T-Cell Replete Haploidentical Donor Hematopoietic Stem Cell Plus Natural Killer (NK) Cell Transplantation in Patients With Hematologic Malignancies Relapsed or Refractory Despite Previous Allogeneic Transplant

Patients with refractory hematologic malignancies, including those who develop recurrent
disease after allogeneic hematopoietic cell transplantation, have a dismal prognosis.
Historically, both regimen-related mortality and disease recurrence have been significant
causes of treatment failure in this heavily pre-treated patient population. Our institution
has utilized mismatched family member (haploidentical) donors for these patients for a
number of years for the following reasons: (1) Only 30% of patients have matched related
donors available; (2) transplantation can be performed more rapidly since the time to
unrelated donor transplantation averages 3 to 4 months; (3) no other curative treatment
options are available. These therapeutic interventions have been largely successful given
the dismal prognosis in this patient group; however disease recurrence remains the most
significant cause of treatment failure. To provide maximum benefit for this challenging
population, the goals of a therapeutic transplant protocol should include: (1) a
conditioning regimen that is well tolerated, even in a heavily pre-treated population; but
it should also provide substantial antileukemia effects, and (2) should establish rapid
immune recovery such that the patient may benefit from graft versus leukemia effect and
early protection from life threatening infections while also limiting dangerous and
counter-productive graft versus host disease.

The primary aim of this protocol will be to evaluate if the one-year survival is
significantly improved in the group of patients receiving T-cell replete haploidentical
donor HCT with a novel clofarabine, cytarabine, busulfan, plerixafor, cyclophosphamide, and
ATG based reduced intensity conditioning regimen whose hematologic malignancy has relapsed
or is refractory after prior allogeneic transplant. Toxicity will be evaluated by the rate
of transplant related mortality and the rates of moderate and severe graft versus host
disease at day 100. The investigators will also describe event-free, and disease-free
survival at one year, as well as the rates of hematopoietic recovery and donor engraftment.
Additionally, the investigators will study comprehensively immune reconstitution following
T-cell replete haploidentical transplantation.

PRIMARY OBJECTIVE:

- Evaluate if the one-year survival is significantly improved in a group of children
receiving a therapeutic regimen for high-risk hematologic malignancy that is relapsed
or refractory despite previous allogeneic hematopoietic cell transplantation (HCT)
using a novel reduced intensity conditioning and T-cell replete haploidentical donor
hematopoietic stem cell plus NK cell transplantation.

SECONDARY OBJECTIVES:

- Estimate the incidence of malignant relapse, event-free survival, and disease free
survival (DFS) at one-year post-transplantation.

- Estimate incidence and severity of acute and chronic (GVHD).

- Estimate the rate of transplant related mortality (TRM) in the first 100 days after
transplantation.

Inclusion Criteria - for transplant recipient:

- Age less than 21 years.

- One of the following hematologic malignancies that has relapsed or remains refractory
after prior allogeneic HCT:

- Acute lymphoblastic leukemia (ALL)

- Acute myeloid leukemia (AML) (including myeloid sarcoma)

- Chronic myelogenous leukemia (CML), juvenile myelomonocytic leukemia (JMML),
myelodysplastic syndrome (MDS), Hodgkin or non-Hodgkin lymphoma (NHL)

- Has a suitable single haplotype matched (≥ 3 of 6) family member donor.

- Does not have any other active malignancy other than the one for which this
transplant is indicated.

- If prior central nervous system (CNS) leukemia, it must be treated and have no
evidence of CNS disease

- Does not have current uncontrolled bacterial, fungal, or viral infection per the
judgment of the principal investigator.

- Patient must fulfill pre-transplant evaluation:

- Left ventricular ejection fraction greater than 40%, or shortening fraction
greater than or equal to 25%.

- Creatinine clearance or Glomerular Filtration Rate of ≥70 ml/min/1.73m^2.

- Forced vital capacity (FVC) ≥ 40% of predicted value; or pulse oximetry ≥ 92% on
room air if patient is unable to perform pulmonary function testing.

- Karnofsky or Lansky (age-dependent) performance score ≥ 50.

- Total bilirubin ≤ 1.5 times the upper limit of normal for age.

- Alanine aminotransferase (ALT) ≤ 3 times the upper limit of normal for age.

- Not pregnant. If female with child bearing potential, must be confirmed by
negative serum or urine pregnancy test within 14 days prior to enrollment.

- Not breast feeding.

- Does not have active acute bronchiolitis obliterans or bronchiolitis obliterans
organizing pneumonia.

Inclusion Criteria - for donor:

- At least single haplotype matched (≥ 3 of 6) family member,

- At least 18 years of age.

- Human immunodeficiency virus (HIV) negative.

- Not pregnant as confirmed by negative serum or urine pregnancy test within 14 days
prior to enrollment (if female).

- Not breast feeding.

- A suitable donor is identified as either:

- Has completed the process of donor eligibility determination as outlined in 21
CFR 1271 and agency guidance; OR

- Does not meet 21 CFR 1271 eligibility requirements, but has a declaration of
urgent medical need completed by the principal investigator or physician
sub-investigator per 21 CFR 1271.

Exclusion Criteria:

- Does not meet above inclusion criteria.