Blood and Lymph Conditions

All Conditions

Respiratory Tract (Lung and Bronchial) Diseases

Neoplasms

Rare Diseases

Erdheim-Chester Disease

Histiocytosis, Langerhans-Cell

Histiocytosis

Histiocytosis, Sinus

Sarcoma

Histiocytic Sarcoma

Lymphatic Diseases

Lung Diseases

Lung Diseases, Interstitial

Respiratory Tract Diseases

Histiocytosis, Non-Langerhans-Cell

Histiocytic Disorders, Malignant

Neoplasms by Histologic Type

Lipogranulomatosis

Langerhans Cell Histiocytosis

Rosai-Dorfman Disease

Polymorphic Reticulosis

Soft Tissue Sarcoma

Non-Langerhans-Cell Histiocytosis

Gaurav Goyal, MD

The purpose of the study is to describe the burden of chronic health conditions, psychological dysfunction, chronic pain, healthcare utilization, worse health-related quality of life, overall mortality, and cause-specific mortality among individuals with histiocytic disorders

Background

Over the last decade, major advances have occurred in histiocytic disorders with the discovery of MAPK-ERK pathway mutations leading to targeted therapeutics using BRAF- and MEK-inhibitors. However, there is a lack of large studies informing the burden of morbidity and mortality among people with histiocytosis. Institutional studies in pediatric LCH suggest that survivors suffer from long-term impairment of health related quality of life, cognitive dysfunction, pituitary dysfunction, and hearing difficulties in 20-50% cases. Studies from the investigative team and others have also shown a high incidence of acute myeloid leukemia and other second primary malignancies in pediatric and adult LCH. Chronic medical conditions may arise as a function of the disease biology or due to cancer therapy, as seen in other hematologic malignancies.

Design

Retrospective cohort study aimed at determining the risk of chronic health conditions and cause-specific mortality in pediatric and adult patients with histiocytic disorders. The study will include patients from the Histiocytosis Association registry and other institutions including UAB (n\~6000). The participants will complete a validated questionnaire capturing details of chronic health conditions, health related quality of life, cognitive/psychological function, and healthcare utilization.

Future directions

The results from our study will be instrumental in formulating follow-up guidelines for histiocytic disorders and developing targeted survivorship programs to improve overall outcomes.

Histiocytic Disorder Follow-up Study

The CTCAE criteria for CHCs distinguishes each acute and chronic condition (including SPMs) in persons with cancer from grades 1 through 4 with unique clinical descriptions of severity (grade 1, mild; grade 2, moderate; grade 3, severe; grade 4, life-threatening/disabling). The main outcome will be the number of distinct CTCAE grade 3-4 conditions among LCH cases compared with unaffected (non-cancer) controls.

Causes of death will be grouped into primary cancer (LCH)-related mortality (PCRM) and non-primary cancer-related mortality (NPCRM - death from all causes other than the index LCH diagnosis) by two independent investigators.

We will build a prediction model that has a good discrimination for predicting CHC, SPMs, and psychological outcomes separately using data from the LCH (case) cohort.

University of Alabama at Birmingham

Principal Investigator

Immune System Diseases

Symptoms and General Pathology

Leukemia

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Hematologic Neoplasms

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Preleukemia

Myelodysplastic Syndromes

Lymphoma

Hematologic Diseases

Lymphoproliferative Disorders

Immunoproliferative Disorders

Myeloproliferative Disorders

Bone Marrow Diseases

Chronic Disease

Disease Attributes

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Chronic Graft Versus Host Disease

Acute Non Lymphoblastic Leukemia

Chronic Myeloid Leukemia

Acute Graft Versus Host Disease

Lymphosarcoma

Chronic Myeloproliferative Disorders

All Drugs and Chemicals

Antineoplastic Agents

Antirheumatic Agents

Antibodies

Cyclophosphamide

Fludarabine

Fludarabine phosphate

Melphalan

Immunomodulating Agents

Immunoglobulins

Thiotepa

Muromonab-CD3

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Participants who meet the eligibility criteria for this study. Donor cells will be obtained using the Miltenyi Biotec CliniMACS device.

Interventions: Chemotherapy and antibodies, allogeneic stem cell transplantation.

Study participants will receive a non-TBI based preparative regimen consisting of Cyclophosphamide, fludarabine, thiotepa, melphalan, and muromonab-CD3 (OKT3) followed by an infusion of a T-lymphocyte depleted haploidentical hematopoietic stem cell graft. Seven days posttransplant, participants will receive an infusion of additional donor derived cells called NK cells.

Chemotherapy and antibodies

Miltenyi Biotec CliniMACS

Allogeneic natural killer (NK)cell infusion

Allogeneic stem cell transplantation

Brandon Triplett, MD

Recent studies of conventional chemotherapy for infants with high-risk hematologic malignancies show that the long-term disease-free survival is low. Although blood and marrow stem cell transplantation using an HLA identical sibling has improved the outcome for these children, less than 25% have this donor source available. Another option is haploidentical transplantation using a partially matched family member donor (i.e. parental donor).

Although haploidentical transplantation has proven curative for some patients, this procedure has been hindered by significant complications, primarily regimen-related toxicity including infection and graft versus host disease (GVHD). Building on prior institutional trials, this study will provide patients a haploidentical graft depleted of T lymphocytes using the investigational device, CliniMACS selection system. One week after the transplant procedure, patients will also receive an infusion of additional donor derived white blood cells called Natural Killer (NK) cells in an effort to decrease risks for rejection of the graft, disease relapse, and regimen related toxicity. The primary objective of the study is to evaluate 1 year survival in infants with high risk hematologic malignancies who receive this study treatment.

Secondary objectives for this study include the following:

* To estimate the incidence of three transplant-related adverse outcomes (i.e., regimen-related mortality, engraftment failure, and fatal acute GVHD) in the first 100 days after transplantation.
* To estimate the incidence of chronic graft-versus-host disease.
* To evaluate those factors that affect one-year survival.
* To assess the kinetics of lymphohematopoietic reconstitution.
* To assess the frequency and clinical relevance of minimal residual disease (MRD) before and after transplantation.
* To evaluate the incidence of and risk factors for long-term neurocognitive deficit and organ dysfunction.

HLA-Nonidentical Stem Cell and Natural Killer Cell Transplantation for Children Less the Two Years of Age With Hematologic Malignancies

The one-year survival of infants with high-risk hematologic malignancies who receive a haploidentical transplant procedure using a total body irradiation (TBI)-excluding conditioning regimen followed by an HLA-nonidentical family donor hematopoietic stem cell (HSC) graft depleted of T cells ex vivo using the CliniMACS CD34+ selection system, with a subsequent infusion of donor NK cells purified ex vivo using the CliniMACS CD3+ depletion and CD56+ enrichment system.

The Kaplan-Meier estimate for one-year survival is reported.

The cumulative incidences of regimen-related mortality will be estimated using method of Kalbfleisch and Prentice.

Engraftment failure is defined as \<10% donor cell chimerism at any time point between 28 and 100 days after transplant with no evidence of disease relapse or requiring stem cell boost.

The cumulative incidence estimate for occurrence of fatal acute GVHD by the end of the first 100 days post-transplant was calculated using method of Kalbfleisch and Prentice.

Chronic GVHD was graded according to Seattle Criteria: limited or extensive. Limited is defined as localized skin and/or hepatic dysfunction. Extensive is defined as one or more of the following:

* generalized skin involvement
* liver histology showing chronic aggressive hepatitis, bridging necrosis or cirrhosis
* eye dryness with Schirmer's test \<5 mm wetting
* oral: involvement of salivary glands or oral mucosa
* other: another target organ involvement

Due to small sample size (n=14) and total number of events (n=7), the analysis to check the various factors that affect the one-year survival was not performed (using logistic and cox model).

HLA typing determined the degree of match by looking at 6 different HLA loci. The results indicate the number of the 6 loci that matched for each participant. Due to small sample size (n=14) and total number of events (n=7), the analysis to check the various factors that affect the one-year survival was not performed (using logistic and cox model).

Detection of leukemia blasts in bone marrow by flow cytometry

The organ dysfunction will be summarized using summary statistics and assessed in a longitudinal manner and analyzed accordingly.

The long-term neurocognitive deficit will be summarized using summary statistics and assessed in a longitudinal manner and analyzed accordingly.

The presence or absence of MRD before and after the bone marrow transplant (BMT) and its frequency distribution will be obtained for each time point separately.

The lymphohematopoietic reconstitution will be summarized using summary statistics and assessed in a longitudinal manner and analyzed accordingly.

Assisi Foundation

St. Jude Children's Research Hospital

Study participants received a non-TBI based preparative regimen consisting of Cyclophosphamide, fludarabine, thiotepa, melphalan, and muromonab-CD3 (OKT3) followed by an infusion of a T-lymphocyte depleted haploidentical hematopoietic stem cell graft. Seven days post-transplant, participants received an infusion of additional donor derived cells called natural killer (NK) cells.

Stem cells were obtained from donors using the Miltenyi Biotec CliniMACS stem cell selection device.

Study Participants

Group of participants who survived to at least one year post HSCT.

Study participants received a non-TBI based preparative regimen consisting of Cyclophosphamide, fludarabine, thiotepa, melphalan, and muromonab-CD3 (OKT3) followed by an infusion of a T-lymphocyte depleted haploidentical hematopoietic stem cell graft. Seven days posttransplant, participants received an infusion of additional donor derived cells called natural killer (NK) cells.

Stem cells were obtained from donors using the Miltenyi Biotec CliniMACS stem cell selection device.

Alive

Those participants who did not survive to at least one year post HSCT.

Study participants received a non-TBI based preparative regimen consisting of Cyclophosphamide, fludarabine, thiotepa, melphalan, and muromonab-CD3 (OKT3) followed by an infusion of a T-lymphocyte depleted haploidentical hematopoietic stem cell graft. Seven days posttransplant, participants received an infusion of additional donor derived cells called natural killer (NK) cells.

Stem cells were obtained from donors using the Miltenyi Biotec CliniMACS stem cell selection device.

Expired

Total

Age, Continuous

Sex: Female, Male

Black

Other

White

Race/Ethnicity, Customized

The study was limited due to the unavailability of the study drug OKT3 beginning in June 2011. The study was temporarily closed to accrual. Because OKT3 is still unavailable, the study was formally closed to accrual in March 2015.

Study participants received a non-TBI based preparative regimen consisting of Cyclophosphamide, fludarabine, thiotepa, melphalan, and muromonab-CD3 (OKT3) followed by an infusion of a T-lymphocyte depleted haploidentical hematopoietic stem cell graft. Seven days posttransplant, participants received an infusion of additional donor derived cells called natural killer (NK) cells.

Stem cells were obtained from donors using the Miltenyi Biotec CliniMACS stem cell selection device.

One-year Survival

Number of Transplant-Related Adverse Outcomes: Regimen-Related Mortality

Number of Transplant-Related Adverse Outcomes: Engraftment Failure

Number of Transplant-Related Adverse Outcomes: Fatal Acute Graft-Versus Host Disease (GVHD)

Number of Incidences of Chronic GVHD.

Group of participants who survived to at least one year post HSCT.

Those participants who did not survive to at least one year post HSCT.

Fourteen study participants were evaluable for the outcome measures. Study participants received a non-TBI based preparative regimen consisting of Cyclophosphamide, fludarabine, thiotepa, melphalan, and muromonab-CD3 (OKT3) followed by an infusion of a T-lymphocyte depleted haploidentical hematopoietic stem cell graft. Seven days posttransplant, participants received an infusion of additional donor derived cells called natural killer (NK) cells.

Stem cells were obtained from donors using the Miltenyi Biotec CliniMACS stem cell selection device.

Factors Affecting One-year Survival: Median Age of Donor at HSCT

Factors Affecting One-year Survival: Median Dose of CD34

Factors Affecting One-year Survival: Median Dose of NK Cells

Active Disease

Complete Remission-1

Complete Remission-2

Progressive Disease

Relapse

Factors Affecting One-year Survival: Disease Status at HSCT

Father

Mother

Uncle

Factors Affecting One-year Survival: Donor Type

3/6 HLA Loci

4/6 HLA Loci

Factors Affecting One-year Survival: Match N/6 HLA Loci

Negative for MRD

Positive for MRD

MRD data were collected on four study participants. Study participants received a non-TBI based preparative regimen consisting of Cyclophosphamide, fludarabine, thiotepa, melphalan, and muromonab-CD3 (OKT3) followed by an infusion of a T-lymphocyte depleted haploidentical hematopoietic stem cell graft. Seven days posttransplant, participants received an infusion of additional donor derived cells called natural killer (NK) cells.

Stem cells were obtained from donors using the Miltenyi Biotec CliniMACS stem cell selection device.

Only four of the 14 participants had MRD measured at the one-year time point.

Factors Affecting One-year Survival: Minimal Residual Disease (MRD)

There was not enough data available after 1 year post-transplant to evaluate long term outcomes on this study.

Incidence of and Risk Factors for Organ Dysfunction.

Incidence of and Risk Factors for Long-term Neurocognitive Deficit.

Patient 1

Patient 2

Patient 3

Patient 4

All study participants as previously described.

Study Participants: Before HSCT

Study Participants: 1 Year Post HSCT

Study Participants: 5 Years Post HSCT

MRD data was collected on only four participants during at least one time point.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Histiocytic Disorder Follow-up Study	NCT05915208	Histiocytosis Langerhans Cell... Erdheim-Chester... Rosai Dorfman D... Xanthogranuloma Malignant Histi...		18 Years - 89 Years	University of Alabama at Birmingham
HLA-Nonidentical Stem Cell and Natural Killer Cell Transplantation for Children Less the Two Years of Age With Hematologic Malignancies	NCT00145626	Acute Myeloid L... Acute Lymphocyt... Myelodysplasia Chronic Myeloid... Histiocytosis	Chemotherapy an... Miltenyi Biotec... Allogeneic stem...	- 24 Months	St. Jude Children's Research Hospital
Phase I/IIa Study to Evaluate the Safety, PK, PD, and Preliminary Efficacy of PLX8394 in Patients With Advanced Cancers.	NCT02012231	Melanoma Thyroid Cancer Colorectal Canc... Non-small Cell ... Cholangiocarcin... Histiocytosis Hairy Cell Leuk...	PLX8394	18 Years -	Fore Biotherapeutics

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