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Alemtuzumab

Participants will undergo a non-myeloablative allogeneic hematopoietic stem cell transplant.

NOTE: The - sign is the number of days before the transplant and the + sign is the number of days after the transplant.

* Alemtuzumab 0.2mg/kg Day-14,-13,-12,-11,-10
* Fludarabine 30 mg/m2 on Day -8,-7,-6,-5,-4
* Melphalan 140mg/m2 on Day -3

The GVHD prophylaxis will consist of the following:

* Cyclosporine on Day -3 to Day +100, maintaining a level of 250-500 ng/mL, then taper to Day +180.
* Methylprednisolone 2 mg/kg/day on Day -2 and -1, 1 mg/kg/day on Day 0 to Day +28, then taper over 1 month. Oral prednisone may be substituted starting on Day 0 (1.2 mg/kg/day)

Hematopoietic Stem Cell Transplant

Mary Horowitz, MD, MS

HLH, HLH-related disorders, Chronic Granulomatous (CGD), HIGM1, Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX) and severe LAD-I represent primary immune disorders that are typically fatal without Hematopoietic Cell Transplant (HCT). However, transplant is often complicated by inflammation, infection and other co-morbidities. In addition, these disorders have been shown to be cured with partial chimerism, making them an ideal target for the use of reduced intensity approaches, where a portion of patients may not achieve full donor chimerism, but instead achieve stable mixed chimerism. Reduced-intensity conditioning strategies have demonstrated improved survival with decreased Treatment Related Mortality (TRM) in institutional series for patients with HLH (Cooper et al., 2006; Marsh et al., 2010; Marsh et al., 2011). However, graft loss and unstable chimerism remain challenges. An institutional case series from Cincinnati Children's Hospital demonstrated full or high-level chimerism and improved durable engraftment using intermediate (Day -14) timing alemtuzumab (Marsh et al., 2013b). This study aims to test the efficacy of the Intermediate RIC strategy in a prospective multi-center study including HLH as well as other primary immunodeficiencies where allogeneic transplant with RIC has been shown to be feasible and stable chimerism is curative.

The primary goal of this Phase II clinical trial is to determine the one-year overall survival of patients treated for immune deficiencies including HLH, HLH-like disorders, CGD, HIGM1, IPEX syndrome, and severe LAD-I with Matched Related Donor (MRD)/ Matched Unrelated Donor (MUD) bone marrow transplant using a reduced-intensity conditioning strategy including intermediate-timing of alemtuzumab. The donor choice is an unaffected related bone marrow donor who is a 6/6 match at HLA-A, -B (intermediate or higher resolution) and -DRB1 (at high resolution using DNA-based typing) OR a 7/8 or 8/8 match for human leukocyte antigen (HLA)-A, -B, -C and -DRB1 (at high resolution using DNA-based typing), OR an unrelated bone marrow donor who is a 7/8 or 8/8 match at HLA-A, -B, -C and -DRB1 (at high resolution using DNA-based typing). The transplant conditioning regimen will include fludarabine, melphalan, and alemtuzumab starting at Day -14 (Flu/Mel/Alem). Graft Versus Host Disease (GVHD) prophylaxis will consist of cyclosporine and corticosteroids through engraftment. Post-transplant supportive care will include infection surveillance and prophylaxis, and disease-specific supportive care.

Reduced Intensity Conditioning for Hemophagocytic Syndromes or Selected Primary Immune Deficiencies (BMT CTN 1204)

Reduced-Intensity Conditioning for Children and Adults With Hemophagocytic Syndromes or Selected Primary Immune Deficiencies (RICHI) (BMT CTN #1204)

Findings will be published in a manuscript.

Overall survival is defined as survival of death from any cause.

Systemic HLH Reactivation: Post-transplant HLH reactivation is defined by clinical and lab evidence of pathologic inflammation (persistent fever, progressive cytopenias, rising ferritin and soluble IL2Rα, decreasing fibrinogen, hepatosplenomegaly, end-organ damage) not attributable to other causes.

Central nervous system (CNS) HLH Reactivation: Reactivation of CNS inflammation in patients with HLH may present with or without altered mental status and is defined by pleocytosis in Cerebrospinal fluid (CSF) or an MRI consistent with CNS inflammation not attributable to other causes.

Time to absolute neutrophil count (ANC) engraftment is defined as the first of three measurements on different days that the patient has an absolute neutrophil count of ≥ 500x10\^6/liter following conditioning regimen induced nadir.

Platelet engraftment is defined as the first day of a minimum of three measurements on different days that the patient has achieved a platelet count \> 20,000 / microliter AND the patient is platelet transfusion independent for a minimum of seven days following conditioning regimen induced nadir.

Sustained engraftment is defined as the occurrence of whole blood donor chimerism \> 5% by Day 42 accompanied by the absence of any primary or secondary graft failure. Primary graft failure is defined as \< 5% donor chimerism by Day +42, second stem cell infusion, DLI (except in the case of donor CTLs given for infection control), or second HCT following original HCT. Secondary graft failure is defined as \< 5% donor chimerism following initial engraftment.

Acute GVHD is graded according to the scoring system proposed by Przepiorka et al.1995:

Skin stage:

0: No rash

1. Rash \<25% of body surface area
2. Rash on 25-50% of body surface area
3. Rash on \> 50% of body surface area
4. Generalized erythroderma with bullous formation

Liver stage (based on bilirubin level)\*:

0: \<2 mg/dL

1. 2-3 mg/dL
2. 3.01-6 mg/dL
3. 6.01-15.0 mg/dL
4. \>15 mg/dL

GI stage\*:

0: No diarrhea or diarrhea \<500 mL/day

1. Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD
2. Diarrhea 1000-1499 mL/day
3. Diarrhea \>1500 mL/day
4. Severe abdominal pain with or without ileus \* If multiple etiologies are listed for liver or GI, the organ system is downstaged by 1.

GVHD grade:

0: All organ stages 0 or GVHD not listed as an etiology I: Skin stage 1-2 and liver and GI stage 0 II: Skin stage 3 or liver or GI stage 1 III: Liver stage 2-3 or GI stage 2-4 IV: Skin or liver stage 4

Chronic GVHD is classified per 2005 NIH Consensus Criteria (Filipovich et al. 2005) into categories of severity: none, mild, moderate, and severe.

Chronic GVHD is classified per 2005 NIH Consensus Criteria (Filipovich et al. 2005) into categories of severity: none, mild, moderate, and severe. Occurrence of chronic GVHD is defined as the occurrence of mild, moderate, or severe chronic GVHD per this classification.

National Heart, Lung, and Blood Institute (NHLBI)

Blood and Marrow Transplant Clinical Trials Network

National Cancer Institute (NCI)

National Marrow Donor Program

Medical College of Wisconsin

Participants will undergo a non-myeloablative allogeneic hematopoietic stem cell transplant.

Hematopoietic Stem Cell Transplant: NOTE: The - sign is the number of days before the transplant and the + sign is the number of days after the transplant.

* Alemtuzumab 0.2mg/kg Day-14,-13,-12,-11,-10
* Fludarabine 30 mg/m2 on Day -8,-7,-6,-5,-4
* Melphalan 140mg/m2 on Day -3

The GVHD prophylaxis will consist of the following:

* Cyclosporine on Day -3 to Day +100, maintaining a level of 250-500 ng/mL, then taper to Day +180.
* Methylprednisolone 2 mg/kg/day on Day -2 and -1, 1 mg/kg/day on Day 0 to Day +28, then taper over 1 month. Oral prednisone may be substituted starting on Day 0 (1.2 mg/kg/day)

Participants with Hemophagocytic Lymphohistiocytosis

Hemophagocytic Lymphohistiocytosis (HLH)

Participants with other primary immune deficiencies, including chronic active EBV disease, chronic granulomatous disease, hyper-immunoglobulin M syndrome, and immune dysregulation, polyendocrinopathy, enteropathy and X-linked (IPEX) syndrome

Other Primary Immune Deficiencies (PID)

Total

Age, Customized

Sex: Female, Male

Race (NIH/OMB)

KPS describes patient-perceived global quality of life and functioning on a scale of 0-100.

100: No evidence of disease; 90: Normal activity. Minor signs or symptoms of disease; 80: Normal activity with effort. Some signs or symptoms of disease; 70: Cares for self. Unable to continue normal activity; 60: Needs occasional assistance, but cares for most personal needs; 50: Needs considerable assistance and medical care; 40: Disabled. Needs special care and assistance; 30: Severely disabled. Hospital admission indicated; 20: Very sick. Active supportive therapy needed; 10: Moribund; 0: Dead

Karnofsky Performance Score (KPS)

Participants with Primary Immune Deficiencies

Primary Immune Deficiency Type

HLA matching and relatedness of donor to recipient

Donor Type

Adam Mendizabal, PhD

1 year OS

18 month OS

Percentage of Participants With Overall Survival (OS)

Percentage of Participants With Overall Survival (OS) by Disease Type

Percentage of HLH Participants With HLH Reactivation Post-Transplant

Percentage of Participants With Neutrophil Engraftment

Percentage of Participants With Platelet Engraftment

Percentage of Participants Alive With Sustained Engraftment

Percentage of Participants Alive With Sustained Engraftment by Disease Type

Number of Participants With Acute Graft-Versus-Host Disease (GVHD)

Grade II-IV Acute GVHD at Day 100

Grade II-IV Acute GVHD at 6 Months

Grade III-IV Acute GVHD at Day 100

Grade III-IV Acute GVHD at 6 Months

Percentage of Participants With Grade II-IV and Grade III-IV Acute GVHD

Number of Participants With Chronic GVHD

Percentage of Participants With Chronic GVHD

Overall Study

Neoplasms

Hematologic Neoplasms

Cyclophosphamide

Mycophenolic Acid

Tacrolimus

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Calcineurin Inhibitors

Enzyme Inhibitors

Anti-Bacterial Agents

Antibiotics, Antitubercular

Antitubercular Agents

Patients undergoing hematopoietic stem cell transplant from a partially matched related donor

TBI twice daily days 6-9 prior to transplant (HSCT)

Total Body Irradiation (TBI)

DLI given 6 days prior to transplant (HSCT).

Donor Lymphocyte Infusion (DLI)

Cyclophosphamide given once daily at 60 mg/kg on days 2 and 3 prior to transplant (HSCT).

Cyclophosphamide (CY)

Tacrolimus given one day prior to transplant (HSCT).

MMF given one day prior to transplant (HSCT).

Mycophenolate Mofetil (MMF)

CD34+ selected Hematopoietic Stem Cell Transplant (HSCT) is performed. This is the day of transplantation.

Hematopoietic Stem Cell Transplant (HSCT)

Neal Flomenberg, MD

The purpose of this study is to develop a way of treating patients who do not have a completely matched family donor or a readily available unrelated donor with bone marrow transplant by using a partially-matched family donor. Patients receiving this type of transplant will receive chemotherapy and/or radiation to treat their disease. They will also receive their donor's cells in 2 parts. During the first part, the donor's lymphocytes will be exposed to one of the chemotherapy agents to help the patient become tolerant to the lymphocytes. In the second part of the transplant, the patient will receive their donor's stem cells to help recover their peripheral blood counts and establish long-term engraftment. The hypothesis of this study is that in partially-matched allogeneic transplant, there is a defined number of donor T-cells that can be treated and given to the recipient to avoid post-transplant infection without causing severe graft-versus-host disease.

Haploidentical hematopoietic stem cell transplant is a life-saving therapy for patients who are without well matched donors. This type of therapy has been associated with poor outcomes in the past due to complications such as infection. The Jefferson 2 Step approach was designed to allow the infusion of an exact dose of tolerized lymphocytes in haploidentical transplant in order to allow for immune reconstitution post transplant to avoid infectious complications while still having acceptable rates of GVHD. In this approach, patients with high-risk hematological malignancies undergo 8 fractions of TBI (12 Gy) followed by an exact dose of donor lymphocytes. The phase I portion of the study determined the optimal dose of lymphocytes. Two days after receiving the donor lymphocytes, the patients receive 2 daily doses of cyclophosphamide. One day after receiving cyclophosphamide, the patients receive stem cell from their donor. Tacrolimus and mycophenylate mofetil are used as GVHD prophylaxis.

A Two-Step Approach to Bone Marrow Transplant Using Cells From A Partially-Matched Relative

A Two Step Approach To Allogeneic Hematopoietic Stem Cell Transplantation for Hematologic Malignancies From HLA Partially-Matched Related Donors

To determine overall survival at 6 months post-transplant.

To determine the optimal dose of CD3+ donor lymphocytes required for consistent engraftment without the development of grade III/IV GVHD.

Measured as CD3+ donor lymphocytes given as n x 10\^8/kg.

"n" was found to be 2 and was found to be the optimal dose and was the only dose given.

To assess hematopoietic engraftment rates.

To assess the pace of lymphoid recovery in this patient population.

To determine the incidence and severity of GVHD in these patients using a combination of cyclophosphamide, tacrolimus and mycophenolate mofetil (MMF) as GVHD prophylaxis.'

Severity was graded using CTCAE 3.0 (1=mild, 2=moderate, 3=severe, 4=life threatening/disabling, 5=death)

Sidney Kimmel Cancer Center at Thomas Jefferson University

Haploidentical Allogeneic Transplantation

Age, Categorical

Age, Continuous

United States

Region of Enrollment

Limitations of the trial include small sample size and single institution

27 Patients undergoing haploidentical transplant at Thomas Jefferson University

Overall Survival of Participants

Two patients died prior to expected day of engraftment

Optimal Dose of CD3+ Donor Lymphocytes (T-cells) for Consistent Engraftment Without GVHD

Two patients died prior to expected engraftment day

Engraftment Rates

Two patients did not engraft, two patients died prior to expected day of engraftment

Lymphoid Recovery

Two patients died prior to expected engraftment. Two patients who rejected were retransplanted and were evaluable for GVHD.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Reduced Intensity Conditioning for Hemophagocytic Syndromes or Selected Primary Immune Deficiencies (BMT CTN 1204)	NCT01998633	Hemophagocytic ... Chronic Active ... Chronic Granulo... HIGM-1 Leukocyte Adhes... IPEX	Hematopoietic S...	4 Months - 45 Years	Medical College of Wisconsin
A Two-Step Approach to Bone Marrow Transplant Using Cells From A Partially-Matched Relative	NCT00429143	Hematologic Mal...	Total Body Irra... Donor Lymphocyt... Cyclophosphamid... Tacrolimus Mycophenolate M... Hematopoietic S...	18 Years -	Thomas Jefferson University
Reduced Intensity Conditioning for Hemophagocytic Syndromes or Selected Primary Immune Deficiencies (BMT CTN 1204)	NCT01998633	Hemophagocytic ... Chronic Active ... Chronic Granulo... HIGM-1 Leukocyte Adhes... IPEX	Hematopoietic S...	4 Months - 45 Years	Medical College of Wisconsin
Bone Marrow Transplantation of Patients in Remission Using Partially Matched Relative Donor	NCT01350245	Acute Myeloid L... Myelodysplastic... Biphenotypic Le... Acute Lymphocyt... Chronic Myeloid... Chronic Lymphoc... Plasma Cell Neo... Lymphoma Hodgkin's Disea... Aplastic Anemia	Total Body Irra... Donor Lymphocyt... Cyclophosphamid... Mycophenolate M... Tacrolimus Hematopoietic s...	18 Years -	Thomas Jefferson University
Blood Stem Cell Transplant With Low Dose Chemotherapy for Relapsed Follicular Non-Hodgkin's Lymphoma (BMT CTN 0701)	NCT00912223	Lymphoma, Non-H...	Hematopoietic S...	1 Year - 75 Years	Medical College of Wisconsin
Reduced-Intensity Conditioning (RIC) and Myeloablative Conditioning (MAC) for HSCT in AML/MDS	NCT02626715	Acute Myeloid L... Myelodysplastic... Hematopoietic S...	Reduced-Intensi... Myeloablative C...	0 Months - 26 Years	University of Pittsburgh

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