Repetitive cycles of high-dose cytarabine benefit patients with acute myeloid leukemia and inv(16)(p13q22) or t(16;16)(p13;q22): results from CALGB 8461.

PURPOSE: To study the impact of repetitive (three to four courses) versus a single course of high-dose cytarabine (HDAC) consolidation therapy on outcome of patients with acute myeloid leukemia (AML) and inv(16)(p13q22) or t(16;16)(p13;q22). PATIENTS AND METHODS: We examined the cumulative incidence of relapse (CIR), relapse-free survival (RFS), and overall survival (OS) for 48 adults younger than 60 years with inv(16)/t(16;16) who had attained a complete remission on one of four consecutive clinical trials and were assigned to receive HDAC consolidation therapy. Twenty-eight patients were assigned to either three or four courses of HDAC, and 20 patients were assigned to one course of HDAC followed by alternative intensive consolidation therapy. RESULTS: Pretreatment features were similar for the two groups. The CIR was significantly decreased in patients assigned to receive three to four cycles of HDAC compared with patients assigned to one course (P=.03; 5-year CIR, 43% v 70%, respectively). The difference in RFS also approached statistical significance (P=.06). In a multivariable analysis that adjusted for potential confounding covariates, only treatment assignment (three to four cycles of HDAC) predicted for superior RFS (P=.02). The OS of both groups was similar (P=.93; 5-year OS, 75% for the three to four cycles of HDAC group v 70% for the one cycle of HDAC group), reflecting a high success rate with stem-cell transplantation salvage treatment administered among patients in both treatment groups. CONCLUSION: We conclude that, in AML patients with inv(16)/t(16;16), repetitive HDAC therapy decreases the likelihood of relapse compared with consolidation regimens including less HDAC.     

Lymphoid blastic crisis of chronic myelogenous leukaemia with inv(16)(p13;q22)

We report a case of chronic myelogeneous leukaemia (CML) in B-lineage lymphoid blastic crisis (BC) having chromosome abnormality, inv(16)(p13;q22) in addition to Philadelphia chromosome, in 20/20 marrow metaphase. Inv(16)(p13;q22) was not observed in cells of chronic phase or accelerate phase. Abnormalities of chromosome 16, including inv(16)(p13;q22), del(16)(q22) and t(16;16)(p13;q22), have been reported mostly in acute myelomonocytic leukaemia (AML), (FAB M4-Eo), and some in CML-BC and myelodysplastic syndrome (MDS) cases. Most of the cases showed increase of myelomonocytic components and abnormal eosinophils with dysplastic granules in the bone marrow (BM). However, our case was diagnosed as lymphoid BC without increase of myelomonocytic components, although some abnormal eosinophilia was seen. To date, lymphoid BC of CML having inv(16)(p13;q22) abnormality has not been reported. The case presented here could be a clue to understand the pathophysiology of inv(16)(p13;q22) leukaemia.     

Acute minimally differentiated myeloid leukemia (M0) with inv(3)(q21q26)

We describe a 55-year-old Japanese man with acute minimally differentiated myeloid leukemia (M0) with an inversion in the long arm of chromosome 3, i.e., inv(3)(q21q26). Patients with this chromosomal abnormality usually show normal or elevated platelet counts. However, our case had a low platelet count with megakaryocytic dysplasia at diagnosis. Furthermore, the 3q21q26 aberration is generally detected in patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome. To the best of our knowledge, it has also been reported in two cases of AML-M0 with 3q21q26 and this is the third case of AML-M0 with 3q21q26. Thus it is suggested that there is some relationship between this type of karyotype abnormality and leukemogenesis and/or thrombopoiesis.     

Acute myeloid leukemia with inv(8)(p11q13)

A patient with acute monoblastic leukemia (AML M5a) and the pericentric inversion inv(8)(p11q13) as well as additional chromosome abnormalities in her bone marrow cells is described. This is the fourth known case of inv(8)(p11q13)-positive acute leukemia, and the second such case in which gain of 1q material occurred during clonal evolution. All patients with acute leukemia and inv(8)(p11q13) have been females, most have been young, and there has been a tendency for the disease to run an aggressive course. Both hematologically and cytogenetically, therefore, inv(8)(p11q13)-positive leukemia may be viewed as a variant of AML with t(8;16)(p11;p13). This similarity is also apparent at the molecular genetic level, in-as-much as the MOZ gene in 8p11 is rearranged in both the translocation and the inversion; in t(8;16)-positive leukemia, a MOZ-CBP chimeric gene is generated, whereas inv(8) has been shown to generate a MOZ-TIF2 fusion gene. Southern blot analysis of the present case after MOZ0.8 hybridization of Bam HI digested DNA gave an 11 kb aberrant band in addition to the germline band, corresponding to a breakpoint immediately upstream of the 4 kb long MOZ exon that begins at position 3746. Also previously investigated inv(8)-positive leukemias have shown breaks in this intron indicating that it contains sequence motifs predisposing to illegitimate recombination.     

Efficacy and clinical cross-resistance of a new combination therapy (AMSA/VP16) in previously treated patients with acute nonlymphocytic leukemia

We investigated the tolerance, efficacy, and clinical cross-resistance of a new combination chemotherapy in 38 patients with previously treated acute myeloblastic leukemia (AML). It consisted of 120 mg2/d 4'(9-acridinylamino) methanesulfon-m-Anisidide (m-AMSA) in a one-hour infusion and 80 mg/m2/d etoposide (VP-16) in a 24-hour infusion, both administered for 5 days. The first 27 patients also received vinblastine, 6 mg/m2 on day 8, but this therapy was discontinued because of intestinal complications. Thirteen of 23 patients (56%) at first or subsequent relapse and five of 15 patients (33%) who were primarily resistant to an anthracycline/cytarabine combination achieved a complete response (CR) (hemoglobin level not taken into account) with a median CR duration of 5 months and 2 months, respectively. The response rate was as high as 63% for patients at first or second relapse whether the remission was maintained or not. The median times to recovery of normal bone marrow cellularity, of blood granulocyte counts greater than 500/microL, and of platelets greater than 20,000/microL were 34, 27, and 22 days, respectively. Marked but reversible gastrointestinal toxicity was observed in 24% of the patients, and two patients died of infection during induction. The one-hour AMSA/continuous VP-16 combination is effective for patients with relapsing AML and shows no cross-resistance in a proportion of patients refractory to the standard anthracycline-cytarabine combination.     

伴t(8;21)(q22;q22)易位的急性双表型白血病的临床研究

目的:报道新发现4例伴t(8;21)(q22;q22)易位的急性双表型白血病(biphenotypic acute leukemia,BAL),分析其细胞形态学、免疫表型、染色体核型分型及临床特征。方法:将4例伴t(8;21)(q22;q22)易位的BAL(A组),与随机挑选同期发现的伴其他克隆性染色体改变的BAL(B组)和伴t(8;21)(q22;q22)的M2b(C组)病例对照,对染色体核型分型及临床特点比较分析。结果:伴t(8;21)(q22;q22)易位的BAL特点如下:①无显著男女性别差异;②发病年龄较轻;③外周血白细胞计数不增高;④骨髓细胞形态学显示为粒细胞白血病,且原始细胞显著增多;⑤免疫表型均为B淋巴系和髓系共表达的BAL,CD34表达阳性,且为高表达;⑥染色体改变除t(8;21)(q22;q22)易位外,亦常见性染色体缺失,与(acute myeloid leukemia,AML)AML-M2b的特点相符;亦出现复杂染色体改变,符合BAL的特点。⑦对兼顾髓系和淋巴系的联合治疗方案反应较好,与B组的BAL类似,1例单用AML方案(MA)治疗者NR,后死亡。结论:报道新发现的一组伴t(8;21)(q22;q22)易位的BAL,提示此类患者的白血病细胞克隆起源可能较早。     

伴t(8;21)(q22;q22)易位的急性双表型白血病的临床研究

Objective： To report 4 cases of biphenotypic acute leukemia （BAL） with t（8;21）（q22;q22）, and analyze the characteristics of morphology, immune phenotype, chromosome karyotype （MIC） and clinical manifestations. Methods： The BAL patients with t（8;21）（q22;q22） （group A） were compared with the randomly selected BAL patients with other clonical chromosomal changes （group B） and acute myeloid leukemia M2 cases with t（8;21）（q22;q22） （group C） in MIC and clinical features. Results： BAL with t（8;21）（q22;q22） showed acute myeloid leukemia with high percentages of blast cells morphologically; revealed co-positive to B-lymphoid and myeloid lineages, frequent and high expressions of CD34 and CD33; were responsive to chemotherapy for myeloid and lymphocytic leukemia simultaneously well. Conclusion： A new subset of BAL with t（8;21）（q22;q22） was reported, and this suggests that the leukemia colony with t（8;21）（q22;q22） might originate from early phase of hematopoiesis.     

Expression of fragile site 8q22 in peripheral blood lymphocytes taken from patients with acute leukemia M2 having t(8;21)(q22;q22)

The relation between the expression of common fragile sites and chromosomal breakpoints in neoplastic cells in the same patients has not been well studied. In the present study, the frequency and distribution of aphidicolin-induced breaks on chromosomes 8 and 21 in peripheral blood lymphocytes (PBL) taken from three patients with acute myeloid leukemia, French-American-British classification type M2, having chromosomal translocation t(8;21)(q22;q22) (M2t) were studied prior to any initial treatment. Seven patients with other types of acute leukemia without t(8;21) and 13 healthy people were also studied. In PBL from patients with M2t, the numbers of chromosomal breaks were 1, 7 and 3/216 metaphasees at bands 8q21, 8q22 and 8q24, respectively; the frequencies at 8q22 and 8q24 being significantly higher than those for patients with the other leukemias and for the healthy subjects (p less than 0.001 and p less than 0.01, respectively). These results suggest that the fragility on chromosome 8q21-24 is related to a predisposition to this particular type of leukemia.     

The importance of IGHV mutational status in del(11q) and del(17p) chronic lymphocytic leukemia

BACKGROUND: Most patients with CLL with a poor-risk cytogenetic profile have an unmutated IGHV sequence. Limited clinical information exists for patients with CLL who have a poor-risk cytogenetic profile and a mutated or good-risk IGHV status. We retrospectively screened all patients with CLL seen at our institution from 2006 onward who harbored a del(11q) or del(17p) CLL detected by fluorescence in situ hybridization (FISH) analysis for whom an IGHV analysis was requested. In 66 evaluable patients, 50 (76%) had an unmutated IGHV sequence. Thirty-nine patients (59%) had del(11q) and 27 patients (41%) had del(17p); no patient in this series had both del(11q) and del(17p). The patients' initial clinical presentations were similar in both mutational groups. Patients with an unmutated IGHV sequence were more likely to receive treatment and to have a shorter survival, with an estimated 3-year overall survival (OS) of 81% compared with 100% in the group with a mutated IGHV sequence (log rank, P = .06). These data suggest that IGHV mutational status has prognostic relevance even in patients with CLL who are defined as poor risk by genomic FISH analysis.