Introduction: The management of pregnancy during the course of BCR-ABL1-negative myeloproliferative neoplasms (MPN) is an increasingly relevant problem. This is mostly due to earlier and better ...diagnosis of MPN together with the trend in modern society toward delaying pregnancy until later life.
Areas Covered: The present review aims to provide an overview of the available literature data concerning outcome of pregnancy in MPN. Possible therapeutic modalities are discussed and a management algorithm is suggested.
Expert Commentary: Most data are available for women with essential thrombocythemia and we present 793 published pregnancies. Live birth rate is 68.5% with 31.5% miscarriages. Spontaneous abortion is the most frequent complication with 26.5%, followed by stillbirth with 4.8%. Maternal complications are relatively low with 1.8% major thrombotic and 2.4% major bleeding events. In polycythemia vera the situation is clinically more complex and roughly 150 pregnancy reports are available. There is very limited information in primary myelofibrosis with less than 20 reported pregnancies. With active management including control of blood counts, aspirin, low molecular weight heparin and in higher risk cases interferon alpha pregnancy in MPN is manageable with a success rate not far below the normal situation with 80%.
To determine the usefulness of fine needle aspiration cytology (FNAC) in combination with flow cytometry on the new World Health Organization (WHO) classification of malignant lymphoma.
Smears and ...flow cytometry reports of patients who underwent both methods at the same time were independently examined. Both methods were classified according to the new WHO classification of malignant lymphoma.
A group of 131 smears were examined. In 89 cases exact diagnosis was made by cytomorphology. Twenty-five cases were not classified exactly or were classified incorrectly, resulting in a sensitivity of 96.4% and a specificity of 85%. With flow cytometry, only 30 of 131 patients could be classified exactly, resulting in a sensitivity of 27% and specificity of 100%, respectively. The combination of methods showed a sensitivity of 85% and specificity of 100%.
The combination of FNAC and flow cytometry obtained by FNAC can distinguish between benign and malignant lymphoid infiltrates and support a diagnosis of lymphoma.
The effect of imatinib mesylate (imatinib) therapy on angiogenesis and myelofibrosis was investigated and compared with interferon (IFN) and hydroxyurea (HU) in 98 patients with newly diagnosed ...Philadelphia chromosome-positive/BCR-ABL+ (Ph+/BCR-ABL+) chronic myeloid leukemia in first chronic phase and no other pretreatment. By means of immunostaining (CD34) and morphometry, a relationship between microvessel frequency and fiber density was detectable in initial bone marrow (BM) biopsies and sequential examinations after at least 8 months of therapy. First-line monotherapy with imatinib induced a significant reduction (normalization in comparison with controls) of microvessels and reticulin fibers. In most patients, decrease in BM vascularity was associated with a complete cytogenetic response. A significant anti-angiogenic effect was also observed after HU treatment, contrasting with IFN administration or combination regimens (IFN plus HU). In conclusion, our data support the anti-angiogenic capacity of imatinib by normalization of vascularity. In contrast, hematologic response following IFN treatment is independent from BM angiogenesis. (Blood. 2004;103:3549-3551)
Purpose
Most cancer-related deaths worldwide are associated with lung cancer. Subtyping of non-small cell lung cancer (NSCLC) into adenocarcinoma (AC) and squamous cell carcinoma (SqCC) is of ...importance, as therapy regimes differ. However, conventional staining and immunohistochemistry have their limitations. Therefore, a spatial metabolomics approach was aimed to detect differences between subtypes and to discriminate tumor and stroma regions in tissues.
Methods
Fresh-frozen NSCLC tissues (
n
= 35) were analyzed by matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) of small molecules (< m/z 1000). Measured samples were subsequently stained and histopathologically examined. A differentiation of subtypes and a discrimination of tumor and stroma regions was performed by receiver operating characteristic analysis and machine learning algorithms.
Results
Histology-guided spatial metabolomics revealed differences between AC and SqCC and between NSCLC tumor and tumor microenvironment. A diagnostic ability of 0.95 was achieved for the discrimination of AC and SqCC. Metabolomic contrast to the tumor microenvironment was revealed with an area under the curve of 0.96 due to differences in phospholipid profile. Furthermore, the detection of NSCLC with rarely arising mutations of the isocitrate dehydrogenase (IDH) gene was demonstrated through 45 times enhanced oncometabolite levels.
Conclusion
MALDI-MSI of small molecules can contribute to NSCLC subtyping. Measurements can be performed intraoperatively on a single tissue section to support currently available approaches. Moreover, the technique can be beneficial in screening of
IDH
-mutants for the characterization of these seldom cases promoting the development of treatment strategies.
Purpose Interim positron emission tomography (PET) using the tracer,
Ffluorodeoxyglucose, may predict outcomes in patients with aggressive non-Hodgkin lymphomas. We assessed whether PET can guide ...therapy in patients who are treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Patients and Methods Newly diagnosed patients received two cycles of CHOP-plus rituximab (R-CHOP) in CD20-positive lymphomas-followed by a PET scan that was evaluated using the ΔSUV
method. PET-positive patients were randomly assigned to receive six additional cycles of R-CHOP or six blocks of an intensive Burkitt's lymphoma protocol. PET-negative patients with CD20-positive lymphomas were randomly assigned or allocated to receive four additional cycles of R-CHOP or the same treatment with two additional doses rituximab. The primary end point was event-free survival time as assessed by log-rank test. Results Interim PET was positive in 108 (12.5%) and negative in 754 (87.5%) of 862 patients treated, with statistically significant differences in event-free survival and overall survival. Among PET-positive patients, 52 were randomly assigned to R-CHOP and 56 to the Burkitt protocol, with 2-year event-free survival rates of 42.0% (95% CI, 28.2% to 55.2%) and 31.6% (95% CI, 19.3% to 44.6%), respectively (hazard ratio, 1.501 95% CI, 0.896 to 2.514; P = .1229). The Burkitt protocol produced significantly more toxicity. Of 754 PET-negative patients, 255 underwent random assignment (129 to R-CHOP and 126 to R-CHOP with additional rituximab). Event-free survival rates were 76.4% (95% CI, 68.0% to 82.8%) and 73.5% (95% CI, 64.8% to 80.4%), respectively (hazard ratio, 1.048 95% CI, 0.684 to 1.606; P = .8305). Outcome prediction by PET was independent of the International Prognostic Index. Results in diffuse large B-cell lymphoma were similar to those in the total group. Conclusion Interim PET predicted survival in patients with aggressive lymphomas treated with R-CHOP. PET-based treatment intensification did not improve outcome.
Introduction: Hydroxyurea (HU) is an S-phase specific oral chemotherapeutic agent that inhibits ribonucleotide diphosphate reductase. It is the most common used cytoreductive drug in patients (pts) ...with BCR-ABL1 negative myeloproliferative neoplasms (MPN) and sickle cell disease (SCD). The World Health Organization lists HU as an ,,essential drug". Although most patients tolerate HU well, cutaneous adverse events (CAE) are frequent side effects and may limit its long-term use. This has become increasingly evident in recent years, especially in MPN patients, where CAE were previously underestimated and underdiagnosed.
Areas covered: In this review, we present the available literature on HU-related CAE in MPN patients. In particular, data from a recently published and so far, only prospective non-interventional study investigating CAE in 172 MPN patients will be discussed in detail and compared with previously available data. Finally, we give an overview of the management of HU-related CAE in MPN patients and provide recommendations on the practical clinical approach.
Expert opinion: In clinical practice, HU associated CAE are common and have important diagnostic and therapeutic consequences. Therefore, they should be considered in all MPN patients treated with HU in the future.
Venous thromboembolism (VTE) is a major burden in patients with
BCR-ABL
-negative myeloproliferative neoplasms (MPN). In addition to cytoreductive treatment anticoagulation is mandatory, but optimal ...duration of anticoagulation is a matter of debate. In our single center study, we retrospectively included 526 MPN patients. In total, 78 of 526 MPN patients (14.8%) had 99 MPN-associated VTE. Median age at first VTE was 52.5 years (range 23–81). During a study period of 3497 years, a VTE event rate of 1.7% per patient/year was detected. 38.4% (38/99) of all VTEs appeared before or at MPN diagnosis and 55.6% (55/99) occurred at “uncommon” sites like splanchnic or cerebral veins. MPN patients with VTEs were significantly more female (
p
= 0.028),
JAK2
positive (
p
= 0.018), or had a polycythemia vera (
p
= 0.009). MPN patients without VTEs were more often
CALR
positive (
p
= 0.023). Total study period after first VTE was 336 years with 20 VTE recurrences accounting for a recurrence rate of 6% per patient/year. In 36 of 71 MPN patients with anticoagulation therapy after first VTE event (50.7%), prophylactic anticoagulation was terminated after a median time of 6 months (range 1–61); 13 of those 36 patients (36.1%) had a VTE recurrence after a median of 13 months (range 4–168). In contrast, only three of 35 (8.6%) patients with ongoing anticoagulation had a VTE recurrence (
p
= 0.0127). Thus, termination of prophylactic anticoagulation was associated with a significantly higher risk of VTE recurrence. Our data suggest that in MPN patients with VTE, a prolonged duration of anticoagulation may be beneficial.
The clinical course of essential thrombocythemia (ET) is variable, ranging from microvascular circulation disturbances to severe thromboembolic or hemorrhagic complications in patients who do not ...have any symptoms for many years. The identification of patients at risk for major thrombosis who need platelet-lowering therapy is important. During the last two decades, several risk factors for the development of ET-related thrombotic and bleeding complications have been identified. These include platelet counts, previous thrombotic events, older age, cardiovascular risk factors, hereditary thrombophilia, clonality, and the presence of molecular markers such as PRV-1 or the Janus kinase 2 (JAK2) mutation. According to the presence or absence of these risk factors, individual patients with ET are currently stratified as low-, intermediate-, or high-risk patients. The influence of these risk factors on therapeutic decisions in patients with ET is critically reviewed and discussed in detail.
Summary
Ruxolitinib is a potent Janus kinase (JAK) 1/JAK2 inhibitor approved for the treatment of myelofibrosis (MF). Ruxolitinib was assessed in JUMP, a large (N = 2233), phase 3b, expanded‐access ...study in MF in countries without access to ruxolitinib outside a clinical trial, which included patients with low platelet counts (<100 × 109/l) and patients without splenomegaly – populations that have not been extensively studied. The most common adverse events (AEs) were anaemia and thrombocytopenia, but they rarely led to discontinuation (overall, 5·4%; low‐platelet cohort, 12·3%). As expected, rates of worsening thrombocytopenia were higher in the low‐platelet cohort (all grades, 73·2% vs. 53·5% overall); rates of anaemia were similar (all grades, 52·9% vs. 59·5%). Non‐haematologic AEs, including infections, were mainly grade 1/2. Overall, ruxolitinib led to meaningful reductions in spleen length and symptoms, including in patients with low platelet counts, and symptom improvements in patients without splenomegaly. In this trial, the largest study of ruxolitinib in patients with MF to date, the safety profile was consistent with previous reports, with no new safety concerns identified. This study confirms findings from the COMFORT studies and supports the use of ruxolitinib in patients with platelet counts of 50–100 × 109/l. (ClinicalTrials.gov identifier NCT01493414).
Objectives
Pregnancies in women with polycythemia vera (PV) are associated with an increased risk of PV‐related maternal complications and often result in miscarriage. Recommendations for the ...management of PV pregnancies are mainly based on studies with a small number of patients. A correlation between pregnancy outcome and postpartum course has been reported for essential thrombocythemia, but corresponding data for PV are lacking so far.
Methods
In 41 PV pregnancies, the pregnancy outcome, the use of PV‐specific therapies (ie, acetylsalicylic acid, low‐molecular weight heparin and/or interferon‐alpha), and the postpartum PV course were investigated.
Results
A live birth rate of 51.2% (21/41 pregnancies) was observed. 43.9% of pregnancies ended in spontaneous abortion and 4.9% in stillbirth. A significantly increased live birth rate occurred in pregnancies with PV‐specific therapies compared to standard antenatal care (69.0% vs. 8.3%; P < .0019). The use of PV‐specific therapy significantly increased the number of maternal hemorrhages (P = .021) without increasing the risk of fetal complications. During the median postpartum follow‐up period of 1.2 years (range 0.1‐13.7), complicated postpartum PV occurred significantly more often after miscarriages (P = .035).
Conclusions
According to our analysis, PV‐specific therapy improved the live birth rate. Significantly more complicated postpartum PV courses were observed after miscarriages.
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