Salvage chemotherapy using a combination of fludarabine and cyclophosphamide for refractory or relapsing indolent and aggressive non-Hodgkin's lymphomas

The prognosis of patients with refractory or relapsing non-Hodgkin's lymphoma (NHL) after primary therapy is poor and multi-drug salvage treatments are associated with less than 60% response rates, usually of short duration. Here we report the results of a phase II study using a fludarabine-cyclophosphamide (FAMP-Cy) combination as a salvage failure regimen in refractory and relapsing low-grade (6) and intermediate-grade (9) NHL patients. Fifteen patients, who had received up to 4 regimens prior to therapy with FAMP-Cy were treated with fludarabine (25 mg/m2) and cyclophosphamide (300 mg/m2) for 3 consecutive days followed by G-CSF (5 microg/kg). The overall response was 74%, 4 achieving complete responses (CR) and 7 partial responses (PR). All patients with low-grade NHL responded (4 CR, 2 PR); 5 patients with intermediate-grade NHL achieved PR lasting for a median of 5 months. The main toxicity encountered was moderate myelosuppression. Three patients had febrile neutropenia, one had drug-induced fever and a single patient developed severe neurotoxicity. Opportunistic infections due to lymphopenia were not seen. The combination of fludarabine and cyclophosphamide used as a salvage regimen showed an impressive response in a small group of heavily pretreated low-grade NHL patients who had previously received a large number of prior regimens. FAMP-Cy had limited effect in a similar group of intermediate-grade NHL patients. Results with this "failure" regimen are encouraging, however further studies are needed in order to confirm these observations in a larger series of patients.     

氟达拉滨为主的联合化疗方案治疗低度恶性非霍奇金淋巴瘤的临床观察

目的评价以氟达拉滨为主的化疗方案治疗低度恶性淋巴瘤的疗效和不良反应。方法采用氟达拉滨为主的化疗方案(FMD方案:氟达拉滨 米托蒽醌 地塞米松;FMC方案:氟达拉滨 米托蒽醌 环磷酰胺;FC方案:氟达拉滨 环磷酰胺)治疗我院收治的低度恶性非霍奇金淋巴瘤患者32例,其中初发19例,复发、难治13例。结果32例患者平均完成了4.1个疗程,完全缓解(CR)率为65.6%,部分缓解(PR)率为18.8%,总的有效(OR)率为84.4%。初发组CR率71.4%, PR率21.0%,OR率92.4%;复发、难治组CR率46.2%,PR率13.1%,OR率59.3%,两组CR率和OR率差异无统计学意义(P>0.05)。主要不良反应为骨髓抑制和免疫功能抑制。31.3%(10/32)的患者出现Ⅲ～Ⅳ级粒细胞减少,9.4%(3/32)的患者出现Ⅲ～Ⅳ级血小板减少。有7例患者出现感染、发热,其中2例肺部感染患者死亡。非血液学毒性主要为胃肠道反应及轻度的肝肾功能损害。中位随访时间16个月(1～30个月),2年总生存(OS)率(93.8±4.2)%,2年疾病无进展生存(PFS)率(84.4±6.3)%。初发组2年OS率为100%,2年PFS率为(94.7±5.0)%;复发、难治组2年OS率为(76.9±11.3)%,2年PFS率为(69.2±12.3)%,两组差异无统计学意义(P>0.05)。结论氟达拉滨为主的化疗方案患者耐受性较好,对低度恶性淋巴瘤疗效较好,有可能改善患者的预后。     

Fludarabine, cyclophosphamide and mitoxantrone in relapsed or refractory chronic lymphocytic leukemia and low grade non-Hodgkin's lymphoma

A regimen combining fludarabine, cyclophosphamide and mitoxantrone (FCM) was used to treat 29 patients with relapsed or refractory chronic lymphocytic leukemia (CLL, N = 24) and low-grade non-Hodgkin's lymphoma (NHL, N = 5) based on evidence suggesting synergism between the 3 drugs. Patients were treated with mitoxantrone 5mg/m2 i.v. day 1 only, fludarabine 25 mg/m2 i.v. for 3 days or 24 mg/m2 orally for 5 days, cyclophosphamide 250 mg/m2 i.v. for 3 days or 150 mg/m2 orally for 5 days inclusive. Eighteen patients had previously received fludarabine and most were heavily pretreated with 40% having >2 prior treatments. A median number of 4 FCM courses (range of 1-9) were given. The response rate was 78.5%: 32% complete remission, 25% nodular partial remission, 21.5%, partial remission. Median duration of response was 19 months and median survival was 42 months. Sixteen patients (57%) developed neutropenia to < 0.5 x 10(9)/l and 12 (43%) infectious complications. Four patients developed large cell lymphoma (Richter's syndrome) and 2 acute myeloid leukemia. FCM is a useful combination for relapsed or refractory CLL and low grade NHL with high response rates and long duration of response. The role of FCM as first line therapy deserves study as well as its combination with the monoclonal antibody Rituximab.     

Methyl-GAG, ifosfamide, methotrexate and etoposide (MIME) as salvage therapy for Hodgkin's disease and non-Hodgkin's lymphoma. The Swedish Lymphoma Study Group

One hundred and three patients with recurrent or refractory Hodgkin's disease (HD) or non-Hodgkin's lymphoma (NHL) treated with MIME (methyl-GAG, ifosfamide, methotrexate, etoposide) were retrospectively studied. Thirty-seven of the 44 patients with HD, 34/47 with high-grade malignant and 9/12 with low-grade malignant NHL were evaluable for response. Of the 37 evaluable patients with HD, 16 (43%) achieved complete remission (CR) and 4 partial remission (PR), giving a total response rate of 54%. Of the 34 evaluable patients with high-grade NHL, 5 achieved CR and 8 PR, giving a response rate of 38%. Of 9 evaluable patients with low-grade NHL, 2 achieved CR. The main toxicity was leukopenia, thrombocytopenia and infections. Twenty-six per cent of the patients developed septicaemia, which was fatal in 6 cases (6%). We conclude that MIME as salvage regimen can induce complete remissions in lymphoma patients, particularly in HD with previous heavy treatment, and that it is relatively well tolerated.     

Oral cyclophosphamide therapy for patients with residual or relapsed indolent-type lymphoma after initial treatment for aggressive lymphomas. A sub-group of patients with apparent transformed indolent lymphoma

Lymph node or bone marrow biopsy from sixty-one patients affected by aggressive non-Hodgkin lymphomas (NHL) were retrospectively evaluated to assess the histology at relapse. Eighteen cases (29.5%) were proven to have relapsed or persistent low-grade lymphoma after conventional therapy. In 5/18 patients association of low and high-grade lymphoma was detectable at diagnosis by bone marrow biopsy. In the remaining 13/18 no evidence of follicular lymphoma was detected at diagnosis. The outcome of these patients was compared to that of 43 patients relapsed without change in histology and treated by a second line therapy. Of these 43 patients, 13 were not responders (NR), 10 achieved a partial remission (PR) and 18 complete remission (CR). Two were lost during follow-up. The 18 patients with residual/relapsed indolent subtype received oral cyclophosphamide (100 mg/day for 15 days every month for six months): 3 of them had NR, 5 CR, and 10 PR. The overall survival (OS) median time was 39 months in low-grade resistant/relapsed patients and 20 months in patients with aggressive histology. OS at 24 months was 71 and 41%, respectively, (p < 0.02). Most of the patients with high-grade disease were refractory or relapsed after a median of five months, whereas cases with low-grade NHL showed a long lasting stable PR. We suggest that the higher grade patients with residual or relapsed low grade lymphoma were, in fact, transformed low-grade at diagnosis and, after removing the more aggressive component by chemotherapy, it is possible to manage these patients by conventional therapy for indolent lymphomas.     

Phase 2 study of fludarabine and paclitaxel in patients with recurrent low-grade non-Hodgkin's lymphoma

Although numerous options are available for patients with recurrent low-grade non-Hodgkin's lymphoma (NHL), responses are rarely durable. We previously conducted a phase I trial of fludarabine and paclitaxel in the treatment of recurrent low-grade lymphoma. The present phase II study was performed to determine the activity of fludarabine and paclitaxel in patients with recurrent low-grade NHL. Patients with histologically confirmed recurrent low-grade NHL were treated with fludarabine 20 mg/m2/day intravenously (i.v.) on days 1-5 plus paclitaxel 50 mg/m2 given by i.v. continuous infusion over 72 h starting on day 1. Treatment was repeated at 4-week intervals for a maximum of six courses. Twenty-eight evaluable patients were entered into this phase II trial. The median age was 53 years and the median performance status (Zubrod) was 1. Twenty-two (78%) patients had grade 1 or 2 follicular lymphoma, and six patients (21%) had small lymphocytic lymphoma. The median number of prior chemotherapy regimens was 1 (range, 1-3). Objective responses occurred in 16 patients (57%); nine patients (32%) achieved a complete remission with a median duration of 32 months (range 4-84+ months), and seven patients (25%) had a partial remission. Grade 3 and 4 toxicities included neutropenia (72%), neutropenic fever (34%), infection (13%), mucositis (7%), and neuropathy (3%). The combination of fludarabine and paclitaxel has clinical activity in patients with recurrent low-grade NHL.     

Efficacy of high-dose methotrexate,ifosfamide, etoposide and dexamethasone salvage therapy for recurrent or refractory childhood malignant lymphoma

BackgroundChildren with recurrent or refractory malignant lymphoma generally have a poor prognosis. There is a need for new active drug combinations for this high-risk group of patients.Patients and methodsThis study evaluated the activity and toxicity of the methotrexate, ifosfamide, etoposide and dexamethasone (MIED) regimen for childhood refractory/recurrent non-Hodgkin’s lymphoma (NHL) or Hodgkin’s lymphoma (HL). From 1991 through 2006, 62 children with refractory/recurrent NHL (n = 24) or HL (n = 38) received one to six cycles of MIED. Based on MIED response, intensification with hematopoietic stem cell transplantation (HSCT) was considered.ResultsThere were 10 complete (CR) and 5 partial responses (PR) among the 24 children with NHL [combined response rate, 63%; 95% confidence interval (CI) 38% to 73%]. There were 13 CR and 18 PR among the 37 assessable children with HL (combined response rate, 84%; 95% CI, 68% to 94%). Although 59% courses were associated with grade IV neutropenia, treatment was well tolerated and without toxic deaths.ConclusionsMIED is an effective regimen for refractory/recurrent childhood malignant lymphoma, permitting a bridge to intensification therapy with HSCT.     

Fractionated cyclophosphamide, vincristine, liposomal daunorubicin (daunoXome), and dexamethasone (hyperCVXD) regimen in Richter's syndrome.

Approximately 3 to 5% of patients with chronic lymphocytic leukemia (CLL) develop an aggressive large cell non Hodgkin's lymphoma (NHL) known as Richter's syndrome (RS). RS has a poor prognosis and a response rate of < 10% with fludarabine-based or other cytotoxic combination regimens. The aim of this study was to evaluate the efficacy and toxicity of the hyperCVXD regimen in RS. Twenty-nine patients, median age 61 years (36-75) 23 males, were treated. Prior diagnosis was CLL in 26 patients, NHL in 2, and Prolymphocytic leukemia in 1. Treatment consisted of fractionated cyclophosphamide, vincristine, daunoXome and dexamethasone. Six patients (20%) died while receiving study therapy, 4 (14%) during the first cycle of whom 2 had started therapy with overt pneumonia. Grade 4 granulocytopenia occurred in all 95 cycles of therapy with a median time to recovery of 14 days. Twenty three (24%) cycles were complicated by fever, and 15 (15%) by pneumonia. Sepsis was documented in 8 (8%) cycles, and neuropathy in 5 (5%) of cycles. Twenty three patients had a platelet count < 100 x 10(9)/l prior to therapy: a greater than 50% decrease in platelet count over pre-therapy level occurred in 79% of first cycles, overt bleeding occurred in 4 (4%) of all cycles. Eleven of 29 (38%) patients achieved complete remission (CR), 4 of whom have relapsed after 5, 6, 9, and 12 months of remission. Two of 11 CR patients presented with RS without any prior CLL therapy. One patient had a partial remission. Thus the overall response rate was 12/29 (41%). Overall median survival was 10 months, 19 months in patients who achieved CR, 3 months in those who did not (p = 0.0008). A landmark analysis performed at 2 months from start of therapy comparing patients alive in CR versus patients alive but not in CR showed a median survival of 19 months versus 6 months, respectively (p 0.0017). In conclusion the hyper CVXD regimen has a relatively high response rate, significant toxicity and a moderate impact on survival in RS.     

A phase II trial of short course fludarabine,mitoxantrone, rituximab followed by 90Y-ibritumomab tiuxetan in untreated intermediate/high-risk follicular lymphoma

BackgroundA prospective, single-arm, open-label, multicenter, nonrandomised phase II trial to evaluate efficacy and safety of short fludarabine, mitoxantrone, and rituximab (FMR) induction followed by radioimmunotherapy, in untreated, intermediate/high-risk follicular non-Hodgkin’s lymphoma (NHL) patients.Patients and methodsFifty-five patients were treated using a sequential treatment schedule of four induction cycles of FMR chemoimmunotherapy, and a subsequent consolidating single administration of ⁹⁰Y-ibritumomab tiuxetan (⁹⁰Y-IT), 8–14 weeks later. Patients were eligible for radioimmunotherapy if at least in partial response (PR) after induction, with normal platelet and granulocyte counts and a bone marrow infiltration ≤25%. Primary study end points were response rate and hematologic toxic effects; secondary end points were overall survival (OS) and progression-free survival (PFS).ResultsAll the 55 patients received four induction cycles with an overall response rate of 96% (38 complete responses [CR] and 15 PR). Fifty-one patients (38 in CR and 13 in PR) received ⁹⁰Y-IT. By the end of the treatment, 49/55 patients achieved a CR. With a median follow-up of 21 months, the estimated 3-year PFS was 81% and the 3-year OS 100%.ConclusionsThis study has established feasibility, tolerability, and efficacy of a regimen composed by short FMR induction with ⁹⁰Y-IT consolidation in untreated intermediate/high-risk follicular NHL patients.     

Randomized phase III study of fludarabine phosphate versus cyclophosphamide, vincristine, and prednisone in patients with recurrent low-grade non-Hodgkin's lymphoma previously treated with an alkylating agent or alkylator-containing regimen.

PURPOSE: To compare in a phase III study the safety and efficacy of fludarabine to that of cyclophosphamide, vincristine, and prednisone (CVP) in recurrent, low-grade, non-Hodgkin's lymphoma after previous response to systemic treatment. PATIENTS AND METHODS: Patients were randomized to fludarabine (25 mg/m(2) intravenously on days 1 to 5, every 28 days) or CVP (cyclophosphamide 750 mg/m(2) and vincristine 1.2 mg/m(2) both intravenously on day 1 and prednisone 40 mg/m(2) orally on days 1 to 5, every 21 days). The primary outcome assessed was progression-free survival (PFS); secondary outcomes included treatment-free survival (TFS), overall survival (OS), treatment-related toxicity, and quality of life (QoL) according to the European Organization for Research and Treatment of Cancer's Quality of Life Questionnaire C-30 version 1.0 instrument. RESULTS: Ninety-one patients were randomized, 47 to fludarabine and 44 to CVP. There was no difference in response rates, with 64% (complete response [CR], 9%) for fludarabine versus 52% (CR, 7%) for CVP (P =.72). With a median follow-up of 42 months, median PFS (11 months v 9.1 months; P =.03) and TFS (15 months v 11 months; P =.02) were superior in patients receiving fludarabine. No difference in median overall survival was detected (57 months for fludarabine v 44 months for CVP; P =.95). Three patients receiving fludarabine died of treatment-related toxicity compared with none of the patients receiving CVP. Peripheral neuropathy and alopecia were more common with CVP. Patients receiving fludarabine had higher scores for social function (P =.008); no other differences in QoL were detected. CONCLUSION: In recurrent low-grade lymphoma, fludarabine improves PFS, TFS, and social function scores in comparison with CVP but does not improve OS.     

BACOD方案治疗复发及难治性非霍奇金淋巴瘤的临床研究

 目的　观察BACOD方案治疗复发及难治性非霍奇金淋巴瘤（NHL）的疗效及患者不良反应。方法　65例复发及难治性NHL患者,采用BACOD方案进行化疗,具体为：博莱霉素10 mg／m2,静脉滴注,第2、9天;环磷酰胺750 mg／m2,静脉滴注,第1天;长春地辛3 mg／m2,静脉注射,第1、8天;阿糖胞苷150 mg／m2,静脉滴注,第2天至第5天;地塞米松10 mg／m2,静脉滴注,第1天至第7天,3周为1个疗程。结果　完全缓解18例,部分缓解30例,稳定13例,进展4例,有效率70.8 %。有效患者中位缓解时间 10个月（2～35个月）。1年生存率32.3 %,2年生存率24.6 %。患者主要不良反应为骨髓抑制。结论　BACOD方案可作为复发及难治性NHL的解救方案。     

Mitoxantrone and Fludarabine in the Treatment of Patients with Non-Hodgkin's Lymphoma Failing Primary Therapy with a Doxorubicin-or Mitoxantrone-Containing Regimen

Patients with recurrent lymphoma of any grade were treated with mitoxantrone (12 mg/m² given intravenously (IV) over 15-30 minutes on day 1) followed by fludarabine at a dose of (25 mg/m 2 given IV over 30 minutes on days 1-3) every 28 days fludarabine at a dose of(25 mg/m² given IV over 30 minutes on days 1-3) every 28 days. All patients had failed one prior chemotherapy regimen that contained either doxorubicin or mitoxantrone, total dose not exceeding 350 mg/m² doxorubicin or 80 mg/m² mitoxantrone. mitoxantrone. Thirty one patients (22 with intermediate-or high-grade and 9 with low-grade NHL) were enrolled. Median age was 63 years (range: 21 to 87). The objective response rate for patients with intermediate/high-grade NHL was 55% (27% with CR) and 89% (56% with CR) for patients with low-grade NHL. Median time to disease progression was 5.1 months for patients with intermediate/high-grade NHL and 10.8 months for patients with low-grade NHL. Median time to death for patients with intermediate/high-grade disease was 11.4 months. Median time to death for patients with low-grade NHL was not calculable as only one death (due to respiratory failure) occurred in this group 6.5 months after study start. The regimen was well tolerated. Grade 3/4 neutropenia was reported in 80% (24 of 30) of patients and Grade 3/4 thrombocytopenia in 19% (6 of 31) of patients. Nine hospitalizations for adverse events (primarily fever and neutropenia) occurred among eight patients, all with intermediate/high-grade NHL, during a total of 118 cycles of therapy. Further studies of this combination regimen in patients with intermediate/high-grade NHL and studies combined with monoclonal antibodies in low-grade NHL are warranted.     

Mitoxantrone and fludarabine in the treatment of patients with non-Hodgkin's lymphoma failing primary therapy with a doxorubicinor mitoxantrone-containing regimen.

Patients with recurrent lymphoma of any grade were treated with mitoxantrone (12 mg/m2 given intravenously (IV) over 15-30 minutes on day 1) followed by fludarabine at a dose of (25 mg/m 2 given IV over 30 minutes on days 1-3) every 28 days fludarabine at a dose of (25 mg/m2 given IV over 30 minutes on days 1-3) every 28 days. All patients had failed one prior chemotherapy regimen that contained either doxorubicin or mitoxantrone, total dose not exceeding 350 mg/m2 doxorubicin or 80 mg/m2 mitoxantrone. mitoxantrone. Thirty one patients (22 with intermediate- or high-grade and 9 with low-grade NHL) were enrolled. Median age was 63 years (range: 21 to 87). The objective response rate for patients with intermediate/high-grade NHL was 55% (27% with CR) and 89% (56% with CR) for patients with low-grade NHL. Median time to disease progression was 5.1 months for patients with intermediate/high-grade NHL and 10.8 months for patients with low-grade NHL. Median time to death for patients with intermediate/high-grade disease was 11.4 months. Median time to death for patients with low-grade NHL was not calculable as only one death (due to respiratory failure) occurred in this group 6.5 months after study start. The regimen was well tolerated. Grade 3/4 neutropenia was reported in 80% (24 of 30) of patients and Grade 3/4 thrombocytopenia in 19% (6 of 31) of patients. Nine hospitalizations for adverse events (primarily fever and neutropenia) occurred among eight patients, all with intermediate/high-grade NHL, during a total of 118 cycles of therapy. Further studies of this combination regimen in patients with intermediate/high-grade NHL and studies combined with monoclonal antibodies in low-grade NHL are warranted.     

Comparison of ICE (ifosfamide-carboplatin-etoposide) versus DHAP (cytosine arabinoside-cisplatin-dexamethasone) as salvage chemotherapy in patients with relapsed or refractory lymphoma

Background: High dose chemotherapy with autologous stem cell transplantation is currently the treatment of choice for relapsed or refractory lymphoma patients. However, its applicability is mostly restricted to patients responding to salvage chemotherapy. Optimal salvage regimen for these patients is unclear. In this study, our aim was to compare the efficacy and toxicity profiles of DHAP (cytosine arabinoside, cisplatin and dexamethasone) and ICE (ifosfamide, carboplatin and etoposide) regimens in the salvage treatment of relapsed and refractory lymphoma. Patients and Methods: In this retrospective analysis, 53 patients with primary refractory or relapsed Hodgkin's disease (HD) (n = 13) or non-Hodgkin lymphoma (NHL) (n = 40) who received ICE or DHAP salvage regimen were included. Results: Of 53 patients, 21 (39,6%) were female and the median age was 43 years. A total of 73 courses of ICE and 59 courses of DHAP were administered. Response could be evaluated in 49 patients (36 NHL and 13 HD). Of 49 patients, 11 (22.5%) achieved complete remission (CR) and 17 (35%) achieved partial remission (PR), leading to an overall response rate (ORR: CR + PR) of 57.5%. In the evaluable ICE group (n = 22) rates of CR, PR, and ORR were 27%, 41% and 68% and in the DHAP group (n = 27) rates of CR, PR, and ORR were 18%, 30% and 48% (p = 0.24, for ORR). Toxicity with both regimens was within acceptable limits. The major grade III-IV toxicities for both groups were hematological (neutopenia and thrombocytopenia). The main non-hematological toxicity was renal and observed in 8 patients. Conclusion: Although the toxicity profiles of both ICE and DHAP regimens were similar in the treatment of patients with relapsed or refractory HD or NHL, ICE seems to have higher rates of response than DHAP regimen does.     

Traditional treatment approaches in B-cell non-Hodgkin's lymphoma

Current treatment of non-Hodgkin's lymphoma (NHL) is based, to a large extent, on stratification of patients into groups based on disease subtype (indolent or aggressive) and stage, and still relies heavily on traditional approaches based on external beam irradiation and alkylating agent-based chemotherapy. Here, we describe risk-based patient management, and the benefits made possible by different treatments. Early-stage localized disease is effectively managed with irradiation and/or chemotherapy; chlorambucil in the case of indolent disease and CHOP-based therapy in the case of aggressive disease. Progress is underway in two crucial areas of the treatment of advanced-stage low-grade NHL: development of first-line therapies to improve the number and quality of complete responses (CRs), and investigation of novel radioimmunotherapy or monoclonal antibody/chemotherapy combination regimens to combat relapsed and refractory disease. New chemotherapy approaches, such as fludarabine phosphate-based combination chemotherapy for low-grade advanced-stage NHL have improved the number and quality of remissions in chemotherapy-na?ve and relapsed patients, but it remains to be seen what the long-term impact on survival may be. Monoclonal antibody based therapies including radioimmunotherapy, is emerging as a highly effective tool for the treatment of NHL, and shows synergy with fludarabine phosphate-based chemotherapy, though its optimal role has yet to be determined. At present, for patients with untreated disseminated disease; recurrent disease; or high-grade disease in the presence of poor risk factors; alternative treatment strategies are needed.     

Human immunodeficiency virus-related non-Hodgkin lymphoma: activity of infusional cyclophosphamide, doxorubicin, and etoposide as second-line chemotherapy in 40 patients.

BACKGROUND: The prognosis of patients with human immunodeficiency virus (HIV)-related non-Hodgkin lymphoma (NHL) is poor. In fact, despite a high complete response (CR) rate, approximately 50% of these patients die from progressive lymphoma. METHODS: From November 1994 to April 2000, the authors treated 40 patients with resistant or recurrent HIV-related NHL with a 96-hour continuous intravenous infusion of cyclophosphamide (187.5 mg/m(2) per day), doxorubicin (12.5 mg/m(2) per day), and etoposide (60 mg/m(2) per day). RESULTS: The median number of cycles administered was two (range, one to six cycles). A CR was documented in 4 of 40 patients (10%), and a partial remission (PR) was documented in 7 of 40 patients (18%). The CR median duration was 6 months (range, 4--30+ months), whereas PRs lasted for 5 months (range, 2--8 months). The overall median survival was 4 months (range, < 1--33 months), and the median survival for responding patients was 10 months. CONCLUSIONS: The current data confirm that infusional cyclophosphamide, doxorubicin, and etoposide is active in patients with refractory or recurrent HIV-related NHL. However, the median survival of these patients remains poor, and the other innovative approaches should be used.     

Clinical Observation of FMD Regimen:Fludarabine,Mitoxantrone, Dexamethasone, in Treatment of Non-Hodgkin''s Lymphoma

Objective  To evaluate the clinical effectivity and toxicity of the regimen FMD (fludarabine, mitoxantrone, dexamethasone) in patients with non-Hodgkin’s lymphoma. Methods  Thirty-two patients, twenty-four of whom had indolent B-cell lymphoma, 6 peripheral T-cell lymphoma, two diffuse large B-cell lymphoma, received FMD. Treatment comprised: fludarabine 25∼30 mg/m² days 1∼3, mitoxantrone 8∼10 mg/m² day 1, and dexamethasone 20∼30 mg/m² days 1∼5. At the same time, patients received prophylaxis against conditional infection with trimethoprim-sulfamethoxazole, fluconazole, acyclovir and immunoglobulin. Results  Of the thirty-two patients treated, the complete response (CR) rate, partial response (PR) rate and overall response (OR) rate were 56.3%, 21.9% and 78.2% respectively. The CR and OR rate of 24 patients with indolent B-cell lymphoma were 66.7% and 88.3% respectively. Two of six patients with peripheral T-cell lymphoma were of complete response type and one was of partial response type. One of two patients with diffuse large B-cell lymphoma was partial response. The dominating toxicity was myelotoxicity and immunotoxicity. There was no treatment associated death in all patients treated with FMD. Grade 3∼4 neutropenia occurred in 43.8% patients, 12.5% patients had infections and 9.3% developed grade 3∼4 thrombocytopenia. At a median follow-up of 24 (5∼54) months, the 2-year overall-survival rate and progression-free survival rate were (87.5 ± 1.4)% and (83.3 ± 1.6)% respectively. The 2-year OS and PFS rates of the indolent group were (93.75 ± 6.25)% and (87.5 ± 8.54)%. Conclusion  FMD regimen was highly effective with low toxicity in the treatment of non-Hodgkin’s lymphoma, especially in indolent B-cell lymphoma. It also helps to improve the prognosis even in some aggressive lymphoma, such as peripheral T cell lymphoma.     

Infusional CHOP chemotherapy (CVAD) with or without chemosensitizers offers no advantage over standard CHOP therapy in the treatment of lymphoma: a Southwest Oncology Group Study.

PURPOSE: Two phase II studies were conducted to evaluate infusional cyclophosphamide, doxorubicin, vincristine, and dexamethasone chemotherapy, termed the CVAD regimen, alone (Southwest Oncology Group [SWOG] 9240) and with the chemosensitizers verapamil and quinine (SWOG 9125) to assess effects on response, survival, and toxicity in intermediate- and high-grade advanced-stage non-Hodgkin's lymphoma (NHL). The results were compared with the historic group of patients randomized to CHOP chemotherapy on Intergroup (INT) 0067 (SWOG 8516). PATIENTS AND METHODS: All patients had biopsy-proven intermediate- or high-grade NHL (lymphoblastic histology excluded), were ambulatory and previously untreated, and had bulky stage II, III, or IV disease. One hundred twelve patients were registered on SWOG 9240 and received cyclophosphamide 750 mg/m(2) by intravenous bolus day 1, doxorubicin 12.5 mg/m(2)/d and vincristine 0.5 mg/d delivered as a continuous 96-hour infusion on days 1 through 4, and dexamethasone 40 mg/d orally on days 1 through 4 (CVAD). Cycles were repeated every 21 days for eight cycles. One hundred patients on SWOG 9125 received the same chemotherapy and the chemosensitizers verapamil 240 mg bid and quinine 40 mg tid. Chemosensitizers were begun 24 hours before chemotherapy and continued for a total of 6 days. RESULTS: Eighty-one patients were eligible for each study. The complete response (CR) rates were 39% on SWOG 9125 and 31% on SWOG 9240. With a median follow-up of 5.8 years on SWOG 9125 and 4.5 years on SWOG 9240, the 2-year failure-free survival (FFS) rate was 42% on SWOG 9125 and 41% on SWOG 9240. Two-year overall survival (OS) rate was 64% on SWOG 9125 and 58% on SWOG 9240. These results are comparable to a 44% CR rate, a 2-year FFS of 46%, and 2-year OS of 63% observed in 225 patients treated with CHOP on INT 0067 (SWOG 8516). CONCLUSION: CVAD combination chemotherapy alone or with the chemosensitizers verapamil and quinine is not promising therapy with respect to improved response or OS in intermediate- and high-grade advanced-stage NHL.     

Methyl-Gag, Ifosfamide, Methotrexate and Etoposide (Mime) as Salvage Therapy for Non-Hodgkin's Lymphomasa Swedish national prospective study

One hundred and two patients with recurrent or refractory non-Hodgkin's lymphoma (NHL) were treated with MIME (methyl-GAG, ifosfamide, methotrexate, etoposide) in accordance with a prospective protocol. Of 75 patients with high-grade malignant NHL (median age 57 years, range 21-79), 15 patients (20%) obtained a complete response (CR) and 27 patients (36%) a partial remission (PR), giving an overall response rate of 56%. The remissions were usually short when not consolidated with ABMT or radiotherapy. The probability of progression-free survival after 2 years was 13%, and the cause-specific survival was 23%. Of 27 patients with low-grade NHL (median age 46 years, range 37-86), 7% had a CR and 37% a PR giving a response rate of 44%. The remissions were again usually short when not consolidated, and the probability of progression-free survival at two years was 11%, and the cause-specific survival 26%. The main toxicity was hematological with septicemia in 20% of the patients and other severe infections in 19%. Fifteen patients (11 high-grade NHL and 4 low-grade NHL) were consolidated with high-dose therapy followed by ABMT, of whom 6 are in continuous CR. We conclude that MIME can induce remissions in NHL patients, and that the remission rates are comparable with those of many other salvage regimens. The remissions are, however, generally of short duration and need consolidation. There was considerable toxicity therefore patients not suitable for ABMT preferably should be treated with less toxic salvage regimens.     

FLUDAP: salvage chemotherapy for relapsed/refractory aggressive non-Hodgkin's lymphoma

The aim of this study was to investigate the combination of fludarabine phosphate, dexamethasone, cytosine arabinoside and cis-platinum (FLUDAP) in the treatment of patients with relapsed/refractory aggressive non-Hodgkin's lymphoma (NHL). This regimen comprises: dexamethasone 100 mg/d continuous infusion (cont. inf.) d1-3; cytosine arabinoside (ara-C) 1 g/m2/d cont. inf. d 2,3; fludarabine phosphate 30 mg/m2 short inf. 4hr prior to each 24hr ara-C inf.; cis-platinum 50 mg/m2 4hr inf. at the start of each 24hr ara-C inf. G-CSF (lenograstim, Granocyte) is given at 263 microg s.c. daily from day 7 until the neutrophil count reaches 1.0x10(9)/l. The regimen repeats at 21 day intervals. A total of 33 patients were registered (median age 47 years; 24 males, 9 females); the majority (73%) were refractory to their previous treatment and most had advanced disease by Ann Arbor stage. Thirteen (39%) of the 33 enrolled patients (52% of the 25 fully evaluable patients who received at least 2 courses of FLUDAP) responded to treatment. A maximum response of complete remission was achieved in 5 patients, good partial remission in 3, and partial remission in 5. Twelve patients went on to successful stem cell supported intensification therapy. Median survival times were higher in the responding patients, and in those patients transplanted post-FLUDAP. The toxicity associated with the FLUDAP regimen was generally predictable; frequently reported severe events included haematological toxicity and infection. In conclusion, the FLUDAP regimen shows promise as a salvage regimen and increases the available therapeutic options in the treatment of recurrent/refractory aggressive NHL.