Gemtuzumab ozogamicin plus midostaurin in combination with standard '7 + 3' induction therapy in newly diagnosed AML: Results from the SAL-MODULE phase I study.

We conducted a phase I trial in newly diagnosed acute myeloid leukaemia (AML) to investigate the combination of two novel targeted agents, gemtuzumab ozogamicin (GO) and midostaurin, with intensive chemotherapy in FLT3-mutated AML and CBF leukaemia. Three dose levels of midostaurin and one to three sequential doses of 3 mg/m2 GO in combination with '7 + 3' induction were evaluated. Based on safety findings in 12 patients, our results show that 3 mg/m2 GO on Days 1 + 4 and 100 mg midostaurin on Days 8-21 can be safely combined with IC in newly diagnosed AML.

Remission induction versus immediate allogeneic haematopoietic stem cell transplantation for patients with relapsed or poor responsive acute myeloid leukaemia (ASAP): a randomised, open-label, phase 3, non-inferiority trial.

BACKGROUND: Whether high-dose cytarabine-based salvage chemotherapy, administered to induce complete remission in patients with poor responsive or relapsed acute myeloid leukaemia scheduled for allogeneic haematopoietic stem-cell transplantation (HSCT) after intensive conditioning confers a survival advantage, is unclear. METHODS: To test salvage chemotherapy before allogeneic HSCT, patients aged between 18 and 75 years with non-favourable-risk acute myeloid leukaemia not in complete remission after first induction or untreated first relapse were randomly assigned 1:1 to remission induction with high-dose cytarabine (3 g/m2 intravenously, 1 g/m2 intravenously for patients >60 years or with a substantial comorbidity) twice daily on days 1-3 plus mitoxantrone (10 mg/m2 intravenously) on days 3-5 or immediate allogeneic HSCT for the disease control group. Block randomisation with variable block lengths was used and patients were stratified by age, acute myeloid leukaemia risk, and disease status. The study was open label. The primary endpoint was treatment success, defined as complete remission on day 56 after allogeneic HSCT, with the aim to show non-inferiority for disease control compared with remission induction with a non-inferiority-margin of 5% and one-sided type 1 error of 2·5%. The primary endpoint was analysed in both the intention-to-treat (ITT) population and in the per-protocol population. The trial is completed and was registered at ClinicalTrials.gov, NCT02461537. FINDINGS: 281 patients were enrolled between Sept 17, 2015, and Jan 12, 2022. Of 140 patients randomly assigned to disease control, 135 (96%) proceeded to allogeneic HSCT, 97 (69%) after watchful waiting only. Of 141 patients randomly assigned to remission induction, 134 (95%) received salvage chemotherapy and 128 (91%) patients subsequently proceeded to allogeneic HSCT. In the ITT population, treatment success was observed in 116 (83%) of 140 patients in the disease control group versus 112 (79%) of 141 patients with remission induction (test for non-inferiority, p=0·036). Among per-protocol treated patients, treatment success was observed in 116 (84%) of 138 patients with disease control versus 109 (81%) of 134 patients in the remission induction group (test for non-inferiority, p=0·047). The difference in treatment success between disease control and remission induction was estimated as 3·4% (95% CI -5·8 to 12·6) for the ITT population and 2·7% (-6·3 to 11·8) for the per-protocol population. Fewer patients with disease control compared with remission induction had non-haematological adverse events grade 3 or worse (30 [21%] of 140 patients vs 86 [61%] of 141 patients, χ2 test p<0·0001). Between randomisation and the start of conditioning, with disease control two patients died from progressive acute myeloid leukaemia and zero from treatment-related complications, and with remission induction two patients died from progressive acute myeloid leukaemia and two from treatment-related complications. Between randomisation and allogeneic HSCT, patients with disease control spent a median of 27 days less in hospital than those with remission induction, ie, the median time in hospital was 15 days (range 7-64) versus 42 days (27-121, U test p<0·0001), respectively. INTERPRETATION: Non-inferiority of disease control could not be shown at the 2·5% significance level. The rate of treatment success was also not statistically better for patients with remission induction. Watchful waiting and immediate transplantation could be an alternative for fit patients with poor response or relapsed acute myeloid leukaemia who have a stem cell donor available. More randomised controlled intention-to-transplant trials are needed to define the optimal treatment before transplantation for patients with active acute myeloid leukaemia. FUNDING: DKMS and the Gert and Susanna Mayer Stiftung Foundation.

Time from diagnosis to treatment has no impact on survival in newly diagnosed acute myeloid leukemia treated with venetoclax-based regimens.

In newly diagnosed acute myeloid leukemia, immediate initiation of treatment is standard of care. However, deferral of antileukemic therapy may be indicated to assess comorbidities or pre-therapeutic risk factors. We explored the impact of time from diagnosis to treatment on outcomes in newly diagnosed acute myeloid leukemia undergoing venetoclax-based therapy in two distinct cohorts. By querying the Study Alliance Leukemia database and the global health network TriNetX, we identified 138 and 717 patients respectively with an average age of 76 and 72 years who received venetoclax-based firstline therapy. When comparing patients who started treatment earlier or later than 10 days after initial diagnosis, no significant difference in median overall survival was observed - neither in the SAL cohort (7.7 vs. 9.6 months, p=.42) nor in the TriNetX cohort (7.5 vs. 7.2 months, p=.41). Similarly, severe infections, bleeding, and thromboembolic events were equally observed between early and later treatments, both in the overall patient groups and specific subgroups (age ≥75 years or leukocytes ≥20x109/L). This retrospective analysis indicates that delaying the start of venetoclax-based therapy in newly diagnosed acute myeloid leukemia might be a safe option for selected patients, provided that close clinical monitoring is performed.

Mimicking clinical trials with synthetic acute myeloid leukemia patients using generative artificial intelligence.

Clinical research relies on high-quality patient data, however, obtaining big data sets is costly and access to existing data is often hindered by privacy and regulatory concerns. Synthetic data generation holds the promise of effectively bypassing these boundaries allowing for simplified data accessibility and the prospect of synthetic control cohorts. We employed two different methodologies of generative artificial intelligence - CTAB-GAN+ and normalizing flows (NFlow) - to synthesize patient data derived from 1606 patients with acute myeloid leukemia, a heterogeneous hematological malignancy, that were treated within four multicenter clinical trials. Both generative models accurately captured distributions of demographic, laboratory, molecular and cytogenetic variables, as well as patient outcomes yielding high performance scores regarding fidelity and usability of both synthetic cohorts (n = 1606 each). Survival analysis demonstrated close resemblance of survival curves between original and synthetic cohorts. Inter-variable relationships were preserved in univariable outcome analysis enabling explorative analysis in our synthetic data. Additionally, training sample privacy is safeguarded mitigating possible patient re-identification, which we quantified using Hamming distances. We provide not only a proof-of-concept for synthetic data generation in multimodal clinical data for rare diseases, but also full public access to synthetic data sets to foster further research.

Prognostic impact of CEBPA mutational subgroups in adult AML.

Despite recent refinements in the diagnostic and prognostic assessment of CEBPA mutations in AML, several questions remain open, i.e. implications of different types of basic region leucin zipper (bZIP) mutations, the role of co-mutations and the allelic state. Using pooled primary data analysis on 1010 CEBPA-mutant adult AML patients, a comparison was performed taking into account the type of mutation (bZIP: either typical in-frame insertion/deletion (InDel) mutations (bZIPInDel), frameshift InDel or nonsense mutations inducing translational stop (bZIPSTOP) or single base-pair missense alterations (bZIPms), and transcription activation domain (TAD) mutations) and the allelic state (single (smCEBPA) vs. double mutant (dmCEBPA)). Only bZIPInDel patients had significantly higher rates of complete remission and longer relapse free and overall survival (OS) compared with all other CEBPA-mutant subgroups. Moreover, co-mutations in bZIPInDel patients (e.g. GATA2, FLT3, WT1 as well as ELN2022 adverse risk aberrations) had no independent impact on OS, whereas in non-bZIPInDel patients, grouping according to ELN2022 recommendations added significant prognostic information. In conclusion, these results demonstrate bZIPInDel mutations to be the major independent determinant of outcome in CEBPA-mutant AML, thereby refining current classifications according to WHO (including all dmCEBPA and smCEBPA bZIP) as well as ELN2022 and ICC recommendations (including CEBPA bZIPms).

Improving long-term outcomes with intensive induction chemotherapy for patients with AML.

Intensive chemotherapy in combination with allogeneic hematopoietic cell transplantation and supportive care can induce long-term remissions in around 50% of acute myeloid leukemia patients eligible for intensive treatment. Several treatment optimization trials helped to refine schedule and dosing of the historic "7 + 3" combination. Together with the addition of novel agents, increased efficacy and tolerability led to improved long-term outcomes. Unsatisfactory outcomes in fit elderly patients and unfavorable genetic subgroups have raised the question of whether less-intensive venetoclax-based approaches may be beneficial as an alternative. Although tempting and worth exploring, this issue will remain controversial until the results of randomized comparisons appear. To date, intensive chemotherapy remains the only evident curative treatment option for long-term disease eradication in a fixed treatment time. With the advent of more novel agents and advances in minimal residual disease (MRD) detection and maintenance approaches, the face of intensive treatment could change in many ways. Several are being explored in clinical trials, such as (1) combinations of more than 1 novel agent with the intensive backbone, (2) head-to-head comparisons of novel agents, (3) replacement or dose reduction of cytotoxic components such as anthracyclines, and (4) MRD-guided escalation and de-escalation strategies. The combination of intensive treatment with individualized tailored innovative strategies will most certainly reduce treatment-related toxicities and increase the chances for long-term remission in the future.

Steady-state versus chemotherapy-based hematopoietic cell mobilization after anti-CD38-based induction therapy in newly diagnosed multiple myeloma.

BACKGROUND: The incorporation of anti-CD38 monoclonal antibodies (mAb) in induction regimens of newly diagnosed transplant-eligible multiple myeloma (MM) patients has been established as a new standard. However, the optimal strategy of stem cell mobilization in this context is not yet clear. STUDY DESIGN AND METHODS: From May 2020 till September 2022, we retrospectively reviewed patients receiving anti-CD38 mAb-based induction therapy followed by stem cell mobilization either in a steady-state protocol (SSM) using 10 µg/kg granulocyte colony-stimulating factor (G-CSF) for 5 days or in a chemotherapy-based protocol (CM) using 1-4 g/m2 cyclophosphamide and G-CSF. RESULTS: Overall, 85 patients (median age 61 years) were included in the analysis. In total, 90 mobilization attempts were performed, 42 with SSM and 48 with CM. There was no significant difference in the median concentration of CD34+ cells in peripheral blood (PB) prior to apheresis between SSM and CM (61/µL vs. 55.4/µL; p = .60). Cumulative CD34+ yields did not differ between the groups with median of 6.68 and 6.75 × 106 /kg body weight, respectively (p = .35). The target yield (≥4 × 106 CD34+ cells/kg body weight) was reached in 88% (CM) and 86% (SSM), with a high proportion even after a single apheresis session (76% vs. 75%). Plerixafor was found to be more frequently used in SSM (52%) than in CM (23%; p < .01). A total of 83 patients underwent autologous transplantation and all were engrafted. CONCLUSIONS: Stem cell collection in patients undergoing anti-CD38-based induction therapy is feasible with either CM or SSM, although SSM more frequently requires plerixafor.

Ex vivo drug response profiling for response and outcome prediction in hematologic malignancies: the prospective non-interventional SMARTrial.

Ex vivo drug response profiling is a powerful tool to study genotype-drug response associations and is being explored as a tool set for precision medicine in cancer. Here we conducted a prospective non-interventional trial to investigate feasibility of ex vivo drug response profiling for treatment guidance in hematologic malignancies (SMARTrial, NCT03488641 ). The primary endpoint to provide drug response profiling reports within 7 d was met in 91% of all study participants (N = 80). Secondary endpoint analysis revealed that ex vivo resistance to chemotherapeutic drugs predicted chemotherapy treatment failure in vivo. We confirmed the predictive value of ex vivo response to chemotherapy in a validation cohort of 95 individuals with acute myeloid leukemia treated with daunorubicin and cytarabine. Ex vivo drug response profiles improved ELN-22 risk stratification in individuals with adverse risk. We conclude that ex vivo drug response profiling is clinically feasible and has the potential to predict chemotherapy response in individuals with hematologic malignancies beyond clinically established genetic markers.

Mutated IKZF1 is an independent marker of adverse risk in acute myeloid leukemia.

Genetic lesions of IKZF1 are frequent events and well-established markers of adverse risk in acute lymphoblastic leukemia. However, their function in the pathophysiology and impact on patient outcome in acute myeloid leukemia (AML) remains elusive. In a multicenter cohort of 1606 newly diagnosed and intensively treated adult AML patients, we found IKZF1 alterations in 45 cases with a mutational hotspot at N159S. AML with mutated IKZF1 was associated with alterations in RUNX1, GATA2, KRAS, KIT, SF3B1, and ETV6, while alterations of NPM1, TET2, FLT3-ITD, and normal karyotypes were less frequent. The clinical phenotype of IKZF1-mutated AML was dominated by anemia and thrombocytopenia. In both univariable and multivariable analyses adjusting for age, de novo and secondary AML, and ELN2022 risk categories, we found mutated IKZF1 to be an independent marker of adverse risk regarding complete remission rate, event-free, relapse-free, and overall survival. The deleterious effects of mutated IKZF1 also prevailed in patients who underwent allogeneic hematopoietic stem cell transplantation (n = 519) in both univariable and multivariable models. These dismal outcomes are only partially explained by the hotspot mutation N159S. Our findings suggest a role for IKZF1 mutation status in AML risk modeling.

Germ line variant GFI1-36N affects DNA repair and sensitizes AML cells to DNA damage and repair therapy.

ABSTRACT: Growth factor independence 1 (GFI1) is a DNA-binding transcription factor and a key regulator of hematopoiesis. GFI1-36N is a germ line variant, causing a change of serine (S) to asparagine (N) at position 36. We previously reported that the GFI1-36N allele has a prevalence of 10% to 15% among patients with acute myeloid leukemia (AML) and 5% to 7% among healthy Caucasians and promotes the development of this disease. Using a multiomics approach, we show here that GFI1-36N expression is associated with increased frequencies of chromosomal aberrations, mutational burden, and mutational signatures in both murine and human AML and impedes homologous recombination (HR)-directed DNA repair in leukemic cells. GFI1-36N exhibits impaired binding to N-Myc downstream-regulated gene 1 (Ndrg1) regulatory elements, causing decreased NDRG1 levels, which leads to a reduction of O6-methylguanine-DNA-methyltransferase (MGMT) expression levels, as illustrated by both transcriptome and proteome analyses. Targeting MGMT via temozolomide, a DNA alkylating drug, and HR via olaparib, a poly-ADP ribose polymerase 1 inhibitor, caused synthetic lethality in human and murine AML samples expressing GFI1-36N, whereas the effects were insignificant in nonmalignant GFI1-36S or GFI1-36N cells. In addition, mice that received transplantation with GFI1-36N leukemic cells treated with a combination of temozolomide and olaparib had significantly longer AML-free survival than mice that received transplantation with GFI1-36S leukemic cells. This suggests that reduced MGMT expression leaves GFI1-36N leukemic cells particularly vulnerable to DNA damage initiating chemotherapeutics. Our data provide critical insights into novel options to treat patients with AML carrying the GFI1-36N variant.

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.

Unsupervised meta-clustering identifies risk clusters in acute myeloid leukemia based on clinical and genetic profiles.

BACKGROUND: Increasingly large and complex biomedical data sets challenge conventional hypothesis-driven analytical approaches, however, data-driven unsupervised learning can detect inherent patterns in such data sets. METHODS: While unsupervised analysis in the medical literature commonly only utilizes a single clustering algorithm for a given data set, we developed a large-scale model with 605 different combinations of target dimensionalities as well as transformation and clustering algorithms and subsequent meta-clustering of individual results. With this model, we investigated a large cohort of 1383 patients from 59 centers in Germany with newly diagnosed acute myeloid leukemia for whom 212 clinical, laboratory, cytogenetic and molecular genetic parameters were available. RESULTS: Unsupervised learning identifies four distinct patient clusters, and statistical analysis shows significant differences in rate of complete remissions, event-free, relapse-free and overall survival between the four clusters. In comparison to the standard-of-care hypothesis-driven European Leukemia Net (ELN2017) risk stratification model, we find all three ELN2017 risk categories being represented in all four clusters in varying proportions indicating unappreciated complexity of AML biology in current established risk stratification models. Further, by using assigned clusters as labels we subsequently train a supervised model to validate cluster assignments on a large external multicenter cohort of 664 intensively treated AML patients. CONCLUSIONS: Dynamic data-driven models are likely more suitable for risk stratification in the context of increasingly complex medical data than rigid hypothesis-driven models to allow for a more personalized treatment allocation and gain novel insights into disease biology.

There are various ways in which clinicians can predict the risk of disease progression in patients with leukemia, helping them to treat the patients accordingly. However, these approaches are usually designed by human experts and might not fully capture the complexity of a patient's disease. Here, with a large cohort of patients with acute myeloid leukemia, we design an unsupervised machine learning model ­ a type of computer model that learns from patterns in data without human input­to separate these patients into subgroups according to risk. We identify four distinct groups which differ with regards to patient genetics, laboratory values, and clinical characteristics. These groups have differences in response to treatment and patient survival, and we validate our findings in another dataset. Our approach might help clinicians to better predict outcomes in patients with leukemia and make decisions on treatment.

UBTF tandem duplications are rare but recurrent alterations in adult AML and associated with younger age, myelodysplasia, and inferior outcome.

Tandem-duplication mutations of the UBTF gene (UBTF-TDs) coding for the upstream binding transcription factor have recently been described in pediatric patients with acute myeloid leukemia (AML) and were found to be associated with particular genetics (trisomy 8 (+8), FLT3-internal tandem duplications (FLT3-ITD), WT1-mutations) and inferior outcome. Due to limited knowledge on UBTF-TDs in adult AML, we screened 4247 newly diagnosed adult AML and higher-risk myelodysplastic syndrome (MDS) patients using high-resolution fragment analysis. UBTF-TDs were overall rare (n = 52/4247; 1.2%), but significantly enriched in younger patients (median age 41 years) and associated with MDS-related morphology as well as significantly lower hemoglobin and platelet levels. Patients with UBTF-TDs had significantly higher rates of +8 (34% vs. 9%), WT1 (52% vs. 7%) and FLT3-ITD (50% vs. 20.8%) co-mutations, whereas UBTF-TDs were mutually exclusive with several class-defining lesions such as mutant NPM1, in-frame CEBPAbZIP mutations as well as t(8;21). Based on the high-variant allele frequency found and the fact that all relapsed patients analyzed (n = 5) retained the UBTF-TD mutation, UBTF-TDs represent early clonal events and are stable over the disease course. In univariate analysis, UBTF-TDs did not represent a significant factor for overall or relapse-free survival in the entire cohort. However, in patients under 50 years of age, who represent the majority of UBTF-mutant patients, UBTF-TDs were an independent prognostic factor for inferior event-free (EFS), relapse-free (RFS) and overall survival (OS), which was confirmed by multivariable analyses including established risk factors such as age and ELN2022 genetic risk groups (EFS [HR: 2.20; 95% CI 1.52-3.17, p < 0.001], RFS [HR: 1.59; 95% CI 1.02-2.46, p = 0.039] and OS [HR: 1.64; 95% CI 1.08-2.49, p = 0.020]). In summary, UBTF-TDs appear to represent a novel class-defining lesion not only in pediatric AML but also younger adults and are associated with myelodysplasia and inferior outcome in these patients.

Management of Pathological Thoracolumbar Vertebral Fractures in Patients With Multiple Myeloma: Multidisciplinary Recommendations.

STUDY DESIGN: Mutlidisciplinary consensus recommendations for patients suffering from multiple myeloma (MM) involvement of the spinal column by the Spine Section of the German Association of Orthopaedic and Trauma Surgeons. OBJECTIVE: To provide a comprehensive multidisciplinary diagnostic and therapeutic approach and to summarize the current literature on the management of pathological thoracolumbar vertebral fractures in patients with multiple myeloma. METHODS: Multidisciplinary recommendations using a classical consensus process provided by radiation oncologists, medical oncologists, orthopaedic- and trauma surgeons. A narrative literature review of the current diagnostic and treatment strategies was conducted. RESULTS: Treatment decision has to be driven by a multidisciplinary team of oncologists, radiotherapists and spine surgeons. When considering surgery in MM patients, differing factors compared to other secondary spinal lesions have to be included into the decision process: probable neurological deterioration, the stage of the disease and prognosis, patient's general condition, localization and number of the lesions as well as patient's own wishes or expectations. Aiming to improve quality of life, the major goal of surgical treatment is to preserve mobility by reducing pain, secure neurological function and stability. CONCLUSION: The goal of surgery is primarily to improve quality of life by restoring stability and neurological function. Interventions with an increased risk of complications due to MM-associated immunodeficiency must be avoided whenever feasible to allow early systemic treatment. Hence, treatment decisions should be based on a multidisciplinary team that considers patient's constitution and prognosis.

A phase 1b study of venetoclax and alvocidib in patients with relapsed/refractory acute myeloid leukemia.

Relapsed/refractory (R/R) Acute Myeloid Leukemia (AML) is a genetically complex and heterogeneous disease with a poor prognosis and limited treatment options. Thus, there is an urgent need to develop therapeutic combinations to overcome drug resistance in AML. This open-label, multicenter, international, phase 1b study evaluated the safety, efficacy, and pharmacokinetics of venetoclax in combination with alvocidib in patients with R/R AML. Patients were treated with escalating doses of venetoclax (400, 600, and 800 mg QD, orally, days 1-28) and alvocidib (45 and 60 mg/m2 , intravenously, days 1-3) in 28-day cycles. The combination was found to be safe and tolerable, with no maximum tolerated dose reached. Drug-related Grade ≥3 adverse events were reported in 23 (65.7%) for venetoclax and 24 (68.6%) for alvocidib. No drug-related AEs were fatal. Gastrointestinal toxicities, including diarrhea, nausea, and vomiting were notable and frequent; otherwise, the toxicities reported were consistent with the safety profile of both agents. The response rate was modest (complete remission [CR] + incomplete CR [CRi], 11.4%; CR + CRi + partial response rate + morphologic leukemia-free state, 20%). There was no change in alvocidib pharmacokinetics with increasing doses of venetoclax. However, when venetoclax was administered with alvocidib, AUC24 and Cmax decreased by 18% and 19%, respectively. A recommended phase 2 dose was not established due to lack of meaningful increase in efficacy across all cohorts compared to what was previously observed with each agent alone. Future studies could consider the role of the sequence, dosing, and the use of a more selective MCL1 inhibitor for the R/R AML population.

Combinatorial BCL2 Family Expression in Acute Myeloid Leukemia Stem Cells Predicts Clinical Response to Azacitidine/Venetoclax.

The BCL2 inhibitor venetoclax (VEN) in combination with azacitidine (5-AZA) is currently transforming acute myeloid leukemia (AML) therapy. However, there is a lack of clinically relevant biomarkers that predict response to 5-AZA/VEN. Here, we integrated transcriptomic, proteomic, functional, and clinical data to identify predictors of 5-AZA/VEN response. Although cultured monocytic AML cells displayed upfront resistance, monocytic differentiation was not clinically predictive in our patient cohort. We identified leukemic stem cells (LSC) as primary targets of 5-AZA/VEN whose elimination determined the therapy outcome. LSCs of 5-AZA/VEN-refractory patients displayed perturbed apoptotic dependencies. We developed and validated a flow cytometry-based "Mediators of apoptosis combinatorial score" (MAC-Score) linking the ratio of protein expression of BCL2, BCL-xL, and MCL1 in LSCs. MAC scoring predicts initial response with a positive predictive value of more than 97% associated with increased event-free survival. In summary, combinatorial levels of BCL2 family members in AML-LSCs are a key denominator of response, and MAC scoring reliably predicts patient response to 5-AZA/VEN. SIGNIFICANCE: Venetoclax/azacitidine treatment has become an alternative to standard chemotherapy for patients with AML. However, prediction of response to treatment is hampered by the lack of clinically useful biomarkers. Here, we present easy-to-implement MAC scoring in LSCs as a novel strategy to predict treatment response and facilitate clinical decision-making. This article is highlighted in the In This Issue feature, p. 1275.