Hemoglobinopathies & gene edition

Exagamglogene autotemcel (exa-cel [Casgevy, Vertex Pharmaceuticals/CRISPR Therapeutics]) is a nonviral cell therapy designed to reactivate fetal hemoglobin synthesis through ex vivo clustered regularly interspaced short palindromic repeats (CRISPR)–Cas9 gene editing of the erythroid-specific enhancer region of BCL11A in autologous CD34+ hematopoietic stem and progenitor cells (HSPCs); exa-cel is akin to “molecular scissors'' that cleave and disrupt an enhancer, and reactivates γ-globin gene expression. Exa-cel has been approved by regulators in the US and the UK to treat transfusion-dependent β²-thalassemia (TDBT) and sickle cell disease (SCD). Recently the NEJM published two open-label, single-group, phase 3 studies with exa-cel in patients with severe SCD (CLIMB SCD-121 study) or TDBT (CLIMB THAL-111 study). Both studies included patients aged 12 to 35 years, before infusion of exa-cel, they underwent myeloablative conditioning with busulfan.

The CLIMB SCD-121 study (NCT03745287) included patients (n=44) with SCD who had had at least two severe vaso-occlusive crises in each of the two years before screening. The median follow-up was 19.3 months (range, 0.8 to 48.1).  Of the 30 patients who had sufficient follow-up to be evaluated, 29 (97%; 95% confidence interval [CI], 83 to 100) were free from vaso-occlusive crises for at least 12 consecutive months (primary endpoint), and all 30 (100%; 95% CI, 88 to 100) were free from hospitalizations for vaso-occlusive crises for at least 12 consecutive months (P<0.001 for both comparisons).

The CLIMB THAL-111 study (NCT03655678) included patients (n=52) with TDBT a β⁰/β⁰, β⁰/β⁰-like, or non–β⁰/β⁰-like genotype. The median follow-up was 20.4 months (range, 2.1 to 48.1). Among the 35 patients with sufficient follow-up data for evaluation, transfusion independence (primary endpoint) occurred in 32 (91%; 95% CI, 77 to 98; P<0.001). During transfusion independence, the mean total hemoglobin level was 13.1 g/dl, and the mean fetal hemoglobin level was 11.9 g/dl; the fetal hemoglobin had a pancellular distribution (≥94% of red cells).

In both studies, the safety profile of exa-cel was generally consistent with that of myeloablative busulfan conditioning and autologous HSPC transplantation. No cancers occurred. These two publications are accompanied by a “perspective” entitled “Welcoming the Era of Gene Editing in Medicine”, an editorial commentary, and a “correspondence”.

Chimeric antigen receptor T cell (CAR T) therapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT)

In cases of relapsed or refractory acute leukemia or lymphoma, might CAR T therapy serve as a bridge to allo-HSCT? Recently a Chinese group tested a strategy consisting of sequential CD7 CAR T therapy and haploidentical HSCT in 10 patients with relapsed or refractory CD7-positive leukemia or lymphoma (including 7 with acute myeloid leukemia and 3 with T-cell acute lymphoblastic leukemia/lymphoma). All the patients were included in clinical trials studying the use of allogeneic CD7 CAR T therapy in patients with CD7-positive leukemia. After CAR T therapy led to complete remission with incomplete hematologic recovery (CRi), patients received haploidentical HSCT without pharmacologic myeloablation or graft-versus-host disease (GVHD) prophylaxis drugs. All 10 patients had CRi. After haploidentical HSCT, 1 patient died on day 13 (septic shock/encephalitis), 8 patients had full donor chimerism, and 1 patient had autologous hematopoiesis. Three patients had grade 2 HSCT-associated acute GVHD. The median follow-up was 15.1 months (range, 3.1 to 24.0) after CAR T therapy. Six patients remained in minimal residual disease-negative CR, 2 had a relapse of CD7-negative leukemia, and 1 died of septic shock at 3.7 months. The estimated 1-year overall survival was 68% (95% CI, 43 to 100), and the estimated 1-year disease-free survival was 54% (95% CI, 29 to 100). A phase 1 clinical trial of sequential allogeneic CD7 CAR T therapy and haploidentical HSCT in a larger cohort is ongoing (NCT05827835). 

Primary sinonasal diffuse large B-cell lymphoma (PSDLBCL)

PSDLBCL is an uncommon lymphoma affecting the skin and central nervous system that has a variable prognosis and unusual behavior. A study of 117 patients with PSDLBCL was recently published. The distribution in cell-of-origin (COO) was 68 (58%) activated B-cell (ABC), 44 (38%) germinal center B-cell (GCB), and 5 (4%) unclassifiable. COO was significantly associated with progression-free survival (PFS) and lymphoma-specific mortality (LSM) in both the overall cohort (5-year PFS: ABC, 43% vs. GCB, 73%; LSM: ABC, 45% vs. GCB, 14%) and in the subgroup of patients receiving immunochemotherapy (5-year PFS: ABC, 55% vs. GCB, 85%; LSM: ABC, 28% vs. GCB, 0%). ABC lymphomas were mainly MCD (MYD88/CD79B-mutated) class, showing a high prevalence of MYD88 (74%) and CD79B (35%) mutations compared with GCB lymphomas (MYD88 23%; CD79B 10%) (p<0.01). The ABC subtype frequently displayed cMYC/BCL2 co-expression (76% vs. 18% GCB; p<0.001) and HLA-II loss (48% vs. 10% GCB; p<0.001). All lymphomas were Epstein-Barr virus-negative. ABC and GCB subtype sinonasal DLBCLs are geno- and phenotypically distinct entities, exhibiting a contrasting disease course and prognosis. 

Polycythemia vera (PV)

Established risk factors for thrombotic events (TE) in patients with PV include advanced age, TE history, and elevated hematocrit. The Prospective Observational Study of Patients with PV in US Clinical Practices (REVEAL; NCT02252159) included a total of 2510 patients with a median follow-up of 3.7 years, and it is the largest prospective study in PV published to date.  Analysis of 2271 participants identified 142 TE in 106 patients. Significant associations with initial TE occurrence during the study period were observed for hematocrit level >45% (hazard ratio [HR], 1.84; 95% CI, 1.23-2.75; p=0.0028) and leukocytes >11 × 109/L (HR, 2.35; 95% CI, 1.60-3.47; p<0.0001). Leucocyte count was significantly associated with initial TE occurrence in both low- and high-risk PV. When hematocrit was controlled at ≤ 45%, leucocyte count >12 × 109/L was significantly associated with TE occurrence (HR, 1.95; 95% CI, 1.07-3.55; p=0.0300). 

Warts, Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) syndrome

A randomized (1:1), double-blind, placebo-controlled, phase 3 trial (NCT03995108), evaluated the efficacy and safety of mavorixafor (an oral CXCR4 [carboxyl terminus of C-X-C chemokine receptor type 4] antagonist) for patients with WHIM syndrome, a rare immunodeficiency caused by CXCR4  gain-of-function variants: leading to impaired leukocyte trafficking between bone marrow and blood, with key clinical features including chronic and severe neutropenia, lymphopenia, monocytopenia, hypogammaglobulinemia, and myelokathexis. WHIM syndrome treatment options are primarily supportive, consisting of granulocyte colony-stimulating factor (G-CSF), immunoglobulin replacement therapy (IgRT), and antimicrobial prophylaxis. This study included patients aged ≥12 years and an absolute neutrophil count (ANC) ≤400/μL. This clinical trial showed that the treatment with mavorixafor reduced infection frequency, severity, duration, and antibiotic use. Patients received once-daily mavorixafor or placebo for 52 weeks. Primary endpoint was time (hours) above ANC threshold ≥500/μL (TATANC; over 24 hours).  In 31 participants (mavorixafor, n=14; placebo, n=17), mavorixafor least squares (LS) mean TATANC was 15.0 hours, placebo 2.8 hours (p<0.001). Mavorixafor LS mean TATANC was 15.8 hours, placebo 4.6 hours (p<0.001). Annualized infection rates were 60% lower with mavorixafor versus placebo (LS mean 1.7 versus 4.2; nominal p=0.007) and total infection scores were 40% lower (7.4 [95% CI, 1.6-13.2] versus 12.3 [95% CI, 7.2-17.3]). No discontinuations occurred due to treatment-emergent adverse events (TEAEs) and no related serious TEAEs were observed.

Post-transplant lymphoproliferative disorder (PTLPD)

The TIDaL (ISRCTN32667607) study was a single-arm phase 2 trial investigating the activity and tolerability of ibrutinib combined with risk-stratified therapy for first-line treatment of CD20-positive B-cell PTLPD after solid organ transplant in 39 patients. Initial course of treatment comprised 49 days of ibrutinib at 560mg once daily, with four doses of weekly rituximab. Treatment response on interim scan, and baseline international prognostic index were used to allocate patients to either a low-risk arm (who continued ibrutinib, alongside 4 further doses of 3-weekly rituximab) or high-risk (escalation to R-CHOP immunochemotherapy, ibrutinib continuing in patients aged <65 years). The primary outcome was a complete response on the interim scan, achieved by 11/38 patients (29%, 95% CI 15% - 46%). This did not reach the pre-specified threshold for clinically significant activity.  

Diffuse large B-cell lymphoma (DLBCL)

Genentech, a member of the Roche Group, recently announced  that the phase III STARGLO study (NCT04408638) in patients with relapsed or refractory DLBCL met its primary endpoint of overall survival in favor of Columvi® (     glofitamab: a CD20×CD3 bispecific antibody that brings the T cell in close proximity to the B cell, activating the release of cancer cell-killing proteins from the T cell) combined with chemotherapy (gemcitabine and oxaliplatin [GemOx]) versus rituximab combined with GemOx. Safety of the combination appeared consistent with the known safety profiles of the individual medicines. “The data will be submitted to health authorities and shared at an upcoming medical meeting”.