Jiří Pavlů

Optimizing patient selection for myeloablative allogeneic hematopoietic cell transplantation in chronic myeloid leukemia in chronic phase

Outstanding results have been obtained in the treatment of chronic myeloid leukemia (CML) with first-line imatinib therapy. However, approximately 35% of patients will not obtain long-term benefit with this approach. Allogeneic hematopoietic stem cell transplantation (HCT) is a valuable second- and third-line therapy for appropriately selected patients. To identify useful prognostic indicators of transplantation outcome in postimatinib therapeutic interventions, we investigated the role of the HCT comorbidity index (HCT-CI) together with levels of C-reactive protein (CRP) before HCT in 271 patients who underwent myeloablative HCT for CML in first chronic phase. Multivariate analysis showed both an HCT-CI score higher than 0 and CRP levels higher than 9 mg/L independently predict inferior survival and increased nonrelapse mortality at 100 days after HCT. CML patients without comorbidities (HCT-CI score 0) with normal CRP levels (0-9 mg/L) may therefore be candidates for early allogeneic HCT after failing imatinib.

Treatment and management of graft-versus-host disease: improving response and survival

Graft-versus-host disease (GVHD) is a significant cause of morbidity and mortality following allogenic haematopoietic stem-cell transplantation and thus the focus of much ongoing research. Despite considerable advances in our understanding of the pathophysiology, diagnosis and predisposing factors for both acute and chronic forms of the disease, a standardised therapeutic strategy is still lacking. There is good evidence for initial treatment of both acute and chronic forms of the disease with corticosteroid therapy. However, the most effective approach to steroid-refractory disease remains controversial, with current practice based mainly on smaller studies and varying considerably between local institutions. Timely diagnosis, multidisciplinary working and good supportive care, including infection prophylaxis, are clearly important in optimizing response and survival in such patients. It is hoped that in the future systematic research strategies and the identification of novel therapeutic targets may improve outcome further. The following review aims to outline some of the existing options for the treatment and management of acute and chronic GVHD.

Myocardial infarction in sickle-cell disease

A 50-year-old woman was admitted to our hospital in December, 2005, with a 5 h history of central chest pain of sudden onset. She described dull pain across her chest with radiation to the right arm accompanied by nausea and vomiting. The pain was worse on deep inspiration but not associated with dyspnoea, and it failed to improve after glyceryl trinitrate. She had a history of homozygous sicklecell disease with frequent painful episodes; she managed most of these episodes at home with diclofenac and dihydrocodeine phosphate, although intermittently needed exchange transfusion. The presenting chest pain was diff erent in character from her typical sickle-cell crises. She had no history of coronary heart disease, diabetes, hypertension, or dyslipidaemia, and was a non-smoker. She was apyrexial. Other than mild icterus, physical examination was unremarkable. Electrocardiography showed sinus rhythm with T-wave inversion in V1 to V3, and biphasic T-waves in V4 to V6. A chest radiograph was normal. Arterial blood gas analysis showed PaO2 of 10·6 kPa and SpO2 of 91·1% on room air. Haemoglobin concentration was similar to her steady state at 107 g/L. Serum biochemistry showed increased troponin I at 1·78 μg/L with normal creatinine and electrolytes. Acute coronary syndrome was suspected and enoxaparin sodium, aspirin, and clopidogrel bisulfate were started. Her troponin I peaked at 8·23 μg/L, 12 h after admission, by which time her pain had been superseded by dull pressure over the precordium. Coronary angiography (preceded by automated red-cell exchange to a haemoglobin S level of 19%) showed smooth coronary arteries with no occlusion. No ventilation-perfusion mismatches were shown on lung scintigraphy, and the patient proceeded to a cardiac MRI. An inversion recovery gradient echo sequence acquired 15 min after injection of intravenous gadolinium contrast demonstrated a region of subendocardial hyperenhance ment in the lateral wall of the left ventricle consistent with an infarct (fi gure). Brightblood cine sequences showed that this anomaly was associated with a wall motion abnormality. Her chest pain resolved fully and electrocardiogram became normal within 4 days. When seen for follow-up in August, 2006, she remained asymptomatic. Sickle-cell disease was fi rst described in 1910 by the Chicago physician J B Herrick who contemporaneously postulated that thrombosis in the coronary artery leads to myocardial infarction. Such thrombus generally forms where the coronary arteries are narrowed as a result of atherosclerotic plaque. Case reports of myocardial infarction in sickle-cell disease are uncommon, and in most cases coronary angiography showed no signifi cant coronary-artery occlusion. An autopsy study demonstrated myocardial infarction in the absence of signifi cant obstructive or atherosclerotic lesions in 9·7% of patients. In contrast to the normal fi ndings in major coronary vessels, the small arteries are narrow in many patients with sickle-cell disease. On this background, aggregation of blood cells and their interaction with coagulation factors can cause acute occlusion. Release of infl ammatory mediators from leucocytes and platelets induces coronary vasospasm, to which scavenging of nitric oxide by haemoglobin liberated through intravascular haemolysis may contribute further. Fat embolism, secondary to bonemarrow infarction, has been implicated in occurrence of myocardial infarction during painful sickle-cell crisis. A strength of cardiac MRI is its ability to provide non-invasive myocardial-tissue characterisation at a high spatial resolution. Hyperenhancement of infarcted tissue occurs owing to an increased volume of distribution and delayed wash-out of contrast. Late enhancement can be seen in other causes of cardiomyopathy and in myocarditis, but ischaemic infarction is always characterised by subendocardial enhancement. Myocardial infarction should be included in the diff erential diagnosis of chest pain in sickle-cell disease despite normal coronary angiography.

Dasatinib and Chronic Myeloid Leukemia: Two-Year Follow-up in Eight Clinical Trials

Imatinib is currently regarded as the best initial treatment for patients with chronic myeloid leukemia (CML). However, a significant proportion of patients who relapse, fail to respond, or develop intolerance might benefit from the use of second-generation tyrosine kinase inhibitors. In this review, we report the 2-year results in 8 clinical trials involving more than 2000 patients treated with dasatinib (phases I-III). Patients with CML who had failed to respond or were intolerant to imatinib were enrolled in a phase I trial. The positive results emanating from this study led to a series of 5 phase II trials known as START (SRC/ABL tyrosine kinase inhibition activity: research trials of dasatinib). In addition, 2 phase III dose-optimization trials have now been completed. These trials demonstrate that dasatinib offers clinical benefit to patients resistant or intolerant to imatinib, with a well-described and manageable adverse event profile.

BKV-specific T cells in the treatment of severe refractory haemorrhagic cystitis after HLA-haploidentical haematopoietic cell transplantation

Haemorrhagic cystitis caused by BK virus (BKV) is a known complication of allogeneic haematopoietic cell transplantation (HCT) and is relatively common following HLA‐haploidentical transplantation. Adoptive immunotransfer of virus‐specific T cells from the donor is a promising therapeutic approach, although production of these cells is challenging, particularly when dealing with low‐frequency T cells such as BKV‐specific T cells.

LACE-conditioned autologous stem cell transplantation for relapsed or refractory diffuse large B-cell lymphoma: treatment outcome and risk factor analysis from a single centre

High‐dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a recognized treatment option for patients with relapsed diffuse large B‐cell lymphoma. We have analysed 51 patients who underwent ASCT after LACE (lomustine (CCNU), cytarabine (Ara‐C), cyclophosphamide, etoposide) conditioning for relapsed (n = 34, 67%) or primary refractory (n = 17, 33%) diffuse large B‐cell lymphoma. With a median follow‐up of 60 months (range 2–216) the probabilities of overall survival (OS) and progression‐free survival (PFS) at 5 years were 47 and 42%, respectively. The cumulative treatment‐related mortality was 10% (n = 5). Probabilities for OS and PFS at 5 years were 56 and 50% for patients with chemosensitive and 29 and 27% for patients with chemorefractory disease. In multivariate analysis abnormal pre‐ASCT levels of C‐reactive protein (>5 mg/L) were identified as a risk factor for worse OS, whereas abnormal pre‐ASCT levels of C‐reactive protein and chemoresistance predicted inferior PFS. LACE followed by ASCT is an effective treatment for approximately half of patients with chemosensitive relapsed diffuse large B‐cell lymphoma, and a proportion of chemorefractory patients also benefit. Copyright

Allogeneic Stem Cell Transplantation for Chronic Myeloid Leukemia

In recent years new, more potent tyrosine-kinase inhibitors have been introduced to accompany imatinib for the treatment of chronic myeloid leukemia. Most patients in chronic phase obtain an optimal response to these oral agents with minimal toxicity. Allogeneic stem cell transplantation is therefore indicated only in a minority of patients who do not achieve an adequate response to first, second or third generation agents. Patients in accelerated phase have a lower chance of achieving an optimal response on these drugs. For patients in blast phase, transplantation remains the only therapy with curative potential, although now it is increasingly used in combination with tyrosine-kinase inhibitors. In this review we address the role of allogeneic stem cell transplantation in the treatment of this disease and how patients should be transplanted.

Hypoplastic presentation of acute lymphoblastic leukemia.

A 37-year-old man presented with fever, lethargy and headache followed in two days by abdominal pain and high fever (408C). Swine flu was initially suspected but a blood count showed a white cell count (WBC) of 0.3 3 10/l, hemoglobin concentration (Hb) 4.5 g/dl, platelet count 18 3 10/l and neutrophil count 0.1 3 10/l. A blood film showed toxic changes in neutrophils; there were atypical lymphocytes, which appeared reactive. Liver function was impaired. The patient required an urgent right hemicolectomy for perforation of the colon as a result of neutropenic enterocolitis. A bone marrow aspirate was hypocellular with no abnormal cells being seen and normal cytogenetic analysis. Peripheral blood immunophenotyping showed no abnormal population. A trephine biopsy (left) was hypocellular with an increase of small T and B lymphocytes. There was no increase in CD34-positive cells but cells expressing terminal deoxynucleotidyl transferase (TdT) were increased. The findings were interpreted as toxic damage to the bone marrow with the increased TdT-positive cells possibly representing hematogones and presaging recovery. The patient suffered a further episode of sepsis but then made an uneventful recovery with blood counts showing spontaneous recovery (right). However four months after the initial presentation he developed fatigue. The Hb was found to have fallen to 9.5 g/dl, the platelet count to 31 3 10/l and the neutrophil count to 0.2 3 10/l. A blood film now showed numerous lymphoblasts and these had largely effaced the bone marrow. The immunophenotype was that of common ALL (CD10, CD19, cytoplasmic CD22 and CD79a positive, cytoplasmic l chain negative). The patient entered complete remission with combination chemotherapy (UKALL XII regime) and successfully completed allogeneic stem cell transplantation. An aplastic presentation of ALL occurs in about 2% of childhood ALL and is also sometimes seen in adults. As in our patient, neutropenia is often more severe than thrombocytopenia. Leukemia has followed after an interval varying from 5 weeks to 9 months but the interval is usually less than 6 months. Sometimes a lymphoid infiltrate is present during the aplastic phase and increased reticulin and fibroblasts may provide evidence of stromal damage. In at least five reported patients retrospective molecular analysis has shown the presence of the leukemic clone during the aplastic phase. The pathogenesis of this rare presentation of ALL remains unknown although in a single patient leukemic lymphoblasts were shown to inhibit hematopoiesis.

C-reactive protein prior to myeloablative allogeneic haematopoietic cell transplantation identifies patients at risk of early- and long-term mortality

Patient selection for allogeneic haematopoietic cell transplantation (HCT) is complex and outcome can be predicted by the HCT comorbidity index (HCT-CI) (Sorror et al, 2005) or the European Group for Blood and Marrow Transplantation (EBMT) score (Gratwohl et al, 1998; Gratwohl, 2012). HCTCI accounts for patient factors such as proven or suspected recipient infection, and the EBMT score includes disease and treatment factors. C-reactive protein (CRP) level, performed pre-myeloablative conditioning (MAC) and reduced intensity conditioning (RIC), is an inexpensive and internationally available biomarker that may be associated with clinical outcomes post-allogeneic HCT (Artz et al, 2008; Pavlu et al, 2010; Aki et al, 2012). This study addresses whether CRP elevation above a normal reference range (>9 mg/l) prior to MAC is additive to information provided by the HCT-CI and component factors of the EMBT score, in identifying patients with inferior early (non-relapse mortality [NRM] at 100 days) or late survival at 5 years, compared to patients with a normal CRP (0–9 mg/l). A retrospective cohort study using prospectively acquired routine clinical data was undertaken. Primary endpoints were: survival calculated from the day of HCT until death from any cause; and NRM, defined as any cause of death not related to relapse that occurred within 100 days post-HCT. The secondary outcomes were disease relapse, acute and chronic graft-versus-host disease (GvHD). Further details are presented in the online supplement. Two hundred and sixty-four adults were identified that received MAC prior to allogeneic HCT over the 18-year study period. Eleven patients with incomplete CRP data were excluded (online supplement and Figure S1). The median age of the 253 evaluable patients was 37 years (range 17–63). Indications for transplant are outlined in Table S1. The primary outcome of NRM at 100 days was 19 8% [95% confidence interval (CI) 16–25] and survival at 5 years was 41 9% (95% CI 35–47), with a median follow-up of 60 6 months (range 3–187) for patients alive at last contact. Validation of the HCT-CI and EBMT score, and univariate analyses with CRP are presented in the online supplement (Tables S2 and S3). C-reactive protein was associated with increased NRM independent of the HCT-CI and EBMT score components. In a

Analysis of hematopoietic recovery after autologous transplantation as method of quality control for long-term progenitor cell cryopreservation

Hematopoietic precursor cells (HPC) are able to restore hematopoiesis after high-dose chemotherapy and their cryopreservation is routinely employed prior to the autologous hematopoietic cell transplantation (AHCT). Although previous studies showed feasibility of long-term HPC storage, concerns remain about possible negative effects on their potency. To study the effects of long-term cryopreservation, we compared time to neutrophil and platelet recovery in 50 patients receiving two AHCT for multiple myeloma at least 2 years apart between 2006 and 2016, using HPC obtained from one mobilization and collection attempt before the first transplant. This product was divided into equivalent fractions allowing a minimum of 2 × 106 CD34+ cells/kg recipient’s weight. One fraction was used for the first transplant after median storage of 60 days (range, 17–165) and another fraction was used after median storage of 1448 days (range, 849–3510) at the second AHCT. Neutrophil recovery occurred at 14 days (median; range, 11–21) after the first and 13 days (10–20) after the second AHCT. Platelets recovered at a median of 16 days after both procedures. Considering other factors, such as disease status, conditioning and HPC dose, this single institution data demonstrated no reduction in the potency of HPC after long-term storage.