High incidence of disseminated intravascular coagulation during remission induction of adult patients with acute lymphoblastic leukemia.

We determined the incidence and complications of disseminated intravascular coagulation (DIC) at presentation and during remission induction of previously untreated adults with acute lymphoblastic leukemia (ALL) or de novo Philadelphia chromosome-positive ALL (PCALL) seen at Memorial Hospital between January 1, 1978 and December 31, 1989. DIC was diagnosed in the presence of (1) low fibrinogen (less than or equal to 160 mg/dL), (2) prolonged prothrombin time (PT) and falling fibrinogen, or (3) prolonged PT and positive fibrin split products (FSP). L-Asparaginase was not used during remission induction. Among adequately screened patients with ALL, DIC was detected in 7 of 58 (12%) before initiation of chemotherapy and in 35 of 45 (78%) during remission induction. DIC was not simply the result of infection because clinical and laboratory signs of infection were absent in 16 patients, whereas only 2 of the 22 febrile patients with DIC had positive cultures. Among the 38 patients with DIC at presentation or during remission induction, serious complications were seen in 13 in temporal association with DIC (pulmonary embolus in one, sagittal sinus thrombosis in three, and serious hemorrhage in nine) and were major factors in the deaths of three patients. Among the 10 patients with thorough screening but no evidence of DIC there was only one hemorrhage during the same time interval. In patients with PCALL, DIC was detected in 9% at presentation and in 80% during remission induction. We conclude that DIC is rare at presentation but common during remission induction of adult ALL and PCALL and may be associated with significant thrombotic and hemorrhagic complications. We suggest daily screening for DIC during the first 14 days of remission induction. The treatment of DIC in ALL and PCALL should be a subject of future clinical studies.     

急性白血病合并DIC53例临床分析

对５３例ＡＬ合并ＤＩＣ作回顾分析，并发ＤＩＣ的ＡＬ类型为ＡＰＬ２８例，非Ｍ３型ＡＮＬＬ１５例、ＡＬＬ１０例，发生于初发期、诱导化疗和化疗间歇期、难治期的ＤＩＣ分别占２５、１１、１７例。结果显示，ＡＰＬ合并ＤＩＣ６８％发生于初发期、非Ｍ３期ＡＮＬＬ并ＤＩＣ发生于难治期占６０％，而ＡＬＬ并ＤＩＣ５０％与诱导化疗有关。４０例经全程治疗者，ＤＩＣ治愈８例，其中６例为初发期患者（６／１６）。讨论了ＤＩＣ发生     

Thrombotic events are not exclusive to the remission induction period in patients with acute lymphoblastic leukemia: a report of two cases of cerebral sinus thrombosis

 It is well established that in acute lymphoblastic leukemia (ALL) patients l-asparaginase (l-Ase) provokes thrombotic events reducing coagulation inhibitors in both adults and children. A tight correlation between thrombotic and hemorrhagic complications and ALL has also been hypothesized because of the high incidence of disseminated intravascular coagulation (DIC) found during the early period of chemotherapeutic treatment apart from l-Ase. All the authors reporting on this subject, however, consider the remission induction phase of treatment the most risky, if not exclusive, for the development of a thrombotic event, in particular if it includes the administration of l-Ase. We report here two cases of ALL patients who experienced a cerebral sinus thrombosis in a later phase of treatment, demonstrating that the thrombotic risk is surely exacerbated by chemotherapy but is not exclusive to the remission induction period. Received: 1 April 1997 / Accepted: 11 June 1997     

Ph1 positive acute lymphoblastic leukemia with DIC after operation of colon and lung cancer

We reported a rare case of triple cancers with acute lymphoblastic leukemia (ALL) associated with disseminated intravascular coagulopathy (DIC) after the operations of colon cancer and primary lung cancer. A 78-year-old Japanese male, who had been operated upon for colon cancer (adenocarcinoma) on March 1981, metastatic brain tumor (adenocarcinoma) on December 1986, and primary lung cancer (squamous cell carcinoma) on February 1987, was admitted to our hospital because of severe general malaise on December 6 1987. On admission, he had mild hepatosplenomegaly and hemorrhage diathesis such as purpura. Serum LDH increased to 2,515 mU/ml. The white blood cell count was 6,210/microliters with 53% leukemia cells, and the platelet count was 12,000/microliters. A bone marrow was infiltrated with 96.0% leukemia cells. The leukemia cells stained positively for PAS and negatively for peroxidase. Immunological examination of leukemia cells showed that HLA-DR, TdT, B1 and J5 were positive and cytoplasmic Igmu and surface Ig were negative, indicating common ALL. The coagulation studies revealed that the activated partial thromboplastin time was prolonged to 42.0 seconds, FDP increased to 79.9 micrograms/ml, and antithrombin-III decreased to 62%. Chromosome analysis showed a 48, XY, +2, +21q-, t(9;22) karyotype. He was diagnosed as having Ph1 positive ALL associated with DIC. He was treated with vindesine, prednisolone, L-asparaginase, and adriamycin and complete remission (CR) was achieved after two months. But on August 1988, 8 months after CR, ALL and brain tumor relapsed and he died of pneumonia on September 19, 1988.     

Clinical significance of fibrinopeptide A in acute lymphocytic and non-lymphocytic leukaemia

Summary Fibrinopeptide A (FPA) was systematically investigated in 74 patients with acute leukaemia at different stages of the disease (50 with non-lymphocytic leukaemia, ANLL; 24 with lymphocytic leukaemia, ALL). At diagnosis, 75% of the cases had high FPA levels (86% in ANLL and 54% in ALL) with significantly higher levels in ANLL than in ALL (13.4 vs 4.4 ng/ml; p<0.001). Patients with DIC (20 cases in ANLL and 1 case in ALL) had significantly higher levels (p<0.001). FPA levels were neither correlated with fibrinogen or FDP levels nor with blast cell count. During chemotherapy, median FPA did not show significant changes whereas, at the end of therapy, a return toward normality was generally observed both in ALL and ANLL apart from the group of patients with acute promyelocytic leukaemia. Among the 24 patients who entered post-remission follow-up (13 ANLL and 11 ALL), 10 cases out of the 11 relapsing (6/6 with ANLL and 4/5 with ALL) had increased FPA 1 to 2 months before the ascertainment of the relapse. However, 16% and 9% of the samples obtained on different occasions, respectively from ANLL and ALL cases in maintained first remission, showed FPA above the normal limit. This study demonstrates that subclinical activation of blood coagulation, as indicated by high FPA level, is common both in lymphocytic and non-lymphocytic leukemia and suggests that this phenomenon is related to disease activity.     

Activity of procoagulant and fibrinolysis in homogenate of leukemic cells

We examined activities of procoagulant and fibrinolysis in homogenate of leukemic cells. Procoagulant activity (PCA) was increased in patients with acute myelocytic leukemia (AML) and acute promyelocytic leukemia (APL), but it was significantly decreased in patients with chronic myelocytic leukemia (CML) and adult T cell leukemia. In CML, PCA was increased in the blastic phase. Plasminogen activator activity (PLGAA) was also increased in patients with AML, APL and acute lymphocytic leukemia (ALL) associated with disseminated intravascular coagulation (DIC). Elastase-like activity, trypsin-like activity and chymotrypsin-like activity (CTLA) were increased in those with myelocytic leukemia, but they were low in those with lymphocytic leukemia. PCA, PLGAA and CTLA were significantly higher in patients with DIC than in those without DIC. Measurement of procoagulant and fibrinolytic activity in leukemic cells homogenate may be useful not only for studying hemostatic abnormalities but also for classification of leukemic cells.     

Disseminated intravascular coagulation in acute leukemia at presentation and during induction therapy.

Between January 2001 and December 2003, 67 patients with acute leukemia were evaluated prospectively for hemostatic abnormality at presentation, of which 43 (64.2%) had acute lymphoblastic leukemia and 24 (35.8%) had acute myelogenous leukemia. At presentation, 27 patients (40.3%) had bleeding manifestations. Thrombocytopenia was present in 57 patients (85%), and 33(49.3%) had some abnormality of global coagulation markers. Disseminated intravascular coagulation was defined by International Society of Thrombosis and Hemostasis criteria. Disseminated intravascular coagulation was more often associated with bleeding manifestations in acute myelogenous leukemia cases than in acute lymphoblastic leukemia cases. Two patients presented disseminated intravascular coagulation on day 7 of chemotherapy, without any bleeding manifestations. Four of 15 evaluated cases who had a bleeding or infection complication after day 7 of induction therapy also had disseminated intravascular coagulation. It is recommended that all patients with leukemia be investigated for disseminated intravascular coagulation at presentation.     

Comparison of diagnostic criteria for disseminated intravascular coagulation (DIC): diagnostic criteria of the International Society of Thrombosis and Hemostasis and of the Japanese Ministry of Health and Welfare for overt DIC

We compared the criteria set by the International Society of Thrombosis and Hemostasis (ISTH) for the diagnosis of disseminated intravascular coagulation (DIC) with the criteria of the Japanese Ministry of Health and Welfare (JMHW) set for the diagnosis of overt DIC. We studied 1,284 Japanese patients with DIC. The rate of agreement in the diagnosis of DIC by the two diagnostic systems was 67.4%. In addition, only 2.0% of non-DIC patients by JMHW criteria were diagnosed with overt DIC by ISTH criteria, suggesting that ISTH for overt DIC includes typical cases of DIC. The concordance of diagnosis for DIC by ISTH and JMHW was significantly high in patients with trauma or acute promyelocytic leukemia. About 70% of DIC or overt DIC patients had more than 1 point in the scoring system for prothrombin time, but >50% of those patients had 0 point for plasma fibrinogen level. Abnormal fibrin and fibrinogen degradation product (FDP) levels and platelet counts were observed in >88% of DIC and overt DIC patients but were observed in >50% of non-DIC patients, indicating that these parameters are sensitive markers but not specific markers for the diagnosis of DIC. Considered together, our results suggest that the diagnostic criteria for DIC and overt DIC could be improved by changing the cut-off values of the global coagulation tests.     

Use of peripheral blood instead of bone marrow to monitor residual disease in children with acute lymphoblastic leukemia

In children with acute lymphoblastic leukemia (ALL), response to treatment is assessed by bone marrow aspiration. We investigated whether minimal residual disease (MRD) can be effectively monitored in peripheral blood. We used flow cytometric techniques capable of detecting 1 leukemic cell among 10 000 or more normal cells to compare MRD measurements in 718 pairs of bone marrow and peripheral blood samples collected from 226 children during treatment for newly diagnosed ALL. MRD was detected in marrow and blood in 72 pairs and in marrow but not in blood in 67 pairs; it was undetectable in the remaining 579 pairs. Remarkably, findings in marrow and blood were completely concordant in the 150 paired samples from patients with T-lineage ALL: for each of the 35 positive marrow samples, the corresponding blood sample was positive. In B-lineage ALL, however, only 37 of 104 positive marrow samples had a corresponding positive blood sample. Notably, peripheral blood MRD in these patients was associated with a very high risk for disease recurrence. The 4-year cumulative incidence of relapse in patients with B-lineage ALL was 80.0% +/- 24.9% for those who had peripheral blood MRD at the end of remission induction therapy but only 13.3% +/- 9.1% for those with MRD confined to the marrow (P =.007). These results indicate that peripheral blood may be used to monitor MRD in patients with T-lineage ALL and that peripheral blood MRD may provide strong prognostic information in patients with B-lineage ALL.     

THE IMPACT OF LEUKEMIA STATUS AT THE TIME OF HLA-IDENTICAL SIBLING MARROW TRANSPLANTATION ON SUBSEQUENT COMPLICATION RATE AND SURVIVAL OF ADULTS WITH ACUTE LEUKEMIA

Between March 1981 and March 1985, 76 patients with acute leukemia were treated with cyclophosphamide (120 mg/kg), 12 or 14 Gy total body irradiation, and an HLA-identical sibling marrow transplant. Forty-seven patients had acute non-lymphoblastic leukemia (ANLL) and 29 had acute lymphoblastic leukemia (ALL). Forty-one were transplanted during first remission and 28 during or after first relapse of their disease. An additional six patients were transplanted because their leukemia was refractory to conventional cytotoxic chemotherapy, and one was transplanted as initial therapy. Actuarial 42 month survival for those transplanted during first remission was 47% and for those transplanted in first relapse or later it was 22% (p = 0.02). There was no difference in either group between those with ANLL and those with ALL. Two of the six patients with refractory leukemia are alive more than 22 and more than 15 months after the transplant. The incidence of acute graft-versus-host disease and interstitial pneumonitis was 90% and 39%, respectively, for the first remission group, and 96% and 37% for those transplanted in first relapse or later. There was no significant difference in transplant-related mortality between the two groups (29% and 43%, respectively). The leukemia recurrence rate, however, was 13% for those transplanted in first remission and 67% for those transplanted in first relapse or later (p = 0.0003). Thus, the major factor determining the incidence of leukemia recurrence and survival after transplant was the status of the leukemia at the time of transplantation. These findings indicate that adults with acute leukemia who have an HLA-identical sibling should be transplanted in first remission, and that transplant-related mortality must be reduced urgently. (Aust NZ J Med 1986; 16: 462–469.)     

The t(1;14)(p34;q11) is nonrandom and restricted to T-cell acute lymphoblastic leukemia: a Pediatric Oncology Group study

We report the nonrandom occurrence, frequency, and degree of immunophenotype association of the t(1;14)(p34;q11) in children with acute lymphoblastic leukemia (ALL). This chromosomal abnormality occurred in leukemia cells from 5 of 1,630 (0.3%) consecutive children with newly diagnosed ALL who were entered on a single Pediatric Oncology Group classification study (POG 8600) between January 1986 and February 1989. The frequency of the t(1;14) was 3% (5 of 168 cases) in children with T-cell ALL. All five cases had pseudodiploid karyotypes, and in 3 cases the t(1;14) was accompanied by a deletion of the long arm of chromosome 6. This translocation is of special interest because the breakpoint on chromosome 14 in band q11 corresponds to the assigned locus of the T-cell receptor alpha/delta chain gene. All five of our patients and three cases reported previously have had T-cell ALL. These findings, considered together, suggest that this translocation is specific for T-cell ALL and that a gene in the 1p34 region may play an important role in malignant transformation of thymocytes.     

Acute myeloblastic leukemia in a patient with hereditary protein C deficiency

The patient had been diagnosed with hereditary protein C deficiency. She recently developed acute myeloblastic leukemia (AML). Chemotherapy for AML by cytosine arabinoside, aclarubicin followed by granulocyte colony-stimulating factor (CAG) was started. Disseminated intravascular coagulation (DIC) was observed, however thromboembolic complication was not observed during the hospital course. Hematological remission was not obtained, and the patient died of pseudomembranous pancolitis. Whether the development of these rare disorders of hereditary protein C and AML are coincidental, or involve a causal relationship remains unknown.     

Prevalence and Clinical Characteristics of Acute Myeloid Leukemia Associated with Disseminated Intravascular Coagulation

Disseminated intravascular coagulation (DIC) is one of the important complications to develop in patients with acute myeloid leukemia (AML). While acute promyelocytic leukemia (APL) is a strong risk factor for DIC, other clinical features have not been fully defined. We retrospectively analyzed 161 consecutive adult patients with de novo non-APL AML. DIC was diagnosed in 52 patients (32%); 28 patients at diagnosis and 24 soon after the initiation of induction chemotherapy. Leukocyte counts, C-reactive protein, and lactate dehydrogenase were significantly higher in the DIC+ group. Negative expressions of CD13, CD19, CD34, and HLA-DR were more prevalent in the DIC+ group. On multivariate logistic-regression analysis, variables that were independently associated with the development of DIC were high C-reactive protein, high leukocyte count, negative expressions of CD13 and HLA-DR, and cytogenetics with a normal karyotype or 11q23 abnormality. Although DIC is considered to be associated with serious morbidity and occasional mortality, we did not find any significant differences in the complete remission rate, overall or disease-free survival between DIC+ and DIC- groups. This study is the first to define the clinical characteristics associated with DIC in patients with non-APL AML, but exactly how and when DIC should be treated remains to be determined.     

Characterization of childhood acute leukemia with multiple myeloid and lymphoid markers at diagnosis and at relapse

To define the clinical and biologic significance of childhood acute mixed-lineage leukemia diagnosed by stringent criteria, we studied 25 cases of acute lymphoblastic leukemia expressing greater than or equal to 2 myeloid-associated antigens (My+ ALL), and 16 cases of acute myeloid leukemia expressing greater than or equal to 2 lymphoid associated antigens (Ly+ AML). These cases represented 6.1% of 410 newly diagnosed ALLs (two treatment protocols) and 16.8% of 95 AMLs (two protocols). T-lineage--associated antigens were identified in 9 of the My+ ALL cases and in 14 of those classified as Ly+ AML; all but 1 of the 19 cases that could be subclassified had an early thymocyte stage of differentiation. The My+ ALL cases had an increased frequency of French-American-British (FAB) L2 morphology (36%); the Ly+ AML cases were characterized by FAB M1 or M2 morphology, low levels of myeloperoxidase reactivity and combined populations of myeloperoxidase-positive large blasts and small blasts generally of hand-mirror morphology. Karyotypic abnormalities included t(9;22)(q34;q11) in three cases of My+ ALL, 11q23 translocations in two cases of My+ ALL, and 14q32 translocations in three My+ ALL and five Ly+ AML cases. Mixed-lineage expression lacked prognostic significance in either ALL or AML; however, the findings indicate that some patients with Ly+ AML may respond to prednisone, vincristine, and L-asparaginase after failing on protocols for myeloid leukemia. At relapse, two My+ ALLs had converted to AML and two Ly+ AMLs to ALL; one case in each group showed complete replacement of the original karyotype. Acute mixed-lineage leukemia does not adequately describe the heterogeneity of the cases identified in this study and should be replaced by a set of more restrictive terms that indicate the unique biologic features of these leukemias.     

Chronic lymphocytic leukemia in China

Chronic lymphocytic leukemia (CLL) is a very common form of leukemia among middle-aged and elderly persons in Western countries. In the Japanese, or in those with Japanese ancestry born and living in the USA, CLL is rather rare. It is also rare in China, but convincing data to support this statement are found primarily in the Chinese literature. We have reviewed previously unpublished data from Peking Union Medical College (PUMC) concerning the frequency of CLL among adult patients with the four common types of leukemia. Of 4,174 such patients (1952-1986), 4.6% had CLL; 22.9% chronic myeloid leukemia (CML); 50.3% acute myeloid leukemia (AML); and 22.3% acute lymphoblastic leukemia (ALL). This low frequency of CLL is none the less higher than that found in a multiinstitutional collection of Chinese patients with leukemia. Various clinical and laboratory aspects of a carefully studied, previously published group of patients with CLL from PUMC were compared to similar published findings in patients from the University of Utah. No differences in the overall nature of the disease were detected between these groups. However, not unexpectedly, the duration of symptoms before the diagnosis was made longer in Chinese than in USA patients and the proportion diagnosed at a time when no CLL related symptoms had been noted was less in Chinese. Neither differences in life span in the two populations nor an excess of CML, AML, and ALL at the expense of CLL were viable hypotheses to explain the rarity of CLL in China. We suggest that the dearth of CLL in Chinese is on a genetic basis, as it is thought to be in the Japanese.     

Analysis of the cellular DNA and RNA content in acute leukemias by flow cytometry

Summary In the present study bone marrow samples from 573 patients with newly diagnosed acute myeloid (AML) and lymphoblastic or undifferentiated leukemias (ALL/AUL), were analysed for their cellular DNA und DNA/RNA content, respectively, by means of flow cytometry. From 237 patients with AML 35.4% revealed aneuploid DNA stemlines. While no relation of DNA aneuploidy with other pretherapeutic parameters, including FAB subtype, white blood cell count, lactate dehydrogenase, S-phase index and percentage of blasts in the bone marrow, was observed, cases with aneuploid DNA stemlines revealed a tendency towards longer remission duration. In ALL/AUL 21.8% of 280 patients expressed DNA aneuploidies, which were less frequently found in T-cell ALL (11.1%) as compared to common(C)-ALL (21.4%) or null-cell(null)-ALL (23.5%). DNA aneuploidy was not related with other clinically defined risk factors such as age, white blood cell count, and rapid achievement of remission. Patients with DNA indices <1.0, however, tended to have shorter remissions. A significant difference in RNA indices was observed between AML and ALL/AUL with median values of 14.4 and 10.1, respectively (P<0.05). These data indicate the usefulness of flow cytometric analyses of cellular DNA and RNA content for the characterization and classification of acute leukemias, complementing the identification of clinical risk factors, immuno-phenotyping and cytogenetics.Abbreviations AML acute myeloid leukemia - ALL acute lymphoblastic leukemia - AUL acute undifferentiated leukemia - T-ALL, C-ALL and Null-ALL T-cell, common and Null-cell ALL     

Prognostic impact of persistent cytogenetic abnormalities at complete remission in adult patients with acute lymphoblastic leukemia

In acute myelogenous leukemia, the persistent detection of abnormal cytogenetics at complete remission (ACCR) is associated with inferior outcomes. However, the prognostic significance of ACCR in adult patients with acute lymphoblastic leukemia (ALL) is unknown. We evaluated 272 adult patients with ALL and abnormal cytogenetics at baseline who were treated with frontline induction chemotherapy, achieved complete remission (CR) and had cytogenetic analysis performed at the time of CR. ACCR was observed in 26 patients (9.6%). Median relapse‐free survival was 22 months (95% CI, 12 months to not reached) for patients with ACCR vs. 48 months (range, 30–125 months) in patients with normal cytogenetics at CR (NCCR; P = 0.31). Median overall survival also did not differ significantly between the ACCR (99 months [range, 17 months to not reached]) and NCCR groups (67 months [range, 47 months to not reached], P = 0.86). The specificity of ACCR for minimal residual disease (MRD) positivity by multi‐parameter flow cytometry (MFC) was 43%, and there was overall poor correlation between these two methods for the detection of residual disease. When patients were stratified by MRD status, the presence or absence of persistent cytogenetic abnormalities at CR did not add additional prognostic information. This study suggests that there is poor association between MRD assessment by MFC and the presence or absence of cytogenetic abnormalities at CR in adult patients with ALL. ACCR was not associated with adverse outcomes in ALL and did not add additional prognostic information when MRD status by MFC was known. Am. J. Hematol. 91:385–389, 2016. © 2016 Wiley Periodicals, Inc.     

Roles of protein C, protein S, and antithrombin III in acute leukemia

Protein C, protein S, and antithrombin III were measured in 35 patients with acute leukemia (13 with AML and 22 with ALL). Low levels of proteins C and S were present in 15 (42.9%) and 20 (57.1%) patients, respectively, and 6 patients had low levels of antithrombin (ATIII). Seven patients also had DIC at presentation. There were no significant differences in the levels of protein C, protein S, and ATIII in patients with or without DIC. Twenty patients were available for re-evaluation at the end of induction therapy. The low levels of protein C and ATIII found at diagnosis had risen to normal levels at the end of the induction therapy, while low =levels of protein S remained in 75% of the patients. One patient with low protein C at presentation developed myocardial infarction on day 15, and another patient died of progressive neuropathy. No other thrombotic manifestations were seen. Whether the low protein C, protein S, or antithrombin levels predispose patients with acute leukemia to thrombosis in the absence of DIC is not known.     

Disseminated intravascular coagulation (DIC) in adult patients with acute leukaemia

Abstract: In 71 patients with acute leukaemia admitted for remission induction, disseminated intravascular coagulation (DIC) was looked for in 50 patients and diagnosed in 10 (20%). Of 10 patients with acute lymphoblastic leukaemia, 3 had DIC, and of 40 patients with acute myeloblastic leukaemia, 7 had DIC. The presence of DIC was related to bleeding manifestations within the first 2 weeks. A haemorrhagic diathesis was present in all DIC patients: 4 had minor and 6 had major bleeding, i.e. WHO grade ≥ 2. In addition to blood product support, most DIC patients were treated with low doses of heparin and tranexamic acid. In all DIC patients the haemorrhagic symptoms preceded the heparin administration. Among 40 screened patients without DIC, 17 patients had minor and 3 had major haemorrhagic manifestations. Thus, the proportion of patients with major bleeding was significantly greater among the DIC patients (6/10 vs 3/40, p< 0.001). In conclusion, DIC at presentation was associated with a significantly increased risk for severe haemorrhagic complications and should be looked for in adults with acute leukaemia.     

Cerebrovascular disease in acute leukemia: a clinicopathological study of 14 patients

OBJECTIVE: Cerebrovascular disease (CVD) is a serious complication of acute leukemia, and the underlying conditions are different from the common risk factors for CVD. The aim of this study was to characterize the clinical and pathological features of CVD in patients with acute leukemia. PATIENTS OR MATERIALS: In our series of 116 autopsied cases of acute leukemia during the period between January 1978 and December 1998, we had 14 patients who had CVD during the course of acute leukemia. The neuropathological and clinical features of those patients were examined. RESULTS: Neuropathological examination showed hemorrhagic infarction due to disseminated aspergillosis or mucormycosis (5 cases), multiple hemorrhages due to leukemic cell infiltration (2 cases) and a single massive hemorrhage with petechial hemorrhages in various regions of the brain (4 cases). Three patients had CVD due to miscellaneous causes. Clinicopathological correlation revealed that fungal disseminations occurred under agranulocytosis, while leukemic cell infiltration occurred under a marked leukocyotosis (peripheral white blood cell count >100,000/microl). Four patients with coagulopathy, including three with disseminated intravascular coagulation (DIC) had a single massive hemorrhage. CONCLUSION: Our study demonstrated that there were at least three types of CVD with specific clinicopathological features. Hemorrhagic infarction under agranulocyotosis was due to disseminated aspergillosis or mucormycosis. Multiple cerebral hemorrhages under marked leukocyotosis was due to leukemic cell infiltration into the brain. Massive cerebral hemorrhage was associated with coagulopathy including DIC.