Fludarabine Melphalan Research Articles

Transplantation for myelofibrosis patients in the ruxolitinib era: a registry study from the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire.

In this SFGM-TC registry study, we report the results after stem cell transplantation (HSCT) in 305 myelofibrosis patients, in order to determine potential risk factors associated with outcomes, especially regarding previous treatment with ruxolitinib. A total of 102 patients were transplanted from an HLA-matched-sibling donor (MSD), and 143 patients received ruxolitinib. In contrast with previous studies, our results showed significantly worse outcomes for ruxolitinib patients regarding overall survival (OS) and non-relapse mortality (NRM), especially in the context of unrelated donors (URD). When exploring reasons for potential confounders regarding the ruxolitinib effect, an interaction between the type of donor and the use of ATG was found, therefore subsequent analyses were performed separately for each type of donor. Multivariable analyses did not confirm a significant negative impact of ruxolitinib in transplantation outcomes. In the setting of URD, only age and Fludarabine-Melphalan (FM) conditioning were associated with increased NRM. For MSD, only Karnoksfy <70% was associated with reduced OS. However, a propensity score analysis showed that ruxolitinib had a negative impact on OS but only in non-responding patients, consistent with previous data. To conclude, with all the precautions due to confounders and bias, ruxolitinib itself does not appear to increase mortality after HSCT.

An Open Label Study Comparing Photobiomodulation Therapy to Cryotherapy in Patients at High Risk for Drug-Induced Oral Mucositis

Background and rationale Oral mucositis (OM) is one of the most common side effects of chemotherapy and may lead to weight loss and increased risk for infection ultimately impairing overall survival. Evaluated options for mucositis prophylaxis in patients receiving a high-dose chemotherapy include oral cryotherapy (CT) and photobiomodulation therapy (PBMT) using laser diodes to reduce incidence and severity of OM. However, standards of mucositis prophylaxis in German hospitals differ substantially. While CT has been standard of care in melphalan treated patients, the German guidelines for supportive oncology do not recommend the use of PBMT for patients receiving high-dose chemotherapy. Several clinical trials have demonstrated the beneficial effect of PBMT, however, no randomized clinical trials (RCT) exist to compare the efficacy of oral CT versus PBMT. Study design This is a single-center, open-label, randomized, two-arm interventional trial to evaluate the efficacy of PBMT and CT as prophylaxis of OM in patients with hematological malignancies receiving high-dose chemotherapy as part of a conditioning regimen prior to hematopoietic cell transplantation (HCT) or high-dose methotrexate (MTX, defined as ≥ 500 mg/m 2). Randomization will occur 1:1, stratified according to conditioning regimen/chemotherapy protocol. The primary endpoint of the trial is rate of severe OM as assessed by the world health organization (WHO) OM grading scale grade 3 or higher. Key secondary endpoints include duration of OM, patient reported pain, total parenteral nutrition, opioid usage, weight loss, length of in-patient stay and overall survival. Eligible patients randomized to receive PBMT will undergo daily laser therapy at 4 J/cm² of the oral mucosal areas most frequently affected by OM, starting on the first day of the administration of chemotherapy, until neutrophil engraftment or resolution of OM, whatever occurs first. Eligible patients randomized to oral CT will receive ice chips (IC) made from filtered tap water or flavored ice popsicles on days of chemotherapy infusions only, starting 5 min prior to chemotherapy until 30 min after the end of infusion. Patients ≥ 18 years of age, receiving therapies with high potential to induce OM, including the conditioning regimen high-dose melphalan, carmustine/etoposide/cytarabine/melphalan (BEAM), thiotepa/etoposide/cytarabine/melphalan (TEAM), fludarabine/thiotepa/melphalan (FTM) and fludarabine/melphalan (FM) or chemotherapy protocols with high-dose MTX, are included in this trial. The trial tests the null hypothesis (H 0) that the observed rate of severe OM with PBMT and CT prophylaxis are equal versus the alternative hypothesis (H 1) that the observed rate of severe OM differs between CT and PBMT. We estimate a rate of severe OM of 45 % in our trial population (H 0). With a power of 80 %, a type 1 error rate of 5 %, and an expected difference in severe OM rate of 30 % considered relevant between both arms, with an expected dropout rate of 5 %, n = 86 patients should participate in the study to ensure discrimination of H 0 and H 1. Conclusion This study aims to compare PBMT and CT with regard to their effectiveness in the prevention of severe OM in a randomized trial for the first time. Our objective is to provide data that may guide the development of a standardized OM prophylaxis for patients undergoing high-dose chemotherapy. At the time of abstract submission, 8 patients have been randomized in the study. Acknowledgments This is an independent academic trial conducted under the sponsor role of the University Cancer Center Schleswig-Holstein, Germany. This study is conducted in compliance with the protocol, Good Clinical Practice (GCP), all applicable regulatory requirements and the ethical principles of the Declaration of Helsinki.

Fludarabine melphalan versus fludarabine treosulfan for reduced intensity conditioning regimen in allogeneic hematopoietic stem cell transplantation: a retrospective analysis.

Various reduced-intensity conditioning (RIC) regimens are used to decrease toxicity while providing comparable outcomes to myeloablative regimens. We compared toxicity and outcomes between two RIC regimens, fludarabine with melphalan (Flu-Mel) and fludarabine with treosulfan (Flu-Treo), retrospectively over a 10-year period in two donor groups, matched related donor (MRD)/matched unrelated donor (MUD) and haploidentical (Haplo) transplants. The study included 138 patients, of which 105 received MRD/MUD (Flu-Mel: 94, Flu-Treo: 11) and 33 Haplo (Flu-Mel: 17, Flu-Treo: 16) transplants. In the MRD/MUD group, 44 (47%) of patients who received Flu-Mel had grade 3/4 oral mucositis compared to 1 (9%) who received Flu-Treo (P = 0.02). Corresponding numbers in the Haplo group were 7 (41%) and 1 (6%). Grade 3/4 diarrhoea was more frequent with Flu-Mel than Flu-Treo in the Haplo group (41% vs 6%; P = 0.039), but not the MRD/MUD group. Median follow-up time for all patients was 4.8years. Five-year OS in the MRD/MUD group was 62% with Flu-Mel versus 53% with Flu-Treo (P = 0.0694). Similarly, 5-year OS was 41% with Flu-Mel and 28% with Flu-Treo (P = 0.770) in the Haplo group. Severe mucositis and diarrhoea were significantly less frequent with Flu-Treo than Flu-Mel. Flu-Treo provided comparable outcomes to Flu-Mel in all donor transplants.

BI11 Cutaneous presentation of Kaposi sarcoma following allogeneic haematopoietic stem cell transplantation for myeloma

Abstract Iatrogenic Kaposi sarcoma (KS) is a relatively frequent occurrence following solid-organ transplants (0–5%), in part due to prolonged immunosuppression. However, its occurrence after haematopoietic stem cell transplantation (HSCT) is rare, with only 15 cases described in the literature. We report a case of KS presenting in the skin of a patient who had received a matched unrelated donor allogeneic HSCT for IgG kappa myeloma. A 55-year-old HIV-negative white man with myeloma underwent an allogeneic HSCT from a matched, unrelated donor following conditioning chemotherapy with fludarabine–melphalan and antithymocyte globulin. Post-transplant, he was maintained on ciclosporin as graft-versus-host disease (GVHD) prophylaxis. On day 14 post-transplant, he developed a widespread eczematous eruption that rapidly evolved into an erythroderma; a skin biopsy was consistent with acute GVHD. He was managed with superpotent topical steroids and a 5-day course of oral prednisolone. He began extracorporeal photopheresis (ECP) on day 33 post-transplant, having failed to respond adequately to systemic steroids. He also completed four cycles of rituximab. Ciclosporin was stopped by day 130 post-transplant. He had completed 14 cycles of ECP by day 139 post-transplant, with resolution of cutaneous GVHD; however, he had developed a rapidly growing solitary dusky-red nodule on his right neck that was excised due to diagnostic uncertainty. Histology revealed a dermal haemorrhagic exophytic vascular tumour composed of lobules and sheets of epithelioid cells with an eosinophilic cytoplasm and pleomorphic nuclei. Immunoperoxidase staining was negative for S100, MNF-116 and AE1/AE3. The same cells were strongly and diffusely positive for the vascular markers CD31, CD34 and ERG. The lesional cells were positive for human herpesvirus (HHV)-8 confirming a diagnosis of Kaposi sarcoma. He subsequently developed a second lesion on his left forearm, despite being off all immunosuppression. A repeat bone biopsy confirmed that he remains in morphological remission from his myeloma. Positron emission tomography–computed tomography has not identified extracutaneous disease. KS following HSCT is rare, but it can be fatal. Skin lesions are the dominant clinical presentation. HHV-8 has an important role in the pathogenesis, and transplant-related KS may occur secondary to reactivation of the virus as a result of significant immunosuppression following HSCT. However, it could also occur as primary infection or be transmitted with donor cells. The outcome of KS after HSCT is variable. A watch and wait strategy can be applied if immune recovery is expected. In our patient, it developed 5 months after HSCT; shortly after immunosuppression had been tapered, he remains well and will be closely monitored for further suspicious lesions.

Complex Restrictive Lung Disease Patterns Affecting Survival and Outcomes in Patients Undergoing Allogeneic Stem Cell Transplant: A Single-Institution Retrospective Analysis

Background: Allogeneic stem cell transplant is the only curative therapy for some patients with hematologic malignancies. While pulmonary function impairment related to diffusion capacity and air flow obstruction is part of the predictive Hematopoietic Cell Transplant-Comorbidity Index (HCT-CI), restrictive changes are poorly reflected. A new entity known as complex restrictive lung disease (CRLD) refers to a discrepancy between Forced Vital Capacity percent predicted (FVCpp) and Total Lung Capacity percent predicted (TLCpp). FVCpp being disproportionately lower than TLCpp occurs due to impaired lung emptying from neuromuscular disease, obesity, bronchiectasis, occult obstruction, pulmonary hypertension and chest wall limitations. In simple restrictive lung disease (SRLD) such as pulmonary fibrosis, FVCpp is proportionately decreased compared to TLCpp. Methods: Over three years, 124 patients received myeloablative (MA) or reduced intensity conditioning (RIC) followed by matched unrelated donor (MUD) or matched related donor (MRD) grafts. Patients had complete pulmonary function tests (PFT) within 60 days prior to transplant and 6 months post-transplant. Simple Restriction was defined as TLCpp - FVCpp <10%. Complex Restriction was defined as TLCpp - FVCpp >10%. Our primary outcome in this study was Median Overall Survival (mOS). Median follow up was 14 months. Results: For the 124 enrolled patients, demographics included median age of 55 years (range: 18-70), 60% male, MUD status (73%) with male donor (75%); half received RIC (52%) with fludarabine melphalan (62%) vs fludarabine/busulfan (FLU/BU2) (32%) compared to MA (40%) with FLU/BU4 conditioning (77%). The demographics of diagnosis include Acute Myeloid Leukemia (40%), Lymphoma (17%) and Acute Lymphoblastic Lymphoma (16%) and Myelodysplastic Syndrome (16%). The median HCT-CI/Age score was 4 (0-11). Half (62) developed acute graft-versus-host disease (aGVHD) with 80% as Grade 1-2. One patient was lost to follow up, 65 patients were still alive and 22 had relapse of their initial disease with 17 deaths related to relapse. Out of 58 deaths in this study, 41 deaths (71%) were attributed to non-relapse mortality (NRM) with NRM at 33% and relapse mortality rate at 14%. Out of 124 patients, 10 patients had complex restriction prior to transplant and 9 patients developed complex restriction at 6 months post-transplant. The mOS was 7 months for patients with CRLD prior to transplant (1-14 months) compared to 13 months for patients without CRLD (1- 36 months) (p=0.0026). Eight patients with CRLD before transplant were deceased at follow-up of 14 months, with four (50%) out of those eight deaths related to acute respiratory distress syndrome (25%) and hypoxic respiratory failure (25%). The non-relapse mortality rate for this population was 60% and relapse mortality rate was 10%. For all patients with aGVHD, mOS was greater than 30 months for aGVHD Grades 0-1, 16 months for Grade 2, 6 months for Grade 3 and 5 months for Grade 4 (p=0.0048). Six out of six patients with GVHD and CRLD prior to transplant died from acute respiratory distress syndrome (ARDS) hypoxia, or other cause. Out of the 4 patients with CRLD without GVHD, one patient developed respiratory failure as cause of death. There was no statistical difference in mOS due to BMI (p=0.2895). Nonsmokers and past smokers had a m0S of 22 months, with current smokers at 10 months m0S (p=0.13). We found no statistical difference in survival for the 9 patients who developed CRLD after transplant (p=0.45), the 10 patients with simple restriction prior to transplant (p=0.55), the 21 patients who developed Bronchiolitis Obliterans Syndrome (B0S) after transplant (p=0.25), or the 26 patients with Chronic Obstructive Pulmonary Disease (COPD) prior to transplant compared to normal PFT (p=0.14). The mOS for these groups was 12 months. Conclusion: Patients with complex restrictive lung disease prior to allogeneic stem cell transplant are at high risk for poor outcomes from respiratory and non-respiratory disease when compared to the overall population. As complex restriction is not included in the current HCT-CI, patients with this lung disease should have closer monitoring and scrutiny prior to allogeneic stem cell transplantation. Based on the results of this study, addition of complex restrictive lung disease to the HCT-CI to improve predictability of HCT outcomes warrants further investigation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Comparison of fludarabine–melphalan and fludarabine–treosulfan as conditioning prior to allogeneic hematopoietic cell transplantation—a registry study on behalf of the EBMT Acute Leukemia Working Party

In recent years considerable variations in conditioning protocols for allogeneic hematopoietic cell transplantation (allo-HCT) protocols have been introduced for higher efficacy, lower toxicity, and better outcomes. To overcome the limitations of the classical definition of reduced intensity and myeloablative conditioning, a transplantation conditioning intensity (TCI) score had been developed. In this study, we compared outcome after two frequently used single alkylator-based conditioning protocols from the intermediate TCI score category, fludarabine/melphalan 140 mg/m2 (FluMel) and fludarabine/treosulfan 42 g/m2 (FluTreo) for patients with acute myeloid leukemia (AML) in complete remission (CR). This retrospective analysis from the registry of the Acute Leukemia Working Party (ALWP) of the European Society of Bone Marrow Transplantation (EBMT) database included 1427 adult patients (median age 58.2 years) receiving either Flu/Mel (n = 1005) or Flu/Treo (n = 422). Both groups showed similar 3-year overall survival (OS) (54% vs 51.2%, p value 0.49) for patients conditioned with FluMel and FluTreo, respectively. However, patients treated with FluMel showed a reduced 3-year relapse incidence (32.4% vs. 40.4%, p value < 0.001) and slightly increased non-relapse mortality (NRM) (25.7% vs. 20.2%, p value = 0.06) compared to patients treated with FluTreo. Our data may serve as a basis for further studies examining the role of additional agents/ intensifications in conditioning prior to allo-HCT.

Reduced intensity conditioning for acute myeloid leukemia using melphalan- vs busulfan-based regimens: a CIBMTR report

AbstractThere is a lack of large comparative study on the outcomes of reduced intensity conditioning (RIC) in acute myeloid leukemia (AML) transplantation using fludarabine/busulfan (FB) and fludarabine/melphalan (FM) regimens. Adult AML patients from Center for International Blood and Marrow Transplant Research who received first RIC allo-transplant between 2001 and 2015 were studied. Patients were excluded if they received cord blood or identical twin transplant, total body irradiation in conditioning, or graft-versus-host disease (GVHD) prophylaxis with in vitro T-cell depletion. Primary outcome was overall survival (OS), secondary end points were leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and GVHD. Multivariate survival model was used with adjustment for patient, leukemia, and transplant-related factors. A total of 622 patients received FM and 791 received FB RIC. Compared with FB, the FM group had fewer transplant in complete remission (CR), fewer matched sibling donors, and less usage of anti-thymocyte globulin or alemtuzumab. More patients in the FM group received marrow grafts and had transplantation before 2005. OS was significantly lower within the first 3 months posttransplant in the FM group (hazard ratio [HR] = 1.82, P < .001), but was marginally superior beyond 3 months (HR = 0.87, P = .05). LFS was better with FM compared with FB (HR = 0.89, P = .05). NRM was significantly increased in the FM group during the first 3 months of posttransplant (HR = 3.85, P < .001). Long-term relapse was lower with FM (HR = 0.65, P < .001). Analysis restricted to patients with CR showed comparable results. In conclusion, compared with FB, the FM RIC showed a marginally superior long-term OS and LFS and a lower relapse rate. A lower OS early posttransplant within 3 months was largely the result of a higher early NRM.

Fludarabine Melphalan Versus Fludarabine Treosulfan As Reduced Intensity Conditioning Regimens in Allogeneic Hematopoietic Stem Cell Transplant - a Retrospective Analysis

Introduction Allogeneic hematopoietic stem cell transplantation (AHSCT) has evolved as a curative therapy for various hematological malignancies. Regimen-related toxicity and transplant-related mortality (TRM) preclude the use of myeloablative conditioning (MAC) regimens in older and unfit patients. Reduced intensity conditioning (RIC) regimens have enabled AHSCT in such patients. There is a recent rise in use of RIC regimens even in younger patients in view of decreased toxicity and equal efficacy as reported in some studies. Fludarabine + Melphalan (FM) and Fludarabine + Treosulfan (FT) are 2 such regimens. There are no prospective randomised comparisons between these regimens. We retrospectively analysed these 2 regimens for toxicities and outcomes. Methods This is a retrospective single centre analysis of all consecutive patients with haematological cancers who received either FM or FT from April 2008 to December 2018. The entire cohort was divided into two groups - Matched Sibling Donor (MSD)/Matched Unrelated Donor (MUD) and Haploidentical (Haplo) transplants for analysis. We compared patient characteristics, toxicities and outcomes in both the groups based on conditioning regimen. The FT regimen consisted of fludarabine (30 mg/m2 on days − 6 to − 2) combined with treosulfan (12-14 gm/m2 on days − 6 to − 4) with or without 2 Gy TBI on day-1. The FM regimen consisted of fludarabine (30 mg/m2 on days − 7 to − 3) combined with melphalan (140 mg/m2 on day -1).Prophylaxis for GVHD consisted of calcineurin inhibitor (CNI) plus methotrexate (MTX)or mycophenolate mofetil (MMF) in MSD/MUD. Rabbit ATG (2.5-5 mg/kg) was used for MUD. Haplo transplant patients received post-transplant cyclophosphamide with CNI and MMF. Comorbidities were scored according to the HCT-CI. Disease Risk Index(DRI) and EBMT score were recorded for all patients. Neutrophil (NE) and platelet engraftment (PE) were defined as per standard criteria. Early toxicity after AHCT was graded according to CTCAE version 4. Total parenteral nutrition (TPN) was used in patients as per the physician's discretion. Acute GVHD and chronic GVHD were recorded according to standard criteria. All patients underwent chimerism studies at day 15, 30 and then monthly for 1 year. Mixed chimerism was defined as &gt; 5% to &lt; 95% donor chimerism. The toxicities in various arms were compared by Chi-square test or Fisher exact test, while OS was calculated by Kaplan Meier method and the survival probabilities were compared using log-rank test. Competing risk analysis was used to calculate cumulative incidence of relapse and TRM. Results The study included 138 patients, 98 males and 40 females. The diagnoses were AML- 53, ALL- 30, MDS/MPN- 49 and lymphoma -6. Patient characteristics are outlined in Table 1. MSD/MUD transplants were 105 (FM- 94; FT-11); 33 were Haplo (FM-17; FT-16) transplants. PBSC was the stem cell graft in 136 (99%) patients. In both MSD/MUD and Haplo groups, there were no significant differences in median age, gender, pre transplant CMV status, HCT-CI and EBMT score between the two conditioning regimens. In MSD/MUD group, significantly more patients had high/very high DRI in FT arm (45% vs 17%; P=0.056) Comparison of engraftment and toxicity variables of both FM and FT arms are outlined in Table 2. In MSD/MUD group, 44 (47%) patients in FM arm had grade 3/4 oral mucositis compared to 1 (9%) in FT arm (P=0.02). Corresponding numbers were 7 (41%) and 1 (6%) in Haplo group (P=0.039). Grade 3/4 diarrhoea was higher in the FM vs FT arm of Haplo group (41% vs 6%; P=0.039) but not in the MSD/MUD cohort. More patients received TPN in the FM arms of both MSD/MUD and Haplo groups (Table 2). Incidence of grade III-IV acute GVHD was higher in FT vs FM in MSD/MUD group (27% vs 17%; P=0.04). The median follow up of entire cohort was 4.8 years. The OS (figure 1) at 5 years was 62% in FM arm of MSD/MUD group vs 53% in FT arm (P=NS). Similarly OS (figure 2) at 5 years was 41% and 28 %( P=NS) in FM and FT arms respectively of Haplo group. The cumulative incidence of TRM and relapse at 2 years were not different in FM and FT arms of both MSD/MUD and Haplo groups (Table 2). Conclusion Grade 3 and 4 oral mucositis and diarrhoea were significantly less with FT than FM in both MSD/MUD and Haplo groups. FT provided comparable outcomes to FM in the MSD / MUD group in spite of having higher proportions of patients with high / very high DRI. Prospective randomised studies are required to compare various RIC regimens. Disclosures No relevant conflicts of interest to declare.

Haploidentical transplantation for acute myeloid leukemia patients with minimal/measurable residual disease at transplantation.

There have been conflicting results regarding the impact of minimal/measurable disease at transplant on acute myeloid leukemia (AML) outcomes after haploidentical transplantation (haplo-SCT). We assessed the impact of pre-transplant disease status on post-transplant outcomes of 143 patients treated with haplo-SCT using fludarabine-melphalan (FM) conditioning and post-transplant cyclophosphamide (PTCy). With a median follow-up of 29 months, the two-year PFS for all patients was 41%. Compared to patients in complete remission (CR) at transplant, those with active disease (n = 29) and CR with incomplete count recovery (CRi) (n = 39) had worse PFS. They had hazard ratios (HR) of 3.5 (95% CI: 2.05-6.1; P < .001) and 2.3 (95% CI: 1.3-3.9; P = .002), respectively. Among patients who were in CR at transplant, there were no differences in PFS between those who had minimal residual disease (MRD) positive (n = 24), and MRD negative (n = 41) (HR 1.85, 95%CI: 0.9-4.0; P = .1). In multivariable analysis for patients in CR, only age was predictive for outcomes, while MRD status at transplant did not influence the treatment outcomes. Our findings suggest that haplo-SCT with FM conditioning regimen and PTCy-based GVHD prophylaxis has a protective effect, and may potentially abrogate the inferior outcomes of MRD positivity for patients with AML. Patients with positive MRD may benefit from proceeding urgently to a haplo-SCT, as this does not appear to negatively impact transplant outcomes.

Long-Term Outcomes after Reduced-Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndrome

Introduction Reduced-intensity conditioning (RIC) regimens have expanded allogeneic hematopoietic stem cell transplantation (allo-HSCT) to patients (pts) with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) who are unfit for myeloablative regimens. Several RIC regimens are typically used. We and others have previously shown that fludarabine-melphalan (FM) has a lower risk of relapse compared to fludarabine-busulfan (FB). Objectives Herein, we re-examine these findings with a larger cohort and longer follow-up. We also compare the composite endpoint graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS), and elucidate factors that predict for relapse and NRM. Methods After IRB approval, we conducted a study of pts (age ≥18) diagnosed with AML or MDS who underwent allo-HSCT from January 1st, 2008 to March 1st 2017 at Mayo Clinic Rochester. Only pts who received FM (melphalan 140 mg/m2) or FB (busulfan 0.8 mg/kg IV for 10 doses with therapeutic AUC target of 900-1500 mcmol/L[min]) were included. Grade III-IV acute GVHD, systemic therapy-requiring chronic GVHD, relapse, or death counted as events for GRFS. Statistical analyses were performed using JMP 13 and EZR 1.36. Results We identified 184 pts who underwent RIC allo-HSCT: 135 with AML and 49 with MDS. The median age for the entire cohort was 61 (range, 18-74). FM was used in 123 pts, while 61 received FB. Baseline characteristics were comparable (Table 1a). The median follow-up was 5 years (95% CI, 4-5.6). In line with previous findings, the cumulative incidence of relapse (CI-R) was significantly higher with FB compared to FM: 3-year CI-R was 31.7% for FB vs. 17.3% for FM (p= .04)(Figure 1a). On the other hand, there was a nonsignificant trend towards an increased CI-NRM in the FM group; at Day +100, CI-NRM was 6.5% for FM vs. 1.6% for FB (p= .24). Acute and chronic GHVD were comparable (Table 1b). The median GRFS for the entire cohort was 7.3 months (95% CI, 6.1-8.4); there was no difference between the two regimens (p=.94). Overall survival (OS) was comparable (p= .61), as were causes of death (Figure 1b). In a multivariate Fine-Gray proportional hazard model for relapse vs. NRM, which included factors in Table 2; disease status (CR1 vs. CR2 or active disease) predicted relapse (HR 0.42, 95% CI 0.21-0.84, p=.01). There was also a trend towards a decreased risk of relapse with FM (HR 0.54, 95% CI 0.28-1.03, p=.06). On the other hand, age was predictive of NRM (HR 1.05 per year, 95% CI 1.01-1.09, p=.01). Conclusion In the present follow-up study, there were no significant differences in GRFS or OS between FM and FB regimens for RIC allo-HSCT in AML/MDS, despite FB having a significantly higher risk of relapse. Likely, the OS was balanced by continuing NRM after FM conditioning, particularly in older pts. Further studies, ideally prospective, are required to elucidate the optimal RIC regimen matched to disease biology and pt fitness.

Reduced Intensity Conditioning (RIC) Regimens Hematopoietic Cell Transplantation (HCT) for Acute Myeloid Leukemia (AML): A Comparison of Fludarabine/Busulfan (FB) and Fludarabine/Melphalan (FM) Based Regimens from the CIBMTR

Background: There is limited data comparing the outcomes of the two most common (FM or FB) RIC regimens in AML. Previous smaller retrospective studies suggest increased non-relapse mortality (NRM) but decreased relapse with FM based RIC with a variable effect on overall survival as compared to FB.Methods: AML patients aged ≥18 years who had their 1st allo HCT using FM or FB (iv Bu only) RIC between 2001-2015 who had data reported to CIBMTR were studied. Patients with cord blood or identical twin donors, TBI as a part of conditioning, GVHD prophylaxis with T cell depletion/CD34 selection or post HCT Cyclophosphamide were excluded. Primary endpoint was overall survival (OS), and secondary endpoints included non-relapse mortality (NRM), relapse, leukemia free survival (LFS) and acute and chronic GVHD. Cox proportional hazards multivariable regression was used to compare the two RIC regimens while adjusting for significant patient, disease and transplant related factors. Major subgroup analysis included patients in CR pre-HCT.Results: 622 patients received FB and 791 had FM RIC. Median age of the FM group was 59 years, range (18 to 76) and median age of FB group was 61 years, range (18- 77). Compared to FB RIC regimen, FM group had more patients with active disease (36% vs 18%), with mismatched donors (24% vs 15%), with bone marrow grafts (19% vs 9%), HCT before 2005 (29% vs 12%) and without ATG/alemtuzumab (58 % vs 48%); but fewer patients in CR1 (46% vs 62%) and matched sibling donor grafts (21% vs 30%). There was significantly increased NRM in the FM vs FB within 3 mo post HCT (hazard ratio (HR)=3.85 (95% confidence intervals [CI] 2.46-6.03), but not beyond 3 mo FM vs FB , HR= 1.14 (95% CI 0.88-1.47). There was significantly decreased relapse for FM vs FB, (HR=0.65 (0.55-0.76), p<0.001) and a marginally superior LFS for FM vs FB, (HR=0.89 (95% CI 0.78-1.00), p=0.05). There was a lower OS FM vs FB within 3 mo post HCT (HR=1.82 (95% CI 1.36-2.45), p<0.001) but similar OS for FM vs FB beyond 3 mo post HCT (HR=0.87 (95% CI 0.76-1.00), p=0.05). Analysis restricted to only patients in CR pre-HCT showed similar results: equivalent survival, higher early NRM and lower relapse with FM.Conclusion: The current study of this large CIBMTR AML transplant cohort has showed that in these two most common RIC regimens for allogeneic HCT, long-term survival with FM was similar to FB. While the FM regimen showed higher early NRM, it was associated with lower risks of relapse. Further analysis to evaluate FB and FM regimens in relationship to comorbidities, comprehensive geriatric assessments, and presence of minimal residual disease is warranted to better define the relative efficacy of these two RIC regimens in AML. [Display omitted] DisclosuresWeisdorf:Pharmacyclics: Consultancy; Seattle Genetics: Consultancy; SL Behring: Consultancy; FATE: Consultancy; Equillium: Consultancy.

Choosing a reduced intensity conditioning, fludarabine melphalan versus fludarabine busulfan: A meta-analysis and systematic review.

e19017Background: Of the various reduced intensity conditioning (RIC) regimens, fludarabine combined with reduced intensity dose melphalan (FM) or busulfan (FB) are commonly used prior to allogenei...

Comparison of Conditioning with Fludarabine/Busulfan and Fludarabine/Melphalan in Allogeneic Transplantation Recipients 50 Years or Older

The optimal conditioning regimen for elderly patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT) remains unclear. We retrospectively analyzed 1607 patients aged 50 years or older with acute myeloid leukemia (AML), acute lymphoblastic leukemia, or myelodysplastic syndrome (MDS) who underwent allo-HCT using fludarabine/busulfan (FB) or fludarabine/melphalan (FM) between 2007 and 2014. We compared the clinical outcomes among FB2 (busulfan at 6.4 mg/kg iv, n = 463), FB4 (busulfan at 12.8 mg/kg iv, n = 721), and FM140 (melphalan at 140 mg/m2, n = 423). The nonrelapse mortality (NRM) rates in the FB4 and FM140 groups were higher than that in the FB2 group (hazard ratio [HR], 1.63 [P < .001]; and HR, 1.71 [P < .001], respectively). Conversely, the relapse rates in the FB4 and FM140 groups were lower than that in the FB2 group (HR, .73 [P = .011]; and HR, .56 [P < .001], respectively). There were no significant differences in overall survival (OS) among the FB2, FB4, and FM140 groups. The 3-year OS in patients with high-risk AML and MDS in the FM140 group (37.0% and 60.2%) were superior to those in the FB2 group (24.4% and 45.5%) and the FB4 group (24.6% and 40.6%) (P = .016 and P = .023), whereas there were no differences in OS in the other patients among the 3 groups. In conclusion, the lower rates of relapse in the FB4 and FM140 groups were largely offset by a worse NRM. However, FM140 might be associated with better OS in patients with high-risk AML and MDS.

Ex Vivo Mesenchymal Precursor Cell–Expanded Cord Blood Transplantation after Reduced-Intensity Conditioning Regimens Improves Time to Neutrophil Recovery

We previously showed the safety of using cord blood (CB) expanded ex vivo in cocultures with allogeneic mesenchymal precursor cells (MPC) after myeloablative conditioning with faster recovery of neutrophils and platelets compared with historical controls. Herein, we report the transplantation outcomes of 27 patients with hematologic cancers who received 1 CB unit expanded ex vivo with MPCs in addition to an unmanipulated CB (MPC group) after reduced-intensity conditioning (RIC). The results in this group were compared with 51 historical controls who received 2 unmanipulated CB units (control group). The analyses were stratified for 2 RIC treatment groups: (1) total body irradiation 200 cGy + cyclophosphamide + fludarabine) (TCF), and (2) fludarabine + melphalan (FM). Coculture of CB with MPCs led to an expansion of total nucleated cells by a median factor of 12 and of CD34+ cells by a median factor of 49. In patients in whom engraftment occurred, the median time to neutrophil engraftment was 12 days in the MPC group, as compared with 16 days in controls (P = .02). The faster neutrophil engraftment was observed in both RIC groups. The cumulative incidence of neutrophil engraftment on day 26 was 75% with expansion versus 50% without expansion in patients who received FM as the RIC regimen (P = .03). Incidence of neutrophil engraftment was comparable in MPC and control groups if treated with TCF (82% versus 79%, P = .40). Transplantation of CB units expanded with MPCs is safe and effective with faster neutrophil engraftment even after RIC regimens.

Comparison of Reduced-Intensity Conditioning with Fludarabine/Busulfan and Fludarabine/Melphalan in Patients 50 Years or Older

Introduction: Reduced-intensity conditioning (RIC) regimens have been increasingly used in allogeneic hematopoietic stem cell transplantation (allo-HCT), because they can reduce non-relapse mortality in comparison with standard myeloablative conditioning regimens and allow previously ineligible patients such as older patients and patients with comorbidities to receive allo-HCT. However, the optimal RIC regimen in allo-HCT remains unclear. Therefore, we conducted a nationwide retrospective study to compare the transplant outcomes between fludarabine/busulfan (FB) and fludarabine/melphalan (FM) regimens which are two most widely used RIC regimens for allo-HCT.Methods: We retrospectively analyzed 2008 patients aged 50 years or older with acute myeloid leukemia (AML) (n=1219), acute lymphoblastic leukemia (ALL) (n=209), or myelodysplastic syndrome (MDS) (n=580) who underwent allo-HCT using fludarabine/busulfan (FB) or fludarabine/melphalan (FM) between 2001 and 2014. The patients who underwent cord blood transplantation were excluded in this study, but those who received low dose of total body irradiation in addition to the FB or FM regimen were included. Acute leukemia in the first or second remission and MDS excluding refractory anemia with excess blasts or leukemic transformation were defined as standard-risk diseases. Clinical data for these patients were obtained from the Transplant Registry Unified Management Program (TRUMP), which includes clinical data of HCT performed in Japan. We compared the outcomes between FB2 (busulfan at 8 mg/kg po or 6.4 mg/kg iv, n=738), FB4 (busulfan at 16 mg/kg po or 12.8 mg/kg iv, n=749), and FM140 (melphalan at 140 mg/m2, n=521).Results: The median ages were 60 (50-74), 60 (50-75), 59 (50-71) years in the FB2, FB4, and FM140 groups, respectively. The cumulative incidences of grade II-IV and III-IV acute GVHD were 30.7% (95% confidence interval (CI), 27.3-34.1%) and 10.1% (95% CI, 8.0-12.4%), 36.8% (95% CI, 33.3-40.2%) and 12.5% (95% CI 10.2-15.0%), and 39.3% (95% CI, 35.0-43.5%) and 15.2% (95% CI, 12.2-18.4%) in the FB2 group, the FB4 group, and FM140 group, respectively (p=0.0061 and p=0.050). The incidence of relapse at 3 years was higher in the FB2 group (38.2%; 95% confidence interval (CI), 34.5- 41.9%) than the FB4 group (31.5%; 95% CI, 28.0- 35.0%) or the FM140 groups (28.3%; 95% CI, 24.2- 32.4%, p<0.001, Figure 1A). Conversely, the incidence of non-relapse mortality was lower in the FB2 group (19.7%; 95% CI, 16.7- 22.9%) than the FB4 group (27.4%; 95% CI, 23.9- 30.9%) or the FM140 group (26.2%; 95% CI, 22.3- 30.3%, p=0.0015, Figure 1B). Overall survival (OS) at 5 years in patients with high-risk AML and MDS in the FM140 group (35.3%; 95% CI, 26.2-44.6% and 57.0%; 95% CI 45.2-67.2%) was superior to that in the FB2 group (15.2%; 95% CI 9.3-22.3% and 38.1%; 95% CI 28.8-47.2%) or FB4 group (20.8%; 95% CI, 14.5- 27.8% and 33.8%; 95% CI 23.9-43.9%) (p=0.0028 and p=0.0065, Figure 2A, B), although OS in patients with standard-risk AML or MDS did not differ among the 3 groups. On the other hand, no statistically significant differences were found in OS in patients with standard- and high-risk ALL in the FB2, FB4, and FM140 groups (OS at 5 years in standard-risk ALL patients: 54.9%; 95% CI 40.2-67.4%, 33.6%; 95% CI 10.9-58.4%, and 49.2%; 95% CI 34.8-62.1%; p=0.32, and OS at 3 years in high-risk ALL patients: 20.8%; 95% CI 0.9-59.5%, 0%; 95% CI NA-NA, and 11.3%; 95% CI 0.7-38.3%; p=0.54, respectively). In multivariate analysis (Table 1), the non-relapse mortality rate was significantly higher in the FB4 and FM140 groups than that in the FB2 group (hazard ratio (HR) 1.49; 95% CI 1.17-1.90; p=0.0012 and HR 1.46; 95% CI, 1.14-1.87; p=0.0029). On the other hand, the relapse rate was significantly lower in the FB4 and FM140 groups than that in the FB2 group (HR 0.69; 95% CI, 0.56-0.86; p<0.001 and HR 0.54; 95% CI, 0.43-0.68; p<0.001), and overall survival (OS) was better in the FM140 group than in the FB2 group (HR 0.81; 95% CI, 0.68-0.97; p=0.021), although there were no significant differences between the FB4 and FB2 groups (HR 1.08; 95% CI, 0.91-1.27; p=0.39).Conclusion: FM140 was associated with better OS in patients with high-risk AML and MDS than FB2 because of lower relapse rate and FB4 was not superior to FB2 in OS, although OS in patients with standard-risk disease did not differ among the 3 groups. A large prospective study is warranted to confirm these findings. [Display omitted] [Display omitted] [Display omitted] DisclosuresKako:Otsuka Pharmaceutical: Honoraria. Kanda:Otsuka Pharmaceutical: Honoraria, Research Funding.

Day +30 and Day +100 CD33 Chimerisms Predict Survival after Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Myelofibrosis

Background:Donor cell chimerisms are tested at frequent intervals after allogeneic hematopoietic stem cell transplantation (alloHSCT). However, the predictive value of this testing in patients with myelofibrosis (MF) is not well-defined. In this study, our primary objective is to evaluate the correlation of day 30 and day 100 donor cell chimerism and overall survival (OS) in patients (pts) who undergo alloHSCT for MF.Methods:Charts were reviewed for pts who underwent alloHSCT for MF at Mayo Clinic in Arizona, Minnesota and Florida between January 2005 and December 2015. Patients who died within 30 days of alloHSCT were excluded. Chimerism studies were evaluated in the peripheral blood for CD3 and CD33 fractions at day +30 (D30) and day +100 (D100). Cut-off value of 100% and less than 100% was used because of limited variability below 100%. Standard statistical methods were used to compare continuous and categorical variables. The Kaplan-Meier method was used to provide survival curves.Results:Baseline characteristics: Sixty three consecutive patients who underwent alloHSCT for MF since January 2005 until December 2015, and had D30 and/or D100 chimerism studies available were included in the study. Of these, 24 (38%) were female. Median age at diagnosis was 56 years (range, 19 - 73 years) and median age at AHSCT was 58 years (range, 19 - 73 years). Dynamic International Prognostic Scoring System-Plus (DIPSS-Plus) risk category at the time of alloHSCT was high in 31 (49%), intermediate-2 in 30 (48%) and intermediate-1 in 2 (3%) pts. JAK2 V617F mutation status was available in 61 pts and was positive in 35 (57%) pts. Nineteen (30%) pts had been treated with a JAK2 inhibitor prior to alloHSCT. Fifty-two (83%) pts had at least grade-2 fibrosis in bone marrow at the time of HCT.Transplantation: Median time from diagnosis to AHSCT was 12.9 months (range, 2.3 - 248.2 months). Fifty-five (87%) received a reduced intensity conditioning (RIC) regimen while 8 (13%) received myeloablative conditioning regimen. Of these 55 pts, RIC regimens used were busulfan fludarabine based regimen in 15 (27%), fludarabine melphalan based regimen in 18 (33%) and fludarabine melphalan carmustine in 22 (40%) pts. Donor source was matched related in 30 (48 %), matched unrelated in 28 (44%), single-antigen mismatched related in 4 (6%) and mismatched unrelated in 1 (2%). Peripheral blood stem cells were used in all AHSCTs.Outcomes: Median follow-up was 24.4 months (range, 1.5 - 83.6 months). Amongst pts who had <100% donor chimerism at D30 in CD33 fraction, 2 had 90%, 1 had 80% and 2 had zero% donor chimerism. At D100, 1 pt had 95%, 1 had 90%, 1 had 60%, 2 had 5% and 1 had zero% donor chimerism. Eighteen out of 57 (32%) pts who had 100% donor chimerism in CD33 fraction at D30 had died at the time of analysis compared to 4 out of 5 (80%) patients with less than 100% (p=0.03). Eight out of 38 pts (21%) who had 100% donor chimerism in CD33 fraction at D100 died versus 3 out of 6 (50%) with less than 100% (p=0.12). There was no significant survival effect of CD3 chimerism (p values=0.68, 0.59). Of the 23 deaths that had occurred at the time of analysis, cause of death was disease progression or relapse in 8 (35%), graft versus host disease in 6 (26%), transplant related (sepsis / engraftment failure) in 5 (22%) and unrelated causes in 4 (17%).Survival analysis: As depicted in the Kaplan Meier curve (figure 1), median overall survival (OS) for pts with 100% donor chimerism in CD33 fraction at day 30 was not reached while for <100% donor chimerism was 16 months (p=0.04). Survival at 3 years for patients with 100% CD33 donor chimerism at D30 was 65% while it was 40% for pts with less than 100%. Also, survival at 3 years for patients with 100% CD33 donor chimerism at day 100 was 75% compared to 50% for patients with less than 100%.Conclusions:In our study, 100% donor chimerism in CD33 fraction is associated with improved survival after alloHSCT for MF compared to pts with less than 100%. Further understanding regarding the reason for this relationship is critical. Larger studies to replicate these results would be imperative to validate these findings. [Display omitted] DisclosuresMesa:Incyte: Research Funding; Ariad: Consultancy; Promedior: Research Funding; Novartis: Consultancy; Celgene: Research Funding; Gilead: Research Funding; CTI Biopharma: Research Funding; Galena: Consultancy.

Gemcitabine, Fludarabine, and Melphalan for Reduced-Intensity Conditioning and Allogeneic Stem Cell Transplantation for Relapsed and Refractory Hodgkin Lymphoma

Forty patients (median age, 31 years; range, 20 to 63) with Hodgkin lymphoma underwent an allogeneic stem cell transplant with the gemcitabine–fludarabine–melphalan reduced-intensity conditioning regimen. Thirty-one patients (77%) had undergone a prior autologous stem cell transplant, with a median time to progression after transplant of 6 months (range, 1 to 68). Disease status at transplant was complete remission/complete remission, undetermined (n = 23; 57%), partial remission (n = 14; 35%), and other (n = 3; 8%). Twenty-six patients (65%) received brentuximab vedotin before allotransplant. The overall complete response rate before allotransplant was 65% in brentuximab-treated patients versus 42% in brentuximab-naive patients (P = .15). At the latest follow-up (October 2015) 31 patients were alive. The median follow-up was 41 months (range, 5 to 87). Transplant-related mortality rate at 3 years was 17%. Pulmonary, skin toxicities, and nausea were seen in 13 (33%), 11 (28%), and 37 (93%) patients, respectively. At 3 years, estimates for overall and progression-free survival were 75% (95% CI, 57% to 86%) and 54% (95% CI, 36% to 70%). Overall incidence for disease progression was 28% (95% CI, 16% to 50%). We believe the gemcitabine–fludarabine–melphalan regimen allows moderate dose intensification with acceptable morbidity and mortality. The inclusion of gemcitabine affected nausea, pulmonary, and likely skin toxicity. Exposure to brentuximab vedotin allowed more patients to reach allogeneic stem cell transplantation in complete remission. With over 50% of patients progression-free at 3 years, allogeneic stem cell transplantation with reduced-intensity conditioning remains an effective and relevant treatment option for Hodgkin lymphoma in the brentuximab vedotin era.

Outcome after Transplantation According to Reduced-Intensity Conditioning Regimen in Patients Undergoing Transplantation for Myelofibrosis

Allogeneic hematopoietic stem cell transplantation remains the sole curative option for myelofibrosis. Many transplantation recipients receive a reduced-intensity conditioning (RIC) regimen owing to age or comorbidities; however, there is little published evidence to guide the choice of RIC regimen. In this study, we compared outcomes in patients who received 1 of 2 frequently used RIC regimens for patients with myelofibrosis: fludarabine-busulfan (FB) and fludarabine-melphalan (FM). A total of 160 patients underwent a RIC allograft procedure (FB group, n = 105; FM group, n = 55). We have developed a complex statistical model involving weighting and adjustment to permit comparison between these 2 groups. After weighting, the incidence of acute graft-versus-host disease (GVHD) was 62% in the FM group and 31% in the FB group (P = .001), and the corresponding incidence of chronic GVHD was 49% and 53%, respectively. The 7-year progression-free survival was were 52% in the FM group versus 33% in the FB group, and the 7-year overall survival rate 52% in the FM group versus 59% in the FB group. Nonrelapse mortality (NRM) was 43% in the FM group and 31% in the FB group. Multivariable analyses revealed no significant differences in PFS between the 2 groups; however, the relapse rate was significantly lower in the FM group (hazard ratio, 9.21; P = .008), whereas a trend toward reduced NRM was seen in the FB group (hazard ratio, 0.51; P = .068). In conclusion, both regimens appear to be efficient in mediating disease control and can be used to successfully condition patients with myelofibrosis. The FM regimen appears to induce more NRM than the FB regimen, but with augmented control of disease, leading to comparable overall survival rates for both regimens.

Early T-Lymphocyte Chimerism Kinetics Is Influenced By Conditioning Regimen in Reduced Intensity Allogeneic Stem Cell Transplantation

Introduction: Disease relapse remains one of the major causes of treatment failure in hematopoietic stem cell transplant (HSCT) following reduced-intensity conditioning (RIC) regimens. Donor chimerism assessment early after HSCT may help identify patients at risk for relapse who may benefit from additional therapeutic interventions but its precise role in this setting is unclear. In addition, the differential impact of conditioning regimen is not well studied.Aim:1. Study the impact of early full T-lymphocyte chimerism (T-lymphocyte chimerism ≥ 90% on day 30 to 60) on relapse incidence (RI) and acute graft versus host disease (aGVHD) in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) following RIC-HSCT.2. Looking at the tempo of achievement of complete donor T-lymphocyte chimerism based on the two most common RIC regimens, Fludarabine/Melphalan (FM) and Fludarabine/Busulfan (FB).Method:After IRB approval, patients with AML or MDS who underwent RIC-HSCT with FB or FM between 2008 and 2014 at our institution were identified. Post-transplantation CD3 (lymphocyte) and CD33 (myeloid) donor chimerism were measured per protocol using PCR-based analysis of short tandem repeats. Categorical and continuous variables were analyzed using Pearson's chi-squared and Wilcoxon / Kruskal-Wallis, respectively. Survival estimates were calculated using the Kaplan-Meier and log-rank test. RI was estimated accounting NRM on a competing event analysis using Grey's model. Cox proportional regression was used to compute hazard ratios (HR).Results:Baseline characteristics: Out of 134 patients who received FM or FB, 75 patients had evaluable early sorted chimerism data. 42 and 33 patients received FB and FM, respectively. Patient, disease and transplant variables were balanced in both FM and FB (Table 1). The median follow up of the cohort was 37 months (2.4-43) and at last follow up 29.1% of patients relapsed and 59% died. All patients achieved early complete myeloid chimerism whereas T-lymphocyte chimerism was complete in 50 patients and mixed in 25 patients. Characteristics of early lymphocyte chimerism by status are shown in table 1. Notably, likelihood of achieving complete T-lymphocyte chimerism ≥ 90% at 60 days was 100% versus 47% in FM and FB respectively (p <0.0001).Acute graft versus host disease: There was no significant difference in incidence of grade II-IV aGVHD between patients with full early donor T-lymphocyte chimerism in comparison to those with early mixed donor chimerism (46% vs. 48%, p =0.87).Impact of full chimerism and conditioning regimen on RI and overall survival (OS): Among the entire cohort, patients achieving early full T-lymphocyte chimerism had a significantly lower RI compared to those with mixed chimerism with a HR of 0.38 (CI 0.14-0.97; p=0.044) but OS was not significantly different with HR 0.69 (CI 0.33-1.51; p=0.34). In patients conditioned with FB, there was no difference in 2-year RI between complete or mixed early T-lymphocyte chimerism at 38.2% and 40.7% respectively (p = 0.9). After FM conditioning, all patients achieved early T-lymphocyte chimerism and the 2-year RI was 6.9%. Achievement of early complete lymphocyte chimerism post FB in comparison to FM was associated with significantly higher risk of relapse (HR 8.6 CI 2.07-57, p=0.0025). Furthermore, there was a trend towards worse OS with FB vs. FM with a median of 23 vs. 44 months, respectively (p = 0.058).Conclusion:Similar to prior reports, we observed that full T-lymphocyte chimerism is associated with decreased relapse risk without an increase in aGVHD. Our findings also suggest that RIC with FM yields a higher incidence of early complete T-lymphocyte chimerism and is significantly associated with decreased risk of relapse compared to FB. There was a greater risk of relapse in the FB group, even among those achieving early complete donor lymphoid chimerism. This needs further validation given the small sample size. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Intensification of the Regimen Fludarabine Melphalan with the Addition of 400 Cgy of Total Body Irradiation in Allogeneic Stem Cell Transplantation. It Is Feasible, Has a Good Anti-Leukemic Effect and a Low Toxicity

Fludarabine 120-160 mgs/m2 plus melphalan 140 mgs/m2 (Flu- Mel) is a well known reduced intensity conditioning protocol used in allogeneic transplantation, however it can be no enough intense to treat high risk acute leukemia, specially in the relapse setting. On the other hand, 400 cGy of total-body irradiation (TBI 400) has been successfully added to myeloablative dose of fludarabine busulfan without excessive toxicity. We designed a regimen adding TBI 400 to usual dose of Flu-Mel with the idea to increase its anti-leukemic activity. Below we present our experienceMethods and patientsPeripheral blood stem cells were mobilized with figrastim for 5 days, later, 1 or 2 apheresis were done to achieve a minimum of 3 million of CD34 + cells/kg. The conditioning consisted of fludarabine 30-40 mgs/m2 for four days, melphalan 140 mgs/m2 one dose, on day - 1, TBI 400 was administered split in 2 fractions. The prophylaxis against graft versus host disease (GVHD) was done with cyclosporine and methotrexate, all patients were given pegfilgrastim22 patients were transplanted, median age 26.5 years (range 8-49), the diagnosis were; acute lymphoblastic leukemia (13), acute myeloid leukemia (6), chronic myeloid leukemia (1), high risk myelodisplasia(1), mixed acute leukemia(1). 32% were in first remission, 41% in second, 27% were in third or they had active disease. The discrimination according CIBMTR disease risk index (CIBMTR-DRI) was: 54% high risk, 41% intermediate and 5% lowResultsAll donors were matched siblings, a median of 10 millions/kg of CD34+ cells were infused; all patients engrafted, the neutrophil and platelet recovery occurred on days +11 and + 14 respectively. The grade III toxicity was; mucositis, 45% and one case of encephalopathy, there were not any case of sinusoidal obstruction syndrome. The incidence of GVHD acute (GII-IV) and chronic extensive was 10 and 25%. With a median follow up of 11 months (range 6-30) the overall survival (OS)(Kaplan-Meier) at 24 and 36 months is 69 and 55% . Six patients have died, one due to sepsis and five secondary to relapse. The OS according to CIBMTR-DRI at 36 month was 75 and 46% for intermediate and high risk groupsConclusion:The addition of TBI 400 to Flu- Mel regimen is feasibly, the main toxicity is mucositis, the non- relapse mortality is very low and the incidence of GVHD, acute a chronic, is not higher than expectedThis combination shows an encouraging anti leukemic effect, as it is demonstrated by an OS of 75 and 46% in patients classified in intermediate and high risk CIBMTR DRI groups.This preparative protocol can be a low toxicity alternative to more conventional myeloablative regimen. It warrants further studies DisclosuresNo relevant conflicts of interest to declare.