Rare Classroom: Acute Lymphoblastic Leukemia

Welcome to the Rare Classroom, a new series from Patient Worthy. Rare Classroom is designed for the curious reader who wants to get informed on some of the rarest, most mysterious diseases and conditions. There are thousands of rare diseases out there, but only a very small number of them have viable treatments and regularly make the news. This series is an opportunity to learn the basics about some of the diseases that almost no one hears much about or that we otherwise haven’t been able to report on very often.

Eyes front and ears open. Class is now in session.

The disease that we will be learning about today is:

Acute Lymphoblastic Leukemia

Also called acute lymphocytic leukemia or acute lymphoid leukemia.

What is Acute Lymphoblastic Leukemia?

  • Acute Lymphoblastic Leukemia (ALL) is a cancer of the white blood cells
  • In ALL, lymphocytes (a form of white blood cell), grow quickly, crowding out bone marrow, preventing it from making the normal red blood cells, white blood cells, and platelets​
  • Progresses rapidly without treatment​
  • The most common type of cancer in children
    • ALL represents 25% of cancers in those younger than 15​
  • Over the past 25 years there has been a gradual increase in incidence of ALL​
  • Every 4 in 10 cases of ALL are in adults​
  • While most cases occur in children, most deaths occur in adults​​
  • Can affect people of any age: Most common in children followed by those in old age​
  • One of the first cancers for which an effective chemotherapeutic treatment was developed​
  • This cancer differs from acute myeloid leukemia because different cells are affected; in AML, granulocytes or monocytes are impacted.
  • After starting from lymphocytes or lymphoblasts (an immature type of lymphocyte) in the bone marrow, ALL invades the blood and can spread to other organs​
  • ALL does not normally produce tumors​
  • ALL is a group of related diseases or subtypes – treatment depends on the classification of a patient’s ALL​
    • B-cell ALL – About 85% of cases
      • Early pre-B ALL (also called pro-B ALL) – about 10% of cases​
      • Common ALL – about 50% of cases​
      • Pre-B ALL – about 10% of cases​
      • Mature B-cell ALL (Burkitt leukemia) – about 4% of cases​
    • T-cell ALL – diagnosed in 15% of children and adults with ALL
      • Pre-T ALL – about 5% to 10% of cases​
      • Mature T-cell ALL – about 15% to 20% of cases​
    • Genetic Translocations – Many leukemias involve genetic rearrangements, called translocations, in which some of the genetic material (genes) on a chromosome may be shuffled or swapped between a pair of chromosomes.” 
      • Philadelphia (Ph) chromosome – Most common. Occurs more often in adults than children. More difficult to treat.​
      • TEL-AML1 fusion – t(12;21) – Generally indicates a favorable prognosis​

How Do You Get It?

  • ALL occurs when a bone marrow cell develops an error in its DNA​
    • Translocations are the most common type of DNA change that can lead to leukemia​
  • Cause is most likely due to a combination of genetic, biologic and environmental factors​
  • Risk factors include:
    • Radiation exposure
      • Through cancer treatment or atomic bomb survivors​
    • Certain chemical exposure
      • Benzene​
    • Certain viral infections
      • Infection with the human T-cell lymphoma/leukemia virus-1 (HTLV-1) can cause a rare type of T-cell ALL – not common in US​
      • Epstein-Barr virus (EBV) linked to ALL in Africa​
    • Inherited syndromes
    • Race/ethnicity
      • More common in whites than African-Americans​
    • Gender
      • More common in males than females​
    • Having an identical twin with ALL
      • Someone who has an identical twin who develops ALL in the first year of life has an increased risk of getting ALL​
    • Previous chemotherapy
      • Raises risk in adults particularly when combined with radiation​
    • Age
      • Occurs most frequently in the first decade of life, increases in frequency again in older individuals​

What Are The Symptoms?

  • Symptoms usually begin abruptly and intensely, but in some cases may develop more slowly
  • Symptoms develop when:
    • There are not enough healthy mature white blood cells (leukocytes) to mount a defense against infection
    • There are not enough healthy platelets to prevent bleeding
    • The depleted oxygen-bearing red blood cells can’t provide enough oxygen to organs
  • Symptoms of acute lymphoblastic leukemia include:
    • Fatigue​
    • Paleness — patients may have poor coloring from anemia caused by insufficient red blood cells​
    • Recurrent minor infections​
    • Fever without known cause​
    • Bone pain​
    • Abdominal swelling​
    • Bruising — may result from only slight injury​
    • Poor healing of minor cuts​
    • Night sweats​
    • Uncontrolled bleeding — bleeding events increase as the bone marrow fails to produce enough platelets to make a normal blood clot, a condition called thrombocytopenia.​
    • Small, red spots on the skin (petechiae)​
    • Vision changes (rare)​
    • Weight loss/Loss of appetite​
    • Shortness of breath​

How Is It Treated?

  • Because ALL is not a single disease, but a group of related diseases, treatment varies
  • Factors that determine type of treatment:
    • Adult or child​
    • Subtype of ALL​
    • Stage of disease​
  • Treatment may include: 
    • Chemotherapy​
    • Bone marrow transplant​
    • Targeted therapies​
    • Sometimes surgery, radiation and monoclonal antibodies are used​
  • Because there are many different medications, dosing schedules, and combinations, there is no standard treatment and many components are not studied completely​
  • An important part of treatment is ensuring that the leukemia does not spread to the area around the brain and spinal cord if it hasn’t already done so at diagnosis
  • In adults, treatment usually takes place in three phases:
    • Remission induction therapy
      • First phase – puts the leukemia into remission​
      • An intensive phase of chemotherapy, typically lasts about a month​
      • Patients often spend some or much of the time in the hospital​
      • About 80% of adults enter remission after initial treatment
      • Common treatments include:
        • Vincristine ​
        • An anthracycline (such as daunorubicin or doxorubicin)​
        • Prednisone, dexamethasone, or another steroid hormone​
        • Imatinib or dasatinib for those with Philadelphia chromosome positive ALL​
        • Cyclophosphamide, L-asparaginase​​
    • Consolidation/intensification of therapy
      • Used to prevent relapse​
      • Usually includes a fairly short course of chemotherapy lasting several months​
      • Some may receive a stem-cell transplant
      • Uses many of the same drugs as above​
      • May continue to include Imatinib or dasatinib for those with Philadelphia chromosome positive ALL​
      • Stem cell transplant may be considered at this time
        • Allogeneic stem cell transplantation is the most common type of stem cell transplant used to treat ALL​
        • Allogeneic stem cell transplantation involves transferring stem cells from a healthy person (the donor) to the patient after high-intensity chemotherapy​
        • Main reasons for undergoing allogenic stem cell transplant:​
          • To give strong doses of chemotherapy to kill ALL cells​
          • To start a fully-functioning supply of red cells, white cells and platelets with help from the transplanted donor stem cells​
        • What ALL patients are recommended for stem cell transplant:​
          • A patient with high-risk ALL in the first remission period​
          • A patient with standard-risk ALL in the first remission period that fit certain criteria – this remains controversial​
          • A patient with standard-risk ALL following relapse when in the second complete remission​
    • Remission maintenance (continuation therapy)
      • Oral medications are taken on certain days of the month, IV chemotherapy usually given once a month​
      • Most people can return to full activity during this phase
      • Treatment include:
        • Methotrexate​
        • 6-mercaptopurine (6-MP)​
        • Vincristine ​
        • Prednisone​
        • Imatinib for those with Philadelphia chromosome positive ALL​
      • Some doctors feel that maintenance therapy may not be needed for some subtypes such as T-cell ALL and mature B-cell ALL (Burkitt leukemia)​
    • The above regime takes 2-3 years.  Following this, a bone marrow aspiration and biopsy is performed every 3-6 months for at least 2 years to detect any relapse​
  • Treatment in children is divided into three phases:
    • Induction
      • 1 month regime​
      • Includes chemotherapy given IV/PO​
      • Also includes chemotherapy given directly into the cerebrospinal fluid called intrathecal chemotherapy​
      • May include radiation​
      • Usually kills about 99.9% of leukemia cells
      • Treatments include:
        • Vincristine ​
        • Dexamethasone​
        • L-asparaginase​
        • Methotrexate for intrathecal chemotherapy​
        • Hydrocortisone and cytarabine (ara-C) can be added for high risk children​
        • Daunorubicin typically added for high risk children​​
    • Consolidation (also called intensification)
      • 1-2 month regime​
      • Includes standard chemotherapy, intrathecal therapy​
      • Depending on subtype of ALL may receive: targeted therapy or stem cell transplant
      • Treatments include:
        • Methotrexate​
        • 6-mercaptopurine or 6-thioguanine​
        • Vincristine, L-asparaginase, and/or prednisone may be added to the above​
        • Children at high risk may also be given: doxorubicin (Adriamycin), etoposide, cyclophosphamide, and cytarabine (ara-C)​
        • Imatinib may be given for those with Philadelphia chromosome positive ALL​
        • Stem cell transplant may be considered at this time​​
    • Maintenance
      • Begins if ALL remains in remission after induction and consolidation​
      • During the first few months most treatments include 1 or 2 repeat intensified treatments called re-induction or delayed intensification​
      • Because boys are at higher risk for relapse than girls, many doctors favor giving them several more months of treatment
      • Treatments include:
        • Methotrexate – weekly​
        • 6-mercaptopurine (6-MP) – Daily​
        • Vincristine with steroid every 4-8 weeks – IV​
        • Prednisone​​
    • Pediatric treatment often differs from treatment of adult ALL because:
      • They may be more responsive to chemotherapy​
      • Children can generally tolerate a more intensive chemotherapy regime than adults can​
  • The prognosis for those with ALL depends on:​
    • Age – Younger patients have better prognosis​
    • Lab test results – Lower WBC during diagnosis improves outlook​
    • Subtype – In general, T-cell ALL has better prognosis than B-cell​
    • Presence of the Philadelphia chromosome abnormality – Poorer prognosis in those who have it​
    • Response to chemotherapy – Better outlook if there is no evidence of leukemia 4-5 months after starting treatment​​
  • Of all adults diagnosed with ALL, 40% will live for at least 5 years​
  • The rate of adult remission has increased dramatically in the last 10 years. Extended remissions are more frequent.​
  • Prognosis has been shown to be better in those < 35 years old​
  • Patients who achieve complete remission (absence of active cancer) within 4 – 5 weeks of starting treatment tend to have a better prognosis​
  • Patients who do not achieve remission at any time have a poor prognosis​
  • Patients with Ph1-positive t(9;22) ALL have a poor prognosis and represent more than 30% of adult patients​
    • Rarely cured with chemotherapy​
    • Long-term survival has shown improvement when combining chemotherapy with Bcr-abl tyrosine kinase inhibitors​
  • More than 95% of children attain remission​
    • The 5 year survival rate for children is more than 85%​
    • Those who remain free from disease over 5 years are considered cured​
    • Approximately 80% of patients aged 1 to 18 years with newly diagnosed ALL treated on current regimens are expected to be long-term event-free survivors​

Where Can I Learn More???

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