Excellent real-world outcomes of adults with Burkitt lymphoma treated with CODOX-M/IVAC plus or minus rituximab.

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.

Economic impact of genomic diagnostics for intermediate-risk acute myeloid leukaemia.

Acute Myeloid Leukaemia (AML) is a rare but serious group of diseases that require critical decision-making for curative treatment. Over the past decade, scientific discovery has revealed dozens of prognostic gene mutations for AML while sequencing costs have plummeted. In this study, we compared the cost-effectiveness of multigene integrative analysis (genomic analysis) with the standard molecular testing currently used for diagnosis of intermediate-risk AML. We used a decision analytic model with data for costs and outcomes from British Columbia, Canada, to assess the long-term (10-year) economic impacts. Our results suggest that genomic analysis would result in a 26% increase in the use of first-remission allogeneic stem cell transplantation. The resulting treatment decisions and downstream effects would come at an additional cost of $12 556 [2013 Canadian dollars (CAD)] per person and the incremental cost-effectiveness ratio would be $49 493 per quality-adjusted life-year gained. Cost-effectiveness was dependent on quality of life during the long-term (5-10) years of survival, relapse rates following first-remission chemotherapy and the upfront cost of transplantation. Non-relapse mortality rates, short-term quality of life and the cost of genomic sequencing had only minor impacts. Further research on post-remission outcomes can lead to improvements in the cost-effectiveness of curative treatments for AML.

Dielectrophoretic Microfluidic Chip Enables Single-Cell Measurements for Multidrug Resistance in Heterogeneous Acute Myeloid Leukemia Patient Samples.

The front-line treatment for adult acute myeloid leukemia (AML) is anthracycline-based combination chemotherapy. However, treatment outcomes remain suboptimal with relapses frequently observed. Among the mechanisms of treatment failure is multidrug resistance (MDR) mediated by the ABCB1, ABCC1, and ABCG2 drug-efflux transporters. Although genetic and phenotypic heterogeneity between leukemic blast cells is a well-recognized phenomenon, there remains minimal data on differences in MDR activity at the individual cell level. Specifically, functional assays that can distinguish the variability in MDR activity between individual leukemic blasts are lacking. Here, we outline a new dielectrophoretic (DEP) chip-based assay. This assay permits measurement of drug accumulation in single cells, termed same-single-cell analysis in the accumulation mode (SASCA-A). Initially, the assay was optimized in pretherapy samples from 20 adults with AML whose leukemic blasts had MDR activity against the anthracyline daunorubicin (DNR) tested using multiple MDR inhibitors. Parameters tested were initial drug accumulation, time to achieve signal saturation, fold-increase of DNR accumulation with MDR inhibition, ease of cell trapping, and ease of maintaining the trapped cells stationary. This enabled categorization into leukemic blast cells with MDR activity (MDR(+)) and leukemic blast cells without MDR activity (MDR(-ve)). Leukemic blasts could also be distinguished from benign white blood cells (notably these also lacked MDR activity). MDR(-ve) blasts were observed to be enriched in samples taken from patients who went on to enter complete remission (CR), whereas MDR(+) blasts were frequently observed in patients who failed to achieve CR following front-line chemotherapy. However, pronounced variability in functional MDR activity between leukemic blasts was observed, with MDR(+) cells not infrequently seen in some patients that went on to achieve CR. Next, we tested MDR activity in two paired AML patient samples. Pretherapy samples taken from patients that achieved CR to front-line chemotherapy were compared with samples taken at time of subsequent relapse. MDR(+) cells were frequently observed in leukemic blast cells in both pretherapy and relapsed samples, consistent with MDR as a mechanism of relapse in these patients. We demonstrate the ability of a new DEP microfluidic chip-based assay to identify heterogeneity in MDR activity in leukemic blasts. The test provides a platform for future studies to characterize the mechanistic basis for heterogeneity in MDR activity at the individual cell level.

Phase 2 trial of CPX-351, a fixed 5:1 molar ratio of cytarabine/daunorubicin, vs cytarabine/daunorubicin in older adults with untreated AML.

CPX-351 is a liposomal formulation of cytarabine:daunorubicin designed to deliver synergistic drug ratios to leukemia cells. In this phase 2 study, newly diagnosed older acute myeloid leukemia (AML) patients were randomized 2:1 to first-line CPX-351 or 7+3 treatment. The goal was to determine efficacy and identify patient subgroups that may benefit from CPX-351 treatment. Response rate (complete remission + incomplete remission) was the primary end point, with event-free survival (EFS) and overall survival (OS) as secondary end points. The 126 patients entered were balanced for disease and patient-specific risk factors. Overall, CPX-351 produced higher response rates (66.7% vs 51.2%, P = .07), meeting predefined criteria for success (P < .1). Differences in EFS and OS were not statistically significant. A planned analysis of the secondary AML subgroup demonstrated an improved response rate (57.6% vs 31.6%, P = .06), and prolongation of EFS (hazard ratio [HR] = 0.59, P = .08) and OS (HR = 0.46, P = .01). Recovery from cytopenias was slower after CPX-351 (median days to absolute neutrophil count ≥1000: 36 vs 32; platelets >100 000: 37 vs 28) with more grade 3-4 infections but without increase in infection-related deaths (3.5% vs 7.3%) or 60-day mortality (4.7% vs 14.6%), indicating acceptable safety. These results suggest a clinical benefit with CPX-351, particularly among patients with secondary AML, and provide the rationale for a phase 3 trial currently underway in newly diagnosed secondary AML patients. This study is registered at Clinicaltrials.gov as #NCT00788892.

Allogeneic Hematopoietic Stem Cell Transplantation Is an Effective Salvage Therapy for Patients with Chronic Myeloid Leukemia Presenting with Advanced Disease or Failing Treatment with Tyrosine Kinase Inhibitors.

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.

Phase II, multicenter, randomized trial of CPX-351 (cytarabine:daunorubicin) liposome injection versus intensive salvage therapy in adults with first relapse AML.

BACKGROUND: CPX-351 is a liposome-encapsulated fixed-molar-ratio formulation of cytarabine and daunorubicin that exploits molar ratio-dependent drug-drug synergy to enhance antileukemic efficacy. METHODS: This phase II study randomized 125 patients 2:1 to CPX-351 or investigators' choice of first salvage chemotherapy. Patients with acute myeloid leukemia (AML) in first relapse after initial Complete Remission (CR) lasting ≥1 month were stratified per the European Prognostic Index (EPI) into favorable, intermediate, and poor-risk groups based on duration of first CR, cytogenetics, age, and transplant history. Control salvage treatment was usually based on cytarabine and anthracycline, often with 1 or more additional agents. Survival at 1 year was the primary efficacy end point. RESULTS: Patient characteristics were well balanced between the 2 study arms. Improvements in efficacy outcomes were observed following CPX-351, but did not meet prospectively defined statistical criteria for 1-year survival improvement in the overall population. Subset analyses of the EPI-defined poor-risk strata demonstrated higher response rates (39.3% vs 27.6%) and improvements in event-free survival (HR, 0.63; P = .08) and overall survival (HR, 0.55; P = .02). Also, 60-day mortality was lower in the CPX-351 study arm for poor-risk patients (16.1% vs 24.1%). CONCLUSIONS: Taken together, the data suggest possible improved outcomes in CPX-351-treated first relapse AML patients with EPI-defined poor-risk disease.

Oral ciclopirox olamine displays biological activity in a phase I study in patients with advanced hematologic malignancies.

The antimycotic ciclopirox olamine is an intracellular iron chelator that has anticancer activity in vitro and in vivo. We developed an oral formulation of ciclopirox olamine and conducted the first-in-human phase I study of this drug in patients with relapsed or refractory hematologic malignancies (Trial registration ID: NCT00990587). Patients were treated with 5-80 mg/m² oral ciclopirox olamine once daily for five days in 21-day treatment cycles. Pharmacokinetic and pharmacodynamic companion studies were performed in a subset of patients. Following definition of the half-life of ciclopirox olamine, an additional cohort was enrolled and treated with 80 mg/m² ciclopirox olamine four times daily. Adverse events and clinical response were monitored throughout the trial. Twenty-three patients received study treatment. Ciclopirox was rapidly absorbed and cleared with a short half-life. Plasma concentrations of an inactive ciclopirox glucuronide metabolite were greater than those of ciclopirox. Repression of survivin expression was observed in peripheral blood cells isolated from patients treated once daily with ciclopirox olamine at doses greater than 10 mg/m², demonstrating biological activity of the drug. Dose-limiting gastrointestinal toxicities were observed in patients receiving 80 mg/m² four times daily, and no dose limiting toxicity was observed at 40 mg/m² once daily. Hematologic improvement was observed in two patients. Once-daily dosing of oral ciclopirox olamine was well tolerated in patients with relapsed or refractory hematologic malignancies, and further optimization of dosing regimens is warranted in this patient population.

Allogeneic haematopoietic stem cell transplantation for chronic lymphocytic leukaemia: outcome in a 20-year cohort.

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.

Adult dual umbilical cord blood transplantation using myeloablative total body irradiation (1350 cGy) and fludarabine conditioning.

High treatment-related mortality (TRM) and high graft failure rate are serious concerns in HLA-mismatched umbilical cord blood (UCB) transplantation with myeloablative conditioning. We conducted a prospective trial of dual UCB transplantation using modified myeloablation consisting of total-body irradiation (TBI; 1350 cGy) and fludarabine (Flu) (160 mg/m(2)). Twenty-seven patients (median age, 33 years; range: 20-58 years) with hematologic malignancies were enrolled. The median combined cryopreserved total nucleated cell (TNC) dose was 4.3 × 10(7)/kg (range: 3.2-7.7 × 10(7)/kg). The cumulative incidences of neutrophil (≥500/µL) and platelet (≥50,000/µL) engraftment were 80% (95% confidence interval [CI], 58%-91%) and 68% (95% CI, 46%-83%), respectively. Among engrafted patients, a single cord blood unit was predominant by 100 days posttransplantation. A higher cryopreserved and infused TNC dose and infused CD3(+) cell dose were significant factors associated with the predominant UCB unit (P = .032, .020, and .042, respectively). TRM and relapse rates at 2 years were 28% (95% CI, 12%-47%) and 20% (95% CI, 7%-37%), respectively. Cumulative incidences of grades II-IV and grades III-IV acute graft-versus-host disease (aGVHD) were 37% (95% CI, 20%-55%) and 11% (95% CI, 3%-26%), respectively, and that of chronic GVHD was 31% (95% CI, 15%-49%). With a median follow-up of 23 months, overall survival and disease-free survival rates at 2 years were 58% (95% CI, 34%-75%) and 52% (95% CI, 29%-70%), respectively. This study supports the use of TBI 1350 cGy/Flu as an alternative to conventional myeloablative conditioning for dual UCB transplantation.

Older adults with newly diagnosed high-risk/secondary AML who achieved remission with CPX-351: phase 3 post hoc analyses.

CPX-351, a dual-drug liposomal encapsulation of daunorubicin/cytarabine in a synergistic 1:5 molar ratio, is approved for the treatment of adults with newly diagnosed, therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC). In a pivotal phase 3 study, patients aged 60 to 75 years with newly diagnosed, high-risk/secondary AML were randomized to receive CPX-351 or conventional 7+3 chemotherapy. In the primary endpoint analysis, CPX-351 demonstrated significantly prolonged median overall survival (OS) vs 7+3. These exploratory post hoc subgroup analyses evaluated the impact of achieving complete remission (CR) or CR with incomplete neutrophil or platelet recovery (CRi) with CPX-351 (73/153 [48%]) vs conventional 7+3 (52/56 [33%]) on outcomes. CPX-351 improved median OS vs 7+3 in patients who achieved CR or CRi (25.43 vs 10.41 months; hazard ratio = 0.49; 95% confidence interval, 0.31, 0.77). Improved median OS was seen across AML subtypes (t-AML, AML-MRC), age subgroups (60 to 69 vs 70 to 75 years), patients with prior hypomethylating agent exposure, and patients who did not undergo transplantation. Patients who achieved CR or CRi with CPX-351 also had a higher rate of transplantation, a longer median OS landmarked from the date of transplantation (not reached vs 11.65 months; hazard ratio = 0.43; 95% confidence interval, 0.21, 0.89), and a safety profile that was consistent with the known safety profile of 7+3. These results suggest deeper remissions may be achieved with CPX-351, leading to improved OS. This study was registered at www.clinicaltrials.gov as #NCT01696084.

Response to tyrosine kinase inhibitor therapy in patients with chronic myelogenous leukemia relapsing in chronic and advanced phase following allogeneic hematopoietic stem cell transplantation.

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.

Characterization of variant diphtheria toxin-interleukin-3 fusion protein, DTIL3K116W, for phase I clinical trials.

We have produced clinical grade of DTIL3K116W, a variant diphtheria toxin-interleukin-3 fusion protein, for treatment of acute myeloid leukemia. The product was filter sterilized, aseptically vialed, and stored at -80 degrees C. It was characterized by Coomassie-stained SDS-PAGE, endotoxin assay, cytotoxicity assay, sterility, mass spectroscopy, receptor binding affinity, ADP-ribosylation, inhibition of normal human CFU-GM, disulfide bond analysis, immunoblots, stability, size exclusion chromatography-HPLC, sequencing, and immunohistochemistry. Vialed product was sterile in 0.25 M NaCl/5 mM Tris, pH 7.9, and had a protein concentration of 1.08 mg/ml. Purity by SDS-PAGE was >99%. Aggregates by HPLC were <1%. Endotoxin levels were 0.296EU/mg. Peptide mapping and mass spectroscopy confirmed its composition and molecular weight. The vialed drug kept reactivity with anti-IL3 and DT antibodies. Potency study revealed a 48-h EC(50) of 0.5 pM on TF1/H-ras cell. Its binding properties were confirmed by competitive experiments showing IC(50) of 1.4 nM. ADP-ribosylation activity was equivalent to DTGM-CSF. Drug did not react with tested frozen human tissue sections by immunohistochemistry. There was no evidence of loss of solubility, proteolysis aggregation, or loss of potency over 6 months at -80 degrees C. Further, the drug was stable at 4 and 25 degrees C in the plastic syringe and administration tubing for 48 h.

Quality of life and socioeconomic indicators associated with survival of myeloid leukemias in Canada.

Understanding how patient-reported quality of life (QoL) and socioeconomic status (SES) relate to survival of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) may improve prognostic information sharing. This study explores associations among QoL, SES, and survival through administration of the Euro-QoL 5-Dimension, 3-level and Functional Assessment of Cancer Therapy-Leukemia and financial impact questionnaires to 138 adult participants with newly diagnosed AML or MDS in a longitudinal, pan-Canadian study. Cox regression and lasso variable selection models were used to explore associations among QoL, SES, and established predictors of survival. Secondary outcomes were changes in QoL, performance of the QoL instruments, and lost income. We found that higher QoL and SES were positively associated with survival. The Lasso model selected the visual analog scale of the EQ-5D-3L as the most important predictor among all other variables (P = .03; 92% selection). Patients with AML report improved QoL after treatment, despite higher mean out-of-pocket expenditures compared with MDS (up to $599 CDN/month for AML vs $239 for MDS; P = .05), greater loss of productivity-related income (reaching $1786/month for AML vs $709 for MDS; P < .05), and greater caregiver effects (65% vs 35% caregiver productivity losses for AML vs MDS; P < .05). Our results suggest that including patient-reported QoL and socioeconomic indicators can improve the accuracy of survival models.

IPSS poor-risk karyotype as a predictor of outcome for patients with myelodysplastic syndrome following myeloablative stem cell transplantation.

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.

MDR1 and BCRP1 expression in leukemic progenitors correlates with chemotherapy response in acute myeloid leukemia.

OBJECTIVE: Overexpression of members of the adenosine triphosphate binding cassette (ABC) transporter superfamily has been implicated in multidrug resistance in cancer, but results in acute myeloid leukemia (AML) have been inconsistent. We investigated the expression and activity of ABC transporters in patient total blasts and subpopulations along the leukemic stem cell hierarchy. MATERIALS AND METHODS: Using quantitative reverse transcriptase polymerase chain reaction, we measured expression of the ABC transporter superfamily in the blast cells from AML patients prior to chemotherapy. In addition, we measured ex vivo daunorubicin resistance of subpopulations with or without ABC inhibitors. RESULTS: In the total blasts, no consistent difference was observed in 18 patients achieving complete remission (CR) and 13 patients who were refractory to induction chemotherapy (NR). However, among the subpopulation of CD34(+)CD38(-) AML cells (candidate "leukemic stem cells"), elevated expression of MDR1 and/or BCRP1, two ABC transporters associated with drug resistance, was found in 8 of 10 NR patients as compared to 0 of 7 CR patients. No such association was observed in the more differentiated CD34(+)CD38(+) or CD34(-) subpopulations. There was no significant difference in MRP1 expression between CR and NR patient samples in any of the subpopulations examined. The increased expression of MDR1 and BCRP1 in leukemic cells correlated with increased cellular daunorubicin resistance, which could be reversed by the ABC transporter inhibitors verapamil and PSC-833. CONCLUSION: Expression of MDR1 and BCRP1 in leukemic stem cells correlates with chemotherapy response both at the cellular level and in AML patients.

Outpatient Autologous Stem Cell Transplants for Multiple Myeloma: Analysis of Safety and Outcomes in a Tertiary Care Center.

BACKGROUND: Autologous stem cell transplant (ASCT) is the preferred consolidation strategy to treat eligible patients with multiple myeloma (MM) and related plasma cell dyscrasias. Given the increasing volume of patients and longer wait time, outpatient ASCT for MM is the standard of care at the Vancouver General Hospital. PATIENTS AND METHODS: Patients with MM, POEMS syndrome, and amyloidosis undergoing ASCT were included in this analysis. We analyzed patient characteristics, the number of patients requiring admission, duration of admission, 30-day and 100-day mortality, and overall survival. RESULTS: Between January 2007 and June 2016, 724 patients underwent 752 ASCTs. Of these, 702 were first ASCTs, 44 were second, and 6 were third. The median age was 60 years (interquartile range [IQR], 54-65 years). Reasons for ASCTs were MM (96.9%) amyloidosis (2.4%), and POEMS syndrome (0.7%). There were 431 (59.5%) males in this group. The median time from diagnosis to transplant was 5 months. Conditioning was melphalan 200 mg/m2 for 89.6% of the patients. Admission to the inpatient ward was required by 245 (32.6%) patients within the first 30 days. The median time to admission was 9 days post-transplant (IQR, 5-13 days). The median duration of admission was 6 days (IQR, 3-9 days). The day 100 all-cause mortality rate was 0.9%, and transplant-related mortality was 0.4%. CONCLUSION: Outpatient ASCT is a safe and feasible treatment strategy with low transplant-related mortality. Overall resource utilization is significantly lower than inpatient ASCT: however, this requires a multidisciplinary approach with close follow-up.

Outcomes of Intermediate Risk Karyotype Acute Myeloid Leukemia in First Remission Undergoing Autologous Stem Cell Transplantation Compared With Allogeneic Stem Cell Transplantation and Chemotherapy Consolidation: A Retrospective, Propensity-score Adjusted Analysis.

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.

Variant diphtheria toxin-interleukin-3 fusion proteins with increased receptor affinity have enhanced cytotoxicity against acute myeloid leukemia progenitors.

A fusion protein linking a truncated form of diphtheria toxin (DT(388)) to human interleukin-3 (DT(388)IL3) kills malignant progenitors from some patients with acute myeloid leukemia (AML) while sparing normal progenitors. This study evaluated two variants of DT(388)IL3 with increased affinity for the IL-3 receptor (IL-3R) for their cytotoxicity to AML progenitors and determined the ability of quantitative reverse transcription-PCR assessment of expression of the IL-3R subunits to predict the effectiveness of wild-type DT(388)IL3 and its variants. Both the IL-3 deletion variant (Delta125-133) and the amino acid substitution variant (K116W) showed enhanced toxicity against AML colony-forming cells (AML-CFC; but not normal CFC) compared with wild-type DT(388)IL3 with the K116W variant achieving >90% AML-CFC kill with 17 of 23 patient samples. This variant was also more effective against AML cells engrafting in nonobese diabetic severe combined immunodeficient mice. There was a significant correlation between the expression of the alpha and, particularly, the common beta subunit of the IL-3R on AML blasts detected by quantitative reverse transcription-PCR and AML-CFC kill. Thus, the combined use of IL-3R expression to select patients most likely to respond to DT(388)IL3 and the improved cytotoxicity of the K116W DT(388)IL3 variant against leukemic progenitors may enhance the clinical usefulness of these fusion proteins.

High-dose therapy and autologous hematopoietic stem-cell transplantation does not increase the risk of second neoplasms for patients with Hodgkin's lymphoma: a comparison of conventional therapy alone versus conventional therapy followed by autologous hematopoietic stem-cell transplantation.

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.

Philadelphia-negative clonal hematopoiesis following imatinib therapy in patients with chronic myeloid leukemia: a report of nine cases and analysis of predictive factors.

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.