Inherited polygenic effects on common hematological traits influence clonal selection on JAK2V617F and the development of myeloproliferative neoplasms.

Myeloproliferative neoplasms (MPNs) are chronic cancers characterized by overproduction of mature blood cells. Their causative somatic mutations, for example, JAK2V617F, are common in the population, yet only a minority of carriers develop MPN. Here we show that the inherited polygenic loci that underlie common hematological traits influence JAK2V617F clonal expansion. We identify polygenic risk scores (PGSs) for monocyte count and plateletcrit as new risk factors for JAK2V617F positivity. PGSs for several hematological traits influenced the risk of different MPN subtypes, with low PGSs for two platelet traits also showing protective effects in JAK2V617F carriers, making them two to three times less likely to have essential thrombocythemia than carriers with high PGSs. We observed that extreme hematological PGSs may contribute to an MPN diagnosis in the absence of somatic driver mutations. Our study showcases how polygenic backgrounds underlying common hematological traits influence both clonal selection on somatic mutations and the subsequent phenotype of cancer.

Outcomes and characteristics of nonmelanoma skin cancers in patients with myeloproliferative neoplasms on ruxolitinib.

ABSTRACT: Nonmelanoma skin cancers (NMSCs) in ruxolitinib-treated patients with myeloproliferative neoplasms behave aggressively, with adverse features and high recurrence. In our cohort, mortality from metastatic NMSC exceeded that from myelofibrosis. Vigilant skin assessment, counseling on NMSC risks, and prospective ruxolitinib-NMSC studies are crucial.

Tamoxifen for the treatment of myeloproliferative neoplasms: A Phase II clinical trial and exploratory analysis.

Current therapies for myeloproliferative neoplasms (MPNs) improve symptoms but have limited effect on tumor size. In preclinical studies, tamoxifen restored normal apoptosis in mutated hematopoietic stem/progenitor cells (HSPCs). TAMARIN Phase-II, multicenter, single-arm clinical trial assessed tamoxifen's safety and activity in patients with stable MPNs, no prior thrombotic events and mutated JAK2V617F, CALRins5 or CALRdel52 peripheral blood allele burden ≥20% (EudraCT 2015-005497-38). 38 patients were recruited over 112w and 32 completed 24w-treatment. The study's A'herns success criteria were met as the primary outcome ( ≥ 50% reduction in mutant allele burden at 24w) was observed in 3/38 patients. Secondary outcomes included ≥25% reduction at 24w (5/38), ≥50% reduction at 12w (0/38), thrombotic events (2/38), toxicities, hematological response, proportion of patients in each IWG-MRT response category and ELN response criteria. As exploratory outcomes, baseline analysis of HSPC transcriptome segregates responders and non-responders, suggesting a predictive signature. In responder HSPCs, longitudinal analysis shows high baseline expression of JAK-STAT signaling and oxidative phosphorylation genes, which are downregulated by tamoxifen. We further demonstrate in preclinical studies that in JAK2V617F+ cells, 4-hydroxytamoxifen inhibits mitochondrial complex-I, activates integrated stress response and decreases pathogenic JAK2-signaling. These results warrant further investigation of tamoxifen in MPN, with careful consideration of thrombotic risk.

Clonal origin of KMT2A wild-type lineage-switch leukemia following CAR-T cell and blinatumomab therapy.

Children with acute lymphoblastic leukemia (ALL) undergoing anti-CD19 therapy occasionally develop acute myeloid leukemia (AML). The clonal origin of such lineage-switch leukemias1-4 remains unresolved. Here, we reconstructed the phylogeny of multiple leukemias in a girl who, following multiply relapsed ALL, received anti-CD19 cellular and antibody treatment and subsequently developed AML. Whole genome sequencing unambiguously revealed the AML derived from the initial ALL, with distinct driver mutations that were detectable before emergence. Extensive prior diversification and subsequent clonal selection underpins this fatal lineage switch. Genomic monitoring of primary leukemias and recurrences may predict therapy resistance, especially regarding anti-CD19 treatment.

Ruxolitinib Versus Best Available Therapy for Polycythemia Vera Intolerant or Resistant to Hydroxycarbamide in a Randomized Trial.

PURPOSE: Polycythemia vera (PV) is characterized by JAK/STAT activation, thrombotic/hemorrhagic events, systemic symptoms, and disease transformation. In high-risk PV, ruxolitinib controls blood counts and improves symptoms. PATIENTS AND METHODS: MAJIC-PV is a randomized phase II trial of ruxolitinib versus best available therapy (BAT) in patients resistant/intolerant to hydroxycarbamide (HC-INT/RES). Primary outcome was complete response (CR) within 1 year. Secondary outcomes included duration of response, event-free survival (EFS), symptom, and molecular response. RESULTS: One hundred eighty patients were randomly assigned. CR was achieved in 40 (43%) patients on ruxolitinib versus 23 (26%) on BAT (odds ratio, 2.12; 90% CI, 1.25 to 3.60; P = .02). Duration of CR was superior for ruxolitinib (hazard ratio [HR], 0.38; 95% CI, 0.24 to 0.61; P < .001). Symptom responses were better with ruxolitinib and durable. EFS (major thrombosis, hemorrhage, transformation, and death) was superior for patients attaining CR within 1 year (HR, 0.41; 95% CI, 0.21 to 0.78; P = .01); and those on ruxolitinib (HR, 0.58; 95% CI, 0.35 to 0.94; P = .03). Serial analysis of JAK2V617F variant allele fraction revealed molecular response was more frequent with ruxolitinib and was associated with improved outcomes (progression-free survival [PFS] P = .001, EFS P = .001, overall survival P = .01) and clearance of JAK2V617F stem/progenitor cells. ASXL1 mutations predicted for adverse EFS (HR, 3.02; 95% CI, 1.47 to 6.17; P = .003). The safety profile of ruxolitinib was as previously reported. CONCLUSION: The MAJIC-PV study demonstrates ruxolitinib treatment benefits HC-INT/RES PV patients with superior CR, and EFS as well as molecular response; importantly also demonstrating for the first time, to our knowledge, that molecular response is linked to EFS, PFS, and OS.

Cost-effectiveness of a direct to beneficiary mobile communication programme in improving reproductive and child health outcomes in India.

INTRODUCTION: Kilkari is the largest maternal messaging programme of its kind globally. Between its initiation in 2012 in Bihar and its transition to the government in 2019, Kilkari was scaled to 13 states across India and reached over 10 million new and expectant mothers and their families. This study aims to determine the cost-effectiveness of exposure to Kilkari as compared with no exposure across 13 states in India. METHODS: The study was conducted from a programme perspective using an analytic time horizon aligned with national scale-up efforts from December 2014 to April 2019. Economic costs were derived from the financial records of implementing partners. Data on incremental changes in the practice of reproductive maternal newborn and child health (RMNCH) outcomes were drawn from an individually randomised controlled trial in Madhya Pradesh and inputted into the Lives Saved Tool to yield estimates of maternal and child lives saved. One-way and probabilistic sensitivity analyses were carried out to assess uncertainty. RESULTS: Inflation adjusted programme costs were US$8.4 million for the period of December 2014-April 2019, corresponding to an average cost of US$264 298 per year of implementation in each state. An estimated 13 842 lives were saved across 13 states, 96% among children and 4% among mothers. The cost per life saved ranged by year of implementation and with the addition of new states from US$392 ($385-$393) to US$953 ($889-$1092). Key drivers included call costs and incremental changes in coverage for key RMNCH practices. CONCLUSION: Kilkari is highly cost-effective using a threshold of India's national gross domestic product of US$1998. Study findings provide important evidence on the cost-effectiveness of a national maternal messaging programme in India. TRIAL REGISTRATION: NCT03576157.

Can we design the next generation of digital health communication programs by leveraging the power of artificial intelligence to segment target audiences, bolster impact and deliver differentiated services? A machine learning analysis of survey data from rural India.

OBJECTIVES: Direct to beneficiary (D2B) mobile health communication programmes have been used to provide reproductive, maternal, neonatal and child health information to women and their families in a number of countries globally. Programmes to date have provided the same content, at the same frequency, using the same channel to large beneficiary populations. This manuscript presents a proof of concept approach that uses machine learning to segment populations of women with access to phones and their husbands into distinct clusters to support differential digital programme design and delivery. SETTING: Data used in this study were drawn from cross-sectional survey conducted in four districts of Madhya Pradesh, India. PARTICIPANTS: Study participant included pregnant women with access to a phone (n=5095) and their husbands (n=3842) RESULTS: We used an iterative process involving K-Means clustering and Lasso regression to segment couples into three distinct clusters. Cluster 1 (n=1408) tended to be poorer, less educated men and women, with low levels of digital access and skills. Cluster 2 (n=666) had a mid-level of digital access and skills among men but not women. Cluster 3 (n=1410) had high digital access and skill among men and moderate access and skills among women. Exposure to the D2B programme 'Kilkari' showed the greatest difference in Cluster 2, including an 8% difference in use of reversible modern contraceptives, 7% in child immunisation at 10 weeks, 3% in child immunisation at 9 months and 4% in the timeliness of immunisation at 10 weeks and 9 months. CONCLUSIONS: Findings suggest that segmenting populations into distinct clusters for differentiated programme design and delivery may serve to improve reach and impact. TRIAL REGISTRATION NUMBER: NCT03576157.

Continuous Indexing of Fibrosis (CIF): improving the assessment and classification of MPN patients.

The grading of fibrosis in myeloproliferative neoplasms (MPN) is an important component of disease classification, prognostication and monitoring. However, current fibrosis grading systems are only semi-quantitative and fail to fully capture sample heterogeneity. To improve the quantitation of reticulin fibrosis, we developed a machine learning approach using bone marrow trephine (BMT) samples (n = 107) from patients diagnosed with MPN or a reactive marrow. The resulting Continuous Indexing of Fibrosis (CIF) enhances the detection and monitoring of fibrosis within BMTs, and aids MPN subtyping. When combined with megakaryocyte feature analysis, CIF discriminates between the frequently challenging differential diagnosis of essential thrombocythemia (ET) and pre-fibrotic myelofibrosis with high predictive accuracy [area under the curve = 0.94]. CIF also shows promise in the identification of MPN patients at risk of disease progression; analysis of samples from 35 patients diagnosed with ET and enrolled in the Primary Thrombocythemia-1 trial identified features predictive of post-ET myelofibrosis (area under the curve = 0.77). In addition to these clinical applications, automated analysis of fibrosis has clear potential to further refine disease classification boundaries and inform future studies of the micro-environmental factors driving disease initiation and progression in MPN and other stem cell disorders.

Essential thrombocythemia: challenges in clinical practice and future prospects.

Essential thrombocythemia (ET) was first described in 1934, and subsequently, progress has been made in better understanding the molecular pathogenesis and which patients may have greatest risk of progression or vascular events. However, it has been more than a decade since a new therapy has been approved for ET. We are beginning to understand more comprehensively both the heterogeneity of this disease, which is largely driven by driver mutation status, as well as the effect of disease-related symptoms, such as fatigue, on patients. In this review we provide a practical overview of diagnosis and management of ET with focus on challenging patient scenarios and some consideration of what comprehensive care might entail. Finally, we also discuss newer therapies and how these might be assessed.

The impact of a direct to beneficiary mobile communication program on reproductive and child health outcomes: a randomised controlled trial in India.

BACKGROUND: Direct-to-beneficiary communication mobile programmes are among the few examples of digital health programmes to have scaled widely in low-resource settings. Yet, evidence on their impact at scale is limited. This study aims to assess whether exposure to mobile health information calls during pregnancy and postpartum improved infant feeding and family planning practices. METHODS: We conducted an individually randomised controlled trial in four districts of Madhya Pradesh, India. Study participants included Hindi speaking women 4-7 months pregnant (n=5095) with access to a mobile phone and their husbands (n=3842). Women were randomised to either an intervention group where they received up to 72 Kilkari messages or a control group where they received none. Intention-to-treat (ITT) and instrumental variable (IV) analyses are presented. RESULTS: An average of 65% of the 2695 women randomised to receive Kilkari listened to ≥50% of the cumulative content of calls answered. Kilkari was not observed to have a significant impact on the primary outcome of exclusive breast feeding (ITT, relative risk (RR): 1.04, 95% CI 0.88 to 1.23, p=0.64; IV, RR: 1.10, 95% CI 0.67 to 1.81, p=0.71). Across study arms, Kilkari was associated with a 3.7% higher use of modern reversible contraceptives (RR: 1.12, 95% CI 1.03 to 1.21, p=0.007), and a 2.0% lower proportion of men or women sterilised since the birth of the child (RR: 0.85, 95% CI 0.74 to 0.97, p=0.016). Higher reversible method use was driven by increases in condom use and greatest among those women exposed to Kilkari with any male child (9.9% increase), in the poorest socioeconomic strata (15.8% increase), and in disadvantaged castes (12.0% increase). Immunisation at 10 weeks was higher among the children of Kilkari listeners (2.8% higher; RR: 1.03, 95% CI 1.00 to 1.06, p=0.048). Significant differences were not observed for other maternal, newborn and child health outcomes assessed. CONCLUSION: Study findings provide evidence to date on the effectiveness of the largest mobile health messaging programme in the world. TRIAL REGISTRATION NUMBER: Trial registration clinicaltrials.gov; ID 90075552, NCT03576157.

Life histories of myeloproliferative neoplasms inferred from phylogenies.

Mutations in cancer-associated genes drive tumour outgrowth, but our knowledge of the timing of driver mutations and subsequent clonal dynamics is limited1-3. Here, using whole-genome sequencing of 1,013 clonal haematopoietic colonies from 12 patients with myeloproliferative neoplasms, we identified 580,133 somatic mutations to reconstruct haematopoietic phylogenies and determine clonal histories. Driver mutations were estimated to occur early in life, including the in utero period. JAK2V617F was estimated to have been acquired by 33 weeks of gestation to 10.8 years of age in 5 patients in whom JAK2V617F was the first event. DNMT3A mutations were acquired by 8 weeks of gestation to 7.6 years of age in 4 patients, and a PPM1D mutation was acquired by 5.8 years of age. Additional genomic events occurred before or following JAK2V617F acquisition and as independent clonal expansions. Sequential driver mutation acquisition was separated by decades across life, often outcompeting ancestral clones. The mean latency between JAK2V617F acquisition and diagnosis was 30 years (range 11-54 years). Estimated historical rates of clonal expansion varied substantially (3% to 190% per year), increased with additional driver mutations, and predicted latency to diagnosis. Our study suggests that early driver mutation acquisition and life-long growth and evolution underlie adult myeloproliferative neoplasms, raising opportunities for earlier intervention and a new model for cancer development.

Using behavioural design and theories of change to integrate communication solutions into health systems in India: evolution, evidence and learnings from practice.

Between 2011 and 2019, an integrated communication programme to address reproductive, maternal, neonatal and child health was implemented in the Indian state of Bihar. Along with mass media, community events and listening groups, four mobile health services were co-designed with the government of Bihar. These were Mobile Academy-a training course for frontline health workers (FLHWs) supporting them as the last mile of the health system; Mobile Kunji-a job aid to support FLHWs' interactions with families; Kilkari-a maternal messaging service delivering information directly to families' mobile phones, encouraging families to seek public health services through their FLHWs; and GupShup Potli-mobile audio stimulus used by FLHWs in community events. While Mobile Kunji and GupShup Potli scaled to other states (two and one, respectively), neither was adopted nationally. The Government of India adopted Kilkari and Mobile Academy and scaled to 12 additional states by 2019. In this article, we describe the programme's overarching person-centred theory of change, reflect on how the mHealth services supported integration with the health system and discuss implications for the role of health communication solutions in supporting families to navigate healthcare systems. Evaluations of Kunji, Academy and GupShup Potli were conducted in Bihar between 2013 and 2017. Between 2018-2020, an independent evaluation was conducted involving a randomised controlled trial for Kilkari in Madhya Pradesh; qualitative research on Kilkari and Academy and secondary analyses of call record data. While the findings from these evaluations are described elsewhere, this article collates key findings for all the services and offers implications for the role digital and non-digital communication solutions can play in supporting joined-up healthcare and improving health outcomes.

Ten lessons learnt: scaling and transitioning one of the largest mobile health communication programmes in the world to a national government.

There has been exponential growth in the numbers of 'digital development' programmes seeking to leverage technology to solve systemic challenges. However, despite promising results and a shift from pilots to scale-ups, many have failed to realise their full potential. This paper reflects on lessons learnt from scaling and transitioning one of the largest mobile health programmes in the world to the Indian government. The complementary suite of services was designed by BBC Media Action to strengthen families' reproductive, maternal, neonatal and child health behaviours. Mobile Academy was a training course to refresh frontline health workers' (FLHWs) knowledge and improve their interpersonal communication skills. Mobile Kunji was a job aid to support FLHWs' interactions with families. Kilkari delivered weekly audio information to families' phones to reinforce FLHWs' counselling. As of April 2019, when Mobile Academy and Kilkari were transitioned to the government, 206 000 FLHWs had graduated and Kilkari had reached 10 million subscribers. Lessons learnt include the following: (1) private sector business models are challenging in low-resource settings; (2) you may pilot 'apples' but scale 'oranges'; (3) trade-offs are required between ideal solution design and affordability; (4) programme components should be reassessed before scaling; (5) operational viability at scale is a prerequisite for sustainability; (6) consider the true cost of open-source software; (7) taking informed consent in low-resource settings is challenging; (8) big data offer promise, but social norms and SIM change constrain use; (9) successful government engagements require significant capacity; (10) define governance structures and roadmaps up front.