Introduction
Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment landscape for hematologic malignancies, offering durable remissions in patients with refractory disease. CAR T-cell therapy indications continue to expand; to date, there are 6 US Food and Drug Administration-approved therapies, including 2 B-cell maturation antigen-directed CAR T-cell therapies, idecabtagene vicleucel and ciltacabtagene autoleucel, for patients with relapsed or refractory multiple myeloma (MM). However, like most CAR T-cell trials, patients with severe kidney impairment (estimated glomerular filtration rate <40 mL/min/1.73 m 2 ) or those treated with dialysis were excluded from participation.
There are limited data on the safety and efficacy of CAR T-cell therapies in advanced chronic kidney disease, let alone patients with dialysis dependence. Concerns regarding CAR T-cell therapy in patients with advanced chronic kidney disease include potential for excess toxicity from lymphodepleting regimens such as fludarabine and potential for higher incidence/grade of toxicities from CAR T-cell therapy such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome, and immune effector cell-associated hemophagocytic-like syndrome. A series of 2 cases reported successful administration of CAR T-cell therapy for relapsed/refractory diffuse large B-cell lymphoma, with a modified lymphodepletion regimen and dialysis schedule, with both patients achieving a complete response. 1 Another single-institution retrospective study evaluated the outcomes of patients with decreased kidney function receiving CAR T-cell therapy for refractory/relapsed diffuse large B-cell lymphoma. 2 This included 2 dialysis-dependent patients who received tisagenlecleucel, demonstrating the safety and feasibility of administering CAR T-cell therapy in patients with kidney failure. Specific case series on patients with MM receiving CAR T-cell therapy are lacking. Here, we present a 5-case series of dialysis-dependent patients who successfully underwent treatment with ciltacabtagene autoleucel therapy.
Case Descriptions
Case 1
A 53-year-old woman with a history of heart failure with reduced ejection fraction (34%), deep vein thrombosis, and type II diabetes was diagnosed with lambda light chain plasmablastic myeloma with cytogenetic abnormalities t(4;14) and 1q amplification during a hospitalization for acute kidney injury ultimately requiring dialysis. Her chronic kidney disease had progressed rapidly over the year before diagnosis of myeloma from a baseline creatinine of 0.72 mg/dL to 10.15 mg/dL and was attributed to myeloma. She had an initial complete response to daratumumab, carfilzomib, lenalidomide, and dexamethasone (Dara-KRd) and autologous stem cell transplant (ASCT) but relapsed with extramedullary disease within 60 days of ASCT, followed by poor responses to daratumumab, lenalidomide, pomalidomide, and dexamethasone (Dara-KPd) and cyclophosphamide, bortezomib, and dexamethasone (CyBorD). Approximately 2.5 years from diagnosis, she presented for CAR T-cell therapy. Following T-cell harvest, she received 2 cycles of high-dose cyclophosphamide (2,000 mg/m 2 2 months prior and 1,500 mg/m 2 1 month before CAR T-cell infusion) for disease control along with focal radiation therapy for extramedullary disease of the right lower extremity while waiting to undergo CAR T-cell therapy. At the time of CAR T-cell therapy, the patient was undergoing hemodialysis (HD) 3 times weekly via right internal jugular vein catheter.
From days −5 to −3, the patient received lymphodepletion therapy with fludarabine at 20 mg/m 2 (dose reduced from 30 mg/m 2 ) followed by cyclophosphamide at 300 mg/m 2 . She received HD in the morning before initiating lymphodepletion therapy (day −5) and then 12 hours after each lymphodepletion session; see Table 1 for dialysis details. On day 0, the absolute lymphocyte count was 0.02 × 10 3 /μL. She received ciltacabtagene autoleucel (0.6 × 10 6 CAR+ T-cells/kg) and HD that evening to resume her Monday, Wednesday, Friday schedule, which she continued until day +12. Her course was complicated by CRS grade 2 (temperature ≥38 °C and hypotension), immune effector cell-associated neurotoxicity syndrome grade 2 (immune effector cell-associated encephalopathy score 6/10), and grade 2 immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS), all of which resolved following tocilizumab, siltuximab, high-dose corticosteroids, and anakinra. Furthermore, she had anemia and thrombocytopenia requiring daily platelet transfusions and eltrombopag and ultimately received a stem cell rescue at day +65 due to prolonged myelosuppression. Table 1 Dialysis Prescription of the 5 Patients Receiving CAR T-Cell Therapy Case LD Regimen Days Dialysis Days Timing Post-LD Regimen Dialysis Modality/Duration Dialysis Details 1 Day −5, −4, −3 Day −4, −3, −2 12 h after each LD session HD 3 h for each session BFR 300-350 mL/min DFR 600 mL/min UF: Day −4 = 0.5 L, days −3 and −2 = 2 L each day 2 Day −5, −4, −3 Day −4, −3, −2 12 h after each LD session HD 3 h for each session BFR 400 mL/min DFR 800 mL/min UF: Day −4 = 1.5 L, day −3 = 1.2 L, and day −2 = 2 L 3 Patient was on peritoneal dialysis; dialysis details are described within the case description 4 Day −5, −4, −3 Day −4, −3, −2 12 h after each LD session HD 3 h for each session BFR 350 mL/min DFR 600 mL/min UF: Day −4 = 2.5 L, day −3 = 2.6 L, and day −2 = 3 L 5 Day −6, −5, −3 Day −5, −4, −2 12 h after each LD session HD 3 h for each session BFR 300-350 mL/min DFR 600 mL/min UF: Day −5 = 1 L, day −4 = 1.2 L, and day −2 = 1.5L Abbreviations: BFR, blood flow rate; DFR, dialysis flow rate; HD, hemodialysis; LD, lymphodepleting; UF, ultrafiltration.
Table 1
Dialysis Prescription of the 5 Patients Receiving CAR T-Cell Therapy
Abbreviations: BFR, blood flow rate; DFR, dialysis flow rate; HD, hemodialysis; LD, lymphodepleting; UF, ultrafiltration.
| Case | LD Regimen Days | Dialysis Days | Timing Post-LD Regimen | Dialysis Modality/Duration | Dialysis Details | ||
| 1 | Day −5, −4, −3 | Day −4, −3, −2 | 12 h after each LD session | HD 3 h for each session | BFR 300-350 mL/min | DFR 600 mL/min | UF: Day −4 = 0.5 L, days −3 and −2 = 2 L each day |
| 2 | Day −5, −4, −3 | Day −4, −3, −2 | 12 h after each LD session | HD 3 h for each session | BFR 400 mL/min | DFR 800 mL/min | UF: Day −4 = 1.5 L, day −3 = 1.2 L, and day −2 = 2 L |
| 3 | Patient was on peritoneal dialysis; dialysis details are described within the case description | ||||||
| 4 | Day −5, −4, −3 | Day −4, −3, −2 | 12 h after each LD session | HD 3 h for each session | BFR 350 mL/min | DFR 600 mL/min | UF: Day −4 = 2.5 L, day −3 = 2.6 L, and day −2 = 3 L |
| 5 | Day −6, −5, −3 | Day −5, −4, −2 | 12 h after each LD session | HD 3 h for each session | BFR 300-350 mL/min | DFR 600 mL/min | UF: Day −5 = 1 L, day −4 = 1.2 L, and day −2 = 1.5L |
On day +13, the patient was dialyzed emergently for acute hypoxia requiring 6-8 L nasal cannula in the setting of receiving multiple blood products and high-dose steroids. She required daily ultrafiltration for the next 4 days (until day +17, with 7 L removed) and was subsequently transitioned back to her 3 days a week schedule. By day +20, the patient’s kappa/lambda ratio had improved. She was discharged on day +25. She had cranial nerve VII palsy on day +45 that lasted 1 week and resolved on its own. Unfortunately, positron emission tomography scan on day +60 showed a mixed response, with near-complete resolution of some lesions but persistent extramedullary and osseous disease in others. She was re-admitted to the hospital and subsequently underwent therapy with talquetamab (which transiently normalized her kappa/lambda ratio) before progression, followed by elranatamab (without response), and ultimately died on day +293 after a long hospitalization for mixed shock and multiorgan failure.
Case 2
A 79-year-old man with a history of type 2 diabetes mellitus and hypertension was diagnosed with 17p deleted lambda light chain MM after presenting with acute kidney failure, requiring initiation of dialysis 5 years before proceeding with CAR T-cell therapy. The patient had previously undergone treatment with CyBorD and pomalidomide, bortezomib, and dexamethasone (PVd) and ASCT followed by daratumumab, carfilzomib, and dexamethasone (Dara-Kd) maintenance. He had remained in remission for about 1.5 years before meeting progression criteria. At the time of CAR T-cell therapy, the patient was undergoing maintenance HD 3 times weekly via left upper extremity arteriovenous fistula.
From days −5 to −3, the patient was treated with fludarabine at 20 mg/m 2 followed by cyclophosphamide 300 mg/m 2 . He underwent dialysis 12 hours after each lymphodepletion regimen; see Table 1 for dialysis details. On day 0, the absolute lymphocyte count was 0.01 × 10 3 /μL. He received ciltacabtagene autoleucel (0.7 × 10 6 CAR+ T-cells/kg). His course was complicated by neutropenic fever on day +6; no clear infectious source was identified, and he was treated for CRS grade 1 (temperature ≥38 °C). He received acetaminophen and tocilizumab once for a persistent fever and subsequently received dexamethasone with a 4-day taper. During the hospitalization, he also had anemia and thrombocytopenia but did not require any transfusions. The patient was discharged on day +14.
After discharge, he experienced an episode of cranial nerve VII palsy on day +33 and was treated with a 5-day course of dexamethasone with improvement. A bone marrow biopsy at day +60 showed no evidence of disease, including measurable residual disease negativity by next-generation sequencing (10 −6 ), and light chains remained suppressed, consistent with a stringent complete response. He had persistent secondary hypogammaglobulinemia and regularly received intravenous immunoglobulin. His day +390 bone marrow biopsy also showed minimal residual disease negativity, and his response remains excellent. He continues to receive HD 3 times weekly as an outpatient.
Case 3
A 72-year-old woman with a history of type 2 diabetes mellitus was diagnosed with IgA lambda myeloma with plasmablastic features and 1q amplification 3.5 years before CAR T-cell therapy. Her disease was complicated by progressive worsening kidney disease resulting in initiation of dialysis 1 year after diagnosis. Prior treatments included bortezomib, lenalidomide, and dexamethasone (VRd) with early relapse and was followed by salvage ASCT and then daratumumab, lenalidomide, and dexamethasone (Dara-Rd) as post-ASCT therapy due to pomalidomide intolerance. Subsequently, she was treated with selinexor, carfilzomib, and dexamethasone, with a short response, and Dara-CyBorD. After T-cell apheresis, she received 2 doses of bendamustine 70 mg/m 2 as bridging therapy, with a partial response.
During the 6 months before admission for treatment, the patient had been undergoing daily peritoneal dialysis (PD) and was still making urine (about 800-2,100 mL/d were recorded in the first few days of hospitalization). Bendamustine was used for lymphodepletion, partly due to a fludarabine shortage. On days −6 and −5, she received bendamustine 70 mg/m 2 (dose reduced from 90 mg/m 2 ). On day −6, she started PD 4 hours after the dose of bendamustine, and on day −5 she started PD 7 hours after the dose of bendamustine. Both sessions ran for 8 hours overnight with ultrafiltration 265 mL and 55 mL, respectively as she continued to maintain adequate urine output.
The patient developed fever and hypotension to 84/52 mm Hg on day −5, for which the differential was a recent (2 weeks prior) rhinovirus infection, sinusitis (diagnosed by computed tomographic imaging as part of her infectious workup), other infectious process, or a result of the lymphodepletion chemotherapy. Peritonitis was ruled out. She was treated with cefdinir. On day −4, she had recurrent fever that was treated with acetaminophen and experienced an episode of rigors, hypotension, and wheezing that occurred during an intravenous immunoglobulin infusion (which was subsequently stopped due to concern for infusion reaction). She was given a few small boluses of fluid, 1 dose of dexamethasone, broader-coverage antibiotics, and her nightly PD was run with minimal ultrafiltration. By day −2, her examination and symptoms had improved.
On day 0, the absolute lymphocyte count was 0.02 × 10 3 /μL. The patient received ciltacabtagene autoleucel (0.7 × 10 6 CAR+ T-cells/kg). She experienced fevers on day 0 consistent with CRS grade 1. She continued to receive nightly PD until day +5. On day +6, her PD length was reduced to 6 hours with more frequent exchanges, and she began receiving PD every other night until day +8, when her creatinine, electrolytes, and urine output were stable enough that dialysis was held, and she was started on a diuretic and oral bicarbonate therapy. The reason for kidney recovery was unclear but possibly a result of her treatment. Her 24-hour urinary creatinine clearance and cystatin C were consistent with chronic kidney disease stage IV. The patient was discharged on day +12 off dialysis.
As an outpatient, she was initially followed at our institution and then transitioned back to her home institution. She continued to maintain her kidney function and was able to have her PD catheter removed. Her day +62 positron emission tomography/computed tomography and bone marrow biopsy around this time showed no evidence of myeloma (stringent complete response), but at 4 months out from CAR T therapy, she was found to have progression of disease on a repeat positron emission tomography scan, with numerous osseous and extramedullary lesions. She received salvage bendamustine therapy with minimal response, followed by no response to talquetamab; her disease was controlled briefly again with salvage bendamustine therapy, but after undergoing 2 cycles, the patient elected to stop treatment and enroll in hospice. She died 9 months (day +274) after CAR T-cell therapy, having remained off dialysis from day +12.
Case 4
A 61-year-old woman with a history of hypertension was diagnosed with lambda light chain myeloma (1q amplification) 6 years before CAR T-cell therapy. Four years prior, she became dialysis-dependent. Her prior treatments included VRd and KRd followed by ASCT and lenalidomide maintenance. She had progression of disease 3 years later and was then treated with Dara-Kd, which was complicated by acute kidney injury due to a thrombotic microangiopathy from carfilzomib that led to dialysis dependency. She then received daratumumab plus pomalidomide and dexamethasone (Dara-Pd) with a brief response, selinexor for 1 cycle, and daratumumab, bendamustine, and dexamethasone for 5 cycles followed by daratumumab maintenance therapy. After T-cell harvest, she underwent bridging therapy with cyclophosphamide, pomalidomide, and dexamethasone. She was undergoing dialysis 3 times a week via tunneled left internal jugular catheter.
From days −5 to −3, the patient received fludarabine at 15 mg/m 2 and cyclophosphamide at 300 mg/m 2 . She underwent HD 12 hours after the completion of chemotherapy infusions; see Table 1 for dialysis details. On day 0, the absolute lymphocyte count was 0.02 ×10 3 /μL. The patient received ciltacabtagene autoleucel (0.3 × 10 6 CAR+ T-cells/kg out of specification due to low cell dose). She had transient left-sided chest and arm pain during the infusion, but her cardiac workup was unremarkable. Her course to day +9 was unremarkable, and she was discharged. However, on day +10, she was direct admitted for headaches, shortness of breath, and neutropenic fever (CRS grade 1). She was given acetaminophen and tocilizumab and received 4 days of dexamethasone because of concern for grade 1 IEC-HS. On resolution of her symptoms and improvement in her inflammatory marker concentrations, she was discharged on day +14. During this admission, she received intermittent HD as per her usual 3 times a week schedule.
After discharge, she experienced anemia, thrombocytopenia, and neutropenia, requiring 3 doses of filgrastim. At day +60, she had a partial response with a decrease in monoclonal IgG lambda from 2.89 g/dL to 0.68 g/dL; a bone marrow biopsy revealed no evidence of disease and minimal residual disease negativity by next-generation sequencing (10 −6 ). She continues to receive HD 3 times weekly as an outpatient.
Case 5
A 69-year-old woman with kappa light chain MM (with 1q amplification) was diagnosed 5 months before CAR T therapy after evaluation for anemia and incidental spine and pelvic bone lesions. Two months after diagnosis, she was hospitalized with acute kidney injury for myeloma cast nephropathy and ultimately did not regain function, and she was started on HD through a central catheter; she continued to produce 650-1,500 mL of urine output per day and was receiving 4 mg of bumetanide daily on non-HD days. She had primary refractoriness to daratumumab, bortezomib, lenalidomide, and dexamethasone (Dara-VRd). She then underwent urgent cytoreduction with high-dose cyclophosphamide with a partial response, followed by T-cell apheresis; she received bridging therapy with KPd but had no response, so she received another cycle of high-dose cyclophosphamide as a bridge to CAR T-cell therapy.
On days −6 and −5, she received fludarabine 15 mg/m 2 followed by cyclophosphamide 300 mg/m 2 . She received HD 12 hours after each of these infusions; see Table 1 for dialysis details. However, on day −4, the patient developed fevers and chills during her chemotherapy infusion. It was stopped, and she was treated with acetaminophen. On chest x-ray, she was found to have pleural effusions most consistent with volume overload and thus was given 4 mg of bumetanide. On day −3, she was afebrile and asymptomatic. She received the last dose of lymphodepletion therapy and HD session 12 hours; see Table 1 for dialysis details. CAR T-cell infusion was delayed by 1 day due to the alteration in the lymphodepletion schedule.
On day 0, the absolute lymphocyte count was 0.0 × 10 3 /μL. The patient received ciltacabtagene autoleucel infusion at a dose of 0.6 × 10 6 CAR+ T-cells/kg. During the infusion, she had transient hypoxia on room air to 89% requiring nasal cannula. She was making adequate urine with stable laboratory findings, so her next session of HD was on day +3. Her dialysis scheduled was decreased to as-needed HD about 2 times per week (Monday and Friday), and she received bumetanide on nondialysis days. On day +4, the patient developed fever and neutropenia. An infectious workup was negative; she received acetaminophen as well as tocilizumab and 1 dose of dexamethasone for CRS grade 1. She received another 2 doses of tocilizumab over the next 2 nights for recurrent fever and was started on scheduled dexamethasone. The dose of dexamethasone was increased the following day for another fever. On day +9, she was started on anakinra for IEC-HS. On days +10, +11, and +12, she received cryoprecipitate for hypofibrinogenemia. On day +13, the frequency of anakinra was increased, and ruxolitinib was added to the regimen due to persistently rising ferritin. Her ferritin levels began to drop on day +15, and her regimen was tapered down. She required 2 more units of cryoprecipitate as well as 1 unit of packed red blood cells. Over these first 2 weeks, she required 5 intermittent HD treatments.
At the time of discharge (day +26), the patient’s glomerular filtration rate estimated by creatinine and cystatin C was ∼10, so it was thought she would likely need HD at least twice-weekly for the time being. Her day +42 kappa free light chains normalized. She was still experiencing cytopenias but did not require blood products or filgrastim. Unfortunately, by day +99 she had evidence of extramedullary involvement of myeloma. She was undergoing dialysis 3 times weekly as an outpatient at that time.
Discussion
As CAR T-cell therapy continues to transform the treatment of relapsed/refractory MM, its use in patients with kidney failure remains largely unexplored. We have presented 5 cases of treatment with ciltacabtagene autoleucel in patients with relapsed/refractory MM while on renal replacement therapies, including 4 on HD and 1 successfully treated while on PD.
The CARTITUDE-4 trial compared ciltacabtagene autoleucel to standard of care in patients with lenalidomide-refractory MM who had received 1-3 prior therapies. 3 The trial demonstrated a substantial progression-free survival benefit over standard of care, with rapid and sustained deep hematological responses. These outcomes spotlight the potential of CAR T-cell therapy as an effective earlier-line treatment for suitable patients with MM. However, in the current literature, data of successfully administered CAR T-cell therapy in dialysis-dependent patients for the treatment of MM is limited. A retrospective multicenter observational study 4 evaluated patients with relapsed/refractory MM treated with idecabtagene vicleucel. A total of 214 patients were analyzed, 28 (13%) of whom had a creatinine clearance < 50 mL/min at the time of infusion. However, only 1 patient was dialysis-dependent. This study showed higher short-term hematological toxicities and longer hospital stays in patients with advanced kidney disease. However, the efficacy and overall safety were comparable to those of patients without kidney disease, including no difference in survival based on fludarabine dose reduction. Pak et al 5 reported 2 cases of a 50-year-old woman and a 70-year-old man on maintenance dialysis who received ciltacabtagene autoleucel for relapsed/refractory MM; both patients received modified lymphodepletion regimens due to their kidney failure. The female patient had dose-reduced fludarabine, and the male patient did not receive fludarabine due to concerns of neurotoxicity. Both patients achieved significant hematologic responses, one achieving a complete response and the other a very good partial response. HD schedules were tailored around lymphodepletion and CAR T-cell infusion to optimize drug clearance and minimize complications ( Table 2 6 ). Additionally, a large real-world analysis of patients receiving ciltacabtagene autoleucel included 8 (3%) patients who were treated with dialysis at the time of infusion. 7 However, no description of a lymphodepletion regimen or dialysis schedule modification was provided. Table 2 CAR T-Cell Therapy in Dialysis-Dependent Patients With a Diagnosis of Multiple Myeloma Author Case ID Age, y Sex Diagnosis CAR T-Cell Product Lymphodepleting Regimen Hemodialysis Schedule Complications Outcome Pak et al 5 1 50 Female Kappa light chain MM Ciltacabtagene autoleucel CYC 300 mg/m 2 + fludarabine 15 mg/m 2 (days −5, −4, and −3) 12 h after each fludarabine dose Anemia requiring PRBC transfusion Complete hematological response by day +28 2 70 Male Kappa light chain MM Ciltacabtagene autoleucel CYC 300 mg/m 2 only (days −5, −4, and −3) HD on days −6, −3, −1 and +1 Grade 1 CRS Very good partial response on day +28 Sidana et al 4 3 — — Relapsed MM (unknown type) Idecabtagene vicleucel CYC 300 mg/m 2 + fludarabine 24 mg/m 2 (days −5, −4, and −3) — — — Wäsch et al 6 4 74 Male Lambda light chain MM Idecabtagene vicleucel CYC 300 mg/m 2 only (days −5, −4, and −3) — Grade 1 CRS Complete response +60 days Present cases Swamy et al 5 (case 1) 53 Female Lambda light chain plasmablastic myeloma Ciltacabtagene autoleucel CYC 300 mg/m 2 + fludarabine 20 mg/m 2 (days −5, −4, and −3) 12 h after each fludarabine dose Grade 2 CRS Grade 2 ICANS Thrombocytopenia requiring platelet transfusion HLH +60 days persistent extramedullary disease. Died on day +293 6 (case 2) 79 Male Lambda light chain MM Ciltacabtagene autoleucel CYC 300 mg/m 2 + fludarabine 20 mg/m 2 (days −5, −4, and −3) 12 h after each fludarabine dose Neutropenic fever Grade 1 CRS Complete response +60 days 7 (case 3) 72 Female IgA lambda light chain MM Ciltacabtagene autoleucel Bendamustine 70 mg/m 2 (dose reduced from 90 mg/m 2 ) (on day −6 and −5) 8 h session of Peritoneal dialysis on day −6 (4 h after) and on day −5 (7 h after) Grade 1 CRS Complete response +60 days. Progression of disease at +120 days. Died at +274 days 8 (case 4) 61 Female Lambda light chain MM Ciltacabtagene autoleucel CYC 300 mg/m 2 + fludarabine 15 mg/m 2 (days −5, −4, and −3) 12 h after each fludarabine dose Grade 1 CRS Partial response at +30 days. No evidence of disease at +60 days 9 (case 5) 69 Female Kappa light chain MM Ciltacabtagene autoleucel CYC 300 mg/m 2 + fludarabine 15 mg/m 2 (days −6, −5, and −3) 12 h after each fludarabine dose Neutropenic fever Grade 1 CRS HLH, received anakinra Anemia requiring PRBC transfusion +99 days evidence of extramedullary disease Abbreviations: CAR, chimeric antigen receptor; CRS, cytokine release syndrome; CYC, cyclophosphamide; ICANS, immune effector cell-associated neurotoxicity syndrome; HD, hemodialysis; HLH, hemophagocytic lymphohistiocytosis; MM, multiple myeloma; PRBC, packed red blood cells.
Table 2
CAR T-Cell Therapy in Dialysis-Dependent Patients With a Diagnosis of Multiple Myeloma
Abbreviations: CAR, chimeric antigen receptor; CRS, cytokine release syndrome; CYC, cyclophosphamide; ICANS, immune effector cell-associated neurotoxicity syndrome; HD, hemodialysis; HLH, hemophagocytic lymphohistiocytosis; MM, multiple myeloma; PRBC, packed red blood cells.
| Author | Case ID | Age, y | Sex | Diagnosis | CAR T-Cell Product | Lymphodepleting Regimen | Hemodialysis Schedule | Complications | Outcome |
| Pak et al 5 | 1 | 50 | Female | Kappa light chain MM | Ciltacabtagene autoleucel | CYC 300 mg/m 2 + fludarabine 15 mg/m 2 (days −5, −4, and −3) | 12 h after each fludarabine dose | Anemia requiring PRBC transfusion | Complete hematological response by day +28 |
| 2 | 70 | Male | Kappa light chain MM | Ciltacabtagene autoleucel | CYC 300 mg/m 2 only (days −5, −4, and −3) | HD on days −6, −3, −1 and +1 | Grade 1 CRS | Very good partial response on day +28 | |
| Sidana et al 4 | 3 | — | — | Relapsed MM (unknown type) | Idecabtagene vicleucel | CYC 300 mg/m 2 + fludarabine 24 mg/m 2 (days −5, −4, and −3) | — | — | — |
| Wäsch et al 6 | 4 | 74 | Male | Lambda light chain MM | Idecabtagene vicleucel | CYC 300 mg/m 2 only (days −5, −4, and −3) | — | Grade 1 CRS | Complete response +60 days |
| Present cases Swamy et al | 5 (case 1) | 53 | Female | Lambda light chain plasmablastic myeloma | Ciltacabtagene autoleucel | CYC 300 mg/m 2 + fludarabine 20 mg/m 2 (days −5, −4, and −3) | 12 h after each fludarabine dose | Grade 2 CRS Grade 2 ICANS Thrombocytopenia requiring platelet transfusion HLH | +60 days persistent extramedullary disease. Died on day +293 |
| 6 (case 2) | 79 | Male | Lambda light chain MM | Ciltacabtagene autoleucel | CYC 300 mg/m 2 + fludarabine 20 mg/m 2 (days −5, −4, and −3) | 12 h after each fludarabine dose | Neutropenic fever Grade 1 CRS | Complete response +60 days | |
| 7 (case 3) | 72 | Female | IgA lambda light chain MM | Ciltacabtagene autoleucel | Bendamustine 70 mg/m 2 (dose reduced from 90 mg/m 2 ) (on day −6 and −5) | 8 h session of Peritoneal dialysis on day −6 (4 h after) and on day −5 (7 h after) | Grade 1 CRS | Complete response +60 days. Progression of disease at +120 days. Died at +274 days | |
| 8 (case 4) | 61 | Female | Lambda light chain MM | Ciltacabtagene autoleucel | CYC 300 mg/m 2 + fludarabine 15 mg/m 2 (days −5, −4, and −3) | 12 h after each fludarabine dose | Grade 1 CRS | Partial response at +30 days. No evidence of disease at +60 days | |
| 9 (case 5) | 69 | Female | Kappa light chain MM | Ciltacabtagene autoleucel | CYC 300 mg/m 2 + fludarabine 15 mg/m 2 (days −6, −5, and −3) | 12 h after each fludarabine dose | Neutropenic fever Grade 1 CRS HLH, received anakinra Anemia requiring PRBC transfusion | +99 days evidence of extramedullary disease |
Fludarabine, a purine analog, is a critical component of the lymphodepleting regimen administered before CAR T-cell infusion; however, excessive exposure can lead to profound cytopenias and irreversible neurotoxicity 8 and may be implicated in the incidence of second cancers. Fludarabine is dephosphorylated into the active metabolite 2-fluoro-ara-A and has a half-life distribution of 0.6 hours, terminal half-life of 9.3 hours in healthy individuals, and up to 60% fludarabine is renally cleared. 9 , 10 , 11 Kielstein et al 12 demonstrated the average dialysis clearance of fludarabine was 25%, while Horwitz et al 13 showed a 20% dose reduction, paired with dialysis initiated 12 hours after each dose and effectively cleared excess metabolites. However, despite successful engraftment, patients with kidney failure experienced prolonged neutropenia and increased thrombocytopenia, underscoring the need for close follow-up and vigilance.
Cyclophosphamide, an alkylating agent metabolized into several active metabolites (predominantly 4-hydroxy-cyclophosphamide), has a fast distribution and terminal half-life of 6-8 hours. 14 , 15 Haubitz et al 16 showed a 3-hour HD session starting 7 hours after administration of cyclophosphamide eliminated 22% of it, and they recommended holding HD ≥12 hours after cyclophosphamide administration to optimize drug availability and minimize prolonged elimination. 16 , 17
Bendamustine is an alkylating agent with a rapid distribution and a terminal half-life of 40 minutes. 18 Bendamustine is primarily metabolized hepatically through hydrolysis and cytochrome P450 enzymes—particularly CYP1A2—into active metabolites. 18 While renal clearance contributes to its elimination, <10% of the unchanged drug is excreted in urine, and it exhibits high plasma protein binding (>94%), limiting its removal via HD. 19 , 20 Despite these pharmacokinetic features, bendamustine does not appear to accumulate significantly in patients with kidney failure, supporting its use in patients with renal impairment. 20
Fludarabine and cyclophosphamide has remained the lymphodepleting regimen of choice, but the safety and potential efficacy of bendamustine in patients with kidney failure raises the question of whether it should be used in this population. 17 , 20 , 21
We provide evidence here that reduced-dose fludarabine and cyclophosphamide or bendamustine lymphodepletion before ciltacabtagene autoleucel is not only feasible but leads to effective lymphodepletion before CAR T-cell therapy. We provide suggested guidance on this strategy in Table 3 . Table 3 Suggested Lymphodepletion Regimens and Dialysis Schedule for Dialysis-Dependent Patients Receiving CAR T-Cell Therapy Day Lymphodepleting Regimen Hydration Hemodialysis Timing Regimen 1 −5 CYC 300 mg/m 2 + fludarabine a 15 or 20 mg/m 2 Reduce hydration to 500 mL after each CYC dose b Administer LD regimen after HD session if it falls on the same day Allow at least 12 h between fludarabine and CYC administration and next HD session −4 CYC 300 mg/m 2 + fludarabine a 15 or 20 mg/m 2 −3 CYC 300 mg/m 2 + fludarabine a 15 or 20 mg/m 2 −2 No chemotherapy treatment — No HD unless clinically indicated −1 No chemotherapy treatment — No HD unless clinically indicated 0 CAR T-cell therapy infusion — No HD Regimen 2 −4 Bendamustine 70 mg/m 2 Not indicated Administer after HD session if it falls on the same day as bendamustine −3 Bendamustine 70 mg/m 2 −2 No chemotherapy treatment −1 No chemotherapy treatment — No HD unless clinically indicated 0 CAR T-cell therapy infusion — No HD unless clinically indicated Abbreviations: CAR, chimeric antigen receptor; CYC, cyclophosphamide; HD, hemodialysis; LD, lymphodepleting. a If patient is anuric: 15 mg/m 2 ; if patient is oliguric: 20 mg/m 2 . b If patient is anuric: omit hydration; if patient is oliguric: 500 mL after each CYC dose.
Table 3
Suggested Lymphodepletion Regimens and Dialysis Schedule for Dialysis-Dependent Patients Receiving CAR T-Cell Therapy
Abbreviations: CAR, chimeric antigen receptor; CYC, cyclophosphamide; HD, hemodialysis; LD, lymphodepleting.
a If patient is anuric: 15 mg/m 2 ; if patient is oliguric: 20 mg/m 2 .
b If patient is anuric: omit hydration; if patient is oliguric: 500 mL after each CYC dose.
| Day | Lymphodepleting Regimen | Hydration | Hemodialysis Timing |
| Regimen 1 | |||
| −5 | CYC 300 mg/m 2 + fludarabine a 15 or 20 mg/m 2 | Reduce hydration to 500 mL after each CYC dose b | Administer LD regimen after HD session if it falls on the same day Allow at least 12 h between fludarabine and CYC administration and next HD session |
| −4 | CYC 300 mg/m 2 + fludarabine a 15 or 20 mg/m 2 | ||
| −3 | CYC 300 mg/m 2 + fludarabine a 15 or 20 mg/m 2 | ||
| −2 | No chemotherapy treatment | — | No HD unless clinically indicated |
| −1 | No chemotherapy treatment | — | No HD unless clinically indicated |
| 0 | CAR T-cell therapy infusion | — | No HD |
| Regimen 2 | |||
| −4 | Bendamustine 70 mg/m 2 | Not indicated | Administer after HD session if it falls on the same day as bendamustine |
| −3 | Bendamustine 70 mg/m 2 | ||
| −2 | No chemotherapy treatment | ||
| −1 | No chemotherapy treatment | — | No HD unless clinically indicated |
| 0 | CAR T-cell therapy infusion | — | No HD unless clinically indicated |
The patients in this cohort were all heavily pretreated and had multiple aggressive disease features, including high-risk cytogenetic abnormalities (100%), plasmablastic features (40%), and/or extramedullary disease (60%). All patients experienced CRS grade 1-2, 1 patient experienced immune effector cell-associated neurotoxicity syndrome, and 3 patients (60%) experienced IEC-HS. We attribute the high rate of IEC-HS to high disease burden entering into CAR T-cell therapy, but an explicit risk from the lymphodepletion or the treatment itself in the setting of dialysis dependence cannot be ruled out. Kidney failure encountered in the setting of myeloma therapy may be associated with more aggressive disease biology, which in turn may lead to higher grade toxicities from CAR T-cell therapy. It is unclear if the reduced-dose fludarabine/cyclophosphamide or bendamustine lymphodepletion strategy impacted outcomes. On one hand, the overall response rate was 100% and ≥1 patient had a deep and durable response beyond 1 year of therapy, with another patient in ongoing response. The short responses among the other 3 patients may be better attributed to the aggressive high-risk disease features, which are known to be associated with poorer outcomes with CAR T-cell therapy. 22 Renal impairment was not found to be associated with outcomes in a real-world analysis of ciltacabtagene autoleucel. 7
This case series demonstrates that ciltacabtagene autoleucel can be safely and effectively administered to dialysis-dependent patients on HD or PD with refractory/relapsed MM with a dose-adjusted lymphodepleting regimen and tailored dialysis schedules and prescriptions. Standardized protocols to further clarify optimal dosing of lymphodepleting chemotherapy and CAR T-cell products along with assessment of long-term outcomes in patients with kidney failure are needed.
References
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Article Information
Authors’ Full Names and Academic Degrees
Varsha Swamy, MD, Kaitlin Kelly, PharmD, BCOP, Jay L. Koyner, MD, Benjamin A. Derman, MD, and Marco Bonilla, MD
Support
None.
Financial Disclosures
JLK reports research funds and consulting fees from Fresenius Medical and consulting fees from Baxter/Vantive and Alexion. MB declares consulting fees from Amgen, Travere, Calliditas, and Vertex. BAD declares consultancy fees from Janssen, Sanofi, Canopy, and COTA; independent clinical trial reviewer for BMS; and research funding from GSK and Amgen. The remaining authors declare that they have no relevant financial interests.
Patient Protections/IRB Approval
This study was approved by the Institutional Review Board of the University of Chicago (IRB24-0901). Individual patient consent for publication was waived under this approval, as the study involved retrospective review of de-identified data.
Peer Review
Received May 20, 2025. Evaluated by 1 external peer reviewer, with direct editorial input from the Editor-in-Chief. Accepted in revised form July 3, 2025.
Complete author and article information provided before references.