Understanding Acute Lymphoblastic Leukaemia

ALL is a type of cancer that predominantly affects the white blood cells and progresses rapidly, making early diagnosis and immediate treatment crucial. According to the American Cancer Society, about 6,550 cases are diagnosed annually in the United States alone, with higher incidence rates reported in children. Symptoms are often nonspecific and include fever, fatigue, and bruising, necessitating specialised diagnostic techniques for confirmation.

Diagnostic Approaches

In HICs, ALL diagnosis is typically confirmed through blood tests, bone marrow biopsies, and sophisticated imaging technologies. Genetic testing is critical in diagnosing and determining the specific subtype of ALL, which can guide targeted treatment approaches. Dr Jane Hollingsworth, a haematologist at Johns Hopkins University, states, “Genetic profiling has revolutionised our understanding of ALL, enabling personalised treatment plans that significantly improve outcomes.”

Conversely, in many LMICs, such basic diagnostic facilities are not readily available. The World Health Organization (WHO) reports that access to essential diagnostic services, such as complete blood count tests, in some African countries is limited, leading to delayed or inaccurate diagnoses. Dr Abasi Ene-Obong, a clinician in Nigeria, comments, “In regions like ours, the lack of infrastructure means that many leukaemia patients are diagnosed at an advanced stage, where treatment options are limited and less effective.”

“The survival gap between HIC[s] and LMIC[s] (>80% compared to ❤0%) is one of the most profound health inequities across different communicable diseases and NCDs,” according to the WHO Global Initiative for Childhood Cancer (GICC), CureAll Framework

Treatment Protocols and Access to Care

Treatment for ALL typically includes chemotherapy, which can be tailored to the genetic features of the leukaemia cells in HICs. More advanced options, such as immunotherapy and stem cell transplants, are also available, leading to improved survival rates. In the United States, the five-year survival rate for children with ALL has increased to 88.5%.

However, the scenario in LMICs is starkly different. “The availability of chemotherapy drugs can be sporadic, and advanced treatments like bone marrow transplants are often not feasible due to cost constraints,” explains Dr. Ene-Obong. The lack of healthcare infrastructure and trained medical professionals complicates the treatment landscape.

Outcome Disparities

These diagnostic and treatment disparities directly impact patient outcomes. Data from the GICC CureAll Framework indicate that the survival rates for ALL in many LMICs are below 30%, a stark contrast to those in HICs. The socio-economic factors, including poverty and lack of health insurance, exacerbate these outcomes, limiting access to care and continuity of treatment.

Innovative Solutions and Global Initiatives

Addressing these disparities requires innovative solutions and robust global initiatives. Research into more affordable, generic chemotherapy drugs and more straightforward diagnostic tests could make a significant difference.

Pharmaceutical interventions by the companies

By prioritising the development of cost-effective treatments and facilitating more affordable pricing models, pharmaceutical companies can enhance access to essential medicines in underserved regions. Investing in local healthcare infrastructure and training, collaborating with global health organisations, and participating in patent pools or licensing agreements to allow generic manufacturing could dramatically improve treatment accessibility. Engaging in these initiatives aligns with ethical business practices and expands market reach, potentially leading to sustained corporate growth and a stronger global presence in the fight against leukaemia.

Strategies that include task shifting, improving the quality of medicines, and innovative healthcare service delivery routes could make a significant difference. For example, the Observer Research Foundation recently discovered innovation; in South Africa, the Central Chronic Medication Dispensing and Distribution (CCMDD/Dablapmeds) program has significantly improved access to chronic medication for stable patients by allowing them to collect their medication from external contracted pick-up points or fast lanes at public facilities using an SMS code, patients can save time and transport costs.

International efforts and skills sharing

A twinning programme is an innovative approach to enhancing child cancer care by fostering collaboration between hospitals in high-income countries (HICs) and those in low- and middle-income countries (LMICs). These “Twin Centers” are designed to share expertise, resources, and medical practices to improve childhood cancer diagnosis, treatment, and overall management. The programme includes setting up registries, employing data managers to monitor and optimise care, and developing educational tools for nurses to enhance local capacities. This strategic partnership not only aims to transfer knowledge and medical practices but also addresses critical gaps in resources and expertise that often exist in LMIC settings, thereby improving patient outcomes and building sustainable healthcare infrastructures.

A collaborative initiative between St. Jude Global and the World Health Organization (WHO) aims to enhance global access to essential, life-saving cancer treatments for children. This effort responds to widespread challenges in securing safe and effective medications, as underscored by the fact that 71% of low-income countries experience significant shortages in cancer medicines. These shortages stem from inconsistent availability due to supply and demand fluctuations and complex regulatory environments. Additionally, the pursuit of the lowest-cost medications can compromise quality, further endangering patient safety. Financially, the exclusion of pediatric cancer medications from national healthcare budgets frequently imposes severe economic strains on families in low- and middle-income countries. This initiative was bolstered by a resolution for improved access to essential medicines, adopted at the 70th World Health Assembly, highlighting a global commitment to overcoming these barriers in cancer care.

Conclusion

The striking difference in ALL outcomes between HICs and LMICs emphasises the critical importance of developing and implementing a global strategy to promote healthcare equity. Dr. Hollingsworth aptly states, “We need a collective commitment to not only develop medical technologies but also ensure they are accessible where they are most needed.” By working together to bridge this gap, we can save countless lives and make significant progress towards achieving the broader sustainable development goals of health and well-being for all. Addressing the disparities in ALL diagnoses and treatments is a moral imperative and a crucial step in building a more equitable and sustainable future for all.

References

• World Health Organization (2021). Global Initiative for Childhood Cancer (GICC).
• American Cancer Society (2024). Key Statistics for Acute Lymphocytic Leukemia (ALL).
• Leukemia & Lymphoma Society. (2023). Facts and Statistics.
• Observer Research Foundation (2024). Health Equity and Inclusion in Action.
• St. Jude Global (2024): Global Platform for Access to Childhood Cancer Medicines.

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I am sad to report that the medical community lost a compassionate and visionary leader with the passing of Dr. Susan Love. The cause was a leukemia recurrence, according to Allie Cormier, the chief marketing officer at the Dr. Susan Love Foundation for Breast Cancer Research.

I am grateful to have known her. Here is a picture of us from several years ago:

Patient-Centered Care

Dr. Love’s tireless efforts, empathy, and dedication to women’s health have left an indelible mark on the field of medicine, transforming the lives of countless individuals and inspiring future generations.

My tribute seeks to celebrate her remarkable contributions and honor her enduring legacy.

First, I want to share her words from Dr. Susan Love’s Breast Book:

“When I was in medical school, I embarrassed myself horribly when I found a ‘lump’ in my breast and frantically ran to one of the older doctors to find out if I had cancer. I found out I had a rib.”

A Passion for Patient-Centered Care

Dr. Love was a staunch advocate for patient-centered care, recognizing that each person’s journey through illness is unique and deeply personal.

She emphasized the importance of understanding patients’ experiences, concerns, and desires, empowering them to participate in their healthcare management decisions actively.

Dr. Love’s groundbreaking work laid the foundation for a paradigm shift towards personalized medicine, ultimately improving breast cancer patients’ outcomes and quality of life worldwide.

The Revolution of Her Research Foundation

In 1990, Dr. Love founded the Dr. Susan Love Research Foundation, a groundbreaking organization dedicated to eradicating breast cancer through innovative research, education, and advocacy.

The foundation pioneered novel approaches to breast cancer research, emphasizing collaboration, data sharing, and patient engagement.

Dr. Love’s vision of creating a global network of scientists, patients, and advocates fueled the transformation of breast cancer research into a collaborative effort.

Her foundation was pivotal in accelerating scientific discoveries, fostering breakthroughs, and bringing us closer to a world without breast cancer.

Revitalizing Breast Cancer Screening and Prevention

Dr. Love’s work challenged traditional breast cancer screening and prevention notions. She recognized the limitations of mammography and the urgent need for more effective methods.

Her research focused on understanding the underlying causes of breast cancer, exploring risk factors, and developing innovative screening techniques. Dr. Love’s commitment to prevention led her to advocate for increased awareness of environmental factors, lifestyle modifications, and genetic testing.

Love’s holistic approach redefined the field, shaping a new era of prevention strategies tailored to individual needs.

Empowering Women Through Education & Support

Beyond her groundbreaking research, Dr. Love dedicated herself to educating and supporting women affected by breast cancer.

She authored the bestselling book “Dr. Susan Love’s Breast Book,” a comprehensive guide that demystified the disease, empowered patients, and provided them with the knowledge necessary to make informed decisions.

Her writing inspired me to write books for individuals with cancer.

Dr. Michael Hunter’s Breast Cancer Book

www.amazon.com

Dr. Love’s genuine concern for women’s well-being resonated with countless individuals facing breast cancer, offering them hope, comfort, and a sense of empowerment.

Legacy of Collaboration and Inspiration

Dr. Susan Love’s legacy extends far beyond her research and advocacy. She was a bridge-builder, fostering collaboration among researchers, clinicians, patients, and advocates worldwide.

Her belief in the power of collective effort and knowledge-sharing revolutionized the approach to breast cancer research. Dr. Love’s infectious enthusiasm, empathy, and ability to inspire others led to a new generation of researchers and advocates who continue to carry her torch.

Her unwavering dedication to making a difference in the lives of women affected by breast cancer inspired countless individuals to join the fight against this devastating disease.

Through her compassion, determination, and unwavering belief in collaboration, she reshaped the landscape of breast cancer treatment and prevention.

Dr. Love will continue to inspire me, reminding me of the importance of empathy, empowerment, and the relentless pursuit of progress.

The post Dr. Susan Love: A Legacy of Empathy and Empowerment in Medicine appeared first on Medika Life.

Using the body’s own immune cells as anticancer agents has long been part of this dream. I was an early pioneer in creating one of the first proven cell therapies using dendritic macrophages to treat prostate cancer. Today, immune cell therapy offers hope to people with cancer and other previously untreatable diseases.

This series will explain a recent and revolutionary cell therapy called CAR T, delving into current successes and future opportunities.

The “T’ of CAR “T” 

CAR T is short for Chimeric Antigen Receptor T cells. Essential to understanding this therapy is an understanding of T cells and cell-mediated immunity.

Adaptive Immunity 

Adaptive immunity allows humans to form a tailored defense to foreign invaders. Adaptive immune cells memorize the telltale signs of enemies and trigger defensive mechanisms if the signs are detected in the future. This branch of immunity concerts two separate arms—humoral immunity driven by antibody-producing B cells, and cell-mediated immunity driven by “helper” T cells and “killer” T cells.

CAR T technology alters the typical functioning of cytotoxic cells. Instead of indirectly aiding antiviral processes as CD4+ helper T cells do, CAR T borrows the cytotoxic power of CD8+ killer T cells to destroy infected or abnormal host cells, thus transforming into a “living drug.” A typical cytotoxic T cell eliminates threats using the following process:

WIKIPEDIA Link Added

The process (as illustrated in Figure 1) begins with the differentiation of an inactive T cell—in essence, any T cell without a specified purpose. As if waiting for the right key, a T cell does not activate unless it encounters an antigen presenting cell (APC) with its corresponding antigen. In order for an interaction between the two cells to occur, several steps must occur.

Firstly, the antigen presenting cell must process the antigen, the enemy components, into smaller peptides. Then, these peptides must be carried to the antigen presenting cell’s surface by major histocompatibility complexes (MHC). Immature CD8+ T cells require MHC Class I molecules to facilitate this translocation. Around this time, a secondary signal such as CD80 or CD86 must also be received by the T cell. In the final step, the antigen presenting cell releases a protein signal called CD40 and cooperates with helper T cells to finalize the differentiation process.

How Killer T Cells Kill 

DANANGUYEN DERIVATIVE: NAGUALDESIGN

Killer T cells destroy infected and abnormal cells by inducing apoptosis, a form of controlled cell death which does not spark inflammation. Pockets of enzyme within the T cell must make contact with the target cell to trigger its death.

When a cytotoxic T cell recognizes its target, it binds to the class I MHC molecule on the surface of the target cell (see Figure 3) to create a bridge. With the bridge completed, the T cell can then release the enzymes. One enzyme drills pores in the target cell’s membrane, thus ruining its integrity. The other travels through these newly made tunnels, tipping an enzyme cascade inside the target cell which accelerates its degradation.

The crumbling target cell mimics the imagery of bricks falling from castle walls. Nearby phagocytes recognize the “crash of bricks”—more accurately, sense a change in membrane—and begin ingesting the target cell. The target cell breaks down to nothing inside the phagocyte without stimulating inflammation or other side effects.

Construction of a Chimeric Antigen Receptor 

Killer T cells are clearly useful in clearing irregular host cells. Researchers recognized this and sought to harness this natural design to eliminate cancer cells through CAR T. Chimeric antigen receptors are engineered to detect a specific antigen and trigger the destruction of a target cell. The most basic CAR T design accomplishes this by manipulating antigen binding sites normally intrinsic to antibodies—single chain variable fragments (scFV)—to lend cytotoxic T cells higher antigen specificity. The CAR T cell recognizes specific antigens thanks to this domain.

Next comes the flexible hinge region. This region simultaneously stabilizes the CAR while its length provides grants easier access to specific antigens. The transmembrane domain anchors the antibody and hinge structure.

The intracellular domain describes receptors lying within the T cell. Basic CAR T design employs CD3 here, a T cell receptor needed for T cell differentiation (see Figure 4). Second and third generation CAR models included secondary signal receptors such as CD28 to improve target cell elimination and cell signaling (Figure 5).

More recent research developments in CAR design deviate from this foundational model to finetune precision and function. For example, T cell receptor fusion construct (TRuC) CAR tethers the scFV region to the several intracellular CD3 subunits, thereby reducing secondary signaling hypothesized to be unnecessary.

Universal CAR (uCAR), on the other hand, augments antibody specification by fusing biotin to the transmembrane domain and the endodomain. Other research efforts incorporate cytokines (signaling molecules) and other molecules to improve T cell expansion and persistence, as well as synthetic control switches to minimize the therapy’s toxic side effects. The groundwork model inspires many alternative CAR designs beyond those demonstrated here.

The beauty of this science lies in the melding of two previously separate abilities. CAR T therapy replaces the T cell receptor with an antibody-like structure, all while maintaining the transduction machinery of a T cell. Like this, MHC class I binding becomes irrelevant and a response can be immediately triggered.

The CAR T Therapy Process 

What does the CAR T therapy process look like?

Figure 2 illustrates the progression clearly. For a patient receiving CAR T therapy, the process may begin with a medical professional drawing their blood and separating T cells from that sample using apheresis; this would be an autologous treatment, as the cells used originate from the same patient. T cells can also be isolated from a healthy donor’s blood sample, otherwise known as allogeneic transplantation.

The cells must then be genetically altered to recognize a particular target in a cell processing center. To do this, the cells are “expanded”—a process which stimulates T cell proliferation. The new plethora of T cells must be purified and then genetically modified with a gene that encodes the desired chimeric antigen receptor. CRISPR technology can be used here to accomplish the task.

The cells are now ready for infusion. The cells are frozen and sent back to the treatment center. The patient preps for infusion with a lymphocyte-depleting chemotherapy; the chemotherapy reduces the number of white blood cells in the blood to reduce competition for the CAR T cells, thus helping them multiply. With success, the engineered T cells will recognize the antigen on cancerous cells, bind to it, and mark it for destruction via apoptosis. The infusion takes between 30 to 90 minutes to complete, but the patient will be closely monitored for days, weeks or months to watch for any adverse side effects and to receive additional treatments.

Side effects can occur if the “living drug” multiplies too actively, the most common being cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Also commonly known as “cytokine storm,” CRS occurs when proteins called cytokines flood the immune system and send it into overdrive. Symptoms tend to be mild—fever, nausea, headache, rash, and more—and resolve within a couple of days, but they can also be severe or life threatening. ICANS refers to a neurotoxic condition that appears within one to three weeks after T cell infusion. Early signs, such as tremor and lethargy, can lapse into stupor, seizures or coma if untreated. More on managing side effects to come in later installments in this series.

The long term side effects of CAR T are unknown. As a result, the FDA stipulates that gene editing treatments such as CAR T therapy should be monitored for up to 15 years—five years of annual follow ups, followed by ten years of questionnaires and/or other queries.

What Illnesses Can CAR T Treat?

CAR T therapy is FDA approved to treat B cell-derived lymphomas—cancers caused when B cells (not T cells) grow too rapidly—as well as multiple myeloma, cancer of plasma cells found in the bone marrow. These treatments tailor chimeric antigen receptors to target an antigen called CD19 found only on the tumor cells of lymphoma patients. Another target is BCMA, a B cell maturation antigen specific to multiple myeloma.

CAR T therapies may be federally approved, but they are not used as first or second line cancer treatments; usually CAR T therapy is considered after receiving standard chemotherapy treatment and other alternatives. And as a newer treatment, it may be more expensive than other therapies or may not be fully covered by health insurance.

But this field is ever growing. Several hundred clinical trials are in progress to test the boundaries of this mechanism and enhance its design. The next installations in this series will cover some of the most recent discoveries in the CAR T circuit, such as treatment advances in B cell lymphomas, lupus and heart disease, as well as innovations in CAR T precision.

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