Mayo Clinic experience with allogeneic and syngeneic bone marrow transplantation, 1982 through 1990.

Between April 1982 and July 1990, 101 patients underwent allogeneic or syngeneic bone marrow transplantation at the Mayo Clinic. This patient population consisted of 30 with acute nonlymphocytic leukemia, 25 with acute lymphoblastic leukemia, 29 with chronic granulocytic leukemia, and 17 with other diseases (aplastic anemia in 7, myelodysplastic syndrome in 5, and lymphoma in 5). The results achieved in our patients who underwent transplantation in first complete remission of both acute nonlymphocytic leukemia and acute lymphoblastic leukemia compare favorably with previously reported results. Only 1 of 15 patients (7%) with acute nonlymphocytic leukemia and 2 of 8 patients (25%) with acute lymphoblastic leukemia who underwent transplantation in first complete remission had a relapse. Thus, we recommend early bone marrow transplantation during initial complete remission for patients with either of these disorders who have adverse prognostic factors. In contrast, of 12 patients with either acute nonlymphocytic leukemia or acute lymphoblastic leukemia who underwent transplantation during relapse, 11 died within 6 months. Therefore, such patients should be offered new experimental treatments. Our patients with chronic granulocytic leukemia fared better when they underwent transplantation early during the course of their disease rather than during the accelerated or blast phase. Prospective studies are needed to determine the best approach in these patients.     

Chronic granulocytic leukemia: long-term remission in a patient with familial sarcoidosis.

A patient is described who has chronic granulocytic leukemia (CGL) and familial sarcoidosis, and who has been in complete remission for six years after a single course of busulfan therapy. Her bone marrow Philadelphia chromosome persists and the leukocyte alkaline phosphatase activity remains subnormal. Leukocyte alkaline phosphatase levels in nine white patients with sarcoidosis were all found to be low. Bone marrow chromosomes from two patients with active sarcoidosis showed no Philadelphia chromosome, but one of them, and our patient with CGL, exhibited a pericentric inversion of chromosome 9.     

同一供者外周血单个核细胞输注治疗单倍相合骨髓移植后白血病复发

本研究探讨同一供者外周血单个核细胞输注（DMNCI）治疗单倍相合骨髓移植后白血病复发的疗效和安全性。3例单倍相合骨髓移植后白血病复发患者接受G-CSF动员的DMNCI治疗,其中例1和例2骨髓移植前分别为ph＋急性淋巴细胞性白血病伴中枢神经系统侵犯部分缓解及慢性粒细胞性白血病急性变部分缓解,在骨髓移植后这两例均血液学复发,各接受单次DMNCI,单个核细胞剂量分别为8.25×10^8/kg和5.24×10^8/kg;CD3^＋细胞剂量分别为1.87×10^8/kg和1.14×10^8/kg。第3例骨髓移植前为CML急性变,治疗后并达缓解。移植后分子水平复发,接受逐渐提高单次细胞数量的分次输注,首次DMNCI剂量为2.0×10^7/kg,CD3^＋细胞剂量为1.1×10^7/kg。同时观察3例患者输注后白血病缓解情况及并发症。结果显示,3例患者均出现不同疗效,2例血液学复发患者骨髓均暂时缓解,但分别于DMNCI后41、48天死于严重移植物抗宿主病（GVHD）、复发及衰竭。分子水平复发患者分次接受DMNCI,输注2次后达分子水平缓解,STR-PCR测定证实为供者基因型。3例均发生急性GVHD,2例接受单次剂量输注者发生Ⅳ度以上GVHD,1例接受分次输注患者发生Ⅰ度GVHD。3例均未发生明显骨髓抑制,分子水平缓解者随访半年无病生存。结论：DMNCI可能具有抗白血病作用,可用于单倍相合骨髓移植后白血病复发的治疗,对分子水平复发者的疗效较对血液学复发者好;输注MNC为×10^8/kg后GVHD严重。DMNCI起始剂量×10^7/kg并逐渐提高单次剂量的分次输注方法更为安全。     

Dasatinib: a tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia and philadelphia chromosome-positive acute lymphoblastic leukemia

BACKGROUND: The Philadelphia chromosome is formed from a translocation of genetic material involving human chromosomes 9 and 22. The resulting gene product, BCR-ABL, encodes for an abnormal tyrosine kinase (TK) that is a factor in the pathology of chronic myelogenous leukemia (CML). Use of targeted therapy that inhibits BCR-ABL kinase activity may lead to hematologic and cytogenetic responses in affected individuals. The oral TK inhibitor dasatinib was approved in 2006 for use in patients with CML or Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) who are unable to tolerate or have not responded to other treatments. OBJECTIVE: This paper reviews the available data on dasatinib, including its pharmacokinetic and pharmacodynamic properties, findings of in vitro and in vivo studies, adverse effects, and potential place in therapy. METHODS: Pertinent information was identified through searches of MEDLINE (1966-May 2007), EMBASE (1980-first quarter 2007), and International Pharmaceutical Abstracts (1970-May 2007) using the terms dasatinib, BMS-354825, chronic myelogenous leukemia, Sprycel, Philadelphia chromosome, and acute lymphoblastic leukemia. All clinical studies and case reports published at the time of the search were included in this review. RESULTS: Observed mutations in the amino acid sequence of BCR-ABL cause the failure of treatment with existing TK inhibitors. Dasatinib has shown in vitro and in vivo activity against BCR-ABL, including mutations that are resistant to other available TK inhibitors. Preliminary results are available from several noncomparative studies of dasatinib in patients who were unable to tolerate or were resistant to previous therapies. The 5 phases of START (SRC/ABL Tyrosine kinase inhibition Activity Research Trials of dasatinib) represent the largest and most comprehensive evaluation of dasatinib in the treatment of patients in all stages of CML or Philadelphia chromosome-positive ALL who had undergone previous treatment for leukemia. Dasatanib had the greatest benefit in patients in the chronic phase of CML, with complete hematologic responses in 90% of patients, 52% of whom achieved a major hematologic response. Compared with those in the chronic phase, patients in the accelerated phase or blast crisis of CML, or with Philadelphia chromosome-positive ALL had lower responses. In the START-R trial, which compared the response to dasatinib and high-dose imatinib (800 mg/d), both regimens had comparable ability to induce a complete hematologic response (95% and 93%, respectively), although more patients achieved a major cytogenetic response with dasatinib (32% vs 7%). Adverse effects include significant myelosuppression. Dasatinib may have the potential for use in the management of nonleukemic malignancies. CONCLUSIONS: Dasatinib has a wider spectrum of activity against a broader range of BCR-ABL forms than existing TK inhibitors. It has shown clinical benefit and tolerability in patients in all phases of CML, as well as in those with Philadelphia chromosome-positive ALL. Dasatinib illustrates the potential for targeted drug development based on an understanding of the genetic alterations leading to CML and the development of resistance to treatment.     

Transfusion of donor buffy coat cells in the treatment of persistent or recurrent malignancy after allogeneic bone marrow transplantation

BACKGROUND: Patients who experience relapse after allogeneic bone marrow transplantation have a poor prognosis. However, preclinical and clinical data have strongly suggested the existence of an immune- mediated anti-tumor effect of allogeneic bone marrow transplantation. This effect, termed graft-versus-leukemia, may be harnessed purposefully in patients with posttransplant relapses by the administration of immune cells obtained by leukapheresis of the original bone marrow donor. STUDY DESIGN AND METHODS: Thirteen patients with persistent or recurrent hematologic malignancy after HLA-matched sibling-donor allogeneic bone marrow transplantation were treated with transfusion of buffy coat cells collected from the original bone marrow donors. Mononuclear cell dose ranged from 1.18 to 4.28 × 10(8) per kg. Alpha-interferon (1.5-3 × 10(6) U/m2 3-5x/week) was given to seven patients. Patients were observed for the development of graft-versus- host disease and disease response. RESULTS: Three of five patients with chronic myelogenous leukemia had complete remissions. One of five patients with active acute leukemia attained complete remission. A sixth acute leukemia patient treated with buffy coat transfusion after the induction of remission with chemotherapy relapsed 12 months later. One patient with myeloma had a complete but transient response. A patient with Hodgkin's disease did not respond. Four patients remain in remission 4, 16, 17, and 29 months after attaining complete remission. Graft-versus-host disease occurred in eight patients, including all of those with a complete response. One patient developed transient pancytopenia. CONCLUSION: The transfusion of donor buffy coat cells has significant anti-tumor activity in patients with relapsed hematologic malignancy after allogeneic bone marrow transplantation. This effect is strongly associated with graft-versus-host disease.     

Ph阳性慢性粒细胞白血病患者伊马替尼治疗后的Ph阴性异常克隆演变

目的观察Ph阳性慢性粒细胞白血病(Ph+CML)患者在伊马替尼治疗后的Ph阴性异常克隆演变(Ph-CE)。方法对100例伊马替尼单药治疗有效的Ph+CML患者(其中干扰素治疗失败的慢性期患者54例、加速期患者37例、急变期患者9例)在治疗前及治疗后18～30个月内定期监测其细胞染色体核型变化(G显带方法)。结果11例(11%)患者于治疗后3～29个月一过性、间断或连续检出Ph-CE,其中慢性期患者5例、加速期患者5例、急变期患者1例。Ph-CE见于Ph+克隆开始减少时或在Ph+克隆消失之后,同期Ph-CE细胞的比例与Ph+细胞的比例呈负相关(P<0.05)。Ph-CE多为+8(5例,45.5%)和+Y(3例,27.3%),5例患者同时伴有Ph+细胞染色体附加异常。Ph-CE者中,7例获得主要遗传学缓解,9例获得完全血液学缓解。在观察期内,1例加速期患者在持续治疗20个月时进展至急变期。结论Ph+CML患者经伊马替尼治疗后获得不同程度遗传学缓解时约11%被检出Ph-CE,但在随访期内大多数患者未显示病情进展。     

慢性髓系白血病急变期分子遗传学研究进展

9号和22号染色体相互易位产生Ph染色体及BCR-ABL融合基因,几乎在所有慢性髓系白血病（CML）出现,BCR-ABL编码的蛋白具有持续增高的酪氨酸激酶活性,使白血病细胞异常增殖。急变期是CML的晚期,在此期间常常出现其它附加染色体和分子的改变。大量研究表明,BCR-ABL基因与其他失调的基因共同作用并异常激活下游的信号传导通路,促进了疾病的进展。酪氨酸激酶抑制剂伊马替尼对大多数慢性期CML患者治疗效果显著。IRIS5年的临床试验显示：用伊马替尼治疗的98%患者达血液学完全缓解,92%患者达主要细胞遗传学缓解,87%患者达完全细胞遗传学缓解。然而,仍有少数慢性期和大多数进展期患者用伊马替尼治疗疗效欠佳。在耐药机制的研究中发现ABL激酶区点突变与临床耐药关系密切。第二代酪氨酸激酶抑制剂可改善伊马替尼耐药,本文就急性变的分子机制、伊马替尼耐药等做一综述。     

伊马替尼治疗慢性粒细胞白血病加速期疗效评价

目的　评价伊马替尼治疗慢性粒细胞白血病 (CGL)加速期的有效性与安全性。方法　30例成人CGL加速期患者口服伊马替尼 4 0 0mg/d或 6 0 0mg/d ,持续 7～ 9个月。 结果　治疗 7～ 9个月内 ,血液学完全缓解 14例 (4 6 .7% ) ,骨髓缓解 10例 (33.3% ) ,回到慢性期 4例 (13.3% ) ,总有效率为 93.3%。白血病浸润症状或体征消失迅速。 8例在获血液学效应后 30～ 172d复发 ,6例伊马替尼剂量增加为 80 0mg/d继续治疗后 ,4例无效 ,2例再次回到慢性期 ,另 2例未予加量即退出方案。伊马替尼治疗前骨髓或外周血中原始细胞≥ 0 .15、有髓外白细胞浸润并且Hb <10 0 g/L、伊马替尼治疗后未曾获得过血液学完全缓解者复发率显著增高。治疗 3个月时 ,获得完全遗传学缓解 4例(14 .3% ) ,大部分遗传学缓解 2例 (7.1% ) ,遗传学有效应率为 2 1.4 %。轻度的非血液学不良反应发生普遍 ,多可耐受、可控制或可自行消退。严重的白细胞和 (或 )血小板减少占半数以上。结论　伊马替尼治疗CGL加速期安全、有效 ,除血细胞减少外 ,不良反应多可耐受。     

Molecular cytogenetic monitoring of chimerism and minimal residual disease in patient with chronic myeloid leukemia after allogenic and syngenic bone marrow transplantation

AIM: To study trends in restoration of normal and tumor hemopoiesis after transplantation of allogenic and syngenic hemopoietic cells. MATERIAL AND METHODS: The examination of bone marrow before transplantation and 1, 2, 3, 6, 9 months, 1, 2 and 3 years after bone marrow transplantation (BMT) was made in 25 patients with chronic myeloid leukemia (CML) after allogenic transplantation of the bone marrow (TBM) and 4 patients after syngenic TBM. The method of G-differential staining of chromosomes and fluorescent hybridization in situ (FISH) with DNA probe to centromeric sites X/Y of chromosomes and genes BCR/ABL was used. RESULTS: 56% of CML patients after allogenic BMT were in cytogenetic and clinicohematological remission, 16% developed early cytogenetic recurrence. Single metaphase with t(9;22) were identified in 28%; 14.3% developed late cytogenetic and hematological recurrence. In patients in posttransplantation remission there were from 0.1 to 5.8% cells of the host. The number of cells of the host and the number of BCR/ABL-positive cells correlated significantly. CONCLUSION: The results of 8-year monitoring of chimerism and minimal residual disease validate application of molecular-cytogenetic methods for assessing transplant condition.     

达沙替尼治疗伊马替尼耐药的BCR/ABL阳性白血病的临床研究

本研究评价达沙替尼治疗原发或继发伊马替尼耐药的BCR/ABL阳性白血病的疗效和安全性。对27例原发或继发伊马替尼耐药的慢性髓系白血病(CML)或Ph阳性急性淋巴细胞白血病(Ph+ALL)患者,给予达沙替尼100-140 mg/d口服治疗,评估疗效、总体生存和耐受情况。结果表明:27例伊马替尼耐药的BCR/ABL阳性白血病中位达沙替尼治疗时间8(1-66)个月,中位随访时间54(3-75)个月。27例接受达沙替尼治疗的患者中,88.8%获得完全血液学反应(CHR),44.4%获得主要细胞遗传学反应(mCyR),37%获得完全遗传学反应(CCyR),18.5%获得主要分子学反应(MMR)。伊马替尼耐药的进展期(CML-AP、CML-BC、骨髓复发Ph+ALL)患者接受达沙替尼治疗获CCyR率低于疾病稳定期(CML-CP、骨髓缓解Ph+ALL)患者(P=0.0377),且3-4级不良反应发生率明显增高。达沙替尼治疗后获得CCyR的患者生存期(OS)较未达CCyR者明显延长(63个月vs 9个月,P=0.0126)。达沙替尼治疗后最常见的3-4级不良反应包括血液学反应如血小板减少(51.8%)、中性粒细胞减少(48.1%)、贫血(33.3%)和非血液学反应如胸腔积液(18.5%)、肺部感染(18.5%)、心包积液(11.1%)。3-4级不良反应主要发生在疾病进展期时改服达沙替尼者,均发生于服药12个月内。结论:达沙替尼治疗伊马替尼耐药的BCR/ABL阳性白血病有效,且在疾病稳定期改服达沙替尼疗效和耐受性更好。     

Terminal transferase surveillance of remission bone marrows in childhood acute lymphoblastic leukemia: improved sensitivity with countercurrent centrifugal elutriation

In an attempt to better define hematologic remission and relapse in children with TdT positive acute lymphoblastic leukemia (ALL), 101 bone marrow (BM) aspirates were obtained from 74 pediatric patients. The mononuclear cell population of these specimens was isolated using countercurrent centrifugal elutriation (CCE) and characterized by an immunofluorescent terminal deoxynucleotidyl transferase (IF-TdT) assay. Twenty-two children with non-leukemic disorders had a median of 8% (range 0-34%) TdT positive mononuclear bone marrow cells. This was similar to values obtained for 25 children with ALL off therapy and in remission (median 10%, range 1-22%) and 16 children with ALL on continuous anti-leukemic therapy and in remission (median 7%, range 1-26%). Twenty-three BM samples were obtained from 11 children in early or high risk to relapse because of increased immature cells on a routine marrow examination or previous relapse(s). Samples from the early and high risk to relapse groups contained a median of 56% (range 25-80%) and 39% (range 25-72%) TdT positive cells. In contrast, the median percent marrow lymphoblasts identified using standard morphologic criteria for these 2 groups was 12.5% (range 9-23%) and 3% (range 0-5%), respectively. All high risk patients relapsed in their BM 1-4 1/2 months after these TdT determinations. Longitudinal studies in 4 patients at increased risk to relapse consistently demonstrated elevated percentages of TdT positive cells while morphologic surveillance was inadequate in establishing a clinical diagnosis of leukemic relapse. CCE in combination with an IF-TdT assay may enhance detection of recurrent and/or residual leukemia in BM samples from children with TdT positive ALL.     

Treatment of chronic myelogenous leukemia with interleukin-2: a phase II study in 21 patients

We designed a phase II study to assess the activity of recombinant interleukin-2 (rIL-2) in patients with chronic myelogenous leukemia (CML). Study population included 11 patients in the chronic phase of CML (6 in hematologic remission and 5 with active disease), 6 patients in the accelerated phase, and 4 in blastic phase of CML. Patients received three 5-day cycles administrated every other week. rIL-2 was given as intravenous bolus infusions of 8 x 10(6) IU/m2 three times a day during cycle 1 and twice a day during cycles 2 and 3. Response to rIL-2 was assessed on day 45. No hematologic response was achieved in the patients with evaluable disease. One patient in hematologic remission with rIL-2 achieved a major response (from 72% to 9% Ph+ metaphases), and two patients had some degree of reduction of Ph+ metaphases. Responses were short-lived (< 6 months), but two of these three patients achieved a new cytogenetic response with interferon given post-rIL-2. A significant immune activation was achieved with rIL-2 including a marked increase in CD3+/CD25+ cells, CD56+ cells, and in natural killer/lymphokine activated killer cell cytotoxic activity. These results confirm preclinical studies, which showed that IL-2 has antileukemic activity in CML. However, the responses observed were short lived and restricted to a subgroup of patients with low disease burden. This invites further studies testing its impact in situations of minimal disease or in combination with other cytokines.     

Bestatin treatment of myelodysplastic syndromes and chronic myelogenous leukemia

A high remission rate (56%) was achieved in a preliminary study using Bestatin in patients with myelodysplastic syndromes. In particular, 9 out of 13 patients (69%) in the high blast group achieved hematologic remission. After Bestatin treatment, intrinsic hematopoietic stem cell abnormalities as well as hematologic findings were markedly improved. The success of Bestatin therapy in MDS led us to investigate the clinical activity of Bestatin in CML. In the current study the busulfan and Bestatin combination therapy resulted in complete hematologic remission in all of the patients. The most exciting result was the suppression of the Philadelphia chromosomes among the responding patients. Complete cytogenetic response was obtained in 3 patients (21%), partial cytogenetic response in 1 (7%), and minor cytogenetic response in 5 (36%). In particular, the majority of early chronic phase CML patients achieved significant cytogenetic response with sustained Ph1 negativity. The results are very encouraging and warrant further studies.     

Chromosomal aneuploidy in leukemic blast crisis: a potential source of error in interpretation of bone marrow engraftment analysis by VNTR amplification.

BACKGROUND: Polymerase chain reaction (PCR) amplification of polymorphic microsatellite or minisatellite DNA markers has proven to be a fast, sensitive, and specific technique in post-transplantation monitoring of bone marrow engraftment, as well as early detection of residual disease and relapse. Deletion or amplification of chromosomal segments carrying marker loci, as can occur in leukemia and other hematologic malignancies, may result in loss or increased dosage of marker alleles. Examination of these marker alleles by PCR therefore may give aberrant results, which might lead to misinterpretation of bone marrow transplantation (BMT) engraftment studies. METHODS AND RESULTS: We report a case of chronic myelogenous leukemia treated by BMT. PCR amplification of the minisatellite at the apoB locus on chromosome 2 was used to monitor the donor bone marrow engraftment. The patient experienced relapse in blast crisis with a near-haploid karyotype with loss of recipient-specific apoB allele causing an aberrant PCR result for bone marrow engraftment that mimicked full donor engraftment. CONCLUSIONS: Loss or gain of polymorphic DNA markers because of chromosomal losses or gains in some hematologic malignancies may affect the interpretation of bone marrow engraftment studies by PCR. When choosing polymorphic markers for such studies, it is important to avoid those that will be affected by expected chromosomal alteration, if possible. In addition, any abberant post-transplantation typing should prompt further investigation to rule out the possibility of chromosomal aberration. Review of all pertinent laboratory studies is important to avoid misinterpretation of results from a single test for engraftment analysis.     

间期双色双融合荧光原位杂交监测慢性髓系白血病异基因造血干细胞移植后bcr/abl融合基因

本研究探讨bcr/abl双色双融合荧光原位杂交（DD-FISH）的敏感性及临床应用价值.对19例慢性髓细胞白血病（CML）异基因造血干细胞移植（allo-HSCT）后微小残留病灶（MRD）用DD-FISH进行监测,同时与常规细胞遗传学（CC）、逆转录-聚合酶链反应（RT-PCR）结果相比较.样本取自骨髓,少数来源于骨髓片或外周血.结果表明：14例CML患者在Allo-HSCT后CC显示持续正常供者核型,RT-PCR转为阴性,移植2月后均为完全供者嵌合（DC）,DD-FISH检测结果持续为阴性,平均随访11.25月,MRD无增加.1例CC及RT-PCR阴性,而性染色体FISH为混合嵌合,DD-FISH阳性,监测无MRD增加,临床未治疗,疾病稳定.3例骨髓复发患者的DD-FISH及性染色体FISH均提示MRD明显增加,RT-PCR转为阳性,却只有1例CC异常,供者淋巴细胞输注（DLI）及甲磺酸伊马替尼治疗后均为DC,DD-FISH阴性,RT-PCR阴性.1例骨活检证实髓外复发患者骨髓或外周血样本的DD-FISH、CC及PCR均阴性,供受者完全嵌合.结论：间期双色双融合FISH可应用于CML异基因造血干细胞移植后MRD的监测,其操作简易快速,灵敏度高,且骨髓或外周血均可采用.动态监测能及时发现扩大的白血病细胞克隆.     

Discontinuing chemoimmunotherapy in childhood acute lymphoblastic leukemia

We examined the results of discontinuing therapy in Japanese children with acute lymphoblastic leukemia. Of the 209 patients in chemoimmunotherapy study, 120 (57.4%) had all chemotherapy stopped after 3 years of complete remission, and 72 (34.4%) reached the point of discontinuing immunotherapy after 5 years of complete remission. Of the 120 children removed from chemotherapy, 14 (11.7%) have relapsed, mainly in the extramedullary sites (5 testis, 5 bone marrow, 3 central nervous system, 1 bone); relapses occurred 1-23 months after cessation of chemotherapy (median 11 months). Boys had a higher post-chemotherapy relapse rate than girls (0.21 vs. 0.08, P less than 0.05). None of the 72 children removed from immunotherapy have yet relapsed. Long-term remission and possibly cure can be expected in approximately one half of newly-diagnosed Japanese patients. Moreover, the active immunotherapy could be of benefit to elimination of bone marrow relapses after cessation of chemotherapy in children with acute lymphoblastic leukemia.     

初发慢性粒细胞白血病临床研究

目的：探讨初发慢性粒细胞白血病的临床特点、诊断和治疗。方法：回顾性分析1995-2000年收治血液科住院的55例初发患者。结果：55例患者以脾肿大、白细胞增多、外周血及骨髓中出现多量中性中幼、晚幼粒及杆状核粒细胞为特征，88.1%患者Ph染色体阳性，15例（占27.3%）有明显出血表现。结论：慢性粒细胞白血病是血液科的常见疾病，少数患者表现或骨髓涂片检查可不典型，治疗首选羟基脲。     

恶性血液病细胞端粒酶活性检测及其临床意义

目的　研究恶性血液病的端粒酶活性表达情况,探讨端粒酶活性检测对恶性血液病的临床意义。方 法　选取各类恶性血液病病例87例,以良性血液病和骨髓形态学正常的非血液病患者作为对照,采用改良 TRAP 银染法及亚利恩凝胶成像系统检测其骨髓标本内的端粒酶活性水平并随访。结果　良性血液病时端粒 酶阴性或低水平表达;慢性白血病慢性期、骨髓增生异常综合征(MDS)、多发性骨髓瘤(MM)骨髓端粒酶活性轻 度或中度升高,急性白血病和慢性白血病急变期端粒酶活性显著升高,完全缓解后活性水平下降,复发时端粒酶 活性又升高。同时端粒酶活性水平与预后相关,活性高者往往预后较差。结论　端粒酶活化与肿瘤的恶性转化 密切相关,可作为恶性血液病恶性克隆增殖的分子标志,有希望成为监测微量残留白血病的一个新指标。     

Donor lymphocyte infusion in myeloid disorders

A number of modalities including both pharmaceutical and cell-based treatments have long been tested and developed to prevent and treat relapses after allogeneic stem cell transplantation (allo-HSCT). The ability of donor T cells to recognize antigenic structures on leukemic cell surfaces and destroy them is a well-known fact. Based on this fact, the idea of using donor T cells to contribute to the development of adoptive immunotherapy has emerged. Donor lymphocytes are easy to obtain and donor lymphocyte infusions (DLI) have a simple rational while this treatment modality is an effective example of cellular therapy. The group of chronic myeloid leukemia patients who are more likely to benefit from DLI include: a) patients in the chronic phase of hematologic relapse and b) patients with molecular/cytogenetic relapse. DLI appear to be an appropriate treatment option to be used in combination with conventional chemotherapy or hypomethylating agents in the treatment of post-allo-HSCT relapse for acute myeloid leukemia and myelodysplastic syndrome, if:) the burden of tumor is low b) the relapse is at a molecular level rather than an overt hematologic relapse c) the patient has favorable cytogenetic characteristics d) time interval between transplantation and relapse is relatively longer (>5 months) e) response could be obtained after salvage therapies. In the event that minimal residual disease (MRD) or increasing mixed chimerism is detected, prompt administration of DLI for prophylactic purposes without waiting for a manifest relapse, was found to be effective in inducing a full donor chimerism and overcoming MRD and eventually preventing a manifest relapse.     

Is leukemic transformation of donor cells possible?

AIM: To genotype tumor cells in the recurrence of leukemia after allogenic transplantation of bone marrow (TBM). MATERIAL AND METHODS: Standard cytogenetics and fluorescent hybridization in situ (FISH) with a probe to the centrometic sites of X/Y chromosomes were used in examination of 2 patients with acute promyelocytic and acute non-differentiated leukemia after allogenic TBM from donors of the opposite gender. Bone marrow was studied 1, 2, 3, 6, 9, 12, 15, 17, 18 months after the transplantation. RESULTS: One of the patient in leukemia recurrence there were 72% cells with one X chromosome with unknown origin. 28% donor cells were with genotype XX. The primary archival cytological sample of the recipient's bone marrow 68% cells did not contain Y chromosome. Thus, the clone with Y loss is the recipient's clone and leukemia after transplantation developed from the recipient's cells. The other patient had only 8% dividing cells with her karyotype XX with translocation t(10;11) while 92% metaphases were donor's ones; the interphase cells ratio was 75% of host cells and 25% donor cells. This confirms leukemia origin from the recipient's cells. CONCLUSION: High sensitive quantitative method FISH indicates a true correlation between the host and donor cells and is a method of choice for genotyping leukemic cells in recurrence after transplantation of bone marrow. While standard caryotyping depends on mytotic activity of donor and host cell populations, use of only one cytogenetic test for determination of leukemia origin after TBM may provoke diagnostic errors.