Background
The outcome of older patients with newly diagnosed, Philadelphia chromosome (Ph)‐negative acute lymphoblastic leukemia (ALL) is poor. The combination of targeted therapy with low‐intensity ...chemotherapy is safe and effective. The objective of the current analysis was to compare the outcome of patients who received a combination of inotuzumab ozogamicin plus low‐intensity chemotherapy (mini–hyperfractionated cyclophosphamide, vincristine, and dexamethasone mini‐HCVD) with or without blinatumomab versus the outcome of those who received the standard, intensive, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (HCVAD) regimen.
Methods
The authors analyzed 135 older patients with newly diagnosed, Ph‐negative ALL who were treated prospectively with standard HCVAD (n = 77) or with the combination of inotuzumab ozogamicin plus mini‐HCVD with or without blinatumomab (n = 58). A propensity score analysis was conducted using 1:1 matching using the nearest neighbor matching method.
Results
Propensity score matching identified 38 patients in each cohort. The antibody plus low‐intensity chemotherapy combination induced higher response rates (98% vs 88%), with lower rates of early death (0% vs 8%) and lower rates of death in complete remission (5% vs 17%). With propensity score matching, the 3‐year event‐free survival rates for patients who received HCVAD and those who received the combination of inotuzumab ozogamicin plus mini‐HCVD with or without blinatumomab were 34% and 64%, respectively (P = .003), and the 3‐year overall survival rates were 34% and 63%, respectively (P = .004). By multivariate analysis, age (P = .019; hazard ratio, 1.045) and the combination of inotuzumab plus mini‐HCVD with or without blinatumomab (P = .020; hazard ratio, 0.550) were identified as independent prognostic factors for survival.
Conclusions
The combination of inotuzumab ozogamicin plus mini‐HCVD with or without blinatumomab is safe and effective in older patients with newly diagnosed, Ph‐negative ALL and confers a better outcome compared with standard HCVAD chemotherapy.
The combination of inotuzumab ozogamicin plus mini–hyperfractionated cyclophosphamide, vincristine, and dexamethasone with or without blinatumomab is safe and effective in older patients with newly diagnosed, Philadelphia chromosome‐negative acute lymphoblastic leukemia and confers a better outcome compared with standard hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone chemotherapy.
Transcriptome sequencing has identified multiple subtypes of B-progenitor acute lymphoblastic leukemia (B-ALL) of prognostic significance, but a minority of cases lack a known genetic driver. Here, ...we used integrated whole-genome (WGS) and -transcriptome sequencing (RNA-seq), enhancer mapping, and chromatin topology analysis to identify previously unrecognized genomic drivers in B-ALL. Newly diagnosed (n = 3221) and relapsed (n = 177) B-ALL cases with tumor RNA-seq were studied. WGS was performed to detect mutations, structural variants, and copy number alterations. Integrated analysis of histone 3 lysine 27 acetylation and chromatin looping was performed using HiChIP. We identified a subset of 17 newly diagnosed and 5 relapsed B-ALL cases with a distinct gene expression profile and 2 universal and unique genomic alterations resulting from aberrant recombination-activating gene activation: a focal deletion downstream of PAN3 at 13q12.2 resulting in CDX2 deregulation by the PAN3 enhancer and a focal deletion of exons 18-21 of UBTF at 17q21.31 resulting in a chimeric fusion, UBTF::ATXN7L3. A subset of cases also had rearrangement and increased expression of the PAX5 gene, which is otherwise uncommon in B-ALL. Patients were more commonly female and young adult with median age 35 (range,12-70 years). The immunophenotype was characterized by CD10 negativity and immunoglobulin M positivity. Among 16 patients with known clinical response, 9 (56.3%) had high-risk features including relapse (n = 4) or minimal residual disease >1% at the end of remission induction (n = 5). CDX2-deregulated, UBTF::ATXN7L3 rearranged (CDX2/UBTF) B-ALL is a high-risk subtype of leukemia in young adults for which novel therapeutic approaches are required.
Hypomethylating agents (HMAs) improve survival in patients with higher-risk myelodysplastic syndromes (MDS) but are less well-studied in lower-risk disease. We compared the safety and efficacy of ...low-dose decitabine vs low-dose azacitidine in this group of patients. Adults with low- or intermediate 1-risk MDS or MDS/myeloproliferative neoplasm (MPN), including chronic myelomonocytic leukemia, according to the International Prognostic Scoring System, were randomly assigned using a Bayesian adaptive design to receive either azacitidine 75 mg/m2 intravenously/subcutaneously daily or decitabine 20 mg/m2 intravenously daily for 3 consecutive days on a 28-day cycle. The primary outcome was overall response rate (ORR). Between November 2012 and February 2016, 113 patients were treated: 40 (35%) with azacitidine and 73 (65%) with decitabine. The median age was 70 years; 81% of patients were intermediate 1-risk patients. The median number of cycles received was 9. The ORRs were 70% and 49% (P = .03) for patients treated with decitabine and azacitidine, respectively. Thirty-two percent of patients treated with decitabine became transfusion independent compared with 16% of patients treated with azacitidine (P = .2). Cytogenetic response rates were 61% and 25% (P = .02), respectively. With a median follow-up of 20 months, the overall median event-free survival was 18 months: 20 and 13 months for patients treated with decitabine and azacitidine, respectively (P = .1). Treatment was well tolerated, with a 6-week mortality rate of 0%. The use of low-dose HMAs is safe and effective in patients with lower-risk MDS and MDS/MPN. Their effect on the natural history of lower-risk disease needs to be further studied. This trial was registered at clinicaltrials.gov (identifier NCT01720225).
•Low-dose hypomethylating agents are safe and effective in patients with lower-risk MDS and MDS/MPN.•Decitabine was associated higher response rates compared with azacitidine, especially in patients with higher-risk features.
Hypomethylating agents (HMAs) are the standard of care for patients with myelodysplastic syndromes (MDS). Although these agents induce responses in up to 40% of patients, most patients ultimately ...experience loss of response. The purpose of this review is to provide an overview of the different therapies under development for MDS after HMA therapy.
Recent advances in the understanding of MDS pathogenesis have led to the development of new potential therapies after HMA failure. Newer HMAs, less susceptible to in-vivo deamination, such as guadecitabine or ASTX727 have shown activity. Alterations of immune checkpoints in MDS have led to multiple clinical trials evaluating the activity of monoclonal antibodies targeting these proteins (pembrolizumab, nivolumab, ipilimumab). Different combinations and new formulations of cytotoxic agents, such as clofarabine or CPX-351, are newer options for specific subsets of patients. Finally, targeted agents inhibiting multiple kinases (rigosertib), BCL2 (venetoclax) or mutant IDH1 (ivosidenib), IDH2 (enasidenib), FLT3 (sorafenib, midostaurin) or spliceosome components (H3B-8800) are other novel options.
Despite the poor prognosis associated with HMA failure, clinical trials, new cytotoxic agents and allogeneic stem-cell transplantation, can offer therapeutic opportunities for these patients for whom there is no standard of care.
Philadelphia chromosome-positive (Ph+) advanced leukemias, including acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) in myeloid blast phase (MBP), have poor outcomes. Venetoclax has ...shown synergism with BCR-ABL1 tyrosine kinase inhibitors (TKI) in preclinical studies. However, clinical activity of venetoclax and TKI-based regimens is unknown.
We conducted a retrospective study on patients with Ph+ AML (n = 7) and CML-MBP (n = 9) who received venetoclax combined with TKI-based regimens at our institution.
Median patient age was 42 years, and the median number of prior therapy cycles was 5 (range 2-8). Nine patients received decitabine-based, and 7 received intensive chemotherapy-based regimens. Ten patients (63%) received ponatinib. The overall response rate (ORR) in 15 evaluable patients was 60% (1 complete remission CR, 6 CR with incomplete hematologic recovery CRi, 1 morphologic leukemia-free state, and 1 partial response). The ORR was 43% in Ph+ AML and 75% in CML-MBP. The median overall survival (OS) for all patients was 3.6 months, for AML OS was 2.0 months, and for CML-MBP OS was 10.9 months. The median relapse-free survival for AML and CML-MBP was 3.6 and 3.9 months, respectively. Compared to nonresponders, patients achieving CR/CRi had higher baseline Ph+ metaphases and BCR-ABL1 PCR.
Combination therapy of venetoclax with TKI-based regimens shows encouraging activity in very heavily pretreated, advanced Ph+ leukemias, particularly CML-MBP.
The face of remission induction Paul, Shilpa; Rausch, Caitlin R.; Jabbour, Elias J.
British journal of haematology,
January 2020, 2020-Jan, 2020-01-00, 20200101, Letnik:
188, Številka:
1
Journal Article
Recenzirano
Summary
Acute myeloid leukaemia (AML) is a heterogeneous disease in which prognosis is determined by cytogenetic and molecular aberrations as well as patient‐related factors, including age, prior ...haematologic disorders, and comorbidities. Despite the diverse disease biology, the standard of care for remission induction therapy has changed very little since its inception in 1973. Next generation sequencing has helped to increase our knowledge of the disease pathogenesis, allowing us to develop targeted and possibly more effective treatment options. Seven new agents have been approved for the treatment of AML since 2017, all of which are directed toward a specific molecular subtype or patient population. With the advent of these therapies, a more optimal, patient‐specific approach rather than the historical ‘one‐size fits all’ model can be utilised. This review will discuss the role of these novel therapies in the remission induction setting.
PDF
