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CLEVECORD
(HPC, Cord Blood)
WARNING
FATAL INFUSION REACTIONS, GRAFT VERSUS HOST DISEASE, ENGRAFTMENT SYNDROME, AND GRAFT FAILURE
CLEVECORD administration can result in serious, including fatal, infusion reactions. Monitor patients and discontinue CLEVECORD infusion for severe reactions. [See WARNINGS AND PRECAUTIONS]
GVHD is expected after administration of CLEVECORD and may be fatal. Administration of immunosuppressive therapy may decrease the risk of GVHD. [See WARNINGS AND PRECAUTIONS]
Engraftment syndrome may progress to multiorgan failure and death. Treat engraftment syndrome promptly with corticosteroids. [See WARNINGS AND PRECAUTIONS]
Graft failure may be fatal. Monitor patients for laboratory evidence of hematopoietic recovery. Prior to choosing a specific unit of CLEVECORD, consider testing for HLA antibodies to identify patients who are alloimmunized. [See WARNINGS AND PRECAUTIONS]
CLEVECORD consists of hematopoietic progenitor cells, monocytes, lymphocytes, and granulocytes from human cord blood for intravenous infusion. Blood recovered from 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 CLEVECORD contains a minimum of 5 x 108 total nucleated cells with at least 1.25 x 106 viable CD34+ cells at the time of cryopreservation. The cellular composition of CLEVECORD 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 HLA typing are listed in the accompanying records sent with each individual unit.
CLEVECORD 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, DMSO, residual hydroxyethyl starch and CPD.
CLEVECORD, HPC (Hematopoietic Progenitor Cell), 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 risk benefit 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.
Unit selection and administration of CLEVECORD should be done under the direction of a physician experienced in hematopoietic progenitor cell transplantation.
The recommended minimum dose is 2.5 x 107 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 CLEVECORD are documented in the accompanying records.
CLEVECORD should be prepared by a trained healthcare professional.
CLEVECORD 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, prepare and infuse each unit independently. Should a reaction occur, appropriately manage the reaction before another unit is thawed for infusion
Each CLEVECORD unit contains a minimum of 5 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 in the accompanying records.
CLEVECORD is supplied as a cryopreserved cell suspension in a sealed bag containing a minimum of 5 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 W4215). The exact pre-cryopreservation nucleated cell content is provided in the accompanying records.
Store CLEVECORD at or below -150°C until ready for thawing and preparation.
Distributed by: Cleveland Cord Blood Center, 25001 Emery Road, Suite 150, Cleveland, OH 44128. Revised: Apr 2017
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 CLEVECORD is based primarily on review of the data submitted to the FDA dockets from various sources, the dataset from the COBLT Study, and published literature.
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 COBLT Study). The population was 60% male and the median age was 5 years (range 0.05 to 68 years), and included patients treated for hematologic malignancies, inherited metabolic disorders, primary immunodeficiencies, and bone marrow failure. Preparative regimens and graft-versus-host disease prophylaxis were not standardized. The most common infusion reactions were hypertension, vomiting, nausea, and sinus bradycardia. Hypertension and any 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%.
Table 1: Incidence of Infusion-Related Adverse
Reactions Occurring in ≥ 1% of Infusions (the COBLT Study)
| 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 % | 0.0 % |
| Fever | 5.2 % | 0.2 % |
| Sinus tachycardia | 4.5 % | 0.2 % |
| Allergy | 3.4 % | 0.2 % |
| Hypotension | 2.5 % | 0.0 % |
| Hemogloburia | 2.1 % | 0.0 % |
| Hypoxia | 2.0 % | 2.0 % |
Information on infusion reactions was available from voluntary reports for 91 patients who received a total nucleated cell dose of ≥ 2.5 x 107/kg from at least a single unit of CLEVECORD, alone or in combination with another unit of HPC, Cord Blood and who had an HLA match > 3/6. The population included 55% males and 45% females with median age of 38 years (range <1-68 years). Preparative regimens and graft-versus-host disease prophylaxis were not standardized. The reactions were not graded. An infusion reaction occurred in 20% of patients. The most common infusion reactions, occurring in ≥ 1% of infusions, were hypertension (17%), nausea or vomiting (3%), and hypoxia (3%).
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 of ≥ 2.5 x 107/kg. Of these, 66% (n=862) underwent transplantation as treatment for hematologic malignancy. The preparative regimens and graft-versus-host disease prophylaxis varied. The median total nucleated cell dose was 6.4 x 10 /kg (range, 2.5-73.8 x 10 /kg). For these patients, Day-100 mortality from all causes was 25%. Primary graft failure occurred in 16%; 42% developed grades 2-4 acute graft-versus-host disease; and 19% developed grades 3-4 acute graft-versus-host disease.
Data from the 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 insufficient to support reliable estimates of the incidences of these events.
In the COBLT Study, 15% of the patients developed engraftment syndrome.
No Information provided
Included as part of the PRECAUTIONS section.
Allergic reactions may occur with infusion of HPC, Cord Blood, including CLEVECORD. Reactions include bronchospasm, wheezing, angioedema, pruritus, and hives [see ADVERSE REACTIONS]. 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 CLEVECORD.
CLEVECORD 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 CLEVECORD 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]
Infusion reactions may begin within minutes of the start of infusion of CLEVECORD, 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 CLEVECORD. Classic acute GVHD is manifested as fever, rash, elevated bilirubin and liver enzymes, and diarrhea. Patients transplanted with CLEVECORD should receive immunosuppressive drugs to decrease the risk of GVHD. [See ADVERSE REACTIONS]
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 multiorgan failure and death. Once engraftment syndrome is recognized, begin treatment with corticosteroids in order to ameliorate the symptoms. [See ADVERSE REACTIONS]
Primary graft failure, which may be fatal, is defined as failure to achieve an absolute neutrophil count greater than 500 per microliter 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]
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 CLEVECORD 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 and 2, HTLV types I and II, HBV, HCV, T. pallidum, WNV, and T. cruzi. CLEVECORD is tested for sterility. There may be an effect on the reliability of the sterility test results if the cord blood donor's mother was treated with antibiotics. These measures do not totally eliminate the risk of transmitting these or other transmissible infectious diseases and disease agents. Report the occurrence of a transmitted infection to the Cleveland Cord Blood Center at 1-216-378-3032.
Testing is also performed for evidence of donor infection due to cytomegalovirus (CMV).
Test results may be found in the accompanying records.
CLEVECORD may transmit rare genetic diseases involving the hematopoietic system for which donor screening and/or testing has not been performed [see ADVERSE REACTIONS]. Cord blood donors have been screened by family history to exclude inherited disorders of the blood and marrow. CLEVECORD 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 CLEVECORD collection takes place, the ability to exclude rare genetic diseases is severely limited.
There are no data with CLEVECORD use in pregnant women to inform a product-associated risk. Animal reproduction studies have not been conducted with CLEVECORD. 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.
There is no information regarding the presence of CLEVECORD 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 CLEVECORD and any potential adverse effects on the breastfed infant from CLEVECORD 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, ADVERSE REACTIONS, and Clinical Studies]
Clinical studies of HPC, Cord Blood, (from multiple cord blood banks) did not provide sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. In general, administration of CLEVECORD 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.
CLEVECORD contains Dextran 40, which is eliminated by the kidneys. The safety of CLEVECORD has not been established in patients with renal insufficiency or renal failure.
There has been no experience with overdose of HPC, Cord Blood in human clinical trials. Single doses of CLEVECORD up to 45 x 107 TNC/kg have been administered. HPC, Cord Blood prepared for infusion may contain dimethyl sulfoxide (DMSO). The maximum 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.
For DMSO overdose, general supportive care is indicated. The role of other interventions to treat DMSO overdose has not been established.
None.
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 blood counts and function, including immune function, of blood-borne cells of marrow origin. [See Clinical Studies]
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 CLEVECORD as defined by hematopoietic reconstitution, was demonstrated in one single-arm prospective study and in retrospective reviews of data from an observational database for CLEVECORD and in data in the dockets and public information. Of the 1299 patients in the docket and public data, 66% (n=862) underwent transplantation as treatment for hematologic malignancy. Results for patients who received a total nucleated cell dose ≥2.5 x 107/kg are shown in Table 2. Neutrophil recovery is defined as the time from transplantation to an absolute neutrophil count more than 500 per microliter. Platelet recovery is the time to a platelet count more than 20,000 per microliter. Erythrocyte recovery is the time to a reticulocyte count greater than 30,000 per microliter. The total nucleated cell dose and degree of HLA match were inversely associated with the time to neutrophil recovery in the docket data.
Table 2: Hematopoietic Recovery for Patients Trans
planted with HPC, Cord Blood, Total Nucleated Cell (TNC) Dos e ≥ 2.5 x 107/kg
| Data Source | COBLT Study* | Docket* and Public Data* | CLEVECORD |
| Design | Single-arm prospective | Retrospective | Retrospective |
| Number of patients | 324 | 1299 | 91*** |
| Median age (range) | 4.6 (0.07 - 52.2) yrs |
7.0 (<1 - 65.7) yrs |
38 (<1 - 68) yrs |
| Gender | 59 % male | 57 % male | 55 % male |
| 41 % female | 43 % female | 45 % female | |
| Median TNC Dose (range) (x 107kg) | 6.7 (2.6 - 38.8) |
6.4 (2.5 - 73.8) |
4.6 (2.9 - 45.0) |
| Neutrophil Recovery at Day 42 (95% CI) | 76% (71% - 81%) |
77% (75% - 79%) |
96% (92% - 100%) |
| Platelet Recovery at Day 100 (20,000/uL) (95% CI) | 57% (51% - 63%) |
- | 92% (85% - 99%) |
| Platelet Recovery at Day 100 (50,000/uL) (95% CI) | 46% (39% - 51%) |
45% (42% - 48%) |
83% (73% - 93%) |
| Erythrocyte Recovery at Day 100 (95%CI) | 65% (58% - 71%) |
- | - |
| Median time to Neutrophil Recovery | 27 days | 25 days | 18 days |
| Median time to Platelet Recovery (20,000/uL) | 90 days | - | 41 days |
| Median time to Platelet Recovery (50,000/uL) | 113 days | 122 days | 43 days |
| Median time to Erythrocyte Recovery | 64 days | - | - |
| * HPC, Cord Blood (from multiple cord blood banks) **Data from patients who received a suitable allograft (i.e., TNC dose ≥ 2.5 x 107/kg and HLA match > 3/6) with at least a single unit of CLEVECORD. ***All 91 patients had evaluable data for age, sex, and cell dose. Since not all of the 91 patients had evaluable data for all of the listed outcomes parameters, the numbers of patients treated (N) differ for the various listed outcomes parameters. Numbers of patients treated (N) for neutrophil recovery, platelet recovery ≥ 20k, platelet recovery ≥ 50k are: 76 (excludes patients who died prior to D42 and patients with missing data), 63 (excludes patients who died prior to D100 and patients with missing data), and 53 (excludes patients who died prior to D100 and patients with missing data), respectively. |
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Discuss the following with patients receiving CLEVECORD:
Equipment:
Reagents
Supplies
Forms
CLEVECORD is shipped frozen inside a steel canister placed inside a liquid nitrogen (LN2) charged tank specifically designed to keep the temperature at or below -150°C (dry shipper). Dry shippers consist of a protective shipping container with a large rounded lid, carrying a LN2 tank with a flat lid (see Figure 1). CLEVECORD must be stored at or below -150°C either in the LN2 tank inside the dry shipper for short-term storage (up to 48 hours), or inside a LN2 -cooled storage device at the Transplant Center for storage greater than 48 hours. Recharge the tank with fresh LN2 if CLEVECORD is to remain stored in the dry shipper for more than 48 hours.
Figure 1: Dry shipper components and configuration
 |
Use the following instructions to complete the “Dry Shipper and HPC, Cord Blood Receipt Form” confirming receipt of the CLEVECORD unit and verifying the identity of the unit for the intended recipient. Two trained transplant center staff members are required to receive and verify the CLEVECORD unit.
If documentation and product are acceptable, but your facility either has no LN2 freezer, or insufficient LN2 storage space for the frozen CLEVECORD product, the CCBC dry shipper can be used for temporary storage. Inform CCBC that return of the dry shipper will be delayed for purpose of temporary product storage on site.
If storage for more than 48 hours is required, add fresh LN2 to the tank inside the dry shipper to keep  the product frozen until a completely satisfactory resolution for long-term storage and / or use of the frozen product has been reached. Confirm the temperature probe and data logger are properly installed as per step II.f, to ensure continued temperature monitoring.
a. Coordination with the clinical team
b. Prepare the water bath and verify that the temperature is 37°C ± 1°C.
c. Record the manufacturer information, lot number and expiration date (if applicable) of all reagents and disposables. Use only sterile materials when processing the CLEVECORD product.
d. Preparation of Dextran 40/Albumin solution.
NOTE: Use aseptic technique in a Biological Safety
Cabinet for all processing steps, including all open-container processing and
all spiking of container ports.
e. Prepare a portable container with LN2 for storage of the frozen CLEVECORD product
f. With product and recipient files at hand, locate and remove the frozen product from storage in the LN2 freezer, or dry shipper, and verify product identity, labeling, accuracy of information, and container integrity. Two trained members of laboratory staff are required for this verification process.
g. Remove any segment attached to the unit, place into a 2 mL cryovial and store in either vapor or liquid phase of nitrogen (at or below -150°C).
h. Immediately transfer the product from LN2 storage into the portable LN2 container. Rest in vapor phase for 5-10 minutes prior to further manipulation.
Two different procedures for preparation of CLEVECORD for infusion are provided. The first procedure, referred to as the “Dilution” procedure is for dilution of thawed product, yielding ~170 mL product volume for infusion (Section IV.2 below). The second procedure, referred to as the “Dilution and Volume Reduction” procedure, involves centrifugation of thawed and diluted product, followed by supernatant removal, yielding a reduced (25-35 mL) product volume, amenable to infusion in pediatric patients (Section IV.3 below).
Figure 2: Transplant Processing Two-Bag Set
 |
Perform quality control assays per transplant center policies and procedures using the aliquot of thawed product obtained in step IV.2.o. or IV.3.x. Recommended assays include:
Prepare a written summary of the procedure, including:
2. Make a copy of the report for your records
3. Fax a copy of the report to the Cleveland Cord Blood Center at (216) 896-0320
4. Return the dry shipper to the Cleveland Cord Blood Center. The return address is:
Cleveland Cord Blood Center, 25001 Emery Road, Suite 150, Cleveland, OH 44128, Phone: (216) 896-0360, Fax: (216) 896-0320
Use standard procedures and trained personnel to perform post-thaw sampling and/or bag rescue. As cryobags can be very fragile, handle the frozen cord blood bag with extreme care at every step including opening the metal containers, inspecting, thawing and/or washing. Perform all steps on lab benches, under biological safety cabinet, or another surface to prevent inadvertent drop of the frozen unit. To facilitate thawing, gradually remove the CLEVECORD unit from the liquid phase of the LN2 storage area, suspending in the vapor phase for at least five minutes prior to bringing the container to room temperature. Wipe the external surface of the cryobag with isopropyl alcohol before it is placed inside a sterile zip-lock bag. This will allow the cell laboratory to potentially recover the product in the case of an unexpected leak or container failure during thawing, dilution or volume reduction.
a. If the CLEVECORD cryobag is observed to be cracked when removed from the LN2 storage container, or if cracks or leaks occur during thawing, immediately notify Cleveland Cord Blood Center by phone at (216) 378-3032 or (216) 896-0493. Notify the transplant physician and transplant team and the laboratory director as soon as possible.
b. The transplant physician or team will determine whether to use or discard the CLEVECORD product and whether any additional HPC, Cord Blood units should be requested.
c. If the transplant physician or team decides that the product in the leaking cryobag could be used, the CLEVECORD unit may be recovered as follows:
