Significant Difference In Non-relapse Mortality Research Articles

Reassessment of clinical implication of pretransplant surgical procedures for pulmonary invasive fungal lesions.

Dealing with the recent series of allogeneic hematopoietic stem cell transplantation (allo-SCT) performed this decade, we reassessed the clinical impact of pretransplant surgical procedures (SP) for pulmonary lesions of invasive fungal disease (IFD) on subsequent transplant outcome. We focused on the clinical outcomes of seven patients with pulmonary IFD who underwent segmentectomy (n=4), lobectomy (n=2) or abscess incision with drainage only (n=1), and compared results to those of 21 patients carrying pulmonary IFD who never underwent invasive SP before allo-SCT. The rate of exacerbation of pulmonary lesions by 180days after allo-SCT did not differ significantly between groups (32.2% vs 42.9%, P=0.69). Moreover, no significant differences in non-relapse mortality (46.4% vs 42.3%, P=0.93) or overall survival (53.6% vs 30.9%, P=0.45) at 1year were evident between groups. These results indicate that pretransplant SP for pulmonary lesions might have no survival benefit under the current antifungal prophylaxis or treatment modality.

395 - More Intensive Fludarabine/Busulfan (Flu/Bu) Conditioning Regimens Result in Similar Outcomes Without Adding Serious Toxicity When Compared to Fludarabine/Melphalan (Flu/Mel) in Patients Undergoing Allogeneic Hematopoietic Cell Transplant (Allo-HCT)

Abstract Background:Reduced-intensity conditioning (RIC) regimens such as Flu/Bu and Flu/Mel are commonly used for patients who are not medically fit for myeloablative conditioning (Shimoni Leukemia 2006). Recent studies have shown lower incidences of non-relapse mortality (NRM), acute graft-versus-host disease (aGVHD), and toxicity with Flu/Bu using 2 days of busulfan, whereas Flu/Mel has been associated with longer overall (OS) and relapse-free survival (RFS) (Shimoni Leukemia 2007, Baron Cancer 2015, Damlaj BBMT 2016). It is unknown whether use of more intense Flu/Bu regimens result in similar outcomes and toxicity profiles when compared to Flu/Mel. We sought to compare the toxicities and outcomes between patients receiving Flu/Bu using either three or four days of busulfan (Flu/Bu3 and Flu/Bu4, respectively) and Flu/Mel. Methods:We retrospectively evaluated patients with hematologic malignancies who underwent allo-HCT between 2010 and 2015 with Flu/Mel or Flu/Bu as their conditioning regimen. Busulfan was pharmacokinetically (PK) dosed, with a target area under the curve of 4,700 (range 4,100 - 5,200) μmol*min/L. We collected all grade ≥ 3 non-hematologic toxicities from the start of the conditioning regimen up to day +365 or relapse/death, and organized them into organ-based categories. OS and RFS were estimated using the Kaplan-Meier method with differences assessed with a log-rank test. The cumulative incidence method for competing risks was used in estimating non-relapse mortality, GVHD, as well as the incidence of individual toxicities, with differences assessed with Gray's test. Results: We included 167 patients in this toxicity analysis: 42 patients received Flu/Bu and 125 patients received Flu/Mel. Baseline patient and HCT characteristics are shown in Table 1. The most common GVHD prophylaxis in both arms was tacrolimus and mini-methotrexate. Cytomegalovirus (CMV) serostatus was similar in both arms. More patients receiving Flu/Bu had acute leukemia/myelodysplastic syndrome, matched related donors, and lower hematopoietic cell transplant-comorbidity index scores. The median time to neutrophil (12 days vs 13 days) and platelet engraftment (16 days vs 20 days) was similar between Flu/Bu and Flu/Mel, respectively. Though there were no statistically significant differences in the incidence of toxicities by category between Flu/Bu and Flu/Mel (Table 2), certain toxicities varied. Despite a higher proportion of patients in the Flu/Bu arm receiving antithymocyte globulin, patients receiving Flu/Mel had a higher incidence of infections such as bacteremia (20% vs 5%), CMV reactivation (16% vs 7%), and sepsis (16% vs 0%). Patients receiving Flu/Mel also had more metabolic derangements, specifically hypophosphatemia (51% vs 36%), hypocalcemia (40% vs 26%), hypokalemia (30% vs 17%), hyponatremia (28% vs 14%), and anorexia requiring total parenteral nutrition (17% vs 5%), compared to those receiving Flu/Bu. Rates of grade ≥ 3 mucositis (31% vs 31%), nausea/vomiting (21% vs 17%), and diarrhea (19% vs 21%) were similar for Flu/Bu and Flu/Mel, respectively. Patients receiving Flu/Bu were more likely to experience grade ≥ 3 AST (40% vs 26%) and ALT (29% vs 21%) elevations. However, veno-occlusive disease was rare, occurring in 2 patients who received Flu/Bu and 1 patient receiving Flu/Mel. There was a trend toward a lower incidence of aGVHD in patients receiving Flu/Bu compared to Flu/Mel (31% vs 48% at day 100, respectively, p=0.055). There was no significant difference in NRM (4.8% vs 14.4% at 1 year, p=0.234), OS (78.6% vs 66.9% at 1 year, p=0.15) or RFS (59.5% vs 48.8% at 1 year, p=0.15) between Flu/Bu and Flu/Mel, respectively. Conclusions: Our results showed similar survival, incidence of aGVHD, and specific organ toxicities between more intense Flu/Bu regimens and Flu/Mel. Our analysis suggests that utilizing PK-dosed busulfan to target more intense Flu/Bu regimens can maximize disease control without increasing serious toxicities. Moreover, extending a PK-dosing strategy to melphalan may similarly achieve favorable outcomes while minimizing toxicity. Download : Download high-res image (223KB) Download : Download full-size image Disclosures No relevant conflicts of interest to declare.

Prospective randomization of post-remission therapy comparing autologous peripheral blood stem cell transplantation versus high-dose cytarabine consolidation for acute myelogenous leukemia in first remission

We prospectively compared outcomes of autologous stem cell transplantation (ASCT) versus high-dose cytarabine (HiDAC) consolidation as post-remission therapy for favorable- and intermediate-risk acute myelogenous leukemia (AML) in first complete remission (CR1). Two-hundred-forty patients under 65years with AML-M1, M2, M4, or M5 subtypes were enrolled. After induction, 153 patients did not undergo randomization, while the remaining 87 who achieved CR1 were prospectively randomized to HiDAC (n=45) or ASCT arm (n=42). In the HiDAC arm, 43 patients completed three cycles of HiDAC, whereas in ASCT arm 22 patients completed two cycles of consolidation consisting of intermediate-dose cytarabine plus mitoxantrone or etoposide followed by ASCT. The three-year disease-free survival (DFS) rate was 41% in HiDAC and 55% in ASCT arm (p=0.25). Three-year overall survival (OS) rates were 77 and 68% (p=0.67). Incidence of relapse was 54 and 41% (p=0.22). There was no significant difference in nonrelapse mortality between two arms (p=0.88). Patients in the ASCT arm tended to have higher DFS rates and lower relapse rates than patients in HiDAC; however, there was no significant improvement in OS in patients with favorable- and intermediate-risk AML in CR1. Patients with AML are not benefited by the intensified chemotherapy represented by ASCT.

Impact of Obesity in Patients with Multiple Myeloma Receiving High-Dose Melphalan Followed By Autologous Hematopoietic Cell Transplantation

▪Background: Chemotherapy administration to obese patients poses significant challenges due to the potential for augmented toxicities. There are limited guidelines and literature available on the dosing of high-dose therapy followed by autologous hematopoietic cell transplantation (HCT) in obese patients and dosing practices vary widely. We conducted a single-center, retrospective cohort study to compare outcomes and toxicities after high-dose melphalan followed by autologous HCT among non-obese (body mass index [BMI] < 30 kg/m2), obese (BMI 30-34.9 kg/m2), and severely obese (BMI ≥ 35 kg/m2) multiple myeloma patients.Patients and Methods: A total of 462 consecutive patients transplanted between January 2004 and December 2011 were included. Patients who had received a tandem transplant and those with the diagnosis of amyloidosis were excluded. The primary endpoint of the study was to compare the incidence of non-relapse mortality (NRM) and overall survival (OS) rates across all three cohorts. Secondary endpoints included progression-free survival (PFS), incidence of relapse, hospital length of stay, hospital readmission rates, engraftment and grade 3 and 4 non-hematologic toxicities.Results: All three cohorts had similar baseline characteristics except for age ≤ 65 years (yrs) (severely obese 85.3%, obese 66.7%, non-obese 63%; p = 0.001), and the use of adjusted body weight for melphalan dosing (severely obese 41.2%, obese 25.7%, non-obese 4.5%; p < 0.0001). Across all three cohorts, there were no significant differences in NRM, relapse/progression, OS, PFS, engraftment, response to transplant, hospital length of stay, 30-day readmission rates, grade 3 to 4 nausea, vomiting, enteritis, or renal toxicity. In univariate analyses, Durie-Salmon Stage (DSS) 3 was the only independent predictor of inferior OS. DSS 3 and ≥ 2 lines of therapy were significant predictors of inferior PFS. In a multivariate analysis, DSS 3 (hazard ratio [HR] 2.28, 95% confidence interval [CI]: 1.01-5.13, p = 0.05), age > 65 yrs (HR 2.13, 95%CI: 1.19-3.82, p = 0.01), serum creatinine (Cr) ≥ 1 mg/dL were associated with higher NRM, whereas actual weight (AW) dosing was associated with decreased risk of NRM (HR 0.38, 95%CI: 0.19-0.72, p = 0.003). Additionally, age ≤ 65 yrs (HR 1.32, 95%CI: 1.03-1.71, p = 0.03), baseline serum Cr ≤ 1.5 mg/dL were associated with increased risk of relapse/progression, whereas disease status ≥ partial response prior to HCT (HR 0.71, 95%CI: 0.54-0.94, p = 0.02) and BMI ≥ 35 kg/m2 (HR 0.62, 95%CI: 0.44-0.87, p = 0.01) were associated with decreased risk of relapse/progression. In a subgroup analysis evaluating only patients with AW dosing of melphalan, febrile neutropenia was more common in non-obese patients compared to obese and severely obese patients (71.4% versus 56.4% and 62.5%, respectively; p = 0.03).Conclusions: High-dose melphalan and autologous HCT can be performed safely in obese myeloma patients and BMI of ≥ 30 kg/m2 does not appear to be associated with adverse transplant outcomes. Further analysis is needed to evaluate the effect of dose adjustments on outcomes. DisclosuresAlsina:Onyx: Speakers Bureau; Millenium Pharmaceuticals: Research Funding; Novartis: Research Funding; Signal Genetics: Consultancy; Onyx: Consultancy. Nishihori:Signal Genetics: Research Funding; Novartis: Research Funding.

Myeloablative Conditioning Haploidentical Stem Cell Transplantation (MAC-HAPLO) with Post-Transplant Cyclophosphamide (PTCy) As GvHD Prophylaxis in High Risk Leukemias/Myelosdysplastic Syndromes (MDS): Geth Experience

Introduction: Allogeneic transplantation is the only curative option for patients with high risk leukemias or MDS. Only one third of them have an HLA identical sibling donor and around 60-70% will find an unrelated donor, that´s why haploidentical stem cell transplantation (HAPLO-HSCT) offers a therapeutic option to most of these patients. Myeloablative conditioning (MAC) produce better disease control than reduced intensity conditioning regimens (RIC), but with higher toxicity, rendering long term similar results.Patients and methods: We retrospectively evaluated the results of our MAC-HAPLO regimens in patients diagnosed with high risk leukemias or MDS (Fludarabine 30 mg/m2 x5 days, Cyclophosphamide14,5 mg/kg x2 days, IV Busulfan 3,2 mg/kg x 3 days (BUX3), or Fludarabine 40 mg/m2 x4 days and IV Busulfan 3,2 mg/kg x 4 days (BUX4)) with GVHD prophylaxis based on PT-CY (50 mg/kg on days +3 and +4) and a calcineurin inhibitor plus mycophenolate from day +5, performed in GETH centers (Spanish Group for Hematopoietic Transplantation).Results: From Feb-2012, 65 MAC-HAPLO HSCT have been reported by 14 centers. Median age was 41 years (15-67), 66% were males and all were in advanced disease phase or presented high risk features (AML 47/ALL 8/MDS 5/ Others 5). Previous HSCT had been employed in 12% (autologous in 5, allogeneic in 3), and in 88% the HAPLO-HSCT was their first transplant. Disease status at HAPLO-HSCT was morphologic CR in 80%, but disease persisted in 52% (MRD+ by flow or molecular markers 32%, morphologic disease 20%). Their disease risk index (DRI) was high or very high in 65%, and the comorbidity index (HCT-CI) was higher than 2 in 18%. PBSC was the graft source in 56 (86%), non T-cell depleted in all cases. The haploidentical donor was the patient´s mother (21.5%), father (12%), siblings (43%) or offspring (23%). MAC regimen was BUX3 in 25 (38.5%) and BUX4 in 40 patients (61.5%). Median infused CD34+ cells were 5.31 x10e6/kg (2.75-11.42). There were no graft failures. Median neutrophils engraftment was reached at day +17 (12-29) and platelets >20K at day +26 (11-150). Complete chimerism was obtained at a median of 28 days (13-135) in 60 evaluated patients. Cumulative incidence (CI) of non-relapse mortality (NRM) was 12.5% at day +100 and 19% at 1 year. CI of grade II-IV acute GVHD was 28.5% at day +100, and grade III-IV was 6.5%. CI of chronic GVHD at 2 years was 28%, being extensive in 8% . No differences in acute or chronic GvHD CI were seen when comparing BUX3 against BUX4. After a median follow-up of 17 months (5-50), estimated 24-months event-free survival (EFS) and overall survival (OS) were 58,5% and 60% respectively. CI of relapse or progression was 21%. No significant differences in NRM, EFS, OS and relapse incidence were detected between BUX3 and BUX4. The impact of CR prior to MAC-HAPLO, the DRI or chronic GvHD in the disease control have not been apropiately demostrated probably due to the limited number of events in our series.Conclusions: IV Busulfan based MAC-HAPLO with PT-CY in the treatment of high risk leukemias and MDS offers good disease control with manageable toxicity, with either BUX3 or BUX4. These efective MAC regimens combined with peripheral blood HAPLO donors could control high risk hematologic diseases in the long term. Severe acute or chronic GvHD are low frecuency events, but relapses persist as the main problem in this patients population. DisclosuresNo relevant conflicts of interest to declare.

A Novel Prognostic Factor for Allogeneic Hematopoietic Stem Cell Transplantation Based on Bone Marrow Assessment on the Day of Stem Cell Transplantation

[Introduction] Many factors predicting the outcomes of allogeneic hematopoietic stem cell transplantation (HSCT) recipient have been reported so far and widely used to assess the potential risk of undergoing allogeneic HSCT. Residual disease is considered one of the risk factors in HSCT, and mainly evaluated by bone marrow aspiration before HSCT. However, disease statuses at the point of stem cell infusion potentially differ from that of pre-transplant evaluation depending on the sensitivity for conditioning therapy or proliferation speed of the blast. In this study, we assessed residual disease by bone marrow aspiration on the day of stem cell transplantation (called "day 0" of HSCT) in order to analyze the relationship between day 0 marrow statuses and HSCT outcomes.[Methods] This study was designed as a retrospective observational analysis, and we collected the patients who received first allogeneic HSCT for hematological malignant diseases between 2010 and 2014. Extramedullary diseases were excluded from the analysis. All HSCTs were consecutive and performed in our center. Bone marrow aspirated material was examined histopathologically, and residual blasts were evaluated by specific markers by immunostaining. If it has detected residual blasts even if only a few cells, it was defined non complete remission (CR) on day 0 (abbreviated as "non-day0CR"). We divided the patients into two groups according to the existence of residual blast in bone marrow on day 0 of HSCT.[Results] We analyzed 121 HSCT recipients including 35 with acute lymphoblastic leukemia, 3 with acute undifferentiated leukemia, 65 with acute myeloid leukemia, 17 with refractory anemia with excess blasts and 1 with blast phase of chronic myelogenous leukemia. The median follow-up of survivors was 983 days (range 330 - 2092 days), and overall survival (OS) was 72% (95% confidence interval: 63 - 79%) at 1 year after HSCT. In univariate analyses, age higher than median 44 year-old, non-CR at the time of pre-HSCT assessment, hematopoietic cell transplantation specific comorbidity index (HCT-CI) at least 1 point, reduced intensity conditioning, and non-day0CR were extracted as predictors of poor OS. With multivariate analysis, HCT-CI and day 0 marrow status were significantly associated with OS. Furthermore, when patients were limited to pre-transplant non-CR subgroup, the patients achieving complete malignancies-free state on day 0 showed comparable prognosis with those who maintained CR before conditioning (Figure 1). Relapse after allogeneic HSCT was observed in 31 patients, and cumulative incidence of relapse was 11% (95% confidence interval: 6 - 17%) at 1 year after HSCT. With univariate and multivariate analyses, there were significant differences between the patients with CR marrow and those with residual malignancies on day 0 (P = 0.002). There was no significant difference in non-relapse mortality between the two groups (P = 0.18).[Conclusions] We showed that bone marrow status on day 0 was significantly associated with OS and cumulative incidence of relapse. To our knowledge, this is the first report about the association with day 0 marrow status and post-HSCT prognosis. A malignancies-free state on day 0 could predict favorable prognosis in allogeneic HSCT, and the patient with residual malignancies on day 0 had lower OS and higher relapse rate. For the patients with residual malignancies on day 0, rapid tapering of immunosuppressant or arrangement of scheduled donor lymphocyte infusion may improve the outcomes. [Display omitted] DisclosuresMiyamura:Nippon Shinyaku CO, LT: Honoraria; Pfizer Inc: Honoraria; Novartis Pharmaceutical: Honoraria; Alexion Pharmaceutical Inc: Honoraria.

Myeloablative versus reduced intensity allogeneic stem cell transplantation for relapsed/refractory Hodgkin's lymphoma in recent years: a retrospective analysis of the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation

To evaluate long-term outcome of myeloablative allogeneic stem cell transplantation (allo-SCT) (MAC) versus reduced-intensity allo-SCT (RIC) in patients with relapsed/refractory Hodgkin's lymphoma (HL) in recent years. A total of 312 patients (63 MAC and 249 RIC) with relapsed/refractory HL who received allo-SCT between 2006 and 2010 and were reported to the EBMT Database were included in the study. With a median follow-up for alive patients of 56 (26-73) months, there were no significant differences in non-relapse mortality (NRM) between MAC and RIC. Relapse rate (RR) was somewhat lower in the MAC group (41% versus 52% at 24 months, P = 0.16). This lower RR translated into a marginal improvement in event-free survival (EFS) for the MAC group (48% versus 36% at 24 months, P = 0.09) with no significant differences in overall survival (73% for MAC and 62% for RIC at 24 months, P = 0.13). Multivariate analysis after adjusting for disease status at the time of allo-SCT showed that the use of MAC was of borderline statistical significance for predicting a lower RR and EFS [HR 0.7, 95% CI (0.5-1.0), P = 0.1] and [HR 0.7, 95% CI (0.5-1.0), P = 0.07], respectively, after allo-SCT. With modern transplant practices, the NRM associated with MAC for HL has strongly decreased, resulting into non-significant improvement of EFS because of a somewhat better disease control compared with RIC transplants. The intensity of conditioning regimens should be considered when designing individual allo-SCT strategies or clinical trials in patients with relapsed/refractory HL.

Killer Cell Immunoglobulin-Like Receptor–Ligand Matching and Outcomes after Unrelated Cord Blood Transplantation in Acute Myeloid Leukemia

The effect of killer cell immunoglobulin-like receptor (KIR)–ligand matching on outcomes after unrelated cord blood (CB) transplantation was studied in 461 patients with acute myeloid leukemia, categorizing KIR ligand for HLA-C groups C1 and C2 and Bw4. Donor–recipient HLA matching considered allele-level matching at HLA-A, -B, -C, and -DRB1. Separate analyses were conducted for 6-7/8 HLA-matched and 3-5/8 HLA-matched transplants because HLA matching confounded KIR-ligand matching (ie, KIR-ligand mismatching was less likely with better HLA matching). All patients received single CB unit and myeloablative conditioning. There were no significant differences in nonrelapse mortality (NRM), relapse, and overall mortality by KIR-ligand match status. However, among recipients of 3-5/8 HLA-matched transplants, NRM (HR, 2.26; P = .008) and overall mortality (HR, 1.78; P = .008) but not relapse were higher with KIR-ligand mismatched (host-versus-graft direction) compared with KIR-ligand matched transplants. These data do not support selecting CB units based on KIR-ligand match status for transplants mismatched at 1 or 2 HLA loci. Although transplants mismatched at 3 or more HLA loci are not recommended, avoiding KIR-ligand mismatching in this setting lowers mortality risks.

Peripheral blood stem cell graft compared to bone marrow after reduced intensity conditioning regimens for acute leukemia: a report from the ALWP of the EBMT.

Increasing numbers of patients are receiving reduced intensity conditioning regimen allogeneic hematopoietic stem cell transplantation. We hypothesized that the use of bone marrow graft might decrease the risk of graft-versus-host disease compared to peripheral blood after reduced intensity conditioning regimens without compromising graft-versus-leukemia effects. Patients who underwent reduced intensity conditioning regimen allogeneic hematopoietic stem cell transplantation from 2000 to 2012 for acute leukemia, and who were reported to the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation were included in the study. Eight hundred and thirty-seven patients receiving bone marrow grafts were compared with 9011 peripheral blood transplant recipients after reduced intensity conditioning regimen. Median follow up of surviving patients was 27 months. Cumulative incidence of engraftment (neutrophil ≥0.5×10(9)/L at day 60) was lower in bone marrow recipients: 88% versus 95% (P<0.0001). Grade II to IV acute graft-versus-host disease was lower in bone marrow recipients: 19% versus 24% for peripheral blood (P=0.005). In multivariate analysis, after adjusting for differences between both groups, overall survival [Hazard Ratio (HR) 0.90; P=0.05] and leukemia-free survival (HR 0.88; P=0.01) were higher in patients transplanted with peripheral blood compared to bone marrow grafts. Furthermore, peripheral blood graft was also associated with decreased risk of relapse (HR 0.78; P=0.0001). There was no significant difference in non-relapse mortality between recipients of bone marrow and peripheral blood grafts, and chronic graft-versus-host disease was significantly higher after peripheral blood grafts (HR 1.38; P<0.0001). Despite the limitation of a retrospective registry-based study, we found that peripheral blood grafts after reduced intensity conditioning regimens had better overall and leukemia-free survival than bone marrow grafts. However, there is an increase in chronic graft-versus-host disease after peripheral blood grafts. Long-term follow up is needed to clarify whether chronic graft-versus-host disease might increase the risk of late morbidity and mortality.

Effect of Graft Source on Unrelated Donor Hemopoietic Stem Cell Transplantation in Adults with Acute Myeloid Leukemia after Reduced-Intensity or Nonmyeloablative Conditioning: A Study from the Société Francaise de Greffe de Moelle et de Thérapie Cellulaire

This retrospective report compared the 4-year outcomes of allogeneic stem cell transplantation (allo-SCT) in 651 adult patients with acute myeloid leukemia receiving a reduced-intensity (RIC) or nonmyeloablative conditioning (NMA) regimen according to the type of unrelated donors. These were either umbilical cord blood (UCB, n = 205), a 9/10 mismatched unrelated donor (MisMUD, n = 99), or a 10/10 matched unrelated donor (MUD, n = 347) graft. Neutrophil recovery was slower in UCB (74.5% by day 42) compared with MisMUD (94.8%) and MUD (95.6%) (P < .001). There was no significant difference in nonrelapse mortality between UCB and both MUD (hazard ratio [HR], 1.05; 95% confidence interval [CI], .62 to 1.78; P = .85) and MisMUD (HR, 1.58; 95% CI, .88 to 2.83; P = .13) The relapse/progression was similar between UCB and MisMUD (HR, .62; 95% CI, .37 to 1.03; P = .07), but was significantly lower in MUD compared with UCB (HR, .60; 95% CI, .39 to .92; P = .02). The rate of extensive chronic graft-versus-host disease (GVHD) was similar between UCB and both MUD (HR, 2.15; 95% CI, .93 to 4.97; P = .08) and MisMUD (HR, 1.84; 95% CI, .68 to 4.95; P = .23). The rate of severe grade III and IV acute GVHD was significantly increased in MisMUD compared with UCB (HR, 2.61; 95% CI, 1.30 to 5.23; P = .007). There was no significant difference in overall survival between UCB and both MisMUD (HR, .98; 95% CI, .66 to 1.45; P = .92) and MUD (HR, .74; 95% CI, .52 to 1.03; P = .08). These data suggest that in the setting of RIC/NMA, allo-SCT UCB is a valid alternative graft source, with significantly less chronic GVHD, compared with MisMUD, when there is no MUD available or when urgent transplantation is needed.

Myeloablative Versus Reduced Intensity Allogeneic Stem Cell Transplantation in Relapsed Hodgkin’s Lymphoma in Recent Years. a Retrospective Analysis of the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation

Introduction. Allogeneic stem cell transplantation (allo-SCT) is a well established therapeutic alternative for those patients with refractory Hodgkin’s lymphoma (HL) who relapse after an autologous stem cell transplantation (ASCT), have chemosensitive disease and a HLA compatible donor available. The impact of the intensity of the conditioning regimen in the outcome of this procedure is still not well understood. An initial retrospective analysis from the European Group for Blood and Marrow Transplantation (EBMT) Lymphoma Working Party (LWP) (Sureda et al, JCO 2010) that compared myeloablative (MAC) with reduced intensity conditioning (RIC) protocols indicated that the high non-relapse mortality (NRM) associated to MAC-SCT translated into a non-significant improvement in progression free survival (PFS) for RIC recipients in spite of the higher relapse rate of the latter. As NRM for MAC-SCT might have decreased over time due to better patient selection, HLA typing and peri-transplant supportive measures, we hypothesize that overall results of more intensive protocols could compare better to RIC-SCT in recent years.Patients and Methods. We have included in this analysis adult patients with multiply relapsed classical HL treated with an allo-SCT between January 2006 and December 2010 and reported to the EBMT Database. Only first and second allo-SCT was included. Tandem ASCT-allo-SCT was excluded as well as cord blood transplantations and haplo-identical SCT. A total of 313 patients met the inclusion criteria (63 patients treated with a MAC and 250 patients treated with a RIC, definitions following the EBMT criteria). There were 173 males (55%) and 140 females (45%) with a mean age at diagnosis of 29 years and at SCT of 33 years. Mean time from diagnosis to SCT was of 43.3 months. 153 patients (49%) were chemorefractory at the time of allo-SCT and 166 patients (53%) had already failed a prior ASCT. Peripheral blood (PB) was used as the source of stem cells in 88% of the patients. Comparing MAC with RIC groups, the latter one was significantly older at allo-SCT (31 years vs 34 years, p=0.01), had a longer time interval between diagnosis and allo-SCT and preferentially received mobilized PB stem cells (82% vs 91%, p=0.01). There were also more prior autograft failures in the RIC group (56% vs 42%, p=0.006).Results. With a median follow up for alive patients of 32.5 (9.7 – 52.9) months, overall survival (OS) was 75% and 65%, PFS, 54% and 39%, NRM 11% and 12% and relapse rate after SCT of 37% at 1 year. There were no significant differences in NRM between MAC and RIC patients. Relapse rate was higher in the RIC group, although these differences did not reach statistical significance (55% vs 40% at 24 months, p=0.1). This lower relapse rate translated into an improvement in PFS for the MAC group (48% vs 37% at 24 months, p=0.08) with no differences in terms of OS (71% for MAC vs 61% for RIC at 24 months, p=0.4). Multivariate analysis after adjusting for disease status at the time of SCT showed that the use of RIC protocols was the only independent adverse prognostic factor associated to a higher relapse rate after SCT [HR 0.68, 95%CI (0.38 – 0.98), p=0.04] and to a lower PFS after the procedure [HR 0.65, 95%CI (0.43 – 0.98), p=0.04]. The intensity of the conditioning regimen did not have any impact n NRM in the multivariate analysis. Chemosensitive disease at SCT was the only independent prognostic factor for OS after SCT in the multivariate analysis [HR 1.70, 95%CI (1.17 – 2.46), p=0.005].Conclusions. This retrospective analysis shows that NRM after MAC protocols is not a significant clinical issue when allografting patients with HL nowadays. On the other hand, using MAC decreases the relapse risk in this highly resistant population of patients, translating into a significant improvement of PFS. MAC protocols should be considered when designing prospective clinical trials in patients with HL candidates for an allogeneic stem cell procedure. DisclosuresNo relevant conflicts of interest to declare.

A Biomarker Algorithm Defines Onset Grades of Acute Graft-Vs-Host Disease with Distinct Non-Relapse Mortality

The severity of symptoms at the onset of graft versus host disease (GVHD) does not accurately define risk, and thus most patients (pts) are treated alike with high dose systemic steroids. We hypothesized that concentrations of one or more plasma biomarkers at the time of GVHD diagnosis could define distinct non-relapse mortality (NRM) risk grades that could guide treatment in a multicenter setting. We first analyzed plasma that was prospectively collected at acute GVHD onset from 492 HCT pts from 2 centers, which we randomly divided into training (n=328) and validation (n=164) sets; 300 HCT pts who enrolled on multicenter BMT CTN primary GVHD therapy clinical trials provided a second validation set. We measured the concentrations of 3 prognostic biomarkers (TNFR1, REG3α, and ST2) and used competing risks regression to create an algorithm from the training set to compute a predicted probability (p) of 6 mo NRM from GVHD diagnosis where log[-log(1-p)] = -9.169 + 0.598(log2TNFR1) - 0.028(log2REG3α) + 0.189(log2ST2). We then rank ordered p from lowest to highest and identified thresholds that met predetermined criteria for 3 GVHD grades so that NRM would increase 15% on average with each grade. A range of thresholds in the training set met these criteria, and we chose one near each median to demarcate each grade.In the resulting grades, risk of NRM significantly increased with each grade after the onset of GVHD in both the training and validation sets (FIG 1A,B). Most (80%) NRM was due to steroid-refractory GI GVHD, even though surprisingly only half of these pts presented with GI symptoms. We next applied the biomarker algorithm and thresholds to the second multicenter validation set (n=300) and observed similarly significant differences in NRM (FIG 1C). Relapse, which was treated as a competing risk for NRM, did not differ among the three GVHD grades (Figure 1D-F). The differences in NRM thus translated into significantly different overall survival for each GVHD grade (Figure 1G-I). These differences in survival are explained by primary therapy response at day 28, which was highly statistically different for each of Ann Arbor grade (grade 1, 81%; grade 2, 68%; grade 3, 46%; p<0.001 for all comparisons).We performed additional analyses on the multicenter validation set of pts that developed GVHD after treatment with a wide spectrum of supportive care, conditioning and GVHD prophylaxis practices. As expected, the Glucksberg grade at GVHD onset did not correlate with NRM (data not shown). Despite small sample sizes, the same biomarker algorithm and thresholds defined three distinct risk strata for NRM within each Glucksberg grade (FIG 2A-C). Pts with the higher Ann Arbor grades were usually less likely to respond to treatment. Unexpectedly, approximately the same proportion of pts were assigned to each Ann Arbor grade (~25% grade 1, ~55% grade 2, ~20% grade 3) regardless of the Glucksberg grade (FIG 2D-F).Several clinical risk factors, such as donor type, age, conditioning, and HLA-match, can predict treatment response and survival in patients with GVHD. Using Ann Arbor grade 2 as a reference, we found that Ann Arbor grade 1 predicted a lower risk of NRM (range 0.16-0.32) and grade 3 a higher risk of NRM (range 1.4-2.9), whether or not any of these clinical risk factors were present.To directly compare Ann Arbor grades to Glucksberg grades, we fit a multivariate model with simultaneous adjustment for both grades. FIG 3 shows that Ann Arbor grade 3 pts had significantly higher risk for NRM (p=0.005) and Ann Arbor grade 1 pts had significantly less risk for NRM (p=0.002) than pts with Ann Arbor grade 2. By contrast, the confidence intervals for the HRs of the Glucksberg grades encompassed 1.0, demonstrating a lack of statistical significance between grades.In conclusion, we have developed and validated an algorithm of plasma biomarkers that define three grades of GVHD with distinct risks of NRM and treatment failure despite differences in clinical severity at presentation. The biomarkers at GVHD onset appear to reflect GI tract disease activity that does not correlate with GI symptom severity at the time. This algorithm may be useful in clinical trial design. For example, it can exclude pts who are likely to respond to standard therapy despite severe clinical presentations, thus limiting the exposure of low risk pts to investigational agents while also identifying the high risk pts most likely to benefit from investigational approaches. [Display omitted] [Display omitted] [Display omitted] DisclosuresLevine:University of Michigan: GVHD biomarker patent Patents & Royalties. Braun:University of Michigan: GVHD biomarker patent Patents & Royalties. Ferrara:University of Michigan: GVHD biomarker patent Patents & Royalties.

Nonmyeloablative HLA-Haploidentical (NMA Haplo) BMT with High-Dose Posttransplantation Cyclophosphamide (PTCy) Is Associated with Similar Outcomes to Matched BMT When Stratified By Disease Risk Index (DRI)

Background: Recent advances in NMA haplo BMT, including high-dose PTCy for GVHD prophylaxis, have expanded potentially curative treatment options for patients (pts) without a matched donor. The DRI (Blood 2012;120:905), based on disease type and status, was developed to stratify pt risk across histologies and conditioning regimens. The current study evaluated the newly refined DRI (Blood 2014;123:3664) in the largest series of NMA haplo BMT to date.Methods: We retrospectively analyzed the outcomes of 374 consecutive adult hematologic malignancy pts who received NMA related haplo BMT with PTCy at Johns Hopkins. Eligibility included ECOG PS ≤ 2, LVEF ≥ 35%, adequate pulmonary and renal function and absence of uncontrolled infection. All pts received fludarabine (30 mg/m2IV D -6 to -2), Cy (14.5 mg/kg IV D -6 and -5), TBI (200 cGy D -1) and T-cell replete bone marrow. GVHD prophylaxis consisted of high-dose PTCy (50 mg/kg IV D 3 and 4), mycophenolate mofetil and tacrolimus. Maintenance therapy (e.g., imatinib) after engraftment was permitted. The median age was 55 (range 18-75) at BMT, 132 (35%) pts were aged ≥ 60 and 71 (19%) had prior autologous BMT. Diagnoses were acute leukemia or lymphoblastic lymphoma (115 pts; 31%), MDS or MPN (36 pts; 10%), aggressive NHL (95 pts; 25%), Hodgkin lymphoma (36 pts; 10%), mantle cell lymphoma (29 pts; 8%) and indolent lymphoid cancers (63 pts; 17%). By the new DRI, disease risk was low in 72 pts (19%), intermediate (int) in 242 (65%), high in 50 (13%) and very (v) high in 10 (3%).Overall results: With a median follow-up of 3.4 (range 0.5-11.4) years (y) in surviving pts, 3-y probabilities of PFS and OS were 40 (95% CI 35-45)% and 50 (45-56)%, respectively. The probability of neutrophil recovery was 89% by D30 (median 17 d). By competing-risk analyses, the D180 probability of nonrelapse mortality (NRM) was 8 (95% CI 5-10)%, grade 2-4 acute GVHD was 32 (27-37)%, and grade 3-4 acute GVHD was 4 (2-6)%. The 2-y probability of chronic GVHD was 13 (10-17)%.Results by DRI: Among the 3 DRI risk groups (low, int, high/v high), there were no statistically significant differences in histology (lymphoid vs myeloid), HCT-CI risk category, median CD34+ graft dose or pt CMV serostatus. Median pt age was greater in the higher risk groups (P = 0.01). On unadjusted analyses of the new DRI, the probability of relapse by competing-risk differed clearly between the groups (P < 0.0001; Fig. A), with no statistically significant difference in NRM (P = 0.53). This was coupled with statistically significant differences in both PFS and OS. In low, int and high/v high risk groups, 3-y PFS estimates were 64%, 37% and 22%, respectively (P < 0.0001; Fig. B), and 3-y OS estimates were 69%, 49% and 34% (P = 0.0001). Furthermore, on multivariate analyses adjusted for age and year of BMT, the new DRI was independently associated with overall outcomes. Compared to low-risk pts, the HR for relapse was 3.0 (95% CI 1.8-5.2) for int risk pts (P = 0.0001) and 4.7 (2.6-8.5) for high/ v high risk pts (P < 0.0001). HRs for both PFS and OS were ≥ 2-fold greater for int and high/v high risk pts compared to low risk pts (each P ≤ 0.0002). On multivariate analyses, the original DRI (13% low risk, 68% int, 19% high/v high) was also independently associated with relapse, PFS and OS (each P ≤ 0.003). When stratified by DRI, survival outcomes with reduced-intensity, matched related or unrelated BMT (based on 614 pts from the original DRI study cohort; personal communication, P. Armand) and haplo BMT with PTCy appeared similar (Table).Conclusion: The DRI appears to effectively stratify and prognosticate pts undergoing NMA haplo BMT. When stratified by DRI, the efficacy and survival outcomes with NMA haplo BMT with PTCy appear comparable to those reported with matched BMT. Within this transplant platform, the results support the use of the DRI in outcome analyses and randomized clinical trials involving heterogeneous groups of pts. [Display omitted] TableSurvival Estimates by DRI3-y PFS (%)3-y OS (%)Original DRIMatchedHaploMatchedHaploLow66637071Intermediate31394749High / very high15252538 [Display omitted] DisclosuresOff Label Use: High-dose posttransplantation cyclophosphamide.

Association of Donor Killer Immunoglobulin-like Receptor (KIR) Genotype with Outcome after HLA-Matched Related Donor Hematopoietic Cell Transplantation for AML

Although outcomes after allogeneic hematopoietic cell transplantation (alloHCT) for AML have improved, this has mainly been attributed to a reduction in transplant-related mortality rather than reduced leukemia relapse. NK cell alloreactivity is regulated by inhibitory and activating signals mediated through cell-surface receptors including the killer immunoglobulin-like receptors (KIRs). Group A and B KIR haplotypes have distinct centromeric (Cen) and telomeric (Tel) gene-content motifs and donor Cen group B KIR haplotypes have been reported to be associated with decreased relapse and improved survival in AML patients undergoing unrelated donor alloHCT. We hypothesized that donor KIR genotype may also be predictive of outcomes after matched related donor (MRD) alloHCT. We evaluated 93 AML patients in CR1/CR2 who underwent T-cell replete alloHCT using HLA- matched related donors at our institution from 1/2000-3/2013. Sixty-six had myeloablative conditioning (MAC) that that was busulfan/cyclophosphamide-based and 27 had reduced-intensity conditioning (RIC) with fludarabine/total body irradiation or busulfan/fludarabine. Donors were KIR genotyped to assign haplotypes A/A vs. B/X and the distinctive Cen and Tel gene-content motifs of group A and B KIR haplotypes according to the presence or absence of one or more B haplotype-defining KIR genes. KIR B–content score for each KIR genotype was defined as the number of Cen and Tel gene-content motifs containing B haplotype–defining genes (range, 0-4). As compared to those with haplotypes B/X (n=40; B content scores of 1-4) those with haplotype A/A (n=25; B content score of 0) undergoing MAC had significantly lower 100-day, 6-, 12- and 24-month non-relapse mortality (NRM) (8% vs. 0%, 13% vs. 0%, 15% vs. 0%, 25% vs. 0%, respectively, Figure 1) which was confirmed on multivariable analysis (HR 9.19, p=0.03). There were no differences between these groups regarding patient and transplant-related characteristics, or for acute or chronic GVHD, relapse, or survival. The causes of death in the group with haplotypes B/X were most commonly attributed to infection and then GVHD. However, within the group with B/X haplotypes, the B motif content score (1-4) was not associated with significant differences in NRM (HR 0.79, p=0.56). No difference in outcomes was observed for those undergoing RIC. The number of donor activating KIR genes (2SD1, 2DS2, 2DS3, 2DS4, 2DS5, and 3DS1) was then assessed. As compared to those with 3-6 activating KIR genes (n=20) those with 0-2 (n=41) undergoing MAC had significantly lower 100-day, 6-, 12- and 24-month non-relapse mortality (NRM) (15% vs. 0%, 15% vs. 5%, 15% vs. 5%, 29% vs. 8%, respectively, Figure 2) which was confirmed on multivariable analysis (HR 4.07, p=0.01). There were no differences in other post-transplant outcomes when comparing these groups or when considering those undergoing RIC. An increase of 1 donor activating KIR also was highly associated with NRM (HR 1.37, p=0.008). Overall, these results suggest that in the MRD MAC alloHCT setting donor KIR genotype may be predictive of increased NRM risk, particularly for those with B/X haplotypes and greater numbers donor activating KIRs. No comparable effects were observed in the RIC setting. Future strategies to further enhance immune reconstitution post-transplant may be appropriate to pursue for these higher risk patients. These results may have potential implications to improve donor selection for those AML patients with multiple HLA-matched related donors and need to be validated in larger cohorts. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Lower dose of antithymocyte globulin does not increase graft-versus-host disease in patients undergoing reduced-intensity conditioning allogeneic hematopoietic stem cell transplant

The appropriate dose of antithymocyte globulin (ATG) to be utilized in reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplant (alloHSCT) is as yet unknown. We retrospectively compared patients who received 7.5 mg/kg (R-ATG, 39 patients) and 6 mg/kg (r-ATG, 97 patients). The cumulative incidences of acute graft-versus-host disease (aGVHD) grade II–IV at 180 days were 46% and 41% and of aGVHD grade III–IV were 11% and 18% in r-ATG and R-ATG, respectively (p > 0.30). The respective estimated cumulative incidences at 24 months of cGVHD were 42% and 44% (p > 0.30). There was no significant difference in non-relapse mortality (p = 0.22), cumulative incidence of relapse (p = 0.53), progression-free survival (p = 0.69) or overall survival (p = 0.95). In conclusion, a decreased ATG dose of 6 mg/kg was associated with a similar proportion of GVHD to 7.5 mg/kg ATG. Given the increasing number of RIC HSCTs performed worldwide, the correct dose and preparation of ATG should be defined by prospective randomized trials.

The Addition Of Sirolimus To The Gvhd Prophylaxis Regimen In Reduced Intensity Allogeneic Stem Cell Transplantation For Lymphoma: A Multicenter Randomized Trial

The mTOR inhibitor sirolimus has been used in the prevention and treatment of GVHD after allogeneic hematopoietic stem cell transplantation (HSCT). In parallel, mTOR inhibitors have demonstrated clinical activity against various lymphoma histologies. In a retrospective study, we found that patients with lymphoma undergoing reduced intensity conditioning (RIC) HSCT who received a sirolimus-containing GVHD prophylaxis regimen had a lower rate of relapse (Armand et al, J Clin Oncol. 2008;26(35):5767). We therefore performed a multicenter, phase III, open label randomized trial comparing tacrolimus, sirolimus and methotrexate (Tac/Sir/Mtx, with sirolimus starting on day -3 of HSCT) for GVHD prophylaxis to conventional sirolimus-free regimens (tacrolimus + methotrexate (Tac/Mtx) or cyclosporine + MMF (Csa/MMF), pre-specified by center), in patients undergoing RIC HSCT for any lymphoma except Burkitt lymphoma. The primary endpoint was 2-year overall survival (OS); progression-free survival (PFS), acute and chronic GVHD were among the secondary endpoints. 139 patients were enrolled at five institutions between June 2009 and September 2012. The median age was 57 years (range, 23-70). 42 patients had aggressive B-NHL, 31 indolent B-NHL, 28 CLL, 19 T-NHL and 19 Hodgkin lymphoma. 66 were assigned to the Tac/Sir/Mtx arm, and 73 to the control arm (67 to Tac/Mtx and 7 to Csa/MMF). All patients but 1 received the allocated intervention, and all received peripheral blood stem cell products, as mandated by the protocol. Based on a planned interim analysis, the DSMB recommended reporting of the interim results at this time. Median follow-up for survivors is 22 months, and only 12% of living patients have less than 12 months of follow-up. There was no evidence of increased toxicity in the Tac/Sir/Mtx arm. At the time of this analysis, the Kaplan-Meier estimate of 2-year OS by intent to treat (Figure 1A) is 66% (95CI, 51-77) in the Tac/Sir/Mtx arm vs. 71% (95CI, 58-81) in the control arm (p=0.7); the corresponding 2-y PFS (Figure 1B) is 62% (95CI, 48-73) vs. 56% (95CI, 43-68) (p=0.9). The conditional power for finding a significant difference in the primary endpoint of 2y OS is <1%, prompting the current report. There was no significant difference in non-relapse mortality (2y cumulative incidence 14% in both groups, p=0.9) or cumulative incidence of relapse (2y incidence 25% vs. 30%, p=0.8). However, the addition of sirolimus resulted in a significant decrease in the cumulative incidence of grade 2-4 acute GVHD (6-month cumulative incidence 9% vs. 25%, p=0.014; Figure 1C), even after excluding patients who received Csa/MMF. This was apparent in both patients receiving matched related and those receiving matched unrelated grafts. There was no significant difference in the incidence of grade 3-4 acute GVHD (3% vs. 4% at 6 months, p=0.7) or chronic GVHD (2-year cumulative incidence 59% vs. 55%, p=0.5; Figure 1D). [Display omitted] In conclusion, the addition of sirolimus to the GVHD prophylaxis regimen in patients with lymphoma undergoing RIC HSCT is associated with a significant decrease in grade 2-4 acute GVHD after transplantation, without impacting toxicity, severe acute GVHD, chronic GVHD, progression-free or overall survival. These results should be broadly applicable to all recipients of RIC HSCT using T-cell-replete peripheral blood stem cells, and suggest that tacrolimus, sirolimus and methotrexate could be a preferred regimen in this patient population. Pre-specified subgroup analyses by histology and correlative studies will be performed when follow-up is complete in late 2014. Disclosures:Off Label Use: Sirolimus, tacrolimus, methotrexate, cyclosporin, mycophenolate for GVHD prophylaxis.

Impact of Early Blast Clearance Following Induction Chemotherapy On the Outcome of Patients with Acute Myelod Leukemia Undergoing Allogeneic Stem Cell Transplantation in First Complete Remission

AbstractAbstract 1998▪▪This icon denotes a clinically relevant abstract Purpose:In patients with newly diagnosed acute myeloid leukemia (AML) rapid achievement of remission by induction chemotherapy is an important predictor for long-term disease control. In turn, patients who fail to attain early blast clearance after the first chemotherapy course have an inferior outcome. Here, we investigated the impact of early blast clearance on the overall outcome of patients with AML undergoing allogeneic stem cell transplantation (alloSCT) in first complete remission (CR1) as consolidation therapy. Patients and Methods:169 (90 female, 79 male) patients with AML who underwent alloSCT in CR1 at our center between 1994 and 2011 were included. Data were prospectively recorded in our transplant data base and retrospectively analyzed as of December 31st, 2011. In detail, 107 patients (64%) had de novo AML, 31 patients (18%) had AML evolving from myelodysplastic syndrome (MDS), and 31 patients (18%) had therapy-related AML. According to the criteria of the SWOG/ECOG, cytogenetic risk was either favorable (6 patients, 4%), intermediate (104 patients, 62%), or poor (47 patients, 27%). Prior to alloSCT all patients were treated in a German multicenter AML trial and received at least two courses of induction chemotherapy, i.e. either standard “7+3” (daunorubicin 60 mg/m2, day 3–5 and Ara-C 100 mg/m2, day 1–7) or a “high-dose Ara-C” containing regimen (Ara-C 1–3 g/m2). In 98 patients (58%) induction chemotherapy resulted in blast clearance after the first course, whereas 71 patients (42%) failed to achieve early remission, but entered remission after 1 or 2 subsequent courses. Median age at transplantation was 47 years (range: 17–69 years). In 146 patients (86%) alloSCT was performed using peripheral blood stem cells (PBSCs), whereas 23 patients (14%) received a bone marrow (BM) graft. Conditioning consisted of standard myeloablative conditioning (MAC: 6 × 2 Gy TBI and 2 × 60 mg/m2 cyclophosphamide) in 81 patients (48%), whereas 86 patients (52%) received reduced intensity conditioning (RIC: busulfan 2 × 4 mg/kg, fludarabine 6 × 30 mg/m2 and ATG 4 × 10 mg/kg). A matched related donor was available in 82 patients (49%), whereas 68 patients (40%) or 19 patients (11%) were transplanted from a matched-unrelated or mismatched unrelated donor. Results:After a median follow-up of 45 months (range: 3–196 months) for the surviving patients, 91 patients (54%) are alive and in continuous remission. Causes of death were relapse in 38 patients (22%) or NRM in 33 patients (19%). At 1, 3 or 5 years projected overall survival (OS) was 72±6%, 58±6%, or 54±8% for all patients. Probability of relapse or non-relapse mortality (NRM) at 1, 3, and 5 years was 20±10% (20±11%), 31±12% (20±11%), and 34±12% (20±11%). Although there was no statistically significant difference in OS at 3 and 5 years between patients who achieved early blast clearance as compared to patients who failed to do so (p=0.09), disease-free survival (DFS) and probability of relapse differed significantly between the two groups at 3 years (77±8% vs 55±14%) or 5 years (75%±9% vs 52%±14%) following alloSCT (p=0.02). There was no significant difference in NRM between the two subgroups. Likewise, there was no statistically significant difference between patients conditioned with either MAC or RIC. In multivariate analysis cytogenetic risk group and remission status were identified as independent prognostic factors for DFS and probability of relapse. Conclusions:These results suggest that in patients with AML undergoing alloSCT in CR1 early blast clearance, i.e. following the first course of induction chemotherapy, predicts a very favorable outcome. Disclosures:No relevant conflicts of interest to declare.

Bone marrow or peripheral blood stem cell transplantation from unrelated donors in adult patients with acute myeloid leukaemia, an Acute Leukaemia Working Party analysis in 2262 patients

No survival benefit of using blood stem cells instead of bone marrow (BM) has been shown in matched unrelated donor (MUD) transplantation. In a retrospective registry analysis, we compared the use of blood stem cells (n = 1502) and BM (n = 760) from unrelated donors in patients aged 18-60 years with acute myeloid leukaemia (AML) undergoing myeloablative conditioning between 1997 and 2008. The blood stem cell recipients were older (P < 0.01), had more advanced disease (P < 0.0001) and received less total body irradiation (P < 0.0001) and more antithymocyte globulin (P = 0.01). Recovery of neutrophils and platelets was faster with blood stem cells (P < 0.0001). The incidence of acute graft-versus-host disease (GVHD) was similar, but there was more chronic GVHD in the blood stem cell group [hazard ratio (HR) = 1.29, P = 0.02]. There were no significant differences in nonrelapse mortality (NRM), relapse incidence and leukaemia-free survival (LFS) between the two groups amongst patients with AML in remission. In patients with advanced leukaemia, NRM was lower (HR = 0.61, P = 0.02) and LFS was prolonged (HR = 0.67, P = 0.002) when blood stem cells were used. At 3 years, LFS for all patients, regardless of remission status, was 41% for both treatment groups. The outcome was not affected after multivariable analysis adjusted for confounders. Blood stem cells compared with BM in MUD transplantation for patients with AML in remission resulted in the same rates of LFS. In patients with advanced leukaemia, the blood stem cell group had reduced NRM and improved LFS.

Prognostic Impact of a Monosomal Karyotype on the Outcome of Patients with Acute Myeloid Leukemia or Myelodysplastic Syndrome Undergoing Allogeneic Stem Cell Transplantation

Abstract 2028 Purpose:A monosomal karyotype, as defined by the presence of two or more autosomal monosomies or a single autosomal monosomy in the presence of at least one structural chromosomal abnormalities (core binding factor abnormalities excluded), was shown to confer to a highly unfavorable prognosis in patients (patients) with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) treated with conventional chemotherapy. Here, we investigated the prognostic impact of a monosomal karyotype on the outcome of patients with AML or MDS following allogeneic stem cell transplantation (alloSCT). Patients and Methods:254 patients who underwent alloSCT at our center between 1994 and 2010 were retrospectively analyzed. 204 patients (80%) had AML (de novo AML: 167 patients, therapy-related AML (tAML), AML evolving from MDS: 37 patients) and were in CR1 (157 patients (77%) or CR>1 (47 patients (23%). 50 patients had MDS (RA/RCMD: 36 patients, RAEB-I: 7 patients, RAEB-II: 9 patients). Median age was 47 years (range: 17–72 years). 223 patients (88%) received peripheral blood stem cells (PBSCs), 31 patients (12%) received bone marrow (BM). Conditioning consisted of standard myeloablative conditioning (MAC) in 134 patients (53%), whereas 120 patients (47%) received reduced intensity conditioning (RIC). 13 patients (5%) had a core-binding factor leukemia (CBF group), 117 patients (46%) were cytogenetically normal (CN group), 79 patients (31%) had an unfavorable risk MK-negative karyotype (MK– group), 26 patients (10%) had a highly unfavorable MK-positive (MK+ group). In 19 patients (8%) the karyotype was unknown/not evaluable. Results:After a median follow-up of 51 months (range: 3–191 months) for the surviving patients, 134 patients (53%) are alive and in remission. Causes of death were relapse in 53 patients (21%) or NRM in 58 patients (23%). At 1, 3 or 5 years projected OS (DFS) was 70±6% (66±6%), 57±6% (56±6%) or 54±7% (54±7%). At 3 years patients in the MK+ group had a statistically significantly lower OS (DFS) of 29% (29%) as opposed to 52% (52%) in the MK– group, 68% (66%) in the CN group, or 67% (55%) in the CBF-group (p<0.001). Likewise, the probability or relapse was highest in the MK+ group (72%) as compared to the MK- group (37%), the CN group (24%), or the CBF group (14%) (OS: p=0.001, DFS: p=0.003). There was no statistically significant difference in non-relapse mortality between the four groups. Conclusions:These data indicate that karyotypic abnormalities remain the most important prognostic factors predicting the outcome of patients with AML or MDS. In particular, the presence of a monosomal karyotype provides a strong negative prognostic prediction for these patients undergoing alloSCT. Therefore, our data suggest that these patients should be referred to alloSCT in CR (AML) or early stage disease (MDS). Disclosures:No relevant conflicts of interest to declare.

Prognostic Impact of a Monosomal Karyotype in Patients With Acute Myeloid Leukemia Undergoing Allogeneic Stem Cell Transplantation

Allogeneic stem cell transplantation (alloSCT) is a highly effective treatment for patients (pts) with acute myeloid leukemia (AML). Recently, the presence of a monosomal karyotype was shown to confer to a highly unfavorable prognosis in pts with AML treated with conventional chemotherapy. Therefore, we investigated the prognostic impact of a monosomal karyotype on the outcome of pts with AML following alloSCT. We retrospectively analyzed 153 pts with AML (median age: 45 years, range: 17 – 68 years) who underwent alloSCT in complete remission (CR) at our center between 1994 and 2008. 92 pts (82%) had de novo AML, 27 pts (18%) had therapy-related AML (tAML) or AML evolving from myelodysplastic syndrome. As a stem cell source 131 pts (86%) received peripheral blood stem cells (PBSCs), 22 pts (14%) received bone marrow (BM). Conditioning consisted of standard myeloablative conditioning (MAC) (12 Gy TBI, 2x60mg/kg cyclophosphamide) in 90 pts (59%). 63 pts (41%) received reduced intensity conditioning (RIC) (2x4mg busulfan, 6x30 mg/m2 fludarabine, 4x10mg/kg ATG). 10 pts (7%) had a core-binding factor leukemia (CBF group), 64 pts (41%) were cytogenetically normal (CN group), 19 pts (12%) had an unfavorable risk MK-negative karyotype (MK- group) and 19 pts (12%) had a highly unfavorable MK-positive karyotype (MK+ group) (Breems et al., JCO 26: 4791-4797). After a median follow-up of 58 months (range: 13-176 months) for the surviving pts, 86 pts (56%) are alive and in CR. Causes of death were relapse in 33 pts (22%) or infections/GvHD in 32 pts (22%). At 3 years projected OS was 55%, whereas the probability of relapse or non-relapse mortality (NRM) was 32% or 22% for the whole cohort. At 3 years patients in the MK+ group had a statistically significantly lower overall survival (OS) of 25% as opposed to 49% (MK- group), 66% (CN group), or 67% (CBF-group) (p = 0.01). Likewise, the probability or relapse was highest in the MK+ group (72%) as compared to the MK- group (37%), the CN group (24%), or the CBF group (14%) (p = 0.001). There was no statistically significant difference in non-relapse mortality between the four groups. Our results indicate that cytogenetics is still one of the most important prognostic factors. In particular, the presence of a monosomal karyotype provides a strong negative prognostic prediction for patients with AML undergoing alloSCT. These patients should be referred to alloSCT in early in CR1.