Immune therapies of B-cell acute lymphoblastic leukaemia in children and adults.

B-cell acute lymphoblastic leukaemia (B-cell ALL) is a common haematologic cancer in children and adults. About 10 percent of children and 50 percent of adults fail to achieve a histological complete remission or subsequently relapse despite current anti-leukaemia drug therapies and/or haematopoietic cell transplants. Several new immune therapies including monoclonal antibodies and chimeric antigen receptor (CAR)-T-cells are proved safe and effective in this setting. We review data on US Food and Drug Administration (FDA)-approved immune therapies for B-cell ALL in children and adults including blinatumomab, inotuzumab ozogamicin, tisagenlecleucel, and brexucabtagene autoleucel. We also summarize pharmaco-dynamics, pharmaco-kinetics, and pharmaco-economics of these interventions.

Thalassaemia in China.

Because of successful thalassaemia prevention programmes in resource-rich countries and it's huge population China now has the greatest number of new cases of thalassaemia globally as well as more people with thalassaemia than any other country. 30 million Chinese have thalassaemia-associated mutations and about 300,000 have thalassaemia major or intermedia requiring medical intervention. Over the past 2 decades there has been tremendous economic growth in China including per capita spending on health care. There is now nation-wide availability and partial or full insurance for prenatal genetic testing, RBC-transfusions, iron-chelating drugs and haematopoietic cell transplants. Prenatal screening and educational programmes have reduced the incidence of new cases. However, substantial challenges remain. For example, regional differences in access to medical care and unequal economic development require innovations to reduce the medical, financial and psychological burdens of Chinese with thalassaemia and their families. In this review we discuss success in preventing and treating thalassaemia in China highlighting remaining challenges. Our discussion has important implications for resource-poor geospaces challenged with preventing and treating thalassaemia.

Switching from salvage chemotherapy to immunotherapy in adult B-cell acute lymphoblastic leukemia.

About one-half of adults with acute B-cell lymphoblastic leukemia (B-ALL) who do not achieve molecular complete remission or who subsequently relapse are not cured by current chemo- or targeted therapies. Previously, the sole therapeutic option for such persons was a hematopoietic stem cell transplant. Recently, several immune therapies including monoclonal antibodies, bispecific T-cell engagers (BiTEs), antibody-drug conjugates (ADCs), and chimeric antigen receptor T-cells (CARs) have been shown safe and effective in this setting. In this manuscript, we summarize data on US FDA-approved immune therapies of advanced adult B-ALL including rituximab, blinatumomab, inotuzumab ozogamicin, tisagenlecleucel and brexucabtagene autoleucel. We consider the results of clinical trials focusing on efficacy, safety, and quality of life (QoL). Real-world evidence is presented as well. We also briefly discuss pharmacodynamics, pharmacokinetics, and pharmacoeconomics followed by risk-benefit analyses. Lastly, we present future directions of immune therapies for advanced B-ALL in adults.

Cost-Effectiveness of Post-Autotransplant Lenalidomide in Persons with Multiple Myeloma.

Considerable data indicate post-transplant lenalidomide prolongs progression-free survival and probably survival after an autotransplant for multiple myeloma (MM). However, optimal therapy duration is unknown, controversial and differs in the EU and US. We compared outcomes and cost-effectiveness of 3 post-transplant lenalidomide strategies in EU and US settings: (1) none; (2) until failure; and (3) 2-year fixed duration. We used a Markov decision model, which included six health states and informed by published data. The model estimated the lenalidomide strategy given to failure achieved 1.06 quality-adjusted life years (QALYs) at costs per QALY gained of €29,232 in the EU and $133,401 in the US settings. Two-year fixed-duration lenalidomide averted €7,286 per QALY gained in the EU setting and saved 0.84 QALYs at $60,835 per QALY gained in the US setting. These highly divergent costs per QALY in the EU and US settings resulted from significant differences in post-transplant lenalidomide costs and 2nd-line therapies driven by whether post-transplant failure was on or off-lenalidomide. In Monte Carlo simulation analyses which allowed us to account for the variability of inputs, 2-year fixedduration lenalidomide remained the preferred strategy for improving healthcare sustainability in the EU and US settings.

The paradox of haematopoietic cell transplant in Latin America.

Hematopoietic cells transplants are technically complex and expensive imposing a huge burden on health care systems, especially those in developing countries and regions. In 2017 > 4500 transplants were done in 13 Latin American countries with established transplant programmes. We interrogated data on transplant rate, cost, funding source, hospital type, Gini coefficient and the United Nations Development Programme Inequality-Adjusted Human Development Index to determine co-variates associated with transplant development. Transplant rates varied almost 30-fold between the 13 countries from 345 in Uruguay to 12 in Venezuela with a regional transplant rate 7-8-fold lower compared with the US and EU. We found significant correlations between higher transplant cost, public funding, transplants in private hospitals with transplant rate. Low cost per transplant regardless of payor and transplants done in public hospitals were associated with low transplant rates. In contrast, high cost per transplant funded by the government and transplants done in private hospitals were associated with high transplant rates. Surprisingly, we found transplant rates were higher when transplants cost more, when they were done in private for-profit hospitals and payed for with public funds. These data give insights how to increase transplant rates in Latin America and other developing regions.

Economics influences therapy decisions in chronic myeloid leukaemia: should it?

The question whether economic considerations should influence therapy decisions in persons with chronic myeloid leukaemia (CML) is complex touching on many metrics other than medicine including the perceptions, attitudes, and motivations of physicians, patients, their families, and payors', allocation of health care resources, and others. We discuss metrics whereby physicians, patients, and payors make CML therapy choices in settings where cost and availability are or are not considerations. We conclude that economic considerations strongly influence therapy decisions in CML. Whether this should be so and what impact it has on outcomes is also considered. Absent definitive data proving which therapy strategy is best allowing economic considerations to operate may not be as unreasonable or unethical as it appears. In some settings, it may be the best approach. However, because TKIs markedly prolong survival and may even cure some persons with CML, TKI therapy should be available to everyone with CML.

Higher out-of-pocket expenses for tyrosine kinase-inhibitor therapy is associated with worse health-related quality-of-life in persons with chronic myeloid leukemia.

PURPOSE: To explore health-related quality-of-life (HRQoL) profiles and identify socio-demographic and clinical variables associated with HRQoL in persons with chronic myeloid leukemia (CML) receiving tyrosine kinase inhibitors (TKIs). METHODS: A cross-sectional questionnaire was distributed to adults with chronic-phase CML receiving tyrosine kinase-inhibitor (TKI) therapy >3 months in complete cytogenetic response (CCyR). Respondents were anonymous. SF-36 Health Survey was used to measure HRQoL. RESULTS: Data from 828 respondents were analyzable. 524 (63%) were male. Median age was 42 years (range 18-88 years). 648 (78%) were receiving imatinib. Median TKI-therapy duration was 36 months (range 3-178 months). 638 (77%) paid some or all of their TKI costs. Annual out-of-pocket expenses >$4600 USD was associated with lower physical component summary (PCS; -2.8 to -3.8; P = 0.0081 and 0.0009) and mental component summary (MCS; -2.1 to -4.3; P = 0.0394 and 0.0080) in multivariate analyses. Other variables significantly associated with a lower PCS and/or MCS included: (1) female sex; (2) increasing age; (3) education level < bachelor degree; (4) co-morbidity(ies); and (5) generic drug use. TKI-therapy duration 3-5 years was associated with higher PCS and MCS. CONCLUSIONS: Higher out-of-pocket expense for TKI therapy is significantly associated with worse HRQoL in persons with chronic-phase CML in CCyR receiving TKI therapy. These data indicate the importance of drug cost and health insurance policies on people's HRQoL.

Young age and high cost are associated with future preference for stopping tyrosine kinase inhibitor therapy in Chinese with chronic myeloid leukemia.

PURPOSE: To explore therapy-goals and patients' expectations regarding discontinuing tyrosine kinase inhibitors (TKIs) therapy in Chinese with chronic myeloid leukemia (CML). To identify variables associated with these expectations and preferences. METHODS: Noninterventional, cross-sectional study using questionnaires distributed to persons with CML and answered anonymously. RESULTS: With CML in chronic phase, 888 respondents were evaluable. In total, 513 respondents (58 %) were male. Median age was 41 years (range 18-88 years). Median TKI therapy duration was 3 years (range <1-13 years). In total, 735 respondents (83 %) paid part or all of the cost of TKI. As their treatment goal, 430 of 888 respondents (48 %) reported treatment-free remission (TFR). In the future, 734 respondents (83 %) expected to discontinue TKI. Multivariate analyses confirmed younger age [HR = 1.3; (1.1, 1.4); P < 0.001] and higher out-of-pocket expense [HR = 1.2; (1.1, 1.4); P < 0.001] were associated with TFR as a therapy-goal. Both variables were also associated with patients' hope to stop TKI therapy in the future: HR = 1.4; (0.8, 1.7; P < 0.001) and HR = 1.5; (1.3, 1.8; P < 0.001). Achieving a complete molecular response [HR = 1.8 (1.1, 2.9); P = 0.017] and decreased quality of life resulting from adverse effects [HR = 1.2; (1.0, 1.5); P = 0.021] were factors associated with the expectation of discontinuing TKI therapy. CONCLUSIONS: Younger age and higher out-of-pocket cost are associated with patients' preference for stopping TKI therapy.

Frequencies of SF3B1, NOTCH1, MYD88, BIRC3 and IGHV mutations and TP53 disruptions in Chinese with chronic lymphocytic leukemia: disparities with Europeans.

We studied 307 consecutive Chinese with chronic lymphocytic leukemia (CLL) in diverse disease-stages before and after diverse therapies for mutations in several CLL-related genes. Mutation frequencies were SF3B1, 5%, NOTCH1, 8%, MYD88, 8%, BIRC3, 2%, TP53, 15% and IGHV, 60%. Several of these frequencies differ from those reported in persons of predominately European descent with CLL. Biological and clinical associations were detected including SF3B1 and NOTCH1 mutations with un-mutated IGHV, MYD88 mutations with mutated IGHV, SF3B1 mutations with fludarabine-resistant CLL and NOTCH1 mutation with advanced Binet disease stage and with +12. The NOTCH1 correlation with briefer survival was confirmed in multivariate analyses but the SF3B1 correlation was confounded by concurrent mutations in TP53 and germline IGHV. We show differences in incidence and prognostic impact of mutations in Chinese and CLL compared with persons of predominately European descent with CLL. These data may give insights into the etiology and biology of CLL and suggests different risk stratification models may be needed for different CLL populations.

Use of the Functional Assessment of Cancer Therapy--anemia in persons with myeloproliferative neoplasm-associated myelofibrosis and anemia.

BACKGROUND: Anemia is common in myeloproliferative neoplasm (MPN)-associated myelofibrosis. The Functional Assessment of Cancer Therapy (FACT) measurement system is a patient-reported outcomes instrument that documents symptoms of the diverse aspects of cancer treatment. One FACT version, FACT-Anemia (FACT-An), documents symptoms of anemia related to cancer. The FACT-An has been validated in diverse cancer populations, but not in MPN-associated myelofibrosis. OBJECTIVE: Our aim was to evaluate the relationship between anemia response to therapy with pomalidomide with or without corticosteroids and patient-reported outcomes using the FACT-An instrument. METHODS: Data were obtained from a Phase II, randomized, double-blind Bayesian pick-the-winner trial of prednisone and pomalidomide in patients with MPN-associated myelofibrosis and anemia (red blood cell-transfusion dependence). Details of the study, including definitions of anemia, anemia response, red blood cell-transfusion, red blood cell-transfusion dependence, and red blood cell-transfusion independence, are reported. Change in quality of life from randomization to the last cycle of therapy was evaluated using the FACT-An Physical Well Being, Functional Well Being, Trial Outcome Index, and Anemia domains. Clinically important differences were used to determine the smallest difference in scores that patients perceived as beneficial in the FACT-An domains of interest. Patients were classified as meeting clinically important differences for responsiveness if their change score from baseline was >1 SEM, indicating improvement. RESULTS: Eighty-five patients were studied. Thirty-one patients (37%) were classified as anemia responders by prospectively defined criteria. Across all FACT-An domains, anemia responders showed greater improvement in Physical Well Being, Functional Well Being, and Trial Outcome Index scores than did nonresponders. This improvement began at the second 28-day cycle of therapy and was sustained. CONCLUSIONS: We show a correlation between anemia response and improved quality of life measured by the FACT-An instrument in patients with MPN-associated myelofibrosis and anemia.

Role of reduced-intensity conditioning allogeneic hematopoietic stem-cell transplantation in older patients with de novo myelodysplastic syndromes: an international collaborative decision analysis.

PURPOSE: Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders that are more common in patients aged ≥ 60 years and are incurable with conventional therapies. Reduced-intensity conditioning (RIC) allogeneic hematopoietic stem-cell transplantation is potentially curative but has additional mortality risk. We evaluated RIC transplantation versus nontransplantation therapies in older patients with MDS stratified by International Prognostic Scoring System (IPSS) risk. PATIENTS AND METHODS: A Markov decision model with quality-of-life utility estimates for different MDS and transplantation states was assessed. Outcomes were life expectancy (LE) and quality-adjusted life expectancy (QALE). A total of 514 patients with de novo MDS aged 60 to 70 years were evaluated. Chronic myelomonocytic leukemia, isolated 5q- syndrome, unclassifiable, and therapy-related MDS were excluded. Transplantation using T-cell depletion or HLA-mismatched or umbilical cord donors was also excluded. RIC transplantation (n = 132) stratified by IPSS risk was compared with best supportive care for patients with nonanemic low/intermediate-1 IPSS (n = 123), hematopoietic growth factors for patients with anemic low/intermediate-1 IPSS (n = 94), and hypomethylating agents for patients with intermediate-2/high IPSS (n = 165). RESULTS: For patients with low/intermediate-1 IPSS MDS, RIC transplantation LE was 38 months versus 77 months with nontransplantation approaches. QALE and sensitivity analysis did not favor RIC transplantation across plausible utility estimates. For intermediate-2/high IPSS MDS, RIC transplantation LE was 36 months versus 28 months for nontransplantation therapies. QALE and sensitivity analysis favored RIC transplantation across plausible utility estimates. CONCLUSION: For patients with de novo MDS aged 60 to 70 years, favored treatments vary with IPSS risk. For low/intermediate-1 IPSS, nontransplantation approaches are preferred. For intermediate-2/high IPSS, RIC transplantation offers overall and quality-adjusted survival benefit.

A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome.

Bone marrow transplantation (BMT) can cure myelodysplastic syndrome (MDS), although transplantation carries significant risks of morbidity and mortality. Because the optimal timing of HLA-matched BMT for MDS is unknown, we constructed a Markov model to examine 3 transplantation strategies for newly diagnosed MDS: transplantation at diagnosis, transplantation at leukemic progression, and transplantation at an interval from diagnosis but prior to leukemic progression. Analyses using individual patient risk-assessment data from transplantation and nontransplantation registries were performed for all 4 International Prognostic Scoring System (IPSS) risk groups with adjustments for quality of life (QoL). For low and intermediate-1 IPSS groups, delayed transplantation maximized overall survival. Transplantation prior to leukemic transformation was associated with a greater number of life years than transplantation at the time of leukemic progression. In a cohort of patients under the age of 40 years, an even more marked survival advantage for delayed transplantation was noted. For intermediate-2 and high IPSS groups, transplantation at diagnosis maximized overall survival. No changes in the optimal transplantation strategies were noted when QoL adjustments were incorporated. For low- and intermediate-1-risk MDS, delayed BMT is associated with maximal life expectancy, whereas immediate transplantation for intermediate-2- and high-risk disease is associated with maximal life expectancy.