Impact of Covid 19 pandemic on hematopoietic stem cell transplantation activities: Report from a single center

Abstract

The current COVID-19 pandemic has placed unprecedented stress on the healthcare system, including HSCT. Several international organizations have created guidelines for managing different aspects of HSCT in the context of the pandemic. Comparing 2019 and 2020, our transplant center performed the same number of transplants. In both periods, transplants were mainly for patients with acute leukemia; thus, the urgency criteria was respected in light of pandemic restraints. Transplants by sibling donors and cord blood units remained the same, while transplants by unrelated donors were increased, in particular from European registries, and transplants by haploidentical donors were decreased. This change was made in light of the necessity of cryopreserving all apheresis products. We decided against cryopreserving bone marrow products due to the greater risk of drastic reduction in CD34 + cell count during the process. For urgent cases with only a haploidentical donor available, we opted for the use of PBSC following stimulation with G-CSF. GvHD prophylaxis was performed with PTCY on days + 3 + 5, cyclosporine with tapering from day + 100, and mycophenolic acid until day + 90 post-HSCT. Post-transplant outcomes such as graft failure, sepsis, and GVHD were not affected by the changes implemented. As a result of logistic difficulties, we halted our Car-T program from the start of the lockdown in March 2020 until September 2020. In accord with international guidelines, we were able to continue our HSCT program in the order to ensure a lifesaving treatment for patients with hematologic diseases for whom this procedure cannot be postponed.

1. Introduction

The current COVID-19 pandemic, caused by SARS-CoV-2, is responsible for severe acute respiratory syndrome. The infection spread very rapidly in several countries. By 2020, more than 13 million cases of COVID-19 were reported worldwide [1] .

Europe was the first continent heavily hit by the SARS-CoV-2 pandemic after Asia, with a total of 20,296,503 cases and 449,793 deaths from the beginning of the pandemic until December 2020. Italy was the third among the eight hardest-hit European countries, with 8 % of total cases. [2].

The time from exposure to symptom development ranges from 2 to 14 days (median 5 days). Symptoms vary from very mild symptoms to very severe respiratory symptoms resulting in need for intensive care [3] .

Although most infected individuals clear the virus without major complications, in a minority of patients, the infection leads to a life-threatening clinical situation involving any organ (especially the lungs), diffuse intravascular thrombosis, and ultimately acute respiratory distress syndrome (ARDS) and multiorgan failure. Patients with a hematologic malignancy or receiving transplantation are immunosuppressed and may be particularly vulnerable to this infection [1] . The pandemic places unprecedented stress on all aspects of the healthcare system including hematopoietic stem cell transplantation (HSCT), considering that healthcare workers are at risk of contracting the SARS-CoV-2 infection and being carriers themselves [4] .

The European Group for Blood and Marrow Transplantation (EBMT) survey on HSCT activities during 2019 reported a continuous increase in transplants performed with 48,512 total transplants for 43,581 patients, comprising 19,798 (41 %) allogeneic and 28,714 (59 %) autologous transplants performed by 700 centers in 51 countries. Focusing our attention on 92 centers in Italy, 4647 first transplants out of a total of 5490 transplants were performed in 2019. Allogeneic and autologous transplants were, respectively, 1803 and 2844 [5] .

During the Covid 2019 pandemic, cryopreservation became mandatory and was highly adopted in 97.4 % of centers, with an increase in the use of peripheral blood-derived stem cells (+10.7 %). Overall, in 2020 there was a 2.4 % reduction in the number of allogeneic transplants compared to 2019. Interestingly, this reduction was not observed in the setting of acute leukemia, in which allogeneic transplants increased by 5.7 % in 2020 [6] .

Several international organizations, including the EBMT and the Center for International Blood and Marrow Transplant Research (CIBMTR), created guidelines for the management of patients receiving allogeneic SCT and related donors during the pandemic.

2. Material and methods

The aim of our study is to assess how the COVID-19 pandemic modified the internal management of different aspects of HSCT during the pandemic. We compared the period from March to September 2020 (during the first wave of the pandemic) with the same period from March to September 2019 (pre-pandemic).

To this end, we collected clinical data on consecutive patients who received an allogeneic stem cell transplant in the two time periods, focusing our attention on the following characteristics: age, gender, underlying disease, conditioning regimen, stem cell source, number of CD34 + cells infused, GVHD prophylaxis. We then compared these two populations in terms of post-transplant outcomes such as graft failure, incidence of sepsis, GvHD, relapse rate, and overall survival.

Meetings discussing HSCT candidates continued to be held every two weeks during the pandemic. The major inclusion criteria for HSCT were urgency of transplant (malignant disease and high-risk disease) and donor availability.

Statistical analysis was performed using Fisher’s exact test and the chi-square test for categorical variables. The significance level was set at p < 0.05.

3. Results

During the Covid19 pandemic, our transplant center modified its procedures and activities according to the national and international guidelines issued by the Italian competent Authorities and the EBMT [7], [8] .

During the pandemic, meetings continued to be held every two weeks for enrollment of patients in our transplant program. As recommended by the EBMT guidelines, non-urgent transplants were deferred as much as possible, especially for non-malignant diseases. Each decision was made on an individual basis. Comparing HSCT activity between 2019 and 2020, we performed the same number of transplants (34 vs. 33), as reported in Table 1. In both periods, patients receiving HSCT were predominantly affected by acute leukemia (65 % vs. 69 %), and the urgency of the transplant was respected (Table 1). All patients were tested for SARS-CoV-2 before entering the bone marrow unit. For patients with exposure to a COVID19 positive subject, admission was delayed for 14 days.

Table 1.

Patients’ characteristic.

Allogeneic HSCT n°	2019 34	2020 33	p > 0.05
Underlying disease n°(%) Acute leukemia Myelodysplastic syndrome Myeloproliferative neoplasms (MFI) Lymphoproliferative disease Multiple myeloma others	22 (65 %) 3 (9 %) 4 (11 %) 3 (9 %) 0 2 (6 %)	23 (69 %) 1 (3 %) 5 (15 %) 4 (12 %) 0 0	p = 0.7
Donor type Mud Sibling donor Haploidentical donors CBU	10 11 10 3	14 12 4 3	p = 0.2
Stem cell source PBSC BM CBU	17 14 3	28 2 3	p = 0.01
Conditioning regimen Myeloablative Reduced intensity regimen	29 5	26 7	p = 0.5
GvHD prophylaxis PTCY none	31 3	32 1	p = 0.6
Graft failure n°(%)	2/34 (6 %)	2/33 (6 %)	ns
Sepsis n°(%)	18/33 (54 %)	19/34 (56 %)	ns
Relapse n°(%)	8/33 (24 %)	10/34 (29 %)	ns
Overall Survival n°(%)	27/33 (82 %)	27/34 (79 %)	ns

During the first wave of the pandemic, twelve patients who had undergone allogeneic HSCT contracted SARS-CoV-2 infection. All patients except for one developed SARS as outpatients. The exception was a patient with myelofibrosis who developed a Covid infection after engraftment and he was transferred to the infectious disease department for monitoring until he cleared the infection. Seven out of twelve patients received allo-HSCT for acute leukemia, four for myelofibrosis, and one for multiple myeloma. Five out of twelve patients received HSCT in 2020 and all but one were still on immunosuppression at the time of infection. Overall, the SARS-CoV-2 positivity rate among the study population was 15%. All but two patients recovered and are alive at the last follow up. One patient with acute leukemia subsequently died from disease progression and a patient with multiple myeloma died while positive for covid as a result of multidrug-resistant sepsis. Only one patient required intensive care with endotracheal intubation and mechanical ventilation; this was a patient with concomitant risk factors, including obesity and developing infection within 100 days of transplant while still on cyclosporine.

The median duration of COVID-19 infection among the study population was 23 days (range 10–67).

During the first wave of the Covid19 pandemic, the donor selection procedure remained the same.

The number of sibling donors and cord blood units remained the same in the two time periods, while there was an increased use of matched unrelated donors (MUD), in particular from European registries. Selection of European donors was encouraged also for the possibility to organize last minute transport on wheels, in case of border closures or flight cancellations.

We postponed one transplant procedure in a patient with acute leukemia because of Covid infection in the selected unrelated donor, in favor of performing the transplant with a related donor, using PBSC from the haploidentical sister.

The switch from haploidentical bone marrow donors to unrelated peripheral stem cell donors was due to the shortage of operating rooms for BM harvest during the pandemic and to the necessity for cryopreservation.

The final effect was a statistically significant increase in the use of PBSC as the stem cell source (p = 0.01) (Table 1).

Despite these changes, regarding in particular donor type and stem cell source, post-transplant outcomes, including graft failure, sepsis, acute GVHD, and overall survival, did not differ between the two time periods (Table 1) ( Table 2).

Table 2.

Post transplant outcome according donor type.

Allogeneic HSCT n°	2019 34	2020 33	Graft failure n° 2019 2020	Sepsis n° 2019 2020	Relapse n° 2019 2020	OS n° 2019 2020
Donor type MUD Sibling Haploidentical CBU	10 11 10 3	14 12 4 3	0 0 0 1 0 0 2 1	7 8 4 0 6 10 1 1	3 5 2 0 2 5 1 1	1 2 3 0 1 4 2 0

On the other hand, CAR-T activity was halted after the beginning of the lockdown in March 2020 due to logistic difficulties and resumed in September 2020.

Outpatient follow-up was also modified with the implementation of telehealth, using telephone and/or televideo conferences for patients more than six months after transplant and without serious complications.

4. Discussion

The Covid 19 pandemic has represented and continues to represent a global challenge and a monumental stress on the healthcare system.

Despite the logistic and management difficulties, our center was able to reorganize our transplant activity in line with national and international guidelines, with the aim of ensuring clinical care to patients with hematologic malignancies. In the end, our transplant activity was not reduced as a result of the pandemic.

We were in line with the following guidelines, as recommended by the EBMT: staff was screened for symptoms before entering the HCT unit, and personal protective equipment was used at all times during rounds [9] . The number of staff was minimized during rounds, and adequate distance from patients was maintained as best possible. Staff with any symptoms of infection remained at home [3] . Even before the Covid 19 pandemic, to enter the Bone Marrow transplant Unit, medical staff followed a protocol including mask, gown, and head covering before entering patient rooms, and gowns were changed between patients. In light of the covid pandemic, we in turn adopted this protocol in our general hematology ward.

We gave priority to patients with acute leukemia as a result of the urgency in this patient population. A similar approach was adopted by the Seattle transplant group. Their group developed an algorithm in order to decide the temporary deferral of transplants deemed non-urgent based on the risk of the underlying malignancy and the risk of recurrence or progression. They also established patient priority based on the burden of comorbidities [10] .

Donor availability and selection was also importantly modified during the pandemic. All donors selected for donation were tested for Covid 19 within 72 h prior to mobilization of peripheral blood stem cells (PBSC). Physical access to a stem cell donor was restricted as a result of infections, logistical factors at the harvest centers, and travel restrictions across different countries. In general, using PBSC with cryopreservation and testing the quality of thawed product before the start of conditioning were strongly encouraged. In situations where there were no possibilities of cryopreserving the stem cell product, it was mandatory to have an alternative donor as a backup. For certain conditions, such as bone marrow failure, in particular for patients with severe aplastic anemia, bone marrow, rather than PBSC, continued to be strongly recommended.

Cryopreservation of allogeneic PBSC grafts was the most remarkable change in our practice from the beginning of the Covid 19 pandemic. Previously, graft collection was strictly timed according to the conditioning regimen of the recipient. Graft cryopreservation was authorized only in selected cases, such as delays in delivery of unrelated donor product or if the donor refused a priori to donate bone marrow as a backup for poor mobilization. The rationale against cryopreservation was to avoid a loss in cell viability as a result of processing and storage of donor product. In a recent study, Teofili et al. reported that cryopreservation, which was introduced for all related and unrelated apheresis products during the Covid 19 pandemic, did not affect transplant outcomes, including engraftment, acute GVHD, and non-relapse mortality [11].

We did not consider cryopreservation of bone marrow in order to avoid a drastic reduction in CD34 + cell counts during the process.

Due to the mandatory indication to cryopreserve stem cell product, we opted preferentially for sibling and MUD donors, and consequently peripheral blood as stem cell source, which was also suggested by the EBMT and Italian competent Authorities.

Due to logistic problems, the organization of stem cell transport became more complex but remained possible. Majority of the donors we chose were European so that transport on wheels remained possible in case of flight restrictions. With prior authorization, couriers were able to cross borders, and the use of cryopreserved product represented a logistic advantage in the case of any problems encountered during the collection and the transport process.

Consequently, the use of haploidentical donors was drastically reduced, while the number of transplants with cord blood units was unaffected.

If the only available donor was a haploidentical one, we switched to peripheral blood as a graft source. Post-transplant cyclophosphamide (PTCY) on days + 3 and + 5, cyclosporine until day + 180, with tapering from day + 100 and mycophenolic acid from day 0 to day + 35 post-HSCT was adopted as standard GVHD prophylaxis in all cases, as previously reported, independently of graft source [12] . Results were encouraging: post-transplant outcomes, such as GvHD, relapse, and graft failure, did not differ between the two time periods. Our results are in line with data reported in the GITMO survey, which also compared outcomes in the same periods. Their main findings were: a slight decline in the number of allo-HCT compared to the same period in the previous year (−2.4 %); an increase in the number of allo-HCT for acute leukemia (+5.7 %); and a reduction in allo-HCT for patients with less aggressive diseases. The Gruppo Italiano per il Trapianto di Midollo Osseo (GITMO) centers did not change their donor selection policies during this period. Meanwhile, a higher proportion of unrelated donors refused to donate for potential concerns of donation-related infectious risk. The consequence was that more unrelated donors were recruited by Italian Bone Marrow Donor Registry (IBMDR); there was a significant increase in the use of PBSC and cryopreservation, as recommended by the Health Authorities [6] .

In several transplant centers worldwide, the recommendation to cryopreserve stem cells led to shift from the use of bone marrow to peripheral blood stem cells in the setting of haploidentical donors. Mehta et al. reported the outcomes of HCT in BM graft and PB graft recipients who underwent T cell-replete haploidentical HSCT. The engraftment and the incidence of acute GvHD were comparable between the two groups. Among the patients with grade II-IV aGvHD, the rate of steroid-refractory aGvHD was higher in the PBSC group, as was the incidence of chronic GvHD [13] .

Two recent papers have analyzed the impact of the first wave of the COVID-19 pandemic on patients with hematologic diseases receiving HSCT. The first, on the behalf of CIBMTR, reported on 318 HSCT recipients diagnosed with COVID-19 between March and August 2020. The overall 30-day survival after diagnosis of COVID-19 was 68 % for allogeneic HSCT and 67 % for autologous HSCT. Multivariate analysis revealed that older age (>50 years), male sex, and COVID-19 infection within 12 months of transplantation were associated with a higher risk of mortality among allogeneic HSCT recipients. Among autologous HSCT patients, patients with lymphoma had a higher risk of mortality compared with those with plasma cell disorders and multiple myeloma [14] .

The EBMT and “the Spanish Group of Hematopoietic Stem Cell Transplantation” (GETH) survey collected data on 382 patients who developed Covid 19 infections, including 236 allogeneic HSCT patients and 146 autologous HSCT patients. The probability of survival 6 weeks COVID-19 diagnosis were 77.9 % and 72.1 %, respectively, in allogeneic and autologous HCT recipients, which was not statistically different. In multivariate analysis, older age, need for ICU and moderate/high immunodeficiency index represented poor prognostic factors, while better performance status (p = 0.001) decreased the risk of mortality [15] .

During the first wave of the COVID19 pandemic, the use of convalescent plasma (CP) from subjects who recovered from SARS‐CoV‐2 infection was considered a valid therapeutic tool for patients with mild or severe ARDS. Some studies demonstrated a lower mortality in patients who were treated with high titer CP within 3 days of hospital admission. This therapeutic approach appeared to be very promising in the setting of immunocompromised patients, including patients with hematologic diseases. The ITA‐HEMA‐COV (the ITAlian HEMatology Alliance on COVID‐19) performed a retrospective study on patients with hematologic diseases from 64 Italian hematology departments treated with CP between February 2020 and October 2021. Patients who received CP mainly included patients with a very aggressive B cell lymphoma or severe COVID-19 infection. In the CP‐treated group, no adverse events were detected, and there was no difference in mortality between patients who received CP and the non-CP-treated control group [16] .

Similar data were also observed in a recent meta-analysis including 146 previous studies (case report, case series, uncontrolled cohort studies, controlled clinical trials) and involving patients with primary (i.e., inheritable) or secondary immunosuppression (ie, related to hematologic or solid tumors, autoimmune disorders, or organ transplants). There was a high level of concordance among study outcomes, and treatment with COVID-19 convalescent plasma was associated with reduced risk of mortality. For life-threatening COVID-19, the pathogenesis involves exuberant tissue-damaging inflammatory responses that follow an initial viral phase. Antibody-based therapies function primarily as antiviral agents and are much less likely to be effective in individuals who are in the inflammatory phase. However, individuals who are immunocompromised are generally unable to mount strong antibody or inflammatory responses and often cannot clear SARS-CoV-2. Hence, patients who are immunocompromised represent a biologically different population from the population that is not immunocompromised where antibody-based therapies may retain efficacy late into the course of disease [17].

5. Conclusion

HCT patients are at a high risk of developing severe pulmonary infections and have an increased risk of mortality from COVID-19. The lesson we learned from the first wave of the pandemic is that, in order to ensure a lifesaving treatment for HCT patients with an urgent indication for transplant, stringent protocols for infection surveillance and aggressive treatment measures in HSCT recipients with COVID19 infections must be adopted. In the following waves of the COVID 19 pandemic, while the rapid introduction of vaccines, monoclonal antibodies, and antiviral therapies have markedly changed the scenario, the protocols put in place during in the first wave still remain in effect two years later [18] .

CRediT authorship contribution statement

SG, SS and PC wrote the paper; AB and JDM revised the paper; SF, EM and ML were involved in the clinical follow-up of the patients, LT and CGV were responsible for the cell manipulation laboratory and were directly involved in cryopreservation of stem cell products.