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Unique hematopoietic stem cell transplantation system in China

HUANG, Xiao-jun

doi: 10.3760/cma.j.issn.0366-6999.2011.16.001

Peking University Institute of Hematology, Peking University People's Hospital, Beijing 100044, China (Huang XJ) (Tel: 86-10-88356000. Fax: 86-10-88324577. Email: This study was supported by the grants from the National Outstanding Young Scientist's Foundation of China (No. 30725038), the Program for Innovative Research Team in the University (No. IRT0702), the Leading Program of Clinical Faculty accredited by the Ministry of Health of China (2010-2012), and the National Natural Science Fundation of China (No. 30470753).

(Received May 25, 2011)

Edited by SUN Jing

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective, even the only option to cure patients with certain hematological diseases. HSCT has been applied in China for about 30 years, and great improvement has been made during the past decade. A distinctive HSCT system with Chinese characteristics has been gradually stylized, which manifested in the following aspects.

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The most encouraging outcome of related haploidentical HSCT in the world has been proved in the novel system without ex vivo T-depletion due to the contributions that Chinese doctors made.

In contrast to CD34+ selected related haplotype transplants,1 Peking University developed an unmanipulated haploidentical transplantation with granulocyte colony-stimulating factor (G-CSF) primed marrow grafts and G-CSF mobilized peripheral blood grafts (G-PB) as stem cell source. All patients achieved hematological recovery, which was not related to human leukocyte antigen (HLA) disparity. Comparable incidence of graft-versus-host disease (GVHD), transplantationrelated mortality (TRM) and the probability of survival were found among patients who received haplotype transplants and those from HLA identical sibling or unrelated HSCT.2 The probability of leukemia-free survival (LFS) was 70.7% and 55.9% for patients with AML and 59.7%, 24.8% for patients with ALL in the standard-risk group and high-risk group, respectively.3 And that for patients with chronic myeloid leukemia (CML) was 74.5%, 85.7%, 66.7% and 53.8% in chronic phase 1 (CP1), chronic phase 2 (CP2), accelerated phase (AP), and blast crisis (BC), respectively.4 Similar results were reported by the General Hospital of the Air Force, Suzhou group and the Third Military Medical University.5-7 Consequently, the total number of related haploidentical HSCT is increasing during the past four years, and now accounts for about 30% of that of whole allogeneic HSCT.

The establishment and advance of unmanipulated haploidentical transplantation system terminate the era of donor shortage, although clinical trials on a larger scale are needed to confirm its feasibility in more racial and ethnic groups of patients. Primary study on immune reconstitution has started8 and the modified donor lymphocyte infusion (DLI) system has been applied to the clinical field.9-11 Better understand of the mechanisms of immune reconstitution and the establishment of a safe and effective adoptive cellular immunotherapy may decrease the transplantation related mortality and recurrence of disease and result in improvement of the rate and quality of survival.

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It is recommended in the guidelines of USA and Europe that allo-HSCT should be considered after failure of therapy with the 2nd line tyrosinate kinase for patients with CML. However, China is still a developing country. On one hand, the expenses of the 2nd line tyrosine kinase inhibitors (TKIs) are not covered by the health insurance in most area. On the other hand, the clinical outcomes of HSCT for Chinese patients were extremely good. Therefore, the recommendation for transplantation indication and timing in Chinese CML Guideline is dissimilar, at least at present, to that in the guidelines of the National Comprehensive Cancer Network (NCCN) and external iliac lymph node (ELN).12

Basing on the monitoring of BCR-ABL transcripts level after transplantation, individualized intervention might decrease the rate of relapse to 3.9% and achieve leukemia-free survival (LFS) 89.2% at the 4th year. According to the current edition of Chinese CML Guideline, allo-HSCT is acceptable in the experienced transplantation centers for those patients who could not afford the expense of TKI therapy and have strong intention for transplants. Luo et al14 reported a 5-year survival of 66% for CML patients in AP and BC after myeloablative allogeneic HSCT. Peking University evaluated the merits of HSCT and imatinimb for CML patients in AP. The 6-year event-free survival (EFS) were 55.7% vs. 92.9% with imatimb versus allogeneic HSCT in patients with intermediate-risk (P=0.047). And that for high risk patients was 18.8% vs. 100.0% (P=0.006), respectively, which demonstrated significant survival advantage for allogeneic HSCT, compared to imatinimb, for patients with AP CML.15

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Adult patients with advanced leukemia after allo-HSCT have a poor prognosis because of a high rate of relapse and transplant-related mortality. The DLI efficacy has been proved, especially in CML patients, for the treatment of recurrence of disease. The toxicities related to DLI are occurrence of severe GVHD and pancytopenia. The data from Peking Universuty showed that rhG-CSF primed peripheral blood progenitor cell (GPBPC) harvests contained more CD34+ cells, CD14+ cells, Th2 cell and type II cytokines than no-primed peripheral lymphocyte harvests.16,17 This finding was adopted to the modified DLI studies to substitute DLI with steady-state lymphocyte. A comparative study showed that donor GPBPC infusion induced less severe acute GVHD compared with traditional DLI. No lasted pancytopenia was observed. For patients with hematological relapse after transplants, the donor GPBPC infusion group had better outcome.9 Short-term cyclosporine A (CSA)/methotrexate (MTX) further decreased GVHD incidence after GPBSCI. Acute GVHD occurred in 5 of 16 times of infusions, which were all controlled without GVHD related mortality. Analysis of clinical data showed that 2-4 weeks of administration of CSA or MTX after DLI reduced the incidence of DLI-associated acute GVHD without affecting relapse and survival.10 Based on these findings, a series of clinical studies were started to separate graft-versus-leukemia (GVL) effect from GVHD with modified DLI in patients with advanced leukemia.

It has been showed that interleukin-2 (IL-2) may enhance the activity of NK cells against leukemia. Peking University reported the study about prophylaxis of relapse with IL-2 after allo-HSCT in patients with high-risk leukemia. Fourteen of sixteen patients achieved leukemia-free survival with the median follow-up of 10 months after IL-2 administration and 16 months after transplantation.18

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A novel regimen for the therapy of GVHD was reported recently.19 Thirty-two patients with acute GVHD received low dose of MTX (10 mg intravenously or 15 mg orally every 3-7 days) and methylpredinisone (0.5 The overall response at day 28 after treatment was 75% (24 out of 32 patients). And that for GVHD involved organs was 88% (23/26) for skin, 75% (3/4) for liver, and 81% (9/11) for gut. Grade 3 toxicity occurred in three patients as cytopenia. These data suggested MTX in combination with a low dose of methylpredinisone was well-tolerated and effective when used as the first-line treatment for acute GVHD. Lai et al20 reported recently the efficacy of a new GVHD prophylaxis regimen, combining CSA and MTX with a short 30-day course of low dose (500 mg/d) mycophenolate mofetil. After allo-HSCT with identical sibling donors, the incidence of acute GVHD was 16% (9.5% for grades 2-4 GVHD, and 1% for grade 3 and 4 GVHD). The cumulative incidence of chronic GVHD was 53% with 28% extensive type. Chen et al21 reported heterogenetic bone marrow mesenchymal stem cells (MSCs) could suppress T cell activation. MSCs pretreatment might be useful in the prevention of GVHD in HLA-mismatched bone marrow transplantation.

The pathogenesis leading to late-onset hemorrhagic cystitis (LOHC) is still unknown. Although some data supposed virus infection or the allo-immune reactions upon reconstitution of donor hematopoiesis may contribute to the pathogenesis of LOHC, there was no definite evidence to support that. Recent data from Fu HX et al. showed that during LOHC, the proportions of CD19+CD5+ B lymphocytes increased significantly in some patients, who responded to corticosteroid, not to anti-viral therapy. Although prospective trials is needed to approve its efficacy, these primary data seem to suggest some evidence of the immune-related pathogenesis of LOHC and shine light to new therapeutics.

In summary, the unique hematopoietic stem cell transplantation system in China has been established with the efforts of generations of Chinese hematologists. It is characterized with broadened source of donors, practical selection for indications and improved transplantation techniques with acceptable expense for Chinese people. Translational research for transplantation is starting to break the ice. However, studies on the mechanisms related to various aspects of HSCT still lack of fruitful achievements. It should be remained unchanged that the distinctive HSCT system develops to meet the current domestic background. The enhancement of cooperation among transplants centers would be integrant to improve the quality of clinical trials, outcome of transplants and protocols in the field of allo-HSCT of China.

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