Progress in CLL, chemotherapy, antibodies and transplantation.

Over the last decade, major advancements in our understanding of chronic lymphocytic leukemia (CLL) and its variants have occurred. It has become apparent that there is diversity in types of CLL including those patients that do or do not have hyper-mutation of their immunoglobulin genes. Mutated genes confer a favorable prognosis. One of the major advances in our therapy has been the discovery of the activity of purine analogs, which have been demonstrated to be more active than conventional therapy in achieving complete remission, prolonged remission duration, and a suggestion of improved survival. More recently, based on information that purine analogs inhibit DNA repair, rational combinations have been developed. In particular, fludarabine plus cyclophosphamide appeared to have added activity compared to either drug given alone or in sequence. This has led to a higher response rate, longer time to progression, and an improvement in survival in patients treated following prior alkylating agents. Two monoclonal antibodies, Rituximab and Campath-1H, have become available for clinical use and research. Rituximab has modest activity as a single agent, with higher response rates being noted in patients who receive more intensive regimens. Rituximab has been successfully combined with chemotherapy, and in association with fludarabine plus cyclophosphamide (FCR) has a very high response rate and the ability to obtain polymerase chain reaction (PCR) negativity for the immunoglobulin heavy chain region. Campath-1H is very active as a single agent and is being recommended for treatment for patients with fludarabine refractory disease and will receive increased attention as a research agent in earlier-stage patients. Autologous and allogeneic bone marrow transplantation have emerged as significant treatments in CLL. The ability to achieve responses in bone marrow and peripheral blood with newer regimens has given the opportunity to collect stem cells from patients. There is a suggestion that intensification of remissions with autologous transplant can lead to PCR negativity and prolonged remissions. Allogeneic transplantation has been demonstrated to be effective with a strong suggestion of graph versus leukemia effect. This has been utilized in the development of non-ablative marrow allogenaic bone marrow transplant programs. Non-ablative transplants appear to be as effective as ablative transplants in the most recent analysis. Thus, multiple modalities have been brought together to achieve high-quality complete remissions in CLL, giving the prospect of improved survival.     

Non-myeloablative or reduced intensity stem cell transplantation preparative regimens

Allogeneic hematopoietic stem cell transplantation (HSCT) has been based on the use of myeloablative chemotherapy and radiotherapy conditioning regimens to eradicate malignancy and to eliminate host hematopoiesis and immune cells, but this approach is associated with a high risk of complications. A number of non-myeloablative or reduced-intensity preparative regimens for HSCT(NST or RIST) have been proposed to reduce regimen-related toxicities. Two general strategies have emerged, based on the use of (1) immunosuppressive chemotherapeutic drugs, usually a purine analog in combination with an alkylating agent, and (2) low-dose total body irradiation. NST/RIST have been feasible in elderly patients and in patients with organ dysfunction or other comorbidities precluding standard ablative conditioning, however the long-term impact is not yet established. The indication for NST/RIST and the optimal preparative regimen need to be defined for each malignancy in controlled clinical trials.     

Intensive care unit support and Acute Physiology and Chronic Health Evaluation III performance in hematopoietic stem cell transplant recipients

OBJECTIVE: Hematopoietic stem cell transplant (HSCT) recipients admitted to the intensive care unit (ICU) have high mortality. The prognostic importance of peripheral blood stem cell source in critically ill HSCT recipients and the performance of Acute Physiology and Chronic Health Evaluation (APACHE) III have not been well studied. In a previous study, the hospital mortality rate of HSCT recipients admitted to our ICU was 77%. The objectives of this study were to describe the clinical course of HSCT recipients admitted to the ICU and to determine the performance of APACHE III in predicting their mortality. DESIGN: Retrospective cohort study. SETTING: Academic medical center. PATIENTS: HSCT recipients admitted to the ICU. MEASUREMENTS: Demographics, transplant type, stem cell source, APACHE II and III predicted mortality, development of sepsis and organ failure, use of mechanical ventilation, duration of hospital stay, and mortality. RESULTS: Ninety-four percent of the 112 HSCT recipients were white and 64% male. The mean APACHE II and III scores were 25 and 44, respectively. The APACHE II and III hospital predicted mortality rates were 44% and 42%, respectively. Mechanical ventilation was provided to 63%. Organ failure developed in 94% and sepsis in 62%. The ICU, hospital, and 30-day mortality rates were 33%, 46%, and 52%, respectively. Allogeneic transplant and higher APACHE III scores, but not bone marrow stem cell source, were associated with increased mortality. Invasive mechanical ventilation, vasoactive medication use, sepsis, and organ failure during patients' ICU course were also associated with increased mortality. The area under the receiver operating characteristic curve for APACHE III hospital mortality prediction was 0.704 (95% confidence interval, 0.610-0.786). For APACHE III hospital mortality prediction, the value of the Hosmer-Lemeshow statistic showed good model fit. CONCLUSIONS: Current mortality figures of HSCT recipients admitted to the ICU are better than previously reported. The APACHE III prognostic model has moderate discrimination and good calibration in predicting hospital mortality in these patients.     

Non-myeloablative/reduced-intensity hematopoietic stem cell transplantation for chronic myelogenous leukemia]

Allogeneic hematopoietic stem cell transplantation(HSCT) is a curative therapy against a variety of hematological disorders. However, its application has been limited to younger patients without organ dysfunctions due to transplant-related toxicities. Recently, non-myeloablative stem cell transplantation(NST) or reduced-intensity stem cell transplantation(RIST) has been developed as a less toxic HSCT, which enables the application of HSCT to patients of advanced age or with organ dysfunction. The anti-leukemia effect mainly depends on the graft-versus-leukemia(GVL) effect. Chronic myelogenous leukemia(CML) has been known to be one of the best targets for GVL effect, supported by the observation of durable molecular remission after donor lymphocyte infusion for relapse after HSCT. RIST could be a promising treatment modality for patients with CML.     

Successful allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia during respiratory failure and invasive mechanical ventilation

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment option for various hematologic disorders. However, life-threatening adverse events resulting from treatment-related toxicity, severe infections, and/or graft-versus-host disease (GvHD) can occur. We report on a 64-year-old patient suffering from secondary acute myeloid leukemia (AML) who underwent successful allogeneic HSCT while on invasive mandatory ventilation (IMV). The patient received reduced intensity conditioning (RIC) according to the FLAMSA-protocol. Acute respiratory failure occurred one day before scheduled HSCT. Following emergency endotracheal intubation the patient was transferred to the intensive care unit (ICU). Because of respiratory deterioration, stem cell infusion was postponed. After stabilization of respiratory parameters, HSCT was performed during IMV which was continued for seven days. Following hematopoietic regeneration the patient was discharged in good condition on day 35 after HSCT. This case illustrates that intubation and mechanical ventilation do not necessarily exclude leukemic patients from HSCT.     

低强度预处理异基因造血干细胞移植治疗骨髓增生异常综合征研究进展

异基因造血干细胞移植（allo—HSCT）是治疗骨髓增生异常综合征（MDS）的有效手段，MDS发病率随年龄增加而增加，尽管近年来传统清髓性移植治疗MDS取得可喜的成绩，但对于年龄大于60岁的MDS患者，allo—HSCT预后差，低强度预处理异基因造血干细胞移植（RIC allo—HSCT）使老年MDS患者进行allo—HSCT成为可能，利用供者淋巴细胞的移植物抗肿瘤作用显著降低移植相关器官毒性及非复发死亡率．本文就RIC—HSCT治疗MDS的问题诸如RIC allo—HSCT治疗MDS可行性，MDS病例选择，RIC allo—HSCT的时机干细胞来源，RIC预处理方案．疗效及预后评价．GVHD与移植物抗MDS效应等的研究进展做一综述及展望。     

Allogeneic hematopoietic cell transplantation for multiple myeloma.

At the present time, allogeneic hematopoetic stem cell transplantation (AHSCT) is the only proven treatment for multiple myeloma (MM) that is potentially curative. This conclusion is based on observations of patients who have undergone AHSCT and are living disease-free for 5-15 years. While patients who receive either allogeneic or autologous stem cell transplants for MM have similar 3-5 year survival, only allograft recipients appear to enjoy long-term disease free survival. This is most likely due to an allogeneic graft-versus-myeloma effect, demonstrated most dramatically by complete responses observed after the simple infusion of donor lymphocytes for patients who have relapsed after a prior allograft. The very high transplant related mortality associated with standard allogeneic stem cell transplantation is currently the major limitation to wider use of this potentially curative treatment modality. Complications are age-related and thus standard AHSCT is offered only to patients under age 55; further limiting the utility of this treatment. The challenge for clinical investigators will be to reduce the incidence of post-transplant complications for patients receiving AHSCT for MM. These strategies include the use of non-ablative conditioning regimens, the use of peripheral blood stem cells rather than bone marrow, graft engineering and targeted conditioning therapies such as bone-seeking radioisotopes. In one such approach, tandem autologous/non-ablative allogeneic transplants have been shown to result in relatively low mortality, high complete response rates and 1-year survivals of 81%. Further follow-up and randomized trials will help to define the utility of this strategy.     

Nonmyeloablative allogeneic hematopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation (HSCT) is the most effective treatment for selected hematological malignancies. Its curative potential is largely mediated by an immune-mediated destruction of malignant cells by donor lymphocytes termed graft-versus-leukemia (GVL) effect. However, because of its toxicity, conventional allogeneic HSCT is restricted to younger and fitter patients. These observations led several groups to set up new (less toxic) transplant protocols (nonmyeloablative stem cell transplantation or NMSCT) based on a two-step approach: first, the use of immunosuppressive (but nonmyeloablative) preparative regimens providing sufficient immunosuppression to achieve engraftment of allogeneic hematopoietic stem cells and, in a second step, destruction of malignant cells by the GVL effect. Preliminary results showed that NMSCT were feasible with a relatively low transplant-related mortality (TRM), even in patients older than 65 years. In addition, strong antitumor responses were observed in several hematological malignancies as well as in some patients with renal cell carcinoma. After discussing the mechanisms and efficacy of the GVL effect as well as the rationale for NMSCT strategies, this article reviews the first results of ongoing clinical trials. Innovative modalities that may permit amplification of the GVL effect while minimizing the risk of GVHD are discussed. Because the benefits of NMSCT over alternative forms of treatment remain to be demonstrated, this strategy should be restricted to patients included in clinical trials.     

造血干细胞移植与血小板输注

背景:血小板输注被认为是对致死性出血最为有效的治疗措施,已成为治疗造血干细胞移植后血小板减少的标准方法。关于血小板输注临床应用的相关研究资料相对缺乏,各医院间实际情况变化较大。目的:对52例造血干细胞移植患者移植期间血小板输注的情况进行回顾性分析。方法:将出现活动性出血所进行的血小板输注归为治疗性输注,在没有出血表现的情况下进行的血小板输注定义为预防性输注。根据24h血小板回收率和出血改善情况来评价不同血小板输注性质、自体或异基因移植类型等因素对血小板输注疗效的影响。结果与结论:预防性和治疗性血小板输注有效率分别为63.6%和55.6%;接受造血干细胞移植患者血小板输注有效率和平均血小板升高值分别为60.9%和26.8×109L-1。而自体造血干细胞移植组和异基因造血干细胞移植组间预防性和治疗性输注的疗效无差别。回归分析中,凝血功能异常被认为是影响血小板输注疗效的独立风险因素。     

地中海贫血造血干细胞移植供体及预处理方案选择的研究进展

地中海贫血为常染色体隐性遗传疾病,是由于基因突变导致血红蛋白的a或β珠蛋白链生成障碍引起的血液系统疾病.目前,造血干细胞移植(HSCT)是唯一可以治愈地中海贫血的方法.但是,由于受到HSCT供者与患者人类白细胞抗原(HLA)相合程度的限制,以及HSCT后的移植排斥与移植相关不良反应等并发症与预处理方案相关,因此选择合适的造血干细胞供体与预处理方案,对提高HSCT治疗地中海贫血的疗效至关重要.笔者拟就无关供者HSCT、亲缘供者HSCT、脐血移植(UCBT)及预处理方案的研究现状与研究进展进行综述.     

Evolution of treatment strategies in chronic lymphocytic leukemia. Part 2 of a 3-Part series: Advances in the treatment of hematologic malignancies

Over the past few decades, the management of chronic lymphocytic leukemia (CLL) has evolved considerably. This advancement is due in part to increasing awareness of prognostic factors and molecular heterogeneity of the disease which has helped to identify distinct risk groups of CLL. In addition, novel treatment regimens have demonstrated much higher complete and overall response rates than previously seen with conventional CLL therapy. Indeed, as complete response rates exceed 50%, curative therapy for CLL is within reach. Ongoing clinical research may define the optimal treatment strategies and improve outcomes for patients with CLL.     

Cardiac adverse events during stem cell transplantation for hematological malignancies: A single centre experience

Hematopoietic stem cell transplantation (HSCT) is a highly successful treatment option for many hematological malignancies. Several adverse effects can be seen in HSCT due to the infusion and damage caused by the conditioning regimens. Cardiovascular adverse effects are relatively common during HSCT, and they have the potential to cause devastating complications. The aim of present study was to evaluate the transplantation-related cardiac adverse effects and determine the risk factors in patients undergoing HSCT at our institution. A retrospective analysis has been performed in 662 patients who was treated at Hacettepe University Stem Cell Transplantation Unit. Amongst the 622 patients, 318 (51.1 %) underwent autologous and 304 (48.9 %) underwent allogeneic HSCT. The frequency of the cardiac adverse effects was found to be 10.8 % in all the study population. The most common adverse effect was tachyarrhythmia, constituting 7.9 % of all population. These adverse effects were mostly occurred in lymphoma patients (14 %). Nineteen (3.0 %) of all patients developed atrial fibrillation mostly on the 4th day (range of 1–9 days) after transplantation. Life-threatening events are extremely rare. These adverse effects appear to be related to the type of transplantation rather than the underlying disease. Therefore, close follow-up of patients is important during the peri-transplantation period.     

Hematopoietic stem cell transplant in cancer treatment

Hematopoietic stem cell transplantation (HSCT) includes bone marrow, peripheral blood, cord blood, autologous, allogeneic, related or unrelated. These transplants have two main roles in cancer treatment, i.e., supportive treatment for marrow toxicity and immunotherapy for cancer cells. HSCT has also severe adverse reaction such as, bacterial fungal or viral infection by neutropenia, or graft versus host disease by the replacement of immune system. In autologous HSCT the main role is to prevent severe marrow toxicity which enables extreme high dose of anticancer drug administration. In allogeneic HSCT the main roles become both, support for marrow toxicity and immunotherapy, which possibly complicated with immunological adverse reactions. In mini-transplant or allogeneic transplant with reduced intensity, the main role is immunotherapy. These three kinds of transplants have each own indication and conducted in 17,472 patients till 2001 in Japan.     

Allogeneic hematopoietic cell transplantation following nonmyeloablative conditioning as treatment for hematologic malignancies and inherited blood disorders.

Allogeneic hematopoietic cell transplantation (HCT) after myeloablative conditioning regimens has been an effective treatment for many patients with hematologic malignancies or inherited blood disorders. Unfortunately, such regimens have been associated with significant toxicity, limiting their use to otherwise healthy, relatively young patients. In an attempt to extend treatment by allogeneic HCT to older patients and those with comorbid conditions, several groups of investigators have developed reduced-intensity or truly nonmyeloablative conditioning regimens, lacking such toxicity. Analogous to conventional regimens, reduced-intensity regimens both eliminated host-versus-graft (rejection) reactions and produced major anti-tumor effects. In contrast, nonmyeloablative regimens have relied on optimizing both pre-and posttransplant immunosuppression to overcome host-versus-graft reactions, while anti-tumor responses have depended mainly on immune-mediated graft-versus-tumor effects. In this review, we define reduced-intensity and truly nonmyeloablative regimens, describe the preclinical development and clinical application of a very low intensity nonmyeloablative regimen, and review results with reduced-intensity regimens in patients with hematologic malignancies or inherited blood disorders.     

造血干细胞移植与血小板输注

背景：血小板输注被认为是对致死性出血最为有效的治疗措施,已成为治疗造血干细胞移植后血小板减少的标准方法。关于血小板输注临床应用的相关研究资料相对缺乏,各医院间实际情况变化较大。目的：对52例造血干细胞移植患者移植期间血小板输注的情况进行回顾性分析。方法：将出现活动性出血所进行的血小板输注归为治疗性输注,在没有出血表现的情况下进行的血小板输注定义为预防性输注。根据24h血小板回收率和出血改善情况来评价不同血小板输注性质、自体或异基因移植类型等因素对血小板输注疗效的影响。结果与结论：预防性和治疗性血小板输注有效率分别为63.6%和55.6%;接受造血干细胞移植患者血小板输注有效率和平均血小板升高值分别为60.9%和26.8×109L-1。而自体造血干细胞移植组和异基因造血干细胞移植组间预防性和治疗性输注的疗效无差别。回归分析中,凝血功能异常被认为是影响血小板输注疗效的独立风险因素。     

Clinical stem cell therapies for severe autoimmune diseases

Severe autoimmune diseases (ADs) are a major source of disability and reduced quality of life and may result in shortened life expectancy, particularly in treatment-resistant patients. For several decades, allogeneic and autologous haematopoietic stem cell transplantation (HSCT) has been the focus of scientific investigation as a potential means of delivering 'one-off' intensive treatment in severe ADs. Improvements in the clinical safety of HCST were followed by its increasing use in recent years as an experimental treatment for severe and resistant ADs. European and North American registries have accumulated between one and two thousand procedures. Retrospective analyses and prospective studies have demonstrated the feasibility, safety and initial efficacy data in various ADs. Profound cell biological changes induced by HSCT leading to stabilization or reversal of organ damage have been characterized. These have also shed light on basic disease mechanisms and support investigation of more specific cellular therapy in ADs. There is clear potential for harnessing a profound immunological effect through HSCT. However, there is a need for an ongoing balance against evolving non-transplant treatments for ADs. Ideally, these issues should be resolved in phase III studies, in which HSCT approaches are compared with the best comparator.     

Management of bacteremia in patients undergoing hematopoietic stem cell transplantation

Bacteremias represent severe infectious complications following hematopoietic stem cell transplantation (HSCT). Frequency is highest during the pre-engraftment period, both in autologous and in allogeneic HSCT, when patients are granulocytopenic. In the postengraftment period, bacteremias are also frequent in the absence of neutropenia, especially after allogeneic HSCT. Antibacterial prophylaxis with fluoroquinolones during pre-engraftment neutropenia could be justified both in autologous and allogeneic HSCT, but the possibility of infections caused by resistant pathogens should be carefully evaluated. Empirical antibacterial therapy must be chosen on the basis of local epidemiology and should be administered in all febrile HSCT recipients, regardless of the presence of neutropenia. This approach appears to be justified by the high incidence of bacteremia in any post-transplant period and by the high mortality rate that is observed if appropriate treatment is delayed, especially in infections caused by specific pathogens (e.g., Gram-negative rods).     

Chronic lymphocytic leukemia: diagnosis and treatment

Traditionally, the goal of therapy in chronic lymphocytic leukemia (CLL) has been palliative, with first-line therapy using alkylating agents and/or involved field radiotherapy (depending on the stage of disease and sites of involvement) because of the older age of affected patients and the low rate of complete remissions (CRs) with no improvement in overall survival despite treatment. With increasing knowledge about the biology, molecular genetics, and prognostic factors of the disease, the philosophy of care for patients with CLL has evolved from palliation to aiming for a potential cure, especially in younger patients. Furthermore, multiple treatment options have emerged, including purine analogues, monoclonal antibodies, and potentially stem cell transplantation. These have been associated with higher frequencies of CRs and longer durations of responses compared to conventional chemotherapy. In addition, a subset of patients treated with chemoimmunotherapy can achieve durable CRs and molecular remissions. This may translate into improved disease-free survival and potentially a "cure." Because of the heterogeneous nature of CLL, new prognostic markers are currently being incorporated into clinical trials to determine their role in routine clinical practice. This review summarizes current therapeutic regimens that are being evaluated in patients with CLL and management of disease-related complications.     

Clinical roundtable monograph. New alternatives in CLL therapy: managing adverse events

Chronic lymphocytic leukemia (CLL) is a B-cell leukemia mainly affecting older adults. Historically, CLL has been regarded as an incurable disease, and treatment has been confined to cytotoxic chemotherapy regimens. However, prognosis for patients treated with these agents remained poor, prompting the development of new, targeted agents. The introduction of rituximab, a CD20-targeted monoclonal antibody, revolutionized the treatment for this disease. Rituximab in combination with fludarabine improved response rates and length of progression-free survival. The success of rituximab in this setting has prompted the development of many more investigational agents for CLL, including other antibody agents. However, as with any medication, the potential benefit achieved with CLL therapies is mitigated by the safety risk for the patient. These agents have been associated with adverse events such as immunosuppression, reactivation of cytomegalovirus, and infusion-related reactions that can occur with antibody administration. Adverse events can greatly affect the patient’s quality of life and ability to tolerate therapy. Management of adverse events is a critical component of the overall treatment strategy for CLL, particularly in elderly patients. In this clinical roundtable monograph, 3 expert physicians discuss the latest clinical studies evaluating the treatment of CLL, focusing on the adverse events associated with each agent and the potential interventions that can be used to manage their occurrence.     

Autologous stem cell transplantation and stem cell mobilization kinetics in elderly patients with B cell non-Hodgkin lymphoma

As known, the world population is aging and as the life span increases the number of advanced-age lymphomas also shows an upward trend. Autologous hematopoietic stem cell transplantation (HSCT) is the standard treatment modality in chemotherapy-sensitive relapsed or refractory aggressive lymphomas. Increased morbidity and mortality related to both the transplant itself and comorbid diseases can be observed in elderly lymphoma patients. Patients who are 65 years or older and underwent autologous HSCT with B-cell non-Hodgkin lymphoma were retrospectively included in our study. In terms of survival analysis, median follow-up was 34.5 months (8–159) while the overall survival (OS) was 58%. In the univariate analysis of prognostic data in OS, patients who were referred to transplantation with complete response had a statistically significant survival advantage (p = 0.043). In terms of the effect of pre-transplant conditioning regimens on survival, BEAM regimen yielded better results, though not statistically significant. Age, number of chemotherapy cycles received before mobilization and radiation therapy had no significant effect on the CD34 (+) cell count in the final product (p = 0.492, 0.746 and 0.078 respectively). In conclusion, autologous HSCT is a practicable treatment modality that provides survival advantage in suitable advanced-age patients with a diagnosis of B-cell non-Hodgkin lymphoma.