Isochromosome 17q in Ph1-negative leukemia: a clinical, cytogenetic, and molecular study

We report on eight patients who were 35 to 77 years old with an isochromosome 17q as the sole structural chromosomal anomaly. Additional numerical chromosomal changes were a trisomy 8 or 17 in two cases each and a trisomy 19 in one case. Five patients had myelodysplastic syndrome (MDS) diagnosed according to the FAB nomenclature as chronic myelomonocytic leukemia (CMML) in two cases, refractory anemia with excess of blasts in transformation (RAEBt) in two cases, and refractory anemia with excess of blasts (RAEB) in one case. One patient suffered from a myeloproliferative disorder (MPS). All cases progressed to acute nonlymphocytic leukemia (ANLL) type M1, M2, or M4 in a period of 2 to 30 months after initial diagnosis, except one patient with RAEBt who died within 2 months. Two patients presented with ANLL-M2 at time of diagnosis. Treatment during the chronic phase of disease consisted of mild cytoreduction and/or substitution of platelets or red blood cells. One patient with CMML received an allogeneic bone marrow graft and relapsed after 33 months with ANLL-M1. Treatment results for overt leukemia were poor, and survival was short, lasting from 1 to 4 months. Overall survival was 1 to 37 months (median duration, 6.5 months). Molecular studies in two cases revealed neither a BCR rearrangement nor a translocation of the ABL protooncogene, as observed in Ph1-positive chronic myeloid leukemia (CML). Thus, an i(17q) anomaly seems to identify a distinct subgroup of mostly myelodysplastic and, less frequently, myeloproliferative disorders that progress rapidly to ANLL, respond poorly to chemotherapy, and are associated with short survival after transformation.     

Transformation of myeloma into Ph1-negative CML with plasma cell antigens

We report a patient in whom Ph1-negative chronic myelogenous leukemia (CML) developed 15 years after the diagnosis of myeloma. Combined staining of morphologically myeloid elements in the peripheral blood for myeloid and plasmacytoid antigens revealed double-marker expression, suggesting that the two neoplasms arose from a common originator cell.     

Philadelphia chromosome (Ph1)-positive acute lymphoblastic leukemia (ALL) is resistant to effective therapy for Ph1-negative ALL

Amsacrine with high-dose cytarabine is effective therapy for Philadelphia chromosome (Ph1)-negative acute lymphoblastic leukemia (ALL). We examined the effectiveness of this regimen in 19 patients with Ph1-positive lymphoblastic leukemia. Four had an antecedent chronic phase of chronic myelogenous leukemia and 15 presented with ALL. There were no complete responders in either group. All 14 patients whose bone marrow could be assessed after completion of therapy showed persistent leukemia. We conclude that patients with Ph1-positive lymphoblastic leukemia have a disease that is resistant to treatment that is highly effective in patients with Ph1-negative ALL.     

Philadelphia chromosome (Ph1)-negative chronic myelogenous leukemia (CML): a clonal disease with origin in a multipotent stem cell

It has been shown with glucose 6-phosphate dehydrogenase (G-6-PD) mosaicism that Ph1-positive chronic myelogenous leukemia (CML) is a clonal disease that involves multipotent hematopoietic stem cells. We now report G-6-PD studies of a 79-yr-old woman with Ph1-negative CML. Equal amounts of B and A-type activities were found in nonhematopoietic tissues, indicating that the patient was heterozygous for G-6-PD. In contrast, only A-type G-6-PD was found in marrow cells, blood erythrocytes, leukocytes, and platelets and in granulocyte-monocyte and eosinophil colonies grown from blood mononuclear cells. Unlike most cases of PH1-positive CML, colony growth in this patient increased during blastic transformation and the colonies contained only immature monocytic cells. The data indicate that in this patient, Ph1-negative CML is similar to the Ph1-positive form of the disease in involvement of multipotent stem cells and probable clonal origin, but the two disorders differ in the rapidity with which they enter blastic transformation and in the pattern of granulocyte-monocyte colony growth at that time.     

Ph1-positive acute lymphoblastic leukemia associated with an isochromosome 17q.

We report a patient with Ph1-positive acute lymphoblastic leukemia (ALL) having i(17q) in whom bony lesions were the initial clinical manifestation. The patient was a 53-year-old male who began to have pains in his left hip early in March 1985. Relevant findings on admission included: WBC 21,300/microliters; blast cells 73.5%; peripheral blood blast cells, peroxidase (-), PAS (-) and esterase (-); cytoimmunologic markers, Ia(+) cells 49.1%, CD10(+) cells 67.1%, CD20(+) cells 75.1%; positivity for TdT, and Ph1(+); and i(17q) upon chromosomal analysis. These findings led to a diagnosis of ALL with Ph1(+),i(17q). This case seems to represent an exceedingly rare instance of Ph1(+),i(17q) ALL in which the differential diagnosis between blast transformation of CML and Ph1(+) ALL was initially difficult to make.     

“Masked” Ph1-chromosome in chronic myelogenous leukaemia (CML)

Summary The CML patients with so called masked Ph¹-chromosome have been reviewed. Although the importance of c-sis and c-abl oncogenes is gaining popularity yet their role in the genesis of CML remain obscure. Patients with masked Ph¹-chromosomes where chromosome 9 is not involved in the translocation(s) will provide a clue to the role of c-abl and/or c-sis in oncogenesis.     

Exacerbation of acute leukemia bearing isolated i(17q) along with proliferation of blasts with high BMI-1 expression

We report a case of acute leukemia with an isolated isochromosome 17q karyotypic abnormality, which may be transformed from myeloproliferative disease (MPD)/myelodysplastic syndrome (MDS). A 69-year-old male patient with 27% of blasts in the peripheral blood underwent hematological examinations including cytochemical staining of cells such as myeloperoxydase (MPO), surface marker study on blasts, chromosomal test and bcr-abl mRNA analysis. The cytological and molecular findings (MPO-positive, myeloid marker CD13 expression (67.3%) and megakaryocytic marker CD41 expression (24.8%)) indicated that the blasts were consistent with myeloid leukemic cells partially committed to megakaryocytes. He was diagnosed as having leukemic transformation from MPD/MDS based on history of leukocytosis and thrombocytosis, isolated i(17q), bcr-abl negative, hepatosplenomegaly, increased eosinophil/basophil count and cytologic dysplasia. Positivity of BMI-1 in CD34+ blasts was 25.8% at the diagnosis and anti-leukemic drugs including anthracyclines were effective for his disease control during 6 months. However, the CD34+ cells turned out to highly express BMI-1 (83.1%), and leukemic cells started to increase progressively following which the leukemic cells failed to respond efficiently to any anti-leukemic drugs. Thus, expression of BMI-1 was well correlated with the disease progression, growth ability of blasts and resistance to anti-cancer drugs, indicating that BMI-1 positivity in CD34+blasts is an excellent molecular marker for disease progression and prognosis in such patients.     

Significance of Ph1-negative marrow cells in Ph1-positive chronic granulocytic leukemia

Fifty-six of 195 Ph1-positive patients with chronic granulocytic leukemia were found to have Ph1-negative metaphases in marrow aspirates on one or more occasions. In 22 cases, Ph1-negative cells were found prior to initiation of antileukemic therapy. Five patients were in the blastic stage of the disease when Ph1-negative mitoses were seen. The finding of Ph1-negative cells appeared to be related principally to short duration of CGL and to administration of antileukemic therapy (conventional agents and doses, in most cases). Ph1-negative cells were usually not found more than 2 yr after the diagnosis of leukemia, but in a few cases, they were seen as long as 5-10 yr after diagnosis. Only a minority of metaphases analyzed were Ph1-negative, except in the case of 6 patients who transiently had 50% or more Ph1-negative cells after antileukemic therapy. The presence of Ph1-negative cells in marrow was not associated with any survival advantage in this series.     

The chromosomes and causation of human cancer and leukemia: XXXVIII. Cytogenetic experience in Ph1-negative chronic myelocytic leukemia (CML).

Among 300 patients with chronic myelocytic leukemia (CML) followed at our institute during the last ten years, 36 (12%) were thought to have Ph1-negative CML. In eight of these patients, chromosomal abnormalities were found in the leukemic cells; in four, the karyotypic abnormalities were established with banding techniques. The data of the present study and a review of the literature regarding chromosomal changes in Ph1-negative CML indicate that: 1) no characteristic or consistent karyotypic change is present in Ph1-negative CML and that diploidy is more common in this than any other leukemia; 2) the most common changes involve group C chromosomes (particularly +8); and 3) a missing Y is less common in Ph1-negative CML than in its Ph1-positive counterpart. The karyotypic changes in Ph1-negative CML resemble more those encountered in Ph1-positive CML than in acute myeloblastic leukemia (AML). The much shorter survival of the Ph1-negative CML patients vs that of the Ph1-positive group was again substantiated, and some of the previously reported clinical and laboratory findings unique to Ph1-negative CML were confirmed. On the basis of the cytogenetic findings it is concluded that Ph1-negative CML appears to be an entity unto itself.     

Reappearance of t(12;17)-positive primary myelofibrosis following Ph+ CML cell reduction by imatinib

A 67-years old woman was referred to our hospital in October 1992 with thrombocytopenia and splenomegaly. A bone marrow biopsy revealed decreased cellularity, with moderately increased reticulin fibrosis and discrete dysmorphic megakaryocytes but no signs of dysplasia in the erythroid or the myeloid lineages. The karyotype of the bone marrow cells was t(12;17) (q24;q11). She was diagnosed as having agnogenic myeloid metaplasia. The patient received only blood transfusions until November 1998 when leukocytosis with immature cells started to appear. The bone marrow aspiration analysis showed increased cellularity and chromosomal analysis demonstrated the presence of t(9;22) (q34;q11) without any t(12;17) (q24;q11) abnormality. Because IFN therapy and oral administration of hydroxyurea did not show any cytological effect, administration of imatinib mesylate was started from December 2001. The Ph-positive cells as demonstrated by the FISH method had decreased to 7% by April 2003. But the t(12;17)(q24;q11) positive clones, which were observed on the first admission, again appeared in the peripheral blood, whereas Ph clones were detected in only one out of 24 cells examined. During the course of treatment with imatinib mesylate for chronic myelogenous leukemia which developed from agnogenic myeloid metaplasia accompanied with t(12;17)(q24;q11) translocation, the co-existence of two clones derived from, possibly, stem cells was identified.     

Ph1-positive acute lymphoblastic leukemia with a 14q+ chromosome abnormality

A 13-yr-old Japanese female with acute lymphoblastic leukemia (ALL) that was associated with a Philadelphia chromosome (Ph1) as well as a 14q+ chromosome abnormality is reported. The cell surface phenotype of leukemic cells was determined to be non-T, non-B ALL on the basis of positive Ia-like antigen, terminal deoxynucleotidyl transferase activity, and lack of receptors for sheep erythrocytes, surface immunoglobulin, or intracytoplasmic mu-chain immunoglobulin. The combination of both a Ph1 and a 14q+ has not been reported previously in patients with ALL.     

The Philadelphia chromosome (Ph1) in adults presenting with acute leukaemia: a comparison of Ph1+ and Ph1-patients.

To evaluate the frequency and clinical significance of the Philadelphia chromosome (Ph1) in adult acute leukaemia, bone marrow chromosomes were studied in 15 adults with acute lymphocytic leukaemia (ALL) and 55 with acute nonlymphocytic leukaemia (ANLL). Morphology, clinical findings, therapeutic response and survival were compared in patients with and without the Ph1. The Ph1 was found in six newly diagnosed adults presenting with ALL. Adults with Ph1+ ALL differed from those with Ph1-ALL in being older, in having more frequent lymphadenopathy and splenomegaly and in demonstrating higher initial leucocyte counts and more peripheral blasts. Complete remissions were obtained in all nine adults with Ph1-All but in only three of six with Ph1+ ALL. Adults with Ph1-ALL survived significantly longer. Four adults with ANALL were Ph1+. They did not respond to treatment and survived significantly shorter periods than adults with Ph1-ANLL. No clinical or morphologic features indicated which patients with acute leukaemia would have the Ph1. Since the presence of the Ph1 in acute leukaemia has therapeutic and prognostic significance, marrow chromosome studies should be performed in adults presenting with acute leukaemia, especially ALL.     

Translocations (4p+ 6q−) and (12q− Xp+) in blastic phase of a Ph1-positive chronic myeloid leukemia

Summary This paper reports a 28-year-old woman with Philadelphia chromosome (Ph¹)-positive chronic myeloid leukemia (CML) who developed two marrow cell lines during the blastic phase: one with the translocation (12; X) (q 11; p 22) and the other with the translocation (4; 6) (p 16; q 25). The literature on involvement of chromosomes 12 and X in translocations and the appearance of 6 q– aberration in CML is summarized. The relationship between the 6 q– aberration and the blast cells with lymphoid appearance in the plastic phase of CML is discussed.     

Chronic granulocytic leukemia: reassessment of morphologic and cytogenetic characteristics in Ph1-positive and Ph1-negative cases

33 cases of chronic granulocytic leukemia (CGL) were reassessed to determine if, by strict morphologic criteria. Philadelphia chromosome (Ph1)-negative CGL exists as a diagnostic entity and if Ph1-positive CGL could be distinguished from Ph1-negative CGL. Cases were reassessed using published criteria and, of 11 Ph1-negative cases, only 4 could be reclassified as myelodysplastic syndromes or undifferentiated chronic myeloproliferative disorder. Of the morphologic parameters evaluated, peripheral blood basophilia and bicytopenia proved to be good discriminators between Ph1-positive and Ph1-negative cases. As a group, Ph1-negative cases were more heterogeneous and tended to have lower hemoglobin, WBC, platelet count and absolute eosinophilia. Chromosomal abnormalities other than Ph1 were seen only in the Ph1-positive cases. Based on these findings, we conclude that Ph1-negative CGL constitutes a heterogeneous group, a subgroup of which is morphologically identical with the Ph1-positive CGL. The parameters that best discriminate between Ph1-positive and Ph1-negative cases are peripheral blood absolute basophilia and bicytopenia.     

Clonal evolution with isodicentric Ph1 chromosome in Ph1-positive CML: Karyotypic conversion after bone marrow transplantation

Summary Clonal chromosomal evolution was observed in a 16-year-old boy suffering from Ph¹-positive CML. An isodicentric Ph¹ chromosome appeared 20 weeks after the initial diagnosis. At that time an allogeneic bone marrow transplantation was performed.Thereafter, during an observation period of more than 13 months, chromosome analyses showed neither the Ph¹ chromosome nor the abnormal isodicentric variant. Close cytogenetic monitoring is suggested to reveal early unfavourable prognostic signs of the onset of blast crisis before it becomes evident in the bone marrow morphology.