Aclarubicin, Low-Dose Cytarabine Combined With G-CSF (CAG) Regimen For Patients Previously Treated Or Ineligible For Intensive Chemotherapy With Acute Myeloid Leukemia and Myelodysplastic Syndrom: A Single Center Experience

Abstract Background The incidence of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) increases with age. Intensive chemotherapy is unsuitable for older patients because of its intolerable toxicity. CAG (cytarabine, aclarubicin, and G-CSF) regimen is widely used for such elderly patients because of its relatively low toxicity mainly in Eastern Asia such as China and Japan. Several reports showed the efficacy of CAG, but their sample sizes are relatively small. Thus, we here report a retrospective, single-center analysis of 86 cases with AML and MDS treated with CAG regimen Patients and methods Patients of AML and MDS who were treated with CAG regimen at Sapporo Hokuyu hospital from 2008 to 2012 were analyzed retrospectively. To examine the efficacy of CAG, we examined response rate, overall survival (OS), event-free survival (EFS), and rate and duration of being free from transfusion. We also performed subgroup analysis on response rate, OS, and EFS by underlying diseases, chromosomal karyotypes, WBC count and LDH level. Chi-squared test was used to compare the response rate of chemotherapy between subgroups. Overall survival was defined from the time of starting chemotherapy to the time of death from any cause or to the time of last follow-up. Kaplan- Meier method was used to compare survival curves. Cox regression analysis was used to analyze differences between subgroups. Results Among 86 patients enrolled, 60 patients were with AML, and 26 were with MDS. Median age of the patients was 71 (range 17-87) years old and 57 (66.3%) patients were male. Forty-six patients had previous history of chemotherapy other than CAG, and seven had previous history of hematopoietic transplantation. Median time from diagnosis to first cycle of CAG was 169 (range 1-6104) days. Eighty-six patients received total of 136 series of CAG regimen. Each series consisted of several courses of CAG, and median number of cycles was two (range 1-6). Median follow-up duration was 276 (range 18-1718) days and 28 patients (32.6%) were alive at the last follow up. After the first series of chemotherapy, 39 patients achieved complete response (CR), 11 patients remained stable disease, and 36 patients experienced progression of disease. Overall response rate was 58.1%. CR was achieved in 30 out of 60 patients with AML (50%) and 8 out of 23 with MDS (34.8%), respectively. No significant difference of response rate was seen between the two groups (p=0.70). While 6 cases of AML and 4 cases of MDS showed partial response, 24 cases of AML and 11 cases of MDS were resistant to CAG, respectively. Half of the patients of AML were diagnosed as AML with MDS-related changes (AML with MRC). No differences of response rate were seen between AML and AML with MRC. Significant differences of CR rate were seen between three groups according to classification scheme of karyotype reported by SWOG/ECOG. In detail, CR rates were 62.9% in favorable karyotype group, 40.0% in intermediate group and 22.7% in unfavorable group, respectively (p=0.026). Favorable group was also superior on EFS compared to the other two groups (p=0.010). Median duration of OS and EFS were 349 and 457 days in favorable group, 495 and 228 days in intermediate group, 217 and 174 days in unfavorable group, respectively. Patients with normal LDH level survive significantly longer compared to patients with high LDH level (717 days vs. 296 days, p=0.004), although LDH level was not a predictive factor for CR rate (55.8% vs. 34.9%, p=0.084). Low WBC count (<3000/μl) at the time of chemotherapy also predicted longer survival time after treatment (p<0.001). Twenty-five out of 58 patients who were dependent on transfusion at the time of chemotherapy became independent from transfusion. Median duration of free from transfusion was 156 (range 35-483) days. Forty-five patients received two or more series of CAG regimen. CR rate on second or more series of the chemotherapy was 45.7%, and PR or SD was 12.5%, which were comparable to those of prior CAG treatment. Conclusions This study showed the efficacy of CAG regimen for patients with AML and MDS who were not candidate for intensive chemotherapy. CAG was first reported more than 10 years ago. But there are no prospective studies comparing this strategy with other low-dose chemotherapy, hypomethylating agents, and supportive care. To determine the place of this useful approach within the many therapeutic options for AML and MDS, prospective clinical trial is needed. Disclosures: No relevant conflicts of interest to declare.

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Phase 1/2 Study of Venetoclax with Low-Dose Cytarabine in Treatment-Naive, Elderly Patients with Acute Myeloid Leukemia Unfit for Intensive Chemotherapy: 1-Year Outcomes

Blood ◽

10.1182/blood.v130.suppl_1.890.890 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 890-890

Author(s):

Andrew Wei ◽

Stephen A. Strickland ◽

Gail J. Roboz ◽

Jing-Zhou Hou ◽

Walter Fiedler ◽

...

Keyword(s):

Myeloid Leukemia ◽

Research Funding ◽

Low Dose ◽

Intensive Chemotherapy ◽

Employment Equity ◽

Advisory Committees ◽

Treatment Naïve ◽

Equity Ownership ◽

Low Dose Cytarabine

Abstract Background: Older patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy are unlikely to achieve remission with available therapy and have unacceptably short survival. Venetoclax (VEN) is a small molecule inhibitor of BCL-2 that achieved remission rates of >60% combined with low-dose cytarabine (LDAC). Presented are long-term outcomes, including 1-year overall survival (OS) and biomarker analyses. Methods: This phase 1b/2, open-label study (NCT02287233) evaluates the safety and preliminary efficacy of orally administered VEN combined with LDAC in patients ≥65 years with previously untreated AML (except for hydroxyurea). Patients were ineligible for intensive chemotherapy because of comorbidity or other factors and had an ECOG performance score of 0-2, with adequate hepatic and renal function. Exclusion criteria were acute promyelocytic leukemia, active CNS involvement with AML, concominant use of moderate or strong CYP3A inhibitors, or prior treament with cytarabine for a preexisting myeloid disorder. Prior treatment for myelodysplastic syndrome (MDS) was allowed. In cycle 1, VEN was started at 50 mg/day PO and increased over a 5-day ramp-up to reach the designated cohort dose of 600 or 800 mg/day on day 6, which was continued through day 28. In subsequent cycles, the desingated dose of VEN 600 or 800 mg/day was administered on days 1-28. LDAC 20 mg/m2/day SQ was given on days 1-10 of each cycle. Preliminary efficacy was assessed as the overall response rate (ORR, which included complete remission [CR], CR with incomplete blood count recovery [CRi], and partial remission [PR]). Adverse events (AEs) and laboratory values were monitored. Exploratory analysis of biomarkers (eg, cytogenetics, molecular markers) was performed to identify potential predictors of clinical outcomes. Results: Data cutoff was May 30, 2017. All 71 patients were enrolled ≥1 year prior (46 [65%] male; median age, 74 years [range, 66-87 years]): 10 received VEN 800 mg and 61 received VEN 600 mg, the recommended phase 2 dose. Thirty-three patients (47%) had a history of antecedent hematologic disorder (AHD), most commonly MDS. Among 61 patients given VEN 600 mg, median time on VEN treatment was 6 months (range, <1 to 21 months). Thirty-eight (62%) of these patients achieved CR/CRi with a median duration of CR/CRi of 14.9 months (95% CI, 5.6 months to not reached [NR]; Figure). Best responses were 26% CR, 36% CRi, and 2% PR. Median OS was 11.4 months (95% CI, 5.7-15.7 months); the observed 12-month OS was 46% (95% CI, 33-58%). Only 1 patient has subsequently undergone bone marrow transplantation. Treatment-emergent grade 3/4 AEs (in ≥20% of 61 patients) were thrombocytopenia (59%), neutropenia (46%), febrile neutropenia (36%), anemia (28%), and decreased WBC count (26%). One case (2%) of tumor lysis syndrome occurred. Serious AEs (in ≥3 of 61 patients) were febrile neutropenia (20%), malignant neoplasm progression (13%), lung infection/pneumonia (13%), and sepsis (7%). The 30-day mortality rate was 3%; causes of death were disease progression (n=1) and lung infection (n=1). Common recurrent mutations in 53 patients who received VEN 600 mg are shown in the Table. All patients with an NPM1 mutation (including 3 with a co-mutation in FLT3-ITD) achieved CR/CRi. Patients with DNMT3A, FLT3-ITD, and SRSF2 mutations had CR/CRi rates of ≥75%, whereas those with TP53 mutations had the lowest CR/CRi rates of 44%. For patients with CR/CRi, median OS was 18.4 months (95% CI, 13.5 months to NR). The 12-month OS rate for patients in the 600-mg VEN cohort who achieved CR/CRi was 70.4% from Kaplan-Meier estimates, with 11 deaths. Among 19 patients who received study treatment ≥12 months, 17 remain alive. The longest, ongoing, disease-free follow-up after treatment completion is 12 months. Conclusions: The safety profile of VEN 600 mg/day plus LDAC was acceptable for elderly patients with treatment-naive AML who were ineligible for intensive chemotherapy. After ≥1 year of follow-up, the observed median OS was 11.4 months. This cohort included 44% (27/61) of patients with AHDs. Corelations of specified AML mutations with response and duration should be confirmed in later trials. Due to the observced CR/CRi rate of 62%, extended duration of response, and encouraging OS in a cohort of patients with particularly poor-risk features, the 600-mg dose of VEN combined with LDAC is being tested in an ongoing phase 3 study. Figure Figure. Disclosures Wei: AbbVie, Celgene, Novartis, Amgen, Servier: Honoraria; AbbVie, Celgene, Servier: Research Funding; AbbVie, Celgene, Novartis, Amgen, Servier: Membership on an entity's Board of Directors or advisory committees. Strickland: Boehringer-Ingelheim: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Novartis: Consultancy; Tolero: Consultancy; Astellas: Consultancy; CTI BioPharma: Consultancy; Baxalta: Consultancy. Roboz: AbbVie, Agios, Amgen, Amphivena, Array Biopharma Inc., Astex, AstraZeneca, Celator, Celgene, Clovis Oncology, CTI BioPharma, Genoptix, Immune Pharmaceuticals, Janssen Pharmaceuticals, Juno, MedImmune, MEI Pharma, Novartis, Onconova, Pfizer, Roche Pharmace: Consultancy; Cellectis: Research Funding. Hou: Teva Oncology, Seattle Genetics: Speakers Bureau. Fiedler: Amgen, Pfizer: Research Funding; Amgen, Gilead, GSO, Teva, Jazz Pharmaceuticals: Other: Support for meeting attendance; Amgen: Patents & Royalties; Amgen, ARIAD/Incyte: Membership on an entity's Board of Directors or advisory committees. Lin: Jazz Pharmaceuticals: Consultancy. Walter: ADC Therapeutics: Research Funding; Aptevo Therapeutics: Research Funding. Chyla: Abbvie: Employment, Equity Ownership. Popovic: AbbVie: Employment, Equity Ownership. Fakouhi: AbbVie: Employment, Equity Ownership. Shah: AbbVie: Employment, Equity Ownership. Dunbar: AbbVie: Employment, Equity Ownership. Xu: AbbVie: Employment, Equity Ownership. Mabry: AbbVie: Employment, Equity Ownership. Hayslip: AbbVie: Employment, Equity Ownership.

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Response Rates of High and Low Dose Estrogen and Their Combination with DDAVP and/or Aminocaproic Acid in Patients with Menorrhagia and Type I Von Willebrand’s Disease.

Blood ◽

10.1182/blood.v112.11.3391.3391 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3391-3391

Author(s):

Vasundhara Kailasnath ◽

S. Paige Hertweck ◽

Salvatore Bertolone ◽

Sanjay P Ahuja

Keyword(s):

Low Dose ◽

Response Rate ◽

Aminocaproic Acid ◽

Response Rates ◽

High Dose ◽

Von Willebrand's Disease ◽

Von Willebrand’S Disease ◽

History Of ◽

Ristocetin Cofactor

Abstract Background: Von Willebrand’s Disease (VWD) is the most common inherited bleeding disorder affecting women and produces significant menorrhagia as its main symptom. Though combined oral contraceptive pills (OCP’s) are the most common treatment modality for menorrhagia, randomized controlled studies to assess their efficacy are lacking. Data on response rates to different doses and combinations of estrogens and progestins in OCP’s, and data on response rates to combined therapy of OCP’s with desmopressin acetate (DDAVP) and/or aminocaproic acid (Amicar) are sparse. Methods: The patient population consisted of 80 patients aged 9–19 years, who were primary referrals to a combined Hematology/Gynecology clinic for evaluation of menorrhagia. A retrospective chart review was done on these patients following an IRB approval. Collected data included age of menarche, onset of menorrhagia, follow up duration, severity of menorrhagia including PBAC score, co-morbidities, family history of bleeding or clotting disorders, blood group, factor VIII coagulant activity, ristocetin cofactor activity, and VW Ag level. VWD was defined as ristocetin cofactor activity <57 % (57 –149%). Response to treatment modalities as assessed by the gynecologist was subjective (menstrual bleeding lasting less than 7 days and decrease in the number of menstrual products used per day) in most patients and by the PBAC score (Pictorial blood loss assessment chart) in a few. Results: Of the 80 patients with menorrhagia, 26 patients (32.5%) had ristocetin co factor activity <57 % with normal multimers and were diagnosed with VWD type 1. Mean age in years (±SD) at menarche and at diagnosis of menorrhagia were 11.31±1.54 and 12.65±1.77 respectively. Mean follow up period was 1.73 yrs (range 0.2 – 3 yrs). O blood type was present in 73.1% (19/26) patients. Family history of menorrhagia and easy bruising was present in 34.6% (9/26). Table 1: Treatment and Response Rate Treatment* N=26 Response Rate * Patients were on more than one type of OCP prior to achievement of response Low dose Estrogen (20, 25 and 30 mcg) 22 (84.6%) 10 (45.5%) High dose Estrogen (35, 50 mcg) 18 (69%) 15 (83.3%) Progesterone 5 2 (40%) OCP and DDVAP 14 13 (92.9%) OCP and Amicar 6 6 (100%) During the course of treatment, patients were changed from low to high dose estrogen in 38.5% (10/26), high to low dose estrogen in 7.7% (2/26), estrogen to progesterone in 3.8% (1/26), progesterone to estrogen in 11.5%(3/26). Ten patients (38.5%) remained on the same treatment. Table 2: Treatment combinations Treatment Combinations N=26 OCP’s n =9 34.6% OCP + DDVAP n =6 23.1% OCP + Amicar n =2 7.7% OCP + DDVAP+ Amicar n =1 3.8% OCP + DDVAP + Humate P n =3 11.5% OCP + DDVAP+ Amicar + Humate P n =3 11.5% Progesterone only OCP (POCP) n =1 3.8% POCP + DDVAP + Humate P n =1 3.8% Conclusion: In our retrospective analysis, patients on high dose estrogen had a better response rate compared to patients on low dose estrogen or on progesterone only OCP’s. A third of the patients achieved bleeding control with OCP’s alone whereas the rest required a combination of OCP’s with either DDAVP, Amicar, or both. A prospective study is needed to confirm these findings and to determine standards of treatment in patients with menorrhagia and Von Willebrand’s disease.

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Low-dose cytarabine with or without glasdegib in newly diagnosed patients with acute myeloid leukemia: Long-term analysis of a phase 2 randomized trial.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.7010 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 7010-7010 ◽

Cited By ~ 2

Author(s):

B. Douglas Smith ◽

Cristina Papayannidis ◽

Michael Heuser ◽

Pau Montesinos ◽

Mikkael A. Sekeres ◽

...

Keyword(s):

Myeloid Leukemia ◽

Low Dose ◽

Intensive Chemotherapy ◽

Phase 2 ◽

Newly Diagnosed ◽

Term Analysis ◽

Low Dose Cytarabine ◽

Acute Myeloid

7010 Background: Glasdegib is a potent, selective, oral inhibitor of the Hedgehog signaling pathway, approved in the US – in combination with low-dose cytarabine (LDAC) – for treatment of newly diagnosed acute myeloid leukemia (AML) in patients (pts) unable to receive intensive chemotherapy due to comorbidities or age (≥75 y). Methods: In this follow-up analysis from the phase 2 BRIGHT AML trial (NCT01546038), newly diagnosed pts with AML ineligible for intensive chemotherapy were randomized 2:1 to glasdegib + LDAC or LDAC alone (study design: Cortes et al., Leukemia 2018). This long-term analysis evaluated efficacy and safety after ~20 mo of additional follow-up. Results: As of Oct 11, 2018, 116 pts were assigned to treatment with glasdegib + LDAC (n = 78) or LDAC alone (n = 38) (median follow-up: 43.4 and 42.0 mo, respectively). Median overall survival (OS) was higher with glasdegib + LDAC vs LDAC alone (Table). Improvement in OS was consistent across the prespecified subgroups. The main cause of death in both arms was disease progression (both during study and follow-up). The incidence of adverse events (AEs) and serious AEs on glasdegib was generally lower long term (after 90 days) than short term (during the first 90 days) (83.7% and 51.2% vs 98.7% and 65.3%, respectively). Clinical trial information: NCT01546038. Conclusions: Addition of glasdegib to LDAC vs LDAC alone continued to demonstrate improved OS in pts with AML in this analysis; improvement was consistent across groups stratified by cytogenic risk. Long-term follow-up confirmed treatment with glasdegib was associated with an acceptable safety profile.[Table: see text]

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A novel treatment regimen of granulocyte colony-stimulating factor combined with ultra-low-dose decitabine and low-dose cytarabine in older patients with acute myeloid leukemia and myelodysplastic syndromes

Therapeutic Advances in Hematology ◽

10.1177/20406207211009334 ◽

2021 ◽

Vol 12 ◽

pp. 204062072110093

Author(s):

Huan Zhu ◽

Bin Yang ◽

Jia Liu ◽

Biao Wang ◽

Yicun Wu ◽

...

Keyword(s):

Treatment Regimen ◽

Older Patients ◽

Myeloid Leukemia ◽

Low Dose ◽

Response Rate ◽

Intensive Chemotherapy ◽

Granulocyte Colony Stimulating Factor ◽

Novel Treatment ◽

Stimulating Factor ◽

Low Dose Cytarabine

Background: Older patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) unfit for intensive chemotherapy are emergent for suitable treatment strategies. Hypomethylating agents and low-dose cytarabine have generated relevant benefits in the hematological malignancies over recent decades. We evaluated the efficacy and safety of the novel treatment regimen consisting of ultra-low-dose decitabine and low-dose cytarabine, with granulocyte colony-stimulating factor (G-CSF) in this population of patients. Methods and materials: Patients aged more than 60 years with newly diagnosed AML/MDS were enrolled to receive therapy combined of 300 µg subcutaneously per day for priming, decitabine 5.15–7.62 mg/m2/d intravenously and cytarabine 15 mg/m2/d twice a day subcutaneously and G-CSF for consecutive 10 days every 28 days. The study enrolled 28 patients unfit for standard intensive chemotherapy. The median age of patients was 68 years (range 60–83 years) and 20 (71.4%) patients harbored AML. The primary outcome was to evaluate overall response rate. Results: Overall, this novel ultra-low-dose treatment regimen was well tolerated, with 0% of both 4- and 8-week mortality occurrence. Objective response rate (CR + CRi + PR in AML and CR + mCR + PR in MDS) was 57.1% after the first treatment course. Responses of hematologic improvement (HI) aspect were achieved in 18 of 28 (64.3%) patients, 11 (39.3%), 12 (42.9%), and eight patients (28.6%) achieved HI-E, HI-P, HI-N, respectively. Conclusions: Untreated elderly with AML/MDS were well tolerated and benefited from this novel ultra-low-dose treatment regimen.

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Parenchymal mucinous cystadenoma of the kidney: a case report and literature review

African Journal of Urology ◽

10.1186/s12301-021-00203-4 ◽

2021 ◽

Vol 27 (1) ◽

Author(s):

Mahmoudreza Kalantari ◽

Shakiba Kalantari ◽

Mahdi Mottaghi ◽

Atena Aghaee ◽

Salman Soltani ◽

...

Keyword(s):

Renal Cyst ◽

Left Kidney ◽

Previous History ◽

Mucinous Cystadenoma ◽

Single Layer ◽

Renal Cysts ◽

Cystic Mass ◽

Flank Pain ◽

History Of

Abstract Background Mucinous cystadenoma (MC) of the kidney is exceedingly rare. We found 22 similar cases in the literature. These masses are underdiagnosed due to radiologic similarities with simple renal cysts. Case presentation A 66-year-old man with a previous history of hypertension and anxiety was referred to our tertiary clinic with left flank pain. Ultrasound revealed a 60 mm-sized, complex cystic mass with irregular septa in the lower pole of the left kidney (different from last year's sonographic findings of a simple benign cyst with delicate septa). CT scan showed the same results plus calcification. Due to suspected renal cell carcinoma, a radical nephrectomy was performed. Postoperative histopathologic examination revealed a cyst lined by a single layer of columnar mucin-producing cells with small foci of pseudo-stratification, consistent with the MC’s diagnosis. The first follow-up visit showed normal blood pressure without medication and no flank pain and anxiety after a month. Conclusion It is quite challenging to distinguish the primary MC of the kidney from a simple renal cyst based on clinical and imaging findings. The radiologic features of these entities overlap significantly. Thus, complex renal cyst and renal cysts with mural nodules should be followed closely to detect malignancy earlier.

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An Emulation of Randomized Trials of Administrating Antipsychotics in PTSD Patients for Outcomes of Suicide-Related Events

Journal of Personalized Medicine ◽

10.3390/jpm11030178 ◽

2021 ◽

Vol 11 (3) ◽

pp. 178

Author(s):

Noah R. Delapaz ◽

William K. Hor ◽

Michael Gilbert ◽

Andrew D. La ◽

Feiran Liang ◽

...

Keyword(s):

Randomized Clinical Trials ◽

Previous History ◽

Current Treatment ◽

Careful Consideration ◽

P Value ◽

Post Traumatic Stress ◽

Increased Risk ◽

History Of ◽

Almost All

Post-traumatic stress disorder (PTSD) is a prevalent mental disorder marked by psychological and behavioral changes. Currently, there is no consensus of preferred antipsychotics to be used for the treatment of PTSD. We aim to discover whether certain antipsychotics have decreased suicide risk in the PTSD population, as these patients may be at higher risk. A total of 38,807 patients were identified with a diagnosis of PTSD through the ICD9 or ICD10 codes from January 2004 to October 2019. An emulation of randomized clinical trials was conducted to compare the outcomes of suicide-related events (SREs) among PTSD patients who ever used one of eight individual antipsychotics after the diagnosis of PTSD. Exclusion criteria included patients with a history of SREs and a previous history of antipsychotic use within one year before enrollment. Eligible individuals were assigned to a treatment group according to the antipsychotic initiated and followed until stopping current treatment, switching to another same class of drugs, death, or loss to follow up. The primary outcome was to identify the frequency of SREs associated with each antipsychotic. SREs were defined as ideation, attempts, and death by suicide. Pooled logistic regression methods with the Firth option were conducted to compare two drugs for their outcomes using SAS version 9.4 (SAS Institute, Cary, NC, USA). The results were adjusted for baseline characteristics and post-baseline, time-varying confounders. A total of 5294 patients were eligible for enrollment with an average follow up of 7.86 months. A total of 157 SREs were recorded throughout this study. Lurasidone showed a statistically significant decrease in SREs when compared head to head to almost all the other antipsychotics: aripiprazole, haloperidol, olanzapine, quetiapine, risperidone, and ziprasidone (p < 0.0001 and false discovery rate-adjusted p value < 0.0004). In addition, olanzapine was associated with higher SREs than quetiapine and risperidone, and ziprasidone was associated with higher SREs than risperidone. The results of this study suggest that certain antipsychotics may put individuals within the PTSD population at an increased risk of SREs, and that careful consideration may need to be taken when prescribed.

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Prognostic Factors for Developing Thrombosis in Polycytemia Vera: A Retrospective Analysis of 331 Patients with Long-Term Follow-up Highlights the Importance of White Blood Cells Levels

Blood ◽

10.1182/blood-2020-139431 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 48-49

Author(s):

Samantha Ferrari ◽

Chiara Pagani ◽

Mariella D'Adda ◽

Nicola Bianchetti ◽

Annamaria Pelizzari ◽

...

Keyword(s):

Risk Factors ◽

Multivariate Analysis ◽

High Risk ◽

Board Of Directors ◽

Advisory Board ◽

Advisory Committees ◽

Risk Status ◽

History Of ◽

Wbc Count

Polycythemia Vera (PV) is a chronic myeloproliferative neoplasm characterized by erythrocytosis, constitutively active mutations in JAK2 and an increased susceptibility to thrombotic events (TEs). There is still controversy about the role of increased hematocrit and of other variables including elevated white blood cell count as risk factors for the occurrence of TEs. A better definition of the relative prognostic importance of hematologic parameters would help us to better tailor the therapeutic approach to PV patients (pts), which is currently mainly based on the use of acetilsalycilic acid (ASA), venesection and hydroxyurea . The aim of our study was to analyze if any clinical or laboratory variables were significantly associated to the occurrence of TEs both at PV diagnosis and during the course of the disease in a large series of PV pts uniformly followed at a single Center over a period of 29.5 years from January 1986 to June 2019. Clinical and laboratory data were obtained from the time of diagnosis until death, progression to acute leukemia or last follow-up. Hematocrit (Hct), hemoglobin (Hb), white blood cell (WBC) and platelet (PLT) levels were recorded for each patient at least every 6 months. Among a total of 331 pts, the median age was 65 years (range 30-92 years), and 56% were male. "High risk" features (age ≥ 60 years and/or history of prior thrombosis) were present in 221 pts (66.7%). The incidence of cardiovascular risk factors was: hypertension 64%, diabetes 15%, hyperlipidemia 28%, history of active or remote smoking 41%. Patients on ASA were 279 (84%), 19 (6%) were on oral anticoagulation, while 27 (8%) were on ASA+oral anticoagulant. At PV diagnosis 54 pts (16%) presented with thrombosis, arterial in 32 (59%) and venous in 22 (41%). A previous TE was recorded in 57 pts (17%): in 43 (75%) arterial, in 12 (22%) venous and in 2 (3%) mixed (arterial+venous). Previous thrombosis was the only variable significantly associated with the presence of a TE at PV diagnosis (P=0.02). After PV diagnosis, with a median follow-up of 81 months (range 1-374 months), 63 pts (19%) experienced a TE and 11 of them a further episode, for a total of 74 TEs. The incidence rate (pts/year) of TEs was 2.7%. Forty-two events were arterial (57%), 31 were venous (42%) and 1 (1%) was mixed. It was the first TE for 37 pts. Cerebrovascular accidents and deep-venous thrombosis were the most frequent arterial and venous TEs both at PV diagnosis and throughout the disease course, with a relative incidence of 50% and 32% respectively. The table compares the characteristics of patients who did or did not develop a TE after PV diagnosis. At univariate analysis, PV high risk status, a previous TE and hyperlipidemia at PV diagnosis were significantly associated with a subsequent TE. Among hematologic variables an elevated WBC count at the time of thrombosis, but not Hct or PLT levels, was highly significantly associated with the development of a TE. At multivariate analysis, WBC count ≥10.4 x 10^9/L and hyperlipidemia maintained their independent prognostic value, while high risk status and a previous TE lost their prognostic significance. Both at univariate and multivariate analysis, hyperlipidemia at diagnosis (P=0.009 and P=0.002) and high WBC count at thrombosis (P=0.001 and P=<0.0001) predicted for arterial thromboses, while only a history of prior thrombosis (P=0.03) predicted for venous ones. In conclusion, our analysis confirms that elevated WBC count at the moment of the event more than increased hematocrit is associated to the development of thrombosis in PV pts. We also found that hyperlipidemia was an independent risk factor for arterial thrombosis, calling for an accurate management of increased lipid levels. Whether a reduction of the WBC count during the course of PV may reduce the frequency of TE remains to be demonstrated by prospective studies. Table Disclosures D'Adda: Novartis: Other: Advisory board; Incyte: Other: Advisory board; Pfizer: Other: Advisory board. Rossi:Daiichi Sankyo: Consultancy, Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Advisory board; Alexion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

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Mini- Vs. Regular-Dose CLAG-M (Cladribine, Cytarabine, G-CSF, and Mitoxantrone) in Medically Less Fit Adults with Newly-Diagnosed Acute Myeloid Leukemia (AML) and Other High-Grade Myeloid Neoplasms

Blood ◽

10.1182/blood-2019-123542 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1364-1364 ◽

Cited By ~ 1

Author(s):

Anna B. Halpern ◽

Megan Othus ◽

Kelda Gardner ◽

Genevieve Alcorn ◽

Mary-Elizabeth M. Percival ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Research Funding ◽

Intensive Therapy ◽

Treatment Intensity ◽

High Grade ◽

Intensive Chemotherapy ◽

Myeloid Neoplasms ◽

Acute Myeloid

Background: Optimal treatment for medically less fit adults with acute myeloid leukemia (AML) remains uncertain. Retrospective data suggest intensive therapy may lead to better outcomes in these patients. However, these findings must be interpreted cautiously because of the possibility of selection bias and other confounders. Ideally, the optimal treatment intensity is defined via randomized trial but whether patients and their physicians are amenable to such a study is unknown. We therefore designed a trial (NCT03012672) to 1) evaluate the feasibility of randomization between intensive and non-intensive therapy in this population and 2) examine the impact of treatment intensity on response rate and survival. We used CLAG-M as high-dose cytarabine-based intensive induction therapy. Rather than selecting different classes of drugs in the 2 treatment arms- which may have different modes of action and therefore confound the question of treatment intensity - we used reduced-dose ("mini") CLAG-M as the non-intensive comparator. Methods: Adults ≥18 years were eligible if they had untreated AML or high-grade myeloid neoplasms (≥10% blasts in blood or marrow) and were medically less fit as defined by having a "treatment related mortality" (TRM) score of ≥13.1, corresponding to a >10-15% 28-day mortality with intensive chemotherapy. Left ventricular ejection fraction ≤45% was the only organ function exclusion. Patient-physician pairs were first asked if they were amenable to randomized treatment allocation. If so, they were randomized 1:1 to mini- vs. regular-dose CLAG-M. If not, in order to evaluate our secondary endpoints, the patient or physician could choose the treatment arm and still enroll on study. Patients and physicians then completed surveys elucidating their decision-making processes. Up to 2 induction courses were given with mini- vs. regular-dose CLAG-M: cladribine 2 or 5 mg/m2/day (days 1-5), cytarabine 100 or 2,000 mg/m2/day (days 1-5), G-CSF 300 or 480µcg/day for weight </≥76kg in both arms (days 0-5), and mitoxantrone 6 or 18 mg/m2/day (days 1-3). CLAG at identical doses was used for post-remission therapy for up to 4 (regular-dose CLAG) or 12 (mini-CLAG) cycles. The primary endpoint was feasibility of randomization, defined as ≥26/50 of patient-physician pairs agreeing to randomization. Secondary outcomes included rate of complete remission (CR) negative for measurable ("minimal") residual disease (MRD), rate of CR plus CR with incomplete hematologic recovery (CR+CRi), and overall survival (OS). Results: This trial enrolled 33 patients. Only 3 (9%) patient/physician pairs agreed to randomization and thus randomization was deemed infeasible (primary endpoint). Eighteen pairs chose mini-CLAG-M and 12 regular-dose CLAG-M for a total of 19 subjects in the lower dose and 14 subjects in the higher dose arms. The decision favoring lower dose treatment was made largely by the physician in 5/18 (28%) cases, the patient in 11/18 (61%) cases and both in 2/18 (11%). The decision favoring the higher dose arm was made by the patient in most cases 9/12 (75%), both physician and patient in 2/12 (16%) and the physician in only 1/12 (8%) cases. Despite the limitations of lack of randomization, patients' baseline characteristics were well balanced with regard to age, performance status, TRM score, lab values and cytogenetic/mutational risk categories (Table 1). One patient was not yet evaluable for response or TRM at data cutoff. Rates of MRDneg CR were comparable: 6/19 (32%) in the lower and 3/14 (21%) in the higher dose groups (p=0.70). CR+CRi rates were also similar in both arms (43% vs. 56% in lower vs. higher dose arms; p=0.47). Three (16%) patients experienced early death in the lower dose arm vs. 1 (7%) in the higher dose arm (p=0.43). With a median follow up of 4.2 months, there was no survival difference between the two groups (median OS of 6.1 months in the lower vs. 4.7 months in the higher dose arm; p=0.81; Figure 1). Conclusions: Randomization of medically unfit patients to lower- vs. higher-intensity therapy was not feasible, and physicians rarely chose higher intensity therapy in this patient group. Acknowledging the limitation of short follow-up time and small sample size, our trial did not identify significant differences in outcomes between intensive and non-intensive chemotherapy. Analysis of differences in QOL and healthcare resource utilization between groups is ongoing. Disclosures Halpern: Pfizer Pharmaceuticals: Research Funding; Bayer Pharmaceuticals: Research Funding. Othus:Celgene: Other: Data Safety and Monitoring Committee. Gardner:Abbvie: Speakers Bureau. Percival:Genentech: Membership on an entity's Board of Directors or advisory committees; Pfizer Inc.: Research Funding; Nohla Therapeutics: Research Funding. Scott:Incyte: Consultancy; Novartis: Consultancy; Agios: Consultancy; Celgene: Consultancy. Becker:AbbVie, Amgen, Bristol-Myers Squibb, Glycomimetics, Invivoscribe, JW Pharmaceuticals, Novartis, Trovagene: Research Funding; Accordant Health Services/Caremark: Consultancy; The France Foundation: Honoraria. Oehler:Pfizer Inc.: Research Funding; Blueprint Medicines: Consultancy. Walter:BioLineRx: Consultancy; Astellas: Consultancy; Argenx BVBA: Consultancy; BiVictriX: Consultancy; Agios: Consultancy; Amgen: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Boehringer Ingelheim: Consultancy; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Seattle Genetics: Research Funding; Race Oncology: Consultancy; Aptevo Therapeutics: Consultancy, Research Funding; Kite Pharma: Consultancy; New Link Genetics: Consultancy; Pfizer: Consultancy, Research Funding. OffLabel Disclosure: Cladribine is FDA-approved for Hairy Cell Leukemia. Here we describe its use for AML, where is is also widely used with prior publications supporting its use

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Azacitidine for Post-Remission Therapy in Elderly Patients with Acute Myeloid Leukemia : Final Results of the Qoless AZA-Amle Randomized Trial

Blood ◽

10.1182/blood-2019-125562 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 117-117

Author(s):

Esther Natalie Oliva ◽

Anna Candoni ◽

Prassede Salutari ◽

Francesco Di Raimondo ◽

Gianluigi Reda ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Effect Modification ◽

Intensive Chemotherapy ◽

Consolidation Chemotherapy ◽

Advisory Committees ◽

Eortc Qlq C30 ◽

The Difference ◽

Eortc Qlq

Background: Elderly patients with acute myeloid leukemia (AML) experience a low complete remission (CR) rate following intensive chemotherapy, a short duration of CR and high treatment-related mortality. Median survival is 7-12 months. Several reports suggest that maintenance therapy may improve survival. In particular, a recent report (Huls G, et al. Blood 2019) has shown that azacitidine (Aza) maintenance treatment improves 1-year disease-free survival (DFS) when adjusted for cytogenetics at diagnosis and platelet (PLT) count at randomization. Aims: This phase III, randomized, multicenter trial assesses the efficacy of post-remission Aza treatment versus best supportive care (BSC) in 54 AML subjects >60 years of age in CR after homogeneous induction and consolidation chemotherapy. Primary endpoint is the difference in DFS at 2 and 5 years between arms; main secondary endpoints are the difference in overall survival (OS), the number and length of hospitalizations and quality of life (QoL). Methods: AML subjects with >30% blasts, "de novo" or evolving from myelodysplastic syndrome and fit for intensive chemotherapy, received 2 courses of "3+7" therapy (daunorubicin 40 mg/m2 daily days 1-3 and cytarabine 100 mg/m2 daily IV infusion days 1-7). Subjects obtaining a CR received cytarabine 800 mg/m2 3 hour infusion bid days 1-3 and were randomized 1:1 to receive BSC or Aza at 50 mg/m2 s.c./i.v. for 7 days every 28 days and dose increase after 1st cycle to 75 mg/ m2 for further 5 cycles, followed by cycles every 56 days for 4.5 years or until relapse. QoL was assessed by QOL-E and EORTC QLQ-C30. Results: 149 subjects were included of median age 69, interquartile range (IQR) 65-74 years, and male/female 78/71. Amongst subjects not reaching randomization, 59 were relapsed/refractory, 22 died, 10 refused to continue, 3 were excluded for protocol violation, and 1 was lost to follow-up. Randomized patients (27 Aza, 27 BSC) were in study until relapse. Median follow-up was 9.9 months (IQR: 3.2-22.5). At 2 years post-randomization, no deaths occurred and 21 subjects in the BSC arm (median DFS 9 months, 95% CI 0-20) relapsed versus 18 subjects in the Aza arm (median DFS 11 months, 95% CI 1-21; P=0.33; Fig.1a). There was an effect modification by age on the effect of Aza versus BSC on relapse (P for effect modification=0.02) so that the effect of AZA was not significant for subjects <65 years and 65-73 years (P=0.65 and P=0.66, respectively) but was significant in subjects >73 years (P=0.008, Fig.1b). Cytogenetic risk (P=0.84), minimal residual disease (P=0.97), and platelet (PLT) count (below/above 100 Gi/L, P=0.47) did not modify the effect of Aza on DFS. However, cytogenetic risk and PLT count were confounders: after data adjustment, the effect of Aza on DFS just failed to reach statistical significance [HR (Aza vs BSC): 0.53, 95% CI: 0.26-1.05, P=0.068] . At 5 years post-randomization, no subjects died; 2 subjects on Aza and 1 subject on BSC withdrew consent and 1 subject on Aza in CR withdrew for relapse of bladder cancer. In the BSC arm, 23 subjects relapsed (median DFS 9 months, 95% CI: 0-20) versus 20 Aza subjects (median 11 months, 95% CI: 1-21; P=0.31, Fig.1a).Similar to 2 years post-randomization, at 5 years post-randomization an effect modification by age on the effect of Aza versus BSC was confirmed (P for effect modification=0.01) and the effect of Aza was significant only in subjects >73 years of age (P=0.007, Fig.1b). Again, data adjustment for cytogenetic risk and PLT count strengthened the link between Aza and DFS [HR: 0.56, 95% CI: 0.29-1.07, P=0.08]. Grade 3-4 adverse events (mainly neutropenia) were more frequent in the Aza (41%) than in the BSC arm (4%, P=0.002). Two Aza subjects were hospitalized twice for adverse events for a total of 22 and 26 days, respectively, versus no hospitalization for BSC subjects. QOL-E scores were poor at diagnosis and improved significantly at randomization, with further improvement for physical well-being. EORTC QLQ-C30 symptoms improved progressively over time. In linear mixed model analyses, no significant effect of Aza versus BSC was found for any QoL domain, confirming safety of Aza versus BSC. Summary/Conclusion: With the limitation of a small trial, we conclude that post-remission Aza in elderly AML patients receiving standard induction-consolidation chemotherapy is safe and is well-tolerated. Noteworthy, in patients over 73 years of age, Aza significantly prolongs DFS up to 5 years. Figure Disclosures Oliva: Celgene Corporation: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy; Novartis: Consultancy, Speakers Bureau. Candoni:Merck SD: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Celgene: Honoraria; Pfizer: Honoraria; Janssen: Honoraria. Di Raimondo:Takeda: Consultancy; Amgen: Consultancy, Honoraria, Research Funding. Musto:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mannina:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Martino:Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Bristol myers squibb: Membership on an entity's Board of Directors or advisory committees. Alati:Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.

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Outcome of Relapsed or Refractory FLT3-Mutated Acute Myeloid Leukemia before Second-Generation FLT3 Tyrosine Kinase Inhibitors: A Toulouse–Bordeaux DATAML Registry Study

Cancers ◽

10.3390/cancers12040773 ◽

2020 ◽

Vol 12 (4) ◽

pp. 773 ◽

Cited By ~ 2

Author(s):

Sarah Bertoli ◽

Pierre-Yves Dumas ◽

Emilie Bérard ◽

Laetitia Largeaud ◽

Audrey Bidet ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Complete Remission ◽

Myeloid Leukemia ◽

Response Rate ◽

Intensive Chemotherapy ◽

Line Treatment ◽

First Line ◽

Low Intensity ◽

First Line Treatment ◽

Acute Myeloid

A recent phase 3 trial showed that the outcome of patients with relapsed/refractory (R/R) FLT3-mutated acute myeloid leukemia (AML) improved with gilteritinib, a single-agent second-generation FLT3 tyrosine kinase inhibitor (TKI), compared with standard of care. In this trial, the response rate with standard therapy was particularly low. We retrospectively assessed the characteristics and outcome of patients with R/R FLT3-mutated AML included in the Toulouse–Bordeaux DATAML registry. Among 347 patients who received FLT3 TKI-free intensive chemotherapy as first-line treatment, 174 patients were refractory (n = 48, 27.6%) or relapsed (n = 126, 72.4%). Salvage treatments consisted of intensive chemotherapy (n = 99, 56.9%), azacitidine or low-dose cytarabine (n = 9, 5.1%), other low-intensity treatments (n = 17, 9.8%), immediate allogeneic stem cell transplantation (n = 4, 2.3%) or best supportive care only (n = 45, 25.9%). Among the 114 patients who previously received FLT3 TKI-free intensive chemotherapy as first-line treatment (refractory, n = 32, 28.1%; relapsed, n = 82, 71.9%), the rate of CR (complete remission) or CRi (complete remission with incomplete hematologic recovery) after high- or low-intensity salvage treatment was 50.0%, with a bridge to transplant in 34.2% (n = 39) of cases. The median overall survival (OS) was 8.2 months (interquartile range, 3.0–32); 1-, 3- and 5-year OS rates were 36.0% (95%CI: 27–45), 24.7% (95%CI: 1–33) and 19.7% (95%CI: 1–28), respectively. In this real-word study, although response rate appeared higher than the controlled arm of the ADMIRAL trial, the outcome of patients with R/R FLT3-mutated AML remains very poor with standard salvage therapy.

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