Aplastic anaemia associated with a Philadelphia chromosome and monosomy 7 during immunosuppressive therapy

Abstract During an 8-year period, 3,638 children from institutions of the Pediatric Oncology Group (POG) were diagnosed with acute lymphoblastic leukemia (ALL). Fifty-seven patients had Philadelphia chromosome- positive (Ph1) ALL. Blast cells obtained at diagnosis from 13 of these 57 cases (23%) were also found to have partial or complete monosomy 7 (- 7). This subgroup of children with Ph1/-7 ALL was comprised primarily of older males with early B-lineage ALL. Bone marrow specimens from six Ph1/-7 patients were studied further using the polymerase chain reaction and primers that flank the ALL, and chronic myelogenous leukemia breakpoints to determine the molecular characteristic of the 9;22 translocation. Rearrangements were detected in RNA from bone marrow and/or peripheral blood cells of six patients, although four were in hematologic remission at the time of the analysis. Five cases showed the ALL breakpoint, while one child with Ph1/-7 showed the chronic myelogenous leukemia breakpoint. The induction failure rate was much higher in this subgroup (31%) as compared with Ph1-negative cases, and the projected duration of event-free survival reflected the aggressive nature of this subgroup because no children are projected to remain in remission at 2 years. ALL with both the 9;22 translocation and -7 appears to represent a unique and previously undescribed subgroup of childhood ALL associated with a particularly adverse outcome. Leukemic transformation in such patients may involve the interaction of a dominant oncogene (Ph1) and a tumor suppressor gene (- 7).

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Rabbit antithymocyte globulin (r-ATG) plus cyclosporine and granulocyte colony stimulating factor is an effective treatment for aplastic anaemia patients unresponsive to a first course of intensive immunosuppressive therapy

British Journal of Haematology ◽

10.1046/j.1365-2141.1999.01693.x ◽

1999 ◽

Vol 107 (2) ◽

pp. 330-334 ◽

Cited By ~ 111

Author(s):

E. Di Bona ◽

F. Rodeghiero ◽

B. Bruno ◽

A. Gabbas ◽

P. Foa ◽

...

Keyword(s):

Effective Treatment ◽

Immunosuppressive Therapy ◽

Aplastic Anaemia ◽

Antithymocyte Globulin ◽

Granulocyte Colony Stimulating Factor ◽

Colony Stimulating Factor ◽

Rabbit Antithymocyte Globulin ◽

Stimulating Factor ◽

Intensive Immunosuppressive Therapy

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Induction of Effector and Memory Cellular Immunity in a Patient with Long-Term Complete Molecular Response to Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Case Reports in Oncology ◽

10.1159/000508997 ◽

2020 ◽

Vol 13 (2) ◽

pp. 990-996

Author(s):

Tatsuro Jo ◽

Haruna Shioya ◽

Hiroo Tominaga ◽

Takahiro Sakai ◽

Shizuka Hayashi ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Quantitative Polymerase Chain Reaction ◽

Philadelphia Chromosome ◽

Molecular Response ◽

Gene Repertoire ◽

Monosomy 7 ◽

Long Time ◽

Lineage Markers ◽

Complete Molecular Response

This case report is about a patient who suffered from Philadelphia chromosome (Ph1)-positive acute lymphoblastic leukemia. The blasts were positive for myeloid-lineage markers including CD13 and CD33, as well as B-cell-lineage markers. Minor bcr-abl1 mRNA was detected by real-time quantitative polymerase chain reaction. Chromosomal abnormality monosomy 7 was also observed, in addition to Ph1. Despite treatment difficulties that were anticipated based on these findings, the patient had long-time complete molecular response (CMR) for approximately 5 years using chemotherapy and two tyrosine kinase inhibitors, imatinib and dasatinib. Lymphocytes were elevated after the patient switched from imatinib to dasatinib, and a T-cell receptor (TCR) V beta gene repertoire analysis revealed oligoclonal expansion of effector and memory cytotoxic T lymphocytes (CTLs), including Wilms tumor 1-specific CTLs. More specifically, the two memory CTLs expressing TCR V beta 3 and V beta 7.1 gradually increased after dasatinib administration. The activation and maintenance of anti-leukemia immunity may have allowed the patient to obtain long-time CMR. These results highlight that obtaining memory CTLs for leukemia cells may lead to safe withdrawal from dasatinib in the patient.

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Outcome of treatment in children with hypodiploid acute lymphoblastic leukemia

Blood ◽

10.1182/blood-2006-07-038299 ◽

2007 ◽

Vol 110 (4) ◽

pp. 1112-1115 ◽

Cited By ~ 180

Author(s):

James B. Nachman ◽

Nyla A. Heerema ◽

Harland Sather ◽

Bruce Camitta ◽

Erik Forestier ◽

...

Keyword(s):

Overall Survival ◽

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Study Groups ◽

Event Free Survival ◽

Prognostic Implication ◽

Monosomy 7 ◽

Free Survival ◽

Modal Chromosome Number

Abstract One-hundred thirty-nine patients with acute lymphoblastic leukemia (ALL) and hypodiploidy (fewer than 45 chromosomes) were collected from 10 different national ALL study groups and single institutions. Patients were stratified by modal chromosome number into 4 groups: 24 to 29 (N = 46); 33 to 39 (N = 26); 40 to 43 (N = 13); and 44 (N = 54) chromosomes. Nine patients were Philadelphia chromosome (Ph) positive (4 cases: 44 chromosomes; 5 cases: 40-43 chromosomes) and were not considered further. Event-free survival (EFS) and overall survival (OS) of the remaining 130 patients were 38.5% ± 4.4% and 49.8% ± 4.2% at 8 years, respectively. There were no significant differences in outcome between patients with 24 to 29, 33 to 39, or 40 to 43 chromosomes. Compared with patients with fewer than 44 chromosomes, patients with 44 chromosomes had a significantly better EFS (P = .01; 8-year estimate, 52.2% vs 30.1%) and OS (P = .017; 69% vs 37.5%). For patients with 44 chromosomes, monosomy 7, the presence of a dicentric chromosome, or both predicted a worse EFS but similar OS. Doubling of the hypodiploid clone occurred in 32 patients (24-29 chromosomes [n = 25] and 33-39 chromosomes [n = 7]) and had no prognostic implication. Children and adolescents with ALL and hypodiploidy with fewer than 44 chromosomes have a poor outcome despite contemporary therapy.

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Long-term administration of G-CSF for aplastic anaemia is closely related to the early evolution of monosomy 7 MDS in adults

British Journal of Haematology ◽

10.1046/j.1365-2141.1998.01014.x ◽

1998 ◽

Vol 103 (2) ◽

pp. 297-303 ◽

Cited By ~ 61

Author(s):

Ken Kaito ◽

Masayuki Kobayashi ◽

Toshio Katayama ◽

Hidekazu Masuoka ◽

Takaki Shimada ◽

...

Keyword(s):

Aplastic Anaemia ◽

Early Evolution ◽

Monosomy 7 ◽

Term Administration

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Clinical Relevance of Cytogenetics Abnormalities in Adult Patients with Acquired Aplastic Anaemia.

Blood ◽

10.1182/blood.v106.11.3748.3748 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3748-3748

Author(s):

Vikas Gupta ◽

Carol Brooker ◽

Jennifer A. Tooze ◽

Qi-long Yi ◽

Deborah Sage ◽

...

Keyword(s):

Aplastic Anaemia ◽

Clinical Relevance ◽

Cytogenetic Study ◽

Cumulative Risk ◽

Normal Karyotype ◽

Similar Response ◽

Trisomy 8 ◽

Abnormal Karyotype ◽

Monosomy 7 ◽

Poor Prognostic Factor

Abstract The clinical relevance of cytogenetics abnormalities in aplastic anaemia (AA) patients at time of diagnosis is unclear. We evaluated the clinical course of 81 AA patients with successful cytogenetics at diagnosis and treated with immunosuppressive therapy (IST) from January 1993 to March 2004. A cytogenetic study was considered to be successful if there were a minimum of 15 evaluable metaphases in the absence of a clonal abnormality. Response to IST, survival and later clonal complications in patients with an abnormal karyotype (n=10) was compared to those with a normal karyotype (n=71). The cytogenetic abnormalities at diagnosis consisted of trisomy 6 (n=2), trisomy 8 (n=2), trisomy 15 (n=2), monosomy 7 (n=1), add(10) (n=1), t(3;11) (n=1) and t(4;6) (n=1). Four out of five evaluable patients with a trisomy responded to a first or subsequent course of IST. One patient with monosomy 7 achieved a complete response and later developed haemolytic PNH but with no recurrence of the monosomy 7. None of the patients with a non-numerical karyotypic abnormality responded to IST. No significant differences in 4-year event-free survival (EFS) (54% vs. 30%, p=0.15), overall survival (OS) (84% vs. 80%, p=0.33) or later clonal disorders (PNH, MDS and AML) were observed between the patients with a normal karyotype and those with an abnormal karyotype. Advanced age (≥60 years) was the only independent poor prognostic factor for survival in a multivariate analysis. Among the patients with a normal karyotype (n=71), 6 patients later developed a clonal cytogenetic abnormality with a cumulative risk of 10% at 4 years. These abnormalities were trisomy 15 (n=2), trisomy 6(n=1), monosomy 7 (n=2) and t(13;15) (n=1). None of the three patients who acquired trisomies developed any clinically significant problem, while acquisition of monosomy 7 was associated with a transformation to MDS/AML. Our data show that AA patients with a trisomy cytogenetic clone at diagnosis show a similar response to IST, evolution to later clonal abnormalities and survival, compared to those AA patients with a normal karyotype.

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