ALBERT

Description: Introduction: Filgrastim is widely used for mobilizing CD34+ cells into the peripheral blood that are easily collected by apheresis for allogeneic transplantation. With case reports documenting splenomegaly with life-threatening complications in normal donors, we prospectively evaluated spleen size using ultrasonography and clinical examination during PBPC mobilization and collection in a single-arm trial. Methods: Subjects ≥18 yrs eligible to be PBPC donors per institutional guidelines enrolled. Splenic assessments were done before, during, and after PBPC mobilization. Filgrastim dose and schedule and leukapheresis (LK) procedures were per institutional practice. The primary endpoint was fold change from baseline in splenic volume in post-baseline measurements during mobilization (measured by ultrasound [US]). Spleen size by US was measured in 3 dimensions similarly by all centers: longitudinal (craniocaudal), transverse, and diagonal (perpendicular to transverse in transverse image) diameters. Splenic volume was estimated by taking the cross-product of 3 dimensions and multiplying by 0.52, approximating the volume of an ellipse. Physical examination was performed on US days, assessing spleen palpability. US and palpation results were blinded from each other at assessment times. Timepoints included baseline (before first filgrastim dose), first LK (done before LK, typically day 4 or 5 of filgrastim), 2 and 4 days after first LK, and 7 days after last LK. Timepoints in the post-amendment cohort (n=219) were reduced to facilitate enrollment and were baseline and day of first LK (before LK). Results: 309 donors enrolled, median age 44yrs (range 18 to 74), 56% male. Mean daily filgrastim dose was 11.4mcg/kg (SD=3.0). Median number of LK was 1.5 (range 1 to 4). In all donors, the median increase in each measured dimension on first LK day was 1.4cm, 1.4cm, and 0.6cm (12.8%, 12.6%, and 15.0%), and the median fold volume increase from baseline to first LK was 1.47, resolving to near baseline 1 week after last LK. There was no apparent relationship between volume fold change and filgrastim dose, ANC, or CD34+ yield. Of 861 splenic palpation assessments reported in all donors, 98% were reported as nonpalpable (842 assessments), and 2% were palpable (19 assessments, 2 at baseline). Reporting of palpable spleens did not correlate with increased spleen size. Tenderness or guarding upon splenic palpation was reported in 2 donors with a spleen considered palpable and in 6 donors with nonpalpable spleens. No donor experienced a splenic rupture. Adverse events related to filgrastim were generally mild to moderate. Conclusion: During PBPC mobilization with filgrastim in normal donors, the spleen increased a median of approximately 50% from baseline to day of first LK and returned to near baseline 1 week after last LK. Size change was not associated with significant clinical sequelae. Timepoint Median fold change from baseline in splenic volume (Q1, Q3) *statistically significant (p

Description: Abstract 3223 Poster Board III-160 There are concerns that prolonged exposure to lenalidomide (len) impairs the peripheral blood progenitor cell (PBPC) yield in patients (pts) undergoing autologous peripheral blood stem cell transplant (ASCT) for multiple myeloma. To evaluate the effect of len on PBPC yield, we retrospectively analyzed 144 consecutive pts undergoing PBPC harvest prior to ASCT for multiple myeloma between July 1, 2007 and June 30, 2009. Exclusion criteria included prior ASCT or prior treatment with an alkylating agent. Of the evaluable patients, 67 pts received at least one cycle of len as part of their pre-harvest therapy (median # of cycles 4 (range 1-28)) and 63 received non-len containing regimens. Median age for all pts was 57 years and was similar between the two groups. Initial PBPC harvest was unsuccessful (defined as collection of

Description: Abstract 2241 Poster Board II-218 Introduction: T-LGL has the phenotype characteristics of a post-thymus mature T cell. Expansion of T-LGL has been reported to occur in association with viral infections, autoimmune diseases, lymphoproliferative malignancy and HSCT. The clinical significance of finding T-LGL expansion post HSCT is unclear. We recently reviewed the incidence of T-LGL expansion in patients who underwent allogeneic HSCT in our institution. We specifically asked whether T-LGL expansion was associated with increased viral infections, stable chimerism, graft-versus-host disease (GvHD), recurrence of primary disease, and overall survival. Patients and Methods: A retrospective analysis was done on all adult patients who underwent allogeneic HSCT at the Karmanos Cancer Institute between January 1, 2004 to June 30, 2009. In patients with persistent lymphocytosis (〉3000 cells/mm3) post HSCT, expansion of T-LGL phenotype was identified by flow cytometry (CD2, CD3, CD5, CD7, CD8 and CD57 positive) and clonality was confirmed by T cell receptor beta and/or gamma gene rearrangement (TCR-GR) using southern blot analysis and polymerase chain reaction (PCR). Results: A total of 547 patients underwent allogeneic HSCT during the study period. We identified T-LGL expansion in 24 patients with persistent lymphocytosis using flow cytometry. Median age of patients with T-LGL expansion was 50 years (range 24-68 years). Median time to diagnosis was 275 days post HSCT (range 69-1454 days) and median duration of follow-up was 811 days (range 85-1701 days). All 24 patients achieved full donor chimerism post transplantation by STR analysis. Fourteen out of 24 patients with T-LGL expansion had positive TCR-GR, in 2 patients TCR-GR was not done and the remainder was negative. Twenty out of 24 patients had cytomegalovirus (CMV) viremia confirmed by PCR before the onset of T-LGL expansion; the remainder had no CMV viremia. In all patients with T-LGL expansion there was no subsequent recurrence of CMV viremia or infection. All 24 patients had documented graft versus host disease (GvHD). In the group with T-LGL expansion only 2 patients relapsed with primary disease and only one patient died (due to a cardiac event). The cumulative incidence of T-LGL expansion was 4.4% at the end of the study period. Conclusion: To our knowledge, this is the largest reported series of T-LGL expansion post allogeneic HSCT. T-LGL expansion was associated with an interesting sequence of CMV viremia preceding T-LGL expansion and subsequent lack of recurrence of CMV viremia or infection. We also observed a very low number of relapse of primary disease or death in patients with T-LGL expansion. One hypothesis is that T-LGL expansion may be a result of specific stimulation with CMV antigens post allogeneic HSCT. An alternate hypothesis is that T-LGL expansion is a surrogate marker for accelerated immune reconstitution. At present, it is also unclear if T-LGL expansion is a marker of ‘graft-versus-leukemia' effect with respect to relapse of primary disease warranting further research. Disclosures: Lum: Transtarget Corporation: Founder

Description: Lenalidomide (Len) is an immunomodulatory drug approved for use with high-dose dexamethasone (HD) as therapy for relapsed-refractory multiple myeloma (RRMM). Preliminary data suggest Len+HD may be even more active versus newly-diagnosed myeloma (NDMM). SWOG conducted a randomized, double-blinded, placebo-controlled trial (S0232) comparing Len+HD to HD alone. Methods: Original study design: enrollment of 500 pts with NDMM (measurable disease, Cr ≤ 2.5 mg/dL, ineligible for/declining immediate autologous stem cell transplant), with interim analysis after accrual of 300 pts. The trial was closed after 198 pts were enrolled, due to external data affecting acceptability of HD as the control arm. Pts were randomized to Len 25 mg/d (28 of 35 days for 3 induction cycles, then 21 of 28 days as maintenance thereafter) plus HD (40 mg days 1–4, 9–12, 17–20 induction, then days 1–4, 15–18 maintenance) or HD (same induction and maintenance schedules) plus placebo. Therapy was unblinded for disease progression; pts on HD could crossover to Len+HD. After a high initial rate of thrombosis (TEE) was seen in pts on Len+HD, aspirin (ASA) 325 mg/d was mandated. Pts were stratified by ISS stage and SWOG performance status (PS). The primary endpoint is progression-free survival (PFS). Secondary endpoints reported here are overall response rate (ORR), major response rate (MRR), overall survival (OS), and toxicity. Results: Between Oct 2004 and Mar 2007, 100 pts were randomized to Len+HD (arm A) and 98 pts to HD plus placebo (arm B), with no differences in age (median 64.6 yrs overall), sex, race, PS, or stage distribution between arms. As of July 18, 2007, 61 pts on arm A and 72 pts on arm B were assessable for response. Estimated 1-yr PFS was 77% (arm A), vs 55% (arm B) (p=0.002). The ORR was 85.3% (≥ MR 79.4%, CR 22.1%) vs 51.3% (≥ MR 26.2%, CR 3.8%) on arms A and B, respectively (p = 0.001). OS was high in both arms (93% vs 91% at 1 yr; p=NS). Forty pts on arm B crossed over to arm A. Of these, 23 are assessable for response: ORR is 70.4% (14.8% CR). Grade 3–4 neutropenia was more frequent on arm A (13.5% vs 2.4%; p=0.010), as were infections (arm A: n=38, Gr 3–4=13, Gr 5=1; arm B: n=23, Gr 3–4=8, Gr 5=0; p= 0.003). There were 20 TEEs on arm A (14 on ASA prophylaxis) and 12 on arm B (all on ASA; 5 after crossover to Len+HD). Thus, 25 TEEs occurred during either blinded or open-label Len+HD vs 7 on HD alone (p=0.089). Discussion: In NDMM, Len+HD is superior in terms of ORR, MRR, and PFS compared to HD alone. The 1-yr OS in both arms of this study is among the highest reported. ASA at this dose may not be optimal thromboprophylaxis for pts with NDMM treated with Len+HD, although pt compliance with ASA on this study is not known. With recent evidence that dex intensity may affect TEE risk, this study was modified to include lower dose dex (40 mg q wk) with no change in TEE prophylaxis.

Description: Abstract 3346 Poster Board III-234 Background: Patients who receive high-dose chemotherapy with or without radiation preparative regimens prior to allogeneic hematopoietic stem cell transplant (AHSCT) have high incidence of mucositis. The mucositis is usually seen at the nadir of neutropenia and improves with engraftment. At our center we observed late onset mucositis in patients received intravenous IV Busulfan/Fludarabine (IV-BU/FLU) preparative regimen. The onset was within 5 days of engraftment and resolved 5 days after engraftment (peri-engraftment mucositis, PEM). Upon review of literature, no reports were found that detailed this phenomenon. We attempted to determine the incidence of PEM in our patient population, as well as possible risk factors and consequences. Methods: This retrospective chart review was designed as a cohort study. It included 382 patients who received AHSCT at Karmanos Cancer Center between 2004 and 2009; out of these were 207 patients received IV-BU/FLU; 103 patients received myeloablative dose of BU 130mg/m2 daily x 4 doses starting at day -6 and FLU 30mg/m2 daily x five doses starting at day -6. 104 patients received reduced intensity regimen of IV BU 130mg/m2 daily x 2 doses starting day -6, FLU 30mg/ m2 daily x 5 doses starting day -6, and 200 rad total body irradiation TBI (IV-BU/FLU/TBI). All patients received tacrolimus and mycophenolate for GVHD prophylaxis starting at day -3, with no methotrexate. We attempt to define this entity by examining the clinical course and correlations of diagnosis, preparative regimen, patient characteristics (age, race, weight, height, grade and duration of mucositis, opiate use, and engraftment associated acute leukocytosis) and patient outcomes (hospitalization duration, incidence of acute GvHD, survival). Results: A total of 207 patients received IV- BU/FLU and 175 patients received other preparative regimens. The incidence of peri-engraftment mucositis was 19% (39/207), in the group receiving IV-BU/FLU, while with other regimens it was 1 % (2/174). There was no difference in the distributions of the diagnosis, patient characteristics or patient outcomes among those who received IV-BU/FLU versus those who received other preparative regimen. Due to high incidence of this phenomenon observed in patients who received BU/FLU, this patient group was further studied. On evaluation of these patients (n=207), 9 (4%) patients were not assessable for mucositis, 62 (30%) had no mucositis and 136 (66%) developed mucositis. Of the 136 pts with mucositis, 39 (29%) met predefined criteria for peri-engraftment mucositis (PEM). PEM (N=39) group characteristics: Mean age is 50 (20-67). 34 patients had IV-BU/FLU and 5 IV-BU/FLU/TBI. Diagnosis: 22 AML, 6 MDS, 4 CML, 2 NHL, 2 CLL, 1each with CMML, HD, ALL. 16 patients had related AHSCT and 23 had unrelated AHSCT. All PEM patients were tested and found negative for herpes simplex virus infection at the time of PEM. The median engraftment day for both mucositis group (MG) and peri-engraftment mucositis (PEMG) group was day +11. The median duration of mucositis (6 vs. 11 days, p 〈 0.001), incidence of intravenous (iv) opiate usage (62% vs. 82%, p 0.023), median duration of iv opiate usage (5 vs. 7 days, p〈 0.001), Mucositis grade 3 (21% vs. 43 % p 〈 0.001 value) and median duration of hospitalization (24 vs. 31 days, p〈 0.001) were different in MG (N=97) vs. PEMG(N=39) group, respectively. The p values were calculated using wilcoxan rank sum test. No significant differences in other patient characteristics or other patient outcomes were observed in the MG vs. PEMG. Conclusion: BU/FLU regimen has been in use for less than a decade. Peri-engraftment mucositis has not been described previously with this regimen. PEM is a unique phenomenon, with features including; longer duration (Fig1), more incidence of grade 3 mucositis, higher incidence and longer duration of iv opiate use and longer hospitalization. Although the pathophysiology of PEM remains unclear and no specific risk factors have been identified for it, this phenomenon increases patients' morbidity and cost of transplant. Disclosures: Lum: Transtarget Corporation: Founder. Abidi:Merck Pharmaceuticals: Research Funding.

Description: Abstract 2239 Poster Board II-216 Background: Acute graft versus host disease aGVHD continues to affect approximately 60% or more of patients undergoing UHSCT, with significant mortality and morbidity. Furthermore viral infections such as Cytomegalo virus (CMV) affect approximately two thirds of these patients. Methods: In a phase II trial, we prospectively evaluated whether adding Thymo (4.5 mg/kg divided doses on days -1,-2, and -3) to Tacrolimus and Sirolimus combination for aGVHD prophylaxis in recipients of UHSCT would decrease the rate of aGVHD. The primary endpoint is aGVHD, which is calculated as cumulative incidence. Since infections are a concern after T cell depletion, the incidence of infections and adverse events were monitored closely. Results: There were 25 patients (pts) with median age of 51(20-70) years enrolled in the protocol, 10 females and 15 males. There were 10 AML (5CR1, 5CR2), 7 MDS (untreated), 2 ALL (CR1), 1 ALL/AML (uCR1), 1 CML (CP), 1 CMML (untreated), 1 granulocytic Sarcoma (CR1), 1 NKT cell lymphoma (CR3), and 1 DLBCL(CR2). Preparative regimens included Bu/Flu (21 pts), VP16/TBI (2 pts) R-BEAM (1 pt), and Flu/MEL (1 pt). All patients received peripheral blood hematopoietic stem cells (PBHSC) mobilized with granulocyte colony stimulating factor G-CSF with an average CD34+ dose of 8.24×10 6/kg (3.7-14.3). All patients received daily G-CSF starting day +6 till engraftment. After molecular typing, 11 of 25 patients received HLA fully matched graft, 11 of 25 received a 1 antigen (Ag) mismatched graft, and 3 of 25 received a 2 Ag mismatched unrelated PBHSC graft. All patients' engrafted. Median engraftment day is 12 (9,13). Eighteen patients had passed the day 100 time point; seven pts did not reach day 100. Three deaths occurred, due to: relapse (1), multi organ failure (1), and pneumonia (1). Two patients experienced disease relapse. Both went into complete remission once immune suppression was withdrawn, demonstrating clear graft versus Leukemia (GVL) effect, before day 100. Seven of 25 pts developed aGVHD, 1 developed aGVHD after relapse. Three developed grade 1 aGVHD, 3 pts developed grade 2 aGVHD. One pt developed grade 4 aGVHD after immune suppression withdrawal due to disease relapse. Five patients needed systemic steroids, maximum duration 36 days. All aGVHD cases have responded to therapy. The cumulative incidence rate for aGVHD at 100 days is 0.258 ( 0.101, 0.448); the cumulative incidence rates of competing events: relapse is 0.146 (0.034, 0.334) and death without GVHD or relapse 0.050 (0.003, 0.212). Patients tolerated Thymo well. Two patients developed thrombotic thrombocytopenic purpura (TTP), one patient after day 100 that required discontinuation of tacrolimus and sirolimus. Four patients developed CMV PCR sub-clinical activation 16% (95% CI 5.7-33.6%), which resolved with treatment. Six patients developed PCR sub-clinical Epstien-barr virus (EBV) activation 20% (95% CI 8.2-38.4), 5/6 needed Rituximab. Three patients developed Herpese simplex virus (HSV) stomatitis, two rhinovirus upper respiratory tract infections, and 3 BK viral cystitis. 14 patients had a documented bacterial infection all resolved. Apart from 2 oral candidiasis, no fungal infections observed. All infections have resolved. Conclusion: These early results suggest that the combination of Tacrolimus/Sirolimus and Thymo in pts undergoing unrelated HSCT is well tolerated and is associated with a low rate and severity of acute GVHD, and early GVL effect as demonstrated in two patients. Low rates of CMV viral infections were seen. Further accrual and a longer follow-up will be needed to confirm these encouraging results. Disclosures: Al-Kadhimi: Genzyme pharmacutical: Research Funding. Off Label Use: Thymoglobulin is used to prevent graft versus host disease in unrelated transplant in this protocol. That is an off lable drug use.. Abidi:Merck Pharmaceuticals: Research Funding.

Description: Complete remission (CR) is now frequently used as a surrogate marker for survival in multiple myeloma (MM), however its utility in African Americans (AA) has not been studied. Limited literature is available regarding outcomes after autologous stem cell transplantation (ASCT) in AA with MM. We evaluated the outcomes of 106 consecutive AA patients who underwent ASCT for MM between 7/1991 and 6/2006 at 3 centers. Melphalan-based conditioning was used in all the patients except 3 who received Busulfan/Cytoxan/TBI. After ASCT 30/105 (28%) evaluable patients were in CR. With median follow up of 47 months, the median progression free survival (PFS) and overall survival (OS) for all the patients was 16 and 51 months respectively. Effects of disease status at and after ASCT (CR v non CR), Age, gender, number of prior treatment regimens, B2M, LDH, plasma cell (%) at diagnosis, time to ASCT, history of prior radiation therapy (XRT), conditioning (TBI v non TBI), cytogenetics (chromosome 13 deletion (Ch13 del) v normal), immunoglobulin subtype and maintenance therapy (yes v no) were analyzed. No pre-transplant characteristic predicted for post-transplant CR. The median PFS in the CR and non CR group was 18 and 15 months respectively (P=0.84). Median OS was 51 months in both groups. In both univariate and multivariate analyses, only history of prior XRT predicted poor PFS (10 v 24 months, P=0.03) and OS (24 v 63 months, P 〈 0.001). The median time from diagnosis to ASCT was not influenced by prior XRT. Cytogenetic data were available in only 69/106 (65%) patients. Ch13 del was found in 24/69 (35%) patients, consistent with its reported incidence in MM. Patients with Ch13 del (n=24) had PFS and OS of 12 and 37 months while patients with normal cytogenetic (n=39) had PFS and OS of 24 and 57 months (P= 0.42 and 0.057, respectively). Conclusion: CR after ASCT does not appear to be a surrogate marker for survival in AA patients. A trend toward inferior OS in AA with Ch13 del was observed as expected. The finding of inferior PFS and OS in patients with prior history of XRT was unexpected and merits further investigation in both AA and non AA patients. Cytogenetic, prior treatment toxicity and other biological risk factors should be considered in conjunction with the CR status when assessing the risk of relapse and survival in AA patients with MM. Disease status at and after ASCT for 106 patients Response Pre-Transplant (%) Post-Transplant (%) Partial remission; PR, Minimal response; MR, Progressive disease PD, not available; NA CR 8 (8) 30 (28) PR 71 (60) 53 (50) MR 17 (16) 19 (18) PD 8 (7) 3 (3) NA 2 (2) 1 (1) Selected Characteristics Characteristic ALL (%) CR group (%) Non CR group (%) P not available; NA, Chromosome 13 deletion; Ch13 del, Radiation therapy; XRT, total body irradiation; TBI Patients, n 106 30 (28) 76 (72) Prior XRT (Y/N) 0.64 Yes 40 (38) 10 (33) 30 (39) No 64 (60) 20 (67) 44 (58) NA 2 (2) 0 (0) 2 (3) Cytogenetics 0.60 Ch13 del 24 (23) 9 (30) 15 (20) Normal 39 (37) 10 (33) 29 (38) Other 6 (6) 2 (7) 4 (5) NA 37 (35) 9 (30) 28 (37) TBI v Non TBI regimen 0.93 TBI 19 (18) 6 (20) 13 (17) Non TBI 87 (82) 24 (80) 63 (83) Number of prior treatment regimens 0.87 1–2 81 (76) 23 (77) 58 (76) 〉 2 22 (21) 6 (20) 16 (21) NA 3 (3) 1 (3) 2 (3)

Description: Abstract 4659 Introduction Large pericardial effusion (LPE) as a manifestation of polyserositis is a known complication of GVHD. Due to its rarity, the incidence and natural history of LPEs are lacking in adult stem cell transplant recipients and current evidence is based on published case reports. Methods We retrospectively evaluated the incidence post-transplant LPE development for all adult patients who underwent transplants at our institution from 2005 to 2008. Results During this period, 858 transplants were performed, 512 autologous and 346 allogeneic (148 related and 198 unrelated). No LPEs were documented in post-autologous transplant patients. One patient developed polyserositis with LPE after allogeneic transplant on imatinib therapy and was excluded from this analysis. Seven patients (2%) who received unrelated transplant developed LPEs a median 229 days (range 42-525 days) post-transplant (Table 1). Only two patients developed large LPEs less than 100 days post-transplant, however in both cases LPEs developed after the second transplant. Six patients (86%) developed biopsy proven GVHD prior to the detection of LPEs; among them 5 (83%) had skin and GI tract involvement and 1 (17%) had GVHD of the liver. Six patients (86%) had concomitant pleural effusions (PEs). No patients had active manifestations of GVHD besides polyserositis at the time of LPE detection. Six patients (86%) required pericardial window (PW) placement with a pericardial biopsy; none had evidence of a malignant or infectious process involving the pericardium. Four patients were alive a median of 172 days (range 20-274 days) post LPE detection and all 4 had PW placed. Out of 4 survived patients, 3 had steroids initiated or increased with a clinical improvement of polyserositis on subsequent follow up in 2 patients and 1 patient had persistent pleural effusions. One patient had a systemic relapse shortly after LPE detection. Three patients died, among them 2 had PW placed and died less than 100 days after LPE detection; the first patient died at day 93 from MRSA pneumonia and the second one died at day 7 from polymicrobial sepsis and multiorgan failure. Both these patients had undergone a second transplant when the LPE occurred. The third patient, who did not receive a PW, died of progressive bronchiolitis obliterans, 542 days after LPE detection, her polyserositis symptoms resolved while on cyclosporine therapy. Conclusion LPE is a rare complication after allogeneic transplant in adults and in our study developed only after unrelated transplant. PW can be safely performed in these patients and polyserositis can be successfully treated with systemic steroids, although patients might continue having polyserositis despite aggressive immunosupression. Abbreviations MUD= matched unrelated donor, S=skin, L=liver, GI=gastrointestinal tract, Bu= busulfan, Flu= fludarabine, TBI= total body irradiation, CVB= cyclophosphamide, etoposide and BCNU Disclosures: Abidi: Merck Pharmaceuticals: Research Funding. Lum:Transtarget Corporation: Founder.