Reduced Intensity Allogeneic Stem Cell Research Articles

Efficacy of immune suppression tapering in treating relapse after reduced intensity allogeneic stem cell transplantation.

For patients who relapse after allogeneic hematopoietic stem cell transplantation while still on immune suppression, there is anecdotal evidence that tapering the immune suppression may result in graft-versus-tumor activity. We reviewed the medical records of all patients with documented histological or radiographic disease recurrence within 1 year of stem cell transplantation while on immune suppression at our institution. The median time to relapse was 110 days (range, 18-311) after transplant. Among 123 patients with relapse treated with immune suppression tapering without chemotherapy, radiation, or donor lymphocyte infusion, 34 responded (33/101 reduced intensity conditioning transplant and 1/22 myeloablative conditioning transplant, 32.7% and 4.5% respectively; P=0.007). The median time to response after initiation of immune suppression tapering was 82 days (range, 16-189). Thirty-three patients (97.1%) had development or progression of acute or chronic graft-versus-host disease as a consequence of immune suppression tapering, at a median time of 39 days (range, 16-98). Six patients subsequently relapsed late after initial response to immune suppression tapering at a median time of 2 years (range, 0.9-3.8). The median overall survival from immune suppression tapering for responders was 5.1 years (range, 1.9-not estimable). When clinically feasible, immune suppression tapering alone in patients who relapse early after reduced intensity conditioning allogeneic stem cell transplantation can produce durable remissions, but is almost always associated with graft-versus-host disease.

Clinical research of reduced intensity allogeneic hematopoietic stem cell transplantation for relapsed or refractory lymphoma

Objective To explore the efficacy and safety of reduced intensity allogeneic stem cell transplantation(allo-HSCT)in the treatment of relapsed or refractory lymphoma. Methods 5 patients with relapsed or refractory lymphoma received reduced intensity allo-HSCT from January 2012 to December 2013 of Beijing Military General Hospital, including 4 males and 1 female, aged from 20 to 39 years old, with the mean age 28.7 years old. 3 cases were HLA-identical matching and the other two cases were HLA-haploidentical. Donors received granulocyte colony-stimulating factor mobilization, and stem cells were collected from both peripheral blood and bone marrow. Pretreatment scheme reduced the strength of pretreatment for fludarabine combined with busulfex and ATG. Combined immunosuppressive agents were used for graft-versus-host disease(GVHD)prophylaxis, including cyclosporine A, methotrexate, mycophenolate mofetil and soon. The toxicity, GVHD and disease-free survival in patients were observed after transplantation. Results All of the patients acquired hematopoietic reconstitution. The average time of the neutrophils count ≥ 0.5 × 109/L and platelets ≥ 20×109/L were 18.8 d and 24.5 d, respectively. Implantation was confirmed by the evidence of 100 % of donor hematopoiesis. As of follow-up to December 2014 with the median 19.2 months(6-35 months), 2 cases died of recurrence, the other 3 patients remained disease-free survival, and the longest disease-free survival time was up to 35 months. Conclusions Reduced intensity allogeneic hematopoietic stem cell transplantation is an effective and safe method for relapsed or refractory lymphoma, which could be chosen as a salvage treatment method for relapsed or refractory lymphoma. Key words: Allogeneic hematopoietic stem cell transplantation; Rducing strength; Rlapsed; Refractory; Lymphoma

Reduced Intensity Allogeneic Stem Cell Transplantation Followed By Adoptive Cellular Immunotherapy with Donor Derived LMP Specific-CTLs in Patients with EBV Positive Refractory or Recurrent Hodgkin Lymphoma: A Lymphoma Cell Therapy Consortium (LCTC) Trial

Reduced Intensity Allogeneic Stem Cell Transplantation Followed By Adoptive Cellular Immunotherapy with Donor Derived LMP Specific-CTLs in Patients with EBV Positive Refractory or Recurrent Hodgkin Lymphoma: A Lymphoma Cell Therapy Consortium (LCTC) Trial

Myeloablative Versus Reduced Intensity Allogeneic Stem Cell Transplantation in Relapsed Hodgkin’s Lymphoma in Recent Years. a Retrospective Analysis of the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation

Introduction. Allogeneic stem cell transplantation (allo-SCT) is a well established therapeutic alternative for those patients with refractory Hodgkin’s lymphoma (HL) who relapse after an autologous stem cell transplantation (ASCT), have chemosensitive disease and a HLA compatible donor available. The impact of the intensity of the conditioning regimen in the outcome of this procedure is still not well understood. An initial retrospective analysis from the European Group for Blood and Marrow Transplantation (EBMT) Lymphoma Working Party (LWP) (Sureda et al, JCO 2010) that compared myeloablative (MAC) with reduced intensity conditioning (RIC) protocols indicated that the high non-relapse mortality (NRM) associated to MAC-SCT translated into a non-significant improvement in progression free survival (PFS) for RIC recipients in spite of the higher relapse rate of the latter. As NRM for MAC-SCT might have decreased over time due to better patient selection, HLA typing and peri-transplant supportive measures, we hypothesize that overall results of more intensive protocols could compare better to RIC-SCT in recent years.Patients and Methods. We have included in this analysis adult patients with multiply relapsed classical HL treated with an allo-SCT between January 2006 and December 2010 and reported to the EBMT Database. Only first and second allo-SCT was included. Tandem ASCT-allo-SCT was excluded as well as cord blood transplantations and haplo-identical SCT. A total of 313 patients met the inclusion criteria (63 patients treated with a MAC and 250 patients treated with a RIC, definitions following the EBMT criteria). There were 173 males (55%) and 140 females (45%) with a mean age at diagnosis of 29 years and at SCT of 33 years. Mean time from diagnosis to SCT was of 43.3 months. 153 patients (49%) were chemorefractory at the time of allo-SCT and 166 patients (53%) had already failed a prior ASCT. Peripheral blood (PB) was used as the source of stem cells in 88% of the patients. Comparing MAC with RIC groups, the latter one was significantly older at allo-SCT (31 years vs 34 years, p=0.01), had a longer time interval between diagnosis and allo-SCT and preferentially received mobilized PB stem cells (82% vs 91%, p=0.01). There were also more prior autograft failures in the RIC group (56% vs 42%, p=0.006).Results. With a median follow up for alive patients of 32.5 (9.7 – 52.9) months, overall survival (OS) was 75% and 65%, PFS, 54% and 39%, NRM 11% and 12% and relapse rate after SCT of 37% at 1 year. There were no significant differences in NRM between MAC and RIC patients. Relapse rate was higher in the RIC group, although these differences did not reach statistical significance (55% vs 40% at 24 months, p=0.1). This lower relapse rate translated into an improvement in PFS for the MAC group (48% vs 37% at 24 months, p=0.08) with no differences in terms of OS (71% for MAC vs 61% for RIC at 24 months, p=0.4). Multivariate analysis after adjusting for disease status at the time of SCT showed that the use of RIC protocols was the only independent adverse prognostic factor associated to a higher relapse rate after SCT [HR 0.68, 95%CI (0.38 – 0.98), p=0.04] and to a lower PFS after the procedure [HR 0.65, 95%CI (0.43 – 0.98), p=0.04]. The intensity of the conditioning regimen did not have any impact n NRM in the multivariate analysis. Chemosensitive disease at SCT was the only independent prognostic factor for OS after SCT in the multivariate analysis [HR 1.70, 95%CI (1.17 – 2.46), p=0.005].Conclusions. This retrospective analysis shows that NRM after MAC protocols is not a significant clinical issue when allografting patients with HL nowadays. On the other hand, using MAC decreases the relapse risk in this highly resistant population of patients, translating into a significant improvement of PFS. MAC protocols should be considered when designing prospective clinical trials in patients with HL candidates for an allogeneic stem cell procedure. DisclosuresNo relevant conflicts of interest to declare.

Donor lymphocyte infusion is an effective therapy for relapsed Hodgkin lymphoma after reduced-intensity allogeneic hematopoietic stem cell transplantation

A 3-year-old boy with Hodgkin lymphoma relapsed only 2 months after completion of first-line therapy. He received reduced-intensity conditioning and allogeneic hematopoietic stem cell transplantation (RIC allo-HSCT), but relapsed again. To treat the second relapse, donor lymphocyte infusions were performed four times. He showed no evidence of disease and his quality of life was maintained for 500 days after stem cell transplant. However, his condition worsened and he died 3 years and 3 months after onset. In high-risk patients fully intolerant to myeloablative regimens, RIC allo-HSCT followed by subsequent donor lymphocyte infusions must be considered an effective therapeutic approach.

Phase II Trial of Busulfan-Based Tandem High-Dose Chemotherapy with Autologous Stem Cell Transplantation Followed By Reduced Intensity Allogeneic Stem Cell Transplantation for Patients with High-Risk Lymphoma

Many patients with high-risk lymphoma will experience relapse after autologous stem cell transplantation (AutoSCT). There are no therapies given to patients in remission after AutoSCT which are of proven benefit. At time of disease relapse after AutoSCT, patients are often considered for allogeneic stem cell transplantation (AlloSCT) if remission can be achieved by salvage strategies. We conducted a phase II clinical trial of tandem AutoSCT followed by reduced intensity conditioning (RIC) AlloSCT for patients with high-risk lymphoma. High-dose chemotherapy was BuCyE: busulfan (11.2 mg/kg IV total), cyclophosphamide (120 mg/kg IV total), and etoposide (30 mg/kg IV total). RIC AlloSCT was performed any time between 40 days and 6 months after AutoSCT if disease had not progressed. RIC was busulfan (3.2 mg/kg IV total) with fludarabine (120 mg/kg IV total) with GVHD prophylaxis comprised of tacrolimus, sirolimus, and methotrexate. A total of 42 patients were enrolled. All patients had at least a partial remission to their last therapy. Eligible patients in the up-front setting included T-cell lymphoma, mantle cell lymphoma, and B-cell lymphoma with concurrent c-MYC and BCL-2 overexpression or translocations. Other histologies were required to be relapsed / refractory as defined by number of lines of therapy or remission duration < 12 months. All patients underwent BuCyE AutoSCT. RIC AlloSCT was performed in 29 patients, 16 from a matched related donor and 13 from a matched unrelated donor. RIC AlloSCT was not performed in 13 patients because of patient choice (n=4), lack of a suitably matched donor (n=2), disease progression (n=6), and therapy-related AML (n=1). There has been no transplant-related mortality from AutoSCT. Of the 29 patients who underwent both HSCT procedures, median time from AutoSCT to AlloSCT was 96 days (range 48-169). All patients engrafted successfully with day 100 median donor chimerism being 95% (range 85-99). The 6-month cumulative incidence of grades II-IV acute GVHD was 7% (95% CI, 0.3%, 20%). Cumulative incidence of chronic GVHD at one year was 36% (17%, 56%). Non-relapse mortality at one year was 4.6% (0.3%, 20%) with one death from sepsis. Cumulative incidence of disease relapse was 20% (9%, 33%) for the entire group and 8% (1%, 23%) for patients after AlloSCT. At a median follow-up after 15.9 months (range, 3.5-36.5) after AutoSCT for the entire group, 1-yr progression-free survival was 77% (60%, 87%) and 1-yr overall survival was 87% (72%, 95%). For the 28 survivors after AlloSCT, median follow-up is 11.8 months (range, 0.2-33.6), 1-yr PFS is 87% (66%, 96%) and 1-yr OS is 95% (72%, 99%). Busulfan based tandem AutoSCT followed by RIC AlloSCT appears safe and effective in patients with high-risk lymphoma. Prospective trials comparing such a strategy to either AutoSCT or RIC AlloSCT alone in specific lymphoma subtypes are warranted.

Sequential Myeloablative Autologous Stem Cell Transplantation and Reduced Intensity Allogeneic Stem Cell Transplantation in Children, Adolescents and Young Adults with Poor Risk Refractory or Recurrent Hodgkin (HL) and Non-Hodgkin Lymphoma (NHL)

s / Biol Blood Marrow Transplant 20 (2014) S72eS90 S85 Patients were considered to have viral reactivation if CMV, EBV and ADV copies/ml were 600, 1000 and 1000, respectively. Viremia was defined as peri-AlloHCT (d0 d+14), early viremia (d15 d+98) and late viremia (d+99 d+180). From 20082012, 100 consecutive children (median age, 8 yrs; range 0.25-22 yrs; 35F/ 65M) undergoing AlloHSCT for malignant (n1⁄453) and nonmalignant (n1⁄447) disorders, were monitored. Donor sources included: matched family donor (n1⁄4 42, 42%), matched unrelated donors (n1⁄428, 28%) and unrelated cord bloods (n1⁄420, 20%). Patients were conditioned with either myeloablative [MA] (n1⁄443, 43%), reduced toxicity [RT] (n1⁄435, 35%), or reduced intensity [RI] (n1⁄422, 22%) regimens. Additionally, a total of 79 patients (79%) received serotherapy with alemtuzumab (n1⁄448, 48%) or rabbit-Anti-thymocyte globulin [r-ATG] (n1⁄431, 31%). The incidence of pre-AlloHCT viremia was 8%. The incidence of post-AlloHCT single viremia, multiple viremia and viral disease was 41, 15 and 22% respectively. The incidence of peri-AlloHCT, early and late viremia was CMV: 5%, 22.2% and 6.6%; EBV: 1%, 9.1% and 1.1%; ADV: 5%, 10.1%, and 6.6%, respectively. Viremia was noted in 36/80 (45%) of patients who received serotherapy vs. 5/20 (25%) who did not receive serotherapy (Chi-square test p1⁄40.1). Days for neutrophil, platelet engraftment, incidence of graft failure and aGVHD were not statistically significant between patients with and without viremia. We performed univariate and multivariate analysis for risk factors associated with viremia: age, sex, donor, stem cell source, graft failure, CMV risk status, alemtuzumab, r-ATG, malignant vs. non-malignant disease, MA vs. RT vs. RI regimens, absolute neutrophil and lymphocyte count at day +30. Only CMV risk status (p1⁄4.0002) and pre-AlloHCT viremia (p1⁄4 0.0095) were significant on multivariate analysis. Among patients with viremia vs. those without viremia, 1yr transplant related mortality (TRM) and all-cause mortality was 23.7% vs. 16.7 (p1⁄4.4) and 36.8% vs. 18.5% (p1⁄40.04), respectively. Among patients with viremia vs. without viremia, the median length of initial hospitalization (LOH) vs. LOH in the first 180 days were 44 days (9-144) vs. 35(19-180) (p1⁄40.02) and 91 days ( 9-165) vs. 59 days (19-180), (p1⁄40.05) respectively. Post-AlloHSCT viremia remains a significant problem and results in a significantly longer LOH. Potentially due to weekly monitoring the TRM was not significantly higher in patients with viremia.

Reduced Intensity Allogeneic Stem Cell Transplant for Treatment of Blastic Plasmacytoid Dendritic Cell Neoplasm

Blastic plasmacytoid dendritic cell neoplasm is a rare, aggressive tumor characterized by skin and/or marrow infiltration by CD4+ CD56+ cells. Historically, the tumor was variably thought to arise from either monocytes, T cells or NK cells giving rise to terms such as CD4+/CD56+ acute monoblastic leukemia, primary cutaneous CD4+/CD56+ hematodermic tumor and blastic NK-cell lymphoma. Whilst considerable progress has been made in understanding the histogenesis, the best modality of treatment remains to be defined. We are therefore reporting this case which was successfully treated with a T-deplete allogeneic transplant and the patient is currently alive and in remission 4 years post transplant.

Reduced Intensity Allogeneic Stem Cell Transplant In Patients With Multiple Myeloma: A Comparison Of Planned Autologous-Reduced Intensity Allogeneic Stem Cell Transplant (Auto-Allo) and Reduced Intensity Allogeneic Stem Cell Transplant (RIC) As Upfront Transplant In Patients With Multiple Myeloma, An EBMT Analysis

BackgroundDespite the advances in the treatment of multiple myeloma using new targeted therapies and autologous hematopoietic stem cell transplant (HSCT) the disease remains largely incurable. Recent efforts in using reduced intensity allogeneic HSCT have been hampered by increased allograft-related morbidity and mortality. Several prospective studies comparing single or tandem autologous HSCT with planned tandem autologous-reduced intensity allogeneic HSCT (auto-allo) have shown no overall survival advantage despite improvements in progression-free survival (PFS) and lower relapse rates with reduced intensity allograft, mainly due to increased non-relapse related mortality (NRM) rates. However, two of these prospective studies; the European Group for Blood and Marrow Transplantation NMAM 2000 and the Italian group study with long term follow-up reported PFS and overall survival (OS) benefits in favor of the auto-allo arm. Currently allogeneic HSCT is recommended within the context of clinical trials and only in high risk multiple myeloma patients who continue to have a very poor outcome with autologous HSCT. While such clinical trials are ongoing there remains a need to address the role of autologous HSCT prior to reduced intensity allogeneic HSCT. The objective of this retrospective study is to evaluate the role of upfront cytoreductive autologous HSCT prior to allograft in the outcomes of patients who have undergone allograft following induction therapy. StudyWe performed a retrospective analysis of the EBMT database comparing the outcomes of patients who were planned to receive auto-allograft to those who underwent reduced intensity allograft (early RIC) without a prior autologous HSCT within one year from diagnosis. The data in 504 patients were previously reported at the ASH meeting 2010 (abstract 3512). We subsequently included additional patients and requested more information from the participating EBMT centers and updated the study. From 1996 to 2013 a total of 689 patients were registered as reduced intensity allograft. 517 patients were registered as planned auto-allograft; however, 73 did not receive the planned allograft. A total of 172 patients received reduced intensity allograft after induction treatment without prior auto-HSCT. Median age at first transplant was 53 years (range 20-72) in the auto-allo and 51 years (range 31-77) in the early RIC group. Median time from diagnosis was 6.6 months (range 2-156 months) in the auto-allo and 7.7 months (2.8-12.0) in the early RIC group. The disease status at the time of first transplant for the auto-allo group was CR - 8%, PR - 67%, other or missing - 25%; and for the RIC group was CR - 15%, PR - 62%, other or missing - 23%. Donors were HLA matched siblings in 88% and matched unrelated in 12% for the auto-allo group, and 84% siblings and 16% matched unrelated in the RIC group with no significant differences between the two groups. ResultsWith a median follow-up of 93 months in the auto-allo and 84 months in RIC groups, PFS rates were significantly better at 3 and 5 years in the auto-allo group (45.6% and 34.2%) as compared to the RIC group (33.9% and 22.0%, p<0.001). Overall survival was also significantly improved in favor of the auto-allo (3 yr and 5 yr OS 67.9% and 58.9%) as compared to the RIC group (54.3% and 42.7%, P = 0.001). The non-relapse mortality (NRM) rates were lower in the auto-allo group as compared to RIC: 1 yr and 3 yr NRM were 8.1% and 14.1% in the auto-allo and 20.3% and 27.4% in early RIC group, p<0.001. We examined potential differences in outcomes based on use of novel agents, and used the year 2004 as a surrogate for introduction of novel agents to routine clinical practice. There were no significant differences by multivariate analysis in outcomes for patients transplanted before or after 2004. ConclusionThis large multicenter retrospective study suggests that cytoreductive autologous HSCT prior to allograft is associated with improved PFS and OS. We are in the process of conducting an extended analysis to control for possible confounders. If the results are confirmed, future studies should be conducted to verify the importance of autologous stem cell transplant as part of the allograft treatment strategy. Disclosures:No relevant conflicts of interest to declare.

Follow Up On CD8-Depleted Donor-Lymphocyte Infusions After T-Cell Depleted Allogeneic Hemopoietic Stem Cell Transplantation

We applied prophylactic CD8-depleted (CD8depl) donor lymphocyte infusions (DLI) in the setting of T-cell depleted reduced-intensity allogeneic hematopoietic stem cell transplantation (HSCT) in a phase I/II trial. T-cell depletion was carried out by the use of high-dose Alemtuzumab (100 mg or 60 mg for unrelated or sibling donor transplantation, respectively). We have demonstrated the feasibility of this approach after having treated 23 patients in this protocol (Meyer et al. Blood 2007). From 2004 to 2011, 134 patients with different hematologic diseases were included and followed for a median observation time of 1.5 years after transplantation (range, 1.5-9 years). Median age was 56 years (range, 19-71). Stem cell source was peripheral blood from either matched siblings (n=23), matched unrelated (n=62), or donors with single HLA mismatches (unrelated n=48, related n=1). Tapering of cyclosporine A was started in the 6th week after transplantation. Subsequently, CD8depl DLI were administered prophylactically in escalating doses starting with 1x106 CD4 T cells/kg bodyweight. 53 patients received at least one dose of DLI. Among 81 patients who did not qualify for DLI, 60 patients had primary mild GVHD. Following DLI, acute GVHD was the major reason for withholding subsequent DLI-doses (66%), mainly because of acute GVHD ≤ 2°. Extensive chronic GVHD was diagnosed in 9.4% of the patients. Overall survival after 1 and 3 years was 60% and 43%, respectively. Survival significantly differed between the DLI and non DLI group after 3 years (63.8% vs. 30.1%, p=0.002). The inferior outcome of the non DLI group was confirmed when only those patients who did not receive DLI for other reasons than GVHD were considered (28.6%). The largest patient cohort in our trial were patients with AML and MDS (n=21 with and n=33 without DLI). In these patients, the survival benefit for the DLI group after 3 years was significant (75.8% vs 28.9%, p=0.0012). Interestingly, the relapse rate did not differ between DLI and non-DLI patients but the non-relapse mortality. The presence of GVHD at any time was associated with a reduced relapse rate (57.9% vs. 31.4%, p=0.0015), independent of DLI-application. However, GVHD had no impact on overall survival. Decreasing donor T-cell chimerism (TCC) was found in 34 patients who subsequently received DLI and 13 who did not. Following CD8depl DLI, 31 patients (88%) converted to full donor. In contrast, only 2 of the patients with decreasing TCC in the non-DLI group (15.3%) converted spontaneously. In summary, we observed that the application of prophylactic CD8depl DLI was associated with a survival benefit and the re-establishment of full donor T-cell chimerism. In AML/MDS patients the improved survival was associated with lower treatment-related mortality rather than a reduced relapse-rate. Our data strongly suggest randomized trials comparing prophylactic application of CD8depl DLI vs. no DLI as well as CD8depl vs. non-manipulated DLI in a preemptive setting. Disclosures: Off Label Use: MabCampath has been used for T-cell depletion.

The outcome of reduced intensity allogeneic stem cell transplantation and autologous stem cell transplantation when performed as a first transplant strategy in relapsed follicular lymphoma: an analysis from the Lymphoma Working Party of the EBMT

Both auto-SCT and reduced intensity allo-SCT (RIST) are employed in the treatment of relapsed follicular lymphoma (FL). We have analysed the outcome of these two transplant procedures when used as a first transplant in this setting. We conducted a retrospective comparison of 726 patients who underwent an auto-SCT and 149 who underwent a RIST as a first transplant procedure for relapsed FL as reported to the Lymphoma Working Party of the European Bone Marrow Transplant. The non-relapse mortality (NRM) was significantly worse for patients undergoing a RIST (relative risk (RR) 4.0, P<0.001). The 1-year NRM was 15% for those undergoing a RIST compared with 3% for those undergoing an auto-SCT. Disease relapse or progression were significantly worse for those receiving an auto-SCT (RR 3.1, P<0.001). Patients undergoing a RIST had a 5-year relapse rate of 20% compared with 47% for those undergoing an auto-SCT. The PFS at 5 years was 57% for patients receiving a RIST compared with 48% for those receiving an auto-SCT. There was no significant difference in OS between the two groups. RIST is associated with a higher NRM and lower relapse rate in patients with relapsed FL.

Spontaneous Subcapsular Splenic Hematoma Associated with Filgrastim in a Patient Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

To report the development of a spontaneous subcapsular splenic hematoma following filgrastim administration in a patient undergoing an allogeneic hematopoietic stem cell transplant. A 60-year-old female with myelodysplastic syndrome was admitted for a reduced-intensity allogeneic hematopoietic stem cell transplant from an unrelated donor. She received filgrastim 5 μg/kg starting on day 1 to accelerate neutrophil recovery. On day 5, she began reporting severe left chest-wall pain. Contrast-enhanced computed tomography of the abdomen/pelvis revealed a spontaneous subcapsular splenic hematoma. Upon discontinuation of filgrastim, the pain fully resolved. The patient was subsequently rechallenged with filgrastim, which led to recurrence of the left-sided chest-wall pain. Filgrastim was discontinued and the patient reported resolution of the pain. Filgrastim has been associated with splenic hematoma and splenic rupture, predominantly in healthy donors undergoing mobilization of peripheral blood stem cells. Although splenic rupture attributed to filgrastim in a patient undergoing allogeneic hematopoietic stem cell transplantation has been reported, to our knowledge, this is the first case report to establish causality. Using the Naranjo probability scale, an objective causality assessment revealed that the adverse drug event was highly probable. Although filgrastim-induced splenomegaly, splenic hematomas, and splenic rupture are rare, clinicians working in the bone marrow transplant setting should be cognizant of the potential of growth factors to cause these adverse events.

Impact of disease status and stem cell source on the results of reduced intensity conditioning transplant for Hodgkin's lymphoma: a retrospective study from the French Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)

The role of reduced intensity allogeneic stem cell transplantation for the treatment of relapsed/refractory Hodgkin's lymphoma remains controversial. We retrospectively analyzed 191 patients who underwent reduced intensity allogeneic stem cell transplantation between 1998 and 2008 for relapsed or refractory Hodgkin's lymphoma and whose data were reported to the French registry. The median follow-up was 36 months. The estimated 3-year overall survival rate, progression-free survival rate, cumulative incidence of relapse and cumulative incidence of non-relapse mortality were 63%, 39%, 46%, and 16%, respectively. There was no difference in outcome between patients in complete response and in partial response at the time of transplantation with regards to overall survival (70% versus 74%, no significant difference) and progression-free survival (51% versus 42%, no significant difference). Patients with chemoresistant disease had a shorter overall survival (39% at 3 years; P=0.0003) and progression-free survival (18% at 3 years; P=0.001) than patients in complete remission. The use of umbilical cord blood as the source of stem cells was associated with a poor outcome with an increased risk of death with a hazard ratio of 3.49 (95% confidence interval: 1.26 to 9.63; P=0.016). The use of peripheral blood was associated with a better outcome for patients who where alive 1 year after transplantation with a hazard ratio of 0.38 (95% confidence interval: 0.17 to 0.83; P=0.016). Disease status at transplantation remains the most important risk factor for outcome. Our data suggest that the use of peripheral blood should be preferred whereas umbilical cord blood should be used with caution.

Busulfan Does Intensity and Outcomes in Reduced Intensity Allogeneic Stem Cell Transplantation for MDS/AML

Busulfan Does Intensity and Outcomes in Reduced Intensity Allogeneic Stem Cell Transplantation for MDS/AML

Analysis of Stem Cell Transplant Referral in a Cohort of Newly Diagnosed Chronic Lymphocytic Leukemia Patients

AbstractAbstract 4252 Background:Multiple recent studies have demonstrated the survival benefits of reduced intensity allogeneic stem cell transplant for high risk CLL patients. These transplant series, however, represent highly selected cases where age, co-morbidities and performance status preclude transplant in many patients with CLL. The portion of newly diagnosed CLL patients that are eventually considered for transplant is unknown, as well as the proportion that are referred for transplant evaluation; the proportion that actually receive stem cell transplant, and the reasons for not pursuing transplant in referred patients. We conducted a cohort study of newly diagnosed CLL patients to address this gap in knowledge. Methods:We used the Mayo Clinic database to identify all patients with newly diagnosed CLL seen at Mayo Clinic within 1 year of diagnosis between July of 2003 and May of 2011 (time interval during which reduced intensity allogeneic stem cell transplantation was part of routine care at Mayo Clinic). Electronic medical record and laboratory studies were reviewed to identify all patients referred for stem cell transplant evaluation (either allogeneic transplant for progressive CLL or autologous stem cell transplant for Richter's transformation). Patients referred for transplant were analyzed to determine what proportion completed transplant and, for those who were not transplanted, the reason they were not transplanted (e.g. lack of insurance approval, co-morbidity, lack of a donor, inadequate disease control, death prior to transplant or patient preference). Results:A total of 1250 patients with newly diagnosed CLL between July 2003 and May 2011 who were seen at Mayo Clinic within 1 year of diagnosis were identified. The mean age at diagnosis was 63.6 yrs and 34.2% were women. With respect to disease stage, 48.7% were Rai stage 0, 45.5% Rai stage I/II, and 5.8% Rai stage III/IV. CLL FISH analysis revealed 126 (13.6%) patients who had either del (17p) or del (11q) and 801 (86.4%) patients who had other FISH abnormalities or normal FISH results. After a median follow-up of 41 months, 425 (34%) of patients have received treatment.A total of 54 patients (4.3%) were referred for a transplant evaluation during follow-up. Of these 54 patients, 48 (3.8% overall cohort) were referred for consideration of allogenic transplant for treatment of progressive CLL and 6 (0.5%) were referred for autologous transplant for treatment of Richter's transformation.Baseline characteristics associated with subsequent transplant referral included age at diagnosis (median: 56 yrs) (p < 0.0001, Odds Ratio (OR) for each year older = 0.91, 95% Confidence Interval (CI)=(0.88, 0.95)), Rai stage (III/IV vs. 0) (p = 0.0002, OR = 22.7, 95% CI=(5.1, 102.4)) and FISH (del(11q), del(17p) vs Normal, del(13q) or Trisomy 12) (p < 0.0001, OR = 7.3, 95% CI=(3.3, 16.1)). Gender, Rai stage (I/II vs. 0), and patient residence (local vs. not local) were not significant.Among the 54 patients referred for transplant, 28 (51.9%) completed a transplant. This included 22 (45.8%) patients referred for allogenic transplant and 6 (100%) patients referred for autologous transplant. Among the 26 patients referred who did not undergo transplant, the principal reasons were patient preference (n = 6, 23.1%), patient still being evaluated for transplant as of the study end date (n = 6, 23.1%), alternative therapy chosen (n = 5, 19.2%), inadequate disease control (n = 3, 11.5%), death prior to transplant (n = 3, 11.5%), lack of insurance approval (n = 2, 7.7%), and lack of a donor (n = 1, 3.8%). Conclusion:4.3% of the newly diagnosed CLL patients in this series were considered for stem cell transplant at some point during follow-up. Young age, high Rai stage and high risk FISH abnormalities are principal reasons for transplant referral. Only 51.9% of those considered for transplant completed transplant. The principal reasons for referral patients not completing transplant who had adequate time to follow were patient preference, alternative therapy, inadequate disease control and death prior to transplant. The remaining 6 patients (23%) are in process of transplant evaluation with longer follow required. These analyses provide first incidence data for CLL transplant referral in a cohort of newly diagnosed patients. Disclosures:Zent:Biothera: Research Funding; Genzyme: Research Funding; Genentech: Research Funding; Novartis: Research Funding; GlaxoSmithKlime: Research Funding. Shanafelt:Celgene: Research Funding; Teva/Cephalon: Research Funding; GlaxoSmith Klein: Research Funding; Genentech: Research Funding; Hospira: Research Funding; Polyphenon E International: Research Funding.

Late relapses following reduced intensity allogeneic transplantation in patients with multiple myeloma: a long‐term follow‐up study

We analysed the long-term outcomes of 60 multiple myeloma patients who underwent reduced intensity allogeneic stem cell transplantation between August 2000 and March 2008. Regimens included fludarabine and melphalan conditioning (flu-mel regimen) for allogeneic haematopoietic cell transplant (HCT) or a planned tandem regimen consisting of high-dose melphalan conditioning for autograft followed by low-dose total body irradiation conditioning for allogeneic HCT (auto-allo regimen). Donors included human-leucocyte-antigen-matched siblings (n = 55) or matched unrelated donors (n = 5). With a median follow-up of 9·8 years, 7-year overall survival (OS) and progression-free survival (PFS) were 60% and 31%, respectively. By multivariate Cox regression analysis, disease status of complete response (CR) or partial response (PR) at transplant and the presence of chronic graft-versus-host disease were significantly associated with improved OS. Only disease status was significantly associated with improved PFS. We noted a surprising number of very late relapses, with six patients (10%) relapsing between 6 and 12 years post-transplant. Among the six late relapse patients, all were transplanted within 14 months of diagnosis, five had normal karyotypes, and five were in CR/PR. Our data provide additional evidence that, while survival may be extended by reduced intensity allogeneic transplant, ultimately, it may not offer a cure.

Editorial Commentary: Adenovirus Viremia and Infection After Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplant: Should We Institute a Routine Screening Program?

Editorial Commentary: Adenovirus Viremia and Infection After Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplant: Should We Institute a Routine Screening Program?

A Prospective Monocentric Study of Fractionated Gemtuzumab Ozogamicin (GO) Combined to Standard-Dose Cytarabine in Older Patients with Acute Myeloid Leukemia (AML) in First Relapse,

Abstract 3603 Aim.Gemtuzumab Ozogamicin (GO) is a potent antibody-directed chemotherapy against CD33 antigen. We have previously conducted a phase 2 study evaluating fractionated infusion of GO 3 mg/m2 on day 1, 4 and 7 combined to standard 3+7 DNR/cytarabine in patients aged 50 to 70 years with relapsed acute myeloid leukemia (AML) (Farhat et al., AJH, accepted). We decided to determine whether the omission of daunorubicin may retain the efficacy of fractionated GO combined to standard-dose cytarabine. Methods.GO was proposed to patients (pts) with CD33 positive AML in relapse according to the French Temporary Authorization (ATU) program. All consecutive pts from our center were eligible if they were in first relapse and aged of 50 years or more. Refractory patients and patients with a first CR of less than 6 months were excluded. Induction consisted of cytarabine 200 mg/m2/d CI on day 1–7 with GO at 3 mg/m2/d on day 1, 4 and 7. Pts achieving CR/CRp received two consolidation courses with cytarabine 1 g/m2/12h on day 1–2 with GO at 3 mg/m2/d on day 1. A maintenance phase with low-dose cytarabine was allowed. Minimal residual disease (MRD) monitoring based on NPM1 mutation or WT1 expression was assessed in informative and evaluable patients. Results.From October 2007 to June 2011, 22 pts (median age, 67 years) were recruited. All pts received an intensive regimen as part of their first line therapy (3+7 schedule or more intensive). Median duration of first CR was 16 months (6 to 33). Cytogenetic analysis at relapse was successfully assessed in all pts and karyotype was classified as favorable in 3 pts (t(8;21); t(16;16); t(15;17)), intermediate in 18 pts and adverse in 1 pt. Molecular profile analysis of intermediate-risk patients revealed the presence of a FLT3 internal tandem duplication (FLT3 -ITD) in 3 pts, a NPM1 mutation in 8 pts (including 2 cases with a concomitant FLT3 -ITD), a single CEBPA mutation in 1 pt, a EVI1 hyperexpression in 2 pts, and a MLL rearrangement in 1 pt. CR+CRp was achieved in 17/22 pts (77.3%) including 2 CRp. The 5 primary resistant pts corresponded to 1 pt with complex karyotype, 1 pt with a MLL rearrangement, 1 pt with EVI1 hyper expression, 1 pt with FLT3 -ITD, and 1 pt without any identified genetic alteration. There were 2 (9%) induction deaths including one patient that experienced veino-occlusive disease (VOD) and one patient with severe sepsis. A second case of reversible grade 2 VOD was documented during induction. Four patients (18.1%) experienced G3-4 infections and only one severe mucositis was observed. Median duration of G3-4 neutropenia and thrombocytopenia was 24 days (16–30) and 30 days (20–60), respectively. Prolonged grade ≥ 3 thrombocytopenia was observed in 2 patients. With a median follow-up of 22 months, median DFS was 17.2 months and estimated at 66.3% at 18 months. To date, the duration of CR2 was superior to that of CR1 in 5 non transplanted patients. Median overall survival was 22.6 months. Four pts who received a reduced intensity allogeneic stem cell transplantation in CR2, and one of them subsequently died. We were able to compare the molecular response obtained after CR2 and after CR1 using the same MRD marker in 6 patients that achieved CR2. In 5 out of 6 paired samples, MRD levels after CR2 were found equal or inferior to MRD levels after CR1 (see fig 1). [Display omitted] Conclusion.Fractionated doses of GO (3 mg/m2/d on day 1, 4, and 7) combined to standard-dose cytarabine in older pts with AML in first relapse is associated with a high CR rate, a prolonged survival and a low rate of toxic deaths. A gain in MRD levels was noted in paired CR1 and CR2 samples. Disclosures:Castaigne:Pfizer/Wyeth: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Alemtuzumab Use and Survival After Reduced Intensity Allogeneic Stem Cell Transplantation in High-Risk Chronic Lymphocytic Leukemia (CLL),

Abstract 4152 BACKGROUND:Patients with biologically aggressive chronic lymphocytic leukemia (CLL) characterized by being refractory to purine nucleoside analogues and/or possessing the cytogenetic abnormality del (17p13) have poor clinical outcomes with a median survival of <3 years. Several groups have reported that nonmyeloablative allogeneic stem cell transplant (alloSCT) provides long-term disease control in a subset of high-risk CLL patients. The Seattle group also recently reported that alemtuzumab use prior to alloSCT may increase the risk of early relapse/progression (Sorror, ASH 2010). This is a potentially critical observation since alemtuzumab is one of the few active agents in patients with del(17p13) and is frequently used for pre-transplant debulking in patients with this genetic defect. METHODS:We performed retrospective analysis of 38 CLL patients who underwent nonmyeloablative alloSCT for CLL at the Mayo Clinic between 2003 and 2011. The relationship between transplant outcome and debulking regimen used immediately prior to alloSCT, disease status at the time of alloSCT, post transplant engraftment, GVHD development was explored. The degree of marrow involvement prior to alloSCT was assessed using the leukemia index calculated by multiplying the % involvement by CLL cells and the % cellularity. RESULTS:Median age at the time of alloSCT was 55.5 (range, 29–69) and 13 patients (34%) were female. The median duration from CLL diagnosis to alloSCT was 4.7 years. Thirty-two patients (84%) had received more than 3 prior therapies prior to alloSCT. Thirty-seven patients (97%) had received purine analog-based therapies, 18 (47%) patients had received alkylating agents and 25 (66%) had received alemtuzumab. 33 (87%) patients were purine analog refractory. On cytogenetic evaluation by FISH, 17 (45%) patients had del(17p13), 10 (26%) had del(11q23) and 1 (3%) had del(6q23).Nine patients were in complete remission (CR) by IWCLL 2008 criteria at the time of alloSCT and 7 patients were in complete remission with incomplete marrow recovery (CRi). Of the remaining 22 patients, 20 had either a partial remission or stable disease at the time of alloSCT and 2 had progressive disease. Two (5%) patients had bulky lymphadenopathy (≥ 5cm by CT imaging), 11 (29%) patients had splenomegaly, and 8 (21%) patients had more than 30% CLL involvement by the leukemia index.Fludarabine (F) and 200cGy total body irradiation (TBI) was used as the conditioning regimen for 35 patients (92%). 22 patients received unrelated donor grafts (15 matched, 7 mismatched), and 16 received related donor grafts (all matched). Patients received mycophenolate (MMF) and either tacrolimus (unrelated grafts) or cyclosporin (related grafts) for graft versus host disease (GVHD) prophylaxis. 31 out of 37 evaluable patients (84%) achieved initial 100% donor chimerism (22 within 100 days) and 24 (63%) developed ≥grade 2 GVHD.After median follow-up of 1 year (range = 0–5.4 years), 26 of 38 patients (68%) are alive, and the median overall survival is 47 months. To date, 13 (34%) have experienced CLL progression/relapse requiring accelerated taper of GVHD prophylaxis (n = 2), donor lymphocyte infusion (n = 5), or chemo/immunotherapies (n= 6). For the 12 deceased patients, causes of death was CLL relapse/progression (n = 5), GVHD (n = 2) and infectious or other complications without CLL relapse/progression (n = 5).Pre-transplant use of alemtuzumab (A) within 3 months of transplant was the only pre-transplant characteristics associated with overall survival (OS). Median OS of patients receiving A within 3 months of alloSCT was 1 year compared to not reached for those who did not receive A within 3 months of alloSCT (p = 0.011; Figure 1a). A trend was also observed between alemtuzumab use within 12 months of alloSCT; however, it did not reach statistical significance (p=0.069; Figure 1b). No statistically significant associations between residual marrow involvement at time of alloSCT (p = 0.93), type of graft (p = 0.65), or presence of del (17p13) (p = 0.13), number of prior treatments (p = 0.45), patient age (p = 0.80) or disease status at time of alloSCT (p = 0.21) were observed. [Display omitted] [Display omitted] CONCLUSION:In this cohort of patients with high risk CLL, alemtuzumab use prior to transplant was the greatest predictor of OS after nonmyeloablative alloSCT. Non-alemtuzumab based debulking strategies need to be developed for patients with del (17p13). Disclosures:No relevant conflicts of interest to declare.

Favorable Outcomes in Patients with High Donor-Derived T Cell Count Following In Vivo T Cell Depleted Reduced Intensity Allogeneic Stem Cell Transplantation

Abstract 3043In patients undergoing T cell depleted stem cell transplantation (SCT) a high rate of mixed chimerism is seen. Further, chimerism analysis does not consistently predict risks of GVHD or relapse upon withdrawal of immunosuppression (IS) in these patients. Thus, a reliable predictor for the expected evolution of mixed T cell chimerism is needed to help in clinical decision-making for withdrawal of IS and donor lymphocyte infusion (DLI). An alternative immune parameter is T cell recovery post-transplant. We combined this measure with T cell chimerism and examined the predictive value of a calculated donor-derived T cell count for clinical outcomes following SCT.Patients were enrolled in a randomized clinical trial examining two different doses of rabbit anti-thymocyte globulin (ATG 2.5 or 1.7 mg/kg/day; Thymoglobulin®, Genzyme, Cambridge, MA) given IV on day –9 through –7, followed by total body irradiation (4.5 Gray), administered in 3 doses on day –1 and 0 (NCT00709592). Donor engraftment was measured by PCR of short tandem repeat alleles in each donor and patient at 4, 8, 12, and 24 weeks following SCT on whole blood, granulocytes, and total T cells. Between 2008 and 2011, 25 patients were enrolled in this trial, and 22 patients were eligible for this analysis. Nine of the 22 patients had mixed T cell chimerism (≥5% recipient DNA) at 8 weeks post-transplant, and of these 33% (n=3) became fully donor T cell chimeric after withdrawal of IS over the ensuing weeks. One of the 9 patients had improved donor chimerism after DLI. Of the 13 patients who were full donor chimeric in T cells, one patient reverted from full donor to mixed chimerism.Donor-derived CD3+ T cell count (dd CD3) was calculated from T cell chimerism and absolute blood CD3+ T cell count. Median dd CD3+ cell count at 8 weeks following SCT was 433 ƒýL (range: 3–2464). After calculating the sum of receiver operating characteristic area under the curves (AUC), a dd CD3 of 110ƒýL was found to be the optimal cut-off value with both the highest AUC sum and the highest AUC for each measure (cumulative acute and chronic GVHD: 0.79, remission: 0.74, whole blood chimerism: 0.88), and was subsequently used to distinguish between low (<110; n=8) and high (>110; n=14) values of dd CD3. A significant correlation was found between this single dd CD3 level discriminator and higher rates of cumulative GVHD (Fishers Exact Test: p = 0.024), remission (p = 0.0524) and full donor whole blood chimerism at ≥12 weeks following SCT (p < 0.0001) in patients with high-dd CD3 cell counts. Furthermore, Bayesian analysis showed higher whole blood mixed chimerism rates (Posterior Probability = 0.99), lower GVHD rates (PP = 0.99), and lower remission rates (PP = 0.99) in the low-dd CD3 group. Both overall survival and time to relapse favored the high-dd CD3 group (vs. low-dd CD3 group). However, while the relationship was significant for relapse (p = 0.028), it was only marginally significant for overall survival (p = 0.07). When measured after withdrawal of IS, declining donor or persistent mixed T cell chimerism was observed in patients who had mixed T cell chimerism and low- dd CD3 at eight weeks post SCT (Fig 1A), whereas those with high- dd CD3 had increasing donor T cell chimerism (Fig 1B). Granulocyte chimerism too was modulated by dd CD3 in patients with mixed chimerism and early DLI arrested the decline of donor hematopoiesis in a patient with low-dd CD3. NK cell counts were significantly higher in the high-dd CD3 group than in the low-dd CD3 group at 8 weeks (p = 0.044; PP = 0.99). No significant relationships were found between dd CD3 levels and donor age, donor type, total ATG dose, and infused graft CD34+ or CD3+ cell dose. [Display omitted] In conclusion, we report the effect of an easily calculable measure of donor T cell reconstitution on clinical outcomes following SCT (particularly GVHD), stability of engraftment and disease relapse. Donor-derived CD3+ cell count may help in the decision-making regarding IS withdrawal and DLI timing in allogeneic SCT recipients. We will be confirming the optimal dd CD3 cell count parameter in larger patient cohorts with comparable disease biology for validation in regimens of varying myeloablative intensities. Disclosures:Toor:Genzyme: Research Funding. Off Label Use: ATG in stem cell transplantation.