Leukemia Lymphoblastic Leukemia (ALL) is a form of

            Leukemia is a form
of cancer that affects white blood cells. Abnormal blood cells in the bone
marrow are produced and the result is elevated levels of irregular and
underdeveloped white blood cells. Acute Lymphoblastic Leukemia (ALL) is a form
of leukemia that is seen in people of all ages, however, is most common in
children between ages 2 and 5 years of age. ALL is also one of the most common
forms of cancer found in children today. Advancements in treatments have led to
a dramatic increase in survival, with survival rates rising up to 90%. There are
an estimated 6,000 new cases of ALL diagnosed every year. With 60% of new cases
being found in patients under the age of twenty years old. (Inaba et. al)

            ALL, up until the
early 1960’s was fatal in every single diagnosis, however, breakthrough after
breakthrough has allowed for the miraculous 90% survival rate in the modern
world. In 1962, St. Jude’s Children’s Research Hospital commenced a publication
to the therapeutic approach for treating patients who were diagnosed and suffering
from ALL. Through this, four forms of therapy were introduced that are
considered the backbone of ALL treatments today and will be reviewed in depth. The
direct results of this study were extremely successful which allowed for a
positive outlook on the hopes to eventually completely curing ALL.

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            Throughout the
next decade, the survival rating soared up to nearly 70%. This is mostly due to
various studies revealed wide success through intensifying therapy soon after
remission induction. (Pui et. al.). This can be seen below in Figure 1, which portrays
the improved survival rates in children suffering from ALL.

                        Figure 1: Survival
Rates of Patients with ALL over Time

During the 1970’s
a treatment referred to as “triple intrathecal therapy” was introduced, and
this therapy relied on a combination of methotrexate, hydrocortisone, and
cytarabine; followed up with an intermediate dose of another round of
methotrexate. (Cooper et. al.). This last round was administered intravenously.

Through these trials a new door opened known as “Risk-based therapy” and the also
spurred the beginning of bone marrow transplants in patients whose leukemia had

            The first of the
four components involved in ALL treatment is induction chemotherapy. Induction
chemotherapy for ALL patients involves a four or five drug regimen provided
over 4-6 weeks. This will result in 65-85% of patients experiencing complete
remission, which is directly correlated to the outcome of the treatment itself.

(Inaba et. al.). Consolidation chemotherapy is considered the second branch or
step of the four treatments. In 38% of patients that receive the consolidation
therapy saw a 3-year leukemia-free survival rate. The third step in the
treatment of ALL is referred to as the maintenance step. This steps
effectiveness has not been studied in an actual control trial but has undergone
multiple phase 2 studies. Patients who did not undergo the maintenance step experienced
worse results than the patients who had. CNS Prophylaxis is the fourth branch
of treating patients suffering from ALL. This intrathecal chemotherapy is
administered during the induction phase due to the fact that patients suffering
from ALL are also found to be afflicted by meningeal leukemia when they
experience a relapse. (Inaba et. al.)

            A boom in molecular
biology throughout the 90’s allowed for the molecular genetics and pathways for
ALL to be properly studied. Whereas previously it was more of a shot in the dark
as to what type of therapy was to be used, the now accessible genetic pathways
of ALL allowed for more accurate treatments. Furthermore, with the rise in
molecular genetics, researchers were able to identify just what pathways were
affected and therefore were able to more precisely and confidently administer the
correct combinations of chemotherapeutic drugs.

chemotherapy, which is used in the treatment of ALL, is known to have harmful
short and long-term side effects. This treatment is very intensive and in
children it has a remarkably high chance of success, but in adults there is a
much lower rate of success. Recently, the ability to provide patient-specific
therapies has seen a large increase in use, due in part to the rise in understanding
the molecular mutations in patients with ALL.

            A rearrangement of
the CRLF2 gene is prevalent in 8% of all childhood ALL cases. (Inaba et. al.).

This rearrangement is also paired with concomitant activating mutations that
affect both JAK1 and JAK2 genes. This will then result in co-expression of both
the mutants, JAK and CRLF2. Co-expression has then been linked to increased activation
of downstream signaling in the JAK-STAT pathway. (Yokota et. al.)

Mutations in
the JAK-STAT pathway are found in many types of cancer because of its essential
role in multiple cellular processes. The pathway itself has a role in cell
proliferation, apoptosis, and even migration, which are all categories of the
Hallmarks of Cancer. The main treatment method for this pathway has involved the
combination chemotherapy strategy. However, more recently, patient-specific
treatment and genome sequencing have opened the door for more accurate
treatments. One therapeutic pathway for treating acute lymphoblastic leukemia
is to use inhibitors to inhibit JAK kinase. In early lymphoid progenitor cells,
the interleukin-7 receptor complex, which is made up of IL7R, JAK1, and JAK3, has
been the recipient of a lot of attention because of the integral role it plays as
an oncogene for acute lymphoblastic leukemia. Up to 25% of all patients with
T-ALL show mutations in this receptor complex. The vital role that IL7 has in
the development of B and T cells provides a reason as to why it is a focal
point in treatments in patients with ALL. (Degryse et. al.)

            IL7R is a heterodimeric receptor
that associates with both JAK1 and JAK3. When IL7 binds to its receptor, both
JAK1 and JAK3 become activated. Mutations in this pathway allow for increased
cell growth and proliferation. Targeting the IL7R mutants through JAK
inhibitors has yielded success in patients. In the figure below, the arrows are
representative of the 3 common mutations found in the IL7R pathway. (Degryse
et. al.)


2:  IL7R Complex and Associated Mutations


            The development of
new therapies to treat ALL is vital in the hope that one day anybody suffering
from this form of cancer can be cured. Future therapies may include using a patient’s
genetic sequence to determine if the patient is at an elevated risk of relapse.

(Harrison). Early detection of the risk of relapse would allow for more sensitive
methods to be used when they are undergoing treatment. A second direction that
future therapies may consider would be to find a way lower intensity of the
drug regimen that is involved in treating ALL while increasing the overall
survival rate. All of the current drugs have toxic side effects that are hazardous
to the patients, even though it is for a greater good. Therefore, a successful
decrease in the intensity would be crucial in limiting the short and long-term
effects of the chemotherapy. Finally, with survival rates up to 90%, acute
lymphoblastic leukemia is not as grim of a diagnosis as it once was, however,
there is still room for improvement so everyone who receives this diagnosis has
a chance to survive.