Kentaro Horikawa

Severe hemorrhagic complications during remission induction therapy for acute promyelocytic leukemia: incidence, risk factors, and influence on outcome

Background: Even after the introduction of all‐trans retinoic acid (ATRA), early hemorrhagic death remains a major cause of remission induction failure for acute promyelocytic leukemia (APL). Methods: To investigate severe hemorrhagic complications during remission induction therapy with respect to incidence, risk factors, and influence on outcome. Results were analyzed for 279 patients enrolled in the APL97 study conducted by the Japan Adult Leukemia Study Group (JALSG). Results: Severe hemorrhage occurred in 18 patients (6.5%). Although most of them were receiving frequent transfusions, the targeted levels of platelet counts (30 × 109/L) and plasma fibrinogen (1.5 g/L) for this study were reached at the day of bleeding in only 71% and 40%, respectively. Nine of them succumbed to an early death, while the remaining nine patients eventually achieved complete remission (CR). The 5‐yr event‐free survival rate was 68.1% for those who did not suffer severe hemorrhage, and 31.1% for those who did (P < 0.0001). For patients who achieved CR, on the other hand, there was no difference in disease‐free survival between patients with and without severe hemorrhage (P = 0.6043). Risk factor analysis identified three pretreatment variables associated with severe hemorrhage: initial fibrinogen level, white blood cell count, and performance status. Additionally, patients with severe hemorrhage were more easily prone to develop retinoic acid syndrome or pneumonia than patients without hemorrhage. Conclusions: These results indicate that fatal hemorrhage represents a major obstacle in curing APL, and that patients with such high‐risk features may benefit from more aggressive supportive care.

Characteristic mode of action of gangliosides in selective modulation of CD4 on human T lymphocytes

We have explored the possible mechanisms for selective modulation by gangliosides of CD4 on human T lymphocytes and subsequent re-expression of CD4. Indirect immunofluorescence staining with anti-CD4 antibodies revealed newly internalized CD4 in ganglioside-treated cells after membrane permeabilization with 0.1% saponin. Cycloheximide and other metabolic inhibitors did not alter the modulation but inhibited significantly the re-expression of CD4. These results suggest both selective modulation of CD4 by a process of endocytosis and re-expression of CD4 through de novo protein synthesis.

Expression of cryptantigen Th on paroxysmal nocturnal hemoglobinuria erythrocytes in association with a hemolytic exacerbation.

Paroxysmal nocturnal hemoglobinuria (PNH) erythrocytes lack complement regulatory membrane proteins and are susceptible to complement. Although the critical role of complement in intravascular hemolysis in PNH is accepted, the precise mechanism of complement activation in vivo is unknown. Accordingly, in a PNH patient who was suffering from a hemolytic precipitation soon after a common cold-like upper respiratory infection, we analyzed the erythrocytes with lectins and by flow cytometry to detect membrane alteration that lead to complement activation. The lectin reactivity of erythrocytes showed the expression of cryptantigen Th. The patient serum at the time of the hemolysis induced the expression of Th on erythrocytes from PNH patients and from healthy volunteers in vitro, whereas neither the patient serum after recovery from the hemolysis nor blood type-matched control serum from healthy donor showed this activity. Moreover, autologous serum selectively hemolyzed Th+ PNH erythrocytes, but not Th- PNH erythrocytes, or Th+ control erythrocytes. Hemolysis was not observed either in complement-inactivated serum or in blood type-matched cord blood serum, which lacks natural antibodies to cryptantigens. These findings indicate that the immunoreaction of infection-induced Th with natural antibody on PNH erythrocytes is a trigger of the complement activation, leading to intravascular hemolysis.

Monoclonal antibody to galactosylceramide: discrimination of structural difference in the ceramide moiety

A mouse monoclonal antibody (mAb) was developed against monohexaosylceramide. This mAb differentially reacted on thin‐layer chromatograms with 3 types of galactosylceramide (GalCer) obtained from bovine brain. Structural analysis of the 3 glycolipids revealed that they consisted of the same galactose and sphingosine but of apparently different fatty acids. Among the 3 GalCers, the mAb reacted with two GalCers which contained α‐hydroxy fatty acids, but not with GalCer composed of nonhydroxy fatty acids. These findings suggest not only that the mAb discriminated the fatty acid composition in the ceramide moiety of GalCer, but also that the ceramide structure defines the immunological epitope as it is known to do for the carbohydrate moiety of glycosphingolipid.

Long-term outcome and prognostic factors of elderly patients with acute promyelocytic leukemia

Studies focused on elderly acute promyelocytic leukemia (APL) are relatively limited. To evaluate prognostic impact in elderly APL, we compared the long‐term outcome of elderly APL patients (60–70 years) with younger patients (15–59 years) treated with all‐trans retinoic acid combined with anthracycline and cytarabine in the Japan Adult Leukemia Study Group (JALSG) APL97 study. Of 283 evaluable patients, 46 (16.3%) were elderly who had more frequent lower platelet (P = 0.04), lower albumin (P = 0.006) and performance status 3 (P = 0.02), higher induction death rate due to differentiation syndrome (P = 0.03), and non‐relapse mortality (NRM) during consolidation therapy (P = 0.001). Overall survival was significantly inferior in elderly patients (P = 0.005), but disease‐free survival and cumulative incidence of relapse were not. Better therapeutic approaches should be considered to reduce NRM during induction and consolidation therapy in elderly APL. This study was registered at http://www.umin.ac.jp/ctrj/ under C000000206.

NKG2D-mediated immunity underlying paroxysmal nocturnal haemoglobinuria and related bone marrow failure syndromes.

It is considered that a similar immune mechanism acts in the pathogenesis of bone marrow (BM) failure in paroxysmal nocturnal haemoglobinuria (PNH) and its related disorders, such as aplastic anaemia (AA) and myelodysplastic syndromes (MDS). However, the molecular events in immune‐mediated marrow injury have not been elucidated. We recently reported an abnormal expression of stress‐inducible NKG2D (natural‐killer group 2, member D) ligands, such as ULBP (UL16‐binding protein) and MICA/B (major histocompatibility complex class I chain‐related molecules A/B), on granulocytes in some PNH patients and the granulocyte killing by autologous lymphocytes in vitro. The present study found that the expression of NKG2D ligands was common to both granulocytes and BM cells of patients with PNH, AA, and MDS, indicating their exposure to some incitement to induce the ligands. The haematopoietic colony formation in vitro by the patients’ marrow cells significantly improved when their BM cells were pretreated with antibodies against NKG2D receptor, suggesting that the antibodies rescued haematopoietic cells expressing NKG2D ligands from damage by autologous lymphocytes with NKG2D. Clinical courses of patients with PNH and AA showed a close association of the expression of NKG2D ligands with BM failure and a favourable response to immunosuppressive therapy. We therefore propose that NKG2D‐mediated immunity may underlie the BM failure in PNH and its‐related marrow diseases.

Acute promyelocytic leukemia harboring a STAT5B-RARA fusion gene and a G596V missense mutation in the STAT5B SH2 domain of the STAT5B-RARA

To the Editor: Introduction of all-trans retinoic acid (ATRA) has been the major breakthrough in the treatment of acute promyelocytic leukemia (APL) with a characteristic t(15;17) translocation (1, 2). With a great interest we read the report regarding the APL patient with STAT5B-RARa (3). To date, there are only three reported APL patients who harbor the STAT5B-RARa (3–6), therefore, clinical features of this particular subtype, response to therapy and its pathogenesis remain to be determined. This study describes the fourth APL patient harboring the STAT5B-RARa. A 41-yr-old Japanese man was admitted to our hospital because of petechiae and fever in July 2006. His hemoglobin was 9.5 g ⁄dL, platelet count was 51 · 10 ⁄L, and leukocyte count was 77.8 · 10 ⁄L with 91.2% abnormal promyelocytes (Fig. 1A). Promyelocytes were positive for CD13 and CD33 but negative for CD34 and

Expression of CD56 is an unfavorable prognostic factor for acute promyelocytic leukemia with higher initial white blood cell counts

Expression of CD56 has recently been introduced as one of the adverse prognostic factors in acute promyelocytic leukemia (APL). However, the clinical significance of CD56 antigen in APL has not been well elucidated. We assessed the clinical significance of CD56 antigen in 239 APL patients prospectively treated with all‐trans retinoic acid and chemotherapy according to the Japan Adult Leukemia Study Group APL97 protocol. All patients were prospectively treated by the Japan Adult Leukemia Study Group APL97 protocol. The median follow‐up period was 8.5 years. Positive CD56 expression was found in 23 APL patients (9.6%). Expression of CD56 was significantly associated with lower platelet count (P = 0.04), severe disseminated intravascular coagulation (P = 0.04), and coexpression of CD2 (P = 0.03), CD7 (P = 0.04), CD34 (P < 0.01) and/or human leukocyte antigen‐DR (P < 0.01). Complete remission rate and overall survival were not different between the two groups. However, cumulative incidence of relapse and event‐free survival (EFS) showed an inferior trend in CD56+ APL (P = 0.08 and P = 0.08, respectively). Among patients with initial white blood cell counts of 3.0 × 109/L or more, EFS and cumulative incidence of relapse in CD56+ APL were significantly worse (30.8% vs 63.6%, P = 0.008, and 53.8% vs 28.9%, P = 0.03, respectively), and in multivariate analysis, CD56 expression was an unfavorable prognostic factor for EFS (P = 0.04). In conclusion, for APL with higher initial white blood cell counts, CD56 expression should be regarded as an unfavorable prognostic factor.

Low-dose cytarabine and aclarubicin in combination with granulocyte colony-stimulating factor for elderly patients with previously untreated acute myeloid leukemia.

We evaluated the efficacy of low-dose cytarabine and aclarubicin combined with granulocyte colony-stimulating factor (CAG) in elderly patients with previously untreated acute myeloid leukemia. Patients aged between 60 and 70 years who were not eligible for standard chemotherapy protocols and patients aged over 70 years were all registered. Thirty-three of 68 patients (49%) achieved remission. Median disease-free survival was 10 months and overall survival was nine months. Performance status after chemotherapy in patients who achieved remission was generally favorable. The present study demonstrates that CAG therapy is efficacious and well tolerated in the majority of elderly patients.

Successful treatment of Aspergillus liver abscesses in a patient with acute monoblastic leukemia using combination antifungal therapy including micafungin as a key drug

While anti-cancer chemotherapy has improved the survival of patients with hematologic malignancies, it has also exposed such patients to the risk of life-threatening infection due to neutropenia. In intensive chemotherapy for leukemia, invasive aspergillosis resulting in death is infrequently observed. In such cases, aggressive diagnostic and therapeutic intervention is required. Herein, we report a case of Aspergillus liver abscesses in a patient with acute monoblastic leukemia. The patient presented with febrile neutropenia and concomitantly with an elevated serum β-d-glucan level during chemotherapy. The abscesses were finally diagnosed by liver biopsy. Although antifungal monotherapy of voriconazole or liposomal amphotericin B, both of which are recommended for invasive aspergillosis, showed a poor response, when combined with micafungin, an echinocandin, both had a highly favorable effect against the infection. Therefore, our clinical experience suggests that the serum test is useful for the rapid diagnosis of invasive aspergillosis, especially in deep tissues, and that combination antifungal therapy with micafungin should be considered when initial monotherapy for fungal infection shows an insufficient effect.