Nonmyeloablative stem cell transplantation in follicular B-cell lymphoma

Myeloablative allogeneic stem cell transplantation carries the promise of long-term disease control by graft-versus-lymphoma (GVL) immunity but is associated with a 30% to 40% risk of transplant-related mortality. Nonmyeloablative stem cell transplantation (NST) aims to exploit the GVL effect without the attendant toxicity of myeloablative conditioning. At the M.D. Anderson Cancer Center, the standard NST conditioning regimen for patients with follicular lymphoma is fludarabine, cyclophosphamide, and rituximab (FCR). Using this regimen, transplant-related mortality is currently 10%, and 85% of patients remain alive without disease at 3 to 4 years. This review discusses the current issues in NST for follicular lymphomas, including the optimization of conditioning intensity, the use of rituximab in immunomodulation, and the role of donor lymphocyte infusion.     

Nonmyeloablative transplantation for lymphoma

Opinion statement Nonmyeloablative stem cell transplantation, also referred to as minitransplantation or reduced-intensity transplantation, is a novel approach to lymphoma treatment offering the lure of harnessing graft-versus-lymphoma (GVL) effects while decreasing regimen-related toxicity. The general concept is to provide a sufficiently immunosuppressive and moderately myelosuppressive treatment regimen to allow donor and host hematopoietic coexistence or chimerism. The most popular regimens incorporate a purine analog (eg, fludarabine) and an alkylating agent (eg, cyclophosphamide or melphalan). Newer regimens include the monoclonal antibody alemtuzumab, which may reduce the incidence of acute graft-versus-host disease (GVHD). Early reports demonstrate a GVL effect; however, the underlying lymphoma subtype and pace of disease often dictate which patients can capitalize on GVL benefits. Clinical reports show mixed results, which may reflect variations in patient selection. Although most patients successfully engraft, the effect on lymphoma control and GVHD must be evaluated carefully. Future investigations continue to delineate the optimal timing of nonmyeloablative transplantation, the optimal patient population, the optimal preparative regimen, and the optimal GVHD prophylaxis. Supportive care remains a critical component of management because the reduced-intensity regimens do not abrogate the risk of serious infection and many do not appear to decrease the incidence of chronic GVHD. Nonmyeloablative hematopoietic stem cell transplantation may broaden the applicability of allogeneic transplantation in malignant lymphomas, especially for indolent subtypes.     

Nonmyeloablative stem cell transplantation for chronic myeloid leukemia

Conventional myeloablative hematopoietic stem cell transplantation carries risks of morbidity and mortality from regimen-related toxicities that have restricted its use to relatively young patients in good medical condition. In nonmyeloablative allogeneic hematopoietic stem cell transplantation, enhanced immunosuppression rather than myeloablative cytotoxic conditioning has allowed the engraftment of allogeneic stem cells, with lower early transplant related mortality and morbidity. This approach shifts tumor eradication to the graft-versus-leukemia effect mediated by donor T lymphocytes. The development of nonmyeloablative transplantation has allowed the application of a potentially curative procedure to elderly or medically infirm patients who would not be able to tolerate high-dose conditioning regimens.     

Nonmyeloablative allogeneic stem cell transplantation for nasopharyngeal carcinoma

We present a case of a patient with metastatic nasopharyngeal carcinoma who failed two lines of palliative combination chemotherapy and was treated with allogeneic nonmyeloablative stem cell transplantation (NST). This patient achieved a durable tumor response, dramatic relief of his symptoms, and elimination of tumor in his bone marrow-an effect likely achieved via a graft-versus-tumor response. Although NST has been explored previously in solid tumors, such as renal cell carcinoma and breast cancer, it has not been widely explored in nasopharyngeal carcinoma. We also present data from a flow cytometric immune analysis and cytokine enzyme-linked immunosorbent assay analysis in the pre- and post-NST period.     

Nonmyeloablative allogeneic hematopoietic stem cell transplantation for metastatic breast cancer

Previously, there was very little interest in investigating allogeneic hematopoietic stem cell transplantation (alloHSCT) in breast cancer because of the significant morbidity and mortality associated with this procedure, as well as the disappointing results observed in clinical trials with high-dose chemotherapy and autologous hematopoietic stem cell transplantation in advanced breast cancer. However, the development of nonmyeloablative (reduced-intensity) conditioning regimens, which have less treatment-related mortality but preserve the T cell-mediated graft-versus-tumor (GVT) effect, has led to the investigation of nonmyeloablative alloHSCT in diseases that had not previously been considered for conventional alloHSCT, including metastatic breast cancer. Laboratory data demonstrate that T cell-mediated responses to breast cancer that inhibit tumor growth are possible and provide the rationale to pursue allogeneic adoptive cellular therapy as a strategy to eliminate breast cancer. Early reports of nonmyeloablative alloHSCT indicate that a clinical GVT effect against breast cancer does exist. The responses appear to be dependent on the development of complete donor lymphoid chimerism, and responses may be delayed. The results from these initial trials must be interpreted cautiously. It is unlikely that nonmyeloablative alloHSCT by itself will result in complete eradication of metastatic breast cancer; however, it may serve as a therapeutic platform to enhance the effects of currently available immunotherapies (eg, trastuzumab administration) and complement existing cytotoxic therapies. Well-designed studies will be necessary to determine the clinical efficacy of nonmyeloablative alloHSCT as adoptive cellular therapy in metastatic breast cancer.     

Nonmyeloablative hematopoietic cell transplantation

The myeloablative doses of chemotherapy and radiation used with conventional allogeneic hematopoietic cell transplantation produce considerable morbidity and mortality that generally limit this treatment to patients younger than 55 years of age and in good general medical condition. It has become clear that T-cell-mediated graft-versus-tumor effects play an important role in the elimination of malignant disease after allotransplants. Several investigators have sought to reduce regimen-related toxicities while optimizing graft-versus-tumor effects. Strategies can be broadly categorized as reduced-intensity regimens that retain some toxicities and require hospitalization, and minimally myelosuppressive regimens that rely on immunosuppression for allogeneic engraftment and resultant graft-versus-tumor effects. The latter approach can be performed in the ambulatory care setting. Preliminary results are encouraging. If long-term efficacy is demonstrated, such strategies would expand treatment options for patients who would otherwise be excluded from receiving conventional allografts.     

Nonmyeloablative allogeneic stem cell transplantation: early promise and limitations

Allogeneic stem cell transplantation is used to treat a variety of malignant and nonmalignant hematologic diseases. Conventionally, high-dose chemoradiotherapy-based preparative regimens were considered essential both for tumor eradication and facilitation of donor stem cell engraftment. It is now apparent that an immune-mediated graft-versus-tumor effect has a pivotal role in the curative potential of allogeneic stem cell transplantation. This has prompted the development of less toxic, nonmyeloablative but profoundly immunosuppressive preparative regimens, often fludarabine- or radiation-based. Full donor engraftment can be achieved; however, a significant number of patients achieve a mixed chimeric state. Mixed hematopoietic chimerism provides a platform for the use of adoptive immunotherapy using donor lymphocyte infusions to maximize the immune-mediated antitumor effect, but the optimal usage has yet to be determined. Immediate procedure-related mortality with nonmyeloablative regimens has been low, but graft-versus-host disease remains a major clinical concern and treatment challenge. Major tumor responses have been seen in many hematologic malignancies primarily including patients with highly chemorefractory disease. Follow-up data have been short and additional time is needed to determine the efficacy and toxicities of this immunotherapy. This approach has potential for widespread clinical application including HLA mismatched and matched unrelated donor transplantation, exploration of a graft-versus-solid tumor effect, and correction of phenotypic expression in nonmalignant disorders.     

Hematopoietic stem cell transplantation for non-Hodgkin's lymphoma

High-dose myeloablative therapy with autologous or allogeneic stem cell rescue is an effective treatment strategy for non-Hodgkin's lymphoma (NHL), but NHL is much less likely to stay in remission after an autologous transplant than after an allogeneic transplant. The benefit of undergoing an autologous transplant earlier in the course of the disease, especially for patients who present with intermediate or high scores on the International Prognostic Index of risk factors, is still unclear. The addition of immunotherapy, biologic modifiers, and antibody therapy such as rituximab (Rituxan) or radiolabeled antibody to the autologous transplant are approaches undergoing evaluation. Historically, there has been a high regimen-related mortality rate associated with myeloablative allogeneic transplant that has made this approach a less appealing option for therapy. The use of nonmyeloablative allogeneic transplants as treatment for NHL is less well studied and remains to be defined.     

Allogeneic hematopoietic stem cell transplantation for lymphoma

For patients with relapsed or refractory Hodgkin's or non-Hodgkin's lymphomas, allogeneic hematopoietic stem cell transplantation (HSCT) is a treatment option when autologous HSCT fails to achieve durable remission or is deemed inappropriate. Allogeneic HSCT can result in long-term survival even in patients with refractory lymphomas. The efficacy of allogeneic HSCT is attributed, at least in part, to an immune-mediated graft-versus-lymphoma (GVL) effect that can also be associated with significant toxicity resulting from graft-versus-host disease. However, clinical evidence of a potent GVL effect is inconsistent. Reduced-intensity conditioning before allogeneic HSCT can facilitate the use of this treatment in older patients and those at high risk. The decrease in toxicity with reduced-intensity regimens may be associated with a loss of antitumor effects. Patients with lymphoma should be selected for allogeneic HSCT on the basis of characteristics that strongly influence transplant outcomes, including histology, chemosensitivity, and donor source.     

Hematopoietic stem cell transplantation for malignant lymphoma]

Autologous peripheral blood stem cell transplantation (auto-PBSCT) is increasingly performed as a curative therapy for patients with malignant lymphoma. Aggressive lymphomas which have relapsed with chemo-sensitive state, and newly diagnosed cases with high risk prognostic factors are good candidates for auto-PBSCT. Clinical results and indications for hematopoietic stem cell transplantation, including other types of lymphoma, are reviewed in this paper.     

Nonmyeloablative stem cell transplantation: reduced-intensity conditioning for cancer immunotherapy--from bench to patient bedside

Despite major progress in treating hematologic malignancies and, to a lesser extent, metastatic solid tumors, much work remains ahead. With the anticancer potential of immunotherapy not yet fully exploited, patients with leukemia, malignant lymphoma, and other hematologic malignancies for which high-dose chemoradiotherapy is frequently recommended in conjunction with stem cell transplantation (SCT) can now benefit from the advantages of immunotherapy mediated by cytokines or alloreactive donor lymphocytes, while minimizing procedure-related toxicity and mortality. The feasibility of applying allogeneic cell-mediated immunotherapy in conjunction with allogeneic SCT following reduced-intensity conditioning, with minimal toxicity and no serious transplant-related complications, makes it possible to undertake such procedures on an outpatient basis as well as to offer an option for cure to elderly individuals and patients with less than optimal performance status. Being well tolerated, reduced-intensity transplants also offer a chance for cure to patients with otherwise resistant leukemia and malignant lymphoma who have relapsed after autologous SCT. Thus, the traditional obstacle of very high transplant-related toxicity and mortality due to multiorgan failure from cumulative toxicity of multiple anticancer agents and radiation therapy is overcome. Although immunotherapy mediated by allogeneic lymphocytes can be most effective, the immune potential of donor lymphocytes should be maximized by nonspecific or specific activation in vitro or in vivo, or both, for more effective eradication of resistant tumor cells, including in patients with bulky disease. More important is the challenge to target donor lymphocytes to the tumor and minimize their capacity to induce responses against normal host tissues, which frequently results in severe acute and chronic graft-versus-host disease (GVHD). Alternatively, donor lymphocytes should be eliminated as soon as tumor eradication is completed, or as soon as severe GVHD becomes prohibitive. Based on available experience, clinical application of innovative therapy, especially at the stage of minimal residual disease (MRD), may open new horizons for the treatment of malignancies considered until recently to be incurable. The feasibility of controlling cancer by targeted chemotherapy, best illustrated by the phenomenal activity of imatinib in patients with chronic myelogenous leukemia and, more recently, in gastrointestinal stromal tumors (including in patients fully resistant to all known anticancer agents) suggests that in the future, tumor-specific chemotherapy may represent the ultimate goal for achieving a stage of MRD with minimal multiorgan toxicity. Together, the combination of immunotherapy and targeted chemotherapy may provide the most logical approach for making real progress in controlling resistant hematologic malignancies and metastatic solid tumors.     

Hematopoietic stem cell transplantation in mantle cell lymphoma.

BACKGROUND: Patients with mantle cell lymphoma (MCL) have in general, lower response rates and overall survival (OS) than those with other B-cell non-Hodgkin's lymphomas. The role of hematopoietic stem cell transplantation (HSCT) in MCL is unclear. Hence we decided to study the clinical course of patients who received autologous and allogeneic HSCT for MCL. METHODS: Ninety-seven patients, (80 patients-autologous; 17 patients-allogeneic) who received a HSCT for mantle cell lymphoma were included in the study. RESULTS: The complete response rates at day 100 between the two groups were similar (73% vs. 62%). Day-100 mortality was higher in the allogeneic HSCT group (19% vs. 0%) (P < 0.01). The estimated 5-year relapse rates, 5-year event-free survival (EFS) and 5-year OS among the allogeneic HSCT patients were 21%, 44% and 49%, respectively, similar to 56%, 39% and 47% in the autologous group. Ten patients received HyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone + high-dose methotrexate and cytarabine) +/- rituximab prior to transplant. There have been no relapses or deaths amongst these patients at a median follow-up of 16 months. CONCLUSIONS: Patients treated with allogeneic HSCT had a lower relapse rate, but similar EFS and OS to autologous HSCT. Treatment of MCL with HyperCVAD +/- rituximab followed by HSCT seems promising.     

Investigational strategies in autologous stem cell transplantation for follicular lymphoma

Recent retrospective analyses indicate prolonged survival for patients with follicular lymphoma over the past 25 years, attributed most likely to improved supportive care and sequential application of effective therapies. Encouraging results were obtained from several randomized trials evaluating myeloablative therapy followed by autologous stem cell transplantation (ASCT) as consolidation therapy applied to patients with advanced-stage follicular lymphoma either in first remission or as salvage therapy. However, because of the successful introduction of rituximab to the standard therapeutic repertoire, with its long-term beneficial clinical impact, ASCT must be reevaluated in prospective clinical trials, especially taking into account the potential short- and long-term toxicity associated with high-dose therapy. The concept of in vivo purging before or after ASCT and the introduction of radioimmunotherapy as part of the myeloablative regimen may further improve treatment results, reduce toxicity, and increase applicability. Combination of these novel strategies into a multimodal approach justifies hope that the treatment outcome of patients suffering from follicular lymphoma will be further improved.     

Autologous hematopoietic stem cell transplantation for aggressive B-cell non-Hodgkin's lymphoma

To evaluate the results of high-dose chemotherapy (HDT) and autologous hematopoietic stem cell transplantation (ASCT) in patients with diffuse B-cell aggressive non-Hodgkin's lymphoma(NHL). Between 1991 and 2004, 25 patients who did not achieve complete remission and 26 in complete remission from conventional chemotherapy received HDC-ASCT. Of 25 patients with refractory NHL,14 were chemotherapy-sensitive before HDT-ASCT and 11 were chemotherapy-resistant. CR was achieved after HDC-ASCT in 50% of 14 chemotherapy sensitive patients and in none of 11 chemotherapy-resistant patients. The 5-year probability of event-free survival for chemotherapy-sensitive and chemotherapy-resistant patients was 51.3% and 20.8%, respectively (p<0.05, log-rank test). Moreover, the 5-year probability of event-free survival for patients in the low-risk group with International Prognostic Index (IPI) and in the high-risk group with IPI was 75.0% and 16.3%, respectively (p<0.05, log-rank test). HDT-ASCT should be considered for patients with refractory aggressive NHL who are chemotherapy-sensitive rather than chemotherapy-resistant. Twenty-six patients in complete remission received consolidation therapy with HDT-ASCT. The 5-year probability of disease-free survival for patients in the low-risk group and in the high-risk group was 68.8% and 60.0%,respectively (p = 0.9 6). HDT-ASCT should be considered for patients at high risk who achieve complete remission after induction treatment. In future, HDT-ASCT combined with rituximab as induction therapy or as consolidation therapy is needed for patients with aggressive NHL in the high-risk group.     

自体外周血造血干细胞移植治疗T细胞淋巴瘤疗效分析

 【摘要】 目的 评价自体外周血造血干细胞移植（APBSCT）治疗T细胞淋巴瘤的临床疗效。方法 回顾性分析2006年9月至2011年12月于上海瑞金医院行APBSCT的T细胞淋巴瘤患者22例,包括T淋巴母细胞淋巴瘤6例,外周T细胞淋巴瘤（PTCL）16例（间变大细胞淋巴瘤8例,非特异性PTCL4例,皮下脂膜炎样T细胞淋巴瘤1例,鼻型NK／T细胞淋巴瘤2例,皮肤T细胞淋巴瘤1例）。所有病例均按WHO 2001年和WHO 2008年分类进行病理分型。预处理方案包括BEAM方案13例,ICE方案4例,CBV方案5例。采用1998年国际工作小组制定的非霍奇金淋巴瘤疗效评价标准评价疗效,根据患者移植前疾病状态和对化疗敏感性分为完全缓解（CR1）组和未达CR1组、敏感组和耐药组,并对临床治疗疗效以及移植前疾病状态与预后关系进行分析。结果 22例患者移植后中位随访13.1个月（1～60个月）,2年预期的无进展生存率为（67.6±11.0） %,总生存率为（71.1±11.1） %。移植后共6例出现疾病进展或复发,其中5例死亡。CR1和化疗敏感组无进展生存率分别为100 %和91.7 %,高于未达CR1组（42.6 %）和耐药组（19.0 %）,而且两组病例总生存也显著优于未达CR1组和耐药组。结论 T细胞淋巴瘤患者移植时疾病缓解状态和对化疗敏感性对移植疗效有显著影响,提示在化疗敏感阶段和（或）获得CR1后应早期行APBSCT治疗。     

Autologous stem cell transplantation in patients with mantle cell lymphoma

High-dose therapy followed by autologous stem cell transplantation (ASCT) has been considered a potential treatment approach in order to improve the poor prognosis in mantle cell lymphoma (MCL), but its role has not yet been clearly established. We analyzed retrospectively the outcome and prognostic factors in 48 consecutive patients with MCL scheduled for ASCT in five transplant centers. In 14 patients (29%), a sufficient amount of stem cells could not be collected. Mobilization failure was associated with female sex, blastoid cytology, and low hemoglobin level. Altogether 35 patients underwent ASCT, 24 patients as part of the first-line treatment and 11 patients later. After transplantation 28 patients (80%) remained in or achieved remission. Two patients died of transplant-related complications. During the median follow-up time of 38 months, nine patients have relapsed. The median event-free survival (EFS) was 39 months. Age over 60 years and elevated C-reactive protein level at diagnosis were associated with poorer outcome after transelantation. ASCT is an effective treatment in MCL with a high response rate and a longer survival than seen in conventionally treated patients. However, no plateau was seen in the EFS curve after ASCT. Whether cure Can be achieved in a proportion of patients with ASCT is currently unknown and should be studied in larger patient series with a longer follow-up.     

自体造血干细胞移植治疗恶性淋巴瘤的研究进展

自体造血干细胞移植(AHSCT)是治疗恶性淋巴瘤(ML)的重要方法,其治疗过程较为复杂,疗效也受诸多因素影响.近年来AHSCT在ML的治疗中应用更加广泛,寻找有效的预后因素以进一步区分可能从AHSCT中获益的患者以及制订合理的移植方案是临床医生关注的重要问题.文章就AHSCT治疗ML的研究进展作一综述.     

自体造血干细胞移植治疗恶性淋巴瘤的初步临床观察

目的:探讨自体追血干细胞移植(AHSCT)治疗恶性淋巴瘤的疗效.方法:造血干细胞动员采集方案采用移植前化疗敏感方案,如CHOP、DICE和ESHAP,大剂量阿糖胞苷(HD-Ara-C)等联合粒细胞集落刺激因子(G-CSF).预处理则采用BEAC(BCNU、VP-16、Ara-C和CTX)方案.结果:所有患者均采集到足够造血干细胞数,CD34+平均为2.7×108kg-1.移植后所有患者均恢复造血并出现Ⅳ度骨髓抑制,移植相关死亡率为0.移植后8例CR,3例PR.先后有2例进展(复发),其中1例死亡.中位随访时问为24.6个月,2年总生存率为84.6%.结论:AHSCT是一种有效治疗恶性淋巴瘤的方法,安全性好,但对于高危患者仍需探讨新的方法.     

Autologous and allogeneic stem cell transplantation in Hodgkin's lymphoma

Newly diagnosed patients who have advanced-stage Hodgkin's lymphoma have an excellent prognosis because most of them can be cured with initial treatment. In contrast, the prognosis for patients relapsing after first-line therapy with either combination chemotherapy or chemotherapy followed by radiotherapy remains poor in many cases. In most of these cases, high-dose chemotherapy and autologous stem cell transplantation (ASCT) is currently considered to be the treatment of choice. However, results of ASCT in primary refractory patients are poor and new therapeutic alternatives should be sought for these patients. Allogeneic stem cell transplantation has been used increasingly in relapsed or refractory Hodgkin's lymphoma patients, with the introduction of reduced-intensity conditioning protocols.