To our knowledge, this is the first report addressing the identification of predisposing factors for DMSO-related neurotoxicty. We conclude that infusion of DMSO-PBSC can be performed safely in patients with pre-existing cerebral disease despite the rare occurrence of severe neurotoxicity. Retrospective multicenter studies are warranted to identify patients who would benefit from elaborate methods of DMSO-replacement.

Ibrutinib, a recently approved inhibitor of Bruton's tyrosine kinase (BTK), has shown great efficacy in patients with high-risk CLL. Nevertheless, there are few data regarding its use in patients who relapsed after allogeneic stem cell transplantation (alloSCT). We report clinical data from five CLL patients treated with ibrutinib for relapse after first or even second allogeneic transplantation. Additionally, we performed analyses on cytokine levels and direct measuring of CD4 Th1 and CD4 Th2 cells to evaluate possible clinically relevant immunomodulatory effects of ibrutinib. All patients achieved partial responses including one minimal residual disease (MRD)-negative remission. Within 1 year of follow-up, no relapse was observed. One patient died of severe pneumonia while on ibrutinib treatment. Beside this, no unexpected adverse events were observed. Flow cytometry and analyses of T cellmediated cytokine levels (IL10 and TNFα) did not reveal substantial changes in T-cell distribution in favor of a CD4 Th1 T-cell shift in our patients. No acute exacerbation of GvHD was reported. In conclusion, these results support further evaluation of ibrutinib in CLL patients relapsing after alloSCT.

No abstract

We tested the feasibility of a reduced-intensity conditioning regimen for hematopoietic stem cell transplantation (HSCT) perspectively allowing an adapted conditioning for performance and disease status. Treatment consisted of 2–4 Gy total body irradiation (TBI), 120mg/m2 fludarabine, 120mg/kg cyclophosphamide, 0–40 mg/kg anti-thymocyte globulin (ATG) and immunosuppression by ciclosporin-A and mycophenolate mofetil. Up to date, 10 patients (median age 59 years) ineligible for conventional conditioning due to age (>50 years), concomitant disease or previous toxicities have been transplanted on an observational basis after obtaining written informed consent. 2 patients received grafts from related donors, 1 patient an unrelated graft with HLA-C mismatch in GvHD vector and all others unrelated matched grafts. 9 patients (90%) received 2 Gy TBI and ≥30mg/kg ATG. 1 patient received 4 Gy TBI and no ATG since presenting with progressiv disease at time of HSCT and receiving an related graft. Median pre-transplant adapted Charlson index was 2,5 (range 0–6), number of previous chemotherapy protocols 2 (range 1–5). No obvious graft rejection occurred. Of the patients evaluable beyond day +30 (N = 8) 8 patients (100%) achieved consistent neutrophil counts >500/μl and 6 (75%) consistent platelet counts of >25,000/μl. Median duration for neutropenia was 25 days (range 15 – 44 days) and for thrombocytopenia 23 days (range 7–55 days). 14 units (range 2–58) packed red cells and of 7 units (range 1–62) platelets had to be given. Median hospital stay was 49 days (range 34–66 days). Of 8 patients with a follow up beyond day +30, 6 (75%) showed a chimerism of >90% around day +30. 1 patient showed a chimerism of 50% due to parallel relapse while 1 patient was not evaluable due to sepsis. All patients evaluable for toxicity (N=8) had CTC grade 4 hematological toxicity. 6 patients (75%) experienced toxicities CTC ≥3, mainly infections. Two patients (25%) died of treatment-related infections. No gastrointestinal toxicity CTC ≥3° and no case of veno-occlusive disease was observed. Hemorrhagic cystitis CTC 2° was observed in 1 patient (10%). Of the patients with a Charlson index ≥3 (N=5), 2 (40%) died of infections and 3 (60%) experienced only toxicities of ≤3. Of the evaluable patients with neutrophil recovery (N=8), 1 (12,5%) presented with acute GvHD of the skin 2° and 2 (25%) respectively with acute GvHD 1° of the skin or gut. 4 patients (50%) showed no signs of acute GvHD. Of the 2 patients evaluable for day >+100, one has chronic limited GvHD. All cases of GvHD required no therapy. Of the three patients evaluable day +100, one suffered from relapse and two are alive in complete remission. Of the patients evaluable day +30 (N=8) two (25%) presented with relapse or progressive disease around day +30, 1 (12,5%) respectively showed stable disease or further remission and 4 patients (50%) showed persisting complete remission. We conclude that the presented regimen is applicable to patients not elegibile for conventional regimens due to its tolerable overall toxicity and particularly low gastrointestinal side effects. Moreover, due to the use of 3 cytotoxic agents and 3 immunosuppressive substances it offers the option for a conditioning adapted to commorbidity, disease status and graft characteristics. A respective stratification will be presented at the meeting.