CML with De Novo NPM1 Mutation and Rapid Progression to Myeloid Blast Cri-Sis despite Treatment with Imatinib: A Case Report

Case Report

Ann Hematol Onco. 2023; 10(2): 1422.

CML with De Novo NPM1 Mutation and Rapid Progression to Myeloid Blast Cri-Sis despite Treatment with Imatinib: A Case Report

Chaudhry B¹; Parker J¹; Altohami M²; Borghi I²

1HDepartment of Haematology, Northampton General Hospital, UK

2Department of Haematology, Leicester Royal Infirmary, Infirmary Square, UK

3Imperial Molecular Diagnostics, Hammersmith Hospital, UK

*Corresponding author: Bilal Chaudhry Haematology Department, Northampton General Hospital, Northampton NN1, 5BD, UK. Email: [email protected]

Received: April 15, 2023 Accepted: May 12, 2023 Published: May 19, 2023


In this case we present a 41 year old male with chronic myeloid leukaemia who despite scoring low risk for Sokal progressed rapidly to blast crisis without warning and after having achieved a partial response to Imatinib therapy. We investigated using retrospective Next Generation Sequencing (NGS) and identified a novel NPM1 mutation at diagnosis and blast crisis together. We also found tyrosine kinase domain mutations using NGS not found with Sanger sequencing. We believe this case highlights the effectivity of NGS in identifying novel and existing mutations with higher sensitivity, which could help improve existing practice in prognostication and management of CML disease in patients not responding to treatment adequately.

Keywords: CML and NPM1; CML-BP; Next generation sequencing in CML; Imatinib failure; Blast crisis


Chronic Myeloid Leukaemia (CML) is characterised by a triphasic natural history with Chronic (CP), Accelerated (AP) and Blast crisis (BP) phases. Contemporary therapeutic approaches based on Tyrosine Kinase Inhibitors (TKIs) have reduced the annual risk of progression to BP from 20% to around 1 to 1.5%, resulting in a vast improvement in quality of life and overall survival [1].

CML is characterised by the presence of a ‘Philadelphia chromosome’ due to a translocation between chromosome 9 and 22 t(9;22)(q34;q11). This results in production of the BCR/ABL fusion protein with resultant increased tyrosine kinase activity [2,3].

Current prognostic scoring systems include Sokal and more recently, the EUTOS Long-Term Survival score (ELTS). This predicts survival for patients on TKIs and may be more discriminatory than Sokal [4,5]. Although current prognostic scoring systems do not use cytogenetic information to predict outcome, the presence of additional Chromosomal Aabnormalities (ACA) such as trisomy 8 suggest an increased risk of progression to AP or BC [6].Despite the potential increased risk however, initial management remains the same [3,7].

Case Presentation

We report a 41 year-old man diagnosed with CML-CP, who was classed low risk for Sokal, EUTOS and ELTS at diagnosis. He achieved a partial response to imatinib therapy at three months on cytogenetics which was classed in ]accordance with European Leukaemia Net (ELN) 2013 guidance as optimal respon, se to first line TKI therapy, and did not indicate treatment failure [2]. Despite this he progressed to blast crisis one month later. Retrospective testing revealed mutated NPM1 at diagnosis and again at blast crisis.

In August 2019 a 41 year-old gentleman was referred urgently to haematology following an abnormal full blood count and blood film suggestive of CML. Other than a raised body mass index, examination was normal with no splenomegaly. There was no smoking or drinking history except for tobacco chewing and no relevant family history.

A bone marrow aspirate was consistent with CML-CP. Chromosomal analysis showed isolated 46,XY,t(9;22)(q34;q11) in 60% of cells and an additional chromosome 8 (trisomy 8) in 40% of cells. e13a3 BCR-ABL transcripts were detected by multiplex PCR and Q-PCR. Tyrosine kinase domain (TKD) mutation analysis was not carried out at diagnosis as per national practice [7]. He was deemed low risk according to Sokal (0.53), EUTOS (70.9), ELTS (0.817) and commenced on Imatinib 400mg daily rather than a 2nd generation TKI especially as his cardiac risk (QRisk3) was increased (relative risk 3.2) [9].

Molecular and cytogenetic response was assessed at 3 months as per standard national practice, following initiation of Imatinib therapy. Cytogenetics showed 3% of cells 46,XY,t(9;22)(q34;q11) and 97% demonstrating a normal karyotype. The trisomy 8 clone seen at diagnosis was not detected. BCR-ABL transcripts were significantly reduced (1498441 to 126331) and the BCR-ABL/ABL ratio was 43.413%.

Within days of receiving cytogenetic and molecular results, the patient re-presented with severe headaches, leukocytosis and blasts on a blood film. A bone marrow aspirate confirmed the presence of 25% myeloblasts and cytogenetics showed 47,XY,+8,t(9;22)(q34;q11) confirming progression to CML-BP (blast phase). The BCR-ABL/ABL ratio was 390.939%. Sanger sequencing performed across the Tyrosine Kinase Domain (TKD), detected a p.Gly250Glu (c.749G>A) G250E point mutation. There was no evidence of Central Nervous System (CNS) leukaemia on imaging or on Cerebrospinal Fluid (CSF) analysis.

He was treated with FLAG-IDA chemotherapy with additional CNS-directed therapy. Imatinib was changed to Nilotinib 400mg BD in view of the G250E point mutation and sensitivity to Nilotinib. A repeat bone marrow aspirate following blood count recovery showed 2% CD117+, CD34+ myeloid blasts. Cytogenetics showed normal karyotype consistent with complete cytogenetic remission and the BCR-ABL/ABL ratio had fallen to 2.4%.

He developed prolonged pancytopenia following a second cycle of FLAG-IDA plus Nilotinib therapy in February 2020. A repeat bone marrow sample post-chemotherapy showed 0.2% blasts on flow cytommetry, normal cytogenetics and a BCR-ABL/ABL ratio of 0.01%.

The COVID-19 pandemic in early 2020 caused significant delays with his planned allogeneic stem cell transplant. He required GCSF for ongoing significant neutropenia during the height of the first wave of the COVID-19 pandemic although his Measurable Residual Disease (MRD) during this time remained negative. After undergoing reduced-intensity conditioning allogeneic stem cell transplantation in August 2020 he remains alive and well in complete molecular remission, despite catching COVID-19 post-transplant.

This patient had progressed from CML-CP to CML-BP within 4 months following diagnosis despite scoring as low risk on current recommended prognostic scoring systems and after achieving a partial response on imatinib one month earlier without evidence of treatment failure. This seemed a very rapid progression of events, hence we retrospectively investigated his disease for additional genetic mutations using Next Generation Sequencing (NGS) for extended myeloid testing on all peripheral blood and bone marrow samples previously sent for BCR-ABL transcript monitoring.

Interestingly, mutated NPM1 was found in the absence of FLT3-ITD at CML diagnosis in July 2019. The peripheral blood sample three months after starting Imatinib was negative for mutated NPM1. At progression to CML-BP, one month later, mutated NPM1 was detected again and both G250e and T315I point mutations were found in the ABL1 gene, although only the G250e mutation was reported on conventional Sanger sequencing at the time of CML-BP progression.

Following his first cycle of FLAG-IDA chemotherapy in January 2020 his NPM1 status became negative again and no further TKD mutations were detected. Timeline of events can be seen in Table 1 with mutation percentage overtime in figure 1.

Citation: Chaudhry B, Parker J, Altohami M, Borghi I. CML with De Novo NPM1 Mutation and Rapid Progression to Myeloid Blast Cri-Sis despite Treatment with Imatinib: A Case Report. Ann Hematol Onco. 2023; 10(2): 1422.