Sequential CD7 CAR T-Cell Therapy and Allogeneic HSCT without GVHD Prophylaxis.

BACKGROUND: Patients with relapsed or refractory hematologic cancers have a poor prognosis. Chimeric antigen receptor (CAR) T-cell therapy as a bridge to allogeneic hematopoietic stem-cell transplantation (HSCT) has the potential for long-term tumor elimination. However, pre-HSCT myeloablation and graft-versus-host disease (GVHD) prophylaxis agents have toxic effects and could eradicate residual CAR T cells and compromise antitumor effects. Whether the integration of CAR T-cell therapy and allogeneic HSCT can preserve CAR T-cell function and improve tumor control is unclear. METHODS: We tested a novel "all-in-one" strategy consisting of sequential CD7 CAR T-cell therapy and haploidentical HSCT in 10 patients with relapsed or refractory CD7-positive leukemia or lymphoma. After CAR T-cell therapy led to complete remission with incomplete hematologic recovery, patients received haploidentical HSCT without pharmacologic myeloablation or GVHD prophylaxis drugs. Toxic effects and efficacy were closely monitored. RESULTS: After CAR T-cell therapy, all 10 patients had complete remission with incomplete hematologic recovery and grade 4 pancytopenia. After haploidentical HSCT, 1 patient died on day 13 of septic shock and encephalitis, 8 patients had full donor chimerism, and 1 patient had autologous hematopoiesis. Three patients had grade 2 HSCT-associated acute GVHD. The median follow-up was 15.1 months (range, 3.1 to 24.0) after CAR T-cell therapy. Six patients remained in minimal residual disease-negative complete remission, 2 had a relapse of CD7-negative leukemia, and 1 died of septic shock at 3.7 months. The estimated 1-year overall survival was 68% (95% confidence interval [CI], 43 to 100), and the estimated 1-year disease-free survival was 54% (95% CI, 29 to 100). CONCLUSIONS: Our findings suggest that sequential CD7 CAR T-cell therapy and haploidentical HSCT is safe and effective, with remission and serious but reversible adverse events. This strategy offers a feasible approach for patients with CD7-positive tumors who are ineligible for conventional allogeneic HSCT. (Funded by the National Natural Science Foundation of China and the Key Project of Science and Technology Department of Zhejiang Province; ClinicalTrials.gov numbers, NCT04599556 and NCT04538599.).

Cancer mortality in childhood and adolescence: analysis of trends and spatial distribution in the 133 intermediate Brazilian regions grouped by macroregions.

OBJECTIVE: To assess the magnitude, trend, and spatial patterns of childhood and adolescent cancer mortality between 1996 and 2017 in 133 Brazilian intermediate regions by using socioeconomic and healthcare services indicators. METHODS: This is an ecological study for analyzing the trend of mortality from cancer in childhood and adolescence through time series. Data on deaths were extracted from the Brazilian Mortality Information System. Data on population were extracted from the 1991, 2000, and 2010 demographic censuses of the Brazilian Institute of Geography and Statistics, with interpolation for intercensal years. Time series were delineated for mortality by type of cancer in each intermediate region. Such regions were grouped by macroregions to present the results. The calculation and interpretation of mortality trends use the Prais-Winsten autoregression procedure. RESULTS: Mortality rates for all neoplasms were higher in the Northern region (7.79 deaths per 100 thousand population), while for leukemias, they were higher in the Southern region (1.61 deaths per 100 thousand population). In both regions, mortality was higher in boys and in the 0-4 age group. The trend was decreasing (annual percent change [APC] - -2.11 [95%CI: -3.14; - 1.30]) for all neoplasms in the Brazilian regions and stationary (APC - -0.43 [95%CI: -1.61; 2.12]) for leukemias in the analyzed period. CONCLUSION: The mortality rate for all neoplasms showed higher values in regions with smaller numbers of ICU beds in the public healthcare system.

Scedosporium species and Lomentospora prolificans fungaemia is uniformly fatal in patients with haematological malignancy.

Scedosporium and Lomentospora species are environmental moulds that are virulent in immunocompromised hosts and rarely cause bloodstream infection (BSI). Patients with Scedosporium and Lomentospora species BSI were identified by the state public laboratory service in Queensland, Australia, over a 20-year period. Twenty-two incident episodes occurred among 21 residents; one patient had a second episode 321 days following the first. Of these, 18 were Lomentospora prolificans, three were Scedosporium apiospermum complex and one was a nonspeciated Scedosporium species. Seventeen (81%) patients died during their index admission, and all-cause mortality at 30, 90 and 365 days was 73%, 82% and 91% respectively. All 20 patients with haematological malignancy died within 365 days of follow-up with a median time to death of 9 days (interquartile range, 6-20 days) following diagnoses of BSI.

Epidemiological characteristics of leukemia in China, 2005-2017: a log-linear regression and age-period-cohort analysis.

BACKGROUND: Leukemia is a threat to human health, and there are relatively few studies on the incidence, mortality and disease burden analysis of leukemia in China. This study aimed to analyze the incidence and mortality rates of leukemia in China from 2005 to 2017 and estimate their age-period-cohort effects, it is an important prerequisite for effective prevention and control of leukemia. METHODS: Leukemia incidence and mortality data from 2005 to 2017 were collected from the Chinese Cancer Registry Annual Report. Joinpoint regression model was used to estimate the average annual percentage change (AAPC) and annual percentage change (APC) response time trend. Age-period-cohort model was constructed to analyze the effects of age, period and cohort. RESULTS: The age-standardized incidence rate of leukemia was 4.54/100,000 from 2005 to 2017, showed an increasing trend with AAPC of 1.9% (95% CI: 1.3%, 2.5%). The age-standardized mortality rate was 2.91/100,000, showed an increasing trend from 2005 to 2012 with APC of 2.1% (95%CI: 0.4%, 3.9%) and then a decreasing trend from 2012 to 2017 with APC of -2.5% (95%CI: -5.3%, 0.3%). The age-standardized incidence (mortality) rates of leukemia were not only higher in males than that in females, but also increased more rapidly. The incidence of leukemia in rural areas was lower than in urban areas, but the AAPC was 2.2 times higher than urban areas. Children aged 0-4 years were at higher risk of leukemia. The risk of leukemia incidence and mortality increased with age. The period effect of leukemia mortality risk showed a decreasing trend, while the cohort effect showed an increasing and then decreasing trend with the turning point of 1955-1959. CONCLUSIONS: The age-standardized incidence rate of leukemia in China showed an increasing trend from 2005 to 2017, while the age-standardized mortality rate increased first and then decreased in 2012 as a turning point. Differences existed by gender and region. The risk of leukemia incidence and mortality increased accordingly with age. The risk of mortality due to leukemia gradually decreased from 2005 to 2017. Leukemia remains a public health problem that requires continuous attention.

The Association Between Single-Nucleotide Polymorphisms of Co-Stimulatory Genes Within Non-HLA Region and the Prognosis of Leukemia Patients With Hematopoietic Stem Cell Transplantation.

To avoid graft rejection, the hematopoietic stem cells with matched classical human leukocyte antigen (HLA) alleles are the primary choice for clinical allogeneic transplantation. However, even if the fully HLA-matched hematopoietic stem cells are used for transplantation, some patients still have poor prognosis after hematopoietic stem cell transplantation (HSCT), suggesting that the HLA system was not the only determinant of the outcomes of HSCT. In this study, we investigated whether the single-nucleotide polymorphisms (SNPs) of the co-stimulatory genes within non-HLA regions were related to the outcomes of HSCT. The genomic DNAs of 163 patients who had acute leukemia and received HSCT and their respective donors were collected for analysis. Thirty-four SNPs located in the four co-stimulatory genes including cytotoxic T-lymphocyte associated protein 4 (CTLA4), CD28, tumor necrosis factor ligand superfamily 4 (TNFSF4), and programmed cell death protein 1 (PDCD1) were selected to explore their relationship with the adverse outcomes after transplantation, including mortality, cytomegalovirus infection, graft-versus-host disease, and relapse. Our results revealed that nine SNPs in the CTLA4 gene, five SNPs in the PDCD1 gene, two SNPs in the TNFSF4 gene, and four SNPs in the CD28 gene were significantly associated with the occurrence of adverse outcomes post-HSCT. These SNPs may play important roles in immune response to allografts post-HSCT and can be the targets for developing strategy to identify appropriate donors.

Single-Arm Non-Blinded Multicenter Clinical Trial on T-Cell-Replete Haploidentical Stem Cell Transplantation Using Low-Dose Antithymocyte Globulin for Relapsed and Refractory Pediatric Acute Leukemia.

Although approximately 70% of pediatric hematological malignancies are curable, approximately 30% remain fatal. No standard treatment is available in patients showing relapse and those with refractory disease. Although different methods are adopted in different hospitals, its efficacy is extremely limited. In recent years, haploidentical stem cell transplantation, involving high-dose cyclophosphamide administration post-transplanta tion, has been used, mainly in adults; however, its application is limited to removal of alloreactive T cells. Multicenter single-arm clinical trials of T-cell replete haploidentical stem cell transplantation (TCR-haplo-SCT) will be conducted in children with relapsed and refractory acute leukemia. After myeloablative conditioning using total body irradiation or busulfan, intensive graft versus host disease prophylaxis is administered, consisting of low-dose rabbit anti-human thymocyte globulin, tacrolimus, methotrexate, and prednisolone. An external control group is set up for the study. The treatment period is around 3 months, and the follow-up period is 2 years from transplantation completion.The aim of this study is to verify the efficacy and safety of TCR-haplo-SCT and present it as a new immune cell therapy for improving survival rate in children with relapsed and refractory acute leukemia.

ERK activation via A1542/3 limonoids attenuates erythroleukemia through transcriptional stimulation of cholesterol biosynthesis genes.

BACKGROUND: Cholesterol plays vital roles in human physiology; abnormal levels have deleterious pathological consequences. In cancer, elevated or reduced expression of cholesterol biosynthesis is associated with good or poor prognosis, but the underlying mechanisms are largely unknown. The limonoid compounds A1542 and A1543 stimulate ERK/MAPK by direct binding, leading to leukemic cell death and suppression of leukemia in mouse models. In this study, we investigated the downstream consequences of these ERK/MAPK agonists in leukemic cells. METHODS: We employed RNAseq analysis combined with Q-RT-PCR, western blot and bioinformatics to identify and confirm genes whose expression was altered by A1542 and A1543 in leukemic cells. ShRNA lentiviruses were used to silence gene expression. Cell culture and an animal model (BALB/c) of erythroleukemia induced by Friend virus were utilized to validate effects of cholesterol on leukemia progression. RESULTS: RNAseq analysis of A1542-treated cells revealed the induction of all 18 genes implicated in cholesterol biosynthesis. Expression of these cholesterol genes was blocked by cedrelone, an ERK inhibitor. The cholesterol inhibitor lovastatin diminished ERK/MAPK activation by A1542, thereby reducing leukemic cell death induced by this ERK1/2 agonist. Growth inhibition by cholesterol was observed both at the intracellular level, and when orally administrated into a leukemic mouse model. Both HDL and LDL also suppressed leukemogenesis, implicating these lipids as important prognostic markers for leukemia progression. Mechanistically, knockdown experiments revealed that the activation of SREBP1/2 by A1542-A1543 was responsible for induction of only a sub-set of cholesterol biosynthesis genes. Induction of other regulatory factors by A1542-A1543 including EGR1, AP1 (FOS + JUN) LDLR, IER2 and others may cooperate with SREBP1/2 to induce cholesterol genes. Indeed, pharmacological inhibition of AP1 significantly inhibited cholesterol gene expression induced by A1542. In addition to leukemia, high expression of cholesterol biosynthesis genes was found to correlate with better prognosis in renal cancer. CONCLUSIONS: This study demonstrates that ERK1/2 agonists suppress leukemia and possibly other types of cancer through transcriptional stimulation of cholesterol biosynthesis genes.

Comparable Outcomes of Matched Sibling Donor and Matched Unrelated Donor Stem Cell Transplantation in Children With Acute Leukemia in Argentina.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is an effective mode of consolidation therapy for children with high-risk acute leukemia. In high-income countries, match sibling donor (MSD) and match unrelated donor (MUD) HSCT have similar outcomes, but data are scarce in upper-middle-income countries. Our objective was to compare MSD and MUD HSCT outcomes for children with acute leukemia in Argentina. PATIENTS AND METHODS: This was a single-institution retrospective cohort study. We included children with acute leukemia who underwent HSCT with either MSD or MUD between 2014 and 2019. RESULTS: The study included 45 patients who received MSD (n=27) or MUD (n=18) for acute leukemia. Event-free survival was not significantly different between MSD (62.3±10.7%) versus MUD (54.2±15.0%; P=0.54) at 5 years. Similarly, there was no significant difference in 5-year overall survival between MSD (71.9±9.8%) versus MUD (65.1±13.5%; P=0.38). The cumulative incidence of treatment-related mortality (P=0.31), cumulative incidence of relapse (P=0.99), and proportion with acute-graft-versus-host disease (P=0.76) and chronic-graft-versus-host disease (P=0.68) were also not significantly different. CONCLUSIONS: In Argentina, we did not show significant differences in outcomes between MSD and MUD HSCT for children with high-risk leukemia. Future work should focus on strategies to reduce the relapse risk in children with high-risk leukemia in upper-middle-income countries.

Chimerism, the Microenvironment and Control of Leukemia.

Transplantation of allogeneic hematopoietic cells faces two barriers: failure of engraftment due to a host versus graft reaction, and the attack of donor cells against the patient, the graft versus host (GVH) reaction. This reaction may lead to GVH disease (GVHD), but in patients transplanted due to leukemia or other malignant disorders, this may also convey the benefit of a graft versus leukemia (GVL) effect. The interplay of transplant conditioning with donor and host cells and the environment in the patient is complex. The microbiome, particularly in the intestinal tract, profoundly affects these interactions, directly and via soluble mediators, which also reach other host organs. The microenvironment is further altered by the modifying effect of malignant cells on marrow niches, favoring the propagation of the malignant cells. The development of stable mixed donor/host chimerism has the potential of GVHD prevention without necessarily increasing the risk of relapse. There has been remarkable progress with novel conditioning regimens and selective T-cell manipulation aimed at securing engraftment while preventing GVHD without ablating the GVL effect. Interventions to alter the microenvironment and change the composition of the microbiome and its metabolic products may modify graft/host interactions, thereby further reducing GVHD, while enhancing the GVL effect. The result should be improved transplant outcome.

Selective ABO immunoadsorption in hematopoietic stem cell transplantation with major ABO incompatibility.

OBJECTIVE: ABO mismatch between donor and recipient occurs in 40% of allogeneic hematopoietic stem cell transplantations (HCT). Different strategies have been described to reduce isohemagglutinins (IHA) before HCT. We describe the effect of selective ABO immunoadsorption (ABO IA) on erythrocyte transfusion rate and the development of post-transplant pure red cell aplasia (ptPRCA). METHODS: 63 patients with major ABO incompatibility were retrospectively analyzed. Nine patients with major ABO incompatibility and high-IHA titer were treated by ABO IA before HCT. We analyzed the need for transfusion and the occurrence of ptPRCA. We compared the outcome with patients treated by other methods to reduce IHA. RESULTS: In all nine patients treated by ABO IA, IHA decreased in a median four times. PtPRCA occurred in one patient. The median number of transfusions was 8 (range: 0-36) between d0 and d100. In 25 patients with high-IHA titer without treatment or treated by other methods to reduce IHA, the need for transfusions was comparable. No difference in the incidence of ptPRCA was observed. CONCLUSIONS: Selective ABO IA is a feasible, safe, and effective method to reduce IHA before HCT in major ABO incompatibility. No effect on transfusion rate or ptPRCA compared to other strategies could be observed.

Outcomes of Adolescents and Young Adults Compared with Children with Acute Leukemia after Single-Unit Unrelated Cord Blood Transplantation Using Myeloablative Conditioning without Antithymocyte Globulin.

BACKGROUND: Although the use of cord blood transplantation (CBT) is becoming more frequent in acute leukemia, considering the relationship between the low stem cell dose and graft failure, whether use of CBT for adolescents and young adults (AYAs) is appropriate remains uncertain. METHODS: A retrospective registry-based analysis of clinical outcomes and immune reconstitution was conducted for 105 AYAs and 187 children with acute leukemia who underwent single-unit CBT using myeloablative conditioning (MAC) without antithymocyte globulin (ATG). RESULTS: Outcomes were similar between AYAs and children, except for nonrelapse mortality (NRM) and recovery rates of neutrophils and platelets. The 30-day cumulative incidence of neutrophil engraftment was similar between AYAs and children, but children had faster rates of neutrophil and platelet recovery than AYAs. The median time to neutrophil engraftment was earlier in children than in AYAs (AYAs, 19 days, 95% confidence interval [CI] 17.3-21.7; children, 16 days, 95% CI 13.1-19.5, p = 0.00003). The incidence of platelet recovery on day 120 was higher in children than in AYAs (AYAs, 80%, 95% CI 71-81%; children, 88%, 95% CI 82-92%, p = 0.037). CD34+ cell dose was the only independent factor influencing both neutrophil and platelet recovery. The cumulative incidence of NRM at 2 years was higher among AYAs than among children (AYAs, 27.5%, 95% CI 20-37%; children, 15%, 95% CI 10-21%, p = 0.008). Conditioning regimen was an independent factor influencing NRM. With respect to immune reconstitution, natural killer cell counts quickly recovered to normal levels 1-month post-CBT in both children and AYAs. CD8+ T-cell counts were higher in children than in AYAs at 1 and 3 months post-CBT. CD4+ T-cell counts were similar in both children and AYAs after CBT. CONCLUSION: AYAs with acute leukemia have outcomes of single-unit CBT using MAC without ATG that are as good as those of children. Thus, single-unit CBT using modified MAC without ATG is an acceptable choice for both AYAs and children who do not have a suitable donor.

Effect of prophylactic leukapheresis on early mortality and overall survival in acute leukemia patients with hyperleukocytosis.

Hyperleukocytosis has been associated with early mortality owing to the presence of complications including leukostasis, tumor lysis syndrome (TLS), and disseminated intravascular coagulation (DIC). Leukapheresis is a fast and effective cytoreductive procedure that removes leukocytes from the peripheral circulation. This single-center, retrospective, and observational study included 32 patients diagnosed with acute leukemia who underwent leukapheresis due to hyperleukocytosis between 2014 and 2020. This study primarily aimed to investigate the effect of prophylactic leukapheresis on early mortality and overall survival (OS). In the symptomatic group, seven and two patients died in the first and second weeks, respectively. In the prophylactic leukapheresis group, two and one patients died in the first and second weeks (p = 0.792), respectively. OS was significantly longer in the prophylactic leukapheresis group (p = 0.004). The leukapheresis procedure appears to be effective on early mortality and OS. Initiation of prophylactic leukapheresis before the appearance of leukostasis symptoms is effective on OS and possibly early mortality.

Evaluating palliative opportunities in pediatric patients with leukemia and lymphoma.

BACKGROUND: Despite favorable prognoses, pediatric patients with hematologic malignancies experience significant challenges that may lead to diminished quality of life or family stress. They are less likely to receive subspecialty palliative care (PC) consultation and often undergo intensive end-of-life (EOL) care. We examined "palliative opportunities," or events when the integration of PC would have the greatest impact, present during a patient's hematologic malignancy course and relevant associations. METHODS: A single-center retrospective review was conducted on patients aged 0-18 years with a hematologic malignancy who died between 1/1/12 and 11/30/17. Demographic, disease, and treatment data were collected. A priori, nine palliative opportunity categories were defined. Descriptive statistics were performed. Palliative opportunities were evaluated over temporal quartiles from diagnosis to death. Timing and rationale of pediatric PC consultation were evaluated. RESULTS: Patients (n = 92) had a median of 5.0 (interquartile range [IQR] 6.0) palliative opportunities, incurring 522 total opportunities, increasing toward the EOL. Number and type of opportunities did not differ by demographics. PC consultation was most common in patients with lymphoid leukemia (50.9%, 28/55) and myeloid leukemia (48.5%, 16/33) versus lymphoma (0%, 0/4, p = 0.14). Forty-four of ninety-two patients (47.8%) received PC consultation a median of 1.8 months (IQR 4.1) prior to death. Receipt of PC was associated with transplant status (p = 0.0018) and a higher number of prior palliative opportunities (p = 0.0005); 70.3% (367/522) of palliative opportunities occurred without PC. CONCLUSION: Patients with hematologic malignancies experience many opportunities warranting PC support. Identifying opportunities for ideal timing of PC involvement may benefit patients with hematologic cancers and their caregivers.

Drug ranking using machine learning systematically predicts the efficacy of anti-cancer drugs.

Artificial intelligence and machine learning (ML) promise to transform cancer therapies by accurately predicting the most appropriate therapies to treat individual patients. Here, we present an approach, named Drug Ranking Using ML (DRUML), which uses omics data to produce ordered lists of >400 drugs based on their anti-proliferative efficacy in cancer cells. To reduce noise and increase predictive robustness, instead of individual features, DRUML uses internally normalized distance metrics of drug response as features for ML model generation. DRUML is trained using in-house proteomics and phosphoproteomics data derived from 48 cell lines, and it is verified with data comprised of 53 cellular models from 12 independent laboratories. We show that DRUML predicts drug responses in independent verification datasets with low error (mean squared error < 0.1 and mean Spearman's rank 0.7). In addition, we demonstrate that DRUML predictions of cytarabine sensitivity in clinical leukemia samples are prognostic of patient survival (Log rank p < 0.005). Our results indicate that DRUML accurately ranks anti-cancer drugs by their efficacy across a wide range of pathologies.

Cellular Therapy During COVID-19: Lessons Learned and Preparing for Subsequent Waves.

An evidence-based triage plan for cellular therapy distribution is critical in the face of emerging constraints on healthcare resources. We evaluated the impact of treatment delays related to COVID-19 on patients scheduled to undergo hematopoietic cell transplantation (HCT) or chimeric antigen receptor T-cell (CAR-T) therapy at our center. Data were collected in real time between March 19 and May 11, 2020, for patients who were delayed to cellular therapy. We evaluated the proportion of delayed patients who ultimately received cellular therapy, reasons for not proceeding to cellular therapy, and changes in disease and health status during delay. A total of 85 patients were delayed, including 42 patients planned for autologous HCT, 36 patients planned for allogeneic HCT, and 7 patients planned for CAR-T therapy. Fifty-six of these patients (66%) since received planned therapy. Five patients died during the delay. The most common reason for not proceeding to autologous HCT was good disease control in patients with plasma cell dyscrasias (75%). The most common reason for not proceeding to allogeneic HCT was progression of disease (42%). All patients with acute leukemia who progressed had measurable residual disease (MRD) at the time of delay, whereas no patient without MRD at the time of delay progressed. Six patients (86%) ultimately received CAR-T therapy, including 3 patients who progressed during the delay. For patients with high-risk disease such as acute leukemia, and particularly those with MRD at the time of planned HCT, treatment delay can result in devastating outcomes and should be avoided if at all possible.

Matched Targeted Therapy for Pediatric Patients with Relapsed, Refractory, or High-Risk Leukemias: A Report from the LEAP Consortium.

Despite a remarkable increase in the genomic profiling of cancer, integration of genomic discoveries into clinical care has lagged behind. We report the feasibility of rapid identification of targetable mutations in 153 pediatric patients with relapsed/refractory or high-risk leukemias enrolled on a prospective clinical trial conducted by the LEAP Consortium. Eighteen percent of patients had a high confidence Tier 1 or 2 recommendation. We describe clinical responses in the 14% of patients with relapsed/refractory leukemia who received the matched targeted therapy. Further, in order to inform future targeted therapy for patients, we validated variants of uncertain significance, performed ex vivo drug-sensitivity testing in patient leukemia samples, and identified new combinations of targeted therapies in cell lines and patient-derived xenograft models. These data and our collaborative approach should inform the design of future precision medicine trials. SIGNIFICANCE: Patients with relapsed/refractory leukemias face limited treatment options. Systematic integration of precision medicine efforts can inform therapy. We report the feasibility of identifying targetable mutations in children with leukemia and describe correlative biology studies validating therapeutic hypotheses and novel mutations.See related commentary by Bornhauser and Bourquin, p. 1322.This article is highlighted in the In This Issue feature, p. 1307.

Prognostic value of ASXL1 mutations in patients with primary myelofibrosis and its relationship with clinical features: a meta-analysis.

Additional sex combs like 1 (ASXL1) mutations are one of the most common molecular biological abnormalities in patients with primary myelofibrosis (PMF), and the effect of these mutations on prognosis remains controversial. Hence, we conducted a meta-analysis to assess the prognostic value and clinical characteristics of ASXL1 mutations in PMF patients. Eligible studies were systematically searched from PubMed, Embase, and the Cochrane Library. We extracted the hazard ratios (HRs) and their 95% confidence intervals (CIs) of overall survival (OS) and leukemia-free survival (LFS), the number of patients transformed to acute leukemia, and clinical characteristics to carry out a meta-analysis by fixed effect model or random effect model according to the heterogeneity between studies. A total of 4501 PMF patients from 16 cohorts of 14 studies were included in this meta-analysis. The results revealed that ASXL1 mutations might predict a shorter OS (HR = 2.30, 95% CI: 1.79-2.94, P < 0.00001) and a higher probability of transformation to acute leukemia (LFS: HR = 1.77, 95% CI: 1.30-2.42, P = 0.0003; the rate of acute leukemia transformation: OR = 2.06, 95% CI: 1.50-2.83, P < 0.00001). Furthermore, ASXL1 mutations were correlated with patients older than 65 years old, male, a lower level of platelet counts, and a higher risk of the international prognostic score system. These findings indicate that ASXL1 mutations have a significant adverse impact on the prognosis of PMF patients and may contribute to risk stratification and prognostic assessment for PMF patients.

BCR-ABL1-Negative Chronic Myeloproliferative Neoplasms and Pulmonary Hypertension: A Prospective Long-Term Follow-up Study of the Impact of Pulmonary Hypertension on Survival.

PURPOSE: To assess the prevalence of PHT in patients with BCR-ABL1-negative CMPN and to evaluate impact of PHT on survival during long-term follow-up. PATIENTS AND METHODS: A total of 122 patients with BCR-ABL1-negative CMPN underwent transthoracic echocardiographic (TTE) evaluation at the beginning of study. Patients undergoing PHT on TTE examination were also evaluated by a pulmonologist. Patients were divided into 3 groups. Group A comprised patients with CMPN-related PHT; group B, patients with no PHT; and group C, patients with PHT due to secondary causes. Patients were evaluated again every 3 to 6 months. RESULTS: PHT was detected in 33 (27%) of 122 patients. Eight (6.5%) had CMPN-related PHT and the remaining 25 (20.5%) had non-CMPN-related PHT. Positivity for JAK2 V617F mutation in the study population was 72.9%. Groups were similar with respect to hematologic parameters and gender. Follow-up times were as follows: median (range) time from diagnosis to TTE and study end were 34 (1-158) months and 107 (16-251) months, respectively, and from TTE to study end was 88 (7-110) months. No significant differences found among the groups in terms of median time from diagnosis to TTE, follow-up, and overall survival. CONCLUSION: BCR-ABL1-negative CMPN patients had a lower prevalence of PHT compared to earlier studies. There was no statistically significant difference in median overall survival between patients with or without PHT. This may be because patients with PHT were asymptomatic and PHT was mild. The impact of PHT on survival was negligible.

Premature Mortality Due to Hodgkin Lymphoma, Non-Hodgkin Lymphoma, Multiple Myeloma, and Leukemia in Canada: A Nationwide Analysis From 1980 to 2015.

Recently, we introduced a novel measure of "average life span shortened" (ALSS) to improve comparability of premature mortality over time. In this study, we applied this novel measure to examine trends in premature mortality caused by hematological cancers in Canada from 1980 to 2015. Mortality data for Hodgkin lymphoma, non-Hodgkin lymphoma, multiple myeloma, and leukemia were obtained from the World Health Organization mortality database. Years of life lost was calculated according to Canadian life tables. ALSS was defined as the ratio between years of life lost and expected life span. Over the study period, age-standardized rates of mortality decreased for all types of hematological cancers. Our new ALSS measure showed favorable trends in premature mortality for all types of hematological cancers among both sexes. For instance, men with non-Hodgkin lymphoma lost an average of 23.7% of their life span in 1980 versus 16.1% in 2015, while women with non-Hodgkin lymphoma lost an average of 21.7% of their life span in 1980 versus 15.5% in 2015. Results from this study showed that patients with hematological cancers experienced prolonged survival over a 35-year period although the magnitude of these life span gains varied by types of hematological cancers.

Temporal trends in childhood cancer survival in Egypt, 2007 to 2017: A large retrospective study of 14 808 children with cancer from the Children's Cancer Hospital Egypt.

Childhood cancer is a priority in Egypt due to large numbers of children with cancer, suboptimal care and insufficient resources. It is difficult to evaluate progress in survival because of paucity of data in National Cancer Registry. In this study, we studied survival rates and trends in survival of the largest available cohort of children with cancer (n = 15 779, aged 0-18 years) from Egypt between 2007 and 2017, treated at Children's Cancer Hospital Egypt-(CCHE), representing 40% to 50% of all childhood cancers across Egypt. We estimated 5-year overall survival (OS) for 14 808 eligible patients using Kaplan-Meier method, and determined survival trends using Cox regression by single year of diagnosis and by diagnosis periods. We compared age-standardized rates to international benchmarks in England and the United States, identified cancers with inferior survival and provided recommendations for improvement. Five-year OS was 72.1% (95% CI 71.3-72.9) for all cancers combined, and survival trends increased significantly by single year of diagnosis (P < .001) and by calendar periods from 69.6% to 74.2% (P < .0001) between 2007-2012 and 2013-2017. Survival trends improved significantly for leukemias, lymphomas, CNS tumors, neuroblastoma, hepatoblastoma and Ewing Sarcoma. Survival was significantly lower by 9% and 11.2% (P < .001) than England and the United States, respectively. Significantly inferior survival was observed for the majority of cancers. Although survival trends are improving for childhood cancers in Egypt/CCHE, survival is still inferior in high-income countries. We provide evidence-based recommendations to improve survival in Egypt by reflecting on current obstacles in care, with further implications on practice and policy.