E-SHAP: An effective treatment in selected patients with relapsed non-Hodgkin's lymphoma

BACKGROUND:: The optimal treatment of relapsed or refractory non-Hodgkin'slymphoma is unknown. The reported encouraging results of a salvageregimen, E-SHAP (etoposide 40 mg/m²/day x 4, methyl prednisolone500 mg daily x 4, cytosine arabinoside 2 gm/m² one dose andcisplatinum 25 mg/m²/day x 4), at the MD. Anderson Hospitalin Texas, which resulted in a 65% response rate, could not bereproduced in the United Kingdom (0% response). PATIENTS AND METHODS:: Twenty-six patients with relapsed (n = 16) or refractory (n= 10) non-Hodgkin's lymphoma were treated at our Centre by amodified E-SHAP regimen (cytosine arabinoside 1 gm/m² one dose).The treatment was intended as remission induction before BMT(n = 16), as salvage by itself (n = 5) and for palliation ofsymptoms (n = 5). RESULTS:: The overall response rate was 72% (CR = 7 and PR = 11). A comparisonof Kaplan-Meier curves showed a statistically significant improvementin median relapse-free survival in patients who had previouslyachieved CR (p = 0.0012), no bulky disease (P = 0.0006) andno B-symptoms (P = 0.0004). The toxicity was acceptable: 8 instancesof febrile neutropenia, 2 of reversible renal impairment and2 symptomatic electrolyte abnormalities. No fatal toxicitieswere encountered. The median time to treatment failure was 191days and median overall survival was 190 days. CONCLUSIONS:: E-SHAP is an active combination chemotherapy when used as asalvage regimen or for remission induction before bone marrowtransplantation in selected patients with relapsed non-Hodgkin'slymphoma. Patients who previously achieved CR, with low tumourburden and no B-symptoms are the best candidates for this treatment.It has a limited palliative effect. non-Hodgkin's lymphoma, salvage chemotherapy, etoposide, cisplatinum     

Autologous bone marrow transplantation for patients with poor-prognosis lymphoma

Review of prognostic factors at Memorial Hospital in New York City has shown that adult patients with large-cell lymphoma (diffuse histiocytic lymphoma by Rappaport classification) who have high lactic dehydrogenase (LDH) and/or bulky mediastinal or abdominal disease are destined to do poorly with conventional combination chemotherapy, with a 2-year disease-free survival of about 20%. Patients who relapse after conventional combination chemotherapy have a similar poor prognosis. Thirty-one such patients with lymphoma were studied to evaluate the efficacy of intensive radiotherapy (hyperfractionated total body irradiation [TBI] [1,320 rad]), and cyclophosphamide (60 mg/kg/d for two days) followed by autologous bone marrow transplantation (ABMT). Our results show a disease-free survival advantage (P = .002) for 14 patients who underwent ABMT immediately after induction of remission with 79% surviving at a median follow-up 49.2+ months, compared with a median survival of 5.2 months for 17 patients administered ABMT while in relapse and/or after failing conventional treatment. Our results support the use of aggressive therapy as early treatment for patients with poor prognostic features.     

Shortened first-line high-dose chemotherapy for patients with poor-prognosis aggressive lymphoma.

PURPOSE: Randomized trial LNH93-3 was conducted on patients who had poor-prognosis aggressive lymphoma and were younger than 60 years with two to three factors of the age-adjusted International Prognostic Index to evaluate the benefit of early high-dose therapy (HDT) with autologous stem-cell transplantation (ASCT). PATIENTS AND METHODS: Patients were randomized between doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP) chemotherapy followed by sequential consolidation and an experimental shortened treatment consisting of three cycles with escalated doses of cyclophosphamide, epirubicin, vindesine, bleomycin, and prednisone and collection of peripheral-blood stem cells. On day 60, HDT was administered with 1,3-bis(2-chloroethyl)-1-nitrosourea, etoposide, cytarabine, and melphalan followed by ASCT. RESULTS: Eligible patients (n = 370) with aggressive lymphoma were analyzed. For ACVBP (181 patients) and HDT (189 patients), respective complete remission rates were 64% and 63%. With a median follow-up of 60 months, 5-year overall survival and event-free survival for ACVBP and HDT were 60% +/- 8% and 46% +/- 8% (P =.007) and 52 +/- 8% and 39 +/- 8% (P =.01), respectively. Survival was independently affected by age greater than 40 years (P =.0003), T-cell phenotype (P =.009), bone marrow involvement (P =.003), and HDT treatment group (P =.04). CONCLUSION: Early HDT with ASCT in high-risk patients was inferior to the ACVBP chemotherapy regimen. These results indicate that the received dose-intensity before HDT was too low when compared with ACVBP and HDT and was given too early.     

A brief-duration combination chemotherapy for elderly patients with poor-prognosis non-Hodgkin's lymphoma.

Curative combination chemotherapy is available for many patients with aggressive non-Hodgkin's lymphoma (NHL); however, treatment of elderly patients with these regimens is difficult due to excessive toxicity. From 1983 to 1988 the authors treated 26 patients 65 years and older with aggressive NHL with a novel 8-week chemotherapy regimen containing bleomycin, etoposide, cyclophosphamide, doxorubicin, methotrexate with leucovorin, and prednisone (BECALM), designed to preserve dose intensity and minimize toxicity. Median age was 75 years. Histologic types included the following: 20 intermediate grade (16 large noncleaved cell; two large cleaved cell; one intermediate grade, unspecified); six high grade (four small noncleaved cell; one immunoblastic sarcoma B-cell; one high grade, unspecified). Twenty-one patients were Stage III or IV. Twenty-two of 26 patients had one or more of the following: tumor greater than 10 cm; multiple extranodal sites; lactate dehydrogenase (LDH) 400 IU/l or greater; small noncleaved cell histologic type. Chemotherapy consisted of bleomycin 20 U intravenously (IV) weeks 1 and 7; etoposide 75 mg/m2 IV every day x 3 days on week 4; cyclophosphamide 600 mg/m2 IV weeks 1, 4, 7; doxorubicin 40 mg/m2 IV weeks 1, 7; methotrexate 50 mg/m2 IV weeks 1, 2, 4, 5, 7, 8 with oral leucovorin rescue; prednisone 60 mg orally for 10 days on weeks 1, 4, 7. Eighteen patients completed the 8-week treatment course. There were 13 complete responses (CR); seven patients remain in continuous CR at a median follow-up of 37.5 months. There have been five relapses, including one late relapse; and one patient died of an intercurrent illness in CR. Overall and actual event-free survivals are 38% and 27%, respectively. The major toxicities were neutropenic fever and mucositis. There were four treatment-related deaths. The authors conclude that BECALM chemotherapy can be administered to elderly patients with aggressive NHL. Although neurotoxicity and cumulative toxicity from bleomycin and anthracycline are avoided, the regimen remains moderately toxic, particularly with respect to myelosuppression. Treatment results compare favorably with other reported regimens in this group of patients with multiple poor prognostic features.     

High-dose cytosine arabinoside in previously treated patients with poor-prognosis non-Hodgkin's lymphoma

Fourteen previously treated patients with relapsed or refractory poor-prognosis non-Hodgkin's lymphoma were given chemotherapy regimens containing high doses of cytosine arabinoside alone (seven patients) or with an anthracycline or amsacrine (seven patients). Five patients achieved a complete remission and two patients had a partial remission. The durations of remission, however, were short (median, 3 months; range, 2-6 months). Toxicities included conjunctivitis, photophobia, stomatitis, dermatitis, cerebellar dysfunction, diarrhea, nausea, vomiting, liver dysfunction, and severe myelosuppression. Recovery of an absolute granulocyte count greater than 500/microliter and an untransfused platelet count greater than 20,000/microliter required a median of 31 (range, 28-35) and 30 (range, 27-43) days, respectively. Six patients died with recurrent or residual disease before bone marrow recovery. Younger age, good performance status, and a previous complete remission were predictive of a good response. High-dose cytosine arabinoside has major myelotoxicity but significant activity in some patients with poor-prognosis non-Hodgkin's lymphoma.     

Multicenter Phase II study of CyclOBEAP regimen for elderly patients with poor-prognosis aggressive lymphoma

We treated elderly patients (65-69 years) who had aggressive lymphoma with the CyclOBEAP regimen, and we studied the safety and efficacy of this treatment. The CyclOBEAP regimen was administered over a total period of 12 weeks. Doxorubicin 40 mg/m(2) was given every 2 weeks in combination with either cyclophosphamide 800 mg/m(2) or etoposide 70 mg/m(2) qd x 3. During the alternate weeks, non-myelosuppressive vincristine 1.0 mg/m(2) was given either with bleomycin 10 mg/m(2) or alone. Prednisolone 40 mg/m(2) was administered daily for three 14-day periods during weeks 1-2, 5-6 and 9-10. There were 51 eligible patients. A complete response was achieved in 42 patients (82%). The 5-year overall survival (OS) rate was 60.6% and progression-free survival (PFS) rate was 51.8%. WHO grade 4 neutropenia was observed in 32 patients and thrombocytopenia in 8 patients. We showed that the CyclOBEAP regimen can be safely used in the treatment of aggressive lymphoma in elderly patients and it achieved a high rate of remission.     

Thalidomide for patients with recurrent lymphoma

BACKGROUND: Thalidomide has significant clinical activity in patients with multiple myeloma. However, its activity against other lymphoid tumors is unknown. The authors reported their experience with thalidomide in patients with recurrent/refractory non-Hodgkin lymphoma and in patients with Hodgkin disease. METHODS: Nineteen patients (median age, 62 years) who had undergone a median of 5 previous treatment regimens were treated with escalating doses of thalidomide (200-800 mg per day) until disease progression or prohibitive toxicity was observed. The authors measured serum levels of angiogenesis factors before and after treatment. RESULTS: One patient (5%) with evidence of recurrent gastric mucosa-associated lymphoid tissue lymphoma achieved a complete response, and 3 patients (16%) achieved stable disease. CONCLUSIONS: The current study suggests that thalidomide has limited single-agent activity in heavily pretreated patients with recurrent or refractory lymphoma.     

Irinotecan hydrochloride for the treatment of recurrent and refractory non-Hodgkin lymphoma: a single institution experience

BACKGROUND: Irinotecan hydrochloride (CPT-11) has a broad range of antitumor activity and has demonstrated little cross-resistance with doxorubicin or vincristine. In the current study, the authors investigated the efficacy and adverse effects of irinotecan in the treatment of recurrent and refractory non-Hodgkin lymphoma, for which current therapies appear to be unsatisfactory. METHODS: Irinotecan was administered by intravenous infusion at a dose of 40 mg/m(2)/day for 3 days, and this regimen was repeated 2-3 times at weekly intervals, followed by 2 weeks off therapy. The subjects were 48 patients with recurrent or refractory non-Hodgkin lymphoma. The histologic classification (Working Formulation) was low grade in 8 patients, intermediate grade in 36 patients, high grade in 1 patient, and other (angiocentric lymphoma, Ki-1 lymphoma, and unidentified) in 3 patients. RESULTS: Forty-five patients were determined to be evaluable. Therapy resulted in a complete disease remission in 2 patients and a partial remission in 15 patients. The response rate was 37.8%. The median duration of response was 64 days and the median time to disease progression was 77 days. The median survival time was 422 days. Major adverse reactions included myelosuppression and gastrointestinal toxicity. Leukopenia, anemia, and thrombocytopenia of Grade 3 or 4 (according to the National Cancer Institute Common Toxicity Criteria) was observed in 63.0%, 30.4%, and 6.5% of the patients, respectively, and Grade 3 or 4 diarrhea occurred in 30.4% of patients. Treatment was withdrawn because of diarrhea in three patients. Because of myelosuppression and diarrhea, approximately 67% of the patients required changes to the regimen, including dose reduction, prolongation of the interval between treatments, and reducing the number of days of consecutive treatment. CONCLUSIONS: The results of the current study suggest the activity of irinotecan as salvage therapy for patients with recurrent and refractory non-Hodgkin lymphoma. However, the optimum dosing schedule remains to be determined.     

Successful treatment with Erwinia L-asparaginase for recurrent natural killer/T cell lymphoma

We describe a patient with natural killer (NK)/T cell lymphoma who relapsed after autologous peripheral blood stem cell transplantation (auto-PBSCT) and was successfully treated with Escherichia coli (E. coli) and Erwinia L-asparaginase. A 38-year-old male patient with ulcerated tumor at the left thigh was diagnosed as having nasal type NK/T cell lymphoma on the basis of histopathological and flowcytometric findings of tumor, revealing diffuse infiltration of atypical lymphoid cells into blood vessels and expression of CD7 and CD56 antigens, but not CD3. He had tumor infiltration in the bone marrow and at the right lower lung field. After five cycles of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) therapy, the patient achieved complete remission and received high-dose chemotherapy with auto-PBSCT, although the tumor recurred in the right leg 10 months later. Despite salvage chemotherapy, followed by local irradiation and surgical amputation, a tumor recurred at the left upper gingiva 10 days after. Using E. coli L-asparaginase (6000 U/m2/day), the tumor regressed, fever was alleviated and the serum lactate dehydrogenase decreased to normal range after several days. The asparagine synthetase expression in tumor cells was immunohistochemically negative on paraffin-embedded tissues. Because of the anaphylactoid reaction developing after E. coli L-asparaginase, alternative Erwinia L-asparaginase (6000 U/m2/day) was administered, resulting in regression of tumor and fever lysis. L-asparaginase is a promising agent for the treatment of NK/T cell lymphoma.     

Irinotecan (topoisomerase-I inhibitor) for the treatment of recurrent primary intracranial malignant lymphoma

Primary intracranial malignant lymphoma is a fetal disease with poor prognosis, and there is no effective treatment against recurrent primary intracranial malignant lymphomas. We report 3 cases of malignant lymphoma treated with irinotecan (topoisomerase-I inhibitor, camptothecin derivatives), an aromatic drug extracted from camptotheca acuminata. After the initial diagnosis, surgical resection followed by radiation therapy was performed for one cerebral, and two cerebellar malignant lymphomas. The tumors recurred 1 month, 18 months, and 18 months after the initial treatment, respectively. The former two cases were treated with additional radiation therapy and/or radiosurgery for the recurrent tumors; however, the tumors recurred again. All cases were treated finally with a combination therapy of irinotecan and cis-platinum followed by a maintenance therapy with irinotecan only. All cases showed a sharp roentgenographical response to the chemotherapy even after cumulative recurrences. One patient died of systemic infection, and another died of intracranial tumor recurrence 11 and 29 months after the initial diagnosis, respectively. Autopsies revealed multiple tumor recurrences in both these cases. The other patient died 31 months after the initial diagnosis, also due to intracranial tumor recurrences. These results indicate the usefulness of irinotecan for the treatment of recurrent primary intracranial malignant lymphoma; however, further investigation is necessary to establish a better protocol for irinotecan treatment against primary intracranial malignant lymphoma.     

Intermediate-dose cytosine arabinoside in the treatment of recurrent or refractory non-Hodgkin's lymphoma

Twelve patients with recurrent or refractory non-Hodgkin's lymphoma (NHL) were treated with an intermediate-dose of cytosine arabinoside (CA) by continuous i.v. infusion in combination with daunorubicin (DNR). Of the 10 patients evaluated, one obtained a complete response (CR) and three partial responses (PR), and an almost complete disappearance of the tumor for three weeks (minor response) was seen in two patients. Severe myelosuppression was a dose-limiting factor. Intermediate-dose CA is effective for recurrent or refractory NHL but it needs to be combined with the proper partner drugs to obtain better therapeutic results.     

Methotrexate re-challenge for recurrent primary central nervous system lymphoma

The prognosis of primary CNS lymphoma (PCNSL) recurring after methotrexate is poor (objective response rates [ORR] = 26–53 %; 1-year overall survival [OS] = 35–57 %). Salvage PCNSL chemotherapies have been based on the use of different agents to avoid cross-resistance; however, methotrexate is the most active agent in PCNSL, and methotrexate re-challenge may be an effective strategy for recurrent disease. We report our experience with methotrexate re-challenge in PCNSL. We reviewed 39 patients with histologically confirmed PCNSL who responded to methotrexate at initial diagnosis, experienced disease relapse and received methotrexate re-challenge. At the time of re-challenge, median age was 66 and median Karnofsky performance score (KPS) was 70. Median time from initial diagnosis was 26 m. Twenty-six patients were at first relapse and 13 at second or later relapse. At re-challenge, methotrexate was given in combination with other agents to 33 patients and as a single agent to six. The objective response rate was 85 %, with a complete response in 29 (75 %) patients, partial response in four (10 %) and disease progression in six (15 %). At median follow-up of 26 m, the median progression-free survival was 16 m; 1-year OS was 79 % (95 % CI 63–89) and median OS was 41 m. KPS was a prognostic factor for progression free survival (p = 0.04). In this population selected by previous methotrexate response, methotrexate re-challenge was a safe and effective strategy, indicating chemosensitivity was retained. Efficacy compared favorably to other salvage treatments suggesting methotrexate re-challenge should be considered in recurrent PCNSL patients who previously responded to methotrexate.     

Immunological studies on a case of recurrent Burkitt's lymphoma during immune stimulant treatment

Antibodies against several EBV- and non-EBV-associated antigens were titrated in serial sera from a patient with Burkitt's lymphoma who was given immune stimulants during chemotherapeutically induced tumor regression. EBV-associated membrane reactive antibodies gradually declined during BCG treatment 3–4 months prior to triple (pertussis-diphtheria-tetanus, PDT) vaccination, after which they rapidly increased simultaneously with the appearance of multiple recurrent tumors. Prior to vaccination, antibodies to the R component of the EBV-induced early antigen complex became detectable and increased further before the recurrences became evident. Antibodies to EB viral capsid antigens and to the D component of the early antigen complex also increased starting after triple vaccination, whereas most other antibodies studied remained stable during the observation period. Possible interpretations of the serological changes are discussed.     

Low-dose weekly paclitaxel for recurrent or refractory aggressive non-Hodgkin lymphoma

BACKGROUND: Many patients with recurrent, intermediate or high-grade non-Hodgkin lymphoma (NHL) may not respond to or are not candidates for aggressive salvage chemotherapy. Effective, less toxic regimens are needed. Although high-dose taxanes have not been reported to be very effective for the treatment of lymphoma, different delivery rates may allow for different mechanisms of action to be manifest and result in a different toxicity profile and response rate. The current study tested this hypothesis by using low-dose, weekly paclitaxel in patients with recurrent or refractory NHL. METHODS: Adults age > 18 years with refractory or recurrent, aggressive NHL who were not considered curable with standard high-dose therapy received paclitaxel at a dose of 80 mg/m2 weekly for 5 weeks for 2 cycles. RESULTS: Thirty-four patients with refractory NHL and 4 patients with recurrent disease were treated. Approximately 45% of the patients had achieved a prior disease remission. The median number of prior regimens received was 3, 74% of the patients had an International Prognostic Index of > or = 3 at the time of study entry, and 29% had failed high-dose therapy with autologous hematopoietic support. Only one patient encountered severe toxicity (sepsis). Myelosuppression was reported to occur in approximately 20% of patients. A total of 10 patients (26%) achieved a complete disease response and 4 patients (11%) achieved a partial response. CONCLUSIONS: In the current study, low-dose, weekly paclitaxel therapy was found to provide a well tolerated and less toxic approach to the treatment of refractory NHL, with encouraging responses noted in heavily pretreated patients. However, evaluation in patients with an earlier stage of disease is warranted.     

Results of MIME salvage regimen for recurrent or refractory lymphoma

Based on encouraging results of two previous ifosfamide-VP-16 salvage combinations, methyl-gag was added to ifosfamide, methotrexate, and etoposide (VP-16). This combination is called MIME. A total of 208 patients with recurrent lymphoma were treated with this regimen. Response rates were 24% for complete remission and 36% for partial remission. The MIME regimen was more effective in patients who were treated after being off front-line therapy for longer than 6 months. However, responses were also seen in patients with disease clearly resistant to front-line therapy, suggesting that MIME was at least partially non-cross-resistant with front-line doxorubicin-containing regimens. The 15-month median relapse-free survival of complete responders and the 9-month overall median survival time for all patients treated were both similar to results from previous ifosfamide-VP-16 combination use. This regimen has been effective in the treatment of patients with recurrent or refractory lymphoma, but cannot be considered curative in the majority of cases.     

Temozolomide plus rituximab in the treatment of recurrent central nervous system lymphoma： Case report and literature review

Objective  

The aim of our study was to investigate the treatment of recurrent central nervous system lymphoma.