Toshiteru Ohshima

Myeloblastoma formation in acute myeloid leukemia

The cell surface markers on the leukemic cells of 76 patients with adult acute myeloid leukemia (AML) have been analyzed by indirect immunofluorescence, and the presence of CD56+ leukemic cells was detected in ten of these patients. Four of these 10 CD56+ AML patients developed extramedullary myeloblastomas and in two of them an intracranial myeloblastoma. In contrast, in the remaining 66 CD56- AML patients, only one patient developed a myeloblastoma formation of the subcutaneous. It may be that the CD56 antigen which is an isoform of the neural cell adhesion molecule (NCAM), expressed on neurons, satellite cells of skeletal muscle cells, and on stromal cells, binds these tissues by a homophilic mechanism. CD56+ leukemic cells are capable of invading and of surviving in extramedullary tissues, where they proliferate and develop into a myeloblastoma. Because of this possibility, CD56+ AML patients should be carefully monitored for signs of myeloblastoma formation.

A randomized trial of chemoimmunotherapy of acute nonlymphocytic leukemia in adults using a protein-bound polysaccharide preparation

SummaryThe effect of immunotherapy with a protein-bound polysaccharide preparation termed PSK on remission duration and survival of adults with acute nonlymphocytic leukemia (ANLL) was studied in a prospective randomized cooperative trial. After having achieved complete remission and receiving a consolidation therapy, 73 patients were randomized either to maintenance chemotherapy or to maintenance chemotherapy plus immunotherapy with PSK. Ultimately 36 patients in the chemotherapy group and 31 in the chemoimmunotherapy group were evaluable. Six months after the last entry, immunotherapy with PSK showed a borderline beneficial effect on remission duration (P=0.089) and on duration of survival (P=0.062). When the data were analyzed 12, 18, and 24 months after the last entry there were no significant differences in duration of remission and survival between the two groups. However, analysis of the data of patients who had maintained complete remission for more than 270 days revealed that immunotherapy had a suggestive beneficial effect (P=0.105), prolonging the 50% remission period by 418 days (885 vs 467 days). Thus, immunotherapy with PSK seems to be active in the treatment of adult ANLL when used for maintenance therapy in combination with chemotherapy, especially in patients with a good prognosis.

Morphological Diagnoses of the Japan Adult Leukemia Study Group Acute Myeloid Leukemia Protocols: Central Review

A morphological review system of the Japan Adult Leukemia Study Group has developed from the AML-87 through the AML-92 experience.We reviewed 1427 (90%) of 1592 cases enrolled in the AML-87, -89, or -92 protocols for morphology; 1408 (88%) were eligible. The rate of diagnostic concordance between each institute and the Committee on Morphological Diagnosis ranged from 76% to 80%. Acute myeloid leukemia (AML) subtypes were as follows: AML M0, 27 (2%); M1, 179 (13%); M2, 472 (34%); M3, 358 (25%); M4, 265 (19%); M5, 57 (4%); M6, 39 (3%); and M7, 11 (1%). The reason for the high number of patients with AML M3 is that many M3 patients were enrolled in the AML-92 protocol, which contained all-trans-retinoic acid. AML M0, M6 and M7 belonged to the poor prognostic groups. Auer bodies were found in 284 (53%) of 538 patients who survived significantly longer than those without Auer bodies in AML-87/-89. In AML-92 except for AML M3, 259 (43%) of 602 cases were Auer+ and also showed better survival rates. The survival of patients with >50% myeloperoxidase (MPO)-positive blast cells was better than those with ⩽50% MPO+ blast cells in AML-87/-89. This trend was also seen in AML-92 excluding M3. AML with trilineage dysplasia (AML/TLD) is characterized as a subtype of de novo AML that shows morphological dysplasia of mature hematopoietic cells on a background of leukemic blast cells.The number of patients with AML/TLD was 89 (16.5%) of 545 patients reviewed in AML-87/-89. AML-92, except for M3, showed a higher rate of patients with TLD (161 cases; 27.6%) because there were no patients with TLD in the AML M3 group. Survival rates for AML/TLD were worse than those for AML/non-TLD in both the AML-87/-89 and -92 protocols. Eighty percent of all cases (793/986) entered in AML-92 were analyzed cytogenetically. Fifty-one cases were not available for karyotyping because of a lack of mitoses or inappropriate preparations.The most frequent karyotype was normal, which accounted for 34.2%.The t(15;17), t(8;21), and inv(16) karyotypes, which are regarded as good risk factors, were 23.8%, 9.2%, and 1.6%, respectively. Abnormal chromosomes 5, 7, t(9;22), and t(6;9) were considered to be poor or intermediate risk factors. As a new system of karyotyping begins in the ongoing AML protocol, useful chromosomal data will be obtained in the near future.

Cytogenetic studies in adult acute leukemias

Thirty-six patients with acute leukemia (31 with AML, 5 with ALL) were classified by FAB criteria, and their bone marrow cells were analyzed cytogenetically with G-banding. Chromosomal abnormalities were found in 16 patients (44%). The most common abnormality was an 8;21 translocation, accounting for 19.4% of all AML patients, that was restricted to patients with M2. In 29 treated AML patients, those with an 8;21 translocation [t(8;21) patients] showed a higher complete remission rate (83%) and a longer median survival (10.7 months) than did other patients with AML; patients with only abnormal metaphases (AA patients) had the lowest complete remission rate (33%) and shortest median survival (2.7 months). There was no difference in the remission rate and survival between patients with only normal metaphases (N patients) and patients with abnormal metaphases (A patients). Three out of five patients with ALL had karyotypic abnormalities; the Philadelphia (Ph1) chromosome was found in one case.

A long term follow-up of a randomized trial comparing interferon-α with busulfan for chronic myelogenous leukemia

Abstract To evaluate the long-term effectiveness of interferon- α (IFN- α ) therapy in patients with chronic myelogenous leukemia (CML) in chronic phase, we examined the updated outcomes of 159 patients who had been enrolled between 1988 and 1991 into a randomized trial comparing IFN- α with busulfan. At a median follow-up of 73 months, the median survival was 71 months in the IFN- α group and 55 months in the busulfan group ( P =0.0563), and the median time of remaining in chronic phase was 58 months in the IFN- α group and 39 months in the busulfan group ( P =0.4676). Landmark analysis showed a significant advantage in survival ( P =0.009) and duration of chronic phase ( P =0.0001) in patients with any cytogenetic response among the IFN- α group. About half patients were discontinued IFN- α administration in spite of cytogenetic response in this study. It appears that continuation of IFN- α might possibly confer a survival advantage. Pretreatment factors associated with cytogenetic response included high hemoglobin level, low percentage of peripheral basophils and low leukocyte counts. Multivariate analysis identified lower percentage of bone marrow basophilia ( P =0.007) for survival advantage. If a group with a very good prognosis is predicted by a new prognostic model, it might be an option to wait for bone marrow transplantation.

Relationship between responsiveness to colony stimulating factors (CSFs) and surface phenotype of leukemic blasts

We examined the responsiveness of leukemic cells to colony stimulating factors (CSFs) as determined by 3H-TdR incorporation and surface phenotypes of leukemic blasts. In acute myeloid leukemia (AML), CD13 and/or CD33 positive and HLA-DR negative M1 and M3 cases tended to show high response to G-CSF, GM-CSFs and IL-3, however, all HLA-DR positive M1, M2, M4 and M5 cases were unresponsive to CSFs but showed high autonomous growth. In acute lymphocytic leukemia (ALL), no response was observed to any CSFs but high autonomous growth was found in mixed leukemia cases. Sole T or B lineage cases showed low autonomous growth. These results suggest the varied nature of the proliferative state in leukemia and the existence of a subgroup in M1.

Interstitial pneumonitis possibly due to mitoxantrone

A 41-year-old patient with chronic myelogenous leukemia in the accelerated phase was treated with mitoxantrone. She developed pyrexia 7 days after receiving the third administration of mitoxantrone. After 3 more days, she experienced dry cough and dyspnea. Bilateral fine crackles were audible, but no signs of heart failure were found. A chest X-ray film revealed diffuse reticulogranular infiltrates bilaterally. An increase in the prednisolone dosage led to an improvement. Specimens of the bronchoalveolar lavage revealed an increase in CD4-/CD8- lymphocytes. The peripheral lymphocytes also expressed neither CD4 nor CD8. Specimens of a transbronchial lung biopsy disclosed thickening of the alveolar wall with infiltration of lymphoid cells.

Complete Remission in a Patient with Hypoplastic Acute Lymphoblastic Leukemia Induced by Granulocyte-Colony-Stimulating Factor

We report here a case of hypoplastic leukemia with T cell markers in whom complete remission was obtained with granulocyte-colony-stimulating factor (G-CSF) alone. A 23-year-old male was diagnosed with hypoplastic leukemia: Hb 2.6 g/dl, platelet count 29.0 x 10(9)/l after transfusion, WBC 2.9 x 10(9)/l, hypocellular bone marrow with 70.7% blasts. He was given G-CSF 300 micrograms/day by intravenous drip infusion without antileukemic agents for severe pneumonia. After the administration of G-CSF for 15 days, hematological examination and bone marrow findings had improved to normal, and complete remission was obtained. However, the patient relapsed 45 days after discontinuation of G-CSF. The characteristics of the relapsed leukemia cells were similar to those on admission: negative for myeloperoxidase and positive for T cell markers (CD2 and CD7). The possibilities for the differentiation of leukemic cells and the recovery of normal hematopoiesis with G-CSF are discussed.

HEMATOPOIESIS IN PATIENTS WITH ACUTE NATURAL KILLER CELL LEUKEMIA AND LARGE GRANULAR LYMPHOCYTOSIS: RELATIONSHIP BETWEEN CLINICAL FEATURES AND HEMATOPOIETIC INHIBITOR ACTIVITY OF PERIPHERAL MONONUCLEAR CELLS

Large granular lymphocytosis is characterized by a remarkable increase of large granular lymphocytes (LGL) with azurophilic granules in the cytoplasma, and about two-thirds of patients with LGL lymphocytosis do not show severe neutropenia, anemia and thrombocytopenia. If the latter patients, however, show a rash, the prognosis is poor. From 1985 to 1987, two types of LGL lymphocytosis, of which one type had a rash and poor prognosis and another has had a good and mild prognosis, were treated at Nihon University Hospital. This report presents the case reports. Case 1 : In October, 1987, a 28-yr-old male complained of low-grade fever. His leukocyte count was found to be 12.9 x 109/1, with lymphocytes occupying 57% of the leukocytes and showing three forms: lymphoblastoid cells without granulars, amounting to 9.5%; lymphoblastoid cells with azurophilic granules in the cytoplasma (LGL), amounting to 37.5%; and mature lymphocytoid cells, amounting to 10%. Bone marrow aspirates revealed normal cellularity with a mild infiltration of lymphoblastoid cells, with or without granules, amounting to 30%, and mature lymphocytoid cells amounting to 4.9%. An analysis of his PMNC showed the following phenotypes: CD2+, 3-, 4-, 5-, 8-, lo-, 11-, 16-, 19-, 20-, Leu 7-, NKH-1 +, and IgG-FcR-. His PMNC showed low cytotoxicity to K562 cells, percent cytotoxicity was 1 .O (E/T; 20:l). A chromosome analysis of 30/31 cells revealed 46XY, and 1/31 cells, 45-X, -Y, -16,6q +, + 2M. His LGL which, on October 22, had been measured as 33.5 x 109/1, had decreased on November 6 to 16.0 x 109/1, and the lymphoblastoid cells without granules increased from 2.4 x 109/1 to 34.8 x 109/l. Therefore, the patient was diagnosed as having acute natural killer cell leukemia and a combination chemotherapy using L-asparaginase, vincristine, and prednisolone was immediately started on November 6. However, nongranular lymphoblastoid cells increased daily and, finally, severe neutropenia occurred. The patient died of sepsis on December 28, 1987. Case 2: In May, 1985, a 51-yr-old male, complaining of numbness about both elbows, was thought to have leukocytosis (1). His peripheral leukocyte count was 12.4 x 109/1, and LGL occupied 79% of leukocytes. Neither anemia nor thrombopenia were noted. Hepatomegaly, splenomegaly, and lymphadenopathy were not noted. An analysis of PMNC showed the following phenotypes: CDl-, 2+, 3+ , 4-, 5 + , 8 + , lo-, 11+, 16.. 19-, 20-, Leu7+, NKH-I-, and IgG-FcR+. Cytotoxicity to K562 of PMNC was 4.1. Chromsosome analysis revealed 46XY. He was diagnosed as having LGL lymphocytosis, though he did not take therapy. For 3 yr and 9 months following this diagnosis, his leukocyte counts have ranged 12.0 x lo9 to 17.5 x 109/1, and LGL have continued to occupy 76% to 90% of the leukocytes. Case 3: In December, 1975, tests of a 71-yr-old female, complaining of easy fatigability, indicated mild hypertension and leukocytosis (2). Her peripheral leukocyte count was 13.5 x 109/1 with LGL occupying 88%. Her spleen was palpable to 3 cm below the left costal margin, though hepatomegaly or lymphadenopathy were not noted. Her PMNC revealed the following phenotypes: CD1-, 2+, 4+, 5 + , 8-, lo-, 11-, 16-, 19-, 20-, leu7+, NKH-I-, and IgG-FcR-. Cytotoxicity to K562 cells of PMNC was 1.3. Chromosome analysis revealed 46XX. She was diagnosed as having LGL lymphocytosis. For 13 yr and 3 months following diagnosis, she has not taken therapy. Her leukocyte count has ranged between 12.0 x lo9 to 19.0 x 109/1 and LGL have occupied 80% to 90% of leukocytes. Colony assay: Colony assays were done by employing the plasma clot culture method (3). 10% conditioned medium from the GCT cell line for the CFU-g assay and 1 unit/ml of human erythropoietin for the CFU-e assay were used. The influence of the PMNC of these patients was shown by the addition of 2 x 1 6 PMNC in colony assays of 5 x lo4 BMNC from these patients or from healthy donors. When BMNC were cultured with PMNC, the percentage of colony formation was calculated as equaling 100 x (number of colonies in the PMNC added culture number of spontaneous colonies) / (number of colonies in the culture of BMNC alone number of spontaneous colonies). The PMNC of Case 1, remarkably, inhibited the colony formation of autologous allogeneic CFU-g, and autologous CFU-e, p < 0.01. On the other hand, the PMNC of Cases 2 and 3 did not inhibit the colony formation of autologous and allogeneic CFU-g, and PMNC of case 2 did not inhibit the colony formation of CFU-e (Table 1). The influences of the PMNC from

Analysis of 20-year follow-up study of LVP regimen for adult acute lymphoblastic leukemia.

In an attempt to develop a new intensive chemotherapy for adults with untreated acute lymphoblastic leukemia (ALL), 3 sequential programs were designed for 62 patients (age range, 15 to 74 years; median age, 32 years) consisting of the LVP-79 (1979–1984, 27 patients), LVP-85 (1984–1986, 14 patients), and LVP-87 (1987–1989, 21 patients) regimens. The influence of clinical and biologic characteristics on the patient outcome was also examined.L-asparaginase (L-asp), vincristine, and pred-nisolone, defined collectively as LVP, were administered for induction chemotherapy in all protocols.After achieving complete remission (CR), patients underwent 2 years of multi-agent consolidation, intensification, and maintenance therapy consisting of various combinations. No significant differences were noted between the 3 groups regarding CR rate or survival. In total, 47 of 62 patients (75.8%) achieved CR.The median overall survival (OS) and median CR durations were 550 days and 341 days, respectively. Overall, the estimated survival rate at 20 years was 18.1%. The disease-free survival rate at 20 years was 26.2%. According to univariate analysis, the most favorable pretreatment characteristic for achieving CR was age.A younger age (<40 years of age), platelet count >30 × 109/L, having L1 morphology (French-American-British [FAB]classification subtype), female sex, and the absence of chromosomal abnormalities also helped improve survival rate.According to multivariate analysis, presence of Ph chromosome was found to be a major influencing factor for OS.Although higher doses ofL-asp were administered than those used in previous studies, the adverse effect ofL-asp was rarely identified.Therefore, it should be considered one of the key drugs for treatment of adult ALL. Further strategies still need to be developed to obtain better survival in adult ALL.