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.
The investigators' 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 shortened duration tacrolimus. This therapy will be widely applicable
because almost all patients have a half-matched donor available (parent or sibling). The
investigators hope to demonstrate the safety and feasibility of this therapy in anticipation
of combining this platform with additional post-transplantation relapse/progression
prevention therapy such as an immune checkpoint inhibitor.
TREATMENT PLAN Indwelling central venous catheter Placement of a double lumen central venous
catheter will be required for administration of IV medications and transfusion of blood
products.
Pre-treatment Evaluation All patients will require documentation of a detailed history and
physical examination and standard evaluation of cardiac, pulmonary, liver and renal function.
All patients will undergo disease evaluation as specified in Table 1, utilizing whichever
modalities following the guidelines in 6.1.3 (i). Pre-BMT blood will be drawn per section
section 5.12 for correlative labs.
Preparative regimen Fludarabine: administered as an IV infusion over 30 minutes on D-7 to
D-3. The dose will be 30 mg/m2/dose (adjusted for renal function).
Melphalan: Recommended to be administered as an IV infusion over 30-60 minutes, depending on
volume, on D-2. The dose will be 100mg/m2. Other institutional infusion standards are
acceptable and will not be a protocol deviation.
Total body irradiation: 200 cGy AP/PA with 4MV or 6MV photons at 8 12 cGy/min at the point of
prescription (average separation of measurements at mediastinum, abdomen, and hips) will be
administered in a single fraction on day -1.
Day of rest: A day of rest, i.e. after preparative regimen completion and prior to bone
marrow infusion, is not routinely scheduled. Up to one day of rest in-between TBI and the
infusion of bone marrow may be added in this window based on logistical considerations or
clinically as indicated. Bone marrow transplantation. Bone Marrow will be harvested and infused on day 0. Institutional guidelines for the infusion
of bone marrow (i.e. major or minor ABO incompatible bone marrow, etc.) will be followed. The
marrow infusion will be done by designated members of the BMT team. The bone marrow graft
will not be manipulated to deplete T cells. The donor will be harvested with a target yield
of 4 x 108 nucleated cells/kg recipient IBW. The lowest acceptable yield is 1.5 x 108
nucleated cells/kg. The CD 34+, CD4+, CD8+, and CD3+ cell count in the marrow will be
quantified by flow cytometry.
Post-transplantation Cyclophosphamide. Cyclophosphamide 50mg/kg will be given on D+3 post-transplant (within 60-72 hr of marrow
infusion) and on D+4 post-transplant. Cyclophosphamide will be given as an IV infusion over
1- 2 hours (depending on volume). Dosing of cyclophosphamide is based on ideal body weight
for subjects whose ideal body weights less than or equal to their actual body weight. On
occasion, a subject's actual body weight may be less than his/her ideal body weight, in which
case cyclophosphamide will be dosed using the subject's actual body weight.
Patients will be instructed to increase fluids overnight before cyclophosphamide
administration. Hydration with normal saline at 3 cc/kg/hr iv will be started 8 hr prior to
cyclophosphamide, then the rate will be reduced to 2 cc/kg/hr for 1 hr pre-cyclophosphamide
and continued for at least 8 hr post-cyclophosphamide or administered per institutional
standards. Mesna will be given in divided doses IV 30 min pre- and at 3, 6, and 8 hours
post-cyclophosphamide or administered per institutional standards. Mesna dose will be based
on the cyclophosphamide dose being given. The total daily dose of mesna is equal to 80% of
the total daily dose of cyclophosphamide.
Patients will be instructed to increase fluids overnight before cyclophosphamide
administration. Hydration will be administered per institutional standards. Protocol
recommendation of normal saline at 3 cc/kg/hr iv will be started 8 hr prior to
cyclophosphamide, then the rate will be reduced to 2 cc/kg/hr for 1 hr pre-cyclophosphamide
and continued for at least 8 hr post-cyclophosphamide. Mesna will be administered per
institutional standards. Mesna dose will be based on the cyclophosphamide dose being given.
The total daily dose of mesna is equal to 80% of the total daily dose of cyclophosphamide.
It is crucial that no immunosuppressive agents are given until 24 hours after the completion
of the post-transplant Cy. This includes steroids as anti-emetics.
GVHD prophylaxis. Tacrolimus On day +5, patients will begin prophylaxis with Tacrolimus (PO or IV as per
institutional standards for starting this prophylaxis).Tacrolimus begins on Day 5, at least
24 hours after completion of posttransplantation Cy. The tacrolimus starting dose will be
given per institutional standards for adult or pediatric patients. The recommended, but not
required, The starting dose of tacrolimus is 0.015mg/kg IBW/dose IV over 4 hours every 12
hours. , or per institutional standard. Serum trough levels of tacrolimus should be measured
around D+7 and the dose should be adjusted based on this level to maintain a level of 5-15
ng/ml. Tacrolimus should be converted to oral dosing when patient has a stable, therapeutic
level and is able to tolerate food or other oral medications. For pediatric patients, the
oral dosing is approximately two to four times the IV dosing. It is recommended that serum
trough levels should be checked at steady state after any dose modification and when
switching from IV to oral to ensure therapeutic trough concentrations. Serum trough
concentrations should be checked at a minimum weekly thereafter and the dose adjusted
accordingly to maintain a level of 5-15 ng/ml. Tacrolimus will be discontinued after the last
dose on Day 90, or may be continued if active GVHD is present. This should be discussed with
the PI. Tacrolimus may also be discontinued early if patients have progressive disease or
relapse. If tacrolimus is stopped earlier or later than day 90 +/- 7 days , this should be
discussed with the PI This should also be discussed with the PI.
Mycophenolic acid mofetil (MMF) MMF will be given at a dose of 15 mg/kg PO TID (based upon
actual body weight) with the maximum total daily dose not to exceed 3 grams (1 g PO TID). MMF
prophylaxis will be discontinued after the last dose on D35.
Infection prophylaxis and therapy All infection prophylaxis and therapy will be administered
and discontinued as per institutional requirements. The following are recommendations only.
i) During pre-transplant evaluation patients will be screened for respiratory syncytial
virus, influenza A, B and parainfluenza viruses if symptomatic. Assays of these viruses must
be negative for symptomatic patients to be admitted for transplant. Strong consideration
should be given to institution of ribavirin therapy if positive for adenovirus or nalidixic
acid if positive for BK virus.
ii) Oral hygiene will be maintained according to institutional standards.
iii) Prophylactic anti-microbial therapy will be started during the preparative regimen, per
institutional guidelines.
iv) Empiric therapy with broad-spectrum antibiotics will be instituted for the first
neutropenic fever (specific agents as per current practice).
Growth factor support. Patients will receive G-CSF (Filgrastim®) 5µg/kg/d SC or IV starting at Day 5 and continuing
until the ANC>1000/mm3 x 3days or two consecutive measurements over a three day period. For
use in the case of fungal infections or subsequent neutropenia (ANC<500/mm3), G-CSF should be
continued until the WBC>10,000-15,000.
Transfusion support Platelet and packed red cell transfusions will be given per current
institutional recommendations.
Anti-ovulatory treatment Menstruating females will are recommended to should be be started on
an anti-ovulatory agent, such as Lupron prior to the initiation of the preparative regimen.
The treatment administered will be at the discretion of the treating physician.
Post-BMT evaluation Patients will be followed during (i) the initial post-BMT period (ii)
after discharge to the referring physician as per standard practice.
