​Kembara Xtra - Medicine - Acute Lymphoblastic Leukemia in Adult

​Kembara Xtra - Medicine - Acute Lymphoblastic Leukemia in Adult 
ALL develops in adults as a result of immature lymphocytes' clonal proliferation, survival, and poor differentiation. The National Comprehensive Cancer Network (NCCN) utilizes a cutoff of 20% while the World Health Organization (WHO) defines ALL as the presence of 25% lymphoblasts in the bone marrow.
 ALL and lymphoblastic lymphoma (LBL) are regarded to be diseases that fall within the same range and can develop from the same parental cell line:
- LBL manifests as a mass with around 25% blasts in the bone marrow, probably but not exclusively in the mediastinum.
Any organ may be impacted by ALL, which can manifest as a mass lesion but also has 25% bone marrow involvement.

pregnant women's issues
Teratogenicity is a common side effect of chemotherapy (CTX).
Pediatric Considerations The most prevalent childhood cancer, accounting for 30% of all pediatric cancers and 80% of pediatric leukemias, is ALL.


Aspects of Geriatrics

42% of ALL patients over 60 years old die following induction CTX. Relapse or problems connected to CTX are frequently the cause of mortality. Poor CTX tolerance frequently reduces survival, resulting in dose reductions and inefficient medicine delivery.

The incidence of ALL is 1.8/100,000 per year according to epidemiology.
 Higher occurrence in older age groups, men, white people, and people who have had radiation, CTX, or certain genetic abnormalities in the past

Prevalence
The prevalence of ALL rises with age and can range from 15% to 50%.
75-80% of cases occur in children, compared to 20% of cases in adults; bimodal distribution; first peak in childhood, second peak around age 50.

Pathophysiology and Etiology 

The aberrant proliferation and differentiation of clonal lymphoid cells have a role in the pathogenesis of ALL.
Genetics Higher incidence in monozygotic and dizygotic twins Associated chromosomal instability and inherited chromosomal abnormalities with increased risk of ALL

Risk Elements 

Age above 70, exposure to radiation and CTX, and HIV infection are risk factors for developing ALL.
Adult T-cell ALL is related to human T-cell lymphotropic virus type 1.
Epstein-Barr virus and mature B-cell ALL are related.

History The effects of bone marrow suppression and/or leukemic cell organ infiltration result in symptoms.
B signs include a fever, weight loss, and night sweats.
Anemia symptoms include exhaustion, shortness of breath, dizziness, angina, and headaches. Thrombocytopenia symptoms include easy bruising or bleeding.
Lymphocytosis causes bone discomfort; CNS causes disorientation.

clinical assessment 
Anemia: pallor; Thrombocytopenia: Ecchymoses, Petechiae, Epistaxis, Retinal Hemorrhages; Neutropenia: Fever, Infections
Testicular invasion: abnormal testicular exam; lymphocytosis: lymphadenopathy; splenomegaly; less frequently, hepatomegaly; CNS: cranial nerve palsies;

Differential Diagnosis Malignant disorders: multiple myeloma, bone marrow metastases from solid cancers (breast, prostate, lung, kidney), acute myeloid leukemia (AML), chronic myeloid leukemia in lymphoid blast phase, prolymphocytic leukemia, and myelodysplastic syndromes.
Non-cancerous conditions include infectious mononucleosis, pertussis, autoimmune thrombocytopenic purpura, aplastic anemia, myelofibrosis, felty syndrome, and leukemoid reaction to infection.


Laboratory Results 

Initial examinations (lab, imaging)
Peripheral blood smear: lymphoblasts (B cell or T cell); Hepatitis B/C, HIV, CMV, and HSV testing; pregnancy test in female patients; testicular examination and scrotal US if indicated in male patients; Human leukocyte antigen (HLA) typing if post-treatment hematopoietic stem cell transplant might be indicated; and CT of the neck, chest, abdomen, and pelvis with contrast.

Tests in the Future & Special Considerations
B lineage (CD19, CD20, CD22, CD24), T lineage (CD2, CD3, CD5, CD7), common ALL antigen (CD10), HLA-DR, terminal deoxynucleotidyl transferase (TdT), aberrant myeloid antigens (CD13, CD33), and stem cell antigen (CD34) are all used in the immunophenotyping of marrow/blood lymphoblasts.
Myeloperoxidase is normally negative, Sudan black B is often negative, TdT is positive, and periodic acid-Schiff results vary depending on subtype.
Cytogenetics: Particular chromosomal abnormalities are independently significant for prognosis and diagnosis.
Reverse transcriptase-polymerase chain reaction for BCR/ABL1+ ALL fast diagnostic
 Next-generation sequencing genomic analysis: identification of mutations linked to Ph-like ALL
 Patient and sibling HLA typing for hematopoietic stem cell transplant

Diagnostic Techniques/Other Bone marrow aspiration/biopsy with cytogenetics, molecular diagnostics, immunohistochemistry, and immunophenotyping
Lumbar puncture (LP) for CNS involvement and intrathecal (IT) CTX. Lymph node biopsy, if available. If symptoms started earlier than at the time of IT CTX, the first LP should be done then. Repeat LP to assess occult CNS involvement following bone marrow remission.
Interpretation of Tests
The presence of lymphoblasts in the bone marrow provides the basis for the diagnosis. In other circumstances, even though the percentage of blasts is lower, the diagnosis can be determined based on the presence of specific mutations. A bone marrow biopsy often reveals sheets of malignant lymphoblasts, whose T- or B-cell lineage is identified by CD expression, replacing the marrow and lymph node architecture in a diffuse manner.

Management 

Throughout the course of treatment, CTX is administered in three phases with CNS prophylaxis:
 Consolidation, prolonged maintenance, and induction

Medication 

With induction, the intention is to achieve total remission and bring about normal hematopoiesis.
– The most frequently utilized regimen is hyper-CVAD, which stands for hyperfractionated cyclophosphamide, vincristine, anthracycline, and dexamethasone.
– Eight alternating treatment cycles of sections A and B make up a hyper-CVAD:
Hyper-CVAD in Part A and high-dose methotrexate and cytarabine in Part B
Granulocyte colony-stimulating factors are administered following each cycle to prevent therapy delays and speed up bone marrow recovery.○ CNS prevention: 6-mercaptopurine (6-MP), methotrexate, or cytarabine (IT CTX consistent) 
At diagnosis, CNS leukemia requires twice-weekly IT treatment until CSF is clean on three successive LP.
- 40 years of age with complete remission following the initial induction; depending on risk donor availability, consolidation CTX or allogeneic stem cell transplant is the next step.
– Usually 8 months after the commencement of therapy with ongoing CTX, minimal residual disease (MRD), as evaluated by flow cytometry in the US, denotes a disease that is resistant to CTX. The need for an allogeneic bone marrow transplant in these patients should be assessed.
Consolidation: After induction therapy, the aim is to get rid of any remaining leukemic cells.
- Drugs are employed during the induction phase.
- Peg-asparaginase is utilized in youngsters, but it is poisonous to adults and has poor results.
The objective of prolonged maintenance is to sustain remission and prevent recurrence.
- Consist of POMP for two to three years: daily 6-MP, weekly methotrexate, monthly vincristine, and prednisone pulses. A protracted maintenance period of more than three years has yielded little benefit.
– Prednisone, also known as DOMP, can be replaced with dexamethasone.
Considerations unique
- In addition to hyper-CVAD, several pediatric ALL regimens have produced better remission results in adults aged 15 to 39. Nonmyelosuppressive medications like vincristine and pegasparaginase are typically seen in these.
– When ALL has relapsed during the first remission or in cases where there are high-risk genetic characteristics, allogeneic stem cell transplantation is advised.
- Burkitt leukemia takes an 18-week course of treatment and responds better to the initial combination of methotrexate and alkylating drugs.
Rituximab enhances outcomes when >20% of ALL blast cells express CD20.
- Immunotherapy: For relapse/refractory ALL, blinatumomab, a bispecific anti-CD19/anti-CD3 antibody, has been approved.
- Ofatumumab, a second-generation anti-CD20 monoclonal antibody, is a frontline treatment choice for patients with CD20+ pre-B-ALL who have failed rituximab-based therapy.
- Positive PH Tyrosine kinase inhibitors (TKIs) that target BCR-ABL1 translocation have a better prognosis for ALL. In these individuals, consolidation/maintenance with a TKI may be employed instead of an allogeneic stem cell transplant.
Adult T-cell ALL has a recurrence incidence of up to 50% with conventional hyper- CVAD treatment and is significantly less prevalent than B-cell ALL. Nelarabine, a T cell-specific purine nucleoside, is approved for treating relapsed T-cell ALL, and hyper-CVAD in combination with nelarabine is currently the subject of clinical research.
– If an HLA-identical donor is available, patients with unfavorable cytogenetic subtypes should get an allogeneic stem cell transplant after their initial remission.
– In patients with relapsed or refractory ALL, inotuzumab-ozogamicin (InO) combination has demonstrated greater rates of full remission and longer progression free and overall survival compared to conventional therapy.


Referral 
Patients should be referred to and treated by oncologists, ideally at comprehensive cancer centers where the pharmaceutical regimen can be customized as necessary with a combination of various modalities.

Surgical Techniques 

Patients may undergo surgical port implantation for CTX in some facilities. However, PICC lines are preferable because they are simple to remove after therapy to lower the risk of infections, which is crucial because these patients can become neutropenic.

Unproven Alternative Therapies

Patient Follow-Up Monitoring
 Admission as an inpatient during induction CTX for ongoing infusion and oversight of complications
 Outpatient follow-up every three months after that Weekly clinic appointments with remission consolidation CTX Monthly clinic visits Nutritional support; abstain from alcohol Calcium/vitamin D for steroid-induced osteoporosis Outpatient follow-up every six months after that

Patient education, neutropenic precautions, physical therapy for deconditioning, and a focus on quitting smoking are all recommended.

Prognosis Approximately 80–90% of persons under the age of 60 will experience a complete remission; however, due to relapses, only 40–50% will continue to be cured. Compared to youngsters, adults only have a 30- 40% 5-year overall survival rate.


Complications 

 Hyperleukocytosis: WBC >50,000 to 100,000 can cause leukostasis, a medical emergency with microvascular white cell plugs, and it is treated with fluids and cytoreductive therapy when it causes neurologic impairments or respiratory distress.
By using allopurinol before CTX, it may be possible to avoid tumor lysis syndrome (high uric acid, potassium, phosphate, and reduced calcium, which causes renal failure and cardiac arrhythmias). If 6-MP or azathioprine are being utilized, doses should be decreased. If G6PD is not defective, IV urate oxidase (rasburicase) can be used to cure hyperuricemia quickly.
Neutropenia brought induced by myelosuppression
 Cyclophosphamide at high doses produces severe nausea and vomiting. Use the right antiemetic protocol.
Vincristine has been linked to ileus and neurotoxicity.
AVN or osteonecrosis can be brought on by alkylating substances and corticosteroids.
Induced hyperglycemia by steroids
Anthracyclines cause cardiotoxicity; have a transthoracic echocardiogram before starting a hyper-CVAD and keep track of it while you're on the medication to measure your left ventricle's ejection fraction.
The use of asparaginase treatment raises the risk of veno-occlusive illness and deep vein thromboses.
 Infections (Pneumocystis carinii pneumonia, bacterial and fungal pneumonia, or sepsis) CTX may have sterile effects, liver failure, pancreatitis, arachnoiditis, and CNS symptoms. ALL relapse in the testis or extramedullary sites (marrow)

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