Role of frontline autologous stem cell transplantation in young, high-risk diffuse large B-cell lymphoma patients.

BACKGROUND/AIMS: Several studies have demonstrated the effect of autologous hematopoietic stem cell transplantation (auto-HSCT) as a salvage treatment for patients with relapsed diffuse large B-cell lymphoma (DLBCL). However, the role of auto-HSCT as a frontline treatment has not been fully investigated in the rituximab era. We validated the age-adjusted International Prognostic Index (aaIPI) score for high-risk DLBCL patients and identified a possible role for frontline auto-HSCT. METHODS: We recommended frontline auto-HSCT for high-risk DLBCL patients who satisfied the criteria of both a higher Ann-Arbor stage (III to IV) and an elevated lactate dehydrogenase (LDH) level at diagnosis with an aaIPI score ≥ 2. From 2006 to 2011, among the 150 DLBCL patients aged ≤ 60 years who were treated with six cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP), 23 high-risk patients with a complete response (CR) were treated with auto-HSCT. For comparison, we selected 35 well-matched high-risk patients with CR who completed R-CHOP treatment alone. In addition, there were 81 low-risk patients and 11 refractory patients. RESULTS: DLBCL patients with an aaIPI score ≥ 2 showed inferior overall survival (OS; p = 0.040) and progression-free survival (PFS; p = 0.007) compared to the aaIPI score 0 to 1. Between the two treatment arms among the high-risk DLBCL patients, the clinical parameters were not different. The high-risk group treated with frontline auto-HSCT showed similar OS (p = 0.392) and PFS (p = 0.670) to those in the low-risk group. Thus, frontline auto-HSCT showed superior PFS (p = 0.004), but only a trend towards favorable OS (p = 0.091) compared to R-CHOP alone. CONCLUSIONS: We identified the possible role of frontline auto-HSCT for high-risk DLBCL with a higher stage (III to IV) and elevated LDH level.

SOCS1 and SOCS3 are expressed in mononuclear cells in human cytomegalovirus viremia after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: The expression of the SOCS genes in cytomegalovirus (CMV) viremia after hematopoietic stem cell transplantation (HSCT) remains largely unexplored. METHODS: Using quantitative RT-PCR of mononuclear cells, we conducted pairwise comparison of SOCS1 and SOCS3 expression levels among a healthy donor group (N=55), a pre-HSCT group (N=17), and the recipient subgroup (N=107), which were divided according to the occurrence of CMV viremia and acute graft-versus-host disease (aGVHD). RESULTS: Compared to that in the healthy donor group, SOCS1 expression was higher in the CMV+ subgroup, especially in the CMV+GVHD- group, but decreased in the other subgroups. When compared to the expression in the pre-HSCT group, SOCS1 expression was significantly higher in the CMV+ subgroup, especially in the CMV+GVHD+ subgroup. Meanwhile, compared to that in the healthy donor group, SOCS3 expression was significantly lower in all other groups. The CMV-GVHD- subgroup showed significantly lower SOCS3 expression compared to the CMV+ subgroup, the CMV+GVHD+ subgroup, and the CMV+GVHD- subgroup. CONCLUSION: We report differential expression of SOCS genes according to CMV viremia with acute GVHD occurrence after HSCT, suggesting that regulation of SOCS expression is associated with CMV viremia.

A well-tolerated regimen of 800 cGy TBI-fludarabine-busulfan-ATG for reliable engraftment after unmanipulated haploidentical peripheral blood stem cell transplantation in adult patients with acute myeloid leukemia.

Eighty adult patients with acute myeloid leukemia (AML) received peripheral blood T cell-replete HLA haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Disease status at transplantation was either first or second complete remission (CR, n = 69) or relapse/refractory (n = 11). Identical transplant-related procedures with conditioning regimen consisting of fractionated 800 cGy total body irradiation (TBI), fludarabine (30 mg/m(2)/day for 5 days), busulfan (3.2 mg/kg/day for 2 days), and antithymocyte globulin (1.25 mg/kg/day on days -4 to -1) and graft-versus-host disease (GVHD) prophylaxis with tacrolimus and methotrexate were used in all patients. Recovery of neutrophil (median, 11 days) and platelet (median, 10 days) counts was achieved in all patients with full donor chimerism (≥ 99%), and no delayed engraftment failure was observed. The cumulative incidence of grades III to IV acute GVHD and moderate to severe chronic GVHD was 11.2% and 26.3%, respectively. A donor CD8(+) and CD4(+) T cell dose above the median value was significantly associated with the incidences of grades II to IV acute GHVD and moderate to severe chronic GVHD, respectively. After a median follow-up of 28 months for survivors, the 2-year cumulative incidences of relapse (n = 20) and nonrelapse mortality (n = 10) were 26.6% and 12.2%, respectively. Although all but 1 patient in relapse/refractory status died, the 2-year overall and progression-free survival of patients in first CR was 82.5% and 75.1%, respectively. We suggest the strategy of fractionated 800 cGy TBI-based conditioning with unmanipulated peripheral blood stem cell grafts seems feasible with favorable outcomes for adult patients with AML undergoing haplo-HSCT in CR.

Impact of extramedullary plasmacytomas on outcomes according to treatment approach in newly diagnosed symptomatic multiple myeloma.

The prognostic impact of extramedullary plasmacytomas (EMPs) on newly diagnosed symptomatic multiple myeloma (MM) was evaluated in the context of treatment approach including autologous stem cell transplantation (ASCT) and chemotherapy alone. A total of 275 consecutive patients with newly diagnosed MM were included, and 54 patients (19.6 %) had EMPs at diagnosis. Patients with initial EMPs were more likely to have myeloma bone disease but favorable laboratory parameters in hemoglobin and ß2-microglobulin. Patients were treated with different schemas based on transplant eligibility (154 in ASCT-eligible vs. 121 in ASCT-ineligible). After a median follow-up of 24.6 months (range, 0.2-56.3 months) in survivors, patients with initial EMPs had significantly worse progression-free survival (PFS) (P = 0.035) and overall survival (OS) (P = 0.006) compared to those without initial EMPs. In the multivariate analyses, the presence of initial EMPs was an independent prognostic factor for PFS (relative risk (RR) of 2.24, P = 0.024) and OS (RR of 2.47, P = 0.027) in the transplant-ineligible patients, whereas it did not significantly influence PFS (P = 0.341) or OS (P = 0.499) in the transplant-eligible patients. However, the adverse impact of EMPs observed in transplant-ineligible patients was attenuated among the patients treated with bortezomib. These data suggest that ASCT can overcome the negative impact of EMPs and highlight the potential efficacy of bortezomib on EMPs in the non-transplant setting.

Wilms tumor gene 1 expression as a predictive marker for relapse and survival after hematopoietic stem cell transplantation for myelodysplastic syndromes.

Relapse after allogeneic hematopoietic stem cell transplantation (HSCT) is a major concern in myelodysplastic syndromes (MDS), but the role of Wilms tumor gene 1 (WT1) as a predictive marker for post-HSCT relapse remains to be validated. We measured WT1 transcript levels by real-time quantitative PCR from marrow samples of 82 MDS patients who underwent transplantation between 2009 and 2013. Pre-HSCT WT1 expression weakly correlated with marrow blast counts or International Prognostic Scoring System scores and failed to predict post-transplantation relapse. Regarding post-HSCT WT1, transcript levels of relapsed patients were significantly higher in comparison to those in remission. Further analysis using receiver operating characteristics curves showed that higher (>154 copies/10(4)ABL) 1-month post-HSCT WT1 resulted in a higher 3-year relapse rate (47.2% versus 6.9%, P < .001) with poorer disease-free survival (DFS) and overall survival at 3 years (41.7% versus 79.0% and 54.3% versus 82.1%, P = .003 and P = .033, respectively). Multivariate analysis after adjusting for pre-HSCT karyotype and chronic graft-versus-host disease (GVHD) also revealed that higher 1-month post-HSCT WT1 was an independent predictive marker for subsequent relapse (P = .002) and poorer DFS (P = .010). In the higher 1-month post-HSCT WT1 subgroup, patients with chronic GVHD showed lower relapse rate and favorable survival outcome. One month post-HSCT WT1 expression was a useful marker for minimal residual disease and relapse prediction in association with chronic GVHD in the context of HSCT for MDS.

Equivalent outcome of autologous stem cell transplantation and reduced intensity conditioning stem cell transplantation in acute myeloid leukemia patients with t(8;21).

We analyzed the outcome of stem cell transplantation (SCT) for 59 acute myeloid leukemia (AML) patients with t(8;21). The 5-year overall and disease-free survival (OS and DFS) were 70.2 and 68.4%, respectively. The 5-year cumulative incidence of relapse (CIR) and nonrelapse mortality were 16.9 and 13.6%, respectively. OS and DFS in the reduced-intensity conditioning (RIC)-SCT group (70.4%) were not different from in the autologous SCT (ASCT) group (72.4 and 69.0%, respectively). Age was a factor affecting OS (p = 0.007) and DFS (p = 0.008) in the ASCT group, but not in the RIC-SCT group. In the ASCT group, lack of the X chromosome (-X) and an age of >50 years were associated with inferior survival; however, these differences disappeared in the RIC-SCT group. CIR was significantly higher in patients with -X than in those without -X only in the ASCT group (p = 0.038), i.e. not in the RIC-SCT group. ASCT and RIC-SCT are equally effective for the intensification of postremission treatment of AML patients with t(8;21). The subgroups with advanced age or -X should be preferentially considered for RIC-SCT, rather than ASCT. Further investigations with randomized prospective trials of a sizeable study population are warranted.

Bone marrow plasma cell assessment before peripheral blood stem cell mobilization in patients with multiple myeloma undergoing autologous stem cell transplantation.

The current definition of complete response (CR) in multiple myeloma (MM) includes negative serum and urine immunofixation (IFE) tests and <5% bone marrow plasma cells (BMPCs). However, many studies of the prognostic impact of pretransplant response have not included BMPCs. We evaluated the prognostic impact of BMPC assessment before peripheral blood stem cell (PBSC) mobilization on subsequent transplant outcomes. BMPCs were assessed by CD138, kappa, and lambda immunostaining in 106 patients. After a median followup of 24.5 months, patients with <5% BMPCs had a significantly better progression-free survival (PFS) compared to those with ≥ 5% BMPCs (P = 0.005). Patients with <5% BMPCs + serologic CR showed superior PFS compared to those with <5% BMPCs + serologic non-CR (P = 0.050) or ≥ 5% BMPCs + serologic non-CR (P = 0.001). Interestingly, the prognostic impact of BMPCs was more apparent for patients who did not achieve a serologic CR (P = 0.042) compared to those with a serologic CR (P = 0.647). We concluded that IFE negativity and <5% BMPCs before PBSC mobilization were important factors to predict PFS in patients with MM undergoing ASCT. Particularly, a significant impact of <5% BMPCs was observed in patients who did not achieve IFE negativity.

Similar outcomes of peripheral blood stem cells vs. bone marrow for human leukocyte antigen-matched unrelated donor transplantation in adult patients with acute myeloid leukemia using risk-adapted graft-versus-host disease prophylaxis.

BACKGROUND: In unrelated donor allogeneic stem cell transplantation (URD-SCT), most studies reported that peripheral blood stem cells (PBSC) resulted in higher incidence of acute and/or chronic graft-versus-host disease (GVHD) without survival benefits compared with bone marrow (BM). To overcome these shortcomings of PBSC, we have used a risk-adapted GVHD prophylaxis for patients that received HLA-matched URD-SCT, which was adding low-dose rabbit antithymocyte globulin (Thymoglobulin(®) , 1.25 mg/kg for 2 d) to conditioning in the transplants with PBSC and not BM. METHODS: To determine whether this strategy is effective, we analyzed 115 adult patients with acute myeloid leukemia who received HLA-matched URD-SCT with PBSC (n = 70) or BM (n = 45) using our risk-adapted GVHD prophylaxis strategy. RESULTS: The PBSC group showed faster neutrophil (11 d vs. 13 d; P < 0.01) and platelet (12 d vs. 18 d; P < 0.01) engraftment compared with the BM group. No difference was observed in the incidence of acute GVHD grade II-IV at 100 d (54.3% vs. 64.4%; P = 0.38) and chronic GVHD at 4 yr (65.1% vs. 60.0%; P = 0.83). Other outcomes including the incidence of relapse (30.8% vs. 31.2%; P = 0.53), non-relapse mortality (13.5% vs. 6.9%; P = 0.24), disease-free survival (55.7% vs. 61.9%; P = 0.68), and overall survival (62.2% vs. 63.2%; P = 0.96) at 4 yr were not significantly different. CONCLUSION: Our risk-adapted GVHD prophylaxis strategy resulted in similar transplant outcomes including comparable incidence of GVHD between the PBSC and BM groups in HLA-matched URD-SCT.

Validation of Western common recurrent chromosomal aberrations in Korean chronic lymphocytic leukaemia patients with very low incidence.

In Asia, the incidence of chronic lymphocytic leukaemia (CLL) is lower than in Western countries. Only a few studies of CLL have been conducted in Korea, and no long-term clinical outcome data are available. We assessed the frequency of common chromosomal aberrations in Korean CLL patients using interphase fluorescence in situ hybridization (FISH) and investigated their relationship to clinical outcomes. Between 2000 and 2011, conventional cytogenetic studies were performed in 58 patients, and FISH results were available in 48 patients. We used six DNA probes for the detection of del(13q14), trisomy 12, del(11q22), del(17p13), IGH rearrangement and del(6q23). Chromosomal aberrations were identified in 15 of 58 patients (26%) with conventional cytogenetic studies and in 25 of 48 patients (52%) with interphase FISH, including six patients with complex karyotypes. In contrast with the results of Western studies, trisomy 12 was the most common aberration, followed by IGH rearrangement, del(13q14), del(11q22) and del(17p13). Deletion of 6q23 was not observed, and isolated del(13q14) was less frequent than in Western studies. Compared with the other types of chromosomal aberrations, patients with del(11q22) and del(17p13) were more likely to be Rai stage 3-4 and Binet stage C, resulting in poor responses to chemotherapy and worse outcomes. In contrast, patient with trisomy 12 and isolated del(13q14) showed better responses and superior survival outcomes. The incidence of CLL is lower in Korea than in Western countries, and the frequency of chromosomal aberrations differs, perhaps reflecting differences in the pathogenic mechanism between ethnicities. Large prospective studies are needed to further assess the prognostic value of these results in Korean CLL patients.

Implication of higher BAALC expression in combination with other gene mutations in adult cytogenetically normal acute myeloid leukemia.

Data for 125 patients with cytogenetically normal acute myeloid leukemia (CN-AML) regarding BAALC and combinatorial molecular markers at diagnosis were evaluated. Fewer patients with higher BAALC expression at diagnosis achieved a complete remission (CR) (49.2 vs. 75.8%, p = 0.002) after the first cycle of chemotherapy, and there were more primary refractory cases (37.3 vs. 18.2%, p = 0.017). In a combinatorial analysis, FLT3-ITD-positive patients with higher BAALC showed more refractoriness and the worst overall survival (OS) (p < 0.001) and disease-free survival (DFS) (p < 0.001) in CN-AML. When NPM1-mutated CN-AML was combined with either FLT3-ITD mutation or higher BAALC expression, both OS (p = 0.043) and DFS (p = 0.008) were worse; when combined with both, it showed the worst OS (p < 0.001) and DFS (p = 0.004). Higher BAALC expression and FLT3-ITD mutation, both individually and in combination, were associated with worse survival outcomes in CN-AML, and this was also applicable in NPM1-mutated CN-AML, known as a favorable-risk group.

Prognostic factors for outcomes of allogeneic stem cell transplantation in chronic phase chronic myeloid leukemia in the era of tyrosine kinase inhibitors.

The aim of this study was to estimate the prognostic factors for the outcomes of chronic myeloid leukemia (CML) patients receiving allogeneic stem cell transplantation (SCT) in chronic phase (CP) in the era of tyrosine kinase inhibitors (TKIs). Ninety-seven patients who underwent allogeneic SCT in CP were analyzed. Forty-seven were TKI-naïve at the time of transplant, and 50 received TKI(s) treatment before transplantation. After a median follow-up of 115.8 months, the 4-year overall survival and event-free survival were 80.4 and 58.8%, respectively. Multivariate analysis showed that there were no differences in survival outcomes based on prior TKI therapy. Older age was a prognostic factor for higher treatment-related mortality (TRM), and the type of graft source and younger age were associated with relapse, but prior TKI therapy and disease status at the time of transplant were not associated with either TRM or relapse. Additionally, a major molecular response at 1 month and an MR(4.5) at 3 months were important predictors of favorable long-term outcomes. This study demonstrates the prognostic factors for the outcomes of allogeneic SCT in CP CML and shows that survival outcomes were not affected by the administration of long-term multi-TKI treatment prior to transplantation.

Impact of failed response to novel agent induction in autologous stem cell transplantation for multiple myeloma.

The aim of this study was to evaluate the impact of the response to induction therapy on the long-term prognosis of multiple myeloma (MM) after autologous stem cell transplantation (ASCT) in the era of novel agents (NAs). A total of 171 patients who were newly diagnosed with MM and underwent early ASCT were analyzed. One hundred ten had a NA-based induction therapy, and 61 patients had a non-NA-based induction therapy. After a median follow-up of 45.4 months, the 4-year overall survival (OS) and progression-free survival (PFS) from transplantation were 60.5 and 25.5 %, respectively, for the NA-based induction group and 54.6 and 15.6 %, respectively, for the non-NA-based induction group. Multivariate analyses revealed that the patients who had NA-based induction had a significantly shorter OS (P < 0.001) and PFS (P < 0.001) when at least a partial response (PR) was not achieved. In patients who did not receive NAs before ASCT, lack of at least a PR to induction therapy was not associated with a survival disadvantage. These findings suggest that, unlike pretransplantation induction before NAs, patients who do not respond to induction treatment using NAs may not derive a benefit from ASCT. The relevance of induction failure differs for corticosteroid- and NA-based induction.

Stratification of de novo adult acute myelogenous leukemia with adverse-risk karyotype: can we overcome the worse prognosis of adverse-risk group acute myelogenous leukemia with hematopoietic stem cell transplantation?

Karyotype is a powerful prognostic factor for complete remission (CR) and overall survival (OS) in acute myelogenous leukemia (AML). Adverse-risk karyotype AML is now treated with intensive chemotherapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) to overcome relapse. We attempted to stratify patients with this disease using a combination of known factors. We evaluated clinical correlates in 211 adults with AML and adverse-risk karyotypes. We divided the patients into several subgroups based on the number of chromosomal aberrations (NCAs), normal karyotype (NK) mosaicism, and monosomal karyotype (MK) status. CR rates and survival outcomes were compared among the subgroups, and the relapse rate was calculated in the allo-HSCT subgroup. The cutoff of NCA ≥ 5 showed the worst OS (P < .001) compared with NCA ≥ 3 or NCA ≥ 4 even after allo-HSCT. NK mosaicism significantly improved OS in both the NCA <5 (P = .024) and NCA ≥ 5 (P = .030) subgroups, but after allo-HSCT, it showed a favorable effect only in the NCA <5 subgroup. MK showed worse OS (P = .041), but there was no significantly worse effect after allo-HSCT compared with non-MK. Finally, we stratified patients into 4 subgroups, NCA ≥ 5 and NCA <5 with and without NK mosaicism. The most favorable OS and lower relapse rate after allo-HSCT were achieved by the NCA <5 with NK mosaicism subgroup, and the NCA ≥ 5 without NK mosaicism subgroup showed the worst prognosis in both entire group and allo-HSCT subgroup analysis. This study reveals that the combination of NCA and NK mosaicism may predict survival outcomes accurately, and suggests that novel treatment strategies for highly adverse-risk group AML should be tailored in the future.

Influence of ex vivo purging with CliniMACS CD34(+) selection on outcome after autologous stem cell transplantation in non-Hodgkin lymphoma.

The major limitation of autologous stem cell transplantation (auto-SCT) in non-Hodgkin lymphoma (NHL) is relapse. Although autologous graft contamination may be a potential cause, prior purging of the autograft remains controversial. Therefore, we retrospectively analysed 56 consecutive patients with NHL receiving auto-SCT at complete (n = 41) or partial remission (n = 15). Among them, 24 patients underwent autograft manipulation with positive selection of CD34(+) cells using a CliniMACS device (purged group). Twenty-five patients had received ≥2 previous chemotherapy regimens before auto-SCT. After a median follow-up of 41·4 months, transplant-related mortality was observed only in unpurged group (n = 2; 3·6%). The 3-year overall survival (91·7% vs. 56·1%, P = 0·009) and progression-free survival (78·7% vs. 53·1%, P = 0·034) favoured CD34(+) purification. While neutrophil recovery was similar, platelet recovery was delayed in the purged group. Cytomegalovirus reactivation was predominantly observed in the purged group, although no other clinically unmanageable infectious complications occurred. Although this study has the inevitable limitations of heterogeneity in previous treatment and NHL subtypes, and a small number of patients analysed, the high survival rate in the purged group may suggest the need for prospective randomized trials to determine the role of CD34(+) purification in auto-SCT for NHL.

The impact of novel therapeutic agents before and after frontline autologous stem cell transplantation in patients with multiple myeloma.

BACKGROUND: Novel agents (NAs) such as thalidomide and bortezomib have been administered in combination with autologous stem-cell transplantation (ASCT) to effectively treat multiple myeloma (MM). However, whether NAs perform better as induction treatments prior to transplantation, or as post-transplant maintenance therapies remains unclear. METHODS: We retrospectively analyzed 106 consecutive patients with MM who underwent ASCT within 1 year of diagnosis as first-line therapy. RESULTS: Eighty-seven (82.1%) patients received NAs before ASCT, whereas 68 (64.2%) received NAs after ASCT. NAs were administered to each patient as follows: before ASCT alone (N=29, 27.4%), after ASCT alone (N=10, 9.4%) or both before and after ASCT (N=58, 54.7%). High-quality rates before and after ASCT were significantly higher for patients who received NAs as induction treatment compared to those who did not receive pre-transplant NAs. At a median follow-up of 37.9 months, the 3-year progression-free survival (PFS) and overall survival (OS) rates were 42.8% and 70.2%, respectively. The PFS and OS were significantly higher in patients with NAs as post-transplant maintenance treatment (P=0.03 and P=0.04, respectively), but not in those with NAs as pre-transplant induction treatment. The PFS of patients with NAs before and after ASCT was higher than that of the patients with NAs as induction therapy alone (P=0.05). Age, serum ß2-microglobulin level, complete response after ASCT, and NA use post-ASCT independently predicted survival outcomes. CONCLUSION: These findings suggest that integration of NAs post-ASCT could benefit patients with MM undergoing ASCT. Induction therapy using NAs also improves high-quality response rates before and after ASCT.

Outcomes of elderly de novo acute myeloid leukemia treated by a risk-adapted approach based on age, comorbidity, and performance status.

Several criteria to define fitness for induction chemotherapy in elderly acute myeloid leukemia (AML) have been proposed; however, no studies have reported outcomes according to the application of a risk-adapted approach. We treated 256 consecutive patients with elderly AML (≥60 years) with a risk-adapted approach based on age, comorbidity score (CS), and performance status (ECOG). Eighty-five low-risk patients (age ≤ 65 years and ECOG 0-1 with CS < 2), 86 intermediate-risk patients (age > 65 years or ECOG = 2 with CS < 2), and 85 high-risk patients (ECOG > 2 or CS ≥ 2) were treated with induction chemotherapies, including standard intensive regimens, abbreviated-scheduled regimens, and modified low-dose cytarabine with oral etoposide (mLDAC), respectively. Overall response rates (ORR; complete response and complete response with incomplete recovery) for these three groups were 71.8%, 60.5%, and 41.2%, respectively, without a significant difference in early death rate (17.6%, 25.6%, 23.5%, P = 0.415). Among three abbreviated-scheduled regimens, a gemtuzumab ozogamicin (GO)-containing regimen (n = 43) showed a similar ORR rate (72.1%) to the intensive regimen. After achieving remission, 142 patients went on postremission treatments, including reduced-intensity allogeneic transplantation (RIC, n = 41), standard consolidation (n = 71), and repeated mLDAC (n = 30) according to donor availability, age, ECOG, and CS. Multivariate analyses revealed that not only RIC, but also repeated mLDAC, resulted in significantly superior survival outcomes to standard consolidation independent of age, ECOG, and CS. Clinical benefits of mLDAC for high-risk patients and abbreviated induction with GO for intermediate-risk patients should be confirmed with further studies. Our results also suggest that RIC should be actively considered in elderly AML as a postremission treatment.

BAALC and WT1 expressions from diagnosis to hematopoietic stem cell transplantation: consecutive monitoring in adult patients with core-binding-factor-positive AML.

No consecutive analysis of BAALC and WT1 expressions associated with core-binding factor AML (CBF-AML) from diagnosis to hematopoietic stem cell transplantation (HSCT) has yet been reported. We investigated BAALC and WT1 expressions using a method of real-time quantitative polymerase chain reaction (RQ-PCR) at diagnosis, after induction chemotherapy, at pre-HSCT, and at post-HSCT period in 45 consecutive patients [t(8,21) (n = 28), inv(16) (n = 17)], who received HSCT as a post-remission treatment. BAALC and WT1 RQ-PCR decrement ratio (DR) was also calculated at post-induction chemotherapy, at pre-HSCT, and at post-HSCT compared with the diagnostic level. Higher BAALC expression at diagnosis showed significantly inferior OS (P = 0.031), EFS (P = 0.011), and higher CIR (P = 0.002) rates. At post-HSCT, both higher BAALC and WT1 expressions showed significantly inferior OS (P = 0.005, 0.016), EFS (P = 0.002, 0.006), and higher CIR (P = 0.001, 0.003) rates. A subgroup of t(8;21) showing higher BAALC and WT1 expressions at post-HSCT were also associated with inferior OS (P = 0.018, 0.015) and higher CIR rates (P = 0.019, 0.011). While BAALC DR showed no significant results on outcomes, WT1 DR more than 2-log at post-HSCT showed significantly lower CIR rate (P = 0.028). This study showed that higher post-HSCT BAALC and WT1 expressions in patients with CBF-AML may be good markers of minimal residual disease for the prediction of survival and relapse after HSCT.

Serial measurement of WT1 expression and decrement ratio until hematopoietic cell transplantation as a marker of residual disease in patients with cytogenetically normal acute myelogenous leukemia.

Using real-time quantitative PCR, we monitored Wilms tumor gene 1 (WT1) expression from diagnosis to hematopoietic stem cell transplantation (HSCT) in adult patients with cytogenetically normal acute myelogenous leukemia (CN-AML) and FLT3-ITD and NPM1 mutations. The values at diagnosis were evaluated in 104 patients. Data collected after induction chemotherapy were available for all patients, but only 68 patients were treated with HSCT. Significant WT1 expression cut-offs were determined by receiver operation characteristic curve analysis, and rates of overall survival (OS) and disease-free survival (DFS) were estimated. WT1 decrement ratios (DR) at postinduction chemotherapy and at pre- and post-HSCT compared with the diagnostic level were calculated. Higher WT1 expression at diagnosis, postinduction chemotherapy, and pre-HSCT showed inferior OS (P = .015, <.001, and .002) and DFS (P = .006, <.001, and .003). The cut-offs were determined at the median for diagnostic WT1 expression and at the 25% level from the top for other time points excluding post-HSCT. The WT1 DR ≥ 1-log after induction chemotherapy showed superior OS and DFS (P = .009 and .002) and WT1 DR ≥ 1-log preceding HSCT also showed superior OS and DFS (P = .009 and .003). Results of WT1 DR were consistently applicable in each subgroup with higher (≥ 1.0) and lower (<1.0) WT1 expression at diagnosis and also in NPM1-wild-type/FLT3-ITD-negative CN-AML. The WT1 DR therefore predicted survival outcomes after HSCT more accurately than did the diagnostic WT1 expression. WT1 expression may serve as a reliable marker for residual disease and WT1 DR as a prognostic indicator, particularly in NPM1-wild-type/FLT3-ITD-negative CN-AML. These measures may be applied throughout the course of treatment and even after HSCT.

Normal karyotype mosaicism in adult AML patients with adverse-risk and undefined karyotype: preliminary report of treatment outcomes after hematopoietic stem cell transplantation.

Karyotype analysis in acute myeloid leukemia (AML) is one of the powerful prognostic factors for complete remission (CR), relapse, and overall survival (OS). Cytogenetic mosaicism is considered to be one of the important characteristics in expression of phenotypic manifestations. However, it has not come into focus due to emerging molecular biological approaches and the results of a number of mutation studies. Clinical correlates and prognostic relevance of mosaicism were evaluated in 163 AML patients [adverse-risk karyotypes (n = 72) and undefined karyotypes (n = 91)]. All patients were treated by induction and consolidation chemotherapies and finally went on hematopoietic stem cell transplantations (HSCT). Patients were divided into two subgroups, either with or without normal karyotype (NK) mosaicism. Seventy patients exhibited NK mosaicism and 93 did not. There were no significant differences in age, gender, chemotherapy cycles to achieve CR, HSCT donor type, source or intensity properties between the two subgroups. We found that NK mosaicism remaining in adverse-risk and undefined karyotype at diagnosis significantly correlates with better OS (p = 0.001) and lower CIR (p = 0.021) rate after HSCT. Our data show that the poor prognostic properties of unfavorable risk karyotype can be overcome to a great extent by allogeneic HSCT and chronic GVHD, especially in the subgroup with NK mosaicism. Cytogenetic mosaicism at initial diagnosis can be an influential factor for survival outcomes, even after HSCT.

Comparable long-term outcomes after reduced-intensity conditioning versus myeloablative conditioning allogeneic stem cell transplantation for adult high-risk acute lymphoblastic leukemia in complete remission.

The role of reduced-intensity conditioning (RIC) in adult acute lymphoblastic leukemia (ALL) remains unclear because of the small sample size, short follow-up duration, various regimens for conditioning and graft-versus-host disease (GVHD) prophylaxis, and the heterogeneity of selection criteria for transplantation. We compared long-term outcomes of 60 consecutive RIC transplants (fludarabine plus melphalan) with 120 myeloablative conditioning (MAC) transplants (total body irradiation plus cyclophosphamide) for adult high-risk ALL in first or second complete remission. All transplants received a uniform strategy of pretransplant chemotherapy and GVHD prophylaxis. Compared to MAC transplants, RIC transplants had older age (46 years vs. 33 years, P < 0.001) and higher proportions of transplantation using peripheral blood (93.3% vs. 13.3%; P < 0.001) but otherwise showed similar characteristics. After a median follow-up of 67 months, RIC transplants showed comparable nonrelapse mortality (21.2% vs. 24.3%) and disease-free survival (50.8% vs. 54.9%) to MAC transplants, although relapse risk was higher (34.2% vs. 26.4%; HR, 2.07; P = 0.019) in multivariate analysis. Other independent factors associated with better outcomes were the presence of chronic GVHD and transplantation in first complete remission. Interestingly, the negative impact of RIC on relapse risk was seen only for Philadelphia-positive ALL transplants (32.7% vs. 19.6%; HR, 3.46; P = 0.020), while no difference was found between RIC and MAC for Philadelphia-negative ALL transplants (35.0% vs. 32.1%; HR, 1.39; P = 0.429). RIC can be considered as a reasonable choice for providing a sufficient long-term graft-versus-leukemia effect for adult high-risk ALL patients ineligible for MAC.