Chimeric antigen receptor T cell (CAR-T) therapies

A new study has recently been published regarding “second primary malignancies (SPM) after commercial CAR-T therapy”, given the warning reported by the FDA (mentioned in a previous IACH bulletin). In this recent work, they identified 12394 unique CAR-T adverse events (AEs) reports, of which 536/12394 (4.3%) were associated with SPM. Most of the reports comprised axi-cel (51.7%) and tisa-cel (33%). The most frequent SPM were leukemias (333/536, 62.1%), representing 2.7% (333/12394) of all CAR-T reports. Leukemias included myelodysplastic syndromes (MDS) (208/536, 38.8%; representing 208/12394, 1.7%), AML (106/536, 19.8%; representing 106/12394, 0.9%), and 2 cases of T-cell large granular lymphocytic leukemia (T-LGLL). T-cell non-Hodgkin lymphomas were identified in 17/536 (3.2%) reports, representing 0.1% (17/12394) of all CAR-T reports. These included 12 anaplastic large T-cell lymphomas (7 in tisa-cel and 3 in axi-cel, and 2 in ciltacabtagene autoleucel [cilta-cel]), 3 peripheral T-cell lymphomas (1 in tisa-cel, 1 in cilta-cel, and 1 in lisocabtagene maraleucel [liso-cel]), one angioimmunoblastic T-cell lymphoma (axi-cel), and one enteropathy associated T-cell lymphoma (cilta-cel). Hematopoietic neoplasms excluding leukemias and lymphomas were reported (26/536, 4.9%; representing 26/12394, 0.2%) including lymphoproliferative disorder NEC (n=15), myeloproliferative neoplasms (n=7), and histiocytoses (n=4). Other neoplasms were skin cancer, nervous system tumors and respiratory neoplasms.

This recent work identified 19 cases of T-cell malignancy (17 T-cell non-Hodgkin lymphomas and two T-LGLL); two cases associated with cilta-cel and liso-cel were published previously. CAR transgene integration into the 3’ UTR of the PBX2 gene was detected in the cilta-cel case. However, the evidence was inconclusive as to whether the CAR integration was a driver of the malignant transformation, given the presence of pre-existing genetic mutations unrelated to CAR-T infusion. Additional studies have reported viral integrations into key hematopoietic regulatory genes, such as TET2 and CBL, resulting in clonal expansion in two responding CAR-T patients with no malignant transformation reported to date.

The FDA Adverse Event Reporting System database remains a valuable resource for identifying AEs not captured during clinical studies, however, it has limitations such as duplicate report submissions, missing information, inability to establish causal relationships, and underreporting or overreporting based on AE severity. Additionally, the absence of a denominator reflecting the total number of prescribed products limits the ability to establish AE incidence.

Acute myeloid leukemia (AML)

Hypomethylating agents combined with BCL-2 inhibitor venetoclax (VEN) are effective regimens in patients with AML who are ineligible for intensive chemotherapy (VIALE-A trial). Decitabine and cedazuridine (ASTX727) is an oral formulation of decitabine that achieves equivalent area-under-curve exposure to intravenous decitabine. Recently published are the results of a single-centre (MD Anderson Cancer Center) phase 2 clinical trial (NCT04746235)  that evaluated the combination of ASTX727 and VEN in 62 AML patients who were ineligible for intensive chemotherapy (n=49) (aged ≥75 years, an Eastern Cooperative Oncology Group [ECOG] performance status of 2–3, or major comorbidities) or relapsed or refractory AML (n=13). Treatment consisted of ASTX727 (cedazuridine 100 mg and decitabine 35 mg) orally for 5 days and VEN 400 mg orally for 21–28 days in 28-day cycles. The primary outcome was overall response rate. This trial is ongoing and the data cutoff date for this analysis was Sept 22, 2023. With a median age of 78 years (IQR 73–82), 24 (39%) had antecedent myelodysplastic syndromes, 12 (19%) had previously failed a hypomethylating agent, 10 (16%) had therapy-related AML, and 11 (18%) had TP53 mutations. The median follow-up time was 18·3 months (IQR 8·8–23·3). The overall response rate was 30 (64%) of 47 patients (95% CI 49–77) in the frontline cohort and six (46%) of 13 patients (95% CI 19–75) in the relapsed or refractory cohort. The most common grade 3 or worse treatment-emergent adverse events were febrile neutropenia in 11 (18%) of 62 patients, pneumonia in eight (13%), respiratory failure in five (8%), bacteraemia in four (6%), and sepsis in four (6%). Three deaths occurred in patients in remission (one sepsis, one gastrointestinal haemorrhage, and one respiratory failure) and were potentially treatment related.

B-cell malignancies

The first-generation covalent small-molecule BTK inhibitor, ibrutinib, changed the way disorders including Waldenström macroglobulinemia, mantle cell lymphoma, and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) were treated. Though the exact mechanism is unknown, ibrutinib has been linked to cardiovascular toxicities including life-threatening ventricular arrhythmias, when used alone or in combination. Covalent next-generation BTK inhibitors, such as zanubrutinib and acalabrutinib, reduce off-target inhibition. In this study, incidence rates of atrial fibrillation, symptomatic (grade >1) ventricular arrhythmia, and hypertension were evaluated in a pooled analysis of 10 clinical studies with zanubrutinib monotherapy in patients (n=1550) with B-cell malignancies and a pooled analysis of head-to-head studies comparing zanubrutinib with ibrutinib (ASPEN cohort 1; ALPINE). Across the 10 studies, most patients (median age, 67 years) were male (66.3%), and most had CLL  (60.5%). Overall incidence and exposure-adjusted incidence rates (EAIR) for atrial fibrillation, symptomatic ventricular arrhythmia, and hypertension were lower with zanubrutinib versus ibrutinib. Despite a similar prevalence of pre-existing cardiovascular events in ASPEN and ALPINE, atrial fibrillation/flutter incidence rate (6.1% vs. 15.6%) and EAIR (0.2 vs. 0.64 persons/100 person-months; p<.0001) were lower with zanubrutinib than with ibrutinib, respectively. Symptomatic ventricular arrhythmia incidence was low for both zanubrutinib (0.7%) and ibrutinib (1.7%) with numerically lower EAIR (0.02 vs. 0.06 persons/100 person-months, respectively) for zanubrutinib. The hypertension EAIR was lower with zanubrutinib versus ibrutinib in ASPEN but similar between treatment arms in ALPINE. The higher hypertension EAIR in ALPINE was inconsistent with the other zanubrutinib studies. However, fewer discontinuations (1 vs. 14) and deaths (0 vs. 6) due to cardiac disorders occurred with zanubrutinib versus ibrutinib in ALPINE

Central nervous system (CNS) B-cell lymphoma

Although CD20xCD3 bispecific antibodies (BsAb) are effective against systemic B-cell lymphomas, their efficacy in CNS lymphoma is unknown. A recent study reported a case series (n=4) of biopsy-proven CD20+ diffuse large B-cell lymphoma with secondary CNS involvement and heavily pre-treated (all patients relapsed after prior CD19-directed CAR-T cell therapy). They were treated with the CD20xCD3 bispecific, glofitamab. Two patients presented with lymphoma confined to the CNS at the time of CD20 BsAb treatment and two patients had concomitant systemic and CNS disease. Sites of CNS involvement included the CNS parenchyma (n=3) and leptomeninges (n=1). Two patients received concomitant acalabrutinib and focal brain radiation. Two patients received obinutuzumab pre-treatment in accordance with the glofitamab package insert, while obinutuzumab pre-treatment was omitted in two patients due to rapidly progressing disease. The median number of glofitamab cycles was 6.5 (range 2-8). Immune effector cell-associated neurotoxicity syndrome and other treatment-related neurologic adverse effects were not observed in any patient. On-treatment cerebrospinal fluid samples were collected from each patient to determine the extent to which glofitamab penetrated the blood-brain barrier (BBB) as assessed by an ELISA-based assay validated for human serum.  Considering the limitations of association with clinical improvement and co-interventions, they conclude that glofitamab partially penetrants the BBB, stimulates immune-cell infiltration of CNS tumors, and is capable of safely inducing clinical and radiographic responses in patients with CNS lymphoma.

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL)

On March 19, 2024 the Food and Drug Administration (FDA) granted accelerated approval to ponatinib (Inclusig, Takeda Pharmaceuticals U.S.A., Inc.) with chemotherapy for newly diagnosed Philadelphia chromosome negative-(Ph)-ALL.  The PhALLCON study (NCT03589326), was a randomized, controlled, multicenter, open-label phase 3 trial of 245 adult patients with newly diagnosed Ph+ ALL. Patients were randomized (2:1) to receive either ponatinib 30 mg orally once daily or imatinib 600 mg orally once daily with reduced-intensity chemotherapy. Chemotherapy consisted of 3 cycles of induction with vincristine and dexamethasone, 6 cycles of consolidation alternating between methotrexate and cytarabine, and 11 cycles of maintenance with vincristine and prednisone. Efficacy was based on the minimal residual disease (MRD)-negative complete response (CR) rate (BCR::ABL1 ≤0.01%     ) at the end of induction. The ponatinib dose was reduced to 15 mg once daily after completion of the induction phase and achievement of MRD-negative CR. The MRD-negative CR rate at the end of induction was 30% in the ponatinib arm and 12% in the imatinib arm (risk difference 0.18 [95% CI: 0.08, 0.28], p=0.0004). Benefit was observed across all subgroups, particularly for patients ≥60 years and for those with the BCR:ABL1 p190 variant. Ponatinib was associated with deeper and more durable responses and comparable safety versus imatinib.

Myelofibrosis

Splenomegaly at the time of allogeneic hematopoietic cell transplantation (HCT) in patients with primary or secondary myelofibrosis is associated with graft failure and poor graft function. Strategies to reduce spleen size before HCT especially after failure to Janus kinase (JAK) inhibition are scarce. A recent retrospective study included 59 patients (with primary myelofibrosis, post-polycythemia vera, and post-essential thrombocythemia myelofibrosis), that received      irradiation within a median of 2 weeks (range, 0.9– 12 weeks) before HCT. Overall, the median spleen size prior to irradiation was 23 cm (range, 14–35). Splenic irradiation resulted in a significant and rapid spleen size reduction in 57 of 59 (97%)      patients, with a median decrease of 5.0 cm (95% CI, 4.1–6.3 cm). The most frequent adverse event was thrombocytopenia. Independent predictors for survival were severe thrombocytopenia and anemia before irradiation, transplant-specific risk score, higher-     intensity conditioning, and present portal vein thrombosis.  Increased spleen size prior to irradiation was not significantly associated with graft failure (p = .10), worse survival (hazard ratio, 1.06; 95% CI, 0.98–1.16; p = .16), nor with non-relapse mortality or relapse incidence. However, further investigation into massive splenomegaly by dividing spleen size prior to irradiation into <30 versus ≥30 cm showed 3-year survival of 73% versus 41% (p = .01), and non-relapse mortality of 14% versus 58%, respectively (p = .02). No effect of spleen size after irradiation, total administered dose, or radiotherapy technology on outcomes was observed.  After propensity score matching, adjusted for common confounders, splenic irradiation was associated with a significantly reduced relapse incidence (p = .01), showing a 3-year incidence of 12% for splenic irradiation versus 29% for patients with immediate HCT and 38% for patients receiving splenectomy.