ALBERT

Description: Introduction For patients in need of a hematopoietic stem cell transplant (HSCT) but lacking an HLA matched donor, a haploidentical family donor is a particularly appealing alternative. However, to prevent graft-versus-host disease (GVHD), haploidentical HSCT necessitates intensive in vivo or ex vivo T-cell depletion that results in frequent and often lethal infectious complications and/or high relapse rates, thus decreasing overall survival. To overcome this limitation, we have developed a strategy that photodepletes host-reactive cells from the donor T cell graft, while preserving anti-infection and anti-leukemia reactivity. Patients and Methods In an open-label, multi-center phase 2 clinical trial (CR-AIR-007; NCT01794299), 12 of a planned 23 patients with high-risk hematologic malignancies were treated to date with this immunotherapy approach consisting of donor lymphocytes selectively allodepleted of host-reactive T-cells using photodynamic therapy (ATIR). ATIR was infused 28-32 days after haploidentical CD34-selected HSCT. No post-transplant GVHD prophylaxis was used. These patients were compared to a control group of 28 patients treated in a previous Phase 2 study with an investigational product manufactured using a process different from the Phase 1 trial and resulting mainly in dead and inactive cells instead of ATIR (CR-AIR-004). Results Twelve patients, mean age of 45 (range 21-64), 6 females/6 males with AML (n=9) and ALL (n=3) were treated with ATIR so far. ATIR consisted mainly of T-cells (〉90%), with residual B and NK cells (≤10%). Selective depletion of recipient-reactivity in each ATIR cell graft was assessed using a CFSE-based proliferation assay. Cell division numbers upon stimulation were analyzed using Modfit LT software (Fig 1A), which generated a proliferation index representing viable/reactive T-cells in donor cells (blue) and final ATIR product (green)(Fig 1B). Selective depletion of recipient-reactive T-cells with preservation of reactivity towards 3rd party antigens and anti-CD3/CD28 was observed in all ATIR cell grafts and used as a release criteria in the 007 study. Figure 1: A) CFSE-dilution pattern in Modfit LT software of ATIR stimulated with 3rd party cells. B) CFSE-based proliferation confirmed selective depletion of recipient-reactive T-cells in all grafts (representative depiction). Figure 1:. A) CFSE-dilution pattern in Modfit LT software of ATIR stimulated with 3rd party cells. B) CFSE-based proliferation confirmed selective depletion of recipient-reactive T-cells in all grafts (representative depiction). Preparative regimen consisted of A) FTBI (1200 cGy; n=5) or B) melphalan (120 mg/m2; n=7), along with thiotepa (10 mg/kg), fludarabine (30 mg/m2 x5 d) and ATG (2.5 mg/kg x4 d). Neutrophil and platelet engraftment was achieved in all patients at a median of 12 days (range: 9-35). No patient experienced graft rejection. Patients (n=28) in the 004 control group, mean age of 42 (range 18-61), 13 females/15 males had AML (n=19), ALL (n=6) or MDS (n=3). CFSE proliferation in T-cell grafts could not be assessed a posteriori due to low cell viability. These 004 patients received the same A) FTBI- (n=14), B) melphalan- (n= 10) based preparative regimen as 007 patients, except for 4 patients receiving single fraction (800 cGy) TBI. Neutrophil and platelet engraftment was achieved at a median of 16 days (range: 7-54). Three patients showed secondary graft rejection. Two patients in study CR-AIR-007 developed acute GVHD grade I (skin only) approximately 130 days post HSCT, which was of short duration, (18 and 41 days). Two patients died of infection and no patient relapsed at a mean follow-up of 8 months post HSCT (range 1-14 months). In the CR-AIR-004 control group, 2 patients developed grade I, 1 patient grade II and 3 patients grade III GvHD, none of these cases were lethal. Seventeen patients died of transplant related complications and 2 patients of relapse/disease progression. TRM is 20% in 007 group vs 63% in the 004 control group and OS is 80% in 007 group vs 35% in the 004 control group at 9 months post-transplant (Figures 2A and 2B). Figure 2A Kaplan Meier Transplant Related Mortality: 004 vs 007 (p=0.06) Figure 2B Kaplan Meier Overall Survival (OS): 004 vs 007 (p=0.03) Conclusions These data confirm that a novel immunotherapy strategy consisting of donor lymphocytes selectively photodepleted of alloreactive cells (ATIR) can be manufactured consistently and reproducibly. Results to date show that ATIR is safe and does not cause any grade III/IV GvHD. Moreover, haploidentical HSCT patients treated with ATIR demonstrate very promising TRM and OS rates when compared to the control group. Disclosures Roy: Kiadis Pharma: Consultancy, Research Funding. Foley:Hoffman-LaRoche: Advisory Board/Lectures Other, Honoraria; Lundbeck: Advisory Board/Lectures, Advisory Board/Lectures Other, Honoraria; Sanofi: Advisory Board/Lectures, Advisory Board/Lectures Other, Honoraria; Celgene: Advisory Board/Lectures, Advisory Board/Lectures Other, Honoraria; Pfizer: Advisory Board/Lectures Other, Honoraria; Novartis: Advisory Board/Lectures Other, Honoraria; Jansen: Advisory Board/Lectures Other, Honoraria; Alexion: Advisory Board/Lectures, Advisory Board/Lectures Other, Honoraria; Roche Canada: Honoraria, Research Funding, Unrestricted educational grant, Unrestricted educational grant Other. De Jong:Kiadis Pharma: Employment. Velthuis:Kiadis Pharma: Employment. Gerez:Kiadis Pharma: Employment. Reitsma:Kiadis Pharma: Employment. Wagena:Kiadis Pharma: Employment.

Description: Introduction: There is strong evidence that the cytopenia(s) in MDS might be caused by excessive, cytokine induced, intramedullary apoptotic death of progenitor hematopoietic cells. TNFα is a key cytokine that may trigger and sustain the excessive apoptosis processes in early disease. Infliximab is a chimeric human-murine monoclonal antibody with high affinity for human TNFα. Infliximab effectively prevents TNFα specific signaling in immune mediated inflammatory diseases. The therapeutic potential of suppressing TNFα mediated apoptosis in MDS was investigated. Patients and methods: The EORTC LG conducted an open label 2-arm randomized, Simon 2-stage design, phase II study, with the primary objective of assessing the activity of two different dose levels of Infliximab, as single agent, in patients (pts) with low-/intermediate-risk MDS according to IPSS. Activity was assessed by response rate, using the International Working Group criteria: Complete Response (CR) + Partial Response (PR) + Hematological Improvement (HI). Toxicity was assessed as a secondary objective. Results: Between February 2004 and March 2006, 37 eligible/evaluable pts (targeted sample size for the analysis of first stage) were randomly assigned to receive Infliximab, 3 mg/kg (18 pts) vs 5 mg/kg (19 pts), intravenously on days 1 and 15, thereafter every 4 weeks, for a total of 8 courses. Baseline characteristics by treatment arm (3 mg/kg vs 5 mg/kg) were: median age (65 vs 69 years); IPSS risk score: low (2 vs 6 pts), Intermediate-1 (14 vs 10 pts), Intermediate-2 (2 vs 3 pts); cytogenetic risk group: good (9 vs 12 pts), intermediate (5 vs 4 pts), unknown (4 vs 3 pts). Treatment applicability (3 mg/kg vs 5 mg/kg): 20 pts (10 vs 10) completed the 8 cycles of therapy, and 17 pts (8 vs 9) stopped earlier due to: progressive disease (2 vs 4), excessive toxicity (3 vs 0), patient’s refusal (2 vs 2), death due to an unrelated cause (1 vs 1), other reasons (0 vs 2). Activity (3 mg/kg vs 5 mg/kg): 3 pts responded to treatment in the 3 mg/kg arm: 1 CR, 1 PR and 1 HI (neutrophils), while no patient responded in the 5 mg/kg arm. A total of 21 pts (7 vs 14) had stable disease, 11 pts (7 vs 4) had documented disease progression and 2 pts were inevaluable for response (1 vs 1). After a median follow-up of 1.5 years, 8 pts (6 vs 2) died. Adverse events: 3 out of 18 patients died due to infections in the 3 mg/kg arm vs 0/19 in the 5 mg/kg arm. Two of the lethal infections were considered likely related to protocol treatment: one patient developed a fatal mucormycosis during treatment and one patient developed a fatal sepsis shortly after the eighth Infliximab infusion and thereafter also had documented progression to AML. There were few other AE/toxicities. Conclusion: Infliximab in the 3 mg/kg dose/schedule showed some activity in this study. Infliximab has limited activity as single agent but may warrant further investigation in combination with other active agents. Patients must be monitored closely for occurrence of severe infections.

Description: Abstract 4953 Background: Shared decision-making between patients and physicians is broadly advocated in medicine, however little research is available to understand whether this approach would be desirable to all patients regardless of disease type and severity or individual patient characteristics. While clinical decision-making in high-risk myelodysplastic syndromes (MDS) is critical for a number of reasons including: associated comorbidity, symptom burden, and limited life expectancy, no evidence-base data currently exist on patients' preferences. Aim: The objective of this study is twofold: 1) to investigate to what extent high-risk MDS patients prefer to be involved in treatment decision making during consultation just after diagnosis; 2) to identify possible clinical, socio-demographic and patient-reported health status factors associated with patients' preferences for involvement in treatment decisions. Patients and Methods: Data were gathered through an ongoing international prospective observational study involving 15 countries that recruits newly diagnosed patients with intermediate-2 or high-risk IPSS score. All patients were classified according to the WHO histology classification. During the first encounter with their treating physicians, discussing treatment options just after diagnosis, patients were administered a previously internationally validated “control preference scale”. This scale broadly categorizes patients into one of three roles depending on the extent of their preferred involvement in treatment decision-making: “active” (where the patient themselves prefer to decide on which would be the most appropriate treatment option for themselves); “collaborative/shared” (where the patient and the doctor jointly decided on the most appropriate treatment option); “passive” (where the patient prefer to leave decision on the most appropriate treatment option to the doctor). Associations with the following variables were investigated: performance status, comorbidity (“Hematopoietic Cell Transplantation”-“Comorbidity index”), living arrangements, age, gender, education, cultural group, IPSS risk category, evolution from lower IPSS risk scores and patient-reported symptoms (using symptom scales of the EORTC QLQ-C30). Descriptive statistics were used and Mann-Whitney U-test, Kruskall-Wallis test and Fisher's exact test were used as appropriate to test statistical significance of performed comparisons. Results: Study population included overall 121 patients (38% female and 62% male). Mean age of patients was 69 years (min:31.3 max: 87.9) and 80% were diagnosed with IPSS int-2 risk score and 20% with IPSS high risk score. Twenty-six percent evolved from lower IPSS risk scores, while 74% were newly diagnosed with higher-risk. Forty-nine percent favored a passive while only 13% preferred an active role in treatment decision-making; the remaining 38% favored a collaborative/shared decision-making approach. Investigation of factors possibly related to preferred roles, found that passive role was significantly associated with lower education levels (P=.04). Among lower educated patients, 62.5% preferred a passive role compared with only 5% preferring an active role. When investigating relationships with patient-reported symptoms, a general trend for patients preferring a passive role, showing worse outcomes, was also evident. Higher symptom mean scores were found for passive vs. active role groups, being respectively: 46 (sd.26.6) vs. 37 (sd.29.9) for fatigue; 20 (sd.31.8) vs. 2 (sd.8.6) for constipation; 34 (sd.33) vs. 24 (sd.29.5) for dyspnea. Exploratory analysis showed that overall mean symptom score was statistically significant worse in patients preferring a passive role vs. those preferring an active role (P=.01). While other trends of associations were noted, these were not statistically significant. Conclusion: This is the first evidence suggesting that a consistent percentage of high-risk MDS patients prefer a passive role when discussing treatment options with their treating physicians at the time of diagnosis. There is also an indication that these patients are those with lower education levels and presenting with a higher symptom burden. Results need to be confirmed in a larger sample size. Disclosures: No relevant conflicts of interest to declare.

Description: Few studies have reported on the efficacy of donor lymphocyte infusions (DLI) for myelodysplastic syndromes (MDS) relapsing after T-cell depleted allogeneic stem cell transplantation. Since 1996 we have treated 11 patients with DLI as a single therapeutic modality (without chemotherapy) for a relapse of MDS after allogeneic stem cell transplantation. Median age of the patients was 56 years (range 23 to 73 years). Initial diagnosis was RAEB (4 patients), RAEBt (3 patients), secondary AML(3 patients) and MDS with fibrosis (1 patient). Conditioning was myeloablative in 10 patients ( TBI -Cyclophosphamide, Busulfan-Cyclophosphamide or Busulfan-Melphalan) and non-myeloablative in 1 patient (Busulfan-Fludarabine-ATG). Source of stem cells was peripheral blood in all patients. Donors were HLA-identical siblings in 10 patients and HLA-matched unrelated in 1 patient. Allografts were T-cell depleted with Campath 1H in the bag in 8 of 11 patients. GVHD prophylaxis was cyclosporin in all patients combined with methotrexate in the 3 patients receiving unmodified stem cells. Relapse of MDS occurred at a median of 123 days (54 to 373 days) after allograft. At the time of DLI the percentage of blast cells in the bone marrow ranged from 3 % to 50 % (median 6 %); donor chimerism ranged from 14 % to 91 % (median 72%). The total dose of CD3 lymphocytes ranged from 0.1 to 30 x 10 7 /kg (median 0.6 x 10 7/kg) and was administered in 1 to 4 infusions (median 1). Time interval between first and second DLI varied between 7 and 180 days.Three of the 11 patients achieved a durable complete remission with 100 % donor chimerism after DLI. These 3 patients are currently disease free at 20, 30 and 40 months from the first DLI. All durable responses were associated with limited chronic GVHD requiring temporary immunosuppressive therapy. Time interval between the first DLI and the achievement of complete donor chimerism varied between 6 weeks and 9 months. One of the 11 patients achieved a short state of complete chimerism for 4 weeks and died from relapse 146 days after DLI. Five of the 11 patients progressed after DLI and 4 of them died from disease progression at 29 to 112 days after first DLI. Two patients died at 26 and 97 days after the first DLI from acute GVHD grade IV after having received only 1 x 10 6 CD3 lymphocytes /kg from HLA-identical sibling donors. None of the 6 patients with a complex karyotype responded to DLI while 3 of 3 patients with a single chromosomal abnormality ( t(1,14), t(1,17), t(1,3)) had a durable response (p-value = 0.01). We conclude that DLI is a powerful therapy for about 30 % of MDS patients relapsing after T-cell depleted allogeneic stem cell transplantation. DLI may result in durable remissions particularly in patients with non-complex cytogenetic abnormalities. However, even low doses of donor T lymphocytes may cause mortality from severe GVHD.

Description: Abstract 679 Chronic ITP is an autoimmune disease characterized by low platelet counts due to both increased platelet destruction and suboptimal platelet production. Immunosuppressive ITP therapies have variable response rates and may be associated with substantial side effects, limiting their use for long-term treatment. Romiplostim is a novel peptibody that increases platelet counts by a mechanism similar to thrombopoietin, and is approved for the treatment of chronic ITP. We present final results from a phase 3b, randomized, open-label study, comparing the incidence of splenectomy and treatment failure in adult nonsplenectomized ITP patients receiving either romiplostim or medical standard of care (SOC). Patients were randomized (2:1) to romiplostim or SOC. Eligible patients had a platelet count

Description: Introduction: Thrombocytopenia (TCP) is a serious and life-threatening complication of advanced myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML). Eltrombopag (EPAG), an oral thrombopoietin-receptor agonist, is approved for treatment of chronic immune thrombocytopenic purpura and severe aplastic anemia. Preclinical studies showed that EPAG has potential antileukemic effects. A phase 1 study in advanced MDS/AML demonstrated an acceptable safety profile at doses up to 300 mg, with no worsening of leukemia, and it also showed a trend towards efficacy. Eltrombopag as monotherapy in MDS/AML has not been studied in a randomized fashion. Methods: In Study TRC114968 (ASPIRE), after 8 weeks of open-label, dose-defining EPAG treatment (Study Part 1), patients with highly advanced MDS or AML were randomized 2:1 to EPAG 100-300 mg or placebo (PBO) once daily for 12 weeks (Part 2), then entered a 6-month, open-label extension (Part 3). Patients were stratified by baseline platelet count (

Description: The AML-12 randomized phase III trial of EORTC-LG and GIMEMA assessed the efficacy and toxicity of HD-AraC (3 g/m2/12 hrs for 4 days) combined with daunorubicin (50 mg/sqm for 3 days) and etoposide (50 mg/sqm for 5 days) vs SD-AraC (100 mg/sqm for 10 days) with the same drugs. Patients (pts) in complete remission (CR) received consolidation consisting of AraC (500 mg/sqm/12 hrs for 6 days) and daunorubicin. Subsequently an allogeneic (allo-SCT) or autologous stem cell transplantation (auto-SCT) was planned according to donor availability and age. A 2nd randomization was performed after CR in pts without a donor: auto-SCT followed or not by low dose IL-2. The trial was powered to detect an 8% difference in the 5-yr survival rate; secondary endpoints were response to induction, DFS, toxicity. Randomization was performed centrally; the 1st randomization was stratified for age, performance status, WBC and center. Intent-to-treat analysis was done. From 9/1999 till 1/2008, 2005 previously untreated AML pts (APL excluded), age

Description: RW and FB are co-senior authors. Background: The prognosis of younger patients with intermediate/bad risk AML or high-risk MDS remains unsatisfactory. Although with current remission induction chemotherapy, 60-85% of patients achieves complete remission (CR), only 30-50% of them remains alive for more than 5 years. Clofarabine, a second-generation purine analog, is highly active as a single agent in AML. Willemze et al (Ann Hematol, 2014) recently reported the results of phase I of the AML-14A study and identified clofarabine at 10 mg/m2/day for 5 days as the maximum tolerated dose (given either in a 1-h infusion or as push injection) in combination with cytosine arabinoside (Ara-C) and idarubicin. We herein report the final results of the combined phase I and II parts of the AML-14A study that explored the antitumor activity of clofarabine containing induction combination regimens at the aforementioned phase I selected dosage schedules. Methods: Patients aged 18-60 years with intermediate/bad-risk AML or high-risk MDS (≥10% bone marrow blasts), adequate renal and hepatic function, and WBC count 65% or not. Using a Fleming design, the regimen was considered active if ≥ 23 out of 30 patients per arm achieved CR/CRi. Secondary endpoints included safety, CR/CRi rate after consolidation, hematopoietic recovery, ability of CD34 harvesting after consolidation, disease-free survival (DFS) and survival from CR/CRi, and overall survival (OS). Randomization was stratified by institution and by presence of poor prognostic features (WBC at diagnosis 〉=100 x 109/L or very high-risk cytogenetics/FLT3-ITD). Results: A total of 64 patients was randomized: 12 in the phase I part and 52 in the phase II part of the study. Two patients did not meet the inclusion criteria and were excluded. Among the remaining 62 patients, 5 had high-risk MDS. Median age was 50 yrs (range 20-60). Baseline characteristics were well balanced between the two arms. The CR/CRi rate after induction was 84% (26 of 31 patients) in each arm (95% CI: 66-95%) (Table 1). In Arm A vs Arm B, the most frequent grade 〉2 non-hematological and non-infectious adverse events over the induction-consolidation period were anorexia (29% vs 32%), and diarrhea (26% vs 32%). Finally, during treatment period there were 2 toxic deaths in Arm-A and 1 in Arm-B. Table 1: Patient outcomes. Median follow-up was 1.8 (range, 1 – 5.25) yrs. Arm-A (n=31) Arm-B (n=31) CR/CRi after 1-2 courses of induction, # pts (%) 23 (74) / 3 (10) 25 (81) / 1 (3) CR/CRi after 1 course of induction, # pts (%) 23 (74) / 3 (10) 24 (77) / 1 (3) OS median (95%CI), yrs 2.5 (1-NR) NR OS at 1-yr (95%CI), % 74 (55-86) 74 (55-86) # of infectious episodes with G3-4 neutropenia / # of patients with infection episodes 47 / 30 59 / 31 In patients who achieved CR/CRi Time to recovery from start of course 1 # of days with neutrophils

Description: Abstract 791 The AML-12 randomized phase III trial of the EORTC and GIMEMA Leukemia Groups assessed the efficacy and toxicity of HD-AraC (3 g/m2/12 hrs for 4 days) combined with daunorubicin (50 mg/sqm for 3 days) and etoposide (50 mg/sqm for 5 days) vs SD-AraC (100 mg/sqm for 10 days) combined with the same drugs. Patients (pts) in complete remission (CR) received consolidation consisting of AraC (500 mg/sqm/12 hrs for 6 days) and daunorubicin (50 mg/sqm for 3 days). Subsequently an allogeneic (allo-SCT) or autologous stem cell transplantation (auto-SCT) was planned according to donor availability, cytogenetics and age. A 2nd randomization was performed after consolidation in pts without a donor: auto-SCT followed or not by low dose IL-2 (4-8 × 106 IU s.c. for 5 days per month) during one year. A total of 577 patients were required to be randomized for the 2nd question in order to reach 255 events (relapses or deaths) which would allow to detect a 11.5% increase in the 3-year disease-free survival (DFS) from 50% to 61.5% corresponding to hazard ratio (HR) = 0.70 (2-sided alpha=5%, statistical power=80%). Randomization was performed centrally; the 2nd randomization was stratified for induction treatment, cytogenetic/molecular genetic group, number of courses to reach CR, auto-SCT planned (No/Yes) and center. Intent-to-treat analysis was done. From 9/1999 till 1/2008, 2005 previously untreated AML pts (APL excluded), age

Description: Experience with haploidentical stem cell transplantation in elderly patients after non TBI (total body irradiation) containing regimens is limited. We report a single centre experience with haploidentical stem cell transplantation in 16 patients with poor prognosis myeloid and lymphoid malignancies refractory to conventional therapy or relapsing after autologous stem cell transplantation. For none of these patients a HLA matched related or unrelated donor was available. All patients were transplanted between April 2004 and May 2007. Age was between 16 and 71 yrs (median 57 yrs), 11 of 16 were more than 50 yrs old. Of the 16 patients 3 had lymphoid malignancies (1 Hodgkin, 1 myeloma, 1 Phi+ ALL) and 13 had high risk MDS (myelodysplasia) or primary or secondary AML. All patients had relapsed after or were refractory to conventional chemotherapy (11 patients) or had relapsed after autologous stem cell transplantation (5 patients). All patients were prepared with a conditioning regimen consisting of Thiotepa 2 × 5 mg/kg on day −8, ATG Fresenius 5 mg/kg on days −7 to −3, Fludarabine 40 mg/m2 on days −7 to −3, Melphalan 100–140 mg/m2 on days −2. CD34 selection was by Clinimacs without postgrafting GVHD prophylaxis. Grafts contained a median of 9,8 × 106 CD34/kg (range 3,3–16,6 × 106/kg) and a median of 0,11 × 105 CD3/kg (range 0,04–0,3 × 105/kg). All donors were haploidentical family members. 13 of 16 donor-recipient pairs had at least one KIR ligand mismatch in the GVH (graft versus host) direction. Graft rejection occurred in 2 of 16 transplants, 1 patient was rescued with a second transplant from another haploidentical donor. All surviving patients are full chimeras (〉 95% donor chimerism). Median time to ANC 〉 0.5 x10 9/l was 12,5 days (range 7–18 days) and median time to platelets 〉 50 × 109/l was 21,5 days (range 14–199 days). 5 of 16 patients died before they achieved a platelet count 〉 50 × 109/l. Non relapse mortality occurred in 4 of 16 (25%) patients within 1 year after transplantation. Causes of death were: aspergillosis 1, VOD 1, CNS bleeding 1, cGVHD 1. Acute GVHD grade II-IV occurred in 3 patients and was manageable with steroids and/or ATG. Chronic GVHD was observed in 3 patients (after DLI in 2 of them). Infections were the most important complication: aspergillosis in 7 patients, CMV in 4 patients, listeria meningitis in 1 patient. EBV-associated lymphoproliferative disease was seen in 2 patients, both responded to rituximab and DLI (donor lymphocyte infusions). Disease progression and relapse occurred in 6 patients within 1 year after transplantation (myeloma 1, AML 5). None of the relapsing patients responded to escalating doses of DLI. At the time of this report 8 of 16 patients are surviving, 6 of them without evidence of disease between 159 and 1214 days (median 425 days) after transplantation. Of the 6 disease free survivors 4 are older than 50 yrs and 5 have a KIR ligand mismatch in the GVH direction. Kaplan Meier estimate for overall survival and disease free survival is 43% at 2 yrs and 39% at 2 yrs respectively. We conclude that transplantation from natural killer (NK) alloreactive haploidentical family donors offers potential cure to about one third of elderly patients with advanced leukemia or MDS considered incurable by other therapies. TBI does not seem to be required to benefit from this treatment approach. Relapse rate and infectious morbidity remain major obstacles.