Conditioning Regimen For Stem Cell Transplantation Research Articles

Temporal trajectory of quality of life and its predictors in recipients of hematopoietic stem cell transplantation.

This prospective longitudinal study evaluated the temporal trajectory of health-related quality of life (HRQOL) and its associated factors in patients who received hematopoietic stem cell transplantation (SCT) 6months after transplantation. Eighty-nine adult patients who were admitted to Seoul National University Hospital for SCT were consecutively included in the study. The participants completed three standardized questionnaires: Insomnia Severity Index, Hospital Anxiety and Depression Scale, and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire. The participants completed the study questionnaires at three time points: before SCT (T1), immediately after SCT (T1), and 6months after SCT (T3). Immediately after SCT, HRQOL decreased significantly (p < 0.001), followed by recovery over 6months. The conditioning regimen for SCT showed no correlation with HRQOL at T2 (p = 0.283) or T3 (p = 0.799), with no significant difference in HRQOL between allogeneic and autologous SCT recipients at T2 (p = 0.829) or T3 (p = 0.824). Depression (p = 0.042), pain (p = 0.023), and appetite loss (p = 0.004) negatively influenced HRQOL at T1, whereas only pain (p = 0.048) remained an important factor at T2. Six months after SCT, the two most frequent symptoms, fatigue and financial problems, became major factors (p = 0.004 and p = 0.005, respectively). Depression began to play an important role in HRQOL again at T3 (p = 0.040). These findings demonstrate that SCT recipients need both psychological and medical support to achieve a better HRQOL after SCT.

Acute kidney injury after high dose etoposide phosphate: A retrospective study in children receiving an allogeneic hematopoetic stem cell transplantation.

Etoposide phosphate (EP; single injection, 60mg/kg) followed by total body irradiation (TBI) at 12 Gy has been used as an allogeneic stem cell transplantation (allo-SCT) conditioning regimen for children since 2010. In our institution, EP has been suspected of leading to acute nephrotoxicity. The aim of this study was to assess the potential renal toxicity of EP in this context. A retrospective study was carried out on children hospitalized between 2007 and 2015 for allo-SCT with TBI-based myeloablative conditioning associated with cyclophosphamide (CY, 60mg/kg/day×2 days) or EP. The primary endpoint of the study was the occurrence of acute kidney injury (AKI). Additional endpoints were time to recovery for children with AKI, survival, and treatment-related mortality. Thirty-five patients were analyzed (CY: 22 vs. EP: 13). AKI occurred more frequently in the EP group than in the CY one (69% vs. 27%, adjusted odds ratio 6.0, 95% confidence interval [CI] [1.145; 31.445], P=0.03). The median time to recovery was estimated at 3 days, 95% CI (2; 17), with CY and 11 days 95% CI (5; 18) with EP (adjusted hazard ratio of recovery for EP vs. CY 0.262, 95% CI [0.071; 0.969], P=0.04). No significant difference was highlighted between the two treatments for survival or for treatment-related mortality. This study shows that EP at high dosage or one of its excipients is probably responsible for AKI, as compared to CY. Further studies are required to explore the origin of this adverse effect.

Comparison of allogeneic stem cell transplant conditioning regimens in AML, MDS and CLL

Comparison of allogeneic stem cell transplant conditioning regimens in AML, MDS and CLL

Prevention of gastrointestinal side-effects in paediatric oncology: what are the guidelines?

Gastrointestinal side-effects, particularly with regard to alimentary tract mucositis and chemotherapy-induced nausea and vomiting (CINV), continue to be frequent and debilitating symptomatic conditions among children and adolescents receiving cytotoxic cancer therapy. Further avenues of progress for mucositis and CINV prevention in paediatric oncology setting are warranted. The current article reviews the major guidelines and literature published in 2016 pertaining to the prevention of mucositis and CINV. Considerable professional organizational efforts have been made to develop consensus-based or evidence-based guidelines that periodically update to define basic standards of mucositis and CINV prevention. There are a few published works in 2016 that may contribute to the emerging evidence on prevention of mucositis and CINV in the paediatric setting for future guideline updates. The concomitant use of 5-HT3 receptor antagonist and dexamethasone are effective to prevent acute and delayed CINV in children who are to receive highly or moderately emetogenic chemotherapy. Optimal control of acute and delayed CINV can prevent anticipatory CINV. Oral care protocols would be beneficial to prevent mucositis in children across all cancer treatment modalities. Cryotherapy or low-level light therapy may be applied to cooperative children undergoing chemotherapy or haematological stem cell transplant conditioning regimens with a high rate of mucositis.

Comparison of the cytotoxicity of cladribine and clofarabine when combined with fludarabine and busulfan in AML cells: Enhancement of cytotoxicity with epigenetic modulators

Clofarabine (Clo), fludarabine (Flu), and busulfan (Bu) combinations are efficacious in hematopoietic stem cell transplantation for myeloid leukemia. We sought to determine whether the more affordable drug cladribine (Clad) can provide a viable alternative to Clo, with or without panobinostat (Pano) and 5-aza-2'-deoxycytidine (DAC). Both Clad+Flu+Bu and Clo+Flu+Bucombinations showed synergistic cytotoxicity in KBM3/Bu250(6), HL60, and OCI-AML3 cell lines. Cell exposure to these drug combinations resulted in 60%-80% inhibition of proliferation; activation of the ATM pathway; increase in histone modifications; decrease in HDAC3, HDAC4, HDAC5 and SirT7 proteins; decrease in mitochondrial membrane potential; activation of apoptosis and stress signaling pathways; and downregulation of the AKT pathway. These drug combinations activated DNA-damage response and apoptosis in primary cell samples from AML patients. At lower concentrations of Clad/Clo, Flu, and Bu, inclusion of Pano and DAC enhanced cell killing, increased histone modifications and DNA demethylation, and increased the levels of P16/INK4a, P15/INK4b and P21/Waf1/Cip1 proteins. The observed DNA demethylating activity of Clad and Clo may complement DAC activity; increase demethylation of the gene promoters for SFRP1, DKK3, and WIF1; and cause degradation of β-catenin in cells exposed to Clad/Clo+Flu+Bu+DAC+Pano. The overlapping activities of Clad/Clo+Flu+Bu, Pano, and DAC in DNA-damage formation and repair, histone modifications, DNA demethylation, and apoptosis may underlie their synergism. Our results provide a basis for supplanting Clo with Clad and for including epigenetic modifiers in the pre-hematopoietic stem cell transplantation conditioning regimen for myeloid leukemia patients.

Higher Tacrolimus Concentrations Early Post-Transplant Reduce the Risk of Acute Graft-Versus-Host Disease in Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation

s / Biol Blood Marrow Transplant 21 (2015) S355eS373 S369 be more economically responsible in a small group of patients will have a large impact on drug expenditures. As the price of thiotepa continues to rise and alternative regimens are utilized more frequently, there remains a responsibility for the practitioner to report and determine the most effective, safe, and economically responsible pediatric hematopoietic stem cell transplant conditioning regimen.

Identification of a novel intertypic recombinant species D human adenovirus in a pediatric stem cell transplant recipient

BackgroundHuman adenoviruses (HAdV) are known opportunistic pathogens in hematopoietic stem cell transplant (SCT) recipients. The detection of HAdV infection in children after SCT has been implicated as a determinant of poor outcome but specific associations between HAdV species or individual HAdV types and disease are poorly understood. ObjectivesCharacterization of a HAdV-D strain isolated from multiple clinical specimens of an 11-year-old female recipient of a matched unrelated donor peripheral SCT for T-cell lymphoma and case report. Study designArchived HAdV PCR-positive plasma, urine, and stool specimens were processed for virus isolation and detailed molecular typing. Complete genomic sequencing was carried out on 2 isolates. ResultsThe patient tested positive for HAdV DNA by real-time PCR of a stool specimen at 44 days after initiation of a SCT conditioning regimen. In the subsequent 3 months, HAdV was detected in plasma, urine and stool specimens in association with symptoms of gastroenteritis and hemorrhagic cystitis. A novel HAdV-D with a HAdV20-like hexon gene was isolated from both urine and stool specimens. All isolates yielded identical restriction profiles with endonucleases BamHI, BglII, BstEII, HindIII, PstI and SmaI. Analysis of 2 complete genomic sequences further identified the virus as a novel intertypic recombinant HAdV-D (P20/H20/F42) closely related to HAdV42. ConclusionsThis case highlights the identification of a previously unknown HAdV-D from an immunocompromised host. In this patient, the course of adenovirus infection is compatible with reactivation of a latent virus or a primary opportunistic infection. Adenoviremia in this patient resolved without definitive adenovirus-directed antiviral therapy.

Comparison Of Umbilical Cord Blood and Haploidentical Donor Grafts In Adults With High Risk Hematologic Diseases After Fludarabine Cyclophosphamide and TBI 2 Gy Based Reduced-Intensity Conditioning Regimen Stem Cell Transplantation

IntroductionHuman leukocyte antigens (HLA)-matched sibling or unrelated donor are available for around only 50-60% of patients. However, for patients without a suitably matched related donor, Alternative donors such as mismatched unrelated, cord blood and mismatched family donors could be searched. The aim of this retrospective study was to compare the results of graft source on outcome of patients after haploidentical related donor (Haplo), and the unrelated umbilical cord blood (UCB) transplantation in the setting of Non myeloabalative conditioning regimen (NMA). Patients and methodsWe retrospectively analyzed outcomes in 150 adult patients with high risk hematologic diseases who received Allo-SCT from alternative donors from two centers (Institut Paoli-Calmettes at Marseille France and Humanitas cancer center at Rozzano, Italy): These two centres have been applying common transplant approaches and procedures during the study period. 69 patients received Haplo and 81 patients received UCB. In the UCB group, the NMA regimen consisted of fludarabine (Flu), cyclophosphamide (Cy) and low dose TBI (2 Gy) combination in the two groups. The GVHD prophylaxis consisted of Cyclosporine A (CsA) and MMF in all patients in the two groups. In the Haplo group all patients received also 50 mg/kg Cy at day 3 and 4 post transplant. Of note, supportive care was the same during the whole study period. CMV infection management was also homogeneous. Patient characteristics are shown in Table 1.Table 1Patient and transplantation characteristics:Characteristic Total =150 patientsHaplo transplant (n = 69)CB transplant (n = 81)P valuePatients Age years (median) [range]44 (19-68)47 (18-66)Patients sexnsMale39 (57)46 (57)Female30 (43)35 (43)Disease typeAML3 (4)37 (46)<0.0001ALL1 (1)14 (17)<0.0001NHL24 (35)14 (17)nsHL30 (43)2 (2)<0.0001MM4 (6)2 (2)nsCLL5 (7)4 (5)nsCML01 (1)nsMDS/ MPS2 (3)7 (9)nsStatus of diseaseCR37 (54)56 (69)nsPR/SD24 (35)12 (15)0.04PD8 (11)13 (16)nsDonor typeSibiling32 (46)Parent18 (26)Child18 (26)cousin1 (2)Donor/recipient sex mis-match34 (49)56 (69)nsABO incompatibility24560.02Conditioning regimenFlu 5+Cy 1+ TBI075 (93)Flu 5+Cy 2+ TBI69 (100)6 (7)Stem cell sourcePeripheral Blood19 (28)Bone Marrow50 (72)Stem cell dose median [range] CD34+ x 106/kg3,96 (0,8-14)0,9 (0,08-1,28)GvHD prophylaxisCSA+MMF69 (100)81 (100)nsCy post transplant69 (100)0Days with ANC< 500 x 109/l20 (14-39)22 (6-67)nsDays with platelets<20 x 109/l29 (14-50)41 (18-80)ns ResultsWith a median follow-up of 59 months (8-101) and 18 months (3-51), in the UCB group versus the Haplo group, respectively. Nine patients (11%) in the UCB and 8 patients (12%) in the Haplo group had a spontaneous autologous reconstitution subsequent to primary graft failure. The median times to neutrophil and platelet recovery were 20 d (14–39) and 29 d (14–50) after Haplo and 22 d (6–67) and 41 d (18–80) after cord blood. All supportive care measures included red blood cell, and platelet transfusions were significantly increased in cord blood transplantation group. The cumulative incidence of transplant related mortality (TRM) at one year was 23% in the UCB group versus 17% in the Haplo group (P=0.39). Grade 2-4 acute graft-vs.-host disease (GVHD) and extensive chronic GVHD incidences were 52% versus 29% (P=0.05), and 12% versus 6% (P<0.0001), in the UCB group versus the Haplo group, respectively. The Kaplan-Meier estimate of overall survival at 2 years was 45% (95%CI, 34-56%) in the UCB group versus 69% (95%CI, 58-80%) in the Haplo group, (P=0.10). The estimate of progression-free survival at 2 years was 36% (95%CI, 25-47%) in the UCB group versus 65% (95% CI, 53-77%) in the Haplo group (P=0.01). Figure 1 ConclusionIn this study, relapse and PFS was lower in Haplo group than in UCB transplants. The main difference between the 2 groups was the significantly higher incidence of acute and chronic GVHD in the UCB group. Surprisingly, this did not translate into a decrease of the cumulative incidence of OS nor increase of the TRM, which may be explained by a slightly shorter follow-up in this group. Our results suggest that haploidentical transplants are a good and promising alternative option for patients with high risk hematological diseases who lack an HLA-matched donor (sibling or unrelated donor). This should be now investigated in prospective comparative studies. Disclosures:No relevant conflicts of interest to declare.

Risk of Seizures in Children Receiving Busulphan-Containing Regimens for Stem Cell Transplantation

Busulphan (BU) is associated with neurotoxicity and risk of seizures. Hence, seizure prophylaxis is routinely utilized during BU administration for stem cell transplantation (SCT). We collected data on the incidence of seizures among children undergoing SCT in Italy. Fourteen pediatric transplantation centers agreed to report unselected data on children receiving BU as part of the conditioning regimen for SCT between 2005 and 2012. Data on 954 pediatric transplantation procedures were collected; of them, 66% of the patients received BU orally, and the remaining 34%, i.v. All the patients received prophylaxis of seizures, according to local protocols, consisting of different schedules and drugs. A total of 13 patients (1.3%) developed seizures; of them, 3 had a history of epilepsy (or other seizure-related pre-existing condition); 3 had documented brain lesions potentially causing seizures per se; 1 had febrile seizures, 1 severe hypo-osmolality. In the remaining 5 patients, seizures were considered not explained and, thus, potentially related to BU administration. The incidence of seizures in children receiving BU-containing regimen was very low (1.3%); furthermore, most of them had at least 1—either pre-existing or concurrent—associated risk factor for seizures.

Autologous Stem Cell Transplantation in Patients with Acute Myeloid Leukemia: a Single-Centre Experience

Abstract Introduction: Autologous haemopoietic stem cell transplantation (SCT) is an important treatment modality for patients with acute myeloid leukemia with low and intermediate risk disease. It has served advantages over allogenic transplantation, because it does not need a matched donor, there is no graft versus host disease, there are less complications and a faster immune reconstitution than in the allo-setting. The disadvantage is the lack of the graft versus leukaemia effect. Materials and methods: In the Bone Marrow Transplantation Unit Tîrgu Mureș 14 patients with acute myeloid leukemia received an autologous SCT. Mobilization of the stem cells was performed using chemotherapy and granulocytic colony stimulating factor. The conditioning regimen for SCT consists in monotherapy with busulfan (Bu) 16 mg/kg, BuCy: busulfan in combination with Cyclophosphamide (CY) 120 mg/ kg or BuMel: Busulfan in association with Melphalan (Mel) 140 mg/m2. Results: The median patient age was 36 years (range 20-55), 9 (64%) were males and 5 (36) were females and the median time interval from diagnosis to autologous SCT was 9 months (range 3-25). All the patients were transplanted successfully, all of them achieved a sustained neutrophil count (&gt; 0.5 G/L), median time 11 days (9-15) and platelet count (&gt; 20 G/L) median time 14 days (10-19) after transplantation. Conclusions: We conclude that autologous stem cell transplantation is an effective treatment in acute myeloid leukemia with the possibility of long survival, particularly in patients with standard risk disease

Epigenetic modifiers enhance the synergistic cytotoxicity of combined nucleoside analog-DNA alkylating agents in lymphoma cell lines

Hematopoietic stem cell transplantation is used for treatment of lymphoma. In an attempt to design an efficacious and safe prehematopoietic stem cell transplantation conditioning regimen, we investigated the cytotoxicity of the combination of busulfan (B), melphalan (M), and gemcitabine (G) in lymphoma cell lines in the absence or presence of drugs that induce epigenetic changes. Cells were exposed to drugs individually or in combination and analyzed by the MTT proliferation assay, flow cytometry, and Western blotting. We used ~IC(10) drug concentrations (57 μM B, 1 μM M and 0.02 μM G), which individually did not have major effects on cell proliferation. Their combination resulted in 50% inhibition of proliferation. Reduction to almost half concentration (20 μM B, 0.7 μM M and 0.01 μM G) did not have significant effects, but addition of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (0.6 μM) to this combination resulted in a marked (~65%) growth inhibition. The cytotoxicity of these combinations correlates with the activation of the ataxia telangiectasia mutated-CHK2 pathway, phosphorylation of KRAB-associated protein-1, epigenetic changes such as methylation and acetylation of histone 3, and activation of apoptosis. The relevance of epigenetic changes is further shown by the induction of DNA methyltransferases in tumor cells with low constitutive levels of DNMT3A and DNMT3B. The addition of 5-aza-2'-deoxycytidine to (BMG+suberoylanilide hydroxamic acid) further enhances cell killing. Overall, BMG combinations are synergistically cytotoxic to lymphoma cells. Epigenetic changes induced by suberoylanilide hydroxamic acid and 5-aza-2'-deoxycytidine further enhance the cytotoxicity. This study provides a rationale for an ongoing clinical trial in our institution using (BMG+suberoylanilide hydroxamic acid) as pre-hematopoietic stem cell transplantation conditioning for lymphoma.

Aprepitant Pharmacokinetics and Assessing the Impact of Aprepitant on Cyclophosphamide Metabolism in Cancer Patients Undergoing Hematopoietic Stem Cell Transplantation

Aprepitant, a neurokinin antagonist, is an effective antiemetic agent in chemotherapy for delayed nausea and vomiting. The study objective was to evaluate the pharmacokinetics of aprepitant and concurrent cyclophosphamide (CY), often a component of hematopoietic stem cell transplant (HSCT) conditioning regimen, in cancer patients undergoing HSCT. Forty subjects were randomized to either aprepitant or placebo in addition to standard antiemetics. Aprepitant or placebo was started 1 hour before the first chemotherapy or radiation dose for HSCT conditioning and administered daily until 4 days after infusion of the hematopoietic cell graft (for a total of 10-12 days). Serial blood samples were collected for aprepitant and CY plus 2 important CY metabolites. The results indicate that aprepitant is well absorbed and does not auto-induce its metabolism. No significant drug interaction was observed with CY or its metabolites. A significant portion of the patients had subtherapeutic aprepitant concentrations; however, chemotherapy-induced nausea and vomiting were effectively managed. No dosage adjustment was necessary, and administration of aprepitant in HSCT at the prescribed dosage of 125 mg orally on day 1 and 80 mg orally on each consecutive day through day +4 after HSCT was well tolerated with no significant changes in CY pharmacokinetic parameters.

Deferasirox (Exjade®) Given During Conditioning Regimen (FLAMSA/Busulfan/ATG) Reduces the Appearance of Labile Plasma Iron in Patients Undergoing Allogeneic Stem Cell Transplantation

Abstract 3023In patients undergoing allogeneic stem cell transplantation (SCT) non-transferrin-bound iron (NTBI) has been shown to appear quickly after onset of chemotherapy, while not being detectable at baseline. This indicates that cytotoxic therapy is associated with release of catalytically active iron. Pre-transplant iron overload has been associated with a higher risk of complications like infections, liver dysfunction, veno-occlusive disease and acute graft-versus-host disease (GvHD). This could be due to released NTBI catalyzing the generation of reactive oxygen species and being an essential cofactor for pathogen growth.Labile plasma iron (LPI) represents the chelatable, redox-active and toxic fraction of NTBI. It has not yet been assessed in patients undergoing SCT. Treatment with deferasirox (DFR) has been shown to produce sustained reduction in LPI at doses > 20mg/kg/d in patients with β-thalassemia and myelodysplastic syndromes. The aim of this study was to investigate, whether DFR given off-label during conditioning regimen can prevent the formation of NTBI/LPI.A total of 9 patients - all receiving a conditioning regimen with fludarabine, amsacrine, cytosine-arabinoside, busulfan and anti-thymocyte globulin - were enrolled so far. Five consecutive patients received DFR in a mean dose of 16.8mg/kg/d (range 14.5 – 19.7) for the first 5 days of chemotherapy, while 4 patients served as control without DFR. Blood samples were taken daily during chemotherapy and following SCT on day +1, +4, +7 and +14 for assessing selected parameters of iron status (serum iron, transferrin, transferrin saturation (Tfs), serum ferritin) as well as renal and liver function (serum creatinine, ALT, AST, AP, bilirubin). Blood samples for assessment of NTBI and LPI were taken on second (d2) and fifth day (d5) of chemotherapy regimen and d+1 after SCT. NTBI was measured by graphite furnace atomic absorption spectrometry after mobilization of free iron by nitrilotriacetic acid (NTA) and centrifugal filtration of the iron-NTA complex. LPI levels were analyzed according to a previously reported method using an assay kit (Aferrix, Tel Aviv, Israel) that measures iron-specific redox activity in serum in the presence of ascorbate. LPI units > 0.4 were counted as weakly positive and > 0.6 as positive (according to Aferrix).Median baseline Tfs was below the threshold of 80% in both groups (DFR = 38% (range 28–88), control = 59% (range 18–91)). Therefore the presence of NTBI/LPI is very unlikely. During treatment with DFR no LPI was detectable on d2 and d5 whereas in control group 3/4 patients had positive LPI values. On day +1 LPI-values were higher in DFR-group with 3/5 LPI-positive samples (median 0.4 LPI units (range 0–2)) in contrast to 1 positive control sample (1.3 LPI units). Median NTBI-levels in DFR-group on d2 were 3.8 μM (range 3.3–4.8) and decreased notably in 3/5 patients until d5: median 2.1 μM (range 2.0–3.6). In the control group median NTBI values were higher on both days with a median of 5.0 μM (range 2.6–6.3) at d2 and of 4.1μM (range 2.9–6.0) at d5. On day +1 median NTBI-values were similar in both groups: 3.0 μM (range 2.3–4.0) in the DFR and 3.2 μM (range 2.0–3.5) in the control group.Regarding clinical effects the DFR-group had a lower incidence of bacterial bloodstream infections with 2/5 vs. 4/4 control patients.In total DFR was well tolerated and all patients completed chelator therapy. There were no differences between the groups in renal or liver function, except a higher (reversible) increase of bilirubin during ATG treatment in the DFR-group (4/5 patients with grade 3, 1 patient with grade 1 (CTC); median cmax 5.5mg/dl (range 1.4–10.4)) as compared to control (2/4 patients with grade 3, 2 with grade 2; median cmax 3.3mg/dl (range 1.9–4.9)). The DFR-group had a higher incidence of diarrhea during ATG (4/5 patients) and mucositis (5/ 5 patients) than control patients (2/4 and 1/4 patients, respectively). Moreover there were no differences in engraftment or development of acute GvHD.These findings suggest that DFR given during SCT conditioning regimen may prevent the appearance of LPI and reduce the level of NTBI. Therefore it may decrease the risk of infections and organ toxicity by iron-induced radical formation. These preliminary results should be verified in further studies. Disclosures:Off Label Use: Deferasirox (Exjade®) is an oral iron chelator for - the treatment of chronic iron overload due to frequent blood transfusions (≥7 ml/kg/month of packed red blood cells) in patients with beta thalassaemia major aged 6 years and older and - the treatment of chronic iron overload due to blood transfusions when deferoxamine therapy is contraindicated or inadequate in the following patient groups: patients with other anaemias, patients aged 2 to 5 years, patients with beta thalassaemia major with iron overload due to infrequent blood transfusions.

Infusional Mitoxantrone Plus Bolus Melphalan as a Stem Cell Transplant Conditioning Regimen for Multiple Myeloma

This study combined infusional mitoxantrone with bolus melphalan as a transplant preparative regimen for multiple myeloma. Mitoxantrone was infused over 6 hr on days 6 and 5. Melphalan was given as a 15 min bolus on day 1 followed by autologous transplant on day 0. Thirty-five patients were enrolled; 57% of enrollees had received ≥2 prior treatments. The median overall survival was 5 years and 8 months, with 37% of the subjects alive >7 years posttransplantation. Myelosuppression and mucositis were the most frequent adverse events. This regimen is well tolerated and the survival compares well to other transplant trials.

Allogeneic Haematopoietic Cell Transplantation Using Intravenous Busulfan in Myeloablative and Reduced-Intensity Conditioning Regimen in Acute Leukemia Patients. A Comparison Analysis With Oral Busulfan

Recently oral Busulfan (OBu) has been replaced by intravenous Bu (IVBu) in allogeneic stem cell transplantation (HCT) conditioning regimens in acute leukaemia (AL) due more predictable pharmacokinetic and lower toxicity.

Adult Dual Umbilical Cord Blood Transplantation Using Myeloablative Total Body Irradiation (1350cGy) and Fludarabine Conditioning

AbstractAbstract 3523A high graft failure rate and treatment-related mortality (TRM) have historically been major pitfalls of myeloablative adult umbilical cord blood (UCB) transplantation. The goal of this prospective clinical trial was to identify an approach that addresses both of these problems. There is compelling evidence that increasing cell dose with the use of two partially matched UCB grafts reduces the graft failure rate. While non-myeloablative preparative regimens reduce TRM, this comes at the cost of an increased risk of disease relapse. Therefore, there is continued clinical need for myeloablative conditioning regimens that exert potent antitumor activity and provide sufficient immunosuppression to facilitate engraftment of mismatched unrelated UCB grafts. The combination of total body irradiation (TBI) (1320cGy)/fludarabine (Flu)/cyclophosphamide (Cy) has been studied extensively by other groups. In this trial, we hypothesized that elimination of Cy would improve tolerability yet maintain comparable anti-tumor effects and engraftment potential. Methods:The conditioning regimen consisted of TBI 1350cGy and Flu 40mg/m2 × 4 days. Two cord blood units at least HLA 4/6 matched with the recipient (low resolution class I and high resolution class II), with a minimum cryopreserved cell dose of 1.5 × 106/kg were selected for transplantation. Tacrolimus and mycophenolate mofetil were used for graft-versus-host disease (GVHD) prophylaxis and G-CSF was administered until the neutrophil count exceeded 1000/mm3. Disease-free and overall survival was estimated using the Kaplan-Meier method. In the analysis of cumulative incidence of neutrophil and platelet engraftment, a competing event was defined as relapse or death without an event of interest, whereas in the analysis of relapse and acute and chronic GVHD, a competing event was defined as death without an event of interest. Relapse was defined as a competing risk in the analysis of TRM. The Wilcoxon signed rank test was used to evaluate the effect of cell dose on the sustained engraftment of a single cord unit. Results:27 patients from 2 centers (Duke-24, UBC-3) with a median age of 33 (range, 20–58) years with hematologic malignancies were enrolled on the trial. Fifteen had AML (CR1-1 and CR2-14), five had ALL (CR1-2 and 2CR–3), three had MDS, one had CML, and three had NHL. The median combined total nucleated cell dose was 4.3 (range, 3.2–7.7) × 107/kg. The cumulative incidence of neutrophil engraftment (≥500/μl) was 80% (95% confidence interval (CI), 58–91%), with a median of 24 (range, 13–45) days. The cumulative incidences of platelet engraftment ≥20,000 and ≥50,000/μl was 76% (95% CI, 54–88%) and 68% (95% CI, 46–83%), respectively, and a median day of platelet engraftment ≥50,000/μl was 52 (range, 33–78). A single cord blood unit represented ≥79% of hematopoiesis by day 100. Higher cryopreserved and infused total nucleated cell dose and infused CD3+ cell dose were significant factors associated with the predominant UCB unit (P = 0.032, 0.020, and 0.042, respectively). Three patients experienced graft failure, and hematopoiesis was restored in two patients with either autologous or haploidentical hematopoietic stem cells. The cumulative incidences of grades II–IV and grades III–IV acute GVHD were 37% (95%CI, 20–55%) and 11% (95% CI, 3–26%), respectively and that of chronic GVHD was 31% (95% CI, 15–49%). With a median follow-up period of 23 months, the overall and disease-free survival rates at 2 years were 58% (95% CI, 34–75%) and 52% (95% CI, 29–70%), respectively. The 180 day and 2-year incidence of TRM was 19% (95% CI, 7–35%) and 28% (95% CI, 12–47%), respectively. The relapse rate at 2 years was 20% (95% CI, 7–37%). As an indicator of tolerability of this modified myeloablative regimen, we observed a cumulative incidence of total parental nutrition usage of just 56%.In conclusion, we find that the modified myeloablative regimen of TBI (1350cGy)/fludarabine provides dual cord blood engraftment rates comparable to more conventional myeloablative regimens. In contrast to other reports, we found that graft size predicts for the predominant UCB unit. This study supports the use of TBI 1350cGy/fludarabine as an alternative to conventional myeloablative conditioning for dual UCB transplantation and provides justification for larger studies. Disclosures:Off Label Use: Fludarabine; used as part of the stem cell transplant conditioning regimen. Chao:Genzyme: Research Funding. Horwitz:Genzyme: Honoraria, Research Funding.

Evaluating the Impact of Antithymocyte Globulin on Lung Function at 1 Year after Allogeneic Stem Cell Transplantation

The use of antithymocyte globulin (ATG) in hematopoietic stem cell transplantation (HSCT) conditioning regimens has reduced the incidence of graft-versus-host disease, particularly in its chronic form. The impact of this approach on the prevention of lung dysfunction has not been well characterized, however. We performed a retrospective analysis of pulmonary function in patients who underwent HSCT after conditioning with oral busulfan followed by either cyclophosphamide or fludarabine with or without the addition of ATG. A total of 393 patients were included; 75 patients received ATG, and 318 did not. No differences between the 2 groups were seen in the mean percentage of the predicted values for forced expiratory volume in 1 second (FEV(1)), forced vital capacity (FVC), total lung capacity, and lung CO diffusing capacity at 80 days or 1 year after transplantation. However, the mean value of FEV(1)/FVC ratio at 1 year was higher in the patients who received ATG. The difference in mean change in pulmonary function parameters from baseline to 1 year post-HSCT was statistically nonsignificant for all parameters except FEV(1)/FVC ratio, which demonstrated less decline in the ATG group. The risk of developing severe airflow obstruction or a restrictive pattern was similar in the 2 treatment groups at 1 year post-HSCT. Incorporation of ATG into the HSCT conditioning regimen provided protection against a decline in FEV(1)/FVC ratio but did not decrease the risk of other pulmonary events that we evaluated within the first year after HSCT. Further evaluations in larger numbers of patients are needed to better clarify the role of ATG in the development of delayed pulmonary complications.

Conditioning with Treosulfan and Fludarabine followed by Allogeneic Hematopoietic Cell Transplantation for High-Risk Hematologic Malignancies

In this prospective study 60 patients of median age 46 (range: 5-60 years), with acute myelogenous leukemia (AML; n= 44), acute lymphoblastic leukemia (ALL; n = 3), or myelodysplastic syndrome (MDS; n = 13) were conditioned for allogeneic hematopoietic cell transplantation with a treosulfan/fludarabine (Flu) combination. Most patients were considered at high risk for relapse or nonrelapse mortality (NRM). Patients received intravenous treosulfan, 12 g/m(2)/day (n = 5) or 14 g/m(2)/day (n = 55) on days -6 to -4, and Flu (30 mg/m(2)/day) on days -6 to -2, followed by infusion of marrow (n = 7) or peripheral blood stem cells (n = 53) from HLA-identical siblings (n = 30) or unrelated donors (n = 30). All patients engrafted. NRM was 5% at day 100, and 8% at 2 years. With a median follow-up of 22 months, the 2-year relapse-free survival (RFS) for all patients was 58% and 88% for patients without high-risk cytogenetics. The 2-year cumulative incidence of relapse was 33% (15% for patients with MDS, 34% for AML in first remission, 50% for AML or ALL beyond first remission and 63% for AML in refractory relapse). Thus, a treosulfan/Flu regimen was well tolerated and yielded encouraging survival and disease control with minimal NRM. Further trials are warranted to compare treosulfan/Flu to other widely used regimens, and to study the impact of using this regimen in more narrowly defined groups of patients.

Long-Term Complete Responses to Combination Therapies in Sézary Patients.

Abstract 3369Poster Board III-257 Introduction:Sézary syndrome (SS), the leukemic variant of cutaneous T-cell lymphoma (CTCL), is defined as erythroderma and >1000 abnormal T-cells per mm3 in the peripheral blood, and is currently incurable. A recent study of erythrodermic CTCL conducted at our center reported a median overall survival of 5.1 years which is twice that in the literature [Vidulich K, et al. Int. J of Dermatol. 2009; 48: 243-252]. Although complete remissions (CR) may be achieved in earlier stages of CTCL, they are rarely achieved in SS patients. Patients and Methods:A retrospective analysis of a prospective database of 1550 CTCL patients seen at the MD Anderson Cancer Center since 1984 identified a subset of 145 SS patients (9%) whose long-term complete responses (>2 years) to various therapies is reported. The most commonly used combination therapies were topical steroids, psoralen with ultraviolet A (PUVA), oral retinoids (isotretinoin, acetretin, or bexarotene), alpha-interferon, and extracorporeal photopheresis (ECP). A combination of total skin electron beam radiation (TSEB) followed by induction chemotherapy and allogeneic stem-cell transplant was given to 23 CTCL patients. Chronic Staphylococcus aureus carriers identified by cultures were treated with antibiotics and preventive skin care. Results:Of the 145 Sézary Syndrome patients, 13 (8.96%) achieved CRs, including 6 females and 7 males. Their median age was 48 (20 to 85 years) at diagnosis. Nine were Caucasian, 3 were African American, and 1 was Hispanic. At initial diagnosis their stages were IB (n=1), stage III (n=3), stage IVA (n=4), and stage IVB (n=5). Six achieved a CR on front-line combination immunomodulatory therapy consisting of ECP with alpha-interferon and/or oral retinoids, antibiotics, and topical steroids. Seven SS patients failed therapy but were able to obtain CRs after TSEB and allogeneic peripheral blood stem cell transplantation (SCT) from matched related donors (n=6) or unrelated (n=1) donors. The conditioning regimen for SCT was fludarabine and melphalan. The median time between diagnosis and CR was 4.07 years (range 1 to 20 years). The median duration of CR is 5 years (mean 5.15 years, range 2 to 13 years). Conclusion:Sézary Syndrome is extremely symptomatic and usually refractory to current therapies. CRs may be achieved using immunomodulatory therapy with biological response modifiers and photopheresis or with total skin electron beam followed by non-ablative allogeneic stem cell transplant in appropriate patients and may have an impact on overall survival. Disclosures:No relevant conflicts of interest to declare.

Exposure equivalence between IV (0.8 mg/kg) and oral (1 mg/kg) busulfan in adult patients

This study was conducted to retrospectively compare the area under the curve (AUC) and the total clearance of busulfan (Bu) following oral and intravenous (IV) administrations and to determine which intravenous dose generated equivalent exposure to that of the oral form that has been marketed for decades. Patient pharmacokinetics were assessed at dose 9 during a conditioning regimen for stem-cell transplantation and included data from 277 patients for oral Bu (71 from fixed-dose studies and 206 from studies with dose adjustment allowed) and 120 patients for IV Bu (fixed dose). AUCs were compared between patients with fixed dose of oral Bu (n = 71, 1 mg/kg) and those of IV Bu (n = 120, 0.8 mg/kg). Total clearances were calculated for all 277 patients with oral Bu and compared to those with IV Bu, with the ratio of IV-to-oral clearance representing the absolute bioavailability of the oral form. Oral and IV populations differed on disease-type distribution but presented comparable demography parameters. IV Bu dosing was mostly based on the ideal body weight index while actual body weight or adjusted ideal body weight indexes were mostly used for oral. When normalised to comparable indexes, bioequivalent AUCs were achieved between oral and IV populations. Oral Bu bioavailability was about 80% when calculated from the ratio of IV-to-oral total clearances. This retrospective study carried out on a large set of data showed that similar plasma exposures were achieved with 1.0 mg/kg oral Bu or 0.8 mg/kg IV Bu.