key: cord-0713617-wz9jpp6x
authors: Wingard, John R.; Ahn, Kwang Woo; Dandoy, Christopher; Perales, Miguel-Angel; Wood, William A.; Logan, Brent; Riches, Marcie; Rizzo, J. Douglas
title: COVID-19 and Hematopoietic Cell Transplant Center-specific survival analysis: Can we adjust for the impact of the pandemic? Recommendations of the COVID-19 Taskforce of the 2020 CIBMTR Center Outcomes Forum
date: 2021-04-22
journal: Transplant Cell Ther
DOI: 10.1016/j.jtct.2021.04.008
sha: fcb34ce833647afa1a3bf637da234e56a733c9cf
doc_id: 713617
cord_uid: wz9jpp6x

COVID-19 has significantly impacted the practice of hematopoietic cell transplantation (HCT) and likely affected outcomes of HCT recipients. Early reports document substantially higher case fatality rates for HCT recipients than faced by the general population. The threat to individual patients is real, but at present, we do not have a clear picture of how much of this threat is present within the first year after HCT, as the majority of cases in early reports occurred after the first year. Still unknown is how infection rates and outcomes vary with time after HCT. This is important because center-specific survival estimates for reporting purposes focus on 1-year post-HCT mortality. Transplant centers have dramatically changed practices due to the pandemic. For many centers, quality assurance processes and procedures were disrupted, and these changes likely affected team performance. Centers have been affected unevenly by the pandemic, by time, location, and COVID-19 burden. Assessment of center-specific survival depends on the ability to adjust for risk factors such as COVID-19 that are outside center control using consistent methods so that team performance based on controllable risk factors can be ascertained. The Center of International Blood and Marrow Transplantation Research (CIBMTR) convened a working group for the 2020 Center Outcomes Forum (COF) to assess the impact of COVID-19 on both patient-specific risks and center-specific performance. This committee reviewed the factors at play and developed recommendations for a process to determine if adjustments in the methodology to assess center-specific performance are needed.

COVID-19 has significantly impacted the practice of hematopoietic cell transplantation (HCT) and likely affected outcomes of HCT recipients. Early reports document substantially higher case fatality rates for HCT recipients than faced by the general population. The threat to individual patients is real, but at present, we do not have a clear picture of how much of this threat is present within the first year after HCT, as the majority of cases in early reports occurred after the first year. Still unknown is how infection rates and outcomes vary with time after HCT. This is important because center-specific survival estimates for reporting purposes focus on 1-

year post-HCT mortality. Transplant centers have dramatically changed practices due to the pandemic. For many centers, quality assurance processes and procedures were disrupted, and these changes likely affected team performance. Centers have been affected unevenly by the pandemic, by time, location, and COVID-19 burden. Assessment of center-specific survival depends on the ability to adjust for risk factors such as COVID-19 that are outside center control using consistent methods so that team performance based on controllable risk factors can be ascertained. The Center of International Blood and Marrow Transplantation Research (CIBMTR) convened a working group for the 2020 Center Outcomes Forum (COF) to assess the impact of COVID-19 on both patient-specific risks and center-specific performance. This committee reviewed the factors at play and developed recommendations for a process to determine if adjustments in the methodology to assess center-specific performance are needed.

CIBMTR produces an annual report on transplant center-specific survival rates to provide information to potential hematopoietic cell transplant (HCT) recipients, their families, transplant centers, and the general public as called for in the C.W. Bill Young Cell Transplantation Program (CWBYCTP). Reporting center-specific survival rates is a requirement of the Stem Cell Therapeutic and Research Act of 2005 (re-authorized in 2010 and 2015), and prior to that, the 1990 Transplant Amendments Act. HCT center-specific outcomes have been tracked since 1994. Over the years, this analysis has become an essential tool for centers to assess the effectiveness of quality improvement endeavors. It has also become a vehicle for transparent communications to the public providing information about both expected and observed survival rates.

Because centers vary considerably in the risk level of cases treated, the Center Specific Survival Analysis employs a statistical model adjusting for several risk factors known or suspected to influence outcomes. The outcome reported is one-year overall survival, for recipients of first allogeneic HCT in the United States. Methods are published annually (https://www.cibmtr.org/ReferenceCenter/SlidesReports/USStats/Documents/CIBMTR%20HCT %20Center%20Survival%20Report%20Methodology%20FINAL%202020-12-14.pdf). The premise underlying risk adjustment is that different centers vary in the types of diseases and characteristics of patients treated (case mix). Such differences substantially affect outcomes.

Multiple factors that affect survival have been identified and such factors have been included into the statistical model. As science has evolved, new risk factors have been introduced while others have been removed. Without adjusting for such differences, one could not determine if a center's survival rate is driven principally by its case mix or by the skills and performance of the center's team and its practices. Further, not adjusting for such risk factors might lead to an important unintended consequence of centers declining to offer transplant to higher-risk patients to avoid less favorable outcomes.

A crucial underpinning for quality assessment is that one can assess performance associated with controllable risks related to the skill, team cohesiveness, adherence to safety standards and maintaining safeguards to minimize errors, independent of uncontrollable risks.

Adjustments for confounding effects due to uncontrollable risks attributable to patient, disease, and other risks over which the center has no control, are crucial.

COVID-19 arrived in the US in early 2020. Initially, cases were concentrated mainly in several regions. Gradually the disease became distributed across the US, with asymmetric geographic infection rates and health system burdens over time. Rates of infections, hospitalizations, and deaths varied considerably and waxed and waned unpredictably at different locations. Centers have been affected unevenly, by time, location, and COVID-19 burden. At present, it is not satisfactorily known whether these geographic disparities in the regional impact of COVID-19 have translated to differential effects of COVID-19 upon transplant outcomes at centers. If it were determined that the effects of COVID-19 upon centers were evenly distributed, complex adjustment for this uncontrollable risk might not be needed.

Early reports about COVID-19 indicated substantially higher morbidity and mortality in HCT recipients than in the general population (1-6). Thirty-day mortality rates of 22-32% were seen (1, 2) . Risk factors for severe COVID-19 morbidity included some of the same comorbidities, (e.g., male sex and older age) in the general population but also included additional risk factors including active immunosuppressive therapy in one study, occurrence within the first year of transplant in another, and comorbidities at time of infection in an additional study. The relative risk in patients with active GVHD has been less apparent in early reports. Most cases in early reports occurred beyond one year of transplant. As of February 2021, there are only small numbers of cases of COVID-19 infection during the first year after transplant but 37% of COVID infections reported to the CIBMTR have occurred in patients during their first year after HCT (unpublished data). Based on reported outcomes of other early viral infections post HCT, it can be reasonably assumed that patients with SARS-CoV-2 infection early after HCT are more likely to have poor outcomes. This would be supported by early data showing these patients are less likely to clear the virus, which was associated with prolonged shedding as well as increased risk of mutations (7) . As yet, we lack a clear picture of the magnitude of impact of COVID-19 on one-year survival and the HCT-specific risk factors for infection and mortality.

Transplant centers quickly recognized the threats of COVID-19 to HCT recipients and they dramatically changed multiple transplant practices (8, 9) . These practice changes may also alter survival in ways not obvious at present (Figure 1 ) and can be regarded as indirect effects of the pandemic. Some of these changes in practice were likely to have been applied differentially across US centers based on temporal and geographic variation in pandemic intensity, the severity of disease indications, age of recipients, socioeconomic status (SES), and type of donor (family or unrelated donor). Transplants were delayed and the delay necessitated bridging therapies in some patients. Some transplants were not performed, donor stem cell products were collected in advance and frozen to ensure they would be available at the time of need. The effects of cryopreservation on the quality of the allograft and subsequent outcomes are relatively under-explored and several reports raised concerns while others were reassuring (10) (11) (12) . Evaluations of transplant candidates were curtailed to avoid aerosolizing procedures (e.g., spirometry), making risk assessment incomplete. There were fewer donors available since donors were grappling with their own pandemic effects including travel restrictions, illness, and changes in employment. Compounding these issues, blood donations decreased and shortages necessitated alterations in transfusion practices to conserve limited supplies.

Hospital resources became constrained while managing the burden of COVID-19 infected patients. Availability of critical supplies like personal protective equipment (PPE), consultants for certain critical specialties (Infectious Disease, Pulmonary, Nephrology) inpatient beds, as well as intensive care unit (ICU) beds became constricted. Post-discharge outpatient care also dramatically changed. Clinics restricted access to implement stringent infection control measures; that, in turn, resulted in less oversight of ongoing care, monitoring of immunosuppressive regimens and infectious complications. This introduced the potential for delays in identifying and treating GVHD and less scrutiny to evaluate response and need for changing treatment. Center initiatives to provide patient education, encourage health promotion behaviors, and screen for early and late complications were set aside or curtailed. Communal housing was no longer safe and nearby housing for patients living far from the transplant center became more challenging. As a result, patients were discharged to local care networks much sooner than considered appropriate during usual care. The pandemic affected individuals from ethnic minorities and lower socio-economic status to a higher degree than other populations.

Centers serving large numbers of low-income patients were especially affected since their patients found themselves with disproportionately fewer social network resources to assist in their care needs and to support and sustain themselves. The degree to which the various changes to practice described above occurred uniformly vs unevenly across centers is not known.

Data collection. The CIBMTR recognized the urgent need to gather data on the impact of COVID-19 on HCT outcomes and practices. Data collection systems in place in March 2020 did not collect relevant information about SARS-CoV-2 and related outcomes. The CIBMTR responded quickly to collect COVID-19 specific data by modifying data collection forms ( Table   1) patients, private payers, and statisticians to participate. The purpose is to review the current approach to center-specific outcomes reporting and to provide meaningful recommendations for future reports. Summaries of these meetings are available at http://www.cibmtr.org/Meetings/Materials/CSOAForum. As part of the 2020 CIBMTR COF, a task force was convened to provide guidance on how to assess the impact of COVID-19 on evaluation of center-specific outcomes.

The fundamental question considered by the task force was: did the abrupt changes required to respond to the pandemic disrupt centers' quality measures in predictable or unpredictable ways and did that disruption render quality assessment unreliable. (1) COVID-19 Burden. The geographic and temporal burden of COVID-19 on the general population across the US has generally been tracked in data collected by various entities and made publicly available using three parameters: (1) infection numbers (incidence, or prevalence), hospitalizations, and deaths. These parameters generally have tracked closely together over time but not always. Testing capacity was severely limited early on and, even when testing became more readily available, it was not uniformly adopted across the US. In addition, at various times and in different communities, divergences have been seen when infection numbers shifted disproportionately from high-risk groups such as the elderly and congregant groups to lower risk groups such as adolescent and young adult groups resulting in surges in infections without concomitant proportional increases in hospitalizations and deaths.

High infection prevalence would seem to be excellent in gauging higher risk that an individual could become newly infected. On the other hand, higher hospitalization and death rates might be better markers of centers' constraints to accommodate a patient's transplant needs and continuity of quality measures.

(2) Locality of the center and patient. However measured, the burden of COVID-19 affected HCT centers unevenly. Some centers were in a community immersed in a high burden (4) Indirect effects of COVID-19 burden on a center's practices. As daunting as the above three factors are, the most challenging factor to consider is how best to assess the impact of the pandemic on the team, the transplant practices, and the center's quality measures put in place to optimize survival. One could reason that institutions faced with overwhelming demands of seriously ill non-HCT patients had less staff, reassignments of work responsibilities, staff redeployments, and shortages, lower access to diagnostic procedures to evaluate comorbidities before HCT and to evaluate complications after HCT, greater reductions in outpatient clinic services and access, and fewer ICU beds to care for non-COVID-19 patients.

Such centers with fewer resources to maintain quality measures likely responded to COVID-19 very differently than centers less affected. One surrogate marker on how the transplant practices were altered at each center considered was a drop in the numbers of transplants; while simple and attractive, changes in numbers of transplant are affected by multiple factors that have nothing to do with COVID-19, such as changes in personnel, referral patterns, etc.

Another possible indicator considered is the responses from the patient-specific COVID-19 impact reports from the centers using revised forms rolled out by the CIBMTR to assess how COVID-19 affected the transplant procedure for each patient. These CIBMTR form revisions were deployed in late August 2020, and how useful they prove to be in assessing changes to the transplant procedure prompted by the pandemic have yet to be measured. One potential shortcoming is that data were not collected prospectively in the early days of COVID-19

between March and September. However, centers were asked to provide them for all patients during the timeretrospectively and prospectively, but as yet, how complete the data will be is not known.

The task force formulated five recommendations ( Table 2) . An alternate analysis approach was also considered. This approach would be conducted by examining year over year one-year survival rates at each center (pre-pandemic and postpandemic). If the post-pandemic outcomes are lower even after adjustments for changes in known risk factors from prior studies, then an unexplained variation will be noted. That unexplained variation could be due to a drop in team performance not related to COVID-19 effects but also could be due to COVID-19 effects. A methodology would need to be developed to tease out which is more likely. In any given year, 5-10% of centers change from one performance category to another. Thus, this substantial baseline year over year variability in the performance of centers will make it hard (or impossible) to separate that baseline variability from more "systematic" change that is related to COVID. If the analysis confirms that there is a COVID-19 impact and a pseudo-value regression model cannot be adapted, or there are too many time-variable effects, the CIBMTR may make a recommendation to HRSA to defer specific cohorts from inclusion in the model. It may also be appropriate for CIBMTR to include a disclaimer regarding the limitations to fully adjust for potential effects of the pandemic on the analysis and results. Because a main purpose of the center specific survival analysis is to provide an equitable, scientifically valid performance measurement tool for use by centers for quality improvement, it is essential to acknowledge limitations that could cause misuse/misinterpretation or unreliable information to guide quality improvement activities. The Foundation for Accreditation of Cellular Therapy (FACT) performs center accreditation and plays an important role in centers' corrective action plans for performance below expected. FACT processes may prove more important in the next few years depending upon the magnitude of limitations to center specific survival analysis and public reporting. FACT has the capability to review directly at the individual centers, something that may not be available to the payer groups, and this may be useful if the alternative analysis plan (to review

year over year drop in survival rates at a center and investigate each center to determine if that is attributable to COVID-19 effects) were to be developed further.

The major theme of the COF in 2020 was to address methodologic considerations for the cohort of patients who received first allogeneic HCT in 2017-2019 who will be analyzed in 2021. As discussed above, the impacts of COVID-19 on this cohort are limited to the post-HCT period. Subsequent cohorts of allogeneic HCT recipients in 2020 and 2021 can be anticipated to be impacted during the pre-, peri-and post HCT periods. Even if the analyses discussed above do not suggest an impact of COVID-19 on one year survival for patients transplanted in 2019, it will be necessary to re-test those impacts for patients transplanted in subsequent years.

Additionally, new methodologic approaches or risk-adjustment may be necessary for future cohorts more extensively impacted by the pandemic.

The focus of this manuscript is center outcomes reporting and adjustment of potentially differential effects of COVID across centers. Lessons learned from this analysis will be used to refine analytic and adjustment methods for research in which patients are the unit of analysis using the registry when patients transplanted during COVID are included, as appropriate. It is likely that the pandemic will have ramifications for transplant survival rates beyond one year, as is evident in the early reports of HCT survivors' experience with COVID-19 infection beyond one

year. Further, it is unclear if COVID-19 infection in HCT survivors are associated with greater longterm COVID-19-associated morbidity than in the general population or lead to greater risks for HCT-associated complications, such as chronic GVHD, alloreactive lung disease as a consequence of early respiratory viral infections (17, 18) . How the impact of altered patterns of health care of transplant survivors with a greater reliance on telehealth will affect outcomes and the timeliness of evaluation of complications and accuracy of reporting are yet unknown. The psychosocial consequences of the pandemic on HCT outcomes remains to be studied.. Another implication of the pandemic that should be studied is on the outcomes of patients for whom transplant was planned or the desired treatment, but never performed; early reports suggest that the impact differed at various centers (19, 20) .

Further implications of the pandemic include the possibility that higher non-relapse mortality due to COVID-19 might skew future CIBMTR research studies spanning multiple years (before and during the pandemic). Some type of adjustment for the COVID-19 effect may be necessary.

At this time, it is unclear if the COVID-19 effects will be time-limited or persist for multiple years. Either would present different modelling challenges.

COVID-19 has introduced an unpredictable factor that can have important implications for the measurement of center-specific outcomes. Various factors have been identified to serve as potential surrogate markers of COVID impact on both patient-specific outcomes and center-specific performance. This report provides recommendations for collecting needed data to identify data needed to determine effects and a plan for testing new statistical models to adjust for those effects. 

reporting to explore if and how other organizations are making assessments of the impact of COVID-19 on general acute care for geographic areas to inform this effort. 

MorphoSys, Novartis, Nektar Therapeutics, Omeros, and Takeda. Serves on DSMBs for Cidara Therapeutics, Servier and Medigene, and the scientific advisory board of NexImmune. Research support for clinical trials from Incyte, Kite/Gilead, Miltenyi Biotec, and Novartis. Member of the Board of Directors of Be The Match (National Marrow Donor Program, NMDP), as well as on the CIBMTR Cellular Immunotherapy Data Resource (CIDR) Executive Committee

Advisory Board-BioIntelect Ahn, Logan and Rizzo: The CIBMTR is supported primarily by Public Health Service U24CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of

U24HL138660 from NHLBI and NCI; OT3HL147741, and U01HL128568 from the NHLBI

Support is also provided by Be the Match Foundation, Boston Children's Hospital, Dana Farber, St. Baldrick's Foundation, Stanford University, the Medical College of Wisconsin the National Marrow Donor Program, and from the following commercial entities

Bristol Myers Squibb Co.; Celgene Corp.; CSL Behring; CytoSen Therapeutics, Inc.; Daiichi Sankyo Co., Ltd.; ExcellThera; Fate Therapeutics; Gamida-Cell

Merck Sharp & Dohme Corp.; Millennium, the Takeda Oncology Co.; Miltenyi Biotec, Inc.; Novartis Pharmaceuticals Corporation

Pharmacyclics, LLC; Sanofi Genzyme; Stemcyte

The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration (HRSA) or any other agency of the

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