Regimens For Hematopoietic Cell Transplantation Research Articles

Hematopoietic cell transplantation for DOCK8 deficiency: Results from a prospective clinical trial

DOCK8 deficiency is a primary immunodeficiency in which allogeneic hematopoietic cell transplantation (HCT) represents the only known cure. We tested the ability of a busulfan-based regimen to achieve reliable engraftment and high levels of donor chimerism with acceptable toxicity in a prospective clinical trial in DOCK8 deficiency. To both evaluate the ability of HCT to reverse the clinical phenotype and to correct the immunologic abnormalities by 1 year post HCT. We conducted a prospective HCT trial for recipients with DOCK8 deficiency. Subjects were recruited from October 5, 2010, to December 30, 2022. Donor sources included fully matched related and unrelated donors and haploidentical donors. The reduced toxicity, myeloablative conditioning regimen contained no serotherapy. Graft-versus-host disease (GVHD) prophylaxis included either a calcineurin inhibitor with methotrexate or post-HCT cyclophosphamide (PT/Cy) followed by tacrolimus and mycophenolate mofetil. The trial was later amended to study PT/Cy in all patients. (Pilot Study of Reduced-Intensity Hematopoietic Stem Cell Transplant of DOCK8 [NCT01176006].) RESULTS: Thirty-six subjects, both children and adults (median age 16.4 years), underwent HCT for DOCK8 deficiency. Most patients, 33 of 36 (92%), achieved full (≥98%) donor chimerism in whole blood as early as day+30. With a median potential follow-up of 7.4 years, 29 (80.6%) were alive with no evidence of new DOCK8 deficiency-related complications. PT/Cy was effective in reducing the risk of acute GVHD in patients who had received matched unrelated donor and haploidentical transplants, but it was associated with transient delays in immune-reconstitution and hemorrhagic cystitis. A busulfan-based HCT regimen using PT/Cy for GVHD prophylaxis and a broad range of donor types and hematopoietic cell sources were well tolerated, leading to the reversal of the clinical immunophenotype.

Thyroid and Adrenal Dysfunction in Hemoglobinopathies Before and After Allogeneic Hematopoietic Cell Transplant.

To determine the rate and clinical characteristics associated with abnormal thyroid and adrenal function in recipients of nonmyeloablative hematopoietic cell transplantation (HCT) for sickle cell disease (SCD) and beta-thalassemia. We retrospectively reviewed patients who enrolled in 4 nonmyeloablative HCT regimens with alemtuzumab and total body irradiation (TBI). Baseline and annual post-HCT data were compared, which included age, sex, sickle phenotype, thyroid panel (total T3, free T4, thyroid stimulating hormone, antithyroid antibodies), cortisol level, ACTH stimulation testing, ferritin, medications, and other relevant medical history. Among 43 patients in haploidentical transplant and 84 patients in the matched related donor protocols with mostly SCD, the rate of any thyroid disorder pre-HCT was 3.1% (all subclinical hypothyroidism) and post-HCT was 29% (10 hypothyroidism, 4 Grave's disease, and 22 subclinical hypothyroidism). Ninety-two (72%) patients had ferritin >1000 ng/dL, of which 33 patients (35.8%) had thyroid dysfunction. Iron overload was noted in 6 of 10 patients with hypothyroidism and 12 of 22 patients with subclinical hypothyroidism.Sixty-one percent were on narcotics for pain control. With respect to adrenal insufficiency (AI) pre-HCT, 2 patients were maintained on corticosteroids for underlying rheumatologic disorder and 8 had AI diagnosed during pre-HCT ACTH stimulation testing (total 10, 7.9%). Post-HCT, an additional 4 (3%) developed AI from corticosteroid use for acute graft vs host disease, Evans syndrome, or hemolytic anemia. Although iron overload was common in SCD, thyroid dysfunction pre-HCT related to excess iron was less common. Exposure to alemtuzumab or TBI increased the rates of thyroid dysfunction post-HCT. In contrast, AI was more common pre-HCT, but no risk factor was identified. AI post-HCT was infrequent and associated with corticosteroid use for HCT-related complications.

Optimization of Radiolabeling of a [90Y]Y-Anti-CD66-Antibody for Radioimmunotherapy before Allogeneic Hematopoietic Cell Transplantation.

For patients with acute myeloid leukemia, myelodysplastic syndrome, or acute lymphoblastic leukemia, allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment. In addition to standard conditioning regimens for HCT, high-dose radioimmunotherapy (RIT) offers the unique opportunity to selectively deliver a high dose of radiation to the bone marrow while limiting side effects. Modification of a CD66b-specific monoclonal antibody (mAb) with a DTPA-based chelating agent should improve the absorbed dose distribution during therapy. The stability and radioimmunoreactive fraction of the radiolabeled mAbs were determined. Before RIT, all patients underwent dosimetry to determine absorbed doses to bone marrow, kidneys, liver, and spleen. Scans were performed twenty-four hours after therapy for quality control. A radiochemical purity of >95% and acceptable radioimmunoreactivity was achieved. Absorbed organ doses for the liver and kidney were consequently improved compared to reported historical data. All patients tolerated RIT well with no treatment-related acute adverse events. Complete remission could be observed in 4/5 of the patients 3 months after RIT. Two patients developed delayed liver failure unrelated to the radioimmunotherapy. The improved conjugation and radiolabeling procedure resulted in excellent stability, radiochemical purity, and CD66-specific radioimmunoreactivity of 90Y-labeled anti-CD66 mAb. RIT followed by conditioning and HCT was well tolerated. Based on these promising initial data, further prospective studies of [90Y]Y-DTPA-Bn-CHX-A″-anti-CD66-mAb-assisted conditioning in HCT are warranted.

Busulfan Interlaboratory Proficiency Testing Program Revealed Worldwide Errors in Drug Quantitation and Dose Recommendations.

The clinical outcomes of busulfan-based conditioning regimens for hematopoietic cell transplantation (HCT) have been improved by personalizing the doses to target narrow busulfan plasma exposure. An interlaboratory proficiency test program for the quantitation, pharmacokinetic modeling, and busulfan dosing in plasma was developed. Previous proficiency rounds (ie, the first 2) found that 67%-85% and 71%-88% of the dose recommendations were inaccurate, respectively. A proficiency test scheme was developed by the Dutch Foundation for Quality Assessment in Medical Laboratories (SKML) and consisted of 2 rounds per year, with each round containing 2 busulfan samples. In this study, 5 subsequent proficiency tests were evaluated. In each round, the participating laboratories reported their results for 2 proficiency samples (ie, low and high busulfan concentrations) and a theoretical case assessing their pharmacokinetic modeling and dose recommendations. Descriptive statistics were performed, with ±15% for busulfan concentrations and ±10% for busulfan plasma exposure. The dose recommendations were deemed accurate. Since January 2020, 41 laboratories have participated in at least 1 round of this proficiency test. Over the 5 rounds, an average of 78% of the busulfan concentrations were accurate. Area under the concentration-time curve calculations were accurate in 75%-80% of the cases, whereas only 60%-69% of the dose recommendations were accurate. Compared with the first 2 proficiency test rounds (PMID 33675302, October, 2021), the busulfan quantitation results were similar, but the dose recommendations worsened. Some laboratories repeatedly submit results that deviated by more than 15% from the reference values. The proficiency test showed persistent inaccuracies in busulfan quantitation, pharmacokinetic modeling, and dose recommendations. Additional educational efforts have yet to be implemented; regulatory efforts seem to be needed. The use of specialized busulfan pharmacokinetic laboratories or a sufficient performance in busulfan proficiency tests should be required for HCT centers that prescribe busulfan.

Total marrow irradiation in hematopoietic stem cell transplantation for hematologic malignancies.

Total body irradiation (TBI) has been an essential component of the conditioning regimen in hematopoietic cell transplantation for many years. However, higher doses of TBI reduce disease relapse at the expense of more significant toxicities. Therefore, total marrow irradiation and total marrow and lymphoid irradiation have been developed to deliver organ-sparing targeted radiotherapy. Data from different studies show that TMI and TMLI can be safely administered in escalating doses in association with different chemotherapy conditioning regimen protocols, in situations with unmet needs, such as multiple myeloma, high-risk hematologic malignancies, relapsed or refractory leukemias, and elderly or frail patients, with low rates of transplant-related mortality. We reviewed the literature on applying TMI and TMLI techniques in autologous and allogeneic hematopoietic stem cell transplantation in different clinical situations.

Idiopathic Pneumonitis Syndrome After Total Body Irradiation in Pediatric Patients Undergoing Myeloablative Hematopoietic Stem Cell Transplantation: A PENTEC Comprehensive Review

Pulmonary complications, especially idiopathic pneumonitis syndrome (IPS), are potentially life altering or fatal sequelae of hematopoietic cell transplantation (HCT). Total body irradiation (TBI) as part of the conditioning regimen has been implicated in IPS. A comprehensive PENTEC (Pediatric Normal Tissues in the Clinic) review was performed to increase our understanding of the role of TBI in the development of acute, noninfectious IPS. A systematic literature search was conducted using the MEDLINE, PubMed, and Cochrane library databases for articles describing pulmonary toxicity in children treated with HCT. Data pertaining to TBI and pulmonary endpoints were extracted. Risk of IPS was analyzed in relation to patient age, TBI dose, fractionation, dose rate, lung shielding, timing, and type of transplant, with the goal to better understand factors associated with this complication in children undergoing HCT. A logistic regression model was developed using a subset of studies with comparable transplant regimens and sufficient TBI data. Six studies met criteria for modeling of the correlation of TBI parameters with IPS; all consisted of pediatric patients undergoing allogeneic HCT with a cyclophosphamide-based chemotherapy regimen. IPS was variably defined, but all studies that reported IPS were included in this analysis. The mean incidence of post-HCT IPS was 16% (range, 4%-41%). Mortality from IPS, when it occurred, was high (median, 50%; range, 45%-100%). Fractionated TBI prescription doses encompassed a narrow range of 9 to 14 Gy. Many differing TBI methods were reported, and there was an absence of 3-dimensional dose analysis of lung blocking techniques. Thus, a univariate correlation between IPS and total TBI dose, dose fractionation, dose rate, or TBI technique could not be made. However, a model, built from these studies based on prescribed dose using a normalized dose parameter of equivalent dose in 2-Gy fractions (EQD2), adjusted for dose rate, suggested correlation with the development of IPS (P = .0004). The model-predicted odds ratio for IPS was 24.3 Gy-1 (95% confidence interval, 7.0-84.3). Use of TBI lung dose metrics (eg, midlung point dose) could not be successfully modeled, potentially because of dosimetric uncertainties in the actual delivered volumetric lung dose and imperfections in our modeling process. This PENTEC report is a comprehensive review of IPS in pediatric patients receiving fractionated TBI regimens for allogenic HCT. IPS was not clearly associated with 1 single TBI factor. Modeling using dose-rate adjusted EQD2 showed a response with IPS for allogeneic HCT using a cyclophosphamide-based chemotherapy regimen. Therefore, this model suggests IPS mitigation strategies can focus on not just the dose and dose per fraction but also the dose rate used in TBI. More data are needed to confirm this model and to determine the influence of chemotherapy regimens and contribution from graft-versus-host disease. The presence of confounding variables (eg, systemic chemotherapies) that affect risk, the narrow range of fractionated TBI doses found in the literature, and limitations of other reported data (eg, lung point dose) may have prevented a more straightforward link between IPS and total dose from being observed.

Fludarabine plus reduced-intensity busulfan versus fludarabine plus myeloablative busulfan in patients with non-Hodgkin lymphoma undergoing allogeneic hematopoietic cell transplantation

Allogeneic hematopoietic cell transplantation (HCT) offers a possible cure for patients with relapsed and refractory non-Hodgkin lymphoma (NHL) through potentially beneficial graft versus lymphoma effects. However, allogeneic HCT is associated with high nonrelapse mortality (NRM). Fludarabine with reduced-intensity busulfan (Flu/Bu2) and myeloablative busulfan (Flu/Bu4) are commonly used in conditioning regimens for allogeneic HCT; however, data on their use in patients with NHL is limited. We investigated the effect of busulfan dose on outcomes by comparing Flu/Bu2 and Flu/Bu4 in patients with NHL who underwent allogeneic HCT. Our study included 415 adult patients with NHL who received Flu/Bu2 (315 patients) or Flu/Bu4 (100 patients) between January 2008 and December 2019. All patients were enrolled in the Transplant Registry Unified Management Program 2 of the Japanese Data Center for Hematopoietic Cell Transplantation. The primary endpoint was the 5-year overall survival (OS). To minimize potential confounding factors that may influence outcomes, we performed propensity score matching. The 5-year OS was 50.6% (95% confidence interval (CI), 39.4%–60.8%) and 32.2% (95% CI, 22.4–42.4%) in the Flu/Bu2 and Flu/Bu4 groups, respectively (p = 0.006). The hazard ratio comparing the two groups was 2.13 (95% CI, 1.30–3.50; p = 0.003). Both groups had a similar 5-year cumulative incidence of relapse (38.2% vs 41.3%; p = 0.581), and the Flu/Bu4 group had a higher cumulative incidence of 5-year NRM (15.7% vs 31.9%; p = 0.043). In this study, Flu/Bu4 was associated with worse OS compared with Flu/Bu2 because of high NRM in patients with NHL.

Long-term follow up of patients with hematological malignancies treated with total body irradiation using intensity modulated radiation therapy.

With the advent of modern radiation treatment technologies such as intensity modulated radiation therapy (IMRT), there has been increasing interest in its use for total body irradiation (TBI) conditioning regimens for hematopoietic cell transplantation (HCT) to achieve lower doses to critical organs such as the lungs and kidneys. Although this has been reported on in early studies, long-term safety and efficacy data is limited. We performed a single institution matched-pair retrospective analysis of patients treated with IMRT TBI and standard TBI between 2010 and 2020 to provide data on long-term outcomes. Patients with hematologic malignancies, who could not tolerate standing for traditional TBI or who received prior radiation received IMRT TBI. Patients were matched based on age, diagnosis, disease status, and year of transplant, and were matched 2:1 to the standard TBI and IMRT TBI cohorts. Patient and treatment characteristics, toxicity, graft-versus-host disease (GVHD), dosimetry, and outcomes were evaluated for each cohort. A total of 13 patients met inclusion criteria for the IMRT cohort, leading to 26 patients in the standard TBI cohort. There was no significant difference in relevant clinical factors between the cohorts. Reasons for using IMRT over conventional TBI included being unable to stand (n=5), prior radiation (n=5), and pediatric patient requiring anesthesia (n=3). Among living patients, median follow-up for all patients was 5.1 years in the IMRT TBI cohort and 5.5 years in the standard TBI cohort. The 5-yr estimate of OS was 68% in the IMRT TBI cohort and 60% in the standard TBI cohort (p=0.706). The 5-yr estimate of RFS was 54% in the IMRT TBI cohort and 60% in the standard TBI cohort (p=0.529). There was no clinically significant pneumonitis, nephritis, hypothyroidism, or cataracts reported in the IMRT TBI cohort. 41.7% of patients in the IMRT TBI cohort and 79.2% of patients in the standard TBI cohort experienced Grade II-IV acute GVHD (p=0.023). IMRT TBI appears to lead to favorable long-term outcome and dosimetry, and therefore potentially improved long-term toxicity profile compared to conventional TBI. IMRT TBI warrants further investigation as part of larger prospective trials.

Efficacy and Safety of a Novel Non-Myeloablative Conditioning Regimen for Hematopoietic Cell Transplantation in Adults with Severe Aplastic Anemia

Introduction The distinct "age effect" that exists in severe aplastic anemia (SAA) following hematopoietic cell transplantation (HCT) favors the use of reduced intensity conditioning regimens in patients >40 years. For older adults, overall survival and disease-free survival (DFS) is reduced with increasing age and unrelated donor transplant are associated with higher rates of graft failure, Epstein-Barr virus (EBV) reactivation, and post-transplant lymphoproliferative disorders (PTLD) (Rice C, et al. BBMT 2019.). To overcome this, a novel, non-myeloablative conditioning regimen called FCR, which consists of fludarabine, cyclophosphamide, and rituximab, was designed at Vanderbilt University Medical Center (VUMC) and the associated VA Tennessee Valley Healthcare System (TVHS) for use in all SAA patients. This regimen was subsequently evaluated in the first 11 SAA patients treated at VUMC/TVHS and found to result in lower toxicity, graft-versus-host disease (GVHD), and viral reactivation with no graft failure or relapse compared to historical controls (Gatwood KS, et al. BMT 2018.). Given these initial favorable results, FCR has now been expanded as the preferred conditioning regimen for all SAA patients undergoing HCT at our center, warranting follow-up evaluation in a larger cohort. Methods Utilizing institutional registries, all SAA patients were identified who underwent first allogeneic HCT using an FCR regimen (Figure 1) between January 2016 and May 2022. VUMC and TVHS Institutional Review Boards approved this retrospective analysis. Outcomes analyzed included time to engraftment, incidence of graft failure, incidence of acute GVHD (aGVHD) and chronic GVHD (cGVHD), rate of viral reactivation, post-HCT disease status, and number of inpatient hospital days through day +100. An analysis of 1-year GVHD-free, relapse-free survival (GRFS) was conducted in evaluable patients, with differences between the curves determined using log-rank tests. Results Twenty-four SAA patients underwent HCT from January 26, 2016 to May 11, 2022, the majority of which were male with a median age of 43.5 years (range: 22-62). All patients received at least one line of therapy prior to HCT with the most common treatment being the combination of cyclosporin A with anti-thymocyte globulin with or without eltrombopag and/or corticosteroid. Median time from diagnosis to transplantation was 434.5 days (range: 84-6408). Patients received transplants from matched related (n=8), haploidentical (n=2), and matched unrelated donors (n=14) using either a peripheral blood (PB) or bone marrow (BM) stem cell source (PB=15, BM=9). Median time to neutrophil and platelet engraftment was 14 days (range: 10-25) and 18 days (range: 10-38), respectively. No patients experienced graft failure. At median follow-up of 806.5 days (range: 72-2180) post-transplant, all patients were alive and in remission. No patients developed grade III-IV aGVHD and no differences in grade I-II aGVHD rates were noted based on stem cell source. By date of last follow-up, mild to moderate cGVHD graded per 2014 NIH criteria developed in 7 and 3 patients, respectively. There were no cases of severe cGVHD. Only 2 patients experienced a viral reactivation (cytomegalovirus [CMV]=1, EBV=1) by date of last follow-up. The case of EBV reactivation did not require treatment and did not progress to PTLD. The median number of inpatient hospital days required post-engraftment through the first 100 days post-transplant was 5 days (range: 0-21). The unadjusted Kaplan-Meier estimate of 1-year GRFS was 86.3% (95% CI: 72.8%-100%) (Figure 2), with moderate cGVHD accounting for all GFRS events in the study cohort. Conclusions The use of our novel non-myeloablative conditioning regimen in SAA is well tolerated with 0% non-relapse mortality and 100% DFS with low GVHD rates at 1-year post-transplant. Despite a high-risk population with median age >40 years, using primarily matched unrelated donors, and majority peripheral blood stem cell source, there were no deaths and rates of complications remained low. This study further supports the findings of our previous study, redemonstrating low rates of toxicity, severe GVHD and viral reactivation with no graft failure, relapse, or mortality. The use of these regimens needs to be validated in a larger cohort as they have the potential to provide a new standard of care for pre-HCT conditioning in SAA patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Demographic Disparities Related to Fertility Preservation Counseling in Patients Undergoing Bone Marrow Transplantation

Infertility is a well-documented adverse effect associated with certain chemotherapeutic agents and radiation therapy.1 High-dose chemotherapy and/or total body irradiation (TBI) are utilized in preparation for bone marrow transplant (BMT), with the intent of achieving complete myeloablation prior to transplant.2 BMT is commonly used as a curative treatment modality for both malignant and benign hematologic conditions. Given this necessary exposure to high-dose chemotherapy and TBI, both male and female patients undergoing BMT are therefore at extremely high risk of impaired fertility later in life. Discussions concerning fertility preservation are often psychologically challenging for patients preparing to undergo BMT. To address these concerns, many institutions have developed fertility preservation counseling programs that aim to provide patients and caregivers with the necessary information to make informed decisions regarding fertility preservation. As is the case with many resources in healthcare, certain populations have more access to these resources than others. The goal of this study was to gain insight into if demographic features such as age, race, socioeconomic status, and underlying diagnosis/indication for BMT impacted the likelihood that a patient received fertility preservation counseling prior to transplant. It was hypothesized that there would be statistically significant differences in the rates of fertility preservation counseling when patients are compared by age, gender, race, socioeconomic status, and underlying diagnosis. A pre-existing database of BMT patients treated at the University of Rochester Medical Center was used to generate a study population of 244 patients between the ages of 0-39 years old who underwent BMT between 2012-2020. Demographic features including age, gender, race, insurance type, zip code, and indication for transplant were extracted from the database. A retrospective chart review was then conducted to identify if patients had a visit with a reproductive endocrinology and infertility (REI) specialist or if any documented fertility preservation counseling occurred prior to transplant. Odds ratios were then calculated for each of the aforementioned independent demographic variables. The overall prevalence of documented fertility preservation counseling was low. Approximately 20% of patients had a documented REI visit, while 47% had any form of documented fertility preservation counseling. There were differences in the prevalence of fertility preservation counseling related to patient age at transplant and median county income. Adult patients (age >18) were more likely than pediatric patients (age <18) to have a documented visit with an REI specialist (OR 2.99, 95% CI 1.37-6.51, p=0.0059) and more likely to have any documented fertility preservation counseling (OR 3.49, 95% CI 1.97-6.16, p<0.0001). Patients living in counties where the median income was >$60,000/year were more likely than patients living in counties with a median income of <$60,000/year to have a visit with an REI specialist (OR 4.25, 95% CI 1.89-9.54, p=0.0005) or any documented fertility preservation counseling (OR 2.72, 95% CI 1.59-4.64, p=0.0002). There were no statistically significant disparities in the prevalence of fertility preservation counseling based on patient gender, race, insurance type, or indication for transplant. These findings demonstrates that there are statistically significant differences in the prevalence of documented fertility preservation counseling based on demographic features, specifically on the basis of age and socioeconomic status. It is unclear if these findings represent the true prevalence of fertility preservation counseling, as some counseling is likely not adequately documented in the electronic medical record. Future studies are needed to design and implement improved fertility preservation counseling mechanisms, and to ensure adequate documentation of this counseling. Footnotes: 1. Rodriguez-Wallberg KA. Principles of cancer treatment: impact on reproduction. Adv Exp Med Biol. 2012;732:1-8. doi:10.1007/978-94-007-2492-1_1 2. Gyurkocza B, Sandmaier BM. Conditioning regimens for hematopoietic cell transplantation: one size does not fit all. Blood. 2014;124(3):344-353. doi:10.1182/blood-2014-02-514778

Endothelial Complications of Hematopoietic Cell Transplantation for Sickle Cell Disease

Introduction Hematopoietic cell transplantation (HCT) is a curative therapy for sickle cell disease (SCD), with especially favorable outcomes in young patients from HLA-identical donors. Unfortunately, HCT is associated with endothelial injury syndromes (EIS), including veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), transplant-associated thrombotic microangiopathy (TA-TMA), and also acute graft-versus-host disease (GVHD), that increase transplant risk. This is further complicated by hemolysis-mediated endothelial dysfunction in patients with SCD. The impact of EIS in this population is not certain. We thus sought to better evaluate endothelial complications of HCT for SCD in a large, international registry. Methods We examined de-identified records of HCT for SCD that were retrieved from data on patients transplanted between 1991 and 2020 in the United States submitted to the Center for International Blood and Marrow Transplant Research (CIBMTR) obtained through curesickle.org. Patients were followed longitudinally until death, loss to follow-up, or last contact through June 2021 at 3, 6, 12, and 24 months after HCT, and then every 2 years. Donors included HLA-matched siblings, haploidentical relatives, and HLA-matched and HLA-mismatched unrelated donors. We examined overall survival, event-free survival, and acute and chronic GVHD. Cox regression models were used to examine for risk factors associated with TMA and VOD. In addition, one-factor (univariate) analysis was used to identify factors associated with higher risk complications. Results A total of 1641 unique patients underwent a first allogeneic HCT between 1991 and 2020, with a median year of HCT of 2014. Of HCT recipients, 67.7% were below the age of 18 years at HCT and 74.7% had Karnofsky performance score ≥ 90. Acute GVHD grades II-IV developed in 18.3% and 22.3% developed chronic GVHD. Graft failure was reported in 17.6% following HCT, which was from an HLA-identical sibling in 61.5%, mismatched relative in 17.6%, matched unrelated donor in 10.2%, and mismatched unrelated donor in 10.7%. Conditioning regimen was myeloablative (50.8%), reduced intensity (23%), or non-myeloablative (22.3%). Patients were followed for a median of 47.8 months (0.3 - 312.9), with 3-year overall survival 91.2% and 3-year event-free survival 85.2%. Median time to death was 9.6 months for 152 patients. Estimated hazard ratio (HR) of death in 7/8 vs. 8/8 HLA matching was 1.5 (95% CI: 0.752, 2.445), which was not statistically significant. However, HR of death for ≤ 6/8 vs. 8/8 HLA matching was 1.7 (95% CI: 1.215, 2.445), indicating a statistically significant increased risk of death. TA-TMA was reported in 27 patients at a median of 2.8 months post-HCT. Univariate analysis of risk factors for TA-TMA indicated increasing incidence with the year of HCT. Age at HCT, HLA matching, and conditioning regimen intensity were not significantly associated. VOD was reported in 24 cases; Cox proportional hazards analysis indicated decreasing incidence with year of HCT. Estimated HR for VOD of patients who developed grade II-IV AGVHD group was 2.965, (95% C.I. 1.089, 8.074). Age at HCT, conditioning intensity, and donor type were not significant. Acute and chronic GVHD were associated with recipient age > 10 years and donors other than HLA-matched siblings; non-myeloablative conditioning was protective against GHVD development. Conclusion Incidence of endothelial complications following HCT for SCD is low, although TA-TMA has been increasingly recognized in recent years. VOD has been observed less frequently over time and correlates with acute GVHD. Donor type, recipient age, and conditioning intensity have the greatest impact on GVHD development.

Role of radiotherapy in treatment of extramedullary relapse following total marrow and lymphoid irradiation in high-risk and/or relapsed/refractory acute leukemia.

Total Marrow and Lymphoid Irradiation (TMLI) is a promising component of the preparative regimen for hematopoietic cell transplantation in patients with high-risk acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL). Extramedullary (EM) relapse after TMLI is comparable to TBI and non-TBI conditioning regimens. This study evaluates outcomes of patients treated with radiotherapy (RT) with EM relapse previously treated with TMLI. A retrospective analysis of five prospective TMLI trials was performed. TMLI targeted bones and major lymphoid tissues using image-guided tomotherapy, with total dose ranging from 12 to 20 Gy. EM recurrences were treated at the discretion of the hematologist and radiation oncologist using RT ± chemotherapy. Descriptive statistics and survival analysis were then performed on this cohort. In total, 254 patients with refractory or relapsed AML or ALL were treated with TMLI at our institution. Twenty-one patients were identified as receiving at least one subsequent course of radiation. A total of 67 relapse sites (median=2 sites/patient, range=1-16) were treated. Eleven relapsed patients were initially treated with curative intent. Following the initial course of subsequent RT, 1-year, 3-year and 5-year estimates of OS were 47.6%, 32.7% and 16.3%, respectively. OS was significantly better in patients treated with curative intent, with median OS of 50.7 months vs 1.6 months (p<0.001). 1-year, 3-year and 5-year estimates of PFS were 23.8%, 14.3% and 14.3%, respectively. PFS was significantly better in patients treated with curative intent, with median PFS of 6.6 months vs 1.3 months (p<0.001). Following RT, 86.6% of the sites had durable local control. RT is an effective modality to treat EM relapse in patients with acute leukemia who relapse after HCT achieving high levels of local control. In patients with limited relapse amenable to curative intent, radiation confers favorable long-term survival. Radiation as salvage treatment for EM relapse after HCT warrants further evaluation.

Total marrow irradiation (TMI): Addressing an unmet need in hematopoietic cell transplantation - a single institution experience review.

PurposeTMI utilizes IMRT to deliver organ sparing targeted radiotherapy in patients undergoing hematopoietic cell transplantation (HCT). TMI addresses an unmet need, specifically patients with refractory or relapsed (R/R) hematologic malignancies who have poor outcomes with standard HCT regimens and where attempts to improve outcomes by adding or dose escalating TBI are not possible due to increased toxicities. Over 500 patients have received TMI at this center. This review summarizes this experience including planning and delivery, clinical results, and future directions.MethodsPatients were treated on prospective allogeneic HCT trials using helical tomographic or VMAT IMRT delivery. Target structures included the bone/marrow only (TMI), or the addition of lymph nodes, and spleen (total marrow and lymphoid irradiation, TMLI). Total dose ranged from 12 to 20 Gy at 1.5-2.0 Gy fractions twice daily.ResultsTrials demonstrate engraftment in all patients and a low incidence of radiation related toxicities and extramedullary relapses. In R/R acute leukemia TMLI 20 Gy, etoposide, and cyclophosphamide (Cy) results in a 1-year non-relapse mortality (NRM) rate of 6% and 2-year overall survival (OS) of 48%; TMLI 12 Gy added to fludarabine (flu) and melphalan (mel) in older patients (≥ 60 years old) results in a NRM rate of 33% comparable to flu/mel alone, and 5-year OS of 42%; and TMLI 20 Gy/flu/Cy and post-transplant Cy (PTCy) in haplo-identical HCT results in a 2-year NRM rate of 13% and 1-year OS of 83%. In AML in complete remission, TMLI 20 Gy and PTCy results in 2-year NRM, OS, and GVHD free/relapse-free survival (GRFS) rates of 0%, 86·7%, and 59.3%, respectively.ConclusionTMI/TMLI shows significant promise, low NRM rates, the ability to offer myeloablative radiation containing regimens to older patients, the ability to dose escalate, and response and survival rates that compare favorably to published results. Collaboration between radiation oncology and hematology is key to successful implementation. TMI/TMLI represents a paradigm shift from TBI towards novel strategies to integrate a safer and more effective target-specific radiation therapy into HCT conditioning beyond what is possible with TBI and will help expand and redefine the role of radiotherapy in HCT.

Risk of Subsequent Malignant Neoplasms Following Hematopoietic Stem Cell Transplantation with Total Body Irradiation or Total Marrow Irradiation: Insights from Early Follow-Up

Total marrow irradiation (TMI) is an alternative to total body irradiation (TBI) as a component of the conditioning regimen for hematopoietic cell transplantation (HCT), offering the ability to deliver more targeted doses and facilitating organ-sparing. The organ-sparing effect of TMI is theorized to decrease the risk of complications associated with radiation, including subsequent malignant neoplasms (SMNs), while allowing for dosage escalation to improve oncologic outcomes. The purpose of this study was to compare SMNs rates among patients treated with TBI- or TMI-based conditioning regimens. We hypothesized that TMI would yield a rate of SMNs comparable to, if not lower than, TBI. A retrospective matched-pair analysis of patients who underwent allogeneic HCT and received either TBI- or TMI-based conditioning regimens to a total dose of 12 to 20 Gy was performed. A total of 171 patients received TMI-based conditioning and 171 received TBI-based conditioning, matched based on age, sex, diagnosis, and length of follow-up. SMNs were identified from an established long-term follow-up protocol, our institutional cancer registry, and the California Cancer Registry. There were no significant differences in patient and clinical characteristics between the TMI and TBI cohorts except for clinical response status at transplantation and radiation dose. As expected, patients in the TMI received higher radiation doses (median dose, 16.0 Gy for the TMI cohort versus 13.2 Gy for the TBI cohort; P < .001). The median follow-up for both cohorts was 2.0 years (range, .5 to 12.3 years). There was no significant difference in the risk of developing SMNs between the 2 cohorts (P=.81). A total of 9 patients (5.3%) conditioned with TBI and 10 patients (5.8%) conditioned with TMI developed SMNs, at a median of 3.3 years and 1.7 years following HCT, respectively. Excluding nonmelanoma skin cancers and noninvasive neoplasms, 2 patients in the TBI cohort developed SMNs (both melanomas), and 1 patient in the TMI cohort developed an SMN (colon cancer). No patients developed a subsequent hematologic malignancy. TMI-based conditioning is not associated with a significant difference in the risk of developing SMNs compared with TBI-based conditioning during early post-HCT follow-up. Future studies with longer follow-up may be needed to further characterize the risk of SMNs associated with TMI-based conditioning regimens compared with TBI-based regimens.

Favorable outcomes with durable chimerism after hematopoietic cell transplantation using busulfan and fludarabine-based reduced-intensity conditioning for pediatric patients with hemophagocytic lymphohistiocytosis

BackgroundThe incorporation of a reduced-intensity conditioning (RIC) regimen in hematopoietic cell transplantation (HCT) for patients with hemophagocytic lymphohistiocytosis (HLH) has decreased early mortality but is associated with a high rate of mixed chimerism and graft failure. Here, we present a successful single-center experience using busulfan and a fludarabine-based RIC regimen for the treatment of HLH.MethodsThe medical records of pediatric patients with HLH who underwent HCT using a busulfan/fludarabine-based RIC regimen between January 2008 and December 2017 were reviewed retrospectively.ResultsNine patients received HCT with a busulfan/fludarabine-based RIC regimen. Three patients had primary HLH, and the other six patients had secondary HLH with multiple reactivations. All three patients with primary HLH had UNC13D mutations. All patients achieved neutrophil and platelet engraftment at a median of 11 days (range, 10‒21) and 19 days (range, 13‒32), and all eight evaluable patients had sustained complete donor chimerism at the last follow-up. Two patients (22%) experienced grade 2 acute graft-versus-host disease (GVHD). Two patients (22%) developed chronic GVHD, and one died from chronic GVHD. One patient (11%) experienced reactivation 4 months after HCT from a syngeneic donor and died of the disease. The 8-year overall survival and event-free survival rates were 78%. No early treatment-related mortality within 100 days after HCT was observed.ConclusionOur experience suggests that a busulfan/fludarabine-based RIC regimen is a viable option for pediatric patients with HLH who require HCT.

Patterns and Outcomes of Relapse Treated With Radiotherapy Following Total Marrow and Lymphoid Irradiation in High-Risk and/or Relapsed/Refractory Acute Leukemia

Total Marrow and Lymphoid Irradiation (TMLI) is a promising component of the preparative regimen for hematopoietic cell transplantation in patients with high-risk and/or relapsed/refractory acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL), which has poor 5-yr OS at ∼15%. Extramedullary (EM) relapse rates in patients treated with this regimen has been reported to be ∼13%. This study evaluates patterns and outcomes of radiotherapy (RT) used to treat patients with EM relapse previously treated with TMLI.An IRB-approved analysis of 5 prospective TMLI trials was interrogated (IRB 04199, 05013, 05021, 14012, and 14106). Pre-transplant conditioning consisted of TMLI and etoposide (VP-16)/cyclophosphamide, fludarabine/melphalan, or bulsulfan/VP-16. TMLI targeted bones and major lymphoid tissues using image-guided tomotherapy, with total dose ranging from 12 to 20Gy delivered twice daily. EM recurrences were treated at the discretion of the hematologist and radiation oncologist using RT ± chemotherapy. Descriptive statistics and survival analysis were then performed on this cohort.In total, 254 patients with AML or ALL were treated with TMLI at our institution between 2006 and 2018. 21 of these patients were identified as receiving at least one subsequent course of radiation. A total of 67 relapse sites (median = 2 sites/patient, range = 1-16) were treated (6 lymph node, 34 soft tissue, 23 bone, and 4 CNS). At time of transplant, median age was 31 yrs (21-61 years). The median follow-up from date of transplant of these patients was 32.2 mo (3.9-154.1 mo). Of the 21 patients, 17 had active disease (MRD+ and/or bone marrow+) at transplant and 6 had prior history of EM disease. 12 patients had EM relapse only without BM relapse, while 5 had prior BM relapse and 4 had simultaneous EM and BM relapse. 12 recurrences were treated with systemic therapy prior to RT. The median mean TMLI dose to these sites was 12.0 Gy (4.0-20.8 Gy). 1-yr and 5-yr estimates of OS were 80.9% (95% CI = 56.9-92.4%) and 35.6% (95% CI = 13.8-58.3%), respectively. 1 and 2-yr OS following salvage RT to the first site of EM recurrence was 45.4% (95% CI = 23.1-65.3%) and 38.9% (95% CI = 17.7-59.8%), respectively. The median salvage RT dose was 24 Gy (6-30 Gy). Following RT, 86.6% of the sites had durable local control.To our knowledge, this is the largest analysis to date of patients treated with TMLI. Relapse incidence was as frequent in regions receiving ≥12 Gy as those receiving < 12 Gy, suggesting TMLI is not associated with an increased EM relapse risk. These patients did not have significantly different OS compared to historical controls. RT is an effective modality to treat EM relapse in patients with acute leukemia who were previously treated with TMLI.

Intravenous Busulfan-Based Conditioning Regimens in Allogeneic Hematopoietic Cell Transplantation for Patients with Acute Lymphoblastic Leukemia

Introduction: Intravenous busulfan is a common component of high-dose conditioning regimens for hematopoietic cell transplantation (HCT), but it has not been well investigated in acute lymphoblastic leukemia (ALL). We retrospectively evaluated intravenous busulfan-based conditioning regimens for allogeneic HCT for adult patients with ALL.Methods: This study included 195 patients with ALL who were in first complete remission (CR) at the time of allogeneic HCT. All patients received intravenous busulfan-based conditioning regimens: 4-day busulfan (3.2 mg/kg x 4d) plus cyclosphosphamide (n=80), 4-day busulfan plus fludarabine (n=20), and 2-day busulfan (3.2 mg/kg x 2d) plus fludarabine (n=95). Antithymocyte globulin was added at doses between 3.75 and 12 mg/kg in 104 patients.Results: The hematopoietic cell donor was an HLA matched sibling for 82 patients, an unrelated matched volunteer for 79, and a mismatched family member for 34. All but two patients achieved an absolute neutrophil count > 500/μL on median day 12. Acute graft-versus-host disease (GVHD) occurred in 61 patients (31%): grade I in 27, grade II in 17, and grade III/V in 17, while 100 (52%) of 192 assessable patients developed chronic GVHD: mild in 17, moderate in 33, and severe in 50. After a median follow-up of 4.9 years, 72 patients relapsed, and 85 died. Twenty-five deaths were nonrelapse deaths. The probabilities of overall survival, relapse-free survival, and nonrelapse mortality at 2 years were 68%, 66%, and 10%, respectively. Post-transplant outcomes were not significantly different between 4-d busulfan and 2-d busulfan. Patients with chronic GVHD had superior outcomes compared with those without chronic GVHD, mainly because of lower incidence of relapse.Conclusion: Our study results demonstrate that intravenous busulfan-based conditioning regimens provide effective disease control for ALL with relatively low nonrelapse mortality, and graft-versus-leukemia effects are present after allogeneic HCT for patients with ALL. DisclosuresKo:Boehringer Ingelheim: Research Funding. Lee:Boehringer Ingelheim: Research Funding. Park:Boehringer Ingelheim: Research Funding. Choi:Boehringer Ingelheim: Research Funding. Lee:Boehringer Ingelheim: Research Funding.

Outcomes of a Novel Rituximab-Based Non-Ablative Conditioning Regimen for Hematopoietic Cell Transplantation in Severe Aplastic Anemia

IntroductionOlder patients with severe aplastic anemia (SAA) needing hematopoietic cell transplantation (HCT) typically require utilization of reduced intensity conditioning (RIC) regimens; however, use of RIC regimens in this population is limited by graft failure and transplant-related mortality due to toxicity and infections, particularly reactivation of Epstein-Barr virus (EBV). Novel RIC regimens with improved efficacy and decreased toxicity and risk of infectious complications are urgently needed to improve post-HCT outcomes for SAA patients.Patients and MethodsUtilizing institutional registries, we identified all SAA patients who underwent first allogeneic HCT using an FCR regimen (Figures 1A and 1B) between August 2014 and May 2017 at our institution for inclusion in this analysis. Post-transplant immune suppression comprised of tacrolimus and either methotrexate or mycophenolate mofetil. The Institutional Review Board approved this analysis and a waiver of informed consent was obtained. Medical records of all patients were reviewed by participating investigators. Assessment of graft-versus-host disease (GVHD) was performed following standard grading practice. An analysis of 1-year GVHD-free, relapse-free survival (GRFS) was conducted and compared to an historical cohort of all SAA patients transplanted with a non-FCR regimen at our institution since January 1999 (n=27), with differences between the curves determined using log-rank tests.Results11 SAA patients underwent HCT from August 1, 2014 to May 5, 2017, the majority of which were male with a median age of 41 years (range: 19-64). Most patients received one line of treatment prior to HCT (CSA+ATG=6, CSA=1, steroids=1) and received an HCT within a median of 205 days after diagnosis (range: 70-2090). All patients received transplants from matched or haploidentical donors (matched related=4, matched unrelated=5, haploidentical=2) using a peripheral blood stem cell source, except 1 patient who received a bone marrow graft. At median follow-up of 302 (range: 49-911) days post-transplant, all patients were alive and in remission with 100% donor peripheral blood chimerism with bone marrow biopsies documenting normal trilineage hematopoiesis. Average time to neutrophil and platelet engraftment was 15.4 days and 16 days, respectively. The median number of inpatient hospital days required in the first 100 days post-transplant was 11 days (range: 3-29). By day 100 post-transplant, 54.5% of patients developed some degree of acute GVHD (grade I=1, grade II=3, grade III=2). However, by date of last follow-up, all evaluable patients (10/11) had not developed chronic GVHD. Only 2 patients experienced a viral reactivation (1=cytomegalovirus (CMV), 1=CMV+EBV) by date of last follow-up post-transplant. The case of EBV reactivation did not require treatment and no patients developed post-transplant lymphoproliferative disorder. The unadjusted Kaplan-Meier estimate of 1-year GRFS was 81.8% (95% CI: 59.1-104.7%) in the study group versus 61.5% (95% CI: 42.9-80.1%) in the historical group (P=0.256) (Figure 1C) with death accounting for the greatest proportion of GRFS events in the historical population and grade III acute GVHD accounting for the two GRFS events in the study cohort.ConclusionsThe positive results from this study demonstrating low toxicity, GVHD, and EBV reactivation rates with no graft failure or relapse potentially justify the use of these novel outpatient non-myeloablative conditioning regimens in SAA patients of any age receiving transplantation from any donor source. Further prospective investigation in a larger population is warranted. [Display omitted] DisclosuresGatwood:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Byrne:Pfizer: Membership on an entity's Board of Directors or advisory committees; Concert Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Research Funding. Jagasia:Therakos: Consultancy, Research Funding; Mallinckrodt: Consultancy; Janssen: Consultancy, Research Funding. Savani:Jazz Pharmaceuticals: Speakers Bureau.

Yttrium-90 Anti-CD45 Immunotherapy Followed by Autologous Hematopoietic Cell Transplantation for Relapsed or Refractory Lymphoma

Autologous hematopoietic cell transplantation (AHCT) is a standard of care for several subtypes of high-risk lymphoma, but durable remissions are not achieved in the majority of patients. Intensified conditioning using CD45-targeted antibody-radionuclide conjugate (ARC) preceding AHCT may improve outcomes in lymphoma by permitting the delivery of curative doses of radiation to disease sites while minimizing toxicity. We performed sequential phase I trials of escalating doses of yttrium-90 (90Y)-labeled anti-CD45 antibody with or without BEAM (carmustine, etoposide, cytarabine, melphalan) chemotherapy followed by AHCT in adults with relapsed/refractory or high-risk B cell non-Hodgkin lymphoma (NHL), T cell NHL (T-NHL), or Hodgkin lymphoma (HL). Twenty-one patients were enrolled (16 NHL, 4 HL, 1 T-NHL). Nineteen patients received BEAM concurrently. No dose-limiting toxicities were observed; therefore, the maximum tolerated dose is estimated to be ≥34 Gy to the liver. Nonhematologic toxicities and engraftment kinetics were similar to standard myeloablative AHCT. Late myeloid malignancies and 100-day nonrelapse deaths were not observed. At a median follow-up of 5 years, the estimates of progression-free and overall survival of 19 patients were 37% and 68%, respectively. Two patients did not receive BEAM; one had stable disease and the other progressive disease post-transplant. The combination of 90Y-anti-CD45 with BEAM and AHCT was feasible and tolerable in patients with relapsed and refractory lymphoma. The use of anti-CD45 ARC as an adjunct to hematopoietic cell transplantation regimens or in combination with novel therapies/immunotherapies should be further explored based on these and other data.

Allogeneic Transplantation for Myelodysplastic Syndrome in Adults over 50 Years Old Using Reduced Intensity/Non-Myeloablative Conditioning: Haploidentical Relative Versus Matched Unrelated Donor

Background: Allogeneic hematopoietic cell transplantation (HCT) has been a successful strategy to treat myelodysplastic syndrome (MDS). With only approximately one-third of patients having an HLA matched sibling, most transplants use mismatched relative (haploidentical) or unrelated donors. In the current analysis we sought to study outcomes after haploidentical related compared to HLA-matched unrelated donor HCT for MDS (de novo or therapy-related). Methods: We retrospectively studied 176 recipients of haploidentical related donor and 427 recipients of 8/8 HLA-matched unrelated donor HCT in the United States between 2012 and 2017. The primary outcome was overall survival. The effect of donor type on survival and other transplant outcomes were studied using a Cox regression model. Results: Patient and disease characteristics are presented in Table 1. Most transplants (85%) were for de novo MDS in both donor groups. Although all patients received reduced intensity regimens, the predominant conditioning regimens were confounded by donor type. Total body irradiation (TBI) 200 cGy/cyclophosphamide/fludarabine (TBI/Cy/Flu; 82%) was the predominant regimen for haploidentical HCT and fludarabine with busulfan or melphalan (Flu/Bu or Flu/Mel; 79%) without in vivo T-cell depletion was the predominant regimen for unrelated donor HCT. Similarly, graft-versus-host disease (GVHD) prophylaxis was also confounded by donor type. Posttransplant cyclophosphamide/calcineurin inhibitor/mycophenolate (PT-Cy/CNI/MMF) was the prophylaxis regimen for all haploidentical transplants. CNI/MMF (31%) or CNI/methotrexate (69%) was used for unrelated donor transplants. Peripheral blood was the predominant graft for both donor types. The median follow-up was 24 months (range 3-77) after haploidentical and 36 months (range 3-74) after unrelated donor HCT. Results of multivariate analysis, adjusted for HCT-CI, prior treatment with hypomethylating agents (HMAs), and IPPS-R did not show differences in survival by donor type (HR 0.98, p=0.85; 40% vs. 37%), Figure 1. However, the relapse rate (adjusted for prior HMAs, IPSS-R, and recipient sex) was higher after haploidentical compared to unrelated donor HCT (HR 1.60, p=0.002, 53% vs. 34%), which led to lower disease-free survival after haploidentical HCT (HR 1.30, p=0.03; 21% vs. 32%), Figure 1. To further test the effect of regimen intensity, low dose TBI regimens were compared to Flu/Bu and Flu/Mel; we did not observe a difference in relapse risk (HR 0.95, p=0.76). Non-relapse mortality did not differ by donor type (HR 0.88, p=0.46). Interval between diagnosis and transplant was also not associated with outcomes. Acute grade II-IV acute GVHD (HR 0.46, p&lt;0.001) and chronic GVHD (HR 0.34, p&lt;0.001) was less common after haploidentical HCT. The 1-year graft failure rate was higher after haploidentical compared to unrelated donor HCT (15% and 8%, respectively, p=0.02). Conclusion: Although the current analysis did not show differences in survival between haploidentical related and matched unrelated donor HCT, the higher relapse and consequently lower disease-free survival associated with the haploidentical HCT approach in this analysis (primarily TBI/Cy/Flu with PT-Cy/CNI/MMF) warrants caution. A more definitive comparison of the two donor types can be accomplished only if more haploidentical transplants were to use Flu/Bu or Flu/Mel conditioning. Figure 1 Disclosures Grunwald: Celgene: Consultancy; Pfizer: Consultancy; Agios: Consultancy; Merck: Consultancy; Abbvie: Consultancy; Medtronic: Equity Ownership; Incyte: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Amgen: Consultancy; Trovagene: Consultancy; Cardinal Health: Consultancy; Janssen: Research Funding; Genentech/Roche: Research Funding; Novartis: Research Funding; Forma Therapeutics: Research Funding. Bolanos-Meade:Incyte Corporation: Other: DSMB fees. Bredeson:Otsuka: Research Funding. Gupta:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sierra Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Research Funding. Mussetti:Takeda: Honoraria; BMS: Honoraria; Novartis: Honoraria; Italfarmaco: Honoraria. Nakamura:Merck: Membership on an entity's Board of Directors or advisory committees; Celgene: Other: support for an academic seminar in a university in Japan; Alexion: Other: support to a lecture at a Japan Society of Transfusion/Cellular Therapy meeting ; Kirin Kyowa: Other: support for an academic seminar in a university in Japan. Nishihori:Novartis: Research Funding; Karyopharm: Research Funding. Solh:Celgene: Speakers Bureau; Amgen: Speakers Bureau; ADC Therapeutics: Research Funding. Weisdorf:Fate Therapeutics: Consultancy; Pharmacyclics: Consultancy; Incyte: Research Funding.