Hemophagocytosis by leukemic blasts in a case of acute megakaryoblastic leukemia with t(16;21)(p11;q22).

We report the case of a 2-year-3-month-old boy with acute megakaryoblastic leukemia showing hemophagocytosis by leukemic blasts. The chromosome analysis of his bone marrow revealed t(16;21)(p11;q22). In addition to the present case, we found 4 other acute myeloid leukemia (AML) cases associated with hemophagocytosis and t(16;21)(p11;q22) in the literature, of which 3 were megakaryoblastic. Although the syndrome of AML with FAB-M4/5 morphology, t(8;16)(p11;p13), and erythrophagocytosis is well known, leukemic blasts of FAB-M7 morphology showing t(16;21)(p11;q22) may be underscored for their phagocytic activity.     

Acute Myelomonocytic Leukemia with Dysplastic Bone Marrow Eosinophils Showing t(5;17)(q13;q11) and a Secondary Chromosomal Aberration, inv(16)(p13q22)

inv(16)(p13q22) is associated with de novo acute myelomonocytic leukemia with dysplastic bone marrow eosinophils (AMML Eo), which has a relatively favorable clinical course with a longer remission duration and better survival prospects. On the other hand, t(5; 17)(q13;q11), although relatively rare, has been reported to be a component of complex chromosomal abnormalities in myelodysplastic syndromes and secondary acute myeloid leukemia (AML). We treated a 29-year-old woman with the first reported case of de novo AMML Eo with inv(16)(p13q22) in addition to t(5; 17)(q13;q11). Although she attained complete remission (CR) immediately after induction therapy, the disease recurred 1 year after the completion of consolidation therapies. She underwent HLA-matched unrelated allogeneic bone marrow transplantation (UBMT), together with a myeloablative conditioning regimen, after achieving a second CR and has survived without a recurrence for more than 24 months since UBMT. In general, certain secondary chromosomal abnormalities are associated with the phenotype of the disease, which retains its essential biologic characteristics established by the primary abnormality. Accordingly, the primary nature of the leukemic cells in this case differs from the findings for core-binding factor AML with inv(16)(p13q22). We believe this report is the first of de novo AMML Eo with t(5; 17)(q13;q11) showing as a secondary chromosomal aberration with inv(16)(p13q22).     

Two Cases of Secondary Acute Myeloid Leukemia Accompanying Adult T-Cell Leukemia/Lymphoma

We identified 2 cases of secondary acute myeloid leukemia (AML) following adult T-cell leukemia/lymphoma (ATL) in patients who had previously received chemotherapy. Both cases were thought to represent therapy-related AML because the patients had previously received combination chemotherapy including epipodophyllotoxin, anthracycline, and alkylating agents for the ATL. The cases were diagnosed as AML M4 with eosinophilia and AML M2, with the chromosomal abnormalities inv(16)(p13q22) and t(8;21)(q22;q22), respectively. In our hospital, only these 2 cases of secondary AML accompanying ATL were identified among 90 cases of acute- or lymphoma-type ATL diagnosed from October 1999 to July 2006. The frequency of coexisting AML and ATL is lower than that reported for acute leukemia coexisting with other lymphoid malignancies. The low frequency of secondary leukemia with ATL may be associated with the short survival times of ATL patients.     

Acute myelogenous leukemia with a t(2;17;4)(p13;q21;p16) aberration: effective treatment with all-trans retinoic acid and granulocyte colony-stimulating factor

The efficacy of all-trans retinoic acid (ATRA) in patients with acute promyelocytic leukemia (APL) has been well documented. However, ATRA is not as effective against other types of acute myelogenous leukemia (AML) or myelodysplastic syndromes. We present a patient with AML (FAB: M2) associated with a t(2;17;4)(p13;q21;p16) chromosomal defect in which the 17q21 breakpoint was not within the retinoic acid receptor alpha locus which is typically rearranged in APL. This patient was successfully treated with ATRA and granulocyte colony-stimulating factor and improvement of hematological parameters lasted for 19 months without the use of cytotoxic agents.     

Acute promyelocytic leukemia with additional chromosome abnormalities in a renal transplant case

Some cases of acute myeloid leukemia following organ transplant (PT-AML) have been published in the literature. We report the second case of acute promyelocytic leukemia (APL), which developed post-transplant and immunosuppressive treatment, in a 50-year-old male who had undergone a renal transplant. At diagnosis he presented typical t(15;17)(q12;q13) with additional abnormalities, including +8,t(13;22)(q12;q13) and an abnormal chromosome 1 which was better characterized by fluorescence in situ hybridization (FISH). He obtained cytological, karyotypic and molecular complete remission (CR) with induction treatment according to the all-trans retinoic acid + idarubican (AIDA) protocol; after 12 months, he relapsed (molecular relapse) and achieved molecular remission with all-trans retinoic acid (ATRA) plus mitoxantrone and cytosine arabinoside. After a further 14 months, he was treated with arsenic trioxide for cytological relapse and obtained a third CR; at the cytological relapse the karyotype showed 47,XY,+8, t(15;17)(q22;q21),t(13;22)(q12;q13),der(22)t(1;22)(p22;q13). He is alive 3.3 years after diagnosis of APL. Cyclosporin A (CsA) was given during all cycles of chemotherapy. We did not observe any severe infections or kidney failure during treatments. The use of conventional cytogenetic analysis plus FISH may identify complex karyotype also in transplanted patients receiving immunotherapy, and may also contribute to a better assessment of PT-AL.     

Childhood acute myeloid leukemia with bone marrow eosinophilia caused by t(16;21)(q24;q22)

Acute myeloid leukemia with abnormal bone marrow eosinophilia (AML-M4Eo) is often reported in core binding factor (CBF) leukemia, with translocations such as inv(16)(p13q22), t(16;16)(p13;q22) or t(8;21)(q22;q22); however, it is rarely reported with t(16;21)(q24;q22), which produces the RUNX1-CBFA2T3 (AML1-MTG16) chimera. The similarity between this chimera and RUNX1-RUNXT1 (AML1-MTG8) by t(8;21)(q22;q22) remains controversial. Adult leukemia with t(16;21)(q24;q22) was primarily therapy related, and shows poor prognosis; however, pediatric AML with this translocation was quite rare and tended to be de novo AML. We present here a 4-year-old boy with de novo AML-M4Eo and t(16;21)(q24;q22). He received chemotherapy and survived for more than 70 months without transplantation. We speculated that pediatric AML with t(16;21)(q24;q22) showed favorable prognosis, as with t(8;21)(q22;q22).     

Comprehensive profile of cytogenetics in 2308 Chinese children and adults with de novo acute myeloid leukemia

Diagnostic cytogenetic and molecular analysis is recognized as the most valuable prognostic factor in acute myeloid leukemia (AML). Among 2516 consecutive Chinese patients with de novo AML, 2308 patients had successful cytogenetic results including 61 subclasses of cytogenetic abnormalities and 27 kinds of additional cytogenetic abnormalities. The incidence of t(15;17)(q22;q12) was highest (16.7% of 2308 patients), followed by t(8;21)(q22;q22) (15.1%), trisomy 8 (5.5%), loss of Y (4.5%), trisomy 21 (2.4%), inv(16)(p13q22) or t(16;16)(p13;q22) (2.1%), etc. In comparison to children, adults had higher incidence of normal karyotype (41.5% vs. 29.1%, P<0.001) and lower incidences of t(8;21)(q22;q22) (13.4% vs. 25.8%, P<0.001), t(9;11)(p22;q23) (0.2% vs. 1.2%, P=0.001) and other 11q23 rearrangements (1.0% vs. 3.4%, P<0.001). Among 349 AML patients with t(8;21)(q22;q22), 310 (35.5%) were found in 873 patients with M2. The t(15;17)(q22;q12) was exclusively observed in 386 (71.0%) of 544 patients with M3. In 48 AML patients with inv(16)(p13q22) or t(16;16)(p13;q22), 42 (15.2%) were detected in 276 patients with M4. Our study displayed the cytogenetic characteristics in a large series of Chinese patients with de novo AML. Our results revealed the similarities and differences of cytogenetic abnormalities existing between Chinese and western AML patients.     

Two Independent Clones in Myelodysplastic Syndrome Following Treatment of Acute Myeloid Leukemia

We describe a 55-year-old Japanese woman with therapy-related myelodysplastic syndrome (t-MDS) with 2 independent clones, t(1;2)(p36;p21) and t(11;12)(pl5;ql3). She was diagnosed with acute myeloid leukemia (AML) with cytological features of the bone marrow and peripheral blood. Cytogenetic evaluation revealed a 46,XX karyotype. She received chemotherapy and achieved complete remission (CR). Despite maintenance chemotherapy, she suffered a relapse. Chromosomal analysis showed t(1;2)(p36;p21) in 2 of 20 metaphases. At second CR, this clone transiently disappeared. Nine months later, t(1;2) (p36;p21) was detected again in 3 of 20 metaphases while the patient remained in CR. Six months later, bone marrow examination disclosed trilineage dysplasia without an excess of blasts, suggesting MDS. t(1;2)(p36;p21) was observed in 16 of 20 metaphases. The clinical course and serial cytogenetic findings were diagnostic of t-MDS. The duration of t-MDS was 6 years. During this period, persistent t(1;2)(p36;p21) and transient t(11;12)(p15;q13) were found. When t-MDS evolved toAML, cytogenetic evaluation revealed 46,XX,t(1;2)(p36;p21),del(7)(q22),add(19)(p13).     

Additional chromosomal abnormality of inv(16)(p13q22) to del(7)(q32) in a patient with acute myelomonocytic leukemia

We report a 54-year-old man with acute myeloid leukemia (AML) carrying del(7)(q32) and inv(16)(p13q22). He was diagnosed as having AML M4Eo according to the FAB classification. RT-PCR for CBFβ/MYH11 gene was positive. Karyotype analysis revealed the primary chromosomal abnormality to be del(7)(q32) and inv(16)(p13q22) developed as a secondary abnormality. He achieved complete remission after one course of induction chemotherapy and remained in remission after several courses of consolidation therapy. del(7q) is classified into an intermediate risk group or an adverse risk group, while inv(16)/t(16;16) is classified into a favorable risk group. Some AML cases with inv(16)/t(16;16) exhibit del(7q) as an additional chromosomal abnormality. It was reported that such cases showed good prognosis despite the presence of del(7q). However, AML cases with del(7q) and inv(16)/t(16;16) as secondary chromosomal abnormalities are rare. Further study is needed to clarify the clinical manifestations of such cases.     

How high can we increase complete remission rate in adult acute myeloid leukemia?

Unequivocally, complete remission (CR) is a prerequisite for the cure for acute leukemia. The history of drug therapy for acute leukemia has taught us that only after CR rates exceed 90% can a satisfactorily high cure rate be obtained, as is observed in acute lymphoblastic leukemia in children and acute promyelocytic leukemia (APL). In multicenter studies of adult acute myeloid leukemia (AML), CR rates hardly exceed 80% with currently available cytotoxic drugs, except for a small fraction of patients having AML with t(8;21) or inv(16). CR rates and survival of adult patients with AML in 4 studies by the Japan Adult Leukemia Study Group from 1987 to 1997 do not improve at all when appropriately adjusted. The remarkable effects of all-trans-retinoic acid in APL and STI571 in chronic myeloid leukemia have shown us the direction of cancer therapy in the 21st century. We should shift the paradigm from nonspecific cytotoxic chemotherapy to therapy that specifically targets the genes or gene products that are responsible for leukemogenesis.     

Acute myeloid leukaemia with t(8;16)(p11;p13) in a child after intrauterine X-ray exposure

We describe t(8;16)(p11;p13) acute myeloid leukaemia (AML-M4) in a 12-year-old white male with a history of prenatal X-ray exposure. He had skin and bone involvement and some of the leukaemic blasts showed haemophagocytosis, characteristic features seen in t(8;16) AML. 20% of the reported cases of t(8;16)(p11;p13) AML are therapy-related and this case further supports the possible role of the ionizing radiation in the development of this disorder.     

Cytogenetic abnormalities in childhood acute myeloid leukaemia: a Nordic series comprising all children enrolled in the NOPHO-93-AML trial between 1993 and 2001

Between 1993 and 2001, 318 children were diagnosed with acute myeloid leukaemia (AML) in the Nordic countries. The patient group comprised 237 children < 15 years of age with de novo AML, 42 children < 15 years with Down syndrome (DS) and de novo AML, 18 adolescents 15-18 years of age with de novo AML, and 21 children < 15 years with treatment-related AML (t-AML). The first group was all-inclusive, yielding an annual childhood de novo AML incidence of 0.7/100 000. Cytogenetic analyses were successful in 288 cases (91%), and clonal chromosomal abnormalities were detected in 211 (73%). The distribution of ploidy levels were pseudodiploidy (55%), hyperdiploidy (34%) and hypodiploidy (11%). The most common aberrations (> 2%) were + 8 (23%) (as a sole change in 6.2%), 11q23-translocations, including cryptic MLL rearrangements (22%) [t(9;11)(p21-22;q23) in 11%], t(8;21)(q22;q22) (9.0%), inv(16)(p13q22) (6.2%), -7/7q- (5.2%), and t(15;17)(q22;q12) (3.8%). Except for +8, these abnormalities were rare in group 2; only one DS patient had a t(8;21) and none had 11q23-translocations, t(15;17) or inv(16). In the t-AML group, three cases displayed 11q23-rearrangements, all t(9;11); and there were no t(8;21), t(15;17) or inv(16). Overall, the observed frequencies of t(8;21) and t(15;17) were lower, and frequencies of trisomy 8 and 11q23-translocations higher, than in previous studies. Furthermore, seven abnormalities that were previously reported as only single AML cases were also seen, meaning that der(4)t(4;11)(q26-27;q23), der(6)t(1;6)(q24-25;q27), der(7)t(7;11)(p22;q13), inv(8)(p23q11-12), t(11;17)(p15;q21), der(16)t(10;16)(q22;p13) and der(22)t(1;22)(q21;q13) are now classified as recurrent abnormalities in AML. In addition, 37 novel aberrations were observed, 11 of which were sole anomalies.     

11q23少见染色体易位同时具有t（8；21）的急性白血病1例报告并文献复习

目的:报道13号染色体为11q23伙伴染色体的急性髓系白血病(AML)1例,该例患者同时具有t(8;21)染色体易位。方法:用R显带技术进行核型分析。结果:染色体核型分析结果为45,x,-y,t(8;21)(q22;q22),t(11;13)(q23;q13)[5]/44,x,-y,t(8;21),t(11;13)[CP5]。结论:13号染色体为11q23少见的伙伴染色体,国内迄今未见报道,国外报道4例。同时具有11q23异常和t(8;21)的急性白血病,国内文献中尚未见到这种病例。同时具有2个特异的细胞遗传学异常的AML有可能为一新的临床遗传学类型。     

Acute myeloid leukemia associated with FGFR1 abnormalities

Hematologic malignancies associated with FGFR1 abnormalities present in heterogeneous forms, including myeloproliferative neoplasm, acute myeloid leukemia (AML), T- or B-lineage lymphoblastic leukemia/lymphoma, and even mixed phenotype acute leukemia. In the present report, we describe three new cases of AML associated with FGFR1 abnormalities: AML with minimal differentiation with 45,XY,-7,t(8;13)(p11.2;q12), acute myelomonocytic leukemia with eosinophilia with 48,XY,t(8;9)(p11.2;q33),+19,+21, and AML with minimal differentiation with 46,XX,add(8)(p11.2). FGFR1 abnormalities were confirmed by fluorescence in situ hybridization. We reviewed the records of 19 patients reported from Asian countries, and found that approximately 40 % of cases manifested as acute leukemia associated with myeloid lineage, and 47 % were not accompanied with eosinophilia. These findings highlight the need for detection of FGFR1 abnormalities, not only in myeloproliferative disorder, but also in AML patients even without eosinophilia. The prognosis for this group of neoplasms is poor, and there is no recognized effective targeted treatment. Two patients, including our case, who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) survived. Accumulation of long-term follow-up data can help determine the allo-HSCT protocol or the need for new therapeutic trials to improve the survival rate of patients with FGFR1 abnormalities.     

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.     

<Emphasis Type="Italic">MLL/AF-1p</Emphasis> Fusion in Therapy-Related Early Pre-B Acute Lymphoblastic Leukemia with t(1;11)(p32;q23) Translocation Developing in the Relapse Phase of Acute Promyelocytic Leukemia

We report the development of therapy-related early pre-B acute lymphoblastic leukemia in a patient administered a topoisomerase II inhibitor, etoposide, a consolidation therapy agent for acute promyelocytic leukemia. Our case is of interest because of simultaneous relapse of the original leukemia and onset of therapy-related leukemia and relatively rare t(1;11)(p32;q23) translocation with confirmed MLL/AF-1p fusion. This case suggests that careful monitoring for MLL gene rearrangements is necessary after administration of topoisomerase II inhibitors.     

Therapy-Related Acute Myeloid Leukemia 6 Years after Clonal Detection of inv(11)(q21q23) and MLL Gene Rearrangement

Results of recent studies with animal models suggest that expression of MLL fusion proteins promotes acute leukemogenesis. However, the most potent MLL fusion proteins are not sufficient for the development of acute myeloid leukemia (AML). The clinical data on the pathogenesis of this type of leukemia are limited. We analyzed the case of a patient with therapy-related AML with MLL rearrangement. The patient initially developed AML with t(8;21). Although the patient achieved complete remission with chemotherapy, an abnormal karyotype, inv(11)(q21q23), was detected. After 6-year persistence of a clone with the inversion 11 karyotype in the bone marrow, secondary AML developed. Results of fluorescence in situ hybridization analysis combined with magnet-activated cell sorting analysis showed that MLL rearrangement was detected in CD34+ and CD13+ fractions but not in a CD3+ fraction of the bone marrow. There were 2 important clinical findings. One was that MLL rearrangement was not sufficient for the development of leukemia. The other was that MLL rearrangement targets specific lineages.     

Acute myeloid leukemia M2 and t(8;21)(q22;q22) with an unusual phenotype: myeloperoxidase (+), CD13 (–), CD14 (–), and CD33 (–)

 Cases of myeloid surface antigen-negative acute myeloid leukemia (AML) are rare. We describe the morphological, cytochemical, immunologic, and cytogenetic features of two patients with AML with maturation (FAB M2) and the phenotype MPO+, CD13 (–), CD33(–), CD56(+). Cytogenetic studies demonstrated t(8;21)(q22;q22). These findings suggest an association between the lack of CD13 and CD33 in myeloperoxidase-positive AML and the presence of t(8;21). Received: August 8, 1998 / Accepted: January 27, 1999