ALBERT

Description: Introduction The effect of CMV reactivation after allo-HCT on relapse and overall survival (OS) in patients with acute myeloid leukemia (AML) and myelodysplatic syndrome (MDS) is controversial (Green et al blood 2013, Elmaagacli et al Blood 2011, and Erard et al Hematologica 2006). Methods We retrospectively analyzed the effect of CMV reactivation on OS and cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) in AML and MDS patients older than 〉 18 years who had received allo-HCT between 2005-2011 and had not died within 30 days of receiving allo-HCT at MD Anderson Cancer Center. The effect of any CMV antigenemia on allo-HCT outcomes was evaluated by comparing any CMV antigenemia with no CMV antigenemia. Because of potential immunomodulatory effect of CMV infection, the effect of prolonged antigenemia (defined as CMV antigenemia with duration more than 12 days, the median duration of antigenemia for the cohort) on transplant outcomes was analyzed by comparing patients with prolonged antigenemia with patients with no CMV antigenemia or CMV antigenemia with ≤ 12 days. All patients underwent surveillance by pp65 antigenemia test. Preemtive therapy was initiated for 〉 3 pp65 Ag cells/million WBC's. Kaplan-Meier survival curves were used to estimate OS and the log-rank test was used to assess group differences. CIR and NRM were determined using the competing risks method; competing risk for CIR was death and for NRM was relapse. Group differences in CIR and NRM were assessed using Gray's test. Results Table 1 shows baseline characteristics. Comparing R+/D+, R-/D-, R-/D+, and R+/D- groups, the incidence of any CMV antigenemia after HCT was 48%, 16.7%, 13.5%, and 50.9%, respectively (p 0.15) and CIR (p 〉 0.61) in all cohort as well as AML and MDS subgroups. Comparing any antigenemia vs. no antigenemia, CIR at 3 years was 34.6% vs. 35.2% in all cohort, 36.7% vs. 36.6% in AML patients, and 29.5% vs. 30.0% in MDS patients, respectively. In patients with CMV antigenemia, duration of antigenemia ranged from 1 to 535 days (median 12 days). We then investigated the effect of prolonged CMV antigenemia on transplant outcomes. Patients with CMV antigenemia 〉 12 days compared with combined group of ≤ 12 days or no CMV antigenemia had a lower cumulative incidence of relapse and a higher NRM, resulting in a similar OS (Fig. 1). Such a difference was seen in AML but not in MDS subgroup. We then investigated the effect of duration of CMV antigenemia in patients with CMV reactivation. Comparing 1-12 days of antigenemia vs. more than 12 days of antigenemia, CIR at 3 years was 41.9% vs. 26.7% (p = 0.003) in all cohort, 45.8% vs. 26.4% (p = 0.001) in AML patients, and 32.1% vs. 27.4% (p = 0.68) in MDS patients, respectively. Conclusion Prolonged CMV antigenemia is associated with decreased relapse in patients with AML, but not in MDS. Lower relapse is offset by increased NRM resulting in no change in OS. In contrast with published data, lower rate of relapse was not found when any antigenemia was compared with no antigenemia. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction: The revised 2016 WHO classification of MDS has highlighted the value of morphologic evaluation and mutation analysis of bone marrow (BM)/ peripheral blood (PB) to further refine prognostication. These highlights include: (1) increased emphasis on lineage dysplasia compared with cytopenias; (2) objective enumeration of blast % for reproducibility; (3) accurate quantification of ring sideroblasts (RS); and (4) mutation analysis for SF3B1 in cases showing RS 〉5% and TP53 in MDS with isolated del(5q). Most of the proposed changes are within the categories of low-grade MDS. In this study, we evaluated 264 cases of MDS with diploid karyotype using the 2016 WHO system. Methods: We selected consecutive cases of MDS with diploid karyotype with BM morphological evidence of dysplasia and reclassified using the 2016 WHO system. Mutation analysis for SF3B1 (exons 14 and 15), SRSF2 (exon 1) and U2AF1 (exons 2 and 6) was performed using Sanger sequencing. Patient data were collected from the medical record. The Kaplan-Meier method was used to estimate OS and time-to-AML transformation. The associations between outcome and clinical and pathological parameters were determined using univariate and multivariate Cox proportional hazards regression models. Results: The study group included 264 MDS patients: 168 (64%) men and 96 (36%) women with a median age of 66.9 years (range, 28.3 - 89.1). The median hemoglobin, absolute neutrophil count (ANC), platelet count, and white blood cell (WBC) count were 10.0 g/dL, 1.9 x 109/L, 114.5 x 109/L, and 3.5 x 109/L, respectively. The median BM blast percentage was 2.5; 74% of the patients had 〈 5% BM blasts. MDS sub-classification according to the 2008 WHO classification was: RCUD, n=5 (2%); RA, n=9 (3%); RARS, n=16 (6%); RCMD, n=152 (58%); RAEB-1, n=56 (21%); RAEB-2, n=20 (8%), and MDS-U, n=6 (2%). Reclassification using the 2016 WHO classification: MDS with single lineage dysplasia (MDS-SLD, n=14, 5%), MDS with multi-lineage dysplasia (MDS-MLD, n=112, 42%), MDS with RS (including single lineage and multi-lineage dysplasia, MDS-RS, n=56, 21%); MDS-EB1, n=56 (21%), MDS-EB2, n=20 (8%) and MDS-U, n=6 (2%). Grading of fibrosis using reticulin/ trichrome stains showed absent-minimal fibrosis (grades 0-1) in 56/85 (66%) and moderate-severe fibrosis (2-3) in 29/85 (34%) cases. Mutation analysis for splicing factors was performed on 15 cases. Ten cases with 0-5% RS showed 2 cases each with SRSF2 and U2AF1 mutations. No cases had SF3B1 mutation. 5 cases with 〉5% RS showed SF3B1 mutations in 4 cases and 1 case each with SRSF2 and U2AF1 mutations. Over a median follow-up duration of 22.4 months (range, 0-156.8), 128 (48%) patients died. The median OS was 46.1 months (95% CI: 32.3, 58.4). Patients categorized as MDS-SLD by 2016 WHO had the best OS (156.8 months), followed by MDS-RS (58.7 months), MDS-MLD (46.3 months) and MDS-EB (21.2 months) (p1% RS. Figure Figure. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy.

Description: Introduction: Despite the successes of treatment with tyrosine kinase inhibitors (TKIs) in patients with CML, allogeneic hematopoietic stem cell transplantation (ASCT) continues to be a potentially curative option for patients with advanced disease of who fail TKI therapy. Here we analyzed outcomes of patients with advanced CML (aCML) (beyond first chronic phase-CP1) who received an ASCT at our institution to identify factors associated with improved survival. Methods:207 consecutive patients withaCML treated at The University of Texas MD Anderson Cancer Center after year 2000 were included. The median age was 44 years (range 2-70 years), 135 (65%) were male, 77% had less than 5% bone marrow (BM) blasts, 129 (65%) had persistentPh-chromosome positive, and 176 patients (85%) were less than a major molecular response at transplant. Forty of 114 tested patients (35%) had resistant BCR-ABL mutations and 10 patients (8.7%) had T315I mutation at transplant. Conditioning regimen wasmyeloablative (MAC) in 140 patients (68%). Donors were matched related (MRD), matched unrelated (MUD),haploidentical (HAPLO), mismatched unrelated (MMUD), umbilical cord blood (UCB) and 1Ag mismatched related (MMRD) in 79 (38%), 75 (36%), 18 (9%), 17 (8%), 11 (5%) and 7 (3%) patients, respectively. The median time from diagnosis to transplant was 27 months (range 1-318 months) while the median follow-up duration was 20 months (range 1-194 months). Results:At 30 days post-transplant, 180 of 200 tested patients (90%) and 134 of 201 tested patients (67%) achieved a complete cytogenetic and at least a major molecular response, respectively. The response to transplant by day 30assessment correlated significantly with the disease status before transplant. A higher percentage of patients who experienced cytogenetic response before transplant experienced molecular response post-transplant (77%) compared with those who did not (61%; p=0.027). For the entire group, the 1-year cumulative incidence (CI) of acute GVHD (aGVHD) grade II-IV and grade III-IV were 41% and 15%, respectively; 5-year CI of extensive chronic GVHD (cGVHD) was 31%.Haploidentical transplant patients had lesscGVHD compared with HLA matched donor transplants (14% vs. 32% for HLA matched transplants). The CI of non-relapse mortality at 100 days and 1 year was 14% and 30%, respectively. Sixty-five patients (31%) had molecular relapse after transplant, which correlated with the degree of disease control before transplant. The CI of cytogenetic and molecular relapse at 5 years was 22% and 31%, respectively. Overall the 5-year survival (OS), progression free survival (PFS) and GVHD-free, relapse-free survival (GRFS)was49%, 34%, and 22%, respectively. Adjusting for all significant measures, percentage of BM blasts before transplant and donor type were significantly associated with PFS and GRFS (Table1, Figure 1).Haplodenticaltransplant patients had longer PFS and GRFS compared with other donor types including matched related or unrelated donor (5-year GRFS for HAPLO, MRD, MUD, MMUD, UCB and MMRD were 53%, 19%, 23%, 29%, 9%, and 0%, respectively; p=0.033) (Table 1, Figure 1). Cytogenetic and molecular response before transplant as well as year of transplant did not predict survival after transplant. Conclusions: ASCT is curative for a proportion of patients withaCML. PFS and GRFS are favorably influenced by percentage of BM blasts and donor type, withhaploidentical donor having at least as good outcomes as HLA matched donors, while molecular and cytogenetic response before transplant do not appear to correlate with survival post-transplant. Table 1 Multivariable analysis for PFS and GRFS Table 1. Multivariable analysis for PFS and GRFS Figure 1 PFS and GRFS based on percentage of BM blasts before transplant and donor types Figure 1. PFS and GRFS based on percentage of BM blasts before transplant and donor types Disclosures Cortes: Arog: Research Funding; Teva: Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Research Funding; Ambit: Research Funding. Champlin:Intrexon: Equity Ownership, Patents & Royalties; Ziopharm Oncology: Equity Ownership, Patents & Royalties. Ciurea:Spectrum Pharmaceuticals: Other: Advisory Board; Cyto-Sen Therapeutics: Equity Ownership.

Description: Background: Prevention or treatment of relapsed lymphoid malignancies after SCT requires novel strategies. We previously reported on safety and early responses of ipilimumab combined with lenalidomide in 16 treated patients (pts.) (Khouri et al. Clin Cancer Res, 2018). Here, we update the published data on a larger cohort of pts. with a longer follow-up. In addition, we define immune phenotpyes that correlated with response. Patients andMethods: Pts. with lymphoma or CLL who relapsed after alloSCT, with no active GVHD were eligible. Pts. with autologous SCT were included within 6 mos post-SCT if they were still in CR, but had high risk features for relapse. Treatment consisted of 4 total cycles of lenalidomide 10 mg PO daily for 21 days (cycles 1 and 3) alternating with ipilimumab 3 mg/kg IV on day 1 (Cycles 2 and 4). Considering the favorable safety profile in the initial patients treated, number of cycles was amended to 8 cycles in 6/2017. PBMC's from 20 pts (12 responders and 8 non-responders) were analyzed by flow cytometry. Results: Twenty-two pts. were enrolled. Autologous group (n=11): Median age was 57 yrs (range, 33-68). Histologies included diffuse-large-B-cell lymphoma (DLBCL) [n=6; including 3 with double-hit lymphoma (DHL)], mantle cell lymphoma (MCL) (n=2; one with CNS involvement), Hodgkin's disease (n=2; with persistent PET+ post-SCT), and follicular lymphoma (n=1, PIF with response to 4th line of therapy). Median time to enrollment after SCT was 3.8 months (range, 1.4-5.5). With a median follow-up duration of 23.4 months (range, 10.1- 48), median OS was not reached. Three pts. relapsed at a median of 6.7 months; 1 pt. died after developing T-cell lymph proliferative disorder 2 years after finishing treatment and ten pts. remain alive. The most common other AEs were 19 events of neutropenia (n=5, gr 4; n=2 gr 3, n=12 gr 2), two patients had thrombocytopenia gr 2, and one developed pulmonary embolism. All AEs resolved. An immune-related AE occurred in one patient (dermatitis, gr 3) after the second ipilimumab dose and resolved with steroids. AEs were similar in pts. who received 4 or 8 cycles (n=5). Allogeneic group(n=11): Median age was 55 yrs (range, 44- 66). Histologies included [Follicular (n=2), CLL (n=3), MCL (n=2), DLBCL (n=3; 2 of whom were DHL), and T-cell anaplastic lymphoma (n=1)]. Median number of therapies excluding the alloSCT was 3 (range 2-7). Two failed a prior autoSCT, one had 2 prior alloSCT, and three failed prior donor lymphocyte infusions, and one CLL pt. failed prior FCR, lenalidomide/ofatumumab, ibrutinib, idelalisib, CAR-T cell and venetoclax. Two pts. relapsed within 3 mos of their alloSCT prior to enrollment on study. One pt. was taken off study after cycle 1 of lenalidomide due to flare of previously diagnosed liver and skin GVHD, which responded to steroids. Another pt. developed chronic GVHD after cycle 4 which precluded treatment with the pre-planned 8 cycles. No other cases of GVHD were noted. ORR rate was 73%. Five (45%) pts. had CRs (four of which were durable at 14+, 32+, 33+ and 34+ months; including the CLL pt. who failed small molecule inhibitors and CAR-T), and 3 (27%) had PR. With a median follow-up time of 30.8 mos (range, 3-45.1), 9 (82%) pts. remain alive. One PR pt. died secondary to cardiac complications after a hip replacement; and 1 died of progression. AEs included eight episodes of neutropenia (n=2, gr 4; n=2, gr 3; n =4, gr 2), anemia gr 2 (n=1), thrombocytopenia gr 2 (n=1), diarrhea (gr 2; n=1), nausea (gr 2, n=1), headache (gr 2; n=1), hypertension (gr 2; n=1), hypoalbuminemia (gr 2; n=1). All AEs resolved. Immune monitoring of 20 transplant pts showed a Th1 type anti-tumor immune response in responding pts. In the responders, there was a higher frequency of CD4+ICOS+PD-1+ and CD8+PD+1 T effector cells at baseline when compared to non-responding pts. In contrast, the non-responders had a Th2 type response with a higher frequency of CD4+GATA3+ T effector memory cells at baseline when compared to responders (Figure). Conclusions: Follow-up results demonstrate better than expected response rates that are durable in pts. with lymphoid malignancies who relapsed after alloSCT. Continuous remission duration was also observed after autologous SCT. Immune monitoring analysis suggests that CD4+GATA3+ T cells could be a potentially valuable biomarker for stratification of pts. for lenalodimide+ipilimumab combination therapy. Figure. Figure. Disclosures Jabbour: novartis: Research Funding.

Description: Purpose: Rituximab (R) use can attenuate the risks of graft-versus-host disease (GVHD) after non-myeloablative allogeneic (NMA) alloSCT. There is a paucity of information on the impact of this strategy in patients receiving myeloablative (MA) conditioning. Experimental design: We compared the risk of GVHD after an NMA regimen of BFR (bendamustine, fludarabine, rituximab) (Khouri et al. Blood 20014;124:2306-12.) to the MA regimen of bortezomib-R-BEAM (carmustine, etoposide, cytarabine, melphalan) regimen in patients with relapsed lymphoma undergoing alloSCT. Patients were treated on 2 prospective trials at our center between 2009-2013 and 2007-2011, respectively. Patients were considered for NMA if they were not eligible for myeloablative chemotherapy. Primary GVHD prophylaxis consisted of tacrolimus and methotrexate. All patients received rituximab (375 mg/m2 intravenously on day -13 and 1000 mg/m2 on days -6, +1, and +8) as described previously. Patients in both groups also received thymoglobulin 1 mg/kg on days -2 and -1 if the transplant was from matched unrelated donor (MUD). In addition, the MA group received bortezomib (1 mg/m2 per dose) on days -13, -6, -1, and +2. Because the treatment groups were not randomized, we performed inverse probability weighting (Robins JM. Epidemiol. 2000; 11:550-60) to correct for potential bias in patients' selection for the comparison of GVHD. Results: The analysis included 95 patients (MA=39 and NMA=56). The majority of the patients were male (68%) with a median age of 58 years (range: 22-71). The most common histology was diffuse large B-cell lymphoma (26%), followed by chronic lymphocytic leukemia (23%), mantle cell lymphoma (19%), and follicular lymphoma (18%). Transplant characteristics included MUDs in 43 (45%) patients, 23 (24%) female-to-male donors, and 49 (52%) ABO-mismatched. In addition, CMV was reactive in 80% of patients/ and or donors. Most patients (95%) had alloSCT from peripheral blood. Significant differences between treatment groups were observed for patient age, histology, PET scan status, LDH, disease status, and prior number of chemotherapies. On average, patients receiving MA conditioning were younger (p=0.008) and had higher LDH (p=0.026) pre-transplant, compared with NMA group. In addition, a higher percentage of MA patients were diagnosed with diffuse large B-cell lymphoma (41% vs. 16%, p=0.003), had a positive PET scan (p 3 prior number of chemotherapies (p=0.007) compared with the NMA patients. The median follow-up duration for surviving patients was 64.8 and 62.1 months for the MA and NMA groups, respectively. The groups' weighted (adjusting for patient age, donor age, donor type, disease status, sex mismatch status, histology, PET scan status, LDH, and prior number of chemotherapies) cumulative incidences of grade II-IV acute GVHD was 63% and 10%, respectively (p

Description: Introduction Outcomes after allogeneic stem cell transplant (AHSCT) are influenced by both disease and patient related factors. We hypothesized that combining hematopoietic stem cell transplant comorbidity-age index (HCT-CI/Age) and the refined disease risk index (DRI-R) would better predict survival post-transplant and developed a hematopoietic cell Transplant-composite risk (HCT-CR) model, which we tested in a group of patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) treated at MD Anderson Cancer Center (MDACC). Methods The study included consecutively treated patients, 18 years of age or older, with AML and MDS who received first AHSCT at MDACC between 2005-2016. Donors were HLA-matched related (MRD), HLA-matched unrelated (MUD), 9/10 MUD (MMUD), haploidentical (HAPLO) and 9/10 MRD (MMRD). To develop this model, patients were assigned into 4 groups: 1. Patients with low/intermediate DRI-R and HCT-CI/Age 3 (intermediate-risk); 3. Patients with high/very high DRI-R and HCT-CI/Age 3 (very high-risk). Primary endpoint was 5-year overall survival (OS); other outcomes assess were progression-free survival (PFS), non-relapse mortality (NRM) and relapse rate. The stability of the HCT-CR model was tested by bootstrap resampling. The discrimination power of the HCT-CR model on OS was compared with that of the DRI-R, HCT-CI/Age and cytogenetic risk model by the Harrell C-concordance index. Results The analysis included 942 patients (492 male and 450 female) with a median age of 53 years (range 18-65 years). Cytogenetic data at diagnosis was available in 928 (98.5%) patients and was favorable, intermediate and adverse cytogenetic risk in 63 (7%), 523 (56%) and 342 (37%), respectively. Fifty-five (6%), 399 (43%), 392 (42%) and 82 (9%) patients had low, intermediate, high and very high DRI-R, respectively. The HCT-CI/Age was available in 922 (98%) patients with the median score of 3 (range 0-18). Donor types included MRD (n=377), MUD (n=416), MMUD (n=68), HAPLO (n=73) and MMRD (N=8). Using the HCT-CR model, patients were stratified into 4 risk groups: low (N=272), intermediate (N=168), high (N=284) and very high-risk (N=184), with significantly different survival. The 5-year OS rates for patients in low, intermediate, high and very high-risk group were 57%, 48%, 34%, and 26%, respectively (P

Description: Introduction Multiple myeloma (MM) is a disease of elderly with median age of diagnosis 66-years. Autologous hematopoietic stem cell transplantation (auto-HCT) is recommended for eligible patients with newly diagnosed MM, however, it is not offered to many elderly patients due to concerns of excessive toxicity. We have previously reported that auto-HCT can be safely performed in myeloma patients aged ≥ 70 years (Bashir et al. L&L 2012). Here we report the results of a retrospective analysis of MM patients aged ≥ 75 years who underwent auto-HCT at our center. Methods All myeloma patients aged ≥ 75 years who underwent auto-HCT at our institution between 1/1/2000 and 12/31/2015 were retrospectively analyzed. Frequencies of toxicities were compared using Fisher's exact test. The cumulative incidence (CI) of non-relapse mortality (NRM) was assessed using the competing risks method. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Differences in survival between groups were assessed using the log-rank test. The association between survival and patient subgroups of interest was determined using univariate and multivariable Cox proportional hazards regression models. Results 72 patients (median age 76 years; 58% male) were included in the study. Thirty percent (n=19/63) were ISS stage I, 43% (n=27/63) were stage II and 27% (n=17/63) stage III. Seventy-eight percent (n=56) were considered standard-risk (IMWG criteria) and 22% (n=16) had high-risk cytogenetics. Sixty-three percent (n=45) received conditioning with melphalan (MEL) 140 mg/m2, while 38% (n=27) received MEL 〉140. Seventy-five percent (n=54) of the patients received auto-HCT as part of first line therapy and 85% (n=61) had at least partial response (PR) at auto-HCT. Median time from diagnosis to auto-HCT was 7.6 months. Half of the patients (n=36) received post transplant maintenance. Median follow-up time for all survivors (n=48) was 25.5 months. Grade II-IV toxicity was seen in 74% (n=53) of patients, gastrointestinal being most common (49% of all patients). There was no difference in toxicity between MEL 140 vs. MEL 〉140. The median time to neutrophil and platelet engraftment was 11 and 12 days, respectively. The CI of NRM was 1% at Day 100 and 6 months and 4% at the end of the assessment period. Day 100 response rate (at least PR) was 92% (n=66), with 36% (n=26) achieving near complete remission (nCR) or better. Median PFS was 31.4 months (95% CI: 22.6, 36.6, Figure 1). Seventy-five percent of the patients were event free at one year after transplant and 23% were event free at 5 years. Median OS was 72.8 months (95% CI: 45.7, 86.2, Figure 2). The OS rates at 1 year and 5 years post transplant were 93% and 58%, respectively. On multivariable analysis, high-risk cytogenetics and ISS stage III disease were associated with significantly worse PFS and OS. Conclusion Auto-HCT in myeloma patients aged ≥ 75 years is feasible with response rate and survival comparable to that seen in younger patients. Age alone should not be used to determine eligibility for auto-HCT. Figure 1 Progression-free survival (all patients). Figure 1. Progression-free survival (all patients). Figure 2 Overall survival (all patients). Figure 2. Overall survival (all patients). Disclosures Ciurea: Cyto-Sen Therapeutics: Equity Ownership; Spectrum Pharmaceuticals: Other: Advisory Board.