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Chemotherapy remains a primary treatment for younger AML patients, though many relapse. Data from our group have shown that highly phosphorylated S6 in blasts may predict response to sirolimus given with chemotherapy. We report the results of a phase I study of this combination in newly diagnosed AML and the pharmacodynamic analysis of pS6 before and after treatment. Subjects received sirolimus (12 mg on day 1, 4 mg daily, days 2-10), then idarubicin and cytarabine (days 4-10). Response was assessed at hematologic recovery or by day 42 using a modified IWG criteria. Fifty-five patients received sirolimus. Toxicity was similar to published 7 + 3 data, and 53% had high-, 27% intermediate-, and 20% favorable-risk disease. Forty-four percent of the high-risk patients entered into CR/CRp. Seventy-nine percent of the intermediate-risk subjects had a CR/CRp. All favorable-risk patients had a CR by day 42; 9/11 remained alive and in remission with a median follow-up of 660 days. Additionally, 41/55 patients had adequate samples for pharmacodynamic analysis. All patients demonstrated activation of S6 prior to therapy, in contrast to 67% seen in previous studies of relapsed AML. mTORC1 inhibition was observed in 66% of patients without enrichment among patients who achieved remission. We conclude that sirolimus and 7 + 3 is a well-tolerated and safe regimen. mTORC1 appears to be activated in almost all patients at diagnosis of AML. Inhibition of mTORC1 did not differ based on response, suggesting that AML cells may have redundant signaling pathways that regulate chemosensitivity in the presence of mTORC1 inhibition.

The treatment landscape for acute myeloid leukemia (AML) has changed substantially in recent years. The introduction of newer therapies, including oral agents, less myelosuppressive agents, and parenteral regimens suitable for outpatient administration, has made it feasible for select patients to receive therapy in the outpatient setting and in community practices. Thorough patient evaluation (including molecular testing), planned supportive care (eg, transfusion support, antimicrobial prophylaxis), and vigilant patient monitoring (for tumor lysis syndrome and adverse events) by a multidisciplinary team are required for successful management of patients both in the community and at specialized leukemia centers. Some patients are unable or unwilling to travel to larger academic centers for treatment, and treatment of AML in the community setting may have potential advantages compared to less conveniently located academic/leukemia centers. This includes reduction of financial hardship for patients and their families and often better opportunities for family/caregiver support. Additionally, partnership between community practices and academic/leukemia centers is often crucial to optimizing AML management for many patients, as collaboration may facilitate access to additional expertise and trials, multidisciplinary teams for supportive care, easier transition to hematopoietic cell transplantation, and access to sophisticated molecular testing. In this review, we discuss AML treatment and management in the community setting, available therapies, and circumstances in which a referral to and co-management with an academic/leukemia center is more strongly recommended.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the subsequent pandemic have impacted every aspect of oncology care worldwide. Healthcare systems have been forced to rapidly change practices in order to maximize the safety of patients and healthcare providers and preserve scare resources. Patients with acute myeloid leukemia are at increased risk of complications from SARS-CoV-2 not only due to immune compromise related to the malignancy but also due to the acuity of the disease and intensity of treatment. These issues have created unique challenges during this difficult time. In this article, we present the approaches taken by two groups of hematologist/oncologists, one in the United States and one in Italy, who have been caring for acute myeloid leukemia (AML) patients in the face of the pandemic.

BACKGROUND: Patients with relapsed or refractory acute myeloid leukemia (AML) with mutations in the FMS-like tyrosine kinase 3 gene (FLT3) infrequently have a response to salvage chemotherapy. Gilteritinib is an oral, potent, selective FLT3 inhibitor with single-agent activity in relapsed or refractory FLT3-mutated AML. METHODS: In a phase 3 trial, we randomly assigned adults with relapsed or refractory FLT3-mutated AML in a 2:1 ratio to receive either gilteritinib (at a dose of 120 mg per day) or salvage chemotherapy. The two primary end points were overall survival and the percentage of patients who had complete remission with full or partial hematologic recovery. Secondary end points included event-free survival (freedom from treatment failure [i.e., relapse or lack of remission] or death) and the percentage of patients who had complete remission. RESULTS: Of 371 eligible patients, 247 were randomly assigned to the gilteritinib group and 124 to the salvage chemotherapy group. The median overall survival in the gilteritinib group was significantly longer than that in the chemotherapy group (9.3 months vs. 5.6 months; hazard ratio for death, 0.64; 95% confidence interval [CI], 0.49 to 0.83; P<0.001). The median event-free survival was 2.8 months in the gilteritinib group and 0.7 months in the chemotherapy group (hazard ratio for treatment failure or death, 0.79; 95% CI, 0.58 to 1.09). The percentage of patients who had complete remission with full or partial hematologic recovery was 34.0% in the gilteritinib group and 15.3% in the chemotherapy group (risk difference, 18.6 percentage points; 95% CI, 9.8 to 27.4); the percentages with complete remission were 21.1% and 10.5%, respectively (risk difference, 10.6 percentage points; 95% CI, 2.8 to 18.4). In an analysis that was adjusted for therapy duration, adverse events of grade 3 or higher and serious adverse events occurred less frequently in the gilteritinib group than in the chemotherapy group; the most common adv

Avoidance of apoptosis is a key mechanism that malignancies, including acute leukemias and MDS, utilize in order to proliferate and resist chemotherapy. Recently, venetoclax, an inhibitor of the anti-apoptotic protein BCL-2, has been approved for the treatment of upfront AML in an unfit, elderly population. This paper reviews the pre-clinical and clinical data for apoptosis inhibitors currently in development for the treatment of AML, ALL, and MDS.

We report the first published case of acute pancreatitis secondary to disseminated nocardiosis in a hematopoietic stem cell transplant (HSCT) recipient on chronic immunosuppression for graft-versus-host disease (GVHD). Nocardiosis in the HSCT population is relatively rare, and has not yet been described in haploidentical HSCT recipients. Our patient is a 28-year-old male with a history of haploidentical HSCT and GVHD of the skin and lung who was admitted to the hospital with acute pancreatitis. The workup for the etiology of his pancreatitis was initially unrevealing. He subsequently developed worsening sepsis and respiratory failure despite broad spectrum antimicrobials. After multiple bronchoscopies and pancreatic fluid sampling, he was found to have disseminated nocardiosis with Nocardia cyriacigeorgia.

We developed a 2-step approach to myeloablative haploidentical HSCT in which patients receive a large fixed dose of cyclophosphamide (CY)-tolerized T cells separately frm the HSC infusion in the hopes of accelerating post HSCT immune reconstitution (IR). The uniformity of the T cell dosing facilitates comparison of patients without (low risk) and with (high risk) active malignancy at HSCT to ascertain the impact of disease status at HSCT on IR with fewer confounding effects from conditioning or T cell dosing.

Amy MacKenzie, Margaret KasnerDepartment of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, USAAbstract: The standard treatment of adult-onset acute lymphoblastic leukemia (ALL) is based on trials conducted 20–25 years ago and has remained largely unchanged since that time. Treatments are lengthy and have been extrapolated from successful pediatric regimens. However, adult disease is cytogenetically different from pediatric disease. Adults often have comorbidities that make completing treatment challenging, and outcomes subsequently suffer. Advances in the understanding of cytogenetics and molecular biology have led to the identification of prognostic factors, as well as offering fertile ground for the development of new therapeutics. The current research in ALL focuses on the development of monoclonal antibodies and small molecule inhibitors, as well as increasing sensitivity in monitoring minimal residual disease, improving upon current chemotherapy, and improving stem cell transplantation. This monograph reviews the current standard of care for adult ALL and the innovations in clinical investigation that aim to improve the future for adults who suffer from this disease. The adult population is in great need of similar advances and stands to benefit tremendously from the research discussed in this review. The challenges of sustainable remission and reduced morbidity and mortality in treatment remain to be surmounted. The aggressive efforts of current clinical trials that are investigating novel therapies both alone and with standard treatment offer hope for adults that is slowly beginning to be realized.Keywords: adult acute lymphoblastic leukemia, Philadelphia chromosome, monoclonal antibodies, molecular pathways

Studies of haploidentical hematopoietic stem cell transplantation (HSCT) have identified threshold doses of T cells below which severe GVHD is usually absent. However, little is known regarding optimal T-cell dosing as it relates to engraftment, immune reconstitution, and relapse. To begin to address this question, we developed a 2-step myeloablative approach to haploidentical HSCT in which 27 patients conditioned with total body irradiation (TBI) were given a fixed dose of donor T cells (HSCT step 1), followed by cyclophosphamide (CY) for T-cell tolerization. A CD34-selected HSC product (HSCT step 2) was infused after CY. A dose of 2 × 10(8)/kg of T cells resulted in consistent engraftment, immune reconstitution, and acceptable rates of GVHD. Cumulative incidences of grade III-IV GVHD, nonrelapse mortality (NRM), and relapse-related mortality were 7.4%, 22.2%, and 29.6%, respectively. With a follow-up of 28-56 months, the 3-year probability of overall survival for the whole cohort is 48% and 75% in patients without disease at HSCT. In the context of CY tolerization, a high, fixed dose of haploidentical T cells was associated with encouraging outcomes, especially in good-risk patients, and can serve as the basis for further exploration and optimization of this 2-step approach. This study is registered at www.clinicaltrials.gov as NCT00429143.