ALBERT

Description: Introduction Numerous genetic abnormalities (including chromosomal translocations, deletions or amplifications, mutations) affect treatment outcomes in multiple myeloma (MM) and explain the heterogeneity in prognosis of MM patients with similar disease and host factors. Hyperdiploidy is associated with favorable outcomes, in contrast to del 17p, del 13, t(4;14), and gain of 1q2, which are associated with unfavorable outcomes. There is conflicting data about the role of overlap in cytogenetic and molecular abnormalities and their impact on prognosis. We sought from our study to determine the influence of overlapping genetic abnormalities in MM patients who received frontline autologous stem cell transplantation (ASCT) consolidation therapy. Methods Between January 2009 and January 2016, we included all consecutive newly diagnosed MM patients who underwent frontline ASCT at The University of Texas MD Anderson Cancer Center. All adult patients (≥18 years) who received high-dose melphalan conditioning regimen and had available conventional cytogenetics and interphase fluorescence in situ hybridization (FISH) studies at diagnosis were eligible. Patients with primary refractory and relapsed disease were excluded. Hyperdiploidy was defined as any extra copy of one or more of the odd chromosomes. High-risk genetic abnormalities are defined presence of del 17p, del 13, t(4;14), and/or 1q21 gain (detected by FISH and/or conventional cytogenetics). Primary and secondary endpoints were progression-free survival (PFS) and overall survival (OS), respectively. Survival estimates were calculated by Kaplan-Meir method, and Cox proportional hazards regression analysis was used to assess the predictors of PFS on univariate and multivariate analysis. Results A total of 494 patients (57% males, 43% females) with a median age of 61 years (range, 33-80) were eligible and included in final analysis. 154 patients (31%) were identified to have any hyperdiploidy and 189 patients (38%) to have any high-risk abnormality. A total of 84 patients (17%) had hyperdiploidy without any high-risk feature and 121 patients (25%) had a high-risk cytogenetic abnormality without hyperdiploidy. With a median follow up of 27 months (range, 1-76) the 2-year PFS and OS of all study group were 71% and 90%, respectively. Among patients with any hyperdiploidy, the 2-year PFS and OS were 72% and 92%. In contrast, for patients with any high-risk genetic feature, the 2-year PFS and OS were 56%and 81%. Acquisition of any high-risk genetic abnormality, age 〉55 years, and international staging system (ISS) stage III were associated with worse PFS in univariate analysis. Further stratification of patients according to overlapping genetic abnormalities showed that the co-existence of hyperdiploidy with any high-risk genetic abnormalities was associated with significantly worse PFS compared to hyperdiploidy without co-exisiting genetic abnormalities (2-year PFS 59% vs 80%, HR 2.9, p=0.003) (Figure). PFS in patients with co-existing hyperdiploidy and high-risk genetic abnormalities was comparable to that in patients with high-risk genetic abnormalities without hyperdiploidy (59% vs. 55%, HR 0.9, 95%CI: 0.6-1.7; p=0.9) (Figure). The effect of high-risk abnormalities on PFS persisted on multivariate analysis, and was reflected on OS as well (Figure). Conclusions Our findings confirm that the co-existence of hyperdiploidy and high-risk genetic features does not abrogate the poor prognosis of MM patients with associated high-risk genetic abnormalities at diagnosis. Patients with hyperdiploidy and high-risk genetic abnormalities have similar outcomes to high-risk MM patients without hyperdiploidy, and should be considered as high-risk patients to guide future risk-adaptive treatment prospective clinical trials. Figure Figure. Disclosures No relevant conflicts of interest to declare.

Description: Background: Primary mediastinal (PMBL), GCB and non-GCB B-cell lymphoma are three major subtypes of DLBCL with distinct clinical outcomes. PMBL and DLBCL of GCB immunophenotype have a higher chance of cure than patients with non-GCB DLBCL when treated with conventional chemotherapy. In the relapsed/refractory setting, there is paucity of data regarding the impact of histological classification of DLBCL on survival following alloSCT in patients who were not eligible for or who have failed a prior autologous SCT (ASCT). Herein, we compare outcomes of alloSCT in these patients. Methods and Patients: We identified 101 de novo DLBCL patients who were treated at our center from January 1, 1998 to December 31, 2011. Seventeen (17%) tumors were PMBL. We determined the cell-of-origin in the remaining patients, based upon the Visco/Young and Choi immunohistochemical algorithms, and classified 62 (61%) as GCB and 22 (22%) as non-GCB tumors. GCB patients were older than non-GCB [median (range): 54 (21-70) vs 48(24-58) years, p=0.003)] and PMBL [26(19-48), P

Description: Key Points After HSCT with in vivo T-cell depletion using ATG, HLA-DPB1 nonpermissive mismatches at the GVH direction increase the risk for aGVHD. HLA-DPB1–matched pairs have an increased risk for disease progression if intermediate risk by the Disease Risk Index.

Description: Backround: Arsenic trioxide (ATO) has been shown to be synergistic with melphalan both in vitro and in vivo. We conducted a phase I/II trial to determine the safety and efficacy of a combination of arsenic trioxide, melphalan and ascorbic acid (AA) as preparative regimen in patients undergoing high-dose therapy (HDT) and autologous hematopoietic progenitor cell transplantation for multiple myeloma (MM). We also assessed the impact ATO levels on melphalan pharmacokinetics (PK), engraftment and toxicity. Methods: Forty-eight patients with secretory myeloma (23 females, 25 males; median age: 54, range: 3570) were treated between 4/04 and 8/05. All patient received melphalan 100 mg/m2 IV on days -4 and -3 and AA 1000 mg/day IV on days -9 to -3. Patients were randomized to 3 arms; no ATO (arm 1), ATO 0.15 mg/kg IV on days -9 to -3 (arm 2) and ATO 0.25 mg/kg IV on days -9 to -3 (arm 3). Twelve patients had disease progression or relapse after a prior autograft. Median CD34 cells dose infused was 4.5 x 106/kg (range 2.3–10.9). Results: Patients in all 3 arms were evenly matched. With a median F/U of 14.0 months (range 6–25) post autograft, no dose-limiting toxicity or non-relapse mortality was seen. Toxicity was limited to grade I or II nausea, vomiting and diarrhea. Median ATO levels on day 0 in arms 1, 2 and 3 were 0.2, 26.3 and 46.2 ng/ml, respectively. Melphalan PK was not altered by ATO pretreatment. Median time to neutrophil engraftment (ANC 〉500/ dl) was 9 days. There were no engraftment failures or delays in the ATO arms. CR rate for the entire group was 23%, and total response rate (CR + PR) was 75%. 1-year Progression-free survival (PFS) and overall survival (OS) were 75% and 95%, respectively. There was no significant difference in CR, RR, PFS or OS between the 3 arms (p = 0.9, 0.9, 0.4 and 0.6, respectively). A prior autologous transplant (p = 0.02) and abnormal cytogenetics at transplant (p = 0.04) were associated with a significantly shorter remission. Conclusions: ATO + melphalan + ascorbic acid is a safe, effective and well tolerated preparative regimen for patients with multiple myeloma undergoing an autotransplant. A longer follow up is needed to assess the impact of ATO on progression-free and overall survival.

Description: Abstract 4200 Graft-vs.-Host Disease (GVHD) remains a common complication following matched sibling and unrelated donor hematopoietic cell transplantation (HCT). Standard GVHD prophylaxis calls for prolonged immune suppression, typically with a calcineurin-inhibitor. Recently, post-transplant cyclophosphamide (CY) has been studied as sole prophylaxis in matched related and unrelated bone marrow (BM) transplant recipients following an ablative conditioning regimen with busulfan (Bu) and CY and demonstrated comparable rates of acute GVHD and lower rates of chronic GVHD as traditional GVHD prophylaxis regimens. We recently conducted a phase II study of post-transplant CY following a reduced-intensity conditioning (RIC) regimen of Busulfan (Bu) and Fludaribine (Flu) in matched related and unrelated donor transplants and performed a matched-control analysis comparing their results with patients who received traditional GVHD prophylaxis with tacrolimus and mini-dose methotrexate (MTX) during the same time period. Forty-nine (49) patients were enrolled onto this study. They received Flu at a dose of 40mg/m2 over 1hour followed by intravenous Bu over 3 hours targeting a daily AUC of 4,000 microMol-min on days –6 to –3. Recipients of unrelated transplants received ATG on days –3 to –1 (total dose 4 mg/kg). CY was given as sole GVHD prophylaxis at a dose of 50 mg/kg on days +3 and +4. During the same period of time, 133 patients received a RIC regimen with intravenous Bu/Flu or Flu and melphalan (Mel) and received GVHD prophylaxis with tacrolimus plus mini-dose MTX (10mg/m2 on day +1, 5mg/m2on days +3, +6, +11). Unrelated donor transplants also received ATG. A computer generated algorithm was used to identify a comparable control group from our departmental database matching, in order of priority, on age, diagnosis, disease status, donor (matched-related versus unrelated) and graft source (PB versus BM). Matched controls (control group) were successfully identified for 37 study patients (Post-Cy group). Results: The median age for the Post- CY group and control group was 61 (range, 39–72) and 62 years (range, 37–72). Eight-one (81) % of patients in both groups had AML or MDS, 3% had ALL and 16% had NHL or CLL. Fifty-nine (59) % of patients in both groups had unrelated donors and received ATG in the conditioning. Disease status for the Post-CY and control groups respectively were CR1: 14 and 14%, CR2: 8 and 11%, 〉CR2: 38 and 32% and Primary Induction Failure / Untreated: 40 and 32%. Seventy (70) % of the post-CY group received BM versus 48% of the control group, whereas sex mismatching (Male donor for Female patient) occurred in 22% of the post-Cy and 8% of the control group. The cumulative incidence of grade II-IV acute GVHD and chronic GVHD in the post-CY and control groups were: 46% versus 19% (Hazard Ratio (HR): 2.8, 95% CI, 1.1–6.7; p=0.02) and 14% versus 21% (HR: 0.8, 95% CI, 0.2–2.6, p=0.7). Grades III/IV acute GVHD occurred in 14% (95% CI, 6–32) of the patients in the post-CY group whereas there were no cases of grade III/IV in the control group (p=0.02). Overall, progression-free and non-relapse mortality at 2-years are shown in the table below. Conclusion: Post-transplant CY following RIC is associated with higher rates of acute GVHD, with resultant trends for higher non-relapse mortality and lower overall survival when compared to tacrolimus and mini-dose MTX. The use of post-transplant CY as a sole GVHD prophylaxis regimen should be avoided following RIC transplant in matched-related and unrelated donors. Disclosures: Off Label Use: azacitidine: off-label use as maintenance therapy following allogeneic stem cell transplant for MDS/AML.

Description: Background: The addition of rituximab (R) has improved results for pts with relapsed DLBCL who undergo high-dose chemotherapy followed by ASCT (Khouri, JCO, 2005). Recently, the incorporation of radio-labeled antibodies such as Yttrium 90 (90Y) Ibritumomab Tiuxetan (Zevalin®) to conditioning regimens has been evaluated. Herein, we compare the outcome in pts treated with these 2 regimens. Methods: Pts with relapsed chemosensitive DLBCL were treated on 2 consecutive trials. Between 1999 and 2003, 53 pts were enrolled on a protocol with BEAM combined with R at 1000 mg/m2 and on days +1 and +8 after ASCT (R-BEAM). Between 2004 and 2006, 25 pts were entered onto a trial of Zevalin given at the fixed dose of 0.4 mCi/Kg on day -14 followed by BEAM (days −7 to −1) with R on days +1 and +8 after ASCT (Z-BEAM). Both groups received R during stem cell collection at a dose of 375 mg/m2 the day before chemotherapy for stem cell mobilization and at 1000 mg/m2 7 days later. There was no statistical difference in age, sex distribution, # of prior therapies between the 2 groups. LDH, PET and remission status at transplant were comparable. However, serum b2- microglobulin level was higher in R-BEAM pts [median 2.2 vs 1.9, (p=.02)] and they were also more likely to have an IPI ≥ 1: 39% vs 8% (p=0.005). Results: Median follow-up: 18 mos (range, 6–35) in Z-BEAM and 52 mos (range, 21–74) for R-BEAM. Both groups were staged with CT, PET scan and marrow biopsies, every 3 mos for a year, and then every 6 mos. OS and DFS @ 2 yrs were 92% (95% CI, 72–98) and 84% (95% CI, 62–93) for Z-BEAM vs. 83% (95%CI, 70–91) and 72% (95% CI, 57–82) for R-BEAM (P = 0.5 for both OS/DFS). Within the R-BEAM group, PET status and IPI at transplant were important prognostic factors for OS {91% vs 50% for PET (−) and (+), P = 0.004; 94% vs 67% for IPI 0 vs. ≥1, P = 0.02} and DFS. DFS of pts with IPI 0 were 86% vs 81% for Z-BEAM and R-BEAM, respectively (P = 0.9). A comparison for high IPI pts could not be done due to the small number of such pts in the Z-BEAM group. DFS for pts who were PET (+) were 75% vs 44% within the Z-BEAM and R-BEAM groups, respectively: a difference that did not reach significance due to the small number of pts (4 vs 10). Treatment-related mortality was comparable with only one early death within the Z-BEAM group due to sepsis. Results suggest a faster WBC recovery with Zevalin {ANC 〉 500, day +9 vs. day +11 (p

Description: Abstract 3003FN2 Objective: Progressive disease (PD) remains the main cause of treatment failure following RIC allo-SCT in HL (Peggs KS et al, BJH 2008: 143; 468). We elected to explore the feasibility of adding gemcitabine (G), a highly active agent in relapsed/refractory HL (Santoro A et al, JCO 2000 :18; 2615), to our standard fludarabine (F) - melphalan (M) RIC in patients with relapsed and refractory HL undergoing allo-SCT, with the ultimate goal to augment cytoreduction and reduce the incidence of PD. Main G-associated non-hematologic toxicities include pulmonary, skin toxicities and mucositis. Patients and Methods: Between 8/07 and 3/11, fifteen consecutive HL patients (Unique Patient Number/UPNs 1–15) underwent an allo-SCT with the G-FM regimen. They had failed multiple conventional treatments (median prior chemotherapy regimens: 4; range 2–9), radiation therapy (6/15) and a prior auto-SCT (7/15). The median age was 33 years (range 20–46). Disease status at SCT was chemosensitive relapse (n=4), untreated relapse (n=1), induction failure chemosensitive (n=2), complete remission undetermined (CRU1 and CRU2) (n=8). The median time to PD after auto-SCT was 10 months (range 3–19). The donor was an HLA-identical sibling (n=10) or matched unrelated donor (MUD; n=5, with UPN 6 having a 9/10 match). The conditioning regimen was G 800 mg/m sq IV x1 at day -7 (two patients, UPN 6 and UPN 7 received G 1000 mg/m sq IV x2, day -5 and day -2 as part of a dose escalation attempt stopped for excess toxicity), F (32 mg/m sq IV x4, day -5 to day -2), M (70 mg/m sq IV x2, day -3 and day -2; total dose 140 mg/m sq). Thymoglobulin (4 mg/kg IV) was added in MUD allografts. Graft-vs-host disease (GVHD) prophylaxis included tacrolimus and mini-dose methotrexate (5 mg/m sq). Results: Myeloid recovery was prompt, with an absolute neutrophil count (ANC)〉500/mcL at day +12 (range 11–20). Median platelet recovery at 20K/mcL was at day +14 (range 9–26). Chimerism studies indicate 100% donor-derived engraftment in 13/13 evaluable patients (100%). Day 100/overall transplant-related mortality (TRM) were 2/15 (13%) and 2/15 (13%), respectively. Acute GVHD (grade II-IV) occurred in 8/14 evaluable patients, chronic GVHD in 7/13 evaluable patients (extensive in 7). Pulmonary toxicity was seen in four patients (26%). Grade 4 pulmonary toxicity was seen in UPN 6. Otherwise it was grade 1–2 (n=3). Cutaneous toxicity (skin rash, responsive to steroid therapy) was seen in five patients (33%: grade 3 n=1; grade 1–2 n=4). Mucositis was seen in nine patients (60%). It was grade 3 (n=1); grade 1–2 (n=8). Other organ toxicities were not seemingly markedly different from the ones seen with FM140 only. Three patients expired (graft rejection n=1, in UPN 6; CMV pneumonia n=1; PD n=1). Twelve patients are alive (ten progression-free, eleven in CR/CRU) with a median follow-up of 18 months (range 2–33). Actuarial rates of overall survival (OS) and progression-free survival (PFS) at 24 months are 87% (95% CI: 56–96) and 49% (95% CI: 18–74), respectively (see Figure). While a formal comparison with our historical experience with the FM140 regimen is clearly not possible, OS and PFS (actuarial estimates) at 24 months were 64% (95% CI: 49–76), and 32% (95% CI: 20–45), respectively (Anderlini et al, Haematol 2008; 93 :257). Conclusions: The addition of G to FM140 is feasible. Pulmonary, cutaneous toxicities, as well as mucositis, while clinically significant, were manageable and did not contribute to mortality in the patients treated with only one G dose. While quite encouraging, these data remain preliminary. The G-FM regimen deserves further study in a larger cohort of patients. Disclosures: Off Label Use: Gemcitabine, fludarabine and melphalan as part of conditioning regimen for allogeneic stem cell transplantation.

Description: Abstract 894 Background: We previously reported the use of fludarabine, cyclophosphamide and rituximab as a nonmyeloablative allogeneic conditioning for CLL and non-Hodgkin's lymphomas (Khouri et al, Blood 2008;111:5530). Bendamustine is a novel compound which was found to be effective in pts who were refractory to alkylating agents. In order to improve outcomes in nonmyeloablative stem cell transplantation (NST), we substituted cyclophosphamide with bendamustine in the conditioning. Methods: Bendamustine was given iv in an escalated dose of 70, 90, 110, 130 mg/m2 daily on days −5 to - 3 prior to NST, together with 30 mg/m2 of fludarabine given on the same days. Rituximab was given at a dose of 375 mg/m2 on day –13 and 1000 mg/m2 on days −6, +1, and +8, as previously described. Tacrolimus and methotrexate was used for GVHD prophylaxis. In addition, thymoglobulin of 1 mg/kg was given on days −2, and −1 in pts receiving an unrelated donor. Results: The study included 23 pts [Mantle cell=9, CLL=6 (2 with 17p- and 1 Richter's), Follicular =4, Diffuse large cell =3]. All pts had relapsed disease after the best conventional therapy (-ies) available. Median age was 60 (range, 30–70) years. Median prior treatments was 2 (range, 1–5); 3 pts (13%) had failed a prior autotransplant. At NST, 11 pts (48%) were in CR, 7 (31%) in PR, 1 (4%) induction failure/sensitive, and 4 pts (17%) had refractory disease. Fifteen pts (65%) received their transplants from HLA-compatible siblings and 8 (35%) from unrelated donors. Continual Reassessment Method based on target toxicity at day 30 post NST was used for dose finding. The number of pts who received the 70, 90, 110, 130 mg/m2 daily doses of bendamustine were 2, 3, 3, and 15 pts, respectively. No dose-limiting toxicity was observed. Fourteen pts (61%) did not nadir to an ANC〈 500; 3 pts did not require neupogen for ANC recovery; 19 (83%) did not experience a platelet count 〈 20,000/mm3. All pts engrafted donor cells. Median donor T cells at day 30 was 93%. Only one pt developed acute GVHD (it was grade 3); none had acute grade 2 or 4. Chronic extensive GVHD was observed in 2 of 22 (9%) evaluable pts. Fungal infection was the cause of the only death observed. Twenty pts (87%) achieved CR, 2 (9%) have ongoing PR, and 1 (4%) had SD. With a median follow-up time of 8 months (range, 3–25 months), the OS and PFS rates were 92% and 79%, respectively. Conclusions: Our results represent the first report to suggest that combining bendamustine at a dose up 130 mg/m2 daily × 3 days, together with fludarabine and rituximab is safe and constitutes a well tolerated conditioning for NST. We are treating pts with this regimen in the outpatient setting. The study is currently ongoing to assess its efficacy in a larger cohort of pts. Disclosures: Khouri: Cephalon: Research Funding. Off Label Use: Bendamustine use in SCT.

Description: Background: Allogeneic transplantation is a potentially curative approach in patients with myeloma. The potential benefit is offset by a higher risk of transplant-related mortality (TRM), graft-vs.host disease (GVHD) and opportunistic infections. The success of reduced intensity conditioning approaches has renewed interest in allogeneic transplantation. In this randomized phase II trial we evaluated whether lowering the dose of melphalan in a nonablative preparative regimen can lower the toxicity and TRM. Two reduced intensity regimens: fludarabine + melphalan 140 mg/m2 (FM 140) and fludarabine + melphalan 100 mg/m2 (FM 100) were compared in patients undergoing allogeneic stem cell transplantation. Methods: We enrolled 22 patients, 11 in each arm, who were 70 years of age or younger and had an HLA-identical sibling donor. Patients underwent allogeneic transplantation between April 2002 and January 2007. Median age was 52.5 years (Range: 32–63). GVHD prophylaxis consisted of tacrolimus and methotrexate 5mg/m2 on days 1, 3, 6 and 11. Median interval between diagnosis and transplant was 28 months (9–232). Only 6 patients (27%) received transplant for the consolidation of first remission, the rest had relapsed or refractory disease (73%). Twenty-one patients had a prior autotransplant; 3 of these had 2 prior autotransplants. Median number of prior treatment regimens was 5 (1–10). Cytogenetic abnormalities were observed in 8/22 patients (36%). Results: The 2 groups were comparable in terms of age, disease status, prior therapy and other prognostic factors. Median time to neutrophil engraftment in both arms was 12 days. TRM in the first 100 days was zero in both arms. Response rate (CR 18% + PR 64%) was 82%, with no significant difference between the 2 arms. After a median follow up of 25 months (26 months in FM 100, 21 months in FM 140), Kaplan-Meier estimates of 2-year PFS in FM 100 vs. FM 140 were 41% vs. 42%, respectively. Kaplan-Meier estimates of 2-year OS in FM 100 vs. FM 140 were 60 vs. 36%, (p=0.4), respectively. There was no significant difference in the incidence of grade II-IV acute GVHD (27 vs. 36%) or chronic GVHD (50 vs. 43%) between the 2 arms. There was a decrease in overall grade II-IV toxicity in the FM 100 arm (45% vs. 73%) that did not reach statistical significance (p=0.2) Patients transplanted in relapse had shorter PFS (0.09). Conclusions: The dose of melphalan in preparative regimen can be safely reduced without adversely impacting the engraftment in this heavily pretreated patient population. There was a trend towards lower grade II-IV toxicity and prolonged OS in the FM 100 arm. This approach may be more beneficial when used early in the course of treatment.

Description: Non-myeloablative allogeneic stem cell transplantation using the combination of fludarabine/cyclophosphamide/rituximab as a conditioning regimen has been successful in treating patients with relapsed, chemosensitive non-Hodgkin’s lymphoma (Blood98:3595, 2001; J Clin Oncol21:4407, 2004). A more intense regimen however is required to have an early disease control for patients with refractory disease or in kinetic failure. We used the BEAM regimen for that purpose. Because of potential synergy and without overlapping toxicity, Rituximab (375 mg/m2 on days −6, −1, +7 and +14) was added to the preparative regimen. Transplantation was performed on day 0. Fourteen consecutive patients with refractory lymphoma or in kinetic failure were studied. The study group included 11 males and three females of median age of 46 (range, 19–60) yrs. Underlying histologies include diffuse large cell lymphoma (n= 9), follicular (n=1), mantle cell (n=1), lymphoplasmacytic (n=1), and CLL in Richter transformation to diffuse large cell (n=2). Median # of prior chemoregimens received was 3 (range, 1–8). Twelve patients had a matched sibling donor, one a mismatched sibling, and one a matched unrelated donor. The median # of CD34+ cells infused was 5 x 106 CD34 + cells/kg. Twelve patients received blood and 2 received marrow as the source of the hematopoietic graft. Tacrolimus and methotrexate were used for GVHD prophylaxis. The day-100 mortality was 7%. Eleven patients (79%) had a complete, and 2 (14%) had a partial remission. One patient (7%) had no response. All patients engrafted donor cells (median of 100% at day 30) post transplantation. Median time to ANC 〉 500 was 13 (11–15) days and median time to platelets 〉 20K was 14 (9–25) days. The actuarial risk of Gr 2–4 GVHD was 57%, Gr 3–4 GVHD 28%. Eleven of the 13 patients who were alive at day 100 developed chronic GVHD. With a median follow-up time among survivors of 34 (8–48) months, overall survival and disease-free survival were 63% (95% CI, 33–83) and 57% (95%CI, 28–78), respectively. Our results indicate that a pronounced graft-versus-lymphoma occurs after BEAM/Rituximab and allogeneic transplantation for patients with refractory lymphoma or in kinetic failure. This treatment has been associated with a lower than expected treatment-related mortality and a higher chance of durable remission.