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Imatinib Mesylate (imatinib) was once hailed as the magic bullet for chronic myeloid leukemia (CML) and remains a front-line therapy for CML to this day alongside other tyrosine kinase inhibitors (TKIs). However, TKI treatments are rarely curative and patients are often required to receive life-long treatment or otherwise risk relapse. Thus, there is a growing interest in identifying biomarkers in patients which can predict TKI response upon diagnosis. In this study, we analyze clinical data and differentially expressed miRNAs in CD34 + CML cells from 80 patients at diagnosis who were later classified as imatinib-responders or imatinib-nonresponders. A Cox Proportional Hazard (CoxPH) analysis identified 16 miRNAs that were associated with imatinib nonresponse and differentially expressed in these patients. We also trained a machine learning model with different combinations of the 16 miRNAs with and without clinical parameters and identified a panel with high predictive performance based on area-under-curve values of receiver-operating-characteristic and precision-recall curves. Interestingly, the multivariable panel consisting of both miRNAs and clinical features performed better than either miRNA or clinical panels alone. Thus, our findings may inform future studies on predictive biomarkers and serve as a tool to develop more optimized treatment plans for CML patients in the clinic., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Despite the effectiveness of tyrosine kinase inhibitors (TKIs) against chronic myeloid leukemia (CML), they are not usually curative as some patients develop drug-resistance or are at risk of disease relapse when treatment is discontinued. Studies have demonstrated that primitive CML cells display unique miRNA profiles in response to TKI treatment. However, the utility of miRNAs in predicting treatment response is not yet conclusive. Here, we analyzed differentially expressed miRNAs in CD34 + CML cells pre- and post-nilotinib (NL) therapy from 58 patients enrolled in the Canadian sub-analysis of the ENESTxtnd phase IIIb clinical trial which correlated with sensitivity of CD34 + cells to NL treatment in in vitro colony-forming cell (CFC) assays. We performed Cox Proportional Hazard (CoxPH) analysis and applied machine learning algorithms to generate multivariate miRNA panels which can predict NL response at treatment-naïve or post-treatment time points. We demonstrated that a combination of miR-145 and miR-708 are effective predictors of NL response in treatment-naïve patients whereas miR-150 and miR-185 were significant classifiers at 1-month and 3-month post-NL therapy. Interestingly, incorporation of NL-CFC output in these panels enhanced predictive performance. Thus, this novel predictive model may be developed into a prognostic tool for use in the clinic., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

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., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Overcoming drug resistance and targeting cancer stem cells remain challenges for curative cancer treatment. To investigate the role of microRNAs (miRNAs) in regulating drug resistance and leukemic stem cell (LSC) fate, we performed global transcriptome profiling in treatment-naive chronic myeloid leukemia (CML) stem/progenitor cells and identified that miR-185 levels anticipate their response to ABL tyrosine kinase inhibitors (TKIs). miR-185 functions as a tumor suppressor: its restored expression impaired survival of drug-resistant cells, sensitized them to TKIs in vitro, and markedly eliminated long-term repopulating LSCs and infiltrating blast cells, conferring a survival advantage in preclinical xenotransplantation models. Integrative analysis with mRNA profiles uncovered PAK6 as a crucial target of miR-185, and pharmacological inhibition of PAK6 perturbed the RAS/MAPK pathway and mitochondrial activity, sensitizing therapy-resistant cells to TKIs. Thus, miR-185 presents as a potential predictive biomarker, and dual targeting of miR-185-mediated PAK6 activity and BCR-ABL1 may provide a valuable strategy for overcoming drug resistance in patients., (© 2020 by The American Society of Hematology.)

Patients with chronic myeloid leukemia (CML) often require lifelong therapy with ABL1 tyrosine kinase inhibitors (TKIs) due to a persisting TKI-resistant population of leukemic stem cells (LSCs). From transcriptome profiling, we show integrin-linked kinase (ILK), a key constituent of focal adhesions, is highly expressed in TKI-nonresponsive patient cells and their LSCs. Genetic and pharmacological inhibition of ILK impaired the survival of nonresponder patient cells, sensitizing them to TKIs, even in the presence of protective niche cells. Furthermore, ILK inhibition eliminated TKI-refractory LSCs from patients, but not normal HSCs, in vitro and in vivo. RNA-sequencing and functional validation studies implicated an important role of ILK in maintaining a requisite level of mitochondrial oxidative metabolism in highly purified, quiescent LSCs. Thus, these findings point to ILK as a critical survival mediator to TKIs and quiescent stem cells, offering an attractive therapeutic target and model for curative combination therapies in stem-cell-driven cancers., Competing Interests: Declaration of Interests Research funding for this study was supported in part by Novartis Canada (X.J., D.L.F., and C.J.E.) and Bristol-Myers Squibb (X.J.)., (Copyright © 2020 Elsevier Inc. All rights reserved.)

LB100 sensitizes resistant chronic phase CML stem and progenitor cells to TKIs and spares healthy bone marrow cells., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Introduction: Optimal post-remission therapy (PRT) for intermediate risk acute myeloid leukemia remains an area of ongoing research. We aimed to retrospectively compare outcomes following autologous stem cell transplantation (autoSCT) with allogeneic SCT (alloSCT) and consolidation chemotherapy (CMT) in patients with intermediate-risk karyotype AML in first complete remission., Patients and Methods: We compared overall survival (OS) and leukemia-free survival (LFS) using propensity score (PS)-adjusted analysis of patients receiving PRT with autoSCT, matched sibling (MSD) alloSCT, unrelated/mismatch (UD/MM) alloSCT, and CMT. We included patients diagnosed between 1984 and 2003 (period of autoSCT at our center) in CR1 following induction CMT and received at least 2 consolidative cycles., Results: We identified 190 patients (62 MSD-alloSCT, 18 UD/MM-alloSCT, 30 autoSCT, and 80 CMT). Baseline characteristics were used for PS calculation and were well-balanced after weight adjustment. The median follow-up for patients surviving beyond 1 year was 8.7 years. We excluded 55 patients based on PS calculation. Adjusted multivariate hazard ratio (HR), 95% confidence interval (CI) and P-value for OS, considering CMT as reference, were: MSD-alloSCT (HR, 0.4; 95% CI, 0.2-0.8; P = .009), UD/MM-alloSCT (HR, 1.5; 95% CI, 0.6-3.9; P = .363), and autoSCT (HR, 1.2; 95% CI, 0.5-3.1; P = .666), respectively. Adjusted multivariate HR, 95% CI and P-value for LFS were MSD-alloSCT (HR, 0.3; 95% CI, 0.2-0.6; P < .001), UD/MM-alloSCT (HR, 1.1; 95% CI, 0.4-2.7; P = .854), and autoSCT (HR, 0.8; 95% CI, 0.3-2.2; P = .697), respectively., Conclusion: Patients with intermediate risk-karyotype acute myeloid leukemia who underwent MSD-alloSCT in first complete remission had the best outcomes. There were no survival differences between autoSCT, UD/MM-alloSCT, and CMT. Further study incorporating molecular changes and minimal residual disease status is warranted to select appropriate patients for autoSCT., (Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved.)

The majority of patients with TKI failure respond to HCT. However, the relapse risk remains high. This study has evaluated transplant outcomes in 223 CML patients with TKI failure due to resistance (n = 132) or intolerance (n = 29), as well as those that were TKI naïve/responding with advanced disease (n = 35) or with chronic phase (CP, n = 27). We studied outcomes according to post-transplant BCR-ABL transcript level within 3 months. With respect to transplant outcomes according to the post-transplant BCR/ABLtranscript level within 3 months, the group failing to achieve a 1.3 log reduction (n = 14, 12.4%) showed the highest relapse rate of 78.6% at 5 years, compared to 26.2% and 24.1% in the groups achieving 1.3-4.0 log reduction (n = 45, 39.8%), and ≥4.1 log reduction (n = 54, 47.8%) respectively (p < 0.001). Multivariate analysis confirmed that the group failing to achieve a 1.3 log reduction had a 2.3-fold higher risk of death and 6.6 times higher risk of relapse. Poor overall survival after HCT was associated with advanced disease at diagnosis, but not disease status prior to HCT. Of 61 patients who relapsed after HCT, 47 were treated with post-transplant TKI therapy; those receiving TKI after loss of MR2 or MMR showed higher rates of response and survival compared to those receiving TKI after hematologic relapse (p < 0.001). QPCR log reduction level within 3 months post transplantation is prognostic in this population., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

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., (© 2018 John Wiley & Sons Ltd.)

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., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only known curative therapy for chronic myeloid leukemia (CML); however, it is rarely utilized given the excellent long-term results with tyrosine kinase inhibitor (TKI) treatment. The purpose of this study is to examine HSCT outcomes for patients with CML who failed TKI therapy or presented in advanced phase and to identify predictors of survival, relapse, and nonrelapse mortality (NRM). Fifty-one patients with CML underwent HSCT for advanced disease at diagnosis (n = 15), TKI resistance as defined by the European LeukemiaNet guidelines (n = 30), TKI intolerance (n = 2), or physician preference (n = 4). At a median follow-up of 71.9 months, the 8-year overall survival (OS), event-free survival (EFS), relapse, and NRM were 68%, 46%, 41%, and 23%, respectively. In univariate analysis, predictors of OS included first chronic phase (CP1) disease status at HSCT (P = .0005), European Society for Blood and Marrow Transplantation score 1 to 4 (P = .04), and complete molecular response (CMR) to HSCT (P < .0001). Donor (female) to patient (male) gender combination (P = .02) and CMR to HSCT (P < .0001) predicted lower relapse. In multivariate analysis, CMR to HSCT remained an independent predictor of OS (odds ratio [OR], 43), EFS (OR, 56) and relapse (OR, 29). This report indicates that the outlook is excellent for those patients who remain in CP1 at the time of HSCT and achieve a CMR after HSCT. However, only approximately 50% of those in advanced phase at HSCT are long-term survivors. This highlights the ongoing need to try to identify patients earlier, before disease progression, who are destined to fail this treatment to optimize transplantation outcomes., (Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Double-hit lymphoma is characterized by the presence of concurrent MYC (myelocytomatosis oncogene) and BCL2 (B-cell lymphoma 2) gene rearrangements. Prognosis is poor with standard chemoimmunotherapy. Since 2003, the British Columbia Cancer Agency has used CODOX-M/IVAC+R (cyclophosphamide, vincristine, doxorubicin, methotrexate, cytarabine, ifosfamide, and etoposide, combined with rituximab) followed by consolidative hematopoietic cell transplantation as definitive treatment for double-hit lymphoma., Patients and Methods: A retrospective review of the survival outcomes of patients with double-hit lymphoma treated at our institution was conducted. Thirty-two patients diagnosed with non-Hodgkin lymphoma with concurrent MYC and BCL2 translocations from 2003 to 2013 were identified. Cases with MYC or BCL2 amplification and those with overexpression in immunohistochemistry analysis were excluded., Results: Median age at diagnosis was 53.0 years (range, 35.5-70.9 years), 23 (72%) were male, and 30 (94%) had stage III to IV disease. CODOX-M/IVAC+R was administered in 25 (78%) patients and 20 (80%) achieved a partial remission or better, of which 9 (36%) had a complete remission. Nineteen of the 32 (59%) patients underwent upfront hematopoietic cell transplantation. At a median follow-up of living patients of 26.4 months, 14 (44%) were alive in remission, 15 (47%) died, and 3 (9%) were alive in relapse. The 2-year progression-free survival (PFS) and overall survival (OS) of all patients were 41% and 53%, respectively. The sixteen patients treated with CODOX-M/IVAC+R followed by hematopoietic cell transplantation had a 2-year PFS of 60% and 2-year OS of 82%., Conclusion: Patients with double-hit lymphoma treated with CODOX-M/IVAC+R followed by hematopoietic cell transplantation can achieve durable remissions, although disease progression before transplantation remains a significant problem., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Previous studies demonstrated that imatinib mesylate (IM) induces autophagy in chronic myeloid leukemia (CML) and that this process is critical to cell survival upon therapy. However, it is not known if the autophagic process differs at basal levels between CML patients and healthy individuals and if pretreatment CML cells harbor unique autophagy characteristics that could predict patients' clinical outcomes. We now demonstrate that several key autophagy genes are differentially expressed in CD34(+) hematopoietic stem/progenitor cells, with the highest transcript levels detected for ATG4B, and that the transcript and protein expression levels of ATG4 family members, ATG5 and BECLIN-1 are significantly increased in CD34(+) cells from chronic-phase CML patients (P < .05). Importantly, ATG4B is differentially expressed in pretreatment CML stem/progenitor cells from subsequent IM responders vs IM nonresponders (P < .05). Knockdown of ATG4B suppresses autophagy, impairs the survival of CML stem/progenitor cells and sensitizes them to IM treatment. Moreover, deregulated expression of ATG4B in CD34(+) CML cells inversely correlates with transcript levels of miR-34a, and ATG4B is shown to be a direct target of miR-34a. This study identifies ATG4B as a potential biomarker for predicting therapeutic response in treatment-naïve CML stem/progenitor cells and uncovers ATG4B as a possible drug target in these cells., (© 2014 by The American Society of Hematology.)

Background: Diagnostic karyotype and molecular studies represent the most powerful prognostic indicators in acute myeloid leukemia and provide the framework for risk stratification. Risk stratification in ALL has also a vital role in predicting outcome and identifying patients at higher risk of relapse with multiagent chemotherapy, but the role of diagnostic karyotype and molecular markers in adult ALL is limited to few well recognized cytogenetic abnormalities., Patients and Methods: We report a case series of 6 adult ALL patients with a characteristic molecular abnormality that have done poorly with chemotherapy. Between April 2004 and November 2009, 72 adult ALL patients (Pre-B-cell 61; T-cell 11) were referred to and treated at the Leukemia/BMT Program of BC in Vancouver, Canada. FISH for BCR-ABL fusion was positive in 12 of 61 Pre-B cell ALL patients. An additional 6 patients were negative for this typical fusion but had FISH abnormalities related to BCR and/or ABL1., Results: In this report, we describe the clinical and hematopathologic characteristics of these 6 patients and their poor outcome. We review the literature where only 2 similar cases with normal karyotype Pre-B ALL and associated FISH BCR/ABL1 numerical abnormalities were found., Conclusion: We recommend screening all adult pre-B ALL patients with normal karyotype for this clonal abnormality and suggest classifying these ALL patients into the high-risk category., (Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.)

Background: Imatinib mesylate (IM) induces clinical remission of chronic myeloid leukemia (CML). The Abelson helper integration site 1 (AHI-1) oncoprotein interacts with BCR-ABL and Janus kinase 2 (JAK2) to mediate IM response of primitive 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 complex 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 leukemic mice, compared with single agents (combination vs TG 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.

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.

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., (© 2012 Blackwell Publishing Ltd.)

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.

Tyrosine kinase inhibitors (TKI) have been used to treat relapse of chronic myelogenous leukemia (CML) after allogeneic stem cell transplant (HSCT), with responses seen predominantly in chronic phase (CP) patients. This study aimed to analyze the response to TKI therapy and overall survival for patients relapsing predominantly in advanced phase. We retrospectively reviewed 22 patients treated with imatinib (n=20) and/or dasatinib (n=6) for relapsed CML after HSCT; 8 patients were in CP, and 14 patients had advanced disease. Seven patients also received donor lymphocyte infusions. Hematologic, cytogenetic, and molecular responses were analyzed. Nineteen patients (86%) achieved complete hematologic response (CHR), 17 patients (77%) achieved complete cytogenetic response (CCR), and 14 patients (64%) achieved complete molecular response (CMR). In advanced phase patients, 11 (79%) achieved CHR, 10 (71%) CCR, and 8 (57%) achieved CMR. Grade 3 or 4 cytopenias occurred in 10 cases. With median follow-up of 31.5 months from relapse, 14 (64%) patients remain alive, 13 in CMR. In multivariate analysis, the achievement of CMR was significantly correlated with OS with an odds ratio of 20.5 (95% confidence interval 2.3-182) P=.007. TKI therapy is capable of inducing durable molecular responses for CML relapsing after HSCT, both in chronic and advanced phases. The achievement of CMR appears to be crucial in providing long-term disease control for these patients., (Copyright 2010 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Cytogenetic and molecular responses to standard-dose imatinib (IM) were correlated with trough IM plasma levels for 78 patients with chronic myeloid leukemia (CML) after a minimum of 12 months of IM therapy. The mean trough IM plasma level was 1065 ng/ml (range, 203-2910). There was no correlation of mean plasma trough IM levels and complete cytogenetic response (CCR) at 1 year (CCR 1010 ng/ml vs no CCR 1175 ng/ml P=.29) or major molecular response (MMR) (MMR1067 ng/ml vs no MMR 1063 ng/ml P=.74) after a median of 1298 days of IM therapy. CCR and MMR did correlate with Sokal risk scores with the odds of achieving CCR or MMR for a low risk vs high risk score of 10.8 (95% CI 2.2-53.5) and 6.4 (95% CI 1.4-29.4), respectively. Furthermore, a longer duration of IM therapy also was associated with a greater likelihood of achieving MMR (P=.02).

The optimal therapy for myelodysplastic syndrome (MDS) is allogeneic bone marrow (BM) or blood (BSC) stem cell transplantation (SCT), although outcomes are limited by nonrelapse mortality (NRM) and relapse. A retrospective review was performed of 156 patients who underwent SCT (114 BM, 42 BSC) for MDS or secondary acute myelogenous leukemia (sAML) at our institution. Fifty-five patients remain in continuous complete remission: 35 BM recipients and 20 BSC recipients (median follow-up 139 and 89 months, respectively). Estimated 7-year event-free survival (EFS), NRM, and risk of relapse (ROR) are 33% (95% confidence intervals [CI] 25%-43%), 42% (CI 33%-51%), and 25% (CI 17%-33%) for the BM cohort and 45% (CI 32%-64%, P= .07), 32% (CI 18%-47%, P= .15), and 23% (CI 11%-37%, P= .79) for the BSC cohort. Multivariate analysis showed IPSS poor-risk cytogenetics (P< .001), time from diagnosis to SCT (P< .001), FAB subgroup (P= .001), recipients not in complete remission (CR1) at SCT (P= .005), and the development of acute graft-versus-host disease (aGVHD) (P= .04) were all predictive of an inferior EFS. The FAB subgroup (P= .002), poor-risk karyotype (P= .004), and non-CR1 status also correlated with ROR in multivariate analysis. EFS for poor-risk karyotype patients was superior after receiving BSC compared to BM (39% versus 6%, P< .001). SCT outcomes in MDS/sAML are strongly associated with the IPSS cytogenetic risk group, although the use of BSC in poor-risk karyotype patients may lead to a more favorable long-term EFS.

Familial platelet disorder with propensity to myeloid malignancy (FPD/AML) is an autosomal dominant syndrome characterized by platelet abnormalities and a predisposition to myelodysplasia (MDS) and/or acute myeloid leukemia (AML). The disorder, caused by inherited mutations in RUNX1, is uncommon with only 14 pedigrees reported. We screened 10 families with a history of more than one first degree relative with MDS/AML for inherited mutations in RUNX1. Germ- line RUNX1 mutations were identified in 5 pedigrees with a 3:2 predominance of N-terminal mutations. Several affected members had normal platelet counts or platelet function, features not previously reported in FPD/AML. The median incidence of MDS/AML among carriers of RUNX1 mutation was 35%. Individual treatments varied but included hematopoietic stem cell transplantation from siblings before recognition of the inherited leukemogenic mutation. Transplantation was associated with a high incidence of complications including early relapse, failure of engraftment, and posttransplantation lymphoproliferative disorder. Given the small size of modern families and the clinical heterogeneity of this syndrome, the diagnosis of FPD/AML could be easily overlooked and may be more prevalent than previously recognized. Therefore, it would appear prudent to screen young patients with MDS/AML for RUNX1 mutation, before consideration of sibling hematopoietic stem cell transplantation.

Chromosomal translocations involving the platelet-derived growth factor receptor beta gene (PDGFRB) have been reported in a subset of patients with atypical myeloproliferative disorders (MPDs). The fusion of the PDGFRB gene, which encodes a tyrosine kinase receptor, with different partner genes results in its constitutive activation. We present the cases of two patients with atypical MPD carrying t(4;5)(q21;q33) and t(2;5)(p21;q33), respectively. Fluorescence in situ hybridization demonstrated that PDGFRB was involved in both translocations. Further characterization of the 4q21 breakpoint using a bacterial artificial chromosome probe revealed PRKG2 as the likely gene partner to PDGFRB. Characterization of the 2p21 breakpoint identified a novel gene partner to PDGFRB, the SPTBN1 gene. Both patients achieved a complete molecular remission after introduction of imatinib mesylate therapy.

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.

Allogeneic stem cell transplantation (alloSCT) has been used in the hopes of harnessing the curative potential of the graft-versus-myeloma effect. This study examines the long-term outcomes of a large cohort of patients with myeloma who were treated with myeloablative alloSCT at a single center. Comparisons are made with those who were treated with autologous stem cell transplantation (ASCT). Between January 1989 and February 2002, 158 patients age10 years post myeloablative alloSCT, similarly there are long-term survivors post-ASCT. Myeloablative alloSCT should not be considered standard treatment, and should only be considered in the context of a clinical trial.

Background: The objective of this study was to establish the incidence and risk factors for the development of second solid cancers after allogeneic hematopoietic stem cell transplantation (allo-HSCT)., Methods: The authors reviewed the case files of 926 consecutive patients who underwent allo-HSCT at their institution between 1985 and 2003., Results: Twenty-eight patients developed 30 solid malignancies at a median of 6.8 years after allo-HSCT (range, 0.12-17.3 years) for a 10-year cumulative incidence of 3.1% (95% confidence interval [95% CI], 2-5%; all solid tumors) and 2.3% (95% CI 1-4%; excluding basal cell carcinoma and carcinoma in situ). The risk ratio of developing a second solid malignancy after allografting, compared with the general population of British Columbia adjusted for age and sex, was 1.85 (95% CI, 1.04-3.06; P = .019). In multivariate analysis, recipient age at allo-HSCT >40 years (P = .005) and having a woman donor (P = .0008) were associated with a greater risk of developing a second solid cancer., Conclusions: The authors concluded that patients undergoing allografting are at increased risk of developing a second solid cancer compared with the general population, particularly those of advanced age at the time of allograft. It is noteworthy that patients who had women as graft donors had an increased risk for developing a second solid cancer. This unexpected finding is a new observation and has not been reported previously. Extended follow-up will be needed to assess more fully the incidence and risk factors for the development of solid cancers, because the latency can be prolonged., ((c) 2006 American Cancer Society.)

There are increasing reports of Philadelphia-negative (Ph-negative) clonal hematopoiesis developing among patients with chronic myeloid leukemia (CML) treated with imatinib mesylate (IM). To establish the incidence and significance of these chromosomal abnormalities, we analyzed data on 141 consecutive patients with CML treated with IM at the British Columbia Cancer Agency and Vancouver General Hospital from 1999 to 2004. The cumulative incidence of developing a Ph-negative clone three years from the start of IM was 8.7% at a median of 13.3 months. The Ph-negative clonal abnormalities included monosomy 7 and/or trisomy 8 (seven patients), monosomy for chromosomes X and 22 (one patient), and a (12;16) translocation (one patient). Two of the patients presented with the same chromosomal abnormality in both Ph-negative and Ph-positive cells. None of the Ph-negative clonal abnormalities was associated with myelodysplasia. In a multivariate analysis, an interval from diagnosis to initiation of IM of 1 year or less was associated with an increased risk of developing a Ph-negative clone (relative risk = 20.2; P = 0.025). There was no difference, however, in event-free survival between patients who did and did not develop Ph-negative clones. Therefore, while the development of Ph-negative clonal hematopoiesis in patients with CML treated with IM is uncommon, it appears to be more frequent than that previously seen with IFN, but it does not seem to confer a worse prognosis.

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.

Primary refractory acute leukemia (AL) has a poor prognosis, although some patients can be salvaged with allogeneic stem cell transplantation (SCT). Induction of complete remission (CR) with conventional chemotherapy before SCT may improve outcome in this patient population. Between March 1991 and October 2003, 59 adults with primary refractory AL were treated with continuous-infusion etoposide (VP) 2.4 to 3.0 g/m(2) followed by cyclophosphamide (Cy) 6.0-7.2 g/m(2) intravenously over 3 to 4 days with the intention of proceeding to SCT in CR1. Forty-two patients had acute myelogenous leukemia (AML), 13 patients had acute lymphoblastic leukemia (ALL), and 4 patients had acute biphenotypic leukemia. The most frequent nonhematologic toxicities were oral mucosal, gastrointestinal, and hepatic toxicities (44%, 20%, and 15% of patients, respectively). Thirty-two (57%) of 56 evaluable patients entered CR1 with a median time to platelet and neutrophil recovery of 22 and 26 days, respectively. CR1 rates were similar in AML (54%) and ALL/acute biphenotypic leukemia (67%; P = .52), and analysis of baseline characteristics did not reveal any predictors of response to VP/Cy. Twenty-nine of 32 CR1 patients subsequently underwent SCT (24 allogeneic and 5 autologous). Estimated 5-year event-free survival (EFS) and overall survival for the entire cohort are 23% and 26%, respectively. In the allogeneic SCT group, 5-year EFS was 52% for AML patients and 14% for ALL patients (P = .04), and only male sex was predictive of a favorable outcome (P = .03). VP/Cy is able to induce CR1 in most patients with primary refractory AL with an acceptable toxicity profile. Subsequent allogeneic SCT can lead to long-term EFS in a significant proportion of patients.

Purpose: To determine the incidence of second malignancies among patients with Hodgkin's lymphoma (HL) treated with autologous hematopoietic stem cell transplantation (AHSCT) compared with patients receiving conventional therapy alone and to identify potential risk factors for their occurrence., Patients and Methods: We analyzed data on 1,732 consecutive patients with HL treated at the British Columbia Cancer Agency from 1976 to 2001, including 202 patients undergoing AHSCT. The median follow-up duration was 9.8 years for the whole cohort, 9.7 years for those patients treated with conventional therapy, and 7.8 years from AHSCT., Results: The cumulative incidence of developing any second malignancy 15 years after therapy for HL was 9% (risk ratio = 3.5; P < .001); however, the incidence did not differ between those patients receiving conventional therapy alone compared with those undergoing AHSCT (10% and 8%, respectively; P = .48). In multivariate analysis, the only factor significantly associated with an increased risk of developing any second neoplasm or solid tumor was age > or = 35 years (P < .0001). An increased risk of therapy-induced acute myeloid leukemia and therapy-induced myelodysplastic syndrome was seen for patients aged > or = 35 years (P = .03) and stage III/IV (P = .04)., Conclusion: Patients with HL are at increased risk of developing a second neoplasm. However, those patients undergoing AHSCT do not seem to be at greater risk compared with those patients receiving conventional therapy alone, at least during the first decade after therapy.

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.

Beginning in 1985, patients in British Columbia with Hodgkin lymphoma (HL) that was not controlled by conventional chemotherapy routinely underwent high-dose chemotherapy and autologous stem cell transplantation (HD-ASCT). Long-term complications of HD-ASCT have become apparent as more patients survive without recurrence of HL. Data were obtained retrospectively on the first 100 patients that underwent HD-ASCT for HL in Vancouver, focusing on relapse, treatment-related complications, and the occurrence of late events. Fifty-three patients remain alive (median follow-up, 11.4 years [range, 10.0-17.4 years]) with an overall survival (OAS) of 54% at 15 years. OAS was significantly better in patients in first relapse (67%) than in patients with primary refractory-induction failure (39%) and advanced disease (29%) (P = .002). The major cause of death was progression of HL (32% at 15 years). Treatment-related mortality, including death from second malignancy, was 17% at 15 years. Cumulative risk of a second malignancy was 9% at 15 years. Karnofsky performance status was at least 90% in 47 patients although hypogonadism (20 patients), hypothyroidism (12 patients), unusual infections (10 patients), anxiety or depression (7 patients), and cardiac disease (5 patients) were not uncommon in survivors. HD-ASCT can lead to durable remissions in relapsed or refractory HL with acceptable but definite late toxicity. The occurrence of late events necessitates lifelong medical surveillance.

The impact of karyotype on the outcome of patients who undergo autotransplant for acute myeloid leukemia (AML) in second remission (CR2) has not been explored. We evaluated the outcomes of 40 patients who proceeded to autotransplant for AML in CR2 at 2 centers. The median age at autotransplant was 50 years (18-64 years) and the median duration of first remission was 15 months (0.8-51 months). High-dose therapy was melphalan 140-160 mg/m2 plus etoposide 60 mg/kg with or without total body irradiation (22), a busulfan-based regimen (17), and cyclophosphamide alone (1). Six patients (15%) died of treatment-related causes within the first 100 days. Event-free and overall survival at 3 years were both 38% (95% confidence interval 23-53%). At a median follow-up of 76 months (2?-?170) in surviving patients, 13 (32.5%) are alive and disease free. Graft purging did not significantly influence survival outcome (P=0.94), although platelet engraftment was significantly delayed (P=0.02). The relative risk of an event (relapse or death) for the karyotype risk groups was favorable 1.0; intermediate 4.2 (1.2-14.7); adverse 9.9 (1.5-63.9); unknown 2.3 (0.6-8.8) (P=0.028). We conclude that patients with AML in CR2 who undergo autotransplant can have durable remissions and those with a good risk karyotype are the most likely to obtain long-term disease-free survival.

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.

Since 1998, there has been a marked increase in incidence of pure red cell aplasia secondary to development of anti-erythropoietin antibodies (Ab+ PRCA) in patients who have chronic kidney disease (CKD) and receive recombinant erythropoietin. The relationship between incidence of Ab+ PRCA and specific erythropoietin products has not been examined rigorously. Manufacturers provided data regarding exposure to erythropoietin products and incidence of Ab+ PRCA between January 1998 and March 2003 in patients with CKD. Assuming a Poisson distribution, a maximum likelihood estimate for the Poisson rate parameter was calculated for each product. A test for homogeneity of Poisson rates was conducted to compare likelihood estimates between products. Global incidence of Ab+ PRCA was relatively low. Likelihood estimates were not significantly different for Epogen, Procrit, and Aranesp, independent of their formulation or route of administration. Eprex lacking human serum albumin (HSA) and administered subcutaneously was associated with the greatest risk of Ab+ PRCA. HSA-containing Eprex administered subcutaneously was associated with a lower risk than HSA-free Eprex administered subcutaneously, but this risk exceeded that of intravenous Epogen and intravenous HSA-free Eprex. NeoRecormon administered subcutaneously was associated with less risk than subcutaneous HSA-free Eprex but more risk than intravenous Epogen. HSA-free Eprex should not be administered subcutaneously to patients with CKD due to increased risk of Ab+ PRCA. Although the subcutaneous administration of HSA-containing Eprex is riskier than intravenous Epogen and intravenous HSA-free Eprex, and the use of subcutaneous NeoRecormon is riskier than intravenous Epogen, there is currently no evidence that other products are safer.

Acute myelogenous leukemia with t(8;21) is a distinct clinicopathologic entity in which the malignant myeloblasts display a characteristic pattern of surface antigen expression. Quantitative analysis of surface marker expression in patients with this chromosomal abnormality compared to acute myelogenous leukemia patients with a different karyotype has not been reported. From 305 consecutive newly diagnosed acute myelogenous leukemia patients underwent immunophenotyping and cytogenetic analysis at our center; 16 patients (5.2%) had a t(8;21). Fluorescence intensity values were obtained, using a set of reference microbeads, by conversion of mean channel fluorescence to molecular equivalent of soluble fluorochrome. Patients with t(8;21) displayed higher levels of CD34, HLA-DR and MPO expression (P < 0.001 for each) and lower levels of CD13 (P = 0.03) and CD33 (P = 0.02) expression. In order to study the sensitivity, specificity and predictive value of these markers, molecular equivalent of soluble fluorochrome thresholds were statistically determined. The statistically established threshold for each of the individual markers (CD34 > 60.5 x 10(3), HLA-DR > 176.1 x 10(3), MPO > 735.1 x 10(3), CD13 < 24.3 x 10(3) and CD33 < 17.3 x 10(3)) had a sensitivity of 100%, a specificity of 62-92% and a positive predictive value of 7-45%. In multivariate analysis, two quantitative patterns (CD34 > 60.5 x 10(3) and MPO > 176.1 x 10(3); CD33 < 17.3 x 10(3) and MPO > 176.1 x 10(3)) had a sensitivity, specificity and positive predictive value of 100%. These aberrant phenotypic patterns might help identify patients with t(8;21) at diagnosis and could be useful in minimal residual disease monitoring.

Acute and chronic renal dysfunction are common after hematopoietic stem cell transplantation (HSCT). Although the pathology of chronic HSCT nephropathy is well described, the histologic changes that accompany acute renal dysfunction after HSCT are less well known because renal biopsies are rarely undertaken in the peritransplantation period. Archival renal tissue from consecutive HSCT recipients who died and underwent autopsy at a single center during an 8-year period was studied. Abnormalities of renal pathology were described, and associations of histologic abnormalities with clinical events were systemically studied. Abnormalities of renal histology were common among the 26 patients in this study. The 3 most common histologic abnormalities were glomerular sclerosis (19/26; 73%), tubular epithelial atypia (19/26; 73%), and tubular calcification (18/26; 69%). Tubulitis (16/24; 67%) and interstitial fibrosis (16/26; 62%) were also frequently observed. Clinical veno-occlusive disease was not associated with histologic evidence of thrombotic microangiopathy in the kidney at autopsy. Also, clinical graft-versus-host disease was not associated with renal tubulitis. Unexpectedly, the proportion of patients with tubular atrophy (54%) or interstitial fibrosis (62%) was high, considering the young age of the patients at transplantation and their normal pretransplantation creatinine clearance. Well-recognized histologic abnormalities are common in the kidneys of patients who die after HSCT. Although we did not demonstrate associations of these histologic changes with clinical variables before death, larger studies with prospectively collected renal tissue are warranted.

Abnormalities of chromosome 7 are a frequent finding in myelocytic malignancies and are associated with a poor prognosis. Based on chromosome banding analysis, two critical regions have been identified: one in band 7q22 and the second in region 7q32 approximately q35. The chromosomal breakpoint in band 7q22 appears to be heterogeneous and may involve tumor suppressor gene(s). Constitutional rearrangements of 7q22 have rarely been reported in myeloid malignancies. To our knowledge, this is the first report in the literature of a myeloproliferative disorder with a constitutional t(1;7)(q42;q22).