A randomised comparison of FLAG-Ida versus daunorubicin combined with clofarabine in relapsed or refractory acute myeloid leukaemia: Results from the UK NCRI AML17 trial.

The prognosis for younger patients with relapsed acute myeloid leukaemia (AML) is generally dismal. Allogeneic stem cell transplantation is the preferred therapy for these patients. As part of the UK NCRI AML17 trial, daunorubicin/clofarabine (DClo) was compared with fludarabine, cytarabine, granulocyte colony-stimulating factor with idarubicin (FLAG-Ida) in 311 patients designated high-risk following course one of induction therapy, which has previously been reported. We now report the results of the same randomisation in patients who were refractory to two induction courses or subsequently relapsed. A total of 94 relapsed or refractory AML patients, usually less than 60 years of age and with mainly favourable or intermediate-risk cytogenetics, were randomised to receive up to three courses of DClo or FLAG-Ida, with the aim of proceeding to transplant. Complete remission was achieved in 74% of patients with no difference between the arms. Overall, 57% of patients received a transplant with no difference between the arms, likewise overall survival at five years showed no significant difference (21% for DClo vs. 22% for FLAG-Ida). No patient who did not receive a transplant survived beyond 21months. A stratified analysis including the 311 post course 1 high-risk patients who underwent the same randomisation showed a consistent treatment benefit for FLAG-Ida.

Clinicopathological characterisation of myeloproliferative neoplasm-unclassifiable (MPN-U): a retrospective analysis from a large UK tertiary referral centre.

Myeloproliferative neoplasm-unclassifiable (MPN-U) presents an MPN-type phenotype that fails to meet diagnostic criteria for other MPN variants. Variability in the clinicopathological phenotypes presents many challenges. Amongst a registry cohort of 1512 patients with MPN, 82 with MPN-U were included, with a median (range) age of 49·7 (13-79) years. Albeit heterogeneous, common presentation features included raised lactate dehydrogenase, thrombocytosis and clustered/pleomorphic megakaryocytes on trephine biopsy. Thrombosis was common (21%), necessitating vigilance. The median event-free survival was 11·25 years (95% confidence interval 9·3-not reached), significantly shortened in cases with lower platelet counts (<500 × 109 /l) and a leucocytosis (≥12 × 109 /l) at presentation. Generation of potential MPN-U prognostic scores is required.

Real-world tyrosine kinase inhibitor treatment pathways, monitoring patterns and responses in patients with chronic myeloid leukaemia in the United Kingdom: the UK TARGET CML study.

Management of chronic myeloid leukaemia (CML) has recently undergone dramatic changes, prompting the European LeukemiaNet (ELN) to issue recommendations in 2013; however, it remains unclear whether real-world CML management is consistent with these goals. We report results of UK TARGET CML, a retrospective observational study of 257 patients with chronic-phase CML who had been prescribed a first-line TKI between 2013 and 2017, most of whom received first-line imatinib (n = 203). Although 44% of patients required ≥1 change of TKI, these real-world data revealed that molecular assessments were frequently missed, 23% of patients with ELN-defined treatment failure did not switch TKI, and kinase domain mutation analysis was performed in only 49% of patients who switched TKI for resistance. Major molecular response (MMR; BCR-ABL1IS ≤0·1%) and deep molecular response (DMR; BCR-ABL1IS ≤0·01%) were observed in 50% and 29%, respectively, of patients treated with first-line imatinib, and 63% and 54%, respectively, receiving a second-generation TKI first line. MMR and DMR were also observed in 77% and 44% of evaluable patients with ≥13 months follow-up, receiving a second-generation TKI second line. We found little evidence that cardiovascular risk factors were considered during TKI management. These findings highlight key areas for improvement in providing optimal care to patients with CML.

Blinatumomab for Acute Lymphoblastic Leukemia: The First Bispecific T-Cell Engager Antibody to Be Approved by the EMA for Minimal Residual Disease.

On November 15, 2018, the Committee for Medicinal Products for Human Use (CHMP) recommended the extension of indication for blinatumomab to include the treatment of adults with minimal residual disease (MRD) positive B-cell precursor acute lymphoblastic leukemia (ALL). Blinatumomab was authorized to treat relapsed or refractory B-precursor ALL, and the change concerned an extension of use. On March 29, 2018, the U.S. Food and Drug Administration (FDA) granted accelerated approval to blinatumomab to treat both adults and children with B-cell precursor ALL who are in remission but still have MRD. On July 26, 2018, the CHMP had originally adopted a negative opinion on the extension. The reason for the initial refusal was that although blinatumomab helped to reduce the amount of residual cancer cells in many patients, there was no strong evidence that it led to improved survival. During the re-examination, the CHMP consulted the scientific advisory group. The CHMP agreed with the expert group's conclusion that, although there was no strong evidence of patients living longer, the available data from the main study (MT103-203) indicated a good durable response to blinatumomab, with an overall complete response rate for the primary endpoint full analysis set (defined as all subjects with an Ig or T-cell receptor polymerase chain reaction MRD assay with the minimum required sensitivity of 1 × 10-4 at central lab established at baseline [n = 113]) as 79.6% (90/113; 95% confidence interval, 71.0-86.6), with a median time to complete MRD response of 29.0 days (range, 5-71). Therefore, the CHMP concluded that the benefits of blinatumomab outweigh its risks and recommended granting the change to the marketing authorization. The Committee for Orphan Medicinal Products, following reassessment, considered that significant benefit continued to be met and recommended maintaining the orphan designation and thus 10 years market exclusivity (the Orphan Designation is a legal procedure that allows for the designation of a medicinal substance with therapeutic potential for a rare disease, before its first administration in humans or during its clinical development). The marketing authorization holder for this medicinal product is Amgen Europe B.V. IMPLICATIONS FOR PRACTICE: Immunotherapy with blinatumomab has excellent and sustainable results, offering new hope for patients with minimal residual disease-positive acute lymphoblastic leukemia, a disease with poor prognosis. New recommendations and change of practice for treatment of this patient group are detailed.

EMA Recommendation for the Pediatric Indications of Plerixafor (Mozobil) to Enhance Mobilization of Hematopoietic Stem Cells for Collection and Subsequent Autologous Transplantation in Children with Lymphoma or Malignant Solid Tumors.

On March 28, 2019, the Committee for Medicinal Products for Human Use adopted a positive opinion recommending the marketing authorization for the medicinal product plerixafor. The marketing authorization holder for this medicinal product is Genzyme Europe B.Th. The adoption was for an extension of the existing adult indication in combination with granulocyte colony-stimulating factor (G-CSF) to pediatric patients (aged 1 year to <18 years) to enhance mobilization of hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in children with lymphoma or solid malignant tumors. This treatment is indicated either preemptively, when circulating stem cell count on the predicted day of collection after adequate mobilization with G-CSF (with or without chemotherapy) is expected to be insufficient with regard to desired hematopoietic stem cells yield, or in children who previously failed to collect sufficient hematopoietic stem cells. The efficacy and safety of plerixafor were evaluated in an open label, multicenter, phase I/II, dose-ranging, and randomized controlled study (DFI12860) in pediatric patients with solid tumors, including neuroblastoma, sarcoma, Ewing sarcoma, or lymphoma, who were eligible for autologous hematopoietic stem cell transplantation. Forty-five patients (aged 1 year to <18 years) were randomized, 2:1, using 0.24 mg/kg of plerixafor plus standard mobilization (G-CSF with or without chemotherapy) versus control (standard mobilization alone). The primary analysis showed that 80% of patients in the plerixafor arm experienced at least a doubling of the peripheral blood (PB) CD34+ count, observed from the morning of the day preceding the first planned apheresis to the morning prior to apheresis, versus 28.6% of patients in the control arm (p = .0019). The median increase in PB CD34+ cell counts from baseline to the day of apheresis was 3.2-fold in the plerixafor arm versus by 1.4-fold in the control arm. The observed safety profile in the pediatric population was consistent with that in adults, with adverse events mainly related to injection site reactions, hypokalemia, and increased blood bicarbonate. Importantly, plerixafor exposure did not seem to negatively affect transplant efficiency. This article summarizes the scientific review of the application leading to regulatory approval in the European Union. IMPLICATIONS FOR PRACTICE: This review of the marketing authorization of plerixafor will raise awareness of pediatric indication granted for this medicinal product.

EMA Review of Axicabtagene Ciloleucel (Yescarta) for the Treatment of Diffuse Large B-Cell Lymphoma.

On June 28, 2018, the Committee for Advanced Therapies and the Committee for Medicinal Products for Human Use adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Yescarta for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma, after two or more lines of systemic therapy. Yescarta, which was designated as an orphan medicinal product and included in the European Medicines Agency's Priority Medicines scheme, was granted an accelerated review timetable. The active substance of Yescarta is axicabtagene ciloleucel, an engineered autologous T-cell immunotherapy product whereby a patient's own T cells are harvested and genetically modified ex vivo by retroviral transduction using a retroviral vector to express a chimeric antigen receptor (CAR) comprising an anti-CD19 single chain variable fragment linked to CD28 costimulatory domain and CD3-zeta signaling domain. The transduced anti-CD19 CAR T cells are expanded ex vivo and infused back into the patient, where they can recognize and eliminate CD19-expressing cells. The benefits of Yescarta as studied in ZUMA-1 phase II (NCT02348216) were an overall response rate per central review of 66% (95% confidence interval, 56%-75%) at a median follow-up of 15.1 months in the intention to treat population and a complete response rate of 47% with a significant duration. The most common adverse events were cytokine release syndrome, neurological adverse events, infections, pyrexia, diarrhea, nausea, hypotension, and fatigue. IMPLICATIONS FOR PRACTICE: Yescarta (axicabtagene ciloleucel) was the first chimeric antigen receptor T-cell therapy to be submitted for evaluation to the European Medicines Agency and admitted into the "priority medicine" scheme; it was granted accelerated assessment on the basis of anticipated clinical benefit in relapsed/refractory diffuse large B-cell lymphoma, a condition of unmet medical need. Indeed, Yescarta showed an overall response rate of 66% and a complete response rate of 47% with a significant duration and a manageable toxicity that compared very favorably with historical controls. Here the analysis of benefits and risks is presented, and specific challenges with this important novel product are highlighted, providing further insights and reflections for future medical research.

The European Medicines Agency Review of Kymriah (Tisagenlecleucel) for the Treatment of Acute Lymphoblastic Leukemia and Diffuse Large B-Cell Lymphoma.

Chimeric antigen receptor (CAR)-engineered T-cell therapy is becoming one of the most promising approaches in the treatment of cancer. On June 28, 2018, the Committee for Advanced Therapies (CAT) and the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Kymriah for pediatric and young adult patients up to 25 years of age with B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse after transplant, or in second or later relapse and for adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy. Kymriah became one of the first European Union-approved CAR T therapies. The active substance of Kymriah is tisagenlecleucel, an autologous, immunocellular cancer therapy that involves reprogramming the patient's own T cells to identify and eliminate CD19-expressing cells. This is achieved by addition of a transgene encoding a CAR. The benefit of Kymriah was its ability to achieve remission with a significant duration in patients with ALL and an objective response with a significant duration in patients with DLBCL. The most common hematological toxicity was cytopenia in both patients with ALL and those with DLBCL. Nonhematological side effects in patients with ALL were cytokine release syndrome (CRS), infections, secondary hypogammaglobulinemia due to B-cell aplasia, pyrexia, and decreased appetite. The most common nonhematological side effects in patients with DLBCL were CRS, infections, pyrexia, diarrhea, nausea, hypotension, and fatigue. Kymriah also received an orphan designation on April 29, 2014, following a positive recommendation by the Committee for Orphan Medicinal Products (COMP). Maintenance of the orphan designation was recommended at the time of marketing authorization as the COMP considered the product was of significant benefit for patients with both conditions. IMPLICATIONS FOR PRACTICE: Chimeric antigen receptor (CAR)-engineered T-cell therapy is becoming the most promising approach in cancer treatment, involving reprogramming the patient's own T cells with a CAR-encoding transgene to identify and eliminate cancer-specific surface antigen-expressing cells. On June 28, 2018, Kymriah became one of the first EMA approved CAR T therapies. CAR T technology seems highly promising for diseases with single genetic/protein alterations; however, for more complex diseases there will be challenges to target clonal variability within the tumor type or clonal evolution during disease progression. Products with a lesser toxicity profile or more risk-minimization tools are also anticipated.

The EMA Review of Mylotarg (Gemtuzumab Ozogamicin) for the Treatment of Acute Myeloid Leukemia.

On February 22, 2018, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product gemtuzumab ozogamicin (Mylotarg; Pfizer, New York City, NY), intended for the treatment of acute myeloid leukemia. Mylotarg was designated as an orphan medicinal product on October 18, 2000. The applicant for this medicinal product was Pfizer Limited (marketing authorization now held by Pfizer Europe MA EEIG).The demonstrated benefit with Mylotarg is improvement in event-free survival. This has been shown in the pivotal ALFA-0701 (MF-3) study. In addition, an individual patient data meta-analysis from five randomized controlled trials (3,325 patients) showed that the addition of Mylotarg significantly reduced the risk of relapse (odds ratio [OR] 0.81; 95% CI: 0.73-0.90; p = .0001), and improved overall survival at 5 years (OR 0.90; 95% CI: 0.82-0.98; p = .01) [Lancet Oncol 2014;15:986-996]. The most common (>30%) side effects of Mylotarg when used together with daunorubicin and cytarabine are hemorrhage and infection.The full indication is as follows: "Mylotarg is indicated for combination therapy with daunorubicin (DNR) and cytarabine (AraC) for the treatment of patients age 15 years and above with previously untreated, de novo CD33-positive acute myeloid leukemia (AML), except acute promyelocytic leukemia (APL)."The objective of this article is to summarize the scientific review done by the CHMP of the application leading to regulatory approval in the European Union. The full scientific assessment report and product information, including the Summary of Product Characteristics, are available on the European Medicines Agency website (www.ema.europa.eu). IMPLICATIONS FOR PRACTICE: This article reflects the scientific assessment of Mylotarg (gemtuzumab ozogamicin; Pfizer, New York City, NY) use for the treatment of acute myeloid leukemia based on important contributions from the rapporteur and co-rapporteur assessment teams, Committee for Medicinal Products for Human Use members, and additional experts following the application for a marketing authorization from the company. It's a unique opportunity to look at the data from a regulatory point of view and the importance of assessing the benefit-risk.

Ruxolitinib vs best available therapy for ET intolerant or resistant to hydroxycarbamide.

Treatments for high-risk essential thrombocythemia (ET) address thrombocytosis, disease-related symptoms, as well as risks of thrombosis, hemorrhage, transformation to myelofibrosis, and leukemia. Patients resistant/intolerant to hydroxycarbamide (HC) have a poor outlook. MAJIC (ISRCTN61925716) is a randomized phase 2 trial of ruxolitinib (JAK1/2 inhibitor) vs best available therapy (BAT) in ET and polycythemia vera patients resistant or intolerant to HC. Here, findings of MAJIC-ET are reported, where the modified intention-to-treat population included 58 and 52 patients randomized to receive ruxolitinib or BAT, respectively. There was no evidence of improvement in complete response within 1 year reported in 27 (46.6%) patients treated with ruxolitinib vs 23 (44.2%) with BAT (P = .40). At 2 years, rates of thrombosis, hemorrhage, and transformation were not significantly different; however, some disease-related symptoms improved in patients receiving ruxolitinib relative to BAT. Molecular responses were uncommon; there were 2 complete molecular responses (CMR) and 1 partial molecular response in CALR-positive ruxolitinib-treated patients. Transformation to myelofibrosis occurred in 1 CMR patient, presumably because of the emergence of a different clone, raising questions about the relevance of CMR in ET patients. Grade 3 and 4 anemia occurred in 19% and 0% of ruxolitinib vs 0% (both grades) in the BAT arm, and grade 3 and 4 thrombocytopenia in 5.2% and 1.7% of ruxolitinib vs 0% (both grades) of BAT-treated patients. Rates of discontinuation or treatment switching did not differ between the 2 trial arms. The MAJIC-ET trial suggests that ruxolitinib is not superior to current second-line treatments for ET. This trial was registered at www.isrctn.com as #ISRCTN61925716.

Guidelines for the diagnosis and management of acute myeloid leukaemia in pregnancy.

Pregnant women should be managed by a multidisciplinary team that includes haematologists, obstetricians, neonatologists and anaesthetists (Grade 1C) As for non-pregnant patients, acute myeloid leukaemia (AML) should be diagnosed using the World Health Organization (WHO) classification (Grade 1A) Women diagnosed with AML in pregnancy should be treated without delay (Grade 1B) When the diagnosis of AML is made in the first trimester, a successful pregnancy outcome is unlikely and spontaneous pregnancy loss in this situation carries considerable risks for the mother. The reasons for and against elective termination should be discussed with the patient (Grade 2C) In the case of presentation beyond 32 weeks gestation, it may be reasonable to deliver the foetus prior to commencement of chemotherapy (Grade 2C) Between 24 and 32 weeks, risks of foetal chemotherapy exposure must be balanced against risks of prematurity following elective delivery at that stage of gestation (Grade 1C) The risk-benefit ratio must be carefully considered before using any drugs in pregnancy (Grade 1C) Where AML induction chemotherapy is delivered, a standard daunorubicin, cytarabine 3 + 10 schedule should be used (Grade 1B) Chemotherapy should be dosed according to actual body weight and adjustments made for weight changes during treatment (Grade 1C) Quinolones, tetracyclines and sulphonamide use should be avoided in pregnancy (Grade 1B) Amphotericin B or lipid derivatives are the antifungal of choice in pregnancy (Grade 2C) Cytomegalovirus (CMV)-negative blood products should be administered during pregnancy regardless of CMV serostatus (Grade 1B) A course of corticosteroids should be considered if delivery is anticipated between 24 and 35 weeks gestation, given over a 48-h period during the week prior to delivery (Grade 1A) Use of magnesium sulphate should be considered in the 24 h prior to delivery if this is before 30 weeks gestation (Grade 1A) Where possible, delivery should be planned for a time when the woman is at least 3 weeks post-chemotherapy to minimize risk of neonatal myelosuppression (Grade 1C) Planned delivery is easier to manage than spontaneous labour; induction of labour is usually advised (Grade 2C) Epidural analgesia should be avoided in a woman who is significantly thrombocytopenic (platelet count <80 × 10(9) /l) and/or neutropenic (white blood cell count <1 × 10(9) /l): (Grade 1C) Elective caesarean section should only be recommended for obstetric indications (Grade 2C) Antibiotics should be administered during and after premature rupture of membranes and delivery (Grade 1C).

Response to ruxolitinib in patients with intermediate-1-, intermediate-2-, and high-risk myelofibrosis: results of the UK ROBUST Trial.

Myelofibrosis is characterized by splenomegaly and debilitating constitutional symptoms that negatively impact patients' quality of life. ROBUST, a UK, open-label, phase II study, evaluated the safety and efficacy of ruxolitinib in patients with myelofibrosis (N = 48), including intermediate-1 risk patients. The primary composite endpoint was the proportion of patients achieving treatment success [≥ 50% reduction in palpable spleen length and/or a ≥ 50% decrease in Myelofibrosis Symptom Assessment Form Total Symptom Score (MF-SAF TSS)] at 48 weeks. This was the first time that efficacy of ruxolitinib in myelofibrosis has been evaluated based on these criteria and the first time the MF-SAF was used in a population of patients solely from the United Kingdom. Overall, 50% of patients and 57% of intermediate-1 risk patients, achieved treatment success; reductions in spleen length and symptoms were observed in all risk groups. The majority of patients (66.7%) experienced ≥ 50% reductions from baseline in spleen length at any time. Improvements in MF-SAF TSS were seen in 80.0%, 72.7%, and 72.2% of intermediate-1, intermediate-2, and high-risk patients, respectively. Consistent with other studies of ruxolitinib, the most common haematological adverse events were anaemia and thrombocytopenia. Results indicate that most patients with myelofibrosis, including intermediate-1 risk patients, may benefit from ruxolitinib treatment.

Clofarabine doubles the response rate in older patients with acute myeloid leukemia but does not improve survival.

Better treatment is required for older patients with acute myeloid leukemia (AML) not considered fit for intensive chemotherapy. We report a randomized comparison of low-dose Ara-C (LDAC) vs the novel nucleoside, clofarabine, in untreated older patients with AML and high-risk myelodysplastic syndrome (MDS). A total of 406 patients with de novo (62%), secondary disease (24%), or high-risk MDS (>10% marrow blasts) (15%), median age 74 years, were randomized to LDAC 20 mg twice daily for 10 days every 6 weeks or clofarabine 20 mg/m(2) on days 1 to 5, both for up to 4 courses. These patients had more adverse demographics than contemporaneous intensively treated patients. The overall remission rate was 28%, and 2-year survival was 13%. Clofarabine significantly improved complete remission (22% vs 12%; hazard ratio [HR] = 0.47 [0.28-0.79]; P = .005) and overall response (38% vs 19%; HR = 0.41 [0.26-0.62]; P < .0001), but there was no difference in overall survival, explained by poorer survival in the clofarabine patients who did not gain complete remission and also following relapse. Clofarabine was more myelosuppressive and required more supportive care. Although clofarabine doubled remission rates, overall survival was not improved overall or in any subgroup. The treatment of patients of the type treated here remains a major unmet need.

Increased inducible heat shock protein 72 expression associated with PBMC isolated from patients with haematological tumours.

BACKGROUND: Heat shock protein 72 (Hsp72) is a highly inducible stress protein and molecular chaperone. Cancers have been shown to be associated with increased Hsp72 expression within the tumour itself and this may lead to resistance to apoptosis. METHODS: Peripheral blood mononuclear cells (PBMC) were isolated from patients diagnosed with chronic lymphocytic leukaemia (CLL) (n = 27) and chronic myelomonocytic leukaemia (CMML) (n = 16) and Hsp72 expression was characterized on both the cell surface and intracellularly by flow cytometry. To allow for comparison PBMC from breast cancer patients (n = 25) and healthy volunteers (n = 19) were included. RESULTS: Both lymphocytes and monocytes from CLL and CMML patients showed high levels of total Hsp72 expression (4-6 fold increase) in comparison to breast cancer and healthy subjects. The majority of Hsp72 in these tumours was determined to be cell-surface expressed (64-93% of cell total Hsp72). CONCLUSIONS: A correlation was observed between lymphocyte and monocyte total Hsp72 expression (p < 0.001) suggesting a common stress response pathway may exist in these blood cells and there are stress conditions present within the circulation. Hsp72 expression was not found to be related to white blood cell count.

A prospective registry-based cohort study of the diagnosis and management of acute leukaemia in pregnancy: Study protocol.

BACKGROUND: Acute leukaemias (AL) are aggressive but potentially curable blood cancers that can potentially affect women of childbearing age. When a pregnancy is complicated by a diagnosis of AL, clinicians face a complex dilemma: to balance risking the mother's survival through delayed AL treatment, against the potential harm to the foetus through exposure to anti-cancer drugs. Up until now, all guidance and advice regarding the management of AL in pregnancy, have been based on expert opinion and small case studies. There is a pressing need for more studies in the subject to address this evidence gap. METHODS AND ANALYSIS: This study is a registry-based observational cohort study which aims to monitor and record the treatment outcomes of patients diagnosed with AL during pregnancy. Additionally, the study aims to assess pregnancy outcomes in patients who become pregnant following successful treatment. Prospective and historical cases from August 2009 onwards will be identified from AL treating haematology units within the UK. Details of diagnosis, AL treatment delivered, antenatal and postnatal outcomes for mother and neonate will be collected. This study will establish a new research database for Leukaemia in Pregnancy. TRIAL REGISTRATION: The study was registered on Clinicaltrials.gov (NCT04182074) on the 2nd December 2019.

Large Scale Internet-based Survey of Patients With a Myeloproliferative Neoplasm: Opinions and Experiences Regarding SARS-CoV-2 (COVID-19) Vaccination Strategies in 2021.

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