Cycles Of High-dose Cytarabine Research Articles

Toxicity and outcome of adults with acute myeloid leukemia receiving consolidation with high-dose cytarabine

IntroductionHigh-dose cytarabine is considered standard of care as consolidation chemotherapy in adults with acute myeloid leukemia (AML) who are not eligible for allogeneic hematopoietic cell transplantation, but may be associated with significant toxicity. We evaluated the toxicity associated with high-dose cytarabine given as consolidation in AML patients treated at a Brazilian public hospital. MethodsWe retrospectively reviewed the charts of all patients with AML treated between 2008 and 2020 who obtained complete remission (CR) after one cycle of induction chemotherapy and received consolidation with at least one cycle of high-dose cytarabine (defined as 3 g/m2 every 12 h days 1, 3 and 5). ResultsAmong 61 patients who received induction remission, 32 obtained CR and 28 received at least one cycle of high-dose cytarabine, for a total of 67 cycles (median 2 cycles per patient, range 1 – 4). In 45 cycles (67.2%) the patient was discharged after the end of chemotherapy, with a median of 6 days at home (range 3 – 8). Readmission occurred in 31 of the 45 cycles (68.9%). The most frequent toxicities were febrile neutropenia (56.7%), nausea and vomiting (23.9%), oral mucositis (14.9%) and diarrhea (11.9%). Bacteremia was documented in 13 cycles (34.2%). There were three cases of typhlitis and two of invasive fungal disease (aspergillosis and candidemia). Four patients died (14.3%), with two deaths considered treatment-related (candidemia and typhlitis). ConclusionIn the setting of a Brazilian public hospital, high-dose cytarabine as consolidation therapy is feasible, with manageable toxicity profile.

Impact of Allogeneic Hematopoietic Cell Transplantation in First Complete Remission in Addition to FLT3 Inhibition with Quizartinib in Acute Myeloid Leukemia with FLT3-Internal Tandem Duplication: Results from the Quantum-First Trial

Background Patients with acute myeloid leukemia (AML) exhibiting an FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD+), face particularly poor outcomes, even after allogeneic hematopoietic cell transplantation (allo-HCT), which appears to only partially mitigate the poor prognosis associated with this mutation. (Döhner H et al., Blood 2017, Stone RM et al., NEJM 2017; Larson RA et al., Leukemia 2021). QuANTUM-First (NCT02668653) is a phase 3, global, randomized, double-blind, placebo-controlled trial evaluating the novel, highly potent, and selective type II FLT3 inhibitor quizartinib (Quiz) for patients with newly diagnosed FLT3-ITD+ AML who were treated with curative intent. This pivotal trial demonstrated that the addition of Quiz to intensive induction, consolidation including allo-HCT in CR1, followed by single-agent continuation therapy for up to 3 years resulted in a significant improvement in overall survival (OS) for this population. The objectives of our analyses were to evaluate the impact of allo-HCT in CR1 and the interrelationship with Quiz on clinical outcomes of QuANTUM-First and on the feasibility of continuation therapy with Quiz after allo-HCT. Methods Patients aged 18-75 years with newly diagnosed AML were centrally screened for FLT3-ITD before initiation of standard induction therapy. Patients were randomized to Quiz (40 mg/d, on days 8-21) or placebo (PBO) and stratified by region (North/South America, Europe, and Asia/other regions), age (<60 years, ≥60 years), and white blood cell count (WBC; <40 × 109/L, ≥40 × 109/L) at diagnosis. Patients who achieved complete remission (CR) or CR with incomplete hematologic recovery (CRi) received up to 4 cycles of high-dose cytarabine plus Quiz (40 mg/d) or PBO and/or allo-HCT followed by up to 3 years of continuation therapy with Quiz (30-60 mg/d) or PBO. Patients who underwent allo-HCT could start continuation therapy 30 to 180 days after allo-HCT. The primary endpoint was OS. The impact of allo-HCT in CR1 on OS was assessed as a time-dependent covariable in univariable and multivariable regression analyses. Results In QuANTUM-First, 539 patients with FLT3-ITD+ AML were randomized to Quiz (n=268) or PBO (n=271). There were 294 (54.5%) females and 245 (45.5%) males. Of the 539 randomized patients (median age, 56 years; range, 20-75 years), 297 (55.1% [297/539]; Quiz, 54.9% [147/268]; PBO, 55.4% [150/271]) achieved CR and 71 (13.2% [71/539]; Quiz, 16.8% [45/268]; PBO, 9.6% [26/271]) achieved CRi after 1 to 2 courses of induction. Allo-HCT was performed in CR1 in 157 patients (52.9% of CR patients [157/297]; Quiz, 57.1% [84/147]; PBO, 48.7% [73/150]) predominantly with grafts from unrelated donors (49.7%), followed by siblings (32.5%) and other related donors (17.8%). Patients proceeding toward allo-HCT in CR1 were younger (median age, 51 years) and had a slightly higher proportion of WBC ≥40 × 109/L at diagnosis compared with patients who did not undergo allo-HCT in CR1. After completion of allo-HCT, 61 patients in the Quiz arm (72.6%) and 36 patients in the PBO arm (49.3%) started 3 years of continuation therapy. An additional 115 allo-HCTs were performed within the trial outside CR1 (Quiz, n=60; PBO, n=55). Multivariable regression analysis was stratified by region, age, and WBC, including allo-HCT in CR1 as time dependent and adjusted for FLT3-ITD variant allelic frequency, as well for sex. The analysis revealed Quiz treatment (hazard ratio [HR], 0.770; 95% confidence interval (CI), 0.609-0.973; P = 0.0284) and allo-HCT in CR1 (HR, 0.424; 95% CI, 0.301-0.597; P < 0.0001) as favorable factors with respect to OS. Based on this model, at any given time, the HR was 0.326 (95% CI, 0.216-0.493) for the patients randomized to Quiz and proceeding to allo-HCT in CR1 compared with patients randomized to PBO who had not yet received allo-HCT in CR1 by that time. Conclusions In patients who underwent allo-HCT in CR1, longer survival was observed in those treated with quizartinib versus placebo. Furthermore, irrespective of allo-HCT performed in CR1, quizartinib when combined with standard induction and consolidation therapy and continued for up to 3 years as a single agent improves survival over placebo in patients with newly diagnosed FLT3-ITD+ AML.

AML-029 Quizartinib Prolonged Overall Survival (OS) vs Placebo Plus Intensive Induction and Consolidation Therapy Followed by Single-Agent Continuation in Patients Aged 18-75 Years With Newly Diagnosed FLT3–Internal Tandem Duplication Positive (FLT3-ITD+) Acute Myeloid Leukemia (AML)

Quizartinib is an oral, potent, selective, type II FLT3 inhibitor with prolonged OS as a single-agent in relapsed/refractory FLT3-ITD+ AML. We report results from the global, randomized, double-blind, phase 3 QuANTUM-First trial (NCT02668653), evaluating quizartinib plus standard induction and post-remission consolidation (including allogeneic hematopoietic cell transplant [allo-HCT] in first complete remission [CR1]) followed by single-agent continuation (up to 3 years) vs placebo plus chemotherapy in newly diagnosed FLT3-ITD+ AML. Patients 18-75 years with newly diagnosed FLT3-ITD+ AML received induction with cytarabine 100 or 200 mg/m2/day (days 1-7) and daunorubicin 60 mg/m2/day or idarubicin 12 mg/m2/day (days 1-3). Patients were randomized to quizartinib (40 mg/day [days 8-21]) or placebo; stratified by region, age, and white blood cell count at diagnosis. Patients with CR or CR with incomplete hematologic recovery (CRi) received up to 4 cycles of high-dose cytarabine plus quizartinib (40 mg/day) or placebo and/or allo-HCT followed by continuation with quizartinib (30-60 mg/day) or placebo (up to 3 years). The primary endpoint was OS. Between September 2016 and August 2019, 539 patients were randomized (quizartinib [n=268], placebo [n=271]). Median age was 56 years (range, 20-75 years). As of August 2021 (median follow-up, 39.2 months), 58 patients remained on continuation. Median OS was significantly longer with quizartinib vs placebo (31.9 vs 15.1 months; HR, 0.776; 95% CI, 0.615-0.979; 2-sided P=.0324). CR+CRi rates were 71.6% and 64.9%, respectively. Allo-HCT in CR1 was performed in 157 patients (quizartinib, 31%; placebo, 27%). When censored for allo-HCT, OS trended longer with quizartinib vs placebo (HR, 0.752; 95% CI, 0.562-1.008; 2-sided P=.055). Relapse-free survival was longer with quizartinib vs placebo (HR, 0.733; 95% CI, 0.554-0.969). Grade ≥3 adverse events (AEs) were similar across arms. Discontinuations due to AEs occurred in 20.4% (quizartinib) and 8.6% (placebo). Fifty-six patients died from treatment-emergent AEs (quizartinib, 11.3%; placebo, 9.7%); mostly infections. Grade 3/4 electrocardiographic QT prolongation occurred in 3.0% (quizartinib) and 1.1% (placebo). Quizartinib plus standard therapy, followed by continuation, including after allo-HCT, for up to 3 years was tolerable with statistically significant and clinically meaningful OS improvements in adults ≤75 years with newly diagnosed FLT3-ITD+ AML.

AML-256 A Phase 1 Study of Gilteritinib in Combination With Induction and Consolidation Chemotherapy in Patients With Newly Diagnosed Acute Myeloid Leukemia: Final Study Results

Gilteritinib, an oral FLT3 inhibitor, demonstrated antileukemic responses in patients with FLT3mut+ relapsed/refractory AML. Present final data from a phase 1 study of once-daily gilteritinib plus intensive chemotherapy in newly diagnosed (ND) AML. This 4-part, open-label study (NCT02236013) assessed gilteritinib dose/schedule and effects of alternative anthracycline treatment. Gilteritinib plus 7+3 induction with idarubicin or daunorubicin, plus ≤3 cycles of high-dose cytarabine and gilteritinib consolidation, and 2 years of single-agent gilteritinib maintenance treatment post consolidation or transplant. Adults with ND AML; FLT3 mutation not required for enrollment (known core binding factor fusions excluded). Safety, tolerability, PK, antileukemic effects. Eighty patients were allocated to gilteritinib (safety analysis set, n=78 [age 23-77 y]; FLT3mut+, n=44 [FLT3-ITD, n=33]). Median follow-up was 37.7 months. On-study HSCT was performed in 27/80 (33.8%) patients (FLT3mut+, 26/44 [59.1%]). Dose-limiting toxicities occurred in 15/78 (19.2%) patients (200-mg/d cohort: neutropenia, n=1; neutropenic colitis, n=1). Maximum tolerated dose was 120 mg/d. Across the study, AEs led to gilteritinib discontinuation in 24.4% of patients. At end-of-treatment, composite complete remission (CRc: complete remission [CR] + CR with incomplete hematologic recovery [CRi] + CR with incomplete platelet recovery [CRp]), CR, CRi, and CRp rates were 79.7%, 54.4%, 21.5%, and 3.8%, respectively, in the overall population and 90.9%, 70.5%, 13.6%, and 6.8% among FLT3mut+ patients. In the overall (n=79) and FLT3mut+ populations (n=44), 60-day mortality rates were 1.3% and 0%, respectively, and median (95% CI) disease-free survival was 15.1 (9.5, 31.9) and 15.1 (4.9, 31.9) months. In the overall (n=69) and FLT3mut+ populations (n=41) receiving ≥80 mg/d, median (95% CI) OS was 38.6 (21.7, NE) and 45.9 (30.8, NE) months, respectively, and the estimated 3-year OS rate was 56.0% and 60.1%. Anthracycline choice did not substantially impact CRc rate or toxicity. In patients who achieved CRc with gilteritinib ≥120 mg/d, mutational clearance of FLT3-ITD (summed FLT3 ITD:wildtype signal ratio ≤10-4) after consolidation was 84.6% (11/13). Gilteritinib plus induction and consolidation chemotherapy was well tolerated and resulted in CR, FLT3-ITD clearance, and long-term survival in patients with ND FLT3mut+ AML, supporting ongoing randomized trials testing this approach against current standards.

Extramedullary Acute Myeloid Leukemia: Testicular Myeloid Leukemia, Leukemia Cutis with Leptomeningeal Involvement

Extramedullary Acute Myeloid Leukemia: Testicular myeloid leukemia, leukemia cutis with leptomeningeal involvementZ Saeed, H Aslam, A Weil, M MuzaffarMyeloid sarcoma also called granulocytic sarcoma, myeloblastoma, or chloroma is an extramedullary tumor of immature granulocytic cells. Extramedullary soft tissue manifestations are relatively rare in hematological malignancies. One of the rarest manifestations is myeloid sarcoma (MS). MS develops as part of acute myeloid leukemia, myeloproliferative neoplasm, or myelodysplastic syndrome or at relapse, especially following allogeneic hematopoietic stem cell transplant. Demographically, it has a slight male predominance with a male to female ratio of 1.2: 1. It may occur at any age and any site in the body leading to varied clinical presentations. The most reported sites are lymph nodes, skin and soft tissues, bone, testes, gastrointestinal tract, and peritoneum.44 year old male with past medical history of diabetes mellitus type 2 and morbid obesity presented with right testicular pain and swelling and underwent radical orchiectomy. Pathology reported seminoma and received adjuvant Carboplatin for pT3 disease. He developed left testicular pain and swelling 2 months later and underwent left radical orchiectomy. Pathology reported CD4+, CD56+ high grade hematopoietic neoplasm. It was sent for second opinion to NIH and was consistent with myeloid sarcoma with monoblastic features. Repeat evaluation of right testicular specimen was CD45+. Bone marrow biopsy showed normocellular marrow with multilineage hematopoiesis. PET scan showed hyper metabolic activity in the right hemi scrotum, widespread osseous areas of increased uptake and 3 soft tissue nodules within the subcutaneous tissues of the left abdominal wall. FNA of the subcutaneous nodule showed CD56 positive monocytoid cells. Induction chemotherapy with 7+3 (cytarabine 200 mg/m2, daunorubicin 60mg/m2) with gemtuzumab 3mg/m2 on day 1, 4, 7 was completed. Cerebrospinal fluid studies (CSF) showed monoblastic/monocytic proliferation and received intrathecal (IT) chemotherapy alternating between methotrexate and cytarabine every week. CSF studies were cleared after 2 IT chemotherapy. Patient remained in the hospital for 87 days due to poor count recovery and development of pulmonary embolism. Myeloid mutation screening identified a mutation in NRASG13D. Repeat PET scan showed 7 areas of hypermetabolic foci involving nodular densities of bilateral lower anterior abdominal wall. One of the lesion was biopsied that was negative. He completed 2 cycles of high dose cytarabine for consolidation but had repeated hospital admissions and therapy was switched to azacytidine and venetoclax. Patient was evaluated by bone marrow transplant team. He had disease progression at tenth month when he presented with severe back pain and lower extremity weakness. MRI brain and spine showed new patchy T2 hyperintense signal in the right frontal white matter, increased number and size of marrow replacing lesions throughout the visualized skeleton. Patient underwent bone biopsy that showed >90% marrow involvement (sheets of infiltrative cells with identical phenotype. Positive for CD56 (>90% of marrow cellularity), CD4 and lysozyme. Hospital course was complicated with renal failure, electrolytes imbalance and hemodynamically instability requiring vasopressor support. Discussions were held for re-induction with CLAG (cladribine 5mg/m2, and cytarabine 2gm/m2) vs best supportive care. Patient decided to pursue comfort care and passed away peacefully.The uniqueness of this case is the myeloid sarcoma of testes as initial presentation with normal bone marrow. Misdiagnosis is not uncommon and can delay the appropriate treatment. Extra medullary involvement from leukemia is very aggressive and needs high suspicious and prompt treatment. Systemic chemotherapy using AML-like regimens should be commenced early, even in non leukemic disease. Allogeneic hematopoietic stem cell transplantation has demonstrated promising results, particularly in patients who achieved complete remission with AML-induction protocols, and recent advances in genetic profiling may enable the development of novel targeted therapies. Prospective multicenter controlled trials are required to further refine management decisions and investigate the role of novel targeted therapies. DisclosuresNo relevant conflicts of interest to declare.

MEK Inhibition Demonstrates Activity in Relapsed, Refractory Patients with Juvenile Myelomonocytic Leukemia: Results from COG Study ADVL1521

▪Background: Juvenile myelomonocytic leukemia (JMML) is a hematologic malignancy of infants and toddlers with both myelodysplastic and myeloproliferative features. The prognosis for patients (pts) with relapsed or refractory (r/r) JMML is poor and hematopoietic stem cell transplant (HCT) is the only curative therapy. The molecular hallmark of JMML is activation of the Ras/MAPK pathway. In preclinical studies, MEK inhibition was shown to be effective at reducing spleen sizes, restoring normal hematopoiesis, and extending survival compared to placebo in several genetically engineered mouse models of JMML. Trametinib is an orally bioavailable MEK1/2 inhibitor and is approved for treatment of several malignancies in adults. This Children's Oncology Group study (ADVL1521, NCT03190915) is the first clinical trial for pts with r/r JMML conducted in the United States. Pts are eligible if they have persistent clinical or molecular evidence of JMML after 1 cycle of high dose cytarabine, 2 cycles of a hypomethylating agent or HCT. Pts receive daily trametinib for up to 12 cycles (28 days) in the absence of disease progression or dose-limiting toxicity (DLT). Dosing is age-based with pts less than 6 years of age receiving 0.032mg/kg/day and those 6 years or older receiving 0.025mg/kg/day. An oral suspension is available for pts unable to swallow tablets. Using a Simon 2-stage design (10 pts in each stage), trametinib would be deemed effective if 3 or more pts achieved an objective response.Results: From 2018-2021, 9 pts were enrolled; all 9 were eligible and evaluable for toxicity and response. Each pt had a detectable Ras mutation at the time of enrollment and was monitored for response using clinical and molecular criteria developed by an international consensus panel (Niemeyer et al, 2015). Five pts were less than 2 years of age. Three patients had relapsed post-HCT prior to enrolling and 6 patients were refractory to a median of 1.5 prior therapies (range 1-3). Four pts had an objective response (1 clinical complete response (cCR), 3 clinical partial responses, (cPR); 2 pts had stable disease and 3 had progressive disease (Table 1). Both pts with stable disease completed the maximum 12 cycles permitted on study. Two pts who achieved a cPR proceeded to HCT. One patient who achieved a cCR remains on study. No molecular responses were achieved. There were no dose-limiting toxicities; one pt had grade 4 thrombocytopenia probably related to trametinib. Of the 8 patients who consented to correlative studies, 7 had DNA methylation testing, 6 had kinome profiling, and 5 had RNASeq testing performed on both pre- and post-trametinib paired samples. DNA methylation testing revealed stable intrapatient methylation signatures across diagnostic, relapse and post-trametinib timepoints using the international consensus criteria (Schönung et al, 2020). Integrated kinome and RNASeq analysis revealed downregulation of proteins and genes involved in Ras/MAPK signaling.Conclusions: In the first clinical trial for r/r JMML patients in the United States, 4 objective responses were observed among the initial 9 patients meeting the pre-defined criteria to deem trametinib effective. While clinical responses including resolution of splenomegaly, resolution of monocytosis and increased platelets counts were observed, no molecular responses were noted. The treatment of r/r JMML has historically depended on HCT. Recently, azacitidine has shown promise in treating r/r JMML. This trial demonstrates that trametinib is active in r/r JMML and has a favorable side effect profile. Ongoing analysis of extensive correlative testing results have revealed potential mechanisms of response and resistance to MEK inhibition. Future studies will focus on children with newly diagnosed JMML and combine trametinib with azacitidine with or without HCT. [Display omitted] DisclosuresLoh: MediSix therapeutics: Membership on an entity's Board of Directors or advisory committees. Barkauskas: Genentech: Current Employment.

A Phase 1/2 Trial of Cladribine, High-Dose Cytarabine, G-CSF, and Dose-Escalated Mitoxantrone (CLAG-M) Plus Gemtuzumab Ozogamicin in Adults with Newly-Diagnosed Acute Myeloid Leukemia (AML) or Other High-Grade Myeloid Neoplasm

A Phase 1/2 Trial of Cladribine, High-Dose Cytarabine, G-CSF, and Dose-Escalated Mitoxantrone (CLAG-M) Plus Gemtuzumab Ozogamicin in Adults with Newly-Diagnosed Acute Myeloid Leukemia (AML) or Other High-Grade Myeloid Neoplasm

Two Cycles of Consolidation Chemotherapy Are Associated with Similar Clinical Outcomes to Three Cycles in AML Patients with Favorable Risk Cytogenetics

Background: Patients with core-binding factor acute myeloid leukemia (CBF-AML) have favourable outcomes when treated with standard anthracycline based induction and repeated cycles of cytarabine based consolidation. CBF-AML exhibit high rates of remission, overall survival, and relapse-free survival even without allogenic stem cell transplant (alloSCT). The exact number of consolidation cycles necessary for optimal outcomes, however is unknown. While early studies suggested that 3 or 4 cycles of high dose cytarabine (HiDAC) are associated with better outcomes relative to 1 cycle (Byrd, 1999 & Byrd, 2004), the effects of 2 cycles, has not been studied in this patient group. In this study, we evaluated the impact of 2 cycles of consolidative chemotherapy on the clinical outcomes of patients with CBF-AML.Methods: Prior to 2012 patients with CBF-AML treated in Edmonton, Canada, were intended to receive 2 cycles of HiDAC after a complete remission (CR) following a single induction cycle ± intensification treatment (given if having >5% blasts on a day+14 marrow). Following a change in institutional policy, patients treated after 2012 were intended to receive 3 cycles of consolidation treatment. c-kit testing was not available prior to 2009 but thereafter all patients with c-kit mutations were offered alloSCT in first CR. In contrast, patients treated in Vancouver, Canada underwent similar induction but were intended to receive three consolidative cycles throughout the entire study period. Pooled data was retrospectively analyzed for all patients with CBF-AML treated in these two Canadian centres between 2003-2017 using an intention to treat approach.Results: Overall, 108 patients were identified with a median age of 48 (range 17-75). Sixty-four patients (59%) were male. Seventy-four patients (68.5%) were intended for 3 cycles of consolidation therapy and 34 patients (31.5%) for 2 cycles. There were no differences in baseline characteristics of the analyzed patients (Table 1). There was also no significant difference in the number of patients who received intensification chemotherapy due to day +14 residual disease, the number of induction deaths, or CR rate at end of induction. Six patients intended to receive 2 cycles of consolidation were transplanted in CR1 compared with 5 who were intended to receive 3 cycles (p=0.09). Rates of hospitalization, median length of hospital stay, bacteremic events, intensive care requirements, and deaths during consolidation therapy did not differ significantly between the two groups.Median follow-up time from CR was significantly longer in the 2 consolidation cycle group relative to the 3 consolidation cycle group (85 months vs. 30 months, p<0.0001). Of the 34 patients intended for 2 cycles of consolidation, there were 9 deaths and an additional 4 relapses, for a total event rate of 38.2%. Within the 74 patients intended to receive 3 cycles of consolidation there were 18 deaths and an additional 13 relapses for a total event rate of 41.9% (p=0.83)There was no significant difference in overall survival (p=0.96; Figure 1, 5-year OS 73% for the 2 cycle consolidation group v 71% for the 3 cycle consolidation group), relapse-free survival when censored for transplant (p=0.61; Figure 2, 5-year RFS 63% for the 2 cycle consolidation group v 57% for the 3 cycle consolidation group, or event-free survival (p=0.88; 5-year EFS 54% for the 2 cycle consolidation group v 52% for the 3 cycle consolidation group) within the two groups. Multivariate analysis revealed that patients age, cytogenetics [t(8;21), inv(16)/t(16;16)], or transplantation in CR1 did not influence rates of overall survival or relapse-free survival between the two cohorts.Conclusions: These data suggest that the use of 2 chemotherapy consolidation cycles compared with 3 does not diminish relapse-free survival or overall survival in patients with CBF-AML. Reduction in chemotherapy may provide both economic and quality of life benefits for patients. Larger prospective studies are necessary to confirm these findings. [Display omitted] DisclosuresHogge:Novartis, Roche, and Sanofi: Consultancy.

Clinical Relevance of Minimal Residual Disease Monitoring in NPM1 Mutated AML: A Study of the AML Study Group (AMLSG)

Clinical Relevance of Minimal Residual Disease Monitoring in NPM1 Mutated AML: A Study of the AML Study Group (AMLSG)

An Analysis of Maintenance Therapy and Post-Midostaurin Outcomes in the International Prospective Randomized, Placebo-Controlled, Double-Blind Trial (CALGB 10603/RATIFY [Alliance]) for Newly Diagnosed Acute Myeloid Leukemia (AML) Patients with FLT3 Mutations

An Analysis of Maintenance Therapy and Post-Midostaurin Outcomes in the International Prospective Randomized, Placebo-Controlled, Double-Blind Trial (CALGB 10603/RATIFY [Alliance]) for Newly Diagnosed Acute Myeloid Leukemia (AML) Patients with FLT3 Mutations

NPM1+ /FLT3- Acute Myeloid Leukemia after JAK2-V617F+ Essential Thrombocythemia. Management and Prognosis

NPM1+ AML after Essential Thrombocythemia (ET) or Myeloproliferative neoplasms is extremely rare. Only 2 cases have been previously reported after Primary Myelofibrosis. Given the extremely poor prognosis of the Blastic phase of Myeloproliferative neoplasms (MPN-BP), the only curative treatment of these patients is allogeneic stem cell transplantation (allo-SCT) after achieving Complete Response (CR). De novo NPM1+/FLT3- AML is considered a good prognosis entity in which allo-SCT is not contemplated as the first option. A 41 year old diagnosed of ET JAK2 V617F+ 4 years before the diagnosis of AML with normal karyotype and NPM1+/FLT3- was treated with conventional AML induction with Cytarabine and Idarubicine and 3 cycles of high dose Cytarabine. At the diagnosis of AML other 2 mutations were noted: EZH2 and IKZ1. After treatment of AML, NPM1+ clone disappeared, and JAK2 V617F clone reappeared. We opted to treat NPM1+ AML as a de novo AML and we decided to follow up during 2 years without allo-SCT. The patient remains in complete response with NPM1 minimal residual disease negative during the follow up. This case exemplifies the nature of NPM1+ AML secondary to MPD as an extremely sensitive disease to induction therapy plus high dose cytarabine and makes that these type of patients perhaps could be managed without the use of allo-SCT.

S2991 Gastric Myeloid Sarcoma as a Presentation of Relapsed Acute Myelomonocytic Leukemia - A Case Report

INTRODUCTION: Myeloid sarcoma is an extramedullary proliferation of myeloid blasts that may be associated with a concurrent myeloid neoplasm involving the bone marrow, but such an association is not required. In some cases, myeloid sarcoma may herald a relapse in a patient with previously treated disease. In others, it may be the first indication of acute leukemia. CASE DESCRIPTION/METHODS: A 48-year-old male presented with nausea, vomiting and epigastric pain. Physical examination showed tachycardia, and epigastric tenderness. Nine months earlier he was diagnosed with acute myelomonocytic leukemia; cytogenetics showed 47,XY,+8,t(9;11)(p21.3;q23.3). At that time, he was treated with standard induction therapy with the 7 + 3 regimen with Cytarabine and Daunorubicin followed by 3 cycles of High-Dose Cytarabine (HiDAC). Lab results showed pancytopenia including Leukopenia with 19% blasts. Peripheral blood flow cytometry showed 18% monoblasts. CT chest and abdomen revealed diffuse lobular thickening of the gastric wall, segmental thickening of the small bowel loops, and pancreatic, paraspinal, and infiltrative right ventricular wall masses. Upper GI endoscopy showed thickened gastric folds with a nodular mucosa. Gastric mucosal resection was performed, and biopsy showed abnormal blasts infiltrating through the mucosal glands, consistent with myeloid sarcoma. A bone marrow biopsy was consistent with relapsed AML. Urgent therapy was instituted however the patient suffered a cardiac arrest and resuscitation was unsuccessful. DISCUSSION: Myeloid sarcoma (aka granulocytic sarcoma, myeloblastoma, or chloroma) may present simultaneously with, or precede bone marrow disease and may be seen in relapse or as progression of a prior myeloproliferative neoplasm. The most common sites of isolated myeloid sarcoma are the skin, followed by mucous membranes, orbits, central nervous system, and other internal organs. Myeloid sarcoma is more common in pediatric AML, although the true incidence in adults is unknown. In adults, roughly one third of myeloid sarcomas present with concurrent myeloid disease, and one third have a history of a prior myeloid neoplasm. The presence of a myeloid sarcoma is diagnostic of AML, regardless of the bone marrow status, or blast count. The diagnosis of myeloid sarcoma should be restricted to tumors that form space-occupying lesions. The approach to treatment of patients with myeloid sarcoma without evidence of AML on bone marrow biopsy is similar to that for patients with overt AML.Figure 1.: CT Abdomen showing lobular thickening of the gastric wall.Figure 2.: Upper GI endoscopy showing thickened gastric folds with nodular mucosa in the gastric body. Findings are concerning of infiltrative malignancy.Figure 3.: High power (10x) view of Hematoxylin and Eosin stain of gastric body biopsy showing abnormal monoblasts infiltrating through the mucosal glands, consistent with myeloid sarcoma.

AML-005: Primary Central Nervous System Myeloid Sarcoma Evolving from a Myeloid Neoplasm with Eosinophilia Associated with FIP1L1-PDGFRA

Background Myeloid sarcoma (MS) is an extramedullary tumor of immature myeloid cell origin usually concurrently or in the evolution of acute leukemias or with known chronic myeloproliferative disorders. It has been rarely identified isolated without medullary involvement. Most common sites of involvement are skin, lymph nodes, soft tissues and bone. Isolated central nervous system (CNS) primary MS are extremely rare. They may involve the subperiosteum and dura mater and, on rare occasions, can also invade the brain parenchyma. Aims To describe a case of an isolated CNS myeloid sarcoma. Methods Case. A 42-year-old man with a history of chronic eosinophilia with FIP1L1-PDGFRa rearrangement was admitted with headache, aphasia and confusional syndrome. MRI showed a 49 × 47 mm heterogeneous left temporal tumor. Laboratory findings were as follow: hematocrit 46%, WBC 13×103/l (neutrophils 66% eosinophils 12%), platelet count 150×103/ul. Renal and hepatic function tests were normal. Hepatitis and HIV serology were negative. A positron emission tomography scan showed no abnormal uptake. Brain tumor exeresis was done. Pathology findings were compatible with myeloid blastic infiltration. Immunohistochemical analysis was positive for CD45 (leukocyte common antigen) and myeloperoxidase. Bone marrow biopsy showed no infiltration. Cytogenetics was 46, XY, +7, +8, +10. Molecular analyses of FLT3, inv16, t(8;21), BCR-ABL1 and JAK2V16F were negative. Results Based on the diagnosis of myeloid sarcoma evolving from a myeloid neoplasm with eosinophilia associated with FIP1L1-PDGFRA, he was treated with 3+7 (cytarabine + daunorubicine) plus imatinib induction chemotherapy. Then, he received 1 consolidation cycle of high-dose cytarabine plus mitoxantrone and allogeneic bone marrow transplant. Summary/Conclusion Myeloid sarcoma diagnosis is challenging. De novo MS is rare and unfortunately there is no treatment guidelines. AML-based therapies are recommended.

Feasibility of evidence-based treatment of childhood acute myeloid leukemia in a Sub-Sahara Africa center.

e22508 Background: The proportion of Acute Myeloid Leukemia (AML) among childhood leukemias is putatively higher in Sub-Sahara Africa (SSA) compared to Western experiences. However, the treatment of childhood AML is challenging in SSA settings because of inadequate facilities for supportive care to deliver intensive AML regimens and, hence, high treatment-related mortality (TRM). Many pediatric oncology centers in SSA treat childhood AML with a palliative intent, with or without chemotherapy. At the Mulago National Referral Hospital (MNRH)/Global HOPE Center in Uganda, we treat AML with a curative intent. We distinguish Acute Promyelocytic Leukemia (APL) and AML with Down Syndrome (AML-DS) from other subtypes of AML. We treat APL with Children’s Oncology Group (COG) AAML1331 and AML-DS and other AML with modified reduced intensity regimens. We hereby share our experience of anti-cancer and supportive treatment, TRM, remission rates, and short-term overall survival (OS). Methods: We performed a retrospective cohort analysis of children diagnosed with AML between March 2019 and February 2020. The diagnosis of AML was established by bone marrow or peripheral blood morphology and immunophenotyping by flow cytometry according to WHO criteria. All cases of APL were confirmed by cytogenetics for t(15;17). Children without DS or APL received 2 cycles of Cytarabine 100mg/m2 12 hourly Days 1-10, Daunorubicin 50mg/m2 Days 1,3,5 and a single triple intrathecal chemotherapy for induction and 2 cycles of high dose Cytarabine 3000mg/m2 for consolidation. Supportive care comprised warm saline oral rinses, antiseptic baths, antimicrobial prophylaxis with cotrimoxazole, ciprofloxacin and itraconazole, and blood product support. Results: Of the 74 children diagnosed with leukemia 23 (31%) were AML; 4/23 (17%) of AML were APL and 3/23 (13%) were AML-DS. The mean age at diagnosis of AML was 6.1 (SD 4.3) years and 16/23 (70%) were males. For the 4 cases of APL, TRM 1/4 (25%) due to differentiation syndrome, remission rate 2/4 (50%), 1-year OS 75%; 95% CI 32.5-100. For the 3 cases of AML-DS, TRM 1/3 due to severe sepsis with respiratory failure, remission rate 1/3, and 1 was referred to another treatment center. For the other AML, TRM 2/16 (12.5%) due to severe sepsis, remission rate 9/16 (56%) and 1-year OS 78.6%; 95% CI 57.1-100. Conclusions: It is feasible to treat, manage TRM, and achieve remission in childhood AML in the SSA setting. Although there were several TRMs, a remission rate of 56% in the non-APL non-AML-DS is a promising outcome.

Younger Patients with Newly Diagnosed FLT3-Mutant AML Treated with Crenolanib Plus Chemotherapy Achieve Adequate Free Crenolanib Levels and Durable Remissions

Younger Patients with Newly Diagnosed FLT3-Mutant AML Treated with Crenolanib Plus Chemotherapy Achieve Adequate Free Crenolanib Levels and Durable Remissions

Tolerability and Efficacy of Crenolanib and Cytarabine/Anthracycline Chemotherapy in Older Patients (Aged 61 to 75) with Newly Diagnosed FLT3-Mutated Acute Myeloid Leukemia (AML)

Tolerability and Efficacy of Crenolanib and Cytarabine/Anthracycline Chemotherapy in Older Patients (Aged 61 to 75) with Newly Diagnosed FLT3-Mutated Acute Myeloid Leukemia (AML)

P14.85 Brain metastasis from Hodgkin’s Lymphoma: case report and literature review

Abstract BACKGROUND Central nervous system (CNS) metastases from Hodgkin’s Lymphoma (HL) are very rare, occurring in 0.02–0.5% of cases. They are usually associated to systemic relapse of the disease. Treatment options for HL brain metastases include surgery, radiotherapy, and systemic chemotherapy. CASE REPORT A 54 year-old woman presented with thoracic pain and dyspnea. Chest CT showed a thoracic bulky mass larger than 10 cm. Biopsy confirmed HL stage IIA, nodular sclerosing variant. No typical B symptoms, such as fever, night sweats or weight loss, were observed. The patient underwent chemotherapy with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD scheme), followed by 30Gy mediastinic radiotherapy (RT), which led to complete remission in September 2017. After 3 months, she presented with headache and rapidly progressing gait disorder. MRI showed a contrast-enhanced lesion in the right occipital lobe, with central necrosis and massive edema. Total-body CT scan and FDG-PET ruled out either the presence of new solid tumors or systemic relapses of HL. Gross total resection of the brain lesion was carried out, and HL histology was confirmed. CSF analysis from lumbar puncture was normal. Afterwards, the patient underwent 2 cycles of high dose cytarabine, but she rapidly progressed, and received salvage RT (30 Gy). Nevertheless, further systemic progression occurred: the patient developed headache, diplopia and dysphagia and, unfortunately, she died 6 months after the diagnosis of brain metastasis. DISCUSSION Thus far, only 45 cases of CNS HL have been reported from 2000 to 2018. Whole brain radiotherapy, with or without chemotherapy, was the most common treatment. In our patient, we chose surgical resection for the solitary brain metastasis followed by chemotherapy, delaying RT at recurrence. In the literature, median overall survival of patients diagnosed with brain metastases from HL is 18 months (1–273): 17 patients (38%) showed a progression (local / systemic: 12/17 - 71%), while 28 (62%) showed complete remission after a median follow-up of 20 months (6–273). CONCLUSION Intracranial localisation of Hodgkin’s Lymphoma is a rare entity but still has to be taken into account. Advanced brain imaging could be of help in case of uncertain radiological presentation. A multidisciplinary approach is needed as there is no consensus on the best treatment to choose: surgery, radiotherapy and chemotherapy should be considered on individual basis.

Comparison of Pegfilgrastim and Filgrastim to Prevent Neutropenic Fever during Consolidation with High Dose Cytarabine for Acute Myeloid Leukemia

Background:Granulocyte colony stimulating factor (G-CSF) to prevent neutropenic fever is a well-accepted standard of care to minimize the risk of neutropenic fever during consolidation chemotherapy for acute myeloid leukemia (AML). Although prospective, randomized clinical trials of filgrastim versus depot pegfilgrastim demonstrated biologic equivalency, retrospective studies in patients with solid tumors suggest the use of pegfilgrastim results in reduced rates of admission for neutropenic fever. Patients undergoing AML consolidation may be at higher risk for admission, as with solid tumors. Biosimilars for filgrastim (filgrastim-sndz and tbo-filgrastim) and pegfilgrastim (pegfilgrastim-jmdb) are creating market forces that may make daily administered agents an attractive alternative to pegfilgrastim, and therefore additional observational studies to clarify of the safety of daily administered G-CSF vs depot injections. We hypothesize that the use filgrastim over pegfilgrastim may result in higher hospital admission rates in AML patients undergoing consolidation chemotherapy outside the setting of prospective trials.Methods:Patient charts from the year 2004 through early 2017 diagnosed with AML at the Seidman Cancer Center of University Hospitals Cleveland Medical Center (UHCMC) were reviewed as a retrospective cohort study. Patient were included who received at least one cycle of high dose cytarabine during 1st complete remission, and received filgrastim or pegfilgrastim were considered available for analysis. Individual cycles of chemotherapy were assessed for potential adverse outcomes with the use of different forms of GCSF. The primary outcome of interest is hospitalization during consolidation chemotherapy. The incidence of hospitalization was analyzed using longitudinal logistic regression with generalized estimating equations for statistical inference assuming exchangeable variance-covariance structure of multiple hospitalizations from the same patients.Results436 patient charts were reviewed identifying 165 patients receiving at least one cycle of HiDAC chemotherapy. Of these, 156 patients received either filgrastim or pegfilgrastim, representing 256 cycles of high dose cytarabine chemotherapy supported with GCSF. Patients receiving filgrastims vs pegfilgrastim differed in the number of HiDAC cycles received (1.64 vs 1.97, p = 0.046), the distribution of favorable risk AML (11.9% vs 32.7%, p = 0.035). Groups did not differ based on age, sex, race, initial response to therapy, and proportion of secondary AML. After controlling the effects of age, sex, race and initial clinical response, treatment (filgrastim vs. pegfilgrastim) was significantly associated with hospitalization during consolidation therapy (p = 0.005). Specifically, the odds of having hospitalization for patients treated with Filgrastim is estimated to be 2.31 times the odds of having hospitalization for patients treated Pegfilgrastim with 95% CI (1.28, 4.17). Also, the estimated probability of having hospitalization for patients treated with filgrastim was 0.59 (95% CI: 0.43- 0.73) vs. 0.38 (95% CI: 0.27 - 0.51) for patients treated with pegfilgrastim.Conclusions:The use of filgrastim was found to be statistically significantly associated with and increased risk of hospitalization. [Display omitted] DisclosuresCaimi:Kite Pharma: Other: Advisory Board Participation; Celgene: Speakers Bureau; Genentech: Other: Advisory Board PArticipation, Research Funding; Kite Pharma: Other: Advisory Board Participation. Little:PCORI: Research Funding; Hemex: Patents & Royalties: Patent, no honoraria; Doris Duke Charitable Foundations: Research Funding; NHLBI: Research Funding. Malek:Sanofi: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau.

Indoximod Combined with Standard Induction Chemotherapy Is Well Tolerated and Induces a High Rate of Complete Remission with MRD-Negativity in Patients with Newly Diagnosed AML: Results from a Phase 1 Trial

▪BackgroundSuccessful allogeneic stem cell transplantation (HSCT) in treatment of patients (pts) with acute myeloid leukemia (AML) is dependent upon graft-versus-leukemia, suggesting that intact immune surveillance is essential for eradicating minimal residual disease. Myeloblast-induced T-cell tolerance through overexpression of indoleamine 2,3-dioxygenase (IDO) is thought to play a significant role in immune evasion through upregulation of tryptophan (Trp) catabolism and kynurenine production, resulting in a Trp-poor environment that leads to immune system suppression. Indoximod is a small-molecule inhibitor of the IDO pathway that acts directly on immune cells to reverse IDO pathway-mediated suppression. We are assessing the safety and preliminary efficacy of indoximod in combination with standard induction chemotherapy in patients (pts) with newly diagnosed AML.MethodsIn this open-label, multicenter, phase 1 study (NCT02835729), eligible pts with newly diagnosed AML were treated with indoximod in combination with induction chemotherapy (idarubicin 12 mg/m2/d x3 days with cytarabine 100 mg/m2/d x7 days). Using a “3+3” design, indoximod (600 mg [dose level 0], 1000 mg [dose level 1], 1200 mg [dose level 2]) was given orally every 8 hours (Q8h) starting on day 9 of induction. Regimen limiting toxicity (RLT) was defined as any ≥ grade 3 non-hematologic adverse event (AE) that was not incontrovertibly related to the underlying AML or cytarabine or idarubicin. After induction, pts received up to 4 cycles of high dose cytarabine (HiDAC) consolidation while continuing indoximod. Patients continued on maintenance indoximod for up to 6 months from completion of consolidation therapy. Indoximod was discontinued 4 weeks prior to HSCT in eligible patients and not restarted as maintenance post-HSCT.ResultsAs of July 15, 2018, 31 pts were enrolled (median age 55 years, range 18-78; 77% male). Six patients did not proceed with study therapy due to a diagnosis of acute promyelocytic leukemia, issues with medical insurance coverage, consent withdrawal, critical illness, and intestinal myeloid sarcoma preventing oral intake. Pts who received ≥1 dose of indoximod were included in the intention-to-treat (ITT) analysis (n=25), and pts who received ≥80% of their scheduled indoximod doses were included in the per-protocol (PP) analysis (n=19). Reasons for not completing ≥80% of indoximod doses were: consent withdrawal (n=3), inability to swallow (n=2) and physician decision (n=1). Of the 19 PP patients, 16 (84%) had either unfavorable karyotype or adverse mutation profile and 3 (16%) had secondary AML (s-AML). Indoximod combined with induction chemotherapy was well tolerated; no RLT was observed. The most frequent grade ≥3 non-hematologic treatment-emergent AEs in the ITT population, regardless of attribution, were febrile neutropenia (60%), hypoxia (16%), atrial fibrillation (12%), pneumonia (12%), hypocalcemia (12%), and hypotension (12%). Among 25 ITT pts, 21 (84%) achieved a remission (CR/CRh/CRi/CRp), and 15 of 19 (79%) in the PP analysis achieved remission. Among 12 pts with measurable residual disease (MRD) available in remission, 10 (83%) had MRD <0.02% (MRD-neg). Eleven of 19 pts (58%) received ≥1 cycle of HiDAC and 5 (26%) received maintenance indoximod. All 11 patients who received HiDAC #1 became MRD-neg. Median relapse-free and overall survival have not been reached. IDO Composite Scores in bone marrow were calculated by multiplying percentage of stained mononuclear cells by grade of staining intensity determined by 3 independent pathologists. Median composite IDO1 score in tested pt samples (n=11) was 0.76 (range, 0.1-2.2). Expression of IDO1 mRNA at baseline varied significantly among patient samples analyzed (fold changes (FC) range: 0.1-84, normalized to β-Actin expression). IDO1 mRNA was significantly upregulated in post-induction samples compared to baseline (FC range: 1.7-248) in 10 out of 12 paired samples.ConclusionsIndoximod is well tolerated in combination with standard AML induction therapy. Rates of morphologic response and of MRD-neg status are very promising. The recommended phase 2 dose (RP2D) was 1200 mg oral Q8h and a placebo-controlled randomized phase 2 study is under development. DisclosuresEmadi:NewLink Genetics: Research Funding. Loken:Hematologics, Inc: Employment, Equity Ownership. Kennedy:NewLink Genetics: Employment, Equity Ownership. Link:NewLink Genetics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Munn:NewLink Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Gemtuzumab Ozogamicin in NPM1-Mutated Acute Myeloid Leukemia (AML): Results from the Prospective Randomized AMLSG 09-09 Phase-III Study

Gemtuzumab Ozogamicin in NPM1-Mutated Acute Myeloid Leukemia (AML): Results from the Prospective Randomized AMLSG 09-09 Phase-III Study