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Gemtuzumab ozogamicin for salvage CBF-AML: A case report

Aug 28, 2020

During the 2 ndHow to Diagnose and Treat Acute Leukaemia conference organized by the European School of Haematology (ESH), there was an interactive session dedicated to discussing the off-label use of mutation-based therapy in AML. Nicolas Boissel presented the available data from gemtuzumab ozogamicin (GO) administration in a particular patient with core binding factor (CBF)-AML. 1

In 2018, GO was approved for use in addition to standard induction chemotherapy in newly diagnosed patients with CD33 +AML. This anti-CD33 conjugated monoclonal antibody had been previously authorized in 2000 through an accelerated review process, but was withdrawn in 2010 from the market due to increased mortality rates . With the current indication in a specific population and modified dosing schedule, GO’s safety profile improved, and it is being further investigated in several studies as frontline and salvage therapy for AML (e.g., the AML18 trial ).

Patient details 1

  • 35-year old male
  • Diagnosed with CBF-AML, M2 classification
    • t(8;21) – CBF subunit A (CBFA)
    • KIT mutated (variant allele frequency [VAF], 20%)

M2, according to the French-American-British (FAB) criteria, means AML with maturation. It is defined by the presence of ≥ 20% of blasts in the bone marrow or peripheral blood, < 20% monocytic precursors in the bone marrow, and ≥ 10% of granulocytes at different maturation stages. M2 is diagnosed in approximately 10% of all AML cases. 2

Translocation (8;21) and inv(16) are considered unique entities within AML (CBFA and CBFB, respectively) and together define a heterogeneous subgroup named CBF-AML. Classification of t(8;21) is usually M2 (80–90%) and rarely M1 (AML with minimal maturation; 10%). Additionally, several co-occurring mutations play a crucial role in risk stratification and prognosis: signaling mutations are present in 60–80% of cases, where KIT is the most frequently mutated gene, along with NRAS, FLT3, and KRAS. 3–5

Patients with CBF-AML represent up to 15% of all adult AML, and generally have favorable outcomes since complete remission rates after induction are considered high. Nevertheless, long-term survival is only reported in 40–60% of adult patients. Clinical trials and retrospective analyses focusing only on patients with CBF-AML are needed to describe its characteristics further and to define better therapeutic approaches. Up to date, most randomized trials in AML are underpowered to analyze the results only in this subgroup. 3–5

Treatment 1

Frontline treatment

  • Induction regimen: 7+3 with cytarabine 200 mg/m 2and daunorubicin 90 mg/m 2, followed by three courses with cytarabine 3,000 mg/m 2every 12 hours on Days 1, 3, and 5 as consolidation
  • The patient showed a rapid and profound response, with a more than 3-log reduction in measurable residual disease before the second cycle of treatment
  • Hematopoietic stem cell transplant (HSCT) was saved for salvage therapy, since initial response was satisfactory
  • 15 months after the first reported complete response, the patient experienced a hematological relapse; 3 months earlier, molecular relapse was detected
  • Cytogenetic analysis was repeated, and persistence of KITmutation was found (VAF 47%)

The UK Medical Research Council (MRC) AML10 trial proved that allogeneic and autologous HSCT after intensive chemotherapy reduce relapse rates similarly in patients with CBF-AML. Also, younger patients undergoing allogeneic HSCT showed significantly longer overall survival (OS). 5

To date, HSCT is not necessary to be performed at first response unless in the case of relapsed, refractory, or high-risk disease. Older patients, or those with KIT mutations, present poor prognosis and should be considered for allogeneic HSCT. 5

Mutations on KIT receptors are associated with a higher risk of relapse, especially when present in patients with t(8;21). The allelic ratio is essential for prognosis, since those patients with KIT mutated ≥ 25% allelic ratio present with a significantly higher risk of relapse than those with lower KIT ratios. 1

Treatment at relapse 1

  • Data on relapsed CBF-AML is scarce and generally from retrospective studies ( Table 1)
  • CBF-AML complete responses at relapse are 65–85% when treated intensively, and 5-year OS is 32–51%. Overall, CBFA presents worse survival outcomes than CBFB
  • The most important clinical prognostic factor in relapsed CBF-AML is the duration of the first complete response. The role of allo-SCT at second complete response is controversial when comparing different published studies ( Table 1)

Table 1. Summary of retrospective studies reporting the outcomes of patients with relapsed CBF-AML 1

allo, allogeneic HSCT; auto, autologous HSCT; CALGB, Cancer and Leukemia Group B; CBF, core binding factor; CBFA, CBF subunit A, with t(8;21); CBFB, CBF subunit B, with inv(16); CR, complete response; CR1, first CR; CR2, second CR; m, months; HDAC, high-dose cytarabine; HSCT, hematopoietic stem cell transplant; MDACC, MD Anderson Cancer Center; NR, not reported; OS, overall survival; UK, United Kingdom; US, United States; y, year.

* Intensive salvage;

** HDAC salvage;

$No allogeneic HSCT in CR1.

Study location


CBFA / CBFB, n/n

Median age, years



Univariate analysis for OS









CR1 duration







5-y: 51%










median: 12 m










3-y: 48%






162 $




5-y: 32%










5-y: 14% vs 34% (CBFA vs CBFB)




allo < auto












  • The efficacy of GO has been primarily investigated in first-line randomized studies, and mostly observed in patients presenting a favorable karyotype 1
  • In a recent French study, the ALFA-0701 trial ( NCT00927498 ) , the investigators reported that patients showing the most benefit from first-line GO (more prolonged event-free survival), were those harboring signaling mutations, which are associated with CD33 overexpression 6
    • Of note, patients with CBF-AML were excluded from this posterior analysis. However, as previously published, GO efficacy is higher in those patients with a higher expression of its target, CD33
  • The benefit of GO in relapsed CBF-AML, in terms of OS, was first reported in a retrospective study by the French AML Intergroup, with 78 patients who received allogeneic HSCT in second complete response. They observed that those who received GO before transplant significantly improved post-transplant survival outcomes, without significant increment of treatment-related mortality 7

Conclusion 1

  • Patients with CBF-AML presenting signaling mutations might benefit from GO in first-line and relapse
  • Additional studies are needed to confirm if the use of GO in CBF-AML should be restricted to patients with signaling mutations, which are frequently reported in this AML subtype
  • The efficacy of GO in this setting could be enhanced by combining it with targeted inhibitors
  • Non-CBF-AML might also respond better to GO when signaling mutations are detected

At the Acute Leukemias XVII Biology and Treatment Strategies biennial international symposium in 2019, the AML Hub talked with Alan K. Burnett from Glasgow University, Scotland, UK, about GO’s role in CBF-AML. See below his key messages on this topic:

Alan K. Burnett | ISAL 2019 | Gemtuzumab ozogamicin in CBF AML

  1. Boissel N. Gemtuzumab ozogamicin for salvage AML therapy. Oral abstract. ESH 2nd How to Diagnose and Treat: Acute Leukaemia; Jun 30, 2020; Virtual.
  2. Mihova D. AML with maturation (FAB AML M2). Pathology Outlines. Published Feb 1, 2013. Accessed Aug 26, 2020.
  3. Allen C, Hills RK, Lamb K, et al. The importance of relative mutant level for evaluating impact on outcome of KIT, FLT3 and CBL mutations in core-binding factor acute myeloid leukemia. 2013;27(9):1891–901. DOI: 10.1038/leu.2013.186
  4. Duployez N, Marceau-Renaut A, Boissel N, et al. Comprehensive mutational profiling of core binding factor acute myeloid leukemia. 2016;127(20):2451–2459. DOI: 10.1182/blood-2015-12-688705
  5. Sinha C, Cunningham LC, Liu PP. Core binding factor acute myeloid leukemia: new prognostic categories and therapeutic opportunities.  Semin Hematol. 2015;52(3):215-222. DOI: 10.1053/j.seminhematol.2015.04.002
  6. Fournier E, Duployez N, Ducourneau B, et al. Mutational profile and benefit of gemtuzumab ozogamicin in acute myeloid leukemia. Blood. 2020;135(8):542-546. DOI: 1182/blood.2019003471
  7. Hospital MA, Prebet T, Bertoli S, et al. Core-binding factor acute myeloid leukemia in first relapse: a retrospective study from the French AML Intergroup. Blood. 2014;124(8):1312-1319. DOI: 1182/blood-2014-01-549212