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Remission assessment in acute myeloid leukemia has evolved over the recent years with the advent of molecular and flow-based minimal residual disease determination. Nonetheless, early time point such as day 5 and day 14 (D14), still have prognostic and therapeutic implications. D14 refractory disease is regarded as a poor prognostic factor, however the therapeutic intervention is still under debate, with evidence suggesting a successful re-induction might offer similar long-term outcome as D14 aplasia. Others advocate the use of more intensive salvage protocols as a mean to overcome the negative prognostic effect. In the current study, we compare outcome of D14 refractory AML patients treated with either re-induction or salvage protocol. More importantly, we identify response characteristics that might suggest which patients will benefit from re-induction approach. Accurate identification of chemotherapy refractory patients might allow the early incorporation of non-chemotherapy based protocols in the future.

Patients with FLT3-mutated relapsed or refractory (R/R) acute myeloid leukemia (AML) have a dismal prognosis. Gilteritinib is a FLT3 tyrosine kinase inhibitor (TKI) recently approved for patients with R/R AML. We aimed to characterize real-world data regarding gilteritinib treatment in FLT3-mutated R/R AML and to compare outcomes with matched FLT3-mutated R/R AML patients treated with chemotherapy-based salvage regimens. Twenty-five patients from six academic centers were treated with gilteritinib for FLT3-mutated R/R AML. Eighty percent were treated with a prior intensive induction regimen and 40% of them received prior TKI therapy. Twelve patients (48%) achieved complete response (CR) with gilteritinib. The estimated median overall survival (OS) of the entire cohort was eight (CI 95% 0-16.2) months and was significantly higher in patients who achieved CR compared to those who did not (16.3 months, CI 95% 0-36.2 vs. 2.6 months, CI 95% 1.47-3.7; p value = 0.046). In a multivariate cox regression analysis, achievement of CR was the only predictor for longer OS (HR 0.33 95% CI 0.11-0.97, p = 0.044). Prior TKI exposure did not affect OS but was associated with better event-free survival (HR 0.15 95% CI 0.03-0.71, p = 0.016). An age and ELN-risk matched comparison between patients treated with gilteritinib and intensive salvage revealed similar response rates (50% in both groups); median OS was 9.6 months (CI 95% 2.3-16.8) vs. 7 months (CI 95% 5.1-8.9) in gilteritinib and matched controls, respectively (p = 0.869). In conclusion, in the real-world setting, gilteritinib is effective, including in heavily pre-treated, TKI exposed patients.

Venetoclax in combination with intensive therapies is explored in both the upfront and relapse/refractory (R/R) setting, and available data suggest that such regimens are effective albeit with added hematological and infectious toxicity. We conducted a multicenter retrospective cohort study of patients with acute myeloid leukemia (AML) treated with venetoclax in combination with FLAG-IDA protocol. Twenty-five patients were included in this analysis (median age 53.4 years). Most patients were treated for R/R AML (n = 24, 96%) with a median of one (range 0-3) previous lines of therapy and 44% of patients (n = 11) having prior allogeneic hematopoietic cell transplantation (HCT). Median follow-up was 10 (range, 4-26) months. Platelet and neutrophil recovery were observed at a median of 31 (95% CI 17.6-38.3) and 23 (95% CI 20-28) days, respectively. The most common adverse events were infectious (blood stream infections, 48% and invasive fungal infections, 32%). Thirty-day mortality was 12%. Composite complete remission (CRc) was 72% for the entire cohort and 91% in patients treated for post-HCT relapse. Incidences of relapse-free and overall survival at 12 months were 67% (95% CI 58-76%) and 50% (95% CI 31-69%), respectively. Real-world data show that the addition of venetoclax to FLAG-IDA protocol is effective in patients with high-risk AML, most notably in the post-HCT relapse setting. Prophylaxis and surveillance for infections are crucial.

After decades when intensive chemotherapy remained the only effective anti-acute myeloid leukaemia (AML) treatment, a torrent of novel, less toxic agents are about to revolutionise AML therapy. Prolonged remissions with good quality of life become achievable for many patients previously considered only for palliative care because they could not tolerate intensive therapy. As treatment options multiply, the importance of genetic profile is recognised, even for advanced-age patients for whom cure is unlikely. With lack of randomised comparative trials for most treatment regimens, one can only extrapolate data from existing studies to make evidence-based decisions. We herein present seven common clinical scenarios illustrating the complexity of treating older AML patients and describe our approach to their management. In each case, up-to-date data on relevant agents to be offered to a particular patient are discussed. The current review is limited to the drugs, available and approved in the Western world and many promising agents, still under investigation, are not discussed.

The addition of midostaurin, a FLT3-inhibitor, to intensive chemotherapy (IC) was previously shown to improve outcome of younger patients with FLT3-mutated AML. The toxicity and efficacy of adding midostaurin to IC in patients not originally included in the RATIFY study or with intensified daunorubicin dosing are unknown. We conducted a retrospective, multi-center, historical-control study to characterize the safety and efficacy of adding midostaurin to IC in a “real-world” setting. Sixty-nine adult patients were included in the analysis (midostaurin n = 34, historical controls n = 35) with a mean follow-up of 18.4 (± 15) months. Median age of patients was 60 (range 26–82) years; 32% and 20% of patients were > 65 and 70 years, respectively. No differences in baseline characteristics were noted between the groups. Midostaurin was administered with 90 mg/m2 daunorubicin in 29% of patients; One-third of patients experienced dose reductions/interruptions during midostaurin therapy. Overall toxicity was comparable between the midostaurin and control groups.CR/CRi rates were higher in patients treated with midostaurin compared with controls (80% vs. 57%, p = 0.047) and significantly more patients in the midostaurin group were transplanted in first remission (95% vs. 68%, p = 0.04).Median OS and DFS were higher in the midostaurin vs. control group (not reached vs. 11 months (p = 0.085) and 13 vs. 6 months (p = 0.09), respectively). In our analysis, midostaurin was not associated with increased toxicity including in older patients, in those with secondary AML or when administered with intensified daunorubicin dosage. Higher remission rates in the midostaurin group and increased transplantation rates in first CR were associated with a trend towards better outcomes.

Invasive pulmonary aspergillosis (IPA) has dire consequences in hemato-oncological patients. We report our experience with performing routine baseline chest computed tomography for early diagnosis of IPA. We found high rates of proven or probable IPA diagnosed on admission among patients with newly diagnosed acute myeloid leukemia.

Disclaimer In an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Purpose To report a case of ribavirin-associated severe hyperuricemia in an immunocompromised patient treated for respiratory syncytial virus (RSV) infection. Summary A 21-year-old male with a past medical history of B-cell acute lymphoblastic leukemia was in full remission after allogenic bone marrow transplantation complicated with chronic graft-versus-host disease. He was hospitalized due to fever, malaise, and respiratory syndromes. A diagnosis of RSV upper respiratory tract infection complicated by secondary pneumonia was made, and oral ribavirin (600 mg in 3 divided doses daily) and intravenous levofloxacin (750 mg once daily) were initiated. On day 2 of the hospital admission, the patient’s uric acid levels had increased from a baseline of 4 to 6 mg/dL to values of 19.3 and 22.2 mg/dL after the fourth and fifth doses of ribavirin, respectively, and his serum creatinine steadily had increased from a baseline of 0.7 to 0.8 mg/dL to a value of 1.6 mg/dL. Ribavirin was discontinued after the sixth dose, and a single dose of intravenous rasburicase (7.5 mg) was administered. On day 3, the patient’s serum uric and creatinine concentrations had decreased to 4.7 mg/dL and 1.1 mg/dL, respectively. He continued to recover on antibiotics and was discharged with normal uric acid and serum creatinine levels. Conclusion We report a case of severe hyperuricemia and acute kidney injury that developed early after initiation of ribavirin for RSV infection and suspected bacterial pneumonia in an immunocompromised patient without hepatitis C, requiring ribavirin discontinuation and rasburicase administration. To our knowledge, this is the first reported case of severe hyperuricemia in a patient treated with ribavirin for RSV infection rather than chronic hepatitis C. Clinicians should be aware of the possibility of acute and severe hyperuricemia following ribavirin administration.

Introduction: High-dose Ara-C (HiDAC) is a post-remission consolidation protocol commonly used in patients with acute myeloid leukemia (AML). The optimal regimen of HiDAC administration is not fully established. Recent studies suggest that a short and condensed schedule of HiDAC consolidation therapy given on days 1, 2 and 3 (HiDAC123) may be superior to the traditional days 1, 3 and 5 regimen (HiDAC135). The current retrospective study compared the impact of these two therapeutic approaches on the outcomes of AML patients treated at the Rambam Leukemia Unit. Methods: This retrospective cohort analysis included patients diagnosed with AML between the years 2015-2020 who were candidates for aggressive chemotherapy. Fifty-seven patients received a total of 76 courses of HiDAC135 mainly between 2015 and 2017, while 77 other patients received a total of 135 courses of HiDAC123 mainly between 2017 and 2020. The HiDAC dose in the two groups was 3 g/m 2 for patients aged less than 55 years, and 1.5 g/m 2 for patients aged 55-65 years. Patient demographics, the ELN leukemia risk category and NPM1 status were compared. The analysis also included data on complications per course of HiDAC therapy, need for hospitalization, the number of days of hospitalization if needed, the occurrence of neutropenic fever per course, the need for blood products (packed red blood cells and platelets), neurotoxicity and death within the 28 days of the course. Results: The HiDAC123 and HiDAC135 groups were comparable in terms of the ELN risk category and NPM1 status. The groups significantly differed in age (median of 49.8 years and 55.9 years, respectively; p=0.01), which was most likely to be related to the use of venetoclax and azacitidine during the period when HiDAC123 was prescribed. Similar percentage of patients achieved complete remission (CR) after induction chemotherapy (93.5% and 94.7%, in the HiDAC123 and HiDAC135 groups, respectively). There were no differences in the overall survival (OS) and event-free survival (EFS) between the two groups (Figure 1). Significantly more patients in the HiDAC135 group were hospitalized for more than 4 days compared with the HiDAC123 group (51.3% vs 31.9%; p=0.008) and significantly more patients in the HiDAC135 group needed more than 2 units of packed red blood cells than in the HiDAC123 group (38.2% vs 21.5%, p=0.011). There was no difference in the percentage of patients in need of platelet transfusion. Likewise, there was no difference between the two groups in either the number of hospitalizations post-HiDAC therapy, the occurrence of neutropenic fever events or the incidence of death within the first 28 days after the HiDAC therapy. Conclusions: The present analysis demonstrates that HiDAC123 is as safe and efficacious as HiDAC135 in terms of OS and EFS and is associated with shorter hospitalization and lower requirement for blood products. These results show that HiDAC123 could be the regimen of choice as consolidation therapy in AML patients. Figure 1 Figure 1. Disclosures Zuckerman: Orgenesis Inc.: Honoraria; BioSight Ltd: Honoraria; AbbVie: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Gilead Sciences: Honoraria, Speakers Bureau; Cellect Biotechnology: Honoraria. Ofran: Pfizer: Consultancy; AbbVie: Consultancy; Medison Israel: Consultancy; Astellas: Consultancy; Janssen: Consultancy.

Introduction: Mutations of the NPM1 gene (NPM1mut) are considered a favorable prognostic marker in acute myeloid leukemia (AML). Data from a prospective randomized trial have shown that in young AML patients with NPM1mut upfront allogeneic stem cell transplantation (allo-SCT) performed in first complete remission (CR1) may lead to a significantly improved overall survival (OS) (Dohner K, Blood 2005). However, due to considerable allo-SCT-associated morbidity and mortality and a relatively favorable outcome of these patients outside the transplant setting, many physicians are reluctant to refer NPM1mut AML patients to allo-SCT in CR1. Recently, quantitative NPM1 testing has been adopted in patient selection for allo-SCT; yet, evidence to support such practice is scant. The current single-center retrospective study compared the outcome of fit NPM1mut AML patients before and after the introduction of quantitative PCR monitoring to the routine practice at the Rambam Leukemia Unit. Methods: This retrospective cohort analysis included NPM1mut AML patients who were considered fit for intensive chemotherapy. FLT3 positivity was not an exclusion criterion. The cohort incorporated patients treated between 2011-2014 whose minimal residual disease (MRD) status was not evaluated (n=31) and patients treated between 2015-2019 who underwent MRD assessment as part of their routine follow-up (n= 38). All patients (n=69) received intensive chemotherapy (the "3+7" regimen). In the former period, our practice was to recommend allo-SCT for any NPM1mut fit patient with an available donor. Starting from 2015, bone marrow samples of all patients have been monitored for MRD both post-induction and after each consolidation cycle, using quantitative PCR. Presently, only patients failing to achieve a 3-log reduction in the NPM1mut relative expression level (NPM1/ABL) after the first consolidation are recommended to proceed to allo-SCT during CR1. In case of molecular relapse identified in former MRDneg patients, the aim is to immediately perform allo-SCT in an attempt to avoid morphological relapse. Patient demographics, comorbidities, cytogentic and molecular risk factors were compared. Survival curves were calculated with and without censoring at time of SCT. Results: Comparison of the pre-MRD monitoring cohort with the MRD-evaluated cohort revealed no difference in age (53.5 years and 56.2 years, respectively), comorbidities (ischemic heart disease, insulin-dependent diabetes mellitus, chronic kidney disease grade >2, chronic obstructive pulmonary disease and cirrhosis), high risk features such as FLT3 positive status, complex karyotype or P53 positive (38.8% and 39.5%, respectively) and extramedullary involvement (3.2% and 15.8%, respectively; P=0.12). More women were treated in the earlier period (64.5% and 39.5%, respectively; P=0.053). The use of intensified induction (daunorubicin 90mg/m2 or re-induction) was significantly more prevalent in the second cohort (50%, n=19) than in the first one (12.9%, n=4). Patients were generally prescribed the daunorubicin dose of ≥60mg/m2 or similar, apart from one patient in each group who received high-dose Ara-C as induction therapy. The use of MRD quantitative monitoring allowed reducing the portion of patients transplanted in CR1 from 61% (n=19/31) to 47.3% (n=18/38). Four patients who had not been transplanted in first molecular remission were successfully transplanted at time of molecular relapse without requiring salvage chemotherapy and prior to morphological relapse. To date, these four patients are alive and in remission at a follow-up of 1,8, 17 and 26 months from relapse. The 1- and 2-year OS was identical in the two cohorts (1 year: 77.3% vs. 86.7%; 2 years: 66.3% vs 74.4%, respectively) (Fig 1a). There was no significant change without censoring at time of SCT (Fig 1b). Conclusions: The present analysis demonstrates that in clinical practice quantitative NPM1 monitoring may be safely used for precise selection of NPM1mut fit AML patients for allo-SCT. This approach may allow avoiding transplantation in patients who may have a prolonged remission outside the transplant setting, while reserving allo-SCT for the time when such patients experience molecular relapse. The use of MRD monitoring as decision making tool in the hematologist armamentarium should be evaluated in lager patient cohorts.

Background Newly diagnosed AML patients who cannot tolerate intensive chemotherapy have limited treatment options and poor long-term outcomes. Recently, the U.S FDA approved combination of venetoclax, an anti BCL-2 oral agent with hypomethylating agents or LDAC for this patient population based on a series of phase 1b/2 trials showing high CR/CRi rates. Methods Venetoclax combinations are available in Israel since January 2019 following approval and reimbursement by the health authority. Medical centers participating in the Israeli Acute Leukemia Group were approached for data collection. We specifically sought to collect safety parameters, and short term outcomes were a secondary outcome in this report. Results 35 patients from 5 medical centers are included in this analysis. Median age was 80 years (range 62-95), 16 males and 18 females. Diagnoses were de novo AML in 17, secondary AML (to MDS/MPN) in 16, and t-AML in 2 patients. High risk AML seen in 15 patients, followed by intermediate (n=11) and favorable (n=7) risk categories (data NA in 2). Median ECOG PS was 0 (7 with ECOG≥2). Patients were considered not eligible for intensive therapy due to age (n=28), comorbidity (n=10), poor performance status (n=4) or other reasons (n=3). Median bone marrow blasts at diagnosis was 36% (range 8-90%). The median WBC, ANC, Hb and PLT were 8.0 K/µl (range 0.9-108), 1.7 K/µl (range 0.3-16.4), 8.6 g/dL (range 4.4-13.9) and 77 K/µl (range 9-306), respectively. Median LDH, uric acid and creatinine levels were 1.5 times ULN (range 1-5), 5.3 mg/dl (range 2.3-16), and 0.98 mg/dl (range 0.73-2.25), respectively. The median time from AML diagnosis to start of treatment was 1 month (range 0-6). Venetoclax was combined with azacitidine in most cases (32/35); 2 patients received LDAC as a combination, and 1 additional patient received one cycle with LDAC followed by azacitidine combination. At the time of data analysis, treatment was given for a median 3 cycles (range 1-10). Azacitidine was most commonly administered in a 5+2 regimen (20/33, 61%), followed by a 7 day regimen (12/33, 37%). One patient received 5 days courses. Venetoclax was given with a short ramp up (median 3 days, range 2-11) and then at a median daily dose was 400 mg (range 200-400). Dose reductions occurred in 14 (40%) patients, mainly for potential drug-drug interactions. Therapy was started during hospitalization in 16 patients, with a median hospitalizations duration of 7 days (range 4-30); 12 patients were treated with hydroxyurea for cytoreduction prior to commencing venetoclax combination. Treatment was associated with side effects in all patients, including grade 3-4 neutropenia in 26 (84% of evaluable patients) and grade 3-4 thrombocytopenia in 18 patients (58% of evaluable patients). The most common non-hematologic side effects were infections; Febrile neutropenia in 16 (46%) and non-febrile infections in 19 patients (54%)- 2 pneumonia, 1 periorbital cellulitis, 1 herpes zoster, and 1 pulmonary aspergillosis. Gastrointestinal side effects occurred in 9 (26%), 1 grade 3, and tumor lysis syndrome occurred in 5 patients (14%), 1 grade 4. Cardiac adverse events were reported in 2 and 1 patient experienced ischemic stroke. Responses were assessed after 2 treatment courses and are available in 22 patients, with 15 patients (68%) achieving CR/CRi. Response (CR+CRi) was achieved in 55%, 70% and 50% of patients with high, intermediate and favorable risk groups, respectively. Complete response was seen in 2/2 patients with available data, with prior hypomethylating agents. At a median follow up of 4.1 months (range 0.2-13), 25 patients are alive (70%), with 13/16 (81%) patients with evaluable data in CR/CRi. The most common causes for death were infectious complications (n=4 including 1 in CR), and disease progression (n=3). The median EFS are 3.8 months, and median OS 13 months. Conclusions Treatment with venetoclax combinations in AML patients ineligible for intensive treatment outside of clinical trials was associated with high rates of hematologic and non-hematologic side effects, including tumor lysis syndrome in 14% of patients, which is higher than reported in the original trials. Although the follow up in this cohort is rather short, the CR/CRi rates are similar to those achieved in published clinical trials and encouraging. Disclosures Wolach: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaker; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaker.

Introduction: Failure to achieve remission following standard induction is a poor prognostic sign in patients with acute myeloid leukemia (AML). However, as there is no consensus on the optimal number of induction cycles and/or the best indication and timing for re-induction, the definition of refractory AML is still debatable. A clinically relevant definition of refractoriness should be associated with poor long-term prognosis. This is of particular importance for patients who eventually achieve remission (CR1) and in whom referral for allogeneic stem cell transplantation (alloSCT) in CR1 may be controversial. It was previously reported that AML patients who achieved CR1 following re-induction given on day 14 of therapy, had a long-term survival identical to that of patients who achieved CR1 after one induction cycle. To the best of our knowledge, no data are available regarding the prognosis of patients who achieved CR1 after a second cycle of intensive chemotherapy, administered at the end of neutropenic period. The current study compared the prognosis of AML patients who achieved CR1 after one induction cycle to that of patients who achieved CR1 following a second cycle of chemotherapy given either as re-induction by day 14 or as a second-line therapy administered on days 24-40 of the first induction. Patients and Methods: Data of all leukemia patients admitted to the Rambam Medical Center between the years 1993 and 2015 were retrospectively collected. Adults diagnosed with de-novo AML who achieved CR1 following one or two cycles of therapy were included in the study. Patients diagnosed with APL or high-risk AML, as defined based on a poor-risk karyotype or presence of FLT3-ITD mutation, were excluded from the analysis. It is common practice at our center to assign patients for re-induction according to day 14 bone marrow (BM) results. Yet, for various reasons, this paradigm is not followed in some patients. Overall survival (OS), leukemia-free-survival (LFS), and death rates were compared in the study participants. Multivariate analysis for prediction of death, including the use and timing of second-line therapy, was performed. Results: Six hundred and forty three de novo AML patients were treated at Rambam during the study period. After exclusion of patients with high-risk AML, 492 individuals were left. Of them, 242 patients achieved CR1 after one cycle of induction (control group), 53 after induction + re-induction administered by day 14 (re-induction group) and 38 achieved CR1 after induction followed by second-line therapy prescribed on days 24-40 (second-line group). Median OS was 25.9, 23.5 and 15.1 months for patients in control, re-induction and second-line groups, respectively. Median LFS was 14.7, 10 and 8.16 months for the corresponding groups, respectively. Differences in OS and LFS were statistically significant between the control and second-line groups (p Conclusions: Despite previous reports showing similar outcomes in patients who achieved CR1 post re-induction and those achieving CR1 with one induction cycle, some physicians are reluctant to start re-induction as early as day 14. We herein report a significantly better prognosis in patients achieving CR1 after re-induction given by day 14 compared to those achieving CR1 after a second cycle of therapy prescribed on days 24-40. These data may have 2 practical implications. First, in AML patients with residual disease, an effort should be made to start re-induction as early as day 14. Second, for intermediate-risk patients, a failure to achieve CR1 after one induction cycle should not alter post-remission decisions, if CR1 was achieved with re-induction by day 14. This may not be true for patients who achieved CR1 with second-line therapy prescribed on days 24-40. Our study was not powered to examine whether alloSCT could improve the outcome of these refractory AML patients. Disclosures No relevant conflicts of interest to declare.