Patient case: 4-year-old female with neuroblastoma; genetic feature: ALK

Clinical trial: A Phase II Trial of Reduced Intensity Conditioning and Haploidentical BMT for High-risk Solid Tumors

Summary: The purpose of this study is to see if giving reduced intensity chemotherapy, haploidentical bone marrow, post-transplant cyclophosphamide and sirolimus is safe and feasible for patients with very high-risk solids tumors.

Detailed description: Allogeneic hematopoietic stem cell transplantation (HSCT) may be associated with a clinically significant "graft-versus-tumor" (GVT) effect, even against disease that is unresponsive to chemotherapy and radiation therapy. Graft-vs.-tumor (GVT) effects have been described after allogeneic HCT for neuroblastoma, Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, melanoma and hepatoblastoma.
  Our goal is to maximize a T cell and NK cell mediated graft versus tumor effect in poor prognosis solid tumor patients using haploidentical donors, T cell replete bone marrow, and a unique post-transplant immunosuppression regimen containing post transplantation Cy and an mTOR inhibitor. This therapy will be widely applicable because almost all patients have a half-matched donor available (parent or sibling). We hope to demonstrate the safety and feasibility of this therapy in anticipation of combining this platform with additional post-transplantation therapy such as cryoablation, Donor Lymphocyte Infusion (DLI), stem cell directed therapy, immunologic checkpoint inhibitors, and/or metabolic inhibitors.

Eligibility: Inclusion Criteria:
  -  Patients must have an HLA-mismatched, related donor (3/6 to 5/6 i.e., 3 to 6 antigen match). Patients who have inherited a recombinant HLA haplotype may receive marrow from parent in whose gamete the recombination occurred.
  -  Sarcoma patients: Males and Females < 40 years of age. All other diagnosis: Males and Females < 21 years of age
  -Patients must have a confirmed histopathologic diagnosis and be classified as high risk defined by having an expected survival of < 10%. -
  Examples include:
  -  Neuroblastoma or ganglioneuroblastoma (Failure to achieve at least a PR after induction therapy with COG ANBL0532 or standard chemotherapy; Refractory to induction chemotherapy or standard chemotherapy; Patients with high risk disease as defined in Appendix 1 whose autologous peripheral blood stem cell product is contaminated with neuroblastoma or who do not have an autologous product available; Patients with high risk disease who do not meet eligibility requirements/organ function requirements for myeloablative conditioning; Patients with >5 identified lesions on the end of induction MIBG scan
  -  Stage 4 rhabdomyosarcoma
  -  Metastatic Ewing Sarcoma
  -  Osteosarcoma with metastatic disease beyond the lungs and/or with lung metastases not amenable to resection
  -  Hepatoblastoma not amenable to resection
  -  Metastatic Melanoma
  -  Desmoplastic small round cell tumor
  -  Brain tumors such as astrocytic tumors, oligodendroglial tumors, ependymal tumors, choroid plexus tumors, other neuroepithelial tumors, neuronal and mixed neuronal-glial tumors, tumors of the pineal region, embryonic tumors
  -  Any other solid tumor and soft tissue sarcoma with an estimated <10% chance of survival will be considered on a case by case basis at the departmental tumor board and/or sarcoma meeting
  -  Previous therapy:
  -  It is expected that patients will have received upfront standard of care therapy for their respected disease
  -  Patients who relapse after either single or tandem autologous BMT are eligible (> 6 months must have elapsed from start of last BMT).
  -  Patients must be recovered from the acute toxicities of any prior chemo/radio/immunotherapy or BMT
  -  Patients do not need to have measurable disease at time of enrollment. Patients with measurable disease must have stable disease by RECIST criteria on two scans at least 4 weeks apart.
  -  Patients with adequate organ function as measured by:
  -  Cardiac: Left ventricular ejection fraction at rest must be ≥ 35%, or shortening fraction > 25%.
  -  Hepatic: Bilirubin ≤ 3.0 mg/dL; and ALT, AST, and Alkaline Phosphatase < 5 x ULN.
  -  Renal: Serum creatinine within normal range for age, or if serum creatinine outside normal range for age, then renal function (creatinine clearance or GFR) > 40 mL/min/1.73m2.
  -  Pulmonary: FEV1, FVC, DLCO (diffusion capacity) > 50% predicted (corrected for hemoglobin); if unable to perform pulmonary function tests, then O2 saturation > 92% on room air.
  -  Good performance status (Karnofsky/Lansky 70-100)
  -  Patients (Parents/guardians for those <18) and donors must be able to sign consent forms.
  -  Patients must be willing to participate in all stages of treatment
  Criteria for donor eligibility:
  -  Age >0.5 years
  -  Donors must meet the selection criteria as defined by the Foundation for the Accreditation of Hematopoietic Cell Therapy (FACT).
  -  Lack of recipient anti-donor HLA antibody Note: In some instances, low level, non-cytotoxic HLA specific antibodies may be permissible if they are found to be at a level well below that detectable by flow cytometry. This will be decided on a case-by-case basis by the PI and one of the immunogenetics directors.
  -  In the event that two or more eligible donors are identified, the following order of priority will be used to determine the preferred donor:
  1. Medically and psychologically fit and willing to donate
  2. Killer Immunoglobulin Receptor (KIR) Haplotype B Donor
  3. Red blood-cell compatibility (in order of preference)
  1. RBC cross-match compatible
  2. Minor ABO incompatibility
  3. Major ABO incompatibility
  -  For CMV seronegative recipients, a CMV seronegative donor. For CMV seropositive recipients, a CMV seropositive donor is preferred.
  -  If more than one preferred donor is identified from the above list and there is no medical reason to prefer one of them, then the following guidelines are recommended:
  1. If the patient is male, choose a male donor
  2. Choose the youngest preferred donor
  3. If the patient and family express a strong preference for a particular donor, use that one
  Exclusion Criteria:
  -  Patients will not be excluded on the basis of sex, racial or ethnic background.
  -  HIV-positive
  -  Donor (donor anti-recipient) ABO incompatibility if an ABO compatible donor is available.
  -  Positive leukocytotoxic crossmatch
  -  Women of childbearing potential who currently are pregnant or who are not practicing adequate contraception
  -  Uncontrolled viral, bacterial, or fungal infections.

Relevance to patient case: not relevant