Autologous stem cell transplantation for acute lymphocytic leukemia in adults

Autologous bone marrow transplantation remains an investigational treatment for adult ALL. Despite many anecdotal studies showing efficacy, the rarity of ALL has prevented the large randomized trials necessary to confirm effectiveness. Candidates for autoBMT include adult patients in first CR with adverse risk factors and all patients who have experienced disease relapse. It remains debatable which preparative regimen is optimal, whether purging is necessary, or if chemotherapy or immunotherapy administered after transplantation can decrease disease relapse. Overall, every effort should be made to enter ALL patients on well-designed randomized multi-institutional trials. These trials should compare autologous transplantation to newer more intensive chemotherapy regimens and should take into account the heterogeneity of ALL. A quality of life analysis should be performed as one high-dose treatment may be less toxic and better tolerated than multiple cycles of consolidation chemotherapy. Strategies aimed at enhancing an autologous graft-versus-leukemia effect after transplantation may enhance long-term survival. Many more studies are needed to further define the optimal role of autoBMT in adult ALL.     

Allogeneic hematopoietic stem cell transplantation for adult acute lymphocytic leukemia

Allogeneic hematopoietic stem cell transplantation (alloHCT) is the single most potent treatment modality to prevent relapse in adults with acute lymphocytic leukemia, but its optimal use and timing remains a matter of intense debate and research. There is general agreement that patients with clinical features of high risk for relapse should undergo alloHCT in first complete remission. However, newer studies suggest that even patients without these risk factors may benefit. Monitoring of minimal residual disease may improve risk stratification and may complement or replace conventional risk features. Prognosis in relapsed and refractory patients is dismal, and alloHCT should be performed as soon as possible. AlloHCT also offers the only reasonable chance for cure in Philadelphia chromosome-positive acute lymphocytic leukemia; the role of imatinib is not yet clearly defined. Recent developments in unrelated-donor transplantation and reduced-intensity conditioning allow the beneficial effects of alloHCT to reach a considerably wider patient population.     

Autologous stem cell transplantation for patients with acute promyelocytic leukemia in second molecular remission

Relapse still occurs in approximately 20-30% of patients with acute promyelocytic leukemia (APL) and, after achievement of second complete remission (CR), the optimal strategy is still controversial. We describe therapeutic results from a series of 13 patients autografted in second molecular remission (MR) by a molecular negative apheresis product. In all patients, the disease was confirmed at the molecular level and all had received the GIMEMA/AIDA protocol, achieving molecular remission at the end of consolidation. Relapse was hematological in 12 cases and molecular in one. After consolidation with chemotherapy, all patients achieved MR and received a further course plus granulocyte-colony stimulating factor as mobilizing therapy. A median of 7.6×10(6) (range 2.7-10) CD34-positive cells/kg were collected. In all cases, molecular evaluation of the apheresis product was negative for the promyelocytic leukemia/retinoic acid receptor alpha gene. No case of transplant-related mortality was recorded. No maintenance or consolidation therapy after autologous stem cell transplantation (ASCT) was given to any patient. After a median follow-up of 25 months from ASCT, 10 patients are alive in sustained MR, while two relapsed after ASCT and died in the setting of refractory disease; one patient achieved a third CR and is waiting for allogeneic SCT. These results suggest that ASCT performed with a molecularly negative graft in APL patients in second MR offers a valid chance for achieving a cure. Such an approach should also be considered in relapsed patients with an HLA-compatible donor, namely in those with a first CR lasting more than one year or in unfit or elderly individuals.     

成人急性淋巴细胞白血病自体造血干细胞移植后的维持治疗

目的 探讨成人急性淋巴细胞白血病(ALL)自体造血干细胞移植(ASCT)后维持治疗的可行性。方法 第1次完全缓解期(CRl)进行ASCT成人ALL患者38例,预处理方案为全身照射 环磷酰胺(TBICy)方案或者TBICy联合其他化疗药物,ASCT后19例患者接受VP／MM方案维持化疗,13例间断IL-2治疗,其中8例联合IL-2和维持化疗。结果 随访中位时间991(18～4914)d。复发11例,复发率28．9％,复发中位时间212(79～1008)d,其中8例在1年内复发。3年累积复发风险43．8％(95％可信限：35．1％～52．5％)。移植相关死亡(TRM)5例,TRM中位时间42(18～120)d,其中ASCT后接受维持治疗的24例患者仅2例发生TRM。3年和5年无白血病生存率均为55．7％(95％可信限：47．3％～64．1％)。结论 成人ALL患者ASCT后标准方案维持化疗和免疫治疗安全有效,能够减低移植后复发风险,提高ASCT的疗效。     

Autologous and allogeneic stem cell transplantation for chronic lymphocytic leukemia.

Allogeneic and autologous stem cell transplantation (SCT) are increasingly considered for treatment of patients with chronic lymphocytic leukemia (CLL). In order to assess the potential therapeutic value of SCT for CLL, the present article aims at answering the following crucial questions: (1) Is SCT a curative treatment? (2) Does SCT improve the prognosis of poor-risk CLL? (3) Do risk factors exist which are useful for defining prognostic groups in terms of feasibility and post-transplant outcome? The efficacy of auto-SCT relies exclusively on the cytotoxic therapy administered. To date, there is only limited hope that autotransplantation can cure the disease. Nevertheless, the results of the published series suggest that auto-SCT is capable of improving the prognosis of CLL with poor-risk features. Well defined favorable conditions for successful autografting are the status of the disease (CR or VGPR) and the number of lines of therapy (<2) before transplantation. The crucial anti-leukemic principle of allo-SCT consists in the immune-mediated GVL effects conferred with the graft. The GVL activity explains that allografting seems to be curative for at least a subset of patients. However, as long as allo-SCT in CLL is still associated with an excessively high treatment-related mortality, only selected patients with advanced poor-risk disease should be considered for allografting. The development of conditioning regimens with reduced intensity may allow extending the indications of allogeneic SCT for CLL in the near future.     

Autologous bone marrow transplantation in adult patients with acute lymphoblastic leukemia

Autologous bone marrow transplantation (ABMT) was introduced as a treatment for terminal leukemic relapse more than 40 years ago. For childhood acute lymphoblastic leukemia (ALL) the role of ABMT is well defined. Some studies suggest that it is also beneficial for adult patients with high-risk factors or with relapse. However, these inferences are based on a relatively small number of patients with short follow-up. Nevertheless patients with high-risk ALL are candidates for ABMT if no histocompatible sibling is available. Similarly patients in second or later complete remission (CR) in the absence of a histocompatible donor may derive benefit from ABMT. The different conditioning regimens used by the treatment centers are associated with different toxicities but none has been proven to be superior than others. In the majority of studies the marrow has been purged of leukemic cells, but this maneuver has never been evaluated in a randomized comparative trial. Transplant related mortality rate of ABMT is low compared to allogeneic transplantation. The GvL effect, which is important to eliminate malignant cells in acute and chronic myelocytic leukemia, has not been definitively demonstrated in ALL. The tyrosine-kinase inhibitor STI 571 offers new perspectives for patients with the Phl/bcr/abl translocation. It may be especially useful for treating minimal residual disease (MRD) before and/or after ABMT.     

Autologous peripheral stem cell transplantation

A number of recent reports have now shown that hematopoietic stem cells are present in the circulation, and these cells have the potential to restore complete hematopoiesis following marrow aplasia. Peripheral stem cells have been collected by continuous flow leukapheresis during periods of hematopoietic regeneration after 2 to 3 weeks of intensive chemotherapy. Following marrow ablative chemotherapy or chemoradiotherapy, the autologous peripheral stem cells are thawed and infused intravenously. When a sufficient stem cell dose was given, rapid neutrophil and platelet recovery has been confirmed, as compared with bone marrow transplantation. Acute leukemia, malignant lymphoma and solid tumors may benefit from this approach, and long-lasting remission or cure may result in a significant number of patients.     

Autologous peripheral blood stem cell transplantation for adults with B-lineage acute lymphoblastic leukemia: a pilot study

We conducted a pilot study on autologous peripheral blood stem cell transplantation (PBSCT) for 11 adults with B-lineage acute lymphoblastic leukemia (ALL) in first complete remission (CR) or even in those with more advanced stages. All patients achieved CR by induction therapy, of whom 10 were treated with anthracycline, vincristine and prednisolone-based regimens. After consolidation therapy, all patients except one received high-dose cytarabine followed by granulocyte colony-stimulating factor (G-CSF) administration to collect PBSCs. Ten patients received busulfan 4 mg/kg for 4 days, etoposide 20 mg/kg for 3 days and ranimustine 200 mg/m2 for 2 days as a conditioning regimen. One received a regimen consisting of etoposide, cyclophosphamide and total body irradiation. From day 1, G-CSF was given intravenously, and no additional chemotherapy was administered. At the median follow-up time of 30.8 months, four of six patients with standard-risk B-lineage ALL survived within the range of 19.7 to 85.4 months without relapse. In contrast, only one of five with high-risk B-lineage ALL survived for 36.3 months without relapse. Autologous PBSCT as post-remission therapy may prolong CR in adults with standard-risk B-lineage ALL.     

Hematopoietic stem cell transplantation in adult acute lymphoblastic leukemia: a single-centre analysis

The role of autologous or allogeneic hematopoietic stem cell transplantation (HSCT) in ALL is controversial because of its adverse risk/benefit ratio, and the main policy is to reserve it for high-risk patients. In our Institution, between 1984 and 2002, 40 patients received an allogeneic HSCT and 39 underwent autografting. The conditioning regimen included HD-Ara-C, HD-CTX and 10 Gy fractionated TBI. After allogeneic SCT in first CR, four patients relapsed, leading to a 10-year EFS chance of 78.3%; of the other patients, 5 are still in CR. After autografting in first CR, there was an early death, one secondary AML, one death in CR and six relapses, leading to a 10-year EFS chance of 44.4%; of the other patients, 6 are still in CR. Even considering the limited number of patients and the slow accrual rate, selection bias cannot be considered a sufficient explanation for the favorable outcome of allografting in first CR as the majority of the patients had adverse prognostic factors. It cannot be claimed that allogeneic SCT was performed in patients already cured, as the autografted patients had a notably worse outcome, and a 10-year EFS chance of about 80% is an uncommon finding even in standard-risk ALL patients. It might be inferred that the timing of SCT as late intensification, in addition to a rather aggressive conditioning regimen, helped to minimize the leukemic burden, thus favoring the expression of a GVL effect. Conversely, the results in more advanced disease phases are discouraging, due to poor quality CRs and inefficacy of GVL in managing large residual disease.     

Autologous bone marrow transplantation for acute lymphoblastic leukemia

Forty-four children with acute lymphoblastic leukemia (ALL) who had relapsed (N = 43) or had refractory disease (N = 1) were intensively treated with combination chemotherapy, had remission bone marrow (BM) harvested and purged in vitro with monoclonal antibodies specific for leukemia-associated antigens, underwent postharvest ablative chemotherapy and radiotherapy and subsequently were infused with their autologous marrow. Of the 44 patients treated between November 1980 and January 1988, 19 relapsed, 10 died of complications, and 15 remained in complete remission for a median of 28.5 months (range, 10+ to 94+). Event-free survival (EFS) (+/- SE) at 5 years after autologous transplantation was 29 +/- 8%. For the 26 patients whose initial remission was greater than 2 years, event-free survival was 51 +/- 10%. These results compare favorably with allogeneic transplantation and chemotherapy trials for patients with relapsed ALL, and provide an alternative transplantation option for children without histocompatible donors.     

Hematopoietic stem cell transplantation for treatment of acute leukemia]

Recently, hematopoietic stem cell transplantation has been diversified and classified into several types of transplants, including allogeneic bone marrow, peripheral blood stem cell and cord blood stem cell transplantation (BMT, PBSCT, CBSCT), from related or unrelated donors. In addition, autologous BMT or PBSCT can be used to facilitate hematologic reconstitution after marrow-ablative therapy for hematologic malignancies. At least 50% of patients with acute myeloblastic leukemia (AML) and acute lymphoblastic leukemia (ALL) can be cured by treatment with allogeneic BMT. Autologous BMT has been studied in comparison with allogeneic BMT or intensive chemotherapy in the treatment of AML and ALL. A series of large-scale prospective randomized studies have provided controversial results: relapse rates are significantly low, but treatment-related mortality is significantly high, after allogeneic or autologous BMT as compared to intensive chemotherapy. At present, it is somewhat difficult to determine which treatment modality is indicated as a postremission therapy for AML and ALL. Therefore, risk factors such as leukemia subtype, age, karyotype, and initial response should be taken into consideration when deciding on a postremission therapy. In the 1990's, the use of autologous PBSCT has been replacing autologous BMT, as autologous PBSCT has several advantages over autologous BMT. Consequently, allogeneic PBSCT has come to be increasingly used instead of allogeneic BMT in the treatment of leukemia. Recent clinical data clearly indicate that allogeneic PBSCT can be used as an alternative to allogeneic BMT. With well-designed clinical trials, the places, of allogeneic or autologous BMT and PBSCT will be clarified in the treatment strategy for acute leukemia.     

Allogeneic hematopoietic stem cell transplantation for patients with acute leukemia

Objective

The purposes of this study were to assess the efficacy of allogeneic hematopoietic stem cell transplantation (HSCT) for acute leukemia (AL) and analyze the factors affecting the prognosis of these patients.

Methods

The clinical and follow-up data of 93 AL patients (median age, 30 years) undergoing allogeneic HSCT in Xiangya Hospital over the past 12 years were collected, and the potential factors affecting the efficacy and prognosis of allogeneic HSCT patients were determined.

Results

Hematopoietic reconstitution was achieved in 90 patients. At the last follow-up, the incidences of severe acute graft versus host disease (aGvHD) and extensive chronic GvHD (cGvHD) were 14.0% and 20.0%, the 3-year cumulative incidence of transplantation related mortality (TRM) and relapse rate were 16.8%±6.1% and 21.3%±6.7%, and the estimated 3-year overall survival (OS) and disease-free survival (DFS) of the patients were 64.6%±5.4% and 56.5%±5.5%, respectively. Univariate analysis indicated that age older than 40 years, HLA mismatch, and severe lung infection within the first 100 days after transplantation were risk factors for severe aGvHD, age older than 40 years, HLA mismatch, severe lung infection within the first 100 days after transplantation, and severe aGvHD were risk factors for TRM, high-risk AL and lack of cGvHD were risk factors for relapse (all P<0.05). Survival estimation showed that HLA mismatch, severe lung infection occurring within the first 100 days post-transplantation, high-risk AL severe aGvHD and lack of cGvHD were risk factors associated with poor prognosis (all P<0.05). Further multivariate analyses revealed that severe lung infection within the first 100 days post-transplantation, severe aGvHD and lack of cGvHD were independent risk factors for unfavorable outcomes (all P<0.05).

Conclusions

Allogeneic HSCT can improve the DFS of AL patients, and severe lung infection within the first 100 days post-transplantation, severe aGvHD and lack of cGvHD are independent risk factors affecting the prognosis.Key Words: Leukemia, hematopoietic stem cell transplantation (HSCT), graft-versus-leukemia effect     

Allogeneic stem cell transplantation for acute lymphocytic leukemia in adults

Acute lymphocytic leukemia remains a difficult disease to treat in adults. Allogeneic bone marrow transplantation can cure some patients with ALL, but GVHD transplant-related mortality and disease relapse remain problematic. Immunotherapeutic approaches aimed at eliminating minimal residual disease and enhancing the GVL effect may decrease relapse rates and improve overall survival. Because of the rarity of this disease in adults, every new patient should be entered in well-designed, peer-reviewed, investigational trial.     

Autologous hematopoietic cell transplantation for chronic myelogenous leukemia

Experimental and clinical evidence for persistence of polyclonal Philadelphia chromosome negative (Ph-) progenitors in chronic myelogenous leukemia (CML) patients has provided the rationale for autologous transplantation. Clinical trials of autologous transplantation suggest that this procedure can induce cytogenetic remissions in a subset of patients and may be associated with longer-than-expected patient survival. Most autologous transplant recipients, however, continue to have evidence of persistent leukemia. Recent reports indicating that it is possible to collect sufficient numbers of Ph- peripheral blood stem cells for autologous transplantation from most patients in complete cytogenetic remission on imatinib treatment have rekindled interest in autologous transplantation in CML. Additional approaches to eliminate residual disease in autografts and to sustain cytogenetic response after transplantation, however, will be required to achieve long-term restoration of Ph- hematopoiesis. Several promising methods to improve purging of the autograft and for more effective elimination of residual leukemia are being explored.     

Autologous bone marrow transplantation in acute leukemia

Autologous bone marrow transplantation (ABMT), which was developed in the past decade, is currently under investigation for the treatment of leukemias, lymphomas, and a few solid tumors. It consists of engrafting a patient, after ablative chemotherapy and/or total-body irradiation (TBI), with marrow taken from the patient at a propitious time in the history of the disease and usually cryopreserved. This technique has two major consequences: ABMT by reducing the length and variability of posttreatment aplasia can be considered a super hematologic support. It allows the use of chemotherapeutic agents and/or TBI at doses that surpass the dose for effecting the threshold of myelotoxicity. Therefore, a greater tumor cell kill can be expected at a reasonably low cost in terms of toxicity. In patients with acute leukemia (AL), however, the contribution of ABMT may go far beyond. In the initial trials (1974-79), the marrow of patients with AL was collected during complete remission and cryopreserved, with the idea of preserving "the remission status." At relapse this marrow was re-infused after high-dose chemotherapy and/or TBI, for achieving another complete remission. The result could be considered a chronologic chimera; the autograft, which had stem cells younger than those of the organism, reproduced, over the course of a few months or years, the evolution of the remission during which it was collected. As predicted, however, all patients who received this treatment eventually relapsed. For a more aggressive technique, some teams gave autografts to patients earlier, during remission, to allow ablative therapy in the consolidation mode; the whole procedure, including the pretransplant cytoreductive regimen, was modeled on that of allografting. Because allogeneic bone marrow transplantation currently offers the best chance of long-term survival but remains severely restricted, by age and availability of an HLA-identical donor, to less than 10% of the patients, ABMT may be considered an alternative source of stem cells to the other patients. In addition, ABMT avoids the risks of graft-versus-host disease with its associated immunosuppression. However, one major impediment to effective ABMT may be the persistence of leukemia cells in the marrow autograft, although the marrow was collected during earlier remission. The recent development of numerous techniques to cleanse the marrow prior to ABMT has considerably increased the possibility of ABMT becoming a major tool in the cure of leukemia. This report reviews the early data and essentially focuses on recent results of ABMT effected in or done in remission with use of cleansed and uncleansed marrow.     

A long-term follow-up analysis in adult acute myeloid leukemia patients after hematopoietic stem cell transplantation

AIMS AND BACKGROUND: Over the last 17 years, 119 adult acute myeloid leukemia patients have undergone hematopoietic stem cell transplantation at our Center. STUDY DESIGN: Seventy patients in first complete remission received hematopoietic stem cell transplantation (28 allogeneic and 42 autologous HSCT) as late intensification after conventional chemotherapy; 38 patients received allogeneic hematopoietic stem cell transplantation in a more advanced phase. A reference group was built up by collecting 40 acute myeloid leukemia patients who received high-dose cytosine arabinoside as late intensification and whose complete remission lasted more than 10 months. RESULTS: Results of the study led to conclude that an earlier timing of allogeneic hematopoietic stem cell transplantation can be recommended in order to treat patients who would otherwise suffer an early relapse. CONCLUSIONS: The outcome of autologous hematopoietic stem cell transplantation in patients not in first complete remission supports the possibility of achieving good quality second complete remissions and suggests that autografting may be a life-saving strategy in selected acute myeloid leukemia patients with advanced disease.     

Autologous hematopoietic stem cell transplantation for pediatric solid tumors

While advances in the treatment of pediatric cancers have increased cure rates, children with metastatic or recurrent solid tumors have a dismal prognosis despite initial transient responses to therapy. Autologous hematopoietic stem cell transplantation takes advantage of the steep dose–response relationship observed with many chemotherapeutic agents. While clearly demonstrated to improve outcomes in patients with metastatic neuroblastoma, autologous hematopoietic stem cell transplantation is also frequently used to treat patients with other high-risk diseases such as Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, Wilms’ tumor, retinoblastoma, germ cell tumors, lymphomas and brain tumors. Most published experience consists of retrospective, single-arm studies; randomized clinical trials are lacking, due in part to the rarity of pediatric cancers treatable by autologous hematopoietic stem cell transplantation. These published literature demonstrate that autologous hematopoietic stem cell transplantation results in most cases in equivalent or superior outcomes when compared with conventional therapies. However, patient heterogeneity, patient selection, graft characteristics and processing and the varied conditioning regimens are additional factors to consider. Since the inception of autologous hematopoietic stem cell transplantation, regimen-related toxicity has markedly decreased and the vast majority of treatment failures are now due to disease recurrence. Prospective clinical trials are needed to identify specific high-risk patient populations, with randomization (when possible) to compare outcomes of patients undergoing autologous hematopoietic stem cell transplantation with those receiving standard therapy. In addition, investigators need to better define the role of autologous hematopoietic stem cell transplantation in these solid tumors, particularly in combination with other therapeutic modalities such as immunotherapy and novel cell processing methodologies.     

Autologous bone marrow transplantation in acute leukemia.

Autologous bone marrow transplantation can induce long-term LFS in 20% to 40% of patients with relapsed acute leukemia and should be considered as salvage therapy for patients who lack an HLA-matched donor and for patients over 45. Adult ALL patients and children with ALL in extramedullary relapse beyond second CR should receive alloBMT if at all possible. The role of ABMT in acute leukemia patients in first CR remains unclear despite randomized trials (Table 2). Because protocol deviations, early relapse, and inappropriately high treatment-related mortality unequally affected the ABMT cohort, and because recent randomized trials have used old purging methodologies, it is not possible to conclude that ABMT is not beneficial. More recent studies show that most patients are able to proceed with the intended ABMT and that modern purging may be associated with a treatment-related mortality rate of less then 5%. Immunomodulation and graft engineering uniquely suited to autologous progenitor cells indicate that ABMT should continue to be studied in the management of acute leukemia.     

Acute leukemia of donor origin arising after stem cell transplantation for acute promyelocytic leukemia

We report a patient with PML/RARalpha-positive acute promyelocytic leukemia (APL) who developed PML/RARalpha-negative acute myeloid leukemia 37 months after allogeneic bone marrow (BMT) transplant for molecular relapse. Features of myelodysplasia were noted 11 months earlier, chimerism testing by analysis of short tandem repeats was consistent with development of myelodysplasia and acute leukemia within cells of donor origin. To our knowledge, this is the first report of donor cell leukemia following BMT for APL. We hypothesize that replicative stress may lead to the development of some cases of donor cell acute leukemia.