Abstract
Post-transplant lymphoproliferative disorder (PTLD) is a leading cause of cancer death in solid organ transplant recipients (SOTRs). Relapsed or refractory (R/R) PTLD portends a high risk of death and effective management is not well established. CD19-targeted CAR-T cell therapy has been utilized, but the risks and benefits are unknown. We report the first case of diffuse large B-cell lymphoma (DLBCL) PTLD treated with lisocabtagene maraleucel and present a systematic literature review of SOTRs with PTLD treated with CD19 CAR-T therapy. Our patient achieved a complete response (CR) with limited toxicity but experienced a CD19+ relapse 8 months after infusion despite CAR-T persistence. Literature review revealed 14 DLBCL and 2 Burkitt lymphoma PTLD cases treated with CD19 CAR-T cells. Kidney (12/17), liver (n=2), heart (n=2), and pancreas after kidney (n=1) transplant recipients were analyzed. The objective response rate (ORR) was 82.4% (14/17), with 58.5% (10/17) CRs and a 6.5-month median duration of response. Among kidney transplant recipients, the ORR was 91.7% (11/12). Allograft rejection occurred in 23.5% (4/17). No graft failure occurred. Our analysis suggests that CD19 CAR-T therapy offers short-term effectiveness and manageable toxicity in SOTRs with R/R PTLD. Further investigation through larger datasets and prospective study is needed.
INTRODUCTION
Solid organ transplantation is the most effective treatment for end-stage organ failure but requires life-long immunosuppression (IS). Improvements in IS management have been associated with prolonged graft survival. However, more solid organ transplant recipients (SOTRs) are dying from cancer because IS diminishes immune-mediated control of oncogenic viruses and impairs cancer immunosurveillance.1,2
Post-transplant lymphoproliferative disorders (PTLDs), a heterogenous group of high-risk lymphoid neoplasms, are a leading cause of cancer death in SOTRs.3 Contemporary management yields a 5-year survival rate of 55% and a median survival of 6.6 years.4 The 10-year incidence of PTLD among kidney transplant recipients (KTRs) has been estimated to be 1.6%, and the risk of PTLD is higher among heart and liver transplant recipients.5 Given that Epstein Barr Virus (EBV) is a driver of many PTLDs, EBV-naivete confers a marked risk of developing PTLD. Among EBV-negative KTRs at the time of transplant, the incidence of PTLD is highest within the first year, during which period approximately half of PTLD cases occur.6 Non-EBV-associated PTLDs also occur, possibly due to the effects of ongoing immune dysregulation. The proportion of EBV-negative PTLD has increased over time, now comprising approximately 50% of PTLD diagnoses.7
Initial treatment of PTLD involves reduction of IS (RIS) and rituximab-based chemotherapy regimens.8,9 The pivotal PTLD-1 and PTLD-2 studies, both multicenter prospective phase 2 trials, support the use of sequential rituximab followed by CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy. The PTLD-2 trial demonstrated the selective utility of a risk-adapted treatment approach whereby intensification to chemotherapy may be avoided in low-risk patients achieving a remission.4,10 There are no generally accepted salvage regimens for relapsed or refractory (R/R) PTLD.1 Case reports have described successful outcomes using ESHAP (etoposide, solumedrol, cytarabine, cisplatin),11 RICE (rituximab, ifosfamide, carboplatin, etoposide) and R+GEMOX (rituximab, gemcitabine, oxaliplatin) chemotherapy regimens.12 Although T cells engineered to express a CD19-targeted chimeric antigen receptor (CAR-T) have shown great promise in treating patients with high-risk B cell malignancies,13 SOTRs have been excluded from all clinical trials of CAR-T therapy. The safety and efficacy of this approach for treating R/R PTLD is not well established.
In this report, we describe the clinical course for the first known case of PTLD treated with the commercially approved CD19 CAR-T therapy, lisocabtagene maraleucel (liso-cel). We also review the outcomes for all published cases of R/R PTLD arising in SOTRs treated with CD19 CAR-T therapy and provide clinical practice recommendations.
CASE REPORT
A 47-year-old man with a history of lupus nephritis (diagnosed age 13) status-post 3 kidney transplants (KTs), most recently from his maternal stepsister (9.25 years prior to presentation), was diagnosed with Ann Arbor stage IV monomorphic PTLD, diffuse large B-cell lymphoma (DLBCL) type, with widespread nodal and osseous disease. His International Prognostic Index (IPI) score was 2. Immunohistochemistry (IHC) revealed EBV negative, germinal center B cell subtype. His KT was stable on tacrolimus, MMF, and prednisone. MMF was discontinued upon diagnosis. Initially, he received R-CHOP x6 cycles achieving a partial response (PR).
Progressive disease (PD), detected 2 months later, was treated with R-ICE x3 cycles. Subsequently, positron emission tomography/computed tomography (PET/CT) showed PD with new intramuscular uptake near the right scapula and increased hypermetabolism in the lower extremities (Deauville score 5).
Tacrolimus was discontinued 41 days prior to leukapheresis for CAR-T manufacturing. Prednisone 5 mg daily was continued for allograft maintenance. He underwent bridging chemotherapy with polatuzumab vedotin/bendamustine/rituximab x1 cycle. Preparative lymphodepletion with cyclophosphamide/fludarabine was followed by outpatient infusion of liso-cel (Figure 1). One week after CAR-T infusion, he was admitted for grade 1 cytokine release syndrome (CRS) and elevated serum creatinine (1.1 mg/dL) but required no additional immunosuppression. Donor-derived cell-free DNA (dd-cfDNA) was elevated (7.96%; normal <1%) 16 days post CAR-T infusion. Recovery of renal function coincided with a reduction in dd-cfDNA without additional IS. Three-month interval PET/CT demonstrated a complete response (CR; Deauville score 1). Tacrolimus (goal trough level 5-7 ng/mL) was restarted for allograft maintenance 65 days after CAR-T infusion.
Figure 1.
Lab parameters of our patient relative to lisocabtagene maraleucel CAR-T infusion. The red area denotes 3-day course of lymphodepletion chemotherapy with fludarabine (30 mg/m2/day) and cyclophosphamide (300 mg/m2/day), and the yellow area denotes a 4-day hospitalization for grade 1 cytokine release syndrome. Creatinine (Cr; black), donor-derived cell-free DNA (dd-cfDNA; blue), and FlapEF1α level (percent of maximum [copies/μg DNA]; green) are shown.
Eight months post-CAR-T infusion, a surveillance PET/CT revealed a new 3.0 x 1.7 cm left obturator muscle lesion. Biopsy pathology demonstrated recurrent disease with 100% CD19 positivity. However, peripheral blood CD19+ cells were undetectable by lymphocyte subset analysis, suggesting persistent peripheral CAR-T activity. Peripheral blood CAR-T persistence was verified via qPCR detection of the transgene vector sequence, FlapEF1α (960 copies/μg DNA; 20% peak level). He was treated with RIS (tacrolimus goal trough 3-5 ng/mL) and radiation (total 4000 cGy; 20 fractions) to the muscle lesion. PET/CT at 11 months post-infusion, his most recent evaluation, showed no evidence of disease.
METHODS
Patient evaluation
CRS and ICANS were graded per ASTCT guidelines.14 dd-cfDNA testing was performed using the Natera Prospera assay (Austin, TX). CAR-T persistence was measured via FLAP-EF1α.15
Literature review
English-language case reports and series describing CD19 CAR-T use in SOTRs were inclusion criteria. Google Scholar, Embase, and PubMed were queried on 8/29/22 using the search terms “PTLD” and “CAR-T”. Two independent systematic reviewers (A.P. and C.B.) screened the citations by a two-step filter approach: title and abstract screening, followed by full text review for relevant citations per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) diagram shown in Figure 2.16 Ten articles were identified for inclusion. The following parameters were extracted from all included articles: First author, publication year, PTLD type/subtype, Ann Arbor stage, International Prognostic Index, EBV status, patient age and sex, time from transplant to CAR-T, type of CAR-T product, immunosuppression management, chemotherapy administration, toxicities of CAR-T, allograft rejection history, response to CAR-T, and overall survival. Studies were included in the review if CD19 CAR-T therapy was administered to a SOTR. Categorical data were summarized as median and interquartile range (IQR). The probability of relapse among responders was estimated by the method of Kaplan and Meier. There was no competing risk of death without relapse. Median duration of response (DOR) was estimated as the time at which the probability of relapse among responders crossed the threshold of 50%.
Figure 2.
Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) flow diagram of study selection. Literature search was conducted on 8/29/22.
RESULTS
Patients
Patient characteristics are shown in Table 1. Comprehensive data parameters are described in Supplemental Table 1. The total cohort, including the UW-FHCC patient, contained 17 patients. The median patient age was 46.0 (IQR 38.5-54.0) years with 12 males (70.6%) and 5 females (29.4%). SOTRs included kidney (n=12, 70.6%), liver (n=2, 11.8%), heart (n=2, 11.8%), and pancreas after kidney (n=1, 5.9%). PTLDs included DLBCL (n=15, 88.2%) and Burkitt lymphoma (n=2, 11.8%). Most cases were Ann Arbor stage 4 (13/17, 76.5%) and EBV-negative (14/17, 82.4%). CAR-T products used included axicabtagene ciloleucel (n=11), tisagenlecleucel (n=3), liso-cel (n=1), and 2 study products (ChiCTR2000032211 and ChiCTR1800019622).
Table 1.
Characteristics of solid organ transplant recipients with post-transplant lymphoproliferative disorders treated with CAR T-cell therapy.
| Overall cohort (n, %) | ORR (n, %) | Rejection (n, %) | |||||
|---|---|---|---|---|---|---|---|
| Total * | 17 | - | 14 | 82.4% | 4 | 23.5% | |
| Age (years, median [IQR]) | 46.0 | (38.5-54.0) | 44.5 | (38.5-49.3) | 42.5 | (39.5-45.3) | |
| Sex (n, %) | Male | 12 | 70.6% | 10 | 71.4% | 3 | 75.0% |
| Female | 5 | 29.4% | 4 | 28.6% | 1 | 25.0% | |
| Allograft (n, %) | Kidney | 12 | 70.6% | 11 | 78.6% | 4 | 100.0% |
| Liver | 2 | 11.8% | 2 | 14.3% | 0 | 0.0% | |
| Heart | 2 | 11.8% | 1 | 7.1% | 0 | 0.0% | |
| Pancreas after kidney | 1 | 5.9% | 0 | 0.0% | 0 | 0.0% | |
| Transplant to CAR-T (years, median [IQR]) | 10.0 | (6.5-18.5) | 10.0 | (5.0-17.0) | 12.0 | (8.8-15.0) | |
| NA | 1 | 5.9% | 1 | 7.1% | 0 | 0.0% | |
| PTLD (n, %) | DLBCL | 15 | 88.2% | 12 | 85.7% | 3 | 75.0% |
| Non-GCB** | 4 | 26.7% | 2 | 16.7% | 0 | 0.0% | |
| GCB** | 9 | 60.0% | 8 | 66.7% | 2 | 66.7% | |
| NA** | 2 | 13.3% | 2 | 16.7% | 1 | 33.3% | |
| Burkitt lymphoma | 2 | 11.8% | 2 | 14.3% | 1 | 25.0% | |
| EBV (n, %) | Neg | 14 | 82.4% | 11 | 78.6% | 4 | 100.0% |
| Pos | 3 | 17.6% | 3 | 21.4% | 0 | 0.0% | |
| Ann Arbor Stage (n, %) | 4 | 13 | 76.5% | 12 | 85.7% | 3 | 75.0% |
| 3 | 0 | 0.0% | 0 | 0.0% | 0 | 0.0% | |
| NA | 4 | 23.5% | 2 | 14.3% | 1 | 25.0% | |
| IPI (n, %) | 4 | 5 | 29.4% | 4 | 28.6% | 1 | 25.0% |
| 3 | 5 | 29.4% | 4 | 28.6% | 1 | 25.0% | |
| 2 | 4 | 23.5% | 3 | 21.4% | 1 | 25.0% | |
| NA | 3 | 17.6% | 3 | 21.4% | 1 | 25.0% | |
| CAR-T (n, %) | Axi-cel | 11 | 64.7% | 8 | 57.1% | 1 | 25.0% |
| Tisa-cel | 3 | 17.6% | 3 | 21.4% | 2 | 50.0% | |
| Liso-cel | 1 | 5.9% | 1 | 7.1% | 0 | 0.0% | |
| ChiCTR2000032211 | 1 | 5.9% | 1 | 7.1% | 0 | 0.0% | |
| ChiCTR1800019622 | 1 | 5.9% | 1 | 7.1% | 1 | 25.0% | |
| CRS (n, %) | Any | 15 | 88.2% | 12 | 85.7% | 3 | 75.0% |
| 1 | 11 | 64.7% | 10 | 71.4% | 3 | 75.0% | |
| 2 | 3 | 17.6% | 2 | 14.3% | 0 | 0.0% | |
| 3 | 1 | 5.9% | 0 | 0.0% | 0 | 0.0% | |
| 0 | 2 | 11.8% | 2 | 14.3% | 1 | 25.0% | |
| ICANS (n, %) | Any | 7 | 41.2% | 4 | 28.6% | 1 | 25.0% |
| 1 | 1 | 5.9% | 1 | 7.1% | 0 | 0.0% | |
| 2 | 1 | 5.9% | 1 | 7.1% | 0 | 0.0% | |
| 3 | 4 | 23.5% | 2 | 14.3% | 1 | 25.0% | |
| 4 | 1 | 5.9% | 0 | 0.0% | 0 | 0.0% | |
| 0 | 10 | 58.8% | 10 | 71.4% | 3 | 75.0% | |
IQR = interquartile range, PTLD = post-transplant lymphoproliferative disorder, DLBCL = diffuse large B-cell lymphoma, GCB = germinal center B-cell-like, IPI = international prognostic index for DLBCL, EBV = Epstein-Barr virus, axi-cel = axicabtagene ciloleucel, tisa-cel = tisagenlecleucel, liso-cel = lisocabtagene maraleucel, CRS = cytokine release syndrome, ICANS = immune effector cell-associated neurotoxicity syndrome.
Represents percentage of total cases (N=18).
Represents percentage of subcategory. No comparison testing reached statistical significance by Fisher’s exact test.
Description of published works
Cases of CD19 CAR-T use in KTRs comprised the largest of all organ transplant groups (n=12). All cases in KTRs were EBV-negative monomorphic PTLD, DLBCL type except for the 2 reported by Rosler et al and De Nattes et al, which were EBV-positive and Burkitt lymphoma type, respectively. Feng et al described an investigational CAR-T product (ChiCTR1800019622) in combination with sintilimab. Among KTRs, the ORR was 91.6% (11/12), with a median DOR of 4.2 (IQR 1.0-8.1) months. Four cases of rejection occurred without progression to allograft failure. CRS and ICANS occurred in 83.3% (10/12) and 41.7% (5/12), respectively (Table 2). Most cases of CRS were grade 1 (8/10, 80%). Notable complications included severe pancytopenia, septic shock, hypogammaglobinemia, and B-cell aplasia.17–24
Table 2.
Outcomes and toxicities of CAR-T treatment for the overall cohort as well as the diffuse large B cell lymphoma and kidney transplant recipient subsets.
| Overall cohort | DLBCL | KTRs | |||||
|---|---|---|---|---|---|---|---|
| Total (n, %) * | 17 | - | 15 | 88.2% | 12 | 70.6% | |
| Best response (n, %) | OR | 14 | 82.4% | 12 | 80.0% | 11 | 91.7% |
| CR | 10 | 58.8% | 8 | 53.3% | 8 | 66.7% | |
| PR | 4 | 23.5% | 4 | 26.7% | 3 | 25.0% | |
| Ongoing** | 6 | 42.9% | 5 | 41.7% | 3 | 27.3% | |
| SD | 1 | 5.9% | 1 | 6.7% | 0 | 0.0% | |
| PD | 2 | 11.8% | 2 | 13.3% | 1 | 8.3% | |
| Median DOR (months, 95% CI) | 6.5 | (2.8-NR) | 6.5 | (2.8-NR) | 4.2 | (1.0-NR) | |
| CRS (n, %) | Any | 15 | 88.2% | 13 | 86.7% | 10 | 83.3% |
| 1 | 11 | 64.7% | 10 | 66.7% | 8 | 66.7% | |
| 2 | 3 | 17.6% | 2 | 13.3% | 1 | 8.3% | |
| 3 | 1 | 5.9% | 1 | 6.7% | 1 | 8.3% | |
| 0 | 2 | 11.8% | 2 | 13.3% | 2 | 16.7% | |
| ICANS (n, %) | Any | 7 | 41.2% | 7 | 46.7% | 5 | 41.7% |
| 1 | 1 | 5.9% | 1 | 6.7% | 1 | 8.3% | |
| 2 | 1 | 5.9% | 1 | 6.7% | 1 | 8.3% | |
| 3 | 4 | 23.5% | 4 | 26.7% | 2 | 16.7% | |
| 4 | 1 | 5.9% | 1 | 6.7% | 1 | 8.3% | |
| 0 | 10 | 58.8% | 8 | 53.3% | 7 | 58.3% | |
DLBCL = diffuse large B-cell lymphoma, KTR = kidney transplant recipient, OR = objective response, CR = complete response, SD = stable disease, PD = progressive disease, DOR = duration of response, CI = confidence interval, NR = not reached, CRS = cytokine release syndrome, ICANS = immune effector cell-associated neurotoxicity syndrome.
Represents percentage of total cases (N=18).
Represents percentage of responders.
Two liver transplant recipients (LTRs) were treated with CD19 CAR-T therapy, including a 2-year-old child with a history of neonatal biliary atresia who received an investigational product (2000032211). No cases of allograft rejection occurred. Responses were seen in both cases, of which there was 1 CR and 1 PR, and responses were ongoing at the time of reporting.21,25
Krishnamoorthy et al and Dang et al each reported a case of DLBCL PTLD in a heart transplant recipient treated with axi-cel. Allograft rejection did not occur in either case. The case reported by Dang et al involved a 17-year-old female with a history of hypoplastic left heart syndrome who developed EBV-positive monomorphic PTLD, DLBCL type, with a non-germinal center phenotype. Although she achieved a CR, her course was complicated by persistent pancytopenia.26 The case reported by Krishnamoorthy et al described a 54-year-old female with nonischemic cardiomyopathy who developed EBV-negative monomorphic PTLD, DLBCL type, non-germinal center phenotype. This patient’s post-CAR course was complicated by grade 2 CRS (fever and hypotension) and grade 3 ICANS (decreased level of consciousness) – treated with 3 doses of tocilizumab, 1 dose of siltuximab, and a steroid taper – and additionally she developed persistent lower gastrointestinal bleeding. She passed away from PD on day 44.20
Krishnamoorthy et al reported the sole case of a 20-year-old male pancreas after kidney transplant recipient treated with axi-cel for EBV-negative monomorphic PTLD, DLBCL type, germinal center phenotype. His best response was stable disease. No allograft rejection occurred. The post-CAR course was complicated by grade 1 CRS (fever), acute grade 2 ICANS (depressed level of consciousness), late grade 3 ICANS (intermittent encephalopathy), and asymptomatic pancreatitis – treated with 2 doses of tocilizumab, siltuximab, and dexamethasone – and continued deterioration. He passed away from PD on day 115.20
Cancer control outcomes
The ORR for the overall cohort was 82.4% (14/17) with 58.8% (10/17) CRs (Table 1), and those with DLBCL had an ORR of 80.0% (12/15) with 53.3% (8/15) CRs. Median DOR was 6.5 months (95% confidence interval [CI] 2.8 to not reached [NR]) for the overall cohort as well as for the DLBCL subset, and 4.2 months (95% CI 1.0 to NR) for the KTR subset (Table 2). Among all who achieved a CR, the median DOR was 7.7 months (95% CI 2.8 to NR). Among DLBCL patients who achieved a CR, the median DOR was 7.7 months (95% CI 6.5 to NR).
Of the 10 patients who achieved a CR, PTLD recurred in 50% (5/10), with a median DOR of 7.1 months (IQR 3.5-9.1). Among all responders who relapsed (8/14), median time to relapse was 1.9 months (IQR 0.9-4.8). Five patients (5/17, 29.4%) died of progressive disease (PD).
Toxicity
Most patients developed CRS (15/17, 88.2%), though most cases were grade 1 (11/15, 73.3%). ICANS occurred in a minority of patients (7/17, 41.2%). Among the overall and axi-cel cohorts, grade ≥3 ICANS occurred in 29.4% (5/17) and 36.4% (4/11).
Allograft rejection occurred in 23.5% (4/17), with 3 that were biopsy proven (Table 1). All cases of rejection occurred in KT recipients. Rejection was treated in 2 cases with high-dose steroids, and 2 cases received no specific treatment. No cases of graft failure or rejection-related mortality occurred.
DISCUSSION
CD19 CAR-T therapy is an emerging and feasible treatment option for high-risk R/R PTLD in SOTRs. However, two notable concerns with CAR-T use in the SOTR include diminished CAR-T activity associated with chronic IS, and off-target allograft injury due to CRS.
Based on our case and the available literature, CAR-T therapy offers significant anticancer activity in the SOTR population, though response durability appears to be attenuated. The ZUMA-1 trial data for DLBCL treated with axi-cel reported an 83% ORR with a 58% CR rate and a median DOR of 11.1 months. Among complete responders, the median DOR was not reached (95% CI 12.9 months – not estimable).13 In our DLBCL PTLD subset, the ORR (82.4%) and CR rate (58.8%) were comparable, though the DOR was relatively shorter (6.5 months), particularly among CRs (7.7 months). The diminished DOR in SOTRs may be related to the impact of chronic IS on CAR-T efficacy. This hypothesis is corroborated by the finding of shorter progression free survival in patients treated with a higher cumulative dose of corticosteroids post-CAR-T infusion in non-SOTR patients.27
Occurrence of CRS and ICANS in SOTRs was comparable to ZUMA-1 trial data.13 Allograft rejection occurred in 4 KTRs treated with CD19 CAR-T cells, however, no treatment-related cases of graft failure or death occurred. We recently published a systematic review involving 119 SOTRs treated with immune checkpoint inhibitors (ICIs), showing 41.2% graft rejection and 23.5% failure rates, with 24% (12/50) of deaths attributed to graft failure.28 These data suggest that autologous CAR-T therapy appears to be a less hazardous treatment than ICIs for SOTRs. The impact of allogeneic T-cell immunotherapy products on allograft function and survival is not currently known. In this regard, the phase 3 ALLELE trial (NCT03394365, ClinicalTrials.gov) is investigating the use of the allogeneic EBV-directed cytotoxic T lymphocyte product, tabelecleucel, in treating EBV-positive PTLDs.
We have provided an up-to-date systematic review and clinical interpretation of SOTRs with PTLD treated with CD19 CAR-T therapy. Yet, our study has several limitations. First, data collected from published works may be impacted by reporting bias, which potentially favors the dissemination of particularly good or bad outcomes. Second, the paucity of cases meeting our inclusion criteria greatly limited our statistical analysis, including sensitivity of comparison testing. Third, the reported case information in published works was not complete in all instances and the duration of follow-up was inconsistent. Fourth, cases involving patients treated with allogeneic and/or EBV-directed CAR-T products and patients with a history of allogeneic bone marrow transplantation were excluded to limit the heterogeneity of the cohort analyzed.
CONCLUSION
CD19-targeted CAR-T therapy offers short-term effectiveness and manageable toxicity in a limited cohort of SOTRs with PTLD. However, duration of response may be diminished in this population, possibly due to chronic immunosuppression. In view of these results, CAR-T therapy may be considered in cases of PTLD where no other therapeutic options exist. If CAR-T therapy is to be administered, based on the available literature and our experience we advise the following:
Establish a close partnership between transplant and oncology teams to provide coordinated care
Hold calcineurin inhibitors prior to leukapheresis for >21 days to enable harvesting of adequate T cells
Monitor the organ transplant frequently (ie, every 1-4 weeks) for early signs of toxicity and rejection
Limit systemic immunosuppression in the first 8-12 weeks post-CAR-T infusion to allow for greater CAR-T cell persistence
In summary, available commercial CD19 CAR-T therapies can induce meaningful responses in R/R PTLD patients, yet the treatment responses appear less durable in comparison to non-PTLD patients. CD19 CAR-T treatment in SOTRs is sufficiently well tolerated. These preliminary findings highlight the urgent need for prospective studies of CD19 CAR-T therapy, and other cellular therapies, in PTLD to optimize disease control and allograft integrity, and improve patient outcomes.
Supplementary Material
ACKNOWLEDGMENTS
This work was supported by an institutional training grant from the National Heart, Lung, and Blood Institute (T32 HL007093). We thank Drs. Alberto Mussetti and Edoardo Melilli (Catalan Institute of Oncology) for providing additional information pertaining to their case report.
COMPETING INTERESTS
A.P. has disclosed receiving support from an institutional training grant from the National Heart, Lung, and Blood Institute (T32 HL007093). J.G. has disclosed receiving research funding from Sobi, Juno Therapeutics, and Celgene; receiving consulting fees from Eusapharma, JMP, Larvol, and Multerra Bio; and serving on advisory boards for Legend Biotech and Janssen. S.T. has disclosed receiving grant/research support from AVEO Oncology, Bristol-Myers Squibb, Merck & Co., Genentech, Pfizer, Nektar Therapeutics, Exelixis, and Jounce Therapeutics; receiving consulting fees from PLS Group Services, Exelixis, Merck & Co., Bristol-Myers Squibb, and Intellisphere LLC; serving on an advisory board for Merck & Co., Exelixis, and Bristol-Myers Squibb; receiving honoraria from Natera and General Dynamics Information Technology; and serving as a consultant for Targeted Oncology. C.B. has disclosed serving as a consultant for Natera and Sandoz, and participating in research funded by Natera. E.H. has disclosed serving as a principal investigator for Neoleukin Therapeutics, ImCheck Therapeutics, Checkpoint Pharmaceuticals, and Nektar. A.H. has disclosed receiving research funding from Juno Therapeutics, and NanoString Technologies; receiving honoraria from Bristol-Myers Squibb and Novartis. C.Y. has disclosed receiving grant/research support from Pfizer, Sensei Biotherapeutics, Exicure, Incyte, Signal One, Lonza, OBI; receiving consulting fees from Twinstrands; serving on an advisory board for Merck & Co., and Eli-Lily. The remaining authors have disclosed no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors.
DATA AVAILABILITY STATEMENT
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.