Patient case: 4-year-old female with leukemia; genetic feature: ABL1

Clinical trial: Azacitidine and Combination Chemotherapy in Treating Infants With Acute Lymphoblastic Leukemia and MLL Gene Rearrangement

Summary: This pilot trial studies the side effects of azacitidine and combination chemotherapy in infants with acute lymphoblastic leukemia and myeloid/lymphoid or mixed-lineage leukemia (MLL) gene rearrangement. Drugs used in chemotherapy, such as methotrexate, prednisolone, daunorubicin hydrochloride, cytarabine, dexamethasone, vincristine sulfate, pegaspargase, hydrocortisone sodium succinate, azacitidine, cyclophosphamide, mercaptopurine, leucovorin calcium, and thioguanine work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving more than one drug may kill more cancer cells.

Detailed description: PRIMARY OBJECTIVES:
  I. To evaluate the tolerability of azacitidine in addition to Interfant-06 standard chemotherapy in infants with newly diagnosed acute lymphoblastic leukemia (ALL) with MLL gene rearrangement (MLL-R).
  SECONDARY OBJECTIVES:
  I. To evaluate the biologic activity of azacitidine by pharmacodynamic assessment of global deoxyribonucleic acid (DNA) methylation in peripheral blood mononuclear cells (PBMCs) of infants treated with azacitidine.
  TERTIARY OBJECTIVES:
  I. To determine the 5 year event-free survival (EFS) of infants with MLL-R treated with azacitidine in addition to Interfant-06 standard chemotherapy.
  II. To perform comprehensive genome, exome, methylome, and transcriptome analysis of pre-treatment leukemia blasts, remission PMBCs, and refractory or relapsed leukemia blasts and to correlate with outcome in the context of the protocol therapy.
  III. To correlate minimal residual disease (MRD) with outcome in the context of the protocol therapy.
  IV. To perform pharmacokinetic (PK) testing of azacitidine in infants. V. To test the expansion of infant T lymphocytes by stimulation with artificial antigen presenting cells identical to those used in chimeric antigen receptor T-cell (CART)-19 production.
  VI. To collect pharmacodynamic (PD) data for asparaginase activity following pegaspargase administration in infants.
  OUTLINE:
  INDUCTION CHEMOTHERAPY: Patients receive methotrexate intrathecally (IT) on days 1 and 29, prednisolone intravenously (IV) or nasogastrically (NG) three times daily (TID) on days 1-7, daunorubicin hydrochloride IV over 1-15 minutes on days 8-9, cytarabine IV over 30 minutes on days 8-21 and IT on day 15, dexamethasone orally (PO), NG, or IV TID on days 8-28, vincristine sulfate IV over 1 minute on days 8, 15, 22 and 29, pegaspargase IV over 1-2 hours or intramuscularly (IM) on day 12, and hydrocortisone sodium succinate IT on days 15 and 29 in the absence of disease progression or unacceptable toxicity. Only patients with MLL-R continue to post-induction chemotherapy.
  POST-INDUCTION CHEMOTHERAPY:
  AZACITIDINE BLOCK I: Prior to CONSOLIDATION, patients receive azacitidine IV over 10-40 minutes daily for 5 days in the absence of disease progression or unacceptable toxicity.
  CONSOLIDATION: Following completion of AZACITIDINE BLOCK I, patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29, mercaptopurine PO or NG daily on days 1-28, cytarabine IV or subcutaneously (SC) daily on days 3-6, 10-13, 17-20, and 24-27 and IT on day 10, methotrexate IT on day 24 , and hydrocortisone sodium succinate IT on days 10 and 24 in the absence of disease progression or unacceptable toxicity.
  AZACITIDINE BLOCK II: Prior to INTERIM MAINTENANCE, patients receive azacitidine as in AZACITIDINE BLOCK I
  INTERIM MAINTENANCE: Following completion of AZACITIDINE BLOCK II, patients receive mercaptopurine PO or NG daily on days 1-14, methotrexate IV over 24 hours on days 1 and 8 and IT on days 2 and 9, hydrocortisone sodium succinate IT on days 2 and 9, leucovorin calcium PO or IV on days 2-3 and 9-10, cytarabine IV over 3 hours every 12 hours on days 15-16 and 22-23 for a total of 8 doses, and pegaspargase IV over 1-2 hours or IM on day 23 in the absence of disease progression or unacceptable toxicity.
  AZACITIDINE BLOCK III: Prior to DELAYED INTENSIFICATION PART I, patients receive azacitidine as in AZACITIDINE BLOCK I.
  DELAYED INTENSIFICATION PART I: Following completion of AZACITIDINE BLOCK III, patients receive pegaspargase IV over 1-2 hours or IM on day 1, dexamethasone PO, NG, or IV TID on days 1-14 and 15-21 with a taper on days 15-21, thioguanine PO or NG daily on days 1-28, vincristine sulfate IV over 1 minute on days 1, 8, 15, and 22, daunorubicin hydrochloride IV over 1-15 minutes on days 1, 8, 15, and 22, cytarabine IV or SC on days 2-5, 9-12, 16-19, and 23-26 and IT on days 1-15, and hydrocortisone sodium succinate IT on days 1 and 15 in the absence of disease progression or unacceptable toxicity.
  AZACITIDINE BLOCK IV: Prior to DELAYED INTENSIFICATION PART II, patients receive azacitidine as in AZACITIDINE BLOCK I.
  DELAYED INTENSIFICATION PART II: Following completion of AZACITIDINE BLOCK IV, patients receive thioguanine PO or NG daily on days 1-14, cyclophosphamide IV over 15-30 minutes on days 1 and 15, cytarabine IV or SC on days 2-5 and 9-12 in the absence of disease progression or unacceptable toxicity.
  MAINTENANCE: Following DELAYED INTENSIFICATION PART II, patients receive mercaptopurine PO or NG on days 1-168, methotrexate IT on day 1 and 92 and PO once weekly on days 8-91 and 98-168, hydrocortisone sodium succinate IT on day 1, 57, and 99, and cytarabine IT on day 57. Starting on day 169, patients receive mercaptopurine PO or NG on days 1-84 and methotrexate PO once weekly. Courses repeat every 84 days for 2 years from the start of INDUCTION CHEMOTHERAPY in the absence of disease progression or unacceptable toxicity.
  After completion of study treatment, patients are followed up periodically.

Eligibility: Inclusion Criteria:
  -  Patients must have newly diagnosed B lymphoblastic leukemia (2008 World Health Organization [WHO] classification) (also termed B-precursor acute lymphoblastic leukemia) or acute leukemia of ambiguous lineage; patients with mixed phenotype acute leukemia are eligible, provided the morphology and immunophenotype are at least 50% B lymphoblastic
  -  Central nervous system (CNS) status must be determined based on a sample obtained prior to the administration of any systemic or intrathecal chemotherapy, with the exception of steroid pretreatment
  Exclusion Criteria:
  -  Patients with known MLL germline (MLL-G) leukemia prior to enrollment
  -  Patients with Down syndrome
  -  Patients with secondary B acute lymphoblastic leukemia (B-ALL) that developed after treatment of a prior malignancy with cytotoxic chemotherapy
  -  With the exception of steroid pretreatment or the administration of intrathecal methotrexate per protocol dosing, receipt of any other prior cytotoxic chemotherapy for either the current diagnosis of B-ALL or any cancer diagnosed prior to the initiation of protocol therapy on AALL15P1

Relevance to patient case: not relevant