Response to Therapy, Treatment Intolerance and Tyrosine Kinase Inhibitor Cessation Eligibility in a Real-World Cohort of Chronic Myeloid Leukaemia Patients.

Tyrosine kinase inhibitor (TKI) therapy has revolutionised chronic myeloid leukaemia (CML) management, it is however associated with significant side effects and economic burden. Recent studies have demonstrated that treatment free remission is possible in certain patients. The aim of this study was to characterise a real-world population in terms of response to therapy, treatment intolerance and potential eligibility for stopping treatment. Included were 105 CML patients diagnosed in Northern Ireland from March 2009-February 2018. Response to treatment was defined as per the 2009 and 2013 European Leukaemia Net guidelines. Potential for treatment cessation was assessed as per the 2017 UK Interim Expert Opinion on Discontinuing Tyrosine Kinase Inhibitor Treatment in Clinical Practice for Treatment-Free Remission in Chronic Myeloid Leukaemia. Our cytogenetic data cohort had a 12-month complete cytogenetic response rate of 66% and the molecular data cohort had a 12-month major molecular response rate of 38%. Of those commenced on 2nd line TKI therapy 81% achieved an optimal response at 12 months. Twenty-two patients developed intolerance and required a change in TKI therapy. The commonest side effects were gastro-intestinal upset (18%), transaminitis (16%) and fluid retention (16%). In our cohort, 20% were considered eligible to stop TKI therapy. The commonest reason for ineligibility was insufficient duration of therapy (25%). We observed that 1st and 2nd line TKI therapy are effective but problems with failure and intolerance persist. Additionally, this study identifies a cohort of patients who may attempt TKI cessation using the UK Interim Expert Opinion report on TKI therapy discontinuation.

A Comparison of Inpatient and Outpatient-Based Chemotherapy Regimens for the Treatment of Acute Myeloid Leukaemia In The Elderly.

INTRODUCTION: Acute myeloid leukaemia (AML) is an aggressive haematological malignancy which is more common in the elderly and has a poor 5-year survival. There are no established beneficial interventions to treat AML in elderly patients. It is unclear whether outpatient delivery of palliative chemotherapies could reduce the burden of disease and hospitalisation for this group. AIMS: To compare overall survival, response to treatment and supportive care needs between inpatient and outpatient-based treatments for AML in elderly patients. MATERIALS & METHODS: We undertook a retrospective cohort study in the Haematology Department at Belfast City Hospital comparing overall survival (OS), treatment responses and supportive care needs between inpatient and outpatient treatments for AML in elderly patients. Consecutive entrants to outpatient and inpatient based clinical trials between February 2013 and January 2017 were included. Case notes, chemotherapy charts, clinic letters, blood bank and electronic care records were analysed. RESULTS: OS and rates of CR (complete remission), CRi (CR with incomplete count recovery) and PR (partial response) was not significantly different between inpatient and outpatient regimens with a median OS of 201 vs. 124 days, respectively. No response was observed in 35% of patients in the inpatient group compared with 65% of the outpatient group, however this did not reach significance. Of patients who achieved CR/CRi in the outpatient group, 75% relapsed at a median of 271 days, compared with 60% of the inpatient group at a median of 209 days. At least one grade 3-4 toxicity was experienced by 90% and 83.3% of inpatient and outpatient groups, respectively. There was no difference in six common grade 3-4 toxicities. Patients on the outpatient regimen spent fewer days in hospital but had a median packed red cell use of more than twice that of the inpatient group. No difference was noted in infections, days on antibiotics or platelet use. DISCUSSION: Our data suggests that outpatient chemotherapy is safe and can reduce hospitalisation for elderly patients with AML, without a decline in OS or response rates. These results provide an important rationale to test the comparative efficacy of outpatient chemotherapy. Chemotherapy related toxicities remain a significant source of morbidity in this population and highlight the need to develop novel, targeted therapies for this age group.

Equivalence of BCSH and WHO diagnostic criteria for ET.

This corrects the article DOI: 10.1038/leu.2016.318.

Which patients with myelofibrosis should receive ruxolitinib therapy? ELN-SIE evidence-based recommendations.

Ruxolitinib is an oral Janus-activated kinase 1 (JAK1)/JAK2 inhibitor approved for the treatment of patients with myelofibrosis based on the results of two randomized clinical trials. However, discordant indications were provided by regulatory agencies and scientific societies for selecting the most appropriate candidates to this drug. The European LeukemiaNet and the Italian Society of Hematology shared the aim of building evidence-based recommendations for the use of ruxolitinib according to the GRADE methodology. Eighteen patient-intervention-comparator-outcome profiles were listed, each of them comparing ruxolitinib to other therapies with the aim of improving one of the three clinical outcomes: (a) splenomegaly, (b) disease-related symptoms, and (c) survival. Ruxolitinib was strongly recommended for improving symptomatic or severe (>15 cm below the costal margin) splenomegaly in patients with an International Prognostic Scoring System (IPSS)/dynamic IPSS risk intermediate 2 or high. Ruxolitinib was also strongly recommended for improving systemic symptoms in patients with an MPN10 score >44, refractory severe itching, unintended weight loss not attributable to other causes or unexplained fever. Because of weak evidence, the panel does not recommend ruxolitinib therapy for improving survival. Also, the recommendations given above do not necessarily apply to patients who are candidates for allogeneic stem cell transplant.

A randomized study of pomalidomide vs placebo in persons with myeloproliferative neoplasm-associated myelofibrosis and RBC-transfusion dependence.

RBC-transfusion dependence is common in persons with myeloproliferative neoplasm (MPN)-associated myelofibrosis. The objective of this study was to determine the rates of RBC-transfusion independence after therapy with pomalidomide vs placebo in persons with MPN-associated myelofibrosis and RBC-transfusion dependence. Two hundred and fifty-two subjects (intent-to-treat (ITT) population) including 229 subjects confirmed by central review (modified ITT population) were randomly assigned (2:1) to pomalidomide or placebo. Trialists and subjects were blinded to treatment allocation. Primary end point was proportion of subjects achieving RBC-transfusion independence within 6 months. One hundred and fifty-two subjects received pomalidomide and 77 placebo. Response rates were 16% (95% confidence interval (CI), 11, 23%) vs 16% (8, 26%; P=0.87). Response in the pomalidomide cohort was associated with ⩽4 U RBC/28 days (odds ratio (OR)=3.1; 0.9, 11.1), age ⩽65 (OR=2.3; 0.9, 5.5) and type of MPN-associated myelofibrosis (OR=2.6; 0.7, 9.5). Responses in the placebo cohort were associated with ⩽4 U RBC/28 days (OR=8.6; 0.9, 82.3), white blood cell at randomization >25 × 109/l (OR=4.9; 0.8, 28.9) and interval from diagnosis to randomization >2 years (OR=4.9; 1.1, 21.9). Pomalidomide was associated with increased rates of oedema and neutropenia but these adverse effects were manageable. Pomalidomide and placebo had similar RBC-transfusion-independence response rates in persons with MPN-associated RBC-transfusion dependence.

Congenital erythrocytosis.

INTRODUCTION: Congenital erythrocytosis is by definition present from birth. Patients frequently present in childhood or as young adults and a family history may be present. The erythrocytosis can be primary where there is a defect in the erythroid compartment of secondary where increased erythropoietin production produced due to the defect leads to an erythrocytosis. MATERIAL AND METHODS: Primary causes include erythropoietin receptor mutations. Congenital secondary causes include mutations in the genes involved in the oxygen-sensing pathway and haemoglobins with abnormal oxygen affinity. Investigations for the cause include an erythropoietin level, oxygen dissociation curve, haemoglobin electrophoresis and sequencing for known gene variants. RESULTS: The finding of a known or new molecular variant confirms a diagnosis of congenital erythrocytosis. A congenital erythrocytosis may be an incidental finding but nonspecific symptoms are described. Major thromboembolic events have been noted in some cases. Low-dose aspirin and venesection are therapeutic manoeuvres which should be considered in managing these patients. CONCLUSIONS: Rare individuals presenting often at a young age may have a congenital erythrocytosis. Molecular investigation may reveal a lesion. However, in the majority, currently no defect is identified.

The prevalence of CALR mutations in a cohort of patients with myeloproliferative neoplasms.

INTRODUCTION: To investigate the prevalence of calreticulin (CALR) mutations in JAK2- and MPL-non-mutated patients with suspected myeloproliferative neoplasm (MPN) from a large MPN clinic and confirm a diagnosis of MPN. METHODS: JAK2/MPL-non-mutated patients from the Belfast City Hospital (BCH) with either of the MPNs - ET or MF - and diagnosed between 1988 and 2014 were selected for CALR screen. All cases were validated according to the WHO 2008 classification for MPNs. Statistical analysis was performed with Minitab 16 Statistical Software package. Exon 9 of CALR was amplified by PCR using genomic DNA, and mutations were detected by fragment analysis. RESULTS: Of the 62 JAK2/MPL-non-mutated MPN patients screened, 57 had ET and 5 had MF; 34 patients (53.1%) carried CALR mutations. Three of 5 MF patients were CALR positive. Thirty-one ET patients (54.3%) harboured CALR mutation, whereas 26 (45.7%) were classified as 'triple negatives'. CONCLUSION: Detection of CALR mutations in a cohort of JAK2/MPL-non-mutated patients with suspected MPN confirmed the diagnosis of MPN in around 53% of cases. This is lower than initially reported, but similar to subsequent studies. However, a sizable cohort of patients remains lacking a specific molecular marker.

Management of newly diagnosed chronic myeloid leukaemia during a twin pregnancy using leucapheresis: Case report and review of the literature.

A case of chronic myeloid leukaemia diagnosed as an incidental finding in a 32-year-old woman, pregnant with twins at 11 weeks gestation, is presented. Management of the patient was with leucapheresis and supportive care until spontaneous delivery of two morphologically normal infants (one male, one female) at 37 weeks gestation. Special considerations while employing leucapheresis in pregnant patients are discussed.

Epidemiology of MPN: what do we know?

The myeloproliferative neoplasms, are characterised by overproduction of myeloid cells. Chronic myeloid leukaemia, polycythaemia vera, essential thrombocythaemia, myelofibrosis and the very rare disorders chronic neutrophilic leukaemia, chronic eosinophilic leukaemia not otherwise specified and mastocytosis are all included in the group. Incidence and prevalence rates reported in the worldwide literature are presented in this review. Survival data on each condition is described. Information on the aetiology of the disorders is discussed including body mass index, diet, smoking and alcohol, allergies, associated medical conditions, occupation and environmental exposures with focus on recent new studies. The aetiology of the myeloproliferative neoplasms remains unknown, and this review of the current state of knowledge highlights the need for further comprehensive research.

Establishing optimal quantitative-polymerase chain reaction assays for routine diagnosis and tracking of minimal residual disease in JAK2-V617F-associated myeloproliferative neoplasms: a joint European LeukemiaNet/MPN&MPNr-EuroNet (COST action BM0902) study.

Reliable detection of JAK2-V617F is critical for accurate diagnosis of myeloproliferative neoplasms (MPNs); in addition, sensitive mutation-specific assays can be applied to monitor disease response. However, there has been no consistent approach to JAK2-V617F detection, with assays varying markedly in performance, affecting clinical utility. Therefore, we established a network of 12 laboratories from seven countries to systematically evaluate nine different DNA-based quantitative PCR (qPCR) assays, including those in widespread clinical use. Seven quality control rounds involving over 21,500 qPCR reactions were undertaken using centrally distributed cell line dilutions and plasmid controls. The two best-performing assays were tested on normal blood samples (n=100) to evaluate assay specificity, followed by analysis of serial samples from 28 patients transplanted for JAK2-V617F-positive disease. The most sensitive assay, which performed consistently across a range of qPCR platforms, predicted outcome following transplant, with the mutant allele detected a median of 22 weeks (range 6-85 weeks) before relapse. Four of seven patients achieved molecular remission following donor lymphocyte infusion, indicative of a graft vs MPN effect. This study has established a robust, reliable assay for sensitive JAK2-V617F detection, suitable for assessing response in clinical trials, predicting outcome and guiding management of patients undergoing allogeneic transplant.

The addition of gemtuzumab ozogamicin to low-dose Ara-C improves remission rate but does not significantly prolong survival in older patients with acute myeloid leukaemia: results from the LRF AML14 and NCRI AML16 pick-a-winner comparison.

The treatment of older patients with acute myeloid leukaemia, who are not considered suitable for conventional intensive therapy, is unsatisfactory. Low-dose Ara-C(LDAC) has been established as superior to best supportive care, but only benefits the few patients who enter complete remission. Alternative or additional treatments are required to improve the situation. This randomised trial compared the addition of the immunoconjugate, gemtuzumab ozogamicin (GO), at a dose of 5 mg on day 1 of each course of LDAC, with the intention of improving the remission rate and consequently survival. Between June 2004 and June 2010, 495 patients entered the randomisation. The addition of GO significantly improved the remission rate (30% vs 17%; odds ratio(OR) 0.48 (0.32-0.73); P=0.006), but not the 12 month overall survival (25% vs 27%). The reason for the induction benefit failing to improve OS was two-fold: survival of patients in the LDAC arm who did not enter remission and survival after relapse were both superior in the LDAC arm. Although the addition of GO to LDAC doubled the remission rate it did not improve overall survival. Maintaining remission in older patients remains elusive.

Inclusion of chemotherapy in addition to anthracycline in the treatment of acute promyelocytic leukaemia does not improve outcomes: results of the MRC AML15 trial.

Two hundred eighty-five patients, median age 42, with PML-RARα-positive acute promyelocytic leukaemia were randomised to Ara-C-containing 'Medical Research Council (MRC) Chemotherapy'+ATRA (All-trans-retinoic acid) or anthracycline+ATRA (modified 'Spanish') therapy. MRC treatment comprised four courses with ATRA in courses 1-2. Spanish treatment comprised four anthracycline-based courses with ATRA in courses 1-3. In course 3 patients were randomised to gemtuzumab ozogamicin (GO) or not. The Spanish arm received 24-month maintenance. Patients were sequentially molecularly monitored. Quality of life was assessed at baseline, 3, 6, 9, 12, 24 months. Remission rates were similar in both arms (93%): cumulative incidence of haematological relapse (CIHR) was 6% at 5 years; 5 patients relapsed molecularly. Survival post relapse was 80%. There were more deaths in remission in the MRC arm (4% vs 10%: P=0.2). The overall 5-year relapse-free and overall survival was similar between arms (81% vs 82% and 84% vs 83%, respectively). More supportive care and hospitalisation (81.8 vs 63 days, P<0.0001) was required in the MRC arm. GO did not provide benefit. High white blood cell count (>10 × 10(9)/l) was not prognostic overall, or within treatment arms. Both approaches deliver similar results with minor differences in quality of life. MRC treatment required more hospitalisation. This suggests that additional chemotherapy, Ara-C in particular, is not required.

The addition of arsenic trioxide to low-dose Ara-C in older patients with AML does not improve outcome.

Most patients with acute myeloid leukaemia (AML) are older, with many unsuitable for conventional chemotherapy. Low-dose Ara-C (LDAC) is superior to best supportive care but is still inadequate. The combination of arsenic trioxide (ATO) and LDAC showed promise in an unrandomised study. We report a randomised trial of LDAC versus LDAC+ATO. Patients with AML according to WHO criteria or myelodysplastic syndrome with >10% blasts, considered as unfit for conventional chemotherapy, were randomised between subcutaneous Ara-C (20 mg b.d. for 10 days) and the same LDAC schedule with ATO (0.25 mg/kg) on days 1-5, 9 and 11, for at least four courses every 4 to 6 weeks. Overall 166 patients were entered; the trial was terminated on the advice of the DMC, as the projected benefit was not observed. Overall 14% of patients achieved complete remission (CR) and 7% CRi. Median survival was 5.5 months and 19 months for responders (CR: not reached; CRi: 14 months; non-responders: 4 months). There were no differences in response or survival between the arms. Grade 3/4 cardiac and liver toxicity, and supportive care requirements were greater in the ATO arm. This randomised comparison demonstrates that adding ATO to LDAC provides no benefit for older patients with AML.

British Society of Haematology, Slide Session presented at the Annual Scientific Meeting, Brighton 2009.

Seven cases were discussed by an expert panel at the 2009 Annual Scientific Meeting of the British Society of Haematology. These cases are presented in a similar format to that adopted for the meeting. There was an initial discussion of the presenting morphology, generation of differential diagnoses and then, following display of further presenting and diagnostic information, each case was concluded with provision of a final diagnosis.

British Society for Haematology, slide session, annual scientific meeting, Glasgow, 2008.

A morphology session is held each year at the Annual Scientific Meeting of the British Society of Haematology. Prior to the meeting this year, eight morphology cases were made available to BSH members as glass slides and also digitally as 'virtual slides'. A panel of invited commentators who had no prior knowledge of the diagnosis discussed the eight cases. An initial limited history and blood count are given with representative images from the case material; this is followed by the discussants' comments and suggested diagnosis. The actual clinical diagnosis is then given with other relevant information.

The finding of a reciprocal whole-arm translocation t(X;12)(p10;p10) in association with atypical chronic myeloid leukaemia.

Atypical chronic myeloid leukaemia (aCML) belongs to the myeloproliferative/myelodysplastic category of haematological disease. Main characteristics are marked dysgranulopoiesis, bone marrow dysfunction and the failure to demonstrate the presence of the Philadelphia chromosome or BCR/ABL fusion gene normally associated with CML t(9;22)(q34;q11). It carries a poor prognosis with limited therapeutic options available. Most cases of aCML have one or more karyotypic abnormalities. We highlight a clinical presentation of aCML associated with an acquired reciprocal whole-arm translocation (WAT), t(X;12)(p10;p10), which to our knowledge has not yet been described. We also discuss how such a translocation might lead to tumorigenesis.