Rituximab plus ASHAP for the treatment of patients with relapsed or refractory aggressive non-Hodgkin’s lymphoma: a single-centre study of 20 patients

The anti-CD20 antibody rituximab improves the results of first-line therapy in aggressive non-Hodgkin’s lymphoma (NHL) of B cell lineage. The purpose of this retrospective study was to evaluate its efficacy and toxicity in combination with the doxorubicine, methylprednisolone, high-dose cytarabine, cisplatin (ASHAP) protocol, an established treatment regimen for relapsed or refractory aggressive NHL. After a median of four cycles, 9 of 20 patients treated achieved a complete remission and 6 a partial remission, resulting in a total response rate of 75%. Remissions were not only seen in patients with relapsed lymphomas but also in patients with primary refractory or transformed indolent lymphomas. The outcome in cases with an international prognostic index score ≥2 was poor. Five of 15 responders received consolidating high-dose therapy with autologous stem cell transplantation. All of them are in ongoing remission. The main toxicity was myelosuppression, with neutropenias or thrombocytopenias of World Health Organization (WHO) grades III or IV developing in more than 90% of the cycles. There was one therapy-related death due to neutropenic sepsis. Non-hematologic toxicity was generally mild. At the time of analysis, six patients have died. After a median observation time of 17.5 months, the 2-year overall survival rate is 62%. ASHAP plus rituximab is an active and well-tolerated salvage protocol for patients with relapsed or refractory aggressive NHL, which compares favourably with other immuno-chemotherapy regimens, especially in patients with primary refractory or transformed indolent lymphomas.     

Efficacy of vinorelbine, epirubicin and prednisone combination regimen in pretreated elderly patients with aggressive non-Hodgkin's lymphoma

BACKGROUND AND OBJECTIVES: To assess the efficacy and toxic profile of the NAEPP protocol, a regimen including vinorelbine, epirubicin and prednisone, in a particularly troublesome subset of patients: pretreated elderly patients with aggressive non-Hodgkin's lymphoma (NHL). DESIGN AND METHODS: From November 1998 to January 2000, 20 pretreated patients who had all relapsed after first-line VNCOP-B chemotherapy were enrolled in a phase II trial and treated with the NAEPP regimen: vinorelbine (25 mg/m(2) i.v. on days 1 and 8), epirubicin (40 mg/m(2) i.v. on days 1 and 8), and prednisone (40 mg/m(2) on days 1 and 8) with granulocyte colony-stimulating factor administered at 5 mg/kg/day on days 2-5 and days 9-12. Chemotherapy was repeated every 4 weeks for a total of 6 cycles. RESULTS: Six (30%) patients achieved complete remission (CR) and 7 (35%) had partial responses (PR), giving an overall response rate of 65%. The response rate was not affected either by type of relapse presentation (nodal versus nodal plus extranodal), presence of bulky disease, or time of relapse. No major toxic effects were recorded. INTERPRETATION AND CONCLUSIONS: These preliminary data suggest that the NAEPP regimen is an effective combination with a low toxicity profile in elderly pretreated patients with aggressive NHL. Further trials using NAEPP as a consolidation phase following first-line treatment are needed to establish the advantage in terms of CR rate and relapse-free survival in these patients.     

Interleukin-2 treatment in lymphoma: a phase II multicenter study [see comments]

A phase II study was undertaken to assess whether continuous infusion of high-dose recombinant interleukin-2 (rIL-2) alone was active against different histologic subtypes of heavily pretreated lymphoma. Sixty one lymphomas were included in the study. rIL-2 (Roussel UCLAF, Romainville, France) was administered by continuous infusion at 20 x 10(6) IU/m2 for three cycles of 5 days, 4 days, and 3 days, during the first week, third week, and fifth week, respectively. Twenty-four low- grade non-Hodgkin's lymphomas (NHL) were resistant to an anthracycline- containing regimen. Twenty-three intermediate and high-grade NHL were refractory to initial treatment or to salvage therapy. Seven Hodgkin's diseases were refractory to at least three regimens or relapsed after autologous bone marrow transplantation. Seven mycosis fungoides were refractory to chemotherapy. In low-grade NHL, one complete response (CR) was observed. In aggressive NHL, there were three CRs and two partial responses (PRs). No response was noted in Hodgkin's disease. One CR and four PRs were observed in mycosis fungoides. Complete response durations were 23, 20, 17, 12, and 4 months. Grade 4 toxicity was observed in 29 patients leading to arrest of therapy in 12 patients. The response to rIL-2 therapy in lymphoma differs according to histologic subtypes. Five responses were observed in 23 aggressive lymphomas. Five of seven mycosis fungoides responded; these preliminary results warrant testing of a larger number of patients.     

Phase II study of ifosfamide, etoposide, and oxaliplatin (IFETOx) chemotherapy for relapsed or refractory non-Hodgkin’s lymphoma

As part of an effort to develop a more effective and safe treatment for relapsed or refractory non-Hodgkin’s lymphoma (NHL), we conducted a phase II study of the oxaliplatin, etoposide, and ifosfamide (IFETOx) regimen. Patients with relapsed or refractory NHL and a performance status of 0–2 were eligible. The IFETOx consisted of etoposide at 100 mg/m² on days 1–3, oxaliplatin at 130 mg/m² on day 2, and ifosfamide 5,000 mg/m² on day 2, every 21 days. The primary endpoint was the overall response rate (ORR) for IFETOx regimen. A total of 23 eligible patients were enrolled. The median age was 58 years (range 19–76 years), and the male-to-female ratio was 15:8. The disease status was as follows: 15 patients had relapsed and 8 patients were refractory to treatment. The ORR for IFETOx chemotherapy was 65.2 %. In the 15 patients who responded to the protocol treatment, five underwent hematopoietic stem cell transplantation. The 2-year probability of progression-free survival and overall survival rates were 51.4 and 56.1 %, respectively. Grade 3/4 neutropenia was observed in 73.9 % of the patients. No significant renal impairment was observed. In conclusion, IFETOx chemotherapy shows a tolerable toxicity profile and efficacy as a salvage treatment regimen for relapsed or refractory NHL.     

Low-dose fludarabine and cyclophosphamide in elderly patients with B-cell chronic lymphocytic leukemia refractory to conventional therapy

BACKGROUND AND OBJECTIVES: In recent years fludarabine alone or in combination with other drugs has been reported to be effective in the treatment of B-cell chronic lymphocytic leukemia (B-CLL), both as first line and salvage therapy. Among the different combination regimens, the association of fludarabine and cyclophosphamide has shown a considerable therapeutic efficacy, although a relevant number of infectious complications have been described, particularly in elderly patients. The aim of this work was to evaluate the efficacy, the toxicity, and the incidence of infectious episodes of a regimen combining lower doses of fludarabine and cyclophosphamide in elderly patients with B-CLL refractory to conventional therapy. DESIGN AND METHODS: Twenty patients with progressive B-CLL with a median age of 75 years (4 in stage B and 16 in stage C) and refractory to conventional therapy were enrolled in this study. The combination regimen was as follows: fludarabine 15 mg/m2/day i.v. [max 25 mg] and cyclophosphamide 200 mg/m2/day i.v. for four days. RESULTS: All patients enrolled were evaluable for response. Three out of 20 (15%) patients achieved a complete remission (CR), 14/20 (70%) a partial response (PR) with an overall response rate (CR+PR) of 85%, according to National Cancer Institute-Working Group response criteria. Three patients were considered resistant. In four out of 20 patients (20%), a severe neutropenia (neutrophils < 0.5x10(9)/L) occurred and one of them developed an infectious complication which required treatment with systemic antibiotics and granulocyte colony- stimulating factor (G-CSF). Non-hematologic toxicity was negligible in all patients but one, who despite a adequate therapy with allopurinol and hydration, experienced a tumor lysis syndrome with transient but severe renal impairment. INTERPRETATION AND CONCLUSIONS: The association of low-dose fludarabine and cyclophosphamide appeared to be effective in this subset of B-CLL patients, reproducing a similar overall response rate obtained with other fludarabine-based combination therapies. In addition, in this group of elderly patients, toxic side effects were negligible and infectious complications remarkably low.     

Favorable impact of low-dose fludarabine plus epirubicin and cyclophosphamide regimen (FLEC) as treatment for low-grade non-Hodgkin's lymphomas.

BACKGROUND AND OBJECTIVE: In recent years, conventional dose of fludarabine (FLU) alone or in combination with other drugs has been reported to be effective in the treatment of low-grade non-Hodgkin's lymphomas (LG-NHL). In particular, FLU and cyclophosphamide (CY) or FLU and mitoxantrone or idarubicin combined regimens have shown considerable therapeutic activity both as first line and salvage therapies, producing overall response rates ranging from 40-50% in previously treated patients and up to 70-90% in untreated ones. However severe neutropenia and infective complications have been reported in a significant number of patients. Based on these premises we evaluated the efficacy and toxicity of a new regimen combining low-doses of FLU with epirubicin (EPI) and CY (FLEC) in a group of advanced treatment-requiring LG-NHL patients. The aim of this study was to evaluate a strategy aimed at lowering therapy-related toxic effects without affecting the reported good response rate. DESIGN AND METHODS: Thirty patients with de novo, relapsed or refractory LG-NHL entered the study. FLEC regimen was as follows: EPI 60 mg/m(2) i.v. on day one, plus FLU 15 mg/m(2)/day i.v. (max 25 mg) and CY 250 mg/m(2)/day i.v. for four days. RESULTS: All 30 patients were evaluable for response, 13 (43%) fulfilled the criteria for CR and 11 (36%) for PR with an overall response rate of 79%. None of the 13 patients who achieved CR had relapsed after a follow-up of 2 to 23 months (median duration 13 months). With regard to age, 13/14 older patients (>/= 70 years) responded to the treatment and 9 of them maintained their response after a median of 13 months (range 2-22); six of the 14 (43%) obtained a CR. Therapy-related toxicity was mild regardless of age, neutropenia (43%) and fever of undetermined origin (26%) being the major side effects. Remarkably, a documented infection was recorded only in 2/30 (6%) patients. INTERPRETATION AND CONCLUSIONS: A low-dose FLU-based FLEC regimen appeared to be effective for advanced treatment-requiring LG-NHL, reproducing a similar overall response rate (79%) reported to have been achieved with other FLU based combination therapies. Toxic side effects were negligible and in particular documented infections were remarkably uncommon even in the group of elderly patients.     

High-dose infusional ifosfamide,etoposide plus methylprednisolone followed by dexamethasone,high-dose ara-C and cisplatinum and autologous stem cell transplantation for refractory or relapsed aggressive non-Hodgkin's lymphoma

BACKGROUND AND OBJECTIVES: A salvage program including infusional high-dose ifosfamide plus etoposide (IFOVM) was evaluated in patients with refractory or relapsed aggressive non-Hodgkin's lymphoma. DESIGN AND METHODS: Forty-six patients were included. IFOVM consisted of ifosfamide (10 g/m2 as a 72-hour continuous infusion), etoposide (900 mg/m2) and methylprednisolone; responding patients underwent two cycles of DHAP and subsequently an autologous peripheral blood stem cell transplantation (APBSCT) with BEAM as the conditioning regimen. RESULTS: All but one patient showed tumor regression following IFOVM. Myelosuppression was brief but 26 patients developed neutropenic fever. All but two patients proceeded to DHAP. Overall response rate to IFOVM/DHAP was 59% (29% CR and 30% PR). Refractory patients had a significantly lower response rate than relapsed patients (39% vs. 85% p=0.002). All refractory patients with intermediate-high or high IPI progressed during IFOVM/DHAP. Twenty-seven patients proceeded to APBSCT. Two-year overall survival of patients with low or low-intermediate IPI was 47% [95% CI 25-69%], which was significantly better than that obtained in patients with intermediate-high or high IPI (11% [95% CI 0-22%] p=0.0001). INTERPRETATION AND CONCLUSIONS: This sequential regimen of IFOVM, followed by DHAP and consolidated with BEAM is active in relapsed or refractory patients with low or low-intermediate IPI aggressive lymphoma. However, it has little activity in those patients with intermediate or high IPI, especially in refractory lymphomas.     

High-dose methotrexate with R-CHOP therapy for the treatment of patients with primary central nervous system lymphoma

We describe MR-CHOP therapy, a novel treatment regimen consisting of high-dose methotrexate and R-CHOP that provides systemic anti-tumor activity with penetration of the blood-brain barrier in patients with newly diagnosed primary central nervous system lymphoma. The MR-CHOP regimen was administered with 2 g/m(2) of methotrexate and 375 mg/m(2) of rituximab on day 1, 750 mg/m(2) of cyclophosphamide on day 3, 50 mg/m(2) of doxorubicin on day 3, 1.4 mg/m(2) of vincristine on day 3 and 100 mg of prednisolone on days 1-5 in this pilot study of seven patients. Six cycles of MR-CHOP therapy were administered every 3 weeks, followed by high-dose chemotherapy with stem cell rescue in young patients, or an additional two cycles of 4 g/m(2) methotrexate and rituximab in older patients. The overall response rate was 100%, with 85.7% complete remission (CR). One patient showed partial response, relapsed and subsequently died. Another relapsed following CR, and was rescued by further salvage therapy. The others survive without relapse at a median observation period of 24 months. Hematological toxicity included grade 4 leukocytopenia in 4/7 and neutropenia in 5/7, which were transient and tolerated well. Non-hematological toxicities were tolerated well. The efficacy of this novel regimen as remission induction therapy was found to be promising in this pilot study, although the number of patients was small and follow-up short.     

An effective salvage treatment using ifosfamide, etoposide, cytarabine, dexamethasone, and rituximab (R-IVAD) for patients with relapsed or refractory aggressive B-cell lymphoma

We evaluated the efficacy and toxicity of a new salvage regimen, consisting of rituximab (375?mg/m(2), day 1), ifosfamide (1500?mg/m(2) on days 3-7), etoposide (150?mg/m(2), days 3-5), cytarabine (100?mg/m(2), days 3-5) and dexamethasone (40?mg/body, days 3-5) (R-IVAD) for relapsed or refractory aggressive B-cell lymphoma. In this study, a total of 32 patients with a median age of 64?years (range 38-79) who received an average of 2.6 cycles of R-IVAD from 2001 to 2009 in our institution were retrospectively analyzed. R-IVAD was given every 3?weeks up to a total of three courses with support by granulocyte colony stimulating factor. The overall response rate was 72%, with 56% complete response. On a median follow-up of 16?months (range 2-99), estimated 2-year overall survival (OS) and event-free survival were 55% and 36%, respectively. Of these patients, 10 successfully proceeded to consolidating high-dose chemotherapy followed by autologous stem cell transplantation, accounting for 90% of the 2-year OS. No treatment-related mortality was observed during the investigation. We, therefore, conclude that R-IVAD regimen is a safe and efficacious alternative for patients with relapsed or refractory aggressive B-cell lymphoma.     

An oxaliplatin-based chemotherapy in patients with relapsed or refractory intermediate and high-grade non-Hodgkin's lymphoma

This study was designed to assess the efficacy and safety of substituting cisplatin with oxaliplatin in the DHAP (dexamethasone, cytarabine and cisplatin) regimen for patients with relapsed or refractory non-Hodgkin's lymphoma. Twenty-four evaluable patients with intermediate or high-grade non-Hodgkin's lymphoma were treated at 3-weekly intervals with oxaliplatin (130 mg/m2, d 1), cytarabine (2 g/m2 for two doses, d 2) and dexamethasone (40 mg, d 1-4). The median age of the patients was 58 (range 18-70). Histological subtypes were diffuse large B cell, 20; mantle cell, two; anaplastic large cell, one; and peripheral T cell, one. The overall objective response rate (RR) was 50% [95% confidence interval (CI) = 29-71%] including four complete responses and eight partial responses. RR for those patients treated at first relapse was higher than those treated at second and subsequent relapse (77% versus 29%). Grade 3 and 4 toxicity was mainly haematological: anaemia 17%, neutropenia 75% and thrombocytopenia 75%. No grade 4 non-haematological toxicity was reported. No significant renal and neurotoxicity was demonstrated. Median survival was 10.6 months. Probabilities of 1-year progression-free survival and overall survival were 47% (95% CI = 26-66%) and 50% (95% CI = 23-72%) respectively. In conclusion, dexamethasone, cytarabine and oxaliplatin (DHAX) is a novel combination in salvage therapy for relapsed or refractory non-Hodgkin's lymphoma. It has clinically significant activity with an acceptable toxicity profile. Lack of renal toxicity makes DHAX an attractive cytoreductive regimen before high-dose chemotherapy.     

Combination chemotherapy with low-dose cytarabine, homoharringtonine, and granulocyte colony-stimulating factor priming in patients with relapsed or refractory acute myeloid leukemia

As sensitization of leukemic cells with granulocyte colony-stimulating factor (G-csf) can enhance the cytotoxicity of chemotherapy in acute myeloid leukemia (AML), a pilot study was conducted in order to evaluate the effect of G-csf priming combined with low-dose chemotherapy in patients with relapsed and refractory AML. The regimen, G-HA, consisted of cytarabine 7.5 mg/m2/12 hr by subcutaneous injection, days 1-14, homoharringtonine 1.5 mg/m2/day by intravenous continuous infusion, days 1-14, and G-csf 150 microg/m2/day by subcutaneous injection, days 0-14. Thirty-six AML patients were enrolled, 23 refractory and 13 relapsed. Eighteen patients (50%, 95% confidence interval: 33-67%) achieved complete remission (CR) with a median CR duration of 7.2 months, and two elderly patients continued a regimen of maintenance therapy and remained in remission for 26.3 and 14.1 months, respectively, as of last follow-up. Eight patients (22%) experienced neutropenia (median duration: 6 days; range: 2-22 days). Thirteen of the 36 (36%) developed severe infections. Grade 1-2 nonhematologic toxicities were documented, including nausea and vomiting (20%), liver function abnormality (6%), and heart function abnormality (6%). No central nervous system and kidney toxicity was observed. The G-HA regimen is effective in remission induction for refractory and relapsed AML patients and well tolerated in maintenance therapy in some subgroups of elderly patients. Further studies are necessary to elucidate optimum dose and schedule for this regimen to enhance the treatment efficacy of relapsed or refractory AML patients.     

Phase II study of 3-hour infusion of high dose paclitaxel in refractory and relapsed aggressive non-Hodgkin's lymphomas. Groupe d'Etude des Lymphomes de l'Adulte

BACKGROUND AND OBJECTIVE: The first clinical studies of paclitaxel as a single agent for the treatment of relapsed or refractory low or intermediate grade non-Hodgkin's lymphomas (NHL) yielded controversial results regarding the response rates observed, mainly related to the dose and schedule of administration used. To obtain additional data concerning the efficacy and toxicity of paclitaxel in intermediate and high grade NHL we initiated a phase II study using a 3-hour infusion of high doses of paclitaxel. DESIGN AND METHODS: The eligibility criteria included patients with relapsed or refractory aggressive NHL, a performance status < or = 2 (WHO index), a platelet count > or = 100,000/microL, a neutrophil count > or = 2,000/microL, measurable disease, and adequate hepatic function. Patients were excluded if they were infected with HIV, had a left ventricular ejection fraction < 50%, or prior peripheral neuropathy. Paclitaxel was administered as a 3-hour infusion at a dose of 250 mg/m2 every 3 weeks for a maximum of 6 courses. RESULTS: Of 45 eligible patients, 42 received a total 73 courses of paclitaxel. Forty patients were assessable for response (89%), and 42 for toxicity (93%). Six patients (15%) achieved a partial (n = 4) or a complete remission (n = 2). Responses were observed in intermediate grade (n = 4) as well as in high grade lymphoma (n = 2). The main factor influencing the response to paclitaxel was the median duration of response to previous chemotherapy regimens which was 3 times longer in patients who responded to paclitaxel (16.3 months) than in patients who did not respond to paclitaxel (5.2 months) (p<0.05). The most common serious side effects were related to the hematologic toxicity of paclitaxel, and included grade IV granulocytopenia in 20 cases (48%), grade III/IV thrombocytopenia in 14 cases (33%) and grade III-IV anemia in 13 cases (31%). INTERPRETATION AND CONCLUSIONS: Despite frequent manageable hematologic toxicity, paclitaxel is usually well tolerated at a dose of 250 mg/m2 given by a 3-hour infusion. However, the clinical efficiency as a single therapy seems modest in relapsed or refractory aggressive lymphoma.     

Time sequential chemotherapy for primary refractory or relapsed adult acute myeloid leukemia: results of the phase II Gemia protocol

BACKGROUND AND OBJECTIVE: High-dose cytarabine (HDAra-C), mitoxantrone and etoposide are the mainstay of several active regimens against relapsed or refractory acute myelogenous leukemia (AML). We designed a phase II study to assess the efficacy and side effects of a time sequential application of mitoxantrone plus intermediate-dose Ara-C followed by HDAra-C plus etoposide (GEMIA) in adult patients with refractory or relapsed AML. DESIGN AND METHODS: Patients with refractory or relapsed AML were eligible for GEMIA salvage therapy, which comprised mitoxantrone 12 mg/m2/day on days 1-3, Ara-C 500 mg/m2/day as a 24-hour continuous infusion on days 1-3, followed by HDAra-C 2 g/m2/12-hourly on days 6-8 and etoposide 100 mg/m2/12-hourly on days 6-8. Granulocyte colony-stimulating factor was started on day 14. In patients above the age of 55 the dose of Ara-C in the first sequence (days 1-3) was reduced to 250 mg/m2. RESULTS: Twenty patients were included, of whom 12 achieved complete remission after GEMIA (60%, 95% CI 40-80%), one was refractory and five died early from infection. Two additional patients achieved partial remission after GEMIA and complete remission after consolidation chemotherapy, for a final CR rate of 70% (95% CI 48-88%). Neutrophils recovered at a median of 27 days (range, 22-43) and platelets 46 days (range, 25-59) after the start of treatment. The median duration of remission was 133 days (range, 36-417+) whereas overall survival time lasted for a median of 153 days (range, 13-554+). Treatment-associated toxicity was comprised predominantly of infection, mucositis and diarrhea that reached World Health Organization grades III-V in 40%, 40% and 30% of patients, respectively. Despite the intention to rapidly proceed to a hematopoietic stem cell transplant in patients in remission, only five patients reached the transplant. INTERPRETATION AND CONCLUSIONS: The GEMIA time sequential chemotherapy regimen appears effective in obtaining remissions in refractory and relapsed adult AML. The high toxicity seen, however, suggests that its design is amenable to further improvements, especially in more elderly patients. Since remissions are short-lived, more innovative post-remission strategies are needed.     

Gemcitabine and vinorelbine combination is effective in both as a salvage and mobilization regimen in relapsed or refractory Hodgkin lymphoma prior to ASCT

We investigated the efficacy of gemcitabine and vinorelbine (Gem/Vin) combination chemotherapy as a salvage and mobilization regimen in relapsed or refractory Hodgkin lymphoma (HL) patients prior to autologous hematopoietic stem cell transplantation. We retrospectively reviewed the data of our relapsed or primary refractory HL patients treated with Gem/Vin regimen which consisted of gemcitabine 1,000 mg/m²/day and vinorelbine 30 mg/m²/day on days 1, 8, and 15 every 28 days. The overall response rate was 72.4%. Ten (34.5%) patients achieved complete remission, 11 (37.9%) partial remission, and eight (27.6%) patients had no response. Mobilization with Gem/Vin regimen was successful in 20/23 (87%) patients while mobilization failure was seen in three (13%) patients. Gemcitabine and vinorelbine is an effective salvage regimen with acceptable toxicity and high mobilization potential in relapsed or refractory HL patients.     

Rituximab added to an intensified salvage chemotherapy program followed by autologous stem cell transplantation improved the outcome in relapsed and refractory aggressive non-Hodgkin lymphoma

We investigated the addition of rituximab to an intensified salvage program followed by a myeloablative course with autologous stem cell transplantation (ASCT) in patients with relapsed or refractory aggressive non-Hodgkin lymphoma (NHL). Patients with relapsed or progressive aggressive NHL were treated with two cycles of conventional salvage chemotherapy (DHAP) followed by high-dose sequential chemotherapy (cyclophosphamide, methotrexate with vincristine and etoposide) and a final myeloablative course (BEAM) with ASCT. Rituximab (375 mg/m²) was administered at each treatment cycle. This cohort was compared with a historical control group of patients treated with the same chemotherapy but without rituximab. Patients from both groups were matched by duration of first remission and lactate dehydrogenase serum levels. Forty-five patients were treated with chemotherapy and 22 with immunochemotherapy. The overall response rates (ORR) at the final evaluation were 63% for the immunochemotherapy group and 42% for the chemotherapy group (p = 0.330). In the historical controlled analysis freedom from second failure (FF2F) at 2 years in the immunochemotherapy group was 57% and overall survival (OS) was 77%. FF2F in the chemotherapy group was 18% (p = 0.0051) and OS was 37% (p = 0.0051). In the matched-pair analysis, FF2F was 58% in the immunochemotherapy group compared to 16% in the chemotherapy group (p = 0.0517); OS was 74 vs 33%, respectively (p = 0.0424). The toxicity was tolerable and comparable in both groups. The addition of rituximab to an intensified salvage chemotherapy regimen seems to improve the prognosis. However, only prospective randomized trial can offer sufficient data of the value of rituximab in relapsed and refractory aggressive NHL.     

Intensive conditioning regimen of etoposide (VP-16), cyclophosphamide and carmustine (VCB) followed by autologous hematopoietic stem cell transplantation for relapsed and refractory Hodgkin's lymphoma

Several high-dose therapy regimens are used for autologous hematopoietic stem cell transplantation (auto-HSCT) for relapsed and refractory Hodgkin's lymphoma (HL) with variable disease response. An intensified regimen of etoposide (VP-16) 2,400 mg/m(2), cyclophosphamide 7,200 mg/m(2) and carmustine (BCNU) 600 mg/m(2) (VCB) pre-auto-HSCT was developed to overcome disease recurrence. A total of 43 relapsed and refractory HL patients underwent auto-HSCT between January 1992 and December 2004. At day 100 there were 37 (86%) complete responses. A total of 40 patients survived beyond day 100, 14 of whom subsequently relapsed/progressed. At a median follow-up of 4.9 years (range 1.5-11.4 years), 26 patients (60%) are alive and disease free. Five-year actuarial event-free survival (EFS) was 53% (95% CI 35-70%) and median EFS was 5.9 years. Median progression-free and overall survivals have not been reached. EFS was reduced with an increasing number of prognostic factors (Karnofsky performance status, KPS <90, chemotherapy-resistant disease and >or=3 chemotherapy regimens prior to transplant or=2; P=0.049). Grade III-IV regimen-related toxicity was 9% (n=4). The 1-year cumulative incidence of interstitial pneumonitis (IP) was 36%, however only two patients died of IP complications. Disease progression was the most common cause of death (n=10, 23%). Intensive VCB is an effective and well-tolerated preparative regimen for relapsed and refractory HL auto-HSCT.     

Mitoxantrone and etoposide: an effective regimen for refractory or relapsed acute myelogenous leukemia

23 adult patients with refractory or relapsed acute myelogenous leukemia (AML) received salvage chemotherapy with mitoxantrone and etoposide. The regimen consisted of mitoxantrone, 10 mg/m2/d by 30-min infusion, and etoposide 100 mg/m2/d by 30-min infusion, given 12 h apart for 5 consecutive d. Of 23 patients treated, 13 met the criteria for highly refractory disease (6 primary resistant; 4 with early relapse during maintenance; 3 relapsed and refractory to reinduction). 10 patients had relapsed off-therapy more than 6 months after achieving first CR. Overall, 14 patients (61%) achieved a complete remission (CR): 6/13 (46%) with refractory AML, and 8/10 (80%) with relapsed AML. 2 patients had a partial remission, 2 died in aplasia, and 5 were nonresponders. In responding patients, the median time for recovery of granulocyte count was 27 d. The most important nonhematologic side effect was oral mucositis, which was severe in 35% of cases. No signs of cardiac toxicity were observed. The median CR duration was 5 months (range, 2 to 12+ months). The combination of mitoxantrone and etoposide appears a highly effective and relatively well tolerated salvage regimen for refractory and relapsed AML. Its incorporation into first-line induction and consolidation programs for newly diagnosed AML patients should be considered.     

Safety and feasibility of high-dose ranimustine (MCNU), carboplatin, etoposide, and cyclophosphamide (MCVC) therapy followed by autologous stem cell transplantation for malignant lymphoma

High-dose chemotherapy followed by autologous stem cell transplantation (auto-SCT) is widely used as a salvage therapy in the treatment of refractory malignant lymphoma. To investigate the safety and feasibility of a high-dose MCNU, carboplatin, etoposide and cyclophosphamide (MCVC) regimen, we conducted a prospective multicenter trial. Thirty patients with relapsed/refractory/poor-risk non-Hodgkin lymphoma (NHL n?=?27) or Hodgkin lymphoma (HD n?=?3) were uniformly treated with an MCVC regimen and underwent auto-SCT. The median follow-up duration of the surviving patients was 67?months (56?C133?months). The major toxicities were anorexia (94?%), diarrhea (80?%), nausea (79?%), febrile neutropenia (70?%), alopecia (67?%) and mucositis (60?%). Three patients developed severe left ventricular dysfunction, and two patients developed severe sinusoidal obstructive syndrome (SOS). Of these patients, two died without disease progression. Treatment-related mortality was 6.6?%. Late-onset adverse events including two cases of cytomegalovirus pneumonia and one of interstitial pneumonia were observed. In DLBCL (n?=?13) and transformed FL (n?=?2) patients, OS and EFS at 3?years were 72 and 46?%, respectively. These results suggest that the MCVC regimen followed by auto-SCT is a feasible and tolerable therapy for relapsed/refractory malignant lymphoma. However, cardiac toxicity due to high-dose cyclophosphamide and development of SOS can occur and should be carefully monitored. Further follow-up is needed to evaluate the long-term efficacy and safety of this regimen.     

Salvage chemotherapy with mini-BEAM for relapsed or refractory Hodgkin's disease prior to autologous peripheral blood stem cell transplantation.

BACKGROUND AND OBJECTIVE: High-dose chemotherapy and autologous bone marrow transplantation (ABMT) has become the standard approach for most patients with relapsed or refractory Hodgkin's disease. Disease status at transplant has been correlated with outcome following ABMT. In light of this, we employ mini-BEAM (BCNU, etoposide, cytarabine and melphalan) salvage therapy in order to achieve a state of minimal residual disease prior to transplantation. DESIGN AND METHODS: From February 1992 to June 1998 twenty-four patients receiving mini-BEAM therapy for resistance or relapse of their Hodgkin's disease were included. Four patients had obtained no response with initial chemotherapy (refractory), eight had obtained an incomplete response, seven were in first relapse and five in second or subsequent relapse. Fifteen patients received mini-BEAM as first salvage chemotherapy regimen. The remaining nine patients had previously been exposed to a median of one salvage regimen. Patients received a median of three cycles of mini-BEAM. RESULTS: Sixteen patients achieved complete remission and four partial remission, yielding an overall response rate of 83%. No significant differences in response were observed between patients who received mini-BEAM as initial salvage therapy and those who had received a prior salvage regimen. Eighteen out of the twenty responding patients went on to intensive therapy and peripheral blood stem cell transplantation. With a median follow-up of 52 months, the cumulative probability of 7-year overall survival is 71% for the responders and that of the 6-year disease-free survival is 42%. No treatment-related deaths were observed. INTERPRETATION AND CONCLUSIONS: Mini-BEAM is an effective salvage regimen with moderate toxicity that may be useful for cytoreduction prior to stem cell procedures.     

Conventional second-line salvage chemotherapy regimens are not warranted in patients with malignant lymphomas who have progressive disease after first-line salvage therapy regimens

This study aimed to determine the outcome of patients with relapsed or refractory lymphoma who have an inadequate response to first-line salvage therapy (1 degrees ST) and who subsequently receive a second-line salvage regimen (2 degrees ST) with the intention of ultimately proceeding to high-dose therapy. The outcome of 57 patients [Hodgkin's Lymphoma 17, histologically-aggressive non-Hodgkin's Lymphoma (NHL) 26, histologically-indolent NHL 14] who received more than one modality of conventional-dose salvage therapy was analysed. Sixteen patients had a partial response (PR) to 1 degrees ST, but subsequently received 2 degrees ST because the PR was judged to be inadequate (iPR) because of persisting disease bulk or marrow infiltration. Of these 16 patients, 10 (63%) continued to respond to 2 degrees ST. Of the 15 patients who had stable disease following 1 degrees ST, 5 (33%) responded to 2 degrees ST. Only one of the 24 (4%) with progressive disease (PD) following 1 degrees ST, responded to 2 degrees ST. 25 of the 57 patients ultimately underwent stem cell transplantation. The 2-year progression-free survival (PFS) and the 3-year overall survival (OS) for all patients was 24% and 31%, respectively. Long-term survival was highly dependent on response to 1 degrees ST (P = 0.0001); in patients with PD following 1 degrees ST, the PFS and OS at 3 years was only 4%. This analysis indicates that patients with malignant lymphomas, who have PD on 1 degrees ST, are not rescued by subsequent salvage regimens. They should either be treated palliatively or novel approaches should be explored.