Shuichi Mizuta

Pre-transplant imatinib-based therapy improves the outcome of allogeneic hematopoietic stem cell transplantation for BCR-ABL-positive acute lymphoblastic leukemia.

A high complete remission (CR) rate has been reported in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) following imatinib-based therapy. However, the overall effect of imatinib on the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is undetermined. Between 2002 and 2005, 100 newly diagnosed adult patients with Ph+ALL were registered to a phase II study of imatinib-combined chemotherapy (Japan Adult Leukemia Study Group Ph+ALL202 study) and 97 patients achieved CR. We compared clinical outcomes of 51 patients who received allo-HSCT in their first CR (imatinib cohort) with those of 122 historical control patients in the pre-imatinib era (pre-imatinib cohort). The probability of overall survival at 3 years after allo-HSCT was 65% (95% confidence interval (CI), 49–78%) for the imatinib cohort and 44% (95% CI, 35–52%) for the pre-imatinib cohort. Multivariate analysis confirmed that this difference was statistically significant (adjusted hazard ratio, 0.44, P=0.005). Favorable outcomes of the imatinib cohort were also observed for disease-free survival (P=0.007) and relapse (P=0.002), but not for non-relapse mortality (P=0.265). Imatinib-based therapy is a potentially useful strategy for newly diagnosed patients with Ph+ALL, not only providing them more chance to receive allo-HSCT, but also improving the outcome of allo-HSCT.

Cytomegalovirus antigenemia and outcome of patients treated with pre-emptive ganciclovir: Retrospective analysis of 241 consecutive patients undergoing allogeneic hematopoietic stem cell transplantation

Summary:CMV disease remains a major infectious complication after allogeneic hematopoietic stem cell transplantation (HSCT). To investigate the relationship between CMV antigenemia, treatment with ganciclovir (GCV), and outcome, we retrospectively analyzed 241 consecutive patients at risk for CMV infection who underwent allogeneic HSCT. Antigenemia-guided pre-emptive strategy with GCV was used for all patients. CMV antigenemia developed in 169 patients (70.1%), and CMV disease in 18 patients (7.5%). Multivariate analysis showed that acute GVHD (grades II–IV) was the only risk factor for developing antigenemia, and acute GVHD and advanced age for CMV disease. GCV use, as well as acute GVHD and advanced age, significantly increased the risk for bacterial and fungal infection after engraftment. Those who developed CMV antigenemia had a poorer outcome than those who did not (log-rank, P=0.0269), although the development of CMV disease worsened the outcome with only borderline significance (log-rank, P=0.0526). In conclusion, detection of antigenemia proved to be a poor prognostic factor for HSCT patients, which may be attributed to a combination of factors, including CMV disease itself, the effect of treatment, and a host status that allows for reactivation of CMV. Optimal pre-emptive strategy needs to be determined.

Pretransplant administration of imatinib for allo-HSCT in patients with BCR-ABL–positive acute lymphoblastic leukemia

We aimed to evaluate the impact of pretransplant imatinib administration on the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in adults with Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL). We retrospectively analyzed 738 patients with Ph(+) ALL that underwent allo-HSCT between 1990 and 2010 using data from the Transplant Registry Unified Management Program of the Japan Society of Hematopoietic Cell Transplantation. We compared the allo-HSCT outcomes between 542 patients who received imatinib before allo-HSCT during the initial complete remission period (imatinib cohort) and 196 patients who did not receive imatinib (non-imatinib cohort). The 5-year overall survival after allo-HSCT was significantly higher in the imatinib cohort than in the non-imatinib cohort (59% vs 38%; 95% confidence interval [CI], 31-45%; P < .001). Multivariate analysis indicated that pretransplant imatinib administration had beneficial effects on overall survival (hazard ratio [HR], 0.57; 95% CI, 0.42-0.77; P < .001), relapse (HR, 0.66; 95% CI, 0.43-0.99; P = .048), and nonrelapse mortality (HR, 0.55; 95% CI, 0.37-0.83; P = .005). In conclusion, our study showed that imatinib administration before allo-HSCT had advantageous effects on the clinical outcomes of allo-HSCT in patients with Ph(+) ALL.

Accurate quantitation of residual tumor burden at bone marrow harvest predicts timing of subsequent relapse in patients with common ALL treated by autologous bone marrow transplantation

We have investigated whether the extent of residual leukemia at bone marrow harvest can predict subsequent relapse after autologous bone marrow transplantation (BMT). A total of 29 pre- and post-purged marrow samples from 15 patients with high-risk common acute lymphoblastic leukemia were examined. An accurate quantitation of residual disease was achieved by phage library assay using polymerase chain reaction to amplify the third complementarity determining region of the immunoglobulin gene. The estimated rate of disease-free survival at 3 years was significantly higher for the patients with less than 5% residual disease among total B cells than for those with greater than 5% before purging (87.5% vs 0%, P = 0.0013). Furthermore, among patients with subsequent relapse, there was a linear correlation between the quantitated residual tumor burden of pre-purged marrow and remission duration after BMT (r2 = 0.888). An accurate quantitative assessment of residual disease in the autograft has a high predictive value for subsequent relapse. A serial assay of residual disease would help us to individualize the treatment for each patient after induction or consolidation therapy.

Prognostic factors influencing clinical outcome of allogeneic hematopoietic stem cell transplantation following imatinib-based therapy in BCR–ABL-positive ALL

We investigated prognostic factors for the clinical outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) following imatinib-based therapy. Among 100 adult patients who were prospectively enrolled in the JALSG Ph+ALL202 study, 97 patients obtained complete remission (CR) by imatinib-combined chemotherapy, among whom 60 underwent allo-HSCT in their first CR. The probabilities of overall survival (OS) and disease-free survival (DFS) at 3 years after HSCT were 64% (95% CI, 49–76) and 58% (95% CI, 43–70), respectively. Prognostic factor analysis revealed that the major BCR–ABL transcript was the only unfavorable predictor for OS and DFS after HSCT by both univariate (HR, 3.67 (95% CI 1.49–9.08); P=0.005 and HR, 6.25 (95% CI, 1.88–20.8); P=0.003, respectively) and multivariate analyses (HR, 3.20 (95% CI, 1.21–8.50); P=0.019 and HR, 6.92 (95% CI, 2.09–22.9); P=0.002, respectively). Minimal residual disease status at the time of HSCT had a significant influence on relapse rate (P=0.015). Further study of the BCR–ABL subtype for the clinical impact on outcome of allo-HSCT in Ph+ALL is warranted.

High-Dose Chemotherapy with Autologous Stem Cell Transplantation for Elderly Patients with Relapsed/Refractory Diffuse Large B Cell Lymphoma: A Nationwide Retrospective Study

The number of elderly patients with diffuse large B cell lymphoma (DLBCL) continues to increase but the data regarding autologous stem cell transplantation (ASCT) for elderly patients are limited. We analyzed 484 patients, ages 60 years or over, diagnosed with relapsed/refractory DLBCL who received ASCT from 1993 to 2010 in the Japan Society for Hematopoietic Cell Transplantation database. Median age was 64 years (range, 60 to 78). To evaluate the impact of age at ASCT, patients were classified into 3 groups: those between the ages of 60 to 64, 65 to 69, and 70 years or over. Overall nonrelapse mortality (NRM) at day 100, 1 year, and 2 years was 4.1%, 5.9% and 7.7%, respectively. NRM did not significantly differ among age groups (P = .60). Two-year progression-free survival (PFS) and overall survival (OS) were 48% and 58%, respectively. PFS and OS were significantly longer in patients 60 to 64 years old; however, the survival rate was acceptable even in those 70 or over, with a 2-year OS of 46%. ASCT is feasible in selected elderly patients and age alone should not be a contraindication for ASCT. Eligibility should be individualized and identification of a subset of elderly patients at high risk of treatment-related morbidity or mortality warrants investigation.

Hematopoietic stem cell transplantation for acute promyelocytic leukemia in second or third complete remission: a retrospective analysis in the Nagoya Blood and Marrow Transplantation Group

Acute promyelocytic leukemia (APL) is the most curable subtype of acute myeloid leukemia. Second complete remission (CR2) can be easily achieved with several therapeutic options even after relapse. However, the optimal strategy to treat APL in CR2 is still controversial. We retrospectively compared the outcome of autologous (auto) and allogeneic (allo) hematopoietic stem cell transplantation (HSCT) for patients with APL in CR2 or CR3. Fifteen patients received auto and 13 received allo HSCT between 1999 and 2004 at eight hospitals belonging to the Nagoya Blood and Marrow Transplantation Group. Four-year disease-free survival (DFS) and overall survival (OS) for autografted patients were 68.9 and 75.8%, whereas those for allografted patients were 46.2 (P = 0.350) and 46.2% (P = 0.185), respectively. Three autografted patients and one allografted patient relapsed, and one autografted patient and five allografted patients died without leukemia relapse. Among 14 autografted patients who were evaluated for MRD with molecular analysis, relapse occurred in one with positive MRD (n = 2) and two with negative MRD (n = 12). These data suggest that auto HSCT is very effective for APL in CR2 or CR3, and may be preferable to allo HSCT for a portion of patients. Prospective studies are required to define the role of auto HSCT in the treatment of relapsed APL.

Impact of MRD and TKI on allogeneic hematopoietic cell transplantation for Ph+ALL: a study from the adult ALL WG of the JSHCT

To assess the impact of minimal residual disease (MRD) and tyrosine kinase inhibitor (TKI) administration on allogeneic hematopoietic cell transplantation (allo-HCT) for Ph-positive ALL (Ph+ALL), we retrospectively analyzed data from a registry database for 432 adult Ph+ALL patients in first CR (CR1) who received pre-transplant TKI administration. Negative MRD (MRD(−)) at allo-HCT was achieved in 277 patients. OS in patients transplanted in MRD(−) was significantly better than that in patients transplanted in MRD(+) (MRD(−): 67% vs MRD(+): 55% at 4 years; P=0.001). MRD(−) at allo-HCT was a significant risk factor for survival along with age at allo-HCT in multivariate analyses. Incidence of relapse in patients transplanted in MRD(−) was significantly lower than that in patients transplanted in MRD(+) (MRD(−): 19% vs MRD(+): 29% at 4 years; P=0.006). In multivariate analyses, MRD(+) at allo-HCT was a significant risk factor for relapse. A post-transplant TKI was administered to 103 patients. In subanalyses regarding the effect of post-transplant TKI administration, post-transplant TKI administration was a significant risk factor for relapse in multivariate analyses (P<0.0001). MRD status at allo-HCT is one of the most important predictive factors for Ph+ALL patients transplanted in CR1.

Comparison of Cyclophosphamide Combined with Total Body Irradiation, Oral Busulfan, or Intravenous Busulfan for Allogeneic Hematopoietic Cell Transplantation in Adults with Acute Lymphoblastic Leukemia

We conducted a retrospective analysis to compare outcomes in adult patients with acute lymphoblastic leukemia (ALL) who underwent allogeneic hematopoietic cell transplantation (allo-HCT) with conditioning regimens containing cyclophosphamide (CY) in combination with total body irradiation (TBI), oral busulfan (p.o. BU), or intravenous busulfan (i.v. BU). We used data for January 2000 to December 2012 from the Transplant Registry Unified Management Program of the Japan Society of Hematopoietic Cell Transplantation. We identified 2130 patients treated with TBI/CY (n = 2028), p.o. BU/CY (n = 60), or i.v. BU/CY (n = 42). Two-year overall survival (OS) and 2-year relapse-free survival rates were 69.0% and 62.1%, respectively, in the TBI/CY group, 55.9% and 54.2% in the p.o. BU/CY group, and 71.0% and 46.8% in the i.v. BU/CY group. In multivariate analysis, compared with TBI/CY, p.o. BU/CY, but not i.v. BU/CY, was associated with lower OS (hazard ratio [HR], 1.46; P = .047) and a higher incidence of sinusoidal obstruction syndrome (HR, 3.36; P = .030). No between-group differences were seen in the incidence of nonrelapse mortality, relapse, acute graft-versus-host disease (GVHD), or chronic GVHD. We suggest that i.v. BU/CY might be a possible alternative allo-HCT conditioning regimen for adults with ALL who are not suitable for TBI.

Differences in outcome for consecutive patients with diffuse large B-cell lymphoma before and after the advent of rituximab: a single-center experience

Abstract The beneficial effect of rituximab for first-line treatment of diffuse large B-cell lymphoma (DLBCL) has been demonstrated by several randomized controlled trials. To clarify whether results for selected patient populations also apply to unselected patients, we analyzed long-term outcomes for all the 277 consecutive adults diagnosed with de novo DLBCL in a single center between 1998 and 2008. The study population included 147 and 130 patients diagnosed before (Cohort A) and after the advent of rituximab (Cohort B). Progression-free survival (PFS) was significantly better for Cohort B than for Cohort A (P = 0.005). For patients age 60 or younger, PFS did not differ significantly between Cohort A and Cohort B (P = 0.329), but for patients over 60, Cohort B showed superior PFS (P = 0.002). Patients with high or high-intermediate risk according to the International Prognostic Index score showed less improvement in PFS than did those with low or low-intermediate risk primarily because of still unfavorable outcomes of patients with poor performance status. These results indicate that the advent of rituximab has significantly improved outcome for unselected patients with DLBCL, and that improvement was greater for older patients. Further investigations are warranted in the hope of improving outcomes for younger patients with DLBCL.