No abstract

3759 Imatinib treatment dramatically improves survival in chronic myeloid leukemia (CML) patients, but whether its effects of imatinib can be considered a cure remains controversial. This is because primitive, quiescent, Philadelphia-positive stem cells from patients with CML are insensitive to imatinib in vitro. Nonetheless, it was recently recognized that some patients with a complete molecular response (CMR) could sustain that response after discontinuation of imatinib. In a non-randomized prospective study, Mahon et al. reported that among patients with CMR lasting at least 2 years, CMR was sustained in 41% after discontinuation of imatinib. To characterize the clinical outcomes and profiles of chronic phase CML patients who discontinued imatinib, we conducted a nationwide survey in Japan. Among 3,242 imatinib-treated CML patients, 50 (1.5%) were identified who discontinued imatinib therapy for at least 6 months; of those, 43 were analyzed further. Molecular recurrence was detected in 19 patients, and the complete molecular response (CMR) rate was estimated to be 47% following imatinib discontinuation. Notably, the durations of imatinib therapy and CMR before cessation of therapy were significantly longer, and imatinib dose intensity and the frequency of prior IFN-a administration were significantly higher, in patients sustaining CMR for 12 months after cessation than in those with molecular recurrence. No significant correlations were detected between molecular recurrence and age, sex, Sokal risk, imatinib daily dose, combination with IFN-a, or time to achieve CMR. Moreover, we found a significant difference in estimated CMR rate following discontinuation between patients who had sustained CMR for greater than 24 months prior to imatinib discontinuation and those with less than 24 months (78% vs. 15%, p =0.0002 by Log-rank test, Figure). Based on multivariate regression analysis, only imatinib dose intensity and prior IFN-a administration were independently predictive of molecular recurrence within 12 months (p =0.0035, p =0.0060). The identified prediction formula was: Y= −0.0061 x dose intensity of imatinib(g)-3.17171 x prior IFN-a(Yes=1/No=0) +4.0124. If 1/(1+exp(-1 × Y)) > 0.5, molecular recurrence was predicted; the total accuracy rate of the formula was 82.5%. Although the depth of the molecular response should be a factor influencing long-term sustained CMR after discontinuation of imatinib, other factors, for example an immunological mechanism modified by IFN-a, might control quiescent CML stem cells. To increase the “cure” rate among CML patients, it will be necessary to establish a treatment strategy on the basis of large prospective study of imatinib discontinuation. This should entail the use of a highly sensitive and strict method for monitoring minimal residual disease over the course of a long follow-up period. Disclosures: No relevant conflicts of interest to declare.

Two distinct cell lines (OPM-1 and OPM-2) were established from the peripheral blood of a 56-year-old female myeloma patient at the stage of terminal leukemic evolution associated with loss of cytoplasmic immunoglobulin heavy chain (G lambda----lambda). The lines grew in suspension with a doubling time of 36-42 hr and 30-36 hr, respectively. EBNA was absent from both lines. The lines synthesized cytoplasmic lambda-chain, but had no detectable surface immunoglobulins. Fc receptors and complement receptors could not be detected in either line. The lines had very complex chromosomal abnormalities, but the patterns of chromosomes differed greatly between the two lines. The two lines, together with the RPMI 8226 line established by Matsuoka et al. (1967), were analyzed for phenotypic expression as defined by a panel of monoclonal antibodies to B cells (B1, BA-1, BA-2, BA-3, OKIa-1 and OKT10/BMA0100). Neither OPM-1 nor OPM-2 reacted with any of the antibodies tested except OKT10. OPM-1 cells reacted weakly (less than 30%) with OKT10/BMA0100, while OPM-2 cells showed a fluctuating reactivity, ranging from 40 to 80%, with OKT10/BMA0100. In contrast, RPMI 8226 reacted strongly with OKT10 and BA-2. These results demonstrate the presence of phenotypic heterogeneity in all 3 myeloma cell lines, suggesting that the lines might represent different stages of terminal B-cell development.

To compare the different stem cell sources used in salvage transplantation for graft failure (GF) after cord blood transplantation (CBT), we retrospectively analyzed data of 220 patients who developed GF after undergoing CBT between January 2001 and December 2007 and underwent a second hematopoietic stem cell transplantation (HSCT) within 3 months. The donor sources for salvage HSCT were cord blood (n = 180), peripheral blood stem cells (PBSCs; n = 24), and bone marrow (BM; n = 16). The cumulative incidence of neutrophil engraftment on day 30 after the second HSCT was 39% with CB, 71% with PBSCs, and 75% with BM. Multivariate analysis revealed that PBSC and BM grafts were associated with a significantly higher engraftment rate than CB (hazard ratio [HR], 7.77; P < .001 and HR, 2.81; P = .016, respectively). Although the incidence of grade II-IV acute graft-versus-host disease was significantly higher in the PBSC group than in the CB group (HR, 2.83; P = .011), the incidence of 1-year nonrelapse mortality was lower in the PBSC group than in the CB group (HR, 0.43; P = .019), and 1-year overall survival was superior in the PBSC group compared with the CB group (HR, 0.45; P = .036). Our results suggest that PBSC is the preferable source of stem cells in salvage HSCT for GF after CBT.