Blast Phase Chronic Myeloid Leukemia Research Articles

An Overview of Myeloid Blast-Phase Chronic Myeloid Leukemia

Myeloid blast-phase chronic myeloid leukemia (MBP-CML) is a rare disease with a dismal prognosis. It is twice as common as lymphoid blast-phase CML, and its prognosis is poorer. Despite the success with tyrosine kinase inhibitors in the treatment of chronic-phase CML, the same does not hold true for MBP-CML. In addition to the Philadelphia chromosome, other chromosomal and molecular changes characterize rapid progression. Although some progress in elucidating the biology of MBP-CML has been made, there is need to discover more in order to develop more satisfactory treatment options. Currently, most common treatment options include tyrosine kinase inhibitors (TKIs) as monotherapy or in combination with acute myeloid leukemia-based intensive chemotherapy regimens. Some patients may develop resistance to TKIs via BCR-ABL1-dependent or BCR-ABL1-independent mechanisms. In this paper, we provide an overview of the biology of MBP-CML, the current treatment approaches, and mechanisms of resistance to TKIs. In order to improve treatment responses in these patients, more emphasis should be placed on understanding the biology of myeloid blastic transformation in CML and mechanisms of resistance to TKIs. Although patient numbers are small, randomized clinical trials should be considered.

Intensification of upfront chemotherapy for patients with myeloid blast phase CML: a single center experience.

Outcomes for patients with myeloid blast phase chronic myeloid leukemia (CML-MBP) are dismal, and no preferred chemotherapy regimen has been identified. Recent studies have suggested a higher response rate with administration of timed-sequenced regimens (TSR) (purine analog, high-dose cytarabine, anthracycline) in high-risk acute myeloid leukemia patients. We retrospectively evaluated outcomes of newly diagnosed CML-MBP patients consecutively treated at our institution with a TSR or standard-dose cytarabine and an anthracycline ("7 + 3") combined with a tyrosine-kinase inhibitor (TKI) between 2011 and 2023. Endpoints of interest included hematologic response, clinically significant cytogenetic response (CSCR) defined as achieving at least a minor cytogenetic response (Ph + metaphases 0%-≤65%) after induction therapy, event-free survival (EFS), and overall survival (OS). A total of 18 patients with CML-MBP were included of whom 9 (50%) received a TSR and 9 (50%) received "7 + 3". Hematologic response (55.6% vs. 55.6%) and CSCR (25% vs. 37.5%) were similar between TSR- and "7 + 3" treated patients. Twelve patients (66.7%) experienced at least one grade ≥ 3 non-hematologic, end-organ toxicity with 33.3% and 11.1% of TSR- and 7 + 3-treated patients, respectively, experiencing at least two. Our data suggests that intensification of upfront chemotherapy does not appear to improve treatment outcomes in CML-MBP patients however, further studies are warranted to confirm these findings involving a larger cohort.

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

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. 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. 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. 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.

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.

Treatment outcome of the tyrosine kinase inhibitor (bosutinib) in previously treated chronic myeloid leukemia patients (sample of Iraqi patients)

Abstract: BACKGROUND: Chronic myeloid leukemia (CML) is a type of myeloproliferative neoplasm characterized by the excessive accumulation of malignant myeloid cells in the bone marrow and peripheral blood. This condition is primarily triggered by a specific chromosomal translocation known as t(9;22) (q34.13;q11.23), which leads to the formation of the BCR-ABL fusion gene. The treatment landscape for CML has undergone significant changes with the approval of tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL1 kinase activity. One such inhibitor is bosutinib, which has been available for several years to treat patients with chronic, accelerated, and blast-phase CML who have shown resistance or intolerance to previous therapies. OBJECTIVES: The aim of this study was to assess efficacy and safety of Bosutinib as a 2nd line therapy in CML patients, in addition to effect of adherence to treatment on patients response. PATIENTS AND METHODS: Eighty-five patients with CML were enrolled in a prospective cohort study from October 2021 to October 2022 at Hematology Center in Medical City Complex – Baghdad. All patients failed to at least one TKI, and all of them started escalated dose of bosutinib. The patients were followed-up by assessing molecular and cytogenetic response at 3 and 6 months and monitored carefully for adverse events (AEs) which were graded by common terminology IX criteria for AEs version 5. Adherence to bosutinib was also monitored by a specific adherence scale to optimize the response rate to treatment. RESULTS: The mean age of patients was 47.3 ± 14.9 (range: 18–77), with male:female ratio 1.4:1. Status of CML patients showed that 89.4% were in the chronic phase, 5.8% in accelerated phase, and 4.7% in blast phase. Regarding the number of previous TKIs before bosutinib, 72.9% of patients failed to prior one TKI (imatinib). At 6 months (72.3%), patients achieve optimal response according to European Leukemia Net criteria 2013. Gastrointestinal symptoms and dermatological manifestations were the most common nonhematological AEs of bosutinib. According to 9-item Morisky Medication Adherence Scale, 42% of patients were adherent to medication which showed a significant association with a higher number of optimal response (P = 0.0001). CONCLUSION: Bosutinib is effective with a high and promising response as a subsequent line treatment in CML patients, and it is generally safe and associated with mild-to-moderate tolerable and manageable AEs. Adherence to the drug plays a significant role in optimal response to bosutinib.

MOLECULAR BIOLOGY AND DRUG THERAPIES OF CHRONIC MYELOID LEUKEMIA: A REVIEW OF RECENT LITERATURE

Background: Chronic myeloid leukaemia (CML) is a clonal myeloproliferative disorder of blood stem cells, which is typically characterized by the presence of a Philadelphia chromosome. Even though there have been several studies on the molecular genetics, pharmacogenomics, pharmacological treatments for CML, and its mechanism is still not fully understood. Objectives: This study is designed to provide new updates and better insights into CML molecular biology and drug therapy, along with their benefits and drawbacks. Methodology: For this review, the recent literature was searched from January 2019 to 2023 through various electronic databases. Results: Review findings further suggested that imatinib mesylate was the first tyrosine kinase inhibitor (TKI) licensed as first-line therapy for affected people with CML in the chronic, blast, and rapid phases. Dasatinib is another second-generation multi-target kinase inhibitor, for imatinib-resistant CML treatment in all stages, which is 325 times more effective than imatinib and 16-fold more effective than nilotinib. Nilotinib received approval from the Food and Drug Administration (FDA) for handling imatinib-resistant patients. Bosutinib and ponatinib are other renowned TKIs taken orally. European Medicine Agency (EMA) and FDA-approved asciminib in moderate to severe, rapid, and blast-phase CML patients intolerant to previous therapies. Conclusion: In conclusion, this study indicated the need to include advanced computational tools in addition to the large sample size of cohort studies, which may result in a better understanding of pathophysiology and better clinical outcomes.

Accelerated-phase CML: de novo and transformed.

Despite the dramatic improvements in outcomes for the majority of chronic myeloid leukemia (CML) patients over the past 2 decades, a similar improvement has not been observed in the more advanced stages of the disease. Blast phase CML (BP-CML), although infrequent, remains poorly understood and inadequately treated. Consequently, the key initial goal of therapy in a newly diagnosed patient with chronic phase CML continues to be prevention of disease progression. Advances in genomic investigation in CML, specifically related to BP-CML, clearly demonstrate we have only scratched the surface in our understanding of the disease biology, a prerequisite to devising more targeted and effective therapeutic approaches to prevention and treatment. Importantly, the introduction of the concept of "CML-like" acute lymphoblastic leukemia (ALL) has the potential to simplify the differentiation between BCR::ABL1-positive ALL from de novo lymphoid BP-CML, optimizing monitoring and therapeutics. The development of novel treatment strategies such as the MATCHPOINT approach for BP-CML, utilizing combination chemotherapy with fludarabine, cytarabine, and idarubicin in addition to dose-modified ponatinib, may also be an important step in improving treatment outcomes. However, identifying patients who are high risk of transformation remains a challenge, and the recent 2022 updates to the international guidelines may add further confusion to this area. Further work is required to clarify the identification and treatment strategy for the patients who require a more aggressive approach than standard chronic phase CML management.

Chronic Myeloid Leukemia Presenting with Mixed Phenotype B/Myeloid Blast Phase: A Diagnostic Challenge

Abstract Introduction/Objective Chronic myeloid leukemia (CML) is typically identified in chronic phase, however about 5% of cases present in a more advanced phase. In blast phase (BP), the blasts are most commonly of myeloid lineage, less commonly lymphoid, and rarely mixed lineage cases are encountered. A mixed phenotype at presentation raises the possibility of a de novo mixed phenotype acute leukemia (MPAL) with BCR::ABL1 fusion and requires careful correlation with ancillary studies to confirm the diagnosis. Methods/Case Report The patient is a 60-year-old man who presented with leukocytosis, anemia, normal platelet count, and blasts identified on peripheral blood smear examination. A bone marrow biopsy demonstrated hypercellular marrow and a dimorphic population of large and small blasts, comprising nearly 70% of cellularity. Flow cytometry demonstrated distinct myeloid and B-lymphoid blast populations, both of which expressed CD13 and TdT. Interphase fluorescence in situ hybridization (FISH) showed the BCR::ABL1 fusion in more than 90% of nuclei, including segmented nuclei, and conventional cytogenetic studies showed t(9;22)(q34.1;q11.2) in 19 of 20 metaphases. Molecular studies demonstrated the minor BCR::ABL1 p190 transcript, as well as ASXL1 and dual RUNX1 mutations. The discrepant number of BCR::ABL1 positive cells by FISH and conventional cytogenetic studies compared to the proportion of blasts, and its presence in segmented nuclei, enabled a diagnosis of CML with mixed phenotype blast phase despite absence of features such as basophilia or significant granulocytic left shift. Results (if a Case Study enter NA) NA Conclusion We share this case of CML in mixed phenotype blast phase to highlight the importance of careful evaluation in distinguishing this rare presentation from de novo MPAL, particularly with BCR::ABL1 fusion. Features such as a disproportionate number of nuclei or metaphases carrying the t(9;22) translocation on FISH or conventional cytogenetic studies and the presence of BCR::ABL1 in mature granulocytes can be helpful when other morphologic features of CML are absent.

Tyrosine Kinase Inhibitors with Intensive Chemotherapy in AML with t(9;22)(q34.1;q11.2)/ BCR::ABL1: Time to Reconsider Prognostic Risk? a Study from the Dataml Registry

Introduction De novo AML with t(9;22)(q34.1;q11.2)/ BCR::ABL1 is now a distinct entity of the ICC and WHO 2022 classifications within the group of AML with defining genetic abnormalities. This entity is distinguished from cases with history of chronic myeloid leukemia (CML) and ≥ 20% blasts, which are classified as CML in myeloid blast phase (CML-BP), although the distinction between both entities could be challenging. In the 2022 ELN classification, AML with BCR::ABL1 belong to the adverse risk group. However, this entity is very rare and generally excluded from clinical trials. Thus, there is little data on outcome especially since the era of BCR::ABL1 inhibitors (Orsmark-Pietras C et al.). In this study, we thought to describe treatments and outcome of patients (pts) with de novo AML with t(9;22)(q34.1;q11.2)/ BCR::ABL1 in comparison with CML-BP and ELN 2017 intermediate (Int) or adverse (Adv) risk AML. Methods Inclusion criteria were: pts aged ≥ 18y, included in the DATAML registry between 2000 and 2021, with either de novo BCR::ABL1 AML defined as no previous history of CML, no previous treatment with TKI and ≥ 20% blasts in bone marrow/blood or CML-BP defined as the occurrence of ≥ 20% blasts following the diagnosis of CML in chronic phase. Outcomes of pts with de novo BCR::ABL1 AML were compared with those of CML-BP pts and AML with ELN 2017 Int (n=643) or Adv (n=863) risk treated with intensive chemotherapy (IC) over the same period. A 50-gene NGS panel was retrospectively performed on available samples. Results We identified 20 pts with de novo BCR::ABL1 AML among 5819 AML (0.3%). We only studied the 18 pts who received IC. Their main characteristics were: female to male ratio (55.6%), median age (54y), extramedullary disease (47%) including splenomegaly (35%); high WBC at diagnosis; isolated t(9;22) (67%); p210 isotype (78%), mutations in ASXL1, RUNX1, NPM1, TET2, BCOR, BCORL1, DNMT3A, EZH2, IDH1, KDM6A, NF1, SMC1A, SRSF2, WT1. Comparisons with the 24 pts CML-BP who were treated with IC are shown in the Table. The main differences between both groups was a higher WBC and the presence of NPM1 mutation in de novo pts whereas ABL1 mutations were found in CML-BP only. Induction chemotherapy was mainly cytarabine and daunorubicin (45-90 mg/m²) combined with imatinib (median dose 600 mg, range 400-800). Only 2 patients did not receive imatinib because the drug was not available in 2000-2003. Those 2 pts achieved complete remission (CR) but subsequently relapsed and died from progression. Overall, 17 pts (94.4%) achieved CR or CR with incomplete hematologic recovery (CRi) after one or two induction cycles, one pt failed and there was no early death. Consolidation was mainly high dose cytarabine with imatinib and 12 pts received an allogeneic hematopoietic cell transplantation (alloHCT) in first CR/CRi with myeloablative or reduced intensity conditioning in 7 and 5 pts, respectively. Five pts received maintenance therapy with imatinib (n=4) or nilotinib (n=1). Of note, 4 of the 5 CR/CRi pts who were not transplanted in CR1 did not relapse. With a median follow-up of 76.3 months, median RFS was not reached and 2y-RFS was 82.4% (95%CI, 55-94). Median OS was not reached and 2-y OS was 77.4% (95%CI, 50.3-90.9). Of note, there were 3 late deaths at 48, 60 and 84 months unrelated to AML (1 lung cancer, 1 pancreatic cancer, 1 infection). CR/CRi rate was significantly higher in pts with de novo BCR::ABL1 AML(94.4%) compared with CML-BP (79.2%), AML with ELN 2017 Int (83.4%) or Adv (68.5%) risk (P<0.0001). RFS (median, CML-BP: 100.5 months, IQR 19.7-NR; ELN-Int: 20.6 months, IQR 7.2-115.3; ELN-Adv: 10.3 months, IQR 4.4-48.1; P<0.0001) and OS (median, CML-BP: 33.9 months, IQR 14.6-NR; ELN-Int: 26.9 months, IQR 10.3-117.3; ELN-Adv: 11.8 months, IQR 4.7-40.0; P<0.0001) were also significantly improved. 2-y OS was 77.4%, 57.0%, 53.7% and 33.4% in de novo BCR::ABL1 AML, CML-BP, AML with ELN2017 Int and Adv, respectively (P<0.0001) (Figure). Conclusion De novo AML with t(9;22)(q34.1;q11.2)/ BCR::ABL1 is a very rare event in AML classifications (<1%) with particular features. Pts treated with IC and imatinib have a high rate of CR, very low incidence of relapse and a remarkable OS rate that do not support the ELN2022 risk classification . Pts may have prolonged RFS and OS without alloHCT. Further studies are needed to confirm these results and reclassify these AMLs in the intermediate or even favorable group of the ELN 2022 classification.

Whole Genome and Transcriptome Sequencing of 21 Paired Chronic and Blast Phase CML Cases: Acquisition of Genomic Alterations, Changes in the Transcriptomic Profiles and Occurrence of B-Cell Receptor Rearrangements

Background: Since the introduction of tyrosine kinase inhibitor therapy survival has substantially improved in CML. However, a subset of patients become resistant and progress to blast phase. Still the underlying genomic changes are not completely understood. Cohort & Methods: We studied 21 CML patients with paired sample material available from diagnosis in chronic phase (CP) and from blast phase (BP). All patients received a tyrosine kinase inhibitor starting at diagnosis of CML CP. Samples were analyzed by cytomorphology, chromosome banding analysis, WGS (100x, 2x151bp) and WTS (50 Mio reads, 2x101bp). B-cell receptor (BCR) rearrangements were analyzed with MiXCR software. The transcriptomic phenotype (TP) of each CP and BP sample was estimated by mapping their profiles to representative cases diagnosed with B-ALL, T-ALL, MDS, CMML, AML and CML CP. Results: The median time between diagnosis of CP and BP was 14.7 months (range: 4.7 - 137 months). While 18/21 CML in CP showed a TP corresponding to CML CP, one case each showed a TP corresponding to CMML, AML and B-ALL, respectively, although bone marrow blast counts were 6.5%, 5.5% and 5.5%, respectively. Of note, the case with the CMML-TP harbored a p190 BCR:: ABL1 isoform and also resembled CMML in bone marrow morphology. These three cases progressed to BP after 5.8, 5.3, and 8.9 months. The TP in BP corresponded to B-ALL in 13 cases, while 4, 3, and 1 case showed an AML-, CML CP- and MDS-TP, respectively (figure). In CP recurrent genomic alterations in addition to the BCR:: ABL1 fusion were mutations in ASXL1 (n=5), DNMT3A, TET2, RUNX1, and MGA (2 cases each). In BP the genomic landscape was more complex. Additional genetic alterations compared to CP were detected in all cases. Recurrently gained mutations in BP were mutations in WT1, BCOR, and SETD2 (2 cases each). The gain of copy number alterations (CNA) was more frequent. Recurrent CNA were: loss 9p (n=6), gain Ph-chromosome (n=4), loss 7q (n=3), gain 21q (n=3), gain 1q, loss 3q, gain 8q, loss 12p, and loss 13q in 2 patients each. Only three balanced structural variants were gained: a MECOM-, a NUP98:: HHEX- and a KMT2A:: MLLT3-rearrangement. Further, in 11/21 BP resistance mutations within the BCR:: ABL1 kinase domain were detected. The variant allele frequency (VAF) of RUNX1 mutations increased in BP in both cases with RUNX1 mutation present in CP (5% to 42%, time to BP: 4.7 months; 8% to 59%, time to BP: 11.7 months). DNMT3A and MGA mutations were about stable (VAF CP/BP: DNMT3A: 48%/37%, 33%/46%; MGA: 52%/36%, 40%/52%), while TET2 mutations were stable in one case (46%/49%) and decreased in the second (57%/27%). ASXL1 mutations were stable in 2 cases with an AML-TP in BP and lost in 3/5 cases with a B-ALL-TP in BP. BP with a lymphoid TP differed substantially with respect to the genomic profile from BP with myeloid TP. WTS data revealed a clonal BCR rearrangement in 8/13 BP with B-ALL-TP, of which 4 rearrangements are predicted to be productive. Further, CDKN2A/B deletions, IKZF1 deletions, and SETD2 mutations were only found in BP with B-ALL-TP. Thus, CML in BP with a B-ALL-TP showed a genomic landscape similar to B-ALL with BCR:: ABL1-rearrangement. In contrast CML BP cases with an AML-TP (n=4) had gained either rearrangements typically found in AML such as a KMT2A:: MLLT3 rearrangement and a MECOM rearrangement or acquired mutations in RUNX1, BCOR and WT1, or a CN-LOH 11p in combination with a WT1 VAF increase from 51% to 94%. Cases showing still a CML CP-TP (n=3) in BP acquired rather few additional genetic abnormalities (mutations in BCOR, WT1, CTCF; NUP98:: HHEX-rearrangement, gain of Ph-chromosome, loss of 11p, 17q), which were more myeloid in appearance. Conclusions: 1) Extensive genetic profiling indicated a substantial clonal evolution in the progression from CP to BP CML including loss of ASXL1 mutations, expansion of RUNX1 mutated clones, multiple CNA, and the frequent acquisition of a BCR rearrangement in BP with a transcriptomic phenotype resembling B-ALL. 2) A subset of CML cases in CP already showed a transcriptomic phenotype resembling acute leukemia indicating a rapid progression to BP. 3) The presence of a RUNX1 mutated subclone or a clonal BCR rearrangement seem to represent a warning signal in CML CP. 4) The prognostic validity of an extended genetic profiling including ASXL1, RUNX1, BCR rearrangement, and transcriptional signature in CML CP needs to be assessed in forthcoming prospective studies.

The Promising Third-Generation TKI Olverembatinib in Adult BCR::ABL1-Positive Acute Lymphoblastic Leukemia with T315I Mutation and Relapsed/Refractory Disease

Background Olverembatinib (HQP1351) is a novel third-generation tyrosine kinase inhibitor (TKI) that has shown remarkable efficacy and safety in chronic myeloid leukemia (CML). Still, few reports are available on BCR::ABL1-positive acute lymphoblastic leukemia (BCR::ABL1+ ALL). We first reported the early encouraging outcome of olverembatinib in BCR::ABL1+ ALL patients (pts) with T315I mutation or disease progression last year. Here, we enlarged the sample size and included a case of CML in lymphoid blast phase (CML-LBP) who also benefited from olverembatinib to a certain extent. Methods In this observational study, we retrospectively enrolled BCR::ABL1+ ALL or CML-LBP pts with T315I mutation, disease progression, or intolerant to previous TKIs in our institution from Dec. 2021 to May 2023. All pts received olverembatinib monotherapy (40mg qod) or combination therapy. Efficacy was assessed by CR rate, MRD negative (MRD <10 -4) rate by multiparameter flow cytometry (MFC), CMR (BCR-ABL1 transcript<10 -5) rate by RT-qPCR, as well as the survival data. PFS and OS were both calculated from the start of olverembatinib. Adverse events (AEs) were assessed and graded according to CTCAE v5.0. Results Totally, 30 pts with BCR::ABL1+ ALL (n=29) or CML-LBP (n=1) were analyzed. Among 29 BCR::ABL1+ ALL pts (median age of 60 years [range, 23-76]), 14 were in CR with molecular R/R disease, including 1 with MRD only detected by RT-qPCR. While the other 15 had hematological R/R disease, including 4 with central nervous system leukemia. T315I mutation was detected in 23 pts, including 8 with additional mutations. The baseline characteristics are detailed in Table 1. As for the 23-year-old female pt with CML-LBP, dasatinib was switched to olverembatinib when T315I, E255K, and E255V mutations were detected. T315I and E255V were eliminated rapidly after 1-month treatment of olverembatinib, while E255K still existed. At present, the patient maintained in CR, and blinatumomab will be used for MRD clearance before allo-HSCT. She was only included in the safety analysis. Among 14 pts with molecular R/R disease, 61.5% and 50% achieved MRD flow negativity and CMR with a median time of 1.3 months (range, 0.8-4.4) and 1.2 months (range, 0.9-4.4), respectively. Among 15 pts with hematological R/R disease, 80%, 53.3%, and 46.7% achieved CR/CRi, MRD flow negativity, and CMR, with a median time of 1 month (range, 0.2-2.5), 1 month (range, 0.2-3.3) and 2.1 months (range, 0.7-4.6), respectively. Totally, 8 pts underwent allo-HSCT with a median age of 48.5 years (range, 23-60), of which 6 pts achieved CMR before allo-HSCT, and all attained persistent CMR after allo-HSCT. By June 15, 2023, with a median follow-up time of 9.1 months (range, 1.7-16) in BCR::ABL1+ ALL pts, the median PFS was 7.8 months, and the median OS was not reached. For molecular R/R pts, the median PFS and OS were not reached, and for hematological R/R pts, the median PFS and OS were 6.5 and 8.6 months. MRD flow negativity or CMR responders had significantly better PFS and OS (PFS: p<0.001, p<0.001; OS: p<0.001, p<0.001), and bridging allo-HSCT after olverembatinib-based therapy showed a significant survival superiority (PFS: p=0.001; OS: p=0.017). Among the 23 pts with T315I mutation, the MRD flow negativity rate in pts with T315I single mutation was significantly higher than those with additional mutations (p=0.008), and the CMR rate tended to be better (p=0.089). Meanwhile, pts with T315I single mutation showed significant improvements in PFS and OS (Figure 1). As for safety analysis, the olverembatinib-based therapy was well-tolerated. Most non-hematological AEs were G1-2, and most G3-4 AEs were hematological, possibly related to chemotherapy. The incidence of G3-4 cardiovascular AEs was 6.7%. Five elderly pts (median age of 72 years [range, 63-76]) had temporary treatment suspension or dose reduction. No permanent discontinuation or death related to olverembatinib was observed. Conclusion This study further confirmed the efficacy of olverembatinib-based therapy in Chinese adults BCR::ABL1+ ALL pts with T315I mutation or R/R disease, especially in those with T315I single mutation. In addition, bridging allo-HSCT after deeper molecular remission could further improve survival. The safety profiles were manageable, but there is still a need to explore the optimal dose in elderly pts.

3rd-Generation Tyrosine Kinase-Inhibitors and Azacitidine Are Safe and Effective in Myeloid Blast-Phase Chronic Myeloid Leukaemia and Result in a High Proportion of Subjects in 2 nd Chronic Phase Able to Receive a Transplant

Background Myeloidblast phase of chronic myeloid leukemia (CML-MBP) has a terrible prognosis with a haemopoietic cell transplant the only likely cure. Probability of transplant success is markedly increased if someone can be returned to chronic phase. Purposes Study safety and efficacy of olverembatinib or ponatinib and azacitidine (AZA) in this setting. MethodsCML-MBP was diagnosed according to the WHO 2016 criteria. Ponatinib, 45 mg/d or olverembatinib, 30 mg every other d were combined with azacitidine, 75 mg/mE+2/d for 7 d in 28 d cycles. Subjects achieving 2 nd chronic phase received an allotransplant whereas others continued the therapy specified. 2 nd chronic phase was defined as < 10% blood and bone marrow blasts and no extra-medullary leukaemia for ≥ 4 w. Event-free survival (EFS) was defined as interval from therapy start to no response, progression to accelerated or blast phase or CML-related death. CML-related survival was defined as interval from therapy start to death from blast phase and survival, this interval to death from any cause. Haematologic, cytogenetic and molecular responses were monitored. Targeted DNA sequencing and whole RNA sequencing were done before therapy start. “MOVICS” package in R software was used for multi-omics integrated analyses and molecular sub-type classification. Cox regression models were used to identify co-variates associated with outcomes. The study was registered in Chinese Clinical Trial Registry (ChiCTR2200055887). Results 39 consecutive subjects were registered from October, 2020 to July, 2023. 21 were male. Median age was 50 years (Interquartile range [IQR], 33-54 years). 23 received olverembatinib; 16, ponatinib. Median follow-up was 10 months (mo) (IQR, 3-19 mo). 30 (77%) subjects achieved a 2 nd chronic phase after 1 cycle, 11 of whom received a transplant, 8 progressed to blast phase again; and 9 (23%) others had no response. 25 subjects died of progression (N = 19), transplant-related mortality (N = 3), COVID-19 (N = 2) or heart failure (N = 1). Median EFS, CML-related survival and survival were 4 (95% Confidence Interval [CI], 1-6) months, 12 (8-17) months and 11 (6-15) months. Subjects receiving a transplant had better EFS ( p= 0.03), CML-related survival ( p= 0.009) and survival ( p= 0.04) compared with non-transplant subjects ( Figure 1). Most treatment-related severe adverse events were tolerable and manageable including 25 subjects (65%) developing ≥ 4 grade neutropenia with or without thrombocytopenia except only 1 subject developing early death due to heart failure. In addition, 2 subjects experienced COVID-19 and died subsequently. In adjusted Cox regression analyses of genomic (N = 37) and transcriptomic (N = 34) data KRASmutation was significantly-associated with worse EFS ( p= 0.05), CML-related survival ( p< 0.001) and survival ( p= 0.009). TP53mutation was associated with worse CML-related survival ( p= 0.02) and survival ( p= 0.003). PFKFB3::LINC02649 fusion was associated with better EFS ( p= 0.001), CML-related survival ( p= 0.007) and survival ( p= 0.005). Based on these data 34 subjects were divided into 2 clusters. Subjects in cluster 2 (N = 14) had worse EFS ( p= 0.001), CML-related survival ( p= 0.008) and survival ( p= 0.005) compared with those in cluster 1 (N = 20). In differential gene expression analyses 1,564 genes were up-regulated and 1,000 down-regulated in cluster 2 compared with cluster 1. In KEGG analyses up-regulated genes were enriched in signaling pathways including cytokine-cytokine receptor interaction, cell adhesion molecules, natural-killer (NK) cell mediated cytotoxicity, primary immune deficiency and Toll-like receptor. Down-regulated genes were enriched in cell-cycle and DNA replication pathways. Conclusion s Olverembatinib or ponatinib combined with azacitidine is a safe and effective therapy of CML-MBP allowing many subjects to receive a transplant in 2 nd chronic phase. KRAS and TP53 mutations and PFKFB3::LINC02649 fusions had predictive impact on outcomes. Determining whether adding azacitidine to a 3 rd-generation TKI requires a randomized controlled trial.

Phase I Study of the T-Cell Receptor-like Antibody, Hu8F4 in Patients with Relapsed and Refractory Myeloid Malignancies

Background: Relapse after conventional chemotherapy for newly diagnosed AML is responsible for the majority of treatment failure. Relapsed (R/R) disease is frequently refractory to salvage attempts with further chemotherapy. The effectiveness of stem cell transplant and associated graft vs. leukemia effect implies an important role for immune-based therapy in producing long lasting remissions. Existing approaches using immunotherapy have failed to establish a suitable surface target or treatment paradigm that is effective in myeloid malignancies. Hu8F4 is a humanized T-cell receptor-like monoclonal antibody that binds to the conformational epitope of PR1 bound to HLA-A2, which is highly, differentially expressed on the surface of AML compared to normal progenitors. Methods: This is a first-in-human, Phase I dose escalation trial of Hu8F4 in patients (pts) with myeloid malignancies. Pts with R/R AML, MDS, CMML, and myeloid blast phase of CML with adequate organ function and PS ≤ 2 were eligible. Pts were treated on 7 escalating dose levels, ranging from 0.01 mg/kg to 10 mg/kg IV on D1 & 15. Initial dose levels required 1 pt per dose (0.01, 0.03, 0.1, 0.3, 1), followed by 3 pts per dose (3, 10). Results: Fifteen pts with R/R AML have been enrolled, with a median age of 62 years (range, 23-77 years), including 7 females (47%). Pts had received a median of 4 prior therapies; 5 pts (33%) had a PS of 2. At enrollment, the median WBC was 2 (0.1 - 18.4), median BM blasts were 21% (0 - 76); 9 pts (60%) had complex karyotype and 4 (27%) had a TP53 mutation. All pts had > 98% surface expression of PR1 on the myeloid blasts. Hu8F4 C max ranged up to 160,000 ng/mL with t 1/2 of 48 hours and clearance of 2.61 hr*ng/mL at the highest dose. Weak anti-drug antibodies were observed after week 4 in 2 of 3 pts treated at 3 mg/kg. With a median follow up of 5 months (1.1 - 9.9), pts have received a median of 1 (1-4) cycle of therapy. No DLTs were observed at the 3 mg/kg cohort.; 4 additional pts who were on concomitant tacrolimus were enrolled at this level to assess safety with concurrent use, and no DLTs were observed. Three pts were enrolled at the 10 mg/kg level, and 1 experienced dose limiting thrombocytopenia, triggering expansion to 6 pts. Two pts had a decline in BM blasts and 4 had stable disease. There was rapid decline in peripheral blasts immediately after infusion of Hu8F4 on D1 and 15 with associated elevation in serum LDH in some pts and a rise in normal granulocytes, consistent with drug-mediated anti-leukemia effects. The pharmacokinetic parameters and transient blast reduction indicated a possible sink effect mediated by high levels of circulating blasts. SAEs documented on study were mostly disease-related and included infections, cytopenias, hemoptysis, pneumonia, and GI bleeding. Treatment related AEs were temporally related to the drug infusion, including hypotension (Grade 2: N=2), and rigors (Grade 2: N=10; Grade 1: N=1). Infusion reactions were observed at all dose levels, more common at 3 and 10 mg/kg, but were transient, and managed with steroids and antihistamines. All pts proceeded with their next dose without further issues. Neither cytokine release syndrome nor neurologic toxicities were observed. Correlative studies support antibody dependent cellular cytotoxicity and phagocytosis as important mechanisms of anti-AML activity, which was more effective at lower dose levels. Conclusion: Hu8F4, a first-in-class TCR mimic antibody, was well tolerated with expansion planned at more frequent dose intervals. On-target peripheral blast reduction temporally related to infusion suggests biological activity. Real-time pharmacokinetic data indicate a possible sink effect that may be overcome by a more frequent dosing strategy that is planned.

Equity and Resource Allocation: The Case for Allogeneic Transplant in Emergency Medicaid Patients

Background:When an uninsured, undocumented immigrant presents with an emergency medical condition, they may qualify for Emergency Medicaid. Notably, the care and services related to HSCT are not covered, except in California and Washington state. Therefore, many patients with MRD-positive or relapsed ALL who may otherwise be good candidates for HSCT are unable to receive it. This may lead to months of resource-intensive treatment without the chance of cure. Here we present 3 such patients and their course of treatments and outcomes. Patient 1:A28-year-old male from Mexico was diagnosed with Ph+ B-ALL and treated with three cycles of hyper-CVAD + dasatinib. BCR-ABL PCR remained elevated at 27.9% and the patient was switched to nilotinib for 5 more cycles of hyper-CVAD; nilotinib was continued until later relapse. He began maintenance BCNU/cytoxan, then several cycles 6-MP/MTX/vincristine. On day +554 after diagnosis, he relapsed and started decitabine/venetoclax, then decadron + dasatinib, then MVP, followed by 3 cycles of inotuzumab. Later, he started blinatumomab on day +648, which was discontinued after 22 days due to increasing peripheral blasts. He then started SMILE, then CCE. As his condition worsened he was put on ponatinib, then asciminib before expiring on day +940. Patient 2: A37-year-old male from Mexico was diagnosed with CML and started on nilotinib. On day +212 he progressed to lymphoid blast phase CML with CNS involvement and received hyper-CVAD/dasatinib; was switched to nilotinib on cycle 4 due to concerns about pleural effusion while hospitalized for PNA. On day +447 he started blinatumomab + IT MTX + nilotinib. A brain MRI on day +544 suggested carcinomatous meningitis and he got 4 cycles RMVP. He then switched to ponatinib and HiDAC for 8 cycles despite continued ALL in CSF. He was admitted for worsening ALL-induced headache on day +1016 and imaging discovered multifocal pneumonia. He then had seizure-like activity consistent with metabolic encephalopathy and expired on day +1055. Patient 3: A28-year-old male from Ecuador was diagnosed with Ph+ mixed phenotype (B/myeloid) acute leukemia. The patient underwent leukapheresis and started HiDAC + mitoxantrone + etoposide + dasatinib. Subsequent bone marrow biopsy showed 1% blasts, with BCR-ABL PCR at 1.4%. He was admitted on day +170 with Ph+ B-ALL relapse and underwent leukapheresis + 2 cycles hyper-CVAD. On day +255 he began blinatumomab for 3 cycles. He continues to receive treatment for his B-ALL at this time. See table 1 below. Discussion: There is an increasing population of undocumented immigrants entering the United States and receiving treatment for ALL while on emergency Medicaid. It is important to understand the special considerations in this population, including the inability to have HSCT authorized as a treatment option. Studies comparing the costs of HSCT to chemotherapy have found that chemotherapy is cheaper at the expense of patient mortality. Therefore, HSCT's incremental cost-effectiveness ratio, measured as cost per quality-adjusted life years, may still be favorable. As our case series demonstrates, extensive resources including traditional chemotherapies, immunotherapies like blinatumumab, and targeted oral drugs, can further increase the costs relative to HSCT. Moreover, the National Bureau of Economic research has calculated that undocumented workers add about $45,000 per worker to the US GDP annually. Therefore, offering HSCT and allowing them to continue to work may be a reasonable financial option. Likewise, many undocumented adults are the parents of US citizen minors who would benefit economically from their survival. For consideration we will explore cost analysis to further elucidate the potential benefit of allowing coverage of HSCT.

Targeting FLT3-TAZ signaling to suppress drug resistance in blast phase chronic myeloid leukemia

BackgroundAlthough the development of BCR::ABL1 tyrosine kinase inhibitors (TKIs) rendered chronic myeloid leukemia (CML) a manageable condition, acquisition of drug resistance during blast phase (BP) progression remains a critical challenge. Here, we reposition FLT3, one of the most frequently mutated drivers of acute myeloid leukemia (AML), as a prognostic marker and therapeutic target of BP-CML.MethodsWe generated FLT3 expressing BCR::ABL1 TKI-resistant CML cells and enrolled phase-specific CML patient cohort to obtain unpaired and paired serial specimens and verify the role of FLT3 signaling in BP-CML patients. We performed multi-omics approaches in animal and patient studies to demonstrate the clinical feasibility of FLT3 as a viable target of BP-CML by establishing the (1) molecular mechanisms of FLT3-driven drug resistance, (2) diagnostic methods of FLT3 protein expression and localization, (3) association between FLT3 signaling and CML prognosis, and (4) therapeutic strategies to tackle FLT3+ CML patients.ResultsWe reposition the significance of FLT3 in the acquisition of drug resistance in BP-CML, thereby, newly classify a FLT3+ BP-CML subgroup. Mechanistically, FLT3 expression in CML cells activated the FLT3-JAK-STAT3-TAZ-TEAD-CD36 signaling pathway, which conferred resistance to a wide range of BCR::ABL1 TKIs that was independent of recurrent BCR::ABL1 mutations. Notably, FLT3+ BP-CML patients had significantly less favorable prognosis than FLT3− patients. Remarkably, we demonstrate that repurposing FLT3 inhibitors combined with BCR::ABL1 targeted therapies or the single treatment with ponatinib alone can overcome drug resistance and promote BP-CML cell death in patient-derived FLT3+ BCR::ABL1 cells and mouse xenograft models.ConclusionHere, we reposition FLT3 as a critical determinant of CML progression via FLT3-JAK-STAT3-TAZ-TEAD-CD36 signaling pathway that promotes TKI resistance and predicts worse prognosis in BP-CML patients. Our findings open novel therapeutic opportunities that exploit the undescribed link between distinct types of malignancies.Graphical

A Phase I Study of Asciminib (ABL001) in Combination with Dasatinib and Prednisone for BCR-ABL1-Positive ALL and Blast Phase CML in Adults

Introduction:Oral ABL1 kinase inhibitors rapidly produce deep remissions in BCR::ABL1+ acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia in lymphoid blast crisis (CML-LBC). Second generation TKIs such as dasatinib (DAS) are more effective than imatinib (Foa et al. Blood 2011) but patients may develop resistance. Asciminib (ASC), previously ABL001, is a STAMP (Specifically Targeting the ABL Myristoyl Pocket) allosteric ABL1 inhibitor that binds to a site spatially distinct from ATP-competitive TKIs. Combination treatment with an allosteric and an ATP-competitive TKI may deepen clinical responses and limit mutational resistance as supported by a cell line xenograft model of CML (Wylie et al. Nature 2017) and patient-derived xenograft models of BCR::ABL1+ ALL. We hypothesized that dual ABL blockade with catalytic domain and allosteric inhibitors would be tolerable and active in BCR::ABL1+ ALL and CML-LBC. Methods: This investigator initiated, phase I study (NCT03595917) of asciminib (ASC) in combination with DAS plus prednisone (pred) for BCR::ABL1+ ALL studied ASC in escalating doses in a 3+3 design with the primary objective to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D); a 10 patient (pt) expansion cohort was then accrued. Secondary objectives define the depth and durability of responses. Pts with BCR::ABL1+ ALL or CML-LBC newly diagnosed ≥ 50 years (yrs), or unfit; or relapsed/refractory (no prior DAS or ASC) were eligible in dose escalation; all pts ≥18 yrs were eligible in dose expansion. Pts received DAS 140 mg/day(d) and pred 60 mg/m 2/d 1-24 (max 120 mg/d, tapered d 25-32) with escalating daily doses of ASC (DL1: 40 mg; DL2: 80 mg; DL3: 160 mg). DAS and ASC were given in 28-d cycles indefinitely in setting of clinical benefit, with allogeneic stem cell transplant (SCT) consolidation after d85 per treating physician. Dose-limiting toxicity (DLT) was initially defined as CTCAEv4 non-heme toxicity grade (gr) 3+; the study was amended to assess DLT via CTCAEv5. Correlative science efforts seek to define biomarkers of response and resistance to dual ABL1 blockade. Results:The study enrolled 25 pts (48% female), with 14 in dose escalation (13 evaluable), and 11 in expansion (10 evaluable). Most (92%) had new ALL (p190: 15/23, p210: 8/23; 8% had CML-LBC. Median age was 65 yrs (range 33 - 85; 8 pts 70+). Median WBC was 15.1 K/μL (range 0.9 - 251.9 K/μL). No pt had CNS disease. DL1 and DL2 enrolled 3 pts each without DLT. Two of 3 pts at DL3 developed asymptomatic CTCAEv4 gr 3 amylase elevation during C1 meeting original DLT criteria. A 4 th pt enrolled on re-opened DL3 under an amendment defining asymptomatic CTCAEv4 gr 3 amylase/lipase elevations persisting ≤5d to not be a DLT. This pt experienced an asymptomatic CTCAEv4 gr 3 lipase elevation meeting DLT criteria. Thus, the study de-escalated to DL2, re-opening under an amendment assessing DLTs via CTCAEv5. Of note, all DLTs at DL3 would be gr <3 per CTCAEv5. Four more pts (3 evaluable) enrolled at DL2 without a DLT. Thus, ASC 80 mg/d was declared the RP2D, and 11 pts age ≥18 yrs enrolled in an expansion cohort, 10 of whom initiated study treatment. No pt had symptomatic pancreatitis. Rates of molecular response after 3 cycles among all evaluable patients were 58.3% (14/24) for MRD 3.0 and 25.0% (6/24) for MRD 4.0. Evaluable pts with new ALL treated at the RP2D achieved molecular response rates after 3 cycles of 78.6% (11/14) for MRD 3.0 and 42.9% (6/14) for MRD 4.0. Both patients with imatinib-refractory CML-LBC progressed (C9, C3). Of those with ALL, 8 bridged to SCT after 2-8 cycles; 2 elected local care (C5, C7); 1 transitioned to ponatinib for inadequate response plus recurrent DAS pulmonary toxicity (C4); 6 remained on study treatment until disease progression (C4 - MRD+, C45, C11, C11); 3 remain on study. Correlative science evaluation of serial pt biospecimens in pursuit of predictive biomarkers will be shared at the meeting. Conclusion: Dual ABL1 kinase inhibition with ASC and DAS plus pred in BCR::ABL1+ ALL and CML-LBC is feasible and tolerable in adults with BCR::ABL1+ ALL and CML-LBC. DLTs at ASC 160 mg/d were asymptomatic amylase and lipase elevation, without clinical sequelae. ASC 80 mg/day was declared the RP2D, and an expansion cohort of 10 pts was completed. High rates of molecular response and bridging to transplant highlight encouraging preliminary activity. A phase II expansion cohort incorporating blinatumomab is now open.

Long-Term Follow-Up in Patients With Chronic Myeloid Leukemia Treated With Ponatinib in a Real-World Cohort: Safety and Efficacy Analysis

BackgroundPonatinib is a third-generation tyrosine-kinase inhibitor (TKI), indicated in patients with chronic phase (CP), accelerated phase (AP), or blast phase (BP) chronic myeloid leukemia (CML), who are resistant or intolerant to ≥2 prior TKIs, patients for whom subsequent treatment with imatinib is not appropriate, and patients who have a T315I mutation. Patients and MethodsWe aimed to evaluate outcomes of ponatinib treatment, including safety, with focus on cardiovascular toxicity, in real-world patients from Argentina. Data from patients with CP CML treated with ponatinib was retrospectively retrieved from 2013 to 2023 in 7 centers. ResultsSeventy-two patients were included (median age: 44 years; male: 55.5%; T315I mutation: 32%: median treatment duration: 36 months. At baseline, 57 patients (79%) had a breakpoint cluster region–Abelson (BCR::ABL1) transcript level >10% on the international reporting scale (BCR::ABL1 IS). A molecular response (MR, BCR::ABL1 (IS) <1%) was achieved at 12 months in 51.6% of evaluable patients; 57% maintained MR at last follow-up. Overall, 43% and 25% maintained major MR (MMR) or deep MR (DMR) (MR4.0-MR5.0), respectively at last follow-up. Twelve (16.6%) ponatinib-resistant patients were rescued with allogeneic hematopoietic stem cell transplantation. The estimated 2-year progression-free survival (PFS) was 84%. Ponatinib dose was reduced during treatment in 22 patients; nevertheless, MMR was maintained in 50% of these patients. Severe arterial occlusive events (AOE) were reported in 10.9% of patients after a median treatment of 5 months. ConclusionCV toxicity was consistent with clinical trials and other real-world registries. Older age, hypercholesterolemia and a SCORE risk >2% were significantly associated with higher risk of AOEs. Controlling CV risk factors and reducing doses at optimal time points may help to optimize ponatinib use in daily practice.

Craniospinal Irradiation for CNS Leukemia: Rates of Response and Durability of CNS Control.

Craniospinal irradiation (CSI) is used in the management of leukemia patients with central-nervous-system (CNS) involvement, though the data on response and local control are limited. Given the radioresponsiveness of leukemia, we hypothesized that response to CSI would be high, but CNS control would be influenced by control of systemic disease. This retrospective, single-institution analysis included consecutive pediatric and adult patients between 2009-2021 with leukemia that underwent CSI for CNS involvement, defined as presence of blasts (i.e., >0%) on CSF flow cytometry. Endpoints included CNS response rate (RR), CNS local recurrence (LR), progression-free survival (PFS), and overall survival (OS), which were estimated from start of CSI. The probability of CNS LR was summarized using a cumulative incidence estimate, where death without LR was considered a competing risk. The probabilities of OS and PFS were obtained using Kaplan-Meier estimates. Among the 39 eligible patients (43% AML, 49% ALL, 8% blast-phase CML), most were male (59%). All had CSF confirmation of disease. Median age at CSI was 31 years (range 7-67). CSI (protons 54%, photons 46%) was utilized early within the CNS disease course (median 0 CNS relapses prior to CSI). Twenty-five patients (64%) received CSI immediately prior to a stem-cell transplant (SCT), of which 21 (84%) had TBI conditioning to a median dose of 12 Gy (range 2-13.2). Patients treated with CSI alone received a higher CSI dose (median 18 Gy; range 10.8-24) than those treated with SCT consolidation (median 12 Gy; range 10.8-24). Fifteen patients had CSF-positive disease immediately prior to CSI; all 14 of those assessed for response (RR 100%) had confirmed clearance of blasts at a median of 23 days (range 7-197) from CSI start. With a median follow-up of 48 months (range 0.4-123) for survivors, 2-year PFS and OS estimates were 32% and 43%, respectively. Only 5 CNS relapses were noted (2-year CNS LR of 14%). All CNS relapses either occurred after (n = 4) or concurrently (n = 1) with a systemic relapse. In Cox regression univariate models, age, sex, time to CNS disease, positive CSF immediately prior to CSI, and SCT did not show demonstrable evidence of association with CNS LR. However, systemic relapse after CSI (HR 5.9, 95% CI 2.5-13.8, P<0.0001) and systemic disease at the time of CSI (HR 3.9, 95% CI 1.6-9.5, P = 0.003) were associated with higher risk of CNS LR. No grade-3+ acute toxicity was seen during CSI. CSI is a well-tolerated and effective treatment option for patients with CNS leukemia. Though CNS local recurrence was modest, there was a high risk of systemic relapse and/or death. Control of systemic disease, both before and after CSI, may be important for CNS local control, and raises consideration that CNS recurrence may reflect reseeding from the systemic space.

An Update on the Management of Advanced Phase Chronic Myeloid Leukemia.

While most patients with chronic myeloid leukemia (CML) present in a chronic phase and are expected to have a normal life expectancy, some patients present with or progress to a more aggressive accelerated phase (AP) or blast phase (BP) of CML. Herein, we discuss the diagnostic considerations of advanced phase CML and review its contemporary management. Later-generation, more potent BCR::ABL1 tyrosine kinase inhibitors (TKIs) such as ponatinib may result in superior outcomes in patients with advanced phase CML. For CML-BP, combination approaches directed against the blast immunophenotype appear superior to TKI monotherapy. The role of allogeneic stem cell transplantation is controversial in CML-AP but has consistently been shown to improve outcomes for patients with CML-BP. Advanced phase CML, particularly CML-BP, remains a poor risk subtype of CML. However, novel combination approaches using later-generation TKIs are being explored in clinical trials and may lead to improved outcomes.

Efficacy of Tyrosine Kinase Inhibitor Combined with Decitabine, Homoharringtonine, Interferon in the Maintenance Therapy of Blast Phase Chronic Myeloid Leukemia

To explore the efficacy of tyrosine kinase inhibitor (TKI) combined with decitabine, homoharringtonine, and interferon regimen as maintenance therapy for blast phase chronic myeloid leukemia (CML-BP). The clinical data of CML-BP patients who received the first major hematological response after induction therapy at The Affiliated Cancer Hospital of Zhengzhou University from June 2015 to December 2021 were analyzed retrospectively. The event-free survival, duration of remission, and overall survival of patients in TKI combined with decitabine, homoharringtonine, interferon group(n=18) and TKI combined with conventional chemotherapy group(n=10) were compared by log-rank test. A total of 28 patients were included, with a median age of 46 (24-58) years old. Kaplan-Meier survival analysis showed that patients in TKI combined with decitabine, homoharringtonine, interferon group had longer event-free survival (7.4 vs 4.3 months, P=0.043, HR＝0.44, 95% CI: 0.17-1.14), duration of overall remission (16.1 vs 6.6 months, P=0.005, HR＝0.32, 95% CI: 0.11-0.89), overall survival (34.3 vs 13.5 months, P=0.006, HR＝0.29, 95% CI: 0.10-0.82) compared with patients in TKI combined with conventional chemotherapy group. The TKI combined with decitabine, homoharringtonine and interferon regimen can significantly prolong the survival of CML-BP patients who obtained the major hematological response compared with TKI combined with conventional chemotherapy regimen.