With travel restrictions and reduced transportation options, the global spread of coronavirus disease 2019 has disrupted international networks that supply patients with biological materials needed for sophisticated hematologic therapies.
With travel restrictions and reduced transportation options, the global spread of coronavirus disease 2019 (COVID-19) has disrupted international networks that supply patients with biological materials needed for sophisticated hematologic therapies.
For many patients with hematologic malignancies, the pandemic has delayed or limited hematopoietic stem cell transplantations. Experts have advised weighing the benefits of transplantation versus the risks, with guidance varying by cancer type, according to COVID-19 resources that the American Society of Hematology has compiled.1
For multiple myeloma, for example, the recommendation as of mid-April was to delay stem cell transplantation until the pandemic subsides, while the advice for certain patients with high-risk acute lymphoblastic leukemia considered for allogeneic transplantation was to proceed expeditiously.1 In fact, some experts note that procedures cannot be safely delayed for most patients who are candidates for allogeneic transplantation; in these cases, COVID-19 testing in advance of induction is recommended for donors and recipients.2
Against this backdrop, the ability of health care providers and companies to surmount obstacles presented by the pandemic could be lifesaving for those patients in need of bone marrow or cord blood transplants or chimeric antigen receptor (CAR) T-cell therapies. The National Marrow Donor Program (NMDP)/ Be The Match, which manages an international transplant registry, and Novartis, the Swiss pharmaceutical giant that manufactures the CAR T-cell therapy tisagenlecleucel (Kymriah), have taken unprecedented actions to ensure patients can continue receiving these therapies amid COVID-19 disruptions.
In interviews with OncLive®, officials with these organizations described the precarious nature of transporting essential oncology therapies across international borders during the pandemic and the hurdles they overcame to keep their supply chains rolling.
“Once a patient undergoes their preparative conditioning regimen for transplant, if we are not able to deliver the bone marrow or peripheral blood stem cell [PBSC] product in a timely manner, that leads to fatal consequences,” Brian Lindberg, chief legal officer and chief policy officer of NMDP/Be The Match, said.
Expediency is a critical component of transplantation because donated stem cells “have an efficacious shelf life of about 72 hours,” he explained.
NMDP/Be The Match, which manages a registry that connects approximately 460 medical centers throughout the world,3 obtained exemptions from the ban on travel from Europe that President Donald J. Trump authorized on March 11, 20204 and made other changes in its specimen-handling procedures. Notably, the network was able to facilitate more transports of transplant materials in March (>609 transports) amid COVID-19 challenges than it did in February (564 transports).5
“We have been able to deliver a stem cell product to every patient who has been waiting. We have not failed, and we have not dipped in the number of products that we deliver at all, which is quite remarkable,” said Jamie Margolis, PhD, senior vice president of donor services for NMDP/Be The Match.
Novartis made changes to its protocols so that genetically engineered T cells for tisagenlecleucel therapy could be transported from Europe to the United States via cargo planes, which are exempt from the travel ban. T cells harvested from patients are cryopreserved and transported to a Morris Plains, New Jersey, facility, where they are genetically modified.
“Despite some of the travel restrictions, we are still able to ship our cells to the different places in the world, and all our patients have received their therapies with only a few delays, which have not been more than a day for pick up or delivery,” said Stefan Hendriks, senior vice president, global head of Cell & Gene at Novartis.
Registry Is Built on Travel
International transportation of the bone marrow and PBSC donations that NMDP/ Be The Match facilitates is an unavoidable reality of the nonprofit organization’s day-to-day procedures.
“About 50% of donated bone marrow or PBSCs are umbilical cord blood units that will in fact cross an international border as they make their way from donor to recipient,” said Lindberg.
The global routing of the donations stems from the difficulty inherent in identifying a “perfect” human leukocyte antigen (HLA) match between the transplant recipient and the NMDP/Be The Match registry member, according to Lindberg.
An individual with an HLA type that closely matches the patient’s represents the best possible bone marrow or stem cell donor because the patient’s immune system is less likely to recognize the transplant as foreign, thus reducing the chance of a posttransplant complication such as graft-versus-host disease.6,7
Despite the hereditary nature of a patient’s HLA type, approximately 70% of those who require a bone marrow or stem cell transplant will not have a fully matched donor in their family. Extended family members are not likely to be close HLA matches, and each blood-related sibling has a 25% chance of being a close match.6,7
Because some HLA types are less common than others, the donor identification process will be more complex for some transplant recipients. In an illustration of the difficulty of finding a close HLA match, those who register as donors with NMDP/Be The Match have about a 1 in 430 chance of being asked to donate.
Founded in the late 1980s, NMDP/Be The Match collaborates with transplant centers and donor registries in approximately 40 countries outside the United States. The registry presently includes more than 22 million bone marrow donors and more than 300,000 cord blood units. These transplants are carried out for patients with leukemia, lymphoma, and other life-threatening diseases, many of whom do not have alternative curative options.8,9
Individuals who donate PBSCs undergo apheresis either at a hospital or at an apheresis center; those who donate bone marrow complete the surgical procedure at a participating hospital. Of note, donors do not travel to the patient’s area of residency. Trained couriers carry the donated material to the patient’s location.10
“The majority of the time, stem cell products are not cryopreserved, put into a dry shipper, and shipped in the cargo hold of a plane,” Lindberg explained, referring to the organization’s model before COVID-19. “They’re actually physically accompanied by couriers in the passenger compartment of a commercial aircraft.”
Europe Presents a Challenge
Although NMDP/Be The Match couriers transport bone marrow and PBSC donations throughout the world, Europe is one of the organization’s “most significant partners,” according to Lindberg. He said that the nonprofit had “over 170 scheduled transplants that involved a donated bone marrow product crossing between Europe and the United States” during the first 30 days of the travel ban, 52 of which were slated for the week of March 16, when the international travel ban went into effect.
In accordance with the restrictions, most non-US citizens from the 26 countries that belong to the Schengen Area border-free travel bloc in Europe, including Italy, Spain, and Greece, would not be permitted to enter the United States.4 The ban subsequently was extended to travel from the United Kingdom and Ireland.
“This was obviously of significant concern to us for many reasons―1 being that for 30 years, we have managed the logistics of moving donated products to recipients via trained couriers, and many of our couriers who were scheduled to travel from Europe to the US at that point were not US citizens,” Lindberg said.
The “great majority” of these NMDP/Be The Match couriers were German citizens, Lindberg said, and because Germany was one of the first member states to enter the Schengen Agreement, which eliminated internal borders among the areas of the European Union that elected to become part of the Schengen bloc, the travel ban directly impeded these couriers’ ability to accompany the donated bone marrow into the United States.11
Meanwhile, the couriers’ travel had been scheduled, and the transplant recipients were awaiting the bone marrow products. NMDP/ Be The Match needed an alternative. “We had to scramble,” Lindberg said.
Obtaining the text of the presidential proclamation announcing the travel ban was a turning point for NMDP/Be The Match. “In that proclamation, we identified an exception for travelers who would be traveling in the national interest. The national registry is operated under contracts with the federal government, so we immediately felt that this exclusion would be relevant for our program,” Lindberg explained.
Driven to deliver the donations, the organization quickly got in touch with its contacts on Capitol Hill and later, the Centers for Disease Prevention and Control (CDC). On March 19, 2020 the CDC ruled that NMDP/ Be The Match couriers were exempt from the travel restrictions from Europe to the United States.12 “We were able to [persuade] the CDC to issue a blanket waiver for our program, referring specifically to that national interest exception in the president’s proclamation,” Lindberg said.
Under normal circumstances, when a donor is in Europe and the transplant recipient is in the United States, an international courier picks up the donated product and carries it to the States. In the 8 days between the Trump administration’s institution of the travel ban and the CDC’s extension of the blanket waiver, NMDP/Be The Match had to alter this standard chain of events to conform to the newly imposed COVID-19 limitations.
“We had to send US passport holders to Europe to pick up the product and bring it back to the [United States],” said Ray Hornung, MBA, CEM, CBCP, senior manager of the Logistics and Emergency Preparedness team at NMDP/Be The Match.5
Before the CDC issued the travel waiver, NMDP/Be The Match “was not certain that there was going to be a programmatic solution for the issue,” said Lindberg, who added that the organization preemptively canceled the German couriers’ trips and replaced these couriers with American citizens, who would be able to cross the international border.
“At the very last minute, one of these couriers fell through, so in the absence of the waiver, we almost certainly would have had a patient here in the [United States] not receive their cells on time and that person likely would not have survived,” Lindberg said. “That happened 173 times the first week after the issuance of the travel waiver, and we didn’t miss a single one.”
The couriers are subject to the same customs and immigration screening that any international traveler would be required to complete upon departure and arrival at an airport, according to Lindberg.
Cancelled Flights Affect Network
Although the travel waiver has allowed NMDP/Be The Match to resume its standard processes of bone marrow and PBSC collection and transportation, the reduced availability of commercial flights is another impediment that the organization has faced during the pandemic. “We rely on being able to put couriers in the passenger compartments of commercial aircrafts, and tens of thousands of flights have been canceled over the past few weeks,” Lindberg said.
Of note, recent cancellations have caused some couriers’ flights to be rebooked more than 15 times, according to Margolis. On March 25, by 10 am Central Time, 9188 of NMDP/Be The Match’s flights in and out of the United States booked had already been canceled. “That’s about 40% of the flights that were on the schedule yesterday that are not on the schedule today,” Hornung said.5
Hornung added that “the constantly changing landscape of flights” presently constitutes NMDP/Be The Match’s “biggest barrier” to bone marrow and PBSC routing. “What do you do when [flights are canceled]?” Hornung asked. “You manage each transport 1 at a time, giving it the attention that the patient it is intended for deserves…You can’t throw up your hands and not deliver.”5
Lindberg said NMDP/Be The Match is working with the US Department of Defense (DOD) to determine whether donated bone marrow and PBSCs can be flown on military transports both internationally and domestically should the organization be unable to leverage commercial air transportation. Use of this pathway would be an unprecedented step for the organization. “For the first time, we would not have these donated products personally accompanied by an individual courier,” Lindberg observed.
However, acquiring the necessary permissions to use this model may not be an easy task, according to Lindberg. “My hope is that we can [persuade] the government to do the right thing and allow us to use military transport in these urgent scenarios. I know the DOD is being inundated with requests for use of military transport, but these are truly lifesaving pieces of cargo,” Lindberg said.
In the meantime, NMDP/Be The Match is exploring alternatives to the individual couriers on whom it has traditionally relied. For example, the organization has established respective hubs in Germany and Chicago’s O’Hare International Airport where cryopreserved cells can be delivered, loaded into the cargo holds of planes, and flown from Europe to the United States and vice versa.
“Historically, we have not felt that the benefits of an approach like this outweighed the risks largely because these products have been delivered fresh and not frozen over the course of time,” Lindberg said. However, Lindberg and NMDP/Be The Match are cognizant that the unprecedented nature of the COVID-19 pandemic calls for strategic alterations to preferred distributive practices.
“We have changed our stance and required cryopreservation because we cannot be in a circumstance where we do not have a product for a patient who started their conditioning regimen,” Margolis said. The PBSCs must first arrive in the United States before transplant recipients begin their conditioning regimens, to minimize the risk of patients potentially beginning preparative treatment and not receiving the stem cells on time.
CAR T Cells Require Special Handling
Initially approved in 2017, tisagenlecleucel is indicated for the treatment of patients aged younger than 25 years with refractory B-cell precursor acute lymphoblastic leukemia and adults with relapsed or refractory large B-cell lymphoma, including certain diffuse large B-cell lymphoma subtypes. It was the first gene therapy cleared for use in the United States.13,14
Tisagenlecleucel administration consists of 4 steps: T-cell collection, T-cell manufacturing, infusion, and monitoring. In the first phase, a patient’s T cells are harvested from the blood via leukapheresis during a 3- to 6-hour period. Within 24 hours after leukapheresis, the cells are cryopreserved and shipped via specialized courier to a Novartis manufacturing site for cellular reengineering.15
These cells are transported in a vapor phase liquid nitrogen dry shipper (dewar) that cryopreserves the contents for up to 10 days in a defense against weather-related or logistical delays. Novartis uses a computer-based system to track the cells’ routes throughout the manufacturing process from the time the collection site dispatches the T-cells to a Novartis apheresis center and then to their eventual departure for the clinical infusion center.16
When the cells arrive at the New Jersey facility, Novartis’ cellular scientists reprogram them with a CAR that contains a 4-1BB costimulatory domain and a CD3ζ intracellular signaling domain. Specifically, the 4-1BB domain enhances early expansion and endurance of the tisagenlecleucel cells in vitro and in vivo, improves the persistence of the CAR T cells, and induces central memory T-cell differentiation, bolstering the cells’ capacity for immunosurveillance. The CD3ζ domain prompts T-cell activation and induces other antitumor action.17
In the United States, tisagenlecleucel manufacturing is typically completed in 22 days.18 Afterward, the genetically modified T cells are cryopreserved at a minimum of —120 °C in cryobags and shipped to the clinical infusion center, where they are thawed prior to infusion. A single dose of tisagenlecleucel can be contained in up to 3 cryopreserved bags.16 Two to 14 days before the reprogrammed tisagenlecleucel cells are returned to the patient via an intravenous infusion, the patient completes a short, 4-day course of lymphodepleting chemotherapy.19
In contrast with the 48-hour shelf life of the bone marrow and PBSC transplants that NMDP/Be The Match facilitates, tisagenlecleucel therapy has a shelf life of 9 months.16 However, T cells, whether originating from the initial collection site or from Novartis’ manufacturing facility, necessitate timely delivery to ensure cell viability. For example, if a shipment of T cells harvested during leukapheresis faces an in-transit delay of greater than 10 days, exceeding the cryopreserving capacity of the dewar, the cells will be subject to damage resulting from premature thawing. Cellular compromise can disrupt the tisagenlecleucel manufacturing process, causing a delay in the development and administration of the immunocellular therapy for a patient who may imminently need the treatment.
Despite the logistical complications amid the COVID-19 pandemic, Novartis remains committed to surmounting these challenges to deliver what for many patients, could be a life-saving gene therapy. “It is our goal and our priority to ensure that patients receive their therapy as fast as possible,” said Hendriks.
The prohibition on travel between Europe and the United States, coupled with fewer commercial flight options, has prompted Novartis to adopt alternative approaches to facilitate its international deliveries of tisagenlecleucel.
“In the past, we [predominantly] used passenger flights to transport Kymriah, but when the number of flights across the Atlantic was reduced and when the travel restrictions were announced in the [United States], our team immediately safeguarded enough cargo space for us to continue our transatlantic transports,” Hendriks said.
Novartis is currently leveraging cargo space to move its time-sensitive cellular treatment and will continue to do so for the foreseeable future, according to Hendriks, who added that the developer will also use road transports should a situation affect local distribution.
Importantly, the COVID-19—associated impediments to Novartis’ standard supply chain operations have not affected the company’s ability to provide patients access to tisagenlecleucel treatments in a timely manner, but the pandemic has further underscored the value of a broad network of tisagenlecleucel manufacturing facilities, Hendriks said. Novartis’ New Jersey location is its primary site for commercial and clinical development of tisagenlecleucel, but the company has been working to expand its capacity for the complex manufacturing process.
In 2019, Novartis’ facilities in Stein, Switzerland, and Les Ullis, France, started manufacturing tisagenlecleucel for patients participating in clinical trials.20 These sites are slated to launch commercial production in 2020, according to Novartis.
In an emailed statement, Novartis said its portfolio of tisagenlecleucel production locations also encompasses the Foundation for Biomedical Research and Innovation at Kobe in Japan, which oversees the clinical development of the gene therapy. The company’s map of active sites will soon include Cell Therapies, an Australia-based commercial contract development and manufacturing company specializing in cell therapies, according to Novartis. The developer also disclosed that it had recently established an agreement with Cell Therapies, meaning that Novartis will soon begin commercially developing tisagenlecleucel at its production facility in the Peter MacCallum Cancer Centre in Melbourne.
In addition to this newly forged partnership with Cell Therapies, Novartis has signed a licensing agreement for the clinical manufacturing of tisagenlecleucel in China with Cellular Biomedicine Group.
“At the end of the year, we will have 5 sites operational throughout the globe for the clinical and commercial manufacturing of Kymriah, a global network that will be able to step in for different parts of the world,” Hendriks said. “That allows us fantastic flexibility to mitigate a situation like this should one occur in the future.”
At present, Novartis remains resilient and well equipped to continue confronting COVID-19—related interferences. “This situation is challenging for many people in the healthcare system, including our treatment teams and [patients with] cancer, but our distribution channels are fully operational, and our team has prepared for multiple scenarios and are agilely responding to these scenarios as they arise,” Hendriks concluded.