Prognostic Factors and Clinical Outcomes in Patients with Blast Phase Chronic Myeloid Leukemia.

BACKGROUND: Given the low incidence of patients with advanced chronic myeloid leukemia (CML), comprehensive clinical characteristics and outcomes of cohort studies of patients diagnosed with blast phase chronic myeloid leukemia (BP-CML) are limited. We examined the clinical features of blast phase CML, including the TKI selection, treatment response, and whether they have had hematopoietic stem cell transplantation (HSCT) or not. METHODS: We performed a retrospective cohort study, including BP-CML patients diagnosed in our center from January 2013 to December 2022. Clinical features, treatment therapy, and overall survival (OS) were investigated. RESULTS: Out of the 11 patients, 2 were myeloid type, eight patients were B-lymphoid, and one was T-lymphoid. Four patients suffered from chromosome abnormalities. Four patients were identified with BCR-ABL1 kinase domain mutation, including T315I, E255K, M244v, and E279K. The overall CR, CRi, PR, and MLFS rates were 9%, 54%, 27%, and 9%, respectively. The median follow-up was 21 months (9.5 - 33 months). At the end of the follow-up time, seven patients died. CML patients with lymphoids tended to get a better OS than patients with a type of myeloid, but the difference was not statistically significant (p > 0.05). Patients who received HSCT had an improved OS by two years compared to those who had not received HSCT. CONCLUSIONS: The prognosis of BP-CML patients was poor. Given the rarity of BP-CML and the limitation of clinical trial data, large-scale multi-center prospective studies are urgently needed to confirm and improve the treatment of patients with BP-CML in the future.

Assessment of Total Antioxidant Capacity, 8-Hydroxy-2'-deoxy-guanosine, the Genetic Landscape, and Their Associations in BCR::ABL-1-Negative Chronic and Blast Phase Myeloproliferative Neoplasms.

Myeloproliferative neoplasms (MPNs), namely, polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are clonal stem cell disorders defined by an excessive production of functionally mature and terminally differentiated myeloid cells. MPNs can transform into secondary acute myeloid leukemia (sAML/blast phase MPN) and are linked to alterations in the redox balance, i.e., elevated concentrations of reactive oxygen species and markers of oxidative stress (OS), and changes in antioxidant systems. We evaluated OS in 117 chronic phase MPNs and 21 sAML cases versus controls by measuring total antioxidant capacity (TAC) and 8-hydroxy-2'-deoxy-guanosine (8-OHdG) concentrations. TAC was higher in MPNs than controls (p = 0.03), particularly in ET (p = 0.04) and PMF (p = 0.01). MPL W515L-positive MPNs had higher TAC than controls (p = 0.002) and triple-negative MPNs (p = 0.01). PMF patients who had treatment expressed lower TAC than therapy-free subjects (p = 0.03). 8-OHdG concentrations were similar between controls and MPNs, controls and sAML, and MPNs and sAML. We noted associations between TAC and MPNs (OR = 1.82; p = 0.05), i.e., ET (OR = 2.36; p = 0.03) and PMF (OR = 2.11; p = 0.03), but not sAML. 8-OHdG concentrations were not associated with MPNs (OR = 1.73; p = 0.62) or sAML (OR = 1.89; p = 0.49). In conclusion, we detected redox imbalances in MPNs based on disease subtype, driver mutations, and treatment history.

Targeting MCL1-driven anti-apoptotic pathways overcomes blast progression after hypomethylating agent failure in chronic myelomonocytic leukemia.

RAS pathway mutations, which are present in 30% of patients with chronic myelomonocytic leukemia (CMML) at diagnosis, confer a high risk of resistance to and progression after hypomethylating agent (HMA) therapy, the current standard of care for the disease. Here, using single-cell, multi-omics technologies, we seek to dissect the biological mechanisms underlying the initiation and progression of RAS pathway-mutated CMML. We identify that RAS pathway mutations induce transcriptional reprogramming of hematopoietic stem and progenitor cells (HSPCs) and downstream monocytic populations in response to cell-intrinsic and -extrinsic inflammatory signaling that also impair the functions of immune cells. HSPCs expand at disease progression after therapy with HMA or the BCL2 inhibitor venetoclax and rely on the NF-κB pathway effector MCL1 to maintain survival. Our study has implications for the development of therapies to improve the survival of patients with RAS pathway-mutated CMML.

Treatment approach and outcomes of patients with accelerated/blast-phase myeloproliferative neoplasms in the current era.

ABSTRACT: Progression of myeloproliferative neoplasms (MPNs) to accelerated or blast phase is associated with poor survival outcomes. Since 2017 there have been several therapies approved for use in acute myeloid leukemia (AML); these therapies have been incorporated into the management of accelerated/blast-phase MPNs (MPN-AP/BP). We performed a multicenter analysis to investigate outcomes of patients diagnosed with MPN-AP/BP in 2017 or later. In total, 202 patients were identified; median overall survival (OS) was 0.86 years. We also analyzed patients based on first-line treatment; the 3 most common approaches were intensive chemotherapy (n = 65), DNA methyltransferase inhibitor (DNMTi)-based regimens (n = 65), and DNMTi + venetoclax-based regimens (n = 54). Median OS was not significantly different by treatment type. In addition, we evaluated response by 2017 European LeukemiaNet AML criteria and 2012 MPN-BP criteria in an effort to understand the association of response with survival outcomes. We also analyzed outcomes in 65 patients that received allogeneic hematopoietic stem cell transplant (allo-HSCT); median OS was 2.30 years from time of allo-HSCT. Our study demonstrates that survival among patients with MPN-AP/BP is limited in the absence of allo-HSCT even in the current era of therapeutics and underscores the urgent need for new agents and approaches.

A comparative analysis of the clinical and genetic profiles of blast phase BCR::ABL1-negative myeloproliferative neoplasm and acute myeloid leukemia, myelodysplasia-related.

INTRODUCTION: The classic Philadelphia chromosome-negative myeloproliferative neoplasms (Ph (-) MPNs), have variable potential for progression to the blast phase (MPN-BP) of the disease. Except initiated by distinct driver mutations, MPN-BP frequently carry similar genetic abnormalities defining acute myeloid leukemia myelodysplasia-related (AML-MR). Because of dissimilar initial pathogenesis, MPN-BP and AML-MR are retained under different disease categories. To determine if separately classifying these entities is justified, we compare MPN-BP with AML-MR patients based on mutational landscape and clinical parameters. METHODS: 104 MPN-BP patients and 145 AML-MR patients were identified with available clinical, cytogenetic, and genetic data. RESULTS: AML-MR patients presented with a higher blast count (median, 51% vs. 30%) while MPN-BP patients had higher WBC counts, platelet counts and bone marrow cellularity (all p<0.0001). Patients with MPN-BP showed similar genetic mutations with similar mutation pattern (functional domain, hotspot and locus involved by the mutations) but a different mutation rate from AML-MR, with more frequent JAK2, CALR, MPL, ASXL1, IDH2, SETBP1 and SRSF2 mutations and less frequent TP53 and DNMT3A mutations. The overall survival (OS) of MPN-BP (OS post-BP-progression) is comparable to that of AML-MR (median OS, 9.5 months vs. 13.1 months, p=0.20). In addition, the subgroups of MPN-BP show similar OS as AML-MR. When harboring certain mutation such as TP53, ASXL1, DNMT3A, TET2, RUNX1, IDH1, IDH2, EZH2, U2AF1, BCOR and SRSF2, MPN-BP and AML-MR patients carrying the same somatic mutation show no difference in OS. CONCLUSION: MPN-BP and AML-MR harbor similar somatic mutations and clinical outcomes, suggesting a unified clinical disease entity.

Spotlight on the real-world treatment of CML pts in Germany: a retrospective survey in private oncology practices.

Clinical trials in chronic myeloid leukemia (CML) are usually carried out in specialized centers whereas primary care for patients (pts) with CML is mainly provided by local oncology practices. The aim of this study was to assess treatment practices in pts with CML in the setting of private oncology practices in Germany. We collected data of 819 pts with a confirmed diagnosis (dx) of CML in 2013 or later from 43 practices. At dx, 84.2% (n=690) and 9.4% (n=77) of pts were in chronic or accelerated phase, 0.7% (n=6) had a blast crisis. Molecular monitoring was provided by EUTOS certified laboratories in 87.7% of pts. Typical BCR::ABL1 transcripts were detected in 86.6% (n=709). Molecular response was assessed after 2.8, 6.0, 9.4 and 12.9 m (mean) after start of treatment. Of the pts with available data, 11.1% did not achieve early molecular response and at 18 m, 83.7% had at least a major molecular response. 288 (35.2%) of pts switched to 2nd line (2L) treatment after a mean of 21.0 months. Reasons for 2L treatment were side effects in 43.4% and suboptimal response or failure in 31.4% of pts. 106 pts went on to third line (3L) treatment. 36.8 % of pts switched to and 92.8 % of pts still on 3L treatment achieved BCR::ABL1IS ≤1% at 12 m. In conclusion, in Germany pts with CML are routinely monitored by qPCR and good responses are achieved in the majority. Treatment changes are mainly due to adverse events rather than suboptimal responses.

Management and outcome of patients with chronic myeloid leukemia in blast phase in the tyrosine kinase inhibitor era - analysis of the European LeukemiaNet Blast Phase Registry.

Blast phase (BP) of chronic myeloid leukemia (CML) still represents an unmet clinical need with a dismal prognosis. Due to the rarity of the condition and the heterogeneity of the biology and clinical presentation, prospective trials and concise treatment recommendations are lacking. Here we present the analysis of the European LeukemiaNet Blast Phase Registry, an international collection of the clinical presentation, treatment and outcome of blast phases which had been diagnosed in CML patients after 2015. Data reveal the expected heterogeneity of the entity, lacking a clear treatment standard. Outcomes remain dismal, with a median overall survival of 23.8 months (median follow up 27.8 months). Allogeneic stem cell transplantation (alloSCT) increases the rate of deep molecular responses. De novo BP and BP evolving from a previous CML do show slightly different features, suggesting a different biology between the two entities. Data show that outside clinical trials and in a real-world setting treatment of blast phase is individualized according to disease- and patient-related characteristics, with the aim of blast clearance prior to allogeneic stem cell transplantation. AlloSCT should be offered to all patients eligible for this procedure.

Chronic Myeloid Leukemia, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome resulting from a reciprocal translocation between chromosomes 9 and 22 [t9;22] that gives rise to a BCR::ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase in developed countries. Tyrosine kinase inhibitor (TKI) therapy is a highly effective treatment option for patients with chronic phase-CML. The primary goal of TKI therapy in patients with chronic phase-CML is to prevent disease progression to accelerated phase-CML or blast phase-CML. Discontinuation of TKI therapy with careful monitoring is feasible in selected patients. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with chronic phase-CML.

De novo accelerated phase of chronic myeloid leukemia should be recognized even in the era of tyrosine kinase inhibitors.

Overall survival of patients classified according to the European LeukemiaNet 2020 classification. Chronic phase (CP), accelerated phase (AP), blast crisis (BC), low risk (LR), intermediate risk (IR), high risk (HR).

Incidence of blast phase in myelofibrosis patients according to anemia severity at ruxolitinib start and during therapy.

BACKGROUND: Anemia is frequently present in patients with myelofibrosis (MF), and it may be exacerbated by treatment with the JAK2-inhibitor ruxolitinib (RUX). Recently, a relevant blast phase (BP) incidence has been reported in anemic MF patients unexposed to RUX. METHODS: The authors investigated the incidence of BP in 886 RUX-treated MF patients, included in the "RUX-MF" retrospective study. RESULTS: The BP incidence rate ratio (IRR) was 3.74 per 100 patient-years (3.74 %p-y). At therapy start, Common Terminology Criteria for Adverse Events grade 3-4 anemia (hemoglobin [Hb] <8 g/dL) and severe sex/severity-adjusted anemia (Hb <8/<9 g/dL in women/men) were present in 22.5% and 25% patients, respectively. IRR of BP was 2.34 in patients with no baseline anemia and reached respectively 4.22, 4.89, and 4.93 %p-y in patients with grade 1, 2, and 3-4 anemia. Considering the sex/severity-adjusted Hb thresholds, IRR of BP was 2.85, 4.97, and 4.89 %p-y in patients with mild/no anemia, moderate, and severe anemia. Transfusion-dependent patients had the highest IRR (5.03 %p-y). Progression-free survival at 5 years was 70%, 52%, 43%, and 27% in patients with no, grade 1, 2, and 3-4 anemia, respectively (p < .001). At 6 months, 260 of 289 patients with no baseline anemia were receiving ruxolitinib, and 9.2% had developed a grade 3-4 anemia. By 6-month landmark analysis, BP-free survival was significantly worse in patients acquiring grade 3-4 anemia (69.3% vs. 88.1% at 5 years, p < .001). CONCLUSIONS: This study highlights that anemia correlates with an increased risk of evolution into BP, both when present at baseline and when acquired during RUX monotherapy. Innovative anemia therapies and disease-modifying agents are warranted in these patients.

Chimeric antigen-receptor (CAR) engineered natural killer cells in a chronic myeloid leukemia (CML) blast crisis model.

During the last two decades, the introduction of tyrosine kinase inhibitors (TKIs) to the therapy has changed the natural history of CML but progression into accelerated and blast phase (AP/BP) occurs in 3-5% of cases, especially in patients resistant to several lines of TKIs. In TKI-refractory patients in advanced phases, the only curative option is hematopoietic stem cell transplantation. We and others have shown the relevance of the expression of the Interleukin-2-Receptor α subunit (IL2RA/CD25) as a biomarker of CML progression, suggesting its potential use as a therapeutic target for CAR-based therapies. Here we show the development of a CAR-NK therapy model able to target efficiently a blast crisis cell line (K562). The design of the CAR was based on the scFv of the clinically approved anti-CD25 monoclonal antibody (Basiliximab). The CAR construct was integrated into NK92 cells resulting in the generation of CD25 CAR-NK92 cells. Target K562 cells were engineered by lentiviral gene transfer of CD25. In vitro functionality experiments and in vivo leukemogenicity experiments in NSG mice transplanted by K562-CD25 cells showed the efficacy and specificity of this strategy. These proof-of-concept studies could represent a first step for further development of this technology in refractory/relapsed (R/R) CML patients in BP as well as in R/R acute myeloblastic leukemias (AML).

Spectrum of BCR-ABL mutations in Azerbaijanian imatinib-resistant patients with chronic myeloid leukemia.

Objective: BCR-ABL1 kinase domain (KD) mutations can lead to resistance to first- and second-generation tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML). Here, we present the first report of the spectrum of mutations in the BCR-ABL1 KD of CML patients from Azerbaijan. Materials and methods: Samples for mutation screening were obtained from patients experiencing resistance to first line TKIs or from patients in acceleration phase (AP) or blast crisis (BC) at the time of diagnosis. The cDNA region corresponding to BCR-ABL1 KD was sequenced by pyrosequencing method. The χ2 test was used to assess the association of categorical variables between mutation-positive and -negative groups. In addition, the Kaplan-Meier method was applied to generate survival curves. Results: Eight different point mutations were identified in 22 (13.4%) out of 163 CML patients experiencing resistance to TKIs. The types of mutations detected were as follows: Contact binding site mutations 50% (11), SH2 domain mutations 27.4% (six), P-loop mutations 18.1% (four), and SH3 domain mutations accounting for 4.5% (one). The most common mutation was T315I, accounting for 5% (n = 8) of all patients. Significant association was identified between BCR-ABL1 mutations and additional chromosomal aberrations as well as between the mutations and disease phases (p < 0.05). Twelve out of 22 patients with BCR-ABL1 mutations and seven out of eight with T315I were in BC. Overall survival (OS) of the patients with BCR-ABL1 mutations was significantly lower comparing to the patients with no mutation (p < 0.05) and 8 patients with T315I mutation presented OS of 0%. Conclusion: T315I was the most commonly identified BCR-ABL1 mutation in TKI-resistant CML patients of Azerbaijani origin, being associated with disease progression and poor OS.

Clinical characteristics and prognostic factors of patients with Philadelphia-negative myeloproliferative neoplasm accelerated/blast phase / 中华血液学杂志

Objective: To evaluate the clinical characteristics and prognostic factors of patients with Philadelphia-negative myeloproliferative neoplasm-accelerated phase/blast phase (MPN-AP/BP) . Methods: A total of 67 patients with MPN-AP/BP were enrolled from February 2014 to December 2021 at the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences. Their clinical features and prognostic factors were analyzed retrospectively. Results: ① Sixty-seven patients with MPN-AP/BP with a median age of 60 (range, 33-75) years, including 31 males (46.3% ) and 36 females (53.7% ) , were analyzed. Forty-eight patients progressed from primary myelofibrosis (PMF) , and 19 progressed from other myeloproliferative neoplasms (MPNs) , which included polycythemia vera, essential thrombocythemia, and MPN unclassifiable. Patients who progressed from PMF had higher lactate dehydrogenase (LDH) levels than those who progressed from other MPNs (925.95 vs. 576.2 U/L, P=0.011) , and there were higher proportions of patients who progressed from PMF with splenomegaly (81.4% vs. 57.9% , P=0.05) , a myelofibrosis grade of ≥2 (93.6% vs. 63.2% , P=0.004) , and a shorter duration from diagnosis to the transformation to AP/BP (28.7 vs. 81 months, P=0.001) . ② JAK2V617F, CALR, and MPLW515 were detected in 41 (61.2% ) , 13 (19.4% ) , and 3 (4.5% ) patients, respectively, whereas 10 (14.9% ) patients did not have any driver mutations (triple-negative) . Other than driver mutations, the most frequently mutated genes were ASXL1 (42.2% , n=27) , SRSF2 (25% , n=16) , SETBP1 (22.6% , n=15) , TET2 (20.3% , n=13) , RUNX1 (20.3% , n=13) , and TP53 (17.2% , n=11) . The ASXL1 mutation was more enriched (51.1% vs. 21.1% , P=0.03) , and the median variant allele fraction (VAF) of the SRSF2 mutation (median VAF, 48.8% vs. 39.6% ; P=0.008) was higher in patients who progressed from PMF than those who progressed from other MPNs. ③ In the multivariate analysis, the complex karyotype (hazard ratio, 2.53; 95% confidence interval, 1.06-6.05; P=0.036) was independently associated with worse overall survival (OS) . Patients who received allogeneic stem cell transplantation (allo-HSCT) (median OS, 21.3 vs. 3 months; P=0.05) or acute myeloid leukemia-like (AML-like) therapy (median OS, 13 vs. 3 months; P=0.011) had significantly better OS than those who received supportive therapy. Conclusion: The proportions of patients with PMF-AP/BP with splenomegaly, myelofibrosis grade ≥2, a higher LDH level, and a shorter duration from diagnosis to the transformation to AP/BP were higher than those of patients with other Philadelphia-negative MPN-AP/BP. The complex karyotype was an independent prognostic factor for OS. Compared with supportive therapy, AML-like therapy and allo-HSCT could prolong the OS of patients with MPN-AP/BP.