Outcomes with allogeneic stem cell transplant using cryopreserved versus fresh hematopoietic progenitor cell products.

BACKGROUND: Allogeneic hematopoietic stem cell transplant (alloHSCT) is a mainstay of treatment for hematologic malignancies such as acute leukemias and aggressive lymphomas. Historically, fresh hematopoietic progenitor cell (HPC) products have been preferred to cryopreserved products (cryo-HPC) due to concerns of loss of stem cell viability and number with the cryopreservation procedure. OBJECTIVE: We aimed to analyze the outcomes of patients who received cryo-HPCs during the COVID-19 pandemic and compare this against historical cohorts that received fresh HPC. STUDY DESIGN: A retrospective chart review was conducted on all adult patients who received a peripheral blood alloHSCT in British Columbia, Canada between June 2017 and November 2021. Baseline characteristics, Kaplan-Meier (KM) overall survival (OS), engraftment, and incidences of acute and chronic graft versus host disease were compared between patients who received cryo-HPCs and fresh HPCs. Univariable analysis followed by multivariable analysis was performed using a backward stepwise selection procedure to generate predictors of OS, cumulative incidence of relapse (CIR), nonrelapse mortality (NRM), and primary and secondary graft failure. RESULTS: Three hundred eighty-three patients were included in the analysis, with cryo-HPC representing 40%. Median viability was higher in the fresh-HPC group at 99.2% (IQR 98.3-99.5) versus cryo-HPCs at 97.0% (96.0, 98.6) (P < 0.01). The 12-month actuarial survivals were 77% in the fresh HPC and 75% in the cryo-HPC groups (P = 0.21). There were no differences between cryo-HPCs and fresh HPCs on univariable analysis of OS, CIR, or NRM. There was a shorter median time to platelet engraftment in patients receiving fresh HPC at 17 days (IQR 16, 20) versus cryo-HPC at 21 days (IQR 18, 29), P < 0.001. There was a shorter median time to neutrophil engraftment in the fresh HPC group at 17 days (IQR 14, 20) versus 20 days (17, 23), P < 0.001. Cryo-HPC accounted for 5 out of 6 cases of primary graft failure (P = 0.04), and 3 out of five cases of secondary graft failure (P = 0.39). There were no significant differences in acute GVHD between the fresh HPC and cryo-HPC groups (P = 0.34). The incidence of moderate or severe chronic GVHD was 32% in the fresh-HPC group and 17% in the cryo-HPC group (P < 0.001). In multivariable analysis, cryopreservation did not emerge as an independent predictor of OS, CIR, NRM, primary GF or secondary GF. However, viability <90% on arrival at our center was a significant predictor of OS (HR 5.3, 2.3-12.3, P < 0.01), primary graft failure (OR 36.3, 5.4-210.2, P < 0.01), and secondary graft failure (OR 18.4, 1.7-121.1, P < 0.01). CONCLUSIONS: Patients who received cryo-HPCs had similar OS and relapse rates to those who received fresh-HPCs but typically took 2-3 days longer to achieve engraftment of platelets or neutrophils and were associated increased primary graft failure. However, after accounting for multiple variables, cryopreservation was no longer a significant predictor of survival or engraftment while viability <90% emerged as an important predictor of OS, primary graft failure, and secondary graft failure. If confirmed, this suggests that viability on arrival at the infusion center may be a good quality control indicator used to identify HPC products that may warrant recollection if the risk of graft failure is sufficiently increased.

Real-World Impact of Routine Addition of Antithymocyte Globulin to Standard GVHD Prophylaxis in Myeloablative Unrelated Donor Transplants: Important Gains in Graft-versus-Host Disease Prevention though No Difference in Overall Survival.

INTRODUCTION: Antithymocyte globulin (ATG) has been demonstrated to reduce the incidence of graft-versus-host disease (GVHD); however, it remains controversial whether these gains are offset by an increase in relapse. METHODS: We conducted a retrospective historical control study consisting of patients (n = 210) who underwent myeloablative allogeneic hematopoietic stem-cell transplantation (HSCT) from 2014 to 2020. RESULTS: The incidence of acute GVHD was lower in the ATG group (51.4%) than the non-ATG group (control) (70.0%, p = 0.010). The incidence of chronic GVHD was also lower in the ATG group at 1-year (36.4% vs. 62.9%, p < 0.001) and 2-year (40.0% vs. 65.7%, p < 0.001) post-HSCT. The mortality due to GVHD was higher in the control (18.5%) than the ATG group (4.3%; p = 0.024). The severe GVHD-relapse-free survival was higher in the ATG group (36.4%) than the control (12.9%; p < 0.001). Nevertheless, the 2-year overall survival was similar. CONCLUSION: Our results confirm the effectiveness of ATG in prevention of GVHD in the real-world setting and enhanced GVHD-free survival. An important result is the equalization of overall survival between the ATG and control groups at 1- and 2-year post-HSCT and implies that earlier GVHD-associated mortality may be offset by later relapse mortality producing similar overall survival over time.

Final report of TKI discontinuation trial with dasatinib for the second attempt of treatment-free remission after failing the first attempt with imatinib: Treatment-free Remission Accomplished by Dasatinib (TRAD) study.

Multiple studies have reported a significant treatment-free remission (TFR) rate of 50%-60% in patients with chronic myeloid leukaemia (CML) who discontinue tyrosine kinase inhibitor (TKI) therapy. However, the remaining half of these patients still require re-initiation of TKI therapy for leukaemia control. It remains unclear if TKI drugs should be switched for re-therapy in patients who failed the first TFR (TFR1) attempt. Our study attempted to determine whether dasatinib therapy after TFR1 failure post-imatinib discontinuation could improve the likelihood of TFR2. Of 59 patients who lost molecular response after imatinib discontinuation for TFR1, 55 patients (93.2%) were treated with dasatinib, of whom 49 (89.1%) regained MR4.5 or deeper response, with a median time of 1.85 months to achieve MR4.5. Dasatinib was discontinued in 35 patients for TFR2 attempt, of whom 26 patients (74.28%) lost MMR and 6 (17.14%) MR4. Risk factor analysis for the TFR2 after dasatinib discontinuation suggested three significant factors: (1) doubling time of BCR::ABL1 transcript following TFR1 attempt, (2) rapid regaining of molecular response following dasatinib therapy and (3) undetectable BCR::ABL1 transcript prior to TFR2 attempt. The present study showed that dasatinib does not increase the TFR2 rate in general, but a selected group of patients could benefit from this approach.

BCR-ABL1 transcript doubling time as a predictor for treatment-free remission failure after imatinib discontinuation in chronic myeloid leukaemia in chronic phase.

The doubling time (DT) of the BCR-ABL1 quantitative polymerase chain reaction (qPCR) transcript level reflects the re-growing fraction of leukaemic cells after discontinuation of tyrosine kinase inhibitor (TKI). The present study analyzed monthly DT within six months after imatinib discontinuation in 131 patients. Monthly DT was calculated as x = ln(2)/K, where x is the DT and K is the fold BCR-ABL1 change from the previous value divided by the number of days between each measurement. The optimal DT value was determined as 12·75 days at two months using a recursive partitioning method. The patients were stratified into three groups: the high-risk group (DT<12·75 days but >0, with rapidly proliferating chronic myeloid leukaemia (CML) cells; n = 26) showed the lowest molecular relapse-free survival (mRFS) of 7·7% at 12 months, compared to 53·6% in the intermediate-risk group (DT≥12·75 days, with slowly proliferating CML cells; n = 16) or 90·0% in the low-risk group (DT≤0, i.e., without proliferating CML cells; n = 71; P < 0·001). Monthly assessment of DT helps identify high-risk patients for treatment-free remission failure with an imminent risk of molecular recurrence, and to define low-risk patients who can be spared the frequent monitoring of monthly molecular tests.

The miR-185/PAK6 axis predicts therapy response and regulates survival of drug-resistant leukemic stem cells in CML.

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.

Incidence and socioeconomic factors in older adults with acute myeloid leukaemia: Real-world outcomes from a population-based cohort.

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.

Optimal duration of imatinib treatment/deep molecular response for treatment-free remission after imatinib discontinuation from a Canadian tyrosine kinase inhibitor discontinuation trial.

Although total duration of tyrosine kinase inhibitor (TKI) therapy and of molecular response at 4 log reduction or deeper (MR4) correlates with treatment-free remission (TFR) success after TKI discontinuation, the optimal cut-off values of the duration remain unresolved. Thus, 131 patients were enrolled into the Canadian TKI discontinuation study. The molecular relapse-free survival (mRFS) was defined from imatinib discontinuation till molecular recurrence, that is, major molecular response (MMR) loss and/or MR4 loss. We evaluated mRFS at 12 months after imatinib discontinuation, analyzed it according to the imatinib treatment duration and MR4 duration, and calculated P value, positive (PPV) and negative predictive value (NPV) in the yearly cut-off period of time. The shortest cut-off was sought that met the joint criteria of a P value ≤ 0·05, PPV ≥ 60% and NPV ≥ 60%. We propose six years as the shortest imatinib duration cut-off with a P value 0·01, PPV 68% and NPV 62%: The patients treated with imatinib duration ≥ 6 years showed a superior mRFS rate (61·8%) compared to those with less treatment (36·0%). Also, 4·5 years MR4 duration as the shortest cut-off with a P value 0·003, PPV 63% and NPV 61%: those with MR4 duration ≥ 4·5 years showed a higher mRFS rate (64·2%) than those with a shorter MR4 duration (41·9%).

Improving Revised International Prognostic Scoring System Pre-Allogeneic Stem Cell Transplantation Does Not Translate Into Better Post-Transplantation Outcomes for Patients with Myelodysplastic Syndromes: A Single-Center Experience.

The natural history of patients with myelodysplastic syndromes (MDS) is variable. The Revised International Prognostic Score (IPSS-R) is commonly used in practice to predict outcomes in patients with MDS at both diagnosis and before hematopoietic stem cell transplantation (HSCT). However, the effect of change in the IPSS-R before allogeneic HSCT with chemotherapy or hypomethylating agents on post-transplantation outcomes is currently unknown. We assessed whether improvement in IPSS-R prognostic score pre-HSCT would result in improvement in clinical outcomes post-HSCT. Secondary goals included studying the effect of prognostic factors on post-transplantation survival. All patients with MDS who underwent allogeneic HSCT at the Leukemia/BMT Program of British Columbia between February 1997 and April 2013 were included. Pertinent information was reviewed from the program database. IPSS-R was calculated based on data from the time of MDS diagnosis and before HSCT. Outcomes of patients who had improved IPSS-R pre-HSCT were compared with those with stable or worse IPSS-R. Overall survival (OS) and event-free survival (EFS) were estimated using the Kaplan-Meier method, with P values determined using the log-rank test. Hazard ratios were calculated using multivariable Cox proportional hazards regression models to study the effects of the prognostic variables on OS and EFS. A total of 138 consecutive patients were included. IPSS-R improved in 62 of these patients (45%), worsened in 23 (17%), remained stable in 41 (30%), and was unknown in 12 (9%). OS was not statistically different across the improved, worsened, and stable groups (30% versus 22% versus 40%, respectively; P = .63). The cumulative incidences of relapse and nonrelapse mortality at 5 years were 28.4% (95% confidence interval [CI], 21.1 to 36.1) and 31.6% (95% CI, 23.8 to 39.7), respectively. The rate of relapse was 23% in patients with <5% blasts at the time of HSCT, 69% in those with 5% to 20% blasts, and 66% in those with >20% blasts (P = .0004). In the entire cohort OS was 34% and EFS was 33%. There was no significant difference in outcomes between patients who received myeloablative conditioning and those who received nonmyeloablative conditioning before HSCT (OS, 34% and 39%, respectively; P = .63 and EFS, 34% and 32%, respectively; P = .86). OS was not statistically different among patients with improved, worsened, or stable IPSS-R. On multivariate analysis, only 3 factors were associated with OS: cytogenetic risk group at diagnosis, blast count at transplantation, and the presence or absence of chronic graft-versus-host disease. Improving IPSS-R before HSCT does not translate into better survival outcomes. Blast count pretransplantation was highly predictive of post-transplantation outcomes.

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.

The core autophagy protein ATG4B is a potential biomarker and therapeutic target in CML stem/progenitor cells.

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.

Patients with myeloid malignancies bearing PDGFRB fusion genes achieve durable long-term remissions with imatinib.

Myeloid neoplasms and eosinophilia with rearrangements of PDGFRB are uncommon Philadelphia-negative myeloproliferative neoplasms. Patients are typically male, with morphologic features of a Philadelphia-negative chronic myeloproliferative syndrome or chronic myelomonocytic leukemia with eosinophilia. Reciprocal translocations involving PDGFRB result in fusion genes with constitutively activated receptor tyrosine kinase sensitive to inhibition with imatinib. We present an updated and expanded analysis of a cohort of 26 such patients treated with imatinib. After a median follow-up of 10.2 years (range, 1.8-17 years), the 10-year overall survival rate was 90% (95% confidence interval, 64%-97%); after median imatinib duration of 6.6 years (range, 0.1-12 years), the 6-year progression-free survival rate was 88% (95% confidence interval, 65%-96%). Of the patients, 96% responded; no patients who achieved a complete cytogenetic (n = 13) or molecular (n = 8) remission lost their response or progressed to blast crisis. Imatinib is well-tolerated and achieves excellent long-term responses in patients with PDGFRB rearrangements.

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.

Identification of multivariable microRNA and clinical biomarker panels to predict imatinib response in chronic myeloid leukemia at diagnosis.

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.

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.

Properties of CD34+ CML stem/progenitor cells that correlate with different clinical responses to imatinib mesylate.

Imatinib mesylate (IM) induces clinical remissions in chronic-phase chronic myeloid leukemia (CML) patients but IM resistance remains a problem. We recently identified several features of CML CD34(+) stem/progenitor cells expected to confer resistance to BCR-ABL-targeted therapeutics. From a study of 25 initially chronic-phase patients, we now demonstrate that some, but not all, of these parameters correlate with subsequent clinical response to IM therapy. CD34(+) cells from the 14 IM nonresponders demonstrated greater resistance to IM than the 11 IM responders in colony-forming cell assays in vitro (P < .001) and direct sequencing of cloned transcripts from CD34(+) cells further revealed a higher incidence of BCR-ABL kinase domain mutations in the IM nonresponders (10%-40% vs 0%-20% in IM responders, P < .003). In contrast, CD34(+) cells from IM nonresponders and IM responders were not distinguished by differences in BCR-ABL or transporter gene expression. Interestingly, one BCR-ABL mutation (V304D), predicted to destabilize the interaction between p210(BCR-ABL) and IM, was detectable in 14 of 20 patients. T315I mutant CD34(+) cells found before IM treatment in 2 of 20 patients examined were preferentially amplified after IM treatment. Thus, 2 properties of pretreatment CML stem/progenitor cells correlate with subsequent response to IM therapy. Prospective assessment of these properties may allow improved patient management.

Identification of key microRNAs as predictive biomarkers of Nilotinib response in chronic myeloid leukemia: a sub-analysis of the ENESTxtnd clinical trial.

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.

Mortality from Multiple Myeloma Within One Year Following Autologous Stem Cell Transplantation: Defining an Ultra-high Risk Population.

Despite improvements in therapy, approximately 5% of patients who undergo autologous stem cell transplantation (ASCT) experience early mortality (EM), death within 1 year of transplant (EM post-ASCT). Such patients tend to have few comorbidities suggesting their EM is owing to aggressive underlying disease. We sought to characterize this ultra-high risk population through a retrospective review of patients with newly diagnosed multiple myeloma (MM) treated with first-line ASCT. Patients who died within 1 year of ASCT were matched for age, sex, and year of transplant in a 1:2 fashion with a control group. Of 962 transplants performed between January 1, 2007, and May 1, 2019, 41 patients (4.3%) died within 1 year of ASCT from MM-related causes. In a multivariate analysis, anemia, hypercalcemia, high-risk cytogenetics, and elevated lactate dehydrogenase were associated with EM post-ASCT. Forty patients (97.6%) received at least 1 novel agent. Most patients with EM post-ASCT received second-line chemotherapy (80.5%), although survival from initiation of second-line chemotherapy was only 2.1 months. The primary reason for not receiving second-line therapy was rapid relapse. Clinical parameters reflecting disease burden, as well as high-risk cytogenetics, are associated with EM post-ASCT. These patients have a dismal overall survival despite significant advances in treatment of patients with relapsed or refractory myeloma. Further study of these ultra-high risk patients is required to improve disease management and may give further insights into the biology of relapse and resistance in myeloma.

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.

Five new pedigrees with inherited RUNX1 mutations causing familial platelet disorder with propensity to myeloid malignancy.

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.

Two cases of platelet transfusion refractoriness associated with anti-CD36.

BACKGROUND: Antibodies to platelet (PLT) glycoprotein (GP) IV (CD36) have been implicated in rare cases of PLT refractoriness, particularly in non-Caucasians. We report two cases of PLT transfusion refractoriness linked to anti-CD36. STUDY DESIGN AND METHODS: A 5-year-old female of Lebanese descent and a 70-year-old male of Chinese descent both failed to respond to HLA-matched PLT transfusions during acute myelogenous leukemia induction therapy. Antibody screening was performed using a PLT antibody solid-phase kit (PAKPLUS, GTI Diagnostics), followed by the monoclonal antibody-specific immobilization of PLT antigen (MAIPA) test and, for the second case, the modified antigen capture enzyme-linked immunosorbent assay (MACE). RESULTS: Both patients demonstrated antibody to GP IV (CD36) on the PAKPLUS assay. On MAIPA testing, both phenotyped as CD36 negative. Anti-CD36 was demonstrated by MAIPA in the first case. In the second case, antibodies were not detected by MAIPA and variably detectable by MACE, depending on the mouse monoclonal antibody (MoAb) used. Because no Canadian CD36-negative donors were available, antigen-negative plateletpheresis units from the BloodCenter of Wisconsin were successfully transfused. CONCLUSION: Two cases of clinically significant CD36 antibodies are reported. Investigation of one case was complicated by steric inhibition of binding in the MAIPA and MACE assays with certain MoAbs. The cases demonstrate the importance of maintaining an ethnically diverse pool of rare donors and the value of international cooperation in the management of these patients.