Juvenile Chronic Myelogenous Leukemia Research Articles

Detection of residual malignant cells in juvenile chronic myelogenous leukemia (JCML)

Detection of residual malignant cells in juvenile chronic myelogenous leukemia (JCML)

906 A FAMILY WITH AN INHERITED PLATELET STORAGE POOL DEFECT ASSOCIATED WITH A HIGH INCIDENCE OF MYELOPROLIFERATIVE DISORDERS

A boy, age 5, presented with easy bleeding since birth and was found to have a long bleeding time, thrombocytopenia and abnormal platelet function (absent second wave aggregation with epinephrine, decreased aggregation to collagen but a normal first wave response to ADP and normal aggregation to arachidonic acid). His bone marrow was normal. At age 6½ years this boy developed progressive anemia, thrombocytopenia and splenomegaly, and was diagnosed as having juvenile chronic myelogenous leukemia. This child's father, grandfather and two of the grandfather's sisters were found to have a similar bleeding defect with a long bleeding time, mild thrombocytopenia, abnormal aggregation pattern similar to the propositus, and deficiency of platelet ADP, serotonin and dense bodies. Thrombin-induced arachidonic acid release, conversion of arachidonic acid to thromboxane B2 and phosphorylation of platelet proteins were normal. One of the grandfather's sisters with a lifelong bleeding tendency and a platelet storage pool deficiency documented at age 38, developed myelomonocytic leukemia at age 41. Another sister and a brother of the grandfather, bleeding history uncertain, died at ages 8 and 23 of leukemia. The great grandmother and her sister both with lifelong bleeding histories had died of leukemia. The findings suggest this family has an inherited platelet storage pool deficiency associated with an increased susceptibility to the development of a myeloproliferative disorder.

Splenic reticuloendothelial function in children with cancer

We studied splenic function in children with cancer by quantitation of pitted, or pocked, erythrocytes (pocked RBC count), that is, the percentage of erythrocytes containing one or more membrane-bound vesicles, as determined by phase interference microscopy. The mean pocked RBC count in 93 normal children and adults was 0.49% (range 0% to 2.0%), with only 2.4% of normal subjects having values greater than 1.5%. Mean pocked RBC count in 28 children after splenectomy was 37% (range 3.2% to 81%). Among 181 children with cancer (525 specimens), the mean pocked RBC count was 1.06% (range 0% to 12.6%). Fifty-nine (32%) patients had one or more values greater than 1.5%, and 25 (13.8%) children had measurements greater than 3.0%, a level previously suggested to have clinical significance. Elevated pocked RBC counts (greater than 1.5%) occurred in more than one third of children with Wilms tumor and acute lymphoblastic leukemia, and in both patients with juvenile chronic myelogenous leukemia. Elevations in pocked RBC counts were not related to specific chemotherapy regimens or to disease activity. Mild splenic reticuloendothelial hypofunction occurs in many children with cancer and may contribute to the risk of infection in these patients.

Juvenile chronic myelogenous leukemia with monosomy 7 treated with a mismatched allogeneic bone marrow transplant

Juvenile chronic myelogenous leukemia with monosomy 7 treated with a mismatched allogeneic bone marrow transplant

Chronic Leukemia of Childhood

The chronic leukemias of childhood include chronic myelogenous leukemia (CML) and chronic lymphocytic leukemia. Chronic lymphocytic leukemia in childhood is a monoclonal B-cell neoplasm of great infrequency. CML occurs with enough frequency to warrant a review for the general pediatrician. CML is a clonal (derived from a single cell line) myeloproliferative disorder that has two major forms in childhood, which, as a group, account for 2% to 5% of the childhood leukemias. "Adult" CML is a classic clonal myeloproliferative disease demonstrating the Philadelphia chromosome (Ph1). Its chronic phase lasts 2 to 3 years, then evolves into an acute phase which terminates in the blastic crisis. "Juvenile" CML is more often seen in infants and toddlers and is notable for the presence of rash, adenopathy, absence of the Ph1 chromosome, and elevated level of hemoglobin F. In fact, the two diseases have less in common than the similar names would imply. Approximately one third of CML in childhood is of the juvenile type. A third type of myeloproliferative disorder resembling CML has been reported in two pairs of infant siblings. It clinically resembles juvenile CML, but does not appear to have the nearly universally fatal outcome. Finally, a familial myeloproliferative syndrome, which most closely resembles adult CML, has been reported in a large kindred.

CHRONIC MYELOGENOUS LEUKEMIA IN CHILDREN

We have reviewed the 40 cases of adult-type chronic myelogenous leukemia (ACML) and 21 cases of juvenile chronic myelogenous leukemia (JCML) seen at St. Jude Children's Research Hospital since 1964. The ACML patients ranged in age from 9 mo to 20-4/12 yr (median 11-1/12 yr) and included 23 boys and 17 girls. The JCML patients ranged from 6 mo to 11-8/12 yr (median 2 yr) and included 14 boys and 7 girls. Cytogenetic studies from 32 of the 36 ACML patients demonstrated the Philadelphia chromosome, whereas studies from only 1 of the 15 JCML patients had a structural chromosome abnormality. The range and median of other presenting characteristics are summarized below:The survival of the ACML patients ranged from 5 to 63 mo from diagnosis (median 25) and for the JCML patients from 2 to 28 mo (median 9). Eight ACML patients remain alive in chronic phase, 4 died in chronic phase, 5 had disease acceleration without clear documentation of blast crisis, 23 entered blast crisis 4 to 63 mo after diagnosis (6 lymphoblastic, 17 nonlymphoblastic). Five of the 6 patients entering lymphoblastic crisis achieved remission after 4 weeks of a vincristine-prednisone containing regimen. All 21 JCML patients died of disease despite modern therapy. Our studies suggest that better characterization of blast crisis cells of ACML patients may permit more specific and effective therapy. New therapeutic approaches are needed for both ACML and JCML.

Persistent epstein-barr virus infection mimicking juvenile chronic myelogenous leukemia: immunologic and hematologic studies

Epstein-Barr virus (EBV) infections may induce a diverse clinical picture, ranging from the well characterized infectious mononucleosis (IM) syndrome to the rare X-linked lymphoproliferative syndrome. We describe two unrelated children, a 21-mo-old white boy and a 15-mo-old black girl, who presented with the clinical and laboratory findings characteristically seen in juvenile chronic myelogenous leukemia (JCML). Results of periodic serodiagnostic tests indicated that they likely have persistent infection with EBV. Both had elevated IgG antibody to viral capsid antigen (greater than or equal to 1:320) and antibody to early antigen (1:20–1:40) that have persisted for 3 yr of more. Both patients had EBV-specific suppressor cell activity, decreased natural killer cell activity, and diminished antibody- dependent cell-mediated cytotoxicity (ADCC) activity. These changes suggest an underlying defect in the immunoregulatory network controlling EBV infection. The patients have shown clinical improvement without treatment. It appears that EBV infections are capable of inducing symptoms similar to those seen in JCML. Careful evaluation for evidence of EBV infection in patients presenting with symptoms compatible with JCML seems warranted.

Persistent Epstein-Barr Virus Infection Mimicking Juvenile Chronic Myelogenous Leukemia: Immunologic and Hematologic Studies

Epstein-Barr virus (EBV) infections may induce a diverse clinical picture, ranging from the well characterized infectious mononucleosis (IM) syndrome to the rare X-linked lymphoproliferative syndrome. We describe two unrelated children, a 21-mo-old white boy and a 15-mo-old black girl, who presented with the clinical and laboratory findings characteristically seen in juvenile chronic myelogenous leukemia (JCML). Results of periodic serodiagnostic tests indicated that they likely have persistent infection with EBV. Both had elevated IgG antibody to viral capsid antigen (greater than or equal to 1:320) and antibody to early antigen (1:20-1:40) that have persisted for 3 yr of more. Both patients had EBV-specific suppressor cell activity, decreased natural killer cell activity, and diminished antibody-dependent cell-mediated cytotoxicity (ADCC) activity. These changes suggest an underlying defect in the immunoregulatory network controlling EBV infection. The patients have shown clinical improvement without treatment. It appears that EBV infections are capable of inducing symptoms similar to those seen in JCML. Careful evaluation for evidence of EBV infection in patients presenting with symptoms compatible with JCML seems warranted.

A Case of Juvenile Chronic Myelogenous Leukemia

A Case of Juvenile Chronic Myelogenous Leukemia

“Spontaneous” erythroid progenitor cells in the circulation and monosomy 7 in juvenile chronic myelogenous leukemia

Cytogenetic examination of bone marrow cells from two patients with juvenile chronic myelogenous leukemia (JCML) showed a monosomy 7. Peripheral blood from these two children was found to contain large numbers of cells capable of erythroid colony formation in tissue culture without added erythropoietin. We conclude that erythroid progenitor cells are part of the malignant clone in JCML.

Second Malignancy in Acute Lymphocytic Leukemia

Sir .—We read with interest the article Second Malignancy in Acute Lymphocytic Leukemia: Review of 33 Cases by Drs Mosijczuk and Ruymann in theJournal(1981;135:313-316). In the article the authors state, referring to four patients in whom chronic myelogenous leukemia (CML) developed after treatment of acute lymphocytic leukemia (ALL), that no patients had cytogenetic studies performed at the time of the initial diagnosis of ALL. We wish to point out that in a previous study, 1 quoted by Drs Mosijczuk and Ruymann, we did describe the cytogenetic data at the time of the occurrence of ALL in one of the patients (patient 4) the authors referred to. The karyotype of that initial marrow, as well as six subsequent consecutive remission marrows, were normal. The cytogenetic aspect on this patient was also separately published together with chromosome data from another two patients with juvenile CML. 2 Unlike adult-type CML with

Juvenile Chronic Myelogenous Leukemia in a Seven-Year-Old Boy with Normal Red Cell Carbonic Anhydrase Activity-A Case Report

Juvenile Chronic Myelogenous Leukemia in a Seven-Year-Old Boy with Normal Red Cell Carbonic Anhydrase Activity-A Case Report

Cytogenetic Features Of Juvenile Chronic Myelogenous Leukemia

AbstractConsistent chromosomal abnormalities have been described in several leukemic disorders, but relatively little is known about the cytogenetic features of juvenile chronic myelogenous leukemia (JCML). We report the serial cytogenetic findings over a 2-yr period for a patient with JCML. A large subtelocentric marker chromosome was noted in all metaphases throughout the course of his disease and provided evidence for a clonal etiology of JCML in this patient. Banding analysis identified this marker as a chromosome 8, to which most of the long arm of a chromosome 2 had been translocated. An abnormal chromosome 1 was also noted. The probable stem cell karyotype was 46,XY,t(2;8)(q21 ;q24), del(1)(p33→pter), dup(1)(p21→p32). Two subclones evolved from the stem line population at different times during the course of the disease. We reviewed the cytogenetic findings for 16 other patients with JCML at this institution and for 68 patients reported elsewhere. Over 80% of these patients had normal karyotypes as determined by conventional techniques, and no consistent cytogenetic abnormalities were noted among those with an abnormal karyotype. JCML may be a heterogeneous disorder, with some patients clearly showing evidence of malignant clonal proliferation. A few of the patients with normal karyotypes may have transient or sustained failure of bone marrow maturation.

Cytogenetic features of juvenile chronic myelogenous leukemia

Cytogenetic features of juvenile chronic myelogenous leukemia

A fatal myeloproliferative syndrome in a family with thrombocytopenia and platelet dysfunction

Three siblings with a lifelong history of a bleeding disorder and thrombocytopenia died from a myeloproliferative disease. In 2, the terminal event resembled juvenile chronic myelogenous leukemia, and in the third, the diagnosis was acute monocytic leukemia. A family study revealed that the mother and 5 other siblings had a variety of hematologic abnormalities. These included chronic thrombocytopenia, abnormal platelet function, elevated concentrations of HgbF or serum vitamin B12, and low leukocyte alkaline phosphatase (LAP) scores either singly or in combination. At the time of study, none had evidence of malignancy. Members of this family have a myeloproliferative disorder that has the potential for terminating in nonlymphocytic leukemia, a combination of events which appears not to have been reported previously.

New leukemia in the course of therapy of acute lymphoblastic leukemia

We have recently observed the development of second leukemia of a morphologically different type in three patients with acute lymphoblastic leukemia (ALL) while on therapy. The "second" leukemia occurred while on therapy at 23, 27, and 32 months of initial remission. All three were receiving systemic chemotherapy (CT) and prophylactic fractional irradiation to the central nervous system (CNS). The second leukemias in these three cases were one case of juvenile chronic myelogenous leukemia (JCML) and two cases of acute leukemia of the myeloblastic type by the usual morphologic criteria including the presence of Auer rods in one. In two cases a cytogenetically new clone was detected in the remission marrow 10 and 12 months preceding the overt change in clinical status. These three cases demonstrate that second leukemia occurs in patients with ALL and that some late "relapses" fall into this categpry. The possible etiologic role of modern intensive treatment regimens in the development of second leukemia is discussed.

NEUROFIBROMATOSIS AND CHILDHOOD LEUKEMIA

To clarify the suggested link between childhood leukemia and neurofibromatosis (NF), we ascertained 10 previously unreported cases at 6 medical centers including our own, almost doubling the 15 adequately documented cases in the literature. Among these 25, acute lymphoblastic leukemia (ALL) developed in 9 and various forms of myelogenous leukemia (non-ALL) in 16, including 8 with acute myelomonocytic and 4 with juvenile chronic myelogenous leukemia. The ALL:non-ALL ratio of 9:16 is quite different from the predominance of ALL in U.S. whites, 4:1; Down's syndrome, 7:3; and ataxia-telanglectasia, 7:1. By contrast, only non-ALL has been reported in Fanconi's anemia or Bloom's syndrome. Each of these 4 heritable disorders with high risk of leukemia has characteristic though different chromosomal abnormalities, which may be involved in leukemogenesis. In the 25 NF cases cytogenetic studies were rarely made, an opportunity that should not be missed in the future. Variations in the ALL:non-ALL ratio indicate that host factors apparently influence the form of leukemia that develops. To refine further the relation between NF and leukemia, the existing large collaborative oncology groups could provide a) fuller ascertainment of cases with details of physical findings and family histories, b) a denominator for estimating risk, c) cytochemical and immunological clarification of leukemic subtypes, and d) elucidation of possible variant cases excluded from this series (N-15); eg, “transient leukemia” (as in Down's syndrome) seen in 3 children with NF, and “xantholeukemia” seen in 4 others.

Missing Y chromosome in juvenile chronic myelogenous leukemia.

A child with Ph1-negative juvenile chronic myelogenous leukemia (CML) is presented. The only chromosomal abnormality in hematopoietic tissues consisted of an absent Y chromosome. While a missing Y chromosome in adult patients with CML may be associated with a better prognosis, the clinical course in our patient was as malignant as that usually observed in other children with Ph1-negative juvenile CML.

Similarities of the Erythrocytes in Juvenile Chronic Myelogenous Leukemia to Fetal Erythrocytes

Abstract A 4-yr-old boy was studied who showed typical findings of juvenile chronic myelogenous leukemia, including massive hepatosplenomegaly, thrombocytopenia, low leukocyte alkaline phosphatase, and absence of a Philadelphia chromosome. The erythrocytes of the patient exhibited many characteristic features of erythrocytes of newborn infants: the fetal hemoglobin concentration was greatly elevated (72%); the oxygen dissociation curve of the whole blood was displaced to the left of the curve from normal adult blood; the hemoglobin A2 level and the erythrocyte I antigen titer were reduced; and a structural analysis of the γ-chain of the fetal hemoglobin showed the glycine to alanine ratio in γ-136 to be typical of the neonatal pattern. These findings support the suggestion that juvenile chronic myelogenous leukemia is accompanied by reversion to a fetal pattern of erythropoiesis.