AMSA: in vivo log cell kill for leukemic clonogenic cells versus toxicity for normal hemopoietic stem cells in a rat model for human acute myelocytic leukemia (BNML)

The efficacy of AMSA was evaluated quantitatively in a rat model (BNML) relevant for human acute myelocytic leukemia. The ld₅₀ values observed in normal and leukemic Brown-Norway rats were 26.4 and 28.3 mg/kg respectively. In the higher dose ranges, the major cause of death was acute cardio-pulmonary toxicity. After single dose treatment, 20 mg AMSA/kg resulted in a surviving fraction of 5.5 × 10⁻² for normal pluripotent hemopoietic stem cells and 4.1 × 10⁻⁵ for in vivo clonogenic leukemic cells. With repeated administration of the drug amounting to the same total dose, even a 4 log difference in cell kill was observed between both cell populations. These studies provide quantitative information on the therapeutic index of AMSA and support the inclusion of this drug in first-line treatment regimens for acute myelocytic leukemia.     

Reduced intensity conditioning for allogeneic hematopoietic stem cell transplantation in myelodysplastic syndromes and acute myelogenous leukemia

PURPOSE OF REVIEW: The aim of this article is to summarize the outcome in recent studies of patients with acute myelogenous leukemia/myelodysplastic syndromes after reduced intensity conditioning for allogeneic stem cell transplantation. RECENT FINDINGS: Reduced intensity conditioning has demonstrated the capability to achieve engraftment and to decrease early nonrelapse mortality in older and unfit patients. Most large retrospective studies have demonstrated that reduced intensity conditioning regimens lead to a reduction of nonrelapse mortality in patients with acute myelogenous leukemia and myelodysplastic syndromes, but disease relapse is higher than with standard myeloablative conditioning regimens. Chronic graft-versus-host disease has emerged as one of the more powerful variables reducing relapses and improving overall and disease-free survival. The use of in-vivo T-cell depletion with alemtuzumab or antithymocyte globulin reduces acute graft-versus-host disease but appears to have no impact on survival. Hopefully, a new second generation of reduced intensity conditioning will study new strategies for reducing disease relapse with low nonrelapse mortality. SUMMARY: Allogeneic stem cell transplantation with reduced intensity conditioning allows many patients considered ineligible for standard myeloablative conditioning to benefit from this therapy. Research must now focus on designing new strategies for reducing the increased risk of disease relapse.     

Early lymphocyte recovery is a predictive factor for prolonged survival after autologous hematopoietic stem cell transplantation for acute myelogenous leukemia.

Absolute lymphocyte count (ALC) recovery correlates with survival after autologous hematopoietic stem cell transplantation (AHSCT) for patients with multiple myeloma, non-Hodgkin's lymphoma, and metastatic breast cancer. The role of ALC recovery in relationship to clinical outcome after AHSCT in patients with acute myelogenous leukemia is unknown. We analyzed 45 patients who underwent AHSCT at Mayo Clinic, Rochester, Minnesota between 1990 and 2000. The ALC threshold was selected at 500 cells/microl on day 15 post-AHSCT based on our previous studies. Thirty-two females and 13 males were included in the study with a median age of 45 years (range 12-75). The median follow-up was 14 months with a maximum of 129 months. The median overall and leukemia-free survival were significantly better for the 23 patients with ALC at day 15 > or =500 cells/microl compared with 22 patients with ALC <500 cells/microl (not yet reached vs 10 months, P < 0.0009; 105 vs 9 months, P < 0.0008, respectively). In conclusion, ALC > or =500 cells/microl on day 15 post-AHSCT is associated with better survival in acute myelogenous leukemia and requires further studies.     

Cytotoxicity of doxorubicin for normal hematopoietic and acute myeloid leukemia cells of the rat

Summary The dose response curves of doxorubicin for hematopoietic rat bone marrow cells were investigated and compared with the dose-response curves of doxorubicin for leukemia cells from bone marrow and spleen of rats inoculated with an acute myelocytic leukemia (BNML). Various assays were used to determine the cytotoxicity of doxorubicin. It was found that the inhibition of DNA synthesis by doxorubicin compared well with results obtained with in vivo assays for the determination of clonogenic hematopoietic (CFU-S) and leukemic (LCFU-S) cells. It was found that doxorubicin at concentrations ranging from 0.1–1.0 g · 10^-7 cells inhibits DNA synthesis of leukemic cells to 60% and that of hematopoietic cells to 90%. Higher doxorubicin concentrations further inhibit DNA synthesis of only hematopoietic cells. These results were confirmed with clonogenic assays. Pre-treatment with the S phase-specific drug arabinoside cytosine (ara-C) increased the efficacy of doxorubicin in vitro significantly. In view of the doxorubicin concentrations in bone marrow obtained in vivo (1 g · 10^-7 cells), it is concluded that dosage reduction may reduce toxicity with no concomitant decrease of antileukemic activity of doxorubicin.     

Marrow irradiation with high-dose 153Samarium-EDTMP followed by chemotherapy and hematopoietic stem cell infusion for acute myelogenous leukemia

In four patients, aged 15 - 20 years, with high-risk acute myeloid leukemia (AML), high-dose samarium 153-labelled ethylenediaminetetramethylenephosphonate (153Sm-EDTMP) was used for targeted marrow irradiation before preparative chemotherapy conditioning regimens and allogeneic (three patients) or autologous (one patient) hematopoietic stem cell transplantation. The dose of 153Sm-EDTMP was 703 MBq/kg (n = 1) or 1110 MBq/kg (n = 3). No side-effects occurred during the 30-min infusion of 153Sm-EDTMP. Samarium - melphalan regimens were given to three patients; one had 153Sm-EDTMP - busulfan + cyclophosphamide. Total body radioactivity was below the 133 MBq safe limit before infusion of stem cells (day 14 after 153Sm-EDTMP). No hemorrhagic cystitis, nephrotoxicity or serious infections occurred. Leukocyte engraftment (white blood cell count >0.5 x 10(9)/l) occurred between 12 and 23 days after stem cell infusion (mean of 17 days). Complete cytogenetic and morphologic remission of AML was evident on follow-up marrow aspirate and biopsy specimens from all patients. In two of the four study patients, the disease remains in complete remission and the patients have an excellent quality of life (Eastern Cooperative Oncology Group performance status 0; no medications) and no organ toxicity more than 2 years and more than 4 years, respectively, after their blood and bone marrow transplantations. Thus, in adolescents and adults, 153Sm-EDTMP may provide a relatively simple and effective means for using irradiation to eliminate AML within the marrow.     

Analysis of a chronic myelogenous leukemia patient vaccinated with leukemic dendritic cells following autologous peripheral blood stem cell transplantation.

Dendritic cells (DCs) are believed to be the most potent antigen-presenting cells and may be important in the induction of anti-leukemia specific T cell responses. In this preliminary clinical study, a patient with chronic phase chronic myelogenous leukemia (CML) was vaccinated with autologous leukemic DCs following autologous peripheral blood stem cell transplantation (PBSCT). In an in vitro study, leukemic DCs were generated using granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor-alpha, and interleukin-4 from granulocyte colony-stimulating factor (G-CSF)-mobilized PBSC fraction of this patient, and were found to be Ph1+, and to possess the morphologic and phenotypic characteristics of mature DCs. These cells could also elicit antigen specific immune responses, including a vigorous cytotoxicity specific to CML cells. In the clinical experiment, we obtained evidence that infused leukemic DCs could induce T cell clones expressing the same T cell receptor usage as a cytotoxic T cell line, suggesting that the immune repertoire includes tumor-reactive T cells. These cytotoxic T lymphocytes are activated in vivo. The vaccination of leukemic DC caused a decrease in the number of Ph1+ cells in the peripheral blood and bone marrow. These results indicate that the activity is an immunologically mediated phenomenon and vaccination therapy with leukemic DC following autologous PBSCT may be effective in treating CML.     

Allogeneic hematopoietic stem cell transplantation with non-myeloablative conditioning in patients with acute myelogenous leukemia eligible for conventional allografting: a prospective study

Using a non-myeloablative stem cell trasplantation (NST) program, 25 allografts were prospectively given to 24 patients with acute myelogenous leukemia (AML) eligible for conventional allografting; 2 individuals had secondary forms of AML. The median age of the patients was 35 years, with a range of 12 to 56. All patients engrafted; median time to achieve an absolute neutrophil count > 0.5 x 10(9)/1 was 12 days (range 0-26), whereas the median time to a platelet count > 20 x 10(9)/1 was 13 days (range 0-26). Patients developed mixed chimerism 15 to 100 (median 30) days after the allograft. The follow-up periods range between 33 and 2670 days (median 450). The median post-transplant overall survival of the patients has not been reached and is above 89 months, whereas the 683 days both overall and progression-free survival is 66%. In 14 grafts (56%) acute GVHD ensued; in 12 cases grades I-II and in 2 cases grade IV which was fatal in both. In 9/19 patients (47%) limited chronic GVHD developed. In 22 cases (88%), the procedure could be completed fully on an outpatient basis. The 100-day and the transplant-related mortality were both 8%. NST appears to be an effective additional therapeutic option for patients with AML in remission and a matched donor available.     

Effect of polar organic compounds on leukemic cells. Butyrate-induced partial remission of acute myelogenous leukemia in a child

Polar organic compounds, such as dimethylsulfoxide and butyric acid, are known to induce differentiation in Friend erythroleukemia cells as well as in other cell types. It has been found that many of the compounds that induce cellular differentiation, inhibit 3H-thymidine incorporation and induce cell damage when incubated with leukemic cells from patients with acute or chronic myelogenous or acute lymphocytic leukemia. These effects are time and dose dependent. Among the compounds tested, butyrate was the most potent. Parenteral administration of butyrate (500 mg/kg/day) for ten days to a child with acute myelogenous leukemia in relapse, and resistant to conventional therapy, resulted in elimination of myeloblasts from the peripheral blood, an increase in mature myeloid cells and a reduction in 3H-thymidine uptake by the patient's peripheral blood cells. Bone marrow myeloblasts were reduced from 70-80% to 20% following the course of intravenous butyrate. No impairment of liver or renal function and no coagulation abnormalities were observed during butyrate treatment. Organic agents that induce cell differentiation may provide additional reagents for the clinical management of selected cases of leukemia.     

Syngeneic hematopoietic stem cell transplantation for acute myeloid leukemia: a propensity score-matched analysis

The present study evaluated outcomes and prognostic factors in adult patients with acute myeloid leukemia (AML) after syngeneic hematopoietic stem cell transplantation (HSCT). Among patients in first complete remission (CR1), outcomes of syngeneic HSCT (Syn) were compared with those of autologous HSCT (Auto), allogeneic HSCT from human leukocyte antigen (HLA)-matched sibling donor (MSD), or allogeneic HSCT from HLA-matched unrelated donor (MUD). Among 11,866 patients receiving first HSCT, 26 in the Syn group were analyzed. The 5-year overall survival (OS) rate, the cumulative incidence of relapse, and the cumulative incidence of non-relapse mortality (NRM) were 47.8%, 59.6%, and 4.6%, respectively. The OS was significantly better in patients in CR1 (n = 13) than in patients in non-CR1 (P = 0.012). Furthermore, 39 patients in CR1 each were assigned to the Auto, MSD, and MUD groups using propensity score matching. The 5-year OS in the Syn (68.4%) was not significantly different from those in the Auto (55.9%, P = 0.265), MSD (62.4%, P = 0.419), or MUD (63.7%, P = 0.409) groups. A higher relapse in the Syn than in the MSD and MUD groups was offset by lower NRM. In summary, syngeneic HSCT might be an alternative option for AML patients in CR1.Subject terms: Acute myeloid leukaemia, Cancer immunotherapy     

Development of a cell kinetic approach to curative therapy of acute myelocytic leukemia in remission using the cell cycle-specific drug 1-beta-D-arabinofuranosylcytosine in a rat model

The timing of sequentially administered antineoplastic drugs is one determinant of toxicity and therapeutic benefit. We have conducted a series of studies with 1-beta-D-arabinofuranosylcytosine (ara-C) in the rat model (Lewis X brown Norway F1 hybrid rats bearing brown Norway myelocytic leukemia) for human acute myelocytic leukemia to examine the factors determining optimum timing of sequential administration of this cell cycle DNA synthesis phase-specific drug. Late-stage disease in this model is not curable with ara-C, but the maximum survival is achieved by rats given serial 2-day courses of ara-C 6 days apart. ara-C given in 2- or 4-day-interval sequences to rats with late-stage disease is more toxic and not more effective. However, Lewis X brown Norway F1 hybrid rats bearing brown Norway myelocytic leukemia in early complete remission are curable with ara-C given in optimum timed sequence. In these experiments, groups of rats in early complete remission were given a 2-day course of ara-C in every-8-hr s.c. injections, and then a second 2-day course was given after 2-, 4-, 6-, 8-, 10-, or 12-day intervals. The best cure rate of rats surviving toxicity was achieved when sequentially administered 2-day courses of ara-C were given at 2- to 4-day intervals to rats in early complete remission. In the minimal residual disease state, as in late-stage disease, 2- and 4-day-interval sequencing was the most toxic. No significant number of cures of minimal residual disease could be obtained by even the maximum tolerated dose of ara-C given in longer than 6-day-interval sequences or by various continuous or intermittent schedules. The fact that the Lewis X brown Norway F1 hybrid rats bearing brown Norway myelocytic leukemia, while relatively refractory to ara-C, are curable with this drug when used in optimum timed sequence in early remission is encouraging for similar clinical trials in humans and suggests some principles for the design of such trials.     

急性髓性白血病混合造血干细胞移植后DLI＋IL-2治疗的临床研究

目的：探讨急性髓性白血病（acute myeloid leukemia,AML）患者在接受自体外周血干细胞混合人类白细胞抗原（human leukocyte antigen,HLA）半相合异体骨髓移植（Mixed-HSCT）后,继予供体淋巴细胞输注＋白介素2（DLI＋IL-2）治疗的疗效。方法：对23例AML患者在完全缓解期采用TBI＋VEMAC预处理方案,实施Mixed-HSCT。造血恢复后给予DLI＋IL-2治疗1-8次。结果：所有患者均获得造血重建,中性粒细胞（ANC）≧0.5×109/L的中位时间为14（12-17）天,白细胞（WBC）≧4.0×108/L的中位时间为17（16-21）天。血小板（PLT）≧20×108/L的中位时间为21（19-23）天,PLT≧50×108/L的中位时间为25（24-27）天。＋16至＋21天时骨髓检查示恢复期骨髓象,无移植物抗宿主病（graft versus host disease,GVHD）发生,有6例形成混合嵌合体（46XX/46XY）。经过3年以上随访,存活15例,长期无病存活率（DFS）为65.2%。结论：Mixed-HSCT后应用DLI＋IL-2治疗对急性髓性白血病患者的长期无病生存有积极意义。     

急性髓性白血病混合造血干细胞移植后DLI+IL-2治疗的临床研究

目的:探讨急性髓性白血病(acute myeloid leukemia,AML)患者在接受自体外周血干细胞混合人类白细胞抗原(human leukocyte antigen,HLA)半相合异体骨髓移植(Mixed-HSCT)后,继予供体淋巴细胞输注+白介素2(DLI+IL-2)治疗的疗效。方法:对23例AML患者在完全缓解期采用TBI+VEMAC预处理方案,实施Mixed-HSCT。造血恢复后给予DLI+IL-2治疗1-8次。结果:所有患者均获得造血重建,中性粒细胞(ANC)≧0.5×109/L的中位时间为14(12-17)天,白细胞(WBC)≧4.0×108/L的中位时间为17(16-21)天。血小板(PLT)≧20×108/L的中位时间为21(19-23)天,PLT≧50×108/L的中位时间为25(24-27)天。+16至+21天时骨髓检查示恢复期骨髓象,无移植物抗宿主病(graft versus host disease,GVHD)发生,有6例形成混合嵌合体(46XX/46XY)。经过3年以上随访,存活15例,长期无病存活率(DFS)为65.2%。结论:Mixed-HSCT后应用DLI+IL-2治疗对急性髓性白血病患者的长期无病生存有积极意义。     

Close correlation of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate, an intracellular active metabolite, to the therapeutic efficacy of N(4)-behenoyl-1-beta-D-arabinofuranosylcytosine therapy for acute myelogenous leukemia.

N(4)-Behenoyl-1-beta-D-arabinofuranosylcytosine (BHAC), a prodrug of 1-beta-D-arabinofuranosylcytosine, is used effectively for the treatment of leukemia in Japan. BHAC therapy may be more effective if it is delivered in conjunction with monitoring of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP), the intracellular active metabolite of ara-C derived from BHAC. However, previous monitoring methods for ara-CTP were insufficiently sensitive. Here, using our new sensitive method, we evaluated the ara-CTP pharmacokinetics in relation to the therapeutic response in 11 acute myelogenous leukemia patients who received a 2-h infusion of BHAC (70 mg / m(2)) in combination remission induction therapy. ara-CTP could be monitored at levels under 1 mM. BHAC maintained effective levels of plasma ara-C and intracellular ara-CTP for a longer time, even compared with historical values of high-dose ara-C. The area under the concentration-time curve of ara-CTP was significantly greater in the patients with complete remission than in the patients without response. This greater amount of ara-CTP was attributed to the higher ara-CTP concentrations achieved in the responding patients. There was no apparent difference of plasma ara-C pharmacokinetics between the two groups. Thus, for the first time, the ara-CTP pharmacokinetics was evaluated in relation to the therapeutic effect of BHAC, and the importance of ara-CTP was proven. Administration of optimal BHAC therapy may require monitoring of the ara-CTP pharmacokinetics in each individual patient.     

Serum ICAM-1 concentrations following conventional dose consolidation chemotherapy for acute myeloid leukemia and after high dose chemotherapy with autologous haematopoietic stem cell rescue

Serum concentrations of soluble ICAM-1 (sICAM-1) were studied in patients with acute myeloid leukemia (AML) after conventional dose consolidation chemotherapy and in AML and in breast cancer patients following high dose chemotherapy with autologous haematopoietic stem cell transplantation. Investigations were carried out at 3 phases following treatment; during the chemotherapy induced neutropenic phase (neutrophil counts <0.5x109/l); during early recovery (neutrophil counts 0.5x109/l-1.0x109/l); and at recovery from neutropenia (neutrophil count 1.0x109/l-2.5x109/l). Results showed a significant elevation of serum levels of sICAM-1, above normal, in both groups of patients during the neutropenic phase. A further increase of sICAM-1 was found in conventional dose consolidation chemotherapy treated AML patients during the post-neutropenia recovery phases. By contrast, patients who were treated with high dose chemotherapy plus autologous haematopoietic stem cell transplantation showed a normalisation of sICAM-1 concentration during the post-neutropenic recovery phases. These findings suggest that recovery of neutrophil function do not coincide with recovery of neutrophil count following intensive chemotherapy while rapid recovery of neutrophil function occurred among patients who received autologous haematopoietic stem cell support.     

Lack of differential sensitivity of normal hematopoietic stem cells and murine lymphoblastic leukemic cells to a lysosomotropic agent, N-dodecyl morpholine

The effect of N-dodecyl morpholine (NDM), a lysosomotropic compound, on the clonogenic capacity of GK15, Sp2.0, Hb131, and L1210 lymphoblastic tumor cells and CFU-GM and CFU-S progenitor cells from DBA/2 mice was measured in order to evaluate the potential use of this compound for the purging of tumor-contaminated bone marrow (BM) in autologous BM transplantation. The growth of clonogenic tumor cells from all of the tested cell lines was inhibited with doses of NDM that also killed 100% CFU-GM and CFU-S, and no optimal dose could be found in this animal model to purge marrow while sparing sufficient stem cells to ensure engraftment in syngeneic BM transplantation.     

Loss of P-glycoprotein expression in hematopoietic stem cells does not improve responses to imatinib in a murine model of chronic myelogenous leukemia.

Selective inhibition of the BCR/ABL tyrosine kinase by imatinib has become a first-line therapy for chronic myelogenous leukemia (CML). However, BCR/ABL-positive progenitors often persist despite treatment, and relapse associated with resistance to imatinib has been described in many patients with advanced disease. Drug efflux by P-glycoprotein (P-gp), as well as point mutations in BCR/ABL oncoprotein, has been implicated in the mechanism of resistance to imatinib. In this study, we established a murine transplantation model of CML-like myeloproliferative disease using Mdr1a/1b-null mice and analyzed the effects of loss of P-gp on resistance to imatinib. We found that mice transplanted with Mdr1a/1b-null bone marrow (BM) that had been transduced with a BCR/ABL retroviral vector displayed similar responses to imatinib, compared with those transplanted with BCR/ABL-transduced wild-type BM. In the absence of P-gp, the incidence and latency of disease in secondary recipients was not changed in imatinib-treated mice, relative to wild-type controls. Furthermore, K562 cells engineered to overexpress P-gp remained sensitive to imatinib-induced growth inhibition and cell death. Together, our findings suggest that P-gp expression in hematopoietic stem cells does not significantly contribute to imatinib resistance in CML.     

The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stem cells.

Recent studies suggest that the population of malignant cells found in human acute myelogenous leukemia (AML) arises from a rare population of leukemic stem cells (LSCs). LSCs have been documented for nearly all AML subtypes and have been phenotypically described as CD34+/CD38- or CD34+/HLA-DR-. Given the potentially critical role of these primitive cells in perpetuating leukemic disease, we sought to further investigate their molecular and cellular characteristics. Flow cytometric studies using primary AML tissue showed that the interleukin-3 receptor alpha chain (IL-3Ralpha or CD123) was strongly expressed in CD34+/CD38- cells (98 +/- 2% positive) from 16 of 18 primary specimens. Conversely, normal bone marrow derived CD34+/CD38- cells showed virtually no detectable expression of the CD123 antigen. To assess the functional role of IL-3Ralpha positive cells, purified CD34+/CD123+ leukemia cells were transplanted into immune deficient NOD/SCID mice. These experiments showed that CD123+ cells were competent to establish and maintain leukemic populations in vivo. To begin to elucidate a biological role for CD123 in leukemia, primary AML samples were analyzed with respect to signal transduction activity in the MAPK, Akt, and Stat5 pathways. Phosphorylation was not detected in response to IL-3 stimulation, thereby suggesting CD123 is not active in conventional IL-3-mediated signaling. Collectively, these data indicate that CD123 represents a unique marker for primitive leukemic stem cells. Given the strong expression of this receptor on LSCs, we propose that targeting of CD123 may be a promising strategy for the preferential ablation of AML cells.     

WT1基因水平监测对造血干细胞移植后正常核型急性髓系白血病患者预后的意义

目的探讨WT1基因水平监测对造血干细胞移植(HSCT)后正常核型急性髓系白血病(AML)患者预后的意义。方法回顾性分析2009年7月至2017年3月于苏州大学附属第一医院接受HSCT的115例正常核型AML患者临床资料,采用实时荧光定量聚合酶链反应(RT-PCR)动态检测骨髓WT1基因表达水平。根据患者移植前WT1基因相对表达水平中位数,将115例患者分为两组(<中位数组和≥中位数组)进行生存分析。结果115例患者男性52例,女性63例,年龄(39±10)岁。初诊时中位白细胞计数20.45×10^9/L[(0.5~355.9)×10^9/L],骨髓中原幼细胞比例为0.60±0.28,WT1基因中位相对表达水平为87×10^4。中位随访时间24个月(3~79个月)。115例患者中19例患者复发,对缓解组(96例)及复发组分别进行随访,在移植后1、3、6、12个月进行骨髓穿刺监测WT1基因水平,发现复发组的WT1基因相对表达水平高于缓解组,其中移植后6个月[缓解组(187±50)×10^4,复发组(871±211)×10^4,t=2.519,P=0.014]、12个月[缓解组(51±9)×10^4,复发组(1 797±312)×10^4,t=4.000,P<0.05]的WT1基因相对表达水平差异有统计学意义。WT1基因相对表达水平<87×10^4组2年总生存(OS)率、无进展生存(PFS)率均高于WT1相对表达水平≥87×10^4组,复发率低于WT1相对表达水平≥87×10^4组,两组间比较差异均有统计学意义(均P<0.05)。多因素分析显示,患者移植后12个月的WT1基因水平是影响OS(HR=4.12,P=0.046)及PFS(HR=5.95,P=0.001)的独立因素。19例复发患者中位复发时间11个月(1~60个月)。复发患者在WT1基因相对表达水平明显增高时均首先减停免疫抑制剂,其中6例患者对干预无效,余13例患者中仅5例对干预有效。结论正常核型AML患者移植前的WT1基因表达水平与预后呈负相关。移植后12个月的WT1基因表达水平是影响患者生存的独立因素。复发患者的WT1基因表达水平较高,可对复发患者进行临床干预,较为有效。     

Kinetics of normal hemopoietic stem cells during leukemia growth before and after induction of a complete remission. Studies in a rat model for acute myelocytic leukemia (BNML)

During the invasion of leukemic cells of the rat acute myelocytic leukemia model BNML in the bone marrow, the number of normal bone marrow stem cells (CFU-S) decreased while simultaneously an increase of CFU-S in the leukemic spleen was observed. A small reduction in the tumor load by low dose cyclophosphamide treatment (10 mg/kg) caused a temporary CFU-S recovery in the bone marrow. After a therapeutic dose of cyclophosphamide (100 mg/kg), the CFU-S numbers in femur and spleen decreased to low levels but they rapidly increased immediately thereafter. In the spleen, however, the CFU-S increase halted when femoral CFU-S numbers reached normal levels. Splenectomy following cyclophosphamide treatment revealed that the splenic CFU-S population does not play a role in regeneration of hemopoiesis. During the subsequent leukemia relapse, CFU-S in the femur decreased again while spleen CFU-S tended to rise. It is concluded that the bone marrow CFU-S, which survive both the leukemia and the remission-induction treatment, and not the migrated, extramedullary localized stem cells are the major source for the restoration of normal hemopoiesis.     

异基因造血干细胞移植治疗急性T 淋巴细胞白血病和淋巴瘤：附50例临床报告

目的 探讨异基因造血干细胞移植（allogeneic hematopoietic stem cell transplantation,allo-HSCT）治疗急性T淋巴细胞白血病（T cell acute lymphoblastic leukemia,T-ALL）和急性T淋巴母细胞淋巴瘤（T cell acute lymphoblastic lymphoma, T-LBL）的疗效及预后。方法 回顾性分析2014—2019年于航天中心医院接受allo-HSCT的50例T-ALL/LBL患者的临床资料,分析其临床疗效、并发症及预后。结果 50例患者中男性41例,女性9例,中位年龄20.5岁（范围：9.0~63.0岁）;单倍体移植44例,脐血移植 2例,同胞全合移植 4例;T-ALL 40例,T-LBL 10例;移植前处于完全缓解（CR）状态16例,处于未完全缓解（非CR）状态34例。移植后,中位随访20个月（范围：1~84个月）,存活23例,死亡27例;移植后24个月的总生存率和无复发生存率分别为50.0%和44.0%,36个月的总生存率和无复发生存率分别为45.5%和40.0%。随访期间,共有20例患者复发,复发率为40.0%（20/50）。移植前获CR、无髓外病变、无中枢神经系统受累的患者预后较好,而移植前有无基因突变、不同预处理方案、有无急性/慢性GVHD患者的总生存期及无复发生存期组间比较差异无统计学意义（均P>0.05）。结论 在这项小样本、无对照的临床研究中,T-ALL/LBL患者在缓解期行allo-HSCT可能较挽救性移植的生存预后有所改善,其中复发为移植失败的主要原因。