Kazuistika pojednává o pacientce s multifokálním myelosarkomem v měkkých tkáních, kůži a lymfatických uzlinách v přítomnosti konkomitantního myelodysplastického syndromu, který ani po dvou sériích indukční chemoterapie za hospitalizace (mitoxantron, vysocedávkovaný cytarabin, tzv. protokol HAM) nenavodil kompletní remisi a vymizení extramedulárních ložisek. Ukazuje potenciál kombinované ambulantní terapie azacitidinu (hypometylační látka) s venetoclaxem (bcl-2 inhibitor) překonat chemorezistenci nádoru.
The case report presents a female patient with multifocal myeloid sarcoma in the soft tissues, skin, and lymph nodes in the presence of concomitant myelodysplastic syndrome in whom two series of inpatient induction chemotherapy (high-dose cytarabine and mitoxantrone, i.e. the HAM protocol) failed to induce complete remission and resolution of extramedullary lesions. Combined outpatient treatment with azacitidine (a hypomethylating agent) and venetoclax (a Bcl-2 inhibitor) has been shown to have a potential to overcome tumour chemoresistance.
- Keywords
- venetoclax,
- MeSH
- Azacitidine pharmacology therapeutic use MeSH
- Middle Aged MeSH
- Humans MeSH
- Myelodysplastic Syndromes diagnosis drug therapy MeSH
- Sarcoma, Myeloid * diagnosis drug therapy MeSH
- Antineoplastic Agents pharmacology therapeutic use MeSH
- Antineoplastic Combined Chemotherapy Protocols MeSH
- Treatment Outcome MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Female MeSH
- Publication type
- Case Reports MeSH
Navzdory narůstajícím léčebným možnostem představuje relaps akutní myeloidní leukemie nadále terapeutickou výzvu. Zavedení venetoklaxu do klinické praxe vedlo k rozšíření armamentária účinných protinádorových léků. Článek přináší dvě kazuistiky ukazující použití kombinace venetoklaxu s azacitidinem u pacientů s opakovaně relabovaným onemocněním.
Despite increasing treatment options, acute myeloid leukemia relapse remains a therapeutic challenge. The introduction of venetoclax into clinical practice led to the expansion of the armamentarium of effective antitumor drugs. The article presents two case reports showing the use of the combination of venetoclax and azacitidine in patients with repeatedly relapsed disease.
- Keywords
- venetoklax,
- MeSH
- Leukemia, Myeloid, Acute * drug therapy MeSH
- Azacitidine pharmacology therapeutic use MeSH
- Adult MeSH
- Humans MeSH
- Antineoplastic Combined Chemotherapy Protocols MeSH
- Recurrence MeSH
- Aged MeSH
- Treatment Outcome MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Case Reports MeSH
BACKGROUND: Older patients with acute myeloid leukemia (AML) have a dismal prognosis, even after treatment with a hypomethylating agent. Azacitidine added to venetoclax had promising efficacy in a previous phase 1b study. METHODS: We randomly assigned previously untreated patients with confirmed AML who were ineligible for standard induction therapy because of coexisting conditions, because they were 75 years of age or older, or both to azacitidine plus either venetoclax or placebo. All patients received a standard dose of azacitidine (75 mg per square meter of body-surface area subcutaneously or intravenously on days 1 through 7 every 28-day cycle); venetoclax (target dose, 400 mg) or matching placebo was administered orally, once daily, in 28-day cycles. The primary end point was overall survival. RESULTS: The intention-to-treat population included 431 patients (286 in the azacitidine-venetoclax group and 145 in the azacitidine-placebo [control] group). The median age was 76 years in both groups (range, 49 to 91). At a median follow-up of 20.5 months, the median overall survival was 14.7 months in the azacitidine-venetoclax group and 9.6 months in the control group (hazard ratio for death, 0.66; 95% confidence interval, 0.52 to 0.85; P<0.001). The incidence of complete remission was higher with azacitidine-venetoclax than with the control regimen (36.7% vs. 17.9%; P<0.001), as was the composite complete remission (complete remission or complete remission with incomplete hematologic recovery) (66.4% vs. 28.3%; P<0.001). Key adverse events included nausea of any grade (in 44% of the patients in the azacitidine-venetoclax group and 35% of those in the control group) and grade 3 or higher thrombocytopenia (in 45% and 38%, respectively), neutropenia (in 42% and 28%), and febrile neutropenia (in 42% and 19%). Infections of any grade occurred in 85% of the patients in the azacitidine-venetoclax group and 67% of those in the control group, and serious adverse events occurred in 83% and 73%, respectively. CONCLUSIONS: In previously untreated patients who were ineligible for intensive chemotherapy, overall survival was longer and the incidence of remission was higher among patients who received azacitidine plus venetoclax than among those who received azacitidine alone. The incidence of febrile neutropenia was higher in the venetoclax-azacitidine group than in the control group. (Funded by AbbVie and Genentech; VIALE-A ClinicalTrials.gov number, NCT02993523.).
- MeSH
- Leukemia, Myeloid, Acute drug therapy mortality MeSH
- Intention to Treat Analysis MeSH
- Azacitidine administration & dosage adverse effects MeSH
- Bridged Bicyclo Compounds, Heterocyclic administration & dosage adverse effects MeSH
- Double-Blind Method MeSH
- Remission Induction MeSH
- Kaplan-Meier Estimate MeSH
- Leukopenia chemically induced MeSH
- Middle Aged MeSH
- Humans MeSH
- Follow-Up Studies MeSH
- Pneumonia etiology MeSH
- Antineoplastic Combined Chemotherapy Protocols therapeutic use MeSH
- Recurrence MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Sulfonamides administration & dosage adverse effects MeSH
- Thrombocytopenia chemically induced MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase III MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
- Randomized Controlled Trial MeSH
- Comparative Study MeSH
Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for most children with juvenile myelomonocytic leukemia (JMML). Novel therapies controlling the disorder prior to HSCT are needed. We conducted a phase 2, multicenter, open-label study to evaluate the safety and antileukemic activity of azacitidine monotherapy prior to HSCT in newly diagnosed JMML patients. Eighteen patients enrolled from September 2015 to November 2017 were treated with azacitidine (75 mg/m2) administered IV once daily on days 1 to 7 of a 28-day cycle. The primary end point was the number of patients with clinical complete remission (cCR) or clinical partial remission (cPR) after 3 cycles of therapy. Pharmacokinetics, genome-wide DNA-methylation levels, and variant allele frequencies of leukemia-specific index mutations were also analyzed. Sixteen patients completed 3 cycles and 5 patients completed 6 cycles. After 3 cycles, 11 patients (61%) were in cPR and 7 (39%) had progressive disease. Six of 16 patients (38%) who needed platelet transfusions were transfusion-free after 3 cycles. All 7 patients with intermediate- or low-methylation signatures in genome-wide DNA-methylation studies achieved cPR. Seventeen patients received HSCT; 14 (82%) were leukemia-free at a median follow-up of 23.8 months (range, 7.0-39.3 months) after HSCT. Azacitidine was well tolerated and plasma concentration--time profiles were similar to observed profiles in adults. In conclusion, azacitidine monotherapy is a suitable option for children with newly diagnosed JMML. Although long-term safety and efficacy remain to be fully elucidated in this population, these data demonstrate that azacitidine provides valuable clinical benefit to JMML patients prior to HSCT. This trial was registered at www.clinicaltrials.gov as #NCT02447666.
- MeSH
- Azacitidine adverse effects MeSH
- Child MeSH
- Adult MeSH
- Leukemia, Myelomonocytic, Juvenile * drug therapy genetics MeSH
- Humans MeSH
- DNA Methylation MeSH
- Mutation MeSH
- Hematopoietic Stem Cell Transplantation * MeSH
- Check Tag
- Child MeSH
- Adult MeSH
- Humans MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase II MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
TRIAL REGISTRATION: GA trial is registered under EudraCT#: 2013-001639-38.
- MeSH
- Azacitidine * therapeutic use MeSH
- Granulocyte Colony-Stimulating Factor MeSH
- Humans MeSH
- Myelodysplastic Syndromes * drug therapy MeSH
- Antimetabolites, Antineoplastic therapeutic use MeSH
- Check Tag
- Humans MeSH
- Publication type
- Letter MeSH
- Research Support, Non-U.S. Gov't MeSH
- Randomized Controlled Trial MeSH
Venetoclax-azacitidine is approved for treatment of patients with newly diagnosed acute myeloid leukemia (AML) ineligible for intensive chemotherapy based on the interim overall survival (OS) analysis of the VIALE-A study (NCT02993523). Here, long-term follow-up is presented to address survival benefit and long-term outcomes with venetoclax-azacitidine. Patients with newly diagnosed AML who were ineligible for intensive chemotherapy were randomized 2:1 to receive venetoclax-azacitidine or placebo-azacitidine. OS was the primary endpoint; complete remission with/without blood count recovery (CR/CRi) was a key secondary endpoint. This final analysis was conducted when 100% of the predefined 360 OS events occurred. In VIALE-A, 431 patients were enrolled to venetoclax-azacitidine (n = 286) or placebo-azacitidine (n = 145). At 43.2 months median follow-up, median OS was 14.7 months (95% confidence interval [CI], 12.1-18.7) with venetoclax-azacitidine, and 9.6 months (95% CI, 7.4-12.7) with placebo-azacitidine (hazard ratio, 0.58 [95% CI, 0.47-0.72], p < .001); the estimated 24-month OS rate was 37.5% and 16.9%, respectively. Median OS for patients with IDH1/2 mutations and those with measurable residual disease responses was reached in this final analysis. CR/CRi rate was similar to interim analysis. Any-grade hematologic and gastrointestinal adverse events were most common in venetoclax-azacitidine and placebo-azacitidine arms, including thrombocytopenia (47% and 42%) and neutropenia (43% and 29%). No new safety signals were identified. Long-term efficacy and safety confirm venetoclax-azacitidine is an improvement in standard-of-care for patients with AML who are not eligible for intensive chemotherapy because of advanced age or comorbidities.
- MeSH
- Leukemia, Myeloid, Acute * drug therapy MeSH
- Azacitidine adverse effects MeSH
- Bridged Bicyclo Compounds, Heterocyclic * MeSH
- Humans MeSH
- Follow-Up Studies MeSH
- Neutropenia * MeSH
- Antineoplastic Combined Chemotherapy Protocols adverse effects MeSH
- Sulfonamides * MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Randomized Controlled Trial MeSH
CONTEXT: A novel genomically defined subset of higher-risk myelodysplastic syndrome (HR-MDS) patients with an actionable target characterized by overexpression of RARA has been identified (McKeown 2017). Approximately 30% of HR-MDS patients are RARA-positive by a blood-based biomarker test (Vigil 2017). Tamibarotene is an oral selective RARα agonist with potential for clinical benefit in RARA-positive HR-MDS patients, irrespective of mutation or cytogenetic risk. Initial clinical data in RARA-positive relapsed/refractory HR-MDS showed myeloid differentiation, improved blood counts, and reduced bone marrow blasts, including one patient who achieved marrow complete remission with hematologic improvement (Jurcic 2017). Tamibarotene/azacitidine led to a CR/CRi rate of 61% with rapid onset of response in RARA-positive newly diagnosed (ND) unfit AML patients, including those with low blast count (≤30%) AML, and a majority of patients achieved or maintained transfusion independence (de Botton 2020). Tamibarotene/azacitidine was generally well tolerated with no increase in myelosuppression compared with azacitidine alone (de Botton 2020). Historical precedent demonstrating similar clinical outcomes in HR-MDS and low blast count AML (Estey 2022) supports further development of tamibarotene/azacitidine in HR-MDS to improve clinical outcomes of standard of care treatment with hypomethylating agents (HMAs). OBJECTIVE: To characterize and compare the CR rate of tamibarotene/azacitidine to placebo/azacitidine in RARA-positive ND HR-MDS patients. Secondary objectives include comparisons of overall response rate, event-free survival, overall survival, transfusion independence, and safety. DESIGN: Global, Phase 3, randomized, double-blind, placebo-controlled trial (NCT04797780). Approximately 190 patients will be randomized 2:1, providing 90% power to detect the difference in CR rates between the experimental and control arms. PATIENTS: The included patients will be RARA-positive based on investigational assay and ND with HR-MDS by WHO classification (Arber 2016) with an IPSS-R risk category of very high, high, or intermediate and a blast count >5% at baseline. Patients with prior treatment for MDS with any HMA, chemotherapy, or transplant are excluded. INTERVENTION: Azacitidine will be administered at 75 mg/m2 IV/SC daily on days 1-7 (or 1-5, 8-9) followed by tamibarotene/placebo at 6 mg BID orally on days 8-28 of each 28-day cycle. MAIN OUTCOME MEASURES: Response is assessed per the modified IWG MDS criteria (Cheson 2006).
- MeSH
- Leukemia, Myeloid, Acute * MeSH
- Azacitidine pharmacology therapeutic use MeSH
- Benzoates MeSH
- Adult MeSH
- Humans MeSH
- Modafinil therapeutic use MeSH
- Myelodysplastic Syndromes * diagnosis MeSH
- Tetrahydronaphthalenes MeSH
- Treatment Outcome MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase III MeSH
- Randomized Controlled Trial MeSH
BACKGROUND: Although induction chemotherapy results in remission in many older patients with acute myeloid leukemia (AML), relapse is common and overall survival is poor. METHODS: We conducted a phase 3, randomized, double-blind, placebo-controlled trial of the oral formulation of azacitidine (CC-486, a hypomethylating agent that is not bioequivalent to injectable azacitidine), as maintenance therapy in patients with AML who were in first remission after intensive chemotherapy. Patients who were 55 years of age or older, were in complete remission with or without complete blood count recovery, and were not candidates for hematopoietic stem-cell transplantation were randomly assigned to receive CC-486 (300 mg) or placebo once daily for 14 days per 28-day cycle. The primary end point was overall survival. Secondary end points included relapse-free survival and health-related quality of life. RESULTS: A total of 472 patients underwent randomization; 238 were assigned to the CC-486 group and 234 were assigned to the placebo group. The median age was 68 years (range, 55 to 86). Median overall survival from the time of randomization was significantly longer with CC-486 than with placebo (24.7 months and 14.8 months, respectively; P<0.001). Median relapse-free survival was also significantly longer with CC-486 than with placebo (10.2 months and 4.8 months, respectively; P<0.001). Benefits of CC-486 with respect to overall and relapse-free survival were shown in most subgroups defined according to baseline characteristics. The most common adverse events in both groups were grade 1 or 2 gastrointestinal events. Common grade 3 or 4 adverse events were neutropenia (in 41% of patients in the CC-486 group and 24% of patients in the placebo group) and thrombocytopenia (in 22% and 21%, respectively). Overall health-related quality of life was preserved during CC-486 treatment. CONCLUSIONS: CC-486 maintenance therapy was associated with significantly longer overall and relapse-free survival than placebo among older patients with AML who were in remission after chemotherapy. Side effects were mainly gastrointestinal symptoms and neutropenia. Quality-of-life measures were maintained throughout treatment. (Supported by Celgene; QUAZAR AML-001 ClinicalTrials.gov number, NCT01757535.).
- MeSH
- Leukemia, Myeloid, Acute drug therapy mortality MeSH
- Survival Analysis MeSH
- Administration, Oral MeSH
- Azacitidine administration & dosage adverse effects therapeutic use MeSH
- Double-Blind Method MeSH
- Remission Induction MeSH
- Quality of Life MeSH
- Middle Aged MeSH
- Humans MeSH
- Nausea chemically induced MeSH
- Antimetabolites, Antineoplastic administration & dosage adverse effects therapeutic use MeSH
- Antineoplastic Combined Chemotherapy Protocols therapeutic use MeSH
- Drug Administration Schedule MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Maintenance Chemotherapy * adverse effects MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase III MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
- Randomized Controlled Trial MeSH
BACKGROUND: Azacitidine (AZA) is a nucleoside analog used for treatment of myelodysplasia and the prediction of AZA responsiveness is important for the therapy management. METHODS: Using microarrays and reverse-transcription quantitative-PCR, we analyzed microRNA (miRNA) expression in bone marrow CD34+ cells of 27 patients with higher-risk myelodysplastic syndromes or acute myeloid leukemia with myelodysplasia-related changes before and during AZA treatment. RESULTS: At baseline, we found that future overall response rate was significantly higher in patients with upregulated miR-17-3p and downregulated miR-100-5p and miR-133b. Importantly, the high level of miR-100-5p at baseline was associated with shorter overall survival (HR = 4.066, P= 0.008). After AZA treatment, we observed deregulation of 30 miRNAs in responders (including downregulation of miR-10b-5p, miR-15a-5p/b-5p, miR-24-3p, and miR-148b-3p), while their levels remained unchanged in non-responders. CONCLUSIONS: Our study demonstrates that responders and non-responders have distinct miRNA patterns and that the level of specific miRNAs before therapy may predict the efficacy of AZA treatment.
- MeSH
- Leukemia, Myeloid, Acute drug therapy genetics pathology MeSH
- Azacitidine pharmacology therapeutic use MeSH
- Humans MeSH
- MicroRNAs metabolism MeSH
- Myelodysplastic Syndromes drug therapy genetics pathology MeSH
- Antimetabolites, Antineoplastic pharmacology therapeutic use MeSH
- Aged MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
