Myeloproliferative Neoplasm with Dysplastic Features and CSF3R Mutation: Chronic Neutrophilic Leukemia or Atypical Chronic Myeloid Leukemia with CSF3R Mutation?

PURPOSE Colony-stimulating factor-3 receptor ( CSF3R)-T618I is a recurrent activating mutation in chronic neutrophilic leukemia (CNL) and to a lesser extent in atypical chronic myeloid leukemia (aCML) resulting in constitutive JAK-STAT signaling. We sought to evaluate safety and efficacy of the JAK1/2 inhibitor ruxolitinib in patients with CNL and aCML, irrespective of CSF3R mutation status. METHODS We conducted a phase II study of ruxolitinib in 44 patients (21 CNL and 23 aCML). The primary end point was overall hematologic response rate (ORR) by the end of 6 continuous 28-day cycles for the first 25 patients enrolled. We considered a response as either partial (PR) or complete response (CR). We expanded accrual to 44 patients to increase our ability to evaluate secondary end points, including grade ≥ 3 adverse events, spleen volume, symptom assessment, genetic correlates of response, and 2-year survival. RESULTS ORR was 32% for the first 25 enrolled patients (8 PR [7 CNL and 1 aCML]). In the larger cohort of 44 patients, 35% had a response (11 PR [9 CNL and 2 aCML] and 4 CR [CNL]), and 50% had oncogenic CSF3R mutations. The mean absolute allele burden reduction of CSF3R-T618I after 6 cycles was greatest in the CR group, compared with the PR and no response groups. The most common cause of death is due to disease progression. Grade ≥ 3 anemia and thrombocytopenia were observed in 34% and 14% of patients, respectively. No serious adverse events attributed to ruxolitinib were observed. CONCLUSION Ruxolitinib was well tolerated and demonstrated an estimated response rate of 32%. Patients with a diagnosis of CNL and/or harboring CSF3R-T618I were most likely to respond.

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Recent Progress in Chronic Neutrophilic Leukemia and Atypical Chronic Myeloid Leukemia

Current Hematologic Malignancy Reports ◽

10.1007/s11899-017-0413-y ◽

2017 ◽

Vol 12 (5) ◽

pp. 432-441 ◽

Cited By ~ 10

Author(s):

Kim-Hien T. Dao ◽

Jeffrey W. Tyner ◽

Jason Gotlib

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Recent Progress ◽

Chronic Neutrophilic Leukemia ◽

Atypical Chronic Myeloid Leukemia

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How I treat atypical chronic myeloid leukemia

Blood ◽

10.1182/blood-2016-08-693630 ◽

2017 ◽

Vol 129 (7) ◽

pp. 838-845 ◽

Cited By ~ 25

Author(s):

Jason Gotlib

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Myeloproliferative Neoplasm ◽

Treatment Strategies ◽

Standard Of Care ◽

High Rate ◽

Current Standard ◽

Hematopoietic Stem ◽

Genetic Features ◽

Atypical Chronic Myeloid Leukemia

Abstract Atypical chronic myeloid leukemia, BCR-ABL1 negative (aCML) is a rare myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) for which no current standard of care exists. The challenges of aCML relate to its heterogeneous clinical and genetic features, high rate of transformation to acute myeloid leukemia, and historically poor survival. Therefore, allogeneic hematopoietic stem cell transplantation should always be an initial consideration for eligible patients with a suitable donor. Nontransplant approaches for treating aCML have otherwise largely relied on adopting treatment strategies used for MDS and MPN. However, such therapies, including hypomethylating agents, are based on a paucity of data. With an eye toward making a more meaningful impact on response rates and modification of the natural history of the disease, progress will rely on enrollment of patients into clinical trials and molecular profiling of individuals so that opportunities for targeted therapy can be exploited.

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Atypical Chronic Myeloid Leukemia

Blood ◽

10.1182/blood-2018-99-110189 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5455-5455

Author(s):

Chandralekha Ashangari ◽

Praveen K. Tumula

Keyword(s):

Chronic Myeloid Leukemia ◽

Peripheral Blood ◽

Myeloid Leukemia ◽

Conflicts Of Interest ◽

Philadelphia Chromosome ◽

Myeloproliferative Neoplasm ◽

Peripheral Blood Flow ◽

Current Standard ◽

Atypical Chronic Myeloid Leukemia ◽

Wbc Count

Abstract Introduction: Atypical chronic myeloid leukemia (aCML), BCR-ABL1 negative is a rare myelodysplastic syndromes (MDS)/myeloproliferative neoplasm (MPN) for which no current standard of care exists. We present one of the rare presentations of aCML in an elderly patient. Case: A 76 year old male presented to the Hematology clinic for consultation after discharge from local hospital for elevated WBC count. Past medical history was significant for COPD, acid reflux, peripheral arterial disease and hypertension. Physical exam was unremarkable. Initial labs were significant for leukocytosis of 30 k/cu mm, anemia with Hb 10 gm/dl, thrombocytosis 695,000 with neutrophilia of ANC 25,200. Peripheral blood was negative for JAK2 V617F and BCR-ABL. Peripheral blood flow cytometry showed granulocytic left shift with 1.5% myeloblasts. Bone marrow biopsy suggestive of hypercellular marrow (100%) with myeloid predominance, atypical megakaryocytes, increased ring sideroblasts (49% of NRBC), increased blasts (5%) and dysgranulopoeisis over all suggestive of Myelodyplastic Syndrome/Chronic Myeloproliferative Disorder (MDS/MPD). Cytogenetics were positive for U2AF1 positive, CSF3R T6181, CSF3R Q776 pathognomonicof atypical CML and negative for BCR-ABL, FLT3. He was considered transplant ineligible. He was started on Azacitadine and is currently receiving 2nd cycle therapy. He is also receiving darbepoeitin periodically to avoid frequent transfusions. He is currently transfusion independent. Discussion: Increased WBC count (e.g., cutoffs of >40×109/L or 50×109/L), increased percentage of peripheral blood myeloid precursors, female sex, and older age are adverse prognostic factors for overall survival or leukemia-free survival in aCML. aCML cases lack in Philadelphia chromosome. Overall 50-65% of patients show cytogenetic abnormalities. The most frequent is +8 (25%). Other changes such as -7 and del(12p) have also been recurrently observed. Patients with aCML have an estimated median survival between 14 and 30 months. aCML tends to exhibit a more aggressive clinical course than other MDS/MPN subtypes. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

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Atypical Chronic Myeloid Leukemia: Where Are We Now?

International Journal of Molecular Sciences ◽

10.3390/ijms21186862 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6862

Author(s):

Elena Crisà ◽

Maura Nicolosi ◽

Valentina Ferri ◽

Chiara Favini ◽

Gianluca Gaidano ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Treatment Options ◽

Myeloproliferative Neoplasm ◽

High Rate ◽

Molecular Profile ◽

Poor Survival ◽

Myeloid Neoplasms ◽

Atypical Chronic Myeloid Leukemia ◽

Generation Sequencing

Atypical chronic myeloid leukemia, BCR-ABL1 negative (aCML) is a rare myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) with a high rate of transformation to acute myeloid leukemia, and poor survival. Until now, the diagnosis has been based on morphological grounds only, possibly making the real frequency of the disease underestimated. Only recently, new insights in the molecular biology of MDS/MPN syndromes have deepened our knowledge of aCML, enabling us to have a better molecular profile of the disease. The knowledge gleaned from next generation sequencing has complemented morphologic and laboratory WHO criteria for myeloid neoplasms and can provide greater specificity in distinguishing aCML from alternative MDS/MPN or MPNs. The most commonly mutated genes (>20%) in aCML are SETBP1, ASXL1, N/K-RAS, SRSF2, and TET2, and less frequently (< 10%) CBL, CSFR3, JAK2, EZH2, and ETNK1. Several of these mutations affect the JAK-STAT, MAPK, and ROCK signaling pathways, which are targetable by inhibitors that are already in clinical use and may lead to a personalized treatment of aCML patients unfit for allogeneic transplant, which is currently the only curative option for fit patients. In this review, we present two emblematic clinical cases and address the new molecular findings in aCML and the available treatment options.

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