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REVIEW Update in Haematopoietic Stem Cell Transplantation Berteanu Cristina 1, Stoica Maria 2, Stoica GA 2, Cernea Daniela 2, Tănase Alina 3, Copotoiu Sanda-Maria 4, Brânzaniuc Klara 4, Azamfirei L 4,
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REVIEW Update in Haematopoietic Stem Cell Transplantation Berteanu Cristina 1, Stoica Maria 2, Stoica GA 2, Cernea Daniela 2, Tănase Alina 3, Copotoiu Sanda-Maria 4, Brânzaniuc Klara 4, Azamfirei L 4, Cirstoiu C 1, Rosin A 5 1 Fundeni Bone Marrow Transplant Center Fundeni 2 Bucharest Emergency University Hospital 3 University of Medicine and Pharmacy of Tîrgu Mureș 4 Craiova Emergency University Hospital 5 Bucharest Institute of Haematology The authors review the most important aspects of stem cell transplantation, starting with its objectives, general guidelines and specific issues in rare diseases, and series of complications arising from this complicated therapeutic procedure. Introduction In the 40 years since the first bone marrow transplant for the treatment of a patient suffering from a congenital immune deficiency, this therapeutic modality has become an option to be considered in the treatment of several haematologic, immunologic, metabolic and neoplastic disorders. This has been possible thanks to the progress in our knowledge of the major histocompatibility complex, the supportive therapy for patients with severe pancytopenia and the prevention and treatment of infections and other complications associated to transplantation [1]. Today, Haematopoietic Stem Cell Transplantation (HSCT), in its different modalities, is the treatment of choice in several malignant and non-malignant haematological diseases and one of the best options in many others [1]. By the 1980s, bone marrow transplantion had become a clear therapeutic option for many patients with haematological diseases. The progress made in our knowledge of the major histocompatibility complex, their progressive application to patients with neoplastic diseases in remission and with a better performance status, and the progress made in supportive measures (transfusions, prophylaxis and treatment of infections and other complications, growth factors), generalised the use of this therapeutic modality in patients with HLA-identical siblings or relatives. Only 25 30% of patients, however, had a donor of these characteristics and the falling birth rate in developed countries signalled that this percentage would not be improving in the future [1]. Objectives The original objective of HSCT was to replace neoplastic, absent or malfunctioning haematopoietic cells with normal cells from the bone marrow of a compatible donor. The patients underwent an intensive treatment, called conditioning regimen, based on high doses of chemotherapy and, occasionally, radiotherapy. The goals of this conditioning regimen were: 1. To eradicate the abnormal population of cells causing the disease. 2. To immunosuppress the patient to avoid the rejection of the donor's haematopoietic stem cell (HSC). 3. To make space in the bone marrow to facilitate the engraftment of donor's HSC. Nowadays we know that the conditioning treatment should not necessarily be intensive as a potent immunosuppression prevents graft rejection, facilitates the engraftment of the new HSC and permits the gradual replacement of the patient's haematopoiesis by that of the donor. This modality of transplantation is known as reduced intensity conditioning (RIC) HSCT [1,2,3]. Indications for HSCT A. Allogeneic HSCT As allogeneic HSCT involves the replacement of all body cells derived from the Haematopoietic Stem Cell, its use can be considered whenever the disease originates in one of these cells and can be cured if they are replaced by healthy ones. This is basically the case in: a. Haematological cancers: acute myeloblastic and lym- phoblastic leukaemia, chronic myeloid leukaemia and other myeloproliferative syndromes. Hodgkin's disease and non-hodgkin lymphomas, chronic lymphocytic leukaemia and other chronic lymphoproliferative diseases, multiple myeloma and myelodysplastic syndromes. b. Bone marrow failure syndromes: severe aplastic anaemia and paroxysmal nocturnal haemoglobinuria. c. Immune deficiencies: different types. d. Congenital haemopathies: thalassaemia, Wiskott- Aldrich syndrome and Fanconi's anaemia, among others. e. Other congenital diseases affecting cells derived from the HSC: Gaucher's disease, osteopetrosis, mucopolysaccharidosis, mucolipidosis and different lysosomal disorders [1]. B. Autologous HSCT It is the treatment of choice when medullar toxicity is the main constraint for an intensive therapy. As autologous Update in Haematopoietic Stem Cell Transplantation 385 HSCT always involves the risk of administering residual neoplastic cells present in the bone marrow or peripheral blood inoculum, their principal indications are diseases not affecting the bone marrow (Hodgkin's disease, non-hodgkin lymphomas and solid tumours). However, autologous HSCT is also used to intensify treatment in patients with acute myeloblastic or lymphoblastic leukaemia, multiple myeloma, chronic lymphocytic leukaemia or other chronic lymphoproliferative diseases when there is no compatible donor or in which allogeneic HSCT involves unacceptable toxicity. Autologous HSCT is also used for the treatment of primary amyloidosis, POEMS syndrome and autoimmune diseases refractory to conventional therapies (multiple sclerosis, systemic sclerosis, systemic erythematous lupus and rheumatoid arthritis, among others). To establish the indication of allogeneic or autologous HSCT, besides the underlying disease and the availability or not of a histocompatible donor, other fundamental aspects have to be assessed, including the patient's clinical status and the stage of the disease [1,4]. HSCT in Ph-Negative Acute Lymphoblastic Leukemia (ALL) The role of allogeneic HSCT in young patients with Ph- ALL is controversial. An older retrospective comparison in patients age from the International Bone Marrow Transplant Registry did not show any difference in leukemia-free survival between chemotherapy alone versus matched sibling HSCT in complete remission (CR)-1 [5]; the lower relapse rate in transplanted patients was offset by a higher treatment-related mortality. The LALA-94 study also did not find any difference in survival between standard-risk patients assigned to HSCT compared to chemotherapy alone [6]. In contrast, more recently the MRC/ ECOG study, using a similar design but larger numbers, found a 63% 5-year overall survival (OS) with HSCT versus 52% with chemotherapy (p = 0.02), in standard-risk adults up to age 35 [7]. The 10-year cumulative relapse rate was 24% in transplanted patients versus 49% in the chemotherapytreated group. For those considered at high risk, unrelated HSCT is another option, and recent data suggest the OS with closely matched unrelated donors is comparable to that of matched sibling transplants [8,9]. For adult patients who relapse, the prognosis is dismal, with failure rates approaching 100% using conventional therapy. HSCT is the only approach to date which has been capable of salvaging such patients. However, studies have shown that salvage rates are low; MRC/ECOG data showed a 5-year OS of 23% in patients undergoing matched sibling HSCT following relapse, and only 16% with unrelated HSCT [10]. Therefore, the identification of patients at higher risk of relapse in first CR is of major importance (9). HSCT in Ph-Positive ALL HSCT has been widely used for young patients in CR-1, and most studies demonstrate a survival advantage compared to chemotherapy alone [11,12,13]. A number of other questions remain, particularly the role of allogeneic HSCT in the era of TKIs. It appears that the use of tyrosine kinase inhibitor (TKIs), by increasing CR rates and duration, permits a higher proportion of patients to proceed to HSCT [14]. However, HSCT is still hampered by transplant-related mortality, in the range of 20 30% [15,9]. HSCT in Acute Myeloid Leukemia (AML) While achievement of CR is critical for long-term survival [16], the crucial decision in younger AML patients is selection of the post-remission therapy that provides the best chance of cure. The choice between consolidation chemotherapy and allogeneic hematopoietic stem cell transplant should be based on the risk of relapse, with autologous HSCT as an alternative to consolidation chemotherapy [17]. A recent systematic review and meta-analysis of prospective biologic assignment studies in 3638 patients younger than 60 with AML in CR1 by cytogenetic risk demonstrated a relapse and survival advantage for allohsct over other approaches (chemotherapy or autologous HSCT) in patients with intermediate-risk and unfavorable-risk, but not favorable-risk, karyotypes [18]. The estimated 5-year survival rates were 52% versus 45% and 31% versus 20% for patients with intermediate-risk and unfavorable-risk karyotypes, respectively. This study confirmed the findings of an earlier meta-analysis [19,17]. In patients without a matched sibling donor (MSD) who require transplant in CR1, HLA-matched unrelated donor (MUD) HSCT is another option. Introduction of highresolution allele-level HLA-typing allows better selection of unrelated donors (URD), and recent Center for International Blood and Marrow Transplant Research (CIBMTR) data showed that 47% of AML patients transplanted in CR1 in 2008 received URD allografts [20]. Recent studies have shown similar outcomes for MRD and MUD transplants in high-risk AML patients in first remission [17,21,22]. Another retrospective study of over 1000 patients years old in CR1 demonstrated the benefit of allohsct (61% Reduced-intensity conditioning (RIC), 39% myeloablative) compared to chemotherapy in terms of both relapse free survival (RFS) and overall survival (OS) [23]. Data supporting the role of allohsct in AML patients older than 70 years are limited, as few are referred for transplant evaluation due to concern about transplantrelated toxicity Thus, patients should not be excluded from consideration of allohsct solely based on age, and allohsct may be an attractive option for older AML patients with few comorbidities and good performance status (PS) [17]. 386 Berteanu Cristina et al. Table I. Advantages and disadvantages HSC sources [1] HAEMATOPOIETIC STEM CELLS FROM PERIPHERAL BLOOD Advantages Disadvantages 1. Less agressive method for the donor 2. Obtains more HSC 3. Faster haematopoietic recovery 4. Faster immunological recovery 1. Need to administer G-CSF to the donor 2. It could require a central line 3. Post-donation thrombocytopenia 4. High incidence of chronic GVHD HAEMATOPOIETIC STEM CELLS FROM UMBILICAL CORD BLOOD Advantages Disadvantages 1. Easy to obtain and harmless for the donor 2. Faster availability 3. Prior knowledge of cellularity 4. Progenitors with greater clonogenic activity 5. Less immunological reactivity (less GVHD) 1. Limited number of HSC 2. Impossibility of a second donation 3. Possible transmission of genetic diseases HSCT in non-hodgkin lymphoma Today, most patients with Hodgkin lymphoma (HL) achieve complete remission (CR) with first-line polychemotherapy with or without additional radiotherapy. More than 90% of patients with early favorable disease and over 80% of patients with early unfavorable or advanced disease obtain long-term tumor control with up-to-date regimens [24,25,26]. Thus 15% to 20% of patients cannot be cured, owing to either progressive disease during first-line therapy or later relapse after initial CR. Autologous stem cell transplantation has been evaluated as consolidation treatment after first-line therapy in high-risk patients and as salvage treatment in patients with progressive or relapsed HL [27]. HSCT in non-hodgkin lymphoma High-dose chemotherapy with autologous stem cell transplantation has an established role for treatment of patients with non-hodgkin lymphoma. This treatment is effective not only as a salvage treatment but also as a consolidative treatment [28,29,30,31]. However, a significant portion of patients underwent a relapse or a progression after autologous transplantation. Prognosis of these patients was generally poor and treatment option is limited [32]. To overcome this limitation, allogeneic stem cell transplantation has been performed. Allogeneic transplantation can possibly offer graft-versus-lymphoma effect [33]. Some patients could achieve complete remission after allogeneic transplantation and survive for a long time despite prior progression after autologous transplantation [34,35,36]. However, the role of allogeneic transplantation in these patients has not been clarified yet. Moreover, transplant related mortality (TRM) of allogeneic transplantation was substantial [34,36]. Therefore, development of a specific marker which can predict TRM can help improve treatment results of allogeneic transplantation in these patients. However, no useful clinical marker has yet been identified [28]. HSCT in multiple myeloma (MM) The administration of lethal doses of chemoradiation followed by marrow grafting was first applied to cancer therapy in the 1950s. The approach offered a means by which to intensify chemotherapy and thus increase tumoricidal activity, although at the cost of significant treatment-associated toxicities such as prolonged myelosuppression. After the seminal observation made by McElwain and colleagues [37], several groups pioneered high-dose therapy and autologous stem cell transplantation (ASCT) in patients with relapsed MM, demonstrating the activity of high-dose therapy in patients who had become resistant to conventional therapy. Although early studies of ASCT in MM often utilized preparative regimens consisting of chemotherapy and total body irradiation, strategies using chemotherapy alone proved to be as effective and were associated with less toxicity [38,39]. Bone marrow transplantation in patients with Diamond- Blackfan anemia Allo-HSCT is the only available curative treatment for Diamond-Blackfan anemia (DBA). The first successful allo-hsct treatment of DBA was reported in 1976 [40]. The patient died, but hematopoietic engraftment from donor bone marrow confirmed DBA as a transplantable disease. Since the initial case, more than 70 transplants, the majority of which involved from HLA-matched sibling donors, have been reported in the literature [41,42]. The outcomes of patients who undergo alternative donor stem cell transplantation are significantly inferior to those of HLAmatched sibling donors [42,43]. In one case the transplant was done primarily for DBA and it raises the interesting possibility of allo-hsct s being beneficial in the treatment of associated Duchenne muscular dystrophy (DMD), which is an otherwise incurable disease with 100% mortality. However, further clinical follow-up with serial muscle biopsies and molecular studies is needed to document the extent and duration of mixed chimerism in skeletal muscle in this patient. The purpose of this case report is to describe this interesting observation of a possible benefit in DMD and not to suggest HSCT as a modality of treatment until further studies show an unequivocal benefit, given the inherent risks associated with HSCT [43]. HSCT in Castleman s disease (CD) Castleman s disease (CD) encompasses a group of rare lymphoproliferative disorders. CD was originally described as a solitary lesion without systemic manifestations [44]. However, a subset of patients with systemic symptoms, polylymphadenopathy and multi-organ involvement were later recognized as multicentric CD (MCD). Our understanding of CD has greatly expanded since the identification of its association with human immunodeficiency virus and human herpes virus 8 infections [45]. MCD was found to be associated with the development of malignancies, especially Kaposi s sarcoma and lymphoma. A wide variety of therapeutic approaches have been attempted. Update in Haematopoietic Stem Cell Transplantation 387 However,there is no definitive gold standard treatment for MCD [46] (MCD) [47]. Source of the HSC For many years, HSCT were performed with HSC obtained by multiple aspirations of medullar blood from the posterior, and occasionally anterior, iliac crests [48]. Years later, it was seen that, in certain conditions, large quantities of HSC could temporarily move from the bone marrow to peripheral blood, from which they can be harvested through cytoapheresis methods. This mobilisation occurs both during recovery from the marrow aplasia that follows intensive chemotherapy and after the administration of haematopoietic growth factors, the most frequently used of which is the granulocyte colony stimulating factor (G-CSF) [49]. The third source of haematopoietic progenitors is umbilical cord blood (UCB). Immediately after childbirth, after cutting the umbilical cord, around 100 ml of blood very rich in HSC can be harvested from the umbilical cord and the placenta. With the widespread use of HSC from peripheral and cord blood, the term bone marrow transplantation ceased to make sense, and the current usage is HSCT [1]. Relapse of the underlying host leukemia is the most frequent cause of treatment failure after allogeneic stem cell transplantation (SCT). However, secondary neoplastic complications, including post-transplant lymphoproliferative disorders, therapy-related de novo malignancies and, less commonly, donor cell leukemia (DCL) [50], can also occur in SCT patients. Cord blood (CB) is now recognized as a feasible alternative source for SCT. More than 10,000 CB transplants (CBT) have been performed worldwide, and only ten cases of DCL following CBT have been reported [51]. HSCT from unrelated donors Different publications have confirmed that the outcomes of HSCT from unrelated donors are comparable to those obtained with HSCT from an HLA-identical sibling with regards to survival, transplant-related mortality and disease free survival [28 30]. This is thanks to the progress made in managing the complications presented by these patients and to the widespread search for donors with 10 out of 10 identities (loci A, B, C, DRB1 and DQB1) analysed by high resolution techniques. The only negative effect of this donor search policy is the logical reduction in the likelihood of finding one with such a degree of compatibility. The likelihood of finding a compatible donor with 8/8 or 10/10 identities in the first six months of the search is 40-50%, increasing by a further 10 15% if donors with a single incompatibility are accepted [52]. Given the lower alloreactivity of UCB progenitors, units can be accepted with some degree of incompatibility. Therefore, in spite of the progress made in HLA typing, the degree of unit-recipient identity continues to be evaluated only with loci A and B through low resolution and locus DRB1 through high resolution techniques. This is because the studies which have analysed whether more precise unit typing would improve the outcome have been unable to show a benefit [53]. All these characteristics of UCB mean that it is possible to find a unit with an acceptable degree of compatibility (6/6, 5/6 or 4/6) for most patients. The small volume of the UCB units, however, means that in spite of their high concentration in HSC, the total quantity is insufficient for recipients with a high body volume. The location of valid units is therefore relatively simple in children and low-weight adolescents and more difficult in adults. In view of the good outcomes obtained in children and adults [54,55] with umbilical cord blood HSCT, it is now mandatory to start all searches for unrelated donors at the same time among voluntary donor registries and cord blood banks, choosing one or the other, indistinctly, according to the degree of compatibility, cellularity and urgency of the procedure [1]. Complications of HSTC The complications of HSCT are the consequence of the repeated aggressions suffered by the patient's organs and tissues due to the direct toxicity of the conditioning treatment, the massive release of cytokines, repeated infections, immune phenomena occurring during allogeneic HSCT and the toxicit
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