Q-HAM: a multicenter upfront randomized phase II trial of quizartinib and high-dose Ara-C plus mitoxantrone in relapsed/refractory AML with FLT3-ITD.

BACKGROUND: About 50% of older patients with acute myeloid leukemia (AML) fail to attain complete remission (CR) following cytarabine plus anthracycline-based induction therapy. Salvage chemotherapy regimens are based on high-dose cytarabine (HiDAC), which is frequently combined with mitoxantrone (HAM regimen). However, CR rates remain low, with less than one-third of the patients achieving a CR. FLT3-ITD has consistently been identified as an unfavorable molecular marker in both relapsed and refractory (r/r)-AML. One-quarter of patients who received midostaurin are refractory to induction therapy and relapse rate at 2 years exceeds 40%. The oral second-generation bis-aryl urea tyrosine kinase inhibitor quizartinib is a very selective FLT3 inhibitor, has a high capacity for sustained FLT3 inhibition, and has an acceptable toxicity profile. METHODS: In this multicenter, upfront randomized phase II trial, all patients receive quizartinib combined with HAM (cytarabine 3g/m2 bidaily day one to day three, mitoxantrone 10mg/m2 days two and three) during salvage therapy. Efficacy is assessed by comparison to historical controls based on the matched threshold crossing approach with achievement of CR, complete remission with incomplete hematologic recovery (CRi), or complete remission with partial recovery of peripheral blood counts (CRh) as primary endpoint. During consolidation therapy (chemotherapy and allogeneic hematopoietic cell transplantation), patients receive either prophylactic quizartinib therapy or measurable residual disease (MRD)-triggered preemptive continuation therapy with quizartinib according to up-front randomization. The matched threshold crossing approach is a novel study-design to enhance the classic single-arm trial design by including matched historical controls from previous clinical studies. It overcomes common disadvantages of single-armed and small randomized studies, since the expected outcome of the observed study population can be adjusted based on the matched controls with a comparable distribution of known prognostic and predictive factors. Furthermore, balanced treatment groups lead to stable statistical models. However, one of the limitations of our study is the inability to adjust for unobserved or unknown confounders. Addressing the primary endpoint, CR/CRi/CRh after salvage therapy, the maximal sample size of 80 patients is assessed generating a desirable power of the used adaptive design, assuming a logistic regression is performed at a one-sided significance level α=0.05, the aspired power is 0.8, and the number of matching partners per intervention patient is at least 1. After enrolling 20 patients, the trial sample size will be recalculated in an interim analysis based on a conditional power argument. CONCLUSION: Currently, there is no commonly accepted standard for salvage chemotherapy treatment. The objective of the salvage therapy is to reduce leukemic burden, achieve the best possible remission, and perform a hemopoietic stem-cell transplantation. Thus, in patients with FLT3-ITD mutation, the comparison of quizartinib with intensive salvage therapy versus chemotherapy alone appears as a logical consequence in terms of efficacy and safety. ETHICS AND DISSEMINATION: Ethical approval and approvals from the local and federal competent authorities were granted. Trial results will be reported via peer-reviewed journals and presented at conferences and scientific meetings. TRIAL REGISTRATION: ClinicalTrials.gov NCT03989713; EudraCT Number: 2018-002675-17.

Impact of BMI on patient outcome in acute myeloid leukaemia patients receiving intensive induction therapy: a real-world registry experience.

BACKGROUND: Acute myeloid leukaemia (AML) is treated with intensive induction chemotherapy (IT) in medically fit patients. In general, obesity was identified as a risk factor for all-cause mortality, and there is an ongoing debate on its impact on outcome and optimal dosing strategy in obese AML patients. METHODS: We conducted a registry study screening 7632 patients and assessed the impact of obesity in 1677 equally IT treated, newly diagnosed AML patients on the outcome (OS, EFS, CR1), comorbidities, toxicities and used dosing strategies. RESULTS: Obese patients (BMI ≥ 30) displayed a significant inferior median OS (29.44 vs. 47.94 months, P = 0.015) and CR1 rate (78.7% vs. 84.3%, P = 0.015) without differences in median EFS (7.8 vs. 9.89 months, P = 0.3) compared to non-obese patients (BMI < 30). The effect was predominantly observed in older (≥60 years) patients. Obesity was identified as an independent risk factor for death, and obese patients demonstrated higher rates of cardiovascular or metabolic comorbidities. No differences for OS, EFS, CR1 or treatment-related toxicities were observed by stratification according to used dosing strategy or dose reduction. CONCLUSIONS: In conclusion, this study identifies obesity as an independent risk factor for worse OS in older AML patients undergoing curative IT most likely due to obesity-related comorbidities and not to dosing strategy.

Correlation of nutrition-associated parameters with non-relapse mortality in allogeneic hematopoietic stem cell transplantation.

Outcome of allogeneic stem cell transplantation (alloSCT) is hampered by substantial non-relapse mortality (NRM). Given its impact on organ function and immune response, the nutritional status has been suggested as relevant for NRM. We aimed to evaluate the association of NRM with nutritional status prior to alloSCT and in the post-SCT course. In a retrospective single-center study, we analyzed 128 alloSCTs. Besides standard characteristics, nutrition-associated parameters BMI, serum total protein, and serum albumin were recorded before conditioning and at various time points after alloSCT. Association with NRM was evaluated by univariate and multivariate survival analysis. The cohort comprised patients with a median BMI of 26 kg/m2 (16.7-46.9 kg/m2), median serum total protein of 59 g/l (41-77 g/l), and serum albumin of 36 g/l (22-46 g/l) before SCT. NRM at d+100 was 14.8% and at 1 year 26.6%. Prior to SCT, only serum albumin deficiency was associated with increased NRM (p = .010) in multivariate analysis. After SCT (d+30 and d+100), all nutrition-associated parameters decreased (p < .002), but no association of deteriorating nutritional status with NRM was found. In multivariate analysis, serum albumin (p = .03) and severe albumin deficiency (p = .02) correlated with NRM at d+30 and d+100, while BMI and serum total protein did not. In our study, albumin deficiency, particularly prior to alloSCT, shows a strong correlation with NRM. This finding may add to monitoring, risk evaluation, and counseling of patients and serve as a rational for interventions to improve the nutritional status in patients undergoing SCT.

Maturation trajectories and transcriptional landscape of plasmablasts and autoreactive B cells in COVID-19.

In parasite and viral infections, aberrant B cell responses can suppress germinal center reactions thereby blunting long-lived memory and may provoke immunopathology including autoimmunity. Using COVID-19 as model, we set out to identify serological, cellular, and transcriptomic imprints of pathological responses linked to autoreactive B cells at single-cell resolution. We show that excessive plasmablast expansions are prognostically adverse and correlate with autoantibody production but do not hinder the formation of neutralizing antibodies. Although plasmablasts followed interleukin-4 (IL-4) and BAFF-driven developmental trajectories, were polyclonal, and not enriched in autoreactive B cells, we identified two memory populations (CD80+/ISG15+ and CD11c+/SOX5+/T-bet+/-) with immunogenetic and transcriptional signs of autoreactivity that may be the cellular source of autoantibodies in COVID-19 and that may persist beyond recovery. Immunomodulatory interventions discouraging such adverse responses may be useful in selected patients to shift the balance from autoreactivity toward long-term memory.

Real-world experience of CPX-351 as first-line treatment for patients with acute myeloid leukemia.

To investigate the efficacy and toxicities of CPX-351 outside a clinical trial, we analyzed 188 patients (median age 65 years, range 26-80) treated for therapy-related acute myeloid leukemia (t-AML, 29%) or AML with myelodysplasia-related changes (AML-MRC, 70%). Eighty-six percent received one, 14% two induction cycles, and 10% received consolidation (representing 22% of patients with CR/CRi) with CPX-351. Following induction, CR/CRi rate was 47% including 64% of patients with available information achieving measurable residual disease (MRD) negativity (<10-3) as measured by flow cytometry. After a median follow-up of 9.3 months, median overall survival (OS) was 21 months and 1-year OS rate 64%. In multivariate analysis, complex karyotype predicted lower response (p = 0.0001), while pretreatment with hypomethylating agents (p = 0.02) and adverse European LeukemiaNet 2017 genetic risk (p < 0.0001) were associated with lower OS. Allogeneic hematopoietic cell transplantation (allo-HCT) was performed in 116 patients (62%) resulting in promising outcome (median survival not reached, 1-year OS 73%), especially in MRD-negative patients (p = 0.048). With 69% of patients developing grade III/IV non-hematologic toxicity following induction and a day 30-mortality of 8% the safety profile was consistent with previous findings. These real-world data confirm CPX-351 as efficient treatment for these high-risk AML patients facilitating allo-HCT in many patients with promising outcome after transplantation.

Outcome of a Real-World Patient Cohort with Secondary CNS Lymphoma Treated with High-Intensity Chemoimmunotherapy and Autologous Stem Cell Transplantation.

BACKGROUND: Aggressive non-Hodgkin lymphomas with secondary central nervous system (CNS) involvement bear a dismal prognosis. Optimal treatment remains so far unclear, and effective treatment options remain an unmet clinical need. Remission rates are in general low, resulting in rapid relapses and palliative care in the majority of patients. High-intensity treatment combining effective CNS-directed chemoimmunotherapy with autologous stem cell transplantation was shown in a recent phase 2 trial to induce durable remissions. Here, we report the outcome of the first real-world patient cohort treated according to the published protocol. METHODS: We retrospectively identified 17 HIV-negative lymphoma patients with secondary CNS involvement, either at first diagnosis or at relapse of lymphoma, treated according to the study protocol published by Ferreri et al. [J Clin Oncol. 2015] at two university medical centers in Germany. Treatment consisted of four cycles of chemoimmunotherapy with a consolidating autologous stem cell transplantation. Adverse events and overall outcome were assessed. RESULTS: Five patients had CNS involvement at first diagnosis and 12 patients at relapse of lymphoma. A complete response was achieved in 9 patients. Median survival was 11 months. Five patients died of septic complications and 4 patients succumbed to progression or relapse of disease. CONCLUSIONS: The outcome of our real-world cohort emphasizes the possible toxic character of the treatment protocol by Ferreri et al. [J Clin Oncol. 2015]. Further improvement in treatment regimens is still an unmet need.

A proof of concept phase I/II pilot trial of LSD1 inhibition by tranylcypromine combined with ATRA in refractory/relapsed AML patients not eligible for intensive therapy.

All-trans-retinoic acid (ATRA) is highly active in acute promyelocytic leukemia but not in other types of acute myeloid leukemia (AML). Previously, we showed that ATRA in combination with Lysine-specific demethylase 1 (LSD1) inhibition by tranylcypromine (TCP) can induce myeloid differentiation in AML blasts. This phase I/II clinical trial investigated the safety and efficacy of TCP/ATRA treatment as salvage therapy for relapsed/refractory (r/r) AML. The combination was evaluated in 18 patients, ineligible for intensive treatment. The overall response rate was 20%, including two complete remissions without hematological recovery and one partial response. We also observed myeloid differentiation upon TCP/ATRA treatment in patients who did not reach clinical remission. Median overall survival (OS) was 3.3 months, and one-year OS 22%. One patient developed an ATRA-induced differentiation syndrome. The most frequently reported adverse events were vertigo and hypotension. TCP plasma levels correlated with intracellular TCP concentration. Increased H3K4me1 and H3k4me2 levels were observed in AML blasts and white blood cells from some TCP/ATRA treated patients. Combined TCP/ATRA treatment can induce differentiation of AML blasts and lead to clinical response in heavily pretreated patients with r/r AML with acceptable toxicity. These findings emphasize the potential of LSD1 inhibition combined with ATRA for AML treatment.

Does time from diagnosis to treatment affect the prognosis of patients with newly diagnosed acute myeloid leukemia?

In fit patients with newly diagnosed acute myeloid leukemia (AML), immediate treatment start is recommended due to the poor prognosis of untreated acute leukemia. We explored the relationship between time from diagnosis to treatment start (TDT) and prognosis in a large real-world data set from the German Study Alliance Leukemia-Acute Myeloid Leukemia (SAL-AML) registry. All registered non-acute promyelocytic leukemia patients with intensive induction treatment and a minimum 12 months of follow-up were selected (n = 2263). We analyzed influence of TDT on remission, early death, and overall survival (OS) in univariable analyses for each day of treatment delay, in groups of 0 to 5, 6 to 10, 11 to 15, and >15 days of TDT, adjusted for influence of established prognostic variables on outcomes. Median TDT was 3 days (interquartile range, 2-7). Unadjusted 2-year OS rates, stratified by TDT of 0 to 5, 6 to 10, 11 to 15, and >15 days, were 51%, 48%, 44%, and 50% (P = .211). In multivariable Cox regression analysis accounting for established prognostic variables, the TDT hazard ratio as a continuous variable was 1.00 (P = .617). In OS analyses, separately stratified for age ≤60 and >60 years and for high vs lower initial white blood cell count, no significant differences between TDT groups were observed. Our study suggests that TDT is not related to survival. As stratification in intensive first-line AML treatment evolves, TDT data suggest that it may be a feasible approach to wait for genetic and other laboratory test results so that clinically stable patients are assigned the best available treatment option. This trial was registered at www.clinicaltrials.gov as #NCT03188874.

Chronic active Epstein-Barr virus infection of T-cell type, systemic form in an African migrant: case report and review of the literature on diagnostics standards and therapeutic options.

BACKGROUND: Chronic active Epstein-Barr virus (EBV) infection (CAEBV) of the T-/NK-cell type, systemic form is a rare and potentially life-threatening illness caused by persistent EBV infection. The highest incidence is found in children and adolescents with increased frequency among Asians and Native Americans, while the disease is uncommon in Western countries. Typically patients present with unspecific symptoms, like fever, lymphadenopathy, hepatosplenomegaly and liver dysfunction. Due to fatal complications including hemophagocytic syndrome, coagulopathy, multiple organ failure and development of EBV-positive lymphoproliferative disease (LPD) or lymphoma early diagnosis is critical for successful treatment. However, in consequence of the lack of experience due to the low incidence in Europe, a broad spectrum of clinical manifestations and a particularly unexpected group of patients, diagnosis can be challenging. Inhere we describe the clinicopathological findings of an African adult with CAEBV associated LPD with a brief review of the literature. CASE PRESENTATION: A 42-year-old African man with fever, enlargement of the spleen and a suspected epileptic seizure was referred to our hospital. Diagnostic testing repeatedly revealed a massive EBV-DNA load in peripheral blood. Whole-body PET-CT-scan presented a strong uptake at multiple bone marrow sites, the thyroid and the adrenal glands. Histopathological analysis of bone marrow and thyroid gland revealed a highly proliferating, atypical and predominantly intravascular cytotoxic T-cell population with intracellular EBV-encoded RNA. Clonality analysis revealed the presence of polyclonal T-cell-receptor. Based on these findings a CAEBV of the T-/NK-cell type, systemic form was diagnosed. Subsequent therapy including three cycles of chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisolone resulted in decreased EBV load, clinical improvement and ongoing complete remission. CONCLUSION: Adult-onset CAEBV of T/NK-cell type usually comprises a poor prognosis and is extremely rare in Western countries. Therefore, our case highlights the need for a clinical awareness of this disease in patients with systemic illness and for a comprehensive multidisciplinary diagnostic approach to facilitate diagnosis. Treatment options include antiviral drugs, immunosuppressive agents and systemic chemotherapy with or without allogeneic stem cell transplantation. Given the limited data these options need to be decided upon in each patient individually considering severity of the disease, comorbidities and response.

Value of Different Comorbidity Indices for Predicting Outcome in Patients with Acute Myeloid Leukemia.

Age is a dominant predictor of outcome in acute myeloid leukemia (AML). However, it is not clear to which extent comorbidities contribute to this effect. The objective of this study was to determine the impact of pretreatment comorbidities on survival of AML patients. In a single-center retrospective study 194 adult AML patients were included. The Hematopoietic cell transplantation comorbidity index (HCT-CI), the Adult Comorbidity Evaluation-27 (ACE-27) score and the Cumulative Illness Rating Scale for Geriatrics (CIRS-G) as well as data on demographics, cytogenetics, treatment and outcome were evaluated at the time of initial diagnosis by univariate and multivariate analysis. The study included 102 male and 92 female (median age 60.9 years) of which 173 (89.2%) received intensive chemotherapy. Median overall survival (OS) was 17 months. In univariate analysis, cardiovascular disease (26 vs 12 months, p = .005), severe hepatic disease (19 vs 4 months, p = .013) and renal impairment (17 vs 7 months, p = .016) was associated with inferior OS. For each index, the highest comorbidity burden was associated with reduced OS. However, in multivariate analysis only the ACE-27 score was associated with outcome. Besides ECOG ≥ 2 and poor cytogenetics only the ACE-27 score but not higher age was associated with OS in the group of patients receiving intensive therapy. Adjusted hazard ratios were 3.1, 3.5 and 4.0 for mild, moderate and severe ACE-27-assessed comorbidities, respectively (p = .012). Our study confirms that comorbidities significantly impact survival of AML patients and a pretreatment assessment of comorbidities may help to identify patients with poor outcome.