Anne-Sophie Michallet

Clinicopathologic characteristics and outcome of diffuse large B-cell lymphomas presenting with an associated low-grade component at diagnosis.

PURPOSE Some diffuse large B-cell lymphomas (DLBCL) present at diagnosis with associated morphologic features of small B-cell non-Hodgkins lymphoma (NHL) and may arise from the transformation of a previously unknown indolent low-grade lymphoma. The characteristics and prognosis of these particular DLBCL are not well known. PATIENTS AND METHODS The strict morphologic review of consecutive DLBCL patients diagnosed over 12 years in our department (Hematology Department, Centre Hospitalier Lyon-Sud, Lyon, France) allowed to retrieve 60 DLBCL that could be have occurred from the transformation of marginal zone B-cell NHL (32 patients), follicular NHL (22 patients), and small lymphocytic NHL (6 patients). We compared them to 180 matched patients of de novo DLBCL. RESULTS Patients median age was 55 years and presented the following clinical characteristics: poor performance status in 33%, disseminated disease in 97%, more than one extranodal site in 50%, and increased lactate dehydrogenase level in 55%. Complete remission with multidrug chemotherapy regimens was achieved in 60% of the patients, but 48% relapsed: 28% with aggressive and 20% with indolent histology, respectively. Overall survival (OS) and freedom-from-progression rates at 5 years were 57% and 33%, respectively. The matched-control analysis showed that patients with transformed NHL at diagnosis had lower complete response to chemotherapy (P = .004) and higher progression rate (P = .03), whereas no difference was observed in OS (P = .21). CONCLUSION Compared to de novo DLBCL, transformed NHL at diagnosis have similar overall survival but lower complete response to initial treatment and higher risk of indolent relapses.

Impact of dose intensity on outcome of fludarabine, cyclophosphamide, and rituximab regimen given in the first-line therapy for chronic lymphocytic leukemia

Fludarabine-cyclophosphamide-rituximab is the most efficient first-line treatment for chronic lymphocytic leukemia patients. Many dose adjustments of the original MD Anderson Cancer Center regimen have been proposed. However, whether fludarabine-cyclophosphamide-rituximab relative dose intensity may have an impact on outcome has not yet been investigated. We retrospectively assessed relative dose intensity in 106 community-based patients included in our regional healthcare network from 2004-11, all receiving fludarabine-cyclophosphamide-rituximab as first-line treatment outside clinical trials. Dose reductions were observed in 51.4% of patients, mainly decided by the individual physician and not based on recommendations (52.7%), while there were fewer reports of toxicity or dose reduction because of impaired renal function. Progression-free survival was significantly reduced in patients who had a reduction in dose intensity of more than 20% in fludarabine-cyclophosphamide and/or rituximab. Multivariate analysis showed dose of rituximab had a significant impact on minimal residual disease and progression-free survival. Although prophylactic granulocyte-colony stimulating factor significantly reduced the rate of grade 3-4 neutropenia and febrile neutropenia, it had no impact on relative dose intensity and outcome. This study shows that, in routine clinical practice, there is low adherence to the original MD Anderson Cancer Center fludarabine-cyclophosphamide-rituximab schedule, and that the decision to modify dosage was mostly taken by the individual physician and was based on anticipated toxicity. This study shows that reduction of fludarabine-cyclophosphamide and, more importantly, of rituximab doses seriously interferes with progression-free survival.

Complete remission after first-line radio-chemotherapy as predictor of survival in extranodal NK/T cell lymphoma.

BackgroundExtranodal nasal-type NK/T-cell lymphoma is a rare and severe disease. Considering the rarity of this lymphoma in Europe, we conducted a multicentric retrospective study on nasal-type NK/T cell lymphoma to determine the optimal induction strategy and identify prognostic factors.MethodsThirty-six adult patients with nasal-type NK/T-cell lymphoma were recruited and assessed. In total, 80 % of patients were classified as having upper aerodigestive tract NK/T-cell lymphoma (UNKTL) and 20 % extra-upper aerodigestive tract NK/T-cell lymphoma (EUNKTL).ResultsFor advanced-stage disease, chemotherapy alone (CT) was the primary treatment (84 % vs. 10 % for combined CT + radiation therapy (RT), respectively), while for early-stage disease, 50 % of patients received the combination of CT + RT and 50 % CT alone. Five-year overall survival (OS) and progression-free survival (PFS) rates were 39 % and 33 %. Complete remission (CR) rates were significantly higher when using CT + RT (90 %) versus CT alone (33 %) (p < 0.0001). For early-stage disease, CR rates were 37 % for CT alone versus 100 % for CT + RT. Quality of response was significantly associated with survival, with 5-year OS being 80 % for CR patients versus 0 % for progressive disease patients (p < 0.01).ConclusionEarly RT concomitantly or sequentially with CT led to improved patient outcomes, with quality of initial response being the most important prognosticator for 5-year OS.

Recent developments in the treatment of aggressive non-Hodgkin lymphoma

SUMMARY Options for treating aggressive non-Hodgkin lymphoma (NHL) have expanded in recent years. In phase 3 clinical trials, giving rituximab with cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) every 3 weeks (R-CHOP-21) has been associated with improved survival, without increased toxicity, in all patient groups studied. Giving dose-dense CHOP--CHOP every 2 weeks (CHOP-14)--has also proved appropriate for all patients 18-75 years old. Studies combining these approaches--dose-dense CHOP with rituximab (R-CHOP-14)--have shown improved survival over CHOP-14 in patients 60-81 years old. These results also indicate the importance of delivering chemotherapy at full dose and on schedule, which can improve survival in aggressive NHL. Effective delivery of dose-dense regimens requires granulocyte colony-stimulating factor support, which should also be considered for standard CHOP. A key question for the future is whether R-CHOP-14 is superior to R-CHOP-21.

Early stage follicular lymphoma: what is the clinical impact of the first-line treatment strategy?

BackgroundLess than 20% of patients with follicular lymphoma (FL) present with Ann Arbor Stage I or II disease at diagnosis. Numerous therapeutic options exist, however radiation therapy is considered the standard of care for early-stage disease based on single-institution or retrospective series. Our aim was to revisit the outcome of patients with localized FL in the rituximab era.Patients and MethodsWe analyzed the characteristics and outcomes of 145 early-stage FL patients, who were retrospectively divided into six groups according to their initial treatment: watchful waiting (WW), chemotherapy alone (CT), radiotherapy alone (RT), combined radiotherapy and chemotherapy (RT-CT), rituximab alone (Ri), and immunochemotherapy (Ri-CT).ResultsOf the 145 patients, 84 (57.9%) had stage I disease and 61 (42.1%) stage II. The complete response (CR) rate varied from 57% for the Ri group to 95% for the RT-CT group. Overall survival (OS) at 7.5 y of patients treated after 2000 was better than that of those treated prior to 2000. OS did not significantly differ from one treatment to another. In contrast, a significant difference was found for progression-free survival (PFS) at 7.5 y, which favored Ri-CT (60%) therapy versus the others (p= 0.00135).ConclusionDelayed therapy initiation was associated with a similar OS than that observed in patients receiving immediate intervention. The “watchful waiting” strategy may thus be proposed as first-line therapy, similar to stage III and IV FL patients with a low tumor burden. However, when treatment is required, immunochemotherapy appears to be the best option.

Rituximab–cyclophosphamide–dexamethasone combination in management of autoimmune cytopenias associated with chronic lymphocytic leukemia

Abstract We report our experience on rituximab–cyclophosphamide–dexamethasone (RCD) combination therapy for the treatment of autoimmune disorders in 48 patients with chronic lymphocytic leukemia (CLL). The diagnosis of autoimmune disease (AID) was autoimmune hemolytic anemia (AIHA) in 26 (54%), autoimmune thrombocytopenic purpura (AITP) in nine (18.8%), Evans syndrome in eight (16.7%), and pure red cell anemia (PRCA) in five patients (10.5%). CLL was considered progressive in 40% of subjects upon AID diagnosis. Overall, an 89.5% response rate was obtained with this combination, irrespective of the AID type. Relapse occurred in 19 patients (39.6%). The median duration of autoimmunity was 24 months, but the duration of response of autoimmunity (DR-AI) was higher for patients presenting with: (1) AID early during the CLL course (<3 years), or (2) both and pure red cell aplasia (PRCA) in five patients (10.5%) and AIHA.

Salvage outcomes in patients with first relapse after fludarabine, cyclophosphamide, and rituximab for chronic lymphocytic leukemia: the French intergroup experience.

The optimal management of patients with relapsed chronic lymphocytic leukemia (CLL) is dictated by the type of prior therapy, duration of prior response, presence of genomic aberrations, age, and comorbidities. The patterns of relapses and the clinical outcomes of second‐line options after fludarabine‐cyclophosphamide‐rituximab (FCR) is given as a frontline treatment are currently unknown. In this retrospective and non‐randomized study, we report the outcomes of 132 patients from databases of 14 French CLL study group centers who needed a second‐line treatment after FCR frontline. Bendamustine + rituximab (BR) was the most frequently used second‐line regimen, followed by alemtuzumab‐based regimens, R‐CHOP, and FCR. Median progression‐free survival (PFS) was 18 months after BR with a median overall survival (OS) not reached. We also found that response durations of < 36 months and the presence of del(17p) are critical factors that contribute to poor overall survival. BR appears to be an effective salvage regimen in our series, both in terms of progression‐free and overall survival. Patients who relapsed less than 36 months after FCR have a poor outcome, not significantly different in this study from patients with early relapses less than 12 or 24 months. Am. J. Hematol. 90:511–514, 2015.

Impact of chimaerism analysis and kinetics on allogeneic haematopoietic stem cell transplantation outcome after conventional and reduced-intensity conditioning regimens

This retrospective study aimed to analyse the impact on overall survival (OS) and event‐free survival (EFS) of chimaerism status and kinetics following allogeneic conventional and reduced‐intensity conditioning haematopoietic stem cell transplantation, and to compare this with the impact of other well‐known factors. We investigated the chimaerism status of 187 patients [84 females, 103 males; median age 39·5 years (range, 17–62 years)]. After transplantation, 121 patients (65%) presented full donor chimaerism (FDC) and 63 (34%) mixed chimaerism (MC). For MC, we divided the population into patients who presented regressive mixed chimaerism (RMC) (21 patients: 11%), stable mixed chimaerism (SMC) (20 patients: 11%) and progressive mixed chimaerism (PMC) (22 patients: 12%). At last follow‐up, 71 patients were alive and 116 had died (48% from disease progression and 52% from transplant‐related causes). With a mean follow‐up of 39·4 and 34·8 months, the 5‐year probabilities of OS and EFS for the total group were, respectively, 55% and 43%: 69·5% and 61% for FDC, 35·4% and 25% for RMC, 42·6% and 28·6% for SMC, and 21% and 10·4% for PMC (P < 0·0001 and P < 0·0001). Multivariate analysis only showed a significant impact of chimaerism status on OS, as well as acute and chronic graft‐versus‐host disease on EFS, with a trend for conditioning regimen.

Bendamustine and rituximab combination in the management of chronic lymphocytic leukemia‐associated autoimmune hemolytic anemia: A multicentric retrospective study of the French CLL intergroup (GCFLLC/MW and GOELAMS)

We report our experience on bendamustine and rituximab (BR) combination in 26 patients with chronic lymphocytic leukemia (CLL) complicated by autoimmune hemolytic anemia (AIHA). At the time of BR initiation, 88% of the patients had already been treated for AIHA and CLL was progressive regardless of AIHA in all patients but one. Overall response rates were 81% for AIHA and 77% for CLL. Median time to next treatment was 28.3 months and 26.2 months for AIHA and CLL, respectively. BR therapy may represent a good and safe therapeutic option in this setting where adequate control of CLL seems important for long‐term AIHA response. Am. J. Hematol. 90:204–207, 2015.

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.