Management goals for type 1 Gaucher disease: An expert consensus document from the European working group on Gaucher disease.

Gaucher Disease type 1 (GD1) is a lysosomal disorder that affects many systems. Therapy improves the principal manifestations of the condition and, as a consequence, many patients show a modified phenotype which reflects manifestations of their disease that are refractory to treatment. More generally, it is increasingly recognised that information as to how a patient feels and functions [obtained by patient- reported outcome measurements (PROMs)] is critical to any comprehensive evaluation of treatment. A new set of management goals for GD1 in which both trends are reflected is needed. To this end, a modified Delphi procedure among 25 experts was performed. Based on a literature review and with input from patients, 65 potential goals were formulated as statements. Consensus was considered to be reached when ≥75% of the participants agreed to include that specific statement in the management goals. There was agreement on 42 statements. In addition to the traditional goals concerning haematological, visceral and bone manifestations, improvement in quality of life, fatigue and social participation, as well as early detection of long-term complications or associated diseases were included. When applying this set of goals in medical practice, the clinical status of the individual patient should be taken into account.

Risk factors for treatment failure after allogeneic transplantation of patients with CLL: a report from the European Society for Blood and Marrow Transplantation.

For young patients with high-risk CLL, BTK-/PI3K-inhibitors or allogeneic stem cell transplantation (alloHCT) are considered. Patients with a low risk of non-relapse mortality (NRM) but a high risk of failure of targeted therapy may benefit most from alloHCT. We performed Cox regression analyses to identify risk factors for 2-year NRM and 5-year event-free survival (using EFS as a surrogate for long-term disease control) in a large, updated EBMT registry cohort (n= 694). For the whole cohort, 2-year NRM was 28% and 5-year EFS 37%. Higher age, lower performance status, unrelated donor type and unfavorable sex-mismatch had a significant adverse impact on 2-year NRM. Two-year NRM was calculated for good- and poor-risk reference patients. Predicted 2-year-NRM was 11 and 12% for male and female good-risk patients compared with 42 and 33% for male and female poor-risk patients. For 5-year EFS, age, performance status, prior autologous HCT, remission status and sex-mismatch had a significant impact, whereas del(17p) did not. The model-based prediction of 5-year EFS was 55% and 64%, respectively, for male and female good-risk patients. Good-risk transplant candidates with high-risk CLL and limited prognosis either on or after failure of targeted therapy should still be considered for alloHCT.

Unexpected cure from cutaneous leukocytoclastic vasculitis in a patient treated with N-butyldeoxynojirimycin (miglustat) for Gaucher disease.

Cutaneous leukocytoclastic vasculitis (CLV) is a necrotizing inflammation of the small vessels in the dermis. We report the case of a Swedish man with an untreated N370S/L444P Gaucher disease who developed CLV at the age of 79 years. The patient has been treated for CLV with topical and oral corticosteroids, moisturizing agents, and periodically with antibiotics for 3 years without improvement. Administration of miglustat (N-butyldeoxynojirimycin; Zavesca®) because of progress of Gaucher disease resulted in a prompt and durable cure of the CLV.

Different impact of intermediate and unfavourable cytogenetics at the time of diagnosis on outcome of de novo AML after allo-SCT: a long-term retrospective analysis from a single institution.

Karyotype of myeloblasts at the time of AML diagnosis has been shown to be prognostic significant for pre-remission outcome and outcome after allo-SCT, but the latter requires further studies. We conducted a retrospective analysis of the impact of intermediate and unfavourable cytogenetics at the time of primary diagnosis on outcome after allo-SCT in de novo AML. The study included 169 patients who underwent allo-SCT at Karolinska University Hospital between 1980 and 2010. Intermediate and unfavourable cytogenetics were found in 129 (76%) and 40 patients (24%), respectively. Myeloablative and reduced-intensity conditioning were given to 120 (71%) and 49 (29%) patients, respectively. Allo-SCT was performed in CR1 in 122 patients (72%). TRM was 16% in both cytogenetics groups. Relapse occurred in 29% patients with intermediate and in 45% patients with unfavourable cytogenetics (P=0.01). The probabilities of 5-year OS for patients with intermediate and unfavourable cytogenetics were 60 and 43%, respectively (P=0.02). Multivariate analysis revealed intermediate cytogenetics, chronic GVHD, and recipient CMV-negative serostatus as variables associated with favourable OS. Our study showed that outcome after allo-SCT in de novo AML differs depending on cytogenetic risk-group; however its position in post-remission therapy of eligible AML patients is not threatened.

Comparison of general vs regional anaesthesia for BM harvesting: a retrospective study of anaesthesia-related complications.

This retrospective study was conducted to evaluate the safety and complications profile of general anaesthesia (GA) compared with that of regional anaesthesia (RA) for BM harvesting (BMH). The study included 281 donations carried out between 1992 and 1999. Of these, 204 (73%) were allogeneic donations, and GA was carried out in 69% (140 of 204) and RA in 31% (64 of 204) of cases. The other 77 donations were autologous (27%), using GA in 87% (67 of 77) and RA in 13% (10 of 77) of cases. No life-threatening complications occurred, but there were minor intra- and postoperative events during 26 (9%) and after 58 (21%) donations. Postoperative nausea and vomiting was reported in 40 (14%) cases and post-spinal headache after five out of 58 (8.6%) donations in which spinal anaesthesia was carried out. The incidence of intra- and postoperative events did not differ significantly between the GA and RA groups. However, the incidence of postoperative events was higher in the allogeneic group compared with that in the autologous group (25 vs 10%, P<0.01) and in female donors compared with male donors (29 vs 14%, P=0.002). In conclusion, both GA and RA are comparable with regard to BMH. Nevertheless, non-severe intra- and postoperative events were frequent.

Cidofovir for adenovirus infections after allogeneic hematopoietic stem cell transplantation: a survey by the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation.

Adenovirus is an important cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation and there is no established therapy. Cidofovir has in vitro efficacy against adenovirus. We performed a retrospective analysis of 45 patients treated with cidofovir for adenovirus from 10 centers. In total, 16 patients had definite adenovirus disease, 13 probable disease, and 16 asymptomatic infections. A total of 31 (69%) patients were successfully treated with cidofovir, 10 failed, and four were not evaluable owing to early death from other causes. Cidofovir therapy was successful in 10 patients with adenovirus disease, 10 patients with probable disease, and in 10 patients with asymptomatic infections. The overall survival at 28 days and 6 months after initiation of cidofovir therapy was 76 and 46%, respectively. Of the patients, 18 developed toxicity associated with cidofovir: 14 developed renal toxicity and four other types of toxicities. We conclude that cidofovir may be useful against adenovirus after allogeneic hematopoietic stem cell transplantation but additional studies are needed.

[Hemorrhagic cystitis related to the high-dose conditioning therapy in a bone marrow recipient]. / Krwotoczne zapalenie pecherza moczowego wywolane wysokodozowana chemioterapia kondycjonujaca przed przeszczepieniem szpiku kostnego.

Hemorrhagic cystitis (HC) is the syndrome of hematuria combined with symptoms of lower urinary tract irritation in the absence of bacterial infection or generalized hemorrhagic diathesis. HC often occurs as a difficult complication after autologous as well as allogeneic hematopoietic cell transplantation (HCT). It may be secondary to pretransplant preparative regimen (chemotherapy and/or radiation therapy) or viral infection by adenovirus, JC and BK viruses. The most effective treatment for HC has not been established yet. We report a case of a 17-year-old male with common acute lymphoblastic leukemia (cALL) in second CR, who was treated with high-dose chemotherapy (BuCy conditioning regimen) followed by autologous bone marrow transplantation (ABMT), complicated by hemorrhagic cystitis on day 0 (several hours after infusion of transplant material). The immediate use of increased dose of 2-mercaptoethane sulfonate sodium (mesna), bladder irrigation and intensive hydration with forced diuresis resulted in resolution of macroscopic hematuria on day +3 after the transplant and urinary tract recovery with normalization of urine analysis parameters on day +7.

[Rationale and methods for high dose chemotherapy in oncology]. / Zalozenia i metody chemioterapii wysokodozowanej w onkologii.

Waiting for a new, highly effective cytotoxic drugs it is necessary to improve antineoplastic treatment using presently existing drugs and methods. Chemosensitive tumors should be treated with intensive, short-lasting courses of the induction as well as of the adjuvant chemotherapy. Chemotherapy delay, dose reduction, unproper therapy regimen increases risk of the development of drug-resistance and treatment failure. Autologous hemopoietic cell transplantation allows cytostatics dose escalation (high-dose chemotherapy, HDCT) with an acceptable non-hematological toxicity. HDCT with autologous peripheral blood stem cell transplantation (auto-PBSCT) is increasingly used. Auto-PBSCT has the same efficacy as autologous bone marrow transplantation (ABMT), but it is a safer procedure, allows more rapid hemopoietic recovery and shorter hospitalization.

[The role of autologous hematopoietic cell transplantation in adult acute myelogenous leukemia]. / Rola autologicznego przeszczepiania komórek hemopoetycznych w leczeniu ostrej bialaczki szpikowej u doroslych.

High dose chemotherapy with autologous hemopoietic cell transplantation (AHCT) is a common method of treatment of acute myelogenous leukemia (AML). AHCT is a treatment of choice for patients who have no matched family donor. AHCT is particularly recommended for older patients, excluded from allogeneic transplantation procedures. Prospective randomised trials have shown better efficacy of AHCT comparing with conventional chemotherapy in postremission treatment of AML. Both in vitro and in vivo bone marrow purging allow to achieve better transplantation results. Since two years peripheral blood instead of bone marrow is increasingly used as a source of transplant material. It allows more rapid hemopoiesis regrowth. Various methods of immunotherapy such as interleukin-2, Linomid and mixed hemopoietic cell transplantation (delayed donor lymphocytes transfusion) are used to evoke an autologous graft versus leukemia (GvL) phenomenon and to reduce AML relapse rate. Analysis of prognostic factors allows to identify a group of AML patients for whom AHCT is strongly recommended.

[Nonmyeloablative allogeneic hematopoietic stem cell transplantation: minitransplantation]. / Przeszczepianie allogenicznych komórek hemopoetycznych z zastosowaniem niemieloablacyjnego leczenia kondycjonujacego: minitransplantacja.

Allogeneic hematopoietic stem cell transplantation (alloHCT) is considered as a treatment of choice for many malignant hematologic disorders and genetic diseases. Unfortunately toxicities of conventional alloHCT remain a major limitation to successful application of the procedure. A radically new approach for alloHCT has been developed. Nonmyeloablative preparative regimen allows to establish mixed hematopoietic chimerism after alloHCT. A state of stable mixed chimerism may represent a starting point for induction of full donor derived hematopoiesis. A published results of several clinical trials have confirmed potential benefits of this new approach such as less procedure--related toxicity, protection from severe acute GVHD (graft versus host disease), lower TRM (transplant related mortality). Intensive investigations are done to replace in the future pretransplant chemotherapy and/or radiation by nontoxic anti-T-cell agents. These include antibody to the T-cell receptor alpha beta and blockers of T-cell costimulation (e.g. CTLA4lg).

[Hairy cell leukemia--a potentially curable malignancy. Selected aspects of purine analog therapy]. / Bialaczka wlochatokomórkowa--nowotwór potencjalnie wyleczalny. Wybrane aspekty zastosowania analogów purynowych.

Hairy-cell leukemia (HCL) is a lymphoproliferative B-cell malignancy--it represents about 2% of all adult leukemias. HCL is associated with pancytopenia and splenomegaly. In the late 1980s, introduction of new purine analogs such as 2-deoxycoformycin (pentostatin, DCF) and 2-chlorodeoxy-adenosine (2-CdA) significantly improved the prognosis of HCL patients. 33-89% patients can achieve a complete remission (CR) following DCF treatment and 85% CR after 2-CdA therapy. There is no cross-resistance between pentostatin and 2-CdA. Residual hairy cells are present in bone marrow of almost all patients after purine analogs therapy, detected by immunohistochemical methods. It is called minimal residual disease (MRD). The spleen may be the source of MRD after purine analogs therapy. Thus splenectomy could be a profitable approach after chemotherapy. Hairy-cell leukemia relapse appears in 47.8% of cases in 30 months after pentostatin treatment and in 23% of cases in 3 years after 2-CdA therapy. There is no perfect treatment of HCL relapse. Thanks to new purine analogs hairy-cell leukemia may be considered a potentially curable disease.

[The causes of treatment ineffectiveness in acute myelogenous leukemia--the role of blast resistance to cytotoxic drugs]. / Przyczyny nieskutecznosci leczenia ostrej bialaczki szpikowej--rola opornosci blastów na cytostatyki.

Acute myelogenous leukemia (AML) represents 80% of adult acute leukemias. A standard-dose chemotherapy allows to obtain 52% to 72% of complete remission (CR). A major limitation for success in chemotherapy of AML is dominance of drug-resistant subpopulations of cells. Cytosine-arabinoside (Ara-C) is a basic drug in AML treatment. Myeloblasts resistance to Ara-C could be kinetic or pharmacological. The classical multidrug resistance (MDR) depends on presence in resistant myeloblasts ATP-dependent drug-efflux pump with ability to remove cytotoxic drugs from the cells. It is a product of MDR1 gene called P-glycoprotein (Pgp). Pgp is responsible for cell resistance to cytotoxic compounds of natural origin, such as anthracyclines, vinca alkaloids, epipodophyllotoxins, taxanes, colchicine and amsacrine. There were also identified not Pgp-dependent multidrug resistance mechanisms (non-Pgp MDR) in AML. All mentioned above drugs are involved but not taxol. Non-Pgp MDR depends on topoisomerase II alfa activity alterations, multidrug resistance-associated protein (MRP) expression and lung resistance-related protein (LRP) expression. Pgp positive AML patients have poorer complete remission (CR) rate, decreased remission duration and overall survival. Pgp expression is detected among 70% AML patients older than 55. The most promising drugs in circumventing classical MDR seems cyclosporin A (CsA) and cyclosporin D (SDZ PCS 833). They are successfully used in refractory and relapsed AML.