Juvenile Chronic Myeloid Leukemia Research Articles

Juvenile Myelomonocytic Leukemia – Experience from a Tertiary Care Hospital in Eastern India

Background: Juvenile myelomonocytic leukemia (JMML), previously known as juvenile chronic myeloid leukaemia, is a rare, unique, and aggressive myeloproliferative neoplasm of early childhood. Making a diagnosis of JMML is challenging because of the overlapping clinical and haematological features with other myeloproliferative neoplasms (MPN). However, some unique features like monocytosis, the absence of BCR-ABL translocation, and the presence of specific mutations (PTPN-11, K-RAS, N-RAS, CBL, or NF1) clinch the correct diagnosis.Methods: A prospective analysis of six JMML patients with variable clinical features treated with injection azacytidine as frontline therapy during the study period of 2 years. Results: The median age was 4.5 years with male:female ratio 2:4. Pallor and splenomegaly were the most common presenting signs. Four patients (66.67%) achieved complete remission (CR), two patients (33.33%) had partial remission (PR), and one patient (16.67%) had progressive disease (PD). The overall survival rate was 66.67% (four out of six), and the mortality rate was 33.33%.Conclusion: Azacitidine is an effective treatment option as upfront therapy for JMML, especially in resource poor developing countries.

Long-Term Outcome of Philadelphia Chromosome Positive Leukemia From Eastern Indian Subcontinent: An Experience in the Era of Tyrosine Kinase Inhibitor (TKI) Therapy

IntroductionPhiladelphia chromosome (Ph) marks a group of leukemia with almost all cases of chronic myeloid leukemia (CML), a subset of acute lymphoid leukemia (ALL) and rare cases of acute myeloid leukemia (AML). In the era of precision medicine, such cases are successfully managed with tyrosine kinase inhibitor (TKI) drugs. This study examined the features and long-term outcome of Ph+ve cases from a tertiary cancer care center from Eastern Indian subcontinent. Materials and MethodsReviewing retrospective case-records registered between 2005 and 2015, cases of CML and ALL were documented under Ph+ve category; while no instance of Ph+ve AML was found. ResultsIn CML cohort, adult and juvenile incidences were 95.2% and 4.8% respectively; in ALL cohort, the same was found for 66.67% and 33.33% cases. Among the CML cases, 10-year overall survival (OS) and progression-free survival (PFS) were significantly affected upon the phase of disease at time of detection. Furthermore, both OS and PFS significantly dropped whenever non-TKI-based treatment was applied prior to TKI-commencement. Long-term (10-year) sensitivity to 1st generation TKI, imatinib, was noted 88.51% and 83.33% for adult and juvenile CML cohorts, respectively. For Ph+ ALL cohort, the OS was benefitted upon combinatorial TKI and chemotherapy. However, large fractions of affected individual from CML as well as ALL cohorts were found to discontinue follow-up. ConclusionTogether with differences in outcome on the basis of drug-use from onset, age (juvenile versus adult) and stage at diagnosis, our analyses bring forward the real-world scenario of Ph+ve leukemia managed with precision medicine.

Leucémie myélomonocytaire juvénile : à propos de trois cas

Juvenile myelomonocytic leukemia (JMML), previously known as juvenile chronic myeloid leukemia (JCML), is a rare, myelodysplastic-myeloproliferative disease typically presenting in early childhood. This disorder is difficult to distinguish from other myeloproliferative syndromes such as chronic myeloid leukemia (CML) because of the similarities in their clinical and bone marrow findings. However, because of its unique biological characteristics such as absolute monocytosis with dysplasia, absence of Philadelphia chromosome or BCR-ABL fusion protein, hypergammaglobulinemia, and raised fetal hemoglobin level, this disorder does not satisfy the criteria for inclusion in the CML or chronic myelomonocytic leukemia (CMML) group, as seen in adult patients. We describe three cases of JMML, who had very similar clinical and laboratory findings.

A Novel, Non-canonical Splice Variant of the Ikaros Gene Is Aberrantly Expressed in B-cell Lymphoproliferative Disorders

The Ikaros gene encodes a Krüppel-like zinc-finger transcription factor involved in hematopoiesis regulation. Ikaros has been established as one of the most clinically relevant tumor suppressors in several hematological malignancies. In fact, expression of dominant negative Ikaros isoforms is associated with adult B-cell acute lymphoblastic leukemia, myelodysplastic syndrome, acute myeloid leukemia and adult and juvenile chronic myeloid leukemia. Here, we report the isolation of a novel, non-canonical Ikaros splice variant, called Ikaros 11 (Ik11). Ik11 is structurally related to known dominant negative Ikaros isoforms, due to the lack of a functional DNA-binding domain. Interestingly, Ik11 is the first Ikaros splice variant missing the transcriptional activation domain. Indeed, we demonstrated that Ik11 works as a dominant negative protein, being able to dimerize with Ikaros DNA-binding isoforms and inhibit their functions, at least in part by retaining them in the cytoplasm. Notably, we demonstrated that Ik11 is the first dominant negative Ikaros isoform to be aberrantly expressed in B-cell lymphoproliferative disorders, such as chronic lymphocytic leukemia. Aberrant expression of Ik11 interferes with both proliferation and apoptotic pathways, providing a mechanism for Ik11 involvement in tumor pathogenesis. Thus, Ik11 could represent a novel marker for B-cell lymphoproliferative disorders.

Pomolic Acid-Induced Apoptosis in Cells from Chronic Myeloid Leukemic Patients Is Not Affected by the MDR Phenotype and Status of Disease.

Pomolic acid (PA), isolated from Chrysobalanus icaco, is a pentaciclic triterpene highly effective in inhibiting the growth and promotes cell death in the human chronic myeloid leukemia (CML) K562 cell line. In addition, PA is also very effective in blocking the proliferation of K562-Lucena-1, a vincristine-resistant derivative of K562 that displays multidrug resistance (MDR) phenotype. Due to antiproliferative and antiapoptotic effect of PA on positive and negative MDR leukemic cells, and considering that some patients with CML exhibit resistance to imatinib, the aim of this work was to investigate if PA could have an effective role in induce apoptosis in cells from CML patients. Fourteen peripheral blood samples from CML patients in various stages (three in blastic phase and eleven in chronic phase being one juvenile patient) including previously clinically imatinib resistant patients were studied. Informed consent was obtained according to institutional guidelines. Cells from patients were plated in 96 well tissue culture plates for 24h and then treated with two different concentrations of PA: 12.5 μg/ml and 25 μg/ml. Drug-induced apoptosis was evaluated by annexin V/propidium iodide assessed by fluorescence-activated cell-sorting (FACS). Functional MDR phenotype was performed by measuring the fluorescent dye rhodamine-123 efflux in the presence or absence of the MDR blocker cyclosporin A. These experiments were analysed by FACS. Functional activity of MDR was observed in 9 out of 14 samples and it was independent of CML stage. Using 12.5 μg/ml and 25μg/ml concentrations, the apoptotic effect of PA ranged from 10.5 to 53.1 (median: 31.5) and 14.7 to 65.9 (median: 42.2), respectively. These results were also independent of CML stage being even effective in blastic phase and in juvenile CML, which have a clinically aggressive course. Our data demonstrate that PA is a potent anti-leukemic agent not only for MDR positive CML patients but also especially for the blastic phase in the setting of imatinib resistance.

A pediatric approach to the WHO classification of myelodysplastic and myeloproliferative diseases.

Myelodysplastic and myeloproliferative disorders are rare in childhood and there is no widely accepted system for their diagnosis and classification. We propose minimal diagnostic criteria and a simple classification scheme which, while based on accepted morphological features and conforming with the recent suggestions of the WHO, allows for the special problems of myelodysplastic diseases in children. The classification recognizes three major diagnostic groups: (1) juvenile myelomonocytic leukemia (JMML), previously named chronic myelomonocytic leukemia (CMML) or juvenile chronic myeloid leukemia (JCML); (2) myeloid leukemia of Down syndrome, a disease with distinct clinical and biological features, encompassing both MDS and AML occurring in Down syndrome; and (3) MDS occurring both de novo and as a complication of previous therapy or pre-existing bone marrow disorder (secondary MDS). The main subtypes of MDS are refractory cytopenia (RC) and refractory anemia with excess of blasts (RAEB). It is suggested retaining the subtype of RAEB-T with 20-30% blasts in the marrow until more data are available. Cytogenetics and serial assessments of the patients are essential adjuncts to morphology both in diagnosis and classification.

CHRONIC NEUTROPHILIC LEUKAEMIA: A DISTINCT CLINICAL ENTITY?

CHRONIC NEUTROPHILIC LEUKAEMIA: A DISTINCT CLINICAL ENTITY?

The Relationship between the Myelodysplastic Syndromes and the Myeloproliferative Disorders

As a result of clonal evolution typical cases of one of the myelodysplastic syndromes may develop myeloproliferative features. Similarly, typical cases of one of the myeloproliferative disorders may develop dysplastic features, either as part of the natural history of the disease or as a result of exposure to mutagenic drugs or isotopes. There is also an important group of “overlap syndromes” in which cases, at presentation, have both dysplastic and proliferative features. Chronic myelomonocytic leukaemia and many cases of atypical chronic myeloid leukaemia, juvenile chronic myeloid leukaemia and the childhood monosomy 7 syndrome are “overlap syndromes”. In addition, a significant minority of cases which fit the generally agreed criteria for a diagnosis of one of the myelodysplastic syndromes (refractory anaemia, refractory anaemia with ring sideroblasts or refractory anaemia with excess of blasts) also have thrombocytosis, neutrophilia, monocytosis, eosinophilia or basophilia.

10 Childhood myeloproliferative disorders

Disorders classified as paediatric myeloproliferative disorders (MPD), such as juvenile chronic myeloid leukaemia (JCML), and as paediatric myelodysplastic syndrome (MDS), are essentially diseases characterized by abnormal myeloproliferation and they share similar genetic events on chromosome 7. As such, the abnormalities of increased myeloproliferation in childhood (AIMC) should be considered under the same heading. Constitutional and other genetic factors play an essential role in children and include the NF1 gene, whereas toxic exposure is of greater importance in adults. The most common cytogenetic alteration is that of monosomy or deletion of the long arm of chromosome 7. Critical regions have been identified and mapped by fluorescence in situ hybridization (FISH). It appears that the similar critical regions on chromosome 7 are involved, and suggests that these regions may contain genes important in the pathogenesis of AIMC.

#602 Donor cell derived juvenile chronic myeloid leukemia (JCML) in a child transplanted for JCML from a sibling

#602 Donor cell derived juvenile chronic myeloid leukemia (JCML) in a child transplanted for JCML from a sibling

Preleukaemic disorders in children: Hereditary disorders and myelodysplastic syndrome

The diagnosis of preleukaemic disorders in childhood is often a difficult diagnostic problem. Several factors contribute to the complexity of making such a diagnosis. Firstly, most pathologists have little experience with paediatric bone marrows and there is little information about the normal histology of bone marrows in new born and young children. A second factor of importance is ignorance about the spectrum of diseases in young children that can develop into leukaemia; most of these diseases are very rare and nearly never seen outside specialized children hospitals. A third factor complicating the diagnosis of these diseases is that the bone marrow changes are sometimes very subtle and difficult to diagnose. This paper describes the three main groups of preleukaemic disorders in children. The first group includes the hereditary preleukaemic disorders which are represented both by single-cell cytopenias as well as pancytopenias. The second group comprises the primary myelodysplastic syndromes which include all the adult forms of the FAB-classification as well as juvenile chronic myeloid leukaemia and infantile monosomy 7. The third group are those children who developed a secondary myelodysplasia as a late complication of radiotherapy and/or chemotherapy. The different disease entities within each of these groups are described and criteria for their diagnoses are discussed.

Cytogenetic abnormalities in pediatric myelodysplastic syndrome: A report of three cases

Three consecutive cases of pediatric myelodysplastic syndrome (MDS) diagnosed over a three-year period in Queen Mary Hospital, Hong Kong, were described. Depending on the classification system used, they comprised two cases of chronic myelomonocytic leukemia (CMMoL) of which one can be reclassified as juvenile chronic myeloid leukemia (JCML) and one case of refractory anemia with excess of blasts (RAEB) or an alternative diagnosis of atypical CML. Cytogenetic abnormalities were detected in all of them on examination of bone marrow cells. Of the two CMMoL, one had monosomy 21, whereas the other had hypodiploidy. The patient with RAEB had a complex karyotype of 46,X,del(X)(q24),t(1;7) (p22;q32),add(15)(q26)(8). The balanced translocation (1;7) seen in this patient was exceedingly rare and, to the best of our knowledge, was reported only twice in the literature. The karyotypic abnormalities that we saw in our patients were not well recognized in pediatric MDS. This report emphasizes the importance of cytogenetic study in children suspected of suffering from MDS, which remains a rare disorder of childhood, and a need to rationalize current classification schemes.

Philadelphia Negative BCR-ABL Positive Chronic Myeloid Leukemia Mimicking Juvenile Chronic Myeloid Leukemia in a 2-year-old Child

We present the case of a two-year-old child with an atypical presentation of chronic myeloid leukemia. At diagnosis, he showed clinical and biological features of juvenile chronic myeloid leukemia (CML). However, eosinophilia was observed in blood and bone marrow. The bone marrow karyotype did not demonstrate the Philadelphia chromosome but BCR-ABL rearrangement was shown to be present by reverse transcriptase polymerase chain reaction (RT-PCR) analysis and confirmed by fluorescent in situ hybridization (FISH) analysis. Discussion centres on the differentiation between juvenile CML and childhood chronic myel-ogenous Leukemia and the importance of carrying out RT PCR for all juvenile CML cases.

Juvenile Xanthogranuloma, Neurofibromatosis 1, and Juvenile Chronic Myeloid Leukemia

Neurofibromatosis 1 (NF1) is a common autosomal dominant disorder in which affected children have an approximate 200-fold greater risk of developing juvenile chronic myeloid leukemia (JCML) compared with children without NF1.^1,2A recent article in theArchives³presented the results of a statistical analysis from a compilation of case reports suggesting that children with NF1 have an even higher risk of JCML (>20-fold) if they concurrently have juvenile xanthogranuloma (JXG). Although case reports are useful for generating hypotheses, because case reports are not drawn from defined populations and do not include representative comparison groups they cannot be used to test for the presence of valid statistical associations.⁴The methodological limitations of such a case report analysis coupled with an apparent overestimate of the disease probabilities used by Zvulunov et al³raise several concerns. They estimate the frequency of NF1 to be between 1 per 2500 and

Matched and mismatched unrelated donor bone marrow transplantation for juvenile chronic myeloid leukaemia.

Juvenile chronic myeloid leukaemia (JCML) is a rare haematological condition of childhood curable only by bone marrow transplantation (BMT). We report our experience using matched and mismatched unrelated donor BMT for JCML in five patients. Although the procedure is hazardous in terms of toxicity and relapse, two patients are alive and disease-free 28 and 49 months post BMT.

Role of allogeneic bone marrow transplantation from an HLA‐identical sibling or a matched unrelated donor in the treatment of children with juvenile chronic myeloid leukaemia

Seven children (age range 1.8-11 years) with juvenile chronic myelomonocytic leukaemia (JCML) received an allogeneic bone marrow transplantation (BMT), four from an HLA-identical sibling and three from a matched unrelated donor. In the four children transplanted using an HLA-identical sibling, conditioning regimen included busulfan (BU), cyclophosphamide (CY) and melphalan (L-PAM), whereas graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine-A (Cs-A). The preparative regimen was well tolerated and all patients engrafted promptly. None of the patients have relapsed and all four children remain in haematological remission after an observation time of 7, 24, 25 and 48 months, respectively. Of the three children given BMT from an unrelated volunteer, one was < 2 years of age and she received the BU/CY/L-PAM regimen. In view of the increased risk of graft rejection described in patients transplanted from unrelated donors, we chose to prepare the other two patients with fractionated total body irradiation (TBI), thiotepa and CY. Cs-A, short-term methotrexate and Campath-1G in vivo were employed to prevent GVHD in this group of patients. Graft failure with autologous reconstitution of haemopoiesis occurred in the child given the chemotherapy-based regimen. One of the two girls given TBI relapsed after BMT; therefore only one of the three patients who received a marrow transplant from a matched unrelated donor survives in complete haematological remission 10 months after BMT. Our study suggests that the conditioning regimen we employed for allogeneic BMT from a compatible sibling is an effective means of eradicating the leukaemic clone. In our experience, results obtained using unrelated donors are less satisfactory and, at present, the use of such donors seems to be riskier and associated with a lower success rate as compared with BMT from an HLA-identical sibling.

Genetic analysis of chromosome 13 deletions in BCR/ABL negative chronic myeloproliferative disorders.

Chromosomal deletions of band 13q14 occur recurrently in BCR/ABL negative chronic myeloproliferative disorders (CMPD), including myelosclerosis with myeloid metaplasia (MMM), polycythemia vera (PV), essential thrombocythemia (ET), juvenile chronic myeloid leukemia (JCML), and the so-called BCR/ABL- chronic myeloid leukemia (CML). The RBI tumor suppressor locus, mapping to 13q14, has long since been hypothesized as the important gene. In this report, we have determined the frequency of 13q14 deletions at the molecular level in a large panel of BCR/ABL- CMPD at different disease stages and performed a detailed genetic analysis of gross rearrangements/deletions and point mutations of the RBI gene in these disorders. Our data show that molecular deletions of 13q14 are detected in a relatively large fraction of BCR/ABL- CMPD (38%), that they appear to be more frequent in MMM than in other BCR/ABL- CMPD, and that they may be present at diagnosis or occur during blastic evolution of the neoplasia. The RBI gene displayed a germline configuration in all BCR/ABL- CMPD tested, suggesting that 13q14 deletions in these disorders affect a tumor suppressor locus distinct from RBI.

Rearrangement of the immunoglobulin heavy chain gene in juvenile chronic myeloid leukaemia.

Five patients with clinical and laboratory features typical for juvenile chronic myeloid leukaemia (JCML) are presented. Rearrangement of the j joining region of the immunoglobulin heavy chain (Jh) was demonstrated in three children out of five analysed. As no Vh to DhJh nor kappa light chain rearrangements were demonstrated, it is reasonable to speculate that the transforming event of the stem cell happened at the stage when Dh to Jh rearrangement took place. As the monocytic lineage is prominent in JCML, it is suggested that the transforming event happens in a unique stem cell with intermediate differentiation towards the myelomonocytic as well as the B-lymphatic lineage. This stem cell, which is present at a certain stage of embryogenesis, disappears later. Such an early 'hybrid' cell is sometimes involved in leukaemias of early infancy, and may be the transformed cell in some cases of infantile leukaemia.

Pediatric Myelodysplasia: A Study of 68 Children and a NewPrognostic Scoring System

Clinical, morphologic, and cytogenetic features were examined in a group of 68 children with myelodysplasia (MDS) referred to a single institution between 1971-1991. The morphologic French-American-British (FAB) system of classification proved of limited value in this group of patients because 50% of the cases were categorized as chronic myelomonocytic leukemia and three patients with eosinophilia and MDS were unclassifiable. Cytogenetic analysis was performed in 63 cases and clonal abnormalities were detected in 55%; the most common chromosome involved was number 7. Modification of the FAB system to incorporate additional diagnostic features such as pretreatment fetal hemoglobin (Hb F) and cytogenetics allowed incorporation of the categories of juvenile chronic myeloid leukemia (JCML) and infantile monosomy 7 syndrome (IMo7). The resulting groups of patients had highly significant differences in survival (P = .00009). The overall 5-year survival for the patients was 31.9% (95% CI 21.7 to 44.1) and factors influencing prognosis included: modified FAB type, platelet count, Hb F level, and cytogenetic complexity. We developed a scoring system ("FPC") where each of the following findings at diagnosis scored one point: HbF greater than 10%, platelets < or = 40 x 10(9)/L, and complex karyotypic changes (two or more clonal structural/numerical abnormalities), which produced groups with highly significant differences, patients with a score of 0 having a 5-year survival of 61.6% (CI 33% to 84%), whereas those with a score of two or three all died within 4 years of diagnosis. The revised classification and scoring system may prove helpful in making treatment choices in pediatric MDS and now needs to be tested prospectively in large scale population-based studies.

Malignant Osteopetrosis and Juvenile Chronic Myeloid Leukemia

Malignant Osteopetrosis and Juvenile Chronic Myeloid Leukemia