Hematopoietic Stem Cell Transplantation for Patients with Chronic Myeloid Leukemia

OBJECTIVE To evaluate the effects of autologous and allogeneic hematopoietic stem cell transplantation (HSCT) for patients with chronic myeloid leukemia(CML).METHODS Fifty-seven patients with CML were treated by HSCT, including 8 cases treated with autologous transplantation purged in vivo and in vitro of minimal residual disease (MRD), 39 cases with related donor allogeneic HSCT (allo-HSCT) and 10 cases with unrelated donor alIo-HSCT. The conditioning regimen was a TBI (total-body irradiation) CY (cyclophosphamide, CTX) protocol in 32 patients, a modified BuCY (hydroxyurea, busulfan, Ara-C, CTX) protocal in 24 patients, and a MACC ( Melphalan, Ara-C, CTX and chlorethyl cyclohexyl nitrosourea ) protocol in one patient. Cyclosporine (CsA) and methotrexate (MTX) were used in patients with related-donor allo-HSCT, and CsA and MTX were added to mycophenolate mofetil (MMF) and antithymocyte globulin (ATG) in unrelated donor allo-HSCT for graft versus host disease (GVHD) prophylaxis. Otherwise, CsA was only used for GVHD prophylaxis in patients with accelerated phase (AP) and blast crisis (BC). The Kaplan-Meier survival analysis model was used to estimate the overall survival (OS) and the disease-free survival (DSF) at 5 years after transplantation.RESULTS Eight patients with autologous transplantation, except for 1 case who died of transplantation-related complications, obtained cytogenetic part or complete remission (CR) within 3 months after transplantation. One patient, who was in BC and obtained CR in hematology before transplantation, had been in molecular CR for 92 months after autologous transplantation. Among the 49 patients treated with alIo-HSCT, all obtained CR, except for one patient who died of hepatic veno-occlusive disease (VOD) and one who had not obtained CR. The incidence of infection and VOD was 33.3% and 7.0%, respectively, during transplantation. After transplantation the incidence of hemorrhagic cystitis (HC) and cytomegalovirus (CMV) interstitial pneumonia (IP) was 22.8% and 8.8%, respectively. VOD, HC and CMV IP did not occur in patients with autologous transplantation. The incidence of acute GVHD and the frequency of chronic GVHD was 41.0% and 48.6%, respectively, in patients with related and unrelated transplantation. The rate of relapse in patients with autologous and allogeneic transplantation was 57.1% and 12.8%, respectively. The DFS at 5 years after transplantation was 25.0% and 61.7%, respectively, in patients with autologous and related donor transplantation. The DFS at 5 years was 70.7% and 34.1%, respectively, in patients with CP (chronic phase) or AP and BC before transplantation.CONCLUSION AIIo-HSCT may have a higher clinical cure rate for CML patients with CP. The CsA MTX MMF ATG protocol is more effective for acute GVHD prophylaxis and can decrease the incidence and degree of GVHD in patients with unrelated donor transplantation, Autologous transplantation with purged bone marrow can prolong the survival time of CML patients and some may be cured with transplants of this type.     

Response to imatinib in patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia.

We studied 128 patients with chronic myeloid leukemia (CML) relapsing after allogeneic stem cell transplantation (SCT). Disease at the time of treatment with Imatinib was in chronic phase (CP) in 51 patients, accelerated phase (AP) in 31 and blastic crisis (BC) in 46. Of the 51 patients in CP, 14 were in cytogenetic and two in molecular relapses. The median interval between relapse and Imatinib therapy was 5 months (0-65). A total of 50 patients had failed treatment with donor lymphocyte infusions prior to Imatinib. The overall hemato-logical response rate was 84% (98% for patients relapsing in CP). The complete cytogenetic response (CCR) was 58% for patients in CP, 48% for AP and 22% for patients in BC. Complete molecular responses were obtained in 25 patients (26%), of whom 21 were in CP or AP. With a median follow-up of 9 months, the estimated 2-year survival for CP, AP and BC patients was 100, 86 and 12%, respectively. Out of 79 evaluable patients, 45 (57%) achieved full donor and 11 (14%) mixed chimerism after Imatinib. We conclude that Imatinib has significant activity against CML in relapse after allogeneic SCT. Durable cytogenetic and molecular remissions are obtainable in patients in CP.     

A 10-year median follow-up study after allogeneic stem cell transplantation for chronic myeloid leukemia in chronic phase from HLA-identical sibling donors.

We report long-term outcome in 102 patients with cCML transplanted from an HLA-identical sibling donor from 1982 to 1998. The conditioning regimen was based on cyclophosphamide associated with either total body irradiation (TBI) (37 patients) or with busulfan (63 patients). Graft-versus-host disease (GvHD) prophylaxis consisted of cyclosporin and methotrexate in the majority of the patients. Fifteen year overall survival was estimated at 53% (95% confidence interval (CI), 44-65) with a plateau after 2.5 years. Long-term survival was adversely affected by: longer time from chronic myeloid leukemia (CML) diagnosis to transplantation, older age at time of transplantation and GvHD (acute grade III-IV or chronic extensive). The main cause of death was infection, related to GvHD in 69% of patients. Splenectomy also significantly increased the risk of bacterial infection. 15-year relapse was estimated at 8% (95% CI, 0.1-14). Late malignancies occurred in seven patients, four of whom had an invasive cancer. Other frequent late complications included cataracts, psychological depression, osteonecrosis and hypothyroidism. These complications were more frequent following splenectomy, TBI and in patients with chronic extensive GvHD. We conclude that allogeneic transplantation with a related donor can cure more than half of CML patients in chronic phase, although physicians should be alert to long-term complications.     

Cytogenetic response to prior treatment with interferon-alpha is predictive for survival after allogeneic hematopoietic stem cell transplantation in chronic myeloid leukemia.

We investigated the impact of a cytogenetic response (CyR) to IFN prior to and at the time of allogeneic hematopoietic stem cell transplantation (HSCT) on transplant-related mortality (TRM), relapse rate and survival probability after HSCT in 162 transplanted patients with chronic myeloid leukemia. One-hundred-one patients (62.3%) achieved a CyR prior to HSCT. Survival probabilities were higher in patients, who achieved any CyR prior to HSCT than in patients without CyR (63.6 vs 49.2%: P = 0.019). Survival probabilities in patients, who achieved a major CyR were better than in patients with minimal and minor CyR or in patients with no CyR (69.4 vs 58.8% vs 49.2%: P = 0.040). TRM and survival of chronic phase patients without CyR at the time of HSCT were similar to that of patients transplanted in advanced phase. Both groups combined had an outcome inferior to patients with at least minimal CyR (TRM, Gray test: P = 0.016, survival, log-rank test: P = 0.002). Univariate and multivariate analyses identified CyR prior to or at HSCT as a strong and independently favorable prognostic factor. We therefore conclude that allogeneic HSCT in CyR should be investigated prospectively as an alternative treatment option in defined patient groups.     

Nonmyeloablative stem cell transplantation for chronic myeloid leukemia

Conventional myeloablative hematopoietic stem cell transplantation carries risks of morbidity and mortality from regimen-related toxicities that have restricted its use to relatively young patients in good medical condition. In nonmyeloablative allogeneic hematopoietic stem cell transplantation, enhanced immunosuppression rather than myeloablative cytotoxic conditioning has allowed the engraftment of allogeneic stem cells, with lower early transplant related mortality and morbidity. This approach shifts tumor eradication to the graft-versus-leukemia effect mediated by donor T lymphocytes. The development of nonmyeloablative transplantation has allowed the application of a potentially curative procedure to elderly or medically infirm patients who would not be able to tolerate high-dose conditioning regimens.     

Increased frequencies of CD4(+)CD25(high) T(regs) correlate with disease relapse after allogeneic stem cell transplantation for chronic myeloid leukemia.

The therapeutic efficacy of allogeneic hemopoietic stem cell transplantation (SCT) for chronic myeloid leukemia (CML) largely relies on the graft-versus-leukemia (GvL) effect exerted by donor T cells. CD4(+)CD25(high) regulatory T cells (T(regs)) have been shown to downregulate antitumor responses but their role on GvL has not been evaluated. We performed a cross-sectional study in which we enumerated and characterized CD4(+)CD25(high) T(regs) in the peripheral blood of CML patients undergoing allogeneic SCT. We documented higher frequencies of T(regs) in patients after transplant as compared to normal controls and newly diagnosed patients. The increment was particularly evident in patients who had received their SCT 18 months before. In vitro functional studies demonstrated that the T(regs) purified from SCT patients exhibited a more potent suppressive activity than T(regs) isolated from healthy volunteers. Patients in whom T(regs) numbers were higher than controls more than 18 months after SCT showed evidence of disease relapse. Although the increment in T(regs) might have an advantageous effect on graft rejection in the early phase post-transplant, our data suggest that T(regs) exert an inhibitory effect on GvL.     

Imatinib combined with myeloablative allogeneic hematopoietic stem cell transplantation for advanced phases of chronic myeloid leukemia

To evaluat the efficacy and safety of myeloablative allogeneic hematopoietic stem cell transplantation (allo-HSCT) combined with imatinib for advanced chronic myeloid leukemia (CML), 15 patients with accelerated phase (n = 6) or blast crisis (n = 9) were enrolled in this study. All the patients were conditioned with cyclophosphamide and busulfan, and treated with cyclosporin (CsA)/methotrexate (MTX)/mycophenolate mofetil (MMF) for graft-versus-host disease (GVHD) prophylaxis. Eleven of these 15 patients (73.3%) achieved complete hematologic response to pre-transplant imatinib, and six (40%) achieved a cytogenetic response. No engraftment failure was observed and the early transplant-related mortality was only 6.7%. Grade 3/4 acute GVHD occurred in 13.3% of patients. Chronic GVHD was observed in 61.5%, including 23.1% suffered from extensive disease. The 5-year estimated rates of relapse, transplant-related mortality and overall survival were 21.0 ± 10.8% 13.7 ± 10.8% and 66.0 ± 12.4%, respectively. Ten (66.7%) of 15 patients are alive with complete molecular remission, even after a median follow-up of 25 months after withdrawal of imatinib. In conclusion, even CML in advanced phases may have a satisfactory outcome after myeloablative allo-HSCT combined with imatinib, which may provide good remission prior to transplantation and reduce relapse risk, with low toxicity.     

Allogeneic hematopoietic stem cell transplantation for chronic myeloid leukemia

There never has been a more difficult time to advise patients newly diagnosed with chronic myeloid leukemia (CML). Until recently,the options comprised noncurative but relatively nontoxic chemotherapy or potentially curative allogeneic stem cell transplantation,with its attendant morbidity and mortality. There now is the additional option of the tyrosine kinase inhibitor imatinib mesylate that has been in clinical practice for almost 5 years. Although data are emerging regarding the efficacy of imatinib, solid evidence of any prolongation in survival will be delayed for several years. Future management of CML will continue to depend on a combination of approaches that use allografting and targeted drug therapy. The next decade undoubtedly will witness the introduction of a number of agents capable of inhibiting signal transduction pathways,perhaps controlling CML in cases of primary or acquired imatinib resistance. In the absence of long-term outcome data for imatinib,it remains reasonable to propose that young patients with newly diagnosed CML who have HLA-identical or well-matched unrelated donors should undergo allogeneic transplantation using a standard or nonmyeloablative conditioning regimen. Similarly,patients who fail to respond to imatinib should be rescued with a transplant strategy. The role of molecular monitoring in these two strategies cannot be underestimated.     

阿扎胞苷用于急性髓系白血病移植后维持治疗的临床疗效分析

  目的  探讨阿扎胞苷用于急性髓系白血病（acute myeloid leukemia,AML）患者异基因造血干细胞移植（allogeneic hematopoietic stem cell transplantation,allo-HSCT）后维持治疗的疗效以及安全性。  方法  回顾性分析2018年11月至2021年8月在空军军医大学第二附属医院造血干细胞移植中心接受allo-HSCT且在移植后使用阿扎胞苷维持治疗的30例AML患者的临床资料,观察患者移植后的微小残留病（minimal residual disease,MRD）转阴情况及移植物抗宿主病（graft-versus-host disease,GVHD）的发生情况,采用Kaplan-Meier法计算总体生存（overall survival,OS）率、无病生存（disease-free survival,DFS）率及累积复发率,并评估该方案的安全性。  结果  83.33%（25/30）的患者完成了4个周期的维持治疗,36.67%（11/30）的患者完成了全部6个周期的维持治疗。使用阿扎胞苷维持治疗后10例MRD阳性患者中的9例转为阴性,总体转阴率达90%。随访至2021年11月30日,30例患者的中位生存期为（33.7±1.8）个月,3年OS率为（83.2±9.9）%,3年DFS率为（81.3±9.4）%。至随访截止,共4例（13.33%）患者复发,3年累积复发率为（18.7±9.4）%。治疗中23.33%（7/30）的患者出现Ⅲ～Ⅳ度骨髓抑制。2例患者皮肤慢性移植物抗宿主病（chronic graft-versus-host disease,cGVHD）不同程度减轻,1例患者肝脏cGVHD加重,无患者出现新发GVHD的现象。  结论  应用阿扎胞苷进行AML患者allo-HSCT后的维持治疗,可降低复发率,改善患者生存期,且安全性和耐受性良好,不增加患者GVHD的发生率。      

Reduced-intensity conditioning and allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia

Acute myeloid leukemia (AML) is a hematologic malignancy with a peak incidence over the age of 55 years. AML of older patients is less curable with conventional chemotherapy, and, when it relapses, is almost uniformly fatal. Novel treatments hold the promise of improving the results of therapy, but have failed so far to show dramatic change in the prognosis. Allogeneic stem cell transplantation using traditional myeloablative preparative regimens is not easily tolerated by the elderly and/or frailer patient, and may lead to prohibitive treatment-related mortality rates. Most patients treated in the past were younger and devoid of comorbid clinical conditions. Novel reduced-intensity regimens made allogeneic transplants applicable to the elderly, providing the benefit of the graft-versus-leukemia effect to a larger number of patients in need. Here we review the indications for allogeneic transplants in AML and discuss reduced-intensity conditioning regimens.     

The outcome and characteristics of patients with relapsed adult T cell leukemia/lymphoma after allogeneic hematopoietic stem cell transplantation

Treatment options for patients with adult T cell leukemia/lymphoma (ATLL) who have relapsed disease after allogeneic hematopoietic stem cell transplantation (allo‐HSCT) are limited. To clarify which patients with ATLL are likely to benefit from these treatment options and to define patient populations for novel treatments, we performed a nationwide retrospective analysis of 252 Japanese patients who had relapsed ATLL after allo‐HSCT. Some long‐term survivors remained after tapering and withdrawal of immunosuppressive agents. Thirty‐six patients who received donor lymphocyte infusion had a better overall survival (OS) in comparison to those who did not [hazard ratio (HR), 0.63; 95% confidence interval (CI), 0.43‐0.93; P = .02], suggesting the efficacy of a graft‐versus‐ATLL (GvATLL) effect even after relapse. Multivariate analysis demonstrated that skin lesions at initial relapse of ATLL were independently associated with higher OS (HR, 0.41; 95% CI, 0.22‐0.74; P = .003), indicating that the skin is a susceptible target organ of GvATLL. This study suggested that enhancement of a GvATLL effect is a potential therapeutic option for relapsed disease after allo‐HSCT. Further investigations of incorporation of immune‐based approaches with new molecular target drugs into the therapeutic options of patients with ATLL before and after transplantation are warranted.     

Rare myeloid sarcoma/acute myeloid leukemia with adrenal mass after allogeneic mobilization peripheral blood stem cell transplantation

Myeloid sarcoma （MS） is a rare hematological neoplasm that develops either de novo or concurrently with acute myeloid leukemia （AML）. This neoplasm can also be an initial manifestation of relapse in a previously treated AML that is in remission. A 44-year-old male patient was diagnosed with testis MS in a local hospital in August 2010. After one month, bone marrow biopsy and aspiration confirmed the diagnosis ofAML. Allogeneic mobilization peripheral blood stem cell transplantation was performed, with the sister of the patient as donor, after complete remission （CR） was achieved by chemotherapy. Five months after treatment, an adrenal mass was detected by positron emission tomography-computed tomography （PET-CT）. Radiotherapy was performed for the localized mass after a multidisciplinary team （MDT） discussion. The patient is still alive as of May 2013, with no evidence of recurrent MS or leukemia.     

记忆CD8+T细胞与造血干细胞移植免疫

目的：观察5-氮-2＇-脱氧胞苷（5-aza-2＇-deoxycytidine，又称5-aza-CdR）对卵巢癌细胞SKOV3和3AO增殖凋亡及DNA错配基因hMLH1和hMLH2表达的影响。方法：以特异性甲基转移酶抑制剂5-aza-CdR0．5、5、50μmol／L处理人卵巢癌细胞SKOV3和3AO3d，继续常规培养7d后，采用MTT比色法观察细胞经药物处理前后的增殖活性，用流式细胞术分析5-aza-CdR对细胞凋亡影响，以半定量逆转录-聚合酶链反应（RT—PCR）检测细胞经5-aza-CdR处理前后DNA错配修复基因hMLH1和hMSH2 mRNA表达水平的改变。结果：人卵巢癌细胞SKOV3和3AO经5-aza-CdR处理后，与对照组比较，0．5、5、50μmol／L均能明显抑制肿瘤细胞生长，随着5-aza-CdR浓度增加，细胞增殖速度下降。SKOV3经5-aza-CdR0．5、5、50μmol／L处理后细胞的凋亡率分别为（10．59±1．57）％、（17．52±1．72）％、（34．10±1．45）％，3AO经0．5、5、50μmol/L5-aza-CdR处理后细胞的凋亡率分别为（11．11±2．21）％、（17．24±1．11）％、（26．53±2．00）％，与对照组相比均有统计学意义（P〈0．01）；且凋亡率与剂量成正相关（FSKOV3=227．6，PSKOV3〈0．01；F3AO=108．4，P3AO〈0．01）。经5-aza-CdR处理后的两株卵巢癌细胞中hMLH1和hMLH2的mRNA表达量有不同程度的增加（P〈0．01），且与药物存在剂量依赖性。结论：在人卵巢癌细胞株SKOV3和3AO中，5-aza-CdR可部分逆转hMLH1和hMLH2的失活，恢复其生长调控功能，抑制肿瘤细胞生长，并诱导细胞凋亡。