What are the treatment options for a patient with Monosomy 7 (a chromosomal abnormality) associated with hematological disorders, such as myelodysplastic syndromes or acute myeloid leukemia?

Monosomy 7: Treatment Approach

Allogeneic hematopoietic stem cell transplantation (HSCT) is the definitive treatment for monosomy 7 in myelodysplastic syndromes (MDS), juvenile myelomonocytic leukemia (JMML), and acute myeloid leukemia (AML), as this high-risk cytogenetic abnormality confers poor prognosis with chemotherapy alone and requires immediate evaluation for transplantation. 1

Immediate Risk Stratification

Monosomy 7 represents a high-risk cytogenetic abnormality that mandates urgent transplant evaluation regardless of the underlying hematologic disorder. 1 The American Society of Hematology classifies monosomy 7 as requiring immediate HSCT assessment due to its association with treatment resistance, early relapse, and progression to advanced disease. 1

Key Prognostic Considerations

• Monosomy 7 alone versus complex karyotype: Patients with isolated monosomy 7 in MDS have superior survival compared to those with additional cytogenetic abnormalities (3-year survival 56% vs 24%), though outcomes remain poor without transplantation. 2
• Disease type matters: In AML, monosomy 7 as a sole abnormality paradoxically shows worse outcomes (3-year survival 13%) compared to monosomy 7 with other abnormalities (44%), reflecting the aggressive biology of isolated monosomy 7 in acute leukemia. 2
• Age-related patterns: Median age at presentation is lowest in JMML (1.1 years), with monosomy 7 being characteristic of this rare chronic myeloproliferative disease in young children. 2

Transplant-First Strategy

Proceed directly to allogeneic HSCT without prior intensive chemotherapy for patients with MDS (refractory anemia or RAEB) or JMML with monosomy 7. 1, 2 Patients with RA, RAEB, or JMML treated with BMT without prior chemotherapy achieved 3-year survival of 73%, compared to dismal outcomes with chemotherapy alone. 2

HLA Typing Requirements

• Perform high-resolution molecular HLA typing (classes I and II) at diagnosis for all patients aged <55 years who are transplant candidates. 1
• Initiate donor search immediately upon confirming monosomy 7, as delays worsen outcomes. 1

Role of Chemotherapy

Intensive chemotherapy alone has historically shown poor outcomes in monosomy 7 cases, with frequent treatment resistance and early relapse. 1 Chemotherapy should only be used as a bridge to transplant in cases with excess blasts (≥10%), but never as definitive therapy. 1

Specific Scenarios:

• MDS with low blast count (<5%): Supportive care with transfusions while expediting transplant evaluation; avoid chemotherapy. 2
• RAEB-T or AML with monosomy 7: Consider induction chemotherapy (7+3 regimen: cytarabine 100-200 mg/m² × 7 days plus anthracycline) only to reduce disease burden before transplant. 3 However, remission rates are poor (47.6% in monosomy 7 vs 70% in del(7q)), and death rates are high (62% vs 40%). 4
• JMML: Low-dose chemotherapy or supportive care alone results in 100% mortality (survival 4 months to 4 years); intensive chemotherapy achieved remission in only 50% with frequent relapse. 5

Germline Syndrome Considerations

Monosomy 7 frequently occurs in hereditary bone marrow failure syndromes, requiring specific management:

GATA2 Deficiency

• Monosomy 7 with GATA2 deficiency is a high-risk feature strongly associated with malignant transformation, particularly when accompanied by somatic mutations in SETBP1, ASXL1, RUNX1, and RAS pathway genes. 1
• Proceed directly to allogeneic HSCT without delay. 1

Fanconi Anemia

• Monosomy 7, along with gain of 1q or 3q and somatic RUNX1 mutations, indicates progression to MDS/AML. 1
• Allogeneic HSCT is indicated, but requires specialized conditioning regimens due to DNA repair defects. 1

SAMD9/SAMD9L Mutations

• Approximately 50% of patients with monosomy 7 acquire additional leukemia-driver mutations (SETBP1, ASXL1, RUNX1, RAS pathway genes), indicating progression risk. 1
• Serial somatic gene panels from bone marrow must be performed at baseline and with each evaluation. 1

Monitoring Requirements

• Serial molecular monitoring: Perform somatic gene panels from bone marrow at baseline and with each subsequent evaluation for syndromes including Fanconi anemia, GATA2 deficiency, and germline SAMD9/SAMD9L mutations. 1
• Cytogenetic surveillance: Analyze ≥20 metaphases when possible to detect clonal evolution. 6
• Watch for Ph-negative clonal evolution: Abnormalities of chromosome 7 (monosomy 7 and del(7q)) in Philadelphia-negative cells carry risk of myelodysplasia and acute leukemia, justifying long-term follow-up bone marrow biopsies. 7

Common Pitfalls

• Delaying transplant evaluation: Monosomy 7 requires immediate assessment, not observation. Stable disease can occur in RA/RAEB for several years, but eventual progression is nearly universal without transplant. 2
• Overreliance on chemotherapy: Historical data show 3-year survival of only 8% in RAEB-T and 34% in AML with chemotherapy alone. 2
• Missing germline syndromes: Twenty percent of pediatric monosomy 7 cases have predisposing conditions including familial MDS/AML; failure to identify these affects donor selection and family counseling. 2
• Confusing del(7q) with monosomy 7: While both are adverse, complete monosomy 7 has worse prognosis (median OS 32 months) compared to del(7q) (43 months), though both require transplant. 4