Leukemia: Causes, Symptoms, and Treatments

Leukemia is a type of cancer that affects blood cell formation and the lymphatic system. It can be classified by cell type, lymphoid or myeloid, and the rate of progression, acute or chronic.

There are 4 main subtypes of leukemia: acute lymphoid leukemia (ALL), acute myeloid leukemia (AML), chronic lymphoid leukemia (CLL), and chronic myeloid leukemia (CML). ALL and AML progress rapidly and therefore require more aggressive treatment to improve the life expectancy of the patient, whereas CLL and CML progress slowly over time and may go undiagnosed for years.¹

Even though leukemia is the ninth most common cancer in the United States, it accounts for just 3.7% of all new cancer diagnoses. More than 50% of leukemia cases are in individuals older than 50, and it affects men twice as often as women. The overall 5-year survival rate continues to improve and is at 63.7%, which is quadruple the rate from 1960.²

Epidemiology and Etiology

ALL is more common in children and the other 3 subtypes are more common in adults. Figure 1 portrays a projected incidence and mortality of leukemia in the United States for 2018.² Developed countries have an overall higher incidence than developing countries. Even though the etiology has not been discovered, this could be because of higher rates of risk factors, which can be found in Table 1.³ It could also be because of enhanced medical technology for diagnosis.

Pathophysiology

The hematopoietic stem cell is responsible for producing many blood cells in the human body. The process starts when immature blast cells, lymphoid or myeloid, are released with large nuclei that eventually become mature and specialized blood cells with compacted DNA and smaller nuclei. In leukemia, the immature blast cell cannot progress in maturation because of multiple or single gene mutations that occur in the DNA. Multiple gene mutations are the result of chromosome translocation, which is an error during the cell division process. Single gene mutations arise from exposure to carcinogens or radiation that cause an isolated mutation. Because of mutations, the leukemia blast cells uncontrollably replicate in the bone marrow and take over. This is a problem, because the normal blast cells cannot use resources because of limited space. Therefore, they are unable to make mature specialized cells, such as platelets, red blood cells, and white blood cells.⁴ In chronic leukemia, partially mature cells develop over a long period and do not work as effectively. The most common causes are chromosomal abnormalities, such as deletions, translocation, and trisomy. CML is a result of cells dividing too quickly, while CLL is a result of defective apoptosis.⁵

Symptoms and Diagnosis

Leukemia symptoms mimic common illnesses such as influenza and musculoskeletal discomfort. Therefore, to have an accurate diagnosis of leukemia, certain criteria must be considered. For example, the clinician should perform a complete blood count with differential, a comprehensive physical exam, a medical history, and a peripheral blood smear. Table 2 represents peripheral blood smears of each leukemia subtype.⁶ Table 3 lists common patient-reported symptoms associated with acute and chronic leukemia.^7,8 Table 4 summarizes the diagnosis of the 4 main leukemia subtypes.^9,10

TABLE 3. SYMPTOMS OF ACUTE AND CHRONIC LEUKEMIA^7,8

Acute

Chronic

• Discomfort in bones, joints, or muscles
• Excessive bleeding or bruising
• Flu-like symptoms, such as: Fatigue Fever Night sweats Pale skin Shortness of breath
• Painless lumps in the groin, neck, or underarm area

Flu-like symptoms, such as:

• Fatigue Fever Left-sided stomach pain Night sweats Pale skin Shortness of breath Unexplained weight loss

TABLE 4. DIAGNOSIS OF ACUTE AND CHRONIC LEUKEMIA^9,10

ALL

AML

CLL

CML

Markers

• Increase in immature lymphoblasts
• DNA polymerase

• Auer rods
• Increase in immature myeloblasts
• Myeloperoxidase enzyme

• Increase in lymphocytes
• Increase in smudge cells (immature B cells)
• Monoclonal B lymphocytes>5x10⁹/L
• Partial deletion on chromosome 17 TP53 sequencing

• Increase in granulocytes/ monocytes
• Philadelphia chromosome positive (Ph+) Distinguishes the blast phase from the accelerated phase

Mutation Classification

t(12;21):

• Good prognosis in children

t(9;22):

• Ph+
• Poor prognosis in adults

t(15;17):

• Promyelocytic leading to disseminated intravascular coagulation

• Interference with B-cell receptors leading to increased expression of surface markers CD19 and CD23
• Unknown mutations

t(9;22):

• Continual activation of tyrosine kinase leading to uncontrolled cell division
• Ph+

Lineage Classification

B-ALL:

• Most common
• Surface markers:

• CD10
• CD19
• CD20

T-ALL:

• Surface markers:

• CD2-CD8

Megakaryoblastic:

• Associated with down syndrome (<5 years)
• Myeloperoxidase negative

Monocytic:

• High monoblast count
• Myeloperoxidase negative
• Swollen gums

Not specific

Not specific

^{ALL indicates acute lymphoid leukemia; AML, acute myeloid leukemia; B-ALL, B-cell acute lymphocytic leukemia; CLL, chronic lymphoid leukemia; and CML, chronic myeloid leukemia.}

The 4 main subtypes of leukemia can be differentiated based on occurrences, prognosis, and outcomes.

Treatment

Prior to treatment, a thorough patient workup must be completed. This can be found in Table 5.¹¹ Once the workup has been assessed, individualized therapy can be selected: chemotherapy, radiation therapy, biological therapy, targeted therapy, stem, or cell and bone marrow transplantation. Table 6 lists treatment response terminology to be aware of while taking care of patients.¹²

Tables 7^13,14 and 8^15,16 include a summary of treatments according to the National Comprehensive Cancer Network guidelines.

TABLE 5. PATIENT WORKUP PRIOR TO TREATMENT¹¹

Overall Health Exams

Screenings

Labs

Tests

• Medical history
• Physical exam

• Coagulation studies
• Infections Cytomegalovirus hepatitis B and C HIV

• Pregnancy/fertility awareness

• Blood chemistry panel
• Complete blood count
• Liver function test
• Tumor lysis syndrome panel
• Urinalysis

• Cat scan or magnetic resonance imaging of head, if symptoms are present
• Echocardiogram
• Human leukocyte antigen typing
• Lumbar puncture, if intrathecal chemotherapy

is anticipated

TABLE 6. TREATMENT RESPONSE TERMINOLOGY¹²

Complete Remission

• Absence of leukemia cells in the bone marrow
• All signs and symptoms are resolved
• No more than 5% of blast cells in the bone marrow or in the blood stream
• Normal blood cell counts

Refractory

Small amount of leukemia cells remain in the blood marrow after intense therapy, can be determined by minimal residual disease testing

Relapse

Leukemia cells return in the blood marrow after complete remission has been reached.

TABLE 7. TREATMENT OF ACUTE LEUKEMIA^13,14

ALL (Ph-)

ALL (Ph+)

AML (Non-APL)

AML (APL)

Induction

(Treatment depends on age, health, and the progression of cancer)

Adolescents and young adults (15-39 years):

multiagent chemotherapy + CNS prophylaxis

Patients ³65 years or in poor health:

multiagent chemotherapy + CNS prophylaxis + corticosteroids

Adolescents and young adults (15-39 years):

• multiagent

chemotherapy + TKI:

• Bosutinib
• Dasatinib
• Imatinib mesylate
• Nilotinib
• Ponatinib

• TKI listed above + corticosteroids

Patients ³65 years: multiagent chemotherapy + TKI listed above

Low-intensity treatment:

• 5-azacytidine
• Cytarabine
• Decitabine
• Enasidenib
• Gemtuzumab

Moderate- to high-intensity regimens:

cytarabine alone or with 1 or more of

the following:

• Cladribine
• Daunorubicin
• Fludarabine
• Gemtuzumab
• Growth factors
• Idarubicin
• Midostaurin

All-transretinoic acid + 1 or more of the following:

• Arsenic trioxide
• Gemtuzumab
• Idarubicin

Postremission consolidation and maintenance

• Allogeneic stem cell transplant maintenance: start follow-up testing
• Blinatumomab maintenance: start follow-up testing

• Continue multiagent chemotherapy maintenance:

• Daily:

mercaptopurine (6-MP)

• Monthly:

vincristine/

prednisone pulses

• Weekly: methotrexate

• Allogenic stem cell transplant, if a donor is available

Maintenance Consider post—stem cell transplant TKI

• Continue multiagent chemotherapy regimen + TKI Maintenance
• Daily 6-MP
• Monthly

vincristine/

prednisone pulses

• TKI +

weekly

methotrexate

• 5-azacytidine
• Cytarabine alone or with 1 or more of the following:

• Daunorubicin
• Gemtuzumab
• Idarubicin
• Midostaurin

• Decitabine
• Reduced-intensity blood stem cell transplant

• ATRA + 1 or

more of the

following:

• Arsenic trioxid
• Cytarabine
• Daunorubicin
• Gemtuzumab
• Idarubicin
• Mitoxantrone

Refractory/

relapse

• Augmented hyper-CVAD regimen:

• Cyclophosphamide
• Dexamethasone
• Doxorubicin
• Vincristine

• Blinatumomab

(B cell)

• MOpAD

• Dexamethasone
• Methotrexate
• Pegaspargase
• Rituximab
• TKI
• Vincristine

• Nelarabine (t cell)
• Regimens with

alkylating agents, clofarabine (B cell), or cytarabine

• Vincristine

sulfate liposome

injection

• TKI +

induction

chemotherapy not used before

• MOpAD

• Dexamethasone
• Methotrexate
• Pegaspargase
• Rituximab
• TKI
• Vincristine

• Blood stem cell transplant, if able
• Repeat induction therapy

• Common regimens:

• Anthracycline-based regimens: doxorubicin and epirubicin
• ATRA + 1 or both of the

following: arsenic trioxide and gemtuzumab

• Regimen depends on:

• Months since last treatment
• Previous regimen

^{ALL indicates acute lymphoid leukemia; AML, acute myeloid leukemia; APL, acute promyelocytic leukemia; ATRA, all-trans retinoic acid; CNS, central nervous system; CVAD, central venous access device; MOpAD, methotrexate, vincristine, PEGylated-asparaginase, and dexamethasone; Ph-, Philadelphia negative; Ph+, Philadelphia positive acute lymphoblastic leukemia; and TKI, tyrosine kinase inhibitor.}

TABLE 8. TREATMENT OF CHRONIC LEUKEMIA^15,16

CLL

Without Del(17p) or

TP53 mutations

CLL

With Del(17p) or

TP53 mutations

CML

(Ph+)

Induction

(CLL)

or

Chronic Phase (CML)

(Initial treatment depends on age, health, and progression of cancer)

• Older patients with comorbidities:

• Bendamustine
• Ibrutinib
• Obinutuzumab, ofatumumab, or rituximab ± chlorambucil

• Younger patients without comorbidities:

• FCR:

• Fludarabine
• Cyclophosphamide
• Rituximab

• FR:

• Fludarabine
• Rituximab

• Ibrutinib
• PCR:

• Pentostatin
• Cyclophosphamide
• Rituximab

• Alemtuzumab ± rituximab
• High-dose methylprednisolone + rituximab
• Ibrutinib (standard of care)
• Obinutuzumab

• Clinical trial
• Dasatinib
• Hematopoietic cell

transplant

• Imatinib
• Nilotinib

Regimens may need to be changed, depending on the response to the medication.

Refractory/

Relapse

(CLL)

or

Advanced Phases

(CML)

• Older patients with comorbidities:

• FCR
• Ibrutinib
• Idelalisib, venetoclax, lenalidomide, or alemtuzumab ± rituximab
• Obinutuzumab
• Ofatumumab
• PCR

• Younger patients, without comorbidities:

• Any of the above regimens
• Bendamustine + rituximab
• FR

• HDMP + rituximab
• Ibrutinib
• Ofatumumab
• Venetoclax, idelalisib, lenalidomide, or

alemtuzumab ± rituximab

Therapy is specific to the gene mutation identified.

• Accelerated phase:

• Bosutinib
• Dasatinib
• Imatinib
• Nilotinib
• Omacetaxine
• Ponatinib

• Blast phase:

• Lymphoid cell type: imatinib, dasatinib, nilotinib, bosutinib, or ponatinib + ALL-type chemotherapy or a steroid
• Myeloid cell type: imatinib, dasatinib, nilotinib, bosutinib, or ponatinib ± AML-type chemotherapy

^{ALL indicates acute lymphoid leukemia; CLL indicates chronic lymphoid leukemia; CML, chronic myeloid leukemia; HDMP, high-dose methylprednisolone; and Ph+, Philadelphia positive acute lymphoblastic leukemia;}

Patients may respond diversely to treatments and may need a combination of therapies to achieve complete remission. Patients with relapsed or refractory disease may need multiple courses of different or the same regimens. When complete remission cannot be achieved with conventional treatments, patients may try for a clinical trial, which can be found on the National Cancer Institute website.

Supportive Care

Managing the complications associated with treatment is critical and just as important as the treatment. There are many possible complications associated with chemotherapy, including bladder and skin changes, bruising, constipation, diarrhea, fatigue, hair loss, nausea, neuropathy, unprovoked bleeding, and vomiting.¹⁷ The adverse effect experienced determines the need for treatments, which includes antiemetics, granulocyte-colony stimulating factor, and transfusions.¹⁸ Other agents, such as corticosteroids and antibiotics, may be necessary to help fight infections in a suppressed immune system. In addition to oncology, these patients invariably require an involved interdisciplinary team of case managers, clinical pharmacists, infectious disease specialists, and nutritionists. Additionally, many organizations such as the Leukemia and Lymphoma Society offer useful resources at no cost, such as live chats and a helpline.

Conclusion

Although the disease is often curable or manageable, a cancer diagnosis can be overwhelming for patients. An interdisciplinary team will optimize patients’ access to education, financial assistance, pharmacotherapy, and targeted treatment options. Accurate and timely diagnosis will help facilitate appropriate, prompt, and targeted treatment. With additional research, enhanced patient awareness, individualized chemotherapy, and optimized supportive care, the 5-year survival rate will continue to improve.

Jerry A. Barbee Jr, PharmD, BCPS, CPh, and Glenn Schulman, PharmD, MS, BCPS, BCACP, BCGP, are clinical pharmacists in Pensacola, Florida. Christen Ferguson is a PharmD candidate at the Lake Erie College of Osteopathic Medicine School of Pharmacy in Bradenton, Florida, and Jasmin Tawfic is a PharmD candidate at the University of Florida in Gainesville.

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