4 research outputs found
Loss-of-function but not dominant-negative intragenic IKZF1 deletions are associated with an adverse prognosis in adult BCR-ABL-negative acute lymphoblastic leukemia
Genetic alterations of the transcription factor IKZF1 (“IKAROS”) are detected
in around 15–30% of cases of BCR-ABL-negative B-cell precursor acute
lymphoblastic leukemia. Different types of intragenic deletions have been
observed, resulting in a functionally inactivated allele (“loss-of-function”)
or in “dominant-negative” isoforms. The prognostic impact of these alterations
especially in adult acute lymphoblastic leukemia is not well defined. We
analyzed 482 well-characterized cases of adult BCR-ABL-negative B-precursor
acute lymphoblastic leukemia uniformly treated in the framework of the GMALL
studies and detected IKZF1 alterations in 128 cases (27%). In 20%, the IKZF1
alteration was present in a large fraction of leukemic cells (“high deletion
load”) while in 7% it was detected only in small subclones (“low deletion
load”). Some patients showed more than one IKZF1 alteration (8%). Patients
exhibiting a loss-of-function isoform with high deletion load had a shorter
overall survival (OS at 5 years 28% vs. 59%; P<0.0001), also significant in a
subgroup analysis of standard risk patients according to GMALL classification
(OS at 5 years 37% vs. 68%; P=0.0002). Low deletion load or dominant-negative
IKZF1 alterations had no prognostic impact. The results thus suggest that
there is a clear distinction between loss-of-function and dominant-negative
IKZF1 deletions. Affected patients should thus be monitored for minimal
residual disease carefully to detect incipient relapses at an early stage and
they are potential candidates for alternative or intensified treatment
regimes. (clinicaltrials.gov identifiers: 00199056 and 00198991)
European Myeloma Network perspective on CAR T-cell therapies for multiple myeloma
Chimeric antigen receptor (CAR) T cells (CAR-T) have dramatically
changed the treatment landscape of B-cell malignancies, providing a
potential cure for relapsed/refractory patients. Long-term responses in
patients with acute lymphoblastic leukemia and non Hodgkin lymphomas
have encouraged further development in myeloma. In particular, B-cell
maturation antigen (BCMA)-targeted CAR-T have established very promising
results in heavily pre-treated patients. Moreover, CAR-T targeting other
antigens (i.e., SLAMF7 and CD44v6) are currently under investigation.
However, none of these current autologous therapies have been approved,
and despite high overall response rates across studies, main issues such
as long-term outcome, toxicities, treatment resistance, and management
of complications limit as yet their widespread use. Here, we critically
review the most important pre-clinical and clinical findings, recent
advances in CAR-T against myeloma, as well as discoveries in the biology
of a still incurable disease, that, all together, will further improve
safety and efficacy in relapsed/refractory patients, urgently in need of
novel treatment options
From transplant to novel cellular therapies in multiple myeloma: EMN guidelines and future perspectives.
Survival of myeloma patients has greatly improved with the use of autologous stem cell transplantation and novel agents, such as proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies. Compared to bortezomib- and lenalidomide-based regimens alone, the addition of high-dose melphalan followed by autologous transplantation significantly improves progression-free survival; although an overall survival benefit was not observed in all trials. Moreover, follow-up of recent trials is still too short to show any difference in survival. In the light of these findings, novel agent-based induction followed by autologous transplantation is considered the standard upfront treatment for eligible patients (level of evidence: 1A). Post-transplant consolidation and maintenance treatment can further improve patient outcome (1A). The availability of several novel agents has led to the development of multiple combination regimens as salvage treatment options. In this context, the role of salvage autologous transplantation and allotransplant have not been extensively evaluated. In case of prolonged remission after upfront autologous transplantation, another autologous transplantation at relapse can be considered (2B). Patients who experience early relapse and/or have high-risk features have a poor prognosis and may be considered as candidates for clinical trials that - in young and fit patients - may also include an allograft in combination with novel agents (2B). Ongoing studies are evaluating the role of novel cellular therapies, such as inclusion of antibody-based triplets and quadruplets and Chimeric Antigen Receptor-T cells: despite preliminary encouraging results, longer follow-up and larger patient numbers are needed before their clinical use can be widely recommended
PIM1 inhibition effectively enhances Plerixafor-induced HSC mobilization
The CXCL12/CXCR4 axis regulates the interaction of hematopoietic stem cells (HSCs) with
the niche and interruption of this pathway mobilizes HSCs from the bone marrow. Therefore
CXCR4 antagonists like plerixafor are clinically used to collect HSCs from patients who fail to
mobilize HSCs in response to G-CSF. Nevertheless plerixafor mobilization fails in 30% of the
patients and the collection window lasts only 4-6h. As the CXCR4 surface expression on
HSCs is regulated by the serine/threonine kinase PIM1, we aimed to improve HSC
mobilization by combining CXCR4 and PIM1 inhibition. We found that CXCR4 inhibition
using plerixafor leads to a compensatory upregulation of CXCR4 surface expression on
HSCs. This effect can be reverted by deficiency or inhibition of PIM1. Consequently, HSC
mobilization using plerixafor is strongly enhanced in Pim1-deficient mice. Likewise, treatment
of WT animals with plerixafor in combination with the pan-PIM-inhibitor LGB321 leads to
increased HSC mobilization. Furthermore, Cxcl-12 expression as well as CXCR4 surface
expression in CXCL12-abundant reticular (CAR) cells is dramatically decreased in Pim1-
deficient mice, resulting in impaired retention of HSCs. Targeting PIM kinases in combination
with CXCR4 inhibition could thus improve the collection of stem cells in patients at risk for
poor mobilization