Response of Elevated Serum Soluble Interleukin-2 Receptor (sIL-2R) and Overexpression of Glucose-6-Phosphate Dehydrogenase (G6PD) in Patients with Chronic Myelogenous Leukemia Treated with Imatinib Mesylate.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4695-4695
Author(s):  
Eugene McPherson ◽  
M. Shanmughan ◽  
S.Y. Huang ◽  
J. Kleinfeld ◽  
E. Hazel ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Chronic Myelogenous Leukemia ◽  
Peripheral Blood ◽  
Interleukin 2 ◽  
Philadelphia Chromosome ◽  
Elevated Serum ◽  
Chronic Phase ◽  
Response To Therapy ◽  
Myelogenous Leukemia ◽  
Cell Counts

Abstract Regulation of intracellular redox potential is important for regulation of cell growth. G6PD functions to catalyze the first step in the pentose phosphate pathway physiologically providing the NADPH required for reductive biosynthesis and detoxification of free-radicals and peroxides in mature red blood cells. We present two cases of patients (pts) with Chronic Myelogenous Leukemia-chronic phase (CML-cp) with significant overexpression of sIL-2R and G6PD. Serum elevated levels of sIL-2R and G6PD correlated to CML stage and response to therapy with imatinib; one male pt and one female pt with white blood cell counts of 80 and 21,000 X 109 per liter and a mean sIL-2R and G6PD levels of 26.975 X 103 pg/ml and 14.10 units/gHb respectively. Both pts had BCR/abl-RT-PCR positive gene rearrangements with b2a2 in peripheral blood and bone marrow. Chromosomal abnormalities of female pt was consistent with CML-cp (t 9; 22) ( q34;q11.2) philadelphia chromosome. Treatment of both pts with imatinib 400 mg orally daily resulted in reduction toward normal levels of sIL-2R and G6PD. Our female pt had to have therapy interrupted due to severe gastrointestinal and myelosuppression with cardiac irritation, edema, headaches and arthralgia. She was changed to 300 mg of imatinib with a proton-pump inhibitor, growth factor G-CSF, and a cox-2 inhibitor with excellent tolerance and response to therapy ( see table I). Response of sIL-2R and G6PD To Treatment With Imatinib Mesylate MONTHS LAP-SCORE sIL-2R (pg/ml) CRP (mg/dL) G6PD (units/gHb) LDH (U/L) Lap Score(NL 40-130); sIL-2R (NL 1,770-9,753); G6PD (3.5–5.0) Zero 4 26,975 16.0 11.1 386 Three 12 5,629 2.75 4.1 241 Six 17 12,868 0.75 3.6 266 Twelve 143 6,111 3.75 3.9 203 CONCLUSIONS: Overexpression of sIL-2R and G6PD in CML-cp pts treated with tyrosine kinase inhibitor imatinib mesylate were significantly reduced to levels within normal limits after twelve months of therapy. Peripheral blood sera sIL-2R and erythrocyte G6PD levels in CML-cp pts may be useful clinical and prognostic indicators of leukemic cell burden.

scholarly journals Elevated serum-soluble interleukin-2 receptor (Tac antigen) levels in chronic myelogenous leukemia patients with blastic crisis

Blood ◽  
1989 ◽  
Vol 74 (3) ◽  
pp. 1052-1057
Author(s):  
T Motoi ◽  
T Uchiyama ◽  
T Hori ◽  
K Itoh ◽  
H Uchino ◽  
...  
Keyword(s):  
Cell Surface ◽  
Chronic Myelogenous Leukemia ◽  
Peripheral Blood ◽  
Interleukin 2 ◽  
Elevated Serum ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
Blastic Crisis ◽  
Phase Range

We examined the expression of cell-surface interleukin-2 (IL-2) receptor (Tac antigen) on peripheral blood leukemic cells and measured soluble IL-2 receptor p55(alpha) chain (sIL-2R) levels in sera from chronic myelogenous leukemia (CML) patients with blastic crisis. Flow cytofluorometric analysis performed by dual immunofluorescence in three cases demonstrated coexpression of Tac antigen with myeloid (CD13, CD14, or CD33) or lymphoid (CD10) antigen on significant proportions of peripheral blood leukemic cells. Radiolabeled IL-2-binding assay demonstrated the specific IL-2 binding sites in three cases examined. The exogenous IL-2, however, failed to induce proliferative response. A myeloid cell line, Yut-K3, established from peripheral blood leukemic cells from a CML patient with blastic crisis, also expressed cell- surface Tac antigen and CD13 concurrently. SIL-2R assay showed that Yut- K3 released a detectable amount of sIL-2R in its culture supernatant. The serum sIL-2R levels were significantly elevated (range: 2,580 to 172,000 U/mL) in 12 CML patients with blastic crisis and were slightly elevated in ten patients in chronic phase (range: 250 to 820 U/mL) and in three in accelerated phase (range: 790 to 1,305 U/mL) compared with those in 24 normal controls (range: 70 to 695 U/mL, P less than .01). These results indicated that the leukemic cells from CML patients with blastic crisis expressed and released IL-2 receptor (Tac antigen). Longitudinal studies performed in three cases of CML with blastic crisis showed that the change of serum sIL-2R level was closely associated with that of the number of peripheral blood leukocytes and blasts, the percentage of blasts and serum LDH levels, also suggesting that the serum sIL-2R level is a useful clinical indicator of the leukemic cell burden in vivo.

scholarly journals Elevated serum-soluble interleukin-2 receptor (Tac antigen) levels in chronic myelogenous leukemia patients with blastic crisis

Blood ◽  
1989 ◽  
Vol 74 (3) ◽  
pp. 1052-1057 ◽  
Author(s):  
T Motoi ◽  
T Uchiyama ◽  
T Hori ◽  
K Itoh ◽  
H Uchino ◽  
...  
Keyword(s):  
Cell Surface ◽  
Chronic Myelogenous Leukemia ◽  
Peripheral Blood ◽  
Interleukin 2 ◽  
Elevated Serum ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
Blastic Crisis ◽  
Phase Range

Abstract We examined the expression of cell-surface interleukin-2 (IL-2) receptor (Tac antigen) on peripheral blood leukemic cells and measured soluble IL-2 receptor p55(alpha) chain (sIL-2R) levels in sera from chronic myelogenous leukemia (CML) patients with blastic crisis. Flow cytofluorometric analysis performed by dual immunofluorescence in three cases demonstrated coexpression of Tac antigen with myeloid (CD13, CD14, or CD33) or lymphoid (CD10) antigen on significant proportions of peripheral blood leukemic cells. Radiolabeled IL-2-binding assay demonstrated the specific IL-2 binding sites in three cases examined. The exogenous IL-2, however, failed to induce proliferative response. A myeloid cell line, Yut-K3, established from peripheral blood leukemic cells from a CML patient with blastic crisis, also expressed cell- surface Tac antigen and CD13 concurrently. SIL-2R assay showed that Yut- K3 released a detectable amount of sIL-2R in its culture supernatant. The serum sIL-2R levels were significantly elevated (range: 2,580 to 172,000 U/mL) in 12 CML patients with blastic crisis and were slightly elevated in ten patients in chronic phase (range: 250 to 820 U/mL) and in three in accelerated phase (range: 790 to 1,305 U/mL) compared with those in 24 normal controls (range: 70 to 695 U/mL, P less than .01). These results indicated that the leukemic cells from CML patients with blastic crisis expressed and released IL-2 receptor (Tac antigen). Longitudinal studies performed in three cases of CML with blastic crisis showed that the change of serum sIL-2R level was closely associated with that of the number of peripheral blood leukocytes and blasts, the percentage of blasts and serum LDH levels, also suggesting that the serum sIL-2R level is a useful clinical indicator of the leukemic cell burden in vivo.

Imatinib mesylate (STI571) therapy for Philadelphia chromosome–positive chronic myelogenous leukemia in blast phase

Blood ◽  
2002 ◽  
Vol 99 (10) ◽  
pp. 3547-3553 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Jorge Cortes ◽  
Susan O'Brien ◽  
Francis J. Giles ◽  
Maher Albitar ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Chronic Myelogenous Leukemia ◽  
Response Rate ◽  
Philadelphia Chromosome ◽  
Response To Therapy ◽  
Myelogenous Leukemia ◽  
Control Group ◽  
Blast Phase ◽  
Molecular Abnormalities ◽  
Philadelphia Chromosome Positive

Molecular abnormalities caused by the hybrid Bcr-Abl gene are causally associated with the development and progression of Philadelphia chromosome–positive (Ph+) chronic myelogenous leukemia (CML). Imatinib mesylate (STI571), a specific Bcr-Abl tyrosine-kinase signal-transduction inhibitor, has shown encouraging activity in phase I and II studies of CML. Here, we describe the use of imatinib mesylate to treat 75 patients in blast-phase CML (median age, 53 years; 65 with nonlymphoid and 10 with lymphoid blasts), and compare the results with those of a historical control group treated with standard cytarabine-based therapy. Imatinib mesylate was given as oral doses at 300 to 1000 mg per day and was the first salvage therapy for 47 patients. The objective response rate was 52% (39 of 75 patients: 16 had complete and 3 had partial hematologic response; 12 had hematologic improvement; 7 returned to second chronic phase; and 1 had a complete response in extramedullary blastic disease). Response rates were not different between nonlymphoid and lymphoid groups. The cytogenetic response rate was 16% (12 patients: 5 complete, 3 partial [Ph+ below 35%], and 4 minor [Ph+, 34% to 90%]). The estimated median overall survival was 6.5 months; the estimated 1-year survival was 22%. Response to therapy (landmark analysis at 8 weeks) was associated with survival prolongation. Compared with standard cytarabine combinations, imatinib mesylate therapy was less toxic and produced a higher response rate (55% versus 29%, P = .001), longer median survival (7 versus 4 months, P = .04), and lower 4-week induction mortality (4% versus 15%, P = .07). Imatinib mesylate is currently being tested in combination with other drugs to improve the prognosis for blast-phase CML.

Imatinib mesylate therapy in newly diagnosed patients with Philadelphia chromosome–positive chronic myelogenous leukemia: high incidence of early complete and major cytogenetic responses

Blood ◽  
2003 ◽  
Vol 101 (1) ◽  
pp. 97-100 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Jorge E. Cortes ◽  
Susan O'Brien ◽  
Francis Giles ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Chronic Myelogenous Leukemia ◽  
Quantitative Polymerase Chain Reaction ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Interferon Α ◽  
Combination Regimens ◽  
Philadelphia Chromosome Positive

Abstract Fifty patients with Philadelphia chromosome–positive (Ph+) chronic myelogenous leukemia (CML) in early chronic phase received imatinib mesylate, 400 mg orally daily. After a median follow-up of 9 months, 49 patients (98%) achieved a complete hematologic response and 45 patients (90%) achieved a major cytogenetic response, complete in 36 patients (72%). Compared with similar patients who received interferon-α with or without hydroxyurea or other interferon-α combination regimens, those receiving imatinib mesylate had higher incidences of complete and major (Ph < 35%) cytogenetic responses at 3 months (34% and 74% versus 1%-4% and 9%-24%, respectively), 6 months (52% and 80% versus 3%-7% and 11%-28%, respectively), and 9 months (60% and 77% versus 5%-11% and 14%-30%, respectively; P < .001). Competitive quantitative polymerase chain reaction (QPCR) studies at 9 months showed a median QPCR value (ratio of BCR-ABL/ABL transcripts × 100) of 0.59% overall and of 0.24% (range, 0.001%-29.5%) for complete cytogenetic response.

scholarly journals Incidence of involvement of the B and T lymphocyte lineages in chronic myelogenous leukemia

Blood ◽  
1985 ◽  
Vol 66 (5) ◽  
pp. 1053-1061 ◽  
Author(s):  
M Nitta ◽  
Y Kato ◽  
A Strife ◽  
M Wachter ◽  
J Fried ◽  
...  
Keyword(s):  
B Cells ◽  
Cell Lines ◽  
Chronic Myelogenous Leukemia ◽  
T Lymphocyte ◽  
B Lymphocyte ◽  
Blast Crisis ◽  
Interleukin 2 ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Myelogenous Leukemia

Peripheral blood specimens were obtained from 22 patients with Philadelphia chromosome (Ph1) positive chronic myelogenous leukemia (CML) (16 in chronic phase, 2 in an accelerated phase, and 4 in blast crisis). Studies were performed to determine the frequency of the presence of the Ph1 chromosome in cells of lymphoid lineages. Rosetted (E+) lymphocytes (T lymphocytes) from nine patients in chronic phase and one patient in blast crisis were stimulated with T cell growth factor interleukin 2 (IL-2) and/or phytohemagglutinin (PHA). All ten patients had sufficient T lymphocyte metaphases for analysis and of a total of 461 metaphases examined, only one contained the Ph1 chromosome. Nucleated cells of density less than 1.077 g/mL were infected with Epstein-Barr virus (EBV). Following infection, cell lines were established from individual colonies attached to egg albumin- coated Lab-Tek slide chambers (clonal cell lines) or from suspension culture in 96-well tissue culture cluster dishes (nonclonal cell lines). Cell surface and intracellular marker analysis confirmed the B lymphocyte phenotype of all the cell lines examined. B lymphoblastoid cell lines were established from 16 of the 22 patients. All lines from 12 patients were Ph1-negative. From two chronic phase patients, both Ph1-positive and Ph1-negative lines were established. From one patient in an accelerated phase, only Ph1-positive lines were established. From another patient in blast crisis (of myeloblastic phenotype), only Ph1- positive lines were established initially; however, five months later, after the patient had been treated with mitoxantrone, only Ph1-negative lines were derived from this patient. Based on these results, it appears that most B cells and mature T cells in most CML patients are Ph1-negative, but that about 25% of patients have predominantly Ph1- positive B cells or a mixture of Ph1-positive and Ph1-negative B cells that are capable of growing as established cell lines after transformation with EBV.

scholarly journals Diminished A-LAK cytotoxicity and proliferation accompany disease progression in chronic myelogenous leukemia

Blood ◽  
1990 ◽  
Vol 76 (2) ◽  
pp. 401-408 ◽  
Author(s):  
C Verfaillie ◽  
N Kay ◽  
W Miller ◽  
P McGlave
Keyword(s):  
Nk Cells ◽  
Chronic Myelogenous Leukemia ◽  
Peripheral Blood ◽  
Interleukin 2 ◽  
Chronic Phase ◽  
Lak Cells ◽  
Myelogenous Leukemia ◽  
Proliferative Potential ◽  
Lymphokine Activated Killer Cells ◽  
Normal Individuals

Abstract We have compared the proliferative and cytotoxic capacities of a highly purified population of recombinant interleukin-2 (rIL-2)-activated peripheral blood mononuclear cells (PBMNC), termed adherent lymphokine- activated killer cells (A-LAK), in 15 chronic phase (CP) and 10 advanced disease (AD) Ph-positive chronic myelogenous leukemia (CML) patients. The selective enrichment of CML A-LAK cells depended on their propensity to adhere to plastic and to proliferate when cultured in the presence of rIL-2 for 14 days. In both CP and AD patients, 14-day culture resulted in growth of a uniform population of large granular lymphocytes. While less than 10% of the A-LAK cells were CD56-/CD3+ (mature T lymphocytes), 82% +/- 12% of A-LAK cells from early CP patients (diagnosed less than 1 year from study), 84% +/- 3% of A-LAK cells from late CP patients (studied greater than 1 year after diagnosis), and 87% +/- 3% of A-LAK cells from AD patients were CD56+/CD3- (activated natural killer [NK] cells). No bcr gene rearrangement could be found in A-LAK cells from 13 CP and six AD CML patients studied. A-LAK cells from seven early CP CML patients displayed similar cytotoxicity against K562 (80% +/- 7% lysis at effector:target ratio of 20:1) and against Raji (80% +/- 12% lysis) compared with A-LAK from 17 normal individuals (72% +/- 3% K562 lysis, P = .21; 74% +/- 5% Raji lysis, P = .39). However, the cytotoxicity of A-LAK cells from eight late CP patients (59% +/- 5% K562 lysis, P = .02; 52% +/- 8% Raji lysis, P = .02) and that of 10 AD patients studied at any point after diagnosis (31% +/- 3% K562 lysis, P less than .001; 25% +/- 6% Raji lysis, P less than .001) was significantly lower than that of seven early CP CML patients and 17 normals. The proliferative potential of A-LAK cells from seven early CP CML patients (291 +/- 191- fold) was significantly greater than that of A-LAK cells from 17 normal individuals (23 +/- 3-fold, P = .03), eight late CP patients (46 +/- 17- fold, P = .02), and 10 AD patients (5.4 +/- 1.9-fold, P = .01). In contrast to CML A-LAK, K562 cytotoxicity of unstimulated mature peripheral blood NK cells was significantly lower in early CP CML patients than in normals and remained low at all stages of disease.

scholarly journals Incidence of involvement of the B and T lymphocyte lineages in chronic myelogenous leukemia

Blood ◽  
1985 ◽  
Vol 66 (5) ◽  
pp. 1053-1061 ◽  
Author(s):  
M Nitta ◽  
Y Kato ◽  
A Strife ◽  
M Wachter ◽  
J Fried ◽  
...  
Keyword(s):  
B Cells ◽  
Cell Lines ◽  
Chronic Myelogenous Leukemia ◽  
T Lymphocyte ◽  
B Lymphocyte ◽  
Blast Crisis ◽  
Interleukin 2 ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Myelogenous Leukemia

Abstract Peripheral blood specimens were obtained from 22 patients with Philadelphia chromosome (Ph1) positive chronic myelogenous leukemia (CML) (16 in chronic phase, 2 in an accelerated phase, and 4 in blast crisis). Studies were performed to determine the frequency of the presence of the Ph1 chromosome in cells of lymphoid lineages. Rosetted (E+) lymphocytes (T lymphocytes) from nine patients in chronic phase and one patient in blast crisis were stimulated with T cell growth factor interleukin 2 (IL-2) and/or phytohemagglutinin (PHA). All ten patients had sufficient T lymphocyte metaphases for analysis and of a total of 461 metaphases examined, only one contained the Ph1 chromosome. Nucleated cells of density less than 1.077 g/mL were infected with Epstein-Barr virus (EBV). Following infection, cell lines were established from individual colonies attached to egg albumin- coated Lab-Tek slide chambers (clonal cell lines) or from suspension culture in 96-well tissue culture cluster dishes (nonclonal cell lines). Cell surface and intracellular marker analysis confirmed the B lymphocyte phenotype of all the cell lines examined. B lymphoblastoid cell lines were established from 16 of the 22 patients. All lines from 12 patients were Ph1-negative. From two chronic phase patients, both Ph1-positive and Ph1-negative lines were established. From one patient in an accelerated phase, only Ph1-positive lines were established. From another patient in blast crisis (of myeloblastic phenotype), only Ph1- positive lines were established initially; however, five months later, after the patient had been treated with mitoxantrone, only Ph1-negative lines were derived from this patient. Based on these results, it appears that most B cells and mature T cells in most CML patients are Ph1-negative, but that about 25% of patients have predominantly Ph1- positive B cells or a mixture of Ph1-positive and Ph1-negative B cells that are capable of growing as established cell lines after transformation with EBV.

scholarly journals Philadelphia chromosome-negative chronic myelogenous leukemia without breakpoint cluster region rearrangement: a chronic myeloid leukemia with a distinct clinical course

Blood ◽  
1990 ◽  
Vol 75 (2) ◽  
pp. 445-452 ◽  
Author(s):  
R Kurzrock ◽  
HM Kantarjian ◽  
M Shtalrid ◽  
JU Gutterman ◽  
M Talpaz
Keyword(s):  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Chronic Myelogenous Leukemia ◽  
Myeloid Leukemia ◽  
Clinical Course ◽  
Bone Marrow Failure ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Cell Counts

Abstract The hallmarks of chronic myelogenous leukemia (CML) include the Philadelphia chromosome (Ph) translocation [t (9;22)(q34;q11)] and consistent molecular genetic aberrations: a break within a restricted 5.8 kb DNA segment, bcr, on chromosome 22q11; transposition of the c- abl protooncogene from chromosome 9q34 to 22q11; and formation of a hybrid bar-abl gene encoding an abnormal 210 Kd bcr-abl protein with augmented tyrosine kinase enzymatic activity. These molecular phenomena may occur even in the absence of cytogenetic evidence of the Ph translocation. They are highly specific and sensitive markers for CML, and are presumed to play a significant role in the pathogenesis of this malignancy. Surprisingly, we have encountered 11 patients who lacked the Ph translocation, bcr rearrangement, and (in the four patients with available mRNA) a bcr-abl message, and yet had a disease phenotype at diagnosis that was a morphologic facsimile of classic chronic phase CML. These patients presented with high white blood cell counts, neutrophilia, occasional basophilia, splenomegaly, and a hypercellular bone marrow with granulocytic hyperplasia and a left shift in myeloid maturation. Despite the striking resemblance between the early stages of bcr-negative and bcr-positive CML, disease progression manifests distinctly in these two disorders. In contrast to the blastic transformation that inevitably complicates bcr-positive CML, the natural history of our 11 Ph-negative, bcr-negative CML patients was characterized by increasing leukemia burden with leukocytosis, pronounced organomegaly, extramedullary infiltrates, and eventual bone marrow failure (anemia and thrombocytopenia) without marked increases in blast cells. Our current observations suggest that a chronic myeloid leukemia process can develop without associated changes in the bcr or c- abl genes. Although the initial phase of this disease is indistinguishable from CML, the presence or absence of molecular markers may aid in the prediction of the clinical course of Ph-negative CML.

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