Gemcitabine as a single agent in the treatment of relapsed or refractory low-grade non-Hodgkin's lymphoma

A multicentre phase II trial was conducted to evaluate the efficacy and toxicity of gemcitabine in patients with refractory or relapsed indolent non-Hodgkin's lymphoma. Thirty-six patients were enrolled onto the study, including 11 cases of mantle cell lymphoma (MCL), 10 cases of chronic lymphocytic leukaemia (CLL)/lymphocytic lymphoma, nine cases of follicular lymphoma, four cases of lymphoplasmacytic lymphoma and two cases of T-cell lymphoma. Gemcitabine 1 g/m(2) was administered as a 30-min infusion on d 1, 8 and 15 of a 28-d schedule, up to a maximum of six cycles. Complete responses were observed in two patients with MCL, and partial responses were observed in seven patients, including three patients with CLL/lymphocytic lymphoma, two patients with T-cell lymphoma, one patient with MCL and one patient with follicular lymphoma. Minor responses were observed in three patients, including two patients with MCL and one patient with CLL. The median duration of response was 150 d and the overall progression-free survival was 342 d. Haematological toxicity was observed as grade 3-4 leucopenia in 12 patients (33%) and grade 3-4 thrombocytopenia in 18 patients (50%). Severe non-haematological toxicity included one case of fatal veno-occlusive disease, one case of thrombotic microangiopathy leading to terminal renal failure, one case of capillary leak syndrome, one case of myocardial infarction and drug-induced fever in two patients. These data suggest that gemcitabine displays activity in patients with MCL and CLL/lymphocytic lymphoma. Haematological toxicity was frequent in these heavily treated patients. Severe non-haematological toxicity was significant and should be taken into account in the design of future trials.     

Mini-BEAM is effective as a bridge to transplantation in patients with refractory or relapsed Hodgkin lymphoma who have failed to respond to previous lines of salvage chemotherapy but not in patients with salvage-refractory DLBCL

Patients with relapsed or refractory lymphoma can be cured with stem cell transplantation if they are shown to have disease that is responsive to salvage chemotherapy. Patients who fail to respond to first-line salvage chemotherapy tend to do very poorly. Here we report on 39 such patients who received mini-BEAM (carmustine, etoposide, cytarabine, melphalan) chemotherapy as second or subsequent-line salvage chemotherapy. Fifty-six percent of these patients had primary refractory disease and a further 28% had responses to first-line therapy that lasted <12 months. Seventy-two percent had progressive disease following the salvage chemotherapy administered immediately prior to mini-BEAM and the remaining 28% had stable disease. Overall there was a 38% response to mini-BEAM (complete response = 28%, partial response = 10%). Patients with Hodgkin lymphoma (HL) had a higher response rate compared to those with diffuse large B cell lymphoma (DLBCL) (63% vs. 20%). Seventy-four percent of HL patients were able to proceed to transplantation compared with 30% of patients with DLBCL. Mini-BEAM is a very effective bridge to transplantation in very poor risk patients with HL who have failed to respond to first-line salvage chemotherapy. Its efficacy in non-Hodgkin lymphoma is more modest.     

Gemcitabine, vinorelbine and prednisone for refractory or relapsed aggressive lymphoma,results of a phase II single center study

The optimum therapy for patients with relapsed or refractory aggressive non-Hodgkin’s lymphomas (NHL) not qualifying for platinum-based and/or high-dose chemotherapy is not known. We conducted a prospective phase II study evaluating a regimen consisting of gemcitabine (1 g/m², days 1 and 8), vinorelbine (30 mg/m², days 1 and 8) and prednisone (100 mg/day, days 1–8) (GVP) given every 21 days. Fifteen patients with a median age of 68 years and a median of three previous therapies were enrolled. Diagnoses included B lymphoblastic (n=1), diffuse large B cell (n=10), anaplastic large T cell (n=2) and peripheral T-cell NHL (n=2). The median international prognostic index score was 3 (six patients with a score of 4 or 5). Five patients achieved a complete remission and three patients a partial remission. The median overall survival was 13.8 months, and the median time to next treatment was 4.4 months. Haematological toxicities of World Health Organisation grades 3/4 were leucopenia in 58%, thrombocytopenia in 33% and anaemia in 17% of all courses. Three patients had grade 3 infections. There was no treatment-related mortality. GVP shows substantial activity in poor prognosis relapsed or refractory aggressive lymphomas and is generally well tolerated, but haematological toxicity is dose limiting.     

Etoposide, mitoxantrone and prednisone: a salvage regimen with low toxicity for refractory or relapsed non-Hodgkin's lymphoma

BACKGROUND AND OBJECTIVES: Relapsed non-Hodgkin's lymphoma (NHL) is preferably treated with high-dose therapy and stem cell support. However, not all patients qualify for intensive chemotherapy. We evaluated the efficacy and toxicity of a new salvage chemotherapy regimen designed for patients with relapsed or refractory NHL who are not appropriate candidates for high-dose therapy (HDT). DESIGN AND METHODS: Seventy-nine patients received a regimen consisting of etoposide (350 mg/m(2) i.v. day 1), mitoxantrone (14 mg/m(2) i.v. day 1) and prednisone (80 mg/m(2) p.o. days 1-5) (EMP). The majority had aggressive NHL. Twenty-one patients were elderly, i.e. >60 years of age; RESULTS. The overall response rate in the 79 patients was 38% as compared to 67% in the elderly. The progression-free survival was 54% and 30% at 12 months and 24 months, respectively. The toxicity of the regimen was relatively low. No toxic deaths have occurred. In 28 of 231 cycles (12%) a CTC-grade 2-4 infection was encountered. Twenty-one hospital admissions were necessary because of infection or fever. Other toxicity was rare. Toxicity was not greater in the elderly patients. WHO performance status 2-4 and elevated serum lactate dehydrogenase (LDH) concentrationv were adverse prognostic factors for response as well as for overall survival. Another adverse prognostic factor for response was age <60 years. INTERPRETATION AND CONCLUSIONS: EMP is a new salvage regimen with a relatively low toxicity. It should be considered for patients with relapsed or refractory NHL who are not candidates for standard reinduction therapy and stem cell transplantation.     

Ifosfamide,epirubicin and etoposide regimen as salvage and mobilizing therapy for relapsed/refractory lymphoma patients

BACKGROUND AND OBJECTIVES: Therapy for relapsed/refractory lymphomas should be based only on drugs not included in the front-line chemotherapy regimens. We adopted the strategy of using salvage chemotherapy to debulk disease and simultaneously mobilize stem cells, using a regimen based on ifosfamide and etoposide, (drugs not usually used for front-line treatment). DESIGN AND METHODS: A three-drug combination of ifosfamide, epirubicin and etoposide (IEV) was used to treat 62 patients with relapsing or refractory aggressive non-Hodgkin's lymphoma (NHL; n=51) or Hodgkin's disease (HD; n=11). Forty-five of the patients were studied for the feasibility of peripheral blood stem cell (PBSC) harvest. RESULTS: The overall and complete response (CR) rates were, respectively, 77% and 32% in the NHL subset and 81% and 45% in the HD subset. Among the 17 patients who achieved CR after IEV but did not have a subsequent transplantation, the median duration of the response was 9 months (range, 2 to 14 months). Mobilization was successful in 33 of 45 (71%) patients. Among the 45 who proceeded to autotransplantation, 27 (60%) were in CR status after the autograft; 23/45 (51%) patients are currently in continuous CR with a median follow-up of 25 months (range, 10-68 months); the relapse-free survival curve shows 83% in this state at 60 months. Twenty-three (37%) patients are currently in continuous CR with a median follow-up of 25 months. Clinical and hematologic toxic effects were mild. INTERPRETATION AND CONCLUSIONS: Our results indicate the efficacy of the IEV regimen in inducing a good remission rate. IEV is a predictable and highly effective mobilization regimen in relapsed/refractory patients with aggressive NHL or HD.     

Allogeneic SCT in refractory or relapsed adult ALL is effective without prior reinduction chemotherapy

We present 60 patients with refractory (n=8) or relapsed (n=52) adult ALL who received allogeneic hematopoietic SCT (HSCT) with (n=41) or without (n=19) prior reinduction chemotherapy. In our center, omission of reinduction is recommended if a suitable donor is promptly available, tumor burden is moderate and disease features suggest a highly aggressive course. Overall survival (OS) of the whole cohort at 1, 2 and 5 years was 42, 33 and 28%, respectively. Leukemia-free survival at 1, 2 and 5 years was 37, 33 and 24%. Deaths were due to relapse (n=25), acute or chronic GVHD (n=7), infections (n=8) or toxicity (n=4). Interestingly, patients who did not receive reinduction before HSCT had better outcomes than patients who received reinduction with OS at 1, 2 and 5 years being 58 vs 34%, 47 vs 25% and 47 vs 18%, respectively (P=0.039). Importantly, even achievement of a second CR after reinduction was not associated with improved survival compared to patients directly proceeding to HSCT. We conclude that patients who undergo HSCT for refractory or relapsed ALL can achieve long-term survival. In selected patients, reinduction chemotherapy can be omitted if immediate HSCT is feasible.     

Phase-II trial with M-CAVe-CEC as a salvage chemotherapeutic regimen for early relapsed or primary refractory Hodgkin's disease

Summary We describe five patients with hematologic Munchausen syndrome who were discovered within 5 years. The patients presented for hematologic evaluation of coagulopathy, iron-deficiency anemia, or macrohematuria with severe anemia. The final diagnoses were phenprocoumon intake (2x), self-inflicted phlebotomy (2x), and urogenital manipulation (1x). All five patients were female ranging in age between 23 and 45 years; two were nurses. In four cases we were able to unmask the patient. We think that hematologic Munchausen syndrome has a rather uniform pattern and may be divided into three subtypes: (a) anticoagulation type, (b) anemia type, and (c) pretended hematologic form. Hematologic Munchausen syndrome should especially be considered if there is an unexplained coagulation disorder or therapy-resistant iron-deficiency anemia, and if the patient is a young female nurse who has had many hospitalizations.     

GEMOX-R regimen is a highly effective salvage regimen in patients with refractory/relapsing diffuse large-cell lymphoma: a phase II study

Objectives:  The prognosis of old or immunocompromised patients with refractory or relapsing diffuse large-cell lymphoma (DLCL) is very poor as the current standard of salvage therapy with autologous stem cell transplantation (ASCT) is not feasible for most of them. New active regimens with an acceptable toxicity profile are needed. We aim to report the results of a phase II trial of the GEMOX-R regimen in DLCL.
Methods:  A total of 32 patients received GEMOX-R regimen in 2-wk intervals if feasible or every 3 wk for a planned six to eight courses.
Results:  Median age of the population was 69 yr. Forty-one percent of the patients were primary refractory and 59% after relapsing. At GEMOX-R, 75% of patients had a stage III–IV and an adjusted International Prognostic Index > 1 was observed in 69%. The response rate was 43% with 34% complete response. Neutropenia and thrombopenia grade III–IV were observed in 43% of the patients and neurotoxicity grade III–IV in 7% of cases. Median follow-up for alive patients was 13 months and the median survival was 9.1 months. At 12 months, the overall survival and progression-free survival were 41% and 29%, respectively.
Conclusions:  GEMOX-R is a new salvage regimen for DLCL with high activity and relatively safe toxicity profile, which can be offered to elderly patients not candidates of ASCT consolidation. The high efficacy of the regimen in this unfavorable population and also in immunocompromised situations warrant further investigation of this regimen in all salvage situations of this type of lymphomas.     

Ifosfamide and vinorelbine: an active regimen for patients with relapsed or refractory Hodgkin's disease

Twenty-six patients with relapsed or refractory Hodgkin's disease (HD) were treated with an intensive salvage regimen combining ifosfamide (3000 mg/m²/d, days 1–4 through continuous intravenous infusion) and vinorelbine (25 mg/m², i.v. days 1 and 5) with mesna uroprotection and G-CSF support. Courses were given at 3-week intervals.
Ten patients achieved a complete and 10 patients a partial response, yielding an overall response rate of 77%. The main toxic effect was neutropenia and the combination was well tolerated.     

DexaBEAM versus ICE salvage regimen prior to autologous transplantation for relapsed or refractory aggressive peripheral T cell lymphoma: a retrospective evaluation of parallel patient cohorts of one center

High-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) is considered standard in the treatment of patients with relapsed or refractory aggressive peripheral T cell lymphoma (PTCL). However, the optimal salvage regimen before ASCT has not yet been established. We retrospectively analyzed 31 patients with relapsed or refractory aggressive PTCL after anthracycline-based first-line chemotherapy who received either DexaBEAM (dexamethasone, carmustine, etoposide, cytarabine, and melphalan; n?=?16) or ICE (ifosfamide, carboplatin, and etoposide; n?=?15) regimen as first salvage chemotherapy followed by HDT/ASCT. The overall response rate (OR) was significantly higher for patients treated with DexaBEAM (69 %; 95 % confidence interval 46.0–91.5 %) as compared to the ICE group (20 %; 95 % confidence interval ?0.2–40.2 %; P?=?0.01), with higher complete response (CR; 38 %; 95 % confidence interval 13.8–61.2 %; vs. 7 %; 95 % confidence interval ?6.0–19.6 %) as well as partial response (PR; 31 vs. 13 %) rate. Changing regimen due to failure of first salvage therapy, 12 patients initially receiving ICE still achieved an OR of 58 % (33 % CR, 25 % PR) with DexaBEAM as second salvage therapy, whereas in three patients receiving ICE after DexaBEAM failure, only one achieved an OR (1 PR). Median progression-free survival was significantly higher in the DexaBEAM group (6.4 vs. 2 months; P?=?0.01). Major adverse event in both groups was myelosuppression with higher but tolerable treatment-related toxicity for patients in the DexaBEAM group. For all patients proceeding to HDT/ASCT, a 3-year overall survival was 50 %. Together, considering the limitations of the retrospective design of the evaluation and the small sample size, our data suggest that DexaBEAM salvage chemotherapy is superior to ICE for patients with relapsed or refractory aggressive PTCL for remission induction prior to autologous transplantation, with higher but manageable treatment-related toxicity.     

Bendamustine in combination with thalidomide and dexamethasone is a viable salvage option in myeloma relapsed and/or refractory to bortezomib and lenalidomide

Treatment options are limited in myeloma relapsed or refractory to both bortezomib and lenalidomide (double-relapsed/refractory multiple myeloma; DRMM). Bendamustine is an antitumour agent that has efficacy in relapsed myeloma. We retrospectively analysed data from 30 DRMM patients who received a combination of bendamustine, thalidomide and dexamethasone (BTD) in 28-day treatment cycles. Bendamustine was administered with a cumulative dose of up to 200 mg/m². Thalidomide (50–150 mg) was given daily as tolerated, and dexamethasone was given at an equivalent dose of up to 160 mg per cycle. A median of 5 (2–9) treatment cycles were administered per patient. Twenty-six patients (87 %) achieved stable disease or better. At a median follow-up time of 12.1 (2.3–21.5) months, median (95 % CI) progression-free survival and overall survival were 4.0 (2.6–5.3) months and 7.2 (5.2–9.2) months, respectively. The most common grade 3–4 adverse events were haematological: anaemia (n?=?8, 34.8 %), neutropenia (n?=?16, 69.6 %) and thrombocytopenia (n?=?10, 43.5 %). Non-haematological toxicities included pain (n?=?3, 13.0 %), infection (n?=?7, 30.4 %) and sensory neuropathy (n?=?1, 4.3 %). We propose that BTD is a viable salvage treatment option for DRMM patients.     

A phase 2 multicenter study of lenalidomide in relapsed or refractory classical Hodgkin lymphoma

Relapsed or refractory (rel/ref) classical Hodgkin lymphoma (cHL) remains a clinical challenge, with limited effective treatment options available after stem cell transplantation. In a multicenter phase 2 study, the efficacy of lenalidomide in rel/ref cHL patients was evaluated at a dose of 25 mg/d on days 1-21 of a 28-day cycle. Patients remained on lenalidomide until disease progression or an unacceptable adverse event (AE) occurred. Thirty-eight cHL patients were enrolled with a median of 4 (range, 2-9) prior therapies; 87% had undergone prior stem cell transplantation and 55% of patients did not respond to their last prior therapy. Of 36 evaluable patients, responses were 1 complete remission (CR), 6 partial remissions (PRs), and 5 patients with stable disease (SD) for ≥ 6 months resulting in an International Working Committee (IWC) objective overall response rate (ORR) of 19% and a cytostatic ORR of 33%. Decreased chemokine (CCL17 and CCL22) plasma levels at 2 weeks were associated with a subsequent response. The treatment was well tolerated, and the most common grade 3/4 AEs were neutropenia (47%), anemia (29%), and thrombocytopenia (18%). Four patients discontinued lenalidomide because of rash, elevated transaminases/bilirubin, and cytopenias. We provide preliminary evidence of lenalidomide's activity in patients with rel/ref cHL, and therefore exploration of lenalidomide in combination with other active agents is warranted. This trial is registered at www.ClinicalTrials.gov as NCT00540007.     

Cladribine combined with rituximab (R-2-CdA) therapy is an effective salvage therapy in relapsed or refractory indolent B-cell non-Hodgkin lymphoma

Although cladribine has been reported to be an active purine analog against indolent B-cell non-Hodgkin lymphoma (B-NHL), there are few reports of combination use of cladribine and rituximab. This multicenter phase II study evaluated the efficacy and toxicity of cladribine with rituximab (R-2-CdA) therapy in relapsed or refractory indolent B-NHL. Twenty patients with the median age of 58.5 yrs (range, 42-72) were enrolled and received R-2-CdA therapy from April 2005 to July 2007. The median number of prior regimens was 2 (range, 1-3), and fifteen patients (75%) were previously treated with rituximab-containing regimens. Disease histology included follicular lymphoma in 16 patients, MALT lymphoma in two patients, nodal marginal B-cell lymphoma in one patient, and lymphoplasmacytic lymphoma in one patient. The overall response rate (ORR) was 90%, with a complete response rate (CRR) of 70%. Estimated median progression-free survival (PFS) time was 22.4 months (95%CI, 10.9-32.6 months) at a median follow-up time of 27 months (range, 12-43). Two-year PFS and 2-yr overall survival (OS) were 52.6% (95%CI, 31.0-73.2%) and 89.5% (95%CI, 66.1-97.3%), respectively. Grade 3 or grade 4 toxicities were neutropenia in 74% and thrombocytopenia in 11%. R-2-CdA therapy was demonstrated to have a high activity with durable PFS and acceptable toxicity in relapsed or refractory indolent B-NHL mostly pretreated with rituximab-containing therapy. Although a large-scale trial is needed for confirmation, R-2-CdA therapy could be a good salvage therapy option in relapsed or refractory indolent B-NHL.