RARE DISEASE
Atypical chronic myeloid leukemia
Atypical chronic myeloid leukemia
Atypical chronic myeloid leukemia
Synonyms: Subacute myeloid leukemia
Synonyms: Subacute myeloid leukemia
Synonyms: Subacute myeloid leukemia
Drug discovery
11
drugs
With orphan designations
Overview
Atypical chronic myeloid leukemia (aCML) is a rare, aggressive BCR-ABL1-negative myelodysplastic/myeloproliferative neoplasm (MDS/MPN) characterized by granulocytic dysplasia, leukocytosis with immature myeloid precursors, and a high risk of acute myeloid leukemia (AML) transformation. Diagnosis requires exclusion of genetic markers (e.g., PDGFRA, BCR::ABL1) and monocytosis. Prognosis is poor, with median survival of 14–24 months [1][4][6][14].
Therapies
First-line: Allogeneic hematopoietic stem cell transplantation (HSCT) for eligible patients [1][6][18].
Non-transplant: Hypomethylating agents (e.g., decitabine), JAK inhibitors (ruxolitinib for CSF3R/JAK2 mutations), or cytoreductive therapies (hydroxyurea, PEG-IFN-α) [1][3][6][14].
Research focus: Targeted therapies (e.g., MEK inhibitors for RAS mutations) and clinical trials to address high relapse rates [1][4][6].
Categories: rare hematological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
138 drug discovery papers about Atypical chronic myeloid leukemia, with 9 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
138 drug discovery papers about Atypical chronic myeloid leukemia, with 9 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-26 | Vision loss as the first manifestation of isolated cns relapse in CML blast crisis during flumatinib maintenance therapy: A case report.
Central nervous system (CNS) involvement following blast crisis (BC) of chronic myeloid leukemia (CML) represents a challenging complication, particularly when atypical symptoms such as progressive vision loss obscure the diagnosis and delay timely intervention. A 65-year-old male presented with isolated CNS relapse following CML-BC, manifesting as progressive visual loss. Despite being in intramedullary complete remission and having received prophylactic intrathecal chemotherapy, the patient's atypical ocular symptom raised suspicion of CNS involvement. Cerebrospinal fluid (CSF) analysis confirmed the presence of blast cells, establishing the diagnosis of CNS relapse. Treatment with intrathecal chemotherapy, systemic high-dose chemotherapy combined with tyrosine kinase inhibitor therapy. The patient demonstrated visual recovery and sustained disease remission at the 14-month follow-up. This case underscores the importance of clinical vigilance in patients with a history of leukemia who present with blurred vision or progressive vision impairment, as such manifestations,even in the absence of overt neurological symptoms, may be indicators of CNS relapse. Additionally, further investigation through animal models is warranted to characterize the blood-brain barrier penetrance of novel tyrosine kinase inhibitors (TKIs).
2026-06-22 | Chronic Myeloid Leukemia Masked by Massive Splenomegaly: Splenectomy as a Strategy in a Resource-Limited Setting.
Massive splenomegaly may obscure the diagnosis of underlying hematologic malignancies, particularly in resource-limited settings. Chronic myeloid leukemia (CML) typically presents with marked leukocytosis; however, atypical presentations may lead to diagnostic delay and inappropriate initial management. A 40-year-old male presented with progressive splenomegaly and abdominal fullness. Preoperative laboratory evaluation demonstrated leukocytosis with associated mild anemia. Imaging revealed massive hepatosplenomegaly, and a provisional diagnosis of Banti syndrome was made. The patient underwent open splenectomy for symptomatic massive splenomegaly. Histopathological examination of the resected spleen was non-diagnostic. Postoperatively, persistent, progressive leukocytosis and thrombocytosis prompted further hematologic evaluation. Bone marrow examination suggested a myeloproliferative neoplasm. Due to limited access to molecular diagnostics, confirmatory testing was delayed. Subsequent real-time polymerase chain reaction (PCR) confirmed BCR-ABL1 positivity, establishing the diagnosis of classical CML. The patient was treated with cytoreductive therapy, followed by imatinib, with a favorable clinical and hematologic response. This case highlights the potential for massive splenomegaly to mask CML and emphasizes the importance of early molecular testing. Splenectomy may unmask underlying hematologic malignancy through significant postoperative hematologic changes.
2026-06-17 | Final analysis of phase 2 clinical trial of ruxolitinib and azacitidine combination therapy in patients with myelodysplastic syndrome/myeloproliferative neoplasms.
Myelodysplastic syndrome and myeloproliferative neoplasm (MDS/MPN) overlap syndromes are characterized by the presence of features of both MDS and MPN and have a poor prognosis. We conducted a phase 2 clinical trial evaluating the combination of Azacitidine (AZA) and Ruxolitinib (RUX) in MDS/MPN, with interim analysis showing an objective response rate of 57%. Herein, we report the final analysis from this clinical trial, including long-term survival data. This was an open-label phase 2 clinical trial including adult patients in 2 diagnostic arms: myelofibrosis (arm 1) and MDS/MPN (arm 2). This manuscript reports outcomes of MDS/MPN patients. RUX 5-20 mg twice daily (per RUX label) was administered in 28-day cycles, and AZA 25 mg/m2 on days 1-5 was added starting cycle 4. Primary endpoint was objective response rate per the 2015 International Consortium Proposal (ICP) MDS/MPN response criteria. From 5/2013 to 8/2022, 52 patients were treated with a median age of 68 years (range, 39-82). Disease subtypes were MDS/MPN-Unclassifiable in 24 patients (46%), chronic myelomonocytic leukemia in 23 patients (44%), and atypical chronic myeloid leukemia in 5 patients (10%). Majority of patients (n = 40, 77%) had intermediate-2/high-risk disease by Dynamic International Prognosis Scoring System criteria. Objective responses were attained in 30 patients (58%), with a median duration of response of 13.6 months (95% CI: 6.4-41.1). After a median follow up of 88.5 months, 13 (25%) patients are alive, with median overall survival (OS) of 26.7 months (95% CI: 16.5-52.7), 5-year OS 33%. Median OS in MDS/MPN-U and CMML was 52.7 months (5-year OS 46%) and 17.5 months (5-year OS 27%), respectively. Twelve patients (23%) underwent allogeneic stem cell transplantation; with median OS not reached, 5-year OS 51%. Transformation to acute myeloid leukemia occurred in 13 patients (25%). The most common grade 3-5 adverse events (AEs) regardless of attribution were anemia (31, 60%), thrombocytopenia (27, 52%) and pneumonia (17, 33%). AE-related treatment discontinuation occurred in only 3 patients (6%). AZA-RUX therapy led to durable responses and encouraging OS in MDS/MPN with a manageable safety profile. NCT01787487, (clinicaltrials.gov, date: 2/6/2013).
2026-05-07 | Reduced levels of ITGB1 cause activation of p38MAPK-ERK-LYN axis of BCR::ABL1 signaling despite inactivation of the oncoprotein by imatinib - novel resistance mechanism in blast crisis of chronic myeloid leukemia unraveled.
Oncogenic tyrosine kinase activity of BCR::ABL1 is causally associated with chronic phase (CP) of chronic myeloid leukemia (CML) and its inhibition by tyrosine kinase inhibitors (TKIs) induces remission in majority of patients. However, in the terminal blast crisis (BC) phase, 80% patients are resistant to TKIs. Forty percent among them are resistant despite inhibition of BCR::ABL1 activity by TKIs and in earlier study, we observed similar antithesis in K562 cells resistant to TKI-imatinib. We demonstrated active BCR::ABL1 signaling downstream of inactivated BCR::ABL1 and its causal association with resistance. This study explores the involvement of ITGB1, integrin with significant role in genesis of CML and differentially expressed in resistant K562 cells, in mediation of atypical activation of BCR::ABL1 pathway and thus resistance. Imatinib-sensitive and resistant K562 cells as well as sensitive cells with ITGB1 knockdown (KD) to mimic resistant cells, were analyzed for proteome and phosphoproteome by mass spectrometry and kinome was profiled by quantification of kinase activities in an array-based assay. The commonality between differentially expressed proteins (DEPs) identified in resistant cells and ITGB1-KD cells together with ITGB1 interactors, identified from ITGB1-immunoprecipitate by mass spectrometry, provided a comprehensive sketch of ITGB1-mediated signaling in resistant cells. The proteins identified as key players in ITGB1-mediated activation of BCR::ABL1 signaling were validated in K562 and KU812 cells, CD34+ cells from patient samples and their functional significance was assessed by inhibition studies in K562 cells. It was observed that the reduced levels of ITGB1 in resistant cells activated BCR::ABL1 downstream signaling kinases- p38MAPK and ERK. Though not influenced by ITGB1, LYN was active in resistant cells. Inhibition studies revealed that p38MAPK, ERK and LYN regulate the activity of each other, thereby explaining ITGB1-independent activation of LYN. The three kinases in turn activate members of CDK, MAPK, AKT and PKC families while ERK alone modulates EPH activity. Thus, reduction in level of ITGB1 in resistant cells leads to activation of ERK and p38MAPK belonging to BCR::ABL1 pathway, despite inactivation of BCR::ABL1, which in turn leads to activation of LYN. Together, these kinases activate members of vital pro-survival pathways, thereby imparting imatinib resistance in CML-BC cells.
2026-04-21 | Chronic myeloid leukemia presenting with isolated central nervous system lymphoid blast crisis: A case report.
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm driven by the Philadelphia chromosome, typically progressing through chronic, accelerated, and blast phases. Blast crisis may be myeloid or lymphoid. Isolated central nervous system (CNS) involvement is rare and represents a diagnostic and therapeutic challenge. We report a 40-year-old man with no prior hematologic history who presented with four months of progressive lower-limb paresthesias, neuropathic pain, and subacute weakness impairing ambulation. Neurologic examination revealed asymmetric paraparesis, hyporeflexia, and distal hypoesthesia in a stocking distribution, consistent with a subacute asymmetric sensorimotor polyradiculoneuropathy. Complete blood count demonstrated marked leukocytosis with neutrophilia, left shift, and circulating blasts. Contrast-enhanced spinal magnetic resonance imaging showed extensive leptomeningeal enhancement. Cerebrospinal fluid (CSF) analysis revealed pleocytosis, hypoglycorrhachia, and elevated protein levels; flow cytometry identified 14% B-lymphoid blasts (CD34+, CD19+, CD20+, CD22+). Bone marrow aspirate and biopsy showed hypercellularity with trilineage hematopoiesis, basophilia, and small hypolobated megakaryocytes, without a significant increase in blasts (<5%). Cytogenetic analysis identified t (9; 22), and molecular testing confirmed the BCR::ABL1 p210 transcript, consistent with chronic-phase CML. An isolated CNS lymphoid blast crisis was diagnosed. Treatment with HyperCVAD (Block B only) plus dasatinib 140 mg daily resulted in neurologic improvement and hematologic normalization. After five cycles, CSF clearance was achieved, followed by consolidation with haploidentical allogeneic hematopoietic stem cell transplantation. The patient remains in complete remission. Isolated CNS blast crisis may represent the initial manifestation of CML. Prompt recognition through integrated neurologic, hematologic, and molecular evaluation is critical to enable timely, targeted therapy.
cell therapies
2025-10-24 | Data Sheet 1_Case Report: Dual resistance to dasatinib/olverembatinib in accelerated-phase cml: identification of a novel SPECC1L-inserted e8a2 BCR::ABL1 transcript and ABL1 V379I mutation.docx
In chronic myeloid leukemia (CML), less than 2% of cases express atypical or rare BCR::ABL1 transcripts. The e8a2 BCR::ABL1 fusion transcript, a rare variant, has been reported in only 20 cases to date, primarily in case reports or case series. The direct junction between BCR exon 8 and ABL1 exon 2 generates a premature stop codon at position 7 after the fusion, while the insertion of certain sequences can result in the formation of an in-frame e8a2 transcript. To date, the insertion of SPECC1L gene sequences into e8a2 BCR::ABL1 fusion transcripts has been reported in two CML cases, and the V379I mutation (in ABL1) has been identified in two additional CML cases. We describe a case of accelerated-phase CML involving three key molecular abnormalities: the insertion of a 154 bp SPECC1L exon 4 sequence into the e8a2 BCR::ABL1 fusion transcript, a concomitant ABL1 V379I mutation, and deletions near the t(9;22) breakpoint on derivative chromosome 9 (der(9)). The patient’s clinical manifestations, cytogenetic features, and molecular genetic characteristics were summarized and discussed. Despite sequential therapy with full-dose dasatinib for 10 months and the third-generation tyrosine-kinase inhibitor (TKI) olverembatinib for 7 months, the patient experienced progressive disease. She ultimately achieved Major Molecular Response (MMR) after haploidentical hematopoietic stem-cell transplantation (haplo-HSCT). This case highlights the importance of comprehensive molecular profiling at diagnosis and the need to develop alternative therapeutic strategies for rare BCR::ABL1 variants.
2024-10-03 | [Allogeneic transplantation as a therapeutic option for atypical chronic myeloid leukemia].
Atypical chronic myeloid leukemia (aCML) is a rare disease classified as a myelodysplastic/myeloproliferative neoplasm (MDS/MPN). Recent advances in gene mutational profiling have clarified the characteristics of aCML as a disease entity relative to other MDS/MPNs. Although some studies suggest the efficacy of DNA demethylating agents and tyrosine kinase inhibitors, data about these agents are limited due to the small number of patients. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is only therapeutic option that can provide durable remission for aCML and other MDS/MPNs. Retrospective studies from Europe and Japan revealed the clinical results of allo-HSCT for aCML. This review summarizes the pathogenesis of aCML and the development of allo-HSCT and other therapeutic options.
2023-07-06 | Haploidentical donor hematopoietic cell transplantation for myelodysplastic/myeloproliferative overlap neoplasms: results from a North American collaboration
Haploidentical donors offer a potentially readily available donor, especially for non-White patients, for hematopoietic cell transplantation (HCT). In this North American collaboration, we retrospectively analyzed outcomes of first HCT using haploidentical donor and post-transplantation cyclophosphamide (PTCy) in myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap neoplasms (MDS/MPN). We included 120 consecutive patients who underwent HCT using a haploidentical donor for MDS/MPN across 15 centers. Median age was 62.5 years and 38% were of non-White/Caucasian ethnicity. The median follow-up was 2.4 years. Graft failure was reported in seven of 120 (6%) patients. At 3 years, nonrelapse mortality (NRM) was 25% (95% confidence interval [CI]: 17-34), relapse 27% (95% CI: 18-36), grade 3-4 acute graftversus- host disease 12% (95% CI: 6-18), chronic graft-versus-host disease requiring systemic immunosuppression 14% (95% CI: 7-20), progression-free survival (PFS) 48% (95% CI: 39-59), and overall survival (OS) 56% (95% CI: 47-67). On multivariable analysis, NRM was statistically significantly associated with advancing age at HCT (per decade increment, subdistribution hazard ratio [sdHR] =3.28; 95% CI: 1.30-8.25); relapse with the presence of mutation in EZH2/RUNX1/SETBP1 (sdHR=2.61; 95% CI: 1.06-6.44); PFS with advancing age at HCT (per decade increment, HR=1.98, 95% CI: 1.13-3.45); and OS with advancing age at HCT (per decade increment, HR=2.01; 95% CI: 1.11-3.63) and splenomegaly at HCT/prior splenectomy (HR=2.20; 95% CI: 1.04-4.65). Haploidentical donors are a viable option for HCT in MDS/MPN, especially for those disproportionately represented in the unrelated donor registry. Hence, donor mismatch should not preclude HCT for patients with MDS/MPN, an otherwise incurable malignancy. In addition to patient age, disease-related factors including splenomegaly and high-risk mutations dominate outcomes following HCT.
2013-09-27 | Allogeneic hematopoietic cell transplantation in adult patients with myelodysplastic/myeloproliferative neoplasms
Background In adults, the 2 main types of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are chronic myelomonocytic leukemia (CMML) and atypical chronic myeloid leukemia (aCML). Both are associated with a poor prognosis. Allogeneic hematopoietic cell transplantation (HCT) is the only known curative treatment modality for these diseases, but data on outcomes following such treatment are limited. We analyzed the outcomes of patients with MDS/MPN after allogeneic HCT. Methods This retrospective study included 10 patients with MDS/MPN who received allogeneic HCT at Asan Medical Center from 2002 to 2010. Of these 10 patients, 7 had CMML, 2 had aCML, and 1 had unclassifiable MDS/MPN. Five patients received a myeloablative conditioning (MAC) regimen (busulfan-cyclophosphamide), and 5 received reduced-intensity conditioning (RIC) regimen. Results Neutrophil engraftment was achieved in all patients. After a median follow-up of 47.5 months among surviving patients, 4 had relapsed and 5 had died. There was only 1 treatment-related death. The 5-year rates of overall, relapse-free, and event-free survival were 42.2%, 51.9%, and 46.7%, respectively. Relapse was the leading cause of treatment failure, and all relapses were observed in patients who had received RIC and who did not develop chronic graft-versus-host disease. Conclusion Allogeneic HCT can induce durable remission in patients with MDS/MPN, but RIC cannot replace MAC in patients eligible for myeloablative treatments.
2002-12-17 | Autologous stem cell transplantation for patients with chronic myeloid leukemia. The Argentine Group of Bone Marrow Transplantation (GATMO) experience.
The objective of this analysis was to evaluate the role of autologous stem cell transplantation (ASCT) in prolonging disease free survival (DFS) and overall survival (OS) in patients with chronic myeloid leukemia (CML) who received autografts of Philadelphia chromosome (Ph) positive or Ph negative cell harvests. Over a 4-year period (1994-1999), 53 patients who underwent ASCT for CML were reported to the Argentine Group of Bone Marrow Transplantation (GATMO) Registry. Ph negative cell products were harvested in only 18 patients (34%). Comparison of disease status at the time of autograft, duration of neutropenia, thrombocytopenia, days of antibiotics, and transfusional requirements of red blood cells and platelets did not reveal statistical significant differences between the Ph positive group and the Ph negative group. Only days of hospitalization were increased significantly in patients who received Ph positive autografts. Although DFS at 36 months was significantly longer after infusion of Ph negative cell products (54% vs. 14%; P
small molecules
2026-09-26 | Vision loss as the first manifestation of isolated cns relapse in CML blast crisis during flumatinib maintenance therapy: A case report.
Central nervous system (CNS) involvement following blast crisis (BC) of chronic myeloid leukemia (CML) represents a challenging complication, particularly when atypical symptoms such as progressive vision loss obscure the diagnosis and delay timely intervention. A 65-year-old male presented with isolated CNS relapse following CML-BC, manifesting as progressive visual loss. Despite being in intramedullary complete remission and having received prophylactic intrathecal chemotherapy, the patient's atypical ocular symptom raised suspicion of CNS involvement. Cerebrospinal fluid (CSF) analysis confirmed the presence of blast cells, establishing the diagnosis of CNS relapse. Treatment with intrathecal chemotherapy, systemic high-dose chemotherapy combined with tyrosine kinase inhibitor therapy. The patient demonstrated visual recovery and sustained disease remission at the 14-month follow-up. This case underscores the importance of clinical vigilance in patients with a history of leukemia who present with blurred vision or progressive vision impairment, as such manifestations,even in the absence of overt neurological symptoms, may be indicators of CNS relapse. Additionally, further investigation through animal models is warranted to characterize the blood-brain barrier penetrance of novel tyrosine kinase inhibitors (TKIs).
2026-06-22 | Chronic Myeloid Leukemia Masked by Massive Splenomegaly: Splenectomy as a Strategy in a Resource-Limited Setting.
Massive splenomegaly may obscure the diagnosis of underlying hematologic malignancies, particularly in resource-limited settings. Chronic myeloid leukemia (CML) typically presents with marked leukocytosis; however, atypical presentations may lead to diagnostic delay and inappropriate initial management. A 40-year-old male presented with progressive splenomegaly and abdominal fullness. Preoperative laboratory evaluation demonstrated leukocytosis with associated mild anemia. Imaging revealed massive hepatosplenomegaly, and a provisional diagnosis of Banti syndrome was made. The patient underwent open splenectomy for symptomatic massive splenomegaly. Histopathological examination of the resected spleen was non-diagnostic. Postoperatively, persistent, progressive leukocytosis and thrombocytosis prompted further hematologic evaluation. Bone marrow examination suggested a myeloproliferative neoplasm. Due to limited access to molecular diagnostics, confirmatory testing was delayed. Subsequent real-time polymerase chain reaction (PCR) confirmed BCR-ABL1 positivity, establishing the diagnosis of classical CML. The patient was treated with cytoreductive therapy, followed by imatinib, with a favorable clinical and hematologic response. This case highlights the potential for massive splenomegaly to mask CML and emphasizes the importance of early molecular testing. Splenectomy may unmask underlying hematologic malignancy through significant postoperative hematologic changes.
2026-06-17 | Final analysis of phase 2 clinical trial of ruxolitinib and azacitidine combination therapy in patients with myelodysplastic syndrome/myeloproliferative neoplasms.
Myelodysplastic syndrome and myeloproliferative neoplasm (MDS/MPN) overlap syndromes are characterized by the presence of features of both MDS and MPN and have a poor prognosis. We conducted a phase 2 clinical trial evaluating the combination of Azacitidine (AZA) and Ruxolitinib (RUX) in MDS/MPN, with interim analysis showing an objective response rate of 57%. Herein, we report the final analysis from this clinical trial, including long-term survival data. This was an open-label phase 2 clinical trial including adult patients in 2 diagnostic arms: myelofibrosis (arm 1) and MDS/MPN (arm 2). This manuscript reports outcomes of MDS/MPN patients. RUX 5-20 mg twice daily (per RUX label) was administered in 28-day cycles, and AZA 25 mg/m2 on days 1-5 was added starting cycle 4. Primary endpoint was objective response rate per the 2015 International Consortium Proposal (ICP) MDS/MPN response criteria. From 5/2013 to 8/2022, 52 patients were treated with a median age of 68 years (range, 39-82). Disease subtypes were MDS/MPN-Unclassifiable in 24 patients (46%), chronic myelomonocytic leukemia in 23 patients (44%), and atypical chronic myeloid leukemia in 5 patients (10%). Majority of patients (n = 40, 77%) had intermediate-2/high-risk disease by Dynamic International Prognosis Scoring System criteria. Objective responses were attained in 30 patients (58%), with a median duration of response of 13.6 months (95% CI: 6.4-41.1). After a median follow up of 88.5 months, 13 (25%) patients are alive, with median overall survival (OS) of 26.7 months (95% CI: 16.5-52.7), 5-year OS 33%. Median OS in MDS/MPN-U and CMML was 52.7 months (5-year OS 46%) and 17.5 months (5-year OS 27%), respectively. Twelve patients (23%) underwent allogeneic stem cell transplantation; with median OS not reached, 5-year OS 51%. Transformation to acute myeloid leukemia occurred in 13 patients (25%). The most common grade 3-5 adverse events (AEs) regardless of attribution were anemia (31, 60%), thrombocytopenia (27, 52%) and pneumonia (17, 33%). AE-related treatment discontinuation occurred in only 3 patients (6%). AZA-RUX therapy led to durable responses and encouraging OS in MDS/MPN with a manageable safety profile. NCT01787487, (clinicaltrials.gov, date: 2/6/2013).
2026-05-07 | Reduced levels of ITGB1 cause activation of p38MAPK-ERK-LYN axis of BCR::ABL1 signaling despite inactivation of the oncoprotein by imatinib - novel resistance mechanism in blast crisis of chronic myeloid leukemia unraveled.
Oncogenic tyrosine kinase activity of BCR::ABL1 is causally associated with chronic phase (CP) of chronic myeloid leukemia (CML) and its inhibition by tyrosine kinase inhibitors (TKIs) induces remission in majority of patients. However, in the terminal blast crisis (BC) phase, 80% patients are resistant to TKIs. Forty percent among them are resistant despite inhibition of BCR::ABL1 activity by TKIs and in earlier study, we observed similar antithesis in K562 cells resistant to TKI-imatinib. We demonstrated active BCR::ABL1 signaling downstream of inactivated BCR::ABL1 and its causal association with resistance. This study explores the involvement of ITGB1, integrin with significant role in genesis of CML and differentially expressed in resistant K562 cells, in mediation of atypical activation of BCR::ABL1 pathway and thus resistance. Imatinib-sensitive and resistant K562 cells as well as sensitive cells with ITGB1 knockdown (KD) to mimic resistant cells, were analyzed for proteome and phosphoproteome by mass spectrometry and kinome was profiled by quantification of kinase activities in an array-based assay. The commonality between differentially expressed proteins (DEPs) identified in resistant cells and ITGB1-KD cells together with ITGB1 interactors, identified from ITGB1-immunoprecipitate by mass spectrometry, provided a comprehensive sketch of ITGB1-mediated signaling in resistant cells. The proteins identified as key players in ITGB1-mediated activation of BCR::ABL1 signaling were validated in K562 and KU812 cells, CD34+ cells from patient samples and their functional significance was assessed by inhibition studies in K562 cells. It was observed that the reduced levels of ITGB1 in resistant cells activated BCR::ABL1 downstream signaling kinases- p38MAPK and ERK. Though not influenced by ITGB1, LYN was active in resistant cells. Inhibition studies revealed that p38MAPK, ERK and LYN regulate the activity of each other, thereby explaining ITGB1-independent activation of LYN. The three kinases in turn activate members of CDK, MAPK, AKT and PKC families while ERK alone modulates EPH activity. Thus, reduction in level of ITGB1 in resistant cells leads to activation of ERK and p38MAPK belonging to BCR::ABL1 pathway, despite inactivation of BCR::ABL1, which in turn leads to activation of LYN. Together, these kinases activate members of vital pro-survival pathways, thereby imparting imatinib resistance in CML-BC cells.
2026-04-21 | Chronic myeloid leukemia presenting with isolated central nervous system lymphoid blast crisis: A case report.
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm driven by the Philadelphia chromosome, typically progressing through chronic, accelerated, and blast phases. Blast crisis may be myeloid or lymphoid. Isolated central nervous system (CNS) involvement is rare and represents a diagnostic and therapeutic challenge. We report a 40-year-old man with no prior hematologic history who presented with four months of progressive lower-limb paresthesias, neuropathic pain, and subacute weakness impairing ambulation. Neurologic examination revealed asymmetric paraparesis, hyporeflexia, and distal hypoesthesia in a stocking distribution, consistent with a subacute asymmetric sensorimotor polyradiculoneuropathy. Complete blood count demonstrated marked leukocytosis with neutrophilia, left shift, and circulating blasts. Contrast-enhanced spinal magnetic resonance imaging showed extensive leptomeningeal enhancement. Cerebrospinal fluid (CSF) analysis revealed pleocytosis, hypoglycorrhachia, and elevated protein levels; flow cytometry identified 14% B-lymphoid blasts (CD34+, CD19+, CD20+, CD22+). Bone marrow aspirate and biopsy showed hypercellularity with trilineage hematopoiesis, basophilia, and small hypolobated megakaryocytes, without a significant increase in blasts (<5%). Cytogenetic analysis identified t (9; 22), and molecular testing confirmed the BCR::ABL1 p210 transcript, consistent with chronic-phase CML. An isolated CNS lymphoid blast crisis was diagnosed. Treatment with HyperCVAD (Block B only) plus dasatinib 140 mg daily resulted in neurologic improvement and hematologic normalization. After five cycles, CSF clearance was achieved, followed by consolidation with haploidentical allogeneic hematopoietic stem cell transplantation. The patient remains in complete remission. Isolated CNS blast crisis may represent the initial manifestation of CML. Prompt recognition through integrated neurologic, hematologic, and molecular evaluation is critical to enable timely, targeted therapy.
cell therapies
2025-10-24 | Data Sheet 1_Case Report: Dual resistance to dasatinib/olverembatinib in accelerated-phase cml: identification of a novel SPECC1L-inserted e8a2 BCR::ABL1 transcript and ABL1 V379I mutation.docx
In chronic myeloid leukemia (CML), less than 2% of cases express atypical or rare BCR::ABL1 transcripts. The e8a2 BCR::ABL1 fusion transcript, a rare variant, has been reported in only 20 cases to date, primarily in case reports or case series. The direct junction between BCR exon 8 and ABL1 exon 2 generates a premature stop codon at position 7 after the fusion, while the insertion of certain sequences can result in the formation of an in-frame e8a2 transcript. To date, the insertion of SPECC1L gene sequences into e8a2 BCR::ABL1 fusion transcripts has been reported in two CML cases, and the V379I mutation (in ABL1) has been identified in two additional CML cases. We describe a case of accelerated-phase CML involving three key molecular abnormalities: the insertion of a 154 bp SPECC1L exon 4 sequence into the e8a2 BCR::ABL1 fusion transcript, a concomitant ABL1 V379I mutation, and deletions near the t(9;22) breakpoint on derivative chromosome 9 (der(9)). The patient’s clinical manifestations, cytogenetic features, and molecular genetic characteristics were summarized and discussed. Despite sequential therapy with full-dose dasatinib for 10 months and the third-generation tyrosine-kinase inhibitor (TKI) olverembatinib for 7 months, the patient experienced progressive disease. She ultimately achieved Major Molecular Response (MMR) after haploidentical hematopoietic stem-cell transplantation (haplo-HSCT). This case highlights the importance of comprehensive molecular profiling at diagnosis and the need to develop alternative therapeutic strategies for rare BCR::ABL1 variants.
2024-10-03 | [Allogeneic transplantation as a therapeutic option for atypical chronic myeloid leukemia].
Atypical chronic myeloid leukemia (aCML) is a rare disease classified as a myelodysplastic/myeloproliferative neoplasm (MDS/MPN). Recent advances in gene mutational profiling have clarified the characteristics of aCML as a disease entity relative to other MDS/MPNs. Although some studies suggest the efficacy of DNA demethylating agents and tyrosine kinase inhibitors, data about these agents are limited due to the small number of patients. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is only therapeutic option that can provide durable remission for aCML and other MDS/MPNs. Retrospective studies from Europe and Japan revealed the clinical results of allo-HSCT for aCML. This review summarizes the pathogenesis of aCML and the development of allo-HSCT and other therapeutic options.
2023-07-06 | Haploidentical donor hematopoietic cell transplantation for myelodysplastic/myeloproliferative overlap neoplasms: results from a North American collaboration
Haploidentical donors offer a potentially readily available donor, especially for non-White patients, for hematopoietic cell transplantation (HCT). In this North American collaboration, we retrospectively analyzed outcomes of first HCT using haploidentical donor and post-transplantation cyclophosphamide (PTCy) in myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap neoplasms (MDS/MPN). We included 120 consecutive patients who underwent HCT using a haploidentical donor for MDS/MPN across 15 centers. Median age was 62.5 years and 38% were of non-White/Caucasian ethnicity. The median follow-up was 2.4 years. Graft failure was reported in seven of 120 (6%) patients. At 3 years, nonrelapse mortality (NRM) was 25% (95% confidence interval [CI]: 17-34), relapse 27% (95% CI: 18-36), grade 3-4 acute graftversus- host disease 12% (95% CI: 6-18), chronic graft-versus-host disease requiring systemic immunosuppression 14% (95% CI: 7-20), progression-free survival (PFS) 48% (95% CI: 39-59), and overall survival (OS) 56% (95% CI: 47-67). On multivariable analysis, NRM was statistically significantly associated with advancing age at HCT (per decade increment, subdistribution hazard ratio [sdHR] =3.28; 95% CI: 1.30-8.25); relapse with the presence of mutation in EZH2/RUNX1/SETBP1 (sdHR=2.61; 95% CI: 1.06-6.44); PFS with advancing age at HCT (per decade increment, HR=1.98, 95% CI: 1.13-3.45); and OS with advancing age at HCT (per decade increment, HR=2.01; 95% CI: 1.11-3.63) and splenomegaly at HCT/prior splenectomy (HR=2.20; 95% CI: 1.04-4.65). Haploidentical donors are a viable option for HCT in MDS/MPN, especially for those disproportionately represented in the unrelated donor registry. Hence, donor mismatch should not preclude HCT for patients with MDS/MPN, an otherwise incurable malignancy. In addition to patient age, disease-related factors including splenomegaly and high-risk mutations dominate outcomes following HCT.
2013-09-27 | Allogeneic hematopoietic cell transplantation in adult patients with myelodysplastic/myeloproliferative neoplasms
Background In adults, the 2 main types of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are chronic myelomonocytic leukemia (CMML) and atypical chronic myeloid leukemia (aCML). Both are associated with a poor prognosis. Allogeneic hematopoietic cell transplantation (HCT) is the only known curative treatment modality for these diseases, but data on outcomes following such treatment are limited. We analyzed the outcomes of patients with MDS/MPN after allogeneic HCT. Methods This retrospective study included 10 patients with MDS/MPN who received allogeneic HCT at Asan Medical Center from 2002 to 2010. Of these 10 patients, 7 had CMML, 2 had aCML, and 1 had unclassifiable MDS/MPN. Five patients received a myeloablative conditioning (MAC) regimen (busulfan-cyclophosphamide), and 5 received reduced-intensity conditioning (RIC) regimen. Results Neutrophil engraftment was achieved in all patients. After a median follow-up of 47.5 months among surviving patients, 4 had relapsed and 5 had died. There was only 1 treatment-related death. The 5-year rates of overall, relapse-free, and event-free survival were 42.2%, 51.9%, and 46.7%, respectively. Relapse was the leading cause of treatment failure, and all relapses were observed in patients who had received RIC and who did not develop chronic graft-versus-host disease. Conclusion Allogeneic HCT can induce durable remission in patients with MDS/MPN, but RIC cannot replace MAC in patients eligible for myeloablative treatments.
2002-12-17 | Autologous stem cell transplantation for patients with chronic myeloid leukemia. The Argentine Group of Bone Marrow Transplantation (GATMO) experience.
The objective of this analysis was to evaluate the role of autologous stem cell transplantation (ASCT) in prolonging disease free survival (DFS) and overall survival (OS) in patients with chronic myeloid leukemia (CML) who received autografts of Philadelphia chromosome (Ph) positive or Ph negative cell harvests. Over a 4-year period (1994-1999), 53 patients who underwent ASCT for CML were reported to the Argentine Group of Bone Marrow Transplantation (GATMO) Registry. Ph negative cell products were harvested in only 18 patients (34%). Comparison of disease status at the time of autograft, duration of neutropenia, thrombocytopenia, days of antibiotics, and transfusional requirements of red blood cells and platelets did not reveal statistical significant differences between the Ph positive group and the Ph negative group. Only days of hospitalization were increased significantly in patients who received Ph positive autografts. Although DFS at 36 months was significantly longer after infusion of Ph negative cell products (54% vs. 14%; P
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Drug Discovery Landscape
11 orphan drug designations for Atypical chronic myeloid leukemia, including 1 approved therapy.
11 orphan drug designations for Atypical chronic myeloid leukemia, including 1 approved therapy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
nilotinib [Danziten] | small molecules | FDA | Approved | Azurity Pharmaceuticals, Inc. |
Bosutinib [Bosulif] | small molecules | EMA | Pfizer Limited | |
Bafetinib [INNO-406] | small molecules | EMA | [INACTIVE] Eudax S.r.l. | |
Ponatinib hydrochloride [Iclusig] | small molecules | EMA | Incyte Biosciences Distribution B.V. | |
Allogeneic umbilical cord blood cells-derived CD133+ cells ex vivo expanded [StemEX] | cell therapies | EMA | Regulatory Resources Group Limited | |
Nilotinib hydrochloride monohydrate [Tasigna] | small molecules | EMA | Novartis Europharm Limited | |
Dasatinib [Sprycel] | small molecules | EMA | [INACTIVE] Bristol-Myers Squibb Pharma EEIG | |
Tanespimycin | small molecules | EMA | [INACTIVE] Bristol Myers Squibb International Corporation | |
Val-Leu-Gln-Glu-Leu-Asn-Val-Thr-Val | peptides | EMA | [INACTIVE] Accelsiors CRO & Consultancy Services GmbH | |
Omacetaxine mepesuccinate [Tekinex] | small molecules | EMA | TEVA GmbH | |
Imatinib mesilate [Glivec] | small molecules | EMA | Novartis Europharm Limited |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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