Bone Marrow Transplantation in Low-Grade Non-Hodgkin's Lymphoma

The low-grade histologic types constitute one quarter of all non-Hodgkin's lymphomas (NHL). Conventional chemotherapy and chemo-radiation therapy have failed to significantly alter the course of this disease, and most patients eventually succumb to lymphoma. Despite the fact that NHLs exhibit a steep dose-response relation to cytotoxic therapy, fewer than 30% of eligible patients undergo bone marrow transplantation. Reasons for fewer patients receiving this course of treatment include: elderly patient population, extensive previous chemotherapy and/or radiation therapy, high incidence of bone marrow involvement, and transformation to higher grade NHLs. In recent years, improvements in several areas have enhanced the therapeutic index for bone marrow transplantation. These advances include the use of more effective preparative regimens, recombinant hematopoietic growth factors, extended-spectrum antibiotics, and an increased expertise in blood transfusion techniques and practices. Other, more effective strategies include sophisticated in vitro bone marrow purging approaches and peripheral blood progenitor cell collection. As a result, more patients have been able to receive dose-intensive therapy followed by hematopoietic cellular rescue. Although follow up is short in most series, encouraging results have stimulated some centers to begin transplanting responding patients earlier in their disease course; in more than 200 patients treated in this fashion, long-term disease-free survival has been achieved in nearly 70% of patients, some patients for a period of greater than 6 years. The new purine analogues fludarabine, pentostatin, and 2-chlorodeoxyadenosine also have shown promise in both initial and salvage treatment of low-grade NHLs. It remains to be determined whether this group of drugs will be complimentary to the bone marrow and/or peripheral blood progenitor cell transplant approach.     

The Use of Myeloablative Therapy with Autologous Bone Marrow Transplantation in the Treatment of Follicular Lymphoma

Follicular lymphomas are rarely curable by conventional treatment despite temporary responsiveness to chemotherapy and radiotherapy. The use of intensive treatment with autologous bone marrow support is being investigated at several centres and this article reviews the results to date. Although the follow-up is short the toxicity of the procedure appears tolerable and the initial results are encouraging. The relevance of residual bone marrow infiltration at the time of harvest and ex-vivo treatment are discussed.     

Cisplatin-CBV with Autologous Bone Marrow Transplantation for Relapsed Hodgkin's Disease

The use of high-dose cyclophosphamide, carmustine, and etoposide (CBV) with autologous bone marrow transplantation (ABMT) results in long-term disease-free survival of about 30% in patients with relapsed Hodgkin's disease. Laboratory and clinical data show that cisplatin is synergistic with etoposide and carmustine, with non-overlapping extramedullary toxicity. Twenty-one patients with relapsed Hodgkin's disease that had progressed after both MOPP-like and ABVD-like regimens were treated with CBV plus cisplatin (90 mg/m²) and ABMT. The CR rate was 55%; the three-year disease-free and overall survival were 29% and 38% respectively; these results are comparable to prior experience with CBV. Performance status was strongly correlated with achievement of CR, survival, and time to treatment failure. Nephrotoxicity was seen in 3 patients, and ototoxicity in 1 patient. Although cisplatin could be added to CBV with minimal additional toxicity, the results obtained in this small patient population were not better than those of the earlier regimen. A larger trial in patients not previously exposed to cisplatin may better define the role of its addition to CBV.     

Results of a Salvage Regimen in Refractory or Relapsed Non-Hodgkin's Lymphoma

After therapy with adriamycin-containing regimens, relapsed or refractory non-Hodgkin's lymphomas (NHL) have a very poor prognosis. Although high dose chemotherapies are widely employed, their related costs and the controversial results achieved justify the development of new second-line conventional therapies. Forty-three patients with relapsed or refractory NHL were consequently treated with an outpatient polychemotherapy schedule including ifos-famide, mitoxantrone and etoposide on day 1, and vindesine, cisplatinum and cytosine ara-binoside on day 15. The courses were repeated on day 29. All of the patients were pretreated with at least one chemotherapy regimen. Twenty-two patients had diffuse large cell lymphoma, 8 had bone marrow involvement, and 17 altered baseline lactate dehydrogenase (LDH) values. After a median number of 4 cycles (range 2-8), we registered 20 complete (46%) and 4 partial remissions, for an overall remission rate of 56% (95% confidence interval: 40-71%). All of the responses occurred in patients who had achieved at least partial remission during first-line therapy. Four patients are long term responders after 31, 39, 49 and 52 months, and are possibly cured. Univariate analysis of prognostic factors showed that baseline LDH values and response to front-line therapy significantly affected both time to disease progression and survival, whereas the number of previous treatments given, significantly affected only the time to progression. Therapy was administered in an out-patient setting and no life-threatening toxicity was observed. Side effects consisted of nausea/vomiting, alopecia and reversible myelosuppression. The results suggest that different treatment strategies for relapsed and refractory patients should be considered on the basis of prognostic factors. The proposed schedule may be potentially curative in a subgroup of relapsed patients at better risk; poor risk refractory patients should be considered for investigational trials involving high-dose chemotherapy.     

Autologous Bone Marrow Transplantation Followed by Involved Field Radiotherapy in Patients with Relapsed or Refractory Hodgkin's Disease

Twenty-six patients with refractory or relapsed Hodgkin's disease were treated with high dose cyclophosphamide, BCNU, etoposide, and thiotepa followed by autologous hematopoietic stem cell rescue. Involved field radiotherapy was given following hematologic recovery in selected patients. The overall response rate to the high dose chemotherapy was 69% with 34% complete responses. Following radiotherapy, the complete response rate increased to 50%. The predicted disease-free survival at two years is 22%. Toxicity with this regimen was significant, with five patients dying as a result of transplant related complications. We conclude that the addition of thiotepa to the standard CBV regimen did not result in improved therapeutic efficacy and possibly contributed significantly to the toxicity of the treatment.     

Cost Analysis of Autologous Peripheral Stem Cell Transplantation Versus Autologous Bone Marrow Transplantation for Patients with Non Hodgkin's Lymphoma and Acute Lymphoblastic Leukaemia

We evaluated the costs of unpurged autologous stem cell transplantation in a non-randomised study of 54 consecutive patients with lymphoproliferative malignancies who have been transplanted at the Nijmegen University Hospital between July 1992 and March 1998. Thirty-five patients were transplanted with autologous peripheral stem cells (APSCT): 30 had non Hodgkin's lymphoma (NHL) and 5 acute lymphoblastic leukaemia (ALL). Nineteen patients were transplanted with autologous bone marrow stem cells (ABMT): 17 had NHL and 2 ALL. The number of progenitor cells (CFU-GM, BFU-E) and nucleated cells was significantly higher in peripheral blood transplants. The duration of cytopenia was shorter after APSCT. The leucocyte recovery to 0.5 × 10⁹ /L was 13 days for recipients of peripheral stem cells compared to 20 days for bone marrow recipients (P 4.001). The platelet recoveries to 20 × 10⁹L were 13 and 29 days, respectively (P = 0.001). This resulted in significantly shorter admission duration 24 days after APSCT versus 30 days (P = 0.003) after ABMT.

Furthermore, a statistically significant difference between both groups was observed for antimicrobial costs (mean: fl 2,939 vs fl 4,888; P = 0.008), platelet transfusions (median: 3 vs 7 units; P = 0.01) and erythrocyte transfusions (median: 6 vs 10 units; P = 0.03). The mean overall costs were lower in patients transplanted with stem cells from' peripheral blood: fl 34, 178 versus fl 43, 469 (P = 0.007). This study suggests that the APSCT results in significant cost savings due to shorter hospital stay and less costs of supportive care, despite higher mobilisation costs. The costs of blood transfusions and antimicrobials for patients with ALL were significantly higher when compared to patients with NHL.     

高剂量化放疗合并自体骨髓移植治疗晚期难治性恶性淋巴瘤

我们采用高剂量化放疗合并自体骨髓移植治疗５例晚期难治性恶性淋巴瘤，其中何杰金病３例，非何杰金淋巴瘤２例。获得４例完全缓解、１例部分缓解。治疗期间５例病人均来发生与移植有关的致命毒性反应。本研究结果显示高剂量化疗合并自体骨髓移植治疗晚期难治性恶性淋巴瘤，作为诱导治疗后一线方案确能提高临床近期疗效，可使部分病人得以较长期无病生存或治愈。     

Prognosis of High Dose Chemotherapy/Autologous Bone Marrow Transplantation Candidates not Receiving This Treatment after Failure of Primary Therapy of Hodgkin's Disease

In a multicenter study on the therapy of Hodgkin's disease, in 88 out of 297 patients with primary advanced stages IIIB/IV, a failure to the treatment with the alternating chemotherapy COPP/ABVD ± radiation was recorded. The cause of failure was as follows: tumor progression under current therapy (PD) 23/88, partial response at the end of therapy (PR) 28/ 88, early nodal relapses 13/88, late nodal relapses 16/88, extranodal relapses 7/88, undetermined localization 1/88.36 months after manifestation of the failure to treatment, 45% of all patients were still alive. In cases of primary PD the prognosis was the worst of all. Only 1/23 of these patients received a long-term continuous complete remission (cCR) with the salvage therapy. 11 patients with only a nodal relapse received a cCR with irradiation alone. These cases could be regarded as low risk relapses. For the high risk relapse group (n = 57) an indication for high dose chemotherapy with subsequent autologous bone marrow transplantation (HDC/ABMT) would have been imperative, following the present-day definition. The probability of survival of these patients who, however, only received a conventional salvage therapy was up to 38% (95% confidence interval 22-54%). Comparing these data with the literature our results seem not to be substantially worse than those for patients who underwent HDC/ABMT. Only in a randomized comparison can the decision be made on whether HDC/ABMT would be superior to high dose conventional chemotherapy supported by hematopoietic growth factors. It is suggested that such a therapy study be performed as soon as possible.     

大剂量化疗联合应用G-CSF治疗难治或复发性非霍奇金淋巴瘤的临床观察

目的:观察大剂量化疗联合应用粒细胞集落刺激因子在没有干细胞支持情况下,治疗难治或复发性非霍奇金淋巴瘤的疗效和不良反应。方法:采用大剂量化疗。MIE方案:异环磷酰胺1500mg/m2,iv,d1～6;美斯纳800mg/次,于异环磷酰胺后0、4、8小时,iv,并同时水化;足叶乙甙250mg/m2,iv,d1～6;粒细胞集落刺激因子5～10μg·kg-1·d-1,于末次化疗结束后24小时开始应用,至白细胞达2.0×109/L持续3天停用,4周重复下1个疗程。17例患者共接受化疗24个疗程。结果:大剂量化疗总有效率76.5%(13/17),其中6例(35.3%)获完全缓解,7例(41.2%)获部分缓解,稳定1例(5.9%),无效和恶化2例(11.8%),1例(5.9%)于大剂量化疗后第7天死于颅内出血。大剂量化疗主要不良反应为骨髓抑制,白细胞和血小板降到最低的中位时间分别为6天和5天,其恢复时间分别为10天和12天;13例(76.5%)为发热性粒细胞减少,中位时间为6天,应用抗生素的中位时间为7天,应用粒细胞集落刺激因子的中位时间为7天。结论:在无干细胞支持的情况下,采用大剂量化疗辅以粒细胞集落刺激因子支持是治疗难治或复发性非霍奇金淋巴瘤的有效措施,具有疗效高,早期死亡率低,不良反应能够耐受,无需全环境保护,费用较低的特点,是值得临床推广的治疗模式。     

Childhood B-Cell Non-Hodgkin's Lymphoma in Israel

The non-Hodgkin's lymphomas of childhood and adolescence are a heterogeneous group of diseases that constitute 7-10 percent of all pediatric malignancies. Major strides have been made in recent years in understanding the pathogenesis of lymphomas at a molecular level but have not yet led to a modification of clinical management. Between 1973 and 1992, 112 children with B-cell non-Hodgkin's lymphoma were diagnosed. The median age was 5.7 years, with male to female ratio of 3 to 1. Fifty percent presented with abdominal masses, mostly confined to the ilco-ccccal region and to the retroperitoneum. In 39 percent there was head and neck involvement, with 15 percent jaw lesions. Until 1978 patients were treated with the Beilinson Medical Center (BMC) protocol, which yielded only 26 percent disease-free survival for stage IV patients. The introduction of the LMB-86 regimen significantly improved the disease-free survival of patients with advanced stage III and IV disease (84 and 68 percent, respectively). Bone marrow (over 70 percent blasts) and central nervous system involvement remain the major prognostic criteria.     

Intensified Preparative Regimens and Allogeneic Transplantation in Refractory or Relapsed Intermediate and High Grade Non-Hodgkin's Lymphoma

Between September 1986 and June 1998, 32 patients with relapsed or refractory intermediate or high grade lymphoma received intensified preparative therapy and underwent allogeneic transplantation at a single institution. Patients were considered for allogeneic transplantation if they failed to respond to initial therapy, failed to respond to salvage therapy, relapsed after autologous transplantation, had bone marrow involvement, or failed attempts to harvest autologous stem cells. Patients had a median age of 39 years and had generally received at least two chemotherapy regimens. Five year actuarial survival (S) was 16% × 6%; median survival was 4 months. Survival was significantly worse in patients who had received high intensity brief duration chemotherapy prior to transplantation and was also significantly worse in patients who did not receive total body irradiation (TBI). This likely reflects the fact that the patients with the most resistant disease had required local radiotherapy and could not receive TBI. While treatment related mortality played a major role in limiting the effectiveness of allogeneic transplantation, in this heavily pre-treated population of patients with resistant disease, only 39% of patients achieved a complete response following allogeneic transplantation, and in only 40% of that group was long term disease free survival achieved.     

Autologous Bone Marrow Transplantation in Relapses of Chemotherapy-Sensitive Aggressive Non-Hodgkin's Lymphoma: Long-Term Outcome

Abstract

Eleven patients with relapsed intermediate to high grade non-Hodgkin's lymphoma (NHL) responding to induction treatment were treated with high-dose chemotherapy (CBV or ICBV conditioning regimen) plus autologous bone marrow transplantation as early consolidation treatment. At 6 years, relapse-free survival is 27.3% and overall survival is 36.4%. Patients with bone marrow involvement from NHL before the induction therapy did not have a worse prognosis. Despite the long-term follow-up, no secondary myelodysplasia or acute leukemia occurred in our patients. Within the limitations of patient number and selection, our retrospective study confirms the importance of tumor responsiveness and long-term follow-up. Patients with relapsed, but chemotherapy-sensitive NHL can achieve prolonged survival after high-dose chemotherapy plus autologous bone marrow transplantation.     

非霍奇金淋巴瘤骨髓受累的诊断技术与预后评估

骨髓受累（bone marrow involvement, BMI）是非霍奇金淋巴瘤不良预后的标志,因其在评估预后和指导治疗中举足轻重的地位,而成为非霍奇金淋巴瘤（NHL）初诊时必备的评估内容。在其检出手段中,骨髓活检（bone marrow biopsy, BMB）具备基石的地位,但随着抽吸物的流式细胞学技术、细胞遗传学技术以及分子生物学技术等技术进步,其诊断意义也在提升,并展现出评估预后的价值。同时,PET-CT作为一种有效的检出方法,也逐渐成为研究热点。本文将综述这些检出方法,同时对BMI新近的预后研究进行回顾,以展望其研究前景。     

DICE作为二线方案治疗难治或复发性非霍奇金淋巴瘤

目的:观察DICE作为二线方案治疗难治或复发性非霍奇金淋巴瘤(NHL)有效性及不良反应耐受性。方法:采用DICE方案治疗28例复发或难治性非霍奇金淋巴瘤。其中,复发组16例,难治组12例并探讨足三里穴位封闭或粒细胞集落刺激因子(G-CSF)预防化疗对造血系统的抑制作用。结果:28例中,完全缓解CR7例(25.0%),部分缓解PR8例(28.6%),有效率53.6%。复发组的有效率明显高于难治组(10/16比4/12;P<0.01)。乳酸脱氢酶(LDH)升高12例中CR2例,LDH正常组16例CR5例,有显著性差异(P<0.01)。DICE方案的不良反应主要表现为恶心呕吐、脱发和可逆性骨髓抑制,患者均能耐受,无1例出现治疗相关性死亡。结论:DICE方案对复发性NHL有效,但对难治性NHL相对无效,提示复发性和难治性NHL可能有不同的生物学行为,对两者应该选择不同的治疗措施,LDH可以作为NHL化疗是否敏感的指标之一。     

盐酸帕洛司琼联合GDP方案治疗老年复发性非霍奇金淋巴瘤的临床研究

目的评价盐酸帕洛司琼联合GDP (Palonosetron-GDP) 方案治疗老年复发性非霍奇金淋巴瘤的临床疗效和不良反应。方法采用Palonosetron-GDP方案治疗28例老年复发性非霍奇金淋巴瘤患者,对接受3个疗程以上患者进行临床疗效评估和不良反应分析,同时随访患者疾病进展情况。结果26例患者接受3个疗程以上Palonosetron-GDP方案化疗,其中6例完全缓解 (完全缓解率23.1%),10例部分缓解(部分缓解率38.5%),总有效率61.5%。26例患者中位肿瘤进展时间为5.3月(95%CI: 4.7~7.0)。主要不良反应为骨髓抑制,而非血液学毒性尤其是消化道不良反应轻微,其中化疗诱导恶心和呕吐不良反应Ⅰ级2例,Ⅱ级1例,没有Ⅲ~Ⅳ级呕吐反应。结论Palonosetron-GDP方案是老年复发性非霍奇金淋巴瘤的有效挽救治疗方案,其中盐酸帕洛司琼能有效预防化疗诱导的消化道不良反应而不影响其疗效。     

A Pilot Study of Autologous Bone Marrow Transplantation Followed by Recombinant Interleukin-2 in Malignant Lymphomas

In this study, we investigated the impact of recombinant interleukin-2 (rIL-2) after high dose chemotherapy and autologous bone marrow transplantation (ABMT) in 25 patients with refractory or relapsed Hodgkin's disease (HD) (11 patients) and non Hodgkin's lymphoma (NHL) (14 patients). 48% of patients had resistant disease, 84% achieved complete remission after ABMT. rIL-2 was started at a median of 54 days post-transplant and consisted of a first cycle of 5 days followed by 4 cycles of 2 days every other week. Patients received a mean of 160 × 10⁶ IU/m² rIL-2 and hematological toxicity was moderate and transient. None of the 5 evaluable patients with measurable disease responded to rIL-2. After a 5 year median follow-up, the probability of survival and DFS is 72% (HD: 73% and NHL: 70%, p = NS) and 45% (HD: 36% and NHL: 48%, p = NS) respectively. These somewhat encouraging results warrant further evaluation of rIL-2 after ABMT in controlled studies, especially in NHL patients stratified for previous chemosensitivity.     

Experience with 9-Cis Retinoic Acid in Patients with Relapsed and Refractory Non-Hodgkin's Lymphoma

We conducted a phase II study to determine the efficacy and toxicity of 9-cis-retinoic acid (9-cis RA), a pan-retinoid receptor agonist, in the treatment of patients with relapsed and refractory NHL. Patients were eligible if they had histologically documented relapsed or refractory T cell or indolent B cell NHL. The first three patients enrolled received 70 mg/m² of 9-cis RA orally twice a day, but the remaining patients received a single oral daily dose of 100 mg/m². After 6 weeks of therapy, tumor response was assessed objectively. Response rate and toxicity were determined in all 29 eligible patients based on an intent-to-treat analysis. Four patients (14%) responded (3 PRs and 1 CR; 95% CI 4%- 33%). One patient had a minor response, and eight had stable disease. Responses were observed in two (11%) of 19 patients with B-cell lymphoma and in two (20%) of 10 patients with T-cell lymphoma. The median time-to-treatment failure for the 29 eligible patients was 8 weeks. The most frequent toxic effects were dry skin, headache, hypertriglyceridemia, and hypercalcemia. Five patients discontinued therapy due to toxic side effects, but no toxic deaths occurred during the study. We conclude that 9-cis RA has a modest activity in relapsed and refractory NHL. In this study, responses were observed in patients with B-cell lymphomas and those with T-cell lymphomas.     

自体骨髓移植辅助强化疗治疗晚期肺癌

对７例晚期肺癌病人采用自体骨髓移植辅助强化疗，并对治疗后的骨髓造血功能进行了观察。所有病人的症状均获缓解，该方法为晚期肺癌病人提供了一种新的治疗途径。     

原发骨非霍奇金淋巴瘤临床分析

目的:探讨原发骨非霍奇金淋巴瘤的临床特点、诊断、治疗及预后。方法:选择1970年11月～2003年2月我院收治的21例原发于骨的非霍奇金淋巴瘤,其中Ⅰ期14例(66.7%),Ⅱ期2例(9.5%),Ⅳ期5例(23.8%)。弥漫性大B细胞型12例(57.1%),混合细胞型4例(19.0%),小淋巴细胞型1例(4.8%),T细胞型1例(4.8%),未分型3例(14.3%)。采用单纯放疗6例(28.6%),放疗和化疗综合治疗15例(71.4%)。结果:中位随访86个月,2例(9.5%)局部复发,9例(42.9%)出现远处受侵,3年、5年、10年无进展生存率分别为56.7%、38.9%、29.1%;3年、5年、10年总生存率分别为69.1%、42.2%、42.2%。结论:原发于骨的非霍奇金淋巴瘤首选放疗和化疗的综合治疗;放疗剂量推荐45Gy～46Gy。