Conditioning Regimens For Hematopoietic Stem Cell Transplantation Research Articles

Translational Research Efforts in Biomarkers and Biology of Early Transplant-Related Complications

In the time since the first allogeneic hematopoietic stem cell transplantation (HSCT) was performed over 40 years ago, this life-saving procedure has been used increasingly for patients with hematologic, metabolic, and malignant diseases. Despite major advances in our understanding of the immunologic processes (both beneficial and injurious) that are associated with HSCT and improvements in supportive and critical care medicine, successful outcomes are still limited by several serious complications. As such, the establishment of effective therapeutic strategies for these complications will be crucial as increasing numbers of high-risk transplants are performed each year. The development of such approaches is fundamentally dependent upon a basic understanding of pathophysiologic mechanisms of disease and also on our ability to successfully translate these insights back to the bedside. This brief review will highlight breakthroughs in translational research endeavors that have paved the way for the development of novel strategies intended to change the standard of care and optimize outcomes for patients in whom allogeneic HSCT offers the only hope for a cure.

Stem Cell Transplantation for Relapsed and Refractory Burkitt Lymphoma.

AbstractAbstract 4589 Background:Burkitt lymphoma is a highly aggressive and rapidly proliferating hematologic malignancy. Various chemotherapy regimens (HyperCVAD, CODOX-M/IVAC, REPOCH) have been shown to improve overall survival rate. However, in instances of relapsed or refractory disease, there is no clear-cut standard of care. Hematopoietic stem cell transplantation (HCT) has shown benefit in these patients. Here, we report our institutional experience using HCT for relapsed/refractory Burkitt lymphoma. Methods:Between February 1994 and January 2010, 13 patients (10 males, 3 females) with refractory or relapsed Burkitt lymphoma were retrospectively evaluated. The patients in question were administered a particular conditioning regimen followed by stem cell transplantation (11 autologous, 2 allogeneic). The average age at transplant was 41.8± 3.4 years (range 24 to 67). Stem cell source was from peripheral blood in all transplants including allogeneic (2 HLA-identical sibling transplants). The conditioning regimens for HCT consisted of the following: TBI/Rituximab/Cytoxan/VP16, TBI/Cytoxan/VP16, BEAM, Cranial Spinal boost/TBI/Cytoxan/VP16 or Cranial boost/TBI/Cytoxan. Results:On average, patients received transplant 299 ± 36 days after initial diagnosis (range 153 to 582). All patients achieved engraftment. For the 5/13 deceased patients (38%), cause of death was attributed to relapsed/refractory disease (n=2) and treatment related causes (n=3). Using the Kaplan-Meier method, the average survival time after transplant was computed at 27.7 ± 5.3 months and 75% were alive 2-years after transplant. Likely due in part to the small sample size, no covariates (age, gender, conditioning regimen, HIV status, presence of B symptoms, and CNS or bone marrow involvement) were found to be predictive of survival rates. Conclusion:Patients with Burkitt lymphoma, known for its rapid growth, can achieve long-term complete remission (CR) with intense, combination chemotherapy. Despite successful long-term remission rates, a substantial portion of patients die from uncontrolled disease. At the first sign of refractory or relapsed disease, resources should be mobilized to proceed with HCT. Our study, though limited in size, provides further compelling evidence that long-term CR, and potentially cure, may be achieved using HCT as a treatment modality. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

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.

Non‐myeloablative autologous HSCT for relapsing remitting multiple sclerosis (RRMS) and new onset type 1 diabetes mellitus (TIDM)

Autologous non‐myeloablative hematopoietic stem cell transplantation (HSCT) is a method of delivering intense immune suppression. We, therefore, evaluated the safety and clinical outcome of autologous non‐myeloablative HSCT in 2 autoimmune diseases relapsing‐remitting multiple sclerosis (RRMS) failing interferon therapy and new onset Type 1 Diabetes mellitus. Peripheral blood hematopoietic stem cells (HSC) were mobilized with cyclophosphamide (2.0 g/m2) and granulocyte colony stimulating factor (10 ug/kg/day). HSCT conditioning regimen was cyclophosphamide (200 mg/kg) and rabbit anti‐thymocyte globulin (either 6 mg/kg or 4.5 mg/kg).Eligible patients with RRMS had, despite interferon beta, 2 corticosteroid treated relapses within the prior 12 months, or 1 such relapse and gadolinium enhancing lesion(s) on magnetic resonance imaging (MRI) demonstrated on an occasion distinct from the relapse. All patients are surviving, 17 patients (81%) improved by at least 1.0 or more EDSS points, and five patients (24%) relapsed but achieved another remission after further immunosuppression. After a mean of 3 years, progression‐free survival is 100%, and relapse‐free survival is 76%. Significant improvement occurred in neurologic disability determined by extended disability status scale (EDSS), neurologic rating score (NRS), paced auditory serial addition test (PASAT), and 25 foot walk, as well as quality of life as measured by the short form‐36 (SF‐36). Non‐myeloablative autologous HSCT in RRMS appears capable of reversing neurologic deficits.Eligible patients for HSCT of T1DM were diagnosed in the previous 6 weeks by clinical findings and hyperglycemia and confirmed with positive antibodies against glutamic acid decarboxylase. 23 type 1 diabetic patients (aged between 13 and 31 years) were treated. During a 7‐to 58‐month follow‐up (mean 29.8) 20 patients without previous ketoacidosis and not receiving steroids during the preparative regimen became insulin‐free; 12 patients maintained this status for 14 to 52 months (mean 31) while 8 patients relapsed and resumed insulin use at low dose (0.1 to 0.3 IU/kg). In the continuous insulin‐independent group, HbA1c levels were always <7.0%, continuous glucose monitoring was within normal levels and mean AUC of C‐peptide levels increased significantly from 225.0 ng/mL pre‐transplantation to 785.4 ng/mL at +24 months (P <0.001) and to 728.1 ng/mL at +36 months (P = 0.03). In the transient insulin‐independent group mean AUC of C‐peptide levels also increased from 148.9 ng/ml before transplantation to 546.8 ng/mL at +36 months (P = 0.001) that was sustained at + 48 months In this group, two patients regained insulin independence after treatment with sitagliptin which was associated with increase in C‐peptide levels. HSCT induces insulin and drug free remission for up to 5 years post HSCT and appears to preserve or allow regeneration of islet cell mass with maximal C‐peptide levels reached 2–3 years after HSCT.

Antithymocyte Globuline Given as Part of the Conditioning Regimen Has No Impact On Lung Function at 1 Year After Transplantation.

Abstract 3306Poster Board III-194 BackgroundPulmonary dysfunction is common following allogeneic hematopoietic stem cell transplantation (HSCT) and is associated with significant morbidity and mortality. The use of Antithymocyte globuline (ATG) has reduced the incidence of graft versus host disease (GVHD), particularly in its chronic form, but the impact of this approach on the prevention of lung dysfunction is not well characterized. MethodsWe performed a retrospective analysis of pulmonary function in all patients transplanted from January 2001 through December 2005 following conditioning with oral busulfan (BU) followed by either cyclophosphamide (CY) or fludarabine (FLU) with or without the addition of ATG. Pulmonary function tests (PFTs) were performed per transplant protocol before and around day 80 and 1 year after transplantation. ResultsOf 406 patients, 13 (3%) were excluded due to lack of pre-transplant PFTs. Seventy five patients received ATG (thymoglobulin, given on days -3 to -1 for total doses of 4.5 – 6 mg/kg), and 318 did not. The median patient age was 49 years for both the ATG (range 9-65) and non-ATG (range 7-66) groups; the median follow-up was 956 (range 19-2071) days and 903 (range 8-2697) days, respectively. The ATG group had proportionally more patients with high risk diseases (62.7% vs 45.7%, p= .03), whereas the use of bone marrow as stem cell source was higher in the non-ATG group (14.6% vs 5.3%, p=.03). The proportion of patients with PFTs at 1 year was similar for both groups (49.3% vs 54.6%, p=.55). No significant statistical differences between the 2 groups were seen in the mean percentage of the predicted values for FEV1, FVC, TLC and DLco at 80 days or 1 year after transplantation. The mean value of FEV1/FVC ratio at 1 year was higher for ATG patients (0.81±0.05 vs 0.77±0.09, p=.003). The mean change in PFT parameters from baseline to 1 year after HSCT also did not show a statistically significant difference between the 2 groups for any PFT parameters except for the FEV1/FVC ratio, which decline was lower in the ATG group (0.4±3.9 vs -2.8±7.3 p=.0002). This difference remained significant in multivariate analysis. The lung function score at 1 year after transplantation was similar in the 2 groups; they also had similar rates of lung function decline (expressed as the annualized rate of FEV1 decline) from baseline to 1 year after HSCT. The risk of developing severe airflow obstruction (AFO) or a restrictive pattern (RP), as well as the cumulative incidence of AFO and RP were not statistically significantly different between the 2 treatment groups at 1 year after HSCT. ConclusionsIn this retrospective analysis, incorporation of ATG into the HSCT conditioning regimen did not appear to be associated with superior outcome in terms of post transplant pulmonary function. However, further evaluations are needed to better clarify the role that ATG might have in the development of late-term pulmonary complications. DisclosuresNo relevant conflicts of interest to declare.

Infectious complications associated with alemtuzumab use for allogeneic hematopoietic stem cell transplantation: comparison with anti‐thymocyte globulin

To evaluate the incidence of infectious complications after receiving alemtuzumab as part of a conditioning regimen for allogeneic hematopoietic stem cell transplantation (HSCT) in Korean patients. From November 2004 to January 2006, 12 patients who received alemtuzumab-based conditioning regimens for allogeneic HSCT were evaluated retrospectively until death or until the end of the follow-up in July 2007; they were compared with 18 patients who received rabbit anti-thymocyte globulin (ATG)-containing conditioning regimens from January 2002 to January 2006. Post-engraftment infections occurred more frequently in the alemtuzumab recipients than in the ATG recipients; the mean number of infections, excluding cytomegalovirus (CMV) infections, per patient during the follow-up period was 2.6+/-1.4 vs. 1.0+/-0.8 (P=0.003), respectively. Although there was no statistical difference in the cumulative incidence of CMV infection between the 2 groups (91.7% vs. 55.6%, P=0.381), the alemtuzumab recipients had a higher incidence of CMV diseases (41.6% vs. 0%, P=0.0006) and a higher recurrence rate of CMV infection (90.0% vs. 27.3%, P=0.008) than did the ATG recipients, irrespective of the dose of alemtuzumab. Hemorrhagic cystitis (HC) (66.7% vs. 16.7%, P=0.009) and BK virus-associated HC (41.7% vs. 5.6%, P=0.026) developed more frequently in the alemtuzumab recipients. The all-cause mortality rate was not significantly different between the alemtuzumab and the ATG recipients (75% vs. 55.6%, P=0.28). Alemtuzumab recipients had a high incidence of CMV disease as well as BK virus-associated HC compared with the ATG recipients. The dose of alemtuzumab should be tailored to patients' risk; in addition, the implementation of the appropriate prophylaxis for CMV and early detection strategies for BK virus are recommended.

The Effectiveness of Once-daily Intravenous Busulfan as a Conditioning Regime for Hematopoietic Stem Cell Transplantation in Children with Acute Myelogenous Leukemia

Background There have recently been some reports suggesting that once-daily intravenous busulfan (IV Bu) as a conditioning regime for hematopoietic stem cell transplantation (HSCT) possibly reduces the toxicities without influencing the clinical outcome as compared with the traditional 4 times daily dosage schedule. We report here on the clinical outcome of once-daily IV Bu as a conditioning regime for HSCT in children with AML at a single treatment center. Methods We retrospectively analyzed nine AML children who received HSCT with using the once-daily IV Bu (110∼130 mg/m2 on 4 consecutive days) conditioning regimen at the Department of Pediatrics, Pusan National University Hospital from 2003 to 2007. Results The median age at HSCT was 8.25 years. As for the conditioning regimens, the HLA-matched sibling peripheral HSCT (N=4) was Flu/Bu, the CBT and unrelated BMT (N=4) was Flu/Bu/ATG and the autologous HSCT (N=1) was Bu/Cy. There was only one case of primary graft failure in an unrelated donor CBT recipient. The median time to neutrophil engraftment was 14 days and the median time to platelet engraftment was 19 days. The transplant-related toxicities were acceptable; there were no case with CNS toxicity and VOD was observed in two cases (1 mild case of VOD and 1 moderate case of VOD). Acute GVHD was noted in two cases (1 case of grade I and 1 case of IV). With a median follow up of 33 months, there were two cases of relapse and two cases of death. Conclusion Once-daily IV Bu as a conditioning regimen for HSCT in children with AML was well tolerated and convenient with relatively moderate toxicities, but additional studies are needed to determine the therapeutic efficacy and pharmacokinetics of once-daily IV Bu in children who are undergoing HSCT.

Efficacy, Safety and Tolerability of Biotene Mouthwash Versus Aloe Vera Juice and Active Manuka Honey for Prophylaxis of Oral Mucositis Following Chemoradiotheray

Background: Oral mucositis (OM) is a common and debilitating complication following high dose Methotrexate (MTX) as well as conditioning regimen for hematopoietic stem cell transplantation (HSCT). The mucosal injury varies in severity, ranging from mild inflammation to full thickness mucosal ulceration extending into submucosal layer. In the setting of damaged mucosal layer and neutropenia, secondary infection may happen which can lead to systemic sepsis. The vicious cycle of inflammation and secondary sepsis will trigger greater release of cytokines, such as tumor necrosis factor alpha and interleukin 1 beta that further worsen the mucosal insult. Patients who develop OM not only suffer from pain and poor quality of life but also infections which can be life-threatening. Obviously, OM causes increased duration of hospital stay, use of parenteral narcotics and nutrition support with increased treatment costs. Currently, there are no definitive approved methods/agents except Palifermin (Keratinocyte growth factor, KGF) that can prevent and/or reduce the severity, incidence and duration of OM. However, the use of Palifermin in our centre is constrained by its cost. Therefore, we explored the feasibility of locally available cheaper agents such as Biotene mouthwash, and the Aloe Vera juice and active Manuka Honey.Biotene mouthwash is alcohol free and contains antibacterial enzymes that reduce bacterial growth, oral irritation and promote gingival health. Aloe barbodensis inner leaf juice and honey is claimed to contain nutrients, minerals and vitamins.Patients and Methods: A total of 76 patients were enrolled between September 2007 and February 2008. Application of Biotene mouthwash was done every 6 hourly whereas Aloe Vera juice was consumed twice a day. All HSCT patients received oral Ciprofloxacin, Acyclovir and Fluconazole until Day +21 as prophylaxis. Patients receiving high dose MTX were hyperhydrated with urinary alkalinization. The degree of mucositis was assessed daily by nurses using the WHO grading of mucositis. Physicians were allowed to prescribe intravenous narcotics, analgesics and TPN and ICU care as required. Patients were requested to filll a self reported OM daily questionnaire based on usual analogue scale.Results: A total of 46 patients received Biotene mouthwash and 30 patients received Aloe Vera juice.29/46 (63%) vs. 13/30 (43.3%) received high dose MTX in the Biotene arm and Aloe Vera juice arm, respectively, whereas 17/46 (37%) vs. 17/30 (56.7%) received HSCT.The prevalence of grade 0, 1–2, 3–4 mucositis in patients received Biotene mouth wash and Aloe Vera juice are 17.4%, 52.2%, 30.4% and 26.7%, 56.7%, 16.7% respectively (Chi Square for trend, p = 0.145).Requirement for intravenous opioid was 0/46(0%) vs. 4/30(13.3), and TPN requirement was 0/46(0%) vs. 2/30(6.7).None of the patients required ICU management.Conclusions: Biotene mouthwash is similar to Aloe Vera juice in reducing/preventing the severity of mucositis in patient underwent MTX or conditioning regimen for HSCT. Both are safe and well tolerated. The can be considered as useful local measures in the prophylaxis of OM following chemoradiotheray.

Outcomes of Second Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) in Children.

Introduction: Relapse of the malignancy, secondary malignancy and rejection of the graft (GF) remain important risk factors for mortality after HSCT. The optimal treatment strategy for GF is second HSCT, but for recurrent malignancy it has yet to be determined; however, second HSCT provides a chance for long term survival. This study reports outcomes and clinical experience of HSCT retransplantation in pediatric patients with GF, relapse or secondary malignancy after primary HSCT.Methods: Outcomes of all pediatric recipients of second HSCT for recurrent malignancy or GF between June 1, 1996 and June 30, 2006 at SickKids Hospital were reviewed. Demographic data, the conditioning regimen chosen, morbidity and mortality after second HSCT were described. EFS was defined as evidence of relapse of malignancy or failure to engraft. Univariate analysis was utilized to assess factors that may influence survival.Results: Forty-one children (25 male; median age 7.8yrs (range 0.6–17.5yrs)) received a second HSCT during the study period. Initial diagnosis was malignancy in 25 (AML/MDS-11, ALL-6, lymphoma-4, CML-3, JMML-1) and nonmalignant disease in 16 (SAA-4, SCID-4, inherited marrow failure symdrome-5, HLH- 1, MPS-1, thalasemia-1). Indications for second HSCT were: malignancy (recurrent/ secondary) in 21 and GF in 20. Mean time to second HSCT in children with GF was 10.5 months (range: 0.8–57.2 months) compared to 22.7 months (range: 10.1–58.1months) for malignancy (p=0.004). All patients transplanted for malignancy received the second HSCT ≥ 6 months from the first HSCT and only 5 (24%) were transplanted within a year from first HSCT. 8 patients (40%) receiving a second HSCT for GF were retransplanted within the first 6 months. Conditioning regimens at second HSCT included myeloablative treatment (23); reduced intensity (RIC) (16) and none (2). The following factors were not statistically associated with survival: underlying disease, type of conditioning regimen (myeloablative vs reduced intensity) and indication for second HSCT (GF vs. malignancy). Overall survival (OS) and EFS rates are summarized below. Non-relapse related mortality was 45%; 9 patients died from infections.parametersOSEFSUnderlying diseaseMalignant0.37±0.1Non-Malignant0.49±0.13p=0.64Reason for second HSCTRecurrent/secondary malignancy0.43±0.11Graft failure0.42±0.12p=0.69Conditioning regimenMyeloablative0.48±0.1Reduce-intensity0.33±0.13p=0.3All patients0.4250.44Discussion and conclusion: Children who underwent second HSCT had an OS of 43%. We conclude that a second HSCT can result in prolonged EFS in children relapsing more than 6months after first HSCT and provides an acceptable therapeutic option for patients with GF.

Long-Term Follow-up of Allogeneic Hematopoietic Stem Cell Transplantation for De Novo Acute Myelogenous Leukemia with a Conditioning Regimen of Total Body Irradiation and Granulocyte Colony-Stimulating Factor-Combined High-Dose Cytarabine

We retrospectively evaluated the efficacy and safety of total body irradiation (TBI) and granulocyte colony-stimulating factor (G-CSF)-combined high-dose cytarabine as a conditioning regimen for allogeneic hematopoietic stem cell transplantation (HSCT) in patients with de novo acute myelogenous leukemia (AML). The conditioning regimen consisted of 12 Gy of TBI followed by high-dose cytarabine (3 g/m 2) every 12 hours for 4 days in combination with the continuous administration of G-CSF. Stem cell sources included bone marrow or peripheral blood stem cells (PBSC) from human leukocyte antigen (HLA)-identical siblings (n = 24), or bone marrow from HLA serologically matched unrelated donors (n = 26). Fifty patients (median age, 38 years) were evaluated. At HSCT, 35 patients were in the first or second complete remission (CR1/2), and 15 patients were not in remission (n = 14) or in the third CR (n = 1). Thirty-six of 50 patients are currently alive, with a median follow-up period of 5.6 years (range: 1.1-12.1 years). The 5-year estimated overall survival (OS) and disease-free survival (DFS) rates were 85.5% (95% confidence interval [CI], 73.7%-97.3%) and 82.1% (95% CI, 69.0%-95.2%) in patients with AML in the first or second CR, 46.7% (95% CI, 21.4%-72.0%), and 40.0% (95% CI, 15.3%-64.7%) in patients with AML in other stages. The 2-year cumulative incidence of treatment-related mortality (TRM) of all patients was 10.4% (95% CI, 1.8%-18.6%). The only factors affecting the OS and DFS were disease status at transplant and cytogenetics by multivariate analysis. These results suggest that G-CSF-combined high-dose cytarabine could be a promising component of the conditioning regimen for allogeneic HSCT for AML, providing a high DFS and low TRM.

Non-myeloablative hematopoietic stem cell transplantation is of limited value in advanced or refractory acute myeloblastic leukemia. The Mexican experience

Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective strategy for preventing relapse of acute myelogenous leukemia (AML). We analyzed the outcome of 31 primary AML patients who received a reduced-intensity conditioning regimen for allogeneic HSCT in first or second remission. Thirty-one AML patients, 20 in first complete remission (FCR), 8 in second complete remission (SCR) and 3 in a partial remission (SPR) were included. All received busulfan 4 mg/kg/d/2 days, fludarabine 30 mg/m2/d/3 days and cyclophosphamide 350 mg/m2/d/3 days as conditioning regimen. The median number of CD34+ cells infused was 5.6 × 106/kg and 5.2 × 106 in FCR and SCR group, respectively. All patients received cyclosporine-A (CsA) and methotrexate as graft vs. host disease (GvHD) prophylaxis. All patients showed myeloid engraftment (neutrophils >0.5 × 109/l) after a median of 13 days in FCR group and 15 days in SCR group. Platelet recovery >20 × 109/l was achieved after a median of 13 days in both groups. Relapse for 20 patients in FCR was 35% compared to 91% for 11 in SCR/SPR (p < 0.05). Conclusions. Reduced-intensity conditioning followed by allogeneic HSCT can induce stable remission in primary AML patients transplanted in FCR. A high relapse rate was documented in patients with refractory or relapsed AML.

Prevalence and Reversibility of Cardiac Dysfunction in Systemic Lupus Erythematosus: Improved Ventricular and Valvular Function after Disease Remission Following Hematopoietic Stem Cell Transplantation.

Patients with cardiac abnormalities undergoing hematopoietic stem cell transplantation (HSCT) are considered at increased risk of cardiac toxicity which has traditionally precluded them from undergoing HSCT. However, cardiac involvement in patients with systemic lupus erythematosus (SLE) is not uncommon with a reported prevalence of up to 75%, often disease-related and may even be the indication for HSCT. Therefore, we undertook a retrospective analysis of all SLE patients who had undergone autologous HSCT (auto-HSCT) to determine the prevalence and nature of cardiac involvement, safety and effect of HSCT on cardiac function. Between April 1997 and January 2006, a total of 55 patients with SLE underwent auto-HSCT. Stem cell mobilization was with cyclophosphamide 2g/m^2 with subcutaneous filgrastim and peripheral blood stem cells (PBSC) were harvested via apheresis upon neutrophil recovery. The PBSC product was lymphocyte-depleted via CD34-positive selection with an Isolex cell separator in 51 patients and unmanipulated in the other 4 patients. HSCT conditioning regimens were cyclophosphamide 200mg/kg over 4 days and equine antithymocyte globulin (ATG) 90mg/kg over 3 days. The PBSC product was re-infused 36h after the completion of cyclophosphamide on day 0 and the patient received subcutaneous filgrastim from either day 0 or day+6 until neutrophil recovery. Fourteen patients were found to have baseline cardiac abnormalities, either clinically or on baseline radionuclide technetium multi-gated acquisition scans or two-dimensional echocardiogram. Of these, 13 were female and the median age at the time of HSCT was 39.8 years (range 15.7 to 55.5 years). The median baseline SLE Disease Activity Index of this cohort was 16 (range 10 to 35). The cardiac abnormalities were impaired left ventricular function (n=6), pulmonary hypertension (n=5), mitral valve dysfunction (n=3), significant pericardial effusion (n=1) and accelerated coronary artery disease (n=1). At a median follow up of 23.5 months (8 to 103 months), 2 of the patients are dead, one from disease progression/relapse at 11.5 months after HSCT and the other died from an accident at 8 months post-transplant. There were no cardiac or transplant-related deaths or significant cardiac toxicities. All patients with impaired ejection fraction (range 25% to 47%) stabilized or improved post-HSCT induced remission. The median pulmonary artery systolic pressure was 39mmHg (range 27 to 50 mmHg). Among the 5 patients with pulmonary hypertension, 3 improved paralleling remission from SLE. Again paralleling disease remission, 2 patients with severe disability from symptomatic mitral valve disease improved, obviating the need for valve replacement which had been planned pre-HSCT for one. In conclusion, we found that our patients with ventricular systolic and valvular dysfunction, and possibly pulmonary hypertension, improved following HSCT if they achieved remission from SLE. Our experience suggests auto-HSCT may be safely performed in selected patients with SLE with cardiac dysfunction and furthermore, improvement of cardiac function may occur following HSCT-induced disease remission. This warrants further study in a larger cohort of patients.

Duration of ulcerative mucositis and outcomes of autologous (AU) hematopoietic stem cell transplantation (HSCT) following high-dose melphalan (MP) conditioning for multiple myeloma (MM)

Background: OM is a common toxicity of conditioning regimens for HSCT that has been associated with adverse clinical and economic outcomes. Methods: A retrospective study of approximately 400 consecutive HSCT recipients was undertaken at a single academic center. Data were collected via chart review on days with ulcerative mucositis and selected outcomes including days with fever, days of parenteral narcotic therapy, incidence of Grade III or IV (Common Toxicity Criteria) infection, total inpatient days (LOS), and total inpatient charges.

Oral Mucositis (OM) and Outcomes of Allogeneic (AL) Hematopoietic Stem Cell Transplantation (HSCT) in Patients with Hematologic Malignancies.

Background. OM is a common toxicity of conditioning regimens for HSCT that has been associated with adverse clinical and economic outcomes.Methods. A retrospective chart review study of ~400 consecutive HSCT recipients with hematologic malignancies was undertaken at a single academic center. OM severity was assessed across eight oropharyngeal sites using a validated scale which was scored as follows: no erythema/ulceration = 0; erythema only = I; ulceration one site = II; two sites = III; three sites= IV; and four or more sites = V. OM assessments began on the day of conditioning and continued bi-weekly until hospital discharge. Outcomes of interest included number of days of fever, total parenteral nutrition (TPN), and parenteral narcotic therapy, incidence of Grade III or IV (Common Toxicity Criteria) infection, and inpatient days and charges. We report data here for the 281 AL HSCT recipients in the study cohort.Results. Mean age was 41 yrs. Most common diagnoses were acute (33%) and chronic (19%) myeloid leukemia. Most patients (96%) received total body irradiation. Fifty-one percent of grafts were from unrelated donors. Seventy-six percent of patients experienced OM ≥ grade II. The relationship between worst recorded grade of OM and each of the outcomes of interest is reported below.Conclusions. OM is associated with worse clinical and economic outcomes in patients with hematologic malignancies undergoing AL HSCT.Outcomes of AL HSCT in patients with hematologic malignancies, by worst recorded grade of OMWorst Grade of OM (N=281)0IIIIIIIVVOutcomen=34n=33n=70n=60n=43n=41-value pFever days*3.1 (3.0)4.8 (4.4)5.3 (4.9)5.7 (4.7)5.9 (4.7)7.3 (4.6)<0.001TPN days*6.7 (7.2)7.7 (7.8)8.8 (7.8)10.2 (7.8)13.2 (7.2)14.0 (6.2)<0.001Narcotic days*7.6 (6.3)10.8 (5.0)10.7 (7.4)11.5 (5.1)14.0 (6.8)17.2 (5.0)<0.001Infection (%)85.390.992.993.3100.0100.00.002Mortality (%)8.83.08.615.07.022.00.042Inpatient days*28.1 (8.8)30.3 (10.6)34.5 (15.1)32.7 (14.5)35.9 (10.4)42.4 (15.1)<0.001Inpatient charges* (x 1,000 USD)214 (102)252 (156)313 (251)280 (198)305 (140)437 (233)<0.001*mean, SD; **test for linear trend; Cochran-Armitage for dichotomous measures, GLM for continuous measures

Secondary Malignancies after Hematopoietic Stem Cell Transplantation in Patients Treated with Total Body Irradiation.

We have analyzed the incidence and risk factors of developing a secondary malignancy after total body irradiation (TBI) and hematopoietic stem cell transplantation (HSCT). From March 1986 to December 2002, 205 patients received TBI as a part of the HSCT conditioning regimen. TBI was administered in 6 fractions, twice a day, up to a total dose of 12 Gy, with a median dose rate of 11.44 cGy/min. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) was performed in 119 patients and the other 86 patients received an autologous hematopoietic stem cell transplantation (AHSCT). Median age was 30 years (5–63). We have calculated the cumulative incidence of solid tumors and secondary hematologic malignancies among these patients. Death due to noncancerous causes and patients lost to follow-up were entered as a competitive risk. With a median follow-up of 32 months (0.2–229)- including patients deceased in the first three months- 13 (6.3%) developed a secondary malignancy, 7 of them (3.4%) developed a solid tumor and 6 (2.9%) developed a secondary hematologic malignancy. The 7 patients who developed a solid tumor-1 glioblastoma, 2 head and neck carcinoma, 2 basocelular carcinoma, 1 osteosarcoma and 1 cervical intraepithelial neoplasia- had received an allo-HSCT. The 6 patients that developed a secondary hematologic malignancy- 5 therapy-related leukemia/myelodisplasia (t-AML/MDS) and 1 B cell non Hodgkin's lymphoma- had received an AHSCT. The overall probability of developing a secondary malignancy after HSCT is 2.5% at 3 years (95% confidence interval (CI) 1.1– 6); 5% at 10 years (95% CI 2.6–9.3), and 9% at 15 years (95% CI 5–16.5). The probability of developing a solid tumor after HSCT is 0.5% at 3 years (95% CI 0.1–3.6), 1.8 % at 10 years (95% CI 0.6–5.5), and 6 % at 15 years (95% CI 2.6–13.7) and the probability of developing a secondary hematologic malignancy is 2 % at 3 years (95% CI 0.8–5.3), and 3,1 % at 10 and 15 years (95% CI 1.4–6.9). Median time to develop a solid tumor was 134 months (29–229). Median time to develop a secondary hematologic malignancy was 31 (3–60) months. Multivariate analysis proved that allo-HSCT was the only risk factor of developing a solid tumor, and that AHSCT and advanced age were risk factors of developing secondary hematologic malignancy (mean age 30 vs. 50 years ). To conclude, the probability of developing a solid tumor after HSCT is higher if an allo-HSCT has been performed and increases with time. AHSCT and advanced age are risk factors for the development of a secondary hematologic malignancy, a risk that decreases 5 years after AHSCT.

Oral Mucositis (OM) and Outcomes of Autologous (AU) Hematopoietic Stem Cell Transplantation (HSCT) Following High-Dose Melphalan (MP) Conditioning for Multiple Myeloma (MM).

Background. OM is a common toxicity of conditioning regimens for HSCT that has been associated with adverse clinical and economic outcomes.Methods. A retrospective chart review study of ~400 consecutive HSCT recipients was undertaken at a single academic center. OM severity was assessed across eight oropharyngeal sites using a validated scale which was scored as follows: no erythema/ulceration = 0; erythema only = I; ulceration one site = II; two sites = III; three sites= IV; and four or more sites = V. OM assessments began on the day of conditioning and continued bi-weekly until hospital discharge. Outcomes of interest included number of days of fever, total parenteral nutrition (TPN), and parenteral narcotic therapy, incidence of grade III or IV (Common Toxicity Criteria) infection, and inpatient days and charges. We report data here for the 115 MM patients in the study cohort who underwent AU HSCT after high-dose MP conditioning.Results. Mean age was 54 yrs. Seventeen percent of patients received total body irradiation. Bone marrow was the source of most grafts. Forty-eight percent of patients experienced OM ≥ grade II. The relationship between worst recorded grade of OM and each of the outcomes of interest is reported below.Conclusions. OM is associated with worse clinical and economic outcomes in MM patients undergoing AU HSCT following high-dose MP conditioning.Outcomes of AU HSCT following high-dose MP conditioning for MM, by worst recorded grade of OMWorst Grade of OM (N=115)0IIIIIIIVVOutcomen=37n=23n=24n=15n=8n=8-value pFever days*1.2 (2.8)2.5 (3.1)2.1 (2.3)1.9 (1.4)3.0 (2.1)3.6 (6.2)0.057TPN days*0.0 (0.0)0.1 (0.4)0.0 (0.0)0.0 (0.0)0.0 (0.0)2.3 (6.0)0.003Narcotic days*1.5 (3.1)4.7 (3.8)4.6 (4.4)4.4 (3.7)7.9 (3.3)9.9 (7.4)<0.001Infection, %51.473.962.580.0100.075.00.014Mortality, %0.00.04.20.00.012.50.085Inpatient days*18.6 (3.4)21.0 (3.5)19.6 (3.6)19.7 (2.3)23.3 (2.4)23.4 (5.6)<0.001Inpatient charges* (x 1,000 USD)119 (36)130 (35)118 (25)121 (28)141 (31)184 (92)<0.001*mean, SD; **test for linear trend; Cochran-Armitage for dichotomous measures, GLM for continuous measures

Oral mucositis (OM) and outcomes of allogeneic (AL) hematopoietic stem cell transplantation (HSCT)

6107 Background: OM is a common toxicity of conditioning regimens for HSCT that has been associated with adverse clinical and economic outcomes. Methods: A retrospective chart review study of 300 c...

Non-myeloablative conditioning for allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia. The impact of the remission status

Background: Multicentre randomized trials have shown that allogeneic hematopoietic stem cell transplantation (HSCT) is the most effective strategy for preventing relapse in patients in first complete remission (CR) of acute myeloblastic leukemia (AML), offering up to 50% disease-free survival. However in adult patients with good risk AML, allogeneic HSCT is usually indicated in second complete remission or first untreated relapse. We analyzed the outcome of 16 AML patients who received a reduced intensity conditioning regimen for allogeneic HSCT in first or second remission.

Time limitations and the challenge of providing infection-preventing dental care to hematopoietic stem-cell transplantation patients.

Oral-dental infection foci should be eradicated before the ablative chemo-radiotherapy regimen of hematopoietic stem cell transplantation (HSCT) commences. The rationale of oral-dental treatment is to prevent the future development and spread of infections in patients with compromised immune systems. This study aims to shed light on the challenges facing hospital dentists in the implementation of optimal oral-dental treatment prior to HSCT. Data regarding the medical status and dental treatment needs before HSCT were retrieved from the files of 86 consecutive patients post-HSCT. The timing of the oral-dental examination was also recorded. Dental treatments required before the HSCT were mainly combinations of scaling, plastic fillings, and extractions (47.8%, 39.1%, and 19.5% of the patients respectively). Patients presented at the clinic for oral-dental examination an average of 20.65+/-16.82 days before HSCT with a median of 15 (quarter interval range 10-15) days. Our data indicate a dense distribution of dental needs preceding the ablative conditioning regimen for HSCT. These facts accentuate the vital need for cooperation between hospital dentists and treating physicians.

Non-overt disseminated intravascular coagulation in patients during treatment with antithymocyte globulin for unrelated allogeneic hematopoietic stem cell transplantation.

We assessed the effect of rabbit antithymocyte globulin manufactured by Fresenius (ATG-F) on the hemostatic system in patients (n=12) with various hematological malignancies undergoing hematopoietic stem cell transplantation (HSCT) from HLA-matched unrelated donors. For this purpose, we monitored different parameters of coagulation before, during and after the administration of ATG-F. As a control group, we recruited patients (n=10) undergoing HSCT from their HLA-identical siblings who did not receive ATG-F as part of their preparative regimens. At 24 and 48 h after ATG-F treatment had been initiated, we found a temporary rise in D-Dimer, tissue factor, soluble thrombomodulin and thrombin-antithrombin III complex levels and a significant decrease of platelet counts in patients treated with ATG-F as compared to the control group. No differences between the two groups could be detected with regard to global coagulation tests as well as the incidence of bleeding manifestations, thromboembolic complications or the development of vascular-occlusive-disease of the liver. This temporary state of a stressed but compensated coagulation system under ATG-F therapy can be addressed as nonovert disseminated intravascular coagulation (DIC). The effect was independent from the different conditioning regimens and eased off after cessation of ATG-F. We conclude that ATG-F can induce nonovert DIC in patients receiving antithymocyte globulin as part of their conditioning regimen for HSCT.