Abstract
In patients who are or develop resistance to IM and without access to therapeutic alternatives as second generation tyrosine kinase (TKI) inhibitors or hematopoietic stem cell transplantation, the use of alkylating drugs or investigational agents is indicated. NF Kappa B pathway is constitutively activated in CML patients therefore the combination of IM with a NF Kappa β inhibitor (as thalidomide) contributes a new very interesting field of research. Thalidomide has antiproliferative activity in Hemato-oncologic diseases, therefore we decided to use in patients with CML Ph + resistant to IM with excellent results.
Herein we report 14 cases of CML Ph (+): 6 males, 8 females with a median age of 38 years (19-62) treated with Imatinib (median maximum tolerated dose of 600 mg [200-800 mg/day]) plus Thalidomide 100 mg PO/day. At diagnosis (79%) were classified as high risk according with EUTOS scale. Follow up was done every month (Mo) with CBC, Hepatic and Renal Function Test and FISH test for BCR/ABL every 3 months. Median time of diagnosis 20 months (5-49); Imatinib treatment median time 20 months (3-60). The main reason to add thalidomide was lost of Cytogenetic Response (CgR) in 7, and suboptimal response in 7. Median Follow-up since Thalidomide addition 16 months (6-54 months) Table 1.
Demographics and Evolution of Patients.
| Gender | Age | Time from diagnosis to Imatinib (Months) | Initial Response to Imatinib | Evolution and start Thalidomide 100 mg/day (Months) | Response to IM + Thalidomide | Time to response (Months) | Follow up Months |
|---|---|---|---|---|---|---|---|
| Male | 38 | 11 | No Response | No CgR 16 months | No Response | - | 24 |
| Female | 44 | 6 | MCgR | Lost of CgR 36 months | MCyR | 3 | 18 |
| Male | 19 | 16 | MCgR | Lost of CgR 14 months | mCgR | 3 | 6 |
| Female | 62 | 6 | Suboptimal Response | No CgR 18 months | CCgR | 3 | 20 |
| Female | 36 | 20 | Suboptimal Response | No Response 11 months | MCyR | 6 | 12 |
| Female | 54 | 7 | MCgR | Lost of CyR 24 months | MCyR | 9 | 54 |
| Female | 38 | 8 | CCgR | Lost of CyR 60 months | CCyR | 12 | 19 |
| Female | 32 | 11 | No Response | No CgR 48 months | No Response | - | 8 |
| Female | 61 | 6 | MCgR | Lost of CgR 6 months | No Response | - | 16 |
| Female | 26 | 18 | Suboptimal Response | mCgR 12 Months | CCgR | 5 | 13 |
| Male | 53 | 6 | CCgR | Lost of CgR 6 months | CCgR | 6 | 16 |
| Male | 38 | 5 | No Response | No CgR | No Response | - | 12 |
| Male | 26 | 6 | MCgR | Lost CgR 6 months | mCgR | 6 months | 9 |
| Male | 39 | 49 | No Response | No CgR 18 months | No Response | - | 24 |
| Gender | Age | Time from diagnosis to Imatinib (Months) | Initial Response to Imatinib | Evolution and start Thalidomide 100 mg/day (Months) | Response to IM + Thalidomide | Time to response (Months) | Follow up Months |
|---|---|---|---|---|---|---|---|
| Male | 38 | 11 | No Response | No CgR 16 months | No Response | - | 24 |
| Female | 44 | 6 | MCgR | Lost of CgR 36 months | MCyR | 3 | 18 |
| Male | 19 | 16 | MCgR | Lost of CgR 14 months | mCgR | 3 | 6 |
| Female | 62 | 6 | Suboptimal Response | No CgR 18 months | CCgR | 3 | 20 |
| Female | 36 | 20 | Suboptimal Response | No Response 11 months | MCyR | 6 | 12 |
| Female | 54 | 7 | MCgR | Lost of CyR 24 months | MCyR | 9 | 54 |
| Female | 38 | 8 | CCgR | Lost of CyR 60 months | CCyR | 12 | 19 |
| Female | 32 | 11 | No Response | No CgR 48 months | No Response | - | 8 |
| Female | 61 | 6 | MCgR | Lost of CgR 6 months | No Response | - | 16 |
| Female | 26 | 18 | Suboptimal Response | mCgR 12 Months | CCgR | 5 | 13 |
| Male | 53 | 6 | CCgR | Lost of CgR 6 months | CCgR | 6 | 16 |
| Male | 38 | 5 | No Response | No CgR | No Response | - | 12 |
| Male | 26 | 6 | MCgR | Lost CgR 6 months | mCgR | 6 months | 9 |
| Male | 39 | 49 | No Response | No CgR 18 months | No Response | - | 24 |
CCgR: Complete Cytogenetic Rersponse; MCgR: Major Cytogenetic Response; mCgR: Major Cytogenetic Response.
Within the median time of follow-up all patients achieved Complete Hematologic Response. There was 9/14 (64%) Cytogenetic Responses (CgR): 7 Major CgR (4 Complete, 3 Majors), and 2 minor CgR. Five (5/14) patients (36%) do not achieve any type of response. The median time of thalidomide treatment was 12 months and median time to response 8 months (Table 2). The responses still on during follow-up and there is no lost of responses.
Cytogenetic Response.
| mCgR 14% |
| MCgR 50% |
| 36% |
| 64% |
| mCgR 14% |
| MCgR 50% |
| 36% |
| 64% |
MCgR: Major Cytogenetic Response; mCgR: minor Cytogenetic Response.
In all cases no studies were carried out ABL mutations because lack of financial resources. Toxicity has been minimal, mainly grade 1 peripheral neurotoxicity, constipation and none had severe adverse event.
Immunomodulatory drugs (thalidomide and its analogues) have several effects and do modify signals induced by receptor-ligand and include generation of Inflammatory Cytokines, anti angiogenic responses of cellular and immune adherence and antiproliferative direct effect perhaps by inhibition of transcriptional factor NF-κβ (Nuclear Factor KB) signaling, which promotes the survival of malignant cells and recognizes their activity in leukemias and myelodysplastic syndromes, therefore it is suggested as a potential therapeutic objective, immunomodulators block the activation of NF-κβ and may be a therapeutic option in CML. Our patients achieved the CyR cases of primary resistance and secondary Imatinib Resistance. As previously we reported (ASH 2012), this is the second communication of the use of Thalidomide with Imatinib with promising results, which may represent a therapeutic alternative in CML with antiproliferative enhancer and/or synergistic effect in patients with resistance to IM without opportunity of access to other treatments.
No relevant conflicts of interest to declare.
