Background: High levels of MCL-1 and BCL-2 proteins have been found in Chronic Lymphocytic Leukemia (CLL), and inversely correlated with response to treatment. BCL-2/Bax ratio is the main director of apoptosis in CLL. The study aimed to clarify the prognostic role of MCL-1, BCL-2 and BCL-2/ Bax ratio in B-CLL. Patients & method: Estimation of MCL-1, BCL-2 and Bax expressions by a flow cytometry in 45 B-CLL patients and the prognostic value of these markers were correlated with other well-known established prognostic markers and treatment response. Results: MCL-1 was expressed in 60% of cases while BCL-2 was expressed in 82.2% of cases. MCL-1 expression was significantly high in male gender, short lymphocyte doubling time (LDT), and high expression of CD 38 ( p < 0.001). High (Serum LDH, serum β2M, CD38 expression), low ZAP-70 expression, splenomegaly and higher Rai stage were significantly increased in patients with high expression of BCL-2 ( p < 0.001); also a significant decrease in (HB level, platelet count), and increase in serum LDH, serum β2M, high C-D38 expression, low ZAP-70 expression, the poor cytogenetic and splenomegaly in patients with high expression of BCL-2/ Bax ratio ( p < 0.001). Among the 39 patients who started treatment when indicated responding patients had statistically significant lower BCL-2/Bax ratio than non-responding patients, although their lower mean of MCL-1 and BCL2 expressions values were insignificant. In conclusion: MCL-1, BCL-2 expressions and BCL-2/Bax ratio could be useful potential predictive and prognostic markers in B-CLL.
The most prevalent form of adult leukemia is B-Chronic lymphocytic leukemia (B-CLL); it is characterized by accumulation of CD5+ and CD23+ B-cell lymphocytes [
We enrolled 45 denovo B-CLL patients, who were presented to Clinical patholo- gy, Medical Oncology, Clinical oncology and Internal Medicine departments, Zagazig University Hospitals. In the period between June 2013 and May 2015, complete history taking was done for all patients, clinical examination, and labo- ratory investigations; CBC, direct Coombs’ test, LDH and β2M estimation.
An international scoring system based on expression patterns of immunophe- notyping markers in CLL has been established. Patients with Chronic B lympho- proliferative disorders were diagnosed by evidence of persistent absolute lymphocytosis > 5000/µl (5 × 109/liter) for 3 months. Immunophenotyping was performed by monoclonal antibodies panels: CD3, CD7, CD5, CD19, CD20, CD22, Κ/λ, CD23, CD79b, and FMC7, also estimation of cytoplasmic ZAP-70 expression and surface CD38 [
Flow cytometric analysis of MCL-1, BCL-2 and Bax expressions by using FITC- conjugated MoAb (Dako, Glostrup, Denmark). Peripheral blood samples (EDTA blood) were tested initially with diagnosis or before any treatment. All samples were initially incubated with CD19 PE and CD5 APC MoAbs for 30 min at 4˚C. Subsequently the cells after washing twice in PBS were fixed and permeabilized with Cell Permeabilizationkit. Samples were then incubated at 4˚C for 30 min with 10 uL anti-MCL-1, anti-BCL-2, and anti BAX FITC conjugated. We evaluated MCL-1, BCL-2 and Baxas relative mean fluorescence intensities (rMFIs). The ratio between BCL-2 and Bax (rMFIs), and non-specific MoAb MFI on B cells also were calculated. In current study, a cut-off of 25% of positive cells was chosen to determine MCL-1 positive in CLL cases [
By using fluorescence in situ hybridization (FISH) technique, Cytogenetic analysis was done on peripheral blood, a locus specific identifier DNA probe (LSI) Kit was used, Vysis (Abbott Park, Ill, USA).
There are indications to begin treatment for CLL patients including: elevated total leucocytes count with a lymphocytes doubling time < 12 months, having ane- mia or thrombocytopenia as a result of bone marrow infiltration, development
of systemic B-symptoms, bulky lymphadenopathy, increasing organomegally, and recurrent infection. For patients <60 years fludarabine/cyclophos-phamide + Rituximab (FCR) protocol was given, and for CLL patients >60 years chlorambucil + Rituximab were given. Complete and partial remission of the disease were measured as overall response, while failure of response was defined as stable (did not achieve any remission) or progressive disease. To determine when to start first treatment with early stages disease and to evaluate the disease outcome we followed up patients up to 18 months. Six months post start of treatment; re-evalu- ation was done for our patients for response assessment according to guidelines of National Cancer Institute-sponsored group [
Continuous variables were expressed as the mean ± SD & median (range), and the categorical variables were expressed as a number (percentage). Continuous variables were checked for normality by using Shapiro-Wilk test. Mann Whitney U test was used to compare between two groups of non-normally distributed variables. Kruskal Wallis H test was used to compare between more than two groups of normally distributed variables. Percent of categorical variables were compared using the Pearson’s Chi-square test or Fisher's exact test when was appropriate. Trend of change in distribution of relative frequencies between ordinal data were compared using Chi-square test for trend. Receiver operating characteristic (ROC) curve analysis was used to identify optimal cut-off values of BCL-2/Bax ratio with maximum sensitivity and specificity for prediction of overall response of CLL patients to treatment. Area under Curve (AUROC) was also calculated, criteria to qualify for AUC were as follows: 0.90 - 1 = excellent, 0.80 - 0.90 = good, 0.70 - 0.80 = fair; 0.60 - 0.70 = poor; and 0.50 - 0.6 = fail. The optimal cutoff point was established at point of maximum accuracy. Strength of relationship between time to start first treatment and flow-cytometry markers were determined by computing Spearman’s correlation coefficient, (+) sign was indicating direct relationship & (−) sign was indicator for inverse relationship was indicated by (−) sign, values near to 0 was indicator for weak relationship & values near 1 was indicating strong relationship. All tests were two sided. A significant p-value was <0.05. SPSS 22.0 for windows (SPSS Inc., Chicago, IL, USA) and MedCalc windows (MedCalc Software bvba 13, Ostend, Belgium) was used in performing all statistics.
The clinical, laboratory, and outcome of all B-CLL patients are summarized in
To establish the clinical significance of BCL-2/Bax ratio, we calculated the index of test validity for responders to treatment (CR + PR) and non-responders (NR). The best results of sensitivity and specificity were obtained at the cut-off point of 1.6.
There was statistically significant decrease in (HB level, platelet count), and increase in serum LDH, serum β2M, high CD38 expression, low ZAP-70 expression, poor cytogenetic and splenomegaly in patients with high expression of BCL-2/Bax ratio compared to those with low ratio (p < 0.001),
We classified our patients according to Rai staging system, and divided them into two groups; low risk group (stage 0-II) and high risk group (stage III?IV). There were significant associations between BCL-2, BCL-2/Bax ratio, and Rai staging system (p < 0.05), while MCL-1 expression has no relation to Rai system (p > 0.05).
Thirty-nine patients (86.6%) received chemotherapy during the follow-up period, and demonstrated variable response; 8 patients achieved CR, 12 achieved PR, and 19 were non-responders (NR) to treatment. Six patients did not require starting treatment for CLL, and one patient lost follow-up.
Characteristics Age (year) | No. | (%) | Characteristics Cytogenetic Analysis | No. | (%) |
---|---|---|---|---|---|
Mean ± SD | 56.31 | ±12.3 | Normal | 20 | (44.4%) |
Median (Range) | 54 | (38 - 74) | del 13 | 4 | (8.9%) |
≤60 years | 25 | (55.6%) | del 11 | 5 | (11.1%) |
>60 years | 20 | (44.4%) | Trisomy 12 | 6 | (13.3%) |
Sex | del 17 | 5 | (11.1%) | ||
Male Female | 26 (57.8%) 19 (42.2%) | Complex | 5 | (11.1%) | |
CD19 (%) | |||||
Rai classification | Mean ± SD | 82.92 | ±15.67 | ||
Stage 0, 1 & 2 | 20 | (44.4%) | Median (Range) | 89.10 | (32.84 - 97.61) |
Stage 3 & 4 | 25 | (55.6%) | CD23 (%) | ||
Clinical mainfestaion | Mean ± SD | 69.40 | ±27.74 | ||
Hepatomegally | 22 | (48.9%) | Median (Range) | 79.27 | (0.38 - 95.74) |
Lymphadenopathy | 31 | (68.9%) | CD5/CD20 (%) | ||
Spleenomegally | 33 | (73.3%) | Mean ± SD | 73.22 | ±23.52 |
WBCs (×103/mm3) | Median (Range) | 79.90 | (8.41 - 96.02) | ||
Mean ± SD | 46.80 | ±31.71 | CD79b (%) | ||
Median (Range) | 31.60 | (17.50 - 122.8) | Mean ± SD | 57.18 | ±33.93 |
<100 × 103/mm3 | 39 | (86.7%) | Median (Range) | 66.57 | (1.93 - 95.51) |
≥100 × 103/mm3 | 6 | (13.3%) | FMc7 (%) | ||
Absolute lymphocytes (×103/mm3) | Mean ± SD | 17.01 | ±24.89 | ||
Mean ± SD | 26.27 | ±16.42 | Median (Range) | 4.85 | (0.06 - 88.44) |
Median (Range) | 18 | (9.10 - 67) | CD22 (%) | ||
<30 × 103/mm3 | 33 | (73.3%) | Mean ± SD | 24.95 | ±14.39 |
≥30 × 103/mm3 | 12 | (26.7%) | Median (Range) | 20.79 | (7.12 - 70.69) |
Platelet count (×103/mm3) | CD38 (%) | ||||
Mean ± SD | 121.13 | ±47.20 | Mean ± SD | 23.79 | ±25.41 |
Median (Range) | 111 | (45 - 205) | Median (Range) | 8 | (0.30 - 91.59) |
<100 × 103/mm3 | 19 | (42.2%) | <30% | 28 | (62.2%) |
≥100 × 103/mm3 | 26 | (57.8%) | >30% | 17 | (37.8%) |
Hemoglobin (g/dl) | MCL-1 (%) | ||||
Mean ± SD | 10.73 | ±2.29 | Mean ± SD | 60.60 | ±41.98 |
Median (Range) | 10.20 | (6.60 - 14.30) | Median (Range) | 91.30 | (0.60 - 99.70) |
<12 g/dl | 25 | (55.6%) | <25% | 18 | (40%) |
≥12 g/dl | 20 | (44.4%) | >25% | 27 | (60%) |
LDH (U/L) | BCL-2 (%) |
Mean ± SD | 354 | ±107.94 | Mean ± SD | 52.20 | ±29.24 |
---|---|---|---|---|---|
Median (Range) | 340 | (190 - 540) | Median (Range) | 53.90 | (2 - 93.20) |
≤350 U/L | 23 | (51.1%) | <10% | 8 | (17.8%) |
>350 U/L | 22 | (48.9%) | >10% | 37 | (82.2%) |
B2-microglobulin (mg/L) | ZAP-70 | ||||
Mean ± SD | 2.91 | ±0.99 | <20% | 27 | (60%) |
Median (Range) | 3 | (1.40 - 5) | >20% | 18 | (40%) |
<3.5 mg/L | 29 | (64.4%) | Time to begin ttt (months) for all Pt | ||
≥3.5 mg/L | 16 | (35.6%) | Mean ± SD | 5.07 | ±4.23 |
Coomb’s test | Median (Range) | 7 | (2 - 14) | ||
Negative | 38 | (84.4%) | Response* | ||
Positive | 7 | (15.6%) | |||
Lymphocytic doubling time (LDT) | No response (NR) | 19 | (42.2%) | ||
<12 months | 21 | (46.7%) | Overall response (ORR) | 20 | (44.5%) |
>12 months | 24 | (53.3%) |
Continuous variables were expressed as mean ± SD & median (range); categorical variables were expressed as number (percentage). *6 patients (13.3%) were not received treatment.
Characteristics | All (N = 45) | MCL-1 | p-value | ||||
---|---|---|---|---|---|---|---|
<25% (N = 18) | >25% (N = 27) | ||||||
No. | (%) | No. | (%) | No. | (%) | ||
Age (years) | |||||||
Mean ± SD | 56.31 | ±12.3 | 52.33 | ±11.77 | 58.96 | ±12.01 | 0.074• |
Median (Range) | 54 | (38 - 74) | 50.50 | (38 - 73) | 61 | (42 - 74) | |
≤60 years | 25 | (55.6%) | 13 | (52%) | 12 | (48%) | 0.066 |
>60 years | 20 | (44.4%) | 5 | (25%) | 15 | (75%) | |
Sex | |||||||
Male | 26 | (57.8%) | 14 | (53.8%) | 12 | (46.2%) | 0.027 |
Female | 19 | (42.2%) | 4 | (21.1%) | 15 | (78.9%) | |
Rai classification | |||||||
Stage 0, 1 & 2 | 20 | (44.4%) | 9 | (45%) | 11 | (55%) | 0.540 |
Stage 3 & 4 | 25 | (55.6%) | 9 | (36%) | 16 | (64%) | |
Hepatomegally | |||||||
Absent | 23 | (51.1%) | 7 | (30.4%) | 16 | (69.6%) | 0.181 |
Present | 22 | (48.9%) | 11 | (50%) | 11 | (50%) |
Lymphadenopathy | |||||||
---|---|---|---|---|---|---|---|
Absent | 14 | (31.1%) | 7 | (50%) | 7 | (50%) | 0.357 |
Present | 31 | (68.9%) | 11 | (35.5%) | 20 | (64.5%) | |
Spleenomegally | |||||||
Absent | 12 | (26.7%) | 7 | (58.3%) | 5 | (41.7%) | 0.175 |
Present | 33 | (73.3%) | 11 | (33.3%) | 22 | (66.7%) | |
WBCs (×103/mm3) | |||||||
Mean ± SD | 46.80 | ±31.71 | 49.00 | ±38.39 | 45.33 | ±27.06 | 0.651• |
Median (Range) | 31.60 | (17.50 - 122.80) | 31 | (17.50 - 122.80) | 37.20 | (17.50 - 118.50) | |
<100 × 103/mm3 | 39 | (86.7%) | 14 | (35.9%) | 25 | (64.1%) | 0.199 |
≥100 × 103/mm3 | 6 | (13.3%) | 4 | (66.7%) | 2 | (33.3%) | |
Absolute lymphocytes (×103/mm3) | |||||||
Mean ± SD | 26.27 | ±16.42 | 27.60 | ±21.73 | 25.39 | ±12.06 | 0.487• |
Median (Range) | 18 | (9.10 - 67) | 16 | (9.10 - 67) | 24 | (12.50 - 55.20) | |
<30 × 103/mm3 | 33 | (73.3%) | 13 | (39.4%) | 20 | (60.6%) | 1.000 |
≥30 × 103/mm3 | 12 | (26.7%) | 5 | (41.7%) | 7 | (58.3%) | |
Platelet count (×103/mm3) | |||||||
Mean ± SD | 121.13 | ±47.20 | 126.77 | ±45.62 | 117.37 | ±48.71 | 0.378• |
Median (Range) | 111 | (45 - 205) | 111.50 | (65 - 205) | 102 | (45 - 200) | |
<100 × 103/mm3 | 19 | (42.2%) | 6 | (31.6%) | 13 | (68.4%) | 0.324 |
≥100 × 103/mm3 | 26 | (57.8%) | 12 | (46.2%) | 14 | (53.8%) | |
Hemoglobin (g/dl) | |||||||
Mean ± SD | 10.73 | ±2.29 | 10.81 | ±2.33 | 10.67 | ±2.31 | 0.935• |
Median (Range) | 10.20 | (6.60 - 14.30) | 10.40 | (7.60 - 14.30) | 10.20 | (6.60 - 14) | |
<12 g/dl | 25 | (55.6%) | 9 | (36%) | 16 | (64%) | 0.540 |
≥12 g/dl | 20 | (44.4%) | 9 | (45%) | 11 | (55%) | |
LDH (U/L) | |||||||
Mean ± SD | 354 | ±107.94 | 341.11 | ±106.70 | 362.59 | ±109.91 | 0.479• |
Median (Range) | 340 | (190 - 540) | 340 | (200 - 540) | 340 | (190 - 540) | |
≤350 U/L | 23 | (51.1%) | 9 | (39.1%) | 14 | (60.9%) | 0.903 |
>350 U/L | 22 | (48.9%) | 9 | (40.9%) | 13 | (59.1%) | |
B2-microglobulin (mg/L) | |||||||
Mean ± SD | 2.91 | ±0.99 | 2.91 | ±1.02 | 2.91 | ±0.99 | 0.814• |
Median (Range) | 3 | (1.40 - 5) | 3.15 | (1.40 - 4.40) | 3 | (1.80 - 5) | |
<3.5 mg/L | 29 | (64.4%) | 10 | (34.5%) | 19 | (65.5%) | 0.309 |
≥3.5 mg/L | 16 | (35.6%) | 8 | (50%) | 8 | (50%) |
Coomb’s test | |||||||
---|---|---|---|---|---|---|---|
Negative | 38 | (84.4%) | 16 | (42.1%) | 22 | (57.9%) | 0.684 |
Positive | 7 | (15.6%) | 2 | (28.6%) | 5 | (71.4%) | |
Lymphocytic doubling time | |||||||
<12 months | 21 | (46.7%) | 12 | (57.1%) | 9 | (42.9%) | 0.028 |
>12 months | 24 | (53.3%) | 6 | (25%) | 18 | (75%) | |
Cytogenetic analysis | |||||||
Normal | 20 | (44.4%) | 8 | (40%) | 12 | (60%) | 0.20 |
del 13 | 4 | (8.9%) | 3 | (75%) | 1 | (25%) | |
del 11 | 5 | (11.1%) | 3 | (60%) | 2 | (40%) | |
Trisomy 12 | 6 | (13.3%) | 3 | (50%) | 3 | (50%) | |
del 17 | 5 | (11.1%) | 0 | (0%) | 5 | (100%) | |
Complex | 5 | (11.1%) | 1 | (20%) | 4 | (80%) | |
CD38 (%) | |||||||
Mean ± SD | 23.79 | ±25.41 | 19.07 | ±23.48 | 26.94 | ±26.58 | 0.431• |
Median (Range) | 8 | (0.30 - 91.59) | 5.93 | (0.30 - 91.57) | 32 | (0.60 - 91.59) | |
<30% | 28 | (62.2%) | 16 | (57.1%) | 12 | (42.9%) | 0.003 |
>30% | 17 | (37.8%) | 2 | (11.8%) | 15 | (88.2%) | |
BCL-2 (%) | |||||||
Mean ± SD | 52.20 | ±29.24 | 51.59 | ±30.40 | 52.61 | ±29.03 | 0.981• |
Median (Range) | 53.90 | (2 - 93.20) | 53.90 | (3 - 93.20) | 48.20 | (2 - 91.20) | |
<10% | 8 | (17.8%) | 4 | (50%) | 4 | (50%) | 0.694§ |
>10% | 37 | (82.2%) | 14 | (37.8%) | 23 | (62.2%) | |
ZAP-70 | |||||||
<20% | 27 | (60%) | 9 | (33.3%) | 18 | (66.7%) | 0.264 |
>20% | 18 | (40%) | 9 | (50%) | 9 | (50%) | |
BCL-2/Bax ratio | |||||||
Mean ± SD | 2.01 | ±1.50 | 1.53 | ±1.30 | 2.32 | ±1.56 | 0.085• |
Median (Range) | 1.20 | (0.30 - 5) | 1 | (0.30 - 4.30) | 2 | (0.50 - 5) | |
≤1.6 | 26 | (57.8%) | 13 | (50%) | 13 | (50%) | 0.109 |
>1.6 | 19 | (42.2%) | 5 | (26.3%) | 14 | (73.7%) |
Categorical variables were expressed as number (percentage), continuous variables were expressed as mean ± SD & median (range); •Mann Whitney U test; § Chi-square test; p < 0.05 is significant.
Characteristics | All (N = 45) | BCL-2 | p-value | ||||
---|---|---|---|---|---|---|---|
<10% (N = 8) | >10% (N = 37) | ||||||
No. | (%) | No. | (%) | No. | (%) | ||
Age (years) | |||||||
Mean ± SD | 56.31 | ± 12.3 | 52.62 | ± 12.83 | 57.10 | ± 12.12 | 0.298• |
Median (Range) | 54 | (38 - 74) | 45.50 | (42 - 73) | 54 | (38 - 74) | |
≤60 years | 25 | (55.6%) | 5 | (20%) | 20 | (80%) | 0.716 |
>60 years | 20 | (44.4%) | 3 | (15%) | 17 | (85%) | |
Sex | |||||||
Male | 26 | (57.8%) | 6 | (23.1%) | 20 | (76.9%) | 0.435 |
Female | 19 | (42.2%) | 2 | (10.5%) | 17 | (89.5%) | |
Rai classification | |||||||
Stage 0, 1 & 2 | 20 | (44.4%) | 7 | (35%) | 13 | (65%) | 0.015 |
Stage 3 & 4 | 25 | (55.6%) | 1 | (4%) | 24 | (96%) | |
Hepatomegally | |||||||
Absent | 23 | (51.1%) | 6 | (26.1%) | 17 | (73.9%) | 0.243 |
Present | 22 | (48.9%) | 2 | (9.1%) | 20 | (90.9%) | |
Lymphadenopathy | |||||||
Absent | 14 | (31.1%) | 3 | (21.4%) | 11 | (78.6%) | 0.689 |
Present | 31 | (68.9%) | 5 | (16.1%) | 26 | (83.9%) | |
Spleenomegally | |||||||
Absent | 12 | (26.7%) | 5 | (41.7%) | 7 | (58.3%) | 0.022 |
Present | 33 | (73.3%) | 3 | (9.1%) | 30 | (90.9%) | |
WBCs (×103/mm3) | |||||||
Mean ± SD | 46.80 | ±31.71 | 25.85 | ±8.49 | 51.33 | ±33.11 | 0.014• |
Median (Range) | 31.60 | (17.50 - 122.80) | 25 | (17.50 - 38) | 36 | (17.50 - 122.80) | |
<100 × 103/mm3 | 39 | (86.7%) | 8 | (20.5%) | 31 | (79.5%) | 0.572 |
≥100 × 103/mm3 | 6 | (13.3%) | 0 | (0%) | 6 | (100%) | |
Absolute lymphocytes (×103/mm3) | |||||||
Mean ± SD | 26.27 | ±16.42 | 17.01 | ±6.67 | 28.28 | ±17.25 | 0.085• |
Median (Range) | 18 | (9.10 - 67) | 17 | (9.10 - 26) | 19 | (12.50 - 67) | |
<30 × 103/mm3 | 33 | (73.3%) | 8 | (20.5%) | 25 | (75.8%) | 0.087§ |
≥30 × 103/mm3 | 12 | (26.7%) | 0 | (0%) | 12 | (100%) | |
Platelet count (×103/mm3) | |||||||
Mean ± SD | 121.13 | ±47.20 | 125 | ±46.94 | 120.29 | ±47.86 | 0.778• |
Median (Range) | 111 | (45 - 205) | 111 | (76 - 200) | 112 | (45 - 205) | |
<100 × 103/mm3 | 19 | (42.2%) | 2 | (10.5%) | 17 | (89.5%) | 0.435§ |
≥100 × 103/mm3 | 26 | (57.8%) | 6 | (23.1%) | 20 | (76.9%) | |
Hemoglobin (g/dl) | |||||||
Mean ± SD | 10.73 | ±2.29 | 11.73 | ±2.73 | 10.51 | ±2.17 | 0.191• |
Median (Range) | 10.20 | (6.60 - 14.30) | 12.65 | (7 - 14.30) | 10.10 | (6.60 - 14) | |
<12 g/dl | 25 | (55.6%) | 2 | (8%) | 23 | (92%) | 0.113 |
≥12 g/dl | 20 | (44.4%) | 6 | (30%) | 14 | (70%) |
LDH (U/L) | ||||||||
---|---|---|---|---|---|---|---|---|
Mean ± SD | 354 | ±107.94 | 285 | ±36.25 | 368.91 | ±112.68 | 0.051• | |
Median (Range) | 340 | (190 - 540) | 295 | (200 - 320) | 400 | (190 - 540) | ||
≤350 U/L | 23 | (51.1%) | 8 | (34.8%) | 15 | (65.2%) | 0.004 | |
>350 U/L | 22 | (48.9%) | 0 | (0%) | 22 | (100%) | ||
B2-microglobulin (mg/L) | ||||||||
Mean ± SD | 2.91 | ±0.99 | 2.03 | ±0.44 | 3.10 | ±0.98 | 0.006• | |
Median (Range) | 3 | (1.40 - 5) | 2 | (1.40 - 3) | 3 | (1.70 - 5) | ||
<3.5 mg/L | 29 | (64.4%) | 8 | (27.6%) | 21 | (72.4%) | 0.037 | |
≥3.5 mg/L | 16 | (35.6%) | 0 | (0%) | 16 | (100%) | ||
Coomb’s test | ||||||||
Negative | 38 | (84.4%) | 8 | (21.1%) | 30 | (78.9%) | 0.321 | |
Positive | 7 | (15.6%) | 0 | (0%) | 7 | (100%) | ||
Lymphocytic doubling time | ||||||||
<12 months | 21 | (46.7%) | 7 | (33.3%) | 14 | (66.7%) | 0.017 | |
>12 months | 24 | (53.3%) | 1 | (4.2%) | 23 | (95.8%) | ||
Cytogenetic analysis | ||||||||
Normal | 20 | (44.4%) | 4 | (20%) | 16 | (80%) | 0.210 | |
del 13 | 4 | (8.9%) | 2 | (50%) | 2 | (50%) | ||
del 11 | 5 | (11.1%) | 0 | (0%) | 5 | (100%) | ||
Trisomy 12 | 6 | (13.3%) | 2 | (33.3%) | 4 | (66.7%) | ||
del 17 | 5 | (11.1%) | 0 | (0%) | 5 | (100%) | ||
Complex | 5 | (11.1%) | 0 | (0%) | 5 | (100%) | ||
CD38 (%) | ||||||||
Mean ± SD | 23.79 | ±25.41 | 3.53 | ±2.38 | 28.17 | ±26.03 | 0.013• | |
Median (Range) | 8 | (0.30 - 91.59) | 4.41 | (0.30 - 5.95) | 27.61 | (0.60 - 91.59) | ||
<30% | 28 | (62.2%) | 8 | (28.6%) | 20 | (71.4%) | 0.017 | |
>30% | 17 | (37.8%) | 0 | (0%) | 17 | (100%) | ||
MCL-1 (%) | ||||||||
Mean ± SD | 60.60 | ±41.98 | 36.64 | ±36.07 | 65.78 | ±41.79 | 0.102• | |
Median (Range) | 91.30 | (0.60 - 99.70) | 31.48 | (1.10 - 99.70) | 97.47 | (0.60 - 99.40) | ||
<25% | 18 | (40%) | 4 | (22.2%) | 14 | (77.8%) | 0.694 | |
>25% | 27 | (60%) | 4 | (14.8%) | 23 | (85.2%) | ||
ZAP-70 | ||||||||
<20% | 27 | (60%) | 2 | (7.4%) | 25 | (92.6%) | 0.045 | |
>20% | 18 | (40%) | 6 | (33.3%) | 12 | (66.7%) | ||
BCL-2/Bax ratio | ||||||||
Mean ± SD | 2.01 | ±1.50 | 0.80 | ±0.26 | 2.27 | ±1.53 | 0.006• | |
Median (Range) | 1.20 | (0.30 - 5) | 0.85 | (0.30 - 1.10) | 2 | (0.30 - 5) | ||
≤1.6 | 26 | (57.8%) | 8 | (30.8%) | 18 | (69.2%) | 0.014 | |
>1.6 | 19 | (42.2%) | 0 | (0%) | 19 | (100%) | ||
Categorical variables were expressed as number (percentage), continuous variables were expressed as mean ± SD & median (range); • Mann Whitney U test; § Chi-square test; p < 0.05 is significant.
Cut-off values | SN% (95% CI) | SP% (95% CI) | PPV% (95% CI) | NPV% (95% CI) | Accuracy (95% CI) | AUROC (95% CI) | p-value |
---|---|---|---|---|---|---|---|
BCL-2/Bax ratio ≤1.6 | 100% (83.2 - 100) | 94.7% (74 - 99.9) | 95.2% (76.2 - 99.9) | 100% (81.5 - 100) | 97.4% (78.7 - 100) | 0.982 (0.877 - 1.000) | <0.001 |
ROC curve: Receiver Operating Characteristic curve; SN: Sensitivity; SP: Specificity; PPV: Positive Predictive Value; NPV: Negative Predictive Value; AUROC: Area under Receiver Operating Characteristic curve; 95% CI: 95% Confidence Interval; p < 0.05 is significant; Sig.: significance.
Characteristics | All (N = 45) | BCL-2/Bax ratio | p-value | ||||
---|---|---|---|---|---|---|---|
≤1.6 (N = 26) | >1.6 (N = 19) | ||||||
No. | (%) | No. | (%) | No. | (%) | ||
Age (years) | |||||||
Mean ± SD | 56.31 | ±12.3 | 56.19 | ±12.92 | 56.47 | ±11.55 | 0.927• |
Median (Range) | 54 | (38 - 74) | 53.50 | (38 - 74) | 54 | (42 - 74) | |
≤60 years | 25 | (55.6%) | 15 | (60%) | 10 | (55%) | 0.73 |
>60 years | 20 | (44.4%) | 11 | (55%) | 9 | (45%) | |
Sex | |||||||
Male | 26 | (57.8%) | 16 | (61.5%) | 10 | (38.5%) | 0.550 |
Female | 19 | (42.2%) | 10 | (52.6%) | 9(47.4%) | ||
Rai classification | |||||||
Stages 0, 1 & 2 | 20 | (44.4%) | 17 | (85%) | 3 | (15%) | 0.001 |
Stages 3 & 4 | 25 | (55.6%) | 9 | (36%) | 16 | (64%) | |
Hepatomegally | |||||||
Absent | 23 | (51.1%) | 13 | (56.5%) | 10 | (43.5%) | 0.862 |
Present | 22 | (48.9%) | 13 | (59.1%) | 9 | (40.9%) | |
Lymphadenopathy | |||||||
Absent | 14 | (31.1%) | 9 | (64.3%) | 5 | (35.7%) | 0.553 |
Present | 31 | (68.9%) | 17 | (54.8%) | 14 | (45.2%) | |
Spleenomegally | |||||||
Absent | 12 | (26.7%) | 11 | (91.7%) | 1 | (8.3%) | 0.006 |
Present | 33 | (73.3%) | 15 | (45.5%) | 18 | (54.5%) | |
WBCs (×103/mm3) | |||||||
Mean ± SD | 46.80 | ±31.71 | 47.90 | ±37.22 | 45.30 | ±23 | 0.401• |
Median (Range) | 31.60 | (17.50 - 122.80) | 33.25 | (17.50 - 122.80) | 31.60 | (17.50 - 112.50) | |
<100 × 103/mm3 | 39 | (86.7%) | 21 | (53.8%) | 18 | (46.2%) | 0.222 |
≥100 × 103/mm3 | 6 | (13.3%) | 5 | (83.3%) | 1 | (16.7%) | |
Absolute lymphocytes (×103/mm3) | |||||||
Mean ± SD | 26.27 | ±16.42 | 26.80 | ±17.42 | 25.55 | ±15.37 | 0.881• |
Median (Range) | 18 | (9.10 - 67) | 18.65 | (9.10 - 67) | 17.30 | (13 - 67) | |
<30 × 103/mm3 | 33 | (73.3%) | 19 | (57.6%) | 14 | (42.4%) | 0.964 |
≥30 × 103/mm3 | 12 | (26.7%) | 7 | (58.3%) | 5 | (41.7%) | |
Platelet count (×103/mm3) | |||||||
Mean ± SD | 121.13 | ±47.20 | 134.69 | ±48.89 | 102.57 | ±38.69 | 0.035• |
Median (Range) | 111 | (45 - 205) | 125.50 | (45 - 205) | 90 | (49 - 181) | |
<100 × 103/mm3 | 19 | (42.2%) | 7 | (36.8%) | 12 | (63.2%) | 0.015 |
≥100 × 103/mm3 | 26 | (57.8%) | 19 | (73.1%) | 7 | (26.9%) |
Hemoglobin (g/dl) | |||||||
---|---|---|---|---|---|---|---|
Mean ± SD | 10.73 | ±2.29 | 11.56 | ±2.16 | 9.58 | ±2.01 | 0.009• |
Median (Range) | 10.20 | (6.60 - 14.30) | 12.50 | (7 - 14.30) | 9.10 | (6.60 - 14) | |
<12 g/dl | 25 | (55.6%) | 9 | (36%) | 16 | (64%) | 0.001 |
≥12 g/dl | 20 | (44.4%) | 17 | (85%) | 3 | (15%) | |
LDH (U/L) | |||||||
Mean ± SD | 354 | ±107.94 | 305.76 | ±89.94 | 420 | ±96.37 | 0.001• |
Median (Range) | 340 | (190 - 540) | 300 | (190 - 500) | 440 | (210 - 540) | |
≤350 U/L | 23 | (51.1%) | 19 | (82.6%) | 4 | (17.4%) | 0.001 |
>350 U/L | 22 | (48.9%) | 7 | (31.8%) | 15 | (68.2%) | |
B2-microglobulin (mg/L) | |||||||
Mean ± SD | 2.91 | ±0.99 | 2.67 | ±0.97 | 3.25 | ±0.95 | 0.046• |
Median (Range) | 3 | (1.40 - 5) | 2 | (1.40 - 4.40) | 3.30 | (2 - 5) | |
<3.5 mg/L | 29 | (64.4%) | 18 | (62.1%) | 11 | (37.9%) | 0.433 |
≥3.5 mg/L | 16 | (35.6%) | 8 | (50%) | 8 | (50%) | |
Coomb’s test | |||||||
Negative | 38 | (84.4%) | 24 | (63.2%) | 14 | (36.8%) | 0.114 |
Positive | 7 | (15.6%) | 2 | (28.6%) | 5 | (71.4%) | |
Lymphocytic doubling time | |||||||
<12 months | 21 | (46.7%) | 18 | (85.7%) | 3 | (14.3%) | <0.001 |
>12 months | 24 | (53.3%) | 8 | (33.3%) | 16 | (66.7%) | |
Cytogenetic analysis | |||||||
Normal | 20 | (44.4%) | 15 | (75%) | 5 | (25%) | 0.001 |
del 13 | 4 | (8.9%) | 3 | (75%) | 1 | (25%) | |
del 11 | 5 | (11.1%) | 1 | (20%) | 4 | (80%) | |
Trisomy 12 | 6 | (13.3%) | 6 | (100%) | 0 | (0%) | |
del 17 | 5 | (11.1%) | 1 | (20%) | 4 | (80%) | |
Complex | 5 | (11.1%) | 0 | (0%) | 5 | (100%) | |
CD38 (%) | |||||||
Mean ± SD | 23.79 | ±25.41 | 11.76 | ±13.31 | 40.26 | ±28.94 | <0.001• |
Median (Range) | 8 | (0.30 - 91.59) | 4.90 | (0.30 - 42) | 38 | (0.72 - 91.59) | |
<30% | 28 | (62.2%) | 23 | (82.1%) | 5 | (17.9%) | <0.001 |
>30% | 17 | (37.8%) | 3 | (17.6%) | 14 | (82.4%) | |
MCL-1 (%) | |||||||
Mean ± SD | 60.60 | ±41.98 | 49.14 | ±42.41 | 76.27 | ±36.89 | 0.087• |
Median (Range) | 91.30 | (0.60 - 99.70) | 38.03 | (0.60 - 99.70) | 98 | (9.70 - 99.20) | |
<25% | 18 | (40%) | 13 | (72.2%) | 5 | (27.8%) | 0.109 |
>25% | 27 | (60%) | 13 | (48.1%) | 14 | (51.9%) | |
BCL-2 (%) | |||||||
Mean ± SD | 52.20 | ±29.24 | 46.47 | ±34.34 | 60.04 | ±18.45 | 0.223• |
Median (Range) | 53.90 | (2 - 93.20) | 48.20 | (2 - 93.20) | 66.20 | (35.70 - 93.20) | |
<10% | 8 | (17.8%) | 8 | (100%) | 0 | (0%) | 0.014 |
>10% | 37 | (82.2%) | 18 | (48.6%) | 19 | (51.4%) | |
ZAB-70 | |||||||
<20% | 27 | (60%) | 11 | (40.7%) | 16 | (59.3%) | 0.005 |
>20% | 18 | (40%) | 15 | (83.3%) | 3 | (16.7%) |
Categorical variables were expressed as number (percentage), continuous variables were expressed as mean ± SD & median (range); • Mann Whitney U test; § Chi-square test; p < 0.05 is significant.
Characteristics | All (N = 39) | Response | p-value | ||||
---|---|---|---|---|---|---|---|
No response (N = 19) | OAR (N = 20) | ||||||
No. | (%) | No. | (%) | No. | (%) | ||
Age (years) | |||||||
Mean ± SD | 57.79 | ±12.01 | 56.57 | ±11.45 | 58.95 | ±12.71 | 0.473• |
Median (Range) | 54 | (39 - 74) | 54 | (42 - 74) | 59 | (39 - 74) | |
≤60 years | 20 | (51.3%) | 10 | (50%) | 10 | (50%) | 0.869§ |
>60 years | 19 | (48.7%) | 9 | (47.4%) | 10 | (52.6%) | |
Sex | |||||||
Male | 23 | (59%) | 10 | (43.5%) | 13 | (56.5%) | 0.433§ |
Female | 16 | (41%) | 9 | (56.3%) | 7 | (43.8%) | |
Rai classification | |||||||
Stages 0, 1 & 2 | 16 | (41%) | 3 | (18.8%) | 13 | (81.3%) | 0.002§ |
Stages 3 & 4 | 23 | (59%) | 16 | (69.6%) | 7 | (30.4%) | |
Hepatomegally | |||||||
Absent | 21 | (53.8%) | 11 | (52.4%) | 10 | (47.6%) | 0.621§ |
Present | 18 | (46.2%) | 8 | (44.4%) | 10 | (55.6%) | |
Lymphadenopathy | |||||||
Absent | 13 | (33.3%) | 5 | (38.5%) | 8 | (61.5%) | 0.365§ |
Present | 26 | (66.6%) | 14 | (53.8%) | 12 | (46.2%) | |
Spleenomegally | |||||||
Absent | 9 | (23.1%) | 1 | (11.1%) | 8 | (88.9%) | 0.020§ |
Present | 30 | (76.9%) | 18 | (60%) | 12 | (40%) | |
WBCs (×103/mm3) | |||||||
Mean ± SD | 49.44 | ±33.21 | 47.46 | ±23.50 | 51.32 | ±40.93 | 0.407• |
Median (Range) | 36 | (17.50 - 122.80) | 43 | (17.50 - 112.50) | 32.35 | (17.50 - 122.80) | |
<100 × 103/mm3 | 33 | (84.6%) | 18 | (54.5%) | 15 | (45.5%) | 0.182§ |
≥100 × 103/mm3 | 6 | (15.4%) | 1 | (16.7%) | 5 | (83.3%) | |
Absolute lymphocytes (×103/mm3) | |||||||
Mean ± SD | 27.72 | ±17.09 | 26.61 | ±15.29 | 28.79 | ±18.97 | 0.855• |
Median (Range) | 19.30 | (9.10 - 67) | 19 | (13 - 67) | 21.15 | (9.10 - 67) | |
<30 × 103/mm3 | 27 | (69.2%) | 13 | (48.1%) | 14 | (51.9%) | 0.915§ |
≥30 × 103/mm3 | 12 | (30.8%) | 6 | (50%) | 6 | (50%) | |
Platelet count (×103/mm3) | |||||||
Mean ± SD | 121.61 | ±48.49 | 97.68 | ±33.79 | 144.35 | ±50.05 | 0.004• |
Median (Range) | 112 | (45 - 205) | 89 | (49 - 180) | 159.50 | (45 - 205) |
<100 × 103/mm3 | 17 | (43.6%) | 13 | (76.5%) | 4 | (23.5%) | 0.002§ |
---|---|---|---|---|---|---|---|
≥100 × 103/mm3 | 22 | (56.4%) | 6 | (27.3%) | 16 | (72.7%) | |
Hemoglobin (g/dl) | |||||||
Mean ± SD | 10.79 | ±2.25 | 9.59 | ±2.01 | 11.93 | ±1.87 | 0.002• |
Median (Range) | 10.20 | (6.60 - 14.30) | 9.10 | (6.60 - 14) | 12.95 | (7.70 - 14.30) | |
<11 g/dl | 22 | (56.4%) | 16 | (72.7%) | 6 | (27.3%) | 0.001§ |
≥11 g/dl | 17 | (43.6%) | 3 | (17.6%) | 14 | (82.4%) | |
LDH (U/L) | |||||||
Mean ± SD | 363.84 | ±108.13 | 419.47 | ±96.29 | 311 | ±96.56 | 0.002• |
Median (Range) | 380 | (190 - 540) | 430 | (210 - 540) | 300 | (190 - 500) | |
≤350 U/L | 18 | (46.2%) | 4 | (22.2%) | 14 | (77.8%) | 0.002§ |
>350 U/L | 21 | (53.8%) | 15 | (71.4%) | 6 | (28.6%) | |
B2-microglobulin (mg/L) | |||||||
Mean ± SD | 3.01 | ±0.97 | 3.25 | ±0.95 | 2.78 | ±0.96 | 0.130• |
Median (Range) | 3 | (1.80 - 5) | 3.30 | (2 - 5) | 2.05 | (1.80 - 4.40) | |
<3.5 mg/L | 24 | (61.5%) | 11 | (45.8%) | 13 | (54.2%) | 0.648§ |
≥3.5 mg/L | 15 | (38.5%) | 8 | (53.3%) | 7 | (46.7%) | |
Coomb’s test | |||||||
Negative | 32 | (82.1%) | 13 | (40.6%) | 19 | (59.4%) | 0.044• |
Positive | 7 | (17.9%) | 6 | (85.7%) | 1 | (14.3%) | |
Lymphocytic doubling time | |||||||
<12 months | 18 | (46.2%) | 3 | (16.7%) | 15 | (83.3%) | <0.001§ |
>12 months | 21 | (53.8%) | 16 | (76.2%) | 5 | (23.8%) | |
Cytogenetic analysis | |||||||
Normal | 17 | (43.6%) | 5 | (29.4%) | 12 | (70.6%) | 0.002§ |
del 13 | 3 | (7.7%) | 1 | (33.3%) | 2 | (66.7%) | |
del 11 | 4 | (10.3%) | 3 | (75%) | 1 | (25%) | |
Trisomy 12 | 5 | (12.8%) | 0 | (0%) | 5 | (100%) | |
del 17 | 5 | (12.8%) | 5 | (100%) | 0 | (0%) | |
Complex | 5 | (12.8%) | 5 | (100%) | 0 | (0%) | |
CD38 (%) | |||||||
Mean ± SD | 25.94 | ±26.21 | 41.69 | ±27.74 | 10.98 | ±12.70 | <0.001• |
Median (Range) | 22 | (0.30 - 91.59) | 38 | (0.72 - 91.59) | 4.59 | (0.30 - 42) | |
<30% | 23 | (59%) | 4 | (17.4%) | 19 | (82.6%) | <0.001§ |
>30% | 16 | (41%) | 15 | (93.8%) | 1 | (6.3%) | |
ZAP-70 | |||||||
<20% | 24 | (61.5%) | 16 | (66.7%) | 8 | (33.3%) | 0.005§ |
>20% | 15 | (38.5%) | 3 | (20%) | 12 | (80%) |
MCL-1 (%) | |||||||
---|---|---|---|---|---|---|---|
Mean ± SD | 64.98 | ±41.21 | 80.16 | ±34.13 | 50.55 | ±42.94 | 0.177• |
Median (Range) | 96.60 | (0.60 - 99.70) | 98 | (9.70 - 99.20) | 38.03 | (0.60 - 99.70) | |
<25% | 14 | (35.9%) | 4 | (28.6%) | 10 | (71.4%) | 0.060§ |
>25% | 25 | (64.1%) | 15 | (60%) | 10 | (40%) | |
BCL-2 (%) | |||||||
Mean ± SD | 56.72 | ±27.64 | 59.74 | ±18.60 | 53.86 | ±34.39 | 0.855• |
Median (Range) | 66.10 | (2 - 93.20) | 66.20 | (35.70 - 93.20) | 61.45 | (2 - 93.20) | |
<10% | 5 | (12.8%) | 0 | (0%) | 5 | (100%) | 0.047§ |
>10% | 34 | (87.2%) | 19 | (55.9%) | 15 | (44.1%) | |
BCL-2/Bax ratio | |||||||
Mean ± SD | 2.16 | ±1.54 | 3.50 | ±1.10 | 0.89 | ±0.32 | <0.001• |
Median (Range) | 1.50 | (0.30 - 5) | 3.70 | (1 - 5) | 0.95 | (0.30 - 1.60) | |
≤1.6 | 21 | (53.8%) | 1 | (4.8%) | 20 | (95.2%) | <0.001§ |
>1.6 | 18 | (46.2%) | 18 | (100%) | 0 | (0%) |
Categorical variables were expressed as number (percentage), continuous variables were expressed as mean ± SD & median (range); •Mann Whitney U test; § Chi-square test; p < 0.05 is significant.
Although MCL-1 expression was not significantly affect the treatment response (p = 0.060), better overall response was associated with low MCL-1 expression, as 10/14 of those with low MCL-1developed objective response to treatment (CR + PR).
Low BCL-2 expression was significantly associated with achieving treatment response but when CR and PR were calculated together (p = 0.047), as all patients with low expression of BCL-2 were achieving overall response, and the 19 non responding patients were having high BCL-2 expression. Also low BCL- 2/Bax ratio was significantly associated with better treatment response (CR+PR) (p = 0.001); among the 39 patients who started treatment at diagnosis, responding patients had statistically significant lower BCL-2/Bax ratio mean than non- responding patients (0.89 ± 0.32 vs. 3.5 ± 1.1, respectively; p < 0.001), and none of the patients in the group with high BCL-2/Bax ratio achieving any response, while 95% of responding patients had low BCL-2/Bax ratio.
Our patients were grouped according to Rai staging system, to two categories; low risk group (stage 0-II) and high risk (stage III?IV). The low risk group (20 patients) was followed up to detect time to start treatment ,and to determine factors that influence that time, so 20 patients were followed for up to 18 months; 6 of them didn’t need to start treatment. The time to start chemotherapy treatment ranging from 2 to 14 months, we found a significant difference between patients ≤60 years and those >60 years as regard time to start treatment (p = 0.026). Patients with high BCL-2 expression and those with high BCL-2/Bax ratio experienced shorter time to start treatment, but that was not statistically significant (p > 0.05)
Characteristics | All (N = 20) | Time to start treatment (months) | p-value | ||||
---|---|---|---|---|---|---|---|
No. | (%) | Mean | ±SD | Median | (Range) | ||
Age | |||||||
≤60 years | 12 | (60%) | 11.16 | ±3.37 | 12.50 | (4 - 14) | 0.026• |
>60 years | 8 | (40%) | 7.75 | ±3.28 | 7.50 | (2 - 12) | |
Sex | |||||||
Male | 14 | (70%) | 9.85 | ±4.14 | 11.5 | (2 - 14) | 0.919* |
Female | 6 | (30%) | 9.66 | ±2.58 | 9 | (7 - 14) | |
Hepatomegally | |||||||
Absent | 11 | (55%) | 9.63 | ±3.58 | 11 | (4 - 14) | 0.833* |
Present | 9 | (45%) | 10 | ±4 | 10 | (2 - 14) | |
Lymphadenopathy | |||||||
Absent | 7 | (35%) | 10.14 | ±4.18 | 11 | (2 - 14) | 0.769* |
Present | 13 | (65%) | 9.61 | ±3.54 | 8 | (4 - 14) | |
Spleenomegally | |||||||
Absent | 11 | (55%) | 10.45 | ±3.38 | 12 | (4 - 14) | 0.394* |
Present | 9 | (45%) | 9 | ±4.06 | 10 | (2 - 14) | |
WBCs | |||||||
<100 × 103/mm3 | 15 | (75%) | 10.46 | ±3.52 | 11 | (4 - 14) | 0.157• |
≥100 × 103/mm3 | 5 | (25%) | 7.80 | ±3.76 | 8 | (2 - 12) | |
Absolute lymphocytes | |||||||
<30 × 103/mm3 | 13 | (65%) | 11.15 | ±3.23 | 12 | (4 - 14) | 0.018• |
≥30 × 103/mm3 | 7 | (35%) | 7.28 | ±3.25 | 7 | (2 - 12) | |
Lymphocytic doubling time | |||||||
<12 months | 14 | (70%) | 10.14 | ±3.63 | 10.50 | (2 - 14) | 0.539* |
>12 months | 6 | (30%) | 9 | ±4 | 9.50 | (4 - 14) | |
Cytogenetic analysis | |||||||
Normal | 12 | (60%) | 9.58 | ±3.50 | 9.50 | (4 - 14) | 0.946‡ |
del 13 | 3 | (15%) | 10 | ±3.46 | 8 | (8 - 14) | |
del 11 | 1 | (5%) | 11 | ||||
Trisomy 12 | 4 | (20%) | 10 | ±5.65 | 12 | (2 - 14) | |
CD38 | |||||||
<30% | 17 | (85%) | 10.17 | ±3.35 | 11 | (2 - 14) | 0.288* |
>30% | 3 | (15%) | 7.66 | ±5.50 | 5 | (4 - 14) | |
MCL-1 | |||||||
<25% | 9 | (45%) | 10.66 | ±4.03 | 12 | (2 - 14) | 0.233• |
>25% | 11 | (55%) | 9.09 | ±3.38 | 8 | (4 - 14) | |
BCL-2 | |||||||
<10% | 7 | (35%) | 11.71 | ±2.75 | 13 | (8 - 14) | 0.077• |
>10% | 13 | (65%) | 8.76 | ±3.78 | 8 | (2 - 14) | |
ZAB-70 | |||||||
<20% | 6 | (30%) | 8.50 | ±3.88 | 8 | (4 - 14) | 0.314* |
>20% | 14 | (70%) | 10.35 | ±3.58 | 11 | (2 - 14) | |
BCL-2/Bax ratio | |||||||
≤1.6 | 17 | (85%) | 10.35 | ±3.69 | 11 | (2 - 14) | 0.077• |
>1.6 | 3 | (15%) | 6.66 | ±1.52 | 7 | (5 - 8) |
Categorical variables were expressed as number (percentage), continuous variables were expressed as mean ± SD & median (range); *Independent samples Student’s t-test; •Mann Whitney U test; ‡Kraskall Wallis H test; p < 0.05 is significant.
Also we found a significant indirect correlation between age, WBCS count, Absolute lymphocyte count, B2-microglobulin and time to start first treatment (months)
Nowadays with the development of novel treatment options it necessitate the identification of patients ,with unfavorable prognostic features ,who are more liable for early progression and who would gain the most benefit from early interference with targeted treatment. For this reason, identification of prognostic factors of CLL is the interest of all researchers [
Variables | Time to start first treatment (months) | |
---|---|---|
r | p-value | |
Age (years) | −0.498 | 0.025 |
WBCs (×103/mm3) | −0.511 | 0.021 |
Absolute lymphocytes (×103/mm3) | −0.507 | 0.023 |
Platelet count (×103/mm3) | −0.274 | 0.242 |
Hemoglobin (g/dl) | −0.203 | 0.392 |
LDH (U/L) | −0.010 | 0.967 |
B2-microglobulin (mg/L) | −0.665 | 0.001 |
CD38 (%) | −0.209 | 0.376 |
MCL-1 (%) | −0.239 | 0.310 |
BCL-2 (%) | −0.305 | 0.191 |
BCL-2/Bax ratio | −0.388 | 0.091 |
r: Spearman’s rank correlation coefficient; p < 0.05 is significant.
and interfering with apoptosis independent of cell division promotion [
Our study showed that 27 patients (60%) were positive MCL-1, while Anurag Saxena et al. [
In our study an association between low MCL-1 levels and ability to gain overall response (10/14) to treatment was detected, in Anurag Saxena study [
Regard the clinical impact of BCL-2/Bax ratio in the present study; as independent prognostic factor in CLL patients, we detected that a higher BCL-2/Bax ratio strongly correlated with some unfavorable clinical presentations like low HB, low platelets , high LDH and splenomegaly, also significant associations detected between high BCL-2/Bax ratio and indicators of higher tumor burden (B2M, and LDT, Rai stages) and other prognostic markers such CD38, and cytogenetics, and CD38 overexpression is well known to has adverse prognostic effect in CLL [
By using a flow cytometric method, we detected the prognostic power of MCL-1, BCL-2, and BCL-2/Bax ratio, which is an easy method used in routine laboratory practice. Also we defined the correlations of these proteins expressions with chemo-resistance and clinical outcome in CLL patients. So MCL-1, BCL-2, and BCL-2/Bax ratio can be used to determine CLL cases that can be targeted by new BCL-2 inhibitors therapy.
The authors have declared no conflict of interest.
Baraka, A., El Shorbagy, S., Elfarargy, O.M., Haggag, R., Abdelaziz, L.A., Elsayed, S.F. and Elbana, K.A. (2017) Prognostic Significance of Apo- ptosis Regulators in B-Cell Chronic Lymphocytic Leukemia. Journal of Cancer The- rapy, 8, 360-385. https://doi.org/10.4236/jct.2017.84032