CPX-351 (VYXEOS) for the Treatment of Secondary Myeloid Neoplasms in Patients Under 22 Years Old

Inclusion Criteria

• Patients must be >= 1 year and < 22 years of age at the time of enrollment.
• Treatment-related myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML): Patients with solid organ or hematopoietic neoplasms previously treated with alkylating agents, ionizing radiation, topoisomerase inhibitors, antimetabolites, thiopurines, mycophenolate mofetil, fludarabine, and anti-tubulin agents (vincristine, vinblastine, vindesine, paclitaxel, and docetaxel usually in combination), who develop MDS, or AML are candidates for the CPXSMN protocol. If the bone marrow has between 5% and 20% blasts (higher-risk MDS), patients are discussed with the hematopoietic stem cell transplantation (HSCT) team for consideration to receive chemotherapy before HSCT. If the consensus is that cytoreduction before HSCT is necessary, and the cumulative dose of doxorubicin equivalent is < 500 mg/m^2, (in cases of cardio protection) or < 400 mg/m^2 (cases without cardio protection), patients are eligible for the CPXSMN protocol. OR
• Secondary MDS/AML: Patients with primary MDS in transformation to AML (refractory cytopenia with an excess of blasts), acquired aplastic anemia evolving to AML, myeloid neoplasms arising from inherited bone marrow failure syndromes (including severe congenital neutropenia, Schwachman-Diamond syndrome, MECOM syndrome) or MDS/AML predisposition syndromes (including germline predisposition in GATA2, RUNX1, SAMD9/SAMD9L, ERCC6L2, NF1, ETV6, ANKRD26, ERCC6L2, TP53 or CEBPA genes) are eligible for the CPXSMN trial. If the bone marrow has between 5% and 20% blasts (higher-risk MDS), patients are discussed with the HSCT team for consideration to receive chemotherapy before HSCT. If the consensus is that cytoreduction before HSCT is necessary, the patients are eligible for the CPXSMN protocol.
• Patients must have a performance status corresponding to an Eastern Cooperative Oncology Group (ECOG) score of 0, 1 or 2. Use Karnowski for patients > 16 years of age and Lansky for patients =< 16 years of age. Note: Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) > 70 mL/min/1.73 m^2 , or a serum creatinine based on age/gender as follows: * Age 1 to < 2 years: maximum serum creatinine 0.6 mg/dL for male and 0.6 mg/dL for female * Age 2 to < 6 years: maximum serum creatinine 0.8 mg/dL for male and 0.8 mg/dL for female * Age 6 to < 10 years: maximum serum creatinine 1 mg/dL for male and 1 mg/dL for female * Age 10 to < 13 years: maximum serum creatinine 1.2 mg/dL for male and 1.2 mg/dL for female * Age 13 to < 16 years: maximum serum creatinine 1.5 mg/dL for male and 1.5 mg/dL for female * Age >= 16 years: maximum serum creatinine 1.7 mg/dL for male and 1.4 mg/dL for female
• Direct bilirubin =< 1.5 x upper limit of normal (ULN) for age and institution (unless it is related to leukemic involvement). At institutions that do not obtain a direct bilirubin in patients with a normal total bilirubin, a normal total bilirubin may be used as evidence that the direct bilirubin is not > 1.5 x the ULN.
• Serum glutamic-pyruvic transaminase (SGPT) (alanine transaminase [ALT]) =< 3.0 x ULN for age and institution (unless it is related to leukemic involvement).
• Shortening fraction of >= 27% by echocardiogram, or
• Ejection fraction of >= 50% by radionuclide angiogram or echocardiogram, and
• Corrected QT (QTcB) interval < 500 msecs.
• Patients with seizure disorder may be enrolled if on anticonvulsants and if seizures are well controlled.
• Central nervous system (CNS) toxicity =< grade 2.
• Patients must have recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, HSCT or radiotherapy prior to entering this study. All prior treatment-related toxicities must have resolved to =< grade 2 prior to enrollment.
• Myelosuppressive chemotherapy: Must not have received myelosuppressive chemotherapy within 3 weeks of entry onto this study (excluding hydroxyurea). Cyto-reduction with hydroxyurea can be initiated and continued for up to 24 hours prior to the start of CPX-351.
• Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy with steroids, retinoids or hypomethylating agents. Note: For agents that have known adverse events occurring beyond 7 days after administration (i.e. monoclonal antibodies), this period must be extended beyond the time during which acute adverse events are known to occur.
• Radiation therapy (RT): >= 2 weeks for local palliative RT (small port); >= 6 months must have elapsed if prior craniospinal RT or if >= 50% radiation of pelvis; >= 6 weeks must have elapsed if other substantial bone marrow (BM) radiation. Note: Patients must have received =< than 13.6 gray (Gy) prior radiation to the mediastinum. Patients with prior cumulative doxorubicin equivalent > 400 mg/m^2 and prior radiation (any dose) to the mediastinum are not eligible for the protocol.
• Hematopoietic stem cell transplantation: No evidence of active graft vs. host disease for at least 4 weeks. For allogeneic HSCT patients, >= 3 months must have elapsed since HSCT. * Must have received no more than 1 prior autologous or allogeneic stem cell transplant. * Patients must be off all systemic immunosuppressive therapy for at least 2 weeks, excluding hydrocortisone for physiologic cortisol replacement.
• Intrathecal cytotoxic therapy: * No waiting period is required for patients having received intrathecal cytarabine, methotrexate, and/or hydrocortisone. * At least 14 days must have elapsed since receiving liposomal cytarabine (DepoCyte) by intrathecal injection.
• Growth factors: * Patients must not have received hematopoietic growth factors for 7 days prior to CPX-351. * Patients must not have received pegfilgrastim for 14 days prior to CPX351
• Patients with a known history of human immunodeficiency virus (HIV) are eligible, if they meet all of the following conditions: * No history of HIV complications with the exception of CD4 count < 200 cells/mm^3 * No antiretroviral therapy with overlapping toxicity such as myelosuppression * CD4 count > 500 cells/mm^3 prior to the diagnosis of relapsed AML * HIV viral loads below the limit of detection * No history of highly active antiretroviral therapy (HAART)-resistant HIV
• Patients with residual or relapsed solid malignancy (for example osteosarcoma) at the time of the diagnosis of SMN are not excluded from this trial and the treatment individualized to integrate the management of the two malignancies.
• All patients and/or their parents or legal guardians must sign a written informed consent.

Exclusion Criteria

• Patients with de novo AML (i.e., patients eligible for St. Jude or Children's Oncology Group [COG] frontline AML trials).
• Patients with any of the following: * Constitutional trisomy 21 or with constitutional mosaicism of chromosome trisomy 21 * Patients with Fanconi anemia (FA) Note: Very rarely patients with FA may not display any of the classic constitutional signs and symptoms associated with the disease. Myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) could be the first manifestation of a patient with FA. For patients presenting with MDS/AML without a clear etiology—such as history of chemotherapy or radiation (indicative of treatment-related AML), or any well-defined genetic origins (e.g., mutations in GATA2, SDAM9, SDAM9/L, RUNX1, or ETV6)—genetic testing for FA should be considered, especially if the disease progression is not acutely rapid. In cases where AML is advancing rapidly, consideration for enrolling the patient should follow a thorough discussion with the principal investigator of the protocol. * DNA repair syndromes * Dyskeratosis congenita (telomeropathy) * Wilson disease or other copper-related metabolic disorders * Mixed phenotype acute leukemia * Philadelphia chromosome-positive myeloid neoplasms (AML or chronic myelogenous leukemia [CML]) * Acute promyelocytic leukemia (APL), or * Juvenile myelomonocytic leukemia (JMML) and related RASopathy disorders in chronic phase.
• Patients who have received >= 400 mg/m2 doxorubicin equivalents. For the purposes of determining eligibility for this protocol, the following cardiotoxicity multipliers will be used to determine doxorubicin equivalents: * Doxorubicin (reference): 1 * Daunomycin: 0.5 * Epirubicin: 0.5 * Idarubicin: 5 * Mitoxantrone: 10
• Patients who are currently receiving another investigational drug.
• Patients receiving medications for treatment of left ventricular systolic dysfunction.
• Patients with documented active, uncontrolled infection at the time of study entry.
• Patients with known active hepatitis B virus (HBV) and hepatitis C virus (HCV) infections.
• Patients with prior allergy to daunorubicin and/or cytarabine.
• Pregnancy and breast feeding * Female patients who are pregnant are ineligible due to risks of fetal and teratogenic adverse events as seen in animal/human studies. * Lactating females who are breastfeeding an infant/child * Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained. * Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation and for at least 6 months after the last dose of protocol therapy.