Patrick Thornton

Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia

BACKGROUND In patients with chronic lymphoid leukemia (CLL) or small lymphocytic lymphoma (SLL), a short duration of response to therapy or adverse cytogenetic abnormalities are associated with a poor outcome. We evaluated the efficacy of ibrutinib, a covalent inhibitor of Brutons tyrosine kinase, in patients at risk for a poor outcome. METHODS In this multicenter, open-label, phase 3 study, we randomly assigned 391 patients with relapsed or refractory CLL or SLL to receive daily ibrutinib or the anti-CD20 antibody ofatumumab. The primary end point was the duration of progression-free survival, with the duration of overall survival and the overall response rate as secondary end points. RESULTS At a median follow-up of 9.4 months, ibrutinib significantly improved progression-free survival; the median duration was not reached in the ibrutinib group (with a rate of progression-free survival of 88% at 6 months), as compared with a median of 8.1 months in the ofatumumab group (hazard ratio for progression or death in the ibrutinib group, 0.22; P<0.001). Ibrutinib also significantly improved overall survival (hazard ratio for death, 0.43; P=0.005). At 12 months, the overall survival rate was 90% in the ibrutinib group and 81% in the ofatumumab group. The overall response rate was significantly higher in the ibrutinib group than in the ofatumumab group (42.6% vs. 4.1%, P<0.001). An additional 20% of ibrutinib-treated patients had a partial response with lymphocytosis. Similar effects were observed regardless of whether patients had a chromosome 17p13.1 deletion or resistance to purine analogues. The most frequent nonhematologic adverse events were diarrhea, fatigue, pyrexia, and nausea in the ibrutinib group and fatigue, infusion-related reactions, and cough in the ofatumumab group. CONCLUSIONS Ibrutinib, as compared with ofatumumab, significantly improved progression-free survival, overall survival, and response rate among patients with previously treated CLL or SLL. (Funded by Pharmacyclics and Janssen; RESONATE ClinicalTrials.gov number, NCT01578707.).

Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL

In the phase 3 RESONATE study, ibrutinib demonstrated superior progression-free survival (PFS), overall survival (OS) and overall response rate (ORR) compared with ofatumumab in relapsed/refractory CLL patients with high-risk prognostic factors. We report updated results from RESONATE in these traditionally chemotherapy resistant high-risk genomic subgroups at a median follow-up of 19 months. Mutations were detected by Foundation One Heme Panel. Baseline mutations in the ibrutinib arm included TP53 (51%), SF3B1 (31%), NOTCH1 (28%), ATM (19%) and BIRC3 (14%). Median PFS was not reached, with 74% of patients randomized to ibrutinib alive and progression-free at 24 months. The improved efficacy of ibrutinib vs ofatumumab continues in all prognostic subgroups including del17p and del11q. No significant difference within the ibrutinib arm was observed for PFS across most genomic subtypes, although a subset carrying both TP53 mutation and del17p had reduced PFS compared with patients with neither abnormality. Reduced PFS or OS was not evident in patients with only del17p. PFS was significantly better for ibrutinib-treated patients in second-line vs later lines of therapy. The robust clinical activity of ibrutinib continues to show ongoing efficacy and acceptable safety consistent with prior reports, independent of various known high-risk mutations.

Dialysis-dependent renal failure at diagnosis continues to be associated with very poor outcome in multiple myeloma.

Chang, W.J., Kim, S.J. & Kim, K. (2014) Central nervous system myeloma : a different cytogenetic profile? British Journal of Haematology, 164, 745–748. Gozzetti, A., Cerase, A., Lotti, F., Rossi, D., Palumbo, A., Petrucci, M.T., Patriarca, F., Nozzoli, C., Cavo, M., Offidani, M., Floridia, M., Berretta, S., Vallone, R., Musto, P., Lauria, F. & GIMEMA (Gruppo Italiano Malattie Ematologiche dell’Adulto) Myeloma Working Party (2012) Extramedullary intracranial localizations of multiple myeloma and treatment with novel agents: a retrospective survey of 50 patients. Cancer, 118, 1574–1584.

Co-existing chronic myeloid leukaemia and multiple myeloma: rapid response to lenalidomide during imatinib treatment

We read with particular interest the recent case report by Ide et al. [1] and others [2–5] describing the rare occurrence of a patient with co-existent chronic myeloid leukaemia (CML) and multiple myeloma (MM). Here, we describe a further case in which CML and MM presented simultaneously, and in which commencement of imatinib was followed shortly by MM disease progression. A 71-year-old woman was referred to our department in August 2003 with leucocytosis, anaemia and thrombocytosis. She was asymptomatic and physical examination was unremarkable. Complete blood count (CBC) showed: haemoglobin (Hb) 9.3 g/dL, platelets 564 9 10/L, white cell count (WCC) 12.7 9 10/L with neutrophils 10 9 10/L. Bone marrow aspirate was hypercellular, and showed granulocytic hyperplasia without an increase in blasts. Furthermore, there was an infiltrate of atypical plasma cells accounting for 30% of nucleated cells. Serum protein electrophoresis showed an IgG kappa paraprotein band of 42 g/L with immune paresis. Renal function and serum calcium were normal, and serum b-2-microglobulin was elevated at 5.0 mg/L. Skeletal survey did not show any lytic bone disease. Anti-myeloma treatment was initially deferred, whilst other causes for anaemia were sought. Six months later, the patient’s WCC had risen to 37.2 9 10/L and cytogenetic analysis of a repeat bone marrow aspirate showed 46XX, t(9;22)(q34;q11) in all cell metaphases, confirming a diagnosis of CML. Treatment with imatinib 400 mg once daily was commenced and the patient responded rapidly, achieving a complete molecular remission after 9 months of treatment (measured by reverse transcriptase nested PCR sensitive to 1/10,000 dilution). However after 6-month treatment with imatinib, the patient’s IgG paraprotein had risen to 57.6 g/Lin keeping with MM disease progression. The patient received five cycles of melphalan and prednisolone, resulting in a marginal drop in serum paraprotein to 49.4 g/L. Thereafter, she received five complete cycles of bortezomib (1.3 mg/m) and dexamethasone, which was complicated by grade I peripheral neuropathy without any significant reduction in serum paraprotein, with a repeat bone marrow aspirate showing 60% plasma cells (see Fig. 1 for MM disease course). Thereafter, alternate day oral cyclophosphamide therapy resulted in frequent interruptions in treatment because of neutropenia without reduction in serum paraprotein level. At this point with the serum paraprotein at 50.8 g/L, lenalidomide and dexamethasone treatment was commenced, and the serum paraprotein fell to 9.1 g/L within 3 months (Fig. 1). Lenalidomide was commenced at a dose of 25 mg daily (21 from 28 days) for the first four cycles; however, significant neutropenia led to a dose reduction to 15 mg daily for cycle 5 and further to 5 mg daily from cycle 6 onwards. In addition, G-CSF was administered intermittently to maintain a neutrophil count [1.0 9 10/L but significant thrombocytopenia was not encountered. After 17 months of lenalidomide treatment, the dose was further reduced to 5 mg alternate days, on which she remains. Importantly, imatinib was continued throughout treatment with both lenalidomide and bortezomib, and the patient has maintained a complete molecular response to the present day. Our case is important for a number of reasons. Firstly, we believe this to be the first patient with both CML and MM who has been treated with both bortezomib and lenalidomide in combination with imatinib. Although her condition was bortezomib-refractory, the patient showed C. Offiah (&) J. P. Quinn P. Thornton P. T. Murphy Department of Haematology, Beaumont Hospital, Dublin 9, Ireland e-mail: chikaoffiah@gmail.com

Emergence of Bruton's Tyrosine Kinase-negative Hodgkin Lymphoma During Ibrutinib Treatment of Chronic Lymphocytic Leukaemia

Chronic lymphocytic leukaemia (CLL) is a chronic B‐cell lympho‐proliferative disorder in which lymphomatous transformations occur in 5%‐15% of patients. Histologically these cases resemble diffuse large B‐cell lymphoma, or Richters transformation, in over 80% of cases. Rare cases of transformation to Hodgkin lymphoma (HL) have been reported in the literature with an estimated prevalence of 0.4%. We report a case of a 67‐year‐old female with CLL treated with the novel Brutons tyrosine kinase (Btk) inhibitor, ibrutinib, who subsequently presented with intractable fevers. Bone marrow trephine, and lymph node biopsy revealed classical HL with negative immuno‐histochemistry for Btk in HL cells, on a backdrop of CLL. The patient commenced treatment with Adriamycin, Vinblastine and Dacarbazine (AVD), which resulted in an excellent response. Hodgkin transformation of CLL is rare with a single retrospective study of 4121 CLL patients reporting only 18 cases. Btk expression in HL cells is recently recognised in classical HL; however, the majority of HLs are Btk negative. Given that Btk inhibitors have recently been shown to induce genomic instability in B cells, in the context of their widespread use, such emerging cases are increasingly relevant.

Molecular heterogeneity of familial myeloproliferative neoplasms revealed by analysis of the commonly acquired JAK2, CALR and MPL mutations

The myeloproliferative neoplasms (MPN) are clonal, hematological malignancies that include polycythemia vera, essential thrombocythemia and primary myelofibrosis. While most cases of MPN are sporadic in nature, a familial pattern of inheritance is well recognised. The phenotype and status of the commonly acquired JAK2 V617F, CALR exon 9 and MPL W515L/K mutations in affected individuals from a consecutive series of ten familial MPN (FMPN) kindred are described. Affected individuals display the classical MPN phenotypes together with one kindred identified suggestive of hereditary thrombocytosis. In affected patients the JAK2 V617F mutation is the most commonly acquired followed by CALR exon nine mutations with no MPL W515L/K mutations detected. The JAK2 V617F and CALR exon 9 mutations appear to occur at approximately the same frequency in FMPN as in the sporadic forms of these diseases. The familial nature of MPN may often be overlooked and accordingly more common than previously considered. Characterisation of these FMPN kindred may allow for the investigation of molecular events that contribute to this inheritance.

Haemorrhagic and thrombotic complications in pregnant women with acquired and congenital cardiac disease

Abstract Background: Pregnant patients with cardiac disease have significantly higher predicted maternal morbidity and mortality compared to the general obstetric population. Published guidelines on optimal management of these patients recommend multidisciplinary care provision. There are few published data on the incidence of haematological complications in pregnant women with cardiac disease, although the data that does exist suggests a relatively high rate of bleeding and thrombotic events. Aims: To determine the outcomes in terms of haematological morbidity occurring within a cohort of pregnant women with cardiac disease in the setting of multidisciplinary care provision. Methods: Patients were identified from a database compiled by the obstetric cardiology service listing all cardiac patients managed in the Rotunda maternity hospital during the period from 2004 to 2011. Data were obtained from the medical and obstetric case notes relating to details of perinatal care and the occurrence of antenatal and postnatal complications. Results: During the 8-year review period, 451 women with cardiac disease were assessed. Fifty-nine were determined to have moderate to high-risk disease. Each received consultant-delivered multidisciplinary care, where written management strategies were agreed by collaborating senior colleagues either preconceptually or in early pregnancy. No venous thromboembolic events occurred and a modest rate of post-partum haemorrhage (approximately 5%) was recorded. There were no maternal deaths. Conclusion: The relatively favourable outcomes observed within our institution highlight the importance of a multidisciplinary approach to the management of pregnant women with cardiac disease, particularly in scenarios where limited published evidence exists to guide management.

LONG-TERM EFFICACY AND SAFETY IN THE RESONATE STUDY: IBRUTINIB IN PATIENTS WITH PREVIOUSLY TREATED CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) WITH UP TO FOUR YEARS FOLLOW-UP

included in expansion cohorts at the recommended phase 2 dose (320 mg/d, given once daily [QD] or split as a twice‐daily [BID] dose). Adverse events (AEs) are reported per Common Terminology Criteria for AEs version 4.03, and response per the modified iwCLL criteria (Hallek 2008, Cheson 2012 clarification for novel therapies). Results: As of 15 Dec 2016, 68 pts with CLL/SLL (50 R/R and 18 TN) were enrolled: 4 pts in dose escalation and 64 in cohort expansion at doses of 160 mg QD (n = 3), 160 mg BID (n = 25), and 320 mg QD (n = 40). Patient characteristics are shown in Table 1. Safety: Median follow‐up was 7.2 (range, 0‐23.3) months. The most frequent AEs of any cause were bruising (35%) and petechiae (11%), upper respiratory tract infection (28%), fatigue (25%), cough (22%), and diarrhea (21%). Four serious AEs related to BGB‐3111 were seen in 3 pts: grade (Gr) 2 cardiac failure, Gr 2 pleural effusion, Gr 3 purpura, and Gr 3 pneumonia. The case of Gr 3 purpura (subcutaneous hemorrhage) was the only major bleeding event reported. Atrial fibrillation (Gr 3) occurred in 1 pt. One pt discontinued BGB‐3111 for an AE (pleural effusion). Activity: Of the 54 pts evaluable for response (>12 weeks follow‐up or discontinuation before 12 weeks), the objective response rate was 96% (52/54), with partial response in 67% (36/54), partial response with lymphocytosis in 30% (16/54), stable disease in 1 R/R pt, and no assessment for 1 R/R pt because of AE. No instances of disease progression or Richter transformation were reported. Conclusions: BGB‐3111 is well tolerated and highly active in R/R and TN CLL/SLL. With only 7.2 months of median follow‐up, only 1 toxicity‐related discontinuation, and no progressive disease seen thus far on study.

A 5-day: the favourable way?

Dear editor, We read with interest the article by Pierdomenico et al. [1] reviewing the efficacy and tolerability of a 5-day doseintensified regimen of azacitidine (100 mg/m/day×5 days) in intermediate-2 and high-risk myelodysplastic syndromes (MDS). While the approved regimen is 75 mg/m/day for 7 days every 28 days [2], a 5-day regimen with the elimination of weekend dosing would be more easily delivered, costeffective and conducive to patient convenience. The clinical concern relates to the administration of a potentially suboptimal dose and its subsequent impact on response and overall survival. To date, no large-scale study, including Lyons et al. [3], have demonstrated the superiority of a 7-day over a 5-day regimen. We retrospectively collected data on 32 MDS patients (treatment naïve) who received a 5-day regimen of azacitidine (75 mg/m/day×5 days, n=27; 100 mg/m/ day×5 days n=5) in four Irish institutions (2006– 2012).The dose regimen was dependent on the preference of each centre. Patients were identified through the Irish MDS registry and were risk-stratified according to the WHO Prognostic Scoring System [4]. No inclusion or exclusion criteria were applied. Median age was 73 years (range 36–89 years) with a male predominance (72 %). MDS subtypes included RAEB-2 (n=15), RAEB-1 (n=4), CMML (n=8), RCMD (n=1), RCMDRS (n=1), RA (n=1), RARS (n=1) and MDS/MPD (n=1). The majority (79 %) had high or very high risk disease. Twenty-three (72 %) were transfusion dependent. Cytogenetic data was available in 84 % (26 % with poor karyotype). Patients received a median of 9 cycles (range 2–32). The modified International Working Group criteria (2006) were used to determine response [5] (Table 1). Survival times (Kaplan–Meier estimates) were calculated from the date of initiation of therapy to the date of death or last follow-up. The overall response rate (ORR)was 47%. Three (9%) achieved a complete remission (with persistent marrow dysplasia) and 12 (38 %), a haematological improvement (HI). The median number of cycles of best response was 4 (range 1–21) with a median duration of 5.5 months. Nine (39 %) became transfusion independent after a mean of 5 cycles (range 1–12 cycles) for a mean duration of 7 months (range 2–16months).Median survival was 20 months (range 3–39 months). Seven patients transformed to AML during follow-up. This was a small multicentre retrospective study of a heterogeneous MDS population. However, ORR was comparable with that of the approved regimen [6], albeit the lower complete response (CR) rate. It is arguable, however, whether a CR is a prerequisite for prolongation of survival [7]. The median survival in this cohort was 20 months which is 4 months short of the AZA001 trial [6] but similar to the results of a 5-day-doseintensified regimen [1]. Randomised studies are necessary to address the issue of whether a 5-day regimen (total monthly dose of 375 or 500 mg/m) is nonC. McHale :N. O’Connell : J. McHugh : P. Evans :H. Enright Department of Haematology, Adelaide and Meath Hospital Incorporating the National Children’s Hospital, Dublin 24, Ireland

Pure red cell aplasia complicating chronic lymphocytic leukemia: rapid response to high-dose methylprednisolone and rituximab

We read with great interest the recent study by Michallet et al. [1] who treated autoimmune cytopenias in 48 patients with chronic lymphocytic leukemia (CLL) with a combination of rituximab, cyclop...