Researchers report significant breakthroughs in prevention and treatment for blood disorders affecting women and children
SAN DIEGO, Dec. 7, 2024 /PRNewswire/ — Emerging research findings presented during the 66th American Society of Hematology (ASH) Annual Meeting and Exposition highlight opportunities to improve health outcomes and quality of life for women and children. The studies point to new treatment approaches as well as early detection and prevention strategies that are poised to lower the burden of a range of blood disorders affecting women and children around the globe.
“These studies are practice-changing across multiple settings,” said Ariela Marshall, MD, hematologist and associate professor of medicine at the University of Minnesota Medical School in Minneapolis, who moderated the briefing Putting Women & Children First to Optimize Their Hematology Health. “The pediatric studies are practice-changing from a treatment perspective, and the women’s health studies point to opportunities to better use the treatments we already have. The next step is to bring these findings to our patients.”
Two studies present new therapeutic approaches for B-acute lymphoblastic leukemia (B-ALL), a cancer that disrupts the production of white blood cells known as B-lymphocytes and is among the most common types of cancer affecting children. Standard chemotherapies are highly effective against pediatric B-ALL, resulting in survival rates of about 85-90%. However, achieving lasting cancer eradication for the remaining 10-15% of patients has been challenging, leading researchers to seek alternative treatment options. The first study suggests that adding the immunotherapy blinatumomab to the first-line treatment regimen can help more children with B-ALL avoid a relapse. The second study points to opportunities to improve the efficacy of chimeric antigen receptor (CAR) T-cell therapy for children who do not see a lasting response from their initial treatment.
In a third study, researchers report promising results from the first use of the immune thrombocytopenia (ITP) drug eltrombopag in children with newly diagnosed ITP, suggesting the drug could be incorporated into first-line treatment for the condition.
The fourth study demonstrates how measures to address dangerous bleeding after childbirth (postpartum hemorrhage) can feasibly reduce maternal mortality in sub-Saharan Africa, a region with persistently high rates of maternal mortality, as well as make childbirth safer elsewhere in the world.
In the final study, researchers report that standardizing (and in many cases increasing) the ferritin threshold for defining iron deficiency in women is a cost-effective intervention that may help fill an important gap in women’s health care.
Adding Blinatumomab to First-Line Treatment for Pediatric B-ALL Substantially Improves Disease-Free Survival
1: Blinatumomab Added to Chemotherapy Improves Disease-Free Survival in Newly Diagnosed NCI Standard Risk Pediatric B-Acute Lymphoblastic Leukemia: Results from the Randomized Children’s Oncology Group Study AALL1731
Children with B-ALL who received blinatumomab along with standard chemotherapy were 61% less likely to die or experience a relapse at three years compared with children who received standard chemotherapy alone, according to a new study. Researchers say the results of the trial, which stopped early due to the high efficacy seen in the blinatumomab arm, suggest blinatumomab should be a standard first-line treatment for most children diagnosed with B-ALL.
“Adding blinatumomab was not only better, it was a home run,” said Rachel E. Rau, MD, the study’s co-lead author and associate professor of pediatrics at Seattle Children’s Hospital and the University of Washington, Seattle. “It led to improvements in outcomes beyond even our own expectations, and we saw that across the board in all of the patient subsets we looked at.”
Blinatumomab is a monoclonal antibody approved by the U.S. Food and Drug Administration (FDA) for treating certain types of B-ALL in some patient groups. It works by bringing healthy immune cells into close proximity of leukemia cells, prompting the immune system to attack and kill the cancer cells. This mechanism of action makes it a more targeted treatment than chemotherapies (which eradicate both healthy and cancerous cells), usually resulting in fewer side effects.
The trial was designed to randomize 2,245 patients, but results from a planned interim efficacy analysis conducted five years into the study prompted researchers to stop enrollment after randomizing 1,440 patients. Study participants were diagnosed with B-ALL between one and 10 years old. Patients with a known highly favorable risk profile were excluded from randomization and given standard chemotherapy. Of the patients whose cancers were considered to be of average or high risk, half were randomly assigned to receive two month-long cycles of blinatumomab in addition to standard chemotherapy, and half received standard chemotherapy alone.
At three years after randomization, 96% of participants who received blinatumomab were alive without experiencing any cancer recurrence (the study’s primary endpoint), compared with 87.9% among those who received chemotherapy alone. The superiority of blinatumomab was seen consistently in a variety of patient subgroups, including those with average versus higher-risk cancers, those with various tumor genetics, and participants of different genders and racial and ethnic backgrounds. “It’s almost like we’ve taken all the historically known prognostic factors and to an extent neutralized them with blinatumomab,” said Dr. Rau.
Participants with average-risk B-ALL saw three-year disease-free survival rates of 97.5% for those taking blinatumomab and 90.2% for those taking chemotherapy alone. Among those with high-risk B-ALL, these rates were 94.1% for participants taking blinatumomab and 84.8% for those taking chemotherapy alone.
Based on the findings, researchers said blinatumomab can be considered a new standard first-line therapy along with chemotherapy for all children with B-ALL except those with the most favorable risk profile. This new standard would apply to approximately two-thirds of children diagnosed with B-ALL each year.
Overall, researchers said that the side effects experienced with blinatumomab are generally milder and far less common than those of chemotherapy. The results showed that blinatumomab was well tolerated, with very low rates of cytokine release syndrome and seizures, the agent’s most serious known side effects.
Researchers noted that blinatumomab treatment can be logistically burdensome for families, underscoring the importance of access to care if it becomes a standard treatment going forward. Because the agent must be continuously infused, patients must wear a backpack throughout each month-long infusion cycle and families must replace the infusion bags every few days. In addition, blinatumomab is significantly more expensive than standard chemotherapies. These factors can create challenges for families, especially for those in rural and historically marginalized communities.
“This is a game-changing result that we are all incredibly excited about, but it does families no good if they can’t access the intervention,” said Dr. Rau. “It is incumbent on us to not just recognize and celebrate these results but to make sure that every family that can benefit from these results actually does and doesn’t lack the opportunity because of barriers like cost or distance.”
The researchers will continue to follow participants to assess differences in relapse rates over the longer term. In addition, they are looking into blinatumomab’s effects on healthy B-cells to determine whether the agent may reduce immunity or affect vaccine efficacy, and for how long.
Moving forward, researchers say it would be helpful to study whether blinatumomab or other immunotherapies might potentially replace, rather than only adding to, some elements of the standard chemotherapy regimen for B-ALL.
This study was funded by the National Cancer Institute.
Rachel E. Rau, MD, of Seattle Children’s Hospital and the University of Washington, Seattle, will present this study during a plenary session on Sunday, December 8, 2024, at 2:00 p.m. Pacific time in Hall B in the San Diego Convention Center.
Dual-Target CAR-T Therapy Found Effective for Children with B-ALL
681: Safety and Efficacy of Bicistronic CD19/CD22 CAR T Cell Therapy in Childhood B Cell Acute Lymphoblastic Leukemia
Researchers report that a new chimeric antigen receptor (CAR) T-cell therapy that combines two cancer-targeting receptors in the same cell manufacturing process was safe and effective for children with B-cell acute lymphoblastic leukemia (B-ALL). Based on the outcomes from the investigator-initiated study, the researchers have now launched a phase I clinical trial in hopes of moving the new therapy toward broader implementation.
The dual-target therapy equips a patient’s immune cells to simultaneously target two receptors, CD19 and CD22, that are found on most cancer cells in B-ALL. Study participants showed high overall and event-free survival rates at 12 months, although all participants also experienced cytokine release syndrome (CRS), a common side effect of CAR-T therapy.
“We found that this is a safe and effective regimen, which achieved a durable remission in children with relapsed or refractory B-ALL,” said the study’s lead author, Hua Zhang, MD, PhD, chief scientific officer at SPH Biotherapeutics (Hong Kong) Limited. “We also found in the early-stage clinical study that reducing disease burden was the key to controlling the severity of CRS.”
B-ALL is one of the most common types of cancer affecting children. It disrupts the production of B cells, a type of white blood cells critical to immune system functioning. While chemotherapy eradicates the cancer for about 85-90% of patients, some children do not experience lasting remission and require additional therapeutic options such as a bone marrow transplant or immunotherapy.
CAR T-cell therapy is a type of immunotherapy in which a patient’s T cells are removed, genetically altered, and infused back into the body to attack and kill cancer cells. The genetic alterations used to produce CAR T cells help them recognize specific features – in this case, the CD19 and CD22 proteins – on the surface of cancer cells.
In previous studies, Dr. Zhang and his team found that producing CD19 and CD22 CAR T cells in separate manufacturing processes and co-infusing them into patients showed favorable clinical results compared with infusing CD19 CAR T cells alone. However, the different CAR T cells had different expansion dynamics and often demonstrated imbalanced persistence after infusion, potentially leading to inconsistent benefits for patients. For the new work, the team developed a method to produce CAR T cells that simultaneously express receptors for CD19 and CD22.
“Making two products separately and then mixing them together is cumbersome and costly,” said Dr. Zhang. “We aimed to have one vector carrying two different CARs and to make them express equally, simplifying our product development and manufacturing.”
Researchers administered the dual-target therapy to 343 children with B-ALL who had experienced a recurrence of cancer after their initial treatment (relapse) or had not seen their cancer eradicated with previous therapies (refractory). Almost all patients (99.1%) responded to the treatment, achieving negative minimal residual disease and either complete remission or complete remission with incomplete counts. At 12 months after infusion, 93.5% of participants were alive (overall survival) and 75.5% were alive without experiencing a disease recurrence or new cancer (event-free survival), the study’s two primary endpoints.
B-ALL relapse can occur in the bone marrow or in other tissues. The overall survival and event-free survival rates were similar among the 292 study participants who had experienced relapse in the bone marrow (with or without relapse in the central nervous system or testes) and the remaining 51 participants who had experienced a relapse in tissues other than the bone marrow (most commonly central nervous system or testes). A subset of 38 patients with relapse in the bone marrow subsequently went on to receive a bone marrow transplant after their CAR-T therapy; these patients had slightly higher event-free survival but no significant difference in overall survival.
About half of the patients experienced CRS of grade 3-4 and two patients died as a result of this reaction. The other half of the patients experienced milder forms of CRS. About one in six participants experienced some effects on the brain, including tremors or seizures; in 95% of these cases, the issues resolved without intervention while a few participants required medications to control seizures. These side effects are similar to what has been seen in other trials of mixed use of CD19 and CD22 CAR-T therapies, according to the researchers.
This study is an early look at this dual-target approach, researchers said. In addition to conducting a phase I clinical trial, the researchers are investigating whether the dual-target CAR-T therapy can help to improve response and survival rates for hard-to-treat lymphomas in adults.
The trial was funded by SPH Biotherapeutics (Hong Kong) Limited, maker of the bicistronic CD19/CD22 CAR T-cell therapy used in the study.
Hua Zhang, MD, PhD, of SPH Biotherapeutics (Hong Kong) Limited, will present this study during an oral presentation on Sunday, December 8, 2024, at 5:00 p.m. Pacific time in Marriott Grand Ballrooms 2 – 4 in the Marriott Marquis San Diego Marina.
Eltrombopag Outperforms Standard First-Line Therapies in Children with Newly Diagnosed Immune Thrombocytopenia
709: Efficacy Findings in a Phase 3, Randomized Trial of Eltrombopag Vs. Standard First-Line Treatment for Newly Diagnosed Immune Thrombocytopenia in Children
Children newly diagnosed with the rare blood disorder ITP were significantly more likely to experience sustained improved platelet counts if they took eltrombopag rather than standard first-line therapies, according to results from a planned interim analysis of a clinical trial. Investigators stopped the trial early due to high efficacy of eltrombopag, which is currently used only for chronic ITP and has not previously been tested as a first-line therapy for pediatric ITP.
“This is the first time in 30 years that a new drug is being tested for newly diagnosed pediatric ITP,” said the study’s lead author, Kristin A. Shimano, MD, professor of pediatrics at the University of California, San Francisco Benioff Children’s Hospital. “Patients who received eltrombopag during the first three months of their ITP diagnosis had a more sustained platelet response than patients who were treated with standard therapies. That means during this time period, kids taking eltrombopag were also likely to have a lower risk of having bleeding events.”
ITP is an autoimmune disorder that affects platelets, a component of blood that supports clotting. Having low platelet counts can cause bruising and uncontrolled bleeding, making even minor scrapes and falls potentially dangerous. In children, ITP is often triggered by a viral infection and frequently resolves on its own, although it can also become chronic. Several medications are available to increase platelet counts in children with newly diagnosed ITP, but their effects are temporary, necessitating careful monitoring and often requiring multiple courses of treatment.
The FDA approved eltrombopag, which stimulates the bone marrow to increase platelet production, for use in adults and children with chronic ITP in 2015. In 2019, researchers in the ITP Consortium of North America launched the new trial to test the drug as a first-line treatment for pediatric ITP, enrolling 118 patients at 23 medical centers. All participants had been diagnosed with ITP less than three months before enrolling in the trial and required pharmacologic treatment in the opinion of their treating hematologist. About 40% had not yet taken any medications for ITP before enrolling. The other 60% had taken at least one medication but not seen a lasting benefit; these participants were not given the same medication again once they joined the study.
Two-thirds of participants were randomly assigned to receive eltrombopag and one-third received standard care. For the standard care arm, each patient’s treating physician prescribed corticosteroids, intravenous immunoglobulin, or anti-D globulin at their discretion following dosing guidelines aligned with study protocols.
The trial’s primary endpoint was a sustained platelet response at 12 weeks, defined as having three or four platelet counts higher than 50 x 109/L during weeks 6-12 without any additional treatment. Sixty-three percent of participants receiving eltrombopag achieved this endpoint compared with 35% of participants receiving standard care. This difference was large enough that investigators stopped trial enrollment early.
Participants in both groups experienced improvements in health-related quality of life, and rates of bleeding events were comparable in both study arms. One patient in the eltrombopag arm experienced bleeding in the brain. Overall, researchers concluded that the safety profile was comparable between the two study arms.
To mimic real-world conditions as much as possible, physicians were able to prescribe treatments other than those patients were assigned to receive if they determined that additional treatment would be appropriate in light of events such as falling platelet counts, active bleeding, or planned surgeries. The rate of such “rescue therapy” was significantly lower in the eltrombopag arm (18%) compared with patients receiving standard care (38%).
“Eltrombopag could certainly be added to the medication choices hematologists consider as they are making treatment decisions with families, and it is an option that could potentially raise platelets for a more sustained period in children with ITP in the newly diagnosed period, which is one of the most difficult times for patients with regard to the impact of the disease on bleeding symptoms and quality of life,” said Dr. Shimano.
Researchers noted that eltrombopag works more slowly than some other treatments and is, therefore, not intended for patients with severe bleeding. Although the study stopped enrolling new patients, researchers will continue to follow participants for a total of 12 months to assess the durability of the response and any differences in quality of life, bleeding events, or effects on the development of chronic ITP.
This study was funded by Novartis, maker of eltrombopag, and sponsored by the ITP Consortium of North America.
Kristin A. Shimano, MD, of the University of California, San Francisco Benioff Children’s Hospital, will present this study’s findings during an oral presentation on Monday, December 9, 2024, at 10:30 a.m. Pacific time in Room 29 in the San Diego Convention Center.
Proactive Measures Reduce Maternal Mortality and Postpartum Hemorrhage in Sub-Saharan Africa
796: Post-Partum Hemorrhage in Sub-Saharan Africa: A Prospective, Multi- Faceted Intervention Study in Metropolitan Mozambique
A multifaceted intervention substantially reduced deaths and medical emergencies related to excessive bleeding after childbirth, known as postpartum hemorrhage (PPH), in a study involving over 16,000 women in Mozambique. The study, which is the first large, prospective observational study to test interventions aimed at reducing PPH in sub-Saharan Africa, found that the rate of maternal mortality dropped by about half and the rate of PPH was reduced by approximately two-thirds after the interventions were implemented.
The findings showed that taking steps to increase education and standardization around the use of blood transfusions and other established treatments for PPH can be effective and feasible even in under-resourced environments, according to researchers.
“It’s such low-hanging fruit,” said the study’s principal investigator, Annette von Drygalski, MD, PharmD, professor of clinical medicine and director of the Center for Bleeding and Clotting Disorders and at the University of California, San Diego. “These are smaller but important interventions, which really made a difference when implemented in combination and with significant involvement from hematologists in close collaboration with the obstetrics and transfusion services teams. Mortality is down dramatically, and so is postpartum hemorrhage.”
The study findings also add to the evidence that prenatal iron deficiency is a key contributor to PPH, pointing to a potential opportunity to intervene earlier by providing iron supplements to pregnant women with anemia, a common condition in sub-Saharan Africa where many women do not get sufficient iron from their diet.
Rates of maternal mortality in sub-Saharan Africa are 15-200 times higher than those in developed countries. PPH is a major contributor to maternal deaths following childbirth in the region, though it is largely preventable and treatable. Based on experience working in the region, researchers said that a lack of awareness of PPH prevention and treatment strategies among clinicians has been a significant factor.
To address this gap, researchers designed a multifaceted intervention bringing together experts in hematology, obstetrics and gynecology (OB/GYN), and transfusion medicine to provide clinician education and training, establish and disseminate a standardized PPH care protocol and single-use hemorrhage response kits, increase local capacity for producing cryoprecipitate (a blood product effective in treating PPH), and administer blood transfusions earlier in PPH treatment. They implemented these interventions at a major university hospital in Mozambique’s capital city.
Comparing outcomes among about 8,800 women who gave birth at the hospital before the intervention with about 7,600 women who gave birth after it was implemented, researchers found that maternal mortality decreased from 1.10% to 0.55% and the incidence of PPH dropped from 14% to 4.65%. Infant mortality also decreased somewhat, from 3.44% to 2.58%.
The researchers also analyzed data from a subset of about 2,000 women who had their blood drawn for laboratory evaluations because they were deemed to be in distress. These results revealed that anemia (insufficient red blood cells or decreased oxygen-carrying capacity of red blood cells) and thrombocytopenia (low levels of platelets) were strongly linked with an increased risk of PPH. Other risk factors included eclampsia or pre-eclampsia, having more than four pregnancies, pre-term delivery, and maternal age less than 20 or over 35. Researchers noted that women from rural areas outside the capital city, who comprised about half of study participants, also tended to have a higher prevalence of risk factors and worse outcomes, likely reflecting gaps in access to prenatal care in rural regions.
While the study findings underscore the serious challenges that remain in improving maternal care, researchers said they also offer hope that many lives can be saved with greater awareness of PPH and interventions that are practical to implement almost anywhere. “I hope this work will create more awareness about PPH and how the field of hematology could get involved in a multidisciplinary effort in partnership with OB/GYN and transfusion medicine to address these issues around anemia and bleeding,” said Dr. von Drygalski. “We have lots of work to do, even here in the United States.”
The study was limited to a single medical center in one country, but researchers said that the context and feasibility of the intervention would likely be similar across all of sub-Saharan Africa. Dr. von Drygalski added that the fundamental premise of the study – that greater attention to PPH treatment can make childbirth significantly safer for women – also applies to developed countries where PPH still accounts for a sizeable portion of maternal mortality.
This study was funded by the Stadema Foundation, Munich, Germany, the Health Resources and Services Administration, and discretionary funding from UC San Diego.
Annette von Drygalski, MD, PharmD, of the Center for Bleeding and Clotting Disorders and the University of California, San Diego, will present this study during an oral presentation on Monday, December 9, 2024, at 11:15 a.m. Pacific time in Room 6B in the San Diego Convention Center.
Universal Screening for Iron Deficiency Would Be Cost Effective and Improve Quality of Life for Many
277: Sex, Lies, and Iron Deficiency in 2024: Cost-Effectiveness of Screening Ferritin Thresholds for the Treatment of Iron Deficiency in Women of Reproductive Age
Screening women for iron deficiency using routine blood tests would be a cost-effective strategy to close the gap on this highly prevalent yet underdiagnosed and undertreated health condition, according to a new study. Using epidemiologically informed quantitative models, the researchers estimated that implementing ferritin (iron) screening with a standard cutoff of 25 µg/L for diagnosing iron deficiency would cost just $100 per quality-adjusted life-year, a value proposition better than many health screens that are currently widely used in the United States, such as colonoscopies and mammograms.
“We wanted to use decision science methods to get at the question of what could be an appropriate threshold for ferritin – a biomarker for total body iron stores – for diagnosing and treating iron deficiency in this country, specifically from the perspective of payers in the U.S. health care system,” said the study’s lead author, Daniel Wang, a medical student at the Yale School of Medicine, in New Haven, Connecticut. “Our models show that setting this threshold at 25 µg/L would improve the quality of life for numerous individuals and do it for cents on the dollar. The incremental cost-effectiveness ratio of this strategy compared to no screening is well below all accepted willingness-to-pay thresholds in the U.S.”
Iron deficiency is the most common micronutrient deficiency worldwide and is estimated to affect as many as one in three U.S. adults. People who menstruate are disproportionately affected because of their monthly blood losses, but the condition goes undetected in many women and adolescent girls. In addition to a lack of routine screening, a lack of standardization among clinical laboratories that carry out ferritin testing has led to inconsistencies in diagnosing iron deficiency even when screening does occur.
While the Centers for Disease Control and Prevention and the World Health Organization currently set the threshold for diagnosing iron deficiency at ferritin levels below 15 µg/L, studies in both animal models and human populations suggest a cutoff of 25 or even up to 50 µg/L might be more appropriate.
“The current reference ranges we have for ferritin are outdated and come from a biased sample; a majority of hematologists agree that the current threshold is far too low,” said Wang. “We need to recognize that this is an issue for all persons with the capacity to menstruate, and we need to raise the bar on determining the proper cutoff and effectively disseminate that information to care providers and labs.”
Iron is essential for blood to carry oxygen throughout the body and must be continuously replenished through the foods we eat. Common symptoms of iron deficiency include fatigue, headaches, dizziness, cognitive fog, and poor sleep quality. If left untreated, it can lead to anemia and exacerbate other health conditions such as heart or lung disease. Taking iron supplements, either in the form of tablets or intravenous infusions, can rapidly reverse these symptoms and help patients avoid more serious complications.
Researchers built quantitative decision models informed by real-world epidemiologic and clinical data, with extensive input from leading clinical experts, to estimate cost and quality of life impacts of ferritin-based screening for iron deficiency among U.S. women from age 18 until menopause under three scenarios: no routine screening (the current status quo), routine screening with a threshold of 15 µg/L, and routine screening with a threshold of 25 µg/L. The models accounted for health care costs associated with both screening and treatment, the estimated prevalence of iron deficiency in the U.S., and the likelihood and severity of iron-related adverse events.
To compare the scenarios, researchers calculated a standard metric called the incremental cost-effectiveness ratio, which accounts for both the cost of a health intervention and the improvements in quality of life that would be expected to result from it. The models estimated this ratio at $100 per quality-adjusted life-year for routine ferritin screening with a threshold of 25 µg/L and treatment with oral iron supplementation compared with the current status quo. This is far below the typical threshold health care decision makers use to determine when an intervention is worth paying for in the U.S., which typically ranges from $50,000–$150,000 per quality adjusted life-year. The strategy remains cost effective in a separate scenario that assumed all patients are treated with intravenous iron instead of oral iron supplements.
“Essentially, this suggests that when making decisions about iron deficiency screening and treatment, you don’t need to worry about the cost aspect – you can just look at the clinical risk-benefit on its own,” said Wang. He added that iron supplementation is a well-established treatment that typically brings clear benefits for people with iron deficiency while carrying a very low risk of side effects.
The researchers noted that studies based on such modeling carry inherent limitations, and the cost-effectiveness of implementation may further vary. They also added that further studies of iron deficiency and its treatments in specific subgroups such as pregnant individuals or those with particularly heavy menstrual bleeding could help to further refine strategies for iron deficiency diagnosis and treatment. The research team next plans to investigate the cost-effectiveness of iron deficiency screening in a global context.
This research was a collaborative effort led by the Goshua Lab at the Yale School of Medicine. The lab is supported by the National Heart, Lung, and Blood Institute, the Frederick A. DeLuca Foundation, the NOMIS Foundation and Yale Cancer Center.
Daniel Wang, of the Yale School of Medicine, will present this study during an oral presentation on Saturday, December 7, 2024, at 2:00 p.m. Pacific time in Marriott Grand Ballrooms 2-4 in the Marriott Marquis San Diego Marina.
About the American Society of Hematology
The American Society of Hematology (ASH) (hematology.org) is the world’s largest professional society of hematologists dedicated to furthering the understanding, diagnosis, treatment, and prevention of disorders affecting the blood. Since 1958, the Society has led the development of hematology as a discipline by promoting research, patient care, education, training, and advocacy in hematology.
The Blood journals (https://ashpublications.org/journals) are the premier source for basic, translational, and clinical hematological research. The Blood journals publish more peer-reviewed hematology research than any other academic journals worldwide.
SOURCE American Society of Hematology
