Total Body Irradiation Regimen Research Articles

Long-term outcomes of granulocyte colony-stimulating factor-combined conditioning in allogeneic hematopoietic stem cell transplantation from HLA-identical family donors for myeloid malignancies

Dormant leukemia cells, which might escape the cytotoxic effect of conditioning before hematopoietic stem cell transplantation (HSCT), could be induced to enter the cell cycle by granulocyte colony-stimulating factor (G-CSF) and become more susceptible to the cell-cycle-specific agent cytarabine arabinoside (Ara-C). Based on this effect, we have utilized G-CSF-combined high-dose Ara-C in myeloablative conditioning for allogeneic bone marrow or peripheral blood stem cell transplantation from HLA-identical family donors since 1988. We report on the long-term outcomes of allogeneic HSCT using a conditioning regimen of 12Gy total body irradiation and G-CSF-combined high-dose Ara-C in 89 adult patients with acute myeloid leukemia, chronic myelogenous leukemia, or myelodysplastic syndrome. With a median follow-up of 135 months, the probability of overall survival and cumulative incidence of relapse at 5 years were 67.8% and 19.4%, respectively. In multivariate analysis, disease status at HSCT was associated with survival and relapse. These data demonstrate that G-CSF-combined myeloablative conditioning could be safely and effectively used for patients with myeloid malignancies.

A Safety and Efficacy Study of Medium-Dose Etoposide, Cyclophosphamide and Total Body Irradiation Conditioning Before Allogeneic Stem Cell Transplantation for Acute Lymphoblastic Leukemia.

BackgroundPrognosis for adult patients with acute lymphoblastic leukemia (ALL) has been reported to be approximately 35% to 50%, even after allogeneic stem cell transplantation (allo-SCT). We previously reported retrospective analyses of a conditioning regimen of medium-dose etoposide, cyclophosphamide (CY), and total body irradiation (TBI) before allo-SCT for ALL. To prospectively analyze the efficacy of this conditioning regimen, we conducted a trial prospectively.MethodsThe eligibility criteria of this study were as follows: diagnosis of ALL, aged between 15 and 50 years, in complete remission, and first SCT from HLA serologically matched donor. The primary endpoint of this study was event-free survival at 1 year after SCT, and the events were defined as death and relapse.ResultsFifty eligible patients were treated, and the median age of the patients was 33.5 years. Nineteen patients were Philadelphia chromosome-positive, and 47 were in first complete remission at SCT. All patients achieved neutrophil engraftment. Grade 3 to 4 acute graft-versus-host disease and extensive chronic graft-versus-host disease developed in 4 patients and 18 patients, respectively. No patient died within 100 days after SCT. One-year event-free survival was 76.0%, and 1-year overall survival was 80.0%. The cumulative incidences of relapse and non-relapse mortality at 1-year after SCT were 10.0% and 14.0%, respectively.ConclusionsMedium-dose etoposide + CY + TBI is an effective conditioning before allo-SCT for adult patients with ALL, enabling good disease control without an increase in nonrelapse mortality. A phase 3 trial comparing this regimen with the standard CY + TBI regimen for adult patients with ALL is warranted.

Low Dose Total Body Irradiation Combined With Recombinant CD19-Ligand × Soluble TRAIL Fusion Protein is Highly Effective Against Radiation-resistant B-precursor Acute Lymphoblastic Leukemia in Mice

In high-risk remission B-precursor acute lymphoblastic leukemia (BPL) patients, relapse rates have remained high post-hematopoietic stem cell transplantation (HSCT) even after the use of very intensive total body irradiation (TBI)-based conditioning regimens, especially in patients with a high “minimal residual disease” (MRD) burden. New agents capable of killing radiation-resistant BPL cells and selectively augmenting their radiation sensitivity are therefore urgently needed. We report preclinical proof-of-principle that the potency of radiation therapy against BPL can be augmented by combining radiation with recombinant human CD19-Ligand×soluble TRAIL (“CD19L–sTRAIL”) fusion protein. CD19L–sTRAIL consistently killed radiation-resistant primary leukemia cells from BPL patients as well as BPL xenograft cells and their leukemia-initiating in vivo clonogenic fraction. Low dose total body irradiation (TBI) combined with CD19L–sTRAIL was highly effective against (1) xenografted CD19+ radiochemotherapy-resistant human BPL in NOD/SCID (NS) mice challenged with an otherwise invariably fatal dose of xenograft cells derived from relapsed BPL patients as well as (2) radiation-resistant advanced stage CD19+ murine BPL with lymphomatous features in CD22ΔE12xBCR-ABL double transgenic mice. We hypothesize that the incorporation of CD19L–sTRAIL into the pre-transplant TBI regimens of patients with very high-risk BPL will improve their survival outcome after HSCT.

The Impact of Age and Body Fat on Graft-Versus-Host Disease (GVHD) in Mice

Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative procedure performed for a variety of hematological diseases. Patient populations undergoing HSCT are generally skewed towards either young or old age due to the pathogenesis of hematological cancers. Several retrospective studies have identified age as one of the risk factors that correlate with treatment related mortality (TRM), graft versus host disease (GVHD) and tumor relapse. Aging is characterized by a gradual decline in immune cell function, known as immune senescence, yet is also hallmarked by a chronic, low-grade proinflammatory phenotype termed “inflammaging”. We hypothesized that aged animals develop more severe GVHD as a result of this inflammaging phenomenon. To investigate this, we first transplanted donor cells from B10.D2 mice (H-2d) into either young (< 3 months old) or aged (>15 months old) BALB/c (H-2d) recipients. While young recipients developed typical sclerodermatous chronic GVHD and died by 56 days post transplantation, aged mice developed severe acute GVHD and died at Day 7. Upon pathological examination, aged mice displayed massive lymphocytic infiltration associated with tissue necrosis in the gastrointestinal (GI) tract. Among several cytokines examined, elevated levels of serum TNF-α (97.89±9.83 versus 68.29±1.07 pg/ml, respectively) were observed in aged animals compared to young counterparts. Similarly, TNF-α and IL-6 gene expression levels were also increased in GI tract tissues. Additionally, we found greater frequencies of splenocyte derived TNF-α+ macrophages (CD45+CD19-F4/80+/CD11b+) in aged animals compared to young animals (26.2±1.00% versus 17.233±1.25%, respectively; P< 0.001) following allogeneic HSCT. Macrophage depletion using liposomal clodronate reduced serum TNF-α levels (97.89 ±9.83 versus 57.17±2.86 pg/ml) in aged mice following HSCT.We observed that aged mice had markedly higher levels of visceral body fat compared to young mice. Based on the similarities in the inflammatory status between aged and obese animals, we next sought to verify whether the severity of GVHD can also be attributed to obesity. Eight week old recipient BALB/c mice were maintained on either a low fat diet (10% calories from fat) or a high fat diet (60% calories from fat) for three months. Each cohort of mice then underwent HSCT, following a conditional regimen of total body irradiation (Cs; 800 cGy) and adoptive transfer from donor B10.D2 mice. In line with the results observed from aged recipients, diet induced obese (DIO) mice died at Day 7 and demonstrated a severe acute GVHD response in the GI tract compared to lean mice based on histo-pathological scores correlating with significantly increased TNF-α and IL-6 gene expression in the GI tract. Flow analysis revealed an increase in total numbers of CD8+ T cells infiltrating in the GI tract in obese mice compared to lean mice (0.229± 0.025 x 106 versus 0.071± 0.010 x 106; P<0.01). In addition, obese mice demonstrated an increase in total numbers of TNF-a+ macrophages (CD45+F4/80+CD11b+TNF-α +; 5.18± 1.09 x 104 versus 1.31± 0.75 x 104 ; P<0.05) in the visceral fat tissues. Overall, these data implicate that age and body fat can predispose to severe acute GVHD, which is associated with increased production of proinflammatory cytokines mediated by dysregulated macrophages. DisclosuresNo relevant conflicts of interest to declare.

Impact of ABO Incompatibility on Engraftment , Transfusion Requirement and Survival after Unrelated Cord Blood Transplantation：a Single Institute Experience in China

Few reports have focused on the impact of ABO incompatibility on the clinical outcomes, after unrelated cord blood transplantation (UCBT). Therefore, we retrospectively analyzed the impact of ABO mismatching on the clinical outcomes of 177 patients with hematologic malignancies, which underwent single UCBT in Anhui Provincial Hospital from May 2008 to April 2014. The study patients included 86 ABO-identical, 52 minor, 32 major, and 11 bidirectional ABO-incompatible recipients. All of them received a homogeneous intensified myeloablative pre-transplantation conditioning regimen of total body irradiation (TBI)cyclophosphamide (CY) [TBI (total,12 Gy; four fractions) and CY (60 mg/kg daily for 2 days)] (age≥14 years) or BuCY2 [busulfan (0.8 mg/kg every 6 h for 4 days) and CY]. Medians of 3.85×107/kg (range, 1.03-10.43) total nucleated cell (TNC) and 2.0×105/kg (range, 0.45-6.88) CD34+cells were transfused.Of the 177 patients who underwent UCBT, 169 achieved successful neutrophil engraftment. In patients receiving ABO-identical, minor, major, and bidirectional ABO-incompatible UCBT, the cumulative incidences of neutrophil engraftment were 92.7%, 100%, 96.9% and 90.9%, respectively (P=0.509). The median days to achieve neutrophil engraftment were 17, 18, 17, and 20, respectively (P=0.409). The cumulative incidences of platelet engraftment were 81.7%, 86.5% , 87.5% and 63.6%, respectively(P=0.436) .And the median days to achieve platelet engraftment for the 4 groups were 36, 40, 36, and 38, respectively; (P=0.545). All of the data did not show any significant difference among the 4 groups. Neutrophil engraftment(cumulative incidence, 95.5% versus 95.3% , P=0.861; median day, 17 versus 18, P=0.717) also did not differ significantly between the ABO-identical/minor ABO-incompatible and major/bidirectional ABO-incompatible recipients (HR1.08, P=0.680). And platelet engraftment (83.6% versus 81.4%, P=0.964; median day, 38 versus 37, P=0.699) reached the similar result (HR1.104, P=0.621).We investigated the results from a 169-patient population with neutrophil engraftment, the average units of platelets (Plts) and red blood cells (RBCs) transfused during the hospitalization after the UCBT were 0.204 units/kg(range, 0.03-1.45)and 0.159 units/kg (range, 0-1.56).In patients with ABO-identical, minor, major, and bidirectional ABO-incompatible UCBT, the average units of Plts transfused after UCBT were 0.221, 0.202, 0.169, and 0.195 units/kg(P=0.53), respectively, and the average units of RBCs transfused were 0.151, 0.156, 0.163, and 0.221 units/kg (P=0.847), respectively. No significant differences in the transfusion requirements among the 4 groups were noted, so did the comparison between the ABO-identical/minor ABO-incompatible and major/bidirectional ABO-incompatible recipients.With a median follow-up of 12 months (range, 3-74 months), the disease-free survival (DFS) rates among the ABO-identical, minor, major, and bidirectional ABO-incompatible groups were 67.1%, 57.7%, 62.5 % and 54.5%, respectively (P=0.804), and the overall survival (OS) also did not differ significantly among the four groups (68.3%, 61.5%, 65.6%, and 63.6%, respectively; P=0.929). When it came to the comparison between the ABO identical/minor incompatible group and the ABO major/bidirectional incompatible group, the DFS (63.4% versus 60.5%; P=0.995) and OS estimates (65.7% versus 65.1%; P=0.820) were not significantly different, either. What’s more, none of the patients clinical developed severe immune hemolysis or pure red-cell aplasia after transplantation.In summary, the results above indicated that :1) ABO incompatibility did not seem to have a significant impact on clinical outcomes after UCBT, such as engraftment, transfusion requirements and survival. 2) No patients developed pure red-cell aplasia after UCBT. 3) In addition, we also compared the outcomes between the ABO-identical and bidirectional ABO-incompatible groups, even it did not show any significant difference, the former did better on platelet engraftment (81.7% versus 63.6%) and DFS (67.1 versus 54.5%). The reason led to this result may be the lack of bidirectional ABO-incompatible recipients. Therefore, we’d better avoid selecting bidirectional ABO-incompatible in UCBT to improve the patients’ recovery and survival time. DisclosuresNo relevant conflicts of interest to declare.

Hematopoietic Stem Cell Transplantation for Patients with Refractory Cytopenia of Childhood

Introduction: Refractory cytopenia of childhood (RCC) is an entity of the pediatric myelodysplastic syndrome (MDS) proposed in the World Health Organization (WHO) 2008 classification and is characterized by persistent cytopenia with dysplasia and <5% blasts in the bone marrow (BM). Although the efficacy of immunosuppressive therapy (IST) has been reported in RCC with response rate of 40-60%, hematopoietic stem cell transplantation (HSCT) is still thought as the only curative therapy for children with MDS. However, appropriate setting of HSCT for patients with RCC has not been established. Recently, we described clinical characteristics and treatment outcome in 65 cases with RCC who were prospectively registered through the Japanese Society of Pediatric Hematology/Oncology (JSPHO) (Hasegawa et al, BJH 2014). In this analysis, we focused on a subgroup that underwent HSCT in order to identify the factors that can predict the outcome of patients with RCC after HSCT.Patients and Methods: From July 1999 to February 2008, 618 children who were suspected of having MDS were prospectively registered into the JSPHO database and 65 were diagnosed based on the central review of morphology as having primary MDS without excess blasts, which was compatible with criteria of RCC. Therapeutic strategy was determined by each physician based on the recommendations provided by the Japanese Childhood MDS Study Group MDS99. As a first-line therapy, 25 patients received IST, 12 patients received HSCT, and one patient received intensive chemotherapy. The remaining 27 patients were followed without treatment for more than 2 years. Eventually, 28 (11 male and 17 female) children ended up undergoing HSCT.Results: Median age at HSCT was 10.3 years (range, 1.5 - 17.2 years). Median duration between diagnosis and HSCT was 481 days (range, 123 – 2674 days). Twelve patients had a history of receiving IST. As a stem cell source, 15 patients received BM from an unrelated donor, 5 received BM from matched-sibling donor, 4 received BM from family donor, and 4 received unrelated cord blood. As a conditioning regimen, myeloablative conditioning (MAC) with total-body irradiation regimen was given to 8 patients, MAC with busulfan regimen was given to 7, and 13 patients received reduced intensity conditioning (RIC). As a GVHD prophylaxis, 22 patients received tacrolimus and 6 received cyclosporine (CyA). Engraftment was confirmed in all patients. Grade III-IV acute GVHD was observed in 3 patients. Of 23 evaluable patients, 7 patients had chronic GVHD. Seventeen patients remained in remission after HSCT. Secondary graft failure was observed in 2 patients who received RIC after failure of IST. Nine patients died due to the following causes: transplantation-related mortality (TRM; n=7), relapse (n=1), and secondary brain tumor (n=1). Seven patients died of TRM at a median time of 103 days after HSCT (range, 44-926 days) and 5-year cumulative incidence of TRM was 28±9%. Grade III-IV acute GVHD and the presence of chronic GVHD were associated with a higher probability of TRM (p=0.03 and 0.02, respectively). Five-year event-free survival (EFS) and overall survival (OS) was 58±10% and 66±9%, respectively. No patient characteristics or transplantation-related variables showed statistically significant difference in EFS or OS. Of 13 children receiving RIC, 7 remained in remission, whereas 3 succumbed to TRM, 2 experienced secondary graft failure, and one developed brain tumor.Discussion: TRM was the main cause of treatment failure in patients with RCC receiving HSCT. This analysis suggested appropriate prevention of GVHD might be important to succeed in HSCT for patients with RCC. DisclosuresNo relevant conflicts of interest to declare.

Optimized Cyclophosphamide (CY) Dosing in Combination with Fludarabine, TBI and ATG As Conditioning for Unrelated Donor Bone Marrow Transplantation (BMT) in Severe Aplastic Anemia (SAA): A Phase I/II Study from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN)

▪Objective: To determine toxicity and efficacy of adding fludarabine (FLU) to a standard preparative regimen of low-dose total body irradiation (TBI), anti-thymocyte globulin (ATG) and CY (Deeg J et al, Blood 108:1485, 2006), with de-escalation of the CY dose.Patients and Methods: Between May 2006 and December 2013, the BMT CTN (sponsored by the NHLBI and NCI) conducted a Phase I/II trial of unrelated donor BMT in SAA (BMT CTN 0301; NCT 00326417). Patients were eligible if they were aged < 65 years, with adequate organ function, and an available unrelated marrow donor matched at 7 or 8 of 8 HLA-A, B, C, and DRB1 loci. The trial accrued 97 patients, although analyses are limited to 96; 1 patient withdrew consent prior to BMT. All patients received TBI 200 cGy (day -1), ATG (either thymoglobulin 3 mg/kg IV or ATGAM 30 mg/kg IV daily x 3, days –4 to –2), FLU (30 mg/m2 IV daily x 4, days –5 to –2). The Phase I portion of the trial tested four CY dose levels: 150 mg/kg (days –4 to –2); 100 mg/kg (days –3 to –2); 50 mg/kg (day –2); and 0 mg/kg. The Phase I design allowed enrollment of up to six patients at each CY dose level unless toxicity or graft failure boundaries were crossed. In the Phase II portion, patients were enrolled onto the optimal CY dose level, using adaptive Bayesian criteria to rank desirability of CY doses based on Day 100 outcomes of engraftment and early death. The primary endpoint of the study was determination of the optimal CY dose based on Day 100 assessments of graft failure (primary: absolute neutrophil count <0.5 x 109/L and secondary: sustained decline in absolute neutrophil count to <0.5 x 109/L), major (grade 3 or higher) regimen-related toxicity (RRT) and early death. Early stopping guidelines were based on a composite endpoint of graft failure and treatment-related mortality through day 100.Results: Twenty-one patients accrued to the Phase I portion of the trial and all CY dose levels were tested. CY dose level 0 mg/kg was closed after 3 of the first 3 patients developed secondary graft failure. The Phase II portion of the trial opened with CY dose level 150 mg/kg. However, this dose level was closed for excess toxicity (7 of 14 patients died; organ failure n=4, ARDS n=2 and infection n=1; Tolar et al, Biol Blood Marrow Transplant, 2012). Patients were subsequently assigned to CY dose level 100 mg/kg (CY DL 100; n=41) or CY dose level 50 mg/kg (CY DL 50; n=38), depending on Bayesian assessment of criteria noted above except that the last 20 patients were preferentially assigned to CY DL 50 to balance accrual to the two dose levels. Approximately half of patients were male and 79% Caucasian. The median age was 20.6 years. The median age for CY DL 50 and DL 100 was 24.5 (0.5-65) and 17.6 (1.9-63) years, respectively. The number of transplants with a mismatched (i.e.7/8) donor was 7 (18%) in the CY DL 50 group and 14 (34%) in the CY DL 100 group. All patients reached their Day 100 endpoint. The cumulative incidence of grade 2-4 acute GVHD was comparable between the two CY dose levels: 24% (DL 50) vs 27% (DL 100). All deaths before Day 100 were due to primary or secondary graft failure (CY DL 50; n=1 and CY DL 100; n=2),. Table 1 shows individual Day 100 outcomes for CY DL 50 and CY DL 100. Median follow up is 15 (3-27) and 24 (12-50) months for CY DL 50 and 100, respectively. All surviving patients on CY dose level 100 mg/kg have achieved a minimum follow up of 12 months, as opposed to only 75% of surviving patients on CY dose level 50 mg/kg.Conclusion: Results of the adaptive Bayesian dose selection suggest that the most desirable CY dose is 50 mg/kg followed by CY dose, 100 mg/kg. However, interpretation of data needs to take into account the potential imbalance of donor-recipient HLA disparity in the CY 50 mg/kg dose level. CY dose 150 mg/kg and 0 mg/kg should be avoided.Table 1Day 100 OutcomeCY DL 50 (n=38)CY DL 100 (n=41)Graft Failure, primary and secondary3 (8%)6 (15%)Survival37 (97%)39 (95%)Major RRT (Grade III or higher)4 (11%)9 (22%) DisclosuresNo relevant conflicts of interest to declare.

Should Busulfan Now be Part of the Standard Treatment for Patients with Acute Myeloid Leukemia?

2014 Treatment of acute myeloid leukemia (AML) in nonelderly patients has followed the same paradigm of remission induction with cytarabine and anthracycline with or without a third cytotoxic drug for more than 40 years. These drugs produce complete remissions in the majority of patients, but cure requires intensive postremission treatment. Postremission therapies have also remained similar for many years, but better criteria for selection of postremission treatment for individual patients has improved results. Cytogenetic analysis and molecular markers predict risk of relapse more accurately than previously used factors. Patients at low risk of relapse, including those with core binding factor abnormalities and those with normal cytogenetics and an NPM-1 mutation without FLT3 mutations, are generally best treated with multiple doses of high-dose cytarabine as postremission therapy. Most other patients who have good performance status, minimal comorbidities and a well-matched sibling or unrelated donor, have better long-term survival with allogeneic hematopoietic cell transplantation (HCT) [1]. There is no doubt as to the potent antileukemic efficacy of HCT. This effectiveness, however, comes at the cost of significantly more nonrelapse mortality (NRM) compared with cytarabine. Thomas and colleagues employed a myeloablative regimen of cyclophosphamide and total body irradiation (Cy/TBI) as the preparative regimen for the first successful HCTs in relapsed and refractory acute leukemia. Subsequent patients with AML who underwent transplantation in first remission experienced sustained leukemia-free survival rates in excess of 50% [2]. A few years later, Santos et al. demonstrated the feasibility of a chemotherapy-only preparative regimen of busulfan and cyclophosphamide (BuCy). In a small group of patients with AML in first complete remission (CR1) treated with BuCy and sibling bone marrow grafts, no relapses occurred and the estimated 2-year survival was 44% [3]. This established BuCy as an alternative to Cy/TBI. This was of particular importance because TBI is not universally available, particularly in developing countries. Owing to the high NRM of the original BuCy study, the Cy dose was modified from 200 mg/kg over 4 days to 120 mg/kg over 2 days (BuCy2) in most subsequent studies and the modification appeared to decrease toxicity [4].

Transplantation Of Peripheral Blood Progenitor Cells (PBPC) As Compared To Bone Marrow (BM) From Unrelated Related Donors For Hematologic Cancers Using Fludarabine-Alkylating Agent Based Reduced Intensity Conditioning Regimens

We explored whether there are differences in graft-versus-host disease (GVHD) or mortality risks after transplantation of PBPC and BM from unrelated donors in the setting of reduced intensity conditioning. Included are 219 BM and 887 PBPC recipients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) or non-Hodgkin lymphoma (NHL). Patients received an alkylating agent and fludarabine as their conditioning regimen and for GVHD prophylaxis, calcineurin inhibitor (CNI) with methotrexate (MTX) or mycophenolate (MMF). Recipients of low dose total body irradiation regimen were excluded, as PBPC was the sole graft used with this regimen. Transplantations occurred in the U.S. between 2000 and 2008. The median ages of BM and PBPC recipients were 57 years. The characteristics of the treatment groups were similar except that BM recipients were more likely to have NHL, receive melphalan + fludarabine, in vivo T-cell depletion and, tacrolimus + MTX GVHD prophylaxis. The median follow-up of BM and PBPC recipients were 6 and 5 years, respectively. Preliminary analysis suggested an interaction between graft type and GVHD prophylaxis. Therefore, the effect of graft type was tested as follows: PBPC, CNI + MTX, PBPC, CNI + MMF, BM, CNI + MTX and BM, CNI + MMF. Results are shown in Tables 1 and 2. After adjusting for age, performance score, disease / disease status and HLA-match, mortality risks were higher after transplantation of PBPC or BM when GVHD prophylaxis included MMF compared to MTX (Table 1). There were no significant differences in mortality risks after transplantation of PBPC relative to BM with CNI + MTX GVHD prophylaxis (Table 2). But mortality risks were higher after transplantation of BM compared to PBPC with CNI + MMF (Table 2). Risks of grade 2-4 acute and chronic GVHD were higher after transplantation of PBPC or BM when GVHD prophylaxis included MMF compared to MTX (Table 1). Relapse risks were higher after transplantation of BM compared to PBPC with CNI + MMF (HR 1.55, p=0.02) but not with CNI + MTX GVHD prophylaxis (HR 1.13, p=0.38). Independent of graft type and GVHD prophylaxis regimens, in vivo T cell depletion was associated with lower risks of acute (HR 0.69, p<0.001) and chronic (HR 0.52, p<0.0001) GVHD but relapse risks were higher (HR 1.24, p=0.02). The data support BM and PBPC are suitable for unrelated donor transplantation when using fludarabine-alkylating agent based reduced intensity conditioning regimens and CNI + MTX GVHD prophylaxis. The data support avoiding CNI + MMF GVHD prophylaxis in this setting.Table 1Overall MortalityNon-relapse MortalityAcute GVHDChronic GVHDBMHazard ratioHazard ratioHazard ratioHazard ratioCNI+MMF vs. CNI+MTX*2.06 p<0.00012.85 p<0.00013.30 p<0.00011.75 p=0.02PBPCCNI+MMF vs. CNI+MTX*1.27 p=0.0041.56 p=0.0012.04, p<0.00011.29, p=0.007 Disclosures:No relevant conflicts of interest to declare.

Omission of Methotrexate Doses Due to Toxicity Does Not Influence the Incidence of Gvhd, Relapse, or Survival

AbstractAbstract 4189Methotrexate (MTX) has had a long history of use in graft versus host disease (GVHD) prevention in allogeneic hematopoietic cell transplantation (HCT) and is now most commonly used with a calcineurin inhibitor, such as cyclosporine (CSA) or tacrolimus (Tac). MTX, however, may contribute to severe mucositis and other organ toxicities, which in turn may result in the need to withhold MTX doses. It is not clear whether the omission of doses of MTX has a deleterious effect on relapse, GVHD, and survival. We therefore retrospectively reviewed the experience with MTX at our institution.We identified 109 patients (pts) who underwent a myeloablative HCT with an HLA matched unrelated donor and received MTX in combination with Tac or CSA for GVHD prophylaxis from May 2003 until May 2011. Data was missing on 7 pts, and they were excluded. Of the remaining 102 pts, 70 received all 4 doses of MTX while 32 (31.4%) missed at least 1 dose of MTX. The dose of MTX used was 5mg/m2 on days 1, 3, 6, 11 from May 2003 until July 2009 and was then increased to 15mg/m2 day 1 followed by 10mg/m2 day 3, 6, 11 after July 2009. 80 pts received the lower dose of MTX, with 26 (32%) having missed a dose and 22 pts received the higher dose MTX after July 2009, with 6 (27%) having missed a dose. Severe mucositis or organ dysfunction were the primary reasons for dose omission in all pts and was based on physician discretion. Pts underwent HCT for acute myeloid leukemia (n=42), myelodysplastic syndrome (n=25), acute lymphoblastic leukemia (n=19), non Hodgkin lymphoma (n=6), chronic myeloid leukemia (n=6), myeloproliferative neoplasms (n=2), biphenotypic leukemia (n=1), and plasma cell leukemia (n=1). The two groups did not differ significantly in age, gender, disease, disease status, CMV status, or hematopoietic cell source, but did differ in the number of prior chemotherapy regimens to which the patient had been exposed. 43.8% of pts in the missed MTX group had received 3 or more prior chemotherapy regimens compared with 24.3% in the 4-dose group, (p=0.047). The conditioning regimen most commonly used was cyclophosphamide (Cy) with busulfan (Bu), n=56; but other preparative regimens included Bu/Cy and etoposide (VP-16), n=14; Cy in combination with total body irradiation (TBI), n=3; TBI/VP-16, n=20; and Cy/TBI in combination with ATG or ECP, n=9. There were no statistically significant differences in the preparative regimen or use of TBI between the two groups. Outcomes were compared between full and missed dose groups using the log-rank test or Pepe-Mori test.With the omission of doses of MTX due to toxicities, there was no difference in time to hematopoietic recovery or length of hospital stay. Median time to neutrophil recovery for full dose MTX was 18 days, (range 9–75) compared to 16, (range 10–27) in the missed dose group, (p=0.55). Median time to platelet recovery was 25 days, range (13–51) for the 4 dose group compared to 21 (range 12–75, p=0.36). There was no significant difference in acute GVHD between full and missed dose groups (6 month incidence 38.6% versus 53.1% grade 2–4, p=0.35; 20.0% versus 9.4% grade 3–4, p=0.16). There was also no difference in chronic GVHD (2 year incidence 30.4% versus 41.8% any chronic, p=0.43; 20.0% versus 26.1% extensive chronic, p=0.74). Full dose and missed dose also did not differ with respect to relapse (5-year incidence 31.3% versus 37.7%, p=0.65), overall survival (OS) (5-year 41.3% versus 26.6%, p=0.14), or non-relapse mortality (NRM) (5-year incidence 32.6% versus 57.6%, p=0.13).We have previously shown that severe mucositis is associated with inferior survival (Fanning et al, BJH 2006, 135:374). While the differences in GVHD, NRM and OS did not reach statistical significance, it did appear that those who missed a dose of MTX did worse than those who received all 4 doses; and one can speculate this may be related to the toxicity of severe mucositis. Even with the dose change in our cohort, there was interestingly no difference in the incidence of missed does between the groups assigned to receive low or standard dose MTX. This initial analysis provokes many additional questions, including whether a fourth dose of MTX is needed in all pts. Single nucleotide polymorphisms of the enzymes which MTX inhibits induce differential effects on MTX metabolism which may lead to increased toxicity and a potential protective effect for GVHD for a given dose. Further prospective study of dosing of MTX in GVHD prophylaxis is warranted. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Clinical Significance of Addition of Cytarabine or Thiotepa to TBI/CY Regimen.

Abstract 3028 Introduction:We performed a multicenter retrospective study of the significance of the addition of cytarabine (CA) or thiotepa (TT) to the myeloablative standard regimen consisting of total body irradiation (TBI) and cyclophosphamide (CY). Methods:Among the patients who underwent allogeneic hematopoietic stem cell transplantation between 2,000 and 2,010 in the four institutions related to Yokohama City University Hematology Group, a total of 365 patients who used the TBI/CY-based regimen were included to the cohort. Conditioning regimens were distributed to three groups: TBI/CY group (TC, n=82), TBI/CY/CA group (TCC, n=90), and TBI/CY/TT group (TCT, n=193). A standard TBI and CY regimen consisted of 12 Gy of TBI with four fractions and 60 mg/kg of CY for two days. Two days of CA (2 g/m2/day) or TT (200 mg/m2/day) were added to the TBI/CY regimen. A minimum dose reduction was permitted according to an older age or poorer co-morbidity. Overall survival (OS) and disease-free survival (DFS) were estimated by the Kaplan-Meier method. Gray's test was employed for comparison of cumulative incidence curves for relapse and non-relapse mortality (NRM). NRM and relapse were competing events. Adjusted multivariate Cox regression models were employed for each disease stage. Results:The median age was 42 years old (16–62). Diagnoses were acute myeloid leukemia (AML, n=219), acute lymphoid leukemia (ALL, n=105), and myelodysplastic syndrome (MDS, n=41). Complete remission or refractory cytopenia with multilineage dysplasia was defined as the standard stage (n=211), while the others were advanced (n=154). The stem cell sources were related bone marrow (RBM, n=79), related peripheral blood (RPB, n=51), unrelated bone marrow (UBM, n=161), and unrelated cord blood (UCB, n=74). As for patient characteristics, there was a deviation in the transplant year (P<0.001), disease stage (P=0.001), and stem cell source (P=0.022). Among the 195 patients with a previous transplant year (2000–2005), 187 patients (95.9%) received the TCT regimen, while only 6 patients with the TCT regimen were included in the recent transplant (2006–2010). Among 82 patients of the TC group, 62 patients (75.6%) were defined to be in the standard stage.The cumulative incidence of engraftment was 89.5% with a median of 17 days (8–48). Cumulative incidences of acute graft-versus-host disease (GVHD) (grade 2 to 4, at day 50) and chronic GVHD (at 1 year) were 47.0 and 42.3%, respectively, with no significant difference between the three conditioning regimens. The median follow up period among survivors was 61.4 months (12.4–144). Outcomes at 5 years in each group (TC/TCC/TCT) were as follows: OS rates were 51.2, 34.4, and 40.3 (P=0.107), respectively; DFS rate were 50.8, 31.5, and 38.5 (P=0.177), respectively; NRM rates were 23.8, 35.5, and 40.5 (P=0.045), respectively; relapse incidences (RI) were 21.4, 29.6, and 20.8 (P=0.193), respectively. In standard stage, hazard risks (HR) for each regimen (TC is referent) were as follows; OS (TCC, HR=1.19, 95%CI: 0.64–2.01, P=0.70; TCT, HR=1.08, 95%CI: 0.66–1.78, P=0.75), NRM (TCC, HR=1.32, 95%CI: 0.61–2.85, P=0.48; TCT, HR=1.55, 95%CI: 0.82–2.94, P=0.17), and RI (TCC, HR=0.78, 95%CI: 0.26–2.33, P=0.65; TCT, HR=0.69, 95%CI: 0.28–1.72, P=0.42). In advanced stage, HR for each regimen (TC is referent) were as follows; OS (TCC, HR=0.94, 95%CI: 0.48–1.81, P=0.85; TCT, HR=1.16, 95%CI: 0.62–2.17, P=0.64), NRM (TCC, HR=1.39, 95%CI: 0.51–3.77, P=0.52; TCT, HR=2.68, 95%CI: 1.06–6.78, P=0.04), and RI (TCC, HR=1.05, 95%CI: 0.44–2.50, P=0.92; TCT, HR=0.69, 95%CI: 0.30–1.57, P=0.37). In AML, the TC group showed superior OS and NRM compared with the TCT group (54.0 vs. 36.9%, P=0.034; 23.1 vs. 42.4%, P=0.023, respectively). In MDS, the TCT group showed a lower RI compared with the TCC group (0 vs. 34.5%, respectively, P=0.012). Conclusion:The benefit of the addition of CA or TT to the TC regimen was not demonstrated for each risk group. Especially in AML, TCT lead to inferior survival compared with TC. However, a bias in patient characteristics has to be considered, and a prospective study is needed in the future. Disclosures:No relevant conflicts of interest to declare.

Favorable Outcomes of Autologous Stem Cell Transplantation in Adult Patients with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia in First Remission: On Behalf of the Adult Acute Lymphoblastic Leukemia Working Group of the Japan Society for Hematopoietic Cell Transplantation (JSHCT)

AbstractAbstract 2021 Background:Postremission treatment for adult Philadelphia chromosome-negative acute lymphoblastic leukemia [Ph(-)ALL] in first remission remains elucidated and the role of autologous stem cell transplantation (auto-SCT) is still controversial in the application for Ph(-)ALL patients. We retrospectively analyzed the consolidative role of auto-SCT as a postremission therapy for adult Ph(-)ALL in first remission. Patients and Methods:Among 1962 adult Ph(-)ALL patients registered in the JSHCT database, we selected cases receiving auto-SCT with myeloablative preparative regimens in first complete remission from 1983 to 2009. Results:A total of 155 patients with 86 male patients were analyzed. The median age was 25 years (range: 16 to 74) and 79% of patients were less than 45 years of age at transplant. The number of patients having white blood cell (WBC) count <30000/ul and ≥30000/ul at diagnosis was 81 and 21, respectively. The number of patients showing B- and T-cell phenotypes was 80 and 21, respectively. Cytogenetic data were available in 96 patients, of which 69 patients had normal karyotypes. Most patients (84%) underwent auto-SCT before 2002, and 42 out of 155 patients received TBI combined conditioning regimens. With a median follow-up of 10 years, the 10-year overall survival rate of all 155 patients was 41% (95%CI: 33 to 49). Among patients younger than 45 years, the survival rate of adolescent and young adult (AYA) patients (aged 24 years or less) was comparable to that of patients aged 25 to 44 years (p= 0.110). Cumulative incidence of relapse and non-relapse mortality (NRM) at 10 year after auto-SCT was 47% (95%CI: 39 to 55) and 10% (95%CI: 6 to 16), respectively. In univariate analysis, factors associated with worse overall survival were age 45 years or more [Hazard ratio (HR): 1.67, p=0.038] and usage of conditioning regimens without total body irradiation (TBI) (HR: 1.51, p=0.110). Factors associated with decreasing relapse rates were usage of TBI conditioning regimens (HR: 0.35, p=0.069) and transplant year 2000 and later (HR: 0.35, p=0.141). In multivariate analysis, factors correlated with increasing the overall survival rate and decreasing the relapse rate were age less than 45 years [HR: 0.59 (95%CI: 0.36 to 0.96), p=0.034] and usage of TBI conditioning regimens [HR: 0.55 (95%CI: 0.31 to 0.99), p=0.048], respectively. There were no significant factors associated with NRM in univariate and multivariate analyses.We next performed comparison of auto-SCT with allogeneic stem cell transplantation (allo-SCT) in adult Ph(-)ALL patients. Patients undergoing allo-SCT were selected from the same JSHCT database. A total of 921 patients were identified as cases receiving allo-SCT with myeloablative preparative regimens in first complete remission. With a median follow-up of 4.95 years, the 4-year overall survival rate was 63% (95%CI: 51 to 59). Allo-SCT yielded better overall survival rate than that of auto-SCT (63% vs. 48% at 4 year, p=0.0004). In subset analyses, we limited analyses to the groups of patients younger than 45 years and receiving TBI regimens followed by auto-SCT (n=31) or allo-SCT (n=685). There were no differences in baseline patients’ characteristics between the two groups except age [auto-SCT: 20 years (range: 16 to 40) vs. allo-SCT: 28 years (range: 16 to 44), p<0.001]. The 4-year overall survival rates in patients undergoing auto-SCT and allo-SCT were 71% (95%CI: 52 to 84) and 66% (95% CI: 62 to 70), respectively (p=0.510, Figure. 1). No statistically significant factors were found in the analyses of relapse and NRM. Conclusions:Our analyses demonstrated that auto-SCT produced excellent results showing a plateau in long-term survival and that clinical outcome of auto-SCT was comparable to that of allo-SCT in some part of patients. Candidates who obtained most benefit from auto-SCT was those younger than 45 years and well tolerated with TBI combined myeloablative conditioning regimens. Since optimal timing of postremission therapy is critical for adult Ph(-)ALL patients, auto-SCT in first complete remission could be one of promising treatment strategies for the patients. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Regression of syndesmophyte after bone marrow transplantation for acute myeloid leukemia in a patient with ankylosing spondylitis: a case report

IntroductionDisease progression of ankylosing spondylitis has been considered irreversible. However, we report a case of spontaneous regression of syndesmophyte development following allogeneic peripheral blood stem cell transplantation in a patient with acute myeloid leukemia, who was also diagnosed as having ankylosing spondylitis. To the best of our knowledge, this is the first case report presenting the partial radiologic regression of syndesmophytes.Case presentationA 39-year-old man with active ankylosing spondylitis achieved clinical remission and partial radiological regression of cervical spine syndesmophytes following a peripheral blood stem cell transplantation for acute myeloid leukemia. Our patient received an allogeneic peripheral blood stem cell transplantation following a pre-transplantation conditioning regimen of total body irradiation and cyclophosphamide. The donor was a human leukocyte antigen-matched 29-year-old man. Our patient has remained asymptomatic and has received no medication for ankylosing spondylitis for nearly three years.ConclusionsSeveral explanations are proposed for the regression of syndesmophytes and clinical improvement in active ankylosing spondylitis observed in our patient, including changes in bone remodeling and immune reconstitution following stem cell transplantation, the effect of immunosuppressive agents, or fluctuation in the natural course of ankylosing spondylitis although further studies are required. The regression of syndesmophytes in ankylosing spondylitis in this case raises the possibility that stem cell transplantation might contribute to the development of a novel therapeutic strategy for treatment of the disease.

Bone Loss and Avascular Necrosis of Bone After Hematopoietic Cell Transplantation

Advances in transplantation technology and supportive care measures have resulted in significant decrease in early mortality resulting in continued growth in the number of long-term hematopoietic cell transplantation (HCT) survivors. The intensity of chemotherapy and total body irradiation regimen used pretransplantation to eradicate the primary disease can lead to organ toxicities, including significant bone complications after HCT. Bone loss is frequent in HCT recipients and results from impaired bone mineralization through disturbances of calcium and vitamin D homeostasis, osteoblast and osteoclast dysfunction, and deficiencies in growth or gonadal hormone secretion. Exposure to glucocorticoids and calcineurin inhibitors for prevention and treatment of graft-versus-host disease (GVHD) represents one of the major causes for the increased risk of osteoporosis and avascular necrosis of bone (AVN) in recipients of allogeneic HCT. In this article we review the incidence, pathogenesis, and risk factors for osteoporosis and AVN after allogeneic HCT and discuss general guidelines for their treatment and monitoring based on the limited available reports.

Fludarabine-Based Conditioning for Allogeneic Marrow Transplantation From Unrelated Donors in Severe Aplastic Anemia (SAA): Serious and Unexpected Adverse Events in Pre-Defined Cyclophosphamide (CY) Dose Levels

Abstract 3009▪FN2▪This icon denotes a clinically relevant abstract Objective:To determine toxicity and efficacy of adding fludarabine (FLU) to a regimen of total body irradiation (TBI), anti-thymocyte globulin (ATG) and cyclophosphamide (CY), with de-escalation of the CY dose. The goal is to minimize CY-related toxicities while preserving (or improving) engraftment and survival in patients with SAA receiving an unrelated donor marrow transplant. Patients and Methods:Since May 2006, the Blood and Marrow Transplant Clinical Trials Network (BMT CTN), sponsored by the NHLBI and NCI, has conducted a prospective Phase I/II clinical trial of unrelated donor marrow transplantation in SAA (BMT CTN 0301). Patients with SAA are eligible if they are < 65 years, have adequate organ function, and have an available unrelated marrow donor matched 7 of 8 HLA-A, B, C, DRB1 loci. Patients with Fanconi anemia and other marrow failure syndromes are excluded. All patients receive TBI 200 cGy, ATG (either thymoglobulin: 3 mg/kg IV or ATGAM 30 mg/kg IV daily × 3, days –4 to –2), FLU (30 mg/m2 IV daily × 4, days –5 to –2). The Phase I portion of the trial sequentially tested four CY dose levels: 150 mg/kg (administered days –4 to –2); 100 mg/kg (days –3 to –2); 50 mg/kg (day –2); and, 0 mg/kg, and allowed enrollment of up to six patients at each CY dose level unless toxicity or graft failure boundaries were crossed. In the Phase II portion of the trial, patients enroll onto the optimal CY dose level, which is chosen using adaptive Bayesian criteria to rank desirability of the CY doses. All patients are followed for two years after transplantation. Early stopping guidelines are used to monitor for graft failure and early transplant-related mortality through day 100. Results:Twenty-one patients accrued to the Phase I portion of the trial. CY dose level 0 mg/kg was closed after all three enrolled patients developed secondary graft failure. All received a second allograft. One patient remains alive at 23 months after the first transplantation. The other two died from adult respiratory distress syndrome (ARDS) at 114 days after the first transplant and idiopathic pneumonia at 200 days after the first transplant. Review of Phase I results for the other three dose levels suggested CY dose 150 mg/kg as the optimal dose level for Phase II testing. However, after an additional eight patients were treated at this dose, the level was closed to further accrual because of excess toxicity. Seven of the 14 patients receiving 150 mg/kg of CY (and 7 of the last 8 enrolled) died. Causes of death were cardiac/pulmonary/multi-organ failure (n=4), ARDS (n=2), and parainfluenza virus type 3 pneumonia (n=1). Bayesian evaluation of the two remaining dose levels indicates very similar desirability scores and accrual continues at both the CY 100 mg/kg and 50 mg/kg levels. As of July 15, 2011, a total of 61 patients have been enrolled, 17 on the two closed levels, 33 on the 100 mg/kg level and 11 on the 50 mg/kg level. Conclusions:Early analysis of this trial, made necessary by these unexpected severe adverse events, revealed two important findings among patients receiving low-dose TBI, ATG, and FLU at the doses outlined: 1) CY dose 0 mg/kg is associated with higher than expected graft failure; and, 2) CY dose 150 mg/kg is associated with excess transplant-related toxicity. Neither CY dose level should be tested further in the context of the regimen used in this trial. To date, the two intermediate CY dose levels (100 mg/kg and 50 mg/kg) have not crossed the graft failure or fatality stopping boundaries and accrual is in progress. Disclosures:Pulsipher:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Incidence, risk factors, and clinical outcomes of cataracts following hematopoietic stem cell transplantation

To evaluate the characteristics of cataracts following hematopoietic stem cell transplantation (HSCT), 561 patients without any ocular complications before HSCT were reviewed. Ocular complications occurred in 196 patients (34.9%). Cataract was diagnosed in 45 of 561 patients. The 10-year estimated cataract incidence was 14%. The median onset time was 498 days after transplant (range, 38-4,535 days). The onset of cataracts was later than that of other ocular complications. Phacoemulsification was performed in 13 patients (29%) at a median of 1,028 days after HSCT (range, 375-4,549 days). In 6 of 13 patients (46%) who underwent cataract surgery, visual acuities gradually deteriorated because of the development of posterior capsule opacification. YAG (yttrium-aluminum-garnet) laser posterior capsulotomy successfully recovered their sight without any sequelae. A multivariate analysis revealed that age, acute and chronic graft versus host disease (GVHD), and systemic infection were significant risk factors for cataract, whereas neither steroid nor total body irradiation (TBI)-containing regimens affected the development of cataract. Our results showed that the clinical outcomes of cataract after HSCT are favorable and comparable to those in the general population. Hyperfractionated TBI with eye shielding may be effective for the prevention of cataract.

全身照射+thiotepa+melphalanを前処置とした難治性白血病35例の同種骨髄移植成績

全身照射+thiotepa+melphalanを前処置とした難治性白血病35例の同種骨髄移植成績

Conditioning regimen using busulfan plus melphalan in hematopoietic stem cell transplantation

Conditioning regimen using busulfan plus melphalan in hematopoietic stem cell transplantation

Magnetic resonance imaging in childhood leukemia survivors treated with cranial radiotherapy: A cross sectional, single center study

Children treated with cranial radiotherapy (CRT) for leukemia are at risk of developing central nervous system injuries. Magnetic resonance imaging (MRI) represents the examination method of choice for evaluating radiation-induced brain complications. The purpose of this report is to describe the spectrum of MRI abnormalities detected in a group of survivors of leukemia treated with cranial irradiation. In this cross-sectional, single center study, 56 patients (median age at follow-up 19 years) receiving CRT as cranial prophylaxis (CP) included in the leukemia protocol (total dose 1,800-2,400 cGy) and/or in the total body irradiation regimen (990-1,200 cGy) before hematopoietic stem cell transplant, were evaluated by MRI after a median interval of 11 years (range 2-27) following CRT. Fifty-nine MRI abnormalities (32 cavernomas, nine focal areas of gliosis, seven dystrophic mineralizations, five cerebral atrophies, four pituitary atrophies, one diffuse radiation leukoencephalopathy, and one meningioma) were found in 43 patients. The longest interval between CRT and MRI and oldest age at follow-up represented the two risk factors that were statistically associated with MRI lesions (P = 0.032 and 0.033, respectively). Cerebral cavernomas (CC) were the most frequent MRI abnormalities (57%). All patients with CC were asymptomatic at diagnosis and during follow-up, except one who had aspecific neurological manifestations and micro hemorrhages. These results confirm that total doses and modalities of fractionation dose of CRT were not significantly associated with MRI abnormalities. Moreover, in our experience none of the patients developed neurological symptoms related to MRI abnormalities, and furthermore, the CC remained substantially stable during follow-up.

Impact of Clinical Factors on Platelet Engraftments In Contemporary Stem Cell Transplantation.

AbstractAbstract 4522 Background:Conditioning regimens utilized to prepare patients for stem cell transplantation uniformly result in suppression of marrow function, leading to prolonged recovery of neutrophils and platelets. Neutropenia increases the risk of infection while thrombocytopenia and prolonged platelet engraftment time can result in increased risk of bleeding as well as morbidities associated with subsequent transfusions. The variations in duration of cytopenias are affected by multiple factors including regimen intensity and other clinical factors. Methods:In this retrospective study of consecutive patients undergoing stem cell transplantation at the University of Rochester between 2005 and 2009 for radiation—containing regimens, and between 2007 and 2009 for non-radiation containing regimens, we assessed the relationship between platelet engraftment times and source of stem cells, type of graft, and the effect of conditioning regimen intensity. Platelet engraftment was defined per standard CIBMTR definitions – platelet engraftment occurred at the first of 3 days of platelet count >20,000/μ L without platelet transfusions for 7 days, and/or the first day of platelet count >100,000/μ L. Guidelines for transfusion support stipulated a 10,000/μ L threshold for platelets in the absence of bleeding and a hemoglobin of 8.0 g/dL for red cells in the absence of other symptoms. The time to platelet engraftment and the number of platelet transfusions required prior to engraftment were analyzed in those patients with platelet nadir <20,000/μ L. Among 507 adult patients (older than 18), 49 did not have a platelet count nadir, and these patients were excluded from the analyses. Of those, 29 had TBI regimens, 16 of which utilized 200 cGy and 13 had radiation dosage 400–800 cGy. 280 of 458 adult patients who had nadir of platelets received conditioning regimens with chemotherapy alone, and 178 received regimens including total body irradiation (TBI). Disease diagnoses for which transplantation was performed in the 458 cases with platelet nadir included ALL (n=34), AML (n=112), CLL (n=17), CML (n=17), NL/NHL (n=189), MM (n=69), and others (n=20). Results:The 25th percentile, median and 75th percentile (days) for the time to platelet engraftment in days, calculated using the method of cumulative incidence for the non-TBI and TBI containing conditioning regimens, are shown below:Conditioning regimenTime to platelet engraftment (days)25th percentile50th percentile (median)75th percentileWith TBI161826Without TBI151718With conditioning regimens containing TBI or with chemotherapy alone (non-TBI), both donor type (auto, allo, or matched unrelated donor) and graft type (marrow, PBSCs, or umbilical cord blood) had significant effects on platelet engraftment time, with the longest engraftment times occurring in cord blood transplants. With both TBI and non-TBI conditioning regimens, donor and graft type significantly affected platelet transfusion numbers (p<.0001). Radiation dose-level of TBI had a significant effect on platelet engraftment (p=0.004) and the number of platelet transfusions required. Of the 458 patients who had nadir of platelet counts, 58.7% of the population was female. Gender did not affect the platelet engraftment time for all patients, but affected the platelet and red blood cell transfusion frequencies in TBI patients. Female TBI patients received significantly more platelet transfusions (p<.0001) up to 100 days and significantly more RBC transfusions up to 30 days (p=.007), after which no significant differences were noted up to 100 days (p=.24).With non-TBI conditioning regimens, gender did not affect the number of platelet transfusions, but females received significantly more red cell transfusions up to 100 days post-transplant (p=0.003). Conclusions:These data indicate that times to platelet engraftment in stem cell transplant patients in the era of PBSC and reduced-intensity transplant regimens remains longer than two weeks in cases where conditioning regimens result in platelet nadir. This is associated with considerable utilization of transfusion resources. The increased need of RBC and platelet transfusions in females receiving TBI containing regimens and red cells in non-TBI conditioning cases despite similarity in platelet engraftment times is of interest, and underlying causes remain undetermined. Disclosures:No relevant conflicts of interest to declare.