Asciminib plus dasatinib and prednisone for Philadelphia chromosome-positive acute leukemia [Phase 1 clinical trial].

Highlights:

●       Dasatinib, asciminib (an allosteric inhibitor of BCR::ABL1), and prednisone can be safely combined for the dual targeting of BCR::ABL1 in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).

●       Dasatinib and asciminib combination treatment has promising efficacy for the upfront treatment of Ph+ ALL.

In this phase 1 study (NCT03595017), 24 adults with Ph+ ALL (n = 22) and chronic myeloid leukemia in lymphoid blast crisis (n = 2) were treated with escalating daily doses of asciminib in combination with dasatinib 140 mg daily plus prednisone 60 mg/"m2" daily to determine the maximum tolerated dose. After a 28-day induction, dasatinib and asciminib were continued indefinitely or until hematopoietic stem cell transplant. The median age was 64.5 years (range, 33-85; 50% aged ≥65 years). The recommended phase 2 dose of asciminib was 80 mg daily.

Ibrutinib plus venetoclax in relapsed or refractory mantle cell lymphoma (SYMPATICO): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study [clinical trial].  

Highlights: 

●       The combination of ibrutinib and venetoclax significantly improved progression-free survival (PFS) compared with ibrutinib and placebo in patients with relapsed or refractory mantle cell lymphoma (RR-MCL). The safety profile was consistent with the known safety profiles of the individual drugs.

●       Improvements in PFS were generally robust across prespecified subgroups, including in the subgroup of patients with a TP53 mutation.

SYMPATICO (NCT03112174) is a multicentre, randomized, double-blind, placebo-controlled, phase 3 study performed at 84 hospitals in Europe, North America, and Asia–Pacific. Patients aged ≥18 years (n=267) with pathologically confirmed RR-MCL after one to five previous lines of therapy and an Eastern Cooperative Oncology Group performance status of 0–2 were randomly assigned (1:1) to receive oral ibrutinib 560 mg once daily concurrently with oral venetoclax (5-week ramp-up to 400 mg once daily) or placebo for 2 years, then single-agent ibrutinib 560 mg once daily until disease progression or unacceptable toxicity with a median follow-up of 51 months (IQR, 48–55). The primary endpoint was investigator-assessed PFS in the intention-to-treat population. 

VITT-like Monoclonal Gammopathy of Thrombotic Significance [Case series].

Highlights: 

●       Vaccine-induced immune thrombocytopenia and thrombosis (VITT) is associated with antibodies that target platelet factor 4 (PF4) and are heparin-independent. VITT antibodies are implicated in acute, transient prothrombotic disorders that are triggered by adenoviral vector vaccines against coronavirus disease 2019 or by adenovirus infection.

●       The authors describe chronic prothrombotic disorders featuring anticoagulant-refractory thromboses and intermittent thrombocytopenia that were associated with VITT-like antibodies in five patients (four patients with newly reported cases and the index patient). The patients had low levels of M proteins; in each patient, they found that the M protein was the VITT-like antibody (on mass spectrometry, serum anti-PF4 antibodies matched with serum paraproteins). The antibody clonotype profiles and binding epitopes on PF4 were different from those observed with the acute disorders occurring after vaccination or viral infection, features that reflect distinct immunopathogenesis.

●       Treatment strategies besides anticoagulation alone are needed for the chronic disorders, referred to as VITT-like monoclonal gammopathy of thrombotic significance.

CAR+ T-Cell Lymphoma after Cilta-cel Therapy for Relapsed or Refractory Myeloma [Case series].

The authors describe two patients in whom malignant monoclonal T-cell lymphoproliferation developed after administration of chimeric antigen receptor (CAR) T-cell therapy with ciltacabtagene autoleucel (cilta-cel) in the phase 3 CARTITUDE-4 trial. Monoclonal T-cells from both patients had detectable CAR transgene expression and integration.  In the absence of direct evidence, the contribution of insertional mutagenesis to the development of T-cell lymphoma is currently unclear.

European Myeloma Network Group Review and Consensus Statement on Primary Plasma Cell Leukemia [Guidelines].  

Key points: 

●       According to the criteria recently proposed by the 2021 International Myeloma Working Group, primary plasma cell leukemia (PPCL) is currently defined by the presence of ≥ 5% of clonal, circulating plasma cells in peripheral blood smears (at least 200 circulating nucleated cells per smear should be systematically analyzed by an experienced hematologist), in patients concomitantly (but not previously) diagnosed with symptomatic multiple myeloma (MM).

●       PPCL should be distinguished from secondary plasma cell leukemia, which constitutes the leukemic evolution of a pre-existing MM.

●       The presence of t(11;14) could represent a favorable marker.

●       Preferable first-line approach for transplant-eligible (TE) PPCL patients, the use of quadruplets including anti-CD38 antibodies, immunomodulatory drugs (IMIDs), proteasome inhibitors (PIs) and dexamethasone for four cycles, followed by double autologous stem cell transplantation (AuSCT) with high-dose melphalan as conditioning regimen in fit subjects up to 70 years of age (See Figure 1 in the original article).

●       Consolidation with the same induction treatment, followed by maintenance until progression or lack of tolerability (ideally with a double drug approach, i.e., lenalidomide plus carfilzomib or, preferably, adding an anti-CD38 monoclonal antibody) could be reasonable post-transplant treatments.

●       Most of the panel does not recommend allogeneic stem cell transplantation (AlloSCT) in the context of first-line approaches. However, AuSCT followed by a reduced intensity conditioning AlloSCT, if an appropriate donor is available, could be an option to consider for selected TE patients who do not achieve complete response after induction.

●       In transplant, non-eligible but fit PPCL patients, triplets, or quadruplets (when available), including anti-CD38 antibodies, PIs, and/or IMIDs plus dexamethasone, could be currently an appropriate first-line option for these PPCL patients, ideally until a response is maintained, or significant toxicities occur.

●       In very old and/or frail individuals, personalized treatments (i.e., dose and time-adjusted combinations of lenalidomide or bortezomib plus dexamethasone, along with the generally well-tolerated adjunct of an anti-CD38 monoclonal antibody) should be considered in addition to supportive therapy, aiming to maintain these patients on therapy as long as possible (See Figure 2 in the original paper).

●       The prognosis of refractory/relapsed PPCL is extremely poor, and current salvage therapies are rarely effective. A switch to drugs not used at diagnosis should be considered, favoring combinations with new-generation IMIDs and PIs plus dexamethasone and monoclonal antibodies. According to age and frailty (See Figure 3 in the original article). “Lymphoma-like” chemotherapy, as a bridge to AlloSCT in younger, eligible patients with sensitive disease at relapse, could be an option. However, when available, other treatments with T-cell redirecting therapies could represent preferable alternatives. Venetoclax, as a single agent or combined with other drugs, could be a possible option in patients harboring t(11;14 ).