HEMATOPOIETIC PROGENITOR CELLS, CORD BLOOD- human cord blood hematopoietic progenitor cell solution
University of Texas MD Anderson Cancer Center
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HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use HPC, Cord Blood safely and effectively. See full prescribing information for HPC, Cord Blood.
HPC, Cord Blood Injectable Suspension for Intravenous Use Initial U.S. Approval: 2018
WARNING: FATAL INFUSION REACTIONS, GRAFT VERSUS HOST DISEASE, ENGRAFTMENT SYNDROME, AND GRAFT FAILURE
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Fatal infusion reactions: HPC, Cord Blood administration can result in serious, including fatal, infusion reactions. Monitor patients and discontinue HPC, Cord Blood infusion for severe reactions. [See Warnings and Precautions (5.1, 5.2)]
Graft-versus-Host disease (GVHD): GVHD is expected after administration of HPC, Cord Blood, and may be fatal. Administration of immunosuppressive therapy may decrease the risk of GVHD. [See Warnings and Precautions (5.3)]
Engraftment syndrome: Engraftment syndrome may progress to multi-organ failure and death. Treat engraftment syndrome promptly with corticosteroids. [See Warnings and Precautions (5.4)]
Graft failure: Graft failure may be fatal. Monitor patients for laboratory evidence of hematopoietic recovery. Prior to choosing a specific unit of HPC, Cord Blood, consider testing for HLA antibodies to identify patients who are alloimmunized. [See Warnings and Precautions (5.5)]
Hematopoietic Progenitor Cell (HPC), Cord Blood, is an allogeneic cord blood hematopoietic progenitor cell therapy indicated for use in unrelated donor hematopoietic progenitor stem cell transplantation procedures in conjunction with an appropriate preparative regimen for hematopoietic and immunologic reconstitution in patients with disorders affecting the hematopoietic system that are inherited, acquired, or result from myeloablative treatment.
The benefit-risk assessment for an individual patient depends on the patient characteristics, including disease, stage, risk factors, and specific manifestations of the disease, on characteristics of the graft, and on other available treatments or types of hematopoietic progenitor cells.
For intravenous use only.
Do not irradiate.
Unit selection and administration of HPC, Cord Blood should be done under the direction of a physician experienced in hematopoietic progenitor cell transplantation.
The recommended minimum dose is 2.5 x 107 total nucleated cells/kg at cryopreservation. Multiple units may be required in order to achieve the appropriate dose.
Matching for at least 4 of 6 HLA-A antigens, HLA-B antigens, and HLA-DRB1 alleles is recommended. The HLA typing and nucleated cell content for each individual unit of HPC, Cord Blood are documented on the container label and/or in accompanying records.
HPC, Cord Blood should be prepared by a trained healthcare professional.
HPC, Cord Blood should be administered under the supervision of a qualified healthcare professional experienced in hematopoietic progenitor cell transplantation.
NOTE: If product is being prepared for a multi-unit infusion, infuse units independently. Should a reaction occur, appropriately manage the reaction before the second unit is thawed for infusion.
Each unit of HPC, Cord Blood contains a minimum of 9.0 x 108 total nucleated cells with a minimum of 1.25 x 106 viable CD34+ cells, suspended in 10% dimethyl sulfoxide (DMSO) and 1% Dextran 40, at the time of cryopreservation.
The exact pre-cryopreservation nucleated cell content is provided on the container label and in accompanying records.
Allergic reactions may occur with infusion of HPC, Cord Blood including HPC, Cord Blood manufactured by MD Anderson Cord Blood Bank. Reactions include bronchospasm, wheezing, angioedema, pruritus, and hives [see Adverse Reactions (6.1)]. Serious hypersensitivity reactions, including anaphylaxis, also have been reported. These reactions may be due to dimethyl sulfoxide (DMSO), Dextran 40, hydroxyethyl starch, or a plasma component of HPC, Cord Blood.
HPC, Cord Blood may contain residual antibiotics if the cord blood donor was exposed to antibiotics in utero. Patients with a history of allergic reactions to antibiotics should be monitored for allergic reactions following HPC, Cord Blood administration.
Infusion reactions are expected to occur and may include nausea, vomiting, fever, rigors or chills, flushing, dyspnea, hypoxemia, chest tightness, hypertension, tachycardia, bradycardia, dysgeusia, hematuria, and mild headache. Premedication with antipyretics, histamine antagonists, and corticosteroids may reduce the incidence and intensity of infusion reactions.
Severe reactions, including respiratory distress, severe bronchospasm, severe bradycardia with heart block or other arrhythmias, cardiac arrest, hypotension, hemolysis, elevated liver enzymes, renal compromise, encephalopathy, loss of consciousness, and seizure also may occur. Many of these reactions are related to the amount of DMSO administered. Minimizing the amount of DMSO administered may reduce the risk of such reactions, although idiosyncratic responses may occur even at DMSO doses thought to be tolerated. The actual amount of DMSO depends on the method of preparation of the product for infusion. Limiting the amount of DMSO infused to no more than 1 gram per kilogram per day is recommended. [See Overdosage (10)]
Infusion reactions may begin within minutes of the start of infusion of HPC, Cord Blood, although symptoms may continue to intensify and not peak for several hours after completion of the infusion. Monitor the patient closely during this period. When a reaction occurs, discontinue the infusion and institute supportive care as needed. If infusing more than one unit of HPC, Cord Blood on the same day, do not administer subsequent units until all signs and symptoms of infusion reactions from the prior unit have resolved.
Acute and chronic graft-versus-host disease (GVHD) may occur in patients who have received HPC, Cord Blood. Classic acute GVHD is manifested as fever, rash, elevated bilirubin and liver enzymes, and diarrhea. Patients transplanted with HPC, Cord Blood should receive immunosuppressive drugs to decrease the risk of GVHD. [See Adverse Reactions (6.1)]
Engraftment syndrome is manifested as unexplained fever and rash in the peri-engraftment period. Patients with engraftment syndrome also may have unexplained weight gain, hypoxemia, and pulmonary infiltrates in the absence of fluid overload or cardiac disease. If untreated, engraftment syndrome may progress to multi-organ failure and death. Once engraftment syndrome is recognized, begin treatment with corticosteroids in order to ameliorate the symptoms. [See Adverse Reactions (6.1)]
Primary graft failure, which may be fatal, is defined as failure to achieve an absolute neutrophil count greater than 500 cells per microliter of blood by Day 42 after transplantation. Immunologic rejection is the primary cause of graft failure. Patients should be monitored for laboratory evidence of hematopoietic recovery. Consider testing for HLA antibodies in order to identify patients who are alloimmunized prior to transplantation and to assist with choosing a unit with a suitable HLA type for the individual patient. [See Adverse Reactions (6.1)]
Patients who have undergone HPC, Cord Blood transplantation may develop post-transplant lymphoproliferative disorder (PTLD), manifested as a lymphoma-like disease favoring non-nodal sites. PTLD is usually fatal if not treated.
The incidence of PTLD appears to be higher in patients who have received antithymocyte globulin. The etiology is thought to be donor lymphoid cells transformed by Epstein-Barr virus (EBV). Serial monitoring of blood for EBV DNA may be warranted in high-risk groups.
Leukemia of donor origin also has been reported in HPC, Cord Blood recipients. The natural history is presumed to be the same as that for de novo leukemia.
Transmission of infectious disease may occur because HPC, Cord Blood is derived from human blood. Disease may be caused by known or unknown infectious agents. Donors are screened for increased risk of infection with human immunodeficiency virus (HIV), human T-cell lymphotropic virus (HTLV), hepatitis B virus (HBV), hepatitis C virus (HCV), T. pallidum, T. cruzi, West Nile virus (WNV), transmissible spongiform encephalopathy (TSE) agents, vaccinia and Zika virus. Donors are also screened for clinical evidence of sepsis, and communicable disease risks associated with xenotransplantation. Maternal blood samples are tested for HIV types 1, 2 and O, HTLV types I and II, HBV, HCV, T. pallidum, WNV, and T. cruzi. HPC, Cord Blood is tested for sterility. These measures do not completely eliminate the risk of transmitting these or other transmissible infectious diseases and disease agents. Report the occurrence of a transmitted infection to MD Anderson Cord Blood Bank, The University of Texas MD Anderson Cancer Center at 1-713-563-8000.
Testing of maternal blood is also performed for evidence of donor infection due to cytomegalovirus (CMV).
Test results may be found on the container label and/or in accompanying records.
HPC, Cord Blood may transmit rare genetic diseases involving the hematopoietic system for which donor screening and/or testing has not been performed [see Adverse Reactions (6.1)]. Cord blood donors have been screened by family history to exclude inherited disorders of the blood and marrow. HPC, Cord Blood has been tested to exclude donors with sickle cell anemia, and anemias due to abnormalities in hemoglobins C, D, and E. Because of the age of the donor at the time HPC, Cord Blood collection takes place, the ability to exclude rare genetic diseases is severely limited.
Day-100 mortality from all causes was 25%.
The most common infusion-related adverse reactions (≥ 5%) are hypertension, vomiting, nausea, bradycardia, and fever.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety assessment of HPC, Cord Blood is based primarily on review of the data submitted to the FDA dockets from various sources, the dataset for the COBLT1 Study, and published literature.
Infusion Reactions
The Cord Blood Transplantation study group conducted a prospective study (COBLT1) of unrelated cord blood transplantation (CBT) to better define the role of this stem cell source for subjects requiring unrelated allogeneic transplantation. The primary end point of the study was survival at 180 days. Secondary end points included engraftment, graft-versus-host disease, relapse, and long-term survival. Eligibility criteria for malignant and nonmalignant diseases were specified.
The data described in Table 1 reflect exposure to 442 infusions of HPC, Cord Blood (from multiple cord blood banks) in patients treated using a total nucleated cell dose ≥ 2.5 x 107/kg on a single-arm trial or expanded access use (The COBLT1 Study). The population was 60% male, the median age was 5 years (range 0.05-68 years), and included patients treated for hematologic malignancies, inherited metabolic disorders, primary immunodeficiencies, and bone marrow failure. Preparative regimens and GVHD prophylaxis were not standardized. The most common infusion reactions were hypertension, vomiting, nausea, and sinus bradycardia. Hypertension and grades 3-4 infusion-related reactions occurred more frequently in patients receiving HPC, Cord Blood in volumes greater than 150 milliliters and in pediatric patients. The rate of serious adverse cardiopulmonary reactions was 0.8%.
Any grade |
Grade 3-4 |
|
Any reaction |
65.4% |
27.6% |
Hypertension |
48.0% |
21.3% |
Vomiting |
14.5% |
0.2% |
Nausea |
12.7% |
5.7% |
Sinus bradycardia |
10.4% |
0 |
Fever |
5.2% |
0.2% |
Sinus tachycardia |
4.5% |
0.2% |
Allergy |
3.4% |
0.2% |
Hypotension |
2.5% |
0 |
Hemogloburia |
2.1% |
0 |
Hypoxia |
2.0% |
2.0% |
Information on infusion reactions was available from voluntary reports for 846 patients who received cord blood units manufactured at MD Anderson Cord Blood Bank with a TNC dose ≥ 2.5 x 107/kg and HLA match grade ≥ 4/6. The population included 59% males and 41% females with median age of 25 years (range 0.1-73 years). Preparative regimens and GVHD prophylaxis were not standardized. The reactions, as reported to the MD Anderson Cord Blood Bank by the Stem Cell Outcomes Database (SCTOD) of the Center for International Blood and Marrow Transplant Research (CIBMTR), were not graded. Twenty-two percent of infusions (n=187) were associated with an infusion reaction. The most common infusion reactions, occurring in >1% of infusions, were hypertension (17.1%), nausea (4.3%), vomiting (3.9%), and headache (1.2%).
Other Adverse Reactions
For other adverse reactions, the raw clinical data from the docket were pooled for 1299 (120 adult and 1179 pediatric) patients transplanted with HPC, Cord Blood (from multiple cord blood banks) with total nucleated cell dose ≥2.5 x 107/kg. Sixty-six percent (n=862) underwent transplantation as treatment for hematologic malignancy. The preparative regimens and GVHD prophylaxis varied. The median total nucleated cell dose was 6.4 x 107/kg (range 2.5-73.8 107/kg). For these patients, Day-100 mortality from all causes was 25%. Primary graft failure occurred in 16%; 42% developed grades 2-4 acute GVHD and 19% developed grades 3-4 acute GVHD.
Data from published literature and from observational registries, institutional databases, and cord blood bank reviews reported to the docket for HPC, Cord Blood (from multiple cord blood banks) revealed nine cases of donor cell leukemia, one case of transmission of infection, and one report of transplantation from a donor with an inheritable genetic disorder. The data are not sufficient to support reliable estimates of the incidences of these events.
In the COBLT1 study, 15% of the patients developed engraftment syndrome.
Risk Summary
There are no data with HPC, Cord Blood use in pregnant women to inform a product-associated risk. Animal reproduction studies have not been conducted with HPC, Cord Blood. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Risk Summary
There is no information regarding the presence of HPC, Cord Blood in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for HPC, Cord Blood and any potential adverse effects on the breastfed infant from HPC, Cord Blood or from the underlying maternal condition.
HPC, Cord Blood has been used in pediatric patients with disorders affecting the hematopoietic system that are inherited, acquired, or resulted from myeloablative treatment. [See Dosage and Administration (2), Adverse Reactions (6), and Clinical Studies (14)]
Clinical studies of HPC, Cord Blood (from multiple cord blood banks) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. In general, administration of HPC, Cord Blood to patients over age 65 should be cautious, reflecting their greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
There has been no experience with overdose of HPC, Cord Blood in human clinical trials. Single doses of HPC, Cord Blood up to 5.0 x 108 TNC/kg have been administered. HPC, Cord Blood prepared for infusion may contain dimethyl sulfoxide (DMSO). The maximum tolerated dose of DMSO has not been established, but it is customary not to exceed a DMSO dose of 1 gm/kg/day when given intravenously. Several cases of altered mental status and coma have been reported with higher doses of DMSO.
HPC, Cord Blood consists of hematopoietic progenitor cells, monocytes, lymphocytes, and granulocytes from human cord blood for intravenous infusion. Blood recovered from the umbilical cord and placenta is volume reduced and partially depleted of red blood cells and plasma.
The active ingredient is hematopoietic progenitor cells, which express the cell surface marker CD34. The potency of cord blood is determined by measuring the numbers of total nucleated cells (TNC) and CD34+ cells, and cell viability. Each unit of HPC, Cord Blood contains a minimum of 9.0 x 108 total nucleated cells with at least 1.25 x 106 viable CD34+ cells at the time of cryopreservation. The cellular composition of HPC, Cord Blood depends on the composition of cells in the blood recovered from the umbilical cord and placenta of the donor. The actual nucleated cell count, the CD34+ cell count, the ABO group, and the human leukocyte antigen (HLA) typing are listed on the container label and/or accompanying records sent with each individual unit.
HPC, Cord Blood has the following inactive ingredients: dimethyl sulfoxide (DMSO), citrate phosphate dextrose (CPD), hydroxyethyl starch, and Dextran 40. When prepared for infusion according to instructions, the infusate contains the following inactive ingredients: Dextran 40, human serum albumin, residual DMSO, residual hydroxyethyl starch and residual CPD.
Hematopoietic stem/progenitor cells from HPC, Cord Blood migrate to the bone marrow where they divide and mature. The mature cells are released into the bloodstream, where some circulate and others migrate to tissue sites, partially or fully restoring peripheral blood counts and function, including immune function, of blood-borne cells of marrow origin. [See Clinical Studies (14)]
In patients with enzymatic abnormalities due to certain severe types of storage disorders, mature leukocytes resulting from HPC, Cord Blood transplantation may synthesize enzymes that may be able to circulate and improve cellular functions of some native tissues. However, the precise mechanism of action is unknown.
The effectiveness of HPC, Cord Blood, as defined by hematopoietic reconstitution, was demonstrated in the single-arm prospective COBLT1 study, and in retrospective review of data from an observational database for MD Anderson Cord Blood Bank, using data from the Center for International Blood and Marrow Transplant Research (CIBMTR), the National Marrow Donor Program (NMDP), and data in the FDA dockets and public information. The total nucleated cell dose and degree of HLA match were inversely associated with the time to neutrophil recovery in the docket data. Sixty-six percent (n=862) of the 1299 patients in the docket and public data underwent transplantation as treatment for hematologic malignancy. In the MD Anderson Cord Blood Bank database, 84% of patients (708 of 846) underwent transplantation for a hematologic malignancy.
Table 2 describes the recipient characteristics and hematopoietic recovery of 846 patients who received a total nucleated cell dose of ≥ 2.5 x 107/kg from at least a single cord blood unit manufactured at MD Anderson Cord Blood Bank, alone or in combination with another unit of HPC, Cord Blood and who had an HLA match ≥ 4/6, as well as the outcomes from the COBLT1 study and the docket data.
Neutrophil recovery is defined as the time from transplantation to an absolute neutrophil count greater than 500 cells/μL. Platelet recovery is the time to a platelet count greater than 20,000 cells/μL without a platelet transfusion for the preceding seven days. Erythrocyte recovery is the time to a reticulocyte count greater than 30,000 cells/μL.
Data Source | The COBLT1 Study | Docket and Public Data | MD Anderson Cord Blood Bank Data* |
*Data from patients who received a suitable allograft (TNC ≥ 2.5 x 107/kg and ≥ 4/6 HLA match). Note that evaluable data for outcomes were not available for all patients and there are various amounts of missing data. NA: Not Available | |||
Design | Single-arm prospective | Retrospective | Retrospective |
Number of patients | 324 | 1299 | 846 |
Median age (range) years | 4.6 (0.07 - 52.2) | 7.0 (<1 - 65.7) | 24.8 (0.1 – 73.3) |
Sex | 59% male | 57% male | 58% male |
41% female | 43% female | 42% female | |
Median Weight (range) at transplant (kg) | NA | NA | 59 (2.6-146.0) |
Median TNC Dose (range) (x 107/kg) | 6.7 (2.6 -38.8) | 6.4 (2.5- 73.8) | 5.4 (2.5-76.9) |
Neutrophil Recovery at Day 42 (ANC > 500/µL) (95% Cl) | 76% (71% - 81%) | 77% (75% - 79%) | 88.2% (85.9% - 90.2%) |
Platelet Recovery at Day 100 (20,000/µL) (95% CI) | 57% (51% - 63%) | NA | 73.6% (70%-77%) |
Platelet Recovery at Day 100 (50,000/µL) (95% Cl) | 46% (39% - 51%) | 45% (42% - 48%) | 43% (39%, 46%) |
Erythrocyte Recovery at Day 100 (95% CI) | 65% (58%-7 1%) | NA | NA |
Median Time to Neutrophil Recovery | 27 days | 25 days | 19 days |
Median Time to Platelet Recovery (20,000/µL) | 90 days | NA | 47 days |
Median Time to Platelet Recovery (20,000/µL) | 113 days | 122 days | 65 days |
Median Days to Erythrocyte Recovery | 64 days | NA | NA |
HPC, Cord Blood is supplied as a cryopreserved cell suspension in a sealed bag containing a minimum of 9.0 x 108 total nucleated cells with a minimum of 1.25 x 106 viable CD34+ cells in a volume of 25 milliliters (ISBT 128 Product Code S1393, ISBT 128 Facility Identifier Number W2263). The exact pre-cryopreservation nucleated cell content is provided on the container label and accompanying records.
Store HPC, Cord Blood at or below -150°C until ready for thawing and preparation.
Discuss the following with patients receiving HPC, Cord Blood:
MD Anderson Cord Blood Bank recommends washing of the HPC, Cord Blood unit prior to infusion. Once the wash procedure is complete, the product must be infused within four hours. Included below are instructions for washing HPC, Cord Blood. Prior to thawing of the unit, read the thaw and wash instructions and emergency product recovery procedure below. Prepare all required reagents, supplies, equipment, and forms listed, and ensure they are readily available.
HPC, Cord Blood is shipped frozen at or below -150°C using a liquid nitrogen (LN2) dry shipper. The unit is packed for transport in a stainless steel canister contained within an insulated transport sleeve. Keep HPC, Cord Blood at or below -150°C, either inside the dry shipper container used for shipping or in a liquid nitrogen (LN2) cooled device at the transplant center (recommended). If the HPC, Cord Blood will be stored inside the dry shipper, add liquid nitrogen to the vessel to ensure the unit will be kept at or below -150°C.
Upon receipt of the shipment perform the following steps:
Distributed by:
MD Anderson Cord Blood Bank
1841 Old Spanish Trail
Houston, TX 77054
713-563-8000
U.S. License # 2072
Store/Ship:
-150C or colder
Product: S1393V00
Label Version:
L 082.033.002
MD Anderson
Cord Blood Bank
Houston, TX
CBB 173
Cryopreserved HPC, Cord Blood (Buffy Coat Enriched)
10% DMSO, 1% Dextran 40,
0.8% Hydroxyethyl starch
See Attached Documents
Collection
Date
0150910316
01 APR 2015 03:16
Properly identify intended Recipient and Product
Rx only.
A
Rh POSITIVE
FOR USE BY INTENDED
RECIPIENT ONLY
INTENDED RECIPIENT
Name: Doe, John
DOB: 12/25/1992
ID: 123-456-7
DO NOT IRRADIATE
DO NOT USE LEUKOREDUCTION FILTER
CRYOPRESERVED
HPC, CORD BLOOD
Buffy Coat Enriched
Approx. 25 ml
10% DMSO, 1% DEXTRAN 40,
0.8% Hydroxyethyl starch
Store at -150°C or colder
See package insert for full prescribing
information and instructions for preparation
Expiration
Date
01 APR 2025 03:0316
ADDITIONAL CBU IDENTIFIERS
NMDP ID: 9876-5432-1
Local ID: 012345
Collected and Processed By
MD Anderson Cord Blood Bank
1841 Old Spanish Trail, Houston, TX
US License: 2072
Label Version: L 082.027.002
HEMATOPOIETIC PROGENITOR CELLS, CORD BLOOD
human cord blood hematopoietic progenitor cell solution |
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Labeler - University of Texas MD Anderson Cancer Center (800772139) |
Establishment | |||
Name | Address | ID/FEI | Business Operations |
---|---|---|---|
University of Texas MD Anderson Cancer Center | 117159375 | label(W2263-S1393) , manufacture(W2263-S1393) |