CAT方案治疗难治性急性髓系白血病的临床观察

目的：初步观察CAT(环磷酰胺、阿糖胞苷、拓扑替康)方案对难治性急性髓系白血病(AML)的近期临床疗效并评价此方案的不良副作用。方法：选择8例难治性AML(原发难治性AML3例，AML伴多系形态发育异常，此前有MDS病史患者3例，慢性粒细胞白血病AML变2例)．应用CAT方案治疗，其中4例治疗1疗程，其余4例治疗2疗程。结果：1例在骨髓抑制期死于感染性休克．可评价疗效7例，1例达完全缓解(CR)，3例达部分缓解(PR)，1例CML急变患者经2疗程后回到慢性期，总有效率71．4％(5/7例)，中位生存期为6．5(0．3—22^ )个月。主要不良副作用为骨髓抑制。结论：CAT方案为高危MDS、加速／急变期CML和继发于MDS的AML患者的一个有效且毒性可耐受的治疗新方案。     

Abnormal regulation of the myc gene in myeloid leukemia

To study the regulation of expression of the myc protooncogene, cells from normal individuals and patients with acute myelogenous leukemia (AML), and chronic phase and blastic crisis of chronic myeloid leukemia (CML) cells were put in overnight culture in the presence or absence of fetal calf serum. Myc expression in normal marrow cells and chronic phase CML cells fell after culturein vitro. In contrast, myc expression was maintained or increased in a majority of the AML and blastic crisis CML specimens. These data demonstrate that the regulation of myc expression is disordered in many AML and blastic crisis specimens but not in chronic phase CML cells.     

Breakpoints in Philadelphia chromosome (Ph1)-positive leukemias

We studied chromosome 22 breakpoints in 24 Philadelphia (Ph1)-positive leukemias. Nineteen of 21 patients with chronic myelogenous leukemia (CML) possessed a chromosomal break within the 5.8 kilobase (kb) breakpoint cluster region (bcr). Furthermore, in one of three cases of acute lymphocytic leukemia (ALL), we found a chromosomal rearrangement in the bcr locus. No chromosomal rearrangements were found in two cases of CML and two cases of ALL using several restriction enzymes. The bcr rearrangement is highly specific for CML. Further analyses will be necessary to determine whether some cases without bcr rearrangement have another specific locus of rearrangement. Two of three cases of CML with blastic crisis had rearrangement of the immunoglobulin gene and T-cell receptor gene. One CML patient with blastic crisis, who achieved complete remission but relapsed thereafter, was found to have the same immunoglobulin gene rearrangement in the blastic crisis and relapse phases, suggesting that the same clone was involved in both crisis and relapse.     

白血病细胞端粒酶活性的研究

目的：研究白血病细胞端粒酶活性表达及其意义。方法：采用PCR-ELISA半定量方法测定端粒酶活性。结果：68.6％(59／86)急性白血病(AL)患者和80％(12／15)慢性粒细胞白血病急性变(CML-BP)患者表达高端粒酶活性；而慢性粒细胞白血病慢性期(CML-CP)患者，无一例表达高端粒酶活性。急性淋巴细胞白血病患者端粒酶活性高于急性髓性白血病患者，CML-BP端粒酶活性高于CML-CP，而CML-CP端粒酶活性则低于正常对照组。AL端粒酶活性水平与患者的性别、年龄无关，也与治疗后缓解率无关。结论：激活或上调端粒酶活性在大多数AL发生和慢性粒细胞白血病急性变过程中起着重要作用；端粒酶活性测定可鉴别CML-BP与CML-CP；端粒酶可能是一潜在的治疗白血病的新靶点。     

Successful treatment with chemotherapy and subsequent allogeneic bone marrow transplantation for myeloid blastic crisis of chronic myelogenous leukemia following advanced Hodgkin's disease

A 33-year-old man was treated with intensive chemotherapy for myeloid blastic crisis of chronic myelogenous leukemia (CML), which developed after radiotherapy and chemotherapy for Hodgkin's disease. After achieving a second chronic phase, he underwent allogeneic bone marrow transplantation (BMT). Despite many complications, 1 year after BMT the disease was in complete remission and the patient was in excellent condition. The incidence of CML following treatment for Hodgkin's disease is briefly discussed. This is the first report of prolonged complete remission for blastic crisis of CML, which developed after combined treatment for advanced Hodgkin's disease.     

Expression of nucleolar antigen p145 in bone marrow cells of patients with myeloid leukemias

The expression of a cell cycle-related nucleolar protein (p145) antigen was examined in the bone marrow aspirates of 45 individuals, three of whom had no malignant disease; 30 had a diagnosis of acute myeloid leukemia (AML), and 12 suffered from chronic myeloid leukemia (CML). While no evidence of p145 expression was found in the three normal bone marrow samples, it was noted to be the highest in patients with active leukemia, be they AML or blastic crisis of CML. There was a direct correlation between the percentage of blasts and the percentage of p145-positive cells in all patients. Double labeling with tritiated thymidine and p145 in AML patients with active leukemia showed that the majority of S-phase cells contained p145. Myeloblasts in both chronic phase and blastic crisis of CML expressed p145. Nine of 12 AML patients studied during remission had less than 5% p145-positive cells, but three showed 11%, 16%, and 33% positive cells. Since functionally/morphologically, these marrows were normal, the appearance of p145 may indicate a proliferative abnormality preceding maturation arrest and development of relapse. Thus we conclude that p145 is more commonly associated with immature cells and may serve as an early indicator of relapse in AML, but requires further study with larger numbers of patients.     

Timed-sequential chemotherapy with concomitant granulocyte colony-stimulating factor for newly diagnosed de novo acute myelogenous leukemia.

EMA, consisting of etoposide, mitoxantrone, and cytarabine, is a timed-sequential chemotherapy (TSC) regimen and an efficacious option for induction treatment of acute myelogenous leukemia (AML). Hematopoietic growth factors (HGFs) have been shown to recruit leukemic blasts into cell cycle. We postulated the addition of granulocyte colony-stimulating factor (G-CSF) to EMA (EMA-G) might enhance treatment efficacy. EMA-G consisted of mitoxantrone on days 1-3, cytarabine on days 1-3 and 8-10, etoposide on days 8-10, and G-CSF from day 4 until absolute neutrophil count (ANC) >500/microl. In total, 28 patients were enrolled. All patients had newly diagnosed de novo AML. The median age was 42 years. Of the 27 patients with cytogenetic analysis, six had favorable karyotype, 18 intermediate karyotype, and three unfavorable karyotype. The median follow-up was 37.5 months. The median time for both ANC recovery and last platelet transfusion was 26 days. The toxicities associated with this regimen were no more than those expected with the standard chemotherapy. In all, 24 (86%) patients achieved complete remission (CR), three (11%) patients had no response, and one patient died within 24 h of induction therapy before response could be evaluated. Of the 24 patients who achieved CR, 22 received high-dose cytosine arabinoside and two received allogeneic bone marrow transplant as initial postremission therapy. For the whole cohort, the estimated 3-year survival rate was 67%. The median relapse-free survival was 30.5 months. We conclude that EMA-G regimen is a safe regimen and administration of G-CSF during and after induction treatment is not associated with prolongation of marrow aplasia or acceleration of leukemia relapse. It is efficacious for induction therapy for newly diagnosed de novo AML. A high CR rate can be achieved with only one course of this chemotherapy.     

Efficacy and safety of gemtuzumab ozogamicin in patients with poor-prognosis acute myeloid leukemia

The objective of this work was to determine the safety and efficacy of gemtuzumab ozogamicin in patients with poor prognosis acute myeloid leukemia (AML). Patients with the following diagnoses/characteristics were treated with 1-3 infusions of gemtuzumab ozogamicin at a dose of 9 mg/m2: (1) relapse of AML < or = 6 months of first complete remission (CR); (2) AML refractory to chemotherapy at initial induction or at first relapse; (3) AML in second or greater relapse; (4) myeloid blast crisis of chronic myeloid leukemia (CML); (5) untreated patients > or = 70 years or > or = 55 years with abnormal cytogenetics (excluding inv 16, t(15;17) and t(8;21)) and/or an antecedent hematologic disorder; (6) refractory anemia with excess blasts in transformation (RAEBT). Forty-three patients, ages 19-84 (mean 62), were treated, including 7 patients with untreated AML age > 70 years, 2 with untreated RAEBT, 14 with AML first salvage (first remission 0-6 months), 15 with AML > or = second salvage and 14 with myeloid blast phase of CML. The overall response rate was 14%, with 4/43 (9%) patients achieving CR and 2/43 (5%) achieving CR without platelet recovery. The most significant toxicity was neutropenic fever, which occurred in 84% of patients. In conclusion, in patients with relapsed/refractory AML, gemtuzumab ozogamicin has a comparable response rate to single-agent chemotherapy and may offer a more favorable toxicity profile.     

High levels of 5′-nucleotidase activity in blastic chronic myelogenous leukemia with common all-antigen

The activity of 5′-nucleotidase (5′-N) on the surface of leukemia cells was determined in 44 patients with blast crisis of chronic myelogenous leukemia (CML) and in 52 patients with acute myeloblastic (AML) or acute lymphoblastic (ALL) leukemia. The phenotype of blast cells was classified according to immunological surface markers, including the common ALL-antigen (cALLA). High 5′-N activities were found in the presence of cALLA, whereas low to undetectable levels were characteristic for cALLA-negative leukemias, the difference being highly significant (p 0.0001). While there was a certain overlap of 5′-N levels between cALLA-positive ALL and cALLA-negative AML, no overlap of 5′-N was observed between cALLA-positive lymphoid and cALLA-negative myeloid blast crisis of CML. Thus, 5′-N affords an additional easily-testable biochemical marker that may have its diagnostic and prognostic value especially in the case of blastic chronic myelogenous leukemia.     

Central nervous system relapse in two patients with chronic myelogenous leukemia in myeloid blastic phase on imatinib mesylate therapy

We report two patients with Philadelphia (Ph) chromosome positive chronic myelogenous leukemia (CML) in myeloid blastic phase that developed central nervous system disease while on imatinib mesylate therapy. Patient 1 presented with CML in myeloid blastic phase and responded to imatinib, cytarabine, and idarubicin-based treatment achieving complete cytogenetic remission in the marrow, but developed myeloid blasts in his cerebrospinal fluid (CSF) during treatment. Patient 2 developed CML myeloid blastic phase after initially being in hematologic and cytogenetic remission with imatinib treatment. He represented with an extramedullary mass at the base of his skull and CSF involvement. Both patients were treated with intrathecal chemotherapy and received craniospinal irradiation to clear the spinal fluid of disease. Both patients have undergone related allogeneic stem cell transplant and are in complete hematologic remission; one is in complete cytogenetic remission, the other is too early to evaluate. Central nervous system involvement with myeloid blasts is previously unreported for patients with CML in blastic phase on imatinib and warrants cautious observation and vigilance in these patients.     

Acute myelogenous leukemia with t(6;9)(p23;q34): Report of three patients

Acute myelogenous leukemia (AML) with the translocation t(6;9)(p23;q34) is a rare disease entity with a poor prognosis. We report three patients; two were diagnosed with AML of French-American-British (FAB) Cooperative Group type M2 and one with refractory anemia with an excess of blasts (RAEB) followed by AML type M2. The first patient, a 22-year-old man, achieved complete remission (CR) after three courses of chemotherapy. Two months after the CR was achieved, cytogenetic analysis showed t(6;9) in his morphologically normal bone marrow. After 5 months of remission, the AML relapsed and was resistant to further chemotherapy. The second patient, a 19-year-old man who had not achieved remission after two courses of chemotherapy, was treated with allogeneic bone marrow transplantation (BMT). The transplant resulted in CR and the disappearance of t(6;9). Seventeen months after the transplant, polymerase chain reaction analysis revealed molecular remission, confirmed by the absence of DEK-CAN mRNA. This patient has been in a leukemia-free state for more than 3 years. The third patient, a 54-year-old woman, was diagnosed with RAEB. AML developed 6 months later and she died 12 months after the diagnosis of RAEB. We suggest that BMT should be performed if a suitable donor can be found, otherwise the outcome is poor. Received: October 4, 1996 / Accepted: May 15, 1998     

Human leukemic cells contain transforming growth factor

A transforming growth factor was found in the extracts of leukemic cells obtained from the peripheral blood of 11 patients with leukemia. This factor stimulated the colony formation of anchorage-dependent BALB/c 3T3 cells in soft agar. The high levels of colony-stimulating activities were observed in the cell extracts from patients with chronic myelogenous leukemia in blastic crisis (CML BC), acute myelogenous leukemia and CML in chronic phase. The factor from a CML BC patient was heat- and acid-labile, relatively stable to dithiothreitol treatment and inactivated by pronase treatment. Molecular size of the factor seems more than 10,000 daltons.     

Modern Management of Chronic Myelogenous Leukemia (CML)

INTRODUCTION In the untreated state, patients with chronic myelogenous leukemia (CML) generally are asymptomatic and do not require urgent or intensive therapy. Resolution of the signs and symptoms of the disease using standard therapies is achievable without significant toxicity or risk to the patient. However, unlike acute myelogenous leukemia (AML), where true remissions can be obtained, in CML, despite attaining “hematologic” remission, persistence of the abnormal malignant clone as evidenced by the presence of the Philadelphia chromosome-positive (Ph+) cells is characteristic. Eventually all patients with CML, despite control of their disease in the chronic state, will enter a blastic or terminal phase resembling acute leukemia which, for the most part, is resistant to therapy. Patients with CML can expect a median survival of approximately 36-40 months (1) which has not changed appreciably in the last five decades. The recognition of this has led to the pursuit of more aggressive therapy using chemotherapy, immunotherapy, and chemoradiotherapy with marrow transplantation. This review focuses on the treatment of CML in the chronic phase, the use of aggressive therapy to obtain true remission and possible cure, and the therapeutic options available to patients who have entered the blastic phase.     

Kinetic rationale for cytokine-induced recruitment of myeloblastic leukemia followed by cycle-specific chemotherapy in vitro

In patients with acute myeloblastic leukemia incomplete response to induction chemotherapy and short disease-free survival may be related to cell kinetic quiescence of leukemic cells. In this in vitro study, we tested the hypothesis that treatment with cytokines and subsequent chemotherapy (ARA-C, daunorubicin) can increase proliferation and enhance leukemic cell kill. We evaluated the effects of recombinant human interleukin-3 (rh-IL-3), granulocyte-macrophage colony stimulating factor (rhGM-CSF) and granulocyte colony stimulating factor (rhG-CSF) alone and in combination on AML (N = 11) and blastic phase CML (N = 3) samples. Cellular DNA and RNA, incorporation of bromodeoxyuridine (BrdU), cell growth fraction, cell viability, and differentiation markers were evaluated in vitro. A decrease of the quiescent cell population (p = 0.003) and an increase in S-phase cells (p = 0.001) was observed in 8/11 AML samples treated with cytokine combinations. Pronounced heterogeneity or proliferative response was seen between individual cases and different cytokines, but in the majority of the samples IL-3 was most effective. Significantly increased Ki67 expression (p = 0.009) and BrdU incorporation (p = 0.01) were also found after exposure to cytokines indicating an increase in growth fraction. DNA synthesis time was unaffected. Eight samples of AML were treated for 24 hr with ara-C following 2 days of in vitro cytokine incubation. Evaluation of leukemic cell kill showed increased cytotoxicity in three of those five samples which had significant depletions of G0 cells and increases in S-phase. None of the leukemic samples without recruitment from G0 had an increase in ARA-C cytotoxicity. This study provides detailed cell kinetic analysis of cytokine effects on AML blasts and provides a rationale for a novel approach to the treatment of AML.     

Anti-proliferative effect of the abl tyrosine kinase inhibitor STI571 on the P-glycoprotein positive K562/ADM cell line

STI571, an abl tyrosine kinase inhibitor, is less effective in chronic myelogenous leukemia (CML) patients in the accelerated phase and in blastic crisis. We addressed whether STI571 is effective for the CML blastic crisis cell line K562 and the P-glycoprotein (P-gp) positive, multidrug resistance cell line K562/ADM. The present results demonstrate that P-gp positive K562/ADM cells were more resistant than K562 cells to the anti-proliferative and apoptotic effect of STI571, but the co-addition of a P-gp modulator augmented the sensitivity of K562/ADM cells to STI571. For patients in CML blastic crisis, simultaneous use of a P-gp modulator may increase the efficacy of STI571.     

Megakaryocytic blast crisis as a presenting manifestation of chronic myeloid leukemia

Acute megakaryocytic leukemia is a rare form of acute myelogenous leukemia and may occur either de novo or by transformation of a preexisting myelodysplastic or myeloproliferative process including blast crisis of chronic myeloid leukemia (CML). Megakaryocytic blast crisis as the presenting manifestation of CML is extremely rare. We describe such a patient with no prior hematologic disease who presented with acute megakaryoblastic leukemia and extramedullary involvement, in whom the leukemic cells carried the BCR-ABL1 translocation as part of a complex karyotype. Using targeted sequential fluorescence in situ hybridization (T-FISH) technique, we detected two copies of BCR-ABL1 fusion gene in the leukemic blasts while the neutrophils carried a single copy of BCR-ABL1 fusion gene, thereby proving the origin of the megakaryoblastic leukemia from a previously undiagnosed CML clone. Blast crisis as a presenting manifestation of CML is rare and detecting clonal evolution of acute leukemia by specialized cytogenetic techniques may have important diagnostic and therapeutic implications.     

Combination chemotherapy of carboplatin and cytosine arabinoside for high-risk leukemia: A pilot study

Fourteen patients with high-risk leukemia (six with relapsed AML, three with relapsed ALL, one with AML-M0, four with CML in myeloid blastic crisis) were treated with a combination chemotherapy of carboplatin (200–300 mg/m²/day) and cytosine arabinoside (100 mg/m²/day) by 24 h continuous infusion for 5–7 days. Five patients (35.7%) achieved complete remission including two patients complicated with myelofibrosis (one with AML-M0 and one with CML in myelo-megakaryocytic crisis). Thirteen patients had nausea and vomiting, five patients had severe, prolonged neutropenia for which it was necessary to administer granulocyte colony-stimulating factor and six patients had severe thrombocytopenia. We concluded that this regimen is effective for the treatment of high-risk leukemia.     

Carboplatin plus cytarabine in the treatment of high-risk acute myeloblastic leukemia.

Thirty-one patients (20 male and 11 female; median age 51 years (16-79)) with high-risk acute myeloblastic leukemia (AML) (20 refractory AML and 11 secondary AML (s-AML) (four to myelodysplastic syndrome, five to chemo/radiotherapy, one to aplastic anemia and one blastic chronic myelogenous leukemia (B-CML)) were treated with CBDCA (300 mg/m2/day x 5 days in continuous i.v. infusion) plus intermediate-dose Ara-C (500 mg/m2/day x 3 days in rapid i.v. infusion). Nine patients (29%) achieved CR (five s-AML (three myelodysplastic syndromes, one CML and one ALL) and four refractory AML) and 11 patients had resistant disease. There were 11 early deaths (35%). Median disease-free survival of the nine responders was 4 months. The main toxicity was hematological, febrile episodes took place in nearly all the patients (96%). The CBDCA plus Ara-C regimen showed an evident antileukemic activity in high-risk leukemia. However, the lack of long-term disease-free survivors shows the need for innovative postremission strategies. The high initial response rate seen in AML secondary to myelodysplastic syndromes (MDS) warrants further investigation of CBDCA in combination regimens for MDS patients.     

Piperazinedione, total body irradiation, and autologous bone marrow transplantation in chronic myelogenous leukemia

Eleven patients with Philadelphia chromosome (Ph1)-positive chronic myelogenous leukemia (CML) in blast crisis (ten patients) or accelerated disease (one patient) were treated with piperazinedione (PIP) and fractionated total body irradiation (TBI) followed by autologous bone marrow transplantation (ABMT). Three patients were transplanted with marrow from which the Ph1 clone had been eradicated by prior intensive chemotherapy. All patients responded with disappearance of blasts in bone marrow and peripheral blood. Six patients achieved a second chronic phase lasting 3 to 14 months (median, 6 months). Two patients had incomplete recovery, and three patients failed to engraft and died from infection. Transplantation with Ph1-negative bone marrow did not improve response duration or survival. Recurrence of blast crisis and incomplete engraftment continue to be the two major problems in this patient group, and more active regimens need to be investigated.