Comparison between Hypercvad and CALLG2008 Protocol in Adult Patients with Newly Diagnosed Acute Lymphoblastic Leukemia:a Single Center Study

BACKGROUD: HyperCVAD is one of the most frequent used protocols in adult ALL in routine practice. On the other hand, the CALLG2008 protocol was a published protocol designed by the Chinese Acute Lymphoblastic Leukemia Cooperative Group for adult ALL. In this retrospective study, we analyzed 70 Chinese patients with adult ALL to compare the efficacy, safety and costs of HyperCVAD regimen in comparison to CALLG2008. METHODS: Pts ≥ 15 years old with previously untreated newly-diagnosed ALL were eligible. All pts provided IRB-approved informed consent before chemotherapy. HyperCVAD and CALLG2008 were given as initially described. Imatinib (400 mg daily) was administered concurrently in patients with Ph-positive ALL. Prophylactic antibiotics, antifungals, and antiviral agents were provided according to the institutional guidelines. Red blood cells and platelet transfusions were given for hemoglobin<60 g/L and platelets≤10×109/L or if with hemorrhage. Granulocyte colony-stimulating factor was given routinely. Bone marrow aspiration was performed after the completion of the first course of induction chemotherapy to assess their response to treatment. All patients were evaluated for minimal residual disease (MRD) in bone marrow at the end of the first course of induction by 6-color multi-parametric flow cytometry analysis and reverse-transcription quantitative polymerase chain reaction (RT-qPCR). Primary endpoint of the study was CR rate after the first course of induction therapy. Complete remission (CR) was defined as having <5% marrow blasts, a normalization of peripheral counts (neutrophil count ≥1 × 109/L, platelet count ≥100 × 109/L, and no abnormal peripheral blasts), and absence of extramedullary disease. The criteria for the positive and negative MRD are based on the experience of the European ALL MRD Detection Research Collaborative Group. Adverse events occurring during the first 8 weeks after the first course of induction therapy are reported. Other treatment outcomes including blood transfusion requirement, recovery day of neutrophil count were collected, as well as detailed data regarding hospitalization time, complications and costs. RESULTS: Thirty patients were treated with HyperCVAD, and 40 with CALLG2008. Pre-treatment characteristics are shown in the Table 1. After the first course of induction chemotherapy, complete remission was obtained in 83% and 78% of patients, respectively. The CR rate did not vary significantly by different regimens, gender, age, immunophenotype. However, 96% of those with cytogenetic or molecular evidence of the Philadelphia (Ph) chromosome and 76% of those without such evidence achieved a CR (P=0.045). In Ph-negative group, MRD-negative rates were found to be significantly higher with HyperCVAD (58% vs 27%, P=0.036). The median durations of neutrophil recovery of CALLG2008 group was 4 days longer than HyperCVAD group (P=0.038). Moreover, grade 3-4 thrombocytopenic (<500/μl) was more frequent on CALLG2008 regimens compared with the HyperCVAD regimens (90% vs 63%; P=0.007). Accordingly, a lower platelet transfusion rate was observed in favor of the HyperCVAD group (47% vs 73%, P=0.007). The CALLG2008 regimen had more all-grade hepatic toxicity than HyperCVAD regimen (53% vs 27%; P=0.03). Grade 3-4 hypofibrinogenemia was more frequent on CALLG2008 regimen compared with hyper-CVAD regimen (33% vs 7%; P=0.009). The average time to stay of the first course of chemotherapy were 19.4±3.5 and 24.2±8.6 days in HyperCVAD and CALLG2008 groups, respectively (P=0.002). The average drug-related costs for patients treated with HyperCVAD were significantly lower compared with that for those treated with CALLG2008 (30981.7 vs 59422.9 yuan, P=0.010). CONCLUSION: Although HyperCVAD and CALLG2008 regimens showed relatively similar early CR rate, the former yields deep remissions more powerfully in Ph-negative ALL. Additionally, HyperCVAD was more favorable in hematopoietic recovery than CALLG2008. Differences were also observed in terms of less complications, shorter hospitalization and lower drug-related expenditure in favor of HyperCVAD group. Disclosures No relevant conflicts of interest to declare.

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Ixazomib-based frontline therapy in patients with newly diagnosed multiple myeloma in real-life practice showed comparable efficacy and safety profile with those reported in clinical trial: a multi-center study

Annals of Hematology ◽

10.1007/s00277-020-04234-9 ◽

2020 ◽

Vol 99 (11) ◽

pp. 2589-2598

Author(s):

Jing Li ◽

Li Bao ◽

Zhongjun Xia ◽

Sili Wang ◽

Xin Zhou ◽

...

Keyword(s):

Multiple Myeloma ◽

Induction Therapy ◽

Response Rate ◽

Real Life ◽

Comparable Efficacy ◽

Routine Practice ◽

Newly Diagnosed ◽

Efficacy And Safety ◽

Frontline Therapy ◽

Grade 3

Abstract The induction therapy containing ixazomib, an oral proteasome inhibitor, has shown favorable efficacy and safety in clinical trials, but its experience in real-life remains limited. In routine practice, few patients received ixazomib-based induction therapy due to reasons including (1) patients’ preference on oral regimens, (2) concerns on adverse events (AEs) of other intravenous/subcutaneous regimens, (3) requirements for less center visits, and (4) fears of COVID-19 and other infectious disease exposures. With the aim of assessing the real-life effectiveness and safety of ixazomib-based induction therapy, we performed this multi-center, observational study on 85 newly diagnosed multiple myeloma (NDMM) patients from 14 medical centers. Ixazomib-based regimens included ixazomib-lenalidomide-dexamethasone (IRd) in 44.7% of patients, ixazomib-dexamethasone (Id) in 29.4%, and Id plus another agent (doxorubicin, cyclophosphamide, thalidomide, or daratumumab) in 25.9%. Different ixazomib-based therapies were applied due to (1) financial burdens or limitations on local health insurance coverage, (2) concerns on treatment tolerance, and (3) drug accessibility issue. Ten patients received ixazomib maintenance. The median age was 67 years; 43.5% had ISS stage III disease; 48.2% had an Eastern Cooperative Oncology Group performance score ≥ 2; and 17.6% with high-risk cytogenetic abnormalities. Overall response rate for all 85 patients was 95.3%, including 65.9% very good partial response or better and 29.5% complete responses. The median time to response was 30 days. The response rate was similar across different ixazomib-based regimens. Median progression-free survival was not reached. Severe AEs (≥ grade 3) were reported in 29.4% of patients. No grade 3/4 peripheral neuropathy (PN) occurred. Patients received a median of 6 (range 1–20) cycles of ixazomib treatment; 56.6% remained on treatment at data cutoff; 15.3% discontinued treatment due to intolerable AEs. These results support that the ixazomib-based frontline therapy was highly effective with acceptable toxicity in routine practice and the ixazomib oral regimens could be good alternative options for NDMM patients.

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Phase 1/2 Study of Tandutinib (MLN518) Plus Standard Induction Chemotherapy in Newly Diagnosed Acute Myelogenous Leukemia (AML).

Blood ◽

10.1182/blood.v108.11.158.158 ◽

2006 ◽

Vol 108 (11) ◽

pp. 158-158 ◽

Cited By ~ 6

Author(s):

Daniel J. DeAngelo ◽

Philip C. Amrein ◽

Tibor J. Kovacsovics ◽

Rebecca B. Klisovic ◽

Bayard L. Powell ◽

...

Keyword(s):

Induction Chemotherapy ◽

Induction Therapy ◽

De Novo ◽

Single Agent ◽

Myelogenous Leukemia ◽

High Dose ◽

Hematologic Toxicity ◽

Consolidation Therapy ◽

Newly Diagnosed ◽

Grade 3

Abstract Background: Tandutinib is an orally bioavailable small molecule inhibitor of FLT3, c-KIT, and PDGFR with a single-agent MTD of 525 mg b.i.d. Tandutinib demonstrated single agent anti-leukemic activity in patients with relapsed/refractory AML with FLT3 ITD mutations, with ≥50% decreases in bone marrow and peripheral blast counts in 12/25 patients and 1 CR without platelet normalization. Since tandutinib is synergistic with cytarabine and daunorubicin in vitro, we sought to determine the MTD of tandutinib in combination with standard induction chemotherapy in patients with newly diagnosed AML, with or without FLT3 ITD mutations. Methods: A starting dose of Tandutinib 200 mg b.i.d was administered during induction and consolidation therapy, and for an additional 6 months. Induction therapy consists of cytarabine 200mg/m2/day IVCI, days 1–7, plus daunorubicin 60mg/m2/day, days 1–3. Consolidation therapy is given as 2–4 cycles of standard (3000mg/m2 IV every 12h, days 1, 3, 5) or in older patients modified (2000mg/m2/day IV, days 1–5) high-dose cytarabine. DLT is defined as failure to recover marrow function (ANC ≥500/μL; platelets ≥20,000/μL), or grade 3/4 non-hematologic toxicity not resolved to grade 2 (except anorexia, alopecia, fatigue) by day 42 of induction therapy, or any unexpected grade 3/4 non-hematologic toxicities. Results: 29 patients have been enrolled: median age 60y (range 26–83); 13M, 16F; 23 de novo, 6 secondary AML; 9 with unfavorable cytogenetics; 5 with FLT3 ITD mutations. Cohort 1 consisted of 7 patients treated with continuous daily dosing of tandutinib 200 mg b.i.d. Due to GI intolerance, the protocol was amended so that tandutinib was administered only on days 1–14 of induction therapy and each cycle of consolidation. Under the amended schedule 8 patients were treated with tandutinib 200 mg b.i.d. (Cohort 2) and 14 patients have been treated with tandutinib 500 mg b.i.d. (Cohort 3). Full safety and efficacy data are available for the 15 patients in cohorts 1 and 2. Diarrhea, nausea and vomiting have been the most common drug-related AEs, and were more frequent with continuous daily dosing of tandutinib. GI tolerance in Cohort 2 has been acceptable, with no patients requiring termination or reduction in tandutinib for GI toxicity. Although continuous dosing was not feasible, no DLTs were seen in Cohorts 1 or 2; one DLT consisting of obtundation not clearly related to tandutinib during induction occurred in Cohort 3, One patient in Cohort 3 experienced non-dose limiting generalized muscle weakness, which reversed within 24 hours after discontinuation of tandutinib. Tandutinib was restarted at a reduced dose in this patient without recurrence. 5/7 patients in Cohort 1 and 6/8 patients in Cohort 2 achieved a CR. PK data have been collected for all 15 patients in Cohorts 1 and 2; median steady state tandutinib concentration was 195 ng/mL (range: 52–486). Conclusions: Tandutinib 200 and 500 mg b.i.d. in combination with standard therapy for newly diagnosed AML appears well tolerated using the amended dosing schedule (days 1–14). Updated results from Cohort 3 (tandutinib 500 mg b.i.d) will be presented.

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Probability of Eventual CR After Course 1 of Induction Therapy for Newly-Diagnosed AML As a Function of Platelet and Neutrophil Recovery.

Blood ◽

10.1182/blood.v120.21.2598.2598 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2598-2598

Author(s):

Laura F Newell ◽

Hu Xie ◽

John M. Pagel ◽

Ravinder K Sandhu ◽

Pamela S Becker ◽

...

Keyword(s):

Bone Marrow ◽

Platelet Count ◽

Induction Chemotherapy ◽

Induction Therapy ◽

Blood Count ◽

Newly Diagnosed ◽

Platelet Recovery ◽

Platelet Counts ◽

Bone Marrow Blasts ◽

Count Recovery

Abstract Abstract 2598 Background: After initial induction chemotherapy for acute myeloid leukemia (AML), it is commonplace that reinduction or intensified therapy is not indicated if the bone marrow has <5% blasts, even despite persistently low neutrophil (ANC) and/or platelet counts. This practice suggests that complete remission (CR), i.e. ANC >1000/μl and platelet count >100,000/μl per standard criteria (Cheson BD, et al. J Clin Oncol. 1990;8(5):813-9), might still occur and that the lack of blood count recovery may not bear prognostic significance. However, the time to CR after the first induction has been shown to be inversely related to subsequent duration of disease-free survival (DFS) and survival (OS), independent of age, treatment, and cytogenetics (Estey EH, et al. Blood. 2000;95(1):72-7). Additionally, the level of ANC and platelet recovery at time of CR is prognostic, with significantly better DFS among patients with higher counts (Yanada M, et al. Leuk Res. 2008;32(10):1505-9). Newly-diagnosed AML patients often present with below normal neutrophil and platelet counts, suggesting that persistence of such cytopenias after induction may be a clinical indicator of minimal residual disease (MRD) in the marrow. We therefore examined whether blood count recovery affected the probability of subsequent CR in patients with <5% bone marrow blasts. Methods: We included 85 patients who, by day 21 or thereafter of induction therapy for newly-diagnosed AML, had not met blood count criteria for CR despite a bone marrow in the prior week with <5% blasts by morphology. Patients were classified by type of induction therapy based on cytarabine dosing. G-CSF was not systematically administered. Marrows were planned for day 21 after chemotherapy and/or weekly thereafter to assess for disease status and evidence of marrow recovery. Because patients were often managed as outpatients, counts and marrows were not uniformly available and thus “day 28” included days 21–28, “day 35” included days 29–35, etc. If a patient had more than one marrow evaluation after day 21, we included only the first one. Results: Overall cohort CR rate was 64%. Eventual CR rate was significantly affected by platelet count, with 44% eventual CR for patients with platelets <30,000, 66% CR for platelets 30,000–100,000, and 95% CR for platelets >100,000. The effect of ANC recovery on eventual CR was less dramatic, with an OR 0.4 (0.2–1.0, p=0.049), for ANC <0.1 vs. >0.1 in the univariate analysis. By day 28, patients with either ANC or platelet recovery were significantly more likely to obtain CR than patients with neither count recovery (89% vs. 51%), OR 8.05 (2.2–30, p=0.002). In the multivariate analysis, (a) lack of platelet recovery to >30,000 was associated with significantly lower incidence of CR, OR 0.26 (0.1–0.8, p=0.02), and was independent of cytogenetic risk, antecedent hematologic disorder, and induction regimen, and (b) there was a suggested association between earlier count recovery and CR (>28 days vs. day 21–28), OR 0.31 (0.1–1.0, p=0.051). Conclusion: Persistence of low peripheral blood counts, despite the presence of <5% bone marrow blasts, is predictive of low eventual CR rates after induction chemotherapy. These results suggest that initiation of further and possibly different therapy, rather than continued observation, should be investigated in this setting. Disclosures: Becker: Sanofi: Research Funding.

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Quizartinib with decitabine and venetoclax (triplet) is highly active in patients with FLT3-ITD mutated acute myeloid leukemia (AML).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e19019 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e19019-e19019

Author(s):

Musa Yilmaz ◽

Hagop M. Kantarjian ◽

Muharrem Muftuoglu ◽

Tapan M. Kadia ◽

Marina Konopleva ◽

...

Keyword(s):

Bone Marrow ◽

Induction Chemotherapy ◽

Performance Status ◽

Newly Diagnosed ◽

Highly Active ◽

Flt3 Inhibitor ◽

Grade 3 ◽

Relapsed Disease ◽

Cellular Bone

e19019 Background: The outcomes in patients (pts) with newly diagnosed FLT3 mutated AML who are ineligible for intensive induction chemotherapy are poor. Added to a low intensity chemotherapy backbone, FLT3 inhibitors, such as midostaurin, sorafenib, and quizartinib, result in median OS of 8-17 months in the frontline (Gallogly ASH 2017, Ohanian AJH 2018, Swaminathan ASH 2017), and 4-8 months in relapsed/refractory (R/R) settings (Yilmaz JHO 2020, Ravandi Blood 2013). Quizartinib, a potent second generation FLT3 inhibitor demonstrated synergy with venetoclax (VEN) (a BCL-2 inhibitor) in AML cell lines and PDX models (Mali Haematologica 2020). We designed this study to evaluate the safety and efficacy of quizartinib, venetoclax, and decitabine combination in pts with R/R or newly diagnosed FLT3 mutated AML. Methods: Frontline cohort included pts who are ineligible for intensive induction chemotherapy, and R/R cohort included pts who received 5 or less prior treatments. All patients had a performance status of ECOG ≤2, adequate organ functions, and QTcF <450 msec prior to therapy. All pts underwent day 14 bone marrow, and venetoclax (400 mg/day) was put on hold in patients with bone marrow blasts ≤ 5% (or marrow aplasia). Those with day14 bone marrow blast >5% continued venetoclax for 21 days during cycle 1. All pts induced with 10 days of decitabine (20 mg/m2). In subsequent cycles, decitabine administered for 5 days. Quizartinib (30 or 40 mg/day) was administered daily continuously. Results: 21 pts were enrolled and 17 pts evaluable at the time of this report (4 are still within cycle 1). Of 13 pts with R/R AML (median 3 [range 1-5] prior therapies, 85% with ≥1 prior FLT3 inhibitor), 9 (69%) achieved CRc (2 CR, 7 CRi) with 4/9 and 5/9 responders FLT3-PCR and multicolor flow cytometry (MFC) negative, respectively. Thirty and 60-day mortality rates were 0% and 8%. Of 4 patients with newly diagnosed AML (median age 72), all achieved CRc (2 CR, 2 CRi) with 4/4 and 2/3 responders FLT3-PCR and MFC negative, respectively. 60-day mortality was 0% in the frontline cohort. No pts developed a dose limiting toxicity (DLT) with 30 mg/day quizartinib, however with the 40mg/day quizartinib 2 pts developed hematologic DLT (grade ≥3 neutropenia with a <5% cellular bone marrow lasting ≥42 days). Hence, quizartinib 30 mg/day dose was determined as recommended phase 2 dose for the triplet. Grade 3/5 non-hematologic toxicities in >2 pts included lung infections (N=9) and neutropenic fever (N=6). No QTcF prolongations >450 msec were noted. With a median follow-up of 7.2 months, the median OS was not reached in frontline cohort and was 7.1 months in R/R cohort. 2/4 and 5/9 responders underwent ASCT in frontline and R/R cohorts, respectively. All frontline pts were alive at the last follow-up; 3 were in CR and 1 relapsed disease. Of 9 responders in R/R cohort, 4 were alive (3 CR, 1 relapse) and 5 died (4 relapse, 1 CR). Conclusions: Decitabine + venetoclax + quizartinib is highly active in R/R FLT3-ITD mutated AML pts, with CRc rates of 69% and the median OS of 7.1 months. Accrual to the triplet continues and updated clinical and correlative data will be presented. Clinical trial information: NCT03661307.

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Nutritional Status of the Children with Acute Lymphoblastic Leukemia at Diagnosis and after Completion of Induction

Haematology Journal of Bangladesh ◽

10.37545/haematoljbd202174 ◽

2021 ◽

Vol 5 (02) ◽

pp. 50-56

Author(s):

Noor-A-Sabah Liza ◽

S. M. Rezanur Rahman ◽

Afiqul Islam ◽

Chowdhury Yakub Jamal ◽

Mohosina Sultana Setu ◽

...

Keyword(s):

Nutritional Status ◽

Serum Albumin ◽

Induction Chemotherapy ◽

Induction Therapy ◽

Serum Albumin Level ◽

Albumin Level ◽

Anthropometric Measurements ◽

Newly Diagnosed ◽

Significant Difference ◽

Nutritional Status Of Children

Background: Adequate nutrition is an important concern in children with leukemia. Malnutrition and weight lost are common and are due to verity of mechanism involving the tumor, the host response to the tumor such as infection and pharmacokinetics of chemotherapeutic drugs. Objective: To evaluate and compare the nutritional status of children with ALL at diagnosis and after completion of induction therapy. Methodology: This prospective observational study included 60 children newly diagnosed as ALL, aged 2-15 years, over a period from April 2012 to September 2012 in the Department of Pediatric Hematology and Oncology, BSMMU. The anthropometric measurements and serum albumin level were taken. Anthropometric indices are calculated by NCHS (WHO-2000) and classified as Z score. Children <-2 SD are considered as underweight (WFA), stunted (HFA) and wasted (WFH). Serum albumin level below 21g/dl is considered as severely malnourished. The Hb values of the children are compared with normal values by age. The children got induction chemotherapy according to MRC-11 protocol. They were in regular follow up and again anthropometric measurements and serum albumin level were taken after completion of induction. Results: Out of 60 children with ALL, 48 (70%) were underweight, 45 (75%) were stunted 36 (60%) were wasted at diagnosis. Incidence of malnutrition among leukemia children after completion of induction were 24 (40%) underweight, 45 (75%) were stunted and 6 (10%) were wasted. The results showed that children in the newly diagnosed stage had a higher prevalence of malnutrition. However no statistically significant difference in the nutritional status was found among newly diagnosed and after completion of induction in term of underweight and stunting but newly diagnosed patients had statistically significant wasting than patients who had completed induction chemotherapy. No patient showed severe malnutrition based on the cut-off point for serum albumin on both stages. All the children (100%) had less than normal range hemoglobin levels. Conclusion: Malnutrition was higher in children with newly diagnosed leukemia. Children had significant differences in the nutritional status in term of wasting at diagnosis than after completion of induction therapy. So, the nutritional status of children with leukemia should be monitor periodically.

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Intensively timed induction therapy followed by autologous or allogeneic bone marrow transplantation for children with acute myeloid leukemia or myelodysplastic syndrome: a Childrens Cancer Group pilot study.

Journal of Clinical Oncology ◽

10.1200/jco.1993.11.8.1448 ◽

1993 ◽

Vol 11 (8) ◽

pp. 1448-1457 ◽

Cited By ~ 98

Author(s):

W G Woods ◽

N Kobrinsky ◽

J Buckley ◽

S Neudorf ◽

J Sanders ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Induction Therapy ◽

Myeloid Leukemia ◽

Allogeneic Bone Marrow Transplantation ◽

Allogeneic Bone ◽

Newly Diagnosed ◽

Free Survival ◽

Cancer Group ◽

Acute Myeloid

PURPOSE Childrens Cancer Group (CCG) protocol 2861 was designed to test the feasibility of aggressively timed induction therapy followed by autologous or allogeneic bone marrow transplantation (BMT) as the sole postremission therapy for newly diagnosed children with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). PATIENTS AND METHODS Between April 1988 and October 1989, 142 patients were eligible for study. All patients entered received a timing-intensive five-drug induction of dexamethasone, cytarabine (Ara-C), thioguanine, etoposide, and daunorubicin (DCTER) over 4 days with a second cycle administered after 6 days of rest, irrespective of hematologic status at that time. Most patients subsequently received a second two-cycle induction course. Those who achieved remission were eligible for bone marrow ablative therapy with busulfan and cyclophosphamide, followed by 4-hydroperoxy-cyclophosphamide (4-HC)-purged autologous or allogeneic BMT rescue. RESULTS One hundred eight (76%) patients achieved remission: 19 (13%) died of complications of the leukemia and/or chemotherapy, and 15 (11%) failed to achieve remission. Seventy-four patients subsequently underwent BMT with either autologous (n = 58) or allogeneic (n = 16) rescue. For patients who received autologous rescue with 4-HC-purged grafts, the actuarial disease-free survival (DFS) rate at 3 years from the day of transplant is 51%, compared with 55% for patients who received allogeneic grafts (P = .92). At 3 years, the overall actuarial survival rate for all 142 patients entered on this study is 45%, with an event-free survival (EFS) rate of 37%. Adverse prognostic factors for outcome included an elevated WBC count or the presence of CNS leukemia at the time of AML diagnosis. CONCLUSION Results suggest that aggressively timed induction therapy followed by marrow ablation and BMT rescue with either autologous or allogeneic grafts for children with newly diagnosed AML or MDS is both feasible and effective.

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Mutant Isocitrate Dehydrogenase 1 Inhibitor Ivosidenib in Combination With Azacitidine for Newly Diagnosed Acute Myeloid Leukemia

Journal of Clinical Oncology ◽

10.1200/jco.20.01632 ◽

2021 ◽

Vol 39 (1) ◽

pp. 57-65

Author(s):

Courtney D. DiNardo ◽

Anthony S. Stein ◽

Eytan M. Stein ◽

Amir T. Fathi ◽

Olga Frankfurt ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Complete Remission ◽

Adverse Events ◽

Isocitrate Dehydrogenase ◽

Myeloid Leukemia ◽

Qt Prolongation ◽

Newly Diagnosed ◽

Isocitrate Dehydrogenase 1 ◽

Grade 3 ◽

Acute Myeloid

PURPOSE Ivosidenib is an oral inhibitor of the mutant isocitrate dehydrogenase 1 (IDH1) enzyme, approved for treatment of IDH1-mutant (m IDH1) acute myeloid leukemia (AML). Preclinical work suggested that addition of azacitidine to ivosidenib enhances mIDH1 inhibition–related differentiation and apoptosis. PATIENTS AND METHODS This was an open-label, multicenter, phase Ib trial comprising dose-finding and expansion stages to evaluate safety and efficacy of combining oral ivosidenib 500 mg once daily continuously with subcutaneous azacitidine 75 mg/m2 on days 1-7 in 28-day cycles in patients with newly diagnosed m IDH1 AML ineligible for intensive induction chemotherapy (ClinicalTrials.gov identifier: NCT02677922 ). RESULTS Twenty-three patients received ivosidenib plus azacitidine (median age, 76 years; range, 61-88 years). Treatment-related grade ≥ 3 adverse events occurring in > 10% of patients were neutropenia (22%), anemia (13%), thrombocytopenia (13%), and electrocardiogram QT prolongation (13%). Adverse events of special interest included all-grade IDH differentiation syndrome (17%), all-grade electrocardiogram QT prolongation (26%), and grade ≥ 3 leukocytosis (9%). Median treatment duration was 15.1 months (range, 0.3-32.2 months); 10 patients remained on treatment as of February 19, 2019. The overall response rate was 78.3% (18/23 patients; 95% CI, 56.3% to 92.5%), and the complete remission rate was 60.9% (14/23 patients; 95% CI, 38.5% to 80.3%). With median follow-up of 16 months, median duration of response in responders had not been reached. The 12-month survival estimate was 82.0% (95% CI, 58.8% to 92.8%). m IDH1 clearance in bone marrow mononuclear cells by BEAMing (beads, emulsion, amplification, magnetics) digital polymerase chain reaction was seen in 10/14 patients (71.4%) achieving complete remission. CONCLUSION Ivosidenib plus azacitidine was well tolerated, with an expected safety profile consistent with monotherapy with each agent. Responses were deep and durable, with most complete responders achieving m IDH1 mutation clearance.

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Treatment of refractory adult lymphoblastic leukemia (ALL) with 4'(9- acridinylamino) methanesulfon-M-anisidide (AMSA)

Blood ◽

10.1182/blood.v60.5.1224.1224 ◽

1982 ◽

Vol 60 (5) ◽

pp. 1224-1226 ◽

Cited By ~ 6

Author(s):

ZA Arlin ◽

MP Fanucchi ◽

TS Gee ◽

SJ Kempin ◽

R Mertelsmann ◽

...

Keyword(s):

Bone Marrow ◽

Bone Marrow Transplantation ◽

Complete Remission ◽

Induction Therapy ◽

Marrow Transplantation ◽

Lymphoblastic Leukemia ◽

Maintenance Chemotherapy ◽

Primary Induction

Abstract Twenty-four adults with ALL were treated with AMSA alone or in combination. Twenty-two were treated at time of relapse and two patients after failing primary induction therapy. All had been treated with anthracyclines prior to receiving AMSA. Of the 22 patients with ALL in relapse, 4 achieved a complete remission. Two of these patients have relapsed while receiving maintenance chemotherapy; one died 1 mo after achieving remission due to the occurrence of cholycystitis in the setting of pancytopenia and one patient underwent bone marrow transplantation and is in remission at 8 mo after the second remission. Both patients who failed primary induction therapy remain in remission at 11 and 36 mo, respectively. The use of AMSA should be considered for patients with ALL who fail primary induction as well as those whose leukemia becomes resistant to conventional agents.

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Prolonged Survival of a Patient with De Novo Acute Myeloid Leukemia (AML) and Trisomy 13 with Intensive Chemotherapy and Autologous Peripheral Blood Transplantation (PBSCT): A Case Report.

Blood ◽

10.1182/blood.v106.11.4519.4519 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4519-4519

Author(s):

Nitin D. Joshi ◽

Alpesh Amin ◽

Rajneesh Nath

Keyword(s):

Bone Marrow ◽

Complete Remission ◽

Bone Marrow Biopsy ◽

Induction Chemotherapy ◽

Peripheral Blood ◽

De Novo ◽

Trisomy 13 ◽

Autologous Pbsct ◽

De Novo Aml ◽

First Complete Remission

Abstract Trisomies are uncommon cytogenetic abnormalities in patient with de novo AML. Survival of patients with trisomy 13 ranges from 0.5 to 14.7 months. We present the treatment outcome of a 71-year-old man with de novo AML and trisomy 13 who had PBSCT in first complete remission. A 71-year Puerto Rican male was diagnosed with AML in April 2003. His CBC showed WBC count 177 K/mm3, hemoglobin 10.3 gm/dl, platelets 43 K/mm3 and blast cells 75%. Flow cytometry revealed that the leukemic blasts were CD33, CD13, CD11c and CD56 positive but negative for CD34. Cytogenetics failed to yield any metaphases. Peripheral blood FISH studies revealed trisomy 13 positivity in 300 of 325 cells analyzed. Patient received induction chemotherapy with high dose Ara-c (HiDAC) 3g/m2 QD x 5 doses and mitoxantrone 80mg/m2 on day # 2. Bone marrow done day 28 post induction chemotherapy revealed residual leukemic blasts. Cytogenetics showed that one out twenty metaphases had trisomy 13 along with translocation t (9:18) (q34; q10). 11.9% of cells had trisomy 13 by FISH analysis. The patient then received a second cycle of chemotherapy with HiDAC at 2 g/m2 Q12 x 12 doses. Bone marrow biopsy on day 35 following reinduction chemotherapy revealed normocellular-regenerating marrow in remission and FISH was negative for trisomy 13. On the third cycle of chemotherapy, patient received Etoposide 11 mg/kg. Neupogen was started on day #3 and 10.3 x 106 CD34 positive cells/kg were collected. The patient then underwent autologous PBSCT using Melphalan 160 mg/m2 as the preparative regimen. On Day +87 and Day +182 post transplant, bone marrow biopsy showed complete remission with FISH negative for trisomy 13. The patient is still alive 27 months after initial treatment and 22 months post PBSCT. Autologous PBSCT in first complete remission for AML with trisomy 13 may provide a superior survival than chemotherapy alone.

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Study of Sequential Treatment of Newly Diagnosed De Novo AML Patients with DA and CAG Regimens as Remission Induction Therapy.

Blood ◽

10.1182/blood.v106.11.4630.4630 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4630-4630

Author(s):

Hui ping Sun ◽

Wei Hong Liu ◽

Jun min Li ◽

Qiu sheng Chen ◽

Yu Chen

Keyword(s):

Bone Marrow ◽

Induction Therapy ◽

Peripheral Blood ◽

De Novo ◽

Classification Criteria ◽

Sequential Treatment ◽

Remission Induction ◽

Newly Diagnosed ◽

Fab Classification ◽

De Novo Aml

Abstract Objectives To evaluate the efficacy and safety of sequential treatment of newly diagnosed de novo AML patients with DA and CAG regimens as induction therapy. Methods Those who were newly diagnosed as de novo AML (FAB classification criteria) were enrolled and DA regimen chemotherapy were administered. Bone marrow aspirates were performed and BM smears were examined at 48 hours since the end of chemotherapy. If severe hypocellularities were not achieved, the percentage of blasts in BM was between 20%–60% and peripheral WBC was in the range of (0.5–10) x109/L, the patients would receive CAG regimen therapy since 72 hours. Patients’ general status and the important parameters, such as peripheral blood count, liver function, renal function, thrombosis and hemostasis parameters were monitored throughout the course of the treatment and thereafter. When the clinical symptoms were relieved and peripheral blood counts returned to normal, or it was the end of the second or third week since the end of the CAG regimen, Bone marrow were examined again to evaluate the efficacy of the sequential therapy. Results 14 patients consisted of 9 male and 5 female patients were enrolled. Out of them, 2 were M1, 5 M2, 4 M4 and 3 M5 according to FAB classification criteria. Median of blasts in BM were 38.5%(20%–60%) before CAG regimen. Of the 14 patients, 10 reached CR, 2 PR and 2 NR. CR rate was 71.4% (10/14) and total response rate was 85.7%(12/14). Time to achieve CR was on 15th(14th–29th)day medianly since the end of the treatment. During the CAG therapy courses, the nadir of peripheral blood cell counts and the time when it occurred were as follows: WBC 1.0(0.2–3.5)(x109/L),10(1–23)(d); Hb 57.5(44–69) (g/L), 10(1–27)(d)and PLT 11.5(10–65)(x109/L), 12(3–23)(d), respectively. Neutropenia (WBC<1.0x109/L) and thrombocytopenia (PLT<20.0x109/L) were lasted for 0(0–24) and 11(0–21)days, respectively. Median units of transfusions of platelets and red blood cells required by each patient were 3(0–10)(u) and 4(0–12)(u), respectively. The most commonly observed side effect of the regimen was bone marrow proliferation inhibition. Infections, usually respiratoy tract infections, were the second. However, sepsis was rare, which appeared in 1 out of 14 patients. Conclusions DA and CAG regimens sequential treatment as remission induction chemotherapy in patients with newly diagnose de novo AML was highly effective and well tolerated. It would be beneficial for those who might not be sensitive enough to DA regimen chemotherapy only.

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