SUMMARY

• 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.
• Second Primary Malignancies (SPMs) have been reported in the CARTITUDE-1, CARTITUDE-2 and CARTITUDE-4 studies.^1-9
• CARTITUDE-1 (MMY2001) was a phase 1b/2, open-label, single-arm, multicenter study that evaluated CARVYKTI in patients with relapsed/refractory multiple myeloma (RRMM) who had previously received a proteasome inhibitor (PI), an immunomodulatory drug, and an anti-cluster of differentiation 38 (CD38) antibody. The combined analysis from the phase 1b/2 portions of the CARTITUDE-1 study evaluated the safety and efficacy of CARVYKTI in 97 patients with RRMM.^1,3,4
  • At a median follow-up of 33.4 months (study closeout), a total of 26 SPMs were reported in 20 patients. Complete details are provided in Table: CARTITUDE-1: Second Primary Malignancies.⁴
    • At a median follow-up of 27.7 months, 16 patients had developed a total of 20 SPMs, all unrelated to CARVYKTI.³ Since the 27.7 month median follow-up, 4 new patients developed SPMs with 6 new cases reported.⁴
  • At a median follow-up of 61.3 months, among 97 patients, SPMs were reported in 3 additional patients, 1 each of acute myeloid leukemia (AML; onset at 2.8 years post infusion), lung adenocarcinoma, and anal squamous cell carcinoma.¹⁰ 
    • In progression-free patients (n=32) for ≥5 years, 2 SPMs were reported and both were solid tumors.¹¹ 
• CARTITUDE-2 (MMY2003) is a phase 2, multicohort, open-label study evaluating CARVYKTI in patients with multiple myeloma (MM) in various clinical settings.⁷ Janssen does not recommend the use of CARVYKTI in a manner that is inconsistent with the approved labeling.
  • Cohort A is evaluating the efficacy and safety of CARVYKTI in patients who had progressive MM after 1-3 prior lines of therapy (LOTs) and were refractory to lenalidomide.^5,8,9,12,13
    • Initial Subgroup: evaluated the efficacy and safety of CARVYKTI manufactured with the clinical trial process in 20 patients.^5,8,12,13
      • At a median follow-up of 29.9 months, SPM was reported in 1 patient (grade 3 mucoepidermoid carcinoma; not treatment related).⁵
    • Expansion Subgroup: evaluated the efficacy and safety of CARVYKTI manufactured with a commercial process in 23 patients.⁹
      • At a median follow-up of 15.6 months, SPMs were reported in 2 patients, which were not considered treatment-related per investigator assessment (basal cell carcinoma and cutaneous squamous cell carcinoma in 1 patient; myelodysplastic syndrome [MDS] in 1 patient).⁹
  • Cohort B is evaluating the efficacy and safety of CARVYKTI in 19 patients with MM who had early relapse after initial therapy with a PI and an immunomodulatory drug.⁵
    • At a median follow-up of 27.9 months, SPMs were reported in 2 patients (grade 2 prostate cancer; not treatment related and grade 4 choroid melanoma; not treatment related; n=1 each).⁵
  • Cohort D is evaluating the efficacy and safety of CARVYKTI with or without lenalidomide maintenance in 17 patients in patients who achieved less than complete response (CR) after frontline autologous stem cell transplantation (ASCT).^6,14
    • At a median follow-up of 22.4 months, SPM was reported in 1 patient (grade 3 MDS with an onset on day 353; not treatment related per investigator assessment).⁶
• CARTITUDE-4 (MMY3002) is a phase 3, randomized, open-label study evaluating the efficacy and safety of CARVYKTI versus standard care (physician’s choice of pomalidomide, bortezomib, and dexamethasone [PVd] or DARZALEX FASPRO [daratumumab and hyaluronidase], pomalidomide, and dexamethasone [DPd]) in adult patients with lenalidomide-refractory MM after 1-3 prior LOT.^2,15
  • Adverse events (AEs) were evaluated in the safety population, which included all patients who received any part of study treatment (n=208 in both the CARVYKTI and standard care arms).²
    • At a median follow-up of 15.9 months, SPMs were reported in 9 patients (4.3%) and 14 patients (6.7%) in the CARVYKTI arm and standard care arm, respectively. Complete details are provided in Table: CARTITUDE-4: Second Primary Malignancies (Median Follow-up of 15.9 Months).^2,16
    • At a median follow-up of 33.6 months, SPMs were reported in 27 patients (13%) and 24 patients (11.5%) in the CARVYKTI arm and standard care arm, respectively. Complete details are provided in Table: CARTITUDE-4: Second Primary Malignancies (Median Follow-up of 33.6 Months).¹⁵
  • Subgroup Analysis in Patients with Functional High-Risk MM: efficacy and safety outcomes were evaluated in patients who received 1 prior LOT, including the subset of patients with functionally high-risk MM in the CARTITUDE-4 study.¹⁷
    • At a median follow-up of 15.9 months, SPMs occurred in 3 patients in the CARVYKTI arm, and in 2 patients in the standard care arm among those with 1 prior LOT; all occurred in patients with functionally high-risk MM (one patient in the CARVYKTI arm had peripheral T-cell lymphoma [TCL] unspecified).¹⁷
  • A case series provided details of a 51-year-old male patient and a 54-year-old female patient enrolled in the CARTITUDE-4 study who developed a chimeric antigen receptor-positive (CAR+) peripheral T-cell lymphoma not otherwise specified [PTCL-NOS] after CARVYKTI infusion.¹⁸
• Other relevant literature has been identified in addition to the data summarized above and is listed in the References section for your information.¹⁹ 

PRODUCT LABELING

• CARVYKTI (ciltacabtagene autoleucel) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/CARVYKTI-pi.pdf.
• DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX+Faspro-pi.pdf.

clinical data - Cartitude-1 - Phase 1B/2 STUDY

CARTITUDE-1 (MMY2001; clinicaltrials.gov identifier: NCT03548207) was a phase 1b/2 open-label, single-arm, multicenter study that evaluated the safety and efficacy of CARVYKTI in patients with RRMM who had previously received a PI, an immunomodulatory drug, and an anti-CD38 antibody. The combined analysis from the phase 1b/2 portions of the CARTITUDE-1 study evaluated the safety and efficacy of CARVYKTI in 97 patients with RRMM.^1,3,4

Study Design/Methods

• The study design is presented in the Figure: CARTITUDE-1 Study Design.

Results

Treatment Disposition, Patient Demographics, and Disease/Treatment Characteristics

• Overall, of the 113 patients enrolled/apheresed, 101 patients were lymphodepleted and 97 patients were treated with CARVYKTI in the combined phase 1b/2 study.³
• Prior to lymphodepletion, a total of 12 patients discontinued (progressive disease [PD], n=2; withdrawal by subject, n=2; deaths, n=8). Prior to CARVYKTI infusion, 3 patients withdrew from treatment, and 1 patient died.³
• Patients received a median of 6 prior LOTs, 88% of patients were triplerefractory, 42% of patients were penta-refractory, and 99% of patients were refractory to the last LOT.^3,4

Safety - Adverse Events - Second Primary Malignancies

• At a median follow-up of 33.4 months (range, 1.5-4.2; study closeout), a total of 26 SPMs were reported in 20 patients. Complete details are provided in Table: CARTITUDE-1: Second Primary Malignancies.⁴
  • At a median follow-up of 27.7 months, 16 patients had developed a total of 20 SPMs, all unrelated to CARVYKTI.³
    • Hematologic malignancies occurred in 9 patients; 1 low-grade B-cell lymphoma, 6 MDS (1 case was fatal), 3 fatal acute myelogenous leukemia (AML; 1 patient had both MDS and fatal AML).³
    • A total of 6 non-melanoma skin cancers occurred; squamous cell carcinoma occurred in 4 patients (basal cell carcinoma also occurred in 1 of the patients) and 1 patient had basal cell carcinoma that was present before CARVYKTI infusion.^3,22
    • Malignant melanoma, adenocarcinoma, and myxofibrosarcoma occurred in 1 patient each. Prostate cancer occurred in 1 patient (patient also had squamous cell carcinoma and AML reported above).³
  • Since the 27.7 month median follow-up, 4 new patients developed SPMs, with 6 new cases reported including basal cell carcinoma (n=2) and 1 case each of MDS, B-cell lymphoma, melanoma, and prostate cancer.⁴
  • At a median follow-up of 61.3 months, among 97 patients, SPMs were reported in 3 additional patients, 1 each of AML (onset at 2.8 years post infusion), lung adenocarcinoma, and anal squamous cell carcinoma.¹⁰
    • In progression-free patients (n=32) for ≥5 years, 2 SPMs were reported and both were solid tumors.¹¹

clinical data - CARTITUDE-2 - PHASE 2 STUDY

CARTITUDE-2 (MMY2003; clinicaltrials.gov identifier: NCT04133636) is an ongoing, phase 2, open-label, multicohort, single-arm, multicenter study evaluating the efficacy and safety of CARVYKTI in patients with MM in various clinical settings.⁷

• Cohort A is evaluating the efficacy and safety of CARVYKTI in patients who had progressive MM after 1-3 prior LOTs and were refractory to lenalidomide.^5,8,9,12,13
  • Initial Subgroup: evaluated the efficacy and safety of CARVYKTI manufactured with the clinical trial process in 20 patients.^5,8,12,13
  • Expansion Subgroup: evaluated the efficacy and safety of CARVYKTI manufactured with a commercial process in 23 patients.⁹
• Cohort B is evaluating the efficacy and safety of CARVYKTI in 19 patients with MM who had early relapse after initial therapy with a PI and an immunomodulatory drug.⁵
  • Early relapse was defined as progression within 12 months after ASCT or from start of anti-MM therapy for patients who have not had an ASCT.⁵
• Cohort D is evaluating the efficacy and safety of CARVYKTI with or without lenalidomide maintenance in 17 patients who achieved <CR after frontline ASCT.⁶

Study Design/Methods

• Key eligibility criteria for Cohort A: adult patients with progressive MM after 13 prior LOTs, including a PI and an immunomodulatory drug, who were lenalidomide refractory, had no prior exposure to B-cell maturation antigen (BCMA)-targeting agents or CAR T-cell therapy directed at any target, and had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of ≤1.⁷
• Key eligibility criteria for Cohort B: adult patients who received 1 prior LOT including a PI and an immunomodulatory agent, had disease progression per International Myeloma Working Group (IMWG) criteria ≤12 months after ASCT or ≤12 months from the start of anti-MM therapy (for patients who did not receive ASCT), had no prior exposure to BCMAtargeting agents or CAR T-cell therapy directed at any target, and had an ECOG PS of ≤1.⁷
• Key eligibility criteria for Cohort D: adult patients with a history of 4-8 cycles of initial therapy, including induction, high-dose therapy, and ASCT with or without consolidation; overall best response <CR; no prior exposure to BCMA-targeting agents and CAR T-cell therapy directed at any target; and ECOG PS ≤1.^6,14
• Dosing: patients received a single infusion of CARVYKTI at a target dose of 0.75x10⁶ viable CAR+ T-cells/kg (target range, 0.5-1.0x10⁶) 5-7 days after the start of lymphodepletion/conditioning regimen (cyclophosphamide 300 mg/m² and fludarabine 30 mg/m² daily for 3 days on days -5 to -3).^5-9,14,23
• Primary endpoint: minimal residual disease (MRD) negativity at the 10^-5 sensitivity level as assessed by next-generation sequencing (clonoSEQ^®) or next-generation flow.^5-9,14,23
• Key secondary endpoints: overall response rate per IMWG criteria, duration of response, time to response, time and duration of MRD negativity, and incidence and severity of AEs.^5-9,14,23

Results

Treatment Disposition, Patient Demographics, and Disease/Treatment Characteristics

Cohort A

• Initial Subgroup: Overall, 20 patients were enrolled, lymphodepleted, and treated with CARVYKTI manufactured with the clinical trial process.^5,8,12,13
  • Patients received a median of 2 prior LOTs (range, 1-3); 95% of patients were refractory to their last LOT.⁵
• Expansion Subgroup: Overall, 24 patients were enrolled and 23 patients were treated with CARVYKTI manufactured with a commercial process.⁹
  • Patients received a median of 3 prior LOTs (range, 1-3); 95.7% of patients were refractory to their last LOT.⁹

Cohort B

• Overall, 19 patients were lymphodepleted and treated with CARVYKTI in Cohort B of the CARTITUDE-2 study.²³
• Patients received a median of 1 prior LOT (range, 1-1); 78.9% of patients were refractory to their last LOT.^5,23

Cohort D

• Overall, 17 patients were treated with CARVYKTI in Cohort D of the CARTITUDE-2 study.⁶
• In total, all 17 patients had prior ASCT and were previously exposed to PI and immunomodulatory drug; 17.6% of patients had received prior anti-CD38 monoclonal antibody therapy.⁶

Safety - Adverse Events - Second Primary Malignancies - Cohort A

• Initial Subgroup: At a median follow-up of 29.9 months (range, 3.3-35.6), SPM was reported in 1 patient (grade 3 mucoepidermoid carcinoma; not treatment related).⁵
• Expansion Subgroup: At a median follow-up of 15.6 months (range, 1.0-29.2), SPMs were reported in 2 patients, which were not considered treatment-related per investigator assessment.⁹
  • Basal cell carcinoma and cutaneous squamous cell carcinoma were observed in 1 patient.⁹
  • On day 842 after CARVYKTI infusion, one patient was diagnosed with MDS, which later transformed to acute myeloid leukemia.⁹

Safety - Adverse Events - Second Primary Malignancies - Cohort B

• At a median follow-up of 27.9 months (range, 5.2-32.1), SPMs were reported in 2 patients (grade 2 prostate cancer; not treatment related and grade 4 choroid melanoma; not treatment related; n=1 each).⁵

Safety - Adverse Events - Second Primary Malignancies - Cohort D

• At a median follow-up of 22.4 months (range, 4.7-39.3), SPM was reported in 1 patient (grade 3 MDS with an onset on day 353; not treatment related per investigator assessment).⁶

clinical data - CARTITUDE-4 - PHASE 3 STUDY

CARTITUDE-4 (MMY3002; clinicaltrials.gov identifier: NCT04181827) is an ongoing, phase 3, randomized, open-label study evaluating the efficacy and safety of CARVYKTI versus standard care (physician's choice of PVd or DPd) in adult patients with lenalidomide-refractory MM after 1-3 prior LOTs.²

Study Design/Methods

• The study design is shown in Figure: CARTITUDE-4 Study Design.

Results

Treatment Disposition, Patient Demographics, and Disease/Treatment Characteristics

• Overall, 419 patients were randomized to receive CARVYKTI (n=208) or standard care (n=211; DPd [n=183] or PVd [n=28]).²
  • All 208 patients randomized to the CARVYKTI arm received bridging therapy with either DPd (n=182) or PVd (n=26). A total of 176 patients (84.6%) received CARVYKTI as study treatment (as-treated population).²
    • Prior to receipt of CARVYKTI, 32 patients discontinued study treatment mainly due to disease progression (n=30) or death (n=2) during bridging therapy or lymphodepletion. Of these, 20 patients received subsequent therapy with CARVYKTI.²
  • A total of 208 patients (98.6%) were dosed with standard care.²
    • Treatment discontinuation was reported in 131 standard care patients (63.0%), mostly due to disease progression (56.3%).²
• High-risk cytogenetics were present in 59.4% of CARVYKTI patients and 62.9% of standard care patients. The median prior LOT in both the CARVYKTI and standard care arms were 2 (range, 1-3).^2,25

Safety - Adverse Events - Second Primary Malignancies

• AEs were evaluated in the safety population which included all patients who received any part of study treatment (n=208 in both the CARVYKTI and standard care arms).²

Median Follow-up of 15.9 Months

• At the data cut-off date of November 1, 2022, 143 CARVYKTI patients were ongoing in the post-treatment phase and 77 patients were ongoing on standard care therapy.²
• At a median follow-up of 15.9 months (range, 0.1-27.3), SPMs were reported in 9 patients (4.3%) and 14 patients (6.7%) in the CARVYKTI arm and standard care arm, respectively. Complete details are provided in Table: CARTITUDE-4: Second Primary Malignancies (Median Follow-up of 15.9 Months).¹⁶

Median Follow-up of 33.6 Months

• At the data cut-off date of May 1, 2024, 117 CARVYKTI patients were ongoing in the post-treatment phase and 43 patients were ongoing on standard care therapy.¹⁵
• At a median follow-up of 33.6 months (range, 0.1-45.0), SPMs were reported in 27 patients (13%) and 24 patients (11.5%) in the CARVYKTI arm and standard care arm, respectively. Complete details are provided in Table: CARTITUDE-4: Second Primary Malignancies (Median Follow-up of 33.6 Months).¹⁵

CARTITUDE-4 Subgroup Analysis in Patients with Functional High-Risk MM

• Efficacy and safety outcomes were evaluated in patients who received 1 prior LOT, including the subset of patients with functionally high-risk MM, in the CARTITUDE-4 study.¹⁷

Results

Treatment Disposition, Patient Demographics, and Disease/Treatment Characteristics

• A total of 136 patients received 1 prior LOT in the CARTITUDE-4 study.¹⁷
  • In the CARVYKTI arm, 68 patients underwent apheresis/bridging therapy; 40 patients had functionally high-risk MM. Of the 68 patients, 60 patients received CARVYKTI as study treatment; 35 patients had functionally high-risk MM.¹⁷
  • A total of 68 patients received standard care; 39 of these patients had functionally high-risk MM.¹⁷
  • Functionally high-risk MM defined as PD ≤18 months after receiving ASCT or the start of initial frontline therapy in patients with no ASCT.¹⁷

Safety - Adverse Events - Second Primary Malignancies

• At a median follow-up of 15.9 months (range, 0.1-28.3), SPMs occurred in 3 patients in the CARVYKTI arm, and in 2 patients in the standard care arm among those with 1 prior LOT; all occurred in patients with functionally high-risk MM (one patient in the CARVYKTI arm had peripheral TCL unspecified).¹⁷

clinical data - Case Series: CAR+ TCL post CARVYKTI in CARTITUDE-4

A case series provided details of a 51-year-old male patient and a 54-year-old female patient enrolled in the CARTITUDE-4 study who developed a CAR+ PTCL-NOS after CARVYKTI infusion.¹⁸

Methods

• Diagnostic and staging workups involved biopsy analyses and 18-F-fluorodeoxyglucose-positron emission tomography (FDG-PET). Details of the analysis conducted for each patient are provided in Table: Case Series: Summary of Assays.²⁶ 

Results

Patient 1:

• A 51-year-old male patient with MM (diagnosed in December 2019) and a high-risk cytogenetic profile (del[17p] and gain[1q]) was enrolled in the CARTITUDE-4 study in November 2021.¹⁸
  • The patient received bortezomib, cyclophosphamide, and dexamethasone for 6 months, followed by high-dose melphalan with autologous stem-cell transplantation and lenalidomide maintenance for 1 year. After apheresis, the patient had 2 cycles of DARZALEX, pomalidomide, and dexamethasone (DPd) as bridging therapy, followed by lymphodepletion with fludarabine and cyclophosphamide before a single CARVYKTI infusion in February 2022.
  • On day 14, CAR+ T-cells peaked in the blood at 77 cells/mm³.
  • CAR+ T-cells in the blood decreased to 3 cells/mm³ by day 92 post infusion. The patient achieved a stringent CR and MRD negativity at a sensitivity of 1.0 x 10^-6. This response was maintained for >2 years after CARVYKTI infusion (last follow-up visit, July 2024).
  • Post CARVYKTI infusion, the patient had elevated serum cytokine levels but did not develop cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS).
  • On day 31, the patient developed coronavirus disease 2019 (COVID-19), and the symptoms resolved 12 days later with sotrovimab treatment. During and after COVID-19, the patient had elevated serum cytokine levels (interferon-γ, interleukin-6, and interleukin-10).
  • On day 88, the interleukin-7 level peaked again.
  • At 5 months after infusion, the patient developed a rapidly growing erythematous naso-facial plaque. A biopsy sample of the lesion showed an infiltrate of atypical T-cells positive for CD2 and CD3 but negative for CD4, CD8, CD7, CD56, ALK, Epstein-Barr virus-encoded RNA (EBER), terminal deoxynucleotidyl transferase (TdT), CD30, and cytotoxic T-cell markers (including granzyme B). FDG-PET revealed bilateral FDG-avid cervical lymphadenopathy. Biopsy of this tissue showed a T-cell infiltrate similar to that observed in the naso-facial lesion biopsy. Initially, the lesion was classified as PTCL-NOS according to current diagnostic criteria. Quantitative polymerase chain reaction revealed that the LNB sample contained 0.8 copies of lentiviral DNA per cell while in situ hybridization (ISH)/immunohistochemistry (IHC) and flow cytometry revealed that 90%-100% of the cells were CAR+.
  • On day 162, the CAR+ T-cells were double-negative for both CD4 and CD8 and re-expanded in the blood at 378 cells/mm³, independent of soluble BCMA (sBCMA) levels being undetectable from day 89 onwards.
  • Replication-competent lentivirus was not detected in the blood at baseline and 3 and 6 months after infusion. A monoclonal T-cell receptor (TCR) β-chain sequence accounted for 122,362 of 134,205 (91%) of all T-cells in the LNB. An analysis of the drug product (before infusion) showed the same TCR sequence at a low frequency (approximately 0.0002%).
  • CAR integration site analysis of DNA extracted from the LNB revealed a predominant integration into the 3′ untranslated region (UTR) of PBX2 (19,200 of 21,073 [91%] of total reads).
  • Targeted DNA sequencing of the initial skin biopsy and whole exome sequencing of the LNB both detected a missense mutation in TET2 (H1416R; variant allele frequency [VAF], 39% and 43% respectively). The TET2 variant was not detected by targeted sequencing (VAF, 0.5%) in bone marrow aspirate DNA at trial entry but was detected by TwinStrand duplex sequencing in leukapheresis samples from 2 years before CAR T-cell exposure (VAF, 0.01%) and in nontransduced T-cells (VAF, 0.01%) before CARVYKTI manufacturing. The variant was not detected in control samples. The TET2 H1416R variant increased in VAF from day 112 to day 162, with an increase of similar magnitude as in the malignant clone during the same period.
  • Whole genome sequencing of LNB samples showed a predominantly diploid tumor genome with an estimated tumor mutational burden of 1.26 mutations/million bases and no dominant mutational signature. A germline heterozygous JAK3 variant (V722I) and somatic variants, including a nonsense PTPRB variant (W2059*), a focal duplication involving the 5′ UTR to intron 16 of NFKB2, and a noncoding TET2 splice variant (c.−193+1G→C; VAF, 47%), were detected.
  • The patient was treated with cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone (CHOEP) on a 21-day schedule and achieved a metabolic CR, with a clinical significant reduction of circulating CAR+ T-cells. Relapse was reported after treatment was stopped and this coincided with a second occurrence of COVID-19. Subsequent treatment included gemcitabine, dexamethasone, cisplatin, and alemtuzumab, followed by consolidation with fludarabine-melphalan and allogeneic stem cell transplant. Within 3 months, the patient experienced relapse.
  • The patient received tofacitinib, a JAK3 inhibitor and showed localized progression within a month. He then received local radiotherapy (50 Gy in 25 fractions from August 2023 through September 2023), weekly pegylated interferon alfa-2a (August 2023 through March 2024), and weekly extracorporeal photopheresis (November 2023 through April 2024). CAR+ T-cell counts stayed below the quantification limit in blood since June 2023 and bone marrow since January 2024, with no signs of clinical or radiologic disease. Photopheresis was discontinued in April 2024.

Patient 2:

• A 54-year-old female patient with immunoglobulin G kappa MM (diagnosed in November 2019) and a high-risk cytogenetic profile (t[4;14] and gain[1q]) was enrolled in the CARTITUDE-4 study in October 2021.¹⁸
  • The patient received frontline therapy with bortezomib, lenalidomide, and dexamethasone for 6 months, followed by high-dose melphalan with autologous stem-cell transplantation and lenalidomide maintenance for 1 year. After apheresis, the patient had 2 cycles of DPd as bridging therapy, followed by lymphodepletion with fludarabine and cyclophosphamide before a single CARVYKTI infusion in January 2022.
  • On day 21, CAR+ T-cells in the blood were 29 cells/mm³.
  • On day 42, CAR+ T-cells in the blood decreased to 8 cells/mm³.
  • The patient did not develop CRS or ICANS.
  • On day 364 after infusion, the patient achieved a stringent CR and MRD negativity at a sensitivity of 1.0 x 10^-5. This response was maintained for >2 years after CARVYKTI infusion (last follow-up visit, June 2024).
  • On day 84, the patient developed parvovirus B19 infection with a high viral load (1,341,375 copies/mL), which was treated with high-dose intravenous (IV) immune globulin. The viral load gradually decreased and cleared by 8 months after CARVYKTI infusion. During the infection, CAR T-cell counts increased from 38 cells/mm³ on day 84 post infusion to 457 cells/mm³ on day 196 post infusion and did not return to preinfection levels.
  • The expanded CAR+ T-cells were primarily CD4-CD8 double-negative and EBER-negative. Replication competent lentivirus was not detectable in the blood at 6 and 12 months after infusion.
  • At 16 months after infusion, the patient developed several skin masses on the face, torso, and breasts, which showed spontaneous regression and recurrence in different locations during the following months without treatment. FDG-PET revealed progressive diffuse supradiaphragmatic and infradiaphragmatic lesions, affecting the skin, lymph nodes, breasts, lungs, and bones. ISH/IHC revealed that the LNB cells were predominantly CAR+.
  • The CAR+ T-cells rapidly increased from day 702 and peaked at 15,883 cells/mm³ on day 728. The circulating CAR+ T-cells were CD4-CD8 double-negative and pleiomorphic with small to medium size basophilic cytoplasm.
  • TCR β sequencing in the peripheral blood revealed a monoclonal sequence making up 67% of the total sequences identified. This dominant sequence was not detectable in the first-line autograft apheresis product.
  • CAR integration site analysis of the LNB sample (day 743) and circulating CAR T-cells (day 758) revealed a predominant integration into intron 1 of one copy of the tumor suppressor gene ARID1A (NM_006015.6).
  • Targeted sequencing identified a TET2 variant (Y1902H) and a deletion involving the TET2 locus, consistent with biallelic alteration and clonality. The TET2 Y1902H variant was also detected by targeted high-throughput sequencing from leukapheresis samples collected during autologous stem cell transplantation 22 months before CAR T-cell exposure (VAF, 0.4%).
  • A skin biopsy showed pleiomorphic lymphocytes with blastoid morphologic features in the dermis and hypodermis, and CD4-CD8 double-negative T lymphocytes (CD3+, CD2+, CD5+, CD7+/-, and CD99+). The tumor samples tested positive for T-cell-restricted intracellular antigen and negative for EBER, perforin, CD56, TdT, CD34, and CD1a, with a high Ki-67 proliferation index of 90%. A similar T-cell infiltrate with identical immunophenotype and proliferation index was detected in inguinal lymph nodes and initially classified as PTCL-NOS in accordance with current diagnostic criteria.
  • The patient received chemotherapy (CHOEP) and underwent haploidentical allogeneic stem cell transplantation.
  • At the last follow-up visit in July 2024, flow cytometry confirmed metabolic CR with no detectable circulating CAR+ T-cells (sensitivity threshold, 1.0 x 10^-4).

LITERATURE SEARCH

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File databases (and/or other resources, including internal/external databases) was conducted on 24 June 2025.