Imatinib mesylate, showed encouraging activity in chronic myelogenous leukemia. However, there are few data regarding his efficacy and response monitoring in Sub-Saharan African patients. Our objective was to assess response to imatinib mesylate (Glivec) in Côte d’Ivoire patients with newly diagnosed Chronic Myeloid Leukemia (CML). From May 2005 to September 2009, we treated 42 patients (40 years; range 16–69) with Philadelphia chromosome (Ph+) positive in chronic phase CML with oral imatinib mesylate at daily doses of 400 mg. Overall survival (OS) and frequency of complete or major cytogenetic remission (CCR/MCR) were evaluated. At a median follow up of 32 (range 7.6–113) months, the CHR rate in our study group was 76%. A major CR was found in 19 patients (45%) with 17% and 29% complete and partial CR respectively. There were no significant differences in the incidence of major cytogenetic response by known prognostics factors. Median time to CHR was 8 months (range 0.4–25), and 16 months (range: 0.1–36) for CR. Projected 5-year OS rate was 72% (95%CI 42–88). We conclude that imatinib therapy sub-Saharan African CML patients is very promising and has favorably changed the prognosis for black African patients with CML.
Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of a pluripotent stem cell1 first described by John Hughes Bennett in 1845. It was the first malignancy that had a specific chromosomal abnormality uniquely linked to it after the discovery of a minute chromosome now known as the Philadelphia (Ph) chromosome, later defined to result from a t(9;22) reciprocal chromosomal translocation [
Follow-up patients were treated as long as they continued to respond. They were assessed for response to treatment by weekly physical examination, full blood count, and biochemistry for the first 6-weeks and at 6 week intervals thereafter; bone marrow morphology and cytogenetic were assessed every 3 months. Cytogenetic analysis, using the G-banding technique, was performed all patients before the initiation of therapy and every 3 months during the course of therapy. Cytogenetic response was determined based on the percentage of Ph-positive metaphases.
Cytogenetic responses were classified in accordance with standard UK Medical Research Council practice as complete (0% Ph+ metaphases), partial (1–35% Ph+ metaphases), A major cytogenetic response included complete and partial cytogenetic responses (Ph-positive less than 35%), minor (36–95% Ph+) and no response (96–100% Ph+).
End points sustained hematologic and cytogenetic response. Hematologic response was defined as described previously. Primary hematologic resistance was considered if patients failed to achieve any hematologic response.
Adverse events were graded using the National Cancer Institute/National Institutes of Health Common Toxicity Criteria, Version 2.0. Grade 3/4 hematologic toxicity was assessed regarding the time of first occurrence and duration.
Survival analysis was performed using the Kaplan-Meier method. Duration of hematologic or MCR was assessed for responding patients as the time from the first observation of response to disease recurrence, death, or last visit. Overall survival was calculated from treatment initiation to death from any cause or at the date of the last visit. Event Free Survival (EFS) was calculated from diagnosis to the first observation of disease progression or death or interrupted treatment for toxicities. For comparison of cohorts, the Mann-Whitney test was employed.
Between May 2005 and September 2009, 42 patients with CML were treated with imatinib mesylate (Gleevec).
The clinical characteristics of all patients are shown in Table
Pretreatment characteristics of the study population of 42 patients with CML.
Variable | no. |
---|---|
Gender, | |
Male | 26 |
Female | 16 |
Age (yrs) (median range) | 40 (16–69) |
Time from diagnosis (yr) (median range) | 1.5 (0.1–7) |
ECOG at diagnosis | |
0-1 | 25 (59) |
2-3 | 17 (41) |
Hepatomegaly | 15 (36) |
Splenomegaly, | |
0 cm | 4 (10) |
1–9 cm bcma | 25 (59) |
≥10 cm bcm | 13 (31) |
Peripheral blood (median range) | |
Hemoglobin level (g/dL) | 10.2 (5.7–13.7) |
Platelet count (109/L) | 331.5 (132–1992) |
Leukocyte count (109/L) | 211.7 (50–854) |
Basophils in PB (%) | 0 (0–6) |
Blasts in PB (%) | 1.9 (1–8) |
Blasts in BM (%) | 1 (0–4) |
Ph status before therapy, | |
Ph1+ | 25 (59) |
Additional chromosomal abnormalities | 17 (41) |
Sokal score | |
Low risk. | 11 (16.6) |
Intermediate risk | 16 (44.5) |
High risk | 15 (38.9) |
Cma: centimeters below the costal margin.
Detailed cytogenetic response of 17 CML patients with additional chromosomal abnormalities prior to imatinib therapy.
| |
---|---|
( | 46,XX, t(9;22)(q34;q11)[ |
( | 46, XY, t(9; 22) (q34; q11) |
( | 46,XX, t(9;22)(q34;q11) |
( | 46,XY, t(3;13)(p25;q14),t(9;22)(q34;q11) |
( | 46, XY, del(3)(p12p14), t(9;22)(q34;q11) |
( | 46, XY, t(9;10;22)(q34;p14;q11) |
47, XY, t(9;10;22)(q34;p14;q11),+mar1 | |
( | 46,XX, t(9;22)(q34;q12) |
( | 46,XY,t(9;22)(q34;q11) |
( | 46,XX,t(9;22)(q34;q11),add(13)(p11),add(20)(p13) |
( | 46, XY, t(9;22) ( |
( | 46, XY, t(9;22) |
( | 46, XY, t(9;22),-17,add(19)(q13.4),- mar |
( | 47 XY,+8,t(9;22)(q34;q11) |
( | 46, XY,t(9;22) |
( | 46, XY, add(2)(p25),t(9;22)(q34;q11) |
( | 46,XY,t(2;9;22)(q15;q34;d11) |
The median time from diagnosis to start Imatinib was relatively long, 9.41 months (range: 0.2–25 months). Overall rates of hematological and cytogenetic responses to imatinib mesylate therapy are shown in Table
Hematologic and cytogenetic response.
Characteristics | |
---|---|
Hematologic remission | |
Complete | 32 (76) |
Partial | 10 (24) |
Cytogenetic response | 33 (79) |
Major (Ph ≤ 35%) | 19 (45) |
Complete (Ph+ = 0%) | 7 (17) |
Partial (Ph+ = 1%–35%) | 12 (28) |
Minor (Ph+ 36% –95%) | 14 (33) |
Minimal/no (Ph+ >95%) | 12 (29) |
The CHR rate in our study group was 76%. A major cytogenetic response was noted in 19 patients (45%): complete in 7 (17%) and partial in 12 (29%). Complete cytogenetic response was achieved in only 1 patient (14%) 3 months of therapy, in 2 patients (29%) 6 months, and 4 patients (57%) 9 months. There were no significant differences in the incidence of major cytogenetic response by known prognostic factors (age, splenomegaly, sex, leukocytosis, thrombocytosis, blasts, and Sokal score). However, during clinical follow-up, patients with additional abnormalities showed significant lower CHR (59% versus 88%) (
Hematologic and cytogenetic response according to Ph+ alone or additional chromosomal abnormalities.
CHR | 22 (88) | 10 (59) | .0357 |
MCyR | 15 (60) | 04 (24) | .043 |
CCyR | 6 (24) | 1 (6) | .210 |
CHR: complete hematologic response; MCyR: major cytogenetic response; CCY: complete cytogenetic response.
Incidence of grade 3-4 side effects with imatinib mesylate therapy (
Toxicity | No. (%) with grades 3-4 toxicity |
---|---|
Non Hematologic toxicities | |
Bone or Joint aches | 11 (26) |
Others | 10 (24) |
Skins rash | 3 (7) |
Nausea | 2 (5) |
Diarrhea | 2 (5) |
Muscle cramps | 2 (5) |
Hematologic toxicities | |
Granulocytopenia < 1 | 14 (33) |
Thrombocytopenia <50 | 10 (24) |
Anemia < 8 g/d liter | 5 (12) |
Overall survival of patients with CML imatinib mesylate therapy.
Even-free survival of patients with CML imatinib mesylate therapy.
Our study of patients with newly diagnosed CML chronic-phase Ph+ is unique in sub-Saharan Africa. To our knowledge there are few data regarding imatinib therapy for sub-Saharian African patients with Ph + leukemia [
With the overall median follow-up time of 32 months (range: 7.6–113 months), we found 76% of CHR rate and 79% had cytogenetic response, which was major in 45% and complete in only 17%. Thus, the results with imatinib mesylate therapy continue to be positive with longer follow-up. This result is lower than that of the reported case of literature. The high rate of RCC was reported by Kantarjian et al. and the IRIS study 81% and 86%,respectively [
The median time from diagnosis to commencement of Imatinib was relatively long, t 9.41 months (range: 0.2–25 months), and it is known that this can worsen the prognosis and reduce the probability of response. Our results suggest that there is a small subset of patients whose leukemic cells remain sensitive to imatinib therapy despite the presence of additional chromosome abnormalities. On the other hand, we observed a larger group of patients (12 of 42 patients, 29%) who did not attain a CR with STI571 therapy. This result seems to be high compared to those reported in the literature computer [
There were no significant differences in the incidence of major cytogenetic response, by known prognostic factors (age, splenomegaly, sex, leukocytosis, thrombocytosis, blasts,and Sokal systems scoring) perhaps due to the short effectiveness of our study population. In the large randomized study, found the significant correlation between these classical prognostics parameters with the cytogenetic response rate has been [
Previous experience has led to estimated yearly mortality rates of 10%–15% for patients in chronic-phase CML that had failed to respond or had relapsed during therapy [
Imatinib mesylate therapy is now the new standard of care for patients with chronic-phase CML. Combinations of imatinib mesylate with IFN
Nonetheless, the projected 5-years overall survival rate of 72% (95%CI, 42–88) seems to be impressive for an African population of patients. The extended IRIS study has recently reported a 5-year overall survival estimated as 89% [
Based on this advantage survival, this work has shown that the outcome of imatinib therapy for newly diagnose Ph+ CML chronic phase in the sub-Saharan African country of Côte d’Ivoire is no far different from reports in the Western populations. We conclude that imatinib therapy sub-Saharan African CML patients is very promising despite the high incidence of additional chromosome abnormalities, with the additional advantage of oral availability and tolerability. Imatinib has favorably changed the prognosis for black African patients with CML.
The authors are grateful to Novartis for providing imatinib mesylate (Glivec), the Max Foundation and Axios International for facilitating the delivery of the drug, the National Hematology Teaching Hospital of Yopougon, Côte d’Ivoire. They are especially grateful to Pasteur Cerba of Paris (France) for cytogenetic analysis.