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Keywords:

  • alternative donor;
  • haploidentical;
  • hematopoietic stem cell transplantation;
  • unrelated.

Abstract

  1. Top of page
  2. Abstract
  3. Unrelated donor HSCT
  4. Related haploidentical donor HSCT
  5. Disclosures
  6. References

Hematopoietic stem cell transplantation (HSCT) is a curative therapy for many diseases such as hematological malignancies, bone marrow failure, immunodeficiency and other disorders. Unrelated donor and haploidentical family member are important alternative donors for the patients who need HSCT for otherwise incurable disease but without identical sibling donor. Since the first unrelated HSCT in 1974, the number and the clinical outcomes of unrelated transplant have been progressed significantly over time. More than 16 million adult unrelated donors have been registered worldwide. Near half of the donations from unrelated donors are international in recent years. HLA disparity between donor and recipient and disease status before transplant are key factors on survival after unrelated HSCT. In experienced centers, unrelated transplant has achieved comparable results with identical sibling HSCT. In addition, transplant from unrelated donor has advantage to cure some inherited disorders such as severe combined immunodeficiency disease, thalassaemia, Fanconi anemia, Familial Hemophagocytic Lymphohistiocytosis and so on. Haploidentical HSCT (haplo-HSCT) was initiated in 1981. The early results were poor mainly due to severe graft-versus-host disease (GVHD) and infections post-transplant. To reduce GVHD, T-cell depletion and mega dose CD34 + cells have been employed with certain success. Reduced intensity conditioning has further decreased early transplant-related mortality (TRM), but relapse rate is relatively high. Haplo-HSCT in our group with GIAC regimen has achieved comparable outcomes in terms of severe acute GVHD, chronic GVHD, relapse, TRM, disease-free survival (DFS), and overall survival (OS) with HLA-identical sibling transplant. New strategies have been applied in order to better manage complications post HSCT. As the third party cells, cord blood co-infusion has reduced severe acute GVHD and early TRM significantly. The majority of refractory cytomegalovirus, Epstein–Barr virus and aspergillus infections can be controlled with adoptive cellular therapy. Our clinical results from a large series of transplants have demonstrated that haplo-HSCT in sex-matched donor–recipient pair has survival advantage. Early disease stage before HSCT and high CD34 + cell infused but not age and HLA disparity have positive influence on DFS and OS. Therefore, it is better to consider haplo-HSCT for the patients who need urgent transplant to cure the diseases at earlier disease stage, when matched siblings or unrelated donors are not available. Among all haploidentical family members, sex-matched one should be the first choice as a donor for HSCT.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has more than 50-year history, which has become a curative therapy for many disorders, such as hematological malignancies, bone marrow failure, some immunodeficiency diseases and so on [1]. Although HLA identical sibling is the best donor for allo-HSCT, the chance to have a matched sibling donor is only 25% genetically. For the patients with otherwise incurable diseases but lack of matched sibling, unrelated adult donor and umbilical cord blood (CB), HLA haploidentical family members could be an alternative choice for allo-HSCT [2]. This article will focus on current status of HSCT from unrelated adult donor and haploidentical family member.

Unrelated donor HSCT

  1. Top of page
  2. Abstract
  3. Unrelated donor HSCT
  4. Related haploidentical donor HSCT
  5. Disclosures
  6. References

Unrelated donor HSCT (unrelated-HSCT) has been performed increasingly and its clinical outcomes have been improving over time since the first unrelated-HSCT for severe combined immunodeficiency disease (SCID) in 1974 [3]. Donor registries have grown rapidly worldwide. There are more than 7 million potential donors in National Marrow Donor Program (NMDP) database. By the end of 2010, China Marrow Donor Program (CMDP) has more than 1·2 million registered donors. Total over 17 million unrelated donors have been registered in the world. Near half of stem cell donations from unrelated donors are international in recent years.

According to 2010 annual report of Center for International Blood and Marrow Transplant Research (CIBMTR), more than 30 000 unrelated transplants have been registered by the end of 2008. A large study of unrelated-HSCT from NMDP has shown that HLA disparity between donor and recipient has significant impact on survival. For example, one-year survival rates are 52%, 43% and 33% in HLA 8/8, 7/8 and 6/8 matched transplants, respectively. Multivariate analysis has indicated that disease status before unrelated-HSCT has a greater influence on survival compared with HLA disparity. For the patients with early disease, the survival rates are 63%, 52% in HLA 8/8, 7/8 matched unrelated-HSCT, respectively. However, for the patients with intermediate disease, the survival rate is only 48% even with HLA 8/8 matched unrelated donor [4]. Therefore, it is important to perform unrelated-HSCT for the patients at early disease stage if no matched sibling donor is available.

In recent years, unrelated-HSCT has achieved similar survival compared with identical sibling transplant in experienced transplant centers. The clinical outcomes of a large series of unrelated-HSCT from CMDP showed that 2-year and 5-year overall survival (OS) rates were 65·2% and 56·9%. In our hospital, 5-year disease-free survival (DFS) and OS have achieved 62·8% and 71·1%, respectively. The third-party cells co-infusion in order to induce immune-tolerance has resulted in significantly lower acute graft-versus-host disease (GVHD) and better survival. Around 40% of cases who search for unrelated donor have received unrelated-HSCT finally in our hospital with median 60-day searching period.

In addition, unrelated-HSCT has advantage to cure some inherited disorders such as SCID, thalassemia, Fanconi anemia, Familial Hemophagocytic Lymphohistiocytosis and so on.

Related haploidentical donor HSCT

  1. Top of page
  2. Abstract
  3. Unrelated donor HSCT
  4. Related haploidentical donor HSCT
  5. Disclosures
  6. References

The first haploidentical HSCT (haplo-HSCT) was performed by Reisner to treat acute leukemia with T-cell depleted bone marrow (BM) in 1981 [5]. Haplo-HSCT has been performed increasingly since 1990s. Currently, haplo-HSCT has become an important alternative option for the patients who need urgent transplant but without matched either sibling or unrelated donor. The advantages of haplo-HSCT are easy and quick to find a donor for transplant because nearly all patients have at least one haploidentical family donor readily available, which may include their parents, siblings, children and other relatives.

The results of haplo-HSCT in early years were poor due to graft failure, severe GVHD and infections. Therefore, T-cell depletion has been employed to reduce GVHD, but it has resulted in higher incidences of engraftment failure and disease recurrence. To improve the outcome of haplo-HSCT, mega dose CD34 + cells have been infused with certain success [6]. The group in Johns Hopkins has given one or two doses of cyclophosphamide early after stem cell infusion and resulted in good engraftment and acceptable GVHD, but relapse and infection are main problems [7].

Lu has reported encouraging clinical outcomes of haplo-HSCT with non-T-cell depletion ex vivo and antithymocyte globulin (ATG)-containing conditioning regimen, GIAC protocol. With this protocol, haplo-HSCT has achieved comparable clinical outcomes with identical sibling transplant in terms of severe acute GVHD (aGVHD), chronic GVHD (cGVHD), relapse, transplant-related mortality (TRM), DFS and OS. In this haplo-HSCT setting, two-year DFS and OS are 64% and 71%, respectively [8, 9]. GIAC protocol contains four important components: G-CSF primed graft; intensified and prolonged immune-suppression during conditioning; use of ATG; combined use of BM and peripheral blood stem cell (PBSC) as grafts [10].

A series of new strategies have been applied by the same group in order to better manage the complications of haplo-HSCT such as GVHD, infection and relapse [11].

In a murine model, Zhang and Lu have first demonstrated that the third party cells could reduce aGVHD remarkably due to induction of immune-tolerance. Therefore, Lu’s group has employed unrelated CB as the third party cells in haplo-HSCT just before HSCT, which has resulted in significantly lower overall aGVHD, severe aGVHD and 100-day TRM [12].

Opportunistic infection is one of the main causes of death in haplo-HSCT. In our haplo-HSCT recipients, around 2/3 cases has cytomegalovirus (CMV) viraemia. Approximately 10% of them will develop CMV disease although pre-emptive anti-viral medicines are used [Lu Y, Wu T, Cao XY, et al, unpublished data]. For refractory CMV infection/disease, CMV-specific cytotoxic T-lymphocytes (CMV-CTL) have been administrated which has resulted in 53% complete response and 35% partial response [11]. Epstein–Barr virus (EBV) reactivation could develop life-threatening EBV disease and post-transplant lymphoproliferative disorders (PTLDs) after allo-HSCT, especially in alternative donor transplant. EBV disease and PTLDs respond poorly to anti-viral agents. Reactivation of EBV in our haplo-HSCT cohort is 15·5% and 60·6% of them has complete response to the pre-emptive anti-viral agents [13]. For refractory EBV infection/disease, EBV-specific cytotoxic T-lymphocytes (EBV-CTL) are given, which has achieved 67% complete response and 33% partial response [11]. In addition, CMV-CTL and EBV-CTL are also applied in the prevention of CMV or EBV infection/disease successfully [14]. For the patients with invasive aspergillosis and no response to anti-fungal medicines or intolerance to the side-effects of the drugs, aspergillus-specific cytotoxic T-lymphocytes have been administrated. As a result, 10% of patients have complete response, and 60% of them have partial response [11, 15].

Primary disease recurrence is another leading cause of death after HSCT, especially for high-risk or refractory/relapsed hematological malignancies. In a pilot clinical study, the patients who have early leukemia relapse and no response to donor lymphocyte infusion (DLI) or with active GVHD have received dendritic cell-primed cytokine-induced killer cells (DC-CIK). 83·3% of the patients in molecular or immunological recurrence have obtained complete remission (CR), while 50% of cases with early hematological relapse returned to CR [16]. We further to manage refractory/recurrent myeloid leukemia with salvaged allo-HSCT and prophylactic immunotherapy. The results are encouraging. The median blasts in BM in this series of patients were 36% (20–87%) prior to conditioning. With the median follow-up of 30 months, 3-year DFS and OS have achieved 60·2% and 62·6%, respectively [17].

When a patient needs urgent HSCT but without matched either sibling or unrelated donor, haploidentical family member would be an alternative choice. Each patient usually has several related haploidentical members who could be selected as a donor. To determine the principal of donor selection among all available related haploidentical candidates, the clinical outcomes of a large series of haplo-HSCT in our hospital are analyzed. The results showed that sex-matched donor–recipient pair had the best OS. HLA disparity, donor age and donor–recipient relationship (parents or sibling or children) have no significant impact on OS. However, disease status pre-HSCT and CD34 + cell dose infused were important factors on OS [18]. Patient age has no significant impact on clinical outcomes in haplo-HSCT [19].

HSCT has become important modality to cure hematological malignancies, BM failure and some inherited disorders. Unrelated donor and haploidentical family members are important alternative sources of stem cells. It is recommended when patient with otherwise incurable disease but without matched sibling donor, unrelated and related haploidentical HSCT should be performed at early disease stage. With improved clinical outcomes of unrelated and haploidentical HSCT, more and more patients will be cured by allo-HSCT.

References

  1. Top of page
  2. Abstract
  3. Unrelated donor HSCT
  4. Related haploidentical donor HSCT
  5. Disclosures
  6. References
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