Acute myeloid leukemia (AML)

The ASAP trial (NCT02461537) was a German multicentre, open label, randomised controlled phase 3b trial testing the non-inferiority of immediate allogeneic hematopoietic stem cell transplantation (HSCT) compared with salvage chemotherapy intended to induce complete remission (CR) followed by allogeneic HSCT. Patients with non-favorable-risk AML not in CR after first induction or untreated first relapse were included. The primary endpoint was non-inferiority of CR on day 56 after allogeneic HSCT. Results of the ASAP trial suggest that predominantly AML biology and not the tumour load determines the prognosis after allogeneic HSCT.  281 patients were enrolled: 140 patients were randomly assigned to disease control (Arm A: sequential conditioning consisting of intensive chemotherapy followed by reduced-intensity conditioning) and 141 patients randomly assigned to remission induction (Arm B: high-dose cytarabine-based: 3 g/m2 intravenously [1 g/m2 intravenously for patients >60 years or with substantial comorbidity] twice daily on days 1–3 and mitoxantrone [10 mg/m2 intravenously] on days 3–5). Treatment success was observed in 116 (83%) of 140 patients in the disease control group versus 112 (79%) of 141 patients with remission induction (test for non-inferiority, p=0·036). Non-inferiority of disease control compared with remission induction could thus not be shown at the 2.5% significance level for the intention-to-treat (ITT) and per-protocol population (with a non-inferiority-margin of 5% ). Fewer patients with disease control compared with remission induction had non-hematological adverse events of grade 3 or worse (30 [21%] of 140 patients vs. 86 [61%] of 141 patients, p<0.0001).  In conclusion, non-inferiority of a disease-control strategy compared with remission induction before allogeneic HSCT could not be shown within pre-defined statistical boundaries. 

Infections in secondary hypogammaglobulinemia in hematological malignancies.

Recently an Australian and New Zealand multicenter, open-label, phase 2, randomised controlled feasibility trial  (RATIONAL trial; ACTRN12616001723471), was the first study to directly compare two strategies: immunoglobulin IV (IVIG) or antibiotics to prevent infections in patients with either a history of recurrent/severe infection or an immunoglobulin G level <4 g/L. Patients were randomised in a 1:2 ratio to IVIG (0.4 g/kg, monthly) or daily antibiotics (trimethoprim- sulfamethoxazole 160 mg/800 mg or, if contraindicated, 100 mg doxycycline) for 12 months. The primary outcome was proportion of patients alive on the assigned treatment 12 months after randomization. 63 patients were randomised: 42 to antibiotics and 21 to IVIG. The proportion of participants alive on allocated treatment at 12 months was 76% in the IVIG and 71% in the antibiotic arm (Fisher’s exact test p=0.77; odds ratio, 0.78; 95% CI, 0.22-2.52). The lower quartile for time to first major infection (median, not reached) was 11.1 months for the immunoglobulin and 9.7 months for the antibiotic arm (log-rank test, p=0.65). Three participants in the IVIG and two in the antibiotic arm had grade ≥3 treatment-related adverse events. A similar proportion of participants remained on antibiotic prophylaxis at 12 months to those on IVIG, with similar rates of major infections. The rates of major infections were similar between the two treatment arms. These findings support the feasibility of progressing to a larger phase 3 trial. 

Relapsed/refractory multiple myeloma (RRMM)

Multiple myeloma remains an incurable hematologic malignancy, but recent advances have  improved clinical outcomes. In particular, developments in B-cell maturation antigen (BCMA)–targeted approaches have shown strong results. Teclistamab, a BCMA- and CD3–targeting bispecific antibody, is an effective novel treatment for relapsed/refractory multiple myeloma (RRMM), but efficacy in patients exposed to BCMA-directed therapies and mechanisms of resistance have yet to be fully delineated (in the MajesTEC-1 study, patients with prior anti-BCMA therapy exposure were excluded from participation). Recently, authors at the Memorial Sloan Kettering Cancer Center (New York, USA) published the results of a real-world retrospective study of commercial teclistamab, recording clinical results as well as immunological markers of response to treatment in a patient cohort (n = 52) with advanced RRMM. Teclistamab was highly effective with an overall response rate (ORR) of 64%, including an ORR of 50% for patients with prior anti-BCMA therapy. Pretreatment plasma cell BCMA expression levels had no bearing on response.  Peripheral blood regulatory T cells (Tregs) were associated with teclistamab failure, whereas CD8+ effector T cells were associated with teclistamab response; Tregs expressing T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) can inhibit Th1- and Th17-mediated immune responses and if engaged by teclistamab, may hinder efficacy, and may further contribute to therapy resistance as suggested by previous studies. Several patients with grade 3 or 4 lymphopenia responded well to teclistamab, suggesting that lymphocyte composition, rather than quantity, is a key parameter of response.  

Cardiotoxicity and non-Hodgkin lymphoma (NHL)

Recently, the PROACT study was presented during a Late-Breaking Clinical Trial session at the American College of Cardiology (ACC.24) in Atlanta. To determine whether angiotensin-converting enzyme (ACE) inhibitors could help to prevent anthracycline cardiotoxicity, researchers conducted a UK multicenter, open-label trial which randomised 111 patients undergoing treatment for breast cancer (62%) or non-Hodgkin lymphoma (38%) to enalapril or placebo. All patients had negative troponin results at the start of the study and were due to receive six cycles of chemotherapy (≥300 mg/m2 doxorubicin equivalent). The anthracycline, mean dose was 328 mg/m2 doxorubicin equivalent. There was no significant difference in the primary endpoint of the proportion of patients who experienced a troponin T release, which occurred in 77.8% of the enalapril group, and 83.3% of the standard of care group (adjusted odds ratio, 0.65; p=0.405). Additionally, there was no significant difference between groups in terms of troponin I.  Outcomes were similar in the two groups for left ventricular ejection fraction, with 2% having a >10% reduction to <50%, and left ventricle global longitudinal strain, with 21% having a >15% relative decrease.  Based on the findings, researchers said “the field probably needs to find another [drug] candidate before starting again on another preventative study”. 

Triple negative-primary myelofibrosis (TN-PMF)

SETBP1  (a transcription factor) mutations are found in various clonal myeloid disorders. The involvement of SETBP1 in myeloid transformation is supported by several studies describing recurrent SETBP1 mutations in different clinical subtypes of myeloid malignancy. Recently, Crespiatico et al., showed that  SETBP1 mutations, acting as a first-hit/ early event, drive an aggressive myelofibrosis-like myeloproliferative disorder. The authors developed a mouse model expressing  mutant SETBP1G870S in the entire hematopoietic system. Using single-cell RNA-sequencing data, they found profound alterations in the differentiation program of hematopoietic progenitors and developed a myeloid neoplasm with megakaryocytic dysplasia, splenomegaly, and bone marrow fibrosis; these changes resembled a phenotype that is remarkably similar to the human PMF. The authors then identified SETBP1 mutations in 19.4% of a cohort of 36 TN-PMF patients.  They identified 2 distinct subgroups, one carrying SETBP1 mutations and the other completely devoid of somatic variants. Clinically, a striking difference in disease aggressiveness was noted, with patients with SETBP1 mutation showing a much worse clinical course. In contrast to myelodysplastic/myeloproliferative neoplasms, in which SETBP1 mutations are mostly found as a late clonal event, single-cell clonal hierarchy reconstruction in 3 patients with TN-PMF from our cohort revealed SETBP1 to be a very early event, suggesting that the phenotype of the different SETBP1+ disorders may be shaped by the opposite hierarchy of the same clonal SETBP1 variants. These data suggest that SETBP1 oncogenic mutations are certainly necessary, although perhaps not sufficient, to confer aggressiveness to the disease. A larger cohort of patients will need to be analyzed to confirm these findings. 

Mature T-cell lymphomas (TCL) and chimeric antigen receptor T (CAR T) therapies

Primary refractory or relapsed (R/R) TCL has a poor prognosis. Unfortunately, although CAR T therapies have transformed the care for patients with B-cell lymphomas, CAR T-cell therapy  has not yet had similar success in the treatment of TCL. The development of CAR T therapies to treat TCL often requires additional gene modifications to overcome fratricide because of shared T-cell antigens on normal and malignant T-cells.  Hill et al., recently published the first-in-human phase 1 study (NCT0308190), second-generation autologous CD5-directed CAR T-cells that produce minimal fratricide by down modulating CD5 protein levels in transduced T- cells while retaining strong cytotoxicity against CD5+ malignant cells. They report safety and efficacy data from a cohort of patients with mature TCL. Among the 17 patients enrolled with TCL, CD5 CAR T-cells were successfully manufactured for 13 out of 14 attempted lines (93%) and administered to 9 (69%) patients. The overall response rate (complete remission [CR] or partial response [PR]) was 44%, with CR observed in 2 patients. The most common grade 3 or higher adverse events were cytopenias. No grade 3 or higher cytokine release syndrome or neurologic events occurred. Two patients died during the immediate toxicity evaluation period due to rapidly progressive disease. These results demonstrated that CD5-directed CAR T-cells are safe and can induce clinical responses in patients with RR CD5-expressing TCLs without eliminating endogenous T-cells or increasing infectious complications. More patients and longer follow-up are needed for validation.