Pomalidomide plus low-dose dexamethasone is active and well tolerated in bortezomib and lenalidomide-refractory multiple myeloma: Intergroupe Francophone du Myélome 2009-02.

The combination of pomalidomide and dexamethasone can be safely administered to patients with multiple myeloma (MM) and has significant efficacy, although the optimal regimen remains to be determined. Patients with MM whose disease progressed after multiple lines of therapy have limited treatment options. We designed a multicenter, phase 2 randomized study assessing two different dose regimens of pomalidomide and dexamethasone in advanced MM. Treatment response was assessed centrally. Pomalidomide (4 mg) was given orally on days 1 to 21 (arm 21/28) or continuously (arm 28/28) over a 28-day cycle, plus dexamethasone given weekly. Eighty-four patients (43, arm 21/28 and 41, arm 28/28) were randomized. The median number of prior lines was 5. Overall response rate was 35% (arm 21/28) and 34% (arm 28/28), independent of the number of prior lines and level of refractoriness. Median duration of response, time to disease progression, and progression-free survival was 7.3, 5.4, and 4.6 months, respectively, which was similar across cohorts. At 23 months follow-up, median overall survival was 14.9 months, with 44% of the patients alive at 18 months. Toxicity consisted primarily of myelosuppression, which was manageable. The efficacy and safety data presented here, along with data from other phase 2 trials, suggest that pomalidomide 4 mg per day on days 1 to 21 of 28 with dexamethasone should be investigated in future trials. This trial is registered at ClinicalTrials.gov (No. NCT01053949).

Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma.

The Intergroupe Francophone du Myelome conducted a randomized trial to compare bortezomib-dexamethasone (VD) as induction before high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) to a combination consisting of reduced doses of bortezomib and thalidomide plus dexamethasone (vtD) in patients with multiple myeloma. Overall, a total of 199 patients were centrally randomly assigned to receive VD or vtD. After 4 cycles, the complete response (CR) rate was the same in both groups (13% in the vtD arm, 12% in the VD arm, P = .74). However, the CR plus very good partial response (VGPR) rate was significantly higher in the vtD arm (49% vs 36%, P = .05). After ASCT, the CR plus VGPR rate was significantly higher in the vtD arm (74% vs 58%, P = .02). The reduced doses of bortezomib and thalidomide translated into a reduced incidence of peripheral neuropathy (PN): grade ≥ 2 PN were reported in 34% in the VD arm versus 14% in the vtD arm (P = .001). vtD, including reduced doses of bortezomib and thalidomide, yields higher VGPR rates compared with VD and can be considered a new effective triplet combination before HDT/ASCT.

Mutations in TP53 are exclusively associated with del(17p) in multiple myeloma.

Deletion of the 17p13 chromosomal region [del(17p)] is associated with a poor outcome in multiple myeloma. Most of the studies have targeted the TP53 gene for deletion analyses, although no study showed that this gene is the deletion target. In order to address this issue, we sequenced the TP53 gene in 92 patients with multiple myeloma at diagnosis, 54 with a del(17p) and 38 lacking del(17p). At least one mutation was found in 20 patients, all of them presenting a del(17p). The analysis of the mutation location showed that virtually all of them occurred in highly conserved domains involved in the DNA-protein interactions. In conclusion, we showed that 37% of the myeloma patients with del(17p) present a TP53 mutation versus 0% in patients lacking the del(17p). The prognostic significance of these mutations remains to be evaluated.

Chlorambucil versus observation after anti-Helicobacter therapy in gastric MALT lymphomas: results of the international randomised LY03 trial.

Gastric mucosa-associated lymphoid tissue (MALT) lymphomas are uncommon tumours characterised by a tendency to remain localised for long periods. The aetiological association between MALT lymphomas and Helicobacter pylori is well established. The role of additional chemotherapy after H. pylori eradication in localised MALT lymphomas is unclear. The LY03 trial was designed to establish whether chlorambucil after treatment for H. pylori would help prevent recurrence. Patients were treated with antibiotics for H. pylori infection. Those with successful eradication of H. pylori and no evidence of progression of lymphoma were eligible for randomisation to chlorambucil or observation. Two hundred and thirty-one patients were registered. Ninety-seven percent patients had H. pylori eradicated after antibiotics and 59% achieved macroscopically normal gastric mucosa. One hundred and ten patients were randomised. With a median follow-up of 58 months, six patients were dead and 17 had recurrent/progressive disease. The recurrence/progression rates at 5 years were 11% for chlorambucil, and 21% for observation with a difference of 10%, 95% confidence interval (CI) = -9% to 29%, P = 0.15. No difference was detected in recurrence/progression-free survival [Hazard Ratio (HR) = 0.96, 95% CI = 0.41-2.2, P = 0.91] or overall survival (HR = 1.93, 95% CI = 0.39-9.58, P = 0.42). This is the first randomised trial to show there is no good evidence to support that additional single agent chemotherapy to anti-H. pylori treatment contributes to prevent recurrence in localised gastric MALT lymphomas.

Second treatment with rituximab in B-cell non-Hodgkin's lymphoma: efficacy and toxicity on 41 patients treated at CHU-Lyon Sud.

The purpose of this study was to evaluate retrospectively the effect of a second treatment with rituximab for patients who progressed after a response to a first treatment. We analysed the charts of 41 patients treated at CHU Lyon-Sud between 1997 and May 2003. Patients were treated with rituximab alone or with a combination of rituximab and chemotherapy. The overall response rate (complete and partial response) was 73% for the second treatment. The median time to progression was longer but not significant for the second treatment in comparison with the first one (15.2 versus 11.3 months, P = 0.09). The second treatment was well tolerated. Thus, a second treatment with rituximab should be considered, alone or in combination with chemotherapy, for patients who progress after a first response to rituximab.

Maintenance therapy with a monthly injection of alemtuzumab prolongs response duration in patients with refractory B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL/SLL).

Alemtuzumab, the monoclonal anti-CD52 antibody, has clinical activity in B-cell and T-cell malignancies at the dose of 30 mg three times weekly for 9-12 weeks. This standard regimen induced responses usually shorter than 6 months. To prolong time to progression, we initialized a phase II study with an identical initial scheme until partial response, followed by a maintenance therapy lasting at least 4 months. Eleven heavily pretreated patients (8 with B-chronic lymhocytic leukemia (B-CLL) and 3 with small lymphoctyic lymphoma (SLL)) have been treated with this maintenance regimen (MR patients) and were retrospectively compared to 5 patients (3 B-CLL and 2 SLL) treated with the standard regimen (SR patients). Patients characteristics before treatment were identical in both groups. Objective response was reached by 9 (82%) MR patients and 3 (60%) SR patients (p NS). After the treatment, 8 (73%) MR patients and all SR patients progressed with a median time at 12.2 months and 3 months respectively. Survival time from alemtuzumab was significatively different (P < 0.005). None of the patients died in the MR group with a median follow-up at 16 months. In the SR group, the median survival from alemtuzumab was 5.9 months. We did not observe any differences in terms of hematological toxicites and infections between the two groups. In conclusion, maintenance alemtuzumab therapy seems to increase the time to progression and the survival, without adding hematological toxicities and infectious complications. More patients are needed to confirm this observation.

Long-term follow-up analysis of 100 patients with splenic marginal zone lymphoma treated with splenectomy as first-line treatment.

Splenectomy is considered as one of the first-line treatments for symptomatic patients with splenic marginal zone lymphoma (SMZL). Between 1997 and 2012, 100 hepatitis C virus-negative patients with SMZL were treated by splenectomy as first-line treatment. At 6 months, all patients but three recovered from all cytopenias. The median lymphocyte count at 6 months and 1 year was 11.51 × 10(9)/L and 6.9 × 10(9)/L, respectively. Median progression-free survival (PFS) was 8.25 years. The 5-year and 10-year overall survival (OS) rates were 84% and 67%, respectively. Histological transformation occurred in 11% of patients, and was the only parameter significantly associated with a shorter time to progression (p = 0.0001). Significant prognostic factors for OS were age (p = 0.0356) and histological transformation (p = 0.0312). In this large retrospective cohort, we confirmed that splenectomy as first-line treatment in patients with SMZL corrected cytopenias and lymphocytosis within the first year and was associated with a good PFS.

Long-term analysis of the IFM 99 trials for myeloma: cytogenetic abnormalities [t(4;14), del(17p), 1q gains] play a major role in defining long-term survival.

PURPOSE: In multiple myeloma, many prognostic parameters have been proposed. However, all of these predict shorter survival. To identify patients with a longer life expectancy, we updated the data of patients treated in the IFM (Intergroupe Francophone du Myelome) 99-02 and 99-04 trials. PATIENTS AND METHODS: A series of 520 patients was analyzed. Median follow-up was 90.5 months. To perform a comprehensive analysis of the major prognostic factors, we reanalyzed all patients for 1q gains [in addition to updating del(13), t(4;14), and del(17p) analyses]. RESULTS: It was possible to identify a subgroup of patients (representing 20% of total patients) with an 8-year survival of 75%. These patients were defined by the absence of t(4;14), del(17p), and 1q gain and ß(2)-microglobulin less than 5.5 mg/L. CONCLUSION: We propose that all patients with newly diagnosed multiple myeloma be evaluated for these three chromosomal changes, not only to define high-risk patients but also to identify those with a longer life expectancy.

Groshong or implanted catheter infections in ambulatory haematological patients.

Incidence rates of bacteraemia and catheter-related infections were measured prospectively amongst haematological patients having long-term catheters and hospitalised in the ambulatory care unit between November 2005 and October 2006. The following risk factors were collected: age, sex, catheter type, follow-up duration, level of personal hygiene, pathology, number of lines of treatment, autograft and erythropoietin treatment. 340 patients were included, having 353 catheters (100 of the Groshong-type, followed during 17,621 days, and 253 of the type with implantable ports, followed during 51,049 days). 0.13 catheter-related infections and 0.07 bacteraemia per 100 catheter days were observed with the Groshong-type catheter, whereas 0.05 (P<10(-5)) catheter-related infections and 0.05 (P=0.048) bacteraemia were observed amongst patients with implantable ports. A multivariate analysis (Cox method taking into account the length of follow-up) on risk factors highlighted a significant effect of the type of catheter on catheter-related infections (Groshong versus implantable port OR=5.74, P<10(-3)), and of several factors on bacteraemia (lymphoma versus other pathologies OR=3.19, P=0.041; erythropoietin treatment OR=2.88, P=0.009; autograft OR=3.35, P=0.011; number of lines of treatment OR=0.68, P=0.047). It was not possible to determine if poor levels of personal hygiene had a significant impact, due to large numbers of missing data. These results, consistent with other studies, are not only useful in validating prevention policy but also in demonstrating lack of catheter traceability.

Retreatment with rituximab in 178 patients with relapsed and refractory B-cell lymphomas: a single institution case control study.

The role of rituximab retreatment in relapsed B-cell lymphoma is not well known. We undertook a single center retrospective cohort study to investigate the efficacy of retreatment with rituximab with or without chemotherapy in patients with relapsed and refractory B-cell lymphomas. We only included patients treated first-line and in first progression; 178 patients were included in the study, of whom 29% had diffuse large B-cell lymphoma (DLBCL) and 28% had follicular lymphoma (FL). The overall response rate for the first treatment was 81% and for the second treatment was 66%. The median progression-free survival (PFS) for all patients from diagnosis was 13.2 months and from relapse was 12.5 months (not statistically different). For DLBCL the median PFS from diagnosis was 9.6 months and from relapse was 8.4 months, and for FL the median PFS from diagnosis was 26.4 months and from relapse was 19.2 months (not statistically different). The 5-year overall survival was 57%. In a historical comparison with rituximab-naive patients, rituximab-retreated patients had a shorter time to initial relapse than control patients, but there was no difference between the two groups for PFS from relapse. In conclusion, retreatment with rituximab, with or without chemotherapy, yields a high overall response rate in patients with relapsed and refractory B-cell lymphomas. Relapse occurring after rituximab-containing therapy appears to be more aggressive than that occurring after chemotherapy alone. The outcome of retreatment, in terms of progression-free survival, is similar to that of primary treatment.

Evolving role of rituximab in the treatment of patients with non-Hodgkin's lymphoma.

Rituximab is the first monoclonal antibody to have been registered for the treatment of B-cell lymphomas. Randomized studies have demonstrated its activity in follicular lymphoma, mantle cell lymphoma, and diffuse large B-cell lymphoma in untreated or relapsing patients. Rituximab has transformed the outcome of these patients because of its high activity and low toxicity. A combination of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone, has the highest efficacy ever described with any chemotherapy in diffuse large B-cell lymphoma and follicular lymphoma.

Chemotherapy with rituximab followed by high-dose therapy and autologous stem cell transplantation in patients with mantle cell lymphoma.

BACKGROUND: The authors evaluated the efficacy of chemotherapy combined with rituximab followed by high-dose therapy (HDT) plus autologous stem cell transplantation in patients with mantle cell lymphoma (MCL). METHODS: This was a retrospective analysis of 34 patients who were treated in 2 departments of hematology, including 29 patients (85%) who received first-line treatment. Rituximab was administered as 4 injections just before harvest in 25 patients (73%) or simultaneously with chemotherapy in 9 patients (27%). HDT included total body irradiation in 26 patients (77%). RESULTS: After induction therapy, all patients except one reached a response: There were 14 (41%) complete responses (CR) and 19 (56%) partial responses (PR). Stem cell harvest was successful in all patients but 2, with a median number of 5.9 CD34-positive cells per 10(6)/kg. Three months after transplantation, 24 patients (71%) were in CR, and 7 patients (21%) were in PR. At 3 years from the day of transplantation, the estimated overall survival was 87%. With a median follow-up at 2.6 years, the estimated median time to disease progression was 3.4 years. Rituximab treatment before harvest did not delay hematopoietic reconstitution: The median time it took patients to recover absolute neutrophil count to > 0.5 G/L was 10 days. CONCLUSIONS: Chemotherapy combined with rituximab followed by HDT improved the overall survival and progression-free survival in patients MCL without adding toxicities.

Conservative treatment of primary gastric low-grade B-cell lymphoma of mucosa-associated lymphoid tissue: predictive factors of response and outcome.

OBJECTIVES: Primary gastric low-grade B-cell lymphoma of mucosa-associated lymphoid tissue may regress with conservative treatment such as anti-Helicobacterpylori therapy or monochemotherapy. The aims of the present study were to analyze the predictive factors of response to anti-H. pylori treatment, to assess the effects of an adjuvant therapy in responding patients, and to evaluate an alternative therapy in nonresponding patients. METHODS: From 1995 to 2000, 48 H. pylori-infected patients with localized primary gastric low-grade B-cell lymphoma of mucosa-associated lymphoid tissue were treated with anti-H. pylori therapy. Endoscopic and endoscopic ultrasonography features and histological grading of large cells' proportion were analyzed. Eradication of H. pylori and tumoral response were assessed at 2 and 6 months, respectively. From 1996, patients in remission at 6 months were randomized to receive either chlorambucil p.o. for 6 months or no treatment. Patients who did not respond to H. pylori eradication received chlorambucil p.o. for 1 yr. RESULTS: Among the 48 treated patients, 33 (69%) were in complete (n = 28) or in partial (n = 5) remission, and 15 (31%) were in treatment failure at 6 months. H. pylori was eradicated in 47 patients. The response was not correlated with the endoscopic features or with the histological grade. In contrast, it was related to ultrasonographic features: remission was achieved in 76% of patients when no perigastric lymph node was detected versus only 33% when endoscopic ultrasonography showed presence of lymph nodes (p = 0.025). All responding patients remained in remission (median 34 months) whatever the treatment they received (no treatment or chlorambucil). Remission could be achieved with chlorambucil in 58% of the nonresponding patients to anti-H. pylori treatment. CONCLUSIONS: The major negative predictive factor of the tumoral response to anti-H. pylori treatment in patients with primary gastric low-grade B-cell lymphoma of mucosaassociated lymphoid tissue was the presence of perigastric lymph nodes on endoscopic ultrasonography. In responding patients, remission remained stable, suggesting that adjuvant chemotherapy was not useful. In patients who failed to respond to H. pylori eradication, monochemotherapy with chlorambucil proved to be efficient, but new therapeutic modalities should be evaluated to improve the control of the tumoral process.

Three cycles of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) or epirubicin, bleomycin, vinblastine, and methotrexate (EBVM) plus extended field radiation therapy in early and intermediate Hodgkin disease: 10-year results of a randomized trial.

From 1990 to 1996, a total of 386 adult patients with early/intermediate Hodgkin disease (HD) were randomly assigned to receive 3 cycles of adriamycin, bleomycin, vinblastine, dacarbazine (an alkylating agent), and methylprednisolone (ABVDm, arm A) or epirubicin, bleomycin, vinblastine, methotrexate, and methylprednisolone (EBVMm, arm E), a combination without alkylating agent. Responding patients received extended field radiation therapy (RT). Postchemotherapy complete remission and 10-year freedom from progression rates were higher in arm A (79.5% and 91.4%) than in arm E (70.4%, P =.04, and 80%, P <.002). HD mortality (HDM), treatment-related mortality (TRM), and overall survival (OS) were similar in both arms (A, 2.1%, 7.5%, and 90.4%; B, 3.9%, 5.5%, and 90.3%). However TRM and OS rates were lower in patients aged 40 years or older (P <.005), reflecting the increasing incidence of background fatal events with increasing age. Finally, event-free survival (EFS) was higher in arm A (84.6%) than in arm E (74.9%, P <.02). In patients aged younger than 40 years in arm A (74%), 10-year EFS and OS rates were 88.9% and 95.4% with HDM and TRM rates as low as 0.7% and 3%. Three courses of ABVDm plus RT are the best available option for treating early or intermediate HD.

Treatment of patients with advanced or bulky Hodgkin disease with a 12-week doxorubicin, bleomycin, vinblastine, and dacarbazine-like chemotherapy regimen followed by extended-field, full-dose radiotherapy: long-term results of the Groupe Ouest et Est des Leucémies et Autres Maladies de Sang H90-A/B Multicenter Randomized Trial.

BACKGROUND: This Phase II study was performed in patients with advanced or bulky Hodgkin disease (HD) to evaluate the results of a 7-drug chemotherapy (CT) regimen that was administered over 12 weeks according to 2 randomized modalities followed by high-dose lymph node irradiation. METHODS: From 1990 to 1996, 162 patients with HD at clinical stages (CS) I-III with bulky disease (mediastinal mass ratio >or= 0.45 and/or unilateral or bilateral pelvic plus lumboaortic disease; 86 patients) or CS IV (76 patients) were randomized to receive the same cumulated dose of a CT regimen consisting of epirubicin (240 mg/m(2)), bleomycin (60 mg/m(2)), vinblastine (20 mg/m(2)), vincristine (4 mg/m(2)), cyclophosphamide (4000 mg/m(2)), etoposide (900 mg/m(2)), and methotrexate (180 mg/m(2)) plus methylprednisolone (1500 mg/m(2)) over 12 weeks either every 4 weeks (Arm Y, 79 patients) or every 3 weeks (Arm Z, 83 patients). Patients with disease in complete remission (CR) or partial remission after CT received extended-field lymph node irradiation (involved areas, 40 grays [Gy]; noninvolved areas, 30 Gy). RESULTS: Forty-two percent of patients achieved a post-CT CR, and 86% of patients achieved a CR after the completion of irradiation (there was no difference between Arm Y and Arm Z). Thirty-five patients developed recurrent disease; most of those patients were in post-CT partial remission. The 10-year freedom from first progression rate was 63.9% (there was no difference between Arm Y and Arm Z). Thirty-eight patients died: 24 patients from HD, 3 patients from CT-related early sepsis, 1 patient from radiation-induced pneumonitis, 6 patients from a second malignancy, and 4 patients from causes unrelated to treatment. The overall 10-year survival rate was 76.7%. Survival was slightly higher among patients in Arm Y (83.3%) compared with patients in Arm Z (70.2%; P = 0.12). CONCLUSIONS: No differences were found when the same amount of CT was delivered in three courses or in four courses. In 1997, because most recurrences of the H90-A/B trial occurred in patients who achieved a post-CT partial remission, the authors decided to reinforce the intensity of the initial CT and designed a new randomized study comparing two modalities of more intensive CT plus consolidative radiotherapy (H97-LM trial).