Peripheral Blood HPC Counts Are Augmented in CML Patients with Cytogenetic Findings of Disease as Compared to Patients in Cytogenetic Remission.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4691-4691
Author(s):  
Ernesto de Meis ◽  
Rita C.B. Morais ◽  
Luize O. Carvalho ◽  
Arthur Moellmann-Coelho ◽  
Maria M.K. Martinez ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Leukocyte Count ◽  
Philadelphia Chromosome ◽  
Cell Disease ◽  
Differential Leukocyte Count ◽  
Non Invasive ◽  
Cd34 Cells ◽  
High Prevalence ◽  
Cytogenetic Remission

Abstract Chronic Myeloid Leukemia (CLM) is a stem cell disease characterized by inhibition of apoptosis and increased proliferation of bone marrow (BM) compounds. Evaluation of hematopoetic precursors cells on the peripheral blood (PB) of these patients show a high prevalence of leukemic CD34+ cells. Recently it was demonstrated that measurement of HPC by IMI channel on Sysmex showed an acceptable correlation between Hematopoetic Progenitors CD34+ cells counts. The aim of this work was to compare precursor cells (HPC) numbers in the PB of CML patients with disease and under remission. For this we studied 61 CML patients that had been treated with different protocols. From these 22 were in cytogenetic remission but 39 still presented more than 5% BM cells with Philadelphia chromosome (Ph+). Although the normal levels of CD34+ HPC in PB is considered to be very low, we considered less than 0.05% of leukocytes as normality. HPC in PB were counted using an automated peripheral blood counter (Sysmex XE-2100). We found that Ph+ CML patients had a significant increased number of PB HPC compared to CML patients under remission (with a confidence interval of 95%, and a corrected Yates analyses with X2 16.78 and p<0.0001). The increase in PB HPC was not related with the number of white cells counts at moment of the exam. These findings suggest that the presence of a high number of PB HPC in CML can be used as a non-invasive marker of the disease, more reliable than total and differential leukocyte count.

scholarly journals Pathological Fracture: An Unusual Presentation in Childhood Chronic Myeloid Leukemia

2019 ◽  
Vol 13 (4) ◽  
pp. 140
Author(s):  
Mururul Aisyi ◽  
Ayu Hutami Syarif ◽  
Anita Meisita ◽  
Agus Kosasih ◽  
Achmad Basuki ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Pathological Fracture ◽  
Hematological Malignancy ◽  
Blast Crisis ◽  
Philadelphia Chromosome ◽  
Molecular Response ◽  
Invasive Treatment ◽  
Non Invasive ◽  
Blast Count

Introduction: Chronic Myeloid Leukemia is a hematological malignancy driving from myeloproliferative process. It is typified by the presence of the Philadelphia chromosome manifesting in certain distinct complications, including pathological fracture. Pathological fracture is recognized as an extramedullary disease that occurs as a result of transformation of CML into blast crisis phase.Case Presentation: Here, we report a case of pediatric male CML. After being failed with imatinib therapy, he turned to nilotinib and was unable to achieve a major molecular response. He presented with high blast count and pain in the left arm. He was diagnosed with pathological fracture and blast crisis phase CML. Taken the young age and displacement of fracture into consideration, he was conservatively treated by a combination of immobilization and a higher dose of targeted therapy, nilotinib. The 2-month evaluation revealed clinical union and reduction of blast cells.Conclusions: Regarding the minimal displacement and age presentation, pathological fracture in pediatric CML requires non-invasive treatment and optimization of antileukemic therapy.

scholarly journals Stem Cell Factor as a Single Agent Induces Selective Proliferation of the Philadelphia Chromosome Positive Fraction of Chronic Myeloid Leukemia CD34+ Cells

Blood ◽  
1998 ◽  
Vol 92 (7) ◽  
pp. 2461-2470 ◽  
Author(s):  
Sarah Moore ◽  
David N. Haylock ◽  
Jean-Pierre Lévesque ◽  
Louise A. McDiarmid ◽  
Leanne M. Samels ◽  
...  
Keyword(s):  
Stem Cell ◽  
Chronic Myeloid Leukemia ◽  
Stem Cell Factor ◽  
Myeloid Leukemia ◽  
Single Agent ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Leukemic Cell ◽  
Proliferative Effect ◽  
Cd34 Cells

Abstract The interaction between p145c-KIT and p210bcr-abl in transduced cell lines, and the selective outgrowth of normal progenitors during long-term culture of chronic myeloid leukemia (CML) cells on stroma deficient in stem-cell factor (SCF) suggests that the response of CML cells to SCF may be abnormal. We examined the proliferative effect of SCF(100 ng/mL), provided as the sole stimulus, on individual CD34+ cells from five normal donors and five chronic-phase CML patients. Forty-eight percent of isolated single CML CD34+ cells proliferated after 6 days of culture to a mean of 18 cells, whereas only 8% of normal CD34+ cells proliferated (mean number of cells generated was 4). SCF, as a single agent, supported the survival and expansion of colony-forming unit–granulocyte-macrophage (CFU-GM) from CML CD34+CD38+ cells and the more primitive CML CD34+CD38− cells. These CFU-GM colonies were all bcr-abl positive, showing the specificity of SCF stimulation for the leukemic cell population. Coculture of CML and normal CD34+ cells showed exclusive growth of Ph+cells, suggesting that growth in SCF alone is not dependent on secretion of cytokines by CML cells. SCF augmentation of β1-integrin–mediated adhesion of CML CD34+cells to fibronectin was not increased when compared with the effect on normal CD34+ cells, suggesting that the proliferative and adhesive responses resulting from SCF stimulation are uncoupled. The increased proliferation may contribute to the accumulation of leukemic progenitors, which is a feature of CML.

scholarly journals Autografting with cultured marrow in chronic myeloid leukemia: results of a pilot study [see comments]

Blood ◽  
1994 ◽  
Vol 84 (3) ◽  
pp. 724-732 ◽  
Author(s):  
MJ Barnett ◽  
CJ Eaves ◽  
GL Phillips ◽  
RD Gascoyne ◽  
DE Hogge ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Intensive Therapy ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Phase Group ◽  
Cytogenetic Remission ◽  
Group 2 ◽  
Group 1

Abstract Incubation of chronic myeloid leukemia (CML) marrow for 10 days in vitro causes a marked and selective loss of very primitive Philadelphia chromosome (Ph)+ as compared with Ph- progenitors. We have autografted 22 patients with CML (16 in first chronic phase [group 1] and 6 with more advanced disease [group 2]) with marrow treated in this way to facilitate restoration of Ph- hematopoiesis after intensive therapy. Hematologic recovery to greater than 0.5 x 10(9)/L neutrophils occurred in 16 patients, and to greater than 20 x 10(9)/L platelets in 15 of 21 evaluable patients at a median of 29 and 48 days postautograft, respectively. Regenerating marrow cells were 100% Ph- in 13 patients and 75% to 94% Ph- in 3. Between 4 and 36 months (median 12) postautograft, Ph+ cells became detectable in all but 1 (who died in remission) of the 13 patients who achieved complete cytogenetic remission. Four of 7 evaluable patients treated with low-dose interferon alpha were returned to complete cytogenetic remission. Thirteen group 1 patients (81%) are alive 1.0 to 5.7 years (median 2.6) after autografting: 4 in complete cytogenetic remission, 2 in hematologic remission, 6 in chronic phase, and 1 in myeloid blast phase. Three group 2 patients (50%) are alive at 2.6, 3.8, and 4.3 years after autografting: 1 in partial cytogenetic remission, 1 in chronic phase, and 1 in accelerated phase. Thus, autografts of cultured marrow can result in prolonged restoration of Ph- hematopoiesis for some patients with CML.

A Phase I/II Study of AMN107, a Novel Aminopyrimidine Inhibitor of Bcr-Abl, on a Continuous Daily Dosing Schedule in Adult Patients (pts) with Imatinib-Resistant Advanced Phase Chronic Myeloid Leukemia (CML) or Relapsed/Refractory Philadelphia Chromosome (Ph+) Acute Llymphocytic Leukemia (ALL).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 22-22 ◽  
Author(s):  
Francis Giles ◽  
H. Kantarjian ◽  
B. Wassmann ◽  
J. Cortes ◽  
S. O’Brien ◽  
...  
Keyword(s):  
Phase I ◽  
Cell Lines ◽  
Dose Level ◽  
Peripheral Blood ◽  
Philadelphia Chromosome ◽  
Brdu Incorporation ◽  
Biologic Activity ◽  
Advanced Phase ◽  
Mutational Status ◽  
Cd34 Cells

Abstract AMN107 is a novel aminopyrimidine ATP-competitive inhibitor of Bcr-Abl. In proliferation assays AMN107 ≥10-fold more is potent than IM against Bcr-Abl expressing cell lines. AMN107 is effective against cell lines expressing the following IM-resistant Bcr-Abl mutants: Glu255Val, Phe317Leu, and Met351Thr. In addition, preliminary studies indicate that AMN107 has similar potency to IM against c-Kit and PDGFR-dependent cell proliferation. The ↑ potency and broader spectrum of activity of AMN107 against Bcr-Abl, relative to IM, may result in clinical benefit for pts with CML or Ph+ ALL. In the phase I portion of this phase I/II study, pts with IM-resistant CML-AP, CML-BC, and Ph+ ALL were eligible for treatment with AMN107 as an oral daily dose. 21 pts [median age:61 yrs (range 29–77); 15 male 6 female; performance status: 0(12 pts), 1(6 pts) or 2(3 pts)] have been enrolled in the following dose cohorts (mg/day): 50(7 pts), 100(7 pts), 200(7 pts) and have been on treatment for 8–70 days. Disease types: CML-AP (12 pts), CML-BC (6 pts), Ph+ ALL (3 pts). Intra-pts dose escalations were permitted for persistent disease in peripheral blood and/or marrow. 6/7 pts in the 50mg dose level, and 7/7 pts in the 100mg dose level have dose-escalated. No AMN107-related AE have been observed. Biologic activity, defined as at least a 50% ↓ in blasts or basophils in the peripheral blood and/or marrow lasting for at least 7 days was observed in 0/7 pts treated with 50mg/day, 4/13 pts treated with 100mg/day, and 7/15 pts treated with 200mg/day. Of the 7 pts who demonstrated biologic activity at 200mg/day, 2 pts with CML-AP had complete hematologic responses in marrow, and 1 pts with CML-AP had return to CP in marrow. Pts were not pre-selected for treatment based on mutational status of Bcr-Abl. Mutational analysis is being performed on all pts and will be correlated with response. Initial data reveal Bcr-Abl mutations in the majority (> 80%) of baseline pts samples. Preliminary data from the 50mg cohort comparing baseline peripheral blood samples with day 2 samples showed: significant ↑ in apoptosis as determined by mitochondrial potential, reduction in proliferation of CD34+ cells as measured by BrdU incorporation, and significant reductions in STAT1 phosphorylation. Reduction in CRKL phosphorylation in CD34+ cells was observed. Similar changes were noted in marrow. PK samples were collected on days 1, 2, 8, 15, 22 & 28 of cycle 1 and at time of any intra-pts dose escalation. Pharmacokinetics after 1 daily oral dose of AMN107 were characterized as little accumulation after multiple administrations with moderate inter-pts variability in exposure. Peak concentrations of AMN107 were generally achieved by 3 hrs post-dose. Preliminary PK data support 1-daily dosing. This phase I study, AMN107 given orally appears to be well tolerated with biologic effects in some pts treated with ≥100mg/day & marrow responses in some pts treated with 200mg/day. Once MTD has been determined, pts will be enrolled to multiple expansion cohorts in the phase II portion to assess activity.

Functional ABCG2 is overexpressed on primary CML CD34+ cells and is inhibited by imatinib mesylate

Blood ◽  
2006 ◽  
Vol 108 (4) ◽  
pp. 1370-1373 ◽  
Author(s):  
Niove E. Jordanides ◽  
Heather G. Jorgensen ◽  
Tessa L. Holyoake ◽  
Joanne C. Mountford
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Cell Line ◽  
Imatinib Mesylate ◽  
Cell Population ◽  
Myeloid Leukemia ◽  
Philadelphia Chromosome ◽  
Drug Transporter ◽  
Cd34 Cells ◽  
Considerable Debate ◽  
Intracellular Concentrations

Abstract Imatinib mesylate (IM) therapy for chronic myeloid leukemia (CML) has transformed the treatment of this disease. However, the vast majority of patients, despite major responses, still harbor Philadelphia chromosome–positive (Ph+) cells. We have described a population of primitive Ph+ cells that are insensitive to IM and may be a source of IM resistance. Cell line studies have suggested that the drug transporter ABCG2 may be a mediator of IM resistance, however there is considerable debate about whether IM is an ABCG2 substrate or inhibitor. We demonstrate here that primitive CML CD34+ cells aberrantly overexpress functional ABCG2 but that cotreatment with IM and an ABCG2 inhibitor does not potentiate the effect of IM. We definitively show that IM is an inhibitor of, but not a substrate for, ABCG2 and that, therefore, ABCG2 does not modulate intracellular concentrations of IM in this clinically relevant cell population.

scholarly journals Atypical Chronic Myeloid Leukemia

Blood ◽  
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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