Treosulfan–fludarabine–thiotepa conditioning before allogeneic haemopoietic stem cell transplantation for patients with advanced lympho‐proliferative disease. A single centre study

In recent years, with the aim of reducing transplant‐related mortality, new conditioning regimens have been explored in patients not eligible for conventional haemopoietic stem cell transplantation. In this setting, we investigated safety and feasibility of the treosulfan–fludarabine–thiotepa combination prior to allogeneic haemopoietic stem cell transplantation in patients with advanced lympho‐proliferative diseases and at high transplant risk. Twenty‐seven consecutive patients, median age 43 years (range 19–60), entered this study. All of them were affected by lympho‐proliferative disease in advanced phase and have been heavily pre‐treated. The median haemopoietic stem cell transplant co‐morbidity index was 1 (range 0–3). Twenty‐five patients had regular engraftment, while the remaining two patients were not evaluable for early deaths. Non‐haematological toxicity was limited. No patient developed veno‐occlusive disease. The estimated probability of overall survival and progression‐free survival with a median follow‐up of 40 months was 52% (95% confidence interval 33–73) and 50% (95% confidence interval 30–70) respectively. Six patients have relapsed; all of them were not in remission before transplantation. The treosulfan–fludarabine–thiotepa combination is a reduced toxicity but myeloablative regimen that can be proposed to patients not fitting criteria for conventional myeloablative transplant regimens. Longer follow‐up and prospective randomized studies are necessary to evaluate this regimen. Copyright © 2015 John Wiley & Sons, Ltd.     

非清除性异基因外周造血干细胞移植治疗难治复发性急性白血病

目的 :探讨非清除性异基因干细胞移植在难治性急性白血病治疗中的作用。方法 :3例难治性急性白血病 ,采用环胞霉素 A、环磷酰胺、阿糖胞苷或抗淋巴细胞球蛋白等作非清除性预处理的异基因外周造血干细胞移植。结果 :移植过程顺利 ,+ 10天～ + 14天中性粒细胞 >0 .5× 10 9/ L。 + 14天～ + 2 1天血象和骨髓象达 CR。 3例均达嵌合性植入。无移植物抗宿主病。 2例随访 116 d仍健在。 1例 + 5 6 d移植排斥及白血病复发。结论 :非清除性异基因干细胞移植简便、安全、并发症轻 ,对难治性急性白血病有较好疗效。     

Acute myeloid leukaemia presenting with mediastinal myeloid sarcoma: report of three cases and review of literature

Although myeloid sarcomas (MS) are frequently associated with acute myeloid leukaemia (AML), the occurrence of mediastinal MS is a much rarer event. The authors describe a distinct group of three AML patients with mediastinal MS and complex cytogenetics presenting at their centre over a 7-year period. Clinical features consistent with superior vena caval obstruction were noted at presentation in two of the three patients. Mediastinal mass was detected on routine chest radiography, and biopsies confirmed the diagnosis of MS. One patient relapsed after consolidation chemotherapy and died from progressive disease. Two patients underwent allogeneic haemopoietic stem cell transplant, but succumbed to transplant related complications. Review of mediastinal MS over the last 20 years shows that a significant proportion of patients have complex cytogenetic abnormalities and a poor long-term prognosis. Early and accurate diagnosis is essential and patients should be managed along the lines of high risk AML.     

Inotuzumab ozogamicin in the management of acute lymphoblastic leukaemia

Whilst most adult patients with acute lymphoblastic leukaemia will go into remission with standard induction chemotherapy, many will relapse. Response rates to standard salvage chemotherapy regimens are low and the outlook on relapse is very poor and associated with significant morbidity and mortality hence the need for newer targeted approaches. Inotuzumab ozogamicin (previously known as CMC-544) is an antibody-drug conjugate and consists of a monoclonal anti-CD22 antibody bound to calicheamicin. The target, CD22, is widely expressed on acute lymphoblastic leukaemia cells making it a potential therapeutic target. The calicheamicin is delivered intracellularly and causes leukaemia cell apoptosis. Overall response rates of 57% were observed in a Phase II study and the final results of a Phase III randomised controlled trial comparing this drug to the investigator choice ‘standard of care’ chemotherapy are eagerly awaited. Whilst initial results are promising, there have been concerns regarding liver toxicity and the incidence of veno-occlusive disease of the liver especially in patients who have previously received or go on to allogeneic stem cell transplant.     

Autologous Bone Marrow Transplantation for Hodgkin's Disease-A Five-Year Single Centre Experience

The results from 40 patients who have undergone autologous bone marrow transplantation (ABMT) for relapsed or refractory Hodgkin's disease between March 1988 and September 1992 have been analysed. In contrast to our results in patients with relapsed HD, our results in patients with refractory HD are comparatively poor. Conventional salvage chemotherapy also seems inappropriate in these patients and we therefore believe they should be offered high-dose chemotherapy before their disease becomes refractory to conventionally scheduled regimens. Peripheral blood stem cell (PBSC) transplant now offers an attractive alternative to ABMT and may replace both intensive salvage chemotherapy and ABMT as the optimum treatment for patients who fail to respond to conventional chemotherapy regimens.     

Clonal evolution of aplastic anaemia to myelodysplasia/acute myeloid leukaemia and paroxysmal nocturnal haemoglobinuria

Aplastic anaemia (AA) is a non-malignant haemopoietic disorder characterised by peripheral blood pancytopenia and a hypocellular bone marrow. Successful management of acquired AA including treatment with immunosuppressive agents, mainly antithymocyte globulin (ATG) and cyclosporin or allogeneic haemopoietic stem cell transplantation, has resulted in long-term survival of many patients. The later evolution of complicating clonal disorders such as paroxysmal nocturnal haemoglobinuria, myelodysplasia and acute myeloid leukaemia in patients treated with immunosuppressive therapy may be a manifestation of the natural history of the aplasia, the development of which may or may not be increased by immunosuppressive therapy. A persistent, profound deficiency and/or defect in the stem cell compartment, despite haematological recovery after immunosuppressive therapy, may create an unstable situation which predisposes to later clonal disorders. A review of the progression of AA to clonal disorders is now outlined.     

Haemopoietic stem-cell transplantation: recent progress and future promise

Transplantation of haemopoietic stem cells is an increasingly important approach in the management of malignant haematological disease. Recent developments in our understanding of stem-cell biology have profoundly influenced the practice of both autologous and allogeneic stem cell transplantation. The demonstration that cytokines, such as granulocyte colony-stimulating factor, mobilise large numbers of haemopoietic progenitors has resulted in the peripheral blood rather than the bone marrow becoming the preferred source of haemopoietic stem cells in autologous, and increasingly in allogeneic, stem-cell transplantation. This has substantially reduced the morbidity of autografting, so that disease relapse now represents the most important cause of treatment failure. Current efforts are aimed at reducing this risk, either by employing novel conditioning regimens or by tumour purging. With regard to allogeneic transplantation, there is a growing realisation of the importance of a graft-versus-leukaemia effect, and this has encouraged the use of strategies which optimise an immunologically-mediated antitumour effect. This, coupled with increased understanding of the biology of stem-cell engraftment, has resulted in the development of less toxic conditioning regimens, designed to allow the benefits of allografting to be extended to patients in whom this procedure is contraindicated.     

Haemopoietic stem cell: a new concept

It is generally accepted that morphologically recognizable bone marrow (BM) cells are derived from progenitor cells committed to a specific line of haematopoietic differentiation [51]. The origin and morphological identity of such progenitor cells is not yet known and the question, whether there is a single pluripotent haematopoietic stem cell (HSC) or a variety of stem cells each with a capacity of self-replication and maintenance is still unresolved [37]. Although progress has been made in segregating [43, 47, 49, 64] various progenitor cells from one another and functional assays [11, 17, 42] have significantly promoted the study of haemopoietic precursor cells, morphological investigations were less rewarding. Even after enrichment, the morphology of haemopoietic stem- and colony-forming cells only remained hypothetical, 'candidate stem cells' [3], because their precursor cell qualities could not be deduced from their morphology, but only retrospectively, and statistically from their function, i.e. in vitro colony-formation or in-vivo haemopoietic reconstitution from an enriched cell suspension [58]. We postulate from our studies on semi-thin sections of undecalcified BM from healthy human fetuses, normal adults and patients with acute myeloid leukaemia (AML) and chronic granulocytic leukaemia (CGL) that the endosteal cells are the precursors of all haematopoietic cells in the bone marrow and are also capable of transformation into either stromal (fibroblast-like cells) or bone-related cells (osteoblasts and osteoclasts).     

急性髓系白血病患者异基因骨髓移植后复发行同一供者二次移植一例

 目的　探索血缘HLA全相合骨髓造血干细胞移植（HSCT）后复发病例进行同一供者外周血造血干细胞二次移植（HSCT2）的可行性。方法　1例急性髓系白血病（M4）患者接受血缘HLA全相合供者骨髓移植后18个月复发,染色体检查提示为受者复发型。给予CY-TBI预处理后输注同一供者外周血HSCT2,同时降低预防移植物抗宿主病（GVHD）强度。结果　患者HSCT2后获得稳定植入,患者并发急性GVHD（肠道Ⅳ级,皮肤Ⅲ级）,完全缓解至+8月。结论　对于血缘造血干细胞供者移植后复发的患者,HSCT2同一供者HSCT是可行的。     

Viewpoint: What is the role of allogeneic haematopoietic cell transplantation in the era of reduced-intensity conditioning--is there still an upper age limit? A focus on myeloid neoplasia.

Allogeneic haematopoietic cell transplantation (HCT) is the most effective curative therapy in acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). Incidence of AML and MDS increases with age, peaking in the seventh decade. Despite improved Ara-C and anthracyclin-based chemotherapy regimens, the prognosis of AML in patients beyond 60 years of age is dismal. The introduction of peripheral blood-derived stem cell grafts into allogeneic HCT and the known anti-leukaemic effect of donor lymphocyte infusions paved the way for reduced-intensity conditioning (RIC) allogeneic stem-cell transplantation, which makes transplant in advanced age possible and significantly reduces transplant-related organ toxicity and mortality. The success of RIC HCT relies on the alloreactivity of the donor immune system and the graft-versus-leukaemia effect. We try to answer the following questions in this paper: who should receive RIC HCT? when and how should the transplant be performed? is there an upper age limit and what is the future of RIC HCT?     

Origin of marrow stromal cells and haemopoietic chimaerism following bone marrow transplantation determined by in situ hybridisation.

The origin and cell lineage of stromal cells in the bone marrow is uncertain. Whether a common stem cell exists for both haemopoietic and stromal cells or whether these cell lines arise from distinct stem cells is unknown. Using in situ hybridisation for detection of the Y chromosome, we have examined histological sections of bone marrow from seven patients who received marrow transplants from HLA-matched donors of the opposite sex. Stromal cells (adipocytes, fibroblasts, endothelial cells, osteoblasts and osteocytes) were identified in these recipients as being of host origin. This result is consistent with the concept of a distinct origin and separate cell lineage for cells of the haemopoietic and stromal systems. It also shows that engraftment of marrow stromal cell precursors does not occur and that host stromal cells survive conditioning regimens for marrow transplantation. With the exception of one case, with a markedly hypocellular marrow, mixed chimaerism was seen in haemopoietic cells, indicating that this is not a rare event after marrow transplantation.     

Allogeneic haemopoietic stem cell transplantation for multiple myeloma or plasma cell leukaemia using fractionated total body radiation and high-dose melphalan conditioning

We have evaluated the outcome of allogeneic haemopoietic stem cell transplantation for multiple myeloma using a conditioning regimen comprising fractionated total body irradiation and high-dose melphalan (110 mg/m2). The study comprised 25 patients (median age 49 years) who had been transplanted by either bone marrow (n = 13) or G-CSF mobilized peripheral blood stem cells (n = 12). Overall transplant-related mortality was 30% but was lower for patients < 50 years of age at transplant (21%). The main cause of treatment-related mortality was viral infection. Of the 19 patients evaluable post-transplant, 17 have so far achieved complete remissions. Currently, with a median follow-up of 3.4 years, 18 out of 25 patients are alive, of whom 15 are in continuing complete remission (CR) and 2 in second remission after suffering localized relapses, which were treated with radiotherapy and donor leucocyte infusions. Patients transplanted after 1 line of previous therapy, < 50 years of age and receiving peripheral blood stem cells (PBSC) rather than bone marrow (BM) had a superior outcome, although there was no statistically significant factor. We conclude that allogeneic transplantation should be considered as a potentially curative option for younger patients with myeloma and that the regimen using fractionated total body irradiation and melphalan has a high CR rate and a relatively low risk of treatment-related mortality, particularly in younger patients.     

Complete remission after autografting for chronic myeloid leukaemia

A previously untreated 31-yr old female with Ph-positive chronic myeloid leukaemia (CML) received busulphan and melphalan at high dosage followed by an autograft of peripheral blood stem cells collected 4 weeks earlier. Though recovering haemopoiesis was at first mainly Ph-positive, Ph-negative haemopoiesis predominated at 12 months and has persisted until the most recent study (24 months post-autograft). Her haemopoietic cells now show no rearrangement of the bcr gene, unlike the cells collected at diagnosis. Autografting carried out soon after diagnosis could be valuable for obtaining cytogenetic remissions in other patients with CML.     

Review of conditioning regimens for haplo-identical donor transplants using post-transplant cyclophosphamide in recipients of G-CSF mobilised peripheral stem cell

Haplo-identical transplant is being increasingly used in patients who do not have a readily available matched related or unrelated donor. Post-transplant cyclophosphamide’s use due to its simplicity and documented efficacy has made this approach readily employable across diverse transplant centres across the globe. The outcomes of regimens used for conditioning in recipients of bone marrow are at times in variance to that from more commonly employed G-CSF mobilised peripheral stem cell (PBSC). This review highlights various conditioning regimens used in PBSC recipients, with emphasis on toxicities, practicalities and transplant related outcomes of relapse, non-relapse mortality and graft versus host disease.     

Managing the toxicity of hematopoietic stem cell transplant

Hematopoietic stem cell transplant is an established treatment modality for a variety of neoplastic, hematologic, and immunologic disorders. Fueled in part by remarkable technologic advances, the number of both autologous and allogeneic transplants has increased dramatically over the past decade. Peripheral blood stem cells have largely replaced bone marrow as the source of hematopoietic progenitors in autologous transplants, and their use in the allogeneic setting has increased substantially. Less toxic transplants, in the form of non-myeloablative conditioning regimens, are being actively investigated, with the promise of expanding indications and age limits for allogeneic transplant. A successful global infrastructure allowing sharing of HLA-typing information has led to increased availability of non-sibling, HLA-matched, unrelated donor transplants for many patients who lack a suitable sibling donor. Finally, umbilical cord blood transplants are being investigated in both children and adult patients. The ability to transplant more individuals with broader indications owes much to a concurrent improvement in supportive care agents and techniques. Although regimen-related mortality and morbidity have decreased, stem cell transplants continue to pose multiple potential complications. A careful proactive assessment to identify, treat, and, hopefully, prevent adverse events is essential to a successful transplant. This review is intended to summarize some of the toxicities of hematopoietic stem cell transplant in a systematic, organ-based fashion and to review the treatment options available for each of these side effects.     

Advances in pediatric hematopoietic stem cell transplantation

Allogeneic and autologous hematopoietic stem cell transplantation (HSCT) has become a therapeutic option for an increasing number of patients with otherwise incurable leukemias, solid tumors, immunodeficiencies, hemoglobinopathies and metabolic diseases. For patients requiring an allogeneic transplant, the addition of unrelated cord blood units and partially matched family member donors as alternate stem cell sources has increased the chances that an appropriate donor can be identified. In addition, new approaches to stem cell graft engineering are yielding insights into potential cellular immune therapies, which may decrease the adverse effects of HSCT such as graft-versus-host disease (GVHD) and harness the alloimmune graft-versus-leukemia effect. Novel conditioning regimens, primarily reduced intensity and non-myeloablative regimens, allow patients with significant co-morbidities to undergo transplantation with reduced morbidity and mortality. Combinations of immune-modulatory cytokines and monoclonal antibodies with autologous and allogeneic transplantation are among the advances being explored in contemporary HSCT.     

Role for high-dose therapy with autologous hematopoietic stem cell support in Waldenstrom's macroglobulinemia

Despite effectiveness of standard chemotherapy regimens, complete responses are infrequent in Waldenstrom's macroglobulinemia (WM) and there are no cures. Since WM shares certain biological and clinical features with myeloma, including responsiveness to alkylating agents, evaluation of high-dose therapy (HDT) with transplant, which is effective in myeloma, is an obvious next step in an effort to achieve high response rates and improve survival. Due to the indolent nature of the disease and older patients with comorbidities, such evaluations have been infrequent in the past. We have evaluated the safety and efficacy of high-dose melphalan with peripheral blood stem cell (PBSC) support in eight patients between the ages of 45 and 69 years with WM. Adequate numbers of stem cells were collected in six patients; however, two patients with more extensive prior fludarabine therapy failed to collect adequate cells and required a second attempt at stem cell collection. Seven patients were treated with melphalan 200 mg/m(2), including two patients who received tandem transplants; one patient received melphalan 140 mg/m(2) with total body irradiation (TBI). There was no treatment-related mortality and toxicities were manageable. Recovery of bone marrow after transplant was prompt except in one patient with extensive prior use of fludarabine. All the eight patients achieved at least partial response (PR), including one complete response (CR). Five patients are alive and with out relapse (77+ to 6+ months post-transplant). Other investigators have reported similar experience suggesting safety and efficacy of HDT in WM. However, therapy with purine analogues leads to stem cell damage with decreased ability to collect adequate numbers of stem cells. This suggests that the PBSCs should preferably be procured prior to extensive use of purine analogues. Future strategies in WM will include a plan to evaluate the role of HDT along with biological agents, role of purging using rituximab, post-HDT maintenance strategies (including immunotherapy), and evaluation of nonmyeloablative regimens containing fludarabine to achieve higher response rates and improve survival.     

High dose chemotherapy with thiotepa, mitoxantrone and carboplatin (TMJ) followed by autologous stem cell support in 100 consecutive lymphoma patients in a single centre: analysis of efficacy, toxicity and prognostic factors

High dose chemotherapy with autologous stem cell transplant is often used in patients with Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) who either do not respond to, or relapse after conventional chemotherapy. There is no consensus on the "ideal" pretransplant conditioning regimen. In this study, we analyzed the results of 100 consecutive patients with HD and NHL who met our eligibility criteria and underwent autologous stem cell transplant at New York Medical College and Zalmen A. Arlin Cancer Institute. All patients received high dose chemotherapy with thiotepa, mitoxantrone and carboplatin (TMJ). One hundred patients, 37 with HD and 63 with NHL underwent autologous stem cell transplant using TMJ as a conditioning regimen. All patients with HD had chemo-sensitive relapse while 50 patients with NHL had chemo-sensitive relapse and 13 patients had first complete remission. The source of stem cells was bone marrow (18 patients), peripheral blood (50 patients) and both bone marrow and peripheral blood (32 patients). With a median follow up of 91 months (range 23 - 147 months), the median survival of patients with HD and NHL who underwent autologous stem cell transplant is 107 months and the 5 years disease free survival is 43%. Median survival of patients with HD and NHL is 87 and 107 months respectively. There were 4 transplant related deaths. Median survival of patients who had sensitive relapse at the time of transplant is 87 months while median survival has not been reached for patients who had first complete remission at the time of transplant. Multivariate analysis identified age > 35 years (P = 0.02) as a predictor for poor survival for the whole group as well as for patients with NHL (P = 0.04). TMJ is a safe and effective regimen when used as a part of autologous stem cell transplant for patients with HD and NHL.     

Long-term survival of patients with resistant lymphoma treated with tandem stem cell transplant

Dose-intensive chemotherapy with autologous stem cell support is commonly used in resistant/refractory cases of Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL). The purpose of this study was to evaluate the role of tandem transplantation in these patients. We used non cross-resistant conditioning regimens with thiotepa, mitoxantrone and carboplatin (TMJ) followed by ifosphamide, carboplatin and etoposide (ICE) with autologous stem cell rescue in an attempt to maximize dose intensity and achieve long-term remission. Seventy-six patients were included in this study. Twenty-nine patients with HD and 47 with NHL underwent autologous stem cell transplant using TMJ as the conditioning regimen for the first transplant. Of these, 49 patients proceeded to the second transplant using ICE as the conditioning regimen. In 57 patients, only peripheral blood cells were used and in 11 patients both bone marrow and peripheral stem cells were used. Twelve patients died due to treatment-related toxicity. On an intent to treat basis, 32.14% of patients with HD refractory to initial or subsequent therapy survived long term as opposed to 12.76% of patients with NHL. With a median follow-up of 83 months (range 25 - 110 months), the median disease-free survival of patients with HD was 7 months, as opposed to 2 months for patients with NHL. Multivariate analysis identified that patients with HD had a superior outcome if they were less than 35 years of age and did not have B symptoms. Dose-intensive chemotherapy with tandem transplantation is an option in patients with resistant/refractory lymphoma who have very limited treatment options and poor prognosis.