Efficacy and toxicity of 2-Chlorodeoxyadenosine (Cladribine)--2 h infusion for 5 days--as first-line treatment for advanced low grade non-Hodgkin's lymphoma

2-Chlorodeoxyadenosine (Cladribine) is a new purine analogue with high activity in pretreated low grade non-Hodgkin's lymphoma (NHL). To evaluate the efficacy of this drug in untreated patients with advanced NHL, we performed a prospective multicentre trial. Cladribine (0.12 mg/kg) was administered intravenously daily for 5 consecutive days in an out-patient setting. The treatment was repeated every 28 days for four cycles. Included were patients with a histological diagnosis of low grade NHL according to the Kiel classification and stage III or IV disease. Stage II patients were included when radiotherapy had failed. 55 patients were entered into the study. 50 patients were evaluable. The remission rate was 44/50 (88%; 95% confidence interval 82-100%), including complete remissions (CR) in 14 (28%) patients. Only 2 patients showed progression while on Cladribine treatment. The estimated overall survival, and time to treatment failure (TTF) were 85% and 51%, respectively, after a median observation time of 92 weeks. 11 (22%) patients showed grade 3 or 4 toxicity according to the WHO grading. Haematological toxicity was responsible for 86% of the overall toxicity and 100% of grade 3 and 4 toxicity. 7 patients (14%) had an infection, two of which were opportunistic. 12 (24%) patients did not experience any toxicity during the treatment. The results of this study clearly demonstrate the safety and considerable activity of this regimen. Cladribine is very effective even at lower doses than have been used so far.     

Paclitaxel plus high-dose cyclophosphamide with G-CSF support in patients with relapsed and refractory aggressive non-Hodgkin's lymphoma

Based on the single-agent activity of both paclitaxel and cyclophosphamide in the treatment of non-Hodgkin's lymphoma (NHL), we conducted a phase II study to evaluate the efficacy of the combination of the two drugs in patients with refractory and relapsed aggressive NHL. All patients received 900 mg/m2 bolus of cyclophosphamide intravenously daily for 3 consecutive days with a concurrent infusion of 150 mg/m2 of paclitaxel over 72 h (50 mg/m2/d). 24 h after the completion of chemotherapy, patients received subcutaneous injections of 5 microg/kg of granulocyte-colony stimulating factor (G-CSF) daily until white cell count recovery. Treatment was repeated every 3 weeks. Patients who had at least a partial response (PR) after two courses continued to receive a maximum of four courses. Patients with responding disease were allowed to undergo high-dose chemotherapy followed by stem-cell/bone marrow transplantation if they were eligible. Of the 77 patients who were eligible for the study, 74 (96%) were evaluable for toxicity and treatment response. The overall response rate was 45% (95% CI 33-57%). Patients who received treatment after their disease relapsed from a complete response (CR) had an 81% response rate (38% CRs), whereas those with primary refractory disease had a 22% response rate. Toxicities of > grade 2 included alopecia (100%) and stomatitis (25%). Neutropenic fever of grade > 2 occurred after 18% of the courses, and platelet count of < or = 20 x 10(9)/l developed after 20% of the courses. Thus, the combination of paclitaxel plus high-dose cyclophosphamide is an effective new regimen in the treatment of refractory and relapsed NHL.     

Alternating triple therapy for the treatment of intermediate grade and immunoblastic lymphoma

BACKGROUND: CHOP is currently considered the gold standard of treatment for intermediate grade lymphomas. We designed a new regimen known as 'ATT' (alternating triple therapy) which uses three non-cross resistant combinations in alternating sequence for nine cycles. MATERIALS AND METHODS: This is a phase II clinical trial with comparison to CHOP/CMED historical controls using prognostic factors. The tumor score system was used to evaluate the results of this trial. Two hundred sixty-eight eligible patients who had one or more of the following adverse features: bulky disease, elevated LDH or > 1 extranodal site were analyzed. Outcome measures consist of survival and failure free survival. RESULTS: At a median follow-up of 32 months, there was no statistically significant difference in survival for those with favorable prognostic factors (tumor score < or = 2). However, there was a statistically significant difference in favor of ATT for those with unfavorable tumor scores. When we examined the failure-free survival of those with unfavorable tumor scores, we again observed a superiority for the ATT regimen over CHOP/CMED but the opposite was true for those with favorable tumor scores. We also found a statistically significant difference in favor of the ATT regimen when compared with CHOP/CMED for patients < or = 60 years old with a tumor score > or = 3, while no advantage was found for those > 60 years. CONCLUSIONS: ATT appears more effective but only for patients < 60 years old with unfavorable tumor scores. In those older than 60 years with favorable tumor score, CHOP/CMED appears superior. ATT might be an adequate regimen for young patients with poor prognostic features while CHOP/CMED might be a better choice for those with good prognosis irrespective of age. For those > 60 years with unfavorable tumor scores neither ATT or CHOP/CMED were adequate treatment. Because of the phase II nature of this study, these conclusions should be considered as hypotheses which require prospective testing.     

硼替佐米治疗复发难治性套细胞淋巴瘤的研究进展

复发难治性套细胞淋巴瘤(MCL)的治疗是临床医师面临的严峻挑战.近年来,蛋白酶体抑制剂硼替佐米的应用给复发难治性MCL患者的治疗提供了新方法.就硼替佐米治疗复发难治性MCL的机制、临床疗效以及MCL细胞对硼替佐米耐药产生的机制和应对策略进行综述.     

Long-term follow-up of non-Hodgkin's lymphoma patients treated with ProMACE-CytaBOM: an effective regimen for the intermediate grade subtype

Long-lasting results achieved in 54 patients with aggressive non-Hodgkin lymphoma treated with Pro-MACE-CytaBOM regimen were evaluated. Twenty-four out of 54 (45%) patients achieved a complete remission and 13 of them are still in continuous remission with a median survival of 53.5 months. Interestingly, in 16 patients with intermediate grade histology we obtained an overall response rate of 100%.     

Combination phase I/II study of irinotecan hydrochloride (CPT-11) and carboplatin in relapsed or refractory non-Hodgkin's lymphoma. CPT-11/Lymphoma Study Group

Irinotecan hydrochloride (CPT-11) is a new derivative of camptothecin which inhibits topoisomerase I. Phase II studies have demonstrated that CPT-11 is active against a broad spectrum of neoplasms including intractable non-Hodgkin's lymphoma. An early phase II study in lymphoma suggested that a schedule of daily infusions of 40 mg/m2/day for three or five consecutive days is more effective than a single infusion of 200 mg/m2 every three to four weeks. Carboplatin is also an active agent against lymphoma, and preclinical studies have shown that CPT-11 and its active metabolite have a synergistic effect with platinum compounds. To evaluate the maximal tolerated dose (MTD) and the therapeutic efficacy of CPT-11 in combination with carboplatin in relapsed or refractory non-Hodgkin's lymphoma, we conducted a combination phase I/II study. The starting dose of CPT-11 was 20 mg/m2/day (days 1 through 3 and 8 through 10), and dose escalations of 5 mg/m2/day increments were planned, with a fixed dose of carboplatin (300 mg/m2, day 1). Six of the eight patients receiving both agents at the starting dose level developed critical toxicities such as grade 4 hematologic (neutropenia 6/8, thrombocytopenia 1/8) and grade 3 non-hematologic toxicities (diarrhea 2/8, transaminase elevation 1/8). Further dose escalation of CPT-11 was halted, and the starting doses were judged to be the MTDs. The response rate (25%, 2/8) to the combination of the MTDs was not superior to that of CPT-11 alone in a previous phase II study (38%, 26/69), and the MTD of CPT-11 in combination with carboplatin was less than half the single-agent dose. We conclude that carboplatin is not recommendable for combination with CPT-11 in lymphoma patients. Other suitable agents for such a combination should be sought.     

难处理低品位铜钴矿的微生物浸出

以赞比亚某典型难处理低品位氧化铜钴矿为研究对象,配入适量硫化铜钴矿,采用人工调配的高效微生物浸矿菌群对铜钴矿进行微生物浸出,同时分别与摇瓶酸浸、搅拌酸浸和柱浸进行了对比.结果表明,采用微生物浸出难处理铜钴矿,随着温度升高和时间延长,铜浸出率增大.浸出温度为40℃时,微生物浸出铜浸出率为90.7%,高于摇瓶酸浸和搅拌酸浸浸出结束时浸出率(69.4%~73.2%)以及柱浸结束时浸出率(约85%).由于微生物浸出群落对该难处理铜钴矿作用时间周期较长,适用于堆浸生产.细菌的存在使得铁离子不断的在二价与三价间循环,通过具有强氧化性的Fe3+与硫化矿物相互作用,使得矿物分解,提高浸出率.     

Phase III comparative trial using CHOP vs CIOP in the treatment of advanced intermediate-grade non-Hodgkin's lymphoma

Until now, literature data support the fact that the CHOP regimen represents the standard first line treatment for patients with advanced intermediate-grade non-Hodgkin's lymphoma. Recently, idarubicin has been introduced in clinical trials because of its favourable preclinical profile: it is more active than daunorubicin and doxorubicin against a number of experimental tumour systems and is significantly less cardiotoxic in animal models. From March 1991 to June 1993, 115 previously untreated patients with stage II to IV intermediate-grade non-Hodgkin's lymphoma, according to the Kiel classification, were enrolled in a phase III comparative trial. The objectives of the study were to compare the efficacy and safety of using idarubicin instead of doxorubicin in the polychemotherapeutic regimen CHOP (cyclophosphamide, doxorubicin, vincristine, and dexamethasone). Of the 115 patients registered for the trial, 103 were evaluable: 52 received CH (doxorubicin)OP and 51 received CI(Idarubicin)OP. Known prognostic factors were equally distributed among the two groups. There were no significant differences between the 2 groups in the rates of partial and complete response. The overall response rate was 87%, with complete response in 62%: 63% in the CHOP group, and 59% in the CIOP group. At 30 months (median 20 months), 86% of all CR patients were alive without disease in the CHOP group and 85% in the CIOP group. Patients treated with CHOP experienced severe alopecia more frequently (P = .004). Only three patients in the CIOP group showed cardiac adverse events (1 moderate and 2 mild), while in the CHOP group 4 mild, 2 moderate and 1 severe were recorded. LVEF monitoring was carried out in 31 patients of the CHOP group and in 27 of the CIOP group. A median drop of 8.3% of the LVEF was observed in patients treated with CHOP regimen as compared to 4.8% in patients with CIOP regimen (P = .0001). In this trial, the "idarubicin arm" (CIOP regimen) was found to have an equivalent therapeutic efficacy and, slightly, reduced clinical toxicity in comparison to the standard doxorubicin-containing CHOP regimen in patients with intermediate-grade non-Hodgkin's lymphoma.     

Allogeneic bone marrow transplantation for relapsed and refractory Hodgkin''s disease and non-Hodgkin''s lymphoma

There is national and international interest in increasing the community-based component of undergraduate medical education, but more research is needed on its potential, practicability and effectiveness. The objective of the study was to examine the feasibility and efficacy of general practitioners teaching basic clinical skills to first year clinical medical students in the community. The structure and methods of evaluation of the programme are described. Evaluation tools included semistructured interviews of general practitioner tutors; student questionnaires; assessment of student performance; and costs of the programme. The great majority of the students found the programme enjoyable (81 out of 81, 100%) and educational (79 out of 81, 97%). Students' performance in the end of rotation Objective Structured Clinical Examination suggested that clinical skills are acquired at least as well in the community as in the hospital. Tutors identified the personal benefits of this teaching as development of their own clinical skills and the stimulation of teaching. The programme has been successfully expanded from 24 students to 230 students annually and has demonstrated that community-based teaching can usefully contribute to undergraduate medical education in the area of clinical skills teaching. Key practical issues for schools contemplating similar initiatives are presented.     

Methylguazone, vindesine and cisplatin for the treatment of patients with relapsed or refractory malignant lymphoma: an Eastern Cooperative Oncology Group Study (PA482)

A new regimen not cross-resistant with standard regimens was developed for patients with relapsed or refractory Hodgkin's disease and non-Hodgkin's lymphoma. The regimen consisted of cisplatin, 70 mg/M2 given intravenously on day 1, vindesine, 3 mg/M2 given intravenously on days 1 and 8 (and also on day 15 of the first cycle only), and methylguazone, 600 mg/M2 given intravenously on days 8 and 15. Courses were repeated every 21 days. Thirty-nine patients (35 with non-Hodgkin's and 4 with Hodgkin's lymphoma) were treated and all were evaluable for response and toxicity. There were 5 complete and 14 partial responses for a total response rate of 49% (C.I. = 35%-63%). The median durations of partial and complete response were only 2.8 and 4.2 months, respectively. Only one patient remained in complete response for more than a year. There was one treatment-related death from renal failure on the study. Although this regimen was, in general. well tolerated the results are disappointing and seem no better than those obtained with many other salvage regimens for lymphoma.     

Radiotherapy results in early stage low grade nodal non-Hodgkin''s lymphoma

Severe lactic acidosis usually accompanies intense endurance exercise. It has been postulated that glycogen depletion working in concert with elevated muscle and plasma lactate levels lead to a concomitant reduction in pH. Their cumulative effect during prolonged physical exertion now leads to muscular fatigue and eventually limit endurance capacity. Therefore in the present study, dichloroacetate (DCA), a compound which enhances the rate of pyruvate oxidation thus reducing lactate formation, has been evaluated in a validated rat model of sub-maximal exercise performance. Male rats (350 g) were divided into two groups (control-saline, i.v. and DCA 5 mg/kg, i.v.) and were exercised to exhaustion in a chamber (26 degrees C) on a treadmill (11 m/min, 6 degrees incline). When compared to controls, the DCA-treated rats had longer run times (169 vs 101 min) and a decreased heating rate (0.020 vs 0.029 degrees C/min). In addition, DCA attenuated the increase in plasma lactate (28 vs 40 mg/dl) and significantly reduced both the rate and absolute amount of depletion of muscle glycogen stores. These results suggest that the activation of pyruvate dehydrogenase activity by DCA resulted in a reduction in the rate of glycogenolysis in addition to decreasing lactate accumulation by presumably limiting the availability of pyruvate for conversion to lactate, therefore increasing muscle carbohydrate oxidation via the TCA cycle. Thus DCA effected a significant delay in muscle fatigue.     

Primary non-Hodgkin's lymphoma of the brain

Between 1980 and 1993, 26 patients were treated for primary lymphoma in the central nervous system at the Norwegian Radium Hospital. This is a rare disease with poor prognosis and thus represents a great therapeutic challenge. Immunocompromised, e.g. AIDS patients, are a group at high risk, but the incidence has increased among immunocompetent patients as well. Median patient age was 64 years; and none of the patients had any signs of immunodeficiency. 23 of the patients received radiation therapy. 13 of the patients received some form of chemotherapy. The overall median survival was 19 months. WHO performance status 0-2, unifocal lesion, absence of steroid dependency and normal serum levels of LDH were all associated with longer survival. Although complete remissions were achieved in most patients, relapses in the central nervous system were frequent.     

Primary non-Hodgkin's lymphoma of the liver

Primary non-Hodgkin's lymphoma of the liver is an extremely rare lymphoma subset that often presents with diagnostic difficulties to both clinicians and pathologists. Using MEDLINE search, 90 cases of primary hepatic lymphomas reported in the literature were reviewed. The epidemiology and etiology, clinical presentation, pathologic features, management, and outcome of these patients have been summarized and described. Results of this review show that middle-aged males are most often affected. Abdominal pain or discomfort, weight loss and fever are the most frequent presenting symptoms. Most cases have a solitary or multiple mass lesions in the liver, and are frequently misdiagnosed as having a primary liver tumor or metastatic cancer. Diffuse large cell lymphoma is the most commonly encountered histologic subtype. Surgery, chemotherapy and radiotherapy have been used alone or in combination as treatment but the outcome is generally poor. Although primary hepatic lymphoma is an aggressive disease, it is resectable, and responsive to chemotherapy and radiotherapy. Because of the profound therapeutic implications, it should be considered in the differential diagnosis for patients presenting with mass lesions in the liver or hepatic disease.     

Phase II clinical trial of bolus infusion anti-B4 blocked ricin immunoconjugate in patients with relapsed B-cell non-Hodgkin's lymphoma

Immunotoxins, composed of a monoclonal antibody conjugated to a protein toxin, mediate cell death through novel cytotoxic mechanisms. Anti-B4-blocked ricin (anti-B4-bR) recognizes CD19-positive cells, which includes most B-cell non-Hodgkin's lymphomas (NHLs). Previous Phase I clinical studies of anti-B4-bR, using both bolus and continuous dosing regimens, demonstrated no safety or efficacy advantage to the continuous infusion regimen. This Phase II trial in 16 patients with relapsed CD19-positive NHL was conducted to evaluate the efficacy of anti-B4-bR when administered at the previously established maximum tolerated dose using a daily bolus for a 5 consecutive days schedule. Serum pharmacokinetics were measured in selected patients. Tissue samples of involved lymph nodes and bone marrow were also obtained from a portion of patients for determination of anti-B4-bR penetration into tissues. Toxicity was similar to what has been described previously for anti-B4-bR and consisted mainly of reversible elevations of hepatic transaminases and mild to moderate thrombocytopenia. No sustained clinical responses were documented. Pharmacokinetic measurements demonstrated that serum levels compatible with 3 logs of cell kill in vitro could be sustained for several hours in most patients. Immunohistochemical analysis of tissue samples provided some insight into the low efficacy. The immunotoxin could be detected in three of the four bone marrow aspirate samples but in only two of the seven lymph node specimens. Thus, anti-B4-bR, using a single daily bolus for a 5 consecutive day schedule, is not an active agent in relapsed NHL. Poor penetration into certain sites of disease may be one explanation for its lack of efficacy.     

Low-dose total body irradiation and G-CSF without hematopoietic stem cell support in the treatment of relapsed or refractory acute myelogenous leukemia (AML), or AML in second or subsequent remission

PURPOSE: Patients with relapsed acute myelogenous leukemia (AML), who are not eligible for bone marrow transplantation, have a poor prognosis when treated with chemotherapy alone. Total body irradiation (TBI) is an effective modality against AML when used in doses of 1000-1400 cGy with hematopoietic stem cell support. We undertook a phase I study of TBI with granulocyte-colony-stimulating factor (G-CSF) support, without stem cell support in patients with AML either in relapse or second or subsequent remission. METHODS AND MATERIALS: Patients with relapsed AML, or AML in second or subsequent remission were treated in a phase I study of TBI followed by G-CSF. The first dose level was 200 cGy. After the initial cohort of patients it was clear that patients with overt leukemia did not benefit from this treatment, and subsequent patients were required to be in remission at the time of TBI. RESULTS: Eleven patients were treated, 4 in overt relapse, and 7 in remission. 200 cGy was used in all, and dose escalation was not possible due to prolonged thrombocytopenia in all patients but one. Neutrophil recovery was adequate in those patients who remained in remission after TBI. Patients with overt leukemia had transient reduction in blast counts, but rapid recurrence of their leukemia. Patients treated in remission had short remissions, with the exception of one patient who is in remission 32 months after treatment. CONCLUSION: There is some antileukemic effect of TBI even at 200 cGy, though this dose appears to be too low to help a significant number of patients. If TBI is to be escalated without stem cell support, then a thrombopoietic agent will need to be used.     

Evaluation of CI-973, a platinum analogue, in refractory or relapsed acute leukemia

Uranium isotopes were given via single intravenous injection into 22 young adult beagle dogs of both sexes to determine the metabolism of this element. Animals were given either 232U, 233U, 238U, or a combination of 232 (+) 233U. Calculations to assign a value of skeletal dose for each dog were performed using published radioactive properties of each uranium isotope and the metabolic data (including measured retention and skeletal distribution) derived from this study during a period of up to 2 y after injection. We believe that the procedures illustrated in this communication can serve as a useful pattern for estimating skeletal radiation doses to humans contaminated with 232U, 233U, or 238U.     

HIV-related primary non-Hodgkin's lymphoma of the vulva

We reported on a 25-year-old HIV-positive woman diagnosed with Ann Arbor Stage IEB primary extranodal immunoblastic lymphoma arising in the vulva. This is the first documented instance of an HIV-associated malignant lymphoma originating in the lower female genital tract, and only the 16th reported case of primary malignant lymphoma of the vulva. The nonspecific clinical presentation coupled with the unanticipated finding of lymphoma made diagnostic confirmation an arduous task, requiring weeks of persistence. The patient's disease was refractory to three courses of chemotherapy, but did respond to a brief palliative course of external beam irradiation prior to her demise 7 months after presentation. Our findings are presented, and 15 cases from the literature, the largest series to date, are discussed.     

Bilateral primary non-Hodgkin's lymphoma of the testis

We report the case of a 72-year-old man with bilateral testicular masses that, on histologic section, were found to be synchronous non-Hodgkin's lymphomas. Workup was negative for systemic disease, indicating the possibility of bilateral primary testicular lymphomas. We discuss the evaluation and treatment of this lesion and review the literature concerning this subject.