Case report Sudden blastic transformation in patient with chronic myeloid leukemia treated with imatinib mesylate Mehrdad Payandeh,MD Hematology, Medical Oncologist kermanshah university of medical science (KUMS)

Introduction Philadelphia chromosome (Ph)–positive chronic myeloid leukemia (CML) has a bi- or triphasic clinical course that includes chronic, accelerated, and blastic phases. Imatinib is first-line therapy for CML, with 80% to 90% achieving a complete cytogenetic response (CGCR) and 60% to 70% achieving a major molecular response.

Introduction Patients who do not respond to therapy will ultimately progress to blast phase, usually going through the accelerated phase or a poorly controlled chronic phase.

Introduction A complete hematologic remission (CHR) was defined as a white blood cell count of less than /L with a normal differential platelet count less than /L, and no splenomegaly lasting for at least 4 weeks.

Introduction CHR was further categorized by the best cytogenetic response: CGCR, Ph- positive 0%; partial cytogenetic response (CGPR), Ph-positive 1% to 34%; minor, Ph-positive 35% to 95%.

Introduction Major molecular response (MMR) was defined as a BCR-ABL/ABL ratio of less than 0.05%.

Introduction Blastic-phase CML was defined by the presence of 30% peripheral or bone marrow blasts or presence of extramedullary disease, and categorized as lymphoid or myeloid by immunohistochemistry and flow cytometry

Case presentation A 54-year-old man was initially treated with imatinib 400 mg daily. he achieved CGCR 6 months later but low levels of BCR-ABL transcripts persisted (nadir ratio, 0.661%).

Acccording to the BCR-ABL transcripts persisted What is your opinion: continue the drug ? change the line of this drug ? increased the dosage ? Other options ???

New treatment decision Dosage of imatinib increased to 600 mg/day

Response evaluation Subsequent evaluations showed progressive increase of transcript levels ( 9 months of beginning ).

Case presentation After 10 months in 600 mg imatinib /day, he developed lymphoid SBT (Sudden blastic transformation)

My opinion The patient achieved a with combination regimen of Vincristine 2 mg weekly 4 doses, danurubicin 40 mg/m2 for 3 days, and high dose dexamethasone 40 mg for 4 days and Nilotinib 200 mg TDS.

In bone marrow aspiration and biopsy after one month, patient is in complete remission response.

In this phase : what is your decision for him

Consolidation and maintenance therapy After one month of this induction chemotherapy he treated with maintenance therapy consist of Nilotinib 200 mg TDS daily with monthly Rituximab 375 mg /m2. After 3 months of this regimen he is in major molecular response.

Curative option he is candidate for an allogeneic stem cell transplant, but do not have a full match related donor.

Pretreatment characteristics for the patient did not reveal significant high-risk features. We then compared whether there were any clinical features that differentiated the patient with SBT from patient with a more gradual transformation.

Characteristics of patients with sudden (n 4) or gradual onset (n 19) of blastic transformation

Results While all 4 patients achieved CGCR, none of the other 19 achieved CGCR. The median time from diagnosis to treatment was shorter for patients with SBT (2.3 vs 73.2 months).

Results Prior IFN- treatment was associated with gradual blastic transformation, while clonal evolution (CE) was more frequent in patients with SBT. Patients with SBT had better response to treatment, results similar to what has been observed for SBT after IFN-.

A sudden onset of blastic-phase CML was defined as having its onset after a documented CGCR in the immediately preceding bone marrow analysis and within 3 months of a normal CBC.

These instances could suggest the selection of an aggressive subclone of Ph-positive cells with a proliferative advantage over the normal hematopoietic cells. It was reported that primitive Ph-positive cells may be insensitive to imatinib and persist despite an apparent optimal clinical response. combination therapies may be required to eliminate these early progenitors and prevent emergence of resistant clones.

Thus, the mechanism of resistance in these patient may be less dependent on abl kinase mutations than among patient with a more “gradual” failure to imatinib.

SBT appears to be an uncommon event after imatinib, possibly less common than after IFN-. Still, the occurrence of these events underscores the need to develop strategies for detecting and eliminating minimal residual disease.

SBT was reported at a rate of 2.2% in patients in CHR after Imatinib. SBT occurring in patients in CGCR has been reported rarely. SBT has also been reported in 5 patients after SCT, and, interestingly, 1 of our patients had a second SBT after SCT.