Building a better blinatumomab Litzow, Mark R.
American journal of hematology,
April 2024, 2024-Apr, 2024-04-00, 20240401, Letnik:
99, Številka:
4
Journal Article
T-cell immunophenotype of acute lymphoblastic leukemia (T-ALL) is an uncommon aggressive leukemia that can present with leukemic and/or lymphomatous manifestations. Molecular studies are enhancing ...our understanding of the pathogenesis of T-ALL, and the discovery of activating mutations of NOTCH1 and FBXW7 in a majority of patients has been a seminal observation. The use of pediatric intensive combination chemotherapy regimens in adolescents and young adults has significantly improved the outcome of patients with T-ALL. The use of nelarabine for relapsed and refractory T-ALL results in responses in a substantial minority of patients. Allogeneic hematopoietic cell transplantation (HCT) still plays a key role in patients with high-risk or relapsed/refractory disease. γ-Secretase inhibitors hold promise for the treatment of patients with NOTCH1 mutations, and the results of clinical trials with these agents are eagerly awaited. It is recommended that younger patients receive a pediatric-intensive regimen. Older and unfit patients can receive suitable multiagent chemotherapy and be allocated to HCT based on their response, risk factors, and comorbidities. Although advances in the treatment of T-ALL have lagged behind those of B-cell ALL, it is hoped that the molecular revolution will enhance our understanding of the pathogenesis and treatment of this aggressive lymphoid malignancy.
N
-methyladenosine (m
A) on mRNAs is critical for various biological processes, yet whether m
A regulates drug resistance remains unknown. Here we show that developing resistant phenotypes during ...tyrosine kinase inhibitor (TKI) therapy depends on m
A reduction resulting from FTO overexpression in leukemia cells. This deregulated FTO-m
A axis pre-exists in naïve cell populations that are genetically homogeneous and is inducible/reversible in response to TKI treatment. Cells with mRNA m
A hypomethylation and FTO upregulation demonstrate more TKI tolerance and higher growth rates in mice. Either genetic or pharmacological restoration of m
A methylation through FTO deactivation renders resistant cells sensitive to TKIs. Mechanistically, the FTO-dependent m
A demethylation enhances mRNA stability of proliferation/survival transcripts bearing m
A and subsequently leads to increased protein synthesis. Our findings identify a novel function for the m
A methylation in regulating cell fate decision and demonstrate that dynamic m
A methylome is an additional epigenetic driver of reversible TKI-tolerance state, providing a mechanistic paradigm for drug resistance in cancer.
Patients 70 years of age or younger with previously untreated CLL were randomly assigned to receive ibrutinib plus rituximab or chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab. ...The ibrutinib-based regimen led to prolonged progression-free and overall survival.
The likelihood of finding HLA-matched unrelated donors for rare HLA types and non-white European ancestry continues to be a challenge with less than a 70% chance of finding a full match. Mismatched ...transplants continue to have high rates of transplant-related mortality. With the near-universal ability to find a haploidentical donor in families, haploidentical transplants have become of more critical importance in ethnic minority groups and patients with rare HLA types.
Data was collected through clinical trials, review articles, and case reports published in the National Library of Medicine.
The use of improved lymphodepleting conditioning regimens, graft versus host disease (GVHD) prophylaxis using regimens such as post-transplant cyclophosphamide, mycophenolate, and tacrolimus have improved engraftment to nearly 100 percent and reduced transplant-related mortality to less than 20 percent. Attention to donor-specific antibodies (DSAs) with interventions using bortezomib, rituximab, and plasmapheresis has decreased graft failure rates.
With improved prevention of GVHD with interventions such as post-transplant cyclophosphamide and management of DSAs, haploidentical transplants continue to improve transplant-related mortality (TRM) compared to patients who received matched-related donor transplants. While TRM continues to improve, ongoing research with haploidentical transplants will focus on improving graft and donor immunosuppression and identifying the best regimens to improve TRM without compromising relapse-free survival.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The Philadelphia chromosome positive arm of the UKALLXII/ECOG2993 study for adult acute lymphoblastic leukemia (ALL) enrolled 266 patients between 1993 and 2003 (pre-imatinib cohort). In 2003 ...imatinib was introduced as a single-agent course following induction (N = 86, late imatinib). In 2005 imatinib was added to the second phase of induction (N = 89, early imatinib). The complete remission (CR) rate was 92% in the imatinib cohort vs 82% in the preimatinib cohort (P = .004). At 4 years, the overall survival (OS) of all patients in the imatinib cohort was 38% vs 22% in the preimatinib cohort (P = .003). The magnitude of the difference between the preimatinib and imatinib cohorts in event-free survival (EFS), OS, and relapse-free survival (RFS) seen in univariate analysis was even greater in the multivariate analysis. In the preimatinib cohort, 31% of those starting treatment achieved hematopoietic stem cell transplant (alloHSCT) compared with 46% in the imatinib cohort. A Cox multivariate analysis taking alloHSCT into account showed a modest additional benefit to imatinib (hazard ratio for EFS = 0.64, 95% confidence interval 0.44-0.93, P = .02), but no significant benefit for OS and RFS. Adding imatinib to standard therapy improves CR rate and long-term OS for adults with ALL. A proportion of the OS benefit derives from the fact that imatinib facilitates alloHSCT. This trial was registered at clinicaltrials.gov as NCT00002514.
•Imatinib improves outcomes for adults with Ph+ ALL at least in part by facilitating allogeneic stem cell transplant.•Allogeneic hematopoietic stem cell transplant is not dispensible in Ph+ ALL in the imatinib era.
Before the advent of tyrosine kinase inhibitors (TKIs), Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) was associated with dismal survival without allogeneic hematopoietic ...stem cell transplantation (allo-HSCT). Recent evidence has demonstrated that the combination of TKI and chemotherapy can result in a high rate of complete remission, thereby enabling more patients to proceed to allo-HSCT. However, with more studies reporting non-inferior outcomes with TKI and chemotherapy combination without allo-HSCT, the need for allo-HSCT in Ph+ ALL has become less certain. This review summarizes evidence that will address the relevance of allo-HSCT in Ph+ ALL.
The initial encouraging activity of ruxolitinib in myelofibrosis appears to need some caveats when long-term efficacy is examined. The control of splenomegaly may not be durable, and the likelihood ...of leukemic progression or death is not dramatically lowered.
To the Editor:
JAK-STAT is an attractive drug target in patients with myelofibrosis because they often carry a
JAK2
mutation and also have an abnormally increased level of inflammatory cytokines.
1
Ruxolitinib (INCB018424) is a small-molecule ATP mimetic that inhibits both JAK1 and JAK2 and has been evaluated for its therapeutic activity in patients with myelofibrosis in phase 1, 2, and 3 clinical trials. The results of a phase 1/2 study of ruxolitinib involving 153 patients with myelofibrosis were recently published.
2
Our report constitutes a sponsor-independent analysis of long-term outcomes in the 51 patients at the Mayo Clinic who participated in . . .
Chromosomal rearrangements are a hallmark of acute lymphoblastic leukemia (ALL) and are important ALL initiating events. We describe four different rearrangements of the erythropoietin receptor gene ...EPOR in Philadelphia chromosome-like (Ph-like) ALL. All of these rearrangements result in truncation of the cytoplasmic tail of EPOR at residues similar to those mutated in primary familial congenital polycythemia, with preservation of the proximal tyrosine essential for receptor activation and loss of distal regulatory residues. This resulted in deregulated EPOR expression, hypersensitivity to erythropoietin stimulation, and heightened JAK-STAT activation. Expression of truncated EPOR in mouse B cell progenitors induced ALL in vivo. Human leukemic cells with EPOR rearrangements were sensitive to JAK-STAT inhibition, suggesting a therapeutic option in high-risk ALL.
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•Multiple EPOR rearrangements are recurrent in high-risk acute lymphoblastic leukemia•EPOR rearrangements truncate the C terminus of EPOR and stabilize expression of the receptor•Truncated EPOR is hypersensitive to EPO stimulation•Truncated EPOR is leukemogenic and sensitive to JAK-STAT inhibition
Iacobucci et al. show that recurrent EPOR rearrangements occur exclusively in Ph-like acute lymphoblastic leukemia (ALL), resulting in the expression of C-terminal truncated EPOR mutants that have heightened JAK-STAT signaling in response to erythropoietin and confer sensitivity to JAK-STAT inhibition in cases with these rearrangements.
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