Management of adults and children receiving CAR T-cell therapy: 2021 best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Haematology Association (EHA).

BACKGROUND: Several commercial and academic autologous chimeric antigen receptor T-cell (CAR-T) products targeting CD19 have been approved in Europe for relapsed/refractory B-cell acute lymphoblastic leukemia, high-grade B-cell lymphoma and mantle cell lymphoma. Products for other diseases such as multiple myeloma and follicular lymphoma are likely to be approved by the European Medicines Agency in the near future. DESIGN: The European Society for Blood and Marrow Transplantation (EBMT)-Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Haematology Association collaborated to draft best practice recommendations based on the current literature to support health care professionals in delivering consistent, high-quality care in this rapidly moving field. RESULTS: Thirty-six CAR-T experts (medical, nursing, pharmacy/laboratory) assembled to draft recommendations to cover all aspects of CAR-T patient care and supply chain management, from patient selection to long-term follow-up, post-authorisation safety surveillance and regulatory issues. CONCLUSIONS: We provide practical, clinically relevant recommendations on the use of these high-cost, logistically complex therapies for haematologists/oncologists, nurses and other stakeholders including pharmacists and health sector administrators involved in the delivery of CAR-T in the clinic.

Second reduced intensity conditioning allogeneic transplant as a rescue strategy for acute leukaemia patients who relapse after an initial RIC allogeneic transplantation: analysis of risk factors and treatment outcomes.

Limited therapeutic options are available after relapse of acute leukaemia following first reduced intensity conditioning haematopoietic stem cell transplantation (RIC1). A retrospective study on European Society for Blood and Marrow Transplantation (EBMT) registry data was performed on 234 adult patients with acute leukaemia who received a second RIC transplantation (RIC2) from 2000 to 2012 as a salvage treatment for relapse following RIC1. At the time of RIC2, 167 patients (71.4%) had relapsed or refractory disease, 49 (20.9%) were in second CR and 18 (7.7%) in third or higher CR. With a median follow-up of 21 (1.5-79) months after RIC2, 51 patients are still alive. At 2 years, the cumulative incidence of non-relapse mortality (NRM), relapse incidence (RI), leukaemia-free survival (LFS) and overall survival (OS) were 22.4% (95% confidence interval (CI): 17-28.4), 63.9% (56.7-70.1), 14.6% (8.8-18.5) and 20.5% (14.9-26.1), respectively. In patients with acute myelogenous, biphenotypic and undifferentiated leukaemia (representing 89.8% of all patients), duration of remission following RIC1 >225 days, presence of CR at RIC2, patient's Karnofsky performance status >80 at RIC2 and non-myeloablative conditioning were found to be the strongest predictors of patients' favourable outcome.

Association of hematological parameters with insulin resistance in type 1 diabetes.

AIM: Previous studies reported independent associations of hematological parameters with insulin resistance. The aim of this study was to explore the associations of hematological parameters, including red blood cell count (RBC), hemoglobin (Hgb), white blood cell count (WBC), and platelets with insulin resistance in type 1 diabetes. METHODS: Study included 353 patients with type 1 diabetes. None showed signs of acute or chronic inflammatory, renal and cardiovascular diseases. Insulin sensitivity was measured with estimated glucose disposal rate (eGDR) calculated with the equation: eGDR=24.31-(12.22xWHR)-(3.29xAHT)-(0.57xHbA1c). The units were mg.kg-1min-1; WHR=waist to hip ratio; AHT=hypertension. RESULTS: RBC, Hgb, and WBC significantly correlated with insulin resistance measured by eGDR (r=-0.12, -0.21, and -0.14, respectively, all P≤0.01), and its components disorders, most notably WHR (r=0.38, 0.44, and 0.16, respectively, all P≤0.001). In a multiple logistic regression analysis after adjustment for age, sex, duration of diabetes and BMI, the presence of insulin resistance was independently associated with WBC count (odds ratio=1.28, P<0.01). The risk of insulin resistance increases by a factor of 4.41 for those in the 4th quartile of WBC, compared to those in 1st quartile. CONCLUSION: The significant independent association of WBC with the presence of insulin resistance suggests a role of subclinical inflammation in its pathogenesis.

Influence of additional criteria from a definition of cachexia on its prevalence--good or bad thing?

BACKGROUND/OBJECTIVES: Cachexia is a state of involuntary weight loss. The latest generic definition states that aside from weight loss, patient needs to fulfill additional criteria to be diagnosed with cachexia. New, condition-specific definitions also take the weight loss as a principal criterion, and additional criteria are not mandatory but are a part of further assessment. The aim of this study was to reveal the influence of additional criteria on the prevalence of cachexia in patients with various diseases linked to cachexia. Owing to this, we used the last generic definition. Possible differences in clinical presentations of patients with documented weight loss, with the respect of fulfillment of additional criteria were sought. SUBJECTS/METHODS: Clinical and anthropometric data on 137 consecutive patients with malignant diseases and chronic heart failure from a single institution were collected. RESULTS: Fourty-two (30.6%) patients had >5% weight loss in the last 12 months. Only 30 (21.8%) of them were found to meet additional three out of five criteria proposed by the new definition. This observed difference in the prevalence of cachexia diagnosed with or without using additional criteria was found to be significant (P=0.0006). Comparison of clinical/laboratory data showed significantly higher levels of C-reactive protein and lower levels of albumin, as well as lower measurements of mid-arm circumference, triceps and suprailiac skinfolds in patients that fulfilled additional criteria. Survival analysis did not show reduced survival of patients fulfilling additional criteria. CONCLUSIONS: Additional criteria 'reduce' the prevalence of cachexia. They are indicative of differences in laboratory and clinical features of cachectic patients but do not influence their survival.

Ruxolitinib for the treatment of myelofibrosis.

Ruxolitinib is an orally available, ATP-competitive inhibitor, selective for tyrosine-protein kinases JAK1 and JAK2 and is the most advanced JAK1/JAK2 inhibitor in development for the treatment of myeloproliferative neoplasms. The suggested mechanism of action of ruxolitinib is attenuation of cytokine signaling via the inhibition of JAK1 and JAK2 (wild-type or mutated forms), resulting in antiproliferative and proapoptotic effects. In the phase III COMFORT-I trial conducted in patients with myelofibrosis, ruxolitinib demonstrated durable reductions in splenomegaly. The proportion of patients that achieved spleen volume reduction ≥ 35% from baseline to 24 weeks was 41.9 % with ruxolitinib versus 0.7% with placebo (P < 0.0001), as evaluated by magnetic resonance imaging or computed tomography. In the phase III COMFORT-II trial, reductions in spleen volume ≥ 35% were observed in 31.9% of patients treated with ruxolitinib versus 0% with best available therapy at week 24, and 28.5% versus 0% at week 48 (both P < 0.0001). Low toxicity, alleviation of constitutional symptoms, weight gain and improvement in general physical condition were observed with ruxolitinib treatment which may substantially improve quality of life in patients with myelofibrosis.

Clinical tumor cell distribution pattern is a prognostically relevant parameter in patients with B-cell chronic lymphocytic leukemia.

BACKGROUND AND OBJECTIVES: B-cell chronic lymphocytic leukemia (B-CLL) cells are variably distributed among the major lymphoid compartments contributing to the heterogeneous clinical presentation and course of this disease. In order to evaluate this variable distribution we propose a model for its clinical assessment. DESIGN AND METHODS: We introduce the model for tumor distribution (TD) assessment based on TTM scoring system, where TD value represents percentage of total tumor mass infiltrating peripheral blood and bone marrow (TD=TM(1)/TTM). TD in B-CLL can be categorized into 3 subgroups: pure leukemia if TD=100%, predominantly leukemia if TD=50-99% and predominantly lymphoma TD<50%. RESULTS: Among 341 B-CLL patients there were 22.6%, 55.1%, 22.3%, pure leukemia, predominantly leukemia and predominantly lymphoma cases, respectively. TD parameter was strongly associated in univariate analysis with TTM size, Rai and Binet stages, spleen size and beta(2) microglobulin. TD was associated with response to therapy and survival, with higher TD values translated into higher response rates and longer survival. However, in univariate and multivariate Cox analysis TD displayed much stronger relationship with prognosis in female patients, where it is the strongest independent predictor of survival along with age and Binet stage. INTERPRETATION AND CONCLUSIONS: TD, a quantitative and simple clinical parameter, easily assessed in all patients, offers a reliable tool for evaluation of tumor cell distribution in B-CLL. It has independent and strong prognostic power in females, as opposed to males, possibly unmasking important, yet unrecognized, biological difference in B-CLL patients.

Knowledge of and attitudes to pharmacotherapy in medical inpatients.

OBJECTIVE: To analyze different aspects of patients' knowledge and attitudes to pharmacotherapy in medical inpatients. PATIENTS: 183 patients hospitalized in the Department of Medicine of University Hospital "Merkur", Zagreb, Croatia were investigated. METHODS: A questionnaire was designed to investigate patients' knowledge of drugs they were taking before admission to the hospital and drugs they are receiving during hospitalization. Patients were asked to give drug names, dosage and reasons for their prescription. Patients' rating of the importance of some drug characteristics (dosage, indication, precautions, side-effects, mode of action) was evaluated. RESULTS: A representative group of patients (mean age 55.5 years, range 17-86, SD 16.1; 89 men, 94 women; 50 hematological, 44 cardiological, 50 gastroenterological and 39 nephrological patients) showed a significantly better (p < 0.000001) overall knowledge of drugs taken prior to admission compared to the knowledge of drugs that they were receiving during hospitalization. Overall drug knowledge did not differ significantly between groups of patients stratified according to gender, ward, number of drugs they were taking or duration of treatment. In older patients (p < 0.0001) and in those with lower education (p < 0.001) a significantly worse overall knowledge was observed. On a 1-5 semiquantitative scale patients rated dosage as the most important and mode of action as the least important drug characteristic (average 3.62 and 2.08, respectively). Of all patients, 94.5% pointed out physicians as one of their sources of drug information, written drug information followed in 40.4% and pharmacists in only 11.5% of patients. CONCLUSIONS: Our results agree with the results of the few similar studies published to date. A need for better health education of patients is underlined and possible ways of providing drug information for patients are discussed. The need for improvement of physician-patient transfer of drug information as well as the need for written drug information tailored according to patients' needs is underlined.

Cyclin D1 overexpression allows identification of an aggressive subset of leukemic lymphoproliferative disorder.

The conjunction of clinical features, cell morphology and immunological characteristics allows an accurate diagnosis in most cases of B cell chronic lymphoproliferative disorders (CLD). However, the diagnosis remains uncertain in a small percentage of cases, often referred as to unclassified B cell proliferation or atypical chronic lymphocytic leukemia (CLL). We have studied retrospectively the 192 cases of leukemic CLD seen in our institution over a 3-year period, for which both clinical and routine biological data at presentation were available. Forty cases (20%) did not fit into any of the well-identified categories according to the FAB criteria and remained unclassified. We assessed cyclin D1 expression in all of these cases and found that 10 of them expressed a high level of cyclin D1 protein. We compared the characteristics of these 10 cases with those of the 30 cyclin D1 negative CLD. Despite non-distinctive cytological and phenotypic features, the 10 cyclin D1 positive patients exhibited a strikingly uniform clinical presentation with elevated leukocytosis, massive spleen enlargement and no superficial lymphadenopathy. Their outcome was very poor with a median survival of 10 months, contrasting with the prolonged survival of the cyclin D1 negative patients. The cytological features of tumor cells from these 10 patients with cyclin D1 positive unclassified leukemic CLD were similar to those of the circulating lymphoid cells from 15 patients with histologically proven mantle cell lymphoma (MCL) and primary or secondary blood involvement. Therefore, cyclin D1 expression allowed identification among the unclassified CLD, a subset of aggressive disorders which represent a leukemic counterpart of MCL (mantle cell leukemia). We suggest that determination of cyclin D1 expression by any technique available should be systematically included when investigating atypical CLL.

Prognostic significance of the cell cycle inhibitor p27Kip1 in chronic B-cell lymphocytic leukemia.

B-cell chronic lymphocytic leukemia (B-CLL) is characterized by the accumulation of resting lymphocytes. The identification of p27(kip1), a cyclin-dependent kinase inhibitor that contributes to cell cycle arrest and represents a link between extracellular signals and cell cycle, prompted us to study p27 protein in the lymphocytes from 88 patients with B-CLL and 32 patients with other chronic B-lymphoproliferative disorders. The expression of p27 protein was higher in B-CLL samples with variations among them. In B-CLL, p27 levels were independent of absolute number of circulating lymphocytes, but strongly correlated with both lymphocyte and total tumor mass (TTM) doubling time. High p27 expression was associated with a poorer overall prognosis. In vitro, there was an increased spontaneous survival of B-CLL cells expressing high p27 levels. Interleukin-4 (IL-4) upregulated p27 levels in B-CLL cells, while fludarabine decreased p27 levels. Thus, our results indicate that p27 may be a valuable kinetic marker in B-CLL by providing instantaneous estimation of the disease doubling time. In addition, these results suggest that there is a link between p27 expression and the ability of CLL cells to undergo apoptosis.

Myeloid hemopoietic growth factors. Review article.

The article is a critical review of recent publications on myeloid hemopoietic growth factors. They are glycoproteins that regulate the proliferation and differentiation of hemopoietic progenitor cells and the function of mature blood cells. They are also named colony stimulating factors after the experimental technique that led to their discovery. Myeloid growth factors are: granulocyte macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), macrophage colony-stimulating factor (M-CSF) and interleukin-3. Studies of hemopoietic growth factors in the past years have revealed many potential beneficial effects, but some limitations as well. They have been proved effective, above all, in neutropenic conditions of different origin. A large number of clinical trials have shown their beneficial effect in myelosuppressive conditions after cytotoxic chemotherapy, in post-transplant period in bone marrow transplantation procedures and in neutropenic conditions as part of other clinical entities. Although a number of studies that should determine their clinical role more clearly is still underway, it seems certain that myeloid hemopoietic growth factors already have an important role in modern pharmacotherapy.

[A critical report on drugs in 1991]. / Kriticki prikaz lijekova u 1991. godini.

Principal changes in the drug field in this country in 1991 were caused by the armed aggression committed against Croatia and the succession of disturbances that this aggression induced. Abroad as many as 13.6% of drugs could be ranked as category A. Here dominate some drugs for AIDS, which is a significant problem in medicine, but also some drugs for rare diseases ("orphan drugs"), like Gaucher's disease, precocious puberty etc. In this country (until the sovereignty was reached on October 8, 1991) 13.8% of drugs belonging to category B were approved. In category C ranked were 83.0% of drugs, abroad 75%. Two in this country (rutoside and creatinephosphate), one abroad (ditiocarb) were classed in category D. At preparing new Drug Law of independent Croatia, caution is necessary over numerous details which will enable us to become, in this field too, as soon as possible a part of the developed Europe. The latest List of Drugs that is paid by the Croatian Health Insurance is discussed. It comprises up to 230 generic names, excluding those that are--unjustifiably--most prescribed. The List's aim is to rationalize drug therapy, allowing other modes of prescribing improvement. To a large degree drug prescribing is not rational. The latest data (1990) have shown that only 4 out of 10 most prescribed drugs in Zagreb are undoubtedly efficacious, 9 out of 10 in Ljubljana, 5 out of 10 (1989/90) in former Yugoslavia, and abroad ("in the world") all 10. The characteristics of drug filed in war are reviewed as well as problems connected with drug donations. The importance of concern that "aimed" donations replace those that are not optimally used is stressed. The article ends with the question of the importance of objective information sources in drug field.

[Critical review of drugs in 1990]. / Kriticki prikaz podrucja lijekova u 1990. godini.

New chemical entities approved abroad (43) and in Yugoslavia (37) were presented. Discussions on several "old" drugs (41) open at the Yugoslav Federal Drug Committee for any reason (new formulation, new dose, new packaging, dosage regimen or indication) and renewal of registration (114) were also included. Special attention was given to the drugs which had been refused the renewal of registration (8). Critical drug re-evaluation as an important element of the improvement of pharmacotherapy was emphasized. A total of 78 drugs was discussed or registered in 1990-1.28% of drugs from the group A (vancomycin), 10.2% from the group B (aclarubicin, dexfenfluramine, warfarin, alprazolam, colestipol, lovastatin, combination: cetrimonium + lidocain and estradiol vag.), 87.1% (the greatest number so far!) from the group C and 1.28% from the group D. Surveys of the most prescribed drugs in Zagreb, in Yugoslavia and in the world were also given having proved largely non-rational drug prescribing in this country. Further development of drug formulary concept was discussed, primarily for the drugs paid by the Health Insurance, as well as the unsatisfactory ADR reporting in Yugoslavia. Presented were also the activities of the Committee for Diagnosis, Pharmacotherapy and ADR of the Yugoslav Federal Institute for Health Protection. Publishing of Yugoslav daily defined doses is, according to the authors essential for further systematic monitoring of drug consumption on different levels in this country. It would be impossible to rationalize pharmacotherapy without these data.

Drug trials on healthy volunteers in Yugoslavia.

Ninety-seven healthy volunteers who participated in different clinical trials (phases III and IV) in a clinical pharmacology unit were interviewed over the period December 1988-February 1990 using questionnaire method. The aim of the investigation was to analyze the examinees' occupational distribution, the degree of insight in the trials they participated in, their opinion about the remuneration they get and their estimate of the importance or inconveniences of numerous trial elements. Only 39 volunteers (40.2%) were members of medical staff: 17 (17.5%) physicians, 17 (17.5%) medical students and 5 (5.2%) nurses. The volunteers assessed the importance of different elements related to the trial marking them from 1-5. They were more afraid of possible adverse drug reactions (ADR) occurring during the trial (median 3.87) than of those that might occur afterwards (2.94). Significant was their concern about the kind of investigated drug (3.49). "Potential contribution of the trial to the medicine and society" (3.30) and "length of time spent in the laboratory" (3.17) followed. The conduct of clinical trials on healthy volunteers in Yugoslavia and legal regulations are discussed at the end of the paper.

[Critical analysis of drugs in 1989]. / Kriticki prikaz podrucja lijekova u 1989. godini.

Changes and trends in the drug field in the world and in Yugoslavia in 1989 are presented and discussed. 1. World. There appeared only a few new drugs all over the world, and new chemical entities (NCE) rather rarely represent a significant contribution to materia medica. Japan is the first in producing NCE (12) followed by United Kingdom and the USA (4 NCE each). 2. Yugoslavia. In Yugoslavia were 125 drugs discussed approval, new dose, new formulation or generic parallel. More than 84% of these have been related to generic or clinical ("me too") parallels; less than 9% of drugs had a certain contribution to materia medica, while, according to the authors, the number of drugs that contributed significantly to the materia medica and of those which should not have been approved was equal (3.2%). Octreotide, erythropoietin, almitrine and flumazenil were placed in category A. Insulin appeared in the largest number of parallels (as many as 19) succeeded by cardiovascular, antimicrobial and gastrointestinal drugs. 3. Drug formularies exist in all the developed countries and represent a way of limiting prescribing. Yugoslav list of drugs expenses of which will be covered by the Health Insurance will be prepared. 4. The Federal Institute for Health Protection through its special committee for diagnostics, pharmacotherapy and side effects represents a useful activity in rationalizing drug use. 5. Yugoslav publication of defined daily doses (DDD) is being prepared. 6. A review of causes of deficient or inadequate drug supply in Yugoslavia, which still represents a major problem in this country, has been given at the end.