Histone deacetylase inhibitors in cancer therapy Rasheed, Walid K; Johnstone, Ricky W; Prince, H Miles
Expert opinion on investigational drugs,
05/2007, Letnik:
16, Številka:
5
Journal Article
Recenzirano
Histones are a family of nuclear proteins that interact with DNA, resulting in DNA being wrapped around a core of histone octamer within the nucleosome. Acetylation/deacetylation of histones is an ...important mechanism that regulates gene expression and chromatin remodeling. Histone deacetylase (HDAC) inhibitors are a new class of chemotherapeutic drugs that regulate gene expression by enhancing the acetylation of histones, and thus inducing chromatin relaxation and altering gene expression. HDAC inhibitors have been shown in preclinical studies to have potent anticancer activities. A range of structurally diverse HDAC inhibitors have been purified as natural products or synthetically produced. Due to the promising preclinical activity of these agents, numerous clinical trials have been initiated. In this review, the results of published data of single agent and combination trials of these drugs are reviewed, with a focus on dosing, scheduling and toxicity. Although still early in drug development, there is a picture that is starting to develop as to the common toxicities and which tumors seem to be the most susceptible to this class of drugs.
Multiple myeloma (MM) is a heterogeneous hematologic malignancy involving the proliferation of plasma cells derived by different genetic events contributing to the development, progression, and ...prognosis of this disease. Despite improvement in treatment strategies of MM over the last decade, the disease remains incurable. All efforts are currently focused on understanding the prognostic markers of the disease hoping to incorporate the new therapeutic modalities to convert the disease into curable one. We present this comprehensive review to summarize the current standard prognostic markers used in MM along with novel techniques that are still in development and highlight their implications in current clinical practice.
To study the outcomes of allo-HCT in patients with hematological malignancy who received BU3 (9.6 mg/kg) based conditioning from matched related or unrelated donors.
A retrospective analysis of ...KFSHRC- BMT Database, we identified 65 patients who received Allo-HCT between October 2005 and December 2019 at King Faisal Specialist Hospital & Research Center. The patients received SCT from full HLA matched related or unrelated donors. We excluded Mismatched MUD, Cord & Haplo-identical Stem Cell sources.
We identified 47 AML (72.3%), 8 MDS (12.3%), 8 Myelofibrosis (12.3%) & 2 CML (3.1%) patients. Acute GvHD grade II-IV and III-IV occurred in 29% and 14% respectively. Chronic GvHD occurred in 55% and was extensive in 24% of patients. With Median follow-up 60.5 months, 2 years and 5 years OS were 58.5 % and 44.1% respectively. The 2 years and 5 years DFS were 52.9% and 44.5% respectively. Cumulative incidence of relapse and NRM at 2- years were 29.5% and 17.4% respectively. Day +100 TRM were 10.7%
Allogeneic SCT using BU3 based regimen appears feasible to use in patients who are not suitable for fully myeloablative (BU4) regimen. TRM, DFS & OS rate were comparable to reports from studies using BU4 based regimen, warranting prospective studies in these patients.
Pediatric-inspired non-transplant regimens for adolescent and adult ALL patients are becoming standard in many institutions. We aimed to compare a cohort of patients receiving a pediatric-inspired ...protocol to a cohort of patients treated with adult type ALL therapy followed by allografting after achieving CR1.
Eighty-five adolescent and adult ALL patients treated with CALGB 19802 protocol who received MSD transplant in CR1 were retrospectively compared to a matched cohort of 72 adolescent and adult ALL patients treated with a modified version of Children's Cancer Group (CCG) 1900 protocol.
The five years OS in the allo-HCT cohort was 63.1% compared to 80.2% in the pediatric-inspired chemotherapy arm (P = 0.03). The five years EFS in the allo-HCT arm was 58.8% compared to 61.6% in the pediatric-inspired chemotherapy arm (P = 0.07). The five years DFS in the allo-HCT arm was 58.8% as compared to 71.9% in the pediatric-inspired chemotherapy arm (P = 0.07). The relapse rate in the allo-HCT cohort was 30.58% compared to 21.68% in the pediatric-inspired chemotherapy arm (P = 0.16). The NRM in the allo-HCT cohort was 10.59 as compared to 6.45 in the pediatric-inspired chemotherapy arm (P = 0.3).
For adolescent and adult patients with Ph-negative ALL, pediatric-inspired chemotherapy resulted in higher OS compared to allo-HCT.
The FMS-like tyrosine kinase 3 (FLT3) pathway has an important role in cellular proliferation, survival, and differentiation. Acute myeloid leukemia (AML) patients with mutated FLT3 have a large ...disease burden at presentation and a dismal prognosis. A number of FLT3 inhibitors have been developed over the years. The first-generation inhibitors are largely non-specific, while the second-generation inhibitors are more specific and more potent. These inhibitors are used to treat patients with FLT3-mutated AML in virtually all disease settings including induction, consolidation, maintenance, relapse, and after hematopoietic cell transplantation (HCT). In this article, we will review the use of FLT3 inhibitors in AML.
Health care costs attributed to biologics have increased exponentially in the recent years, thus biosimilars offer a possible solution to limit costs while maintaining safety and efficacy. Reducing ...expenditure is vital to health care especially in developing countries where affordability and access to health care is a major challenge. We discuss the opportunities and the challenges of biosimilars in the field of hematopoietic cell transplantation (HCT) in low- and lower-middle income countries. Developing countries can potentially invest in the forecasted costs reduction by utilizing biosimilars. This can be used to decrease the costs of procedures such as HCT, which is a rapidly growing field in many developing regions. The introduction of biosimilars in the developing regions faces many challenges which include, but are not limited to: legal and regulatory issues, lack of research infrastructure, and the presence of educational barriers. Thus, collaborative efforts are needed to ensure an effective and safe introduction of biosimilars into low- and lower-middle income countries.
Priming donors with G-CSF before BM harvest is reported to improve engraftment and GvHD in recipients. These effects are highly desirable when transplanting patients with non-neoplastic hematologic ...diseases, particularly AA patients. Here we retrospectively report the outcomes of 39 AA patients receiving a primed BM graft from MSD to 43 patients receiving a steady-state BM graft from MSD, otherwise transplanted using a uniform transplant platform. The graft had higher TNC and CD34 cell concentrations in the primed group (
p
< 0.001), and that was reflected in higher TNC and CD34 doses per kilogram of recipient in the primed group (
p
= 0.004 and 0.03, respectively). The OS for primed BM graft recipients was 97.4% and 78.9% for the steady-state BM graft recipients,
p
-value = 0.01. The cumulative incidence of death without GF was 2.6% in the primed group and 16.3% in the steady-state group,
p
-value = 0.03. There was no difference in GvHD incidence between the two groups. We confirm that priming improved the TNC and CD34 graft concentration and cell dose; this evidence along with other reported studies constitute reasonable evidence to prove that BM priming improve engraftment. We observed no increase in GvHD using primed BM graft.
Multiple myeloma (MM) represents the second most common hematologic malignancy (15%). Induction with bortezomib, cyclophosphamide, and dexamthasone VCd (d: low dose dexamthasone) regimen is widely ...used due to its high effectiveness, low toxicity and good tolerability, particularly with renal impairment. Real-world data on the use of VCD in clinical practice is lacking.
Evaluate the real-world experience of the VCD regimen.
Retrospective.
Tumor registry database of tertiary cancer care center.
newly diagnosed MM patients who received VCD induction and underwent autologous stem cell transplant (ASCT) from July 2007 to July 2020.
response evaluation, progression-free survival (PFS) and overall survival (OS).
87 patients.
Of 102 patients who started induction with VCd, 87 patients experienced a partial response or more overall response rate of 85%). The median age of these 87 patients at diagnosis was 52 years, of which 29.9% presented with renal impairment and 60.3% of patients had stage 2 by the Revised International Staging System (R-ISS). Patients with a standard cytogenetic risk achieved a better response compared to those with a poor cytogenetic risk (
=.044). The post-induction response rates were 6.9% stringent complete remission (sCR), 35% complete remission (CR); 41.4% very good partial response (VGPR), and 16.1% partial response (PR), respectively; the response rates became greater for sCR and CR post-transplantation at day 100 with 16.1% sCR, 35.6% CR, 32.2% VGPR and 16.1% PR, respectively. The median PFS was 49 months and 5 years OS was 84%. PFS was better in patients who achieved sCR vs PR (83 vs 35 months,
=.037). High LDH, high-risk cytogenetic and stage 3 R-ISS showed a worse median PFS and OS.
VCD induction in newly diagnosed MM is highly effective, convenient, tolerable and affordable regimen, especially in low and middle-income countries with limited resources, also with favorable outcomes and survival. while those who did not respond successfully shifted to VRD or VTD.
The usual limitations of a retrospective analysis using registry-level data, no data on quality of life.
Patients between 14 and 22 years old are underrepresented in both adult and pediatric studies. We analyzed the outcomes of 94 consecutive patients aged between 14 and 22 who underwent myeloablative ...matched related-donor transplant while in first or second complete remission. We studied the impact of disease type, remission status, ELN risk group, ABO mismatch, time from diagnosis to transplant, patient and donor age, conditioning type, stem cell source, and the year of transplant on transplant outcomes. The cumulative incidences of relapse, NRM, OS, and DFS at 5 years were 42%, 10%, 59%, and 48%, respectively. Absence of ABO mismatch and donor age > 20 were associated with better OS and DFS on univariate and multivariate analysis. The cumulative incidence of aGVHD and cGVHD were 18% and 44%, respectively. Donor age > 20 and peripheral blood stem cell source were significantly associated with higher incidence of cGVHD on univariate and multivariate analysis. Younger patient age was significantly associated with higher incidence of aGVHD. In this age group, the determinants of survival seem to be dependent on donor variables rather on the traditional disease and patient related variables. Relapse still a significant factor for transplant failure while NRM was low.
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