Intensive Chemotherapy Regimens Research Articles

Extra-abdominal and intra-abdominal FET::CREM fusion mesenchymal neoplasms: comparative clinicopathological study of 9 new cases further supporting a distinct potentially aggressive sarcoma and report of novel sites.

With the wide use of RNA sequencing technologies, the family of FET::CREB fusion mesenchymal neoplasms has expanded rapidly to include potentially aggressive neoplasms, not fitting any well established WHO entity. Recently, a group of intra-abdominal FET(EWSR1/FUS)::CREB(CREM/ATF1) fused unclassified neoplasms has been reported followed by recent recognition of an analogous extra-abdominal category of unclassified neoplasms carrying EWSR1::ATF1 fusions. We describe 9 additional tumors (5 extra-abdominal and 4 abdominal) carrying an EWSR1::CREM (n = 8) and FUS::CREM (n = 1) fusion. Patients were 7 females and 2 males aged 10 to 75years (median, 34). Extra-abdominal tumors originated in the head and neck (2 sinonasal, 1 orbital) and soft tissues (1 gluteal, 1 inguinal). Abdominal tumors involved stomach (2), mesentery (1), and kidney (1). Tumor size ranged from 3.5 to 11cm (median, 6). Treatment was radical surgery with (5) or without (2) neo/adjuvant radio/chemotherapy. Extended follow-up of 5 patients (21-52months; median, 24) showed an aggressive course in two (40%); one died of disseminated metastases 52months after several intensified chemotherapy regimens, and one was alive with progressive abdominal disease at 21months. The immunophenotype of the two subcohorts was significantly overlapping with variable expression of EMA (7 of 8), keratin AE1/AE3 (5 of 9), CD99 (4 of 7), MUC4 (2 of 8), ALK (3 of 8), synaptophysin (3 of 9), chromogranin (1 of 8), CD34 (3 of 6), CD30 (1 of 6), PAX8 (1 of 7), and inhibin (1 of 7), but no reactivity with desmin (0 of 8), S100 (0 of 8), and SOX10 (0 of 8). This series further solidifies the notion that FET::CREB fusions are not limited to the triad of angiomatoid fibrous histiocytoma, clear cell sarcoma, and malignant gastrointestinal neuroectodermal tumor, but characterize an emerging family of potentially aggressive neoplasms occurring at both intra- and extra-abdominal sites. These tumors underscore the promiscuity of the FET::CREB fusions and highlight the pivotal role of phenotype-oriented classification of these neoplasms that share the same genotype, still featuring significant biological and behavioral distinctness.

BIRC5 upregulation enhances DNMT3A-mutant T-ALL cell survival and pathogenesis

AbstractT-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic neoplasm. Although the prognosis of pediatric T-ALL has improved with intensified chemotherapy regimens, this benefit has largely not translated to the adult T-ALL population. Development of new treatments requires understanding the mechanisms driven by specific mutations. DNMT3A mutations are identified in ∼10% to 18% of adult patients with T-ALL and are associated with poor clinical outcomes. Here, using primary human specimens, we show that cells from patients with T-ALL with DNMT3A mutations are resistant to apoptosis and certain chemotherapies. Elevated JAK/STAT signaling drove prosurvival programs in patients with mutant DNMT3A, and JAK/STAT inhibition restored sensitivity to chemotherapy. The prosurvival gene BIRC5 was upregulated in patients with DNMT3A-mutant T-ALL, and these cells were specifically sensitive to the BIRC5 inhibitor YM155. Genetic inhibition of BIRC5 in vivo lead to rapid depletion of DNMT3A-mutant T-ALL cells in patient-derived xenografts, positioning BIRC5 as a precision medicine target for these patients.

Prognostic factors and outcome of relapsed/progressive pediatric Ewing sarcoma: single-center 10-year experience

BackgroundEwing sarcoma (ES) is the second most common primary malignant bone tumor in children and adolescents. Despite more intensive chemotherapy regimens and improved local control therapy, there is still a considerable rate of recurrent/progressive disease.MethodsA retrospective study of 50 relapsed/progressive ES patients who were treated at the National Cancer Institute (NCI), Cairo University, during the period from 1st of January 2008 to the end of December 2018, to assess different prognostic variables and disease outcomes.ResultsOut of fifty eligible cases, 32 patients (64%) had disease recurrence, and 18 (36%) developed disease progression on treatment. The median follow-up period was 7.4 months. The median overall survival (OS) was 7.5 months, and the cumulative OS was 64% at 6 months and 32.6% at 1 year. The cumulative event-free survival (EFS) was 41.3% at 6 months and 22.3% at 1 year. Patients with disease recurrence had better OS and EFS than patients with disease progression (p = 0.019). Patients who underwent local control at relapse/progression had a significantly better outcome than patients who received chemotherapy only (p < 0.001). Recurrence > 2 years from initial diagnosis was the only independent predictor of better survival outcome.ConclusionsPatients with relapsing/progressive ES portended a poor outcome, with disease progression on treatment faring worse than relapse. Better outcome was observed in patients who experienced recurrence > 2 years after diagnosis, patients with disease recurrence rather than disease progression on treatment, and patients who underwent local control along with intensive chemotherapy.

Intensive pediatric chemotherapy regimen (PNET HR+5) in adult high-risk medulloblastoma and pinealoblastoma patients

Abstract Background High-risk medulloblastoma (HRMB) is rare in adults. The 5-year overall survival rate is less than 60%. We present here a retrospective analysis of adults treated with an intensive pediatric chemo-radiotherapy regimen PNET HR+5: NCT00936156. Methods 18 patients over the age of 20 (range, 20-33 years) with HRMB (n = 13), pinealoblastoma (n = 4) and central nervous system embryonal tumor (n = 1) were treated with 2 courses of carboplatin-etoposide followed by 2 courses of high-dose thiotepa (HDT) with autologous hematopoietic stem-cell rescue. A craniospinal irradiation (CSI) (36 Gy craniospinal axis then a boost of 18 Gy to the primary tumor site) was then initiated within 150 days of surgery, completed with 6 cycles of temozolomide; the axis irradiation was not mandatory for non-metastatic pinealoblastoma. Results We observed no progression under chemotherapy and no toxic death. Four patients received only 1 HDT. Two non-metastatic pinealoblastoma received only focal irradiation. One medulloblastoma received only 25 Gy on axis. 56% (10/18) received 6 cycles of temozolomide. No long-term toxicity was recorded. Median time between surgery and CSI was 175 days (range, 115-250). With a median follow-up of 6.0 years (range, 2.6-9), the progression-free survival and overall survival rates for medulloblastoma were respectively 65% (95% CI: 31-86%) and 76% (95% CI: 42-91%) at 5 years. Conclusions The PNET HR+5 regimen showed promising results in an adult population, with a meaningful improvement in progression-free survival and overall survival in patients with HRMB.

The clinical implications of BCOR mutations in a large cohort of acute myeloid leukemia patients: a 5-year single-center retrospective study

To elucidate the effect of BCOR mutation (BCOR mut) on clinical outcomes, we included a total of 899 consecutive AML patients in a single-center during July 2016 to December 2021. Fifty cases (5.6%) had BCOR mutations, which co-occurred with mutations of RUNX1, DNMT3A, IDH2, BCORL1, STAG2, SF3B1 and U2AF1, but were exclusive with KIT and CEBPA mutations. BCOR mut was also found to be exclusive with t(8;21)(q22;q22.1) AML in all patients and MLL rearrangements in the European Leukemia Net (ELN) adverse group. In those receiving intensive chemotherapy regimens, BCOR mut was associated with lower complete remission (CR) rates and worse prognosis. Subgroup analysis showed that BCOR mut mainly conferred a poor prognosis in the intermediate and adverse groups of the ELN2017 risk. These results suggest that BCOR mutation is an independent prognostic parameter in AML, implying BCOR mutation as a novel marker for chemorefractory disease and inferior prognosis.

Outcomes of children with clear cell sarcoma of kidney following NWTS strategies in Shanghai China (2003-2021).

Although clear cell sarcoma of kidney (CCSK) is rare, it is the second most common renal tumor in children after Wilms' tumor. NWTS and SIOP are two major groups which had made tremendous efforts on renal tumors, but the strategies are different, for NWTS follows the upfront surgery principle providing definite pathology and the SIOP follows the upfront chemotherapy principle, each has its own advantages. Here we aimed to evaluate the outcomes of CCSK in China following NWTS strategies to analyze the prognostic factors. For this multicenter retrospective study, a total of 54 patients were enrolled from three children's hospitals, between April 2003 and December 2021. Treatment comprised upfront radical nephrectomy, followed by radiotherapy and intensive chemotherapy. Clinical records were regularly updated. Prognostic factors and survival rates were evaluated. The 54 enrolled patients had a median age of 37 months (range, 4 months to 11.4 years). The stage distribution was 16% stage I (n = 9), 30% stage II (n = 16), 39% stage III (n = 21), and 15% stage IV (n = 8). Among stage IV, metastasis sites included the lung (n = 6), bone (n = 1), and intra-orbital/cervical lymph node (n = 1). After a median follow-up of 5.6 years, the 5-year event-free survival (EFS) was 82.4±5.4%, and overall survival was 88.1±4.6%. The EFS was 100% for stage I, 93.8 ±6.1% for stage II, 71.1±10.0% for stage III, and 68.6±18.6% for stage IV. Univariate analysis revealed that staging (III/IV), tumor rupture, and inferior vena cava tumor thrombus were inferior prognostic factors. Multivariate analysis revealed that tumor rupture was independent poor prognostic factor (P = 0.01, HR 5.9). Among relapsed patients, relapse occurred a median of 11 months after diagnosis (range, 4-41 months), and 50% (4/8) achieved a second complete remission after multiple treatment. None of the six lung metastasis patients received lung RT, only one patient developed a relapse and was salvaged by RT after relapse. Tumor rupture was independent poor prognostic factor. Upfront surgery of NWTS strategies can make a definite pathology diagnosis, but how to reduce tumor rupture during surgery is important especially in developing countries. The outcomes of patients with stage I-III CCSK in China were comparable to findings in other developed countries. Better outcomes were achieved in stage IV CCSK by using an intensive chemotherapy regimen including carboplatin, which require further confirmation by AREN0321. Lung RT may be safely omitted in selected patients who achieve a compete radiographic response after 6 weeks of systemic treatment (including surgery). Treatment should be encouraged even in CCSK cases with metastasis and relapse.

Burkitt lymphoma in a scalp region: a case report of it’s recurrence in a 13-year-old child

Introduction: Burkitt lymphoma (BL) is an aggressive non-Hodgkin lymphoma characterized by chromosome 8 MYC gene translocation. It manifests in three clinical types: immunodeficiency-related, sporadic (nonendemic), and endemic (African), each differing in epidemiology and clinical behavior. Treatment typically involves enrollment in clinical trials or intensive chemotherapy regimens like R-CODOX-M/IVAC. The authors present a case of recurrent BL following treatment. Case report: A 13-year-old female presented with a gradually progressive swelling in the left parieto-occipital region. Examination revealed normal vital signs and a Glasgow coma scale, with seronegative findings on investigations. An excision of a subganglion soft tissue tumor was performed, revealing histopathological features suggestive of a small round blue cell tumor. After chemotherapy, the patient experienced a recurrence in the scalp region, diagnosed as BL. Discussion: While scarce reports exist on BL in the scalp region, cases have been documented in various body locations. Treatment strategies, including chemotherapy and surgery, have shown promising results in managing the disease and improving symptoms. Conclusion: The recurrence of BL is rare, highlighting the importance of vigilance in monitoring patients post-treatment. The authors report a case of recurrent BL in a 13-year-old female, emphasizing the need for continued research and surveillance in managing this aggressive malignancy.

Trends on treatment patterns in patients with newly diagnosed AML: Preliminary findings from a real-world analysis.

e18506 Background: In the last two decades, new therapeutic options have emerged to complement traditional intensive chemotherapy (IC) regimens in the treatment of Acute myeloid leukemia (AML). Hypomethylating agents (HMAs), the B-cell lymphoma 2 (BCL-2) protein inhibitor Venetoclax, and other targeted therapies are examples. Guideline-based treatment decisions are intricate, considering both patient fitness to IC and disease characteristics. AML real-word studies on treatment patterns typically focus on specific subpopulations (e.g., elderly or unfit patients), and few studies analyze broader populations. We analyzed an US electronic health records (EHR) database to describe AML treatment patterns. Methods: Study was designed as retrospective, descriptive analysis of deidentified secondary data from COTA database in the US. Data was abstracted for AML patients diagnosed for the first time between January 2017 and September 2022. Follow-up period (FP) was defined as the period starting at the diagnosis until the last information available for: death, or last contact, or the emergence of other malignancies. To improve descriptive analysis, treatment categories were classified accordingly: IC and non-IC. We conducted descriptive statistics (expressed as counts, percentages or means and medians [with SD or IQR]) for the different assessed features. Results: From the 3,500 patients included on the database, 1,436 were eligible for the analysis with a newly diagnosed AML disease after January 2017. Individuals’ age at diagnosis falls between 60 and 74 years old for 41% of the cohort with mean age of 64[15] years and 60% were followed on community centers. Male patients slightly outnumber female patients (53% and 47%, respectively). Primary AML accounted for 41% of the population and secondary for 28%. Mean time to first treatment after diagnosis was 14[42] days for the overall cohort, the main reason for the end of follow-up was death for 58% of individuals and 47% of the patients had a follow-up inferior to one year. While analyzing treatment patterns according to line of therapies (LoT) sequences, IC only was predominant for 30% of the population, followed by non-IC only for 28%. Remaining counts (42%) correspond to association of both categories. Most prevalent regimen on IC only group was High-dose Cytarabine monotherapy (HIDAC) (12%), and HMA (Azacitidine)+Venetoclax (27%) for the non-IC only group. Conclusions: Our preliminary and recent findings demonstrate that incidence of AML remains high in elderly groups. Despite the introduction of novel therapies, IC remains the predominant treatment approach for newly diagnosed AML patients. Our ongoing real-world analysis aims to assess a more detailed description of LoT sequences in AML population.

Oral Malignant Burkitt’s Lymphoma and It’s Problems

A non-Hodgkin lymphoma with rapid growth and aggressive behavior is Burkitt's lymphoma. Burkitt's lymphoma (BL) is also an oral cancer of lymphoid origin with a high percentage of occurrences and includes an advanced B-cell neoplasm. Fundamentally, the exact cause of BL is unknown. This disease commonly occurs in people with weakened immune systems or children related to the Epstein-Barr virus (EBV) and chronic malaria. Burkitt lymphoma can be fatal. Burkitt lymphoma is a rare but highly aggressive (fast-growing) B-cell non-Hodgkin lymphoma (NHL). This disease may affect the jaw, central nervous system, bowel, kidneys, ovaries, or other organs Cancer cells in BL can spread to all parts of the body. Inhibiting the proliferation of BL oral cancer cells requires a viable and efficient plan. One of them is using medicinal plants whose antitumor potential needs to be scientifically tested. However, Burkitt lymphoma is often very responsive to the currently recommended intensive chemotherapy regimens, and cure rates for this disease remain high. Studies show people who receive treatment right away have high rates of remission, meaning after treatment they don’t have symptoms or signs of the condition. The aim of this review is to discuss Burkitt's lymphoma (BL) in diagnosis and treatment. Burkitt's lymphoma, or Raji cell, is a B-cell non-Hodgkin lymphoma that is very aggressive

Abstract 73: Spatial profiling of pediatric rhabdomyosarcoma to elucidate their immunosuppressive tumor microenvironment

Abstract Background: Pediatric rhabdomyosarcoma (RMS) is a mesenchymal soft tissue malignancy. Despite intensive chemotherapy regimens, there is currently a gap in improving treatment outcomes for RMS. Chemotherapy can modulate the tumor microenvironment (TME) by altering the immune cell composition or their functions. However, the impact of chemotherapy in pediatric RMS TME is unclear. RMS tumors are also considered as “cold” tumors due to low immune infiltration, which could be a determinant of why immunotherapy is unlikely to work. Additional investigations are required to determine the reasons of why RMS is “cold” and whether a combined immunotherapy and chemotherapy approach should be administered for this hard-to-cure cancer. Methods We conducted for the first time spatial GeoMx whole transcriptome atlas and 51-plex Akoya CODEX profiling for a tissue microarray (TMA) from a cohort of pediatric RMS patients (n = 12) with pre-chemotherapy (n = 5) and post-chemotherapy (n = 5) samples. Regions of interest (ROIs) were selected based on tumor areas with immune cell infiltration, with the lymphocytes, tumor cells, and nuclei visualized using fluorescent morphological markers CD45, Desmin, and DAPI. ROIs were segmented into tumor stroma compartments and immune cell compartments. Computational analyses were conducted on the transcriptomics data using R package standR including quality control, normalization, differential expression analysis, gene set enrichment analysis, and cell type deconvolution. For CODEX data, we preformed cell segmentation, followed by further quality control, cell phenotyping, cellular neighborhood and cellular interaction analysis. Results: From differential expression analysis of the immune compartment, we have identified type I interferon-related genes (DTX3L, ADAP2, RNF135) and reactive oxygen species (ROS)-induced gene (NCF1) are upregulated, and an antioxidant enzyme gene (PRDX2) is downregulated in post-chemotherapy samples compared to pre-chemotherapy samples. Gene set enrichment analysis of the immune compartment revealed an enriched antigen presentation pathway in post-chemotherapy samples. In the tumor stroma compartment, we identified increased TGF-β binding pathway in post-chemotherapy samples. Cellular deconvolution revealed a higher proportion of endothelial cells in post-chemotherapy samples, which is validated via CODEX imaging analysis. Cellular neighborhoods and cell-cell interaction analysis for CODEX data also reveal how chemotherapy affect functional units and cellular interactions in RMS TME with spatial context preserved. Conclusion: By applying spatial transcriptomic and multiplexed imaging to RMS samples, we have revealed key genes, pathways and cell types involved in chemotherapy-induced alterations in the TME. This will provide a new perspective for developing novel chemoimmunotherapy for RMS patients. Citation Format: Cui Tu, Chin Wee Tan, Ning Liu, Arutha Kulasinghe, Fernando Souza-Fonseca-Guimaraes. Spatial profiling of pediatric rhabdomyosarcoma to elucidate their immunosuppressive tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 73.

Chronic Myeloid Leukemia Presenting with Megakaryocytic Blast Crisis: a Case Report with a Favorable Outcome

Chronic myeloid leukemia (CML) belongs to the chronic myeloproliferative neoplasms, a clonal disorder of pluripotent hematopoietic stem cells, arising because of a hallmark genetic anomaly- reciprocal translocation between chromosomes 9 and 22, known as the Philadelphia chromosome, which generates the BCR::ABL fusion gene. The disease can have a biphasic/triphasic evolution, comprised of an accelerated phase and a terminal blast phase (usually biphasic when blastic phase is lymphoid in nature). Most cases present during the chronic phase of the disease, with only 10% of cases presenting in the blast phase. Megakaryocytic blast crisis is an unusual form of presentation, accounting for less than 3% of cases and it commonly carries an unfavorable prognosis compared to the classic myeloid, lymphoid or even mixed lineage blast crises. Aim: To bring forth an unusual case of CML presenting with megakaryocytic blast crisis and the therapeutic challenges associated with this particular presentation, unexpectedly ending with a favorable outcome. Matherial and methods: we hereby present the case of a 50 year old female patient, diagnosed in 2015 with CML- megakaryocytic blast crisis, who underwent treatment with a tyrosine kinase inhibitor (TKI)- imatinib and intensive chemotherapy regimen 3+7, without satisfactory response. A second induction chemotherapy regimen followed (MEC), alltogether with the same TKI and cytoreductive treatment (hydroxyurea/HU), but still without achieving a complete remission. Thus, the TKI was switched to dasatinib and complete normalisation of blood counts followed (including thrombocytes). However, there was still inadequate molecular and cytogenetic response. Therefore, TKI dosage was increased and after 4 months the patient achieved complete remission, with no detectable BCR::ABL transcript. She spent 9 years on the same TKI until important pleural effusion developed, which required switching to another 2nd generation TKI- bosutinib, based on the patients age, genetic profile and commorbidities. She is still in complete remission without detectable BCR::ABL transcript/Philadelphia chromosome to this day (2024). Results and conclusions: this is the case of a rare presentation of CMLmegakaryocytic blast crisis, who underwent both TKI and intensive chemotherapy induction regimens, marked by a favorable unexpected outcome.

Targeting the TNF/IAP pathway synergizes with anti-CD3 immunotherapy in T-cell acute lymphoblastic leukemia

AbstractT-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. Current treatments, based on intensive chemotherapy regimens provide overall survival rates of ∼85% in children and <50% in adults, calling the search of new therapeutic options. We previously reported that targeting the T-cell receptor (TCR) in T-ALL with anti-CD3 (αCD3) monoclonal antibodies (mAbs) enforces a molecular program akin to thymic negative selection, a major developmental checkpoint in normal T-cell development; induces leukemic cell death; and impairs leukemia progression to ultimately improve host survival. However, αCD3 monotherapy resulted in relapse. To find out actionable targets able to re-enforce leukemic cells’ vulnerability to αCD3 mAbs, including the clinically relevant teplizumab, we identified the molecular program induced by αCD3 mAbs in patient-derived xenografts derived from T-ALL cases. Using large-scale transcriptomic analysis, we found prominent expression of tumor necrosis factor α (TNFα), lymphotoxin α (LTα), and multiple components of the “TNFα via NF-κB signaling” pathway in anti-CD3–treated T-ALL. We show in vivo that etanercept, a sink for TNFα/LTα, enhances αCD3 antileukemic properties, indicating that TNF/TNF receptor (TNFR) survival pathways interferes with TCR-induced leukemic cell death. However, suppression of TNF-mediated survival and switch to TNFR-mediated cell death through inhibition of cellular inhibitor of apoptosis protein-1/2 (cIAP1/2) with the second mitochondrial-derived activator of caspases (SMAC) mimetic birinapant synergizes with αCD3 to impair leukemia expansion in a receptor-interacting serine/threonine-protein kinase 1–dependent manner and improve mice survival. Thus, our results advocate the use of either TNFα/LTα inhibitors, or birinapant/other SMAC mimetics to improve anti-CD3 immunotherapy in T-ALL.

Hypomethylating agents plus venetoclax compared with intensive induction chemotherapy regimens in molecularly defined secondary AML.

Molecularly defined secondary acute myeloid leukemia is associated with a prior myeloid neoplasm and confers a worse prognosis. We compared outcomes of molecularly defined secondary AML patients (n = 395) treated with daunorubicin and cytarabine (7 + 3, n = 167), liposomal daunorubicin and cytarabine (CPX-351, n = 66) or hypomethylating agents (HMA) + venetoclax (VEN) (n = 162). Median overall survival (OS) was comparable between treatment groups among patients aged >60 years. In a multivariable model HMA + VEN vs. 7 + 3 was associated with better OS (hazard ratio [HR] 0.64 [95% confidence interval (CI) 0.42-0.98, p = 0.041]), whereas CPX-351 vs. 7 + 3 was not (HR 0.79 [CI 95% 0.50-1.25, p = 0.31]). Allogeneic hematopoietic stem cell transplantation, BCOR and IDH mutations were associated with improved OS; older age, prior myeloid disease, NRAS/KRAS mutations, EZH2 mutation, and monosomal karyotype were associated with worse OS. When analyzed in each treatment separately, the IDH co-mutations benefit was seen with 7 + 3 and the detrimental effect of NRAS/KRAS co-mutations with HMA + VEN and CPX-351. In pairwise comparisons adjusted for age, HMA + VEN was associated with improved OS vs. 7 + 3 in patients with SF3B1 mutation and improved OS vs. CPX-351 in those with RNAsplicing factormutations. In molecularly defined secondary AML treatment with HMA + VEN might be preferred but could further be guided by co-mutations.

Chemotherapy With Eribulin Following Potentially Curative Surgery in Patients With Localized Liposarcoma.

Soft tissue sarcomas are rare and heterogenous malignancies with high recurrence rates following resection and a poor prognosis in advanced stages. Eribulin is used in metastatic soft tissue sarcoma patients, who have failed first line chemotherapy and has been approved for patients with pretreated advanced liposarcoma (LPS) in the United States and Europe following the publication of data of a phase III trial. In addition, no data are available for eribulin as postoperative treatment after potentially curative surgery. We, thus, retrospectively evaluated efficacy and tolerability of adjuvant eribulin in patients with LPS not suitable for intensive chemotherapy in the routine clinical setting. In this retrospective single center analysis, efficacy and safety of eribulin were retrospectively evaluated in five high risk LPS patients. Eribulin as treatment was administered to five patients with LPS following surgical resection. Median progression-free survival and overall survival were 12.3 months and 44.3 months, respectively. Toxicity was generally manageable, and grade 3+4 events were rare. Postoperative eribulin may be feasible in selected high risk LPS patients, who are not candidates for intensive chemotherapy regimens. Further prospective trials, however, are needed.

Venetoclax: A Game Changer in the Treatment of Younger AML Patients?

The combination approach based on venetoclax (VEN) with azacytidine (AZA) has significantly improved outcomes for elderly patients with acute myeloid leukemia (AML). This innovative approach has led to higher rates of overall response, measurable residual disease (MRD)-negative remissions, and overall survival compared with AZA monotherapy. As a result, this combination has emerged as the gold-standard treatment for elderly or unfit patients with AML who are not eligible for intensive therapy. In younger, fit patients with AML, intensive induction and consolidation chemotherapy is commonly used as a first-line approach; however, relapse continues to be the main reason for treatment failure in approximately 30-40% of patients. Efforts to improve MRD-negative response rates and to facilitate the transition to allogeneic hematopoietic stem cell transplantation, particularly in high-risk AML, have inspired trials exploring the combination of intensive chemotherapy with targeted agents. VEN, a first-in-class anti-BCL2 agent, combined with intensive chemotherapy regimens has shown deep MRD-negative remissions, producing prolonged event-free survival and enhancing the transition to allogeneic transplant in first-complete-remission patients. These benefits support the incremental advantages of adding VEN to intensive chemotherapy approaches across ELN risk subcategories, and provides a robust benchmark to design future trials. In this review, we will discuss current studies assessing the efficacy of frontline regimens integrating VEN into intensive chemotherapy in younger patients with AML and specific molecularly defined subgroups.

Incidence, Clinical Characteristics and Risk Factors for Poor Mobilization of Hematopoietic Stem Cells in a Colombian Bone Marrow Transplantation Unit: A Retrospective Cohort Study

Background: mobilized peripheral hematopoietic stem cells (PHSC) are the main cell source for autologous bone marrow transplantation. Failure to mobilize an appropriate number of PHSC can jeopardize autologous bone marrow transplantation procedure. Objective: our aim was to describe the clinical and demographics characteristics, the incidence of mobilization failure and the prevalence of risks factors for poor mobilization in patients in whom PHSC mobilization were attempted for autologous bone marrow transplantation between January 1st 2017 and 31 December 2022. A univariate and multivariate analysis (binary logistic regression) were done to determinate the association between risk factors and mobilization failure. Results: 129 patients were included , the patients median age was 54 years. Indications for autologous bone marrow transplantation were multiple myeloma in 50,4 %, lymphoma in 46,5 % and systemic sclerosis in 2,3 % of patients respectively. Mobilization was attempted with Filgrastim in 71,1 %, Filgrastim plus Plerixafor in 26,6 % and chemotherapy (Cyclophosphamide) plus Filgrastim in 2,3 % of patients respectively. Mobilization failure occurred in 9,3 % of patients (12 patients) occurring in 11 % of patients who received Filgrastim, in 5,6 % who received Filgrastim plus Plerixafor and in none of patients who received chemotherapy plus Filgrastim. No difference in mobilization failure was found between patients who received Filgrastim monotherapy versus those who received Filgrastim plus Plerixafor ( χ 2 p=0,388, relative risk: 1,8, confidence interval 95% 0,43 - 8,1). Patients who received Filgrastim plus Plerixafor had been treated more frequently (four of more cycles of Lenalidomide) compared with patients who received Filgrastim alone (63,3 % versus 18,7 %, χ 2 p &amp;lt; 0,001, RR=4,01, CI 95 %; 2,32-6,87).The median age of patients was superior in patients who received Filgrastim plus Plerixafor compared with those who received Filgrastim (58 vs 51 years, U Mann Whitney p = 0,02). The median number of treatment lines tended to be superior in patients receiving Filgrastim plus Plerixafor compared to those receiving Filgrastim (2 lines versus 1 line of therapy, U Mann Withney p= 0,054). Patients who had been treated with intensive chemotherapy regimens like DHAP, ESHAP or Hyper CVAD (p=0,004, RR: 4,3, CI 1,5-12,3)) and patients older than 60 years (p=0,018, RR: 3,4 (1,2-9,85)) were significant more prone to mobilization failure in bivariate and multivariate analysis. Conclusion: mobilization failure occurred in 9,3 % of patients , Filgrastim monotherapy was more frequently used, no difference in mobilization failure was found between those who received Filgrastim versus Filgrastim plus Plerixafor, history of treatment with more than 4 cycles of lenalidomide and older age were more frequently in patients who received Filgrastim plus Plerixafor. History of a treatment intensive chemotherapy regimen and being older than 60 years were consistently associated with mobilization failure in univariate and multivariate analysis.

Concurrent BCR::-ABL1 and CBFB Rearrangement in De Novo Acute Myeloid Leukemia

Introduction Acute myeloid leukemia (AML) is known for its genetic heterogeneity. Several recurrent genetic variants have been characterized including AML-defining chromosomal rearrangements involving the core binding factor (CBF), such as inv(16)/t(16;16)/ CBFB:: MYH11. 1 Less common is a subset of AML characterized by the Philadelphia chromosome (Ph+), generating a BCR::ABL1 fusion protein. 2 The Ph+ AML subtype is associated with poor prognosis and treatment resistance. 3,4 Co-occurrence of CBFB rearrangement and BCR::ABL1 fusion is rare, representing a subgroup with unique clinical and molecular features. To date, there have been less than 30 cases reported in the literature. 5-8 Case Description A 62-year-old male presented to hospital with headaches, visual changes, weakness, and a nodular rash on his back, with leukocytosis, thrombocytopenia, and 42.5% circulating blasts. A bone marrow (BM) aspirate and biopsy was diagnostic of AML with 56% myeloblasts. RT-PCR was positive for an e19a2 BCR::ABL1 fusion transcript coding for p230 kDa fusion protein (p230) and CBFB: :MYH11 fusion gene transcript. Cytogenetics identified a complex karyotype with an inv(16) and a Ph chromosome (46,XY,t(1;14)(p32;q24),t(9;22)(q34;q11.2),inv(16)(p13.1q22)[10]), consistent with concurrent BCR::ABL1 and CBFB::MYH11 rearrangements within the same clonal population of cells. Treatment consisted of hydroxyurea for cytoreduction, 7+3 induction, one cycle of low dose cytarabine consolidation, and oral azacytidine maintenance, in combination with dasatinib. He did not receive Gemtuzumab ozogamicin (GO) given patient preference and comorbidities. Post-induction course was complicated by febrile neutropenia due to Enterococcus Faceium bacteremia, pre-renal acute kidney injury, and dasatinib-related complications including rash and transaminitis. These issues resolved by holding dasatinib for 15 days. Complete morphologic remission (CR) was obtained by Day 33 post-induction and no fusion gene transcripts were detectable by nested RT-PCR from BM aspirate on day 49 post-induction, nor day 76 post-consolidation The patient was ineligible for an allogeneic stem cell transplant given his poor performance status. At present, the patient remains alive and well, continuing on maintenance with oral azacytidine and dasatinib. Discussion We present the only case, to our knowledge, of a concurrent BCR::ABL1 p230 isoform and CBFB::MYH11 with de novo AML. Based on our literature search, 26 cases have been reported. BCR::ABL1 and CBFB::MYHII rearrangements in de novo AML potentially confers an intermediate to favorable prognosis with outcomes comparable to those of CBF-AML. Studies suggest that this entity may be more akin to AML with inv(16) rather than CML-BP with inv(16), thereby retaining favorable prognosis. 5,9-11 There are no formal guidelines for management of de novo AML with concurrent BCR::ABL1 and CBFB rearrangements. Traditional chemotherapy treatment strategies for Ph+ AML are often ineffective in these cases. The presence of BCR::ABL1 fusion transcript raises the possibility of utilizing TKIs targeting the BCR::ABL1 kinase domain. In our case, the patient achieved rapid CR with induction chemotherapy and dasatinib, but experienced multiple complications, precluding further intensive chemotherapy and allogeneic stem cell transplantation. This case raises a number of questions, including the optimal timing, combination, and duration of TKI therapy in the context of dual rearrangement de novo AML. This patient subgroup may benefit from intensive chemotherapy regimens and TKIs. Prospective monitoring of these cases is warranted to assess outcomes in comparison to Ph+ AML without coinciding CBFB rearrangement. This case report underscores the importance of comprehensive genetic profiling in Ph+ AML to determine the genetic landscape and individualize therapeutic strategies.

Functional Ex-Vivo Testing Combined with Machine Learning Predicts Clinical Response to Azacitidine+Venetoclax in AML

Background: The combination of Venetoclax + hypomethylating agents such as Azacitidine (Ven/Aza) has revolutionized the treatment of Acute Myeloid Leukemia (AML). Ven/Aza is currently the standard of care for patients with newly diagnosed AML who are not candidates for intensive chemotherapy (IC), as well as a recurrent therapeutic choice for IC-relapsed/refractory patients. Despite widespread adoption, the predictive biomarkers of Ven/Aza response/resistance available today are not sufficiently conclusive (Griffioen et al. Cancers 2022). In fact, a current hot topic in the field is whether Ven/Aza can also become a frontline therapy for fit patients as an alternative to IC. Several worldwide studies are addressing this issue, including an ongoing clinical trial named “Survival of the Fittest” exploring this concept in the US (NCT04801797). An open question is whether functional ex-vivo testing could become a powerful actionable tool that overcomes limitations presented by genetic and molecular indicators. Aim &amp; Methods: In this study, we utilized an innovative ex-vivo functional platform of Patient Micro Avatars (PMAs) developed at OncoPrecision (García et al, Blood 2022 140 (Supplement 1): 13027-13028) to assess the predictive power for Ven/Aza treatment in a cohort of 11 AML patients. Patient-Derived Cells (PDCs) were obtained from the patients' PBMCs and Ven/Aza activity was assessed using high-throughput flow cytometry. An in-house Machine Learning (ML) tool was developed to identify the optimal variables that predict clinical outcome (Complete Remission: Yes/No). Clusters of predictive Response/Non-Response were defined by analyzing a cohort of &amp;gt;60 previously profiled AML patients and by leveraging the two most predictive populational features generated by the platform that better correlate with clinical outcome from &amp;gt;12,000 combinations of variables. Results: Our findings revealed differential ex-vivo activity of Ven/Aza in AML, with remarkably contrasting outcomes that defined clearly separate clusters of response (Figure - Left Panel). Such ML clustering led to 80% Overall Predictive Power and 100% Positive Predictive Value, meaning that all the patients for whom the platform predicted response achieved complete clinical remission. Moreover, by comparing the performance of other targeted therapies such as Gilteritinib, as well as IC regimens such as AraC-FaraA-IDA, side by side we were able to identify patients for whom Ven/Aza is the optimal regimen (e.g., Patient #169), and others for whom IC or Gilteritinib emerge as more promising therapeutic options (e.g., Patient #170) (Figure - Right Panel). Conclusions: This work presents a groundbreaking approach to predict Aza/Ven responders versus non-responders in AML. Combining the phenotypic outcomes of functional ex-vivo testing with ML tools presents the opportunity to more comprehensively predict response to cutting-edge therapies such as Ven/Aza than traditional genetic testing. This potential is particularly compelling for therapeutic schemes not directly associated with the acquisition of genetic mutations.

Acute Leukemias of Ambiguous Lineage Have Durable Response to Hypomethylating Agents Plus Venetoclax in Older Patients

Background: The standard of care for frontline therapy of acute leukemias of ambiguous lineage (ALAL) remains controversial due to their rarity; however, outcomes are generally poor. Intensive chemotherapy (IC) regimens are standard, with evidence suggesting that acute lymphoblastic leukemia regimens are more effective than those used for acute myeloid leukemia (AML). Strategies for treating older or frail patients are limited. Although treatment with a hypomethylating agent plus venetoclax (HMA/Ven) is standard therapy for IC-ineligible AML patients, the role of HMA/Ven in ALAL remains poorly characterized. We performed a retrospective chart review of patients at our institution with Philadelphia-negative ALAL, comparing the outcomes of those treated with HMA/Ven and those who received IC. Method: Patients ≥ 18 years treated at Weill Cornell Medical Center with newly diagnosed, pathologically confirmed acute undifferentiated leukemia (AUL), T/myeloid, or Philadelphia chromosome-negative B- and B/T-myeloid leukemia were included. Frontline HMA/Ven was defined as Ven plus azacytydine, decitabine, or oral decitabine/cedazuridine (one patient had initial HMA monotherapy followed by HMA/Ven). Intensive chemotherapy included patients who received variations of standard ALL or AML IC regimens (hyper- or mini-hyper-CV[A]D, cytarabine plus daunorubicin or idarubicin, or cladribine plus idarubicin and cytarabine) with or without Ven. Tyrosine kinase inhibitors including midostaurin or gilteritinib were added for patients with fms-like tyrosine kinase 3 ( FLT3) mutations. Baseline and disease characteristics were collected as well as disease response, subsequent lines of therapy, whether the patient proceeded to allogeneic hematopoietic cell transplantation (HCT), rate of morphologic complete remission (CR), and overall survival (OS). Results: Of 16 patients, 7 received frontline HMA/Ven. B/myeloid was the most common disease type (n=8), followed by T/myeloid (n=4), AUL (n=3), and 1 patient with B/T/myeloid disease. The median age was 74 years (interquartile range [IQR] 62-80). Patients who received HMA/Ven were older than those who received IC, with median ages of 79 (IQR: 77-82) and 62 (IQR: 56-70; p = 0.01), respectively. Baseline white blood cell, hemoglobin, platelet counts, and lactate dehydrogenase, as well as blast percentages in both peripheral blood and bone marrow were similar between the groups. Although not validated in ALAL, markers of adverse myeloid disease as per the ELN 2022 schema were prevalent in both groups, including mutations in RUNX1, ASXL1, SRSF2, and TP53 (Figure A). One HMA/Ven patient and 3 IC patients underwent HCT. Of evaluable patients, 83% and 88% of HMA/Ven and IC patients achieved CRs, respectively. At 2 years, both groups had 50% overall survival (95% CI 22.5-100 in both). Among HMA/Ven recipients, overall survival ranged from 10-56 months, not including two patients with ongoing follow-up at 3 and 46 months (Figure B). Discussion: The treatment of ALAL remains a challenge, particularly in older patients who may be unfit for intensive treatment strategies. In our study, patients who received HMA/Ven had similarly durable disease control to younger patients who received IC in the frontline setting. Prolonged responses were seen in both AUL and MPAL. Multicenter registry and prospective analyses are needed; however, given the rarity of these diagnoses, our findings suggest that HMA/Ven should be considered as a frontline therapy for unfit patients with ALAL.

Single-Center Experience of Decitabine/Venetoclax in Newly Diagnosed Older AML Patients with Non-Favorable Genetics: Bridging to Allo-HCT or Treatment Continuation

Background DNA-hypomethylating agents (HMAs) have improved the prognosis of patients (pts) with acute myeloid leukemia (AML) unfit for standard induction chemotherapy. AML pts aged &amp;gt;60 years eligible for allografting (HCT) can be effectively bridged to HCT by HMA monotherapy. This was demonstrated in the EORTC randomized phase III trial AML21 (NCT02172872) comparing 10-day decitabine (DEC) to “7+3” induction (Lübbert et al., EHA 2022, S125), with similar transplant rates and post-HCT outcomes in both arms. Also the combination of an HMA with venetoclax (VEN) is not only effective in pts unfit for more intensive treatment (DiNardo et al., New Engl. J. Med. 2020) but also in pts fit for HCT (Pollyea et al., BMT 2021, Maiti et al., ASH 2022, #7725). A recent analysis demonstrated that HMA+VEN as pretransplantation therapy can attain post-HCT outcomes comparable to intensive chemotherapy regimens (Winters et al., TCT 2022). Patients and Methods We retrospectively analyzed 47 consecutive older AML pts receiving firstline treatment with DEC+VEN. DEC was administered on five consecutive days per cycle. VEN was administered up to 28 days per cycle (see Table 1). All pts who had received at least one dose of DEC and VEN were included. Data on all pts were retrospectively collected as reported in the medical charts. Written informed consent of all pts to analysis of their records for scientific purposes was provided. Key parameters captured and analyzed were: age, ECOG performance status (PS), ELN 2017 risk, number of cycles of DEC+VEN administered, response rates and overall survival (OS). Common safety parameters (e.g., prolonged neutropenia, tumor lysis syndrome, etc.) were assessed. Results Between 2/2019 and 2/2023, 47 pts with AML received DEC+VEN as firstline treatment. Of those, 18 pts (38%) proceeded to HCT, 29 (62%) did not (ineligibility for HCT, wish of pt, intercurrent events etc.). Median follow-up was 25.0 (HCT) and 14.8 months (no HCT). Key pt characteristics in the two groups were i. median age: 69 and 79 years, ii. ECOG PS 0: 50 and 27%, iii. de novo AML: 39 and 72%, iv. ELN 2017 adverse risk: 67 and 59%, median number of treatment cycles administered were 2.0 and 3.0. Safety data are shown in Table 1. A hematologic response before HCT (CR, CRi, MLFS) was attained in 8/18 pts (44%), with only 2/18 receiving &amp;gt;2 cycles. Median time from treatment start to HCT was 2.5 months (for transplant details, refer to Table 1). For non-transplanted pts, CR, CRi, MLFS as best response were attained in 16/29 (55%), 13/29 receiving &amp;gt;4 cycles. In pts receiving HCT, graft-versus-host-disease occurred in 10/18 pts (56%), median OS was not reached (16/18 pts alive; Fig. 1). In pts not receiving HCT, median OS was 9.0 months. A direct comparison of treatment outcomes between the two groups is not possible, given the different selection factors operative for pts attaining HCT or not. Conclusions Among these older AML pts with non-favorable genetics, administration of a limited number of DEC+VEN cycles followed by HCT was well feasible in almost 40% of pts (median age 69 years) and resulted in very encouraging post-HCT OS in this first analysis. In pts not able to receive HCT (median age 79 years), DEC+VEN resulted in response rates, treatment continuation and OS comparable to “real-world” older AML pts treated with AZA+VEN, suggesting equivalent efficacy of both regimes.