2nd Stem Cell Transplantation Research Articles

Outcomes of Older Patients with Aplastic Anemia Treated with Frontline Anti-Thymocyte Globulin (ATG)-Based Immunosuppressive Therapy

Background: Advances in the treatment of aplastic anemia (AA), such as the addition of eltrombopag (EPaG) to immunosuppressive therapy (IST) and the expanded use of unrelated and haploidentical stem cell transplant (SCT) have steadily improved outcomes. However, little is known about the characteristics and outcomes of patients (pts) ≥ 60 years (yrs) of age with newly diagnosed AA who have been treated with an ATG-based regimen. Presumed low bone marrow (BM) reserves, higher frequency of underlying clonal hematopoiesis, intolerance to therapy, comorbidities, and challenges in proceeding to salvage SCT have led to the speculation that response and survival of these pts to IST may be inferior than their younger counterparts. Methods: We retrospectively analyzed the characteristics and outcomes of pts ≥ 60 yrs of age (OLDER) at the time of diagnosis of AA treated with frontline (F/L) ATG based therapy at our center and compared them to pts < 60 yrs of age (YOUNG) treated with F/L ATG over the same time period. We captured their clinical characteristics, cytogenetic abnormalities, mutations in DNMT3A (D), ASXL1 (A) and TET2 (T), exposure to EPaG, response, time to response (TTR) and survival. Overall response included complete and partial response per the standard definitions. Relapse free survival (RFS) was tabulated from the time of best response to loss of response, 2nd ATG infusion, salvage SCT or death (whichever was earlier) and overall survival was tabulated from the time of response to death from any cause. Results: From Jan 2011-May 2012, 43 OLDER pts were treated as F/L for AA of whom 41 (95%) received ATG based therapy; 68 YOUNG pts were treated as F/L for AA over the same time period of whom 62 (91%) received ATG based regimen. Four YOUNG pts vs. no pts in the OLDER group received upfront SCT, and 2 pts in each group were treated with non ATG based therapy: single agent CSA, EPaG, or alemtuzumab. Comparative baseline characteristics are depicted in Table 1. There were no differences in the baseline WBC, peripheral blood lymphocyte percentage and platelet counts between the ATG treated OLDER and YOUNG groups. Both groups had similar frequencies of cytogenetic abnormalities and PNH clones, though OLDER pts had mutations in D-A-T genes compared to the YOUNG group (62% vs. 38%, p=0.05). Both groups had equal concurrent exposure to EPaG with ATG. Cumulatively 23/41 (56%) pts in the OLDER group had an overall response (OR) compared to 43/62 (70%) pts in the YOUNG group (p=0.1); 11/23 (48%) and 23/43 (53%) responders in each group attained CR respectively. There were no differences in OR rates in both groups based on concurrent EPaG exposure: 61% vs. 46% with and without EPaG, respectively, in the OLDER group (p=0.5) and 74% vs 60%, respectively, (p=0.38) in the YOUNG group. On logistic regression analysis using baseline platelet counts, PB lymphocyte (%), D-A-T mutations, karyotype, and EPaG use as covariates, none affected the odds of OR in the 2 groups. The median TTR was 111 days (range, 10-323 days) and 177 days (51-410) in YOUNG AND OLDER groups, respectively; and this was not affected by EPaG use in either group. At a median follow of 38 months (mos) from ATG initiation (53 mos for the OLDER group and 32 mos for the YOUNG group), the median RFS was 49 mos and 39 mos (p=0.6) and median OS 55 vs. not reached (NR) (p <0.0001) in OLDER and YOUNG groups respectively (Fig.1). Significantly more pts in the YOUNG group underwent a subsequent SCT (19% vs. 5%) due to loss of response/ no response, possibly accounting for the higher OS rates. Rates of transformation to MDS or AML was 5% in both groups. Conclusion: Frontline ATG based IST in older pts with AA is a feasible and safe treatment option with promising response rates of 56% and median RFS more than 4 years; figures which are comparable to younger pts with AA treated with IST. The overall risks of transformation to MDS/AML on long term follow-up remain low (≈5%). Further studies assessing the response of the ATG+EPaG combination in these pts and the possibilities of clonal evolution with time needs to be conducted. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

P1309: DYSREGULATED EXPRESSIONS OF INHIBITORY CHECKPOINT MOLECULES AND THEIR LIGANDS ON T-CELLS AND BLASTS IN AML RELAPSES AFTER STEM CELL TRANSPLANTATION (SCT)

Background: Upregulation of inhibitory checkpoint molecules (ICM) on T-cells and their ligands on leukemic blasts may be a mechanism of acute myeloid leukaemia (AML) relapse after allogeneic stem cell transplantation (SCT). Aims: Better understanding of relapse biology could improve treatment efficacy. Methods: We examined peripheral blood (PB) and bone marrow (BM) samples of 5 AML patients (PTs) relapsing after SCT, and PB of 5 healthy individuals (H), including 2 stem cells donors. ICM (PD-1, CTLA-4) expressions on T-cells and their ligands (CD86, PD-L1, PD-L2) on leukemic blasts were assessed through flow cytometry. PTs’ PB was cultivated with and without “KitM” (GM-CSF+PGE-1) to generate leukemia-derived dendritic cells (DCleu), followed by MLC, enriched by PTs’ or donors’ T-cells. After MLC, immune activation and functionality (degranulation, intracellular cytokine production, blast lysis) was assessed. Results: 1. Whilst all patients showed high expressions of PD-1 on their T-Cells, additional overexpression of CTLA-4 was negatively correlated with responses to relapse treatment. Expression of ICM was low on T-cells from 4/5 healthy individuals (Figure 1). 2. Influence of KitM on ICM/ligand expressions on T-cells/blasts - ICM/ligand expressions on uncultured T-cells/blasts: In contrast to H, PTs presented high co-expressions of CTLA-4 and PD-1 on PB T-cells (Figure 1). In addition, PTs showed high frequencies of PB/BM blasts co-expressing CD86. - DC/DCleu in PB: Generation of DCleu in AML as well as generation of DC in H was successful with KitM pretreated PB vs. Control. - ICM co-expression on T-cells after MLC with KitM pretreated PB: MLC of KitM treated PB enriched with unstimulated PTs T-cells resulted in reduced frequencies of ICM-positive T-cells in 3/5 PTs, and increased frequencies of activated (leukemia specific) T-cells in 3/5 PTs. Beyond, blast lysis was improved in 4/5 samples treated with KitM. Both findings were not observed when PB cells were cultivated in the absence of KitM. 3. Possible impact of ICM profiles on clinical outcome in a particular casePT1 suffered from early relapse both after 1st and 2nd SCT from her healthy father. A role of ICM in relapse mechanisms was suggested by CTLA-4/PD-1 expression on her T-cells and CD86 expression on AML blasts. In addition, >90% of the healthy father’s T-cells expressed CTLA-4/PD-1, which might have contributed to treatment failure. In contrast, T-cells from PT1’s mother presented with low ICM levels (Figure 1), suggesting that the mother might have been a better donor. Stimulation of PT1’s PB cells with KitM generated DCleu, decreased ICM-expressions and increased T-cell activity. KitM pretreated samples also revealed improved blast lysis after MLC. Image:Summary/Conclusion: T-cells and blasts of AML PTs relapsing after SCT uniformly co-expressed ICM and their ligands, which could be a reason for inferior immune responses. High aberrant ICM-expressions, in particular CTLA-4, on donor T-cells could be responsible for relapse after SCT by inactivating antileukemic immune reactions. Hence, checkpoint-inhibitory antibodies might represent a specific therapeutic option in these patients. Further, interactions between ICM-expressions on healthy (fresh) donor T-cells could have an impact in therapy responses and should be evaluated in donor selection. Finally, generation of DCleu by treatment with KitM triggers immune responses in MLC alongside with reduced ICM-expressions on T-cells, possibly reducing their inhibitory effects and therefore improving antileukemic responses.

PB2098: ‘REAL-WORLD’ TREATMENT PATTERNS AND PATHWAYS OF SECOND LINE DIFFUSE LARGE B-CELL LYMPHOMA PATIENTS IN UK, CANADA, FRANCE, GERMANY, ITALY AND SPAIN USING A PROSPECTIVE SURVEY OF PHYSICIANS

Background: Diffuse large B-cell lymphoma (DLBCL) is the most prevalent form of Non-Hodgkin Lymphoma, representing 25% to 35% of cases annually1. Despite this, there is a lack of research into treatment patterns of real-world patients, especially in the 2nd line (2L) setting. Aims: To determine the ‘real-world’ treatment patterns and treatment pathway of DLBCL patients treated at the second line, with a focus on patients who are ‘fast progressors’ as defined below. Methods: In this study ‘real-world’ data were drawn from the Adelphi DLBCL Disease Specific Programme™ (DSP), a point-in-time survey of clinicians and their next 6 presenting patients with DLBCL. The survey was conducted in France, Germany, Italy, Spain, the United Kingdom (UK) and Canada between Jan-May 2021. Patients who were refractory/relapsed <12 months from 1st line (1L) therapy, eligible for a stem cell transplant (SCT) at initial relapse/refractory, had an ECOG performance score of 0-1 and had no history of hepatitis B or C or CNS events were studied. Results: 47 patients met the criteria. Mean age of the patients was 58.0 (SD: 11.7) years, 68% were male and 26% were retired. At 1L, 94% of patients received R-CHOP with a median of 171.2 days (IQR: 61.0-247.5) between the end of their 1L and the start of their 2L treatments. All patients received salvage chemotherapy (SC) in the form of R-ESHAP, R-DHAP or R-GDP in most cases (Figure 1). 49% of the patients had a complete response (CR) to SC, 21% had partial response (PR), 30% stable/no response. In total 26 (55%) patients received high-dose therapy-SCT (HDT-SCT). Figure 1 shows the response to 2L treatments across patients and indicates why some patients did not progress to SCT despite being previously eligible. Patients receiving SCT had a median time from 2nd line SCT to relapse/refractory of 189.0 (IQR: 94.0-333.0) days. 54% of patients received chimeric receptor antigen T-cell (CAR-T) therapies at 3L (Figure 1), with the majority having previously received SCT. CAR-T use was higher in UK (67%), Canada (63%) and Germany (60%) than in other regions. Image:Summary/Conclusion: Despite all patients with DLBCL observed being SCT eligible at their first relapse, only half of these patients went on to receive an SCT. Unacceptable response to SC, progressive disease and patient choice were common reasons for not going on to receive SCT. Despite seemingly favourable responses to SCT, these patients progressed quickly and were likely to receive a CAR-T treatment in 3L, indicating an unmet need and highlighting potentially high resource use and substantial impacts to quality of life.

Cost-Effectiveness Analysis of CTL019 for the Treatment of Pediatric and Young Adult Patients with Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia in the United States

Introduction: CTL019 (tisagenlecleucel) is a chimeric antigen receptor T-cell therapy (CAR-T)for the treatment of relapsed or refractory (r/r) pediatric/young adult patients (pts) with B-cellacute lymphoblastic leukemia(ALL). Current treatments for r/r pediatric ALL (pALL) include clofarabine monotherapy (Clo-M), clofarabine combination therapy (Clo-C), blinatumomab (Blin), other salvage chemotherapies (SC), and allogeneic stem cell transplant (SCT). The prognosis for r/r pALL is poor and SCT is considered as the only potentially curative option. However, less than 50% of pts with multiple relapses achieve CR from existing treatments, and even fewer are eligible for and ultimately receive SCT. CTL019 is a potentially promising treatment option for pALL pts with multiple relapses, with complete remission (CR) rates between 69-95% based on data from phase I/II trials (ELIANA, ENSIGN, and CHP959). The current study aimed to compare the life year (LY) and quality-adjusted life year (QALY) gained using CTL019 vs. comparator treatments, and estimate the value-based prices for CTL019 at different incremental (incr) cost effectiveness ratios (willingness-to-pay [WTP] thresholds) for the treatment of r/r pALL from a US third-party payer perspective.Methods: A partitioned survival model with monthly cycle and 3% discount rate was developed to assess the incr cost effectiveness of CTL019 compared to Clo-M, Clo-C, Blin, SC, and 2nd SCT, for the treatment of r/r pALL over a 20-year time horizon. The model included three health states: event-free survival (EFS), progressive disease, and death. Efficacy inputs (overall survival [OS] and EFS) for CTL019 were based on pooled data of three phase I/II single-arm trials. Efficacy inputs for the comparators were based on publications of clinical trial and SCT registry that enrolled similar pts (although with notable differences); Kaplan-Meier curves of OS and EFS, where available, were used to reconstruct proxy patient-level data. Parametric models were fitted to extrapolate EFS and OS for each treatment until year 5. Afterwards, the model assumed no additional progression, and that all pts alive at 5 years would experience the same mortality risk consistent with long-term survivors of pALL. Pre-treatment (lymphodepleting for CTL019 and induction therapy for SCT) and treatment costs (drug, administration, and hospitalization), adverse event (AE) costs, subsequent SCT costs, and medical costs for each health state were obtained from public databases and literature. All costs were inflated to 2016 USD. Utilities for each health state and disutilities for AEs were based on literature. Incr LY, incr QALY, and incr cost per QALY gained were estimated comparing CTL019 to each comparator. Value-based prices, defined as the price that would achieve the incr cost effectiveness ratios (WTP thresholds) of $100,000, $150,000, $200,000, and, $300,000 per QALY gained, were calculated for CTL019 vs. each comparator. Deterministic sensitivity analyses (DSA) were performed to test the robustness of the results.Results: Over a 20-year time horizon, treatment with CTL019 led to an increase of 4.62, 3.79, 3.68, 2.08 and 2.05 in discounted LYs and an increase of 4.29, 3.64, 3.64, 2.32 and 2.31 in discounted QALYs relative to Clo-M, Clo-C, Blin, SC, and SCT respectively. CTL019 value prices to reach a specified incr cost effectiveness ratio (WTP threshold) of $150,000/QALY ranged from $604,289 to $779,487 across comparators. The value prices ranged between $951,745 and $1,364,525 when the incr cost effectiveness ratio (WTP threshold) was set at $300,000/QALY (Table 1). Results from the DSA generally supported the base case findings, with the largest variation observed when time horizon and the parametric survival functions were varied. Compared to Clo-M, Clo-C, Blin and SC, CTL019 trials enrolled more severe pts who had failed more lines of prior therapies, which suggested that the estimated CTL019 LY and QALY benefits were conservative.Conclusions: Compared to existing treatments, CTL019 showed promising efficacy results for the treatment of pediatric/young adult ALL pts, with incr QALY gains of 2.31-4.29. Using specified incr cost effectiveness ratios (WTP thresholds) from $100,000/QALY to $300,000/QALY, the value-based prices for CTL019 ranged from $488,470 to $1,364,525. [Display omitted] DisclosuresHao:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Eldjerou:Novartis Pharmaceutical Corporation: Employment. Yang:Novartis Pharmaceutical Corporation: Other: Author is an employee of Analysis Group, which received consulting fees from Novartis for this study; Analysis Group Inc.: Employment. Qi:Novartis Pharmaceutical Corporation: Other: Author is an employee of Analysis Group, which received consulting fees from Novartis for this study; Analysis Group Inc.: Employment. Globe:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership.

Outcome of Patients with Myelofibrosis Relapsing after Allogeneic Stem Cell Transplant: A Retrospective Study By the Chronic Malignancies Working Party of EBMT

▪Background: Over the last decade, there has been a significant increase in the number of patients with Myelofibrosis (MF) undergoing allogeneic stem cell transplantation (SCT). However, scarce information exists on the outcome and management of those patients who relapse following SCT. Moreover, the management of relapse occurring post-SCT is often heterogeneous and ranges from palliation to intensive salvage approaches. We therefore conducted a retrospective EBMT registry analysis of adult MF patients who relapsed following first SCT episode.Results: A total of 1216 adult patients (997 (82%) with Primary MF (PMF) and 219 (18%) with secondary MF (sMF)) underwent 1st allogeneic SCT between 2000 and 2010. A total of 251 patients from this cohort (206 with PMF and 45 with sMF) had conformed relapse ≥ day 30 after HSCT and were included in the analysis. Within this relapse cohort, there were 163 males and 88 females; median age was 55 years old (range 21.5-70 years). A total of 84 patients (33%) had received Myeloablative Conditioning (MAC) and 167 patients (67%) Reduced Intensity Conditioning (RIC). Regarding donor type, there were 123 matched siblings (49%) and 128 unrelated donors (51%). Acute GVHD (aGVHD) status was available for 243/251 (97%) patients; no aGVHD was evident in 143 patients, Grade I-II aGVHD 76 patients, Grade III-IV aGVHD 22 patients and 2 patients with aGVHD ungraded.The median time to relapse after SCT was 7.1 months (range 1-111 months). The median Overall Survival (OS) from the time of relapse was 17.7 months (95% Confidence Intervals 11-24). Collectively, there was a significant difference in survival outcome for those relapsing > 7.1 months post-SCT (median survival 30.3 months post relapse) compared to those relapsing within 7.1 months following the initial SCT episode (median survival 7.9 months post relapse; p<0.001). Absence of aGVHD or grade I aGVHD only was associated with a trend towards improved survival following relapse compared to those with Grade II-IV aGVHD (p=0.12). For PMF, disease duration prior to SCT did not significantly affect outcome post relapse. Heterogeneous practice existed as regards management of the relapse episode, with considerable variation in median survival (MS) estimates. 47 patients received Donor Lymphocyte Infusions (DLI) alone (MS 76 months); 21 had chemotherapy alone (MS 23 months) whereas 14 patients had DLI combined with chemotherapy (MS 13.6 months). As regards 2nd allografts: 53 patients underwent 2nd allograft alone (MS 23.6 months) and 26 underwent DLI and 2nd SCT (MS 53.9). In 90 patients active management -if any- was not documented (most likely many were palliative) but represented a very poor risk group with a MS of only 4.8 months. Overall, there was a significant improvement in OS post relapse for those undergoing 2nd SCT (n=79) versus those who did not have a 2nd SCT (n=172; p=0.019).Conclusions: This analysis represents the first study to define the outcome of MF patients who undergo relapse following allogeneic SCT. Treatment of relapse presents huge challenges and the heterogeneous management strategies highlighted above reflects current practice where approaches range from palliation through to intensive chemotherapy and 2nd SCT. It is clear from this analysis that early relapse has a much worse prognosis than those who relapse later than 7.1 months post-SCT. There is a definite survival advantage for those who undergo DLI and/or a 2nd SCT procedure, although we acknowledge that those patients undergoing a 2nd SCT represent a highly selected group who are fit enough to undergo such intervention. Moreover, how relapse management practice will change in the era of novel therapies such as JAK inhibitors to bridge towards 2nd SCT is currently unclear and requires evaluation in prospective studies. DisclosuresMcLornan:Novartis: Research Funding, Speakers Bureau. Finke:Riemser: Research Funding, Speakers Bureau; Neovii, Novartis: Consultancy, Research Funding, Speakers Bureau; Medac: Research Funding. Craddock:Celgene: Consultancy, Honoraria, Research Funding; Pfizer: Speakers Bureau; Sunesis: Honoraria; Johnson and Johnson: Consultancy. Apperley:BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ARIAD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Niederwieser:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Transfer of Ex Vivo Expanded NK and γδT Cells from Untouched Posttransplant PBMCs to Clear Minimal Residual Disease in Acute Myeloid Leukemia

GMP-grade NK cell expansion for clinical purpose has been demonstrated feasible and safe. Here we share our pilot data on posttransplant immunotherapy with ex vivo expanded NK cells to treat minimal residual disease in a pediatric patient with posttransplant relapsed myeloid leukemia. Our patient, a 13 year old boy who underwent 2nd allogeneic stem cell transplantation (haploidentical stem cell transplantation from his mother) due to posttransplant relapsed acute myeloid leukemia. After the 2nd haploidentical stem cell transplantation (SCT) minimal residual disease (MRD) was detected by multiparameter flow cytometry and by two molecular markers CALM-AF10 fusion transcript and a NRAS-mutation. For posttransplant compassionate use immunotherapy by NK cell transfer, NK cells were expanded from untouched isolated PBMCs of the patient post 2nd haploidentical SCT. GMP-grade expansion of the NK cells was done under static conditions in our GMP-facility. Isolated PBMCs were pooled with 100Gy irradiated K562mb15 4-1BBL feeder cells (kindly provided by Dario Campana) in a proportion of 1:20 (NK to K562mb15 4-1BBL). PBMCs and K562mb15 4-1BBL were seeded in conventional cell culture flasks (175cm2) at a density of 1.1E6 cells/ml. Cell culture media contained RPMI1640 supplemented with 10% AB-human serum, 1% L-glutamine and 100IU Proleukine® IL2/ml. Cell culture was monitored daily for cell number, white blood cell differentiation, pH of the cell culture, glucose metabolism, lactate production and microbial sterility testing at the beginning and the end of the expansion period. The cell product was harvested on day 15-17. Fresh isolated PBMCs and the expanded NK cell product were characterized by flow cytometry. NK cells were expanded >1000 fold (3.1 and 3.4 log-fold) in 14-17 days. The product contained a total number of 9.8E9 and 19.9E9 cells, which was 328 and 665E6/kgBW. The expansion protocol supports NK and γδ T cell expansion whereas the number of αβ T cells stays stable. Cytotoxicity assay against various targets revealed excellent cellular cytotoxicity and antibody dependent cellular cytotoxicity. To prevent relapse in our patient with posttransplant MRD positivity, NK cells from the patient post 2nd haploidentical SCT were expanded for cellular immunotherapy. 2 weeks post 1st NK cell transfer (day +170) the patient achieved complete MRD response in the bone marrow. Unfortunately the patient showed detectable MRD one month later. Therefore another NK cell expansion and transfer was done. 2 weeks post 2nd NK cell transfer (day +232) the patient again achieved complete MRD response in the bone marrow and is in complete molecular remission ever since (day +340). The NK cell products were tolerated well. Transient coughing and temporary increase of temperature were registered. Both, in vitro and in vivo effect of the NK cell product were documented. Clinical use of expanded and activated NK cells and γδ T cells can induce molecular remission in posttransplant MRD positive acute myeloid leukemia. DisclosuresNo relevant conflicts of interest to declare.

Upfront Tandem Autologous Stem Cell Transplant Is Superior to Autologous or Allogeneic Stem Cell Transplant After Failure of a 1st Autologous Transplant,

Abstract 4094Disease progression remains the main cause of treatment failure after autologous stem cell transplant (SCT) in patients with multiple myeloma (MM). It is unclear what is the best salvage therapy after failure of a 1st autologous SCT in MM.We performed a retrospective study comparing 2nd autologous (auto-auto) versus 2nd allogeneic (auto-allo) SCT in patients progressing or relapsing after their 1st autologous SCT and compare their outcomes with patients receiving sequential planned double autologous (tandem) SCT as part of their upfront therapy for MM.The data was collected from CIBMT reports and medical records at Texas Transplant Institute from 2001 to 2010. Patient's characteristics and outcomes are described in table 1. Response to 1st and 2nd SCT was determined at 100 days post transplant and classified as good (stringent complete remission [sCR], complete remission [CR], very good partial remission [VGPR]) or poor (partial remission [PR], stable disease [SD] or progressive disease [PD]). All patients in the auto-allo group received a reduced intensity regimen. 20% of the patients in the auto-auto group received maintenance therapy after their 1st transplant with either thalidomide or lenalidomide and 10% of the patients in the auto-allo group received maintenance therapy after their 1st transplant either with thalidomide. None of the patients in the tandem group received maintenance therapy. The overall survival was calculated from the date of the 2nd transplant to the known date of death in all groups. Patients in the auto-allo group (15.9 months) had a worse median survival than in the auto-auto group (39 months) with both of them having a worse survival compared to patients undergoing tandem transplants (64.3) (p value = 0.003) (FIGURE).Table:PATIENT CHARACTERISTICS AND OUTCOMESTandem (n=29)Auto-Auto (n=32)Auto-Allo (n=10)Median age, years (range)62 (41–78)62.5 (45–81)54 (43–63)Median days from diagnosis to 1st transplant224.5 (93–1344)226 (117–1074)254.5 (101–416)Median days from 1st to 2nd transplant149 (99–189)847 (210–4158)350 (88–1281)Median total CD34+ cell infused 1st transplant3.29 (2–12)5.87 (2–28)6.03 (2–14)2nd transplant3.22 (2–9)4.47 (2–19)5.25 (3–11)Median WBC engraftment11 (9–13)11 (9–47)N/AMedian Platelet engraftment16 (10–19)15 (10–23)N/ACytogenetics High Risk17%3%10%ISS at 1st transplant I31%41%40%II34%12%0III14%6%10%ISS at 2nd transplant I48%53%40%II17%9%0III10%13%10%Response to 1st transplant Good10%63%70%Poor80%25%20%Response to 2nd transplant Good52%47%30%Poor41%41%70%Median Followup (months)57.1 (3.4–76.7)24.6 (10.5–87.8)48.0 (31.9–64.0)Maintenance Therapy after 1st transplant028%10% [Display omitted] Forward stepwise Cox regression analysis was used to measure factors affecting overall survival. Factors used for analysis included age, cytogenetics (high risk = mutated p53, t(14;16), t(4;14), del 13), International Staging System (ISS) before 1st and 2nd SCT, use of maintenance therapy after 1st SCT, days from diagnosis to 1st SCT and days from 1st to 2nd SCT, CD34+ cells infused at 1st and 2nd SCT. Age and ISS of III at 2nd transplant were identified as factors affecting survival in the auto-auto group (hazard ration of 1.081 and 5.700, respectively).In conclusion, overall survival after salvage from 2nd autologous stem cell transplant is longer than after a 2nd allogeneic transplant. Upfront, planned tandem autologous stem cell transplant is superior to both salvage strategies. Larger, randomized trials are needed to confirm these results. Disclosures:Shaughnessy:Otsuka: Honoraria, Speakers Bureau; Millenium: Honoraria, Speakers Bureau; Genzyme: Honoraria, Speakers Bureau.

A Phase I-II Dose Escalation Trial of Clofarabine Plus Melphalan and Thiotepa Followed by Unmodified Allogeneic Stem Cell Transplant (SCT) for the Treatment of High Risk or Advanced Acute Leukemia

AbstractAbstract 2354High-risk or advanced acute leukemias are associated with poor outcome even with the use of stem cell transplantation (SCT) with or without total body irradiation (TBI). Based on encouraging results with the use of clofarabine (CLO) for reinduction treatment of acute leukemias, we have developed a phase I/II protocol using this agent with melphalan (Mel) and thiotepa (Thio) followed by unmodified SCT for the treatment of patients (pts) with high-risk (HR) leukemias. To date, 28 consecutive pts were treated on, or as per protocol, with 26 pts evaluable for follow-up. There were 15 males and 11 females aged 1–58 years (median 5.3 years). Cytoreduction consisted of CLO at dose level I of 20 mg/m2/day × 5 days (n=23) or at dose level II of 30 mg/m2/day × 5 (n=3), Thio 10 mg/Kg/day × 1 day and Mel 70 mg/m2/day × 2 days. Graft-versus-host disease (GvHD) prophylaxis consisted of tacrolimus and mycophenolate mofetil (MMF), or tacrolimus and methotrexate. Twenty pts had acute lymphoblastic leukemia (ALL) in complete remission (CR1; n=5), CR2 (n=5), CR3 (n=9), or relapse (n=1). Five pts had acute myeloid leukemia (AML), in CR1 (n=1), CR2 (n=2), or CR3 (n=2). One pt had myelodysplastic syndrome (MDS) in RAEB. For the pts with ALL in CR1, very HR features included: Infant MLL (N=2), Philadelphia (Ph1) chromosome (N=2) and Induction failure (N=1). For the pts with ALL in CR2, HR features included: Infant MLL (N=1), 2nd SCT (N=1), Ph1 and 2nd SCT (N=2), while 1 pt had prior CNS infarcts precluding the use of TBI. The one pt with AML in CR1 had M7-AML. This was a first SCT for 14 pts, a 2nd SCT for 11 pts and 3rd SCT for 1 pt, with time from previous SCT to the present one being 5–73 months (median 11.3 mo) for those 12 pts. Donors were HLA-matched siblings (n=8), HLA matched unrelated donors (n=8), or HLA mismatched unrelated donors (N=10). Stem cell grafts were bone marrow (n=12), peripheral blood (n=7) or double cord blood (n=7) stem cells.Twenty four of the 26 evaluable pts engrafted, while 2 pts died prior to engraftment. Toxicity of the SCT cytoreduction included elevation of hepatic transaminases in 17 of 26 evaluable pts (AST elevation of 5–19 fold and ALT elevation of 7–16 fold), with a subsequent normalization in all pts. Mucositis was mostly at acceptable grade 1–2 levels. Two pts developed a syndrome of renal and hepatic insufficiency leading to hepatic veno-occlusive disease (VOD) (1 pt at each of the 2 dose levels). Non-relapse mortality included: VOD (N=2), infections (N=3), treatment related sarcoma, a malignancy secondary to the irradiation received with a prior transplant (N=1).With a follow-up of 3–57 mos (median 21 mos), 15 of the 26 pts are alive, disease-free. Five pts relapsed and 4 died subsequently of disease, while 6 pts died of non-relapse morality. Overall (OS) and disease-free survival (DFS) at 2 years were both 58%. DFS was 56% for pts > 18 years and 53% for pts < 18 years (p =0.36); it was 64% for recipients of a first HSCT and 41% (p=0.97) for recipients of a second or third HSCT. Five pts (4 recipients of unrelated donor SCT; 3 from mismatched donors) developed Grade 2–4 acute GvHD. Four of these pts went on to develop chronic GvHD. Immune reconstitution was rapid; for the evaluable pts, it included absolute CD4 counts > 200 cells/L at 1–3 mos for 15 pts and at 4–8 mos for 4 pts.This cytoreductive regimen represents a promising approach for the transplantation of patients with high risk acute leukemias. It was well tolerated for pts requiring a second SCT and is also associated with rapid immune recovery. Ultimately, a large scale study would need to be done to determine if this approach could offer equal or superior results to TBI containing regimens for ALL or AML. Disclosures:No relevant conflicts of interest to declare.

Outcomes Following Salvage Autologous Stem Cell Transplant for Multiple Myeloma

AbstractAbstract 1353 Background:High-dose therapy and stem cell transplant (SCT) has improved the progression-free and overall survival of patients with MM. However all patients eventually develop disease recurrence. In the era of effective novel agents (such as bortezomib, lenalidomide and thalidomide), the optimal salvage strategy is undefined. Methods:We retrospectively analyzed the outcomes of patients who underwent salvage melphalan-based SCT for relapsed MM at Memorial Sloan-Kettering Cancer Center. Results:Between 1995 and 2010, 53 patients with MM received a second autograft for relapsed disease at our center. Conditioning was with melphalan 100 (N=8), 140 (N=18) or 200mg/m2 (N=27). The median age at 2nd SCT was 60 years (range 36–75) and 62% (N=33) were male. Twenty-three percent (N=12) had high risk cytogenetics (including t(4;14), +1q, p53 loss, or del 13q by karyotype) while 77% had standard risk or cytogenetic studies were not available. The median interval between SCTs was 34 mos (range 6.2–88.7). Of evaluable patients, 79% (37/47) had chemotherapy sensitive disease prior to salvage SCT and 21% were chemoresistant. Response was assessed at 2–3 mos post-SCT and 70% of evaluable patients achieved >= partial response (PR), 17% had stable disease (SD), and 13% progressed despite salvage SCT. Following salvage SCT, 6 patients received maintenance therapy and 7 went on to allogeneic SCT. The median progression-free survival (PFS) following second autograft was 13.1 mos (95% CI: 10.1–18.4). Patients with high-risk cytogenetics at the time of second SCT had higher risk of progression (HR 2.5, 95% CI: 1.15–5.24, P = 0.02) compared to patients who had standard risk cytogenetics. However, interval from first to second SCT, chemosensitivity, and response following second transplant had no significant impact on PFS. The median OS following salvage SCT was 24 mos (95% CI: 18 – 41) and was superior for patients with standard versus high risk cytogenetics (HR 3.51, 95% CI: 1.57–7.86, P = 0.002). Again, interval since prior SCT and response following salvage SCT did not impact survival. Chemosensitivity was associated with reduced risk of death (HR 0.42, 95% CI: 0.18–0.96, P = 0.04). Although the sample size was small, the OS was not significantly extended for patients who received maintenance therapy or allogeneic SCT following salvage autologous SCT. Conclusion:Salvage SCT is an effective strategy for relapsed MM following initial autograft and results in responses in the majority of patients. Although OS and PFS following salvage SCT is similar to other salvage strategies, novel conditioning regimens and/or effective maintenance strategies may improve this approach. Disclosures:Comenzo:Millenium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Elan Pharmaceuticals: Consultancy; Genzyme: Research Funding; Celgene: Research Funding; Ortho: Research Funding.

Implication of Faster Neutrophil and Lymphocyte Recovery after Allogeneic Stem Cell Transplantation (SCT) in Children with Leukemia

The repopulating neutrophils and lymphocytes after allogeneic SCT have an important role, not only on the prevention of serious infections in the early transplantation period, but on killing the residual leukemic cells by graft versus leukemia (GVL) effect. Previous studies have suggested that earlier neutrophil recovery was associated with less infections and better survival, while earlier lymphocyte recovery was associated with a lower relapse and a better survival in adult patients. The aim of this study was to compare the impact of neutrophil and lymphocyte recovery after SCT on predicting the survival, relapse, and GvHD in children with hematologic malignancies. We retrospectively evaluated 69 children transplanted for ALL (n=34: CR1, 22; CR2, 10; > CR2, 2), AML (n=26: CR1, 19; secondary AML, 4; > CR1, 3), chronic leukemia (n=7: CML, 6; CEL, 1) and JMML (n=2) at the Chonnam National University Hospital between Jan. 1996 and Mar. 2008. Conditioning regimes were TBI-based (n=41), and non-TBI based (n=28). Stem cell sources were: BM (n=46), PBSCs (n=10), UCB (n = 12), and BM + PB (n=1). Matched sibling donor was used in 26, while unrelated donors in 43. Three AML patients who received the 2nd allogeneic SCTs following autotransplants were included. The patients were grouped according to the absolute neutrophil count (ANC) and absolute lymphocyte count (ALC) at D+21 and D+30. The best discriminating cutoff values for ANC and ALC were 1,000/μL and 500/μL, respectively. The groups were: Low ANC at D+21 (LNC21, n=25) vs. High ANC at D+21 (HNC21, n=44); Low ANC at D+30 (LNC30, n=15) vs. High ANC at D+30 (HNC30, n=54); Low ALC at D+21 (LLC21, n=28) vs. High ALC at D+21 (HLC21, n=41); Low ALC at D+30 (LLC30, n=19) vs. High ALC at D+30 (HLC30, n=50). The patients were 41 males and 28 females. The median age at transplant was 7.1 years (range, 0.4–18). The median day of neutrophil engraftment (≥ 1,000/μL) was D+21 for LLC21 vs. D+16 for HLC21 (P =.001); and D+20 for LLC30 vs. D+17 for HLC30 (P =.02), respectively. The median day of platelet engraftment (≥ 20,000/μL) was D+38 for LLC21 vs. D+19 for HLC21 (P =.04); and D+40 for LLC30 vs. D+22 for HLC30 (P =.07), respectively. The HNC21 and HNC30 group showed a better survival than LNC 21 and LNC30 group, but statistically not significant (69% vs. 58%; 67% vs. 59%, respectively). The HLC30 group exhibited a better 5 year overall survival (71% vs. 53%, P =. 04) and event free survival (72% vs 53%, P =. 06) than LLC30 group. The LNC21 group was associated with a high incidence of aGvHD (36% vs. 14%, P =. 03), but the incidence of Gr II-IV aGvHD and cGvHD was not different by the ALC counts. Relapse rate was not different between ANC and ALC groups. Six of 15 (40%) in LNC30 and 15 of 54 (28%) in HNC30 died, while 9 of 19 (47.4%) in LLC30 and 12 of 50 (24%) in HLC30 died (P = NS). In this study, we found that lymphocyte recovery ≥ 500/μL on D+30 was associated with better survival, faster myeloid and platelet engraftment without increasing the incidence of GvHD or mortality. Also faster neutrophil recovery ≥ 1,000/μL on D+21 was associated with a lower incidence of aGvHD. However, faster lymphocyte recovery was not translated into decreased relapse rate. Further studies incorporating larger number of cases and longer follow-up are warranted in children with leukemias.

Optimal Thalassemia Free Survival and Minimal Regimen Related Toxicity in 50 Consecutive Transplants of High Risk Beta Thalassemia Pediatric Patients Using Myelablative Therapy with Intravenous Busulphan.

In the developed world, the survival and quality of life of patients with beta thalassemia (Bthal) has dramatically improved with optimization of blood transfusions and iron chelation. By contrast, in countries with limited resources most affected children die before the age of 20 because of the unavailability of safe blood products, expensive iron chelating drugs and inadequate management of co-morbidities. For these patients allogeneic stem cell transplantation (SCT) from matched donors offers a cure with low morbidity and mortality. Between June 2005 and May 2008, 47 consecutive Bthal patients underwent SCT from an HLA identical sibling in our center, among these, 3 patients underwent 2 SCTs. Median age was 8 years (2–15), country of origin: Lebanon (9), Iraq (19), Palestine (3), Syria (16). One pt was classified as Lucarelli class I, 24 as class II and 22 as class III. Most patients had severe iron overload evidenced by irregular iron chelation (83%), median ferritin 2973 (956–14280), median liver iron concentration 22 mg Fe/g (6.9–95.7). Most patients had liver toxicity due to iron overload and hepatitis evidenced by median ALT 71 (12–545), AST 59 (18–371), liver fibrosis Ishak 3 (0–5), HepC pos 16/47 (34%). Patients had inadequate transfusional management evidence by a median pre-transfusion Hb of 8 g/dL and anti HLA antibodies in 81% pts. Class I-II patients were conditioned with a regimen based on iv busulphan (iv Bu, Busilvex®, dosage according to weight, adjusted from the 5th dose to a target AUC 1200 umol/min) and cyclophosphamide (Cy) 200mg/kg (n19) with the addition of thiotepa (TT 10mg/kg) if <4 years (n6). Class III pts received a preconditioning based on hydroxiurea and azathioprine followed by fludarabine (Flu) 100mg/m2, iv Bu and Cy 160mg/kg (n6) or, from April 2007, Flu 150mg/m2, iv Bu, Cy 160 mg/kg and Atg (Thymoglobuline®) 7,5mg/kg (n16); patients receiving a 2nd SCT following graft rejection (n3) received preconditioning followed by Flu 150mg/m2, iv Bu, Cy 200 mg/kg, TT 10 mg/kg and Atg Sangstat 7,5mg/kg. Anti seizure prophylaxis consisted of clonazepam; due to liver disease all patients received anti VOD/SOS prophylaxis with oral defibrotide 40 mg/kg. GVHD prophylaxis consisted of cyclosporine A (CyA) and short course methotrexate, in addition methylprednisolone for 30 days was given to pts not receiving ATG. Thirtythree patients (66%) achieved Bu AUC in the expected range of 900–1500 umol/min following the 1st dose. Seventeen patients (34%) required dose adjusted because either above (n9) or below (n8) the expected range. The source of stem cells was unmanipulated bone marrow from an HLA identical sibling; median CD34 cells were 8x10^6/kg (3.3–19), CD3+ cells 73x10^6/kg (36–117). Fourtyseven patients engrafted with donor cells with median ANC take on day 19 (12–39) and median PLT take on day 17 (13–54). Three class III patients had primary graft failure, among these 2 reconstituted with autologous cells and 1 died in aplasia. Post transplant toxicity was mild and characterized by: hemorrhagic cystitis (n4), reversible CyA related posterior encephalopaty (n3), VOD/SOS (n1), grade II-IV stomatitis (n7), reversible lung infiltrates of unknown origin (n4), CMV reactivation requiring preemptive treatment (n23), FUO in aplasia (n33), MOF and death (n1). The incidence of acute GvHD II-IV was 5/47 evaluable patients (4 grade II, 1 grade III). Limited chronic GvHD was observed in 3/47. At a median follow-up of 528 days (112–936), 46/47 patients (98 %) are alive with a 100% Lansky score. Current thalassemia free survival is 94% of which 100% in class I-II pts and 86% in class III. In conclusion, in this population of high risk thalassemic it is recommended to perform Bu pharmacokinetic studies to avoid excessive toxicity or ineffective myeloablation. With appropriate dose adjustment, a myeloablative conditioning based on iv Bu resulted in limited regimen related toxicity and excellent thalassemia free survival in patients affected by Bthal coming from countries with limited resources.

The Use of alpha Interferon To Augment the Graft-Versus-Leukaemia Effect of 2nd Stem Cell Transplants and Donor Lymphocyte Infusions in High Risk Paediatric Leukaemias.

Childhood leukaemia which is refractory to chemotherapy or which relapses early following stem cell transplantation (SCT) has a very poor prognosis, with few patients becoming long-term survivors. Establishing limited graft-versus-host disease (GVHD) in an attempt to exert a graft-versus-leukaemia (GVL) response in these patients remains the only curative option. Second SCT procedures and/or donor lymphocyte infusions (DLI) have achieved some success but the pace of acute leukaemia is often too fast and the occurrence of GVHD/GVL too unpredictable to achieve this goal. We postulated that the addition of alpha interferon (alphaIFN) might induce/augment and control GVHD/GVL in this group of patients and so improve outcome. Thirteen patients underwent initial SCT, for cALL CR2 (n=1), Philadelphia positive ALL CR1 (5), MDS/AML (2), refractory AML (2), and CML (3), with unrelated (9) or sibling donors (4). Eight patients subsequently had a frank haematological relapse and 4 patients a molecular relapse of their leukaemia at a median of 10 months (2–18 months) from 1st SCT. Six patients underwent a 2nd SCT from the same donor, all with reduced intensity conditioned regimes; all received alphaIFN when GVHD did not occur after early withdrawal of immunosuppression. One (ALL CR2) received DLI 2 months after 2nd SCT for mixed chimerism. A further six patients received DLI plus alphaIFN, 3/6 together with low dose DLI (<106/kg); 3/6 had previously received108/kg DLI alone without response. One patient with refractory AML received alphaIFN in conjunction with the initial transplant. The dose of alphaIFN was escalated from 3–5 megaunits/m2 subcutaneously 3–5 days per week as tolerated and continued in the absence of GVHD for up to one year. 3 patients (CML) received concomitant therapy with Glivec, which has now been stopped. Following therapy, 9/13 (69%) patients developed aGVHD: Grade I (1), grade II (4), grade III (4); and 7/11 evaluable patients cGVHD: limited (4), extensive (3). 8 of 13 (62%) remain well and in remission, a median of 23 months (range 12 to 100) from alphaIFN therapy. Five have died: 2 from relapse, one from lung GVHD, one from idiopathic pneumonitis and one from aspergillus infection. Two of 8 surviving patients have ongoing cGVHD requiring immunosuppressive therapy. This data shows promising results for the use of alphaIFN to augment GVL responses in patients with high-risk leukaemia not cured with standard transplant procedures with 62% disease free survival and minimal residual symptoms. Further analysis is warranted.

Short Term Outcome after Allogeneic Stem Cell Transplantation in 70 Cases of Severe Aplastic Anaemia.

Allogeneic stem cell transplantation (SCT) from HLA matched sibling donor is the standard treatment option in younger patients with severe aplastic anaemia (SAA). In the current study outcome of 70 patients with SAA undergoing allogeneic SCT at our institution from July 2001 to June 2007 is presented. Median follow up time was 727 days (range 100–2187). Three patients received 2nd SCT due to graft failure or rejection so actual number of SCT in the patients was 73. Median age of the patients was 16 years (range 5–38), 55 males, and 15 females. Seventeen had major ABO mismatch while sex mismatch in the form of female donor to male patient was present in 23 cases, 7 had both major ABO and sex mismatch. Sixty four patients were CMV positive while 6 had CMV negative status. Conditioning regimens included; cyclophosphamide (Cy) 200 mg/kg with either antilymphocyte globulin (ALG) 45 mg/kg (n=33) or antithymocyte globulin (rabbit ATG) 11.25 mg/kg (n=26); Cy plus Campath 100 mg (n=6), fludarabine 150 mg/m2 plus Cy 300 mg/m2 and ATG (n=8). All patient undergoing 2nd transplant received conditioning with Cy, fludarabine and ATG. GVHD prophylaxis was given with cyclosporin (CSA) plus prednisolone (41) with or without short course of methotrexate (29). Patients received PBSC (10) or bone marrow (12) alone or both (48). Mean mononuclear and CD34+ cell doses were 5.59 x 108/Kg and 4.8 x 106/Kg respectively. Median time to neutrophil recovery was 11 days (range 7–24). Neutropenic fever was seen in 60% cases, with mean duration of fever being 8 days. In majority (66%) no focus of infection could be found. Various isolates included gram negative rods (n=6), staphylococcus (n=2) and fungi (n=5). Other post-transplant infections were tuberculosis (n=2), herpes zoster (n=2) and transfusion associated falciparum malaria (n=2). Post-BMT non-infectious complications included acute GVHD (24%), chronic GVHD (08%), hemorrhagic cystitis (14%), seizures (5%), and VOD (3%). Graft rejection and primary graft failure was seen in 3 and 2 cases respectively. Three of them received 2nd transplant and had successful recovery while the other 2 died of septicemia. Six patients died during peri-transplant period, 3 at day 100, and 8 beyond day 100. One patient died of unrelated cause at 2 years post-transplant. Main causes of death were septicemia (n=4), conditioning regimen toxicity (n=3), VOD (n=2), GVHD (n=2) and disseminated aspergillosis (n=2). The overall and disease free survival was 76%. In univariate analysis using Logrank and Wilcoxon test factors correlated with better survival were patient's age <15 years, disease duration <6 months, previous transfusions <20 events, conditioning with fludarabine/Cy/ATG, and absence of chronic GVHD. SCT from HLA matched sibling donor is effective treatment modality in majority of the young patients with SAA.

Incidence and Outcome of Chronic Graft-Versus-Host Disease (cGVHD) Using National Institute of Health (NIH) Criteria.

BACKGROUND: cGVHD, defined as GVHD after day 100 from allogeneic stem cell transplant (SCT), is a common complication, with impact on morbidity and survival. cGVHD has been previously classified as limited or extensive using Glucksberg criteria, which have not been reproducible or prognostic for late non-relapse mortality (NRM). Recently the NIH consensus criteria were proposed, but the ability of this classification to predict outcome of various subtypes of cGVHD is unknown.HYPOTHESES:Do various subtypes of GVHD affect overall survival (OS) or NRM in patients (pts) with GVHD after day 100 from SCT?Is the NIH severity scale sensitive to change in cGVHD?Does the NIH severity scale predict OS or NRM?METHOD: Pts undergoing their 1st SCT for a hematological malignancy from 1/2001 and 12/2003 were studied. 110 pts alive beyond day 100 after SCT met criteria for the retrospective study, and excluded pts who recieved donor lymphocyte infusion or a 2nd SCT. GVHD after day 100 was classified using NIH consensus criteria as follows: persistent acute GVHD (aGVHD) (assigned at day 100), recurrent aGVHD, delayed aGVHD, classic cGVHD, overlap GVHD (all assigned at time of onset). Severity scores were assigned to pts with classic and overlap GVHD at onset and peak. Survival was measured as OS from time of transplant and time of onset of GVHD. Cumulative NRM was also computed.RESULT: 37 (34%) had no GVHD and 73 (66%) pts had GVHD. The OS was 44% vs. 66% (no GVHD vs. GVHD, P=0.026). Time to death was shorter in pts without GVHD (0.73 yrs vs. 1.27 yrs, P=0.002). Of the 73 pts with GVHD, 14 (19%) had limited and 59 (80%) had extensive cGVHD. Pts with limited GVHD were reclassified as persistent aGVHD (1, 7%), recurrent aGVHD (4, 29%), and classic cGVHD (9, 64%).Pts with extensive cGVHD were reclassified as persistent (2, 3%), delayed (2, 3%), recurrent (18, 31%), classic chronic (22, 37%) and overlap GVHD (15, 26%). 31 (42%) had no worsening and 42 (58%) pts had worsening of GVHD. 65% of pts with classic cGVHD (22/31) had worsening compared to other types (20 of 42, 47%) (P=0.046). Severity score increased in 12 of 31 pts (39%) who had clinical worsening of GVHD (kappa coefficient=0.31). The OS of pts with various types of GVHD as proposed by the NIH criteria were significantly different (P<0.0001). This was more apparent when pts with any acute features of GVHD were compared to classic cGVHD (3-yr OS 47% vs. 66%, P=0.0015). This effect persisted even when survival was measured from onset of GVHD (P=0.0336). Severity at onset or peak of GVHD activity in pts with classic and overlap GVHD did not impact the survival. The 3-yr NRM (with relapse as a competing risk) for the entire cohort was 21% and was not affected by presence or absence of GVHD, or subtypes of GVHD. Significant variables using Cox model with time dependent covariates were any aGVHD feature after day 100 (HR 5.273, P=0.0004), and extensive cGVHD (HR 0.284, P=0.0041).CONCLUSION: The OS with different NIH subtypes of GVHD after day 100 from SCT varies and is superior for pts with classic cGVHD. Global severity score may be useful as a descriptive clinical indicator of morbidity and the need for immunosuppressive therapy, but within the limits of our study, this score has no prognostic value with respect to survival and did not change with clinical worsening of GVHD.

Second Stem Cell Harvest from Unrelated Donors for Patients with Relapse or Graft Failure after First Transplantation: Patient Age >50 Years and Relapse of Malignant Disease Are Associated with Poor Outcome.

Introduction: Hematopoietic progenitor cells from unrelated donors are increasingly used for allogeneic stem cell transplantation (SCT). A second donation of peripheral blood stem cells (PBSC) or bone marrow is widely accepted in case of graft failure of relapse.Patients and methods: We retrospectively investigated the outcome of seventy (n=70) patients with hematological malignancies (AML/MDS n=29, CML n=19, ALL n=17, other n=5) receiving a second SCT using PBSC (n=67) or bone marrow (n=3) from the same unrelated donors. Patients had a median age of 30 years (range 1–59) and the reason for a second donation of stem cells consisted of either relapse (n=37) or graft failure (n=33). Whereas in 21 patients no conditioning was used in the remaining patients it was busulfan or TBI-based in the majority of cases.Results: After a median follow-up of 33 months (range 7.9–76.2) after 2nd SCT a total of 55 patients died due to treatment-related mortality (63%) or relapse (16%) resulting in a median overall survival (OS) for all patients of 3 months. The OS was significantly better in patients < 50 years (38 vs. 8 %, p=0.01) and in case of graft failure (37% vs. 7%, p=0.02). Time interval between SCT, HLA-disparity, disease type (AML/MDS vs. CML vs. ALL), infused CD34+ cells/kg or graft source at first transplant had no impact.Conclusion: These data show the lack of efficacy of a second infusion of HSC from the same donor especially in older patients and in cases in which relapse of malignancy is the reason for second transplant. Given the currently unknown long-term effects of a repeated exposure to G-CSF, the factors mentioned above should be kept in mind whenever a request for a second HSC donation is considered.

Allogeneic Myelo-Ablative Stem Cell Transplant (SCT) as Salvage Therapy of Reduced-Intensity Conditioned (RIC) SCT: Toxicity and Outcome.

RIC regimens are mainly used for patients who cannot benefit from the myelo-ablative (MA) approach, due to age, previous SCT, or comorbidities, based on an expected early toxicity of MA regimen. Some centers may also choose the RIC strategy in young patients because they have no facilities for the management of prolonged neutropenia. The development of RIC has been so encouraging that programs now compare MA and RIC in patients who could tolerate both approaches. However, RIC may fail, and MA SCT be secondary considered.Objective: The goal of this retrospective survey was to assess the toxicity and outcome of MA after RIC SCT.Patients: 17 patients (14–63 y; 6 CML, 4 AML, 2 CLL, 2 myeloma, 1 NHL, 1 CMML, 1 myelodysplastic syndrome) received a MA SCT after RIC, for relapse (n=12), graft rejection (n=4), or in a planned program (n=1), from an HLA-id sibling (n=12), a familial mismatched donor (n=1), an unrelated donor (n=3) or a cord blood (n=1). The reason for initial RIC approach was age in 4, a research program in 6, comorbidities in 3, and previous autologous SCT in 4 patients. RIC included Fludarabin (Flu)-Busulfan (BU) in 8, Flu-2Gy irradiation in 4, Cyclophosphamide (CPM)-antithymocyte globulin (ATG) in 1, and various Flu- regimens in 4. One patient had 2 consecutive RIC SCTs before MA SCT. The median delay between RIC and MA SCT was 9 months (range: 2.5–36 months). The same donor was used for the 1st and 2nd SCT in 12/17 cases. The MA transplant was conditioned with BU-CY (±VP16) in 9, Cyclo-TBI in 4, and other regimens in 4 patients. The median follow-up after MA SCT was 9 monthsResults: After the MA transplant, 1 patient developed veno-occlusive disease, 2 developed interstitial pneumonia. Five patients died from relapse between 8 and 21 mo after the MA SCT. Seven (41%) died from transplant-related causes at a median of 8 months (GVHD:3; infection:1; multi-organ failure:1; thrombotic microangiopathy:1; EBV proliferative disease:1). 5/17 (29.5%) patients are alive and well 4.5 to 26 months after MA transplant. Three of them have extensive chronic GVHD while they did not develop any GVHD after RIC. The delay between the 2 transplants did not influence the outcome.Conclusion: This survey shows that MA after RIC SCT is feasible, and considering that most of these patients have been initially eligible for RIC because of their age or comorbidities, MA SCT had an acceptable toxicity. It may be considered for patients who relapsed or rejected after RIC transplant.