Primary Refractory non-Hodgkin Lymphoma Research Articles

Use of gemcitabine, oxaliplatin, and anti‐CD20 therapy in children and adolescents with non‐Hodgkin lymphoma unfit for intensive therapy

Multiagent immunochemotherapy affords excellent outcomes in pediatric non-Hodgkin lymphoma (NHL); however, scarce data exist for patients unfit for intensive treatment. Rituximab, gemcitabine, and oxaliplatin (R-GemOx) is well tolerated and efficacious in elderly adults with NHL; however, its use has not been described in pediatrics. In this retrospective, single-center study, six children with mature B-cell NHL and significant comorbidities received anti-CD20 therapy with GemOx (rituximab or obinutuzumab or ofatumumab with gemcitabine and oxaliplatin [R/O-GemOx]). R/O-GemOx was well tolerated and resulted in complete response in two of three patients with newly diagnosed NHL and one of three patients with primary refractory NHL. R/O-GemOx is a viable treatment option for children with NHL who cannot tolerate intensive therapy.

The effect of gemcitabine, dexamethasone, and cisplatin chemotherapy in relapsed/refractory NHL and HL patients: A single center experience.

The optimal choice of salvage therapy for patients with relapsed/refractory non-Hodgkin lymphoma or Hodgkin lymphoma remains controversial. In this study, we aimed to share our experience in relapsed/refractory lymphoma patients who received GDP/R-GDP as salvage chemotherapy in our center. Data of 47 relapsed/refractory Hodgkin lymphoma and non-Hodgkin lymphoma patients who received GDP or R-GDP as salvage chemotherapy in our center between July 2014 and October 2017 were retrospectively evaluated. Non-Hodgkin lymphoma and Hodgkin lymphoma patients were divided into two groups as primary refractory and relapsed. The one-year overall survival was 100% (for relapsed) and 36.9% (for refractory) in the non-Hodgkin lymphoma groups, and 82.5% (for relapsed) and 80% (for refractory) in the Hodgkin lymphoma group. The one-year progression-free survival (PFS) was 72.7% (for relapsed) and 38.5% (for refractory) in patients with NHL, and 41% (for relapsed) and 18.2% (for refractory) in patients with HL. GDP/R-GDP seems to be a well-tolerated out-patient salvage regimen for relapsed/refractory non-Hodgkin lymphoma and Hodgkin lymphoma. Although proven efficacy, negative toxicity profile, and ease of administration, the application of gemcitabine-based therapy for patients with primary refractory non-Hodgkin lymphoma and Hodgkin lymphoma provided limited success.

Randomized Phase II Multi-Center Trial of Busulfan, Etoposide, and Cyclophosphamide Versus Busulfan, Etoposide, and Melphalan As Conditioning Therapy for Autologous Transplantation in Patients with Non-Hodgkin's Lymphoma: A Multicenter Study from Consortium for Improving Survival of Lymphoma (CISL)

BackgroundHigh dose chemotherapy followed by autologous stem cell transplantation (ASCT) has become the standard approach for relapsed or high risk non-Hodgkin's lymphoma (NHL). Several different high dose therapy (HDT) conditioning regimens have been used for NHL, such as BEAM(carustine, etoposide, cytosine arabinoside, melphalan), BEAC( carmustine, etoposide, cytosine arabinoside, cyclophosphamide), and CBV(cyclophosphamide, carmustine etoposide). Carmustine is an active drug in the HDT of NHL but the supply of carmustine is limited in some countries. Intravenous busulfan containing regimens as conditioning regimen have been used for both allogeneic and autologous stem cell transplantation in patients with hematologic and non-hematologic malignancies. We and CISL have previously studied that conditioning regimen of i.v. busulfan/melphalan/etoposide was well tolerated and effective in patients with relapsed or high risk NHL. And busulfan/cyclophosphamide/etoposide conditioning regimen has been extensively utilized in ASCT for NHL. Therefore, based on the encouraging results, we conducted a randomized phase II multicenter trial of busulfan/etoposide/cyclophosphamide (BCT) versus busulfan/etoposide/ melphalan/ (BMT) as conditioning therapy for ASCT in patients with NHL.MethodsPatients with chemosensitive high risk NHL or relapsed or primary refractory NHL underwent high dose chemotherapy at 16 centers in Korea. Patients were randomly assigned to receive BCT conditioning chemotherapy or BMT conditioning chemotherapy. BCT regimen consisted of iv busulfan 3.2 mg/kg/day i.v. on days -8,-7, and -6, etoposide 400mg/m2 day i.v. on days -5 and -4 and cyclophosphamide 50mg/kg/day i.v. on days -3 and -2 and BMT regimen were iv busulfan 3.2 mg/kg/day i.v. on days -8,-7, and -6, etoposide 400mg/m2 day i.v. on days -5 and -4 and melphalan 50mg/m2/day i.v. on days -3 and -2. The primary efficacy end points were 2 year progression free survival.ResultsSeventy five patients were enrolled onto the study. Patients randomly assigned to the BCT group (39 patients) or the BMT group (36 patients). Main subgroups were DLBCL (n=42, 56%) and T cell lymphoma (n=27, 36%). Thirteen patients (33.3%) in the BCT group and 11 patients (30.5%) in the BMT group had disease progression or died. 2 year progression free survival rate was 62.5% in the BCT group and 63.1% in the BMT group (p=0.924) (Fig 1). There was no treatment related mortality.ConclusionsNo significant differences were observed in progression free survival between BCT group and BMT group. Accordingly, busulfan based conditioning regimen may be regarded as an important treatment option to substitute for BEAM regimen. Further, considering R-CHOP or CHOP regimes are standard induction regimens, BMT conditioning will be good alternative to patients who can't be used cyclophosphamide. [Display omitted] DisclosuresKim:Celltrion, Inc.: Consultancy, Honoraria.

Allogeneic and autologous stem cell transplantation with busulfan, cyclophosphamide, and etoposide conditioning therapy for relapsed/refractory non-Hodgkin lymphoma

The optimal stem cell transplantation (SCT) conditioning therapy for relapsed/refractory non-Hodgkin lymphoma (NHL) is not clearly defined. In a retrospective analysis, we examined 25 patients with “high risk” relapsed/refractory NHL who received busulfan, cyclophosphamide, and etoposide (Bu/Cy/VP16) conditioning with autologous or allogeneic SCT. The majority of patients had aggressive histology and 52% had primary refractory NHL. Furthermore, 48% of patients had chemotherapy-resistant disease at the time of SCT. Fifty-six percent of patients underwent allogeneic SCT, while 44% had autologous SCT. The median engraftment time for neutrophils and platelets was 13.5 and 14 days, respectively. The 100-day treatment-related mortality (TRM) was 16%, while the 2-year non-relapse mortality (NRM) rate was also 16%. At a median follow-up of 15 months, the estimated 2-year disease-free survival (DFS) rate was 64% (95% confidence interval (CI): 36%-82%) and the estimated 2-year overall survival (OS) was 69% (95% CI: 40%-86%). Furthermore, the 2-year disease-specific survival (DSS) rate was 73% (95% CI: 40%-90%). Using Cox proportional hazard modeling, the International Prognostic Index at time of relapse predicted DFS and OS. Altogether, Bu/Cy/VP16 was associated with early TRM; however, late toxicities (including NRM) were uncommon resulting in relatively good survival rates in a high-risk relapsed/refractory NHL population.

Salvage abdominal irradiation for refractory non-Hodgkin′s lymphoma

Abdominal irradiation, as a part of treatment, is often ignored in the management of refractory non-Hodgkin's lymphoma (NHL). To evaluate the efficacy and the toxicity of this approach after failure of chemotherapy. 27 patients with intraabdominal lymphoma underwent salvage irradiation between 1982 and 2001. All patients were treated with a Cobalt-60 machine. The total dose administered to the abdomen was 18-20 Gy at the rate of 1.5-1.8 Gy per daily fraction, followed by a boost to gross disease up to 20 Gy. All patients had previously been heavily pretreated with chemotherapy. Fourteen patients, nine with follicular and five with diffuse lymphomas, had primary refractory tumors that had never achieved remission. Thirteen patients, six with follicular and seven with aggressive tumors, had refractory relapsed tumors after achieving one or more complete remissions. The response rate was 77%. The median follow-up was 53 months. The 5-year and 10-year survival rates were 25 and 17%, respectively. The in-field and out-of-field recurrence rates were 22 and 33%, respectively. Survival rates were significantly better for patients with refractory relapse compared to those with primary refractory lymphoma (P < 0.01). There was no significant difference in terms of response, recurrence, or survival rates between follicular and aggressive types. Out-of-field recurrence occurred more frequently in initial stage III and IV disease. Toxic deaths occurred in three patients (11%). Salvage radiotherapy for refractory abdominal NHL is a feasible alternative for both follicular and diffuse subtypes and may provide significant palliation and prolongation of survival. It is less effective in patients with primary refractory NHL than in those with refractory relapsed NHL.

The Mobilisation of Peripheral Blood Stemcells in Patients with High Risk or Relapsed Non-Hodgkin Lymphoma Does Not Lead to the Presence of Detectable Tumour Cells in the Stem Cell Harvest.

Consolidation treatment with high dose chemotherapy in combination with an autologous peripheral blood stem celll transplant. is widely used in patients with high risk non-Hodgkin lymphoma (NHL). Also this treatment has its place in patients with relapsed intermediate lymphoma. Earlier studies in patients with breast cancer or multiple myeloma showed evidence for (minimal) tumour contamination in the graft that might lead to the occurence of relapse. For patients with NHL this is less clear. For the present analysis 60 patients (pts) were included: 18 pts with primary high risk NHL, 6 patients with mantle cell lymphoma, and 36 pts with primary refractory or relapsed intermediate NHL. Patients with high risk NHL were treated with induction chemotherapy according to the Hovon-27 or Hovon-40 protocol(www.hovon.nl). Two patients (1 pt with T-Lymphoblastair lymphoma, 1 pt with Burkitt Lymphoma ) received intensive induction chemotherapy according to our leukemia protocols. Stem cells were collected as early as possible, provided the peripheral blood and bone marrow showed no histological evidence of NHL and < 20% lymfocytes. In the patients with mantle cell lymphoma stem cells were collected during the induction chemotherapy (Hovon-45 protocol:www.hovon.nl), irrespective of their presence in the bone marrow. The patients with primary refractory or relapsed intermediate NHL received reinduction chemotherapy with DHAP (Dexamethason, Cytarabin, Cisplatin) or EMP (Etopside, Mitoxantrone, Prednisone). After two or three courses peripheral blood stem cells were mobilised with G-CSF (Neupogen, Amgen) 10 μg/kg sc daily starting day 5 and harvested for autologous stem cell transplant. Before the start of mobilisation patients were required to be responsive to the induction chemotherapy and to have a bone marrow without histological and immunological detectable tumour cells. In all patients a sample of the first day stem cell collection was analyzed with the use of three or four colour Flowcytometry. The sensitivity of the assay was 1/ 104–105 lymphoma cells. Only in 3 pts tumour cells were found at a level > 0.05 %. Interestingly two patients had a primary diagnosis of diffuse large B-cell lymphoma T-cell/ histiocyte rich variant. Both pts relapsed: one within 6 months and the other one within 12 months.The third patient suffered from a anaplastic large cell T-cell lymphoma and relapsed after 15 months. In all other patients no lymphoma cells were detectable in the stemcell harvest at a minimum level of <0.02%. Follow up showed a relapse within 12 months in 16 of 36 patients with relapse or primary refractory NHL (44%) and 6 of 24 patients with high risk NHL (25%). In conclusion, in the vast majority of the above patients, no circulating lymphoma cells were detectable with the use of flowcytometry in the stemcell harvest. Therefore we conclude that with the present techniques and sensitivity immunological analysis of the graft does not give additional information and therefore is not necessary in this patient group. Provided the bone marrow before collection is free of lymphoma cells, we feel that the currently used mobilisation regimen is safe in these patients and does not lead to the presence of detectable tumour cells in the collected stemcells.