Gemtuzumab ozogamicin in infants with AML: results from the Children’s Oncology Group trials AAML03P1 and AAML0531

Guest, Erin; Aplenc, Richard; Sung, Lillian; Raimondi, Susana C.; Hirsch, Betsy A.; Alonzo, Todd A.; Gerbing, Robert B.; Wang, Yi Cheng Jim; Kahwash, Samir B.; Heerema-McKenney, Amy; Meshinchi, Soheil; Gamis, Alan S.

doi:10.1182/blood-2017-01-762336

Cited by 19 publications

(12 citation statements)

References 26 publications

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“…GO is a commercialized humanized anti-CD33 monoclonal antibody coupled to the cytotoxic antibiotic calicheamicin causing DNA damage after endocytosis. This antibody has been shown to be effective in pediatric AML, including infants with similar and especially reasonable hepatic side effects (12,13). Our main concern was to determine how to associate these two immunotherapies, one targeting the B lymphoid component, the other one targeting the myeloid component of the MPAL.…”

Section: Discussionmentioning

confidence: 99%

Case Report: Targeting 2 Antigens as a Promising Strategy in Mixed Phenotype Acute Leukemia: Combination of Blinatumomab With Gemtuzumab Ozogamicin in an Infant With a KMT2A-Rearranged Leukemia

et al. 2021

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Mixed phenotype acute leukemia (MPAL) accounts for 2-5% of leukemia in children. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. The prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children. A lymphoid-type therapeutic approach appears to be more effective but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75-80% of leukemia in infants under one year of age and remains a major pejorative prognostic factor in the Interfant-06 protocol with a 6 years EFS of only 36%. The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue. We describe here the feasibility and tolerance of the combination of two targeted immunotherapies, blinatumomab and Gemtuzumab Ozogamicin, in a 4-year-old infant with a primary refractory KTM2A-rearranged MPAL. Our main concern was to determine how to associate these two immunotherapies and we describe how we decided to do it with the parents’ agreement. The good MRD response on the two clones made it possible to continue the curative intent with a hematopoietic stem cell transplant at 9 months of age. Despite a relapse at M11 post-transplant because of the recurrence of a pro-B clone retaining the initial lymphoid phenotype, the child is now 36 months old, in persistent negative MRD CR2 for 12 months after a salvage chemotherapy and an autologous CAR T cells infusion, with no known sequelae to date. This case study can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.

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Section: Discussionmentioning

confidence: 99%

Case Report: Targeting 2 Antigens as a Promising Strategy in Mixed Phenotype Acute Leukemia: Combination of Blinatumomab With Gemtuzumab Ozogamicin in an Infant With a KMT2A-Rearranged Leukemia

et al. 2021

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“…The first randomized trial testing the addition of GO to first‐line chemotherapy in children reported significant improvement of EFS with GO, by reducing the relapse risk, 22 with acceptable cost impact 23 . This improvement was stronger in low‐ and intermediate‐risk patients.…”

Section: Discussionmentioning

confidence: 99%

Association of fludarabin, cytarabine, and fractioned gemtuzumab followed by hematopoietic stem cell transplantation for first‐line refractory acute myeloid leukemia in children: A single‐center experience

Penel‐Page

Pleşa

Girard

et al. 2020

Pediatric Blood & Cancer

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Context: Acute myeloid leukemia (AML) is a rare disease in children, with only 50% to 60% eventfree survival. Among patients with AML, 10% do not respond to first-line chemotherapy. There is no recommendation concerning second-line treatments. Gemtuzumab ozogamicin (GO) is a monoclonal antibody targeting CD33, linked to calicheamicin. We report the efficacy and tolerance of a salvage regimen of fludarabin, cytarabine, and GO (FLA-GO) in patients refractory to first-line treatment.Methods: Eight patients (median age 14.5 years), who had more than 2% minimal residual disease (MRD) by flow cytometry (MRD flow), received gemtuzumab 3 mg/m 2 on days 1, 4, 7, associated with cytarabine 2000 mg/m 2 and fludarabin 30 mg/m 2 on days 1 to 5.Results: Six patients achieved complete remission (CR) (blast count morphology ≤5 × 10 −2 , CR-MRD flow <1 × 10 −3 for four patients). Five patients received a second course. We observed 11 episodes of febrile neutropenia, including 6 septicemias without complication. There was no fungal infection or toxic death. Two patients received granulocyte colony stimulating factor.One patient had partial platelet recovery; one, prolonged pancytopenia. All patients received hematopoietic stem cell transplantation (HSCT). We observed five mild-to-severe sinusoidal obstruction syndromes during HSCT procedures, particularly in patients who did not receive defibrotide prophylaxis. At the date of last contact (median follow-up: 58 months; range: 22-78), six patients were in continuous CR with negative MRD. Two patients died of post-HSCT relapse. Conclusion:FLA-GO is a good salvage regimen for pediatric refractory AML, with significant but acceptable toxicity. HSCT is mandatory to achieve sustained CR in these patients.

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“…Gemtuzumab is likely to be added to chemotherapy in future protocols based on favorable results, both in pediatrics overall 23 and infants specifically. 24 Cases of AML in infants are relatively unlikely to harbor cytogenetic or molecular abnormalities that confer unfavorable risk or favorable risk, and risk stratification is typically dictated by end-induction minimal residual disease (MRD) testing, although the KMT2A fusion partner may be incorporated in future protocols.…”

Section: Kmt2a (Formerly Mll) Gene Rearrangementsmentioning

confidence: 99%

“…Risk stratification of infant ALL Postinduction, patient 1 was randomized to receive consolidation with multiagent chemotherapy blocks protocol IB and MARMA. His MRD level post-MARMA was ,10e24 (0.01%) by polymerase chain reaction. He received allogeneic HSCT in first remission with an umbilical cord blood donor after a preparatory regimen with busulfan, cyclophosphamide, and melphalan.…”

mentioning

confidence: 97%

How I treat infant leukemia

Brown

Pieters

Biondi

2019

Blood

120

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Leukemia in infants is rare but generates tremendous interest due to its aggressive clinical presentation in a uniquely vulnerable host, its poor response to current therapies, and its fascinating biology. Increasingly, these biological insights are pointing the way toward novel therapeutic approaches. Using representative clinical case presentations, we review the key clinical, pathologic, and epidemiologic features of infant leukemia, including the high frequency of KMT2A gene rearrangements. We describe the current approach to risk-stratified treatment of infant leukemia in the major international cooperative groups. We highlight recent discoveries that elucidate the molecular biology of infant leukemia and suggest novel targeted therapeutic strategies, including modulation of aberrant epigenetic programs, inhibition of signaling pathways, and immunotherapeutics. Finally, we underscore the need for increased global collaboration to translate these discoveries into improved outcomes.

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Gemtuzumab ozogamicin in infants with AML: results from the Children’s Oncology Group trials AAML03P1 and AAML0531

Cited by 19 publications

References 26 publications

Case Report: Targeting 2 Antigens as a Promising Strategy in Mixed Phenotype Acute Leukemia: Combination of Blinatumomab With Gemtuzumab Ozogamicin in an Infant With a KMT2A-Rearranged Leukemia

Case Report: Targeting 2 Antigens as a Promising Strategy in Mixed Phenotype Acute Leukemia: Combination of Blinatumomab With Gemtuzumab Ozogamicin in an Infant With a KMT2A-Rearranged Leukemia

Association of fludarabin, cytarabine, and fractioned gemtuzumab followed by hematopoietic stem cell transplantation for first‐line refractory acute myeloid leukemia in children: A single‐center experience

How I treat infant leukemia

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