Pre-transplant Chemotherapy Research Articles

Comparison of Survival Outcomes of Patients with Mantle Cell Lymphoma (MCL) Treated with Autologous Stem Cell Transplant (ASCT) and Conventional Chemotherapy

Abstract 4491 Background:Mantle cell lymphoma is typically considered to be aggressive and incurable. About 15% of these patients have an indolent course. MCL demonstrates the aggressive features of a rapidly progressive neoplasm but with the negative consequences of an indolent lymphoma, namely incurability and frequent relapses. The median overall survival (OS) was reported at 3–4 years when MCL was first described in the 1990’s. OS has since increased substantially and this is thought to be secondary to more aggressive initial therapy and improvement in supportive care. In many parts of the world, autologous stem cell transplant (ASCT) is incorporated in the front line therapy for MCL patients with good performance status. However, improvement in survival has not deemed MCL a curable disease. Concern for treatment-related morbidity seen with aggressive therapy in an incurable disease has led some centers to practice a more conservative approach. The purpose of our study was to compare patient characteristics and the overall survival of patients treated aggressively with ASCT versus conservatively with either conventional chemotherapy or no treatment at a single institution. Methods:52 cases of confirmed mantle cell lymphoma diagnosed at Rush University Medical Center between January 2000 and November 2010 were studied. Demographic, clinical and treatment data were collected and reviewed. The Social Security Death Index and hospital records were used to assess survival. Comparative survival analysis was performed based on treatment strategies including the following: no treatment (watch and wait), chemotherapy, ASCT at any time during course of treatment. None of these patients had an allogeneic stem cell transplant. Results:43 of the 52 cases met all inclusion criteria and had complete diagnostic and treatment data. The no-treatment group consisted of 5 cases with a median age of 59 years. The chemotherapy group included 23 cases with a median age of 68 years. The most common initial therapy was RCHOP in 14 cases, followed by various other regimens (i.e. bortezomib + rituximab, bendamustine + rituximab) in 7 cases and HyperCVAD in 2 cases. The ASCT group included 15 cases with a median age of 61 years. Pre-transplant chemotherapy was RCHOP in 4 cases, HyperCVAD in 5 cases and other regimens in 6 cases. The comparative survival analysis for the three treatment groups was not statistically significant (p=0.496) and the estimated 3 year OS was 100% for the no treatment group, 74% for the chemotherapy group and 85% for the ASCT group. The estimated 5 year OS was 100% for the no treatment group, 66% for the chemotherapy group and 68% for the ASCT group. There were no cases of allogeneic stem cell transplants.Treatment groups 0, 1, 20=No treatment1=Chemotherapy2=ASCTNumber of cases52315Median age (years)5968613 year overall survival100%74%85%5 year overall survival100%66%68% Conclusions:Our review of MCL cases treated at a single institution supports a role for conservative treatment approaches to this disease entity. This can avoid the potential long term morbidity from ASCT in a subgroup of patients while still keeping the modality of therapy as an option for them at relapse. The incidence of indolent MCL requiring no treatment was 12% which is consistent with those seen in other studies. Further research is necessary to guide treatment decisions for MCL patients whose disease characteristics are intermediate between aggressive and indolent. Disclosures:Gregory:Genentech:.

Clofarabine Does Not Impact Negatively the Outcomes of Patients with Acute Myeloid Leukemia (AML) Undergoing Allogeneic Stem Cell Transplantation and Is Not Associated with Higher Liver Toxicity Rates Compared with Standard Chemotherapy

Abstract 1489 Background:The purine nucleoside analog clofarabine is currently being actively investigated at the M.D. Anderson Cancer Center (MDACC) in combination with idarubicin and cytarabine (CIA) as frontline therapy for younger patients with newly diagnosed acute myeloid leukemia (AML). Hepatotoxicity (i.e. elevation of transaminases and/or bilirubin) is one of the primary adverse events associated with clofarabine and rare instances of severe hepatotoxicity as well as veno-occlusive disease (VOD) have been reported. Allogeneic stem cell transplant (allo-SCT) is indicated for younger AML patients with poor risk features (i.e. adverse cytogenetics, diploid karyotype with FLT3 mutations) in first complete remission (CR). Allo-SCT also places the patient at risk of liver toxicity and VOD. Therefore, we investigated whether pre-transplant clofarabine-containing chemotherapy regimens adversely impacted the outcomes of younger patients with AML compared with those of patients pre-treated with non-clofarabine containing chemotherapy. Methods:We conducted a retrospective review comparing patients who underwent allo-SCT after receiving CIA (clofarabine 20 mg/m2 IV daily for 5 days, idarubicin 10 mg/m2 IV daily for 3 days, cytarabine 1,000 mg/m2 IV daily for 5 days) versus a non-clofarabine containing chemotherapy regimen (IA, idarubicin 12 mg/m2 IV daily for 3 days, cytarabine 1,500 mg/m2 via IV continuous infusion over 24 hours daily for 4 days). Consolidation cycles contained the same agents given according to an attenuated schedule. Patients were all receiving CIA or IA as their frontline regimen for AML. Variables that were extracted from the medical record include age, number of cycles of chemotherapy, CR rate, allo-SCT in CR, stem cell source, conditioning regimen, engraftment day, incidence of VOD, incidence of acute hepatotoxicity post-transplant, incidence of graft versus host disease (GVHD), early death, and early relapse. Results:Overall, 42 younger patients with AML undergoing allo-SCT were identified (n = 20 CIA, n = 22 IA). Patient age in both groups was similar, and there were more females in the IA group. Other patient and transplant characteristics were comparable between cohorts. Most patients underwent a matched related donor or matched unrelated donor allo-SCT (CIA 80% versus IA 82%), and the majority received busulfan-fludarabine based conditioning (CIA 70% versus IA 82%). Two patients in each group received clofarabine as part of their conditioning program. In general, there was not any appreciable difference in acute post-transplant hepatotoxicity or in the incidence of VOD (table 1). Moreover, early mortality, early relapse, and the incidence of GVHD were not increased in the pretransplant clofarabine group compared to the IA group.Table 1Outcomes of Patients Undergoing allo-SCTCIA (n = 20)IA (n = 22)p-valueEngraftment Day (mean)13.914.50.7VOD (total cases)011.0Acute GVHD (total cases)490.19Liver GVHD (total cases)111.0Median Peak 30-day ALT (range)81 (30–830)72 (16–332)0.76Median Peak 30-days bilirubin (range)0.9 (0.5–2.8)0.8 (0.4–3.7)0.8630-day Mortality (%)001.0100-day Relapse (%)15181.0 Conclusions:The use of clofarabine does not appear to impact negatively the outcome of younger patients with AML undergoing allo-SCT. There does not appear to be an increased risk of delayed engraftment, hepatotoxicity, VOD, GvHD, early relapse, or early mortality among patients with AML undergoing allo-SCT who receive pretransplant clofarabine. Disclosures:No relevant conflicts of interest to declare.

5.39 Feasibility Analysis of Non-myeloablative Allogeneic Stem Cell Transplantation in Patients with Chronic Lymphocytic Leukemia and 17p Deletion

Background: Deletion of 17p (17p–) is the principal predictor of poor outcome in chronic lymphocytic leukemia (CLL) patients after conventional chemotherapy. Several reports have shown better outcomes with non-myeloablative allogeneic stem cell transplantation (NST). However, questions have been raised as to the relevance of NST, in particular, the extent that various selection biases lead to selection of only the ‘best’ patients for this procedure. Purpose: Our primary goal was to update our NST experience with 17p–, and report how often patients underwent transplantation and, within the limits of a retrospective analysis, the reasons for not undergoing transplantation. Methods: We reviewed NST outcomes for 17p– CLL patients transplanted between 2005 (when FISH became routinely performed at our institution) and 2010. Given the poor outcome after conventional fludarabine, cyclophosphamide, and rituximab (FCR) therapy, a diligent effort was started by the leukemia service in 2007 to refer patients to transplant sooner rather than later. Therefore, in a subanalysis, we reviewed the number of 17p– CLL patients who were referred to the transplant consult service from 2007 and assessed the reasons for no transplant. Prognostic factors were evaluated using Cox’s regression model. Multivariate analysis was not possible given sample size limitations. Results: Outcome of NST in 17p– CLL patients: Twenty-six patients were transplanted at our institution between 2005 and 2010. The median age was 56 years (range 37–73 years). At NST, 15 patients (58%) had 2-microglobulin ( 2m) 3; 21/24 patients (87%) had Binet stage B/C disease; 4 patients (15%) had Richter’s syndrome; 16/25 patients (64%) were FDG-avid; the median number of prior chemotherapies was 4 (range 2–14); and 14 patients (54%) had refractory disease. Thirteen patients (50%) had complex cytogenetic abnormalities (in addition to 17p–). IGVH was unmutated in 11/12 patients (92%) tested and 14/15 (93%) were ZAP-70 positive. Prior to their transplantation, 24 patients (92%) were exposed to FCR, 11 (42%) to FCR plus alemtuzumab or oxaliplatin, 7 (27%) to hyper-CVAD, and 17 (65%) to alemtuzumab. With a median follow-up of 18 months (range 3–60 months), 2-year overall survival (OS) and progression-free survival (PFS) rates were 62% and 38%, respectively. On univariate analysis, determinants of outcomes included disease status, 2m at NST, and year of transplant. All but 1 patient with chemosensitive disease had 2m 4, compared with 50% of patients with chemoresistant disease. Chemosensitivity was associated with significantly higher PFS (73% vs 12%, p 0.02; Figure) and a trend toward higher OS (91% vs 45%, p 0.09). PFS was also significantly higher for transplants performed after 2007 (44% vs 20%, p 0.03). 2m 4 was associated with lower 18 month OS (36% vs 71%, p 0.05) in chemoresistant patients, but did not significantly impact PFS (38% vs 14%, p 0.5). Two years’ follow-up was not reached for 2m 4 in this group. Transplant consults and transplantation rate: Between September 2007 and March 2010, 59 patients with 17p– CLL received a transplant service consult. Twenty of these patients (34%) had received a transplant at the time of this analysis, whereas 39 (66%) had not. Reasons for not receiving transplants included: (1) death with salvage pre-transplant chemotherapy (n 14, 36%); (2) patient and/or physician became uninterested after achieving a good response to salvage chemotherapy (n 14, 36%); (3) lost to follow-up after the initial consultation (n 3, 8%); (4) age 75 years (n 2, 5%); (5) insurance denial (n 3, 8%); (6) no donor (n 1, 2%); and (7) other (n 2, 5%). Conclusions: NST is plausibly more effective in 17p– CLL patients when recipients have chemosensitive disease. If, as suggested by our analysis, at most 34% of patients receive this procedure, methods to extend the applicability of transplant are needed. Perhaps the most effective method would be to use NST as consolidation after an initial response to conventional chemotherapy. Such a strategy would allow more patients to have chemosensitive disease at NST, and would decrease the death rate in heavily pre-treated patients during pre-transplant cytoreductive therapy.

Development and Validation of a Test Dose Strategy for Once-Daily i.v. Busulfan: Importance of Fixed Infusion Rate Dosing

Intravenous (i.v.) busulfan (Bu) administered once daily in myeloablative transplant regimens is convenient, effective, and relatively well tolerated. Therapeutic drug monitoring is recommended as nonrelapse mortality increases when daily exposure, as determined by the area under the plasma concentration versus time curve (AUC), exceeds 6000 μM·min. We describe sequential studies to achieve accurate prediction of treatment doses of Bu based on the kinetics of a smaller test dose. A total of 335 patients with hematologic malignancies were given daily i.v. Bu 3.2 mg/kg × 4 and fludarabine 50 mg/m(2) × 5. Pharmacokinetic monitoring was conducted for both the test dose and first treatment dose of Bu (day -5). Three different test dose schedules were evaluated: 12 mg Bu administered over 20 minutes, 0.8 mg/kg over 3 hours, and 0.8 mg/kg infused at 80 mg/h. The 3.2 mg/kg treatment doses were infused over a fixed time of 3 hours for the first 2 test dose trials and at a fixed rate of 80 mg/h for the final protocol. All test dose infusions were on day -7. In the first 2schedules, Bu administered over a fixed time had significantly higher clearance for the test dose compared with the treatment dose. However, when both the test and the treatment doses were administered at the same infusion rate, clearance of the drug between the 2 dosing days was equivalent. Predicted day -5 AUC (AUC(-5)) showed a high linear correlation (r(2) = 0.74) to the actual AUC(-5). The error of these predictions was <20% in 98% of patients and <10% in 80%. In 24 individuals, the test dose predicted an AUC >5500μM·min; therefore, the first Bu treatment dose was reduced to a desired target AUC. All adjusted doses fell within 20% of the targeted exposure. We conclude that a test dose strategy for therapeutic drug monitoring of daily i.v. Bu is accurate if the test and treatment doses are infused at the same rate. This approach allows targeting of therapeutic doses of Bu to desired levels and the potential for improved safety and efficacy.

Pre-transplant consolidation chemotherapy may not improve outcomes after reduced intensity conditioning hematopoietic stem cell transplantation for acute myeloid leukemia in first complete remission

The role consolidation chemotherapy prior to reduced-intensity (RIC) HCT is unclear. We reviewed 60 consecutive patients with AML in CR1 undergoing RIC HCT at the University of Minnesota and evaluated outcomes based on exposure to pre-transplant consolidation chemotherapy. The two year incidence of relapse and the probability of overall survival were similar between those who did and did not receive consolidation chemotherapy. The 2 year incidence of transplant-related mortality was slightly higher in those who did not receive consolidation and correlated with a higher HCT comorbidity index (HCT-CI) in that cohort. Our data suggest that exposure to consolidation chemotherapy prior to RIC HCT may not improve post-transplant outcomes for patients with AML in CR1.

Long-term Clinical Outcome of Patients with Severe Combined Immunodeficiency Who Received Related Donor Bone Marrow Transplants without Pretransplant Chemotherapy or Post-transplant GVHD Prophylaxis

Long-term Clinical Outcome of Patients with Severe Combined Immunodeficiency Who Received Related Donor Bone Marrow Transplants without Pretransplant Chemotherapy or Post-transplant GVHD Prophylaxis

Transplantation of hematopoietic stem cells in human severe combined immunodeficiency: longterm outcomes

Severe combined immunodeficiency (SCID) is a syndrome of diverse genetic cause characterized by profound deficiencies of T- and B-cell function and, in some types, also of NK cells and function. Mutations in thirteen different genes have been found to cause this condition, which is uniformly fatal in the first 2years of life unless immune reconstitution can be accomplished. In the 42years since the first bone marrow transplant was given in 1968, the standard treatment for all forms of SCID has been allogeneic bone marrow transplantation. Both HLA-identical unfractionated and T-cell-depleted HLA-haploidentical bone marrow transplants have been very successful in effecting immune reconstitution, especially if performed in the first 3.5months of life and without pre-transplant chemotherapy. This paper summarizes the longterm outcome, according to molecular type, of 166 consecutive SCID infants given non-conditioned related donor bone marrow transplants at this institution over the past 28.3years and reviews published reports of longterm outcomes of transplants in SCID performed at other centers.

Autologous (auto) Versus Allogeneic (allo) Hematopoietic Cell Transplantation (HCT) for T-NHL: A CIBMTR Analysis

AbstractAbstract 689T-cell lymphomas (T-NHL) are aggressive, heterogeneous malignancies, marked by chemoresistance with fewer than one-third of patients achieving disease control with non-transplant therapies. There are no large comparative studies of autoHCT and alloHCT in T-NHL. We analyzed post-transplant outcomes of 241 recipients (≤ 60 yrs) of autoHCT (n=115) and alloHCT (n=126, 76 matched siblings) for T-NHL between 1996–2006 reported to the CIBMTR. Median age was 43 yrs for autoHCT and 38 yrs for alloHCT. In the alloHCT cohort: 59% received myeloablative conditioning, 60% had matched sibling donors. Histology was heterogeneous (Table 1).Table 1Patient characteristicsAutoHCT (N=115)AlloHCT (N=126)P-valueAnaplastic Large Cell (ALCL)53%40%0.04Peripheral T Cell (PTCL)34%50%Angioimmunoblastic (AITL)13%10%Status at HCT CR 1/CR 2+/Relapse35/21/24 (%)14/16/31 (%)0.001Chemotherapy sensitive86%60%0.001>2 lines of prior chemotherapy34%49%0.01Myeloablative conditioningNA59%Median time to transplant after diagnosis was similar in both groups (10m vs. 11m). AutoHCT, compared to alloHCT, was used more in ALCL (53% vs. 40%, p=0.04) and in those with less advanced and more sensitive disease: first complete remission (CR1) (35% vs. 14%, p=0.001), chemosensitive disease (86% vs. 60%, p<0.0001), and ≤ 2 lines prior therapy (65% vs. 44%, p<0.001). Median follow-up was 71m for autoHCT and 49m for alloHCT. Treatment related mortality (TRM) at 100 days in the autoHCT and alloHCT cohorts was 2% and 17%, respectively. For those beyond CR1, overall survival (OS) at 1 yr was 62% vs. 52% and at 3-yrs 53% vs. 41% for the autoHCT and alloHCT cohorts, respectively (Table 2). Relapsing T-NHL was the cause of death in 73% of autoHCT and 44% of alloHCT pts.Table 2Univariate outcomesOutcomes @ 3 yearsAutoHCT Prob (95% CI)AlloHCT Prob (95% CI)P-valueProgression-free survivalAll patients47 (37-56)37 (28-45)NSPTCL29 (14-47)33 (22-45)NSALCL55 (42-67)35 (22-48)0.03Pts beyond CR141 (29-52)33 (24-42)NSOverall survivalAll patients59 (49-68)46 (37-54)0.046PTCL45 (27-62)42 (30-55)NSALCL68 (54-78)41 (27-54)0.003Pts beyond CR153 (40-64)41 (32-51)NSIn multivariate analysis, alloHCT and more pretransplant chemotherapy regimens were associated with a higher risk of TRM. Relapse risk was higher with chemotherapy resistant disease and those not in CR. PFS and OS were similar after autoHCT or alloHCT with a greater number of prior chemotherapy regimens and chemotherapy resistance impacting survival outcomes adversely. Among 101 peripheral T cell lymphoma (PTCL) pts, the risk of relapse was significantly lower with alloHCT (RR 0.5, 95% CI 0.26–0.97) but countered by increased TRM for alloHCT (RR 3.03, 95% CI 1.02 –8.96). PFS and OS after autoHCT or alloHCT for PTCL were similar and adversely affected by pretransplant chemotherapy resistance. Among alloHCT recipients, there were no differences in outcomes based on donor source, conditioning regimen type or intensity.In summary, pts undergoing autoHCT for T cell NHL appear to be selected for less advanced disease and greater chemosensitivity, making direct outcome comparisons with alloHCT difficult. AlloHCT is an effective strategy for high risk patients, albeit with significant TRM. Higher numbers of chemotherapy regimens prior to transplant adversely impacted both TRM and survival, suggesting that HCT should be considered earlier in the disease course. Disclosures:No relevant conflicts of interest to declare.

Early Phase Administration of Hematopoietic Stem Cell Transplantation to Prevent Early Relapse for Infants with Acute Lymphoblastic Leukemia and MLL Gene Rearrangement; a Report From the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) Trial MLL03

AbstractAbstract 529 Background:Infants with acute lymphoblastic leukemia (ALL) and MLL gene rearrangement (MLL-R) confer poor prognosis with approximately 40% probability of long term event-free survival (EFS). The major cause of treatment failure is leukemia relapse which usually occur very early after achieving the first remission (1CR). Prevention of early relapse is a key strategy to improve the outcome of MLL-R infants with ALL. On the basis of promising results in the previous MLL98 study with post-transplant EFS rate of 64.4% among the 29/44 patients transplanted in 1CR, we conducted a multi-center non-randomized trial for infants with MLL-R ALL to test an efficacy of intensive chemotherapy followed by early phase (≤ 4 months after achieving 1CR) hematopoietic stem cell transplantation (HSCT). Patients and Methods:Infants with ALL aged less than 12 months were registered in JPLSG MLL03 study if MLL gene rearrangements were confirmed by Southern Blot analysis. After 7-day prednisolone monotherapy, all patients received induction therapy consisted of dexamethasone, vincristine, doxorubicin, cyclophosphamide, cytarabine, etoposide, and triple intrathecal injections, followed by two intensification courses including high-dose methotrexate and high-dose cytarabine. L-asparaginase was not included. If 1CR was achieved, HSCT either from HLA ≥5/6 phenotypically matched related donor or ≥4/6 matched unrelated cord blood donor was carried out. Conditioning regimen consisted of busulfan, which was dose-adjusted based on individual pharmacokinetics, etoposide, and cyclophosphamide. Results:A total of 63 infants with ALL and MLL-R were registered in MLL03 study between Feb/2004 and Jan/2009. Patient characteristics showed high proportion of young infants; 22 (35 %) aged 0 – 90 days, 21 (33 %) aged 91 – 180 days, and 20 (32 %) aged 181 days or higher. Remission status was evaluated after 2 chemotherapy courses; 49 achieved 1CR, 4 failed to achieve 1CR, and 3 died of infectious complications. Seven patients were removed from the study; 2 for lineage switch to myeloid leukemia, 1 for guardians' refusal, 2 for severe adverse events (AEs), and 2 for protocol violations. Grade 3 and 4 non-hematological AEs during induction phase, such as infections (73 %), tumor lysis syndrome (TLS, 40 %), and liver transaminase elevation (44 %) were relatively common, especially in young infants. Forty-four out of 49 cases who achieved remission were able to undergo HSCT in 1CR; 32 cases from unrelated cord blood and 11 cases from related donor (1 unknown). All the recipients achieved stable engraftment. Ten patients developed grade II – IV acute GVHD and 8 developed chronic GVHD (only 1 with extensive type). Most of the post-HSCT events were leukemia relapses (18 post-HSCT relapses), and two non-relapse death were observed; one of transfusion-related acute lung injury (TRALI) and one of sudden death for unknown cause. Finally, probability of EFS in 18 months was 54.5 % (95 % confidence interval [CI], 41.3 % – 66.0 %) and overall survival in 18 months was 80.8 % (95 % CI, 68.7 % - 88.6 %). Young age (< 90 days old) and CNS leukemia at diagnosis were poor prognostic factors. Conclusions:The strategy of treating MLL-R ALL infants with intensive chemotherapy followed by early phase HSCT was feasible and prevention of early relapse was successful. However, significant improvement in EFS is unlikely compared with that of the previous MLL98 study. This may be due to, 1) high proportion of younger infants in the present study who are both high risk of relapse and severe treatment-related toxicities, 2) lack of sufficient intensity of pre-transplant chemotherapy in the present study to eradicate leukemia burden, and 3) limited efficacy of the strategy to treat MLL-R infant ALL with conventional chemotherapy and HSCT. Disclosures:No relevant conflicts of interest to declare.

P134 Lung function in post-transplant Hodgkin's lymphoma patients

IntroductionPulmonary complications are a prominent cause of morbidity and mortality following stem cell transplant (SCT) accounting for more than 30% of transplantation-related deaths. Exposure to agents associated with pulmonary toxicity...

Diarrhea during the Conditioning Regimen Is Correlated with the Occurrence of Severe Acute Graft-versus-Host Disease through Systemic Release of Inflammatory Cytokines

Graft-versus-host disease (GVHD) is a major obstacle to the success of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although many indicators have been used to predict GVHD, the prediction of GVHD remains very difficult. Determining how to predict the occurrence of acute GVHD (aGVHD) as exactly as possible has been a huge challenge so far. Systemic release of inflammatory cytokines during the conditioning regimen and early-phase post-HSCT plays a crucial role in the generation of aGVHD; additionally, the conditioning regimen causes the damage to the intestinal tract. Diarrhea is a common symptom of intestinal tract damage during the conditioning regimen. We therefore performed a prospective study to investigate the relationship between diarrhea related to the conditioning regimen, systemic release of inflammatory cytokines during the conditioning regimen and the early-phase post-HSCT, and the development of aGVHD. This study demonstrated that duration of diarrhea was >5.5 days, with a maximal volume >8.72 mL/kg and a mean volume of diarrhea for days -3 to 0 >7.94 mL/kg were risk factors of grade II to IV aGVHD. Diarrhea with any 1 risk factor was defined as severe diarrhea. Furthermore, this study first confirmed that the correlation between diarrhea and aGVHD was related to the serum levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6 during the conditioning regimen and during the early phase after transplantation. Our study demonstrated that diarrhea related to the conditioning regimen could be used as a marker for the prediction of aGVHD and further explain the possible mechanism underlying the linkage described here. Therefore, for the patients with severe diarrhea related to the conditioning regimen, low-dose glucocorticoid may be used to reduce the levels of inflammatory cytokine release by a damaged intestinal tract, and possibly further reduce the occurrence of aGVHD. For these patients, prophylaxis of aGVHD may be need to be adjusted individually.

Autologous Peripheral Blood Stem Cell Transplantation in Children with Refractory or Relapsed Lymphoma: Results of Children’s Oncology Group Study A5962

This prospective study was designed to determine the safety and efficacy of cyclophosphamide, BCNU, and etoposide (CBV) conditioning and autologous peripheral blood stem cell transplant (PBSCT) in children with relapsed or refractory Hodgkin and non-Hodgkin lymphoma (HL and NHL). Patients achieving complete remission (CR) or partial remission (PR) after 2 to 4 courses of reinduction underwent a granulocyte-colony stimulating factor (G-CSF) mobilized PBSC apheresis with a target collection dose of 5 × 10⁶ CD34(+)/kg. Those eligible to proceed received autologous PBSCT after CBV (7200 mg/m², 450-300 mg/m², 2400 mg/m²). Forty-three of 69 patients (30/39 HL, 13/30 NHL) achieved a CR/PR after reinduction. Thirty-eight patients (28 HL, 10 NHL) underwent PBSCT. All initial 6 patients who received BCNU at 450 mg/m² experienced grade III or IV pulmonary toxicity compared to none of the subsequent 32 receiving 300 mg/m² (P < .0001). The probability of overall survival (OS) at 3 years for all patients is 51% and for transplanted patients is 64%. The 3-year event-free survival (EFS) is 38% (45% for HL; 30% NHL). The 3-year EFS in transplanted patients is 66% (65% HL; 70% NHL). Initial duration of remission of ≥12 versus <12 months was associated with a significant increase in OS (3 years OS 70% versus 34%) (P = .003). BCNU at 300 mg/m(2) in a CBV regimen prior to PBSCT is well tolerated in relapsed or refractory pediatric lymphoma patients. A short duration (<12 months) of initial remission is associated with a poorer prognosis. Last, a high percentage of patients achieving a CR/PR after reinduction therapy can be salvaged with CBV and autologlous PBSCT.

Systematic Evidence Review of Newborn Screening and Treatment of Severe Combined Immunodeficiency

Severe combined immunodeficiency (SCID) is a group of disorders that leads to early childhood death as a result of severe infections. Recent research has addressed potential newborn screening for SCID. To conduct a systematic review of the evidence for newborn screening for SCID, including test characteristics, treatment efficacy, and cost-effectiveness. We searched Medline and the OVID In-Process & Other Non-Indexed Citations databases. We excluded articles if they were reviews, editorials or other opinion pieces, or case series of fewer than 4 patients or if they contained only adult subjects or nonhuman data. The remaining articles were systematically evaluated, and data were abstracted by 2 independent reviewers using standardized tools. For topics that lacked published evidence, we interviewed experts in the field. The initial search resulted in 719 articles. Twenty-six met inclusion criteria. The results of several small studies suggested that screening for SCID is possible. Interviews revealed that 2 states have begun pilot screening programs. Evidence from large case series indicates that children receiving early stem-cell transplant for SCID have improved outcomes compared with children who were treated later. There is some inconclusive evidence regarding the need for donor-recipient matching and use of pretransplant chemotherapy. Few data on the cost-effectiveness of a SCID-screening program. Evidence indicates the benefits of early treatment of SCID and the possibility of population-based newborn screening. Better information on optimal treatment and the costs of treatment and screening would benefit policy makers deciding among competing health care priorities.

Pre-Transplant Consolidation Chemotherapy Does Not Improve Rates Of Relapse Following Reduced Intensity Conditioning (RIC) Hematopoietic Stem Cell Transplantation (HCT) For AML In CR1

RIC HCT is an evolving post-remission treatment modality for AML. While previous reports demonstrate no benefit to consolidation chemotherapy prior to myeloablative HCT, the impact on outcomes post RIC HCT is unknown.

Allogeneic hematopoietic cell transplantation for acute leukemia in first relapse or second remission

BackgroundThe role of pre-transplant salvage chemotherapy has been controversial in relapsed acute leukemia.MethodsWe investigated post-transplant outcomes in 65 patients with acute leukemia treated with allogeneic hematopoietic cell transplantation (HCT) during first relapse or second remission.ResultsThe 5-year cumulative incidence of relapse (CIR) was 52.3%. Multivariate analysis for CIR revealed that patients with unfavorable cytogenetics and those not in remission at the time of HCT had a significantly high CIR (P = 0.031 and P = 0.031, respectively). Allogeneic HCT was performed in 14 patients after first relapse without salvage chemotherapy ("untreated relapse" group), 15 patients failed chemotherapy for reinduction of remission before HCT ("refractory relapse" group), and 36 patients attained second remission with salvage chemotherapy before HCT ("second remission" group). The 5-year CIR for patients in the untreated relapse group (57.1%) was higher than that for those in the second remission group (42.3%), but it was lower than that for patients in the refractory relapse group (66.7%). Among patients who underwent allogeneic HCT in relapse, those with bone marrow (BM) blasts ≤30% had a lower 5-year CIR than those in florid relapse (BM blasts >30%) (57.7% vs. 70.6%).ConclusionOur results do not support the role of salvage chemotherapy aimed at re-induction of remission before allogeneic HCT in patients with acute leukemia after first relapse. Patients with early relapse do not appear to benefit from salvage chemotherapy before HCT.

Autologous hematopoietic stem cell transplantation in classical Hodgkin's lymphoma

Background Hodgkin's lymphoma has high rates of cure, but in 15% to 20% of general patients and between 35% and 40% of those in advanced stages, the disease will progress or will relapse after initial treatment. For this group, hematopoietic stem cell transplantation is considered one option of salvage therapy. Objectives To evaluate a group of 106 patients with Hodgkin's lymphoma, who suffered relapse or who were refractory to treatment, submitted to autologous hematopoietic stem cell transplantation in a single transplant center. Methods A retrospective study was performed with data collected from patient charts. The analysis involved 106 classical Hodgkin's lymphoma patients who were consecutively submitted to high-dose chemotherapy followed by autologous transplants in a single institution from April 1993 to December 2006. Results The overall survival rates of this population at five and ten years were 86% and 70%, respectively. The disease-free survival was approximately 60% at five years. Four patients died of procedure-related causes but relapse of classical Hodgkin's lymphoma after transplant was the most frequent cause of death. Univariate analysis shows that sensitivity to pre-transplant treatment and hemoglobin < 10 g/dL at diagnosis had an impact on patient survival. Unlike other studies, B-type symptoms did not seem to affect overall survival. Lactic dehydrogenase and serum albumin concentrations analyzed at diagnosis did not influence patient survival either. Conclusion Autologous hematopoietic stem cell transplantation is an effective treatment strategy for early and late relapse in classical Hodgkin's lymphoma for cases that were responsive to pre-transplant chemotherapy. Refractory to treatment is a sign of worse prognosis. Additionally, a hemoglobin concentration below 10 g/dL at diagnosis of Hodgkin's lymphoma has a negative impact on the survival of patients after transplant. As far as we know this relationship has not been previously reported.

Allogeneic Hematopoietic Cell Transplant for Prolymphocytic Leukemia

The poor prognosis of patients with prolymphocytic leukemia (PLL) has led some clinicians to recommend allogeneic hematopoietic cell transplant (HCT). However, the data to support this approach is limited to case-reports and small case series. We reviewed the database of the Center for International Blood and Marrow Transplant Research (CIBMTR) to determine outcomes after allotransplant for patients with PLL. We identified 47 patients with a median age of 54 years (range: 30-75 years). With a median follow-up of 13 months, progression-free survival (PFS) was 33% (95% confidence interval [CI] 20%-47%) at 1 year. The most common cause of death was relapse or progression in 49%. The cumulative incidence of treatment-related mortality (TRM) at 1-year posttransplant was 28%. The small patient population prohibited prognostic factor analysis, but these data support consideration of allotransplant for PLL. Further study of a larger population of patients is needed to determine which patients are more likely to benefit.

A Decade of Reduced-Intensity Conditioned Allogeneic Haematopoietic Stem Cell Transplantation for Myelodysplastic Syndromes Following Conditioning with Fludarabine, Busulphan and Alemtuzumab.

Abstract 2266Poster Board II-243Reduced-intensity conditioning haematopoietic stem cell transplantation has dramatically improved the accessibility and safety of transplantation in groups of patients previously ineligible because of age or comorbidity. We report the long term results of allografting following reduced intensity conditioning with Fludarabine® 30 mg/m2 i.v. ( Day –9 to Day –5); busulphan 4mg/kg/day oral or 3.2mg/kg/day i.v. (Day –3 to Day –2) & alemtuzumab 20mg i.v. ( Day –8 to Day –4) in patients with myelodysplastic syndromes. Immunosuppression comprised cyclosporine 1.5 mg/kg iv 12 hourly from Day –1 titrated to plasma trough levels of 150-200 ng/l. Peripheral blood stem cells (PBSC) or bone marrow was infused on Day 0. Filgrastim 300 mcg iv/sc was administered from Day +7 to neutrophil engraftment (neutrophils ≥ 0.5×109/l).213 patients with Myelodysplastic Syndrome (RCMD-RS=5, RCMD=44, RAEB-1=19, RAEB-2=36, CMML=18, TLD-AML=91)(IPSS Low=7, Int-1=46, Int-2=39, High=12) received transplants from matched sibling donors (57) or volunteer unrelated donors (VUD)(156 ). The median age for sibling recipients was 56 years (38-72) and for VUD recipients 55 years (19-71). All had relative or absolute contraindications to receiving standard myeloablative conditioning allografts. 52 of 57 sibling HSCTs utilised PBSCs compared with 106 of 156 VUD HSCTs, with a median CD34 cell dose of 5.11×106 (0.7-17.5) and 5.2×106 (0.44-19.90) respectively. On high resolution typing 46 VUD grafts were mismatched. There was no difference in engraftment latency between sibling and VUDs, with the median time to neutrophil engraftment (>0.5×109/l) of 14 days (9-57) and 13 days (8-31) and platelets(>20×109/l), 14 days (7-120) and 15 days (3-120) respectively.With a median follow-up of 2202 days (718-3709)(siblings) and 1693 days (29-3659)(VUD), the treatment related mortality (TRM) at Day100, 200 and 360 and 5 years was 4%, 9% 13% and 27% respectively for siblings; 8%, 17% and 25% and 28% for VUD (p=0.48). 12% of TRM deaths were due to CMV and 8% to PTLD. The Kaplan-Meier overall survival at 5 years was 46% for siblings and 41% for VUD(p=0.28), with a disease free survival (DFS) of 30% and 35% (p=0.94) respectively. The prognostic significance of some of the IPSS and diagnostic groups was preserved with a DFS of 46% in the “Low & Int-1” group at 5 years; 23% in “Int-2”; 0 % in “High”, 21% in CMML and 37% in TLD-AML. (p=ns, except Low-Int-1 vs. CMML(0.005), H (0.002) and Int-2(0.014)). The DFS was 80% in RCMD-RS, 49% in RCMD, 19% in RAEB-1 and 13% in RAEB-2.(p=ns except RCMD vs. CMML(0.015), RAEB-2(0.023)).Patients with TLD-AML had received more pre-transplant chemotherapy (median 3 courses (1-6)) compared with IPSS-High (median 1(1-3)). Patients who did not require cytotoxic chemotherapy had a 5 year DFS of 60%(p=0.003). There was no statistical difference in 5 year DFS between patients requiring induction chemotherapy in CR1(29%), CR2 (25%), PR (20%), or with progressive/relapsed disease (22%). The median DFS for these groups were 410, 362, 158 and 271 days.Lineage specific (CD3 & CD15) chimerism results were available on 133 patients. 40% achieved full donor T-cell chimerism (>95%) with 72% achieving full donor engraftment in unfractionated bone marrow by Day100, with a 24% cumulative incidence of Grade II to IV denovo aGvHD and 9% extensive cutaneous cGvHD.83 patients (41(74%) sibling & 42(26%)VUD) received the first dose of incremental DLI at a median of 195 days (60-1323) post transplant. 53 received DLI for persistent mixed or declining donor chimerism, 11 for cytogenetic relapses and 19 morphological relapses. The desired effect was achieved in 67%, 45% and 42% respectively. A graft versus leukaemia effect was demonstrable. RIC allogeneic HSCT with fludarabine, busulphan and alemtuzumab appears to be potentially curative with a plateaux in DFS after 5 years. Further follow-up in patients with Low-Int-1 and Int-2 MDS and CMML is required to determine if there is a survival advantage for transplanted patients. Disclosures:Off Label Use: fludarabine, alemtuzumab- used off-label for transplant conditioning.

Comparison of Unrelated and Sibling Donor Allogeneic Hematopoietic Cell Transplantation (HCT) for Follicular Lymphoma (FL) - From the Lymphoma Working Party, European Group for Blood and Marrow Transplantation (EBMT) and Center for International Blood and Marrow Transplant Research (CIBMTR).

Abstract 874Allogeneic HCT is potentially curative in FL, but wide adoption of this treatment is limited by its toxicity and donor availability. Improvements in HLA-matching have improved the safety of unrelated donor (URD) HCT. We compared the outcomes of 702 recipients of allogeneic HCT for FL (198 URD and 504 sibling donors (sib)) from 171 centers world-wide reporting to the CIBMTR or EBMT between 1997 and 2005. Recipients of mismatched, cord blood or ex vivo T-cell depleted grafts were excluded. Overall and progression-free survival (OS and PFS), transplant-related mortality (TRM) and relapse/progression outcomes were analyzed using Cox proportional hazards regression models with donor type (sib vs. URD) as the main effect. URD HCT was performed more frequently after 2001. Comparing to the sib group, URD HCT recipients were more likely to receive reduced intensity conditioning (70% vs. 54%), antithymocyte globulin or alemtuzumab (in vivo T-cell depletion) or tacrolimus-based graft-versus host disease (GVHD) prophylaxis, and have a longer interval from diagnosis to HCT (median 49 vs. 32 months). URD HCT recipients had poorer risk FL with more pre-transplant chemotherapy, including previous autologous HCT (36% vs. 16%) and prior exposure to rituximab (66% vs. 43%) compared with sib HCT recipients. Adjusted probabilities for three-year PFS and OS were 49% vs. 60% (p=0.02) and 54% vs. 69% ( p<0.001) for URD and sib HCT, respectively. Cumulative incidence of acute GVHD (grade 2-4) at day 100 was 48% and 42% (p=0.3), whereas chronic GVHD at one year was 47% and 41% (p=0.3) for the URD and sib HCT respectively. Relative risks for TRM, relapse/progression, treatment failure and mortality, comparing URD to sib donors, are shown below. Significant risk factors associated with worse outcomes included poor performance status at transplantation and extensive pre-transplant therapy (> 4 lines of therapy or prior autologous HCT). Additionally, in vivo T-cell depletion was associated with a higher risk of relapse/progression and treatment failure. Reduced intensity conditioning was associated with lower TRM, but did not impact other outcomes. In conclusion, this study shows that URD HCTs are performed later in the treatment course for FL, in higher risk patients, most commonly with reduced intensity conditioning, and are associated with worse PFS and OS compared to sib HCT. Considerations for future studies include the use of URD allogeneic HCT earlier in the course of treatment for FL and avoiding T cell depleting agents in the conditioning regimen.Outcome#URD/SibURD vs. sib RR1 (95% CI)PTRM197/5002.04 (1.43 - 2.90)<0.0001Relapse/Progression197/5000.97 (0.61 - 1.52)0.8781Treatment Failure2197/5001.49 (1.11 - 2.01)0.0087All cause Mortality3198/5041.91 (1.40 - 2.61)<0.00011Relative Risk2Relapse/Progression or Death3Opposite of OS Disclosures:No relevant conflicts of interest to declare.

Four Cases of Chronic Active Epstein-Barr Virus Infection That Performed Reduced-Intensity Conditioning Bone Marrow Transplantation.

Abstract 4734Epstein-Barr virus (EBV) is B cell tropic virus. However, the EBV-infected T and NK cells play a critical role on the pathogenesis of chronic active EBV infection (CAEBV). The diagnostic criteria are fever, lymphadenopathy and hepatosplenomegaly with abnormal antibody titer to EBV and increased amount of the EBV genome in the blood. But the mechanism on how EBV infects T and NK cells is not fully known yet. Once leukemic transformation occur the prognosis of the disease becomes very poor. The evidence that hematopoietic stem cell transplantation (SCT) is effective on CAEBV has accumulated, however, controversy still remains on the necessity of pre-transplant chemotherapy, and what kind of conditioning regimen is suitable during SCT.In this article, we reported 2 cases of T cell type CAEBV and 2 cases of NK cell type CAEBV that have been treated by bone marrow transplantation (BMT) with reduced intensity regimen (RIC) without pre-transplant chemotherapy. RIC consists of Cyclophosphamide (CY, 100-120 mg/Kg), Fludarabine (Flu, 120-150 mg/m2) and low dose TBI (3-4 Gy).Case 1 is an 8-year-old boy with EBV infected CD4 positive T cells. He showed elevated serum enzyme, coronary artery aneurysm, generalized rash, and positive EBV DNA in cerebrospinal fluid. The EBV genome in peripheral mononuclear cells was 1.3+105 copies /μgDNA. Southern blot analysis with EBV terminal repeat probe revealed clonal proliferation of virus. Tetramer analysis did not detect EBV specific CTL. He received modified HLH 2004 protocol (Henter et al, 2006). Immediately after normalization of liver dysfunction, BMT were performed from unrelated donor. Now he is in complete remission.Case 2 is an 8-year-old boy with EBV infected CD4 positive T cells. He also showed liver dysfunction, lymphadenopathy and positive EBV DNA in cerebrospinal fluid. The EBV genome in peripheral mononuclear cells is 2.6+105 copies /μgDNA. EBV clonality was detected by Southern bolt analysis. Tetramer analysis of BRLF1, EBNA3A and EBNA3B peptides showed EBV specific CTL. BMT from HLA-matched sibling donor achieved complete chimeras. But the EBV genomes in his peripheral blood increased to 4.7 +103 copies /μgDNA after BMT. EBV positive CD4 T cells were present. At the moment, it is not clear whether the origin of EBV positive T cells is from donor or not.Case 3 is a 21-year-old female with mosquito allergy with EBV infected NK cells. Liver dysfunction and lymphadenopathy were occasionally complained. The EBV genome in her peripheral blood is 1.2+105 copies /μgDNA. EBV showed monoclonal amplification. BRLF1 specific CTL were detected by tetramer analysis. HLA one antigen mismatched BMT from unrelated donor induced complete remission after grade 3 skin GVHD.Case 4 is a 19-year-old boy with CAEBV secondary to EBV-hemophagocytic lymphohistiocytosis. EBV positive NK cells were present. EBV genome in his peripheral blood was 1.2+104 copies /μgDNA. EBV showed monoclonal amplification. EBV specific CTL were not detected. After BMT from HLA-matched unrelated donor, EBV DNA was rapidly eliminated from his blood. But he suffered from pure red cell aplasia caused by major Blood type incompatibility and now treated with Rituximab.Four cases of CAEBV were described. RIC was demonstrated to be effective for engraftment of donor bone marrow cells without any serious adverse effects except pure red cell aplasia. Addition of pre-transplant chemotherapy seemed to be non-essential for engraftment or remission induction. In case 2 EBV infected peripheral CD4 positive cells were demonstrated after BMT. Determining the origin of the EBV infected CD4 positive T cells may provide hints for understanding on how EBV infects T cells or how EBV infected Tcells survive after BMT. Disclosures:No relevant conflicts of interest to declare.