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This study describes the outcome of patients receiving haematopoietic stem cell transplantation (HSCT) to treat severe refractory autoimmune cytopenia. The registry of the European Group of Blood and Marrow Transplantation holds data on 36 patients receiving 38 transplants, the first transplant was autologous for 27 and allogeneic for nine patients. Patients had autoimmune haemolytic anaemia (autologous: 5; allogeneic: 2), Evans's syndrome (autologous: 2; allogeneic: 5); immune thrombocytopenia (autologous: 12), pure red cell aplasia (autologous: 4; allogeneic: 1), pure white cell aplasia (autologous: 1; allogeneic 1), or thrombotic thrombocytopenic purpura (autologous: 3). Patients had longstanding disease having failed multiple prior treatments. Among 26 evaluable patients mobilized for autologous HSCT, three died of treatment-related causes, one died of disease progression, seven were non-responders, six patients had transient responses and nine had continuous partial or complete remission. Of the seven evaluable patients receiving allogeneic HSCT, one died of treatment-related complications, one with transient response died of progressive disease and five had a continuous response. Autologous and allogeneic HSCT may induce a response in a subset of patients with autoimmune cytopenia of long duration albeit at the price of considerable toxicity.

The inv(16)(p13q22) chromosomal rearrangement associated with FAB M4Eo acute myeloid leukemia (AML) subtype is characterized by the presence of the CBFbeta/MYH11 fusion transcript that can be used to detect minimal residual disease (MRD). However, qualitative RT-PCR studies of MRD have so far produced conflicting results and seem of limited prognostic value. We have evaluated retrospectively MRD in a large series of CBFbeta/MYH11-positive patients employing both qualitative and quantitative (real-time PCR) approaches. 186 bone marrow samples from 36 patients were examined with a median follow-up of 27.5 months; 15 patients relapsed during follow-up. In qualitative studies, carried out by 'nested' RT-PCR assay, all patients in complete remission (CR) immediately after induction/consolidation therapy were found to be PCR positive. However, follow-up samples at later time points were persistently negative (except one case) in patients remaining in continuous CR (CCR) for more than 12 months. 16 patients were evaluated by quantitative real-time PCR assay: CBFbeta/MYH11 transcript copy number was normalized for expression of the housekeeping gene ABL, expressed as fusion gene copy number per 10(4) copies of ABL. A 2-3 log decline in leukemic transcript copy number was observed after induction/consolidation therapy. After achieving CR, the mean copy number was significantly higher in patients destined to relapse compared to patients remaining in CCR (151 vs 9, P < 0.0001 by Mann-Whitney test). Moreover, in CCR patients, the copy number dropped below the detection threshold after the treatment protocol was completed and remained undetectable in subsequent MRD analysis in accordance with results obtained by qualitative RT-PCR. On the contrary, in the seven patients who relapsed, the copy number in CR never declined below the detection threshold; thus a cut-off value discriminating these two groups of patients could be established. The findings of our study, if confirmed, might confer an important predictive value to quantitative real-time PCR determinations of MRD in patients with inv(16) leukemia.

Currently, a donor can be virtually found for all patients with an indication for allo-transplantation due to the increased number of hematopoietic stem cell (HSC) donors and increasing use of umbilical cord blood and haplo-transplants. In this study, we have addressed the question of the feasibility of searching HSC donors grafts [HLA-matched sibling donor (MSD), and alternative donors] and performing such transplants or other treatments (such as autologous HSC transplant or chemotherapy) for adults with acute leukemia for whom an indication of allo-HSCT could be planned during the course of their disease. The second objective was to compare in an “intent to treat” analysis, LFS according to planned strategy treatment. Patients were included at HLA typing test. A specific questionnaire was completed specifying the initial strategies planned for each patient and their changes over the period: at HLA typing, after 3, 6, 9, 12 months after the registration, and twice a year for the following 2 years. From 2003 to 2006, 702 adults were enrolled by 31 EBMT centres, 490 had AML, 212 ALL. HLA typing was performed for 443 patients at diagnosis, 172 after first CR, 11 after CR2, and 64 in more advanced phase. Median follow-up was 31 months, median age was 42-years (18–75); 207 patients were aged more than 50 years. A MSD was found for 309 patients (44%). Of 309 patients, 290 patients had 1 MSD, 17 patients 2 MSD and only 2 patients more than 2 donors. In 40 cases where the MDS was found the transplant centres did not planned to perform the transplant. A transplant using a haploidentical donor was planned in 4 cases. At the end, 273 patients were planned to be transplanted from a family donor (269 from a MSD and 4 from an haplo). For the remaining 429 patients, the indication of an auto-HCT was made in 85 (20%) patients, use of chemotherapy as post-remission therapy in 142 (33%) and indication of an allo-HSCT with an alternative donor in 202 (47%). Of those 202 patients, the transplant centres were keen to search for a cord blood donor in 72 cases and for a haplo donor in 11 cases. Analysing the treatment received at the last follow-up and comparing with the strategy planned at the registration, 215 of 270 (80%) patients were transplanted with a family donor, 112 of 142 (79%) patients were still receiving chemotherapy, 53 of 85 (62%) received an autograft and 118 of 202 (58%) received an unrelated transplant. At last follow-up, 448 patients of 702 patients included received an HSCT (64%). Probability of survival at 2 years for 702 patients was 55%. Interval from HLA typing and HSCT was 125 days for MSD, 148 days for unrelated donor, 167 days for unrelated cord blood and 149 days for autologous transplantation. Cumulative incidence function at one year (CIF; using death as a competing event) for receiving an allograft was 81% if the strategy planned was an allograft with a MSD, 57% for those patients for whom an alternative donor was searched and 6% for those patients for whom an allo-transplant was not planed at inclusion. However, CIF at 1-year for really receiving an allograft was 74% in case of MSD, and only 30% for those patients not having an HLA identical siblingAt 2-years, LFS by initial planned strategy at HLA typing was 43% for those patients in whom a donor search was planned, 47% for those with a planned autologous HSCT, 46% for those with planned chemotherapy and 49% for those with a family transplant. In conclusion, the majority of patients (80%) with AL in European centres are HLA typed at diagnosis or CR1. The majority of patients received a MSD as planned treatment in the first year after HLA typing, in the absence of MSD an alternative donor was searched only for 51% of patients and CIF at one year for performing an allotransplant was 30% however in case of searching for alternative donor, transplantation could be performed in 57% of the cases in the first year. Surprisingly, searching for other alternative donors such as unrelated cord blood or haplo-identical donors, was only done for a small proportion of patients, in spite of encouraging results with both strategies. Therefore, in retrospective studies comparing outcomes of HLA identical sibling, and other alternative donor transplants there is a potential bias linked to the decision to search or not in half of the cases, that is probably linked to patients-, disease- and centre-related factors.

Meningeal recurrence in aggressive NHL and ALL occurs in up to 20% of patients and mostly depends on intensity and efficacy of front-line CNS prophylaxis. Liposomal cytarabine (lip araC) is a sustained release formulation of araC with a homogeneous distribution in the neuraxis and a prolonged half life, maintening cytotoxic concentrations in the CSF for more than 14 days. The present study aims to evaluate the safety and tolerability of lip araC in the CNS prophylaxis of NHL and ALL meningeal recurrences. Forty-four patients aged 16–77 years (median 43,9) have been preventively treated with a total of 159 (range: 1–8) doses of lip araC 50 mg. Diagnosis consisted on 33 NHL: 14 high risk-CNS DLBCL (involvement of testes, paranasal sinuses, hard palate, orbit, paravertebral masses and bone marrow or IPI ≥2 with high level of LDH and ≥1 extranodal site involvement), 7 BL, 2 blastoid mantle cell, 7 lymphoblastic, 1 gastric marginal zone lymphoma, 1 anaplastic, 1 follicular, and 11 ALL: 7 B-ALL, 3 T-ALL, 1 hybrid cells. Five patients (1 DLBCL, 1 BL, 2 T-ALL, 1 B-ALL) received lip araC at their 1st systemic recurrence; of them, the DLBCL did not receive previous prophylaxis, instead of the T-ALLs had standard treatment with IT MTX; BL and B-ALL received not specified prophylactic therapy. All patients were treated according to the standard protocols in use for their disease; in particularly, NHL received RCHOP-like treatments, a part of 5 BL (RCODOX-M/R-IVAC-like therapy) and 5 lymphoblastic (hyperC VAD/HD MTX/araC); ALL patients received standard treatments according with GIMEMA, NILG and BMF protocols. Five patients (2 DLBCL, 2 BL and 1 B-ALL) underwent autotransplantation. Four patients received IT or HD systemic MTX during treatment with lip araC. Seven patients received RT, as a part of prophylaxis program. All patients received lip araC 50 mg every 2, 3, 4 or 8 weeks, excepted 2 receiving 30 mg. All patients had corticosteroids for prevention of chemical aracnoiditis. A part of an episode of G2 headache and 18 cases of G1 headache, 8 episodes of G1 nausea/vomiting and 2 cases of localized or diffuse bone pain, no severe toxicity has been noted. So far, after a medium observation period of 9 months (range 1–26) only 1 patient, affected by mantle cell lymphoma, showed CNS recurrence 10 months after diagnosis while in systemic relapse and died. None of the patients developed neurological symptoms or unexpected long term neurological side effects. IT lip araC therapy with concomitant corticosteroids appears to be feasible and well tolerated in the prophylactic setting. Because of only few patients received CNS-directed concomitant therapy, lip araC appears effective towards CNS recurrence in the high risk NHL and ALL. More randomized studies are warranted.