Decitabine-based treatment strategy improved the outcome of HSCT in JMML: a retrospective cohort study.

Introduction: Pre-HSCT disease control, suboptimal long-term prognosis, and a high recurrence incidence (RI) continue to pose significant challenges for hematopoietic stem cell transplantation (HSCT) in juvenile myelomonocytic leukemia (JMML) patients. Methods: This retrospective cohort study assessed the effectiveness of a decitabine (DAC)-based protocol in JMML patients undergoing HSCT. The pre-HSCT treatment includes initial and bridging treatment. The efficacy of DAC monotherapy versus DAC combined with cytotoxic chemotherapy(C-DAC) as initial treatment was compared, followed by DAC plus FLAG (fludarabine, cytarabine, and GCSF) as bridging treatment. The HSCT regimens were based on DAC, fludarabine, and busulfan. Post-HSCT, low-dose DAC was used as maintenance therapy. The study endpoints focused on pretransplantation simplified clinical response and post-HSCT survival. Results: There were 109 patients, including 45 receiving DAC monotherapy and 64 undergoing C-DAC treatment. 106 patients completed bridging treatment. All patients were administered planned HSCT regimens and post-HSCT treatment. The initial treatment resulted in 88.1% of patients achieving clinical remission without a significant difference between the DAC and C-DAC groups (p=0.769). Clinical remission rates significantly improved following bridging treatment (p=0.019). The 5-year overall survival, leukemia-free survival, and RI were 92.2%, 88.4%, and 8.0%, respectively. A poor clinical response to pre-HSCT treatment emerged as a risk factor for OS (hazard ratio: 9.8, 95% CI: 2.3-41.1, p=0.002). Conclusion: Implementing a DAC-based administration strategy throughout the pre-HSCT period, during HSCT regimens, and in post-HSCT maintenance significantly reduced relapse and improved survival in JMML patients. Both DAC monotherapy and the DAC plus FLAG protocol proved effective as pre-HSCT treatments.

Continued decitabine/all-trans retinoic acid treatment: extended complete remission in an elderly AML patient with multi-hit TP53 lesions and complex-monosomal karyotype.

DNA-hypomethylating agents (HMAs) induce notable remission rates in AML/MDS patients with TP53 mutations; however, secondary resistance often develops rapidly. In the DECIDER trial (NCT00867672), elderly AML patients (also those with adverse genetics) randomized to all-trans retinoic acid (ATRA) added to decitabine (DEC) attained significantly delayed time-to-resistance. An 82-year-old patient with a non-disruptive, in-frame TP53 mutation (p.Cys238_Asn239delinsTyr, VAF 90%) and complex-monosomal karyotype attained a complete hematologic and cytogenetic remission with DEC + ATRA, with 3.7 years survival after 30 treatment cycles that were well-tolerated. Further HMA + ATRA studies appear warranted in AML/MDS patients of different genetic risk groups ineligible for more intensive treatment.Trial registration: This trial was registered at ClinicalTrials.gov identifier: NCT00867672.

Successfully treatment of PLZF-RARα positive acute promyelocytic leukemia by Venetoclax combining with decitabine: a case report and literature review.

INTRODUCTION: Acute promyelocytic leukemia (APL) is mainly due to the chromosome translocation t(15; 17) (q22; q12), leading to the formation of PML-RARα fusion protein. However, some patients carried rare translocation involving RARα gene, and they were referred to as variant APL caused by the RAR family (RARα, RARB, and RARG) and partner genes. PLZF-RARα was a rare type of molecular genetic abnormality with unfavorable prognosis that has been reported in few cases in variant APL. Knowledge of PLZF-RARα (+) APL treatment remains limited understood. CASE REPORT: We presented a case of variant APL in a 47-year-old female, who was PLZF-RARα positive detected by reverse transcription polymerase chain reaction (RT-PCR). The patient did not respond to all-trans retinoic acid (ATRA), idarubicin, and arsenic trioxide (As2O3) combined induction chemotherapy. Then, the patient was treated with Venetoclax combining with decitabine as the salvage therapy and achieved morphological remission and PLZF/RARα gene negative. CONCLUSION: Venetoclax combining with decitabine can be used as an effective therapy in the PLZF-RARα positive APL.

Decitabine consolidation after CD19/CD22 CAR-T therapy as a novel maintenance treatment significantly improves survival outcomes in relapsed/refractory B-ALL patients.

OBJECTIVE: We aimed to evaluate the efficacy of decitabine consolidation after treatment with CD19/CD22 chimeric antigen receptor T-cell (CAR-T) for patients with relapsed/refractory B-cell acute lymphoblastic leukaemia (r/r B-ALL). METHODS: We retrospectively analysed 48 patients with r/r B-ALL who received CD19/CD22 CAR-T therapy between September 2017 and May 2021. Sixteen patients received decitabine consolidation (20 mg/m2/day for 5 days at 3-month intervals) after CAR-T therapy (DAC group), while 32 patients did not receive decitabine consolidation (CON group). Overall survival (OS), leukaemia-free survival (LFS), and cumulative incidence of relapse (CIR) were evaluated in both groups. Time-to-event analysis was performed using the Kaplan-Meier method. RESULTS: The median follow-up periods in the DAC and CON groups were 41.2 months and 28.6 months, respectively. The 4-year OS and 4-year LFS rates in both groups were 93.3 % and 64.3 % (P=0.029) and 87.5 % and 55.9 % (P=0.059), respectively. The 1-year CIR was 6.25 % and 28.6 %, respectively. Univariate and multivariate Cox regression analyses showed that decitabine consolidation after CAR-T therapy was significantly associated with superior OS (hazard ratio [HR]: 0.121, 95 % confidence interval [CI]: 0.015-0.947, P=0.044), and bridging to haematopoietic stem cell transplantation after CAR-T therapy was significantly associated with superior LFS (HR: 0.279, 95 %CI: 0.093-0.840, P=0.023). CONCLUSIONS: Our study recommends decitabine consolidation after CD19/CD22 CAR-T therapy as a novel maintenance strategy to improve the survival outcomes of patients with r/r B-ALL.

[Efficacy of Decitabine Combined with Preexcitation Regimen in Treatment of Newly Diagnosed AML Patients Who Did not Respond to Initial Standard Induction Chemotherapy].

OBJECTIVE: To investigate the efficacy of decitabine combined with preexcitation regimen in the treatment of newly diagnosed acute myeloid leukemia (AML) patients who have not been relieved by the first standard induction chemotherapy and its influence on the relative content of regulatory T lymphocytes (Tregs). METHODS: The clinical data of 102 newly diagnosed AML patients (except acute promyelocytic leukemia) who did not relieve after initial standard induction chemotherapy in Shaanxi Provincial People's Hospital from March 2013 to March 2019 were retrospectively analyzed. Fifty-one patients who accepted pre-excitation regimen were divided into regular group, while another 51 patients treated with decitabine combined with pre-excitation regimen were divided into combination group. The efficacy, incidence of toxic and side effects, Core Scale of Quality of Life (QLQ-C30) score before and after treatment, T lymphocyte subsets (CD3+, CD4+, CD4+/CD8+, Tregs) and 3-year overall survival (OS) rate were compared between the two groups. RESULTS: The total effective rate of combination group was 80.39%, which was significantly higher than 62.75% of regular group (P < 0.05). After treatment, the QLQ-C30 score of combination group was 60.27±6.96, which was significantly lower than 65.73±7.96 of regular group (P < 0.001). There was no statistical difference in the incidence of toxic and side effects between the two groups (P >0.05). After treatment, the levels of CD3+, CD4+, CD4+/CD8+ in the combination group were higher than those in the regular group (all P < 0.001), while Treg was lower (P < 0.001). The 3-year OS rate in the combination group was 72.55%, which was significantly higher than 52.94% in the regular group (P < 0.001). CONCLUSION: Decitabine combined with preexcitation regimen has a significant effect on AML patients who have not been alleviated by standard induction chemotherapy in the first course of treatment. It can reduce anti-tumor immune suppression and improve immune function by regulating the relative content of Tregs, thus prolongs survival time and improves life quality of patients without increasing adverse reactions.

Pharmacokinetic assessment of low dose decitabine in combination therapies: Development and validation of a sensitive UHPLC-MS/MS method for murine plasma analysis.

Decitabine is a DNA methyltransferase inhibitor used in the treatment of acute myeloid leukemia and myelodysplastic syndrome. The notion that ongoing trials are presently exploring the combined use of decitabine, with or without the cytidine deaminase inhibitor cedazuridine, and other antileukemic drugs necessitates a comprehensive understanding of pharmacokinetic properties and an evaluation of drug-drug interaction liabilities. We report here the development and validation of a sensitive UHPLC-MS/MS method for quantifying decitabine in mouse plasma, which should be useful for such studies. The method involved a one-step protein precipitation extraction, and chromatographic separation on an XBridge HILIC column using gradient elution. The method was found to be robust, accurate, precise, and sufficiently sensitive (lower limit of quantitation, 0.4 ng/mL) to determine decitabine concentrations in microvolumes of plasma from mice receiving the agent orally or intravenously in the presence or absence of cedazuridine.

Oral Decitabine/Cedazuridine Is an Effective Ambulatory Therapy for Patients With Myelofibrosis Refractory to JAK2 Inhibitor Therapy.

BACKGROUND: Outcomes are dismal for patients with myelofibrosis (MF) who are no longer responsive to JAK2 inhibitors (JAKi) and/or have increasing blast cell numbers. Although prior reports have suggested the benefits of intravenous decitabine (DAC) combined with ruxolitinib for patients with Myeloproliferative Neoplasm (MPN) accelerated/blast phase (AP/BP), decitabine-cedazuridine (DEC-C), an oral fixed-dose combination providing equivalent pharmacokinetic exposure, has not been evaluated in MF. METHODS: We conducted a retrospective analysis of 14 patients with high-risk MF refractory to ruxolitinib or MPN-AP (10-19% blasts) treated with DEC-C +/- JAKi at Mount Sinai Hospital from 2021 to 2024. RESULTS: The cohort was elderly (median age,76 years) and almost uniformly possessed high risk mutations with 13 of the 14 patients progressing on JAKi therapy. With a median follow-up of 9.4 months, the median overall survival (OS) was 29 months for the entire cohort. Median OS was 10.8 months for MPN-AP and was not reached for ruxolitinib refractory MF patients. All patients (n = 9) receiving > 4 cycles of DEC-C had clinical benefit exemplified by a reduction in blast cell numbers, spleen size, and lack of progression to MPN-BP (78%). Furthermore, 3/14 patients proceeded to allogeneic stem cell transplant. Myelosuppression was a common adverse event which was managed by reducing the number of days of administration of DEC-C from 5 to 3 per cycle. CONCLUSIONS: This report demonstrates the feasibility, tolerability, and clinical benefit of an exclusively ambulatory regimen for high-risk, elderly patients with advanced MF which warrants further evaluation in a prospective clinical trial.

Decitabine as epigenetic priming with CLAG induce improved outcome of relapsed or refractory acute myeloid leukemia in children.

BACKGROUND: Decitabine (DAC), a DNA methyltransferase inhibitor, has shown efficacy combined with chemotherapy for relapsed or refractory (R/R) acute myeloid leukemia (AML) in adults, but less is known about its efficacy in children. Accordingly, we conducted a study which involved a priming regimen consisting of DAC with cladribine, cytarabine, and granulocyte-stimulating factor (DAC-CLAG) and compared the efficacy and safety of this regimen with CLAG alone. METHODS: A total of 39 R/R AML children who received the CLAG or DAC-CLAG regimen in Shanghai Children's Hospital were retrospectively enrolled in this non-randomized study. These regimens were studied sequentially over time. Twenty-two patients received CLAG from 2015, while 17 patients were administered epigenetic priming with DAC before CLAG from 2020. Patients were subsequently bridged to stem cell transplantation (SCT) or consolidation chemotherapy. Complete remission (CR) and adverse effects were analyzed by Fisher's exact test, and survival was analyzed by the Kaplan-Meier method. RESULTS: DAC-CLAG conferred a numerically higher CR compared to CLAG (70.59% vs 63.64%; P = 0.740). High CR rates occurred in patients with good cytogenetics (P = 0.029) and prior induction without cladribine (P = 0.099). The 1-year event-free survival (EFS) was 64.71% ± 11.59% and 63.31% ± 10.35% in the DAC-CLAG and CLAG group (P = 0.595), and 1-year overall survival (OS) was 81.45% ± 9.72% and 77.01% ± 9.04%, respectively (P = 0.265). The 1-year OS and EFS after SCT were higher in the DAC-CLAG than in the CLAG cohort (100% vs 92.31% ± 7.39%, P = 0.072; 92.31% ± 7.39% vs 85.71% ± 9.35%, P = 0.158). Univariate analysis revealed that a good prognosis included good cytogenetics (P = 0.002), non-complex karyotype (P = 0.056), CR on reinduction (P < 0.0001), and bridging to SCT (P = 0.0007). Use of a hypomethylating agent (P = 0.049) and bridging to SCT (P = 0.011) were independent prognostic factors. Grade 3/4 hematologic toxicity and infection were the main adverse events. CONCLUSIONS: DAC prior to the CLAG regimen improved remission in pediatric R/R AML, and was feasible and well tolerated. CLAG ± DAC as a salvage therapy prior to SCT induced improved survival.

Decitabine in older patients with AML: quality of life results of the EORTC-GIMEMA-GMDS-SG randomized phase 3 trial.

ABSTRACT: We hypothesized that fit older patients with acute myeloid leukemia (AML) treated with decitabine (DEC) would report better health-related quality of life (HRQoL) outcomes than those receiving intensive chemotherapy (IC). We conducted a phase 3 randomized trial to compare DEC (10-day schedule) with IC (3+7) in older fit patients with AML. HRQoL was a secondary end point, and it was assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) in conjunction with its elderly module (EORTC QLQ-ELD14). The following scales were a priori selected for defining the primary end point: physical and role functioning, fatigue, pain, and burden of illness. HRQoL was assessed at baseline, at regeneration from cycle 2, and at 6 and 12 months after randomization, and also before allogeneic hematopoietic stem cell transplantation (allo-HSCT) and 100 days after transplantation. Overall, 606 patients underwent randomization. At 2 months, the risk of HRQoL deterioration was lower in the DEC arm than in the 3+7 arm; 76% (95% confidence interval [CI], 69-82) vs 88% (95% CI, 82-93); odds ratio, 0.43 (95% CI, 0.24-0.76; P = .003). No statistically significant HRQoL differences were observed between treatment arms at the long-term evaluation combining assessments at 6 and 12 months. HRQoL deteriorations between baseline and after allo-HSCT were observed in both arms. However, these deteriorations were not clinically meaningful in patients randomized to DEC, whereas this was the case for those in the 3+7 arm, in 4 of 5 primary HRQoL scales. Our HRQoL findings suggest that lower-intensity treatment with DEC may be preferable to current standard IC (3+7) in fit older patients with AML. This trial was registered at www.clinicaltrials.gov as #NCT02172872.

A phase 3b study of venetoclax and azacitidine or decitabine in an outpatient setting in patients with acute myeloid leukemia.

Venetoclax, a highly selective BCL-2 inhibitor, combined with hypomethylating agents (HMAs) azacitidine or decitabine, is approved for the treatment of newly diagnosed acute myeloid leukemia (ND AML) in patients who are ineligible to receive intensive chemotherapy. Previous clinical studies initiated venetoclax plus HMA in an inpatient setting owing to concerns of tumor lysis syndrome (TLS). This study (NCT03941964) evaluated the efficacy and safety of venetoclax plus HMA in a United States community-based outpatient setting in patients with ND AML (N = 60) who were treatment naïve for AML, ineligible to receive intensive chemotherapy, had no evidence of spontaneous TLS at screening, and were deemed as appropriate candidates for outpatient initiation of venetoclax plus HMA by the investigator. Patients received venetoclax in combination with azacitidine (75 mg/m2) or decitabine (20 mg/m2) for up to 6 cycles during the study. With a median time on study of 18.3 weeks, the best response rate of composite complete remission was 66.7%, and the overall post-baseline red blood cell (RBC) and platelet transfusion independence rate was 55.0%, consistent with results of studies in which treatment was initiated in an inpatient setting. Key adverse events included nausea, anemia, thrombocytopenia, neutropenia, and white blood cell count decrease of any grade (≥50% of patients). The observed safety profile was generally consistent with that of venetoclax plus HMA observed in inpatient AML studies. With close monitoring, 2 cases of TLS were identified, appropriately managed, and the patients were able to continue study treatment. CLINICAL TRIALS REGISTRATION: This study is registered at ClinicalTrials.gov. The registration identification number is NCT03941964.

Clinical activity, pharmacokinetics, and pharmacodynamics of oral hypomethylating agents for myelodysplastic syndromes/neoplasms and acute myeloid leukemia: A multidisciplinary review.

OBJECTIVE: To review the pharmacokinetic (PK)-pharmacodynamic (PD) profiles, disease setting, dosing, and safety of oral and parenteral hypomethylating agents (HMAs) for the treatment of myelodysplastic syndromes/neoplasms (MDS) and acute myeloid leukemia (AML), and to provide a multidisciplinary perspective on treatment selection and educational needs relating to HMA use. DATA SOURCES: Clinical and real-world data for parenteral decitabine and azacitidine and two oral HMAs: decitabine-cedazuridine (DEC-C) for MDS and azacitidine (CC-486) for AML maintenance therapy. DATA SUMMARY: Differences in the PK-PD profiles of oral and parenteral HMA formulations have implications for their potential toxicities and planned use. Oral DEC-C (decitabine 35 mg and cedazuridine 100 mg) has demonstrated equivalent systemic area under the concentration-time curve (AUC) exposure to a 5-day regimen of intravenous (IV) decitabine 20 mg/m2 and showed no significant difference in PD. The AUC equivalence of oral DEC-C and IV decitabine means that these regimens can be treated interchangeably (but must not be substituted within a cycle). Oral azacitidine has a distinct PK-PD profile versus IV or subcutaneous azacitidine, and the formulations are not bioequivalent or interchangeable owing to differences in plasma time-course kinetics and exposures. Clinical trials are ongoing to evaluate oral HMA combinations and novel oral HMAs, such as NTX-301 and ASTX030. CONCLUSIONS: Treatment with oral HMAs has the potential to improve quality of life, treatment adherence, and disease outcomes versus parenteral HMAs. Better education of multidisciplinary teams on the factors affecting HMA treatment selection may help to improve treatment outcomes in patients with MDS or AML.

[Efficacy and Safety of Allogeneic Hematopoietic Stem Cell Transplantation with Decitabine-containing Regimen in Myelodysplastic Syndromes and Myelodysplastic Syndromes Transformed Acute Myeloid Leukemia].

OBJECTIVE: To evaluate the efficacy and safety of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with decitabine (Dec)-conditioning regimen in the treatment of myelodysplastic syndrome (MDS) and MDS transformed acute myeloid leukemia (MDS-AML). METHODS: The characteristics and efficacy data of 93 patients with MDS and MDS-AML who received allo-HSCT in our center from April 2013 to November 2021 were retrospectively analyzed. All patients were administered by myeloablative conditioning regimen containing Dec (25 mg/m2 /d×3 d). RESULTS: Among the 93 patients, 63 males and 30 females, were diagnosed as MDS（n ＝77）, MDS-AML（n ＝16）. The incidence of I/II grade regimen-related toxicity (RRT) was 39.8%, and III grade RRT was only found in 1 patient (1%). Neutrophil engraftment was successful in 91 (97.8%) patients after a median neutrophil engraftment time of 14 (9-27) days; Successful platelet engraftment was achieved in 87 (93.5%) patients, with a median engraftment time of 18 (9-290) days. The incidence of acute graft versus host disease（aGVHD） and grade III-IV aGVHD was 44.2% and 16.2%, respectively. The incidence of chronic graft versus host disease（cGVHD） and moderate-to-severe cGVHD was 59.5% and 37.1%, respectively. Of the 93 patients, 54 (58%) developed posttransplant infections, among which lung infection (32.3%) and bloodstream infection (12.9%) were the most common. The median follow-up after transplantation was 45 (0.1-108) months. The 5-year overall survival (OS) rate, disease-free survival (DFS) rate, treatment-related mortality, and cumulative incidence of relapse were 72.7%, 68.4%, 25.1%, and 6.5%, respectively. And the 1-year graft-versus-host disease/relapse-free survival rate was 49.3%. The patients in different group of relative high-risk prognostic scoring or low-risk prognostic scoring, with or without poor-risk mutation(s), with mutations number ≥3 or <3 had similar 5-year OS rate (more than 70%). Multivariate analysis showed that the incidence of grade III-IV aGVHD was the independent risk factor affecting OS（P =0.008）and DFS (P =0.019). CONCLUSION: Allo-HSCT with Dec-conditioning regimen is feasible and effective in the treatment of patients with MDS and MDS-AML, especially those in high prognostic risk and with poor-risk mutations.

Aberrant promoter hypermethylation regulates thrombomodulin in high altitude induced deep vein thrombosis.

BACKGROUND: DNA methylation regulates gene expression by inhibiting transcription factor binding to promoter and regulatory regions. Acute hypoxia during altitude exposure is associated with decreased natural anticoagulants and morbid thrombotic events. Thrombomodulin (TM) is a high affinity thrombin binding receptor protein, vital for vascular homeostasis. The purpose of this study is to determine gene expression regulation via methylation of TM gene in high altitude hypoxia induced deep vein thrombosis (DVT) patients. MATERIALS AND RESULTS: Percent 5-methyl cytosine analysis showed increased methylation in high altitude DVT patients (HAP) as compared to high altitude control (HAC) and seal level control (Control) subjects, while TM protein and mRNA levels were decreased in high altitude DVT patients as compared to other two groups. Bisulfite sequencing analysis indicated increased methylation in TM promoter in high altitude DVT patients compared to high altitude controls. Flow cytometry analysis showed decreased TM expression in hypoxia induced primary human umbilical vein endothelial cells (HUVECs). Treatment with specific DNA methyltransferase (DNMT) inhibitor-decitabine during hypoxia, restored TM expression. in vitro global methylation assay showed increased methylation in hypoxia group. Specific concentration of decitabine in hypoxia decreased global methylation showing a direct correlation between DNMTs and methylation. Selective dose of decitabine restored TM levels in HUVECs. DNMT1 and DNMT3B proteins showed to mediate the overall expression of TM. CONCLUSION: TM emerged as a potential candidate for methylation in high altitude DVT patients, regulated by hypoxia-induced epigenetic mechanism. Hypoxia culminates in methylation of DNA sequences in the promoter region of TM gene and increased the expression of DNMT1 and DNMT3B per se in primary HUVECs. Critical DNA methylation events were found to be compromised in high altitude DVT patients.

Platelet Doubling After First Decitabine Cycle Predicts Response and Survival of Myelodysplastic Syndrome Patients.

OBJECTIVE: Although the effect of decitabine on myelodysplastic syndrome (MDS) has been demonstrated, merely a proportion of patients respond to therapy, and no well-recognized predictors have been identified. This study was conducted to investigate the effectiveness of decitabine in real-world clinical practice, and determine the predictive factors of response and overall survival (OS) in MDS patients. METHODS: Clinical and pathological data were collected from 94 patients and analyzed. These patients were reclassified according to the 2016 World Health Organization classification criteria, and restratified by International Prognostic Scoring System prognostic scores. The response evaluation was performed according to the 2006 modified International Working Group response criteria. RESULTS: In this study, 62% of patients responded to decitabine. Among these patients, 15 patients (16%) obtained complete remission (CR), 15 patients (16%) obtained marrow CR with hematologic improvement (HI), 20 patients (21%) obtained marrow CR without HI, and 8 patients (9%) only obtained HI, and no patient botained partial remission. The OS of the responders was significantly longer than that of non-responders (67 months vs. 7 months, P<0.001). The OS in patients with and without platelet doubling was significantly different in both the low/intermediate and high/very high risk groups (P=0.0398 and P=0.0330). The multivariate analysis revealed that platelet doubling after the first decitabine cycle is an independent predictor of response and OS in MDS patients (P=0.002 and P=0.008). CONCLUSION: Decitabine is effective for treating MDS patients in real-world clinical practice. Furthermore, platelet doubling after the first decitabine cycle can be used as a predictor of response and survival in MDS patients.

A phase II study of sequential decitabine and rapamycin in acute myelogenous leukemia.

A phase II study was conducted to ascertain whether sequential exposure to decitabine followed by rapamycin, an mTOR (mechanistic target of rapamycin) inhibitor would result in better responses than decitabine alone. Newly diagnosed acute myelogenous leukemia (AML) patients who were >65 years old and not eligible for intensive induction regimens or patients with relapsed or refractory AML received 10 days of decitabine followed by 12 days of rapamycin in cycle 1 and 5 days of decitabine followed by 17 days of rapamycin in subsequent cycles. The composite complete remission rate (CR) was 33 % (CR plus CR with incomplete count recovery). Median overall survival was 7.7 months in newly diagnosed elderly AML patients and 6.6 months in relapsed/refractory AML patients. Twenty-four evaluable patients were enrolled, and the study did not meet its primary endpoint of demonstrating a significant improvement in composite CR rate with the combination as compared to an established historical CR rate of 25 % with decitabine alone. Despite that, the survival rates in relapsed/refractory cases appear comparable to what is reported with other salvage regimens, and no significant patterns of non-hematologic toxicity were noted. 50 % of subjects in the de novo group achieved a composite CR which is significantly higher (p = 0.02) than the rate of 25 % with decitabine alone. This trial is registered at clinical trials.gov as NCT02109744.

Oral hypomethylating agents: beyond convenience in MDS.

Oral hypomethylating agents (HMAs) represent a substantial potential boon for patients with myelodysplastic syndrome (MDS) who have previously required between 5 and 7 visits per month to an infusion clinic to receive therapy. For patients who respond to treatment, ongoing monthly maintenance visits represent a considerable burden to quality of life, and for those who are early in therapy, these sequential visits may tax transportation and financial resources that would be optimally distributed over the treatment cycle to facilitate transfusion support. The availability of oral HMAs may support the optimal application of these agents by contributing to adherence and lessening the burden of therapy, potentially encouraging patients to stay on longer-term treatment. Distinct pharmacokinetic profiles for the recently approved oral HMAs (oral azacitidine and decitabine-cedazuridine) result in differential toxicity profiles and have prompted their clinical trial development in lower- and higher-risk MDS, respectively.