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Objectives: To analyze the efficacy, safety, prognostic factors, factors affecting treatment continuation, suitable treatment candidates, and optimal administration schedule in patients with acute myeloid leukemia(AML)treated with venetoclax plus azacitidine(VEN+AZA)., Methods: We performed a retrospective analysis of the data of 39 patients with untreated or relapsed/refractory AML., Results: The median duration of follow-up was 6 months, and the median number of treatment cycles was 2. The composite complete remission(CRc)achievement rate(complete remission+complete remission with incomplete hematological recovery)was 61.5%. The treatment discontinuation rate was 76.9%, the median overall survival (OS)was 7.7 months, and event-free survival(EFS)was 4.8 months. In subgroup analyses, significant differences in the OS were observed between subgroups stratified according to the cytogenetic risk, CRc achievement rate, and Charlson comorbidity index(CCI)(≤7 vs <7). A significant difference in the EFS was also observed between subgroups stratified according to the cytogenetic risk and CRc achievement rate. The response rate tended to be lower in the adverse cytogenetic risk subgroup. Patients who received VEN for 21 days or less in the first treatment cycle tended to have a better OS., Conclusions: A lower OS and EFS were associated with a higher treatment discontinuation rate, lower number of treatment cycles, and lower CRc achievement rate than those observed in the VIALE-A trial. We considered that treatment continuation was important to improve the prognosis. We also concluded that it is important to select candidates suitable for VEN+AZA treatment and to modify the administration schedule.

An elevated serum level of NM23-H1 protein is found in acute myelogenous leukemia (AML), and predicts a poor treatment outcome in AML patients. To investigate the potential pathological link between the elevated serum level of this protein and poor prognosis, we examined the extracellular effects of recombinant NM23-H1 protein on the in vitro growth and survival of primary cultured AML cells at concentrations equivalent to the levels found in the serum of AML patients. Extracellular NM23-H1 protein promoted the in vitro growth and survival of AML cells and this activity was associated with the cytokine production and activation of the MAPK and signal transducers and activators of transcription signaling pathways. Inhibitors specific to MAPK signaling pathways inhibited the growth- and survival-promoting activity of NM23-H1. These findings indicate the novel biological action of extracellular NM23-H1 and its association with poor prognosis, and suggest an important role for extracellular NM23-H1 in the malignant progression of leukemia and a potential therapeutic target for these malignancies.

An elevated serum level of NM23-H1 protein is found in acute myelogenous leukemia (AML) and predicts a poor treatment outcome for AML patients. To investigate the potential pathological link between the elevated serum level of this protein and poor prognosis, we examined the extracellular effects of recombinant NM23-H1 protein on the in vitro survival of primary cultured normal peripheral blood mononuclear cells (PBMNC) at concentrations equivalent to the levels found in the serum of AML patients. Extracellular NM23-H1 protein inhibited the in vitro survival of PBMNC and promoted the production of various cytokines, such as GM-CSF and IL-1beta, which in fact promoted the growth of primary cultured AML cells. These findings indicate a novel biological action of extracellular NM23-H1 and its association with poor prognosis of patients with elevated serum levels of NM23-H1 protein. These results suggest an important role of extracellular NM23-H1 in the malignant progression of leukemia and a potential therapeutic target for these malignancies.

A previous study reported that a nondifferentiating myeloid leukemia cell line produced differentiation-inhibiting factors. One of the factors was purified as a homologue of the nm23 genes. The nm23 genes were overexpressed in acute myelogenous leukemia (AML) cells, and a higher level of nm23 gene expression was correlated with a poor prognosis in AML. The present study determined the plasma levels of nm23-H1 protein by enzyme-linked immunosorbent assay and assessed the association between this level and the clinical outcome in 102 patients with AML. The plasma concentration of nm23-H1 was higher in patients with AML than in normal controls (P =.0001). Plasma nm23-H1 levels were correlated with the product of the intracellular nm23 messenger RNA (mRNA) level and the white blood cell count, but not with the mRNA level alone. Therefore, nm23-H1 plasma levels probably depend on the total mass of leukemic cells overexpressing the nm23-H1 gene. Overall survival was lower in patients with higher plasma nm23-H1 levels than in those with lower levels. Multivariate analysis using the Cox proportional hazard model showed that elevated plasma nm23-H1 levels significantly contributed to the prognosis of AML patients. Furthermore, the plasma nm23-H1 levels were investigated in 70 patients with other hematologic neoplasms, including 6 with acute lymphoblastic leukemia, 13 with chronic myelogenous leukemia, and 12 with myelodysplastic syndrome. Plasma nm23-H1 levels were significantly higher in all of these hematologic neoplasms than in normal controls. Increased plasma levels of nm23-H1 may have prognostic value in these hematologic malignancies as well as in AML.

The chromosomal translocation, t(8;21), is found frequently in acute myeloid leukemia (AML) with maturation (FAB-M2). We have previously mapped the translocation breakpoints of t(8;21) in a specific intron of the AML1 gene on chromosome 21. In this study, we cloned cDNAs synthesized from a cell line carrying t(8;21) by reverse transcription polymerase chain reaction (RT-PCR) using an AML1-specific primer. The analysis of the cDNAs structure has led to the identification of the fusion of AML1 with a gene named MTG8 on chromosome 8, which seems to be identical to ETO. Northern analysis using MTG8 (ETO) probes detected 7.8-kb and 6.2-kb RNAs and several minor RNAs in the cell line with t(8;21), but failed to detect any transcripts in a cell line without t(8;21). A set of primers were designed to detect the AML1/MTG8(ETO) fusion by PCR. The PCR amplified identical products in all 6 patients and one cell line with t(8;21), suggesting that the AML1/MTG8(ETO) fusion is a constant feature associated with t(8;21) and the junctions of the AML1/MTG8(ETO) fusion are restricted in a unique site. Because the PCR detection of the AML1/MTG8(ETO) fusion at the RNA level is highly sensitive, it can be used as a sensitive method for diagnosis and detection of minimal residual disease in t(8;21) leukemia.

The AML1 gene was rearranged in leukemic cells with t(8;21)(q22;q22) or its variant, complex t(8;V;21) translocations from 33 acute myeloid leukemia (AML) patients. The AML1 rearrangement was also detected in three AML patients without t(8;21); two had a normal diploid karyotype, and one had a karyotype of 45,X, - X. The AML1 rearrangement in the t(8;21) breakpoint cluster region was not detected in leukemic cells with cytogenetic abnormalities other than t(8;21), or with normal diploidy obtained from 23 AML patients. Because leukemic cells of the five patients with complex t(8;V;21) translocations had a der(8)t(8;21) chromosome with a break in band 8q22 in common, the juxtaposition of the 5' side of AML1 to a predicted counterpart gene located in the breakpoint region of 8q22 may be an essential step in the leukemogenesis of AML with t(8;21). Our findings show that the 8;21 translocation, its variants, and the masked t(8;21) may all be detectable by the Southern hybridization method using the AML1 probes.

The AML1 gene on chromosome 21 was rearranged by the t(8;21) chromosomal translocation in acute myeloid leukemia (AML). Southern blot analysis of 21 AML patients with t(8;21), including three with complex translocations, t(8;V;21), demonstrated that all the breakpoints occurred at random within a single intron between two coding exons of AML1. Clustering of the breakpoints in the restricted intron suggests the formation of a unique fusion gene between the AML1 gene and a presumable counterpart gene on chromosome 8. Nucleotide sequencing of the breakpoint region revealed that the translocation event was accompanied by deletion of a short stretch of nucleotides.

The chromosome der(1;7) (q10;p10) is a derivative chromosome consisting of the short arm of chromosome 7 and the long arm of chromosome 1. We observed this abnormality in three patients with acute myeloblastic leukemia (AML), myelodysplastic syndrome (MDS), or myeloproliferative disorder (MPD). Case 1 was a 76-yr-old male with a history of IgG myeloma treated with melphalan, cyclophosphamide, vincristine, and prednisolone (MEVP). AML-M1 developed one and half years after discontinuation of the MEVP therapy. Case 2 was a 39-yr-old male with MDS. Case 3 was a 56-yr-old male with refractory anemia with excess of blasts in transformation that evolved from primary myelofibrosis. Chromosome analyses revealed der(1;7) (q10;p10) in bone marrow cells of the three patients. All patients failed to respond to chemotherapy, and died within four months after the diagnosis. Thus, der (1;7) (q10;p10) may indicate a very poor prognostic outcome in patients with malignant hematologic disorders.

Two patients of acute myelogenous leukemia (AML) presented with a large intestinal tumor and related symptoms. They had a tumor in the rectum or the ascending colon. Bone marrow cells obtained from both patients showed a karyotype with t(8;21). Chromosomal findings in the former patient has already been reported in detail (Am J Hematol 4, 273, 1978). These findings and reports in the literature indicate that large intestinal tumor may not be rare in AML with an 8;21 translocation. Complete remission was achieved after chemotherapy, when their intestinal tumors disappeared.

Karyotypically unrelated clones were observed in nine of 399 newly diagnosed acute leukemia or myelodysplastic syndrome (MDS) patients: two (3.0%) of 66 French-American-British classification (FAB)-M2 patients, five (12.5%) of 40 M5 patients, one (20%) of five chronic myelomonocytic leukemia (CMMoL), patients, one (12.5%) of eight refractory anemia with excess blasts in transformation (RAEBT) patients, and none (0%) of 177 acute lymphoblastic leukemia patients had such clones. Cytogenetically unrelated clones occurred more frequently in FAB-M5 than in the other subtypes of AL or MDS (p less than 0.01). Five (55%) of the nine patients had trisomy 8, two (22%) had partial deletion of the long arm of chromosome 5 and two had (22%) trisomy 11. Patients had short survival times (median 2 months, range 1-26 months) after detection of unrelated clones; eight of the nine failed to respond to chemotherapy. None of our patients had two phenotypically different leukemic cell populations or underwent phenotypic conversion of leukemic cells during the course of the disease. These findings suggest that the unrelated clones may have been derived from the common leukemic clone without microscopic chromosome changes, and that the different chromosome abnormalities of the unrelated clones may represent additional genetic changes in leukemogenesis.

Five patients with acute nonlymphocytic leukemia and inv(16)(p13q22), all with additional chromosome changes, are reported. Three were diagnosed as having acute myelomonocytic leukemia (FAB-M4), and the other two as having acute monocytic leukemia (FAB-M5b). All five patients had abnormal eosinophils in the bone marrow at diagnosis. Two had a deletion of the long arm of chromosome #7, del(7)(q31), and a trisomy of chromosome #22. These changes have been reported frequently in acute nonlymphocytic leukemia with inv(16), but are extremely rare in leukemias with other specific rearrangements including t(9;22), t(8;21), and t(15;17). Our findings and review of the literature indicate that inv(16) is observed not only in acute myelomonocytic leukemia but also in acute monocytic leukemia, and that del(7q) and +22 are nonrandomly associated with inv(16) as additional abnormalities. No significant differences in the clinical features seem to exist between the patients with only inv(16) and those with inv(16) and additional chromosome changes, except for the lower white blood cell count in the latter group.

We studied chromosomes of BM cells from four neurofibromatosis (NF) patients with leukemia. One patient had a normal diploid karyotype in the chronic phase of juvenile chronic myelogenous leukemia (JCML). When the the leukemia evolved into the accelerated phase, she had cells with 46,XX,-7,+der(7)t(3;7)(q21;p22); the abnormalities resulted in a partial 7p deletion. In another patient with JCML, BM cells in the accelerated phase had 45,XY,-7. The abnormal cells with monosomy 7 disappeared from the BM after chemotherapy but reappeared later in the course. Another patient developed refractory anemia with excess of blasts in transformation (RAEB-T) and had cells with 46,XX,-6,+r(6)(p23?q21?); the abnormalities resulted in partial 6p and 6q deletions. The other patient with ANLL had cells with 45,XX,-7. Our findings and review of data on nine other patients suggest that BM cells of NF patients with JCML in chronic phase have no microscopically detectable chromosome changes and that cells with chromosomal deletion emerge when JCML evolve into the accelerated or blast phase. Thus, deletion of the whole or part of certain chromosomes, such as chromosomes 6, 7, etc., may be an important step towards the evolution of JCML cells or the development of de novo acute leukemias in NF patients.

An 8;21 chromosome translocation was found in cells from myeloblastomas of two acute myeloblastic leukemia (AML) patients. In one patient, a sudden onset of paraplegia, which was caused by an epidural myeloblastoma in the thoracic vertebral canal, was the initial symptom of the disease and that of the first relapse. In the other, myeloblastomas, which occurred in the breasts during a hematologic remission, heralded the first relapse. Karyotypes of tumor cells obtained from both patients showed the t(8;21) and additional chromosome abnormalities. These findings, together with earlier experience and reports in the literature, indicate that myeloblastoma may be unique to the 8;21 translocation, and that certain chromosomal abnormalities additional to the t(8;21) may be necessary for the tumor formation.

Using the human c-erbB-2 cDNA as a probe, we applied in situ hybridization techniques to acute promyelocytic leukemia cells with a 15;17 chromosome translocation, t(15;17)(q;22;q21), and were able to localize the c-erbB-2 gene on chromosome 17 to band q12 or q21 and on the proximal side of the breakpoint in the translocation. From this finding and previous observations by others, we presume that the gene and the breakpoint are both in band q21.1 of chromosome 17. We suggest possible involvement of the c-erbB-2 gene in the development of the t(15;17)-associated acute promyelocytic leukemia.