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Allogeneic transplant (alloHCT) is a curative therapy for patients with acute lymphocytic leukemia (ALL). The curative potential of alloHCT is hampered by relapse, which is the major cause of treatment failure. Overall, relapse rates for these patients are in the range of 30% to 50% with the majority of these relapses occurring within the first year after alloHCT. Currently, there is no standard post-transplant therapy for patients with ALL. Inotuzumab ozogamicin (INO) is a CD22 monoclonal antibody bound to calicheamicin which has been shown to have significant activity against relapsed ALL. We hypothesize that low dose post-alloHCT maintenance therapy of INO will be safe and will reduce relapse rates after alloHCT for ALL. Eligibility included patients aged 16-75 who have undergone alloHCT for CD22+ALL, have a high risk for relapse, have adequate graft and organ function, are between day 40 and 100 post-transplant, do not have active grade III/IV GVHD or any active GVHD of the liver, and have no history of veno-occlusive disease (VOD). The primary objective of this phase I clinical trial is to define a post alloHCT maximum tolerated dose (MTD) of INO. Secondary objectives include describing the safety profile of INO post-alloHCT, determining the rate of VOD, disease free survival (DFS) and overall survival (OS) at 1 year post alloHCT. The trial design is a 3+3 model. The study treatment consists of a total of four 28 day cycles of INO starting at dose level 0 (0.3mg/m2) given on day 1. Dose limiting toxicities (DLT) include VOD, prolonged cytopenia (more than 28 days), and death. If there are no DLTs experienced in a cohort, patients may be enrolled in the next highest dose level (Table 1). As of October 1st, 2019, 9 patients have been treated. One patient went off treatment after 1 cycle of INO (patient choice), two went off treatment after 3 cycles of INO (patient choice and physician choice) and one experienced a DLT due to prolonged thrombocytopenia. We have completed 1 year post-transplant follow up on 5 patients. All patients are alive and in CR. No patients experienced VOD. Significant side effects include thrombocytopenia and neutropenia. The percentage of any aGVHD is 62.5% and the rate of grade III/IV aGVHD is 0%. The percentage of any cGVHD is 42.8%. Patient characteristics are described below (Table 2). In this phase 1 study, INO at doses of 0.3 and 0.4mg/m2 was well tolerated. Thrombocytopenia may be the dose limiting toxicity. The absence of disease recurrence in this small cohort of high risk ALL patients is very promising. [ABSTRACT FROM AUTHOR]

AbstractThe combination of cord blood transplant with progenitor cells from partially HLA-matched adult donors (haplo-cord transplant) has been used over the past two decades. In Europe and the US the adult donor graft is CD34 selected and provides early hematopoiesis, but durable engraftment derives from the cord blood graft (CD34 selected haplo-cord). Neutrophil recovery is prompt and rates of acute and chronic GVHD are low. Recent Chinese studies combine cord blood grafts with T-replete haplo-identical grafts (unmodified haplo-cord). The haplo graft usually establishes dominance and UCB chimerism is rarely detected. Comparison studies suggest considerably decreased rates of relapse and improved outcomes, compared with either haplo-identical transplant or CBU transplant, particularly in patients with advanced leukemia. A recent prospective randomized study confirms this. Haplo-cord mitigates the engraftment delay of UCB transplant. The unique biology of UCB grafts results in low GVHD and improved GVL especially beneficial in high-risk disease. [ABSTRACT FROM AUTHOR]

Graft Versus Host Disease (GVHD) is common, complex and at times difficult to differentiate from other complications. GVHD is the leading cause of non-relapse mortality after hematopoietic cell transplant (HCT). Current treatments for GVHD are only partially effective and response rates for first-line treatment of acute GVHD are < 50%. Clear and complete documentation of GVHD assessment is essential not only for reporting purposes, but also critical to early intervention to progress to next line of treatment sooner. The purpose of this project is to assess deficiencies in documentation across providers and implement a team-based approach to the care of our patients with GVHD. A 12-person multidisciplinary GVHD committee was formed consisting of advanced practice providers, oncologists, and data and quality specialists. This committee meets monthly to systematically review all current cases of acute and chronic GVHD. Documentation review consists of date of incidence, maximum grade, treatment initiation, discontinuation and response to each line of treatment for weekly acute GVHD assessment and the completion of assessment at 100 days, 6 months, and 1 year for chronic GVHD. Documentation feedback and/or request for clarification is entered into the electronic medical record in the form of a documentation clarification entry. Additional efforts to promote a team based approach include GVHD educational opportunities to enhance assessment skills and discussion of treatment options, including GVHD clinical trials. Documentation review triggers an email recommendation to the provider to consider referral to our chronic GVHD multidisciplinary clinic and the resources of a GVHD specialist. Metrics used to evaluate this project include incidence and grade of acute GVHD, frequency of clarification requests, accuracy of provider documentation, and number of referrals to chronic GVHD clinic. Preliminary results at 6 months for 19 acute GVHD and 44 chronic GVHD cases reviewed indicate improved accuracy in documentation. [ABSTRACT FROM AUTHOR]

Azacitidine (AZA) maintenance following allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) may reduce relapse risk and improve survival. Given logistic and toxicity-related challenges, identifying subgroups appropriate for this approach is an unmet need. Using data from two centers, we retrospectively compared event-free survival (EFS) and overall survival (OS) of AML and MDS patients who received AZA maintenance (n = 59) with historic controls (n = 90). Controls were selected according to the following criteria: no death, relapse, or Grade III–IV acute GVHD for 100 days after transplant. In multivariable analysis, AZA maintenance yielded significantly improved EFS (p = 0.019) and OS (p = 0.011). Outcomes differed according to regimen intensity. For reduced-intensity transplant, EFS (p = 0.004) and OS (p = 0.004) were significantly improved and equivalent to myeloablative transplant. A significant benefit following myeloablative transplant was not observed. Within the limitation of its retrospective nature, this study suggests that AZA maintenance improves outcomes following reduced-intensity HCT, comparable to myeloablative HCT. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell transplantation (allo‐HSCT) is a potentially curative treatment for acute myeloid leukemia (AML). Reduced intensity regimens, alternative graft sources, advances in HLA‐matching, improved supportive care, and tailored graft versus host disease (GVHD) prophylaxis have led to a wider application of allo‐HSCT to eligible patients. Unfortunately, 30‐40% of patients with AML will relapse after transplant and this is the major cause of treatment failure. Careful consideration should be paid in choosing the type of graft, graft source, and conditioning regimen to minimize the risk of disease recurrence. In addition, maintenance therapy following allo‐HSCT is a potential method to keep the disease in remission, especially in those with high‐risk disease characteristics. Pharmacological targeted agents with low side effect profile such as tyrosine kinase inhibitors, hypomethylating agents (HMAs), HDAC inhibitors, antibody drug conjugates (ADCs), isocitrate dehydrogenase inhibitors, and hedgehog inhibitors may prevent relapse in posttransplant setting and are under investigation. Immunological therapies including donor lymphocyte infusions (DLIs), natural killer (NK) cell therapy, peptide vaccine targeting tumor antigens, and adoptive T‐cell therapies all hold promises in this area as well. As targeted agents and immunotherapies continue to be developed, patients at high risk of recurrence may benefit from prophylactic maintenance therapy. Here we review the current landscape in this rapidly evolving clinical setting. [ABSTRACT FROM AUTHOR]

PURPOSE: Allogenic hematopoietic stem-cell transplant (HCT) is a curative therapy for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Relapse post-HCT is the most common cause of treatment failure and is associated with a poor prognosis. Pathologist-based visual assessment of aspirate images and the manual myeloblast counting have shown to be predictive of relapse post-HCT. However, this approach is time-intensive and subjective. The premise of this study was to explore whether computer-extracted morphology and texture features from myeloblasts' chromatin patterns could help predict relapse and prognosticate relapse-free survival (RFS) after HCT. MATERIALS AND METHODS: In this study, Wright-Giemsa–stained post-HCT aspirate images were collected from 92 patients with AML/MDS who were randomly assigned into a training set (S t = 52) and a validation set (S v = 40). First, a deep learning–based model was developed to segment myeloblasts. A total of 214 texture and shape descriptors were then extracted from the segmented myeloblasts on aspirate slide images. A risk score on the basis of texture features of myeloblast chromatin patterns was generated by using the least absolute shrinkage and selection operator with a Cox regression model. RESULTS: The risk score was associated with RFS in S t (hazard ratio = 2.38; 95% CI, 1.4 to 3.95; P =.0008) and S v (hazard ratio = 1.57; 95% CI, 1.01 to 2.45; P =.044). We also demonstrate that this resulting signature was predictive of AML relapse with an area under the receiver operating characteristic curve of 0.71 within S v . All the relevant code is available at GitHub. CONCLUSION: The texture features extracted from chromatin patterns of myeloblasts can predict post-HCT relapse and prognosticate RFS of patients with AML/MDS. Allogenic hematopoietic stem-cell transplant (HCT) is a curative therapy for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Relapse post-HCT is the most common cause of treatment failure. In this study, Wright-Giemsa–stained post-HCT aspirate images were collected from 92 patients with AML/MDS. First, a deep learning–based model was developed to segment myeloblasts. A total of 214 texture and shape descriptors were then extracted from the segmented myeloblasts on aspirate slide images. This study found that the texture features extracted from chromatin patterns of myeloblasts can predict post-HCT relapse and prognosticate relapse-free survival of patients with AML/MDS. [ABSTRACT FROM AUTHOR]

Summary: It is not known whether obesity has a differential effect on allogeneic haematopoietic cell transplantation outcomes with alternative donor types. We report the results of a retrospective registry study examining the effect of obesity [body mass index (BMI) > 30] on outcomes with alternative donors (haploidentical related donor with two or more mismatches and receiving post‐transplant cyclophosphamide [haplo] and cord blood (CBU)] versus matched unrelated donor (MUD). Adult patients receiving haematopoietic cell transplantation for haematologic malignancy (2013–2017) (N = 16 182) using MUD (n = 11 801), haplo (n = 2894) and CBU (n = 1487) were included. The primary outcome was non‐relapse mortality (NRM). The analysis demonstrated a significant, non‐linear interaction between pretransplant BMI and the three donor groups for NRM: NRM risk was significantly higher with CBU compared to haplo at BMI 25–30 [hazard ratio (HR) 1.66–1.71, p < 0.05] and MUD transplants at a BMI of 25–45 (HR, 1.61–3.47, p < 0.05). The results demonstrated that NRM and survival outcomes are worse in overweight and obese transplant recipients (BMI ≥ 25) with one alternative donor type over MUD, although obesity does not appear to confer a uniform differential mortality risk with one donor type over the other. BMI may serve as a criterion for selecting a donor among the three (MUD, haplo and CBU) options, if matched sibling donor is not available. [ABSTRACT FROM AUTHOR]

The role of filgrastim during acute myeloid leukemia (AML) induction therapy remains controversial. At our institution, newly diagnosed AML patients from 2003 through 2019 were retrospectively evaluated. Patients were stratified on whether they received filgrastim within 5 days after early assessment bone marrow (BMBx) and divided into early GCSF group (eGCSF) and no-eGCSF group. A total of 121 patients were included. We found significantly shorter hospital stay (median 24 vs 26 days, p <.01), absolute neutrophil count recovery days (median 23 vs 25 days, p =.03), and intravenous antibiotics days (mean 18.5 vs 21.4 days, p =.01) in patients with eGCSF comparing with no-eGCSF. There was no significant difference regarding complete response rates; however, for those failed to achieve remission, eGCSF was associated with higher blast count. There was no significant difference regarding overall survival or progression-free survival. The use of eGCSF was associated with cost savings of $5199 per patient over no-eGCSF. [ABSTRACT FROM AUTHOR]

• Presented a novel end-to-end segmentation architecture AMLcGAN based on conditional generative adversarial net (cGAN) to segment acute myeloid leukemia (AML) in Wright-Giemsa-stained bone marrow aspirate smear images. • Compared with other three popular deep learning-based segmentation models, AMLcGAN can achieve the best segmentation performance. • We validated AMLcGAN on a specific diagnosis task, the comparative clinical indicators show that presented model can provide accurate assistance for pathologists in the diagnosis of AML. The diagnosis of acute myeloid leukemia (AML) requires reliable detection and counting of immature white blood cells called myeloblasts on bone marrow aspirate and biopsy slides. Experienced hematologists/oncologists typically spend many hours manually reviewing blood cells and performing a microscopic morphological examination of myeloblasts on glass slides to determine this diagnosis. While manual counting of myeloblasts is considered the gold standard for an accurate diagnosis of AML, the process is time-consuming and difficult to standardize due to high intra- and inter-observer variability. Machine learning algorithms coupled with deep learning techniques represent potentially promising approaches for automated counting. Since myeloblasts possess very similar texture patterns to other hematopoietic cells (OHCs), accurately differentiating myeloblasts from other blood cells is a challenge for most segmentation models. We present a new conditional generative adversarial network (cGAN)-based segmentation model (AMLcGAN) to efficiently segment myoblasts from slides of patients with AML. Validation of the approach on 204 cytological images reveals a mean dice coefficient (mDICE) of 82.51 % with respect to manual segmentations. We also compared the new AMLcGAN method with three deep learning models: Unet, Segnet and Pix2pix, the corresponding mDICE values were 77.4 %, 78.2 %, and 79.53 %, respectively. We also employed the segmentation results from 4 different models to extract blast statistics feature, Haralick texture feature, Fractal dimension feature and myeloblast shape features to create 4 different prognostic models to predict risk of recurrence in AML patients. TheConcordance Index values for AMLcGAN and the three other models respectively were 0.63, 0.53, 0.58, and 0.56. The comprehensive evaluation results presented suggest that the AMLcGAN approach can enable accurate blast segmentation and for construction of accurate prognostic models for predicting risk of recurrence in AML patients. [ABSTRACT FROM AUTHOR]

• Microbiome composition present at pretransplantation baseline is associated with the incidence and severity of post-transplantation nausea, vomiting, and neutropenic fever, and with the rate of neutrophil engraftment. • The microbial communities present at count nadir are associated with regimen-related gastrointestinal toxicities observed with high-dose melphalan. • Although bacteriome diversity largely recovers within 1 month after transplantation, recovery of oral and gastrointestinal mycobiome diversity takes longer to recover. Microbiome dysbiosis has been associated with adverse outcomes of hematopoietic cell transplantation (HCT). We hypothesized that exposure to high-dose melphalan and antimicrobials in patients undergoing autologous HCT for plasma cell disorders results in oral and gastrointestinal microbial dysbiosis, which in turn is associated with regimen-related toxicities. We conducted a prospective study describing the longitudinal changes in oral and gastrointestinal bacteriome and mycobiome in this patient population. Our findings show that microbiome composition present at baseline is associated with the incidence and severity of post-transplantation nausea, vomiting, and culture-negative neutropenic fever, as well as with the rate of neutrophil engraftment. We also have evidence of an association between the microbial communities at count nadir and the development of regimen-related gastrointestinal toxicities commonly observed after exposure to high-dose melphalan. Although bacteriome diversity largely recovers within 1 month after transplantation, we observed a continuous decrease in oral and gastrointestinal mycobiome diversity, suggesting that the mycobiome requires a longer time to recover compared with the bacteriome. [ABSTRACT FROM AUTHOR]

Anti-thymocyte globulin (ATG) is often added to hematopoietic stem cell transplant conditioning regimens to prevent graft rejection and reduce graft-versus-host disease (GVHD). Doses used in retrospective and prospective clinical trials have ranged from 2.5 to 20 mg/kg with rates of grade II-IV acute GVHD and chronic GVHD up to 40 and 60%, respectively. We retrospectively compared outcomes in recipients of matched unrelated donor (MUD) grafts given low dose rabbit ATG IV 3 mg/kg (n = 52) versus recipients of matched related donor (MRD) grafts (n = 48) without ATG. One year cumulative incidence of chronic GVHD was 25.2% in the MUD group versus 33.3% in the MRD group (p = .5). One-year cumulative incidence of extensive chronic GVHD was 9.6% in the MUD group versus 26.6% in the MRD group (p = .042). Our analysis supports the use of low dose ATG in MUD transplantation as an effective therapy to prevent chronic GVHD. [ABSTRACT FROM AUTHOR]

Relapse after allogeneic hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) remains a major cause of treatment failure with associated poor prognosis. Low-dose post-HSCT maintenance azacitidine (AZA) has proved to be beneficial in preventing relapses (de Lima et al. Cancer 2010). Herein, we retrospectively evaluated outcomes of patients (pts) treated with low-dose AZA post-HSCT. Pts with AML and MDS who underwent allogeneic HSCT between 2012-2018 at two centers were evaluated and categorized into AZA group (with low-dose AZA maintenance) and control group (without AZA maintenance). In control group, pts who died or relapsed prior to day +100, had grade III-IV aGVHD or received maintenance therapy other than AZA (e.g. FLT3 inhibitors) were excluded. Using Kaplan-Meier method, event (defined as relapse or death) free survival (EFS) and overall survival (OS) were computed and compared using log-rank test. A total of 107 patients were included; 53 (49.5%) in AZA and 54 (50.5%) in control groups. Disease and transplant-related characteristics are shown in table 1. Both groups were comparable with respect to age, diagnosis, disease risk stratification, disease status at HSCT, and MRD status at day +30 and day +100 (table 1). More pts received reduced intensity conditioning (RIC) in the AZA group (71.6% vs 37%, p=<0.01). Median time to AZA initiation was day +60 days (range, 34-236). Median number of AZA cycles were 4 (range, 1-16); 32 (58.5%) received < 6 and 21 (41.5%) received ≥ 6 cycles. AZA doses were 16 mg/m2 (n=2, 3.7%), 25 mg/m2 (n=15, 28.3%) and 32 mg/m2 (n=36, 67.9%). The incidence of all-grade adverse effects was 43.4% (n=23). Grade III-IV adverse effects were neutropenia (16.9%), infections (5.6%), fatigue (3.7%), elevated liver enzymes (1.8%), GI toxicity (1.8%) and renal insufficiency (1.8%). Relapse was the most common reason for AZA discontinuation (9.4%). Median duration of follow up was 31 (range, 5.7-68.8) months for AZA group and 29.9 (range, 2.7-86.5) months for control group. EFS and OS were significantly prolonged in the AZA group (mean, 53.1 [95% CI, 46.1-60.2] months vs 49.5 [95% CI, 38.9-60] months; p=0.02) and (mean, 56.8 [95% CI, 50.4-63] months vs 53.4 [95% CI, 43.3-63.6] months; p=0.01); shown in figures 1 and 2, respectively. In our cohort, low-dose AZA maintenance was generally well tolerated. The results of this study indicate that AZA maintenance is feasible and associated with improved EFS and OS. In addition, AZA has the potential of improving relapse rates even in pts who are unable to receive myeloablative conditioning as a significant number of pts in AZA group in this study received RIC. The optimal timing, duration of treatment and selection of pts most suitable for AZA for maximum benefit, however, requires further studies. [ABSTRACT FROM AUTHOR]

Patients (pts) with rapidly progressive lymphoma and urgent need for therapy have worse prognosis and may not be able to receive CAR-T cells. Decreasing apheresis to infusion time can make CAR-T cells available to this patient population. We present the results of a phase I trial using rapid on-site CAR-T manufacture for relapsed/refractory B cell non Hodgkin lymphoma (NHL). Adult pts with CD19+ B NHL who failed ≥ 2 lines of therapy were enrolled. Autologous T cells were transduced with a lentiviral vector (Lentigen Technology, Inc) encoding antiCD19 binding motif, CD8 linker and TNFRS19 transmembrane region, and 4-lBB/CD3z costimulatory domains. GMP compliant manufacture was done using CliniMACS Prodigy, in a 12 day culture. Dose escalation was done using 3+3 design, with 3 dose levels (0.5, 1 and 2 × 106 CAR-T cells/kg). Lymphodepletion was done with cyclophosphamide (60mg/kg × 1) and fludarabine (25mg/m2/d × 3). As of September 30, 2019, 14 pts were enrolled and treated. Table 1 lists baseline characteristics. 12 pts had refractory NHL, 6 had bulky disease and 9 had symptomatic disease at the time of lymphocyte collection. CAR-T cell product manufacture was successful in all pts. Median transduction rate was 48% [range 29-62] with median culture expansion of 41-fold [range 30-79]. All pts received their infusion of antiCD19 CAR-T cells. CAR-T cell doses were 0.5 × 106/kg (n = 4) and 1 × 106/kg (n = 10). Median apheresis to infusion time was 13 days [range 13–20]. CAR-T persistence, based on vector sequence, peaked in peripheral blood MNCs between days 14-21. All evaluable subjects had persistent CAR-Ts on PCR measurements done on days 30, 60 and 90. CAR-T cell dose did not have an impact in the time to peak in vivo CAR-T cell expansion or in the rate of CAR-T cell persistence (fig 1). Six pts experienced CRS. Five pts had grade 1 – 2 CRS and 1 pt died on day 8 due to CRS. Two pts presented grade 4 CRES, resolved after corticosteroids. No other grade ≥3 non-hematologic toxicity was observed. The most common non – hematologic toxicity was fatigue (n=7). Hematologic toxicity was common, with grade ≥ 3 neutropenia observed in all pts. Among 12 evaluable pts, 8 have achieved complete response (CR) and two had partial response (PR). Two pts did not respond. The CR rate was 67% and overall response rate was 83%. Three pts have died, causes of death include progressive disease (n=2) and CRS (n=1). After a median follow up 4.5 months (range 1 – 14) all responding pts are alive; 1 pt relapsed 6 months after treatment with CD19+ disease and entered CR after antiCD19 antibody drug immunoconjugate. AntiCD19 CAR-T cells with TNFRS19 transmembrane domain have potent clinical activity. The short manufacture times achieved by local CAR-T cell manufacture enables treatment of a very high risk NHL population that would otherwise not be able to receive CAR-T products due to rapidly progressive disease. [ABSTRACT FROM AUTHOR]

Anti-CD19 chimeric antigen receptor T (CAR-T) cells have demonstrated activity against relapsed and refractory aggressive lymphomas. Cytokine release syndrome (CRS) is a well-known complication of CAR-T cell therapy. Tocilizumab, a humanized monoclonal antibody targeting the interleukin 6 receptor, is approved for treatment of CRS. Our institutional standard has been recently modified to prescribe tocilizumab prophylaxis prior to CAR-T cell infusion. We present a retrospective review of the outcomes of subjects treated with and without prophylactic tocilizumab (PT). Relapsed / refractory (r/r) lymphoma treated with anti-CD19 CAR-T cells at our institution were included. Baseline demographic and clinical characteristics, as well as laboratory results were obtained from our Hematologic Malignancies and Stem Cell Therapy Database. Prior to institution of prophylactic tocilizumab, patients received this agent only if they presented evidence of CRS grade 2 or higher. In May 2019, our institutional practice changed to provide PT 8mg/kg, 1 hour prior to infusion of CAR-T cell product. CRS was measured according to the ASTCT Consensus Grading. Positron Emission Tests (PET) scans were done to assess response on Day 30. CART cell vector Persistence was measured using PCR and was done at different time points including Day 30. Fourteen relapsed / refractory lymphoma pts were treated with antiCD19 CAR-T cells; 6 pts received prophylactic tocilizumab. Median follow up was 149 days. CAR-T cells dose was 0.5 × 106 CAR-T cells/Kg dose in 4 pts, while 10 pts received 1 × 106/kg CAR-T. Baseline characteristics are listed in table 1.Both groups were similar. There were no differences in the rate of bulky disease, prior ASCT or number or prior lines of therapy. Baseline lymphocyte counts, C – reactive protein (CRP) and ferritin were also comparable between groups (Table 2). CRS of any grade was observed in 6/8 (75%) of patients without PT vs. 1/6 (17%) in patients treated with PT (p = 0.05). There was a statistically significant difference in the peak CRP, with patients receiving PT having a CRP peak of 0.74mg/dl vs. 15.3mg/dl in patients without PT. Complete response was observed in 5/8 (63%) pts without PT vs. 4/5 patients with PT. All patients had detectable Anti-CD19 CAR-T cells on day 30. Our findings suggest prophylactic tocilizumab is associated with reduced incidence of CRS. This decreased rate of CRS is not associated with impaired disease control and response rates are comparable with those previously reported. Use of PT did not appear to affect CAR-T cell persistence. Subsequent studies should evaluate the optimal CRS prophylaxis schedule in patients treated with CAR-T cell therapies. [ABSTRACT FROM AUTHOR]

Immunomodulatory drugs (IMiDs) are backbone of myeloma therapy in induction and maintenance therapy after transplant for patients (pts) with Multiple Myeloma (MM). The incidence of IMiD-associated rash is up to 27% (Nardone, et al, Clinical Lymphoma Myeloma and Leukemia. 2013) and importantly heralds a favorable prognosis (Kojima, et al. Blood. 2016) suggesting more robust immune stimulation by this class of drugs; however, lack of optimal management strategy of this toxicity can deprive large subset of pts from maintenance therapy after transplant and lead to potential detrimental impact on survivals. The concurrent weekly dexamethasone (Dex) does not diminish the incidence of skin eruptions with IMiDs (Sviggum, et al. Archives of dermatology. 2006), therefore we designed a low dose daily and tapering corticosteroid regimen to tame this immune response upon restarting IMiDs and allow desensitization and reinstitution of the same IMiD which may not be achieved by standard weekly Dex. Here, we present our experience with this regimen. In this retrospective study, pts with MM treated with lenalidomide and pomalidomide were reviewed for any IMiD-associated dermatologic toxicity. We followed the same corticosteroid regimen for all IMiD-related rash in our clinic without changing Dex dosing. A total of 160 pts were evaluated. The incidence of rash was found to be 13% (n=21). IMiDs were instituted as part of induction regimen in 71% (n=15) and as maintenance therapy after transplant in 29% (n=6) of pts. Median time to development of rash after IMiD initiation was 28 days (range, 2-232). The rashes were characterized as morbilliform in 86% (n=18), urticaria in 9.5% (n=2) and blisters in 5% (n=1) of pts. Pruritis or pain was associated with 86% of rashes (n=15). According to NCI-CTCAE, rashes were graded as low (I-II) in 89% (n=17) and high (III-IV) in 19% of pts. All pts were managed by temporary treatment interruption and upon clearance of rash, re-institution of the same IMiD concomitantly with a standardized 3-week steroid rash prophylaxis protocol (prednisone at 10 mg daily for 10 days, followed by 5 mg daily for 10 days, followed by 5 mg on alternate days for 10 days). As a result, all pts were able to restart the same IMiD either at same (n=5, 24%) or reduced (n=16, 76%) dose with none re-experiencing any dermatologic adverse effect afterward. There was no association between rash development and changes in creatinine clearance (p=0.42). Median eosinophil count at rash development was observed to be significantly higher as compared to eosinophil count at IMiD initiation (380 × 106 vs 130 × 106 respectively, p=0.01). The proposed 3-week corticosteroid regimen showed 100% success rate in terms of reinstituting IMiDs, therefore it may provide a highly effective and practical short term immunosuppression required to enable pts to restart IMiDs. [ABSTRACT FROM AUTHOR]

Salvage autologous stem cell transplant (sASCT) may be associated with improved survival in multiple myeloma (MM) and is an option for patients with long time to relapse (TTR) after initial Autologous transplant (ASCT1). Due to potential mobilization failure after maintenance therapy (MT), adequate peripheral blood progenitor cells (PBPC) are frequently collected for later sASCT. Evaluate utilization of stored PBPC in MM. Provide a cost analysis of collecting and storing PBPC for sASCT. Determine utilization of sASCT in those eligible who had a prolonged TTR. We included MM patients who received ASCT1 at our institution between 2009 and 2016. Extra day of collection (EDC) was defined as additional collection of ≥2 × 106 cells/kg PBPC for a second transplant. TTR was calculated as months from ASCT1 to relapse. Eligibility for sASCT was defined as TTR ≥18 months without MT or ≥36 months on MT. Patients who underwent tandem transplant (tASCT) (defined as two transplants within 6 months) were excluded from relapse analysis. Patients with inadequate relapse data defined as death or lost to follow up (LTFU) at ≤36 months prior to relapse, or ≤6 months follow up after relapse were excluded. Costs were obtained from the institution charge master. Descriptive statistics were calculated for the final cost benefit analysis. 154 MM patients received ASCT1 from 2009-2016. Median age was 59 years. Median follow up was 151 months. Median TTR was 20 months. 58% were male. Ethnicity was 76% Caucasian and 24% Black. 62% had IgG MM subtype, 23% IgA MM and 15% other. Majority (95%) were European Cooperative Oncology Group (ECOG) 0 or 1. 13% had high risk cytogenetics. 53% received MT. 137(89%) had PBSC stored for sASCT. 3 were used for sASCT and 10 for tASCT. 124 (90.5%) did not use stored cells. 54 (39%) met collection targets for two transplants in single collection while 83 (%) required ≥1 EDC with cumulative 108 EDC. (Figure 1) Cumulative cost savings for plerixafor use, cell collection, processing, analysis and storage was estimated at $2,252,244. (Figure 2). Total 60 doses of plerixafor were used for EDC. (31 patients with 1EDC, 10 with 2EDC and 3 with 3 EDC). 97 patients were studied for relapses. 54 (77.5%) relapsed. 5 deaths and 8 LTFU occurred within ≤6 months of relapse. 42 patients were further analyzed. 25 of them met criteria for sASCT based on TTR and only 2 received sASCT.1 patient with sASCT did not have MT data and was excluded. (Figure 3) Only 25% (24/98) patients who underwent ASCT1 were eligible for sASCT. Only 2% (2/98) received sASCT. Collecting and storing PBPC for sASCT is associated with high cost, but overall utilization at our institution is low. Our findings should be compared against practices at other institutions to help develop guidelines for selection of subset of MM where this practice may be of higher value. [ABSTRACT FROM AUTHOR]

Simple Summary: Multiple Myeloma is the third most common hematologic malignancy. Outcomes have improved significantly, as the result of the introduction of novel agents as well as higher utilization of autologous Hematopoietic Cell Transplant. These complex treatment regimens are quite expensive and their full applicability in the real world remains largely unknown. Several studies have shown that survival in patients with other types of cancer is influenced by their insurance, demographic factors, as well as socioeconomic status. Here we intend to examine the interplay of insurance status and other potential socioeconomic factors driving survival disparity for Multiple Myeloma patients. We used the National Cancer Database (NCDB) to assess the potential influence of these factors in this population. Background: Outcome of Multiple Myeloma (MM) patients has improved as the result of the introduction of novel medications and use of autologous hematopoietic cell transplantation. However, this improvement comes at the expense of increased financial burden. It is largely unknown if socioeconomic factors influence MM survival. Methods: We used the National Cancer Database, a database that houses data on 70% of cancer patients in the US, to evaluate the effect of socioeconomic factors on the survival of 117,926 MM patients diagnosed between 2005 and 2014. Results: Patients aged ≥65 years who were privately insured lived longer than patients with Medicare (42 months vs. 31 months, respectively, p < 0.0001). Treatment in academic institutions led to better survival (HR: 1.49, 95% CI: 1.39, 1.59). Younger age, fewer comorbidities, treatment in academic centers, and living in a higher median income area were significantly associated with improved survival. After adjusting for confounders, survival of Medicare patients was similar to those with private insurance. However, the hazard of death remained higher for patients with Medicaid (HR: 1.59, 95% CI: 1.36, 1.87) or without insurance (HR: 1.62, 95% CI: 1.32, 1.99), compared to privately insured patients. Conclusion: Economic factors and treatment facility type play an important role in the survival of MM patients. [ABSTRACT FROM AUTHOR]

We conducted a prospective study to determine the longitudinal microbial profile in patients undergoing HCT for multiple myeloma (MM), and whether changes in microbial composition correlate with HCT outcomes and/or toxicities. Samples were collected from 15 patients at baseline (T-2), during marrow aplasia (T+7) and after engraftment (T+30). Ion-Torrent PGM workflow was used. Amplicons generated from 16s rRNA and the ITS genes were sequenced for bacterial and fungal identification, respectively. Relative abundance, diversity and richness were determined at the phylum and genus levels at each time point, in oral and fecal microbiome. Diversity and richness of the oral mycobiome decreased at T+7 from baseline with further decrease noted at T+30. Fecal mycobiome diversity (T-2 vs T+7, p=0.05) and richness decreased from baseline to T+7, and richness trended towards significance (p=0.06) with further decrease at T+30. In fecal samples, lower bacterial diversity at T+7 associated with more severe diarrhea (p= 0.03). Anaerobic targeting antibiotic exposure on or before T+7 affected the bacterial genus diversity (p=0.015) and richness at T+7 (p=0.014). The bacterial genus richness at baseline (p=0.03) and the diversity/richness at T+7 (p=0.01) were associated with fever development on or after T+7. Exposure to anaerobic depleting antibiotics correlated with oral mycobiome genus richness at T+30 (p=0.04). At the bacterial phylum level, the oral community composition changed at T+30 compared to baseline (Bray-curtis p=0.046) and T+7 (Bray-curtis p=0.025). When examining the changes in the mycobiome composition, test for dissimilarity showed a significant difference in the fecal fungal genus between baseline and T+30 (BrayPA p=0.025). In fecal samples, a higher abundance of Bacteriodetes present at T+7 was associated with the severity of diarrhea experienced (p=0.03). Blautia and Ruminococcus , both belonging to the Firmicutes phylum and Clostridium Class, when detected at T+7 were associated with a higher severity of vomiting (p=0.05). In oral samples, the presence of the genus Glomerella at T+7 was negatively associated with rates of neutrophil engraftment (p=0.03). Our results show that oral and fecal microbiota undergo dynamic changes in diversity, composition and relative abundance during the course of transplantation. Bacterial and fungal microbiota present specifically at count nadir could be important players. The relative abundance of particularly the anaerobic bacterial phyla, Bacteroidetes and Firciumtes during marrow aplasia, correlated with post transplant toxicities. We identified a correlation between exposure to anaerobic organism depleting antimicrobials and changes in genus diversity and richness. Baseline microbial diversity/richness and changes coinciding with marrow aplasia correlate with the incidence and severity of post transplant toxicities. [ABSTRACT FROM AUTHOR]

Introduction Risk of venous thromboembolism (VTE) is increased in patients (pts) with multiple myeloma (MM) as a result of the biology of the disease and the use of immunomodulatory drugs (IMiDs). These patients frequently undergo autologous hematopoietic cell transplantation (AHCT) transplantation in order to improve disease-free and potentially overall survival. We conducted this study to better understand the incidence and risk factors associated with peri-transplant VTE in this population. Methods 160 MM pts who received IMiD therapy and underwent AHCT between 6/2004 and 11/2016 at our institution were the subjects of this analysis. The peri-transplant period was defined as time from central venous catheter (CVC) insertion up to 60 days post-transplant. None of the pts received VTE prophylaxis during this period. Results All patients received at least one IMiD-based regimen before transplant including thalidomide (31%), lenalidomide (74%), pomalidomide (6%). Imids were stopped at a median of 38 days prior to collection (range 0 days-4 years). CVCs (double lumen n=103, triple lumen n=50, unknown n=7) were inserted a median of 2.5 days prior to mobilized blood collection (range 0-48 days) and were removed a median of 52.5 days after insertion (range 2-303 days). Twenty of 160 patients (12.5%) developed VTE in the peri-transplant period; there was 11 (55%) CVC-related VTE, 6 (30%) lower extremity VTE and 3 (15%) pulmonary embolism. There was no VTE-related death. Median platelet count at the time of VTE was 90 (range, 30-130) x109/L. Eleven VTEs occurred between time of initiation of progenitor cell mobilization and infusion (T-0), and 9 occurred between T-0 and 60 days post-transplant. The rate of catheter-related VTE that occurred before or after T-0 was similar (55%). Thirty-nine percent of pts had a catheter size of less than 14 french; 49% had a catheter size of 14 french or more; the size could not be collected in 12% of the pts. Rate of catheter-related VTE in pts with ≥ 14 and <14 french catheter size was 7.6% and 6.5%, respectively (p = 0.8). We also found no difference in VTE rate between different age, gender, ethnicity, BMI, M protein type, ISS stage at diagnosis, type of IMiD used, response extent before transplant, mobilization regimen (GCSF alone, GCSF + cyclophosphamide, or GCSF + plerixafor), or melphalan dose used (140 mg/m2 vs 200 mg/m2). Conclusion In this retrospective single institution analysis, we found a 12.5% incidence of peri-transplant VTEs, which is higher than what was reported in patients receiving transplant for other malignancies [1]. The size of the catheter did not affect the risk of VTE. About half of the VTEs were catheter-related, half of which occurred before T-0. If confirmed on a larger scale, it may be beneficial to give VTE prophylaxis during mobilization to minimize this risk. [ABSTRACT FROM AUTHOR]

Maintenance therapy has been associated a significantly longer time to disease progression and significantly improved overall survival (OS) among patients with multiple myeloma (MM). However, the impact of maintenance therapy on the nature of MM relapse is largely unknown. Generally relapse can be categorized in two broad categories as symptomatic, or biochemical relapse. We hypothesized that long-term continuous exposure to lenalidomide induces crucial changes in the myeloma microenvironment leading to a discordance between the resurgence of secretory function and the recurrence of aggressive behavior of myeloma cells leading to a higher frequency of biochemical. All MM patients with measurable disease who received HSCT at the University Hospital, Cleveland, OH from 2007 to 2016 were reviewed (Fig. 1). Baseline and treatment characteristics, response status, and monitoring data prior to relapse were extracted. If the serologic relapse had coincided with clinical relapse, defined as per CRAB criteria, patient was categorized as clinical relapse, and otherwise as biochemical relapse. Type of MM was categorized as paraprotein only (PO), paraprotein and light chain (PL), light chain escape (LE) and clinical only (CO) relapse (Table 1). Baseline and treatment characteristics are detailed in Table 2. Study population included 124 pts who relapsed after ASCT (Fig. 1), divided in two cohorts based on history of receiving any maintenance therapy or no maintenance (77 vs. 47 patients, respectively). Median age was 59.8 years old (range: 36-79). The median time from diagnosis to ASCT was 10 months. There was only one CO relapse in the maintenance cohort. There was no difference in rate of high risk disease between two cohorts. The maintenance agents included immunomodulatory drugs in 70 pts (91%), proteasome inhibitors in 5 pts (6%) and a combination of both in 2 pts (3%). PFS was 40.1 months in the maintenance group vs. 29.2 months in the no maintenance group (p=0.0001). There was no statistically significant difference in serum paraprotein values at diagnosis or relapse between the two cohorts (Fig. 1A). LCE was more common in the maintenance group. Thirteen patients (28%) in the no maintenance cohort had CRAB relapse compared to 35 patients (45%) in the maintenance cohort (hazard ratio: 0.71, 95% CI: 0.51-0.92, p=0.031). The type of end organ dysfunction at clinical relapse is shown in bar graphs in Fig. 2B. Taken together, our results suggest that although maintenance therapy postpones disease relapse, it also impacts dynamics of the resurgence of secretory function and shifts the nature of recurrence toward less biochemical relapse. Future studies will employ next generation sequencing combined with high sensitivity flow cytometry to identify the molecular basis of relapse. Genomics and cell surface markers may then more accurately predict relapse in MM patients on maintenance therapy. [ABSTRACT FROM AUTHOR]

Multiple Myeloma (MM) are often treated with high-dose melphalan and autologous stem cell transplant (ASCT). Cardiac toxicity, including Supraventricular tachyarrhythmias (SVT), is a fairly common complication which may be related to Melphalan, the transplanted stem cells or effects of para-proteinemia on the conduction system. Here, we sought to determine the incidence of SVT and its predisposing factors in this setting. Methods We reviewed the 100-day post-ASCT clinical course of all MM patients treated from 2007 to 2017 that had undergone ASCT at our institution. Clinical data, EKG and Echocardiography data were extracted. QRS amplitude was measured in the V2 precordial lead as the distance from the R peak to S peak. Both atrial fibrillation and atrial flutter were classified as SVT. Results A total of 222 patients were included in the study population. Amifostine was used before all ASCT to reduced oral mucositis. Patient median age was 60.6 (range: 36-79), 110 patients (49%) were male and the 112 female (51%). Median pre-ASCT QRS amplitude was 1.7 millivolt (mV) (range: 0.3-4.4). Median QRS duration was 90 millisecond (mS, range: 60-208). Only 166 patients received a pre-ASCT ECHO. Median time of pre-ASCT and post-ASCT ECHO were 38 days (range: 1-333 days) and 55 days (range: 4-118), respectively. Seventeen patients (8%) developed SVT during or after ASCT with a median time of 12 days post-ASCT (range: 1-97 days). Median time of the length of hospital stay between patients without SVT and with SVT was different, 15 vs. 19 days (p-value < 0.001). There was no statistically significant between average melphalan dose utilized as the conditioning regimen, infused CD34 dosage, transplant-associated weight loss, time from diagnosis or length of pre-ASCT exposure to proteasome inhibitors between two cohorts (Table-1 and 2). Also, there was no association between pre-ASCT use of anti-lipid lowering agents, beta-blockers, angiotensin-converting enzyme inhibitor or angiotensin receptor inhibitors. Out of all pre-ASCT comorbidities renal insufficiency (9% vs. 41%, p-value: 0.017) and HTN (49% vs. 76%, p-value: 0.045) were predictor, of SVT occurrence in the univariate analysis. Multivariate analysis indicated that renal insufficiency at baseline (OR: 3.6, 95% CI: 2.1-4.8, p-value < 0.001), left ventricular systolic dysfunction (LVSD, OR: 3.0, CI: 1.1-5.1, p-value: 0.003), and hypertension (OR: 2.5, CI: 1.2-4.6, p-value: 0.028), were significantly associated with the development of SVT after ASCT (Fig. 1). Conclusion Taken together, our results suggest that SVT represents an important cause of morbidity and is associated with longer hospital stay for MM patients undergoing ASCT. The presence of abnormal renal function, LVSD, or hypertension at baseline identifies patients at greater risk of developing SVT following ASCT. [ABSTRACT FROM AUTHOR]

Introduction Tacrolimus (tacro) is commonly used for the prevention of graft vs host disease (GVHD) after allogeneic stem cell transplantation (allo-SCT). Due to concerns of inadequate absorption, tacro is commonly administered intravenously (IV) in the immediate post allogeneic transplant period. Advantages to oral (PO) tacro include decreased need for multi lumen IV catheters, improved patients (pts) convenience, and reduced cost. We retrospectively analyzed differences in safety, tolerability, time to achieve therapeutic levels during the 1st 4 weeks and rates of acute GVHD. Methods IV tacro at 0.02 mg/kg by continuous infusion or PO tacro at 0.03 mg/kg twice daily was started between T-3 and T+5. Levels were assessed 3 times weekly. Dose was titrated to achieve a steady level between 7 and 14 ng/ml. GVHD was graded according to CIBMTR criteria. Results 54 pts were treated between Sep 2016 and July 2018. 21 who received PO tacro and 27 who received IV tacro were studied. 6 pts on PO tacro are still within 100 days post-transplant and will be reported in follow up. The median age was 59 years (range, 21-74), 52% were females, diagnoses were AML (54%), MDS (19%), ALL (15%), CML (6%), NHL (4%) and MF (2%). HCT-CI was 0, 1-3 and >3 in 23%, 54% and 23% of pts, respectively. Donors were match-unrelated (58%), match-related (27%), haploidentical (6%) and double umbilical cord (6%). Conditioning regimens were myeloablative (60%) and reduced intensity (40%). 60% of pts received rabbit ATG (3 mg/Kg). GVHD prophylaxis also included mini-MTX on days +1, +3, +5 and +11 (79%), MMF (15%), and MMF + post-transplant Cy (6%). Pts characteristics were similar between the 2 groups. 7 pts (33%) who initially started on PO tacro switched to IV due to poor absorption (3), mucositis (1), toxicity (1), GVHD (1) and patient's concern (1). Target therapeutic level was reached in 67% vs 81% during week 1, 86% vs 96% during week 2, 95% vs 96% during week 3, and 100% vs 96% during week 4, of pts on PO vs IV tacro, respectively. Median tacro level during the 1st 4 weeks was 12.6 ng/ml vs 11.2 ng/ml, acute kidney injury occurred in 23.8% vs 33.3% (p =.47) and increased bilirubin occurred in 4.7% vs 22.2% (p =.09), in pts on PO vs IV tacro. Posterior reversible encephalopathy was observed in 1 patient on PO tacro. Grade I and Grade II-IV acute GVHD incidence was 47.6% vs 14.8% (p =.01) and 47.6% vs 44.4% (p =.82) of pts on PO vs IV tacro. Stage 1-2 skin aGVHD rate was higher in the PO vs. IV group (90% vs 33.3%; p =.0001). There was no difference in rates of stage 3 skin (4.7% vs 3.7%), stage 1 GI (33.3% vs 33.3%), or stage 2-4 GI (14% vs 7.4%) aGVHD. None of the pts had stage 4 skin or any stage liver aGVHD. Conclusion PO tacro is safe and effective in the prevention of aGVHD in pts receiving myeloablative or RIC allo-SCT. The use of PO tacro during the 1st 4 weeks post-transplant was found to be associated with higher rate of stage 1-2 skin aGVHD and warrants further study. [ABSTRACT FROM AUTHOR]

Achieving and maintaining Complete Response (CR) after autologous hematopoietic cell transplant is the key to improved clinical outcomes in patients (pts) with multiple myeloma (MM). Daratumumab (DARA), an IgG1 Kappa anti-CD38 monoclonal antibody, have shown significant anti-myeloma activity leading to increasing usage in the peri-transplant settings. Frequently, use of DARA may be associated with appearance of low concentration band on serum protein electrophoresis (SPE) impacting CR assessment after transplant. The incidence and factors influencing appearance of this band are largely unknown. This band potentially can be an indirect measurement of the plasma DARA concentration influenced by amount of administered agent and but also with volume of CD38 positive myeloma cells binding to DARA. The objective of this study is to analyze the factors influencing appearance of this band on SPE. Methods: 77 pts who received DARA were retrospectively studied. Pts who did not have available SPE after starting DARA (n: 9) and those who had AL Amyloidosis without Myeloma (n: 3) were excluded. The host and disease characteristics extracted. Pts assigned to two cohorts based on presence (PB) or absence (NB) of the accessory band. The disease response assessment was assessed based on IMWG criteria. Result: Median age for pts in PB and NB was 62 and 64.4 years respectively. All pts received weight-based dosing (16mg/Kg). 31 pts had detectable band assigned to PB cohort and 34 pts without any detectable band assigned to NB. The accessory band appeared over a median of 46 days after starting therapy (range: 7-390 days) and predominantly (74%) during the weekly DARA schedule. No significant difference noted in median weight and serum creatinine between PB and NB cohorts. Median M-spike on SPE at the start of DARA was 1.1 gr/dL (range: 0 - 5.5 gr/dL) in NB cohort vs. 0.3 gr/dL (range: 0 3.8 gr/dL) in PB patients (p-value <0.012). 45% of pts had IgG MM in PB while 55% in NB (p-value: 0.349), 29% of patients had IgA in PB and 20% in NB cohort (p-value: 0.231) and light-chain disease was present in 25% of pts in PB cohort whereas only 4% in NB (p-value: 0.041). 17 pts (55%) had Partial Response (PR) or better in PB while only 5 pts (14%) had PR or better in NB cohort. (p-value: 0.001). In multi-variate analysis the pre-DARA M-spike remained the significant predictor of the band appearance (OR: 2.03, CI: 1.21-4.31, p-value: 0.003). Conclusion: Based on our data, the frequency of detecting this band is not impacted by type of myeloma (i.e., IgG vs. IgA) but by the magnitude of the M-spike. This may be reflective of larger disease volume in bone marrow with less M protein detected in the peripheral blood. The appearance of accessory band associated with DARA treatment during weekly dosing may be a surrogate early marker for predicting disease response. Further large scale studies are required to confirm this findings. [ABSTRACT FROM AUTHOR]

Donor-derived natural killer (NK) cell alloreactivity has been shown to improve clinical outcomes following allogeneic stem cell transplant (HSCT). Host versus graft (HvG) directed NK cell alloreactivity can also occur. Several epitopes of HLA-B and HLA-C are ligands for inhibitory killer immunoglobulin-like receptors (KIRs) that regulate NK cell cytotoxicity. These KIR ligands (KIR-L) may be surrogates of NK cell alloreactivity in the HLA-mismatched setting. To determine the impact of donor/recipient KIR-L mismatch (KIR-L-MM) direction on engraftment, we examined cord blood (CBT) and haploidentical (Haplo) HSCT performed at our institution between 2011 and 2018. We computed KIR-L and direction of KIR-L-MM for recipient/ donor pairs using the KIR ligand calculator (https://www.ebi.ac.uk/ipd/kir/ligand.html). Summary data and the relative risk of graft failure were analyzed. In the CBT cohort (N=70), there were KIR-L mismatches (KIR-L-MM) in the HvG and GvH direction in 32 and 31 recipient-cord blood unit pairs respectively. There were no KIR-L-MM in 26 transplants while seven had KIR-L-MM in both GvH and HvG directions. Overall, 16 CBT failed to engraft (23%). There was an increased risk of graft failure in recipients of HvG KIR-L-MM transplants (R.R 2.15; p=0.063) with this trend most significant when the mismatch was in HLA-C ligand (R.R 2.46; p=0.027); Figure 1. Out of 8 double CBTs where one cord unit had HvG KIR-L-MM, the non-mismatched unit fully engrafted in 7 cases (87.5%). In 6 double CBTs where there was KIR-L-MM from one cord unit in the GvH and the GvG (graft versus other graft) direction, 4 (67%) of such units became the dominant graft. Of 8 double CBTs in which both cord units had KIR-L-MM in the HvG direction there was graft failure in 3 (37.5%). Time to neutrophil engraftment and lymphocyte recovery when engraftment occurred was not significantly impacted by KIR-L-MM. In the Haplo cohort (N=26), all of the 5 graft failures (19%) were KIR-L mismatched only in the GvH direction (R.R 9.53; p=0.114). There were 9 HvG KIR-L-MM transplants and they all engrafted. Fourteen transplant pairs in this cohort had KIR-L-MM in the GvH direction; 2 pairs had both HvG and GvH KIR-L-MM while 3 pairs did not have any KIR-L-MM. Time to neutrophil engraftment was not impacted by GvH or HvG KIR-L-MM. This study suggests an increased likelihood of graft failure in CBT when HvG KIR-L-MM exists. There is also a trend in favor of engrafting the GvH/GvG KIR-L-MM unit in double CBT. These factors should be considered when selecting cord units for CBT. A similar graft failure effect of HvG KIR-L-MM is not seen in this small Haplo cohort; on the contrary the data suggests GvH directed KIR-L-MM associates with graft failure. This association merits exploration in a larger database. [ABSTRACT FROM AUTHOR]