients received a seven- or eight-drug regimen. After this first-line treatment, 91% had disease progression and 9% had a brief partial response. Eighty patients received a second-line treatment; pretransplantation status was as follows: 24% of patients had a complete remission, 38% had a partial remission (PR), 14% had stable disease, and disease progression occurred in 24%. With a median follow-up of 22 months (range, 4 to 105 months) from diagnosis, the 5-year event-free survival and overall survival rates from transplantation were 25% and 35% (95% confidence intervals, 15 to 36 and 23 to 49), respectively. In multivariate analysis, the pretransplantation disease status after salvage therapy was the only significant prognostic factor for survival (PR: relative risk = 2.8, P = .017; progressive disease: relative risk (RR) = 5.26, P < .001). From diagnosis, the 6-year overall survival rates of the graft patients and 258 matched conventionally treated patients were 38% and 29%, respectively (P = .058). CONCLUSION Autologous stem-cell transplantation represents the best therapeutic option currently available for patients with primary induction failure and is associated with acceptable toxicity. Response to second-line treatment before high-dose chemotherapy is the only prognostic factor that can be correlated with survival.

Risk-Adapted Salvage Treatment With Single or Tandem Autologous Stem-Cell Transplantation for First Relapse/Refractory Hodgkin's Lymphoma: Results of the Prospective Multicenter H96 Trial by the GELA/SFGM Study Group

PURPOSE A prospective multicenter trial evaluated a risk-adapted salvage treatment with single or tandem autologous stem-cell transplantation (ASCT) for 245 Hodgkins lymphoma (HL) patients who experience treatment failure with first-line therapy. PATIENTS AND METHODS Poor-risk patients (150 with primary refractory disease or > or = two of the following risk factors at first relapse: time to relapse < 12 months, stage III or IV at relapse, and relapse within previously irradiated sites) or intermediate-risk patients (95 with one risk factor at relapse) were eligible for tandem or single ASCT, respectively. RESULTS Among poor-risk patients, 105 (70%), including 30 of 55 with cytoreductive chemotherapy-resistant disease, received tandem ASCT, whereas 92 intermediate-risk patients (97%) received single ASCT. According to intent-to-treat analysis, the 5-year freedom from second failure and overall survival (OS) estimates were 73% and 85%, respectively, for the intermediate-risk group and 46% and 57%, respectively, for the poor-risk group. Outcomes were similar for primary refractory and poor-risk/relapsed HL. For patients with chemotherapy-resistant disease, the 46% 5-year OS rate achieved with tandem ASCT compares favorably with the previously reported 30%. Outcomes for partial and complete responders to cytoreduction receiving tandem ASCT did not differ significantly and were better than those previously reported for partial responders receiving single ASCT, but not superior to those reported for complete responders receiving single ASCT. Six poor-risk patients (4%) died from toxicity. CONCLUSION Single ASCT is appropriate for intermediate-risk patients. For poor-risk patients, our results suggest a benefit of tandem ASCT for half of the patients with chemotherapy-resistant disease and partial responders, but not for complete responders to cytoreductive chemotherapy.

Structure of the Gene of Tum- Transplantation Antigen-p35b - Presence of a Point Mutation in the Antigenic Allele

Mutagen treatment of P815 tumour cells produces tum‐ variants that are rejected by syngeneic mice because they express new transplantation antigens. These ‘tum‐’ antigens elicit a cytolytic T lymphocyte (CTL) response but no detectable antibody response. The DNA of tum‐ variant P35 was transfected into P815 cell line P1.HTR. Transfectants expressing tum‐ antigen P35B were identified on the basis of their ability to stimulate anti‐P35B CTL. This was repeated with a cosmid library and a cosmid carrying the sequence encoding antigen P35B was recovered from a transfectant expressing the antigen. Gene P35B is 6 kb long and contains 11 exons. The sequence shows no homology with the previously identified tum‐ gene P91A nor with any gene presently recorded in the data banks. The antigenic allele of gene P35B differs from the normal allele by a point mutation located in exon 5. This mutation, which replaces a Ser by an Asn residue, was shown by site‐directed mutagenesis to be responsible for the expression of the antigen. A synthetic decapeptide covering the sequence surrounding the tum‐ mutation rendered P815 cells sensitive to lysis by anti‐P35B CTL. Surprisingly, the homologous peptide corresponding to the normal sequence of the gene had the same effect, indicating that this tum‐ mutation does not exert its effect by generating the aggretope or the epitope of the antigenic peptide. As observed previously with gene P91A, we found that fragments of gene P35B containing only exons 4 and 5, which were cloned in non‐expression vectors, transferred efficiently the expression of the antigen.

Early Positron Emission Tomography Response-Adapted Treatment in Stage I and II Hodgkin Lymphoma: Final Results of the Randomized EORTC/LYSA/FIL H10 Trial.

Purpose Patients who receive combined modality treatment for stage I and II Hodgkin lymphoma (HL) have an excellent outcome. Early response evaluation with positron emission tomography (PET) scan may improve selection of patients who need reduced or more intensive treatments. Methods We performed a randomized trial to evaluate treatment adaptation on the basis of early PET (ePET) after two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in previously untreated-according to European Organisation for Research and Treatment of Cancer criteria favorable (F) and unfavorable (U)-stage I and II HL. The standard arm consisted of ABVD followed by involved-node radiotherapy (INRT), regardless of ePET result. In the experimental arm, ePET-negative patients received ABVD only (noninferiority design), whereas ePET-positive patients switched to two cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc) and INRT (superiority design). Primary end point was progression-free survival (PFS). Results Of 1,950 randomly assigned patients, 1,925 received an ePET-361 patients (18.8%) were positive. In ePET-positive patients, 5-year PFS improved from 77.4% for standard ABVD + INRT to 90.6% for intensification to BEACOPPesc + INRT (hazard ratio [HR], 0.42; 95% CI, 0.23 to 0.74; P = .002). In ePET-negative patients, 5-year PFS rates in the F group were 99.0% versus 87.1% (HR, 15.8; 95% CI, 3.8 to 66.1) in favor of ABVD + INRT; the U group, 92.1% versus 89.6% (HR, 1.45; 95% CI, 0.8 to 2.5) in favor of ABVD + INRT. For both F and U groups, noninferiority of ABVD only compared with combined modality treatment could not be demonstrated. Conclusion In stage I and II HL, PET response after two cycles of ABVD allows for early treatment adaptation. When ePET is positive after two cycles of ABVD, switching to BEACOPPesc + INRT significantly improved 5-year PFS. In ePET-negative patients, noninferiority of ABVD only could not be demonstrated: risk of relapse is increased when INRT is omitted, especially in patients in the F group.

Development and Application of a Real-Time On-Line Blinded Independent Central Review of Interim Pet Scans to Determine Treatment Allocation in Lymphoma Trials

We appreciate the interest shown in our report by Gemici and the opportunity to respond to his comments. He published an excellent review article on tumor lysis syndrome (TLS) in 2006. He suggested that our patient may not be the third reported instance of TLS caused by radiotherapy because three patients had already been cited in his report. However, as we mentioned, only adult patients were included in our report. If pediatric patients were to be included, there would be more than three instances before his review. He also pointed out the inappropriateness of urine alkalinization during treatment of our patient. It is true that routine use of urine alkalinization is not recommended in most instances because of the potential risk of worsening renal problems or neurologic manifestations of hypocalcemia, although it seems not to have affected the clinical course of our patient. Therefore, as he described, physicians should be aware of this controversial issue during management of TLS. He also added that increasing the urinary flow rate is a better alternative than urine alkalinization. However, vigorous hydration with diuretics is not a matter of alternative choice because it is the single most important measure to treat TLS. The only decision to be made would be whether to use additional urine alkalinization for management of TLS. Finally, he mentioned that the daily fractionated dose in addition to total dose should also be considered. We agree on his opinion in the aspect that all reported patients with TLS had received 3 Gy of daily dose. He also suggested that TLS might develop later and at higher total dose if lower daily dose ( 2 Gy) were to be used. However, it is uncertain whether lower daily dose can result in TLS because there has been no such report on the matter. The threshold of radiation dose leading to rapid cell destruction might exist even in radiosensitive tumor cells. For better understanding, more experiences regarding radiotherapy-induced TLS need to be accumulated.