Very little is known about the risk that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection poses to cancer patients, many of whom are immune compromised causing them to be ...more susceptible to a host of infections. As a precautionary measure, many clinical studies halted enrollment during the initial surge of the global Novel Coronavirus Disease (COVID-19) pandemic. In this case report, we detail the successful treatment of a relapsed and refractory multiple myeloma (MM) patient treated with an anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell therapy immediately following clinical recovery from COVID-19.
The 57 year old Caucasian male patient had a 4-year history of MM and was considered penta-refractory upon presentation for CAR T cell therapy. He had a history of immunosuppression and received one dose of lymphodepleting chemotherapy (LDC) the day prior to COVID-19 diagnosis; this patient was able to mount a substantial immune response against the SARS-CoV-2 virus, and antiviral antibodies remain detectable 2 months after receiving anti-BCMA CAR T cell therapy. The recent SARS-CoV-2 infection in this patient did not exacerbate CAR T-associated cytokine release syndrome (CRS) and conversely the CAR T cell therapy did not result in COVID-19-related complications. One month after CAR T cell infusion, the patient was assessed to have an unconfirmed partial response per International Myeloma Working Group (IMWG) criteria.
Our case adds important context around treatment choice for MM patients in the era of COVID-19 and whether CAR T therapy can be administered to patients who have recovered from COVID-19. As the COVID-19 global pandemic continues, the decision of whether to proceed with CAR T cell therapy will require extensive discussion weighing the potential risks and benefits of therapy. This case suggests that it is possible to successfully complete anti-BCMA CAR T cell therapy after recovery from COVID-19. CRB-402 study registered 6 September 2017 at clinicaltrials.gov (NCT03274219).
Dilated dysfunction involving multiple visceral organs has been reported in patients with systemic lupus erythematosus （SLE）. Chronic intestinal pseudoobstruction （CIPO） resulting from intestinal ...smooth muscle damage has presented in conjunction with ureterohydronephrosis and, more rarely, biliary dilatation （megacholedochus）. While the molecular pathogenesis is largely unknown, observed histopathologic features include widespread myositis, myocyte necrosis in the intestinal muscularis propria with subsequent atrophy and fibrosis, preserved myenteric innervations and little vasculitis. High dose immunosuppression usually results in resolution of symptoms with recovery of smooth muscle function, indicative of an autoimmune etiology. We report a patient with SLE who presented with intestinal pseudo-obstruction, ureterohydronephrosis and megacholedochus, and present images that illustrate megaviscera simultaneously involving all 3 visceral organs. Since the co-manifestation of all 3 is unusual and has been reported only once previously, we have termed this rare clinical syndrome generalized megaviscera of lupus （GML）. Although the SLE disease-activity parameters responded to aggressive immunomodulative therapy in our patient, clinical evidence of peristaltic dysfunction persisted in all involved viscera. This is a variation from the favorable outcomes reported previously in SLE patients with GML and we attribute this poor clinical outcome to disease severity and, most importantly, delayed clinical presentation. Since inflammation followed by atrophy and fibrosis are key aspects in the pathogenesis and natural history of GML, the poor response in our patient who presented late in the clinical course may be the result of ＇burnt out＇ inflammation with irreversible end-stage fibrosis. Thus, early recognition and timely initiation of treatment may be the key to recover visceral peristaltic function in patients with GML.
CARTITUDE-1 (NCT03548207) is a phase 1b/2 study of ciltacabtagene autoleucel (cilta-cel; JNJ-68284528), a chimeric antigen receptor T cell (CAR-T) therapy with two B-cell maturation antigen ...(BCMA)–targeting single-domain antibodies, in relapsed/refractory multiple myeloma (RRMM). Updated results from a median 18-month follow-up are reported here.
Eligible patients had MM, received ≥3 prior regimens or were double refractory to a proteasome inhibitor (PI) and immunomodulatory drug (IMiD), and had received a PI, IMiD, and anti-CD38 antibody. After apheresis, bridging therapy was allowed. Patients received a single cilta-cel infusion (target dose: 0.75×106 CAR+ viable T cells/kg; range 0.5-1.0×106) 5–7 days (d) after lymphodepletion (300 mg/m2 cyclophosphamide, 30 mg/m2 fludarabine daily for 3 d). Primary objectives were to characterize cilta-cel safety, confirm the recommended phase 2 dose (phase 1b), and evaluate efficacy (phase 2). Cytokine release syndrome (CRS) was graded by Lee et al (Blood 2014) and neurotoxicity by CTCAE, v5.0 in phase 1b. CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded by American Society for Transplantation and Cellular Therapy (ASTCT) criteria in phase 2. Lee et al and CTCAE v5.0 were mapped to ASTCT for CRS and ICANS, respectively.
As of February 11, 2021, 97 patients (median of 6 prior lines) received cilta-cel. Overall response rate per independent review committee (primary endpoint) was 97.9% (95% CI, 92.7–99.7); 80.4% achieved stringent complete response (sCR) and 94.8% achieved very good partial response or better. Median time to first response was 1 month (mo) (range, 0.9–10.7), and median time to ≥CR was 2.6 mo (range, 0.9–15.2). Median duration of response was 21.8 mo (95% CI, 21.8–NE). Of 61 minimal residual disease (MRD)-evaluable patients, 91.8% were MRD negative at 10−5. The 18-month progression-free survival (PFS) and overall survival rates (95% CI) were 66% (54.9–75.0) and 80.9% (71.4–87.6), respectively; median PFS was 22.8 mo (95% CI, 22.8–NE) for all patients, and not reached for patients with sCR. Grade 3/4 hematologic AEs ≥20% included neutropenia (95%), anemia (68%), leukopenia (61%), thrombocytopenia (60%), and lymphopenia (50%). CRS occurred in 95% of patients (4% grade 3/4); median time to onset was 7 d (range, 1–12) and median duration was 4 d (range, 1–14, excluding 1 patient with 97-d duration). CRS resolved in all but one with grade 5 CRS/hemophagocytic lymphohistiocytosis. 21% of patients had CAR-T neurotoxicity (grade ≥3, 10%). Twenty-one deaths occurred during the study: none ≤30 days; 2 ≤100 days; and 19 >100 days after infusion, among which, 10 were due to disease progression, 6 were treatment-related as assessed by the investigator, and 5 were due to AEs unrelated to treatment.
Cilta-cel is under further investigation in other MM populations in earlier lines of therapy and in outpatient settings.
At a longer median follow-up of 18 mo, a single cilta-cel infusion yielded early, deep, and durable responses with a manageable safety, in heavily pretreated patients with MM.
Cilta-cel (JNJ-68284528) is a chimeric antigen receptor T cell (CAR-T) therapy with two B-cell maturation antigen (BCMA)-targeting, single-domain antibodies designed to confer high avidity binding. ...CARTITUDE-2 (NCT04133636) is a phase 2, multicohort, open-label study assessing the efficacy and safety of cilta-cel in patients with multiple myeloma (MM) in various clinical settings. We describe the mitigation and management strategies implemented to identify and reduce the risk for neurologic adverse events in patients enrolled in Cohort A (progressive MM after 1-3 prior lines of therapy).
Eligible patients (≥18 years of age) had MM per International Myeloma Working Group criteria, measurable disease, Eastern Cooperative Oncology Group performance status ≤1, progressive disease after 1-3 prior lines of therapy (including a proteasome inhibitor and an immunomodulatory drug), were lenalidomide refractory, and had not received BCMA-targeting agents. Cilta-cel (0.75 × 106 range 0.5– 1.0 × 106 CAR+ viable T cells/kg) was given as a single infusion 5–7 days after start of lymphodepletion (cyclophosphamide 300 mg/m2 + fludarabine 30 mg/m2 daily for 3 days). Monitoring and mitigation strategies for neurologic adverse events include providing more effective bridging therapy to reduce tumor burden prior to lymphodepletion, frequent assessment of CAR-T related immune effector cellassociated neurotoxicity syndrome (ICANS) using the immune effector cellassociated encephalopathy tool, regular handwriting assessments to detect micrographia, and neuroimaging (brain MRI) and electroencephalogram for patients with prior neurologic disease. Management strategies include evaluating infectious and paraneoplastic etiologies upon observation of ICANS ≥grade 1, administration of tocilizumab (if concurrent with cytokine release syndrome CRS, all grade of ICANS) and/or dexamethasone (grade 2/3) or methylprednisolone (grade 4). ICANS and CRS were graded by American Society for Transplantation and Cellular Therapy criteria; neurotoxicities not classified as ICANS were graded per common terminology criteria for adverse events, v5.0.
As of 15 Jan 2021 (median follow-up: 5.8 months range: 2.5–9.8), 20 patients in Cohort A received cilta-cel. Median age was 60 years (range: 38–75) and 65% were male. Neurotoxicities occurred in 4 patients (20%). Three patients had ICANS (grade 1/2); median time to onset of symptoms was 8 days (range: 7–11) and median duration was 2 days (range: 1–2). Two of the 3 patients received supportive measures to treat ICANS, including levetiracetam and steroids; all 3 had concurrent CRS and all recovered. One patient developed isolated facial paralysis (grade 2) on Day 29 after cilta-cel infusion and recovered 51 days after onset following treatment with dexamethasone for 28 days. No movement or neurocognitive disorders were reported.
Early detection and management of neurologic adverse events can lead to better treatment outcomes.
Neurologic adverse events were generally manageable in patients with MM following treatment with cilta-cel. With a median of 5.8 months of follow-up, there were no movement or neurocognitive disorders in patients from Cohort A.
PDF
