ALBERT

Description: An inherent difficulty in performing allogeneic transplantation in patients (pts) of African American (AA) descent is finding suitably matched 8/8 unrelated donors. In addition for complicated reasons studies have shown that AA have an inferior survival compared to suitable matched patients from different ethnic groups undergoing allogeneic transplantation. Post transplant cyclophosphamide (PTCy) administered on day + 3 and +4 given in combination with tacrolimus and mycophenolate mofetil (MMF) allows for the safe use of more mismatched transplants, including haploidentical transplants. This has created a new approach for patients who lack suitable donors and may allow more AA pts to proceed to transplant. At our institution, we have used PTCy as graft-versus-host-disease (GVHD) prophylaxis in patients undergoing reduced intensity conditioning (RIC) hematopoietic stem cell transplant (HSCT) from mismatched related and unrelated donors, and this group consisted largely of high-risk AA pts. We retrospectively reviewed 16 pts who underwent HLA mismatched HSCT (5/10 to 8/10 HLA matches) at our institution between July 2012 and 2015. All patients received RIC HSCT with PTCy (days +3 and +4) along with tacrolimus and MMF for GVHD prophylaxis. Patients did not routinely receive growth factor support. Primary endpoints included time to neutrophil and platelet engraftment, length of hospital stay, and rates of acute and chronic GVHD. Secondary outcomes included time to relapse, transplant related mortality, and overall survival. Table 1 shows the demographics of the 16 patients who were transplanted. The median age of the patients was 57 years (range: 25-72). Ten pts were of AA descent. Fifteen donors were haploidentical family donors; 6 were 5/10 matches, 4 were 6/10 matches, and 5 were 7/10 matches. One patient received a 8/10 unrelated donor transplant. Five patients had failed previous transplants which included 3 allogeneic and 2 autologous HSCT. Based on published risk stratification (Armand et al. Blood, 2012) of the remaining 11 pts, 7 pts were high risk and 4 were intermediate risk. Neutrophil engraftment (first of 3 days when ANC was ³500 cells/mm3) occurred a median of 19 days post transplant (range:12-22 days); Platelet engraftment (³20,000/µL without platelet transfusion) occurred a median of 21.5 days post-transplant (range: 14-37 days). Median length of hospitalization was 26 days (range: 22-81 days). Two pts failed to engraft after first HSCT. One of these pts had high levels of anti-HLA antibodies directed against her donor. Both pts went on to a second haploidentical transplant and engrafted their neutrophil counts at 13 days and 21 days; respectively. Grade II acute GVHD occurred in 6/16 patients. No patient developed grade III-IV aGVHD. Chronic GVHD was observed in 8/16 patients with severe chronic GVHD seen in one patient. With a median follow up of 160 days (range: 89-778 days) the Kaplan-Meier estimates of overall survival at one year were 81.3% for all transplanted pts (Figure 1) and 80% for the AA pts (Figure 2). Three pts died; 1 patient from an invasive fungal infection and 2 pts from relapse. One additional patient relapsed but continues on treatment. Our experience suggests that the use of PTCy permits HLA mismatched transplantation, with overall survival of 〉 80% and acceptable rates of acute and chronic GVHD. Moreover, the severity of acute GVHD in patients who received PTCy post-transplant was limited, with no reported acute grade III-IV GVHD. In addition, the early outcomes of HLA mismatched transplantation in 10 African-American patients, a population that is often underrepresented in the donor registry, suggests that this approach may preferentially benefit AA pts from an expanded donor pool derived from utilization of partially HLA-matched donors. Figure 1. Figure 1. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures Lum: Karyopharm Therapeutics Inc: Equity Ownership; Transtarget.Inc: Equity Ownership. Deol:Bristol meyer squibb: Research Funding.

Description: Introduction: Pleural effusions are common clinical finding in patients undergoing hematopoietic stem cell transplantation (HSCT). It can be a manifestation of underlying lung injury or a part of a systemic process. This study will investigate the incidence, risk factors, and clinical outcomes associated with pleural effusion in allogeneic HSCT. Methods: We conducted a retrospective study of 618 consecutive adult patients who underwent allogeneic HSCT for hematological disorders, between January 2008 and December 2013. Results: The baseline characteristics of the groups with and without pleural effusions are shown in table 1. The only significant difference was GVHD prophylaxis (p =0.002). A total 71 patients developed pleural effusions with the cumulative incidence of 12.6 % (95% CI, 10.0% to 15.6%) in five years. The median time of onset of pleural effusion from HSCT was 40 days (range, 1, 869). The onset of pleural effusion had a bimodal distribution with the first peak at 23 days (range 17, 29) and second peak at 362 days (range 277, 450). Based on chest CT criteria, the effusions were judged as large, moderate and small in size in 15%, 51% and 34% of patients respectively. Twenty five (35%) patients with pleural effusions underwent thoracentesis for respiratory difficulty and had a median of 800cc (range, 250 to 13500cc) of pleural fluid removed. Fourteen patients (56%) had exudative and 9 (36%) had transudative pleural effusions. Pleurx catheter was placed in 2 (3%), and chest tube in 3 (4%) patients. Causes of effusion listed in order of frequency are infection (38%), volume overload (23%), chronic GVHD (20%), heart failure (6%), engraftment syndrome (4%), veno-occlusive disease (4%), malignant pleural effusion (3%), hypersensitivity pneumonitis (1%) and iatrogenic (1%). Time of onset is different among various etiologies (p=0.006). Although thoracentesis was performed in 25 patients, the specific etiology by pleural fluid analysis was identified in only 2 patients. Pleural effusion secondary to infections, hypersensitivity pneumonitis, and engraftment syndrome occurred in the first 100 days after transplant, whereas pleural effusion due to chronic GVHD/polyserositis, bronchiolitis obliterans occurred 200 days after transplant.Fifty seven patients (80%) with pleural effusions had evidence of GVHD however; fourteen (20%) patients with pleural effusion had no evidence of acute or chronic GVHD. Twenty three (32%) patients had both pleural effusion and ascites, 27 (38%) had both pleural and pericardial effusion and 29 patients had pleural effusion alone. Multivariate cox regression analysis showed age, African American race, higher comorbidity index, unrelated donor, HLA-match 7/8, intermediate to high risk disease to be associated with worse survival among patients who developed pleural effusion after HSCT. There was no significant difference in overall survival between patients with or without pleural effusion (p=0.257). Conclusion: Majority of the patients who developed pleural effusions responded well with the treatment of the underlying disease. Although thoracentesis was often done for therapeutic reasons, it was a weak diagnostic tool. We did not identify any adverse impact of development of post HSCT pleural effusions on overall survival. Table 1. Characteristics Pleural Effusion (N=71) No Pleural Effusion (N=547) Signif Age - Median (range) year 55(25,73) 58(22,78) 0.514 Sex - no. (%) 0.522 Male/Female 43(61)/28(39) 305(56)/242(44) Diagnosis - no. (%) 0.490 AML 25(35) 213 (39) ALL 9(13) 53 (10) CLL 4(6) 27 (5) CML 2 (3) 16 (3) NHL 13 (18) 94 (17) Multiple Myeloma 3 (4) 16 (3) MDS 9 (13) 74 (14) Myelofibrosis 1 (1) 18 (3) Hodgkin's Lymphoma 1 (1) 8 (1) PLL 4 (6) 7 (1) Aplastic Anemia 0 (0) 17 (3) CMML 0 (0) 4 (1) Comorbidity-Median (range) 3 (0,8) 3 (0,9) 0.055 Disease risk status - no. (%) 0.389 Low 4 (6) 48 (9) Intermediate 32 (45) 284 (52) High 31 (44) 193 (35) Very High 4 (6) 22 (4) HLA - no. (%) 0.566 8/8 56 (79) 413 (76) 7/8 12 (17) 117 (21) 0.99 Matched related 25 (35) 197 (36) Matched unrelated 46 (65) 350 (64) Conditioning regimen - no. (%) 0.761 Full intensity 45 (63) 361 (66) Reduced intensity 26 (37) 186 (34) GVHD prophylaxis - no. (%) 0.002 Mycophenolate-Tacrolimus 41 (58) 328 (60) Mycophenolate-Tacrolimus-Thymoglobulin 26 (37) 131 (24) Tacrolimus- Thymoglobulin 3 (4) 17 (3) Thymoglobulin-Tacrolimus-Sirolimus 0 (0) 64 (12) Others 0 (0) 5 (1) Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Deol: Bristol meyer squibb: Research Funding.

Description: Introduction: Clostridium difficile (C.diff) colitis (CDI) continues to be a common complication in recipients of allogeneic stem cell transplantation (AlloSCT). Multiple risk factors were associated with CDI in this patient population including prior CDI, antibiotic prophylaxis and therapy, acute graft versus host disease (aGVHD), etc. Our aim in this study was to evaluate the effect of thymoglobulin used in GVHD prophylaxis on the incidence of CDI in patients undergoing AlloSCT. Methods: We studied 3 consecutive cohorts of AlloSCT recipients. Group1- related donor AlloSCT without thymoglobulin (N=100, transplanted 3/2010-12/2013); group 2 - unrelated donor AlloSCT with thymoglobulin (N=110, transplanted 4/2012-12/2013); and group 3 - unrelated AlloSCT without thymoglobulin (N=100, transplanted 12/2009-12/2011). Majority of patients except three in group 3 were diagnosed with CDI with a PCR based test. Results: All 3 groups were similar with respect to the baseline characteristics (Table 1). The median follow up for the 3 groups was 2 years. At a median follow up of 2 years the incidence of CDI in the three groups were 19%, 26%, 28% respectively, p=0.2 (table 2). The incidence of CDI prior to aGVHD was similar in three groups (18/100, 25/110 and 19/100 in groups 1, 2 and 3 respectively). The incidence of CDI after development of aGVHD was higher in group 3 (1/100, 4/110 and 9/100 p=0.06 in groups 1, 2 and 3 respectively). The incidence of Grade II-IV aGVHD was significantly higher in group 3 (63%) as compared to groups 1 and 2 (49 and 41%) p=0.006 (Table 2). Similarly the incidence of any grade GI GVHD was higher in group 3 (44% Vs 23% and 24%) p=0.0009. The median time to development of aGVHD was similar in all three groups (28 days in groups 1, 31 days in group 2 and 26 days in group 2). Multivariable analysis revealed that none of the factors examined (age, sex, diagnosis, intensity of conditioning, type of transplant, use of thymoglobulin, acute GVHD) was related to development of CDI. Development of GI GVHD tended to increase the risk of subsequent CDI (40% vs 27%, p=0.06). Development of CDI did not increase the risk of development of subsequent GI GVHD (30% vs. 26%). Use of thymoglobulin improved two year overall survival in patients undergoing unrelated transplant (p=0.006). Conclusion: Thymoglobulin use did not affect the overall incidence of CDI in recipients of Allo-SCT. There is a trend towards increased incidence of late onset CDI in patients undergoing unrelated Allo-SCT and not recieving thymoglobulin probably because of higher incidence of GVHD and steroid use. There was no difference in the incidence of CDI in related vs. unrelated transplant recipients. Use of thymoglobulin improved survival in recipients of unrelated Allo-SCT. Table 1. Baseline Characteristics: Related (N=100) unrelated with Thymo (N=110) Allo unrelated without Thymo (N=100) P-value Age Median 54 58 52 NS Gender F 42 47 51 NS M 58 63 49 Race Caucasian 83 99 91 NS Other 17 11 9 Conditioning regimen Myeloablative 76 59 63 NS RIC 24 51 37 Diagnosis Leukemia 47 61 56 NS Lymphoma 30 21 20 MDS 12 20 11 Other 11 8 13 Source of stem cells BM 9 6 10 NS PBSC 91 104 90 HLA match 10/10 94 71 71 NS* 9/10 2 26 21 8/10 13 8 Haploidentical 4 GVHD** Prophylaxis Tac/MMF 97 100 Tac/MMF/Thymo 101 Tac/Sirolimus/Thymo 9 *No difference in HLA match between the groups 2 and 3. **Tac (Tacrolimus); MMF (Mycophenolate Mofetil); THYMO (Thymoglobulin). Table 2. Results: Groups 1. Related 2. Unrelated with Thymo 3. unrelated without Thymo P value Incidence of aGVHD II-IV 48% 41% 63% p=0.006 Incidence of GI GVHD 23% 23.6% 44% p=0.0009 Use of systemic steroids 38% 32% 61% p=0.0001 Overall Incidence of CDI 19/100 (19%) 29/110 (26%) 28/100 (28%) p=0.20 Incidence of CDI prior to GVHD 18/100 (18%) 25/110 (22%) 19/100 (19%) NS Incidence of CDI after onset of GVHD 1/100 (1%) 4/110 (3.6)% 9/100 (9%) p=0.06 Median Overall survival at 2 year f/u 68% 52% 46% p=0.0057 Disclosures Deol: Bristol meyer squibb: Research Funding. Lum:Karyopharm Therapeutics Inc: Equity Ownership; Transtarget.Inc: Equity Ownership. Revankar:Actelion, Merck, Gilead, Astellas: Research Funding; Dara biosciences: Consultancy. Chandrasekar:Merck, Glaxo, Chimerix,: Research Funding.

Description: Background: Bortezomib has become an integral part of front-line therapy of multiple myeloma in a large majority of patients. There are preliminary reports which show that addition of bortezomib can augment the peripheral blood CD34 count during stem cell mobilization. In this single center prospective trial we added bortezomib to G-CSF to evaluate the effects of bortezomib on peripheral CD34 counts and collection. Methods: Patients aged 18-70 years with diagnosis of multiple myeloma (MM) or non-hodgkin's lymphoma (NHL) who were eligible for autologous stem cell transplantation (ASCT) and had received no more than three prior chemotherapeutic regimens were eligible for the study. Patients were enrolled in two groups. Group A (N=3) received G-CSF 16mcg/kg for 5 days and proceeded to stem cell collection on D5 and then received bortezomib 1.3mg/m2 on D5 after stem cell collection and G-CSF 16mcg/kg on D6, 7, 8 and repeat stem cell collection on D6, 7, 8 till the goal was achieved. Group B (N=17) received G-CSF 16mg/kg on D1-5 and received bortezomib 1.3mg/m2 on D4 and proceeded to stem cell collection on D5. If the patient was not able to collect the predefined goal CD34, G-CSF was continued on D 6, 7, 8 and a second dose of bortezomib 1.3mg/m2 was given on D7. Mobilization procedure was stopped once the predefined goal CD34 collection (4 x 106/kg for MM and 2 x 106/kg for NHL) had been collected. Primary objectives of the study was to determine if addition of bortezomib to G-CSF will result in an increase in PBSCs by 〉 2-fold and to achieve median neutrophil engraftment 12 days post ASCT. Secondary objectiveswere to evaluate the collected product for co-mobilization of lymphoma or myeloma cells and to determine if the use of bortezomib increases the mobilization of immune-stimulatory Dendritic cell (DC) -1 subsets. Results: A total of 23 patients were enrolled and 20 were evaluable for the results. Only one patient with NHL was enrolled and rest had MM. Median age of pts was 57 years, M/F 8/12, median number of previous chemotherapy regimens was 1 (range 1-3). The median peripheral blood CD34 count pre and post bortezomib in all patients were 28.8 x 106/kg and 37 x 106/kg respectively. All three patients in group A had drop in peripheral blood CD34 counts on D6 post bortezomib as they had undergone stem cell collection on day 5. In part B (N=17), 15 patients had increase in peripheral blood CD 34+ve cell counts with 4 patients achieved doubling while 11 pts had less than doubling of peripheral blood CD34 count after receiving bortezomib. Two patients had minimal drop in the peripheral blood CD34 counts post bortezomib. Median number of CD34 cells collected in15 patients (part B) were 5.06 x 106 CD34 cells/kg (range 4-15.1). 18 patients proceeded to ASCT and median time to neutrophil engraftment (ANC ≥500/cumm) post transplant was 12 days (range 11-16) and platelet engraftment (Plt count ≥ 20,000/cumm) was 18 days (range 15-27). There was no significant change in DC1/DC2 ratio in both groups following treatment with bortezomib and G-CSF (Figure 1). In group A all three patients collected goal CD34 count on day 5 and 2/3 patients collected 〉4 x106 CD34 cells/kg on D6 post bortezomib and1/3 patients collected 2.6 x 106 on D6 post bortezomib. In group B (n=17), 2 patients were unable to collect because of low CD34 counts on D4 and D5, 11 pts collected the goal in one day (D 5) and 4 pts required two days of apheresis (D 5 and 6). None of the patients received D7 bortezomib. Conclusion: Use of bortezomib during autologous stem cell collection was safe and well tolerated. Majority of patients had increase in peripheral blood CD34 counts post bortezomib administration on D4. Future trials should explore bortezomib as an alternate strategy to chemo-mobilization in combination with growth factors. Figure 1. DC1/DC2 ratio in group A and group B at various time points. Figure 1. DC1/DC2 ratio in group A and group B at various time points. Figure 2. Figure 2. Disclosures Off Label Use: Bortezomib for stem cell mobilization. Lum:Karyopharm Therapeutics Inc: Equity Ownership; Transtarget.Inc: Equity Ownership. Deol:Bristol meyer squibb: Research Funding. Abidi:celgene: Speakers Bureau; Millenium: Research Funding.

Description: Second autologous stem cell transplant (ASCT) is a treatment option for multiple myeloma (MM) patients (pts) who have disease progression after first ASCT. About 20% of MM pts have evidence of renal dysfunction and many more develop it subsequently. Outcomes of second ASCT in pts with renal dysfunction have not been described. We identified 18 pts at our institution who underwent a second ASCT for relapsed MM and had evidence of renal dysfunction (creatinine clearance ≤ 60ml/min/1.73m2). Pts who underwent a planned tandem transplant were excluded from this analysis. Patient characteristics are shown in Table 1. The median age of pts was 61 years (range, 49-72). The median time between first and second ASCT was 49.8 months (range, 19.2-81.9). Ten pts received one chemotherapy regimen while nine pts received two or more chemotherapy regimens between first and second ASCT. The chemotherapy regimens used between first and second transplant included IMid based (n=6), proteosome inhibitor based (n=3) and combination of both (n=9). Approximately half of the pts had progressive disease at the time of second ASCT. Median creatinine clearance at the time of second ASCT was 43.5 ml/min//1.73m2. All pts received G-CSF 5µg/Kg from day + 6 till absolute neutrophil count was ≥1500/µL, norfloxacin, acyclovir and fluconazole were used for antimicrobial prophylaxis during the hospitalization. One pt was dialysis dependent. Patients received a median dose of melphalan of 140mg/m2 (range 100-200 mg/m2). Median follow up post second ASCT was 17.1 months (range, 2.4- 100). One pt died 74 days after the transplant due to multi- organ failure. Disease status at day 100 post ASCT is shown in Table 2. Thirteen of 17 pts had a partial response or better after second ASCT. Of 17 evaluable pts at day 100, twelve had an upgrade from the disease response category achieved with the last regimen used prior to second ASCT while five pts had stable disease response. Three pts received maintenance therapy after the second ASCT with bortezomib(n=2) and lenalidomide (n=1). Figures 1 and 2 show the overall survival (OS) and relapse free survival (RFS). Median RFS was 22.2 months and median OS was 27 months. The outcomes of patients with renal dysfunction who underwent ASCT in the era of novel agents at our institution are comparable to those reported for second ASCT. The transplant related mortality was not higher than expected and the median PFS of about 2 years makes the option of second ASCT in this group of patients a valuable treatment modality. The utility of maintenance therapy after the second ASCT is not established, but may have contributed to the durable responses seen in some pts assessed herein and deserves to be investigated further. Table 1: Pt Characteristics (N=18) Patient Characteristics N (%) Median Age (range) 61 years(49-72) Median Time from First ASCT (range) 49.8 months(19.2-81.9) Gender Male 9(50%) Females 9 (50%) Race Caucasians 13 (72%) Others 5 (28%) Disease status at time of ASCT PD 9 (50%) SD 5 (28%) PR 1 (5.5 %) VGPR 2 (11%) CR 1 (5.5%) Median creatinine clearance (range) 43.5 (5-59) Subtype IgG Kappa 10 (56%) IgG Lambda 6 (33%) Kappa Light Chain 2 (11%) Cytogenetic Risk Standard 10 (56%) High Risk 4(22%) Unknown 4 (22%) Melphalan Dose median mg/m2( range) 140 (100-200) {100(2pts), 140(10pts), 180(1pt), 200(4pts)} Median CD 34 Cell dose x106/kg (range) 4.66(2.6-27.5) Median Engraftment Day (range) WBC 11 (9-16) Platelets 21 (12-61) Median Days of Hospitalization (range) 19(11-74) PD: Progressive disease, SD: Stable disease; PR: Partial response; VGPR: Very good partial response; CR: complete response; WBC White blood cells Table 2 Disease status at Day 100 post ASCT Disease status at Day 100 post ASCT N(%) CR 4 (22%) VGPR 4 (22%) PR 5 (28%) SD 3 (17%) PD 1 (5.5%) NOT AVAILABLE * 1 (5.5%) PD: Progressive disease, SD: Stable disease; PR: Partial response; VGPR: Very good partial response; CR: complete response; *Pt died at day 74 post second ASCT PD: Progressive disease, SD: Stable disease; PR: Partial response; VGPR: Very good partial response; CR: complete response; * Pt died at day 74 post second ASCT Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Description: Introduction Chronic graft-versus-host disease (cGVHD) is a major factor determining long term outcome and quality of life following allogeneic hematopoietic cell transplantation (AHSCT). In fact, cGVHD is the leading cause of late non-relapse mortality (NRM) and morbidity after AHSCT. The rates of severe cGVHD using NIH consensus criteria reported in the literature are 15-38%. Effective regimens are needed to reduce the severity of cGVHD and improve NRM. We analyzed and updated the long term outcomes of our phase 2 trial evaluating the efficacy of intermediate dose rabbit anti-thymocyte globulin (Thymo) in combination with tacrolimus and sirolimus for the prevention of acute and chronic GVHD after unrelated donor transplantation. Methods In a Phase II trial, 47 adult patients (pts) underwent AHSCT from unrelated donors using Thymo, tacrolimus, and sirolimus for GVHD prophylaxis. Thymo was given as follows: 0.5 mg/kg day -3, 1.5mg/kg day -2, and 2.5mg/kg day -1. Chronic GVHD was measured using NIH consensus criteria. Results Twenty-two pts received 8/8 and 25 received 7/8 HLA matched unrelated grafts. Thirteen pts received a reduced intensity preparative regimen, while 34 pts received a full intensity regimen. The median follow-up duration was 45.2 months (95% CI 37.7-48.8), with minimum follow up of 30 months. At 4 years of follow up, the cumulative incidence of NIH severe cGVHD a, was 6.4 % (95% CI 1.6-15.9), and overall cumulative incidence of cGVHD was 48.9% (95% CI 33.6-62.6). Of 20 pts who are alive and disease free, only 4 pts continue to need systemic immune suppression at the last follow up. At 4 years of follow-up, the cumulative incidence of NRM and disease relapse were 27.7% (95% CI 15.7- 41.0) and 30.0% (95% CI 17.5- 43.6), respectively. There has been one non relapse death beyond 12 months and none after 18 months of follow up. Only one pt died from cGVHD and bronchiolitis obliterans, while two other pts had minimal symptoms from bronchiolitis obliterans. Progression free survival (PFS) and overall survival (OS) at 2 years were 50% (95% CI 35-64) and 56% (95% CI 42-70). Median OS is 33.9 months [95% CI (9.8 -*) *the upper limit of the CI was not calculated due to the pattern of censoring] All patients were censored after 40 months, so PFS and OS could not be calculated at 48 months. The median karnofsky performance status at 2 years was 90%. Conclusion At long term follow up, the combination of Thymoglobulin, Tacrolimus, and Sirolimus was associated with low incidence of severe cGVHD, low incidence of late NRM, and good performance status. Further validation of these results in randomized phase III trials is needed. Disclosures: Al-Kadhimi: Genzyme: Research Funding. Off Label Use: The use of Thymoglobulin® for GVHD prevention.

Description: Introduction: Patients with AML and MDS who are age 60 or above represent a discrete group of patients with a different disease biology compared to younger patients. These patients are often not offered allogeneic hematopoietic stem cell transplant (HSCT) as a curative intent because of concern of increased nonrelapse mortality (NRM) and poor overall survival (OS). Hence, the information on transplant outcomes among this population is very limited. Recently with the use of better supportive care measures and reduced intensity preparative regimens, patients greater than 60 are often recommended to proceed to transplant. This study evaluates our single center experience of allogeneic transplantation in patients with MDS and AML aged 60 and older. Patients and Methods: We retrospectively evaluated 60 years or older consecutive patients with AML and MDS who underwent allogeneic HSCT between January 2005 and December 2014. The primary objectives of our study were to determine NRM, relapse, relapse free survival (RFS) and OS at 1 year following transplant. The secondary objectives were to estimate cumulative incidence of acute (aGVHD) and chronic GVHD (cGVHD) at 1 year, length of stay and readmission rate in the first 100 days following transplant. Results: Between January 2005 and December 2014, 159 patients underwent allogeneic HSCT with the median age of 64 (range, 60-75) years and median follow-up duration for OS of 3.34 (95% CI, 2.51-3.87) years. Increasing number of patients were transplanted in recent years, i.e., 67% patients between 2010-2014 compared to 33% between 2005-2009. One hundred three patients (65%) had AML and 56 patients (35%) had MDS. Forty-nine patients (31%) received full intensity regimen and 110 patients (69%) received reduced intensity regimen. Fifty-two patients (33%) underwent allogeneic related transplant and 107 patients (67%) had allogeneic unrelated transplant. Thymoglobulin based GVHD prophylaxis was given in 77 patients (48%) whereas non-thymoglobulin based GVHD prophylaxis was given in 82 patients (52%). The median day to neutrophil and platelet engraftment was 11 (range, 7-22) days and 16 (range, 0-675) days, respectively. Graft failure occurred in 3 patients. At 1-year follow-up, the cumulative incidence of grade II-IV aGVHD was 39.7% (95% CI, 32.0-47.2%), grade III-IV aGVHD was 20.8% (95% CI, 14.9-27.5%) and cGVHD was 54.1% (95% CI, 46.0-61.5%). The cumulative incidence of chronic extensive GVHD was 39.8% (95% CI, 32.1-47.4%). Blood stream infection, cytomegalovirus reactivation, Epstein-Barr virus reactivation, C. difficile diarrhea occurred in 44%, 35%, 22% and 26% of patients, respectively. At 1-year follow-up, NRM was 25.3% (95% CI, 18.8-32.3%), RFS was 53.3% (95% CI, 46.1-61.7%), relapse rate was 21.4% (95% CI, 15.4-28.1%) and OS was 56.4% (95% CI, 49.2-54.7%). The median day of hospitalization following transplant was 26 (range, 19-112) days and almost half (52%) of patients were readmitted in the first 100 days following transplant. Leukemia recurrence was the most common cause of death. Multivariable analysis demonstrated high disease risk index to be the independent predictor of poor RFS, OS and higher relapse rate (p

Description: Background This study aimed to determine the benefit of early therapeutic intervention with the combination of elotuzumab, Lenalidomide, and Dexamethasone in patients with high-risk smoldering multiple myeloma (SMM). ClinicalTrials.gov Identifier: NCT02279394. Aims The overarching objective of this trial is to determine progression free survival to symptomatic multiple myeloma (MM). Furthermore, the study examined whether genomic studies can help in determining patients who would benefit the most from this early therapeutic intervention. Methods Patients enrolled in this study met eligibility for high-risk SMM based on the newly defined criteria proposed by Rajkumar et al, Blood 2014. Patients were administered weekly elotuzumab (10 mg/kg) on days 1, 8, 15, and 22 for the first two 28-day cycles while receiving lenalidomide on days 1-21. For cycles 3-8, patients were administered elotuzumab infusions on days 1, 8, and 15. dexamethasone (40mg) was given on days 1, 8 and 15 to 40 of the 50 enrolled patients. After 8 cycles or best response, patients were given the option to mobilize with either cyclophosphamide or plerixafor and collect stem cells for future transplant. Patients were then allowed to continue on maintenance therapy where they were administered elotuzumab (20 mg/kg) on day 1, in combination with lenalidomide days 1-21 of a 28-day cycle. Bone marrow (BM) samples of 32 patients were obtained before starting therapy for baseline assessment and whole exome sequencing (WES) of plasma cells. Results In total, 50 patients were enrolled on this study from January 2015 and completed accrual in December 2016, with the participation of eight sites. The median age of enrolled patients was 62 years (range, 29-79) with 18 males (36%) and 32 females (64%). Interphase fluorescence in situ hybridization (iFISH) detected high-risk cytogenetics (defined by the presence of 17p deletion, t(4;14), and 1q gain) in 20 patients. The median time to response was 2.8 months (range, 1.8-4.6). The most common toxicities were fatigue (92%), followed by diarrhea (72%), and hyperglycemia (62%). The most common grade 3 or more adverse events were hypophosphatemia (34%), neutropenia (26%), and lymphocyte count decreased (22%). Three patients (6%) had grade 4 hypophosphatemia during treatment. Additionally, grade 4 cholecystitis, cataract, lymphocyte count increase, hyperglycemia, neutropenia, and thrombocytopenia occurred in one patient (2%). Diabetic Ketoacidosis and sepsis led to death in a patient (2%). Stem cell collection was successful in all mobilized patients to date. As of this abstract date, the overall response rate is 84% (41/49). There were 3 complete responses (6%), 18 very good partial responses (37%), 20 partial responses (41%), 5 minimal responses (10%), 3 stable disease (6%), and 2 unevaluable patients. All the study participants except for three have finished treatment and are currently under follow up. None of the patients showed progression to overt MM to date. We continue to collect data for progression free survival. WES was performed on 32 samples at the time of initiation of therapy. Recurrent mutations in the MAPK pathway (KRAS, NRAS) and tumor suppressor gene, TP53, were detected in 40% of the cases (16% and 24%, respectively), while mutations in the NF-KB and plasma cell differentiation pathways were present in 13% of patients. Somatic copy number alterations (SCNAs) were called based on WES: 1q duplication, 13q, 17p, and 1p deletions were identified in 25, 31, 12, and 7% of cases, respectively. Interestingly, in 6 patients, high-risk SCNAs (1q gain and 17p deletion) were not reported in iFISH but were detected by WES. The analysis of these 32 samples showed that patients who are harboring mutations in the DNA repair pathway genes, had modest response to treatment. Finally, we are analyzing the transcriptomic profile of CD138 negative cells, which represent the BM microenvironment cells (immune and stromal cells) to characterize the BM microenvironment at baseline and end of treatment, and thus, elucidate the role of these cells in the differential response to therapy. Conclusion The combination of elotuzumab, lenalidomide, and dexamethasone is well tolerated and demonstrates a high response rate with no progression to overt MM to date. Correlation with genomic studies can help define patients who benefit the most from this early therapeutic intervention. Disclosures Ghobrial: Takeda: Consultancy; Janssen: Consultancy; BMS: Consultancy; Celgene: Consultancy. Bustoros:Dava Oncology: Honoraria. Badros:GSK: Research Funding; Celgene: Consultancy, Research Funding; Karyopharm: Research Funding. Matous:Celgene: Consultancy, Honoraria, Speakers Bureau. Rosenblatt:Merck: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Jakubowiak:Karyopharm: Consultancy, Honoraria; SkylineDx: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Usmani:Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy; Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding. Zonder:Celgene: Consultancy, Honoraria; Pharmacyclics: Other: DSMC; Janssen: Honoraria; Takeda: Honoraria; Alnylam: Honoraria; Coelum: Honoraria; BMS: Research Funding. Munshi:OncoPep: Other: Board of director. Anderson:Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; C4 Therapeutics: Equity Ownership, Other: Scientific founder; OncoPep: Equity Ownership, Other: Scientific founder; Millennium Takeda: Consultancy; Celgene: Consultancy. Richardson:Amgen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Background: MGRS is a group of heterogeneous disorders characterized by renal dysfunction related to monoclonal immunoglobulin deposition where the underlying plasma cell or B cell clone does not cause tumor complications or meets current hematological criteria for specific therapy (1). The diagnosis of these disorders is established by renal biopsy demonstrating glomerular or tubulointerstitial monoclonal protein deposition. The glomerular disorders include proliferative glomerulonephritis with monoclonal Ig deposition (PGNMID), paraprotein associated C3 glomerulopathy, immunotactoid glomerulopathy, and paraprotein associated fibrillary glomerulonephritis and Type 1 cryoglobulinemic glomerulonephritis. The tubulointerstitial disorders include fanconi syndrome and proximal light chain tubulopathy (2). Given the pathogenesis of the disorders, therapies targeting the underlying plasma cell and/or B cell clone have been used in the past but standard therapy has not been established. Given the rarity of MGRS as defined above, we report our single center experience for therapy of such disorders. Methods: We retrospectively reviewed the charts of patients treated for MGRS at Columbia University Medical Center and collected information on the renal pathologic diagnosis, presence or absence of monoclonal gammopathy and therapy and response. The diagnosis of MGUS and MGRS was based on standard criteria (3). For the assessment of renal response, we used criteria for renal organ response for AL amyloidosis (4). Results: A total of 8 patients were treated at our center for MGRS between 3/2015 and 1/2019. The type of MGRS diagnosis was PGNMID in 5 patients, C3 glomerulopathy in 1 patient, immunotactoid GN in 1 patient and MGUS associated dense deposit disease (DDD) in 1 patient. Monoclonal Ig deposit was IgG kappa type in 3, IgG Lambda in 2, IgM lambda in 1 patient and only Complement deposits C3 glomerulopathy and DDD. All pts had proteinuria at diagnosis with median proteinuria 4g/24hr (range 2.8-11.7g/24hr). Impaired renal function was present 5/8 pts with median serum creatinine 1.4mg/dl (range 1-4.6). None of the patients with PGNMID (N=5) had a concurrent monoclonal gammopathy by standard testing but the rest 3 patients had MGUS with positive SPEP and bone marrow involvement by a clonal plasma cells. First line treatment regimens included use of Bortezomib based regimen (Bortezomib, cyclophosphamide, dexamethasone) in 3 patients, Rituximab based regimens (Rituximab, Prednisone and Rituximab, cyclophosphamide, prednisone) in 4 patients and Daratumumab in one patient. Second line Daratumumab based therapy was used in 2 patients who did not respond to the first line therapy and lead to response in one patient. Improvement in proteinuria was seen in 6/8 patients with 〉30% decrease in proteinuria (range 50-90% reduction). The median time to response was 2 months (range 1-4 months). Improvement in eGFR was seen in 1/8 patients but majority of patients continuing to have stable eGFR and 1/8 patient progressed to ESRD. The responses were durable and after a median follow-up of 11.8 months only one patient had recurrent disease. Conclusion: Currently there is no standard of care therapy for treatment of patients diagnosed with MGRS disorders. Clone directed therapies including Bortezomib, Daratumumab and Rituximab based regimens aimed at suppressing the production of the involved immunoglobulin are effective for treatment of these disorders both in the presence and absence of a concurrent MGUS. These therapies should be explored further in a larger prospective multi-center trial for MGRS disorders. References: 1. Frank Bridoux, Nelson Leung, Colin A. Hutchison et al. Diagnosis of monoclonal gammopathy of renal significance. Kidney International (2015) 87, 698-711. 2. Nelson Leung, Frank Bridoux, Colin A Hutchison et al. Monoclonal gammopathy of renal significance: when MGUS is no longer undetermined or insignificant. Blood.2012;120(22):4292-4295. 3. Leung N, Bridoux F, Batuman V, et al. The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group. Nat Rev Nephrol. 2019 Jan;15(1):45-59. 4. Palladini G, Hegenbart U, Milani P, et al. A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis. Blood. 2014;124(15):2325-2332. Disclosures Bhutani: Sanofi: Membership on an entity's Board of Directors or advisory committees. Lentzsch:Caelum Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Janssen: Consultancy; Takeda: Consultancy; BMS: Consultancy; Proclara: Consultancy; Abbvie: Consultancy; Clinical Care Options: Speakers Bureau; Sanofi: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Honoraria; International Myeloma Foundation: Honoraria; Karyopharm: Research Funding; Columbia University: Patents & Royalties: 11-1F4mAb as anti-amyloid strategy. OffLabel Disclosure: Bortezomib, Cyclophosphamide, Dexamethasone, Rituximab, Daratumumab. For treatment of Monoclonal Gammopathy of renal significance.

Description: Background: Monoclonal gammopathy of renal significance (MGRS) is a monoclonal B cell disorder, not meeting the definition of lymphoma or myeloma, that produces monoclonal proteins which deposit in the kidneys. Permanent renal damage can occur either as a consequence of direct deposition of toxic proteins or by an induced inflammatory response. Due to the low burden of the plasma cell clone, patients do not otherwise qualify for potentially toxic anti-plasma cell treatments and treatment is generally based on consensus opinion. To date there are no clinical trials exploring treatment options. Isatuximab is a chimeric mouse/human IgG1k monoclonal antibody which targets CD38 on both malignant and normal plasma cells and exhibits it antitumor effects primarily by antibody-dependent cellular toxicity. Isatuximab has recently been shown to be an active drug in the treatment of multiple myeloma, with improvements seen in hematologic and renal markers, and has been shown to have manageable toxicity. Given the efficacy of isatuximab in multiple myeloma, we propose a trial evaluating isatuximab monotherapy to treat the small plasma cell clone in MGRS with the hopes of maximizing response and minimizing toxicity. Study Design and Methods: The primary objective of this study is to evaluate efficacy of isatuximab monotherapy in patients with MGRS in order to establish a standard of care treatment for patients with this disease. Adult patients with proteinuria of at least 1 gram in 24 hours and a histopathological diagnosis of MGRS on renal biopsy in the last 24 months will be eligible for the trial. Patients will be excluded if their estimated GFR is below 30 mL/min, they have multiple myeloma, high risk smoldering myeloma, other B cell neoplasm meeting criteria for treatment, concurrent diabetic nephropathy, or require dialysis. Patients will be screened for B cell disorders with bone marrow biopsy and aspirate, serum protein electrophoresis (SPEP) with immunofixation (IFE), 24-hour urine protein electrophoresis (UPEP), free light chain (FLC) testing and screening PET/CT at time of enrollment. Enrolled patients will be administered isatuximab 20 mg/kg IV weekly for 4 weeks and then will receive the same dose every 2 weeks thereafter for a total of 6 months. Patients may be continued on treatment following completion of the 6 months at the discretion of the provider. To reduce the risk of infusion related reactions, patients will receive premedications with corticosteroids, diphenhydramine, H2 blockade and acetaminophen at least 60 minutes prior to infusion. Patients will have repeat SPEP + IFE, 24-hour UPEP + IFE and FLC testing every 4 weeks. There will be an optional repeat kidney biopsy 9-12 months following treatment initiation to assess pathologic response in the kidneys. Statistical Methods: The study will be comprised of 20 patients being treated with isatuximab over a span of 24-30 months. Ten patients will be initiated on the therapy for a period of 6 months. Interim analysis will be done after these patients have completed all the treatment cycles. If 4 out of 10 patients show response in form of improved/stable renal function, the study will proceed to include next 10 patients. If 〉50% of the first group of 10 patients show doubling of creatinine while on therapy, that would be considered as an indication to discontinue the therapy and the study due to drug toxicity. Endpoints: The primary endpoint will be efficacy as measured by renal response and hematologic response. Renal response will be measured by assessing the amount of proteinuria in a 24 hour urine sample. A sustained reduction in proteinuria by 30% from the patient's baseline amount of proteinuria with stable renal function (serum eGFR within 20% of baseline) will be considered a positive renal response. Hematologic response will be quantified per the 2016 International Myeloma Working Group (IMWG) uniform response criteria for multiple myeloma. An important secondary endpoint will be safety and will be analyzed from all patients who receive any study drug. Adverse events will be characterized and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Other endpoints include time to dialysis and rate of minimal residual disease (MRD) negativity. Disclosures Lentzsch: Caelum Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Janssen: Consultancy; Takeda: Consultancy; BMS: Consultancy; Proclara: Consultancy; Abbvie: Consultancy; Clinical Care Options: Speakers Bureau; Sanofi: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Honoraria; International Myeloma Foundation: Honoraria; Karyopharm: Research Funding; Columbia University: Patents & Royalties: 11-1F4mAb as anti-amyloid strategy. Bhutani:Sanofi: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Our trial will be evaluating the efficacy of targeting CD38 on plasma cells with isatuximab in patients with monoclonal gammopathy of renal significance (MGRS). We will evaluate the effects of this drug on 24 hour proteinuria and hematologic response.