Secondary Acute Leukemia Research Articles

Recent Developments and Evolving Therapeutic Strategies in KMT2A-Rearranged Acute Leukemia.

Rearrangements of the histone-lysine-N-methyltransferase (KMT2A), previously referred to as mixed-lineage leukemia (MLL), are among the most common chromosomal abnormalities in patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), involving numerous different fusion partners. KMT2A-rearranged (KMT2A-r) leukemia is characterized by a rapid onset, aggressive progression, and significantly worse prognosis compared to non-KMT2A-r leukemias. Even with contemporary chemotherapeutic treatments and hematopoietic stem cell transplantations (HSCT), patients with KMT2A-r leukemia typically experience poor outcomes and limited responses to these therapies. This review aims to consolidate recent studies on the general gene characteristics and associated mechanisms of KMT2A-r acute leukemia, as well as the cytogenetics, immunophenotype, clinical presentation, and risk stratification of both KMT2A-r-AML and KMT2A-r-ALL. Particularly, the treatment targets in KMT2A-r acute leukemia are examined. A comprehensive review was carried out by systematically synthesizing existing literature on PubMed, using the combination of the keywords 'KMT2A-rearranged acute leukemia', 'lymphoblastic leukemia', 'myeloid leukemia', and 'therapy'. The available studies were screened for selection based on quality and relevance. Studies indicate that KMT2A rearrangements are present in over 70% of infant leukemia cases, approximately 10% of adult AML cases, and numerous instances of secondary acute leukemias, making it a disease of critical concern to clinicians and researchers alike. The future of KMT2A-r acute leukemia research is characterized by an expanding knowledge of the disease's biology, with an emphasis on personalized therapies, immunotherapies, genomic advancements, and innovative therapeutic combinations. The overarching aim is to enhance patient outcomes, lessen the disease burden, and elevate the quality of life for those affected. Ongoing research and clinical trials in this area continue to offer promising opportunities for refining treatment strategies and improving patient prognosis.

Comparative Characteristics of Abnormal Karyotypes in Secondary Acute Leukemia

Comparative Characteristics of Abnormal Karyotypes in Secondary Acute Leukemia

Characteristics and outcomes of secondary acute lymphoblastic leukemia (sALL) after multiple myeloma (MM): SEER data analysis in a single-center institution

BackgroundSecondary acute lymphoblastic leukemia (sALL) is rare in patients diagnosed with antecedent multiple myeloma (MM). This study aimed to elucidate the clinical features and outcomes of patients with sALL after MM. MethodsWe conducted this population-based study using the Surveillance, Epidemiology, and End Results (SEER) database and retrospectively reviewed patients with sALL following MM treatment at our institution. Cox regression analysis was performed to investigate the prognostic factors for survival in patients with sALL. ResultsWe identified 64,629 cases of MM (including 18 sALL from the SEER Plus 9 database, and three sALL from our institution). Younger patients with MM and those who received chemotherapy were at a higher risk of developing sALL. The novel agent era witnessed an increased incidence of sALL (post-novel agent era vs. pre-novel agent era: 0.31% [10/32,640] vs. 0.25% [8/31,989]) and shorter latency time (post-novel agent era vs. pre-novel agent era [median]: 51.5 vs. 74.5 months, P = 0.516), though the difference was not significant. The median age at sALL onset was 65 (range: 47–78) years. Significant cytopenia and absence of BCR/ABL fusion genes were common features in this patient population. The treatment of sALL is complicated by old age and poor performance status. The median survival of patients with sALL is 18 months, whereas those who received chemotherapy had significantly prolonged survival. ConclusionsPatients with sALL combined with an antecedent MM, especially those with long-term exposure to immunomodulatory agents such as thalidomide or lenalidomide, should be cautiously evaluated and managed with a comprehensive approach.

Leukemia Secondary to Lymphoblastic Lymphoma with Development of Aplasia Medullary Post Induction of Hypercvad, Report of Case Clinical and Revision of The Literature

We describe the case of a patient with lymphoblastic lymphoma who received 8 cycles of chemotherapy with subsequent development of secondary acute lymphoblastic leukemia, requiring initiation of a remission induction chemotherapy scheme based on Hyper-CVAD, developing secondary bone marrow aplasia.

Discovery of an Inherited Variant Associated with Susceptibility to Secondary Acute Lymphoblastic Leukemia (ALL) after Lenalidomide Maintenance and Autologous HCT for Multiple Myeloma (MM)

Discovery of an Inherited Variant Associated with Susceptibility to Secondary Acute Lymphoblastic Leukemia (ALL) after Lenalidomide Maintenance and Autologous HCT for Multiple Myeloma (MM)

Clinical Outcomes of Adults Undergoing Allogeneic Stem Cell Transplant for Secondary Acute Lymphoblastic Leukemia

Background: Secondary hematologic malignancies are increasingly recognized due to the rising number of cancer survivors. While therapy related myeloid malignancies have distinct genetic profiles and inferior allogeneic stem cell transplantation (alloHCT) outcomes, there is limited data regarding secondary acute lymphoblastic leukemia (sALL). In one report, patients with therapy related ALL had an inferior OS of 23 months after alloHCT compared to primary (pALL) where OS was not reached [Saygin et al. 2019]. In the past decade, several novel therapies have been FDA approved for adults with B-ALL allowing more patients to achieve molecular remissions prior to alloHCT, therefore, we aimed to examine the role of alloHCT for adults with sALL compared to adults with pALL in a contemporary era. Methods: We identified 247 (n= 25 sALL, n= 223 pALL) patients with ALL who underwent alloHCT at Moffitt Cancer Center from 1/2010 to 12/2022. Matching was performed with a 1:1 nearest neighbor matching on propensity score controlling for age, ALL subtype, MRD status, CR line at transplant, regimen intensity, and lines of therapy received for sALL. Three patients with sALL were excluded from matched analysis due to inability to control for selected covariates. Variable balance was assessed before and after matching. Outcomes measured included overall survival (OS), leukemia free survival (LFS), non-relapse mortality (NRM), and relapse. Survival analysis was evaluated by Kaplan-Meier estimations. Multivariate analysis was performed by Cox regression. Results: After matching, 22 patients in the pALL group and 22 patients in the sALL group were analyzed. The two groups were evenly matched for all baseline characteristics except for donor type ( Table 1 p = 0.019). The majority of patients in both groups were over the age of 40, were diagnosed with Ph(-) B-cell ALL and were transplanted in first complete remission (CR1). Cytogenetic stratification for Ph(-) patients were defined per CIBMTR criteria [Lazaryan et al. 2020]. In patients with Ph(-) sALL, cytogenetics were classified as adverse (n=4), intermediate ( n=7), favorable (n=2) and were missing in 3 patients. In the sALL group, 59% of patients had an antecedent solid tumor malignancy whereas 36% had a hematologic malignancy with one patient having two prior malignancies. Half of the sALL group (n=11) had chemotherapy exposure for primary malignancy. Median follow up time for the pALL and sALL groups was 76 and 55 months respectively. Compared to the pALL group, the sALL group did not have a significant difference in OS ( Figure 1 p = 0.3). The 2 and 5-year OS of the pALL group was 72% and 67% respectively vs. 60% and 48% in the sALL cohort (p = 0.3). The 2 and 5-year LFS of the pALL cohort was 72% and 52% respectively vs 45% and 45% of the sALL cohort (p = 0.3). Cumulative incidence of NRM (27 % vs. 18%, p=0.7) and relapse (27% vs 32% p = 1.0) were not statistically significant between sALL and pALL groups. In a multivariate analysis performed after matching, there was no associated difference in the OS (p= 0.6) between groups. Conclusion: In this study, we observed no significant difference in OS, LFS, NRM or relapse between sALL patients and pALL patients after controlling for key variables in a matched cohort analysis. Most patients included in this analysis were in complete molecular remission at time of transplant underscoring the prognostic impact of MRD. Despite 50% of the sALL cohort having exposure to prior chemotherapy, few patients had adverse cytogenetics suggesting that cytogenetic risk and MRD, and not only exposure to prior therapy are key prognostic factors for sALL patients undergoing alloHCT. Larger studies are needed to validate these findings. Despite small number of patients, we observe encouraging outcomes for this patient population with traditionally poor outcomes with conventional chemotherapy alone.

POSTER: MM-523 Outcomes of Secondary Acute Lymphoblastic Leukemia in Multiple Myeloma

POSTER: MM-523 Outcomes of Secondary Acute Lymphoblastic Leukemia in Multiple Myeloma

MM-523 Outcomes of Secondary Acute Lymphoblastic Leukemia in Multiple Myeloma

MM-523 Outcomes of Secondary Acute Lymphoblastic Leukemia in Multiple Myeloma

Clinical Characteristics and Prognosis of Secondary Acute Lymphoblastic Leukemia in Patients with Multiple Myeloma during Long-Term Thalidomide Maintenance.

Background: Secondary primary malignancies (SPM) have attracted increasing attention with the application of autologous hematopoietic stem cell transplantation (ASCT) and novel agents in multiple myeloma (MM). Secondary acute lymphoblastic leukemia (sALL) has rarely been reported, and the clinical characteristics and prognosis of sALL have not been described in detail. Methods: We retrospectively enrolled 179 consecutive newly diagnosed multiple myeloma (NDMM) patients undergoing bortezomib-based induction regimens followed by upfront ASCT and maintenance therapy from December 2006 to April 2018 in our center. Results: The median follow-up interval was 69.1 months, and 12 patients (6.7%) developed sALL during maintenance therapy. The median time from the diagnosis of MM to the occurrence of sALL was 51.1 (31.7-91.5) months. All sALL patients received thalidomide as maintenance therapy before the onset of sALL, and the median duration of thalidomide maintenance was 39.5 (24-74) months. The cumulative incidence of sALL was 6.6% and 11.2% at 5 and 10 years after the diagnosis of MM, respectively. All sALL patients presented with a B-cell immunophenotype accompanied by myeloid antigen expression according to flow cytometry analysis, and the BCR/ABL fusion gene was all negative. Only one patient had evidence of active MM, and the other patients were in stable status at the time of the diagnosis of sALL. The prognosis of most sALL patients was very poor, and the median overall survival time was 11.9 (1.1-51.2) months since the diagnosis of sALL. Conclusions: sALL should be considered for MM patients who developed unexplained persistent cytopenia while on long-term thalidomide maintenance treatment, particularly if it has been more than 3 years. With the increasing availability of new drugs for MM, thalidomide may be recommended for no more than 3 years. Sequential allogeneic hematopoietic stem cell transplantation was considered as soon as possible after achieving remission in order to achieve a longer survival.

A Comparison of Outcomes in Patients with Secondary Acute Promyelocytic Leukemia (APL) and De Novo APL - a Case-Match Retrospective Analysis of Polish Adult Leukemia Group (PALG)

Introduction Acute promyelocytic leukemia (APL) is a very rare subtype of acute myeloid leukemia. APL might develop de novo or secondary after previous exposure to genotoxic agents or immunosuppression (sAPL). The data regarding sAPL is limited. The prognosis of sAPL patients (pts) and also the presence of any additional prognostic markers as compared to de novo APL, as well as the therapeutic approach still remain unclear. Here we present a case-matched analysis of sAPL diagnosed and treated according to the Polish Adult Leukemia Group/Programa Español de Tratamientos en Hematología (PALG/PETHEMA) protocols, compared with de novo APL. Methods The PALG's database of APL pts from 2006 to 2022 was screened and the cases of sAPL were selected. sAPL pts were matched based on sex, age, time of diagnosis, and treatment protocol with de novo APL pts from the same database. A variety of baseline variables as well as treatment outcomes were compared using U-Mann-Whitney, Chi2, Fisher tests, and Cox models. Results Out of 404 pts in the database, we found 27 pts with sAPL (6.7%), and 18 pts were female (66.6%). The median (Me) age in sAPL group was 58yo (range: 19-70yo). All reported cases of sAPL have developed after previous exposure to chemo- and/or radiotherapy. In 26 (96%) pts sAPL was proceeded with neoplasm treatment and in one (4%) multiple sclerosis therapy. The most often sAPL was diagnosed after treatment of breast cancer (29.6%), followed by therapy for kidney, colon, testis, lung, laryngeal, endometrial, ovarian cancers, and as well as Hodgkin lymphoma, B-acute lymphoblastic leukemia, liposarcoma, Merkel cell tumor, and GIST. In the analysis after pairs matching, we did not find any differences between sAPL and de novo APL regarding the ECOG performance status (p=0.29), WBC (Me 2.4G/L vs. 1.8G/L; p=0.52), coagulopathy described as a platelet counts (Me 24.5G/L vs. 37G/L, p=0.14), fibrinogen concentration (Me 1.0g/l vs. 1.4g/l, p=0.27) and d-dimers (Me 35.2ng/ml vs. 13.8ng/ml, p=0.23). We also did not observe any differences in additional cytogenetic abnormalities (p=0.13) between the examined groups. The frequency of FLT3-ITD expression in sAPL and de novo APL was 28.6% vs. 26.7%, respectively, (p=1.0), and FLT3-TKD expressions was 50% vs. 0%, respectively (p=0.43), however only a small number of pts had assessed FLT-TKD status (n=7 in both groups). The Me overall survival (OS) for the whole group was not reached. The Me OS for sAPL was 156 months (95%CI 26.9-156) and for de novo APL was not reached (p=0.29) (Figure 1A). In the univariate analysis, shorter OS was influenced by a high-risk group according to Sanz Score (HR 3.0, 95%CI 1.1-8; p<0.03), and ECOG 3 or 4 performance status at diagnosis (HR 11.52, 95%CI 3.8-34.9; p=<0.001). In the multivariate analysis shorter OS was associated with the presence of additional cytogenetic abnormalities other than t(15;17) (HR 16.8, 95%CI 2.7-103; p=0.002), older age (continuous variable) (HR 1.1, 95%CI 1-1.1; p=0.02) and lower platelets count (continuous variable) (HR 0.96, 95%CI 0.93-1.0; p=0.03). The relapse rate was not significantly higher in sAPL 19% (n=5) vs. de novo APL 3.7% (n=1)(p=0.2). The Me relapse-free survival (RFS) was not reached for the whole group. The Me RFS was 97.4 months (95%CI 26.3-97.4) in sAPL pts vs. not reached in de novo APL (p=0.31) (Figure 1B). Shorter RFS in the univariate analysis was affected by ECOG 3 or 4 at diagnosis and a high-risk group of Sanz Score (HR 8.6, 95%CI 3.1-23.8; p<0.001 and HR 4.3, 95%CI 1.6-10.8; p=0.002, respectively). In the multivariate analysis older age (continuous variable) (HR 1.1, 95%CI 1.0-1.1; p=0.03), lower platelets count (continuous variable) (HR 0.97, 95%CI 0.95-0.99; p=0.03) and additional cytogenetic abnormalities other than t(15;17) (HR 19.8, 95%CI 3.5-113.9; p=0.0008) negatively influenced RFS. sAPL diagnosis affected neither OS nor RFS. There are some limitations of our analysis, which include a low number of patients with sAPL and a lack of prospective data. Conclusions The results of this case-matched study are in line with the previous suggestions that outcomes of pts with sAPL may be similar to those with the disease de novo. We also conclude that there is no difference in the clinical and biological presentation of sAPL and de novo APL at the time of diagnosis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Maintenance Therapy with Combination of Azacitidine, Danazol and Thalidomide after Intensive Chemotherapy in Acute Myeloid Leukemia Patients

INTRODUCTION Despite the efficacy and outcome of AML patients increases in recent decades, the rate of relapse is still high, especially in the patients who are ineligible for allo-HSCT. How to prevent relapse is still a major therapeutic challenge. Recently, several drugs including Azacitidine (AZA), CC-486, Lenalidomide, androgen, Midostaurin, etc, used as maintenance therapy have shown a better EFS or OS, indicating that maintenance therapy is an important aspect of AML treatment. Herein, we reported the data of 11 AML patients who were administered AZA combined with Danazol (DNZ) and Thalidomide (THD) as maintenance therapy after intensive chemotherapy (IC). The purpose of this study was to observe the efficacy and safety of this maintenance therapy. METHODS Between Feb 2017 and Mar 2021, 11 patients diagnosed with AML were treated at the Baiyun Hospital. The induction therapy involved daunorubicin (DNR) 60 mg/m2/day on days 1-3, cytarabine (Ara-c) 100 mg/m2/day on days 1-7. If the patient did not achieve CR, salvage therapy was administered. Post-remission, three cycles of consolidation chemotherapy with high-dose Ara-c (3g/m2/q12h d1-3) and two cycles of reduced dose of chemotherapy (DA/HA/EA) were administered. Patient remained in CR after IC and was treated with 6-8 cycles of AZA combined with DNZ and THD maintenance therapy. AZA subcutaneous injection at 100 mg/day (approximate 50-75 mg/m2/day) d1-7, DNZ 200 mg Bid and THD 100 mg/day po followed by AZA, every four weeks. After completing the 6-8 cycles, patients continued the maintenance therapy with DNZ and THD for at least three years unless relapse or intolerance occurred. Disease evaluation included bone marrow and blood test until the duration of CR over five years. RESULTS Between Feb 2017 and Mar 2021, 11 patients who were enrolled in this study. Baseline patient and disease characteristics are summarized in Table 1. All 11 patients were treated with DA induction therapy, 10 patients achieved CR, 1 patient achieved remission after salvage therapy. 10 of 11 patients completed all consolidation therapies. 1 patient diagnosed AML with t (8;21) refused to continue chemotherapy because of renal failure after CR, and was directly switched to maintenance therapy. 9 0f 10 patients completed all IC and started on maintenance therapy. 1 AML with t (8;21) patient relapsed after stopping chemotherapy for two months and achieved CR2 by FLAG re-induction therapy refused continued chemotherapy and transplantation, and was directly switched to maintenance therapy. All patients received a median of 7 (6-12) courses of AZA combined with DNZ and THD maintenance therapy. Treatment was well tolerated and accepted by the patients. Common adverse events included mild neutropenia, thrombocytopenia, and elevated aminotransferase. No patient discontinued the maintenance therapy due to adverse events. Until June 2022, the median follow-up time was 37 (14-63) months. The RFS at 1-year and 3-years was 100% and 71.1%; the OS at 3-years was 100%, respectively (Figure 1a, 1b). All 11 patients, 3 died and 8 patients were alive with RFS. Of the 3 patients who died, 1 relapsed at 36 months and died due to disease progression at 46 months. The remaining 2 patients, one was diagnosed and died with secondary mixed phenotypic acute leukemia (NOS, T/My), the other died in a road accident. Notably, 2 cases of AML with t (8; 21) (one patient relapsed after IC, another patient developed renal failure) remained in CR by the end of follow-up. The CR duration was 24 and 13 months, respectively. The clinical outcomes of maintenance therapy after IC treatment for 11 patients are summarized in Figure 1c. Conclusion: AZA combined with DNZ and THD maintenance therapy is safe and effective in AML patients who are ineligible for allo-HSCT. Keywords: Azacitidine; Danazol; thalidomide; maintenance therapy; AML Figure 1 Response and long-term outcomes of the entire cohort Figure 1 legend, a. Relapse-free survival of the 11 patients. b. Overall survival of the 11 patients. c. Swimmer plot of the 11 patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Spatial Organization of Hematopoietic Clones in the Bone Marrow of a Patient with Polycythemia Vera

All humans become genetic mosaics over time as our stem cells acquire somatic mutations throughout life. In the hematopoietic compartment, this phenomenon is termed clonal hematopoiesis (Steensma et al. 2015). Clonal hematopoiesis (CH) increases in prevalence with age and is associated with an increased risk for hematologic malignancy (Genovese et al. 2014; Jaiswal et al. 2014; Xie et al. 2014). CH harboring JAK2 mutations are frequently observed in healthy individuals; and yet JAK2 mutations are also the most frequent drivers of myeloproliferative neoplasms (MPNs) such as polycythemia vera (PV). MPNs are clonal diseases marked by dysregulated hematopoiesis and can progress to a secondary myelodysplastic syndrome or acute leukemia. There is increasing evidence that the clonal mutations driving MPNs arise early in life-potentially in utero-often years before the development of symptoms (Williams et al. 2022). While the intrinsic factors driving clonal expansion are increasingly known (Watson et al. 2020), the extrinsic factors driving the expansion of clones harboring these MPN driver mutations are not well characterized. Prior work has shown that clonal mutations are geographically constrained in solid organs such as skin, colon and esophagus (Lee-Six et al. 2018; Martincorena et al. 2015, 2018). Strikingly, in the esophagus non-malignant NOTCH1 mutant clones can even outcompete nascent malignant clones (Colom et al. 2021). In the hematopoietic compartment, the spatial organization of clones harboring these mutations and their interaction with the niche and each other is largely unknown. We hypothesized that clonal mutations are geographically constrained in the bone marrow niche as is seen in solid organs. To answer these questions, we developed methods for spatially-aware clonal mutation detection. As proof of principle, we characterized the hematopoietic clonal organization within a femur head explant from a 50 year-old man with PV undergoing hip arthroplasty. Briefly, the femur head was sectioned into 2mm slices, which were then further partitioned into approximately 300 bone marrow fragments (2mm3). Approximately 20% of the fragments were snap frozen and pulverized for DNA extraction. The remainder were formalin fixed and decalcified for correlative imaging. Targeted error-corrected sequencing was performed using a myeloid-specific panel (Duncavage et al. 2018) on 24 bone marrow fragments, and bulk peripheral blood and bone marrow aspirate. In the peripheral blood, JAK2 V617F (0.24 VAF) and TET2 L1081* (0.02 VAF) mutations were identified. In the bone marrow aspirate, the same JAK2 (0.62 VAF) and TET2 (0.05 VAF) mutations were identified in addition to a DNMT3A R882C mutation (0.02 VAF). Interestingly, peripheral blood sequencing two years prior identified the JAK2 and DNMT3A mutations, but not the TET2 mutation, suggesting recent clonal expansion of TET2 mutant clone. From the 24 sequenced bone marrow fragments, the geographical organization of clonal mutations in the bone marrow was determined (Figure 1). The JAK2 V617F clone was identified in all bone marrow fragments sequenced (0.12-0.69 VAF). The TET2 L1081* clone was identified in 11/24 bone marrow fragments with some regional constraint (0.03-0.05 VAF). The DNMT3A R882C mutation was detected in only a single bone marrow fragment (0.02 VAF) and co-localized with the JAK2 V617F and TET2 L1081* mutations. A previously undetected clonal SETBP1 E616V mutation was identified in two adjacent bone marrow fragments from sequential slices of the femur head (0.05 VAF and 0.10 VAF). Together this provides the first characterization of spatial organization of clonal mutations in the bone marrow niche for an MPN patient. Currently, we are utilizing digital droplet PCR targeting these detected mutations in ~60 additional bone marrow fragments to accurately quantify clone size across the tissue. We plan to employ multiplex fluorescent imaging of bone marrow fragments adjacent to detected clusters of mutations to identify the surrounding bone marrow niche elements in those regions. These findings suggest that bone marrow biopsy from a small section of bone marrow may not accurately describe disease state and clonal mutation burden in myeloid neoplasms. Future applications of these tools will help describe the extrinsic factors and local microenvironment that drive clonal evolution over time in the bone marrow. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Distinct clonal identities of B-ALLs arising after lenolidomide therapy for multiple myeloma

AbstractPatients with multiple myeloma (MM) who are treated with lenalidomide rarely develop a secondary B-cell acute lymphoblastic leukemia (B-ALL). The clonal and biological relationship between these sequential malignancies is not yet clear. We identified 17 patients with MM treated with lenalidomide, who subsequently developed B-ALL. Patient samples were evaluated through sequencing, cytogenetics/fluorescence in situ hybridization (FISH), immunohistochemical (IHC) staining, and immunoglobulin heavy chain (IgH) clonality assessment. Samples were assessed for shared mutations and recurrently mutated genes. Through whole exome sequencing and cytogenetics/FISH analysis of 7 paired samples (MM vs matched B-ALL), no mutational overlap between samples was observed. Unique dominant IgH clonotypes between the tumors were observed in 5 paired MM/B-ALL samples. Across all 17 B-ALL samples, 14 (83%) had a TP53 variant detected. Three MM samples with sufficient sequencing depth (>500×) revealed rare cells (average of 0.6% variant allele frequency, or 1.2% of cells) with the same TP53 variant identified in the subsequent B-ALL sample. A lack of mutational overlap between MM and B-ALL samples shows that B-ALL developed as a second malignancy arising from a founding population of cells that likely represented unrelated clonal hematopoiesis caused by a TP53 mutation. The recurrent variants in TP53 in the B-ALL samples suggest a common path for malignant transformation that may be similar to that of TP53-mutant, treatment-related acute myeloid leukemia. The presence of rare cells containing TP53 variants in bone marrow at the initiation of lenalidomide treatment suggests that cellular populations containing TP53 variants expand in the presence of lenalidomide to increase the likelihood of B-ALL development.

Impact of conditioning regimen intensity on outcomes of second allogeneic hematopoietic cell transplantation for secondary acute myelogenous leukemia.

Limited data is available on factors impacting the outcomes of second hematopoietic cell transplantation (HCT2) in patients with secondary acute myeloid leukemia (sAML). This study aimed to assess HCT2 outcome for sAML comparing reduced-intensity (RIC) to myeloablative (MAC) conditioning. Two hundred and fifteen patients were included: RIC (n = 134), MAC (n = 81). The median follow-up was 41.1 (95% CI: 26.7-69.3) and 28.5 (95% CI: 23.9-75.4) months, respectively. At two years, the relapse incidence (RI) was 58.3% versus 51.1% in RIC and MAC, respectively. The 2-year leukemia free survival (LFS) was 26.6% versus 26%, and the graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) was 16.4% versus 12.1%, while OS was 31.4% and 39.7%, for RIC and MAC respectively. MVA showed a significantly lower RI [hazard ratio (HR) = 0.46 (95% CI, 0.26-0.8, p = 0.006)] and improved LFS [HR = 0.62 (95% CI, 0.39-0.98, p = 0.042)] with MAC versus RIC. The choice of conditioning regimen did not impact non-relapse mortality [HR = 1.14 (95% CI, 0.52-2.5, p = 0.74)], overall survival (OS) [HR = 0.72 (95% CI, 0.44-1.17, p = 0.18)] or GRFS [HR = 0.89 (95% CI, 0.59-1.36, p = 0.6)]. In conclusion, MAC was associated with a lower RI and superior LFS. These results support the use of MAC for eligible patients with sAML who are being considered for HCT2.

Immunochemotherapy versus rituximab in anti-myelin-associated glycoprotein neuropathy: A report of 64 patients.

Monoclonal immunoglobulin M (IgM) anti-myelin-associated glycoprotein (MAG) neuropathy is a rare disabling condition, most commonly treated with rituximab monotherapy (R), which leads to neurological improvement in only 30%-50% of patients. The combination of rituximab plus chemotherapy has been proven to improve the level of responses. We studied the outcomes of anti-MAG neuropathy patients treated either by R, or by immunochemotherapy (ICT) in our centre, focusing on the incidence of the first neurological response evaluated by the modified Rankin scale (mRS). From 2011 to 2018, 64 patients were studied: 34 were treated with R and 30 with ICT. According to our treatment decision-making process, the median mRS was higher in the ICT group (mRS 2) than in the R group (mRS 1). At one year, improvements of the mRS rates were 46% and 18% in the ICT and R groups of patients respectively, with median times to response of eight and 13months (p=0.023). Adverse effects were higher in the ICT group: 62% vs 15% (p˂0.01), all grades included. One secondary acute leukaemia occurred five years after treatment with ICT. In conclusion, ICT may be used as a valid option for patients with rapidly progressive and/or severe anti-MAG neuropathy symptoms.

257 - Significant Therapy Associated Toxicity Seen in Two Pediatric Survivors of Medulloblastoma Treated with Tisagenlecleucel for Relapsed Secondary B-Cell Acute Lymphoblastic Leukemia

257 - Significant Therapy Associated Toxicity Seen in Two Pediatric Survivors of Medulloblastoma Treated with Tisagenlecleucel for Relapsed Secondary B-Cell Acute Lymphoblastic Leukemia

Secondary Biphenotypic Acute Leukemia Following Rosai-Dorfman-Disease A Coincidence?

Secondary Biphenotypic Acute Leukemia Following Rosai-Dorfman-Disease A Coincidence?

CPX-351 Induction in Secondary Acute Myeloblastic Leukemia: Extended Follow up from the Italian Compassionate Use Program

Introduction:The outcome of patients with acute myeloid leukemia (AML) secondary to myelodisplastic syndrome (MDS) or therapy-related (t-AML) receiving conventional treatment and allogeneic stem cell transplantation consolidation (HSCT) is poor. CPX-351 is a new drug composed by liposomal encapsulated cytarabine and daunorubicin, at a fixed molecular ratio of 5:1. It showed superior results, compared to standard 3+7 induction, in a phase III trial (Lancet et al, JCO 2018) in patients affected by t-AML or AML with myelodisplasia-related changes and it is now commercially available for secondary AML (sAML). We recently published results from CPX-351 Italian Named (Compassionate) Use Program (CUP) which enrolled 73 elderly sAML patients (Guolo et al, Blood Cancer J. 2020) showing that CPX-351 is an effective induction regimen for high risk AML patients treated with a curative aim. With a limited follow up, our data suggested the good activity and tolerability of CPX-351. Good quality remissions with acceptable toxicity in the majority of patients was achieved and CPX-351 increased the feasibility of HSCT in a poor risk AML cohort. Scarce data are available on long term outcome of high risk patients receiving CPX-351 in the real life setting. Here we report the results from the extended follow up analysis of the Italian CUP.Results:Seventy three patients were enrolled between December 2018 and June 2019 in a compassionate use program (CUP) in 33 Italian Hematology Centers. Data collection began on July 2019 and included 71/73 patients (97.2%), enrolled in 31 Centers.As previously reported, median age was 65.5 years (52-79). Sixty-two (88%) patients had at least one relevant comorbidity upon enrollment. Six patients (9%) presented with ECOG 3-4 upon enrollment.With a median follow up of 22 months, median overall survival (OS) was 13 months (21.2 - 22.8 95% IC). Two-years OS was 28.6% in the whole cohort. In order to confirm the positive impact of HSCT in first complete remission (CR) and the correlation with the other variables, a landmark model was applied, including only patients alive and in CR at day 90. In landmark analysis, HSCT performed in first CR after CPX-351 was the only significant predictor of longer survival: median OS was not reached for patients transplanted in first CR Vs 12 months for patients who did not undergo HSCT, p < 0.05, Figure1). Two-year OS for patients who received HSCT was 57.6% vs 15.8% for patients who did not undergo HSCT.Conclusions:Results from the extended follow up of Italian CPX-351 CUP confirm the good activity CPX-351 in such a difficult cohort as sAML. Two-year OS for transplanted patients is high despite the high median age, the high frequency of severe comorbidities in this real life cohort of patients and the high frequency of high risk AML. On the contrary, non-transplanted patients show a poor outcome, thus confirming that CPX-351 induction as an optimal bridge to transplant induction therapy. [Display omitted] DisclosuresGalimberti: Incyte: Speakers Bureau; AbbVie, Janssen: Honoraria, Other: Travel grants. Marco: Insight,: Consultancy; Jazz: Consultancy; Janssen: Consultancy. Fracchiolla: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Speakers Bureau. Tafuri: Roche: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Rossi: Novartis: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Pagano: Gilead Science, MSD, Pfizer, Basilea, Janssen, Novartis, Jazz Pharmaceutical, Cidara: Membership on an entity's Board of Directors or advisory committees; Menarini: Consultancy; Gilead Sciences, MSD, Pfizer Pharmaceuticals, Astellas Pharma: Speakers Bureau.

Unique Metabolic Vulnerabilities of Myelodysplastic Syndrome Stem Cells

Background: The mechanisms that cause the progression of myelodysplastic syndrome (MDS) are poorly understood. Little is known about major signaling networks and energy metabolism in MDS cells as patients progress from low risk (LR) to high risk (HR) disease and from high risk to secondary acute myelogenous leukemia (sAML). As many as 30% of HR MDS patients progress to sAML and a portion of LR MDS patients progress to HR. The goal of this project is preventing progression by identifying MDS-specific targets for therapy. A deeper understanding of the metabolic properties of leukemia stem cells (LSCs) in AML has shown these cells are uniquely vulnerable to venetoclax and azacitidine (Ven/Aza) (Pollyea et al, Nat. Medicine, 2018) and metabolic changes cause resistance to Ven/Aza (Stevens et al, Nat. Cancer, 2021). Little however is known about the contribution of metabolism to the pathogenesis of MDS. The contributing factors to progression including metabolic properties, transcriptional programs, and immunophenotype are examined in this study.Methods: Bone marrow specimens from MDS patients at various disease stages, including serial samples during progression, were obtained. Single cell techniques including mass cytometry, antibody based single cell RNA sequencing (CITE-Seq) and transcriptional profiling with RNA sequencing were used to elucidate novel mechanisms of progression. Selective targeting of primitive MDS cells was tested using several agents.Results: Our previous work characterizing MDS stem cells (MDSC) showed significant similarities between MDSCs and AML LSCs (Stevens et al, Nat. Communications, 2018). However, little is known about lower risk disease. In order to understand transcriptional changes and their relationship to metabolism across pathogenesis, the transcriptome of blasts from patients with LR, intermediate (INT), or HR IPSS scores was investigated. The first major transcriptional difference identified was enrichment of glycolysis pathway at LR and INT stage. In contrast, HR MDS demonstrated enrichment of oxidative phosphorylation. Furthermore, comparison of intermediate to HR MDS showed increased RNA polymerase and Ribosome pathways at the HR stage. These changes demonstrate the progressive alteration of metabolic properties during MDS pathogenesis with cells first relying on mechanisms associated with normal stem cells (i.e. glycolysis) and later transitioning to a state associated with AML stem cells (i.e. reliance on oxidative phosphorylation).Using serial specimens of patients of who progressed from LR to HR MDS we performed CITE-Seq and mass cytometry. CITE-seq in serial specimens showed up-regulation of protein translation and oxidative phosphorylation in a subset of MDS stem and progenitor cells (CD34+ at transcript and antibody level) present at LR stage and conserved at HR stage (Fig 1A-C). MDSCs also acquired surface antigens including CD99 and CD52 upon progression from LR to HR. Analysis of the mass cytometry data showed significant overlap with CITE-Seq data including increased CD123+ and MCL1 expression in MDS stem cells upon progression.In order to understand therapeutic vulnerabilities as they relate to progression, we investigated ex vivo drug response in LR and HR specimens. MDS samples were challenged with two regimens, Ven/Aza, a regimen known to inhibit OXPHOS; and omacetaxine and azacitidine (Oma/Aza), which inhibits translation. CITE-seq showed that MDSC were selectively sensitive to these agents (Fig 1D). Importantly, addition of either drug regimen caused ablation of MDSC at LR and HR stages and these changes were most profound in cells with LSC properties.Based on preclinical findings, we are investigating MDS patients treated with Ven/Aza or Oma/Aza via CITE-seq and metabolomics for correlation of clinical response with properties of MDSC. Preliminary studies show that patients that respond to Oma/Aza present with a population of MDSC with transcriptional signatures of protein translation and LSCs (Fig. 1E). Studies are underway to investigate overlapping properties of ven/aza resistance in AML to resistance in MDS specifically investigating fatty acid metabolism in MDSC.Conclusions: Analysis of MDS patient bone marrow reveals acquisition of aberrant metabolic properties at both low and high risk stages of disease. These distinct aspects of MDSC biology create unique and targetable features. [Display omitted] DisclosuresPollyea: Genentech: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; Syndax: Consultancy; Takeda: Consultancy; Daiichi Sankyo: Consultancy; Celgene/BMS: Consultancy; Amgen: Consultancy; AbbVie: Consultancy, Research Funding; Agios: Consultancy; Glycomimetics: Other.

Anti-inflammatory treatment in MPN: targeting TNFR1 and TNFR2 in JAK2-V617F–induced disease

AbstractChronic nonresolving inflammatory syndrome is a major disease feature in myeloproliferative neoplasms (MPNs). Systemic inflammation promotes the growth of the JAK2-V617F+ hematopoietic stem cell clone and is associated with constitutive symptoms (eg, fever, cachexia, and fatigue). Therefore, it is being discussed whether anti-inflammatory therapy, in addition to the well-established JAK inhibitor therapy, may be beneficial in the control of constitutive symptoms. Moreover, effective control of the inflammatory microenvironment may contribute to prevent transformation into secondary myelofibrosis and acute leukemia. Given the pivotal role of tumor necrosis factor α (TNF-α) in MPN and the distinct roles of TNF-α receptor 1 (TNFR1) and TNFR2 in inflammation, we investigated the therapeutic effects of αTNFR1 and αTNFR2 antibody treatment in MPN-like disease using the JAK2+/VF knock-in mouse model. Peripheral blood counts, bone marrow/spleen histopathology, and inflammatory cytokine levels in serum were investigated. αTNFR2 antibody treatment decreased white blood cells and modulated the serum levels of several cytokines [CXCL2, CXCL5, interleukin-12(p40)], as well as of macrophage colony-stimulating factor, but they lacked efficacy to ameliorate hematocrit and splenomegaly. αTNFR1 antibody treatment resulted in the mild suppression of elevated hematocrit of −10.7% and attenuated splenomegaly (22% reduction in spleen weight). In conclusion, our studies show that TNFR1 and TNFR2 play different roles in the biology of JAK2-V617F–induced disease that may be of relevance in future therapeutic settings.