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Objectives: Acute myeloid leukaemia (AML) is a disease of older adults, who are vulnerable to socio‐economic factors. We determined AML incidence in older adults and the impact of socio‐economic factors on outcomes. Methods: We included 3024 AML patients (1996–2016) identified from a population‐based registry. Results: AML incidence in patients ≥60 years increased from 11.01 (2001–2005) to 12.76 (2011–2016) per 100 000 population. Among 879 patients ≥60 years in recent eras (2010–2016), rural residents (<100 000 population) were less likely to be assessed by a leukaemia specialist (39% rural, 47% urban, p =.032); no difference was seen for lower (43%, quintile 1–3) vs. higher (47%, quintile 4–5) incomes (p =.235). Similar numbers received induction chemotherapy between residence (16% rural, 18% urban, p =.578) and incomes (17% lower, 17% high, p = 1.0). Differences between incomes were seen for hypomethylating agent treatment (14% low, 20% high, p =.041); this was not seen for residence (13% rural, 18% urban, p =.092). Among non‐adverse karyotype patients ≥70 years, 2‐year overall survival was worse for rural (5% rural, 12% urban, p =.006) and lower income (6% low, 15% high, p =.017) patients. Conclusions: AML incidence in older adults is increasing, and outcomes are worse for older rural and low‐income residents; these patients face treatment barriers. [ABSTRACT FROM AUTHOR]

Summary: Treatment of Burkitt lymphoma (BL) with intensive, multi‐agent chemotherapy with aggressive central nervous system (CNS) prophylaxis results in high cure rates, although no regimen is standard of care. We examined population‐based survival outcomes of adults with BL treated with a modified combination of cyclophosphamide, vincristine, doxorubicin, prednisone and systemic high‐dose methotrexate (MTX) (CODOX‐M) with IVAC (ifosfamide, mesna, etoposide, cytarabine and intrathecal MTX) (CODOX‐M/IVAC) ± rituximab over a 15‐year period in British Columbia. For the 81 patients identified (including 8 with CNS involvement and 18 with human immunodeficiency virus‐associated BL), 5‐year progression‐free survival (PFS) and overall survival (OS) were 75% [95% confidence interval (CI): 63–83%] and 77% (95% CI: 66–85%), respectively, with no treatment‐related deaths. Those who completed the regimen per protocol (n = 38) had significantly improved 5‐year PFS 86% (P = 0·04) and OS 92% (P = 0·008), as did those under 60 years with 5‐year PFS 82% (P = 0·005) and OS 86% (P = 0·002), which remained significant in multivariate analysis [PFS: hazard ratio (HR) 3·36, P = 0·018; OS HR 4·03, P = 0·012]. Incorporation of high‐dose systemic methotrexate also significantly affected multivariate survival outcomes (OS HR 0·28, P = 0·025). Stem cell transplant in first remission had no effect on OS or PFS. This large, real‐world analysis of BL patients treated with CODOX‐M/IVAC ± rituximab demonstrates excellent survival outcomes comparable to clinical trials. These results help to serve as a benchmark when comparing curative therapies for BL patients as novel regimens are incorporated into clinical practice. [ABSTRACT FROM AUTHOR]

PP2A inhibitors and BCR-ABL inhibitors synergize to kill drug-insensitive leukemia cells. Drug pair enABLes killing of leukemia: Imatinib, the classic targeted drug for the treatment of cancer, was designed to target the BCR-ABL fusion protein in chronic myeloid leukemia and has saved many patients' lives. Unfortunately, some leukemias are resistant to imatinib despite having the BCR-ABL translocation, and others can develop resistance during treatment. Moreover, imatinib generally does not eradicate the leukemic stem cells and therefore requires continued treatment to maintain efficacy, so combination approaches are still needed. Lai et al. discovered that protein phosphatase 2A is a therapeutic target in imatinib-insensitive leukemia cells, including stem cells, and that the combination of imatinib and related drugs with PP2A inhibition effectively kills these cancer cells. Overcoming drug resistance and targeting leukemic stem cells (LSCs) remain major challenges in curing BCR-ABL+ human leukemia. Using an advanced drug/proliferation screen, we have uncovered a prosurvival role for protein phosphatase 2A (PP2A) in tyrosine kinase inhibitor (TKI)–insensitive leukemic cells, regulated by an Abelson helper integration site–1–mediated PP2A–β-catenin–BCR-ABL–JAK2 protein complex. Genetic and pharmacological inhibition of PP2A impairs survival of TKI nonresponder cells and sensitizes them to TKIs in vitro, inducing a dramatic loss of several key proteins, including β-catenin. We also demonstrate that the clinically validated PP2A inhibitors LB100 and LB102, in combination with TKIs, selectively eliminate treatment-naïve TKI-insensitive stem and progenitor cells, while sparing healthy counterparts. In addition, PP2A inhibitors and TKIs act synergistically to inhibit the growth of TKI-insensitive cells, as assessed by combination index analysis. The combination eliminates infiltrated BCR-ABL+ blast cells and drug-insensitive LSCs and confers a survival advantage in preclinical xenotransplant models. Thus, dual PP2A and BCR-ABL inhibition may be a valuable therapeutic strategy to synergistically target drug-insensitive LSCs that maintain minimal residual disease in patients. [ABSTRACT FROM AUTHOR]

LB100 sensitizes resistant chronic phase CML stem and progenitor cells to TKIs and spares healthy bone marrow cells. [ABSTRACT FROM AUTHOR]

Background: Imatinib mesylate (IM) induces clinical remission of chronic myeloid leukemia (CML).The Abelson helper integra-tion site 1 (AHI-1 ) oncoprotein interacts with BCR-ABL and Janus kinase 2 (JAK2) to mediate IM response of primi-tive CML cells, but the effect of the interaction complex on the response to ABL and JAK2 inhibitors is unknown. Methods: The AHI-1-BCR-ABL-JAK2 interaction complex was analyzed by mutational analysis and coimmunoprecipitation. Roles of the complex in regulation of response or resistance to ABL and JAK2 inhibitors were investigated in BCR-ABL* cells and primary CML stem/progenitor cells and in immunodeficient NSG mice. All statistical tests were two-sided. Results:The WD40-repeat domain of AHI-1 interacts with BCR-ABL, whereas the N-terminal region interacts with JAK2; loss of these interactions statistically significantly increased the IM sensitivity of CML cells. Disrupting this com-plex with a combination of IM and an orally bioavailable selective JAK2 inhibitor (TG101209 [TG]) statistically significantly induced death of AHI-1-overexpressing and IM-resistant cells in vitro and enhanced survival of leu-kemic mice, compared with single agents (combination vsTG alone: 63 vs 53 days, ratio = 0.84, 95% confidence interval [CI] = 0.6 to 1.1, P= .004; vs IM: 57 days, ratio = 0.9, 95% CI = 0.61 to 1.2, P= .003). Combination treatment also statistically significantly enhanced apoptosis of CD34+ leukemic stem/progenitor cells and eliminated their long-term leukemia-initiating activity in NSG mice. Importantly, this approach was effective against treatment-naive CML stem cells from patients who subsequently proved to be resistant to IM therapy. Conclusions: Simultaneously targeting BCR-ABL and JAK2 activities in CML stem/progenitor cells may improve outcomes in patients destined to develop IM resistance. [ABSTRACT FROM AUTHOR]

The curative potential of allogeneic haematopoietic stem cell transplant (allo HSCT) in chronic lymphocytic leukaemia CLL is established, with a demonstrated role for graft-versus-leukaemia and less certainty for other factors in determining outcome. The first two decades of CLL patients proceeding to allo HSCT at the Leukaemia/Bone Marrow Transplant Program of British Columbia ( n = 49 consecutive, 1991-2009) were studied to clarify factors predicting outcome. The donor was related in 29 (59%) and unrelated in 20 (41%). Conditioning was reduced-intensity in 27 (55%) and myeloablative in 22 (45%). Thirty-one of 49 patients survive with median follow-up of 5 years (0·2-15). Cumulative incidence of non-relapse mortality; complete remission ( CR); clearance of fluorescence in situ hybridization ( FISH) abnormality and progression at 10 years was 36%; 69%; 55% and 22%. Overall survival ( OS) was 63% at 2 years; 55% at 5 years and beyond. Factors predicting OS ( P value by log rank <0·05) were: comorbidity index <3, FISH rank (Dohner) and 17p deletion, alemtuzumab pre- HSCT, achievement of CR post- HSCT, donor chimerism >90%, clearance of FISH abnormality post- HSCT and absence of high-grade (3-4) graft-versus-host disease. Results from this province-wide, two-decade cohort demonstrated that a substantial proportion of patients with high-risk CLL become long term disease-free survivors. [ABSTRACT FROM AUTHOR]

Sudden blast phase (SBP) is a rare event that occurs in an unpredictable fashion amongst patients with chronic myeloid leukemia (CML) who otherwise appear to be responding satisfactorily to imatinib (IM) treatment. We investigated the incidence, clinical characteristics, treatment outcome and long-term follow-up of 213 patients with chronic phase CML treated with IM according to the European LeukemiaNet guidelines. Nine patients, eight of whom received IM as first-line therapy, developed SBP (4.2% of the total). They tended to have low or intermediate risk Sokal scores at diagnosis, a predominance of the lymphoid phenotype and a short interval from 'optimal' response to the development of BP. Five of the nine patients with SBP are alive in complete molecular remission; however, all of them underwent allogeneic hematopoietic stem cell transplant. The cumulative incidence of SBP for the patients who received IM as first-line therapy was 5.9% and the 2-year overall survival of the nine patients who developed SBP was 56%. Despite the improved outcome for patients with SBP receiving tyrosine kinase inhibitors (TKIs) and transplant, many of these patients are not salvaged with these therapies. This illustrates the need to develop predictive models to identify patients early whose response to TKI therapy will not be durable and hopefully prevent the transformation to advanced disease. [ABSTRACT FROM AUTHOR]

The treatment of multiple myeloma (MM) has changed with the advent of thalidomide, bortezomib, and lenalidomide, the so-called novel agents (NAs). Given the complexity of MM therapy in the NA era we pursued a population based study to assess for improvements in survival as well as to characterize the relevance of early relapse (within 12 months) and the International Staging System in this clinical setting. We reviewed our experience with 460 patients with MM treated with autologous stem cell transplant (ASCT) between 1988 and 2008, of whom 306 had relapsed. The cohort was divided into two groups based upon relapse pre-2004 and relapse during/after 2004 (2004+), which correlated to availability of bortezomib and lenalidomide. Improvements in both overall survival (OS) (median 32.0 months vs. 71.8 months; p < 0.001) and post-relapse survival (PRS) (median 15.2 months vs. 42.8 months; p < 0.001) correlated with the NA era. Exposure to NAs conferred a better PRS (median 35.7 months vs. 9.1 months; p < 0.001). Although all patients had improvements in survival, those who relapsed late continued to do better. Lastly, in the NA era, the ISS remains an important prognostic tool in relapse, but only in the late relapsing cohort. [ABSTRACT FROM AUTHOR]

High dose chemoradiotherapy and haematopoietic stem cell transplantation (SCT) is used as primary therapy for patients diagnosed with Burkitt lymphoma (BL). Forty-three adults presented with sporadic BL in British Columbia between 1987 and 2003. Twenty patients had bone marrow involvement. Sixteen patients did not proceed to SCT because of chemorefractory disease ( n = 9) or other reasons ( n = 7). Twenty-seven patients proceeded to SCT and had a 3-year event-free survival of 51%. In conclusion, approximately 50% of patients with chemosensitive BL who undergo SCT can be cured; however, a significant number of patients will not proceed to SCT because of early resistance or recurrence. [ABSTRACT FROM AUTHOR]

Forty-four patients with relapsed or refractory aggressive histology non-Hodgkin lymphoma (NHL) (diffuse large B cell, n = 23; peripheral T cell, n = 5; transformed B cell, n = 16) proceeded to allogeneic stem cell transplant (allo-SCT) between 1987 and 2003. Median age at transplant was 40 years (range 19–56 years). At the time of transplant, 35 were chemosensitive and nine were chemorefractory. Thirty-three patients had matched sibling donors and 11 had unrelated donors. Forty-two patients (95%) received radiation-based conditioning regimens. Event-free survival (EFS) and overall survival (OS) at 5 years was 43% [95% confidence interval (CI): 27–58%] and 48% (95% CI: 32–63%) respectively. Treatment-related mortality was 25% at 1 year. Grade III–IV acute graft- versus-host disease (GVHD) was the only significant variable affecting OS and EFS, and had a negative impact. Chronic GVHD did not influence survival. Lymphoma relapse <12 months after initial therapy predicted for increased risk of relapse post-transplant ( P = 0·02). Patients with chemorefractory lymphoma were not at increased risk of relapse ( P = 0·20) with four of nine patients remaining alive without disease 12–103 months post-transplant. In conclusion, allo-SCT for relapsed or refractory aggressive histology NHL results in long-term EFS and OS of 40–50%. Patients with chemorefractory disease can have a durable remission post-transplant. [ABSTRACT FROM AUTHOR]

Myeloablative allogeneic bone marrow transplantation (BMT) may be curative in patients with follicular non-Hodgkin's lymphoma, however, the impact of this therapy on long-term survival, disease progression and functional status is less clear. Twenty-nine patients (median age 42 years, range: 20–53) with advanced stage follicular lymphoma proceeded to allogeneic BMT a median of 25 (range: 8–154) months postdiagnosis, between 1985 and 2001, and have been followed for a minimum of 2 years. Eleven of 29 (38%) had refractory disease (n = 5 induction failure,n = 6 resistant relapse). Most (27 of 29, 93%) received total body irradiation-based conditioning; stem cell source was marrow from a related donor (n = 20) or unrelated donor (n = 9). Seventeen of 29 patients (59%) were alive a median of 5 years (range: 2–11) post-BMT with a median Karnofsky Performance Score of 100%. Death occurred because of transplant complications in seven patients (cumulative incidence of non-relapse mortality 24%), and progressive lymphoma in five patients (cumulative incidence of refractory/recurrent lymphoma 23%). The 5-year probability of overall and event-free survival was 58% and 53% respectively. Allogeneic BMT has resulted in long-term disease-free survival for approximately 50% of this cohort of patients with advanced follicular lymphoma and most of them now enjoy robust health. [ABSTRACT FROM AUTHOR]

Discusses results of findings of bone marrow necrosis (BMN) in adult acute leukemia and non-Hodgkin's lymphoma. Disease characteristics of BMN; Patient characteristics; Cell karyotype; Patient response to treatment regimen.

Serotonin syndrome has been reported with administration of linezolid and serotonin reuptake inhibitors. Meperidine blocks the neuronal reuptake of serotonin. Serotonin syndrome after concomitant linezolid and meperidine therapy has not been described. We describe serotonin syndrome after concomitant use of linezolid and meperidine in a 27-year-old man with acute leukemia. [ABSTRACT FROM AUTHOR]