AML diagnosis and treatment 2022 

Quizartinib, a new FLT3 inhibitor improved overall survival. But for patients who had allogeneic transplantation as a consolidation therapy after remission achieved with induction therapy, the difference in OS was not statistically significant. Patients with newly diagnosed FLT3-ITD positive acute myeloid leukemia who received quizartinib in addition to their standard chemotherapy had improved overall survival compared with a placebo group, according to the phase 3 QuANTUM-First trial presented at the European Hematology Association Congress. In the trial, researchers assessed the OS of 539 patients (median 56 years old) newly diagnosed with FLT3-ITD positive AML who received either quizartinib at 40 mg per day on days 8-21 of treatment (268 patients) or placebo (271 patients) between September 2016 and August 2019. Each group also received standard induction treatment consisting of cytarabine at 100 mg/m2 per day or institution standard for 7 days plus anthracycline (daunorubicin at 60 mg/m2 per day or idarubicin 12 mg/ m2 per day) for 3 days. Participants in the trial were eligible to receive another round of standard induction if a post-induction bone marrow exam revealed residual AML. During the consolidation period, participants who achieved complete response or had a complete response with incomplete hematologic recovery (CRi) underwent 4 cycles of cytarabine with quizartinib at 40 mg per day or placebo, and/or allogenic hematopoietic stem cell transplant. Participants additionally underwent up to 36 cycles of continuation therapy for up to 3 years consisting of quizartinib (30-60 mg per day) or placebo. The results showed a complete response or incomplete hematologic recovery rate of 71.6% in the quizartinib group and 64.9% in the placebo group, with participants followed to a median of 39.2 months and 58 patients remaining on continuation therapy as of the last follow-up. There was a significantly longer OS among patients receiving quizartinib compared with placebo (HR = 0.776; 95% CI, 0.615-0.979; two-sided P = .0324), with a median OS of 31.9 months in the quizartinib group compared with 15.1 months in the placebo group. In the 157 participants who received allogenic hematopoietic stem cell transplant, there was a non-significant improvement in OS favoring the quizartinib group compared with the placebo group (HR = 0.752; 95% CI, 0.562-1.008; two-sided P = .055). The quizartinib group also had longer relapse-free survival compared with the placebo group (HR = 0.733; 95% CI, 0.554-0.969). Regarding adverse events, there were similar rates of grade 3 or higher adverse events between groups except for grade 3 or higher neutropenia, which was higher for participants receiving quizartinib compared with placebo (18.1% vs 8.6%). Grade 3 or grade 4 prolongation of the electrocardiographic QT interval was present at a higher rate among participants taking quizartinib (3%) than placebo (1.1%). There was also a higher rate of discontinuation in the quizartinib group attributed to adverse events (20.4%) compared with the placebo group (8.6%). The researchers reported a higher rate of treatment-emergent adverse events, mostly infections, that led to a fatal outcome in the quizartinib group compared with the placebo group (11.3% vs 9.7%).

Treatment of Blastic Plasmacytoid Dendritic Cell Neoplasm (BODCN): new NCCN guidelines in May 2023 Tagraxofusp-ersz is the preferred therapy for patients with BPDCN who are candidates for intensive remission induction therapy. Alternate options include AML-type (standard-dose cytarabine + anthracycline using 7 + 3), acute lymphocytic leukemia (ALL)-type (hyper-CVAD), and lymphoma-type (CHOP) regimens. Intrathecal chemotherapy should also be included in the presence of CNS disease. If no CNS disease is present at diagnosis, prophylactic intrathecal chemotherapy is still strongly encouraged. Tagraxofusp-ersz should be administered as an intravenous infusion at 12 µg/kg over 15 minutes once daily on days 1 to 5 of each 21-day cycle. If needed for dose delays, an alternate schedule of 5 doses over a 10-day period can be employed. A baseline serum albumin of ≥3.2 g/dL is necessary to commence treatment with this agent. Capillary leak syndrome (CLS) is the most serious adverse effect associated with tagraxofusp. CLS can occur during the first cycle of treatment and may be life-threatening. A decrease in serum albumin in the initial days of treatment appears to be the most consistent predictor of CLS. Management of CLS includes delaying or withholding additional tagraxofusp doses, administering intravenous albumin according to prespecified measures, administering glucocorticoids, and close management of volume status. It is recommended to replace serum albumin if at levels

On May 25, 2022, the FDA approved ivosidenib ( in combination with Azacytidine injection for newly diagnosed acute myeloid leukemia (AML) with a susceptible IDH1 mutation in adults 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. Approval was based on a randomized, multicenter, double-blind, placebo-controlled study (AG120-C-009, NCT03173248) that included 146 patients with newly-diagnosed AML with an IDH1 mutation who met at least one of the following criteria: age 75 years or older, baseline Eastern Cooperative Oncology Group performance status of 2, severe cardiac or pulmonary disease, hepatic impairment with bilirubin > 1.5 times the upper limit of normal, creatinine clearance < 45 mL/min, or other comorbidity. Patients were randomized 1:1 to receive ivosidenib, 500 mg daily (N=72), or matched placebo orally once daily (N=74), on Days 1-28 in combination with azacitidine 75 mg/m2/day subcutaneously or intravenously on Days 1-7 or Days 1-5 and 8-9 of each 28-day cycle until disease progression, unacceptable toxicity, or hematopoietic stem cell transplantation. www.nejm.org/doi/full/10.1056/NEJMoa2117344 Median OS was 24.0 months (95% CI: 11.3, 34.1) in the ivosidenib plus azacitidine arm and 7.9 months (95% CI: 4.1, 11.3) in the placebo plus azacitidine arm (HR 0.44; 95% CI: 0.27, 0.73; p=0.0010). CR was 47% (95% CI: 35%, 59%) in the ivosidenib plus azacitidine arm and 15% (95% CI: 8%, 25%) in the placebo plus azacitidine arm. Median duration of CR was not estimable (NE) in the ivosidenib plus azacitidine arm (95% CI: 13.0, NE) and 11.2 months (95% CI: 3.2, NE) in the placebo plus azacitidine arm. The most common adverse reactions of ivosidenib in combination with azacitidine or as monotherapy (≥ 25% in any trial) were diarrhea, fatigue, edema, nausea, vomiting, decreased appetite, leukocytosis, arthralgia, dyspnea, abdominal pain, mucositis, rash, electrocardiogram QT prolonged, differentiation syndrome, and myalgia. Prescribing information contains a Boxed Warning alerting health care professionals and patients about the risk of differentiation syndrome which may be life-threatening or fatal. The recommended ivosidenib dose is 500 mg taken orally once daily with or without food until disease progression or unacceptable toxicity. Start ivosidenib administration on Cycle 1 Day 1 in combination with azacitidine 75 mg/m2 subcutaneously or intravenously once daily on Days 1-7 (or Days 1-5 and 8-9) of each 28-day cycle. For patients without disease progression or unacceptable toxicity, treatment is recommended for a minimum of 6 months to allow time for clinical response.

First time I hear this wonderful lecture, thank you very much.

The US Food and Drug Administration on 7/21/23, approved quizartinib (Vanflyta) for adults with acute myeloid leukemia (AML) that carries the FLT3-ITD genetic mutation. The FDA also approved the LeukoStrat CDx FLT3 Mutation Assay to determine whether patients have this mutation. The agency granted quizartinib a first-line indication for use in combination with standard chemotherapy - cytarabine and anthracycline induction followed by cytarabine consolidation - and as maintenance monotherapy afterwards, in adults whose tumors express FLT3-ITD. The FLT3 protein is a tyrosine kinase receptor found on hematopoietic stem cells. Wild-type FLT3 promotes cell survival, growth, and differentiation, but ITD [internal tandem duplication] mutated FLT3, which quizartinib targets, is associated with a higher relapse risk and shorter survival. About a quarter of AML patients carry the mutation. Approval was based on the phase 3 QuANTUM-First trial in over 500 patients with the mutation. Median overall survival among patients on standard chemotherapy randomly assigned to quizartinib was 31.9 months vs 15.1 months in patients randomly assigned to placebo, a 22.4% reduction in the risk of death (P = .0324). Quizartinib is not indicated as maintenance monotherapy after allogeneic hematopoietic stem cell transplantation. In a company press release, the drug's manufacturer Daiichi Sankyo said quizartinib will be available in the US soon. Company executive Ken Takeshita, MD, called the approval "an important milestone, as patients with the FLT3-ITD subtype of AML can now be treated with the first ever FLT3 inhibitor approved across the three phases of treatment these patients typically receive." The FDA's original decision date was April 24, but the agency pushed it back 3 months to review updates Daiichi Sankyo made to quizartinib's Risk Evaluation and Mitigation Strategies (REMS) program in response to an agency request. Quizartinib carries a boxed warning of QT prolongation, torsades de pointes, and cardiac arrest. Because of these risks, it's only available through a new program, dubbed "Vanflyta REMS." In the trial, the most common adverse with quizartinib included lymphopenia (60%), hypokalemia (59%), hypoalbuminemia (53%), hypophosphatemia (52%), alkaline phosphatase increased (51%), hypomagnesemia (44%), febrile neutropenia (44%), diarrhea (42%), mucositis (38%), nausea (34%), and hypocalcemia (33%), among others. The most common grade 3/4 adverse events were febrile neutropenia (43% with quizartinib vs 41% with placebo); neutropenia (18% vs 9%); hypokalemia (19% vs 16%); and pneumonia (11% both). Adverse events were fatal in 11.3% of patients receiving quizartinib vs 9.7% of patients on placebo, mostly due to infections. The FDA rejected quizartinib for FLT3-ITD mutated relapsed/refractory AML monotherapy in adults in 2019 after most of its oncology advisors thought the risk of treatment outweighed the benefits in an earlier trial.

ASH meeting in December 2021: (AGILE trial) Elderly unfit patients with IDH1 (+)AML improved DFS and OS with ivosidenib + azacitidine SQ or IV when compared with azaciticine alone ( median OS 24 months vs 7.9 months). Some patients developed differentiation syndrome (14%) and QT prolongation (10%), but infection was less common.

CPX-351 (Vyxeos) efficacy was confirmed in elderly high risk or secondary AML patients: After 5 years of follow-up, the improved overall survival with CPX-351 versus 7+3 was maintained, which supports the previous evidence that CPX-351 can contribute to long-term remission and improved overall survival in patients aged 60-75 years with newly diagnosed high-risk or secondary acute myeloid leukaemia. www.thelancet.com/journals/lanhae/article/PIIS2352-3026(21)00134-4/fulltext

Olutasidenib, another IDH1 inhibitor for relapsed IDH1 (+) AML On December 1, 2022, the FDA approved olutasidenib (Rezlidhia) capsules for adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test. Today, the FDA also approved the Abbott RealTime IDH1 Assay to select patients for olutasidenib. Approval was based on Study 2102-HEM-101 (NCT02719574), an open-label, single-arm, multicenter clinical trial that included 147 adult patients with relapsed or refractory AML with an IDH1 mutation confirmed using the above assay. Olutasidenib was given orally,150 mg twice daily, until disease progression, unacceptable toxicity, or hematopoietic stem cell transplantation. The median treatment duration was 4.7 months (range: 0.1 - 26 months). Sixteen (11%) patients underwent hematopoietic stem cell transplantation following olutasidenib. Efficacy was established on the rate of complete remission (CR) plus complete remission with partial hematologic recovery (CRh), the duration of CR+CRh, and the rate of conversion from transfusion dependence to independence. The CR+CRh rate was 35% (95% confidence interval [CI]: 27%, 43%), including 32% CR and 2.7% CRh. The median time to CR+CRh was 1.9 months (range: 0.9 - 5.6 months), and the median duration of CR+CRh was 25.9 months (95% CI: 13.5 months, not reached). Among the 86 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 29 (34%) became independent of RBC and platelet transfusions during any 56-day post-baseline period. Of the 61 patients who were independent of both RBC and platelet transfusions at baseline, 39 (64%) remained transfusion independent during any 56-day post-baseline period. The most common adverse reactions (≥20%) were nausea, fatigue/malaise, arthralgia, constipation, leukocytosis, dyspnea, fever, rash, mucositis, diarrhea, and transaminitis. The prescribing information contains a Boxed Warning alerting health care professionals and patients about the risk of differentiation syndrome which can be fatal.

Amazingly organized Will there be review and update of ALL?

A randomized trial (ASAP trial) showed that patients with acute myeloid leukemia who have a poor response following induction therapy do just as well going on to immediate allogeneic transplant as they would if they had received an intensive salvage induction regimen to get them into remission before transplant. (American Society of Hematology (ASH) 2022 Annual Meeting: Abstract 4. Presented December 10, 2022) ash.confex.com/ash/2022/webprogram/Paper159962.html If a patient has relapsed or refractory AML, very high doses of chemotherapy is given to try to reduce the tumor burden before a transplant. But this new finding, if these results hold, means that the patient can go straight to a transplant. The ASAP trial was conducted in patients with an unfavorable risk AML who either had a poor response to first induction therapy or a relapse after first induction therapy. They were randomly assigned to either a remission-induction strategy aiming for a better response prior to an allogeneic hematopoietic stem cell transplant (alloHCT), or a disease-control strategy consisting primarily of watchful waiting with low-dose cytarabine and single doses of mitoxantrone as needed, followed by sequential conditioning and alloHCT. The results after 4 years of follow-up showed no differences in either leukemia-free survival or overall survival between patients who underwent additional chemotherapy with the remission-induction strategy and those who went straight to transplant. The remission-inducing arm consisted of cytarabine (3 g/m2 for younger patients or 1 g/m2 for patients over age 60) twice daily on days 1-3 plus 10 mitoxantrone mg/m2 on days 3-5 and subsequent alloHCT. In the other group - disease control prior to sequential conditioning and alloHCT - watchful waiting was recommended, but low-dose cytarabine (LDAC) and single doses of mitoxantrone were permitted for disease control. In an intention-to-treat and per-protocol analysis, the respective rates of DFS at 56 days in the disease control group were 83.5% and 84.1%. In comparison, the respective rates in the remission-induction group were 81% and 81.3%. In addition, after a median follow-up from randomization of 37 months, there were no differences in either leukemia-free survival or overall survival out to 4 years after DFS at day 56. The disease-control strategy was also associated with significantly fewer adverse events grade 3 or greater (23% vs 64%, P < .001), and fewer days in hospital prior to transplant (mean 19 vs. 42, P < .001). There were no significant differences between the trial arms in either deaths within 28 days of randomization or time to discharge from hospital (28 days in each arm). These data support sequential conditioning and alloHCT without prior remission-induction chemotherapy whenever a stem cell donor is readily available.

Nice

Azacytidine + venetoclax was better than intensive chemotherapy (7+3) in overall survival for elderly, adverse risk, and (+) RUNX1 mutation AML patients. www.ncbi.nlm.nih.gov/pmc/articles/PMC8714726/#__ffn_sectitle

WHO 5th Edition modified AML classification by incorporating new molecular markers. It rearranged the classification by genetic, differentiation, molecular factors. www.nature.com/articles/s41375-022-01613-1#Tab8

How does GATA 2 MUTATION INFLUENCE AML... CAN AML WITH GATA 2 MUTATION BE CURED WITH CHEMOTHERAPY?

Hi Sir, my 12 year old son is suffering from accute lukemia. I am from india. Please help.

Hello Sir. I'm a doctor myself and my father is diagnosed of AML recently and he has turned just 60. We have started Azacitidine and Venetoclax and he is tolerating fairly enough. Is it OK to give him induction chemo or BMT after induction considering his age?