Study Summary

Relapsed or refractory Neuroblastoma (NBL) carries a very poor prognosis. Patients, who relapse after the standard intensive treatment regimen, have an overall 3 year survival rate reported as < 10%. Also, 15% of the high risk NBL patients will have minimal response, stable disease or persistent tumor (refractory disease) and are not candidates for continuation of standard treatments and hence, also have very poor prognosis. No treatment with a ‘curative’ intent is available for these groups of patients (only experimental protocols are currently available). Stem Cell Transplant from a different donor (allogeneic), is a form of adoptive cellular therapy that has a high degree of efficacy in fighting tumors. In addition to the conditioning therapy, engraftment of donor immune cells (i.e. T cells, NK cells) mediates Graft versus Tumor (GVT) effect. The recent results of reduced intensity transplants have been encouraging with minimal toxicity and low mortality in heavily pre-treated patients.

This Phase II pilot study is designed to confirm the feasibility of a RIC regimen (Fludarabine, Busulfan and rabbit ATG) for allogeneic HSCT for relapsed or refractory NBL patients. Toxicity, engraftment and incidence of severe GVHD will be monitored after HSCT. Best matched available donors (siblings or from outside family) will be selected for the SCT and the KIR mis-matches in the donor-recipient pairs will be analyzed. The reconstituted donor NK cells repertoire will be followed by both the genotyping and pheno-typing methods at multiple time-points post-transplant to understand better the NK cell growth and how they fight NBL cells.

The major aim of this pilot study is to generate preliminary clinical and laboratory data to confirm the feasibility of a RIC allogeneic HCST for heavily pre-treated NBL patients and elucidate the role of NK cells and KIR mis-matches in mediating the GVT effects against NBL.

Study Summary

Sickle Cell Disease (SCD) is a hemoglobinopathy commonly affecting African- American population. It affects approximately 1 in every 400 African-American newborns and an estimated 70,000 persons in the United States. Common sequelae of the disease are painful vaso-occlusive crisis, stroke (cerebral infarction), pulmonary restrictive disease and pulmonary hypertension. The average life expectancy for male patients with SCD is 42 years, and 48 years for females. 15% of patients die by 20 years of age and 50% by age 40. Of the modalities available for treatment of severe SCD, only hematopoietic stem cell transplantation (HSCT) offers complete cure. The results of HSCT have been very encouraging with ≥85% event free survival (EFS) in all the HSCT studies done using matched family donors. Matched family donors are available for only 15-20% of the SCD patients, severely limiting the application of HSCT for patients who need it the most.

The primary goal of this pilot study is to determine the safety and feasibility of a preparative regimen for HSCT using a novel immunosuppressive regimen for unrelated donors. We want to confirm if an immunosuppressive and myeloablative conditioning regimen, followed by an appropriately HLA-matched unrelated donor (MUD) HSCT, can lead to donor engraftment with minimal toxicity.

We will test this in SCD patients who have high-risk features for significant disease related morbidity and early mortality, and who might benefit from normal donor hematopoiesis but lack suitable family donors. They will undergo HSCT from unrelated donor bone marrow (BM) or umbilical cord blood (UCB) cells using strict matching criteria. Patients will receive an immunosuppressive and myeloablative combination of Rituximab, Fludarabine, Busulfan, and rabbit-ATG (Thymoglobulin) as conditioning prior to transplant and a combination of Tacrolimus and Mycophenolate mofetil (MMF) for GVHD prophylaxis. Post-transplant supportive care will include infection prophylaxis and surveillance, disease specific supportive care; monitoring of Graft versus Host disease (GVHD), iron overload and immune-reconstitution.

Study Summary

Stem cell transplant (SCT) is an important therapeutic option for pediatric patients with malignant diseases.  Although, full myeloablative transplants are widely used for patients with acute leukemia, myeloablative chemo-radiotherapy may not be feasible in some specific settings. These settings include- 1) patients with pre-existing co-morbidities and organ toxicities; 2) patients who have relapsed post-ablative transplant and need a second SCT; and 3) leukemia patients with advanced disease who have been heavily pre-treated (eg. ALL ≥CR3).  Non-myeloablative or reduced intensity conditioning (RIC) regimens have been used in this setting with the aim to decrease toxicity.

Since, the non-myeloablative and RIC regimens do not include intensive chemotherapy; relapse rates may be higher in RIC regimens compared to full myeloablative regimens. One way to improve overall survival in this setting is to add more effective anti-leukemia agents to prevent post-transplant relapses, without increasing TRM. Clofarabine, a new purine nucleoside anti-metabolite, has the advantage of significant antileukemic activity in addition to its possible immuno-suppressive properties. Combining Clofarabine with low dose TBI as a non-myeloablative preparative regimen may improve overall outcomes of SCT in advanced hematological malignancies. Therefore, in this study we plan to determine the maximum feasible dose (MFD) of Clofarabine in combination with 2 Gy TBI that can achieve durable donor engraftment without causing excessive toxicity leading to improved outcomes, low dose preparative regimen.