ALBERT

Description: We analyzed factors having an impact on response to treatment and survival in 78 consecutive patients with chronic myeloid leukemia (CML) in blastic transformation (BT) referred to the Hammersmith Hospital from January 1995 to December 2000. BT was defined as the presence of at least 30% blasts in blood or marrow or extramedullary blastic deposits. Immunophenotyping of blasts showed 57 myeloid, 19 lymphoid, and 2 biphenotypic. The median age of the patients was 39.1 years (range, 11.3-73.4 years), with 55 males and 23 females. The median survival for all patients after onset of BT was 8.2 months (95% CI, 6.4-10). Patients in lymphoid BT survived longer than those in myeloid BT (median, 11.2 months versus 6.9 months, P = .052). Initial treatment varied; 41 patients received cytotoxic drugs, 8 underwent allogeneic or autologous transplantation procedures, 21 received STI571 (imatinib mesylate, Gleevec), 1 received radiotherapy, and 7 received no therapy. Of the 25 (32%) patients who achieved a “second chronic phase” with first therapy, 6 of 21 (29%) were treated with STI571 and 19 of 50 (38%) were treated with chemotherapy, transplantation, or radiotherapy. Patients who achieved a second chronic phase survived longer than those who did not (median time from onset of BT 12.0 months versus 6.3 months, P = .0004). In multivariate analysis the finding of more than 50% blast cells in the blood and the presence of cytogenetic progression were independent adverse prognostic variables for survival. We conclude that survival after onset of BT has improved in recent years but is still unsatisfactory. We speculate that the combined use of STI571 with cytotoxic drugs may offer additional benefit.

Description: Homoharringtonine is a plant alkaloid that inhibits the synthesis of proteins and results in apoptosis. In vitro homoharringtonine shows synergistic or additive effects with imatinib in CML cell lines and in blast cells derived from patients with advanced disease. We undertook a phase I/II study in patients who had achieved a sub-optimal response to imatinib alone to investigate whether the addition of semi-synthetic homoharringtonine (sHHT) (Myelostat®) would reduce the level of residual disease. Patients with CML who had achieved at least 35% Ph-negativity on imatinib were included. All patients were treated with imatinib at ≥ 400mg/day for at least 2 years; and achieved a plateau in BCR-ABL transcripts defined by measuring BCR-ABL transcripts on at least 4 occasions over a minimum period of 1 year with the latest value not lower than the previous minimum value. When sHHT was introduced, imatinib was continued at the previous dosage. sHHT was given subcutaneously at a dose of 1.25 mg/m2 twice daily for one day. Courses were repeated every 28 days. The dose of sHHT was escalated by adding one day of treatment every two courses (eg dose level 2: 1.25mg/m2 BD x 2 days) if the ANC was ≥2.5x109/l and the platelet count ≥200x109/l by day +28 of the previous course, or adding half a day if the ANC was ≥1.5x109/l and the platelet count ≥ 100x109/l. Patients were considered to have reached the maximal tolerable dose (MTD) when the sHHT could not be escalated further. Response was assessed by serial monitoring of peripheral blood levels of BCR-ABL transcripts assayed by RT-PCR at the start of each course. Results 10 patients have been enrolled so far. Patients received a median of six courses of sHHT (range 4–8). The MTD has been achieved in all cases (9 cases in account of myelosuppression and in one case in account of grade III asthenia). The median MDT was 2 days (range 1.5–3 days). The transcript level decline in all patients (table 1). In 7 patients the transcript levels declined by 〉0.5 log and in 5 patients by 〉1 log with respect the baseline value. In 2 patients transcripts became undetectable. The combination was relatively well tolerated with the principal toxicities being grade II asthenia (n=9), grade III astenia (n=1), grade III neutropenia (n=3) and grade III thrombocytopenia (n=1). We believe these preliminary clinical observations justify further study of the use of sHHT in patients on imatinib who fail to obtain low levels of minimal residual disease. Table 1 n Time from onset of imatinib to sHHT therapy (months) Median R-PCR over the year preceding sHHT therapy Minimal R-PCR during the year preceding sHHT therapy R-PCR at screening for sHHT R-PCR at last follow up Transcript levels are expressed as a BCR-ABL/ABL percentage 1 27.2 7.3 5.4 16.9 0.6 2 35.9 2.2 0.04 4.5 1.18 3 34.1 0.012 0.01 0.028