Part 2: Understanding Medical Treatment Protocol for Childhood Leukemia

This article comes in two parts: Part 1: The Tragic Story of An Eleven-Year-Old Boy With Leukemia

Understanding the Symptoms

In leukemia patients, the normal development of the blood cells is disrupted and they are being crowded out by abnormal, immature blood cells. The full blood picture (FBC) of such patient shows abnormal blood counts. The patient is anemic with low red blood cells, haemoglobin, and platelet counts. The white blood cell may be high or low but there is usually neutropenia (low number of neutrophils).  Lactic dehydrogenase (LDH) level is usually raised.

Since leukemia is a disseminated disease it also produces a wide variety of other symptoms such as:

  • Rheumatoid arthritis fever.
  • Hyperparathyroidism (overactivity of the parathyroid glands resulting in excess production of parathyroid hormone).
  • Bone pain which may result in a limp, refusal to walk or localized discomfort of the jaw, long bones, vertebral column, hip, scapula and ribs.
  • Swelling of the liver, spleen and lymph nodes. Hepato-splenomegaly occurs in approximately two thirds of patients with ALL. About fifty percent of patients showed asymptomatic lymphadenopathy.
  • Paratracheal or mediastinal adenopathy and thymus enlargement may result in mild to severe respiratory symptoms.
  • Nephritis (kidney inflammation). Renal involvement by ALL can result in hematuria (blood in urine), hypertension and renal failure associated with nephromegaly.
  • Meningitis (inflammation of the protective membranes covering the brain and spinal cord). Meningeal involvement can result in severe headache, emesis (vomiting) and papilledema (optic disc swelling caused by increased intracranial pressure).

Central Nervous System (CNS) Leukemia

  • Less than 5 percent of children have evidence of CNS 2 at diagnosis (CNS 2 means less than 5 WBCs/ul but blasts are present). Unless adequate CNS preventive therapy is administered the majority of patients will eventually develop CNS disease.
  • CNS leukemia is presumed to develop either from the spreading or seeding of the meninges (membranes enveloping the central nervous system) by circulating leukemic cells or by direct extension from involved cranial bone marrow.

Testicular Leukemia

  • Clinically evident testicular involvement is rare at initial diagnosis but overt disease occurs in approximately 10 to 15 percent of boys with ALL.
  • Clinically overt, testicular leukemia presents as painless testicular enlargement that is usually unilateral.
  • Although it is believed that the testes are a leukemic sanctuary site, protected from systemic chemotherapy by a blood-testes barrier, animal studies suggest this is not the case.

Lymph Nodes

Nodal involvement is a characteristic feature of ALL and is often responsible for bringing the patient to medical attention. Typically the lymphadenopathy is generalized and enlarged nodes are painless and freely moveable. Nodal enlargement is an indirect measure of tumour burden and has been associated with prognosis.

Evaluation of the Patient

The diagnostic evaluation of a patient with acute leukemia is a comprehensive process involving:

  • Detailed history.
  • Complete physical examination.
  • Morphologic and laboratory assessment of peripheral blood and bone marrow, blood chemisty, comprehensive clotting studies, a lumbar puncture and CSF (cerebrospinal fluid) examinations.

Diagnosis

  • The diagnosis of acute leukemia entails a stepwise approach. First in sequence and importance is the distinction of acute leukemia from other neoplastic diseases and reactive disorders. Second is differentiating acute myeloid (AML) and acute lymphoblastic (ALL) leukemia. The third facet is the classification of AML and ALL into categories that define treatment and prognostic groups.
  • Approximately 80% of cases of ALL have a B-cell precursor immunophenotype.
  • Approximately 15% of ALLs have an antigen profile of T-cell precursors (thymic T cells).
  • A small group of cases (<5%) of ALL have the immunophenotypic profile of more mature B cells, i.e., surface immunoglobulin.

Prognosis

The prognosis for ALL differs between individuals depending on a variety of factors:

  • Gender: females tend to fare better than males.
  • Ethnicity: Caucasians are more likely to develop acute leukemia than African-AmericansAsians or Hispanics. However, they also tend to have a better prognosis than non-Caucasians.
  • Age at diagnosis: children between 1–10 years of age are most likely to develop ALL and to be cured of it. Cases in older patients are more likely to result from chromosomal abnormalities (e.g., the Philadelphia chromosome) that make treatment more difficult and prognoses poorer.
  • White blood cell count at diagnosis of less than 50,000/µl
  • Cancer spread into the Central nervous system (brain or spinal cord) has worse outcomes.
  • Morphological, immunological, and genetic subtypes.
  • Patient’s response to initial treatment.
  • Genetic disorders such as Down’s Syndrome 

Cytogenetic, Molecular Studies and Immunonophenotyping

Robert McKenna (Multifaceted Approach to the Diagnosis and Classification of Acute Leukemias in Clinical Chemistry August 2000 vol. 46 no. 8 1252-1259) http://www.clinchem.org/content/46/8/1252.long, wrote:

  • Until recently, the diagnosis and classification of acute myeloid (AML) and acute lymphoblastic (ALL) leukemias was based almost exclusively on well-defined morphologic criteria and cytochemical stains. Although most cases can be diagnosed by these methods, there is only modest correlation between morphologic categories and treatment responsiveness and prognosis.
  • The expansion of therapeutic options and improvement in remission induction and disease-free survival for both AML and ALL have stimulated emphasis on defining good and poor treatment response groups. This is most effectively accomplished by a multifaceted approach to diagnosis and classification using immunophenotyping, cytogenetics, and molecular analysis in addition to the traditional methods.
  • Immunophenotyping is important in characterizing morphologically poorly differentiated acute leukemias and in defining prognostic categories of ALL.
  • Cytogenetic and molecular studies provide important prognostic information and are becoming vitally important in determining the appropriate treatment protocol. With optimal application of these techniques in the diagnosis of acute leukemias, treatment strategies can be more specifically directed and new therapeutic approaches can be evaluated more effectively.

Cytogentics is an important predictor of outcome. Some cytogenetic subtypes have a worse prognosis than others. These include:

  • A translocation between chromosomes 9 and 22, known as the Philadelphia chromosome, occurs in about 20% of adult and 5% in pediatric cases of ALL.
  • Not all translocations of chromosomes carry a poorer prognosis. Some translocations are relatively favorable. For example, Hyperdiploidy (>50 chromosomes) is a good prognostic factor.

Cytogenetic change

Risk category

Philadelphia chromosome Poor prognosis
t(4;11)(q21;q23) Poor prognosis
t(8;14)(q24.1;q32) Poor prognosis
Complex karyotype (more than four abnormalities) Poor prognosis
Low hypodiploidy or near triploidy Poor prognosis
High hyperdiploidy (specifically, trisomy 4, 10, 17) Good prognosis
del(9p) Good prognosis

Source: http://en.wikipedia.org/wiki/Acute_lymphoblastic_leukemia

Immunonophenotyping

The importance of defining the immunophenotype in ALL lies in its correlation with response to treatment and prognosis  In childhood ALL, immunophenotype is a major factor in determining the chemotherapy protocol. The immunophenotypic prognostic groups of ALL are shown in below:

Favorable B-cell precursor (CD10+) (Cytogenetic findings influence prognosis)
Less favorable B-cell precursor (CD10−)
B cell (Slg+; Burkitt cell leukemia)
T cell

B-cell precursor ALLs have a more favorable prognosis than the other groups; however, within the B-cell precursor category, there are subsets with a poor prognosis. Most of the favorable and unfavorable prognostic groups of B-cell precursor ALL can be identified by their cytogenetic karyotype or molecular features.

Treatment for Chilhood ALL

Nearly 30 years ago, Dr. Donald Pinkel developed the concept of total therapy and demonstrated that childhood leukemia could not only be cured but CURED in approximately half of the patients. But note that acute leukemia in children is very different from the adult version of the disease.

The cornerstones of this successful treatment were:

  • Multiple drug combination chemotherapy.
  • Administration of different sets of drugs for induction and continuation of remission.
  • Specific meningeal therapy.
  • Intensive antimetabolites and alkylating agent treatment immediately after remission induction.
  • Cessation of all therapy after 2 to 3 years of continuous complete remission.

One of the most remarkable occurrences in the history of ALL therapy is the fact that there have been NO new agents introduced in the front-line therapy of ALL for the past 25 years. The same eight types of agents have been used in newly diagnosed patients since the early 1970s.

  1. A vinca alkaloid (vincristine).
  2. A corticosteroid (prednisone, prednisolone or dexamethasone).
  3. Asparaginase (four types are currently available).
  4. An anthracycline (daunorubicin or doxorubicin)
  5. An antifoliate (methotrexate).
  6. An antipurine (6-mercaptopurin or 6-thioguanine).
  7. Antipyrimidine (cytarabine), and
  8. An alkylating agent (cyclophosphamide).

Four main treatment phase or blocks are adopted by various treatment centres or international co-operative groups in their treatment protocols for ALL.

  1. Remission Induction phase
  2. CNS Preventive / Sanctuary Therapy
  3. Consolidation or  intensification phase
  4. Maintenance phase

REMISSION INDUCTION PHASE: The goal of this phase is to kill the leukemia cells in the blood and bone marrow. The treatment comprises a backbone of three systemic agents: a glucocorticoid, vincristine and L-asparaginase for standard-risk cases. Many treatment protocols add a fourth agent such as an anthracycline for high-risk cases.

The treatment is delivered over 4 to 5 weeks with the goal of achieving complete remission – meaning that leukemia cells are no longer found in bone marrow samples and the blood counts become normal. A bone marrow test is taken at the end of induction treatment to confirm whether or not there is still has leukemia. The bone marrow sample is looked at under a microscope. But take note that a remission is not the same as a cure.

More than 95% of children with ALL will go into remission after one month of treatment. A rapid early response to treatment, measured by the clearance of blasts from either the bone marrow or peripheral blood, has been shown to predict better treatment outcome.

CENTRAL NERVOUS SYSTEM (CNS) SANCTUARY THERAPY: Intrathecal Chemotherapy / Radiotherapy

Anticancer drugs given by mouth or injected into a vein to kill leukemia cells may not reach leukemia cells in the CNS (brain and spinal cord). The leukemia cells are believed to have the ability to find sanctuary (hide) in the CNS. CNS sanctuary therapy is also called CNS prophylaxis because it is given to stop leukemia cells from growing in the CNS.

All children with ALL receive CNS sanctuary therapy as part of their treatment and may start simultaneously with the remission induction therapy phase.

CNS treatment involves injecting a drug, usually methotrexate, directly into the spinal fluid. This procedure is referred to as intrathecal chemotherapy and is done during a lumbar puncture.

Some patients who have a relapse in which leukemia cells are found in one part of the body (such as the cerebrospinal fluid or the testicles) but are not found in the bone marrow. These children may have intense chemotherapy, sometimes along with radiation treatment to the affected area.  Radiotherapy to their brain (cranial radiotherapy) is not done if the patient is younger than two years old.

Those with T-cell leukemia or cancer cells in the CSF, may need radiation to the head, too.  But recent studies have found that many children even with high-risk ALL may not need radiation therapy if they are given more intense chemo. Doctors try to avoid radiation because, no matter how low the dose, it may cause some problems in thinking and growth.

CONSOLIDATION or INTENSIFICATION PHASE:  Studies from the German BFM (Berline-Frankfurt-Munster) group have shown that the use of drugs such as cyclosphamide, cytarabine, and thioguanine in combination may further reduce the levels of sub-microscopic residual ALL cells. However, this treatment may lead to substantial toxicities and complications, but the cure rate increase far outweighs these risks.

These treatments may be given immediately after remission has been achieved or they may be given later such as between 4 to 6 months after remission – this phase is known delayed intensification.

In high-risk patients, repeated delivery of intensive blocks of chemotherapy courses interspersed by relatively non-myeloablative interim maintenance chemotherapy has improved cure rate substantially.

The epipodophyllotoxins, such as VP-16, are potent anti-leukemia agents, but its use is often restricted in childhood ALL because of is potential for contributing to the secondary development of AML.  But in high-risk patients, its use is currently justified.

The goal of this intensification phase is to get rid of any remaining leukemia cells that may not be active but could begin to regrow and cause a relapse.  This phase lasts about one to two months. Several drugs are used, depending on the child’s risk category. Some children may benefit from a stem cell transplant at this time.

MAINTENANCE PHASE:  If the leukemia stays in remission after the first two phases of treatment, this last phase, maintenance chemotherapy begins. The total length of therapy for all third phases is two to three years for most children with ALL.  The purpose of this third phase of treatment is to kill any remaining leukemia cells that may regrow and cause a relapse. Often the cancer treatments in this phase are given in lower doses than those used for induction and consolidation phases.

In this phase of treatment, a majority of the medications are taken orally with few side effects. This consist of:

  • Daily oral doses of 6-mercaptopurine, best given at night on an empty stomach, combined with
  • Weekly oral doses of methotrexate.
  • Every four weeks,  pulses of intravenous vincristine  combined with 5 days of oral glucocorticoid.

Patients will be able to take part in their normal daily activities for as long as they feel able to. Most children return to school before beginning maintenance treatment.

This phase of treatment lasts for up to two years from diagnosis for girls and up to three years for boys. This is because boys are at higher risk for relapse than girls. The few attempts to reduce the duration of treatment protocols to less than 2 years from remission have been associated with increased risk of relapse. Likewise, there appears to be little benefit to extending the duration of maintenance therapy beyond 3 years.

Testicular radiotherapy

In some situations it may be necessary for boys to have radiotherapy to their testicles. This is because leukemia cells can survive in the testicles despite chemotherapy.

Bone Marrow  (BMT) / Peripheral Blood Stem Cell Transplantation (PBSCT)

Bone marrow contains immature cells known as hematopoietic  stem cells which divide to form more blood-forming stem cells, or they mature into one of three types of blood cells: white blood cellsred blood cells and platelets.  Most hematopoietic stem cells are found in the bone marrow, but some cells, called peripheral blood stem cells (PBSCs), are found in the bloodstream. Blood in the umbilical cord also contains hematopoietic stem cells. Cells from any of these sources can be used in transplants.

Chemotherapy and radiation therapy severely damage or destroy the patient’s bone marrow. Without healthy bone marrow, the patient is no longer able to make the needed blood cells. BMT and PBSCT replace stem cells destroyed by treatment. There are three types of transplants:

  1. In autologous transplantation, patients receive their own stem cells.
  2. In syngeneic transplantation , patients receive stem cells from their identical twin.
  3. In allogeneic transplantation, patients receive stem cells from their brother, sister, or parent. A person who is not related to the patient (an unrelated donor) also may be used.

Stem Cells Matching

To minimize potential side effects, the stem cells must match the patient’s own stem cells as closely as possible. A special blood test is done comparing the human leukocyte-associated (HLAantigens on the surface of the cells. In general, patients are less likely to develop a complication known as graft-versus-host disease (GVHD) if the stem cells of the donor and patient are closely matched.

Transplantation Procedure

High-dose chemotherapy is given before stem cell transplantation, i.e.  giving high doses of anti-cancer drugs to kill cancer cells. This treatment often causes the bone marrow to stop making blood cells and can cause other serious side effects.

After being treated with high-dose anticancer drugs and/or radiation, the patient receives the stem cells through an intravenous (IV) line just like a blood transfusion. This procedure takes one to five hours.

After entering the bloodstream, the stem cells travel to the bone marrow, where they begin to produce new white blood cells, red blood cells, and platelets in a process known as “engraftment.” Engraftment usually occurs within about 2 to 4 weeks after transplantation.

Doctors monitor it by checking blood counts on a frequent basis. Complete recovery of immune function takes much longer, however—up to several months for autologous transplant recipients and one to two years for patients receiving allogeneic transplants.

Doctors evaluate the results of various blood tests to confirm that new blood cells are being produced and that the cancer has not returned. Bone marrow aspiration (the removal of a small sample of bone marrow through a needle for examination under a microscope) can also help doctors determine how well the new marrow is working.

In the initial 2 to 4 weeks after transplantation, the patient’s immune system is not effective and is easily susceptible to infections. Hence, utmost care is required to maintain a sterile environment. The patient is put on antibiotics and other medications to protect against viral and fungal infections.

After this period, the graft begins to settle in the new bone marrow, produces blood cells and gradually improves the host’s condition. Drugs to suppress immunity may be withdrawn once the graft has taken hold in the recipient. Most patients may need re-immunization with vaccines at this stage.

Note:  Besides leukemia,  stem cell transplantation is used to treat lymphoma, multiple myeloma and myelodysplasia.

Possible Side Effects of BMT and PBSCT

  • The major risk is an increased susceptibility to infection and bleeding as a result of the high-dose cancer treatment. Doctors may give the patient antibiotics to prevent or treat infection. They may also give the patient transfusions of platelets to prevent bleeding and red blood cells to treat anemia.
  • Patients who undergo BMT and PBSCT may experience short-term side effects such as nausea, vomiting, fatigue, loss of appetite, mouth sores, hair loss, and skin reactions.
  • Potential long-term risks include infertility (the inability to produce children), cataracts , secondary (new) cancers,  and damage to the liverkidneys, lungs, and/or heart. These arise due to the effects of  the heavy doses of chemotherapy and radiation therapy received before transplantation.
  • With allogeneic transplants, graft-versus-host disease (GVHD) sometimes develops when white blood cells from the donor (the graft) identify cells in the patient’s body (the host) as foreign and attack them. The most commonly damaged organs are the skin, liver, and intestines. This complication can develop within a few weeks of the transplant (acute GVHD) or much later (chronic GVHD). To prevent this complication, the patient may receive medications that suppress the immune system.

Some Notes on T-cell ALL

  • The presence of massive lymphadenopathy or a large mediastinal mass, a particular feature of patients with T-cell disease, has been associated with a poor prognosis.
  • T-cell ALL may release a cytokine osteoclast-activating factor that results in symptomatic hypercalcemia (elevated levels of calcium in the blood) and diffuse osteopenia (mild decrease in bone mineralization, not as severe as osteoporosis.).
  • Facial palsy due to nerve root infiltration may also be an early sign of T-cell ALL.
  • B-cell ALL has a more rapid growth rate and relapses within 6 months, while B-precursor ALL relapses after considerably longer intervals.
  • The growth rate of T-cell ALL tends to be intermediate between B-precursor and B-cell ALL and the duration of risk of relapse is greater than for B-cell but less than for B-precursor ALL.

Overall Outcome of Medical Treatment of Childhood ALL

Conter V et al. of Italy wrote in Acute Lymphoblastic Leukemia:

  • Although the treatment of childhood ALL has been gradually intensified during the last 30 to 40 years, leading to a significant improvement of outcome, still roughly 25 percent of patients suffer from a relapse of the disease.
  • The management of relapse remains controversial but increasingly involves the use of high-dose chemo/radiotherapy and stem cell infusion. Despite recent improvements the overall results remain unsatisfactory worldwide. Relapsed ALL  continues to make a major contribution to the morbidity and mortality of childhood cancer.

(https://www.orpha.net/data/patho/Pro/en/AcuteLymphoblasticLeukemia-FRenPro3732.pdf )

Nita Seibel (Treatment of acute lymphoblastic leukemia in children and adolescents: peaks and pitfalls, Amer. Soc. Hematology Education Prog. Book, 2008) wrote:

  • Survival of children with acute lymphoblastic leukemia (ALL) is often described as the success story for oncology.  In the 1996-2204 SEER data the 5-year survival for patients will ALL was 84 percent for children and young adults less than 19 years of age and 88 percent for children and teens less than 15 years of age. This is in comparison to 3 percent reported in the 1960s. The outlook for children and adolescents diagnosed with ALL today is much better than even before.
  • However, as we all know, cure in not assured and is not obtained without sequelae (Note: sequelae means any abnormal condition that follows and is the result of a disease, treatment, or injury. E.g. deafness after treatment with an ototoxic drug, or scar formation after a laceration).

Martin Schrappe and Matin Stanulla of Germany (in International Society of Paediatric Oncology) wrote:

  • Nowadays … childhood ALL can be successfully treated in about 80 percent of patients by the applications of intensive combination chemotherapy regimens, which in specific patient subgroups may need to be supplemented with radiation therapy and /or hematopoietic stem cell transplantation.
  • However, although the goal of developing effective therapy for the majority of children with ALL has been achieved, significant numbers of patients still die due to recurrent disease or the toxicity of treatment applied.

Muller J et al. (Treatment results with ALL-BFM-95 protocol in children with acute lymphoblastic leukemia in Hungary. Article in Hungarian: Orv Hetil. 2005 Jan 9;146(2):75-80) reported that  the treatment outcome of Hungarian children with acute lymphoblastic leukemia improved remarkably over the last decades. Seventy-eight percent of children suffering from ALL could be cured with the ALL-BFM-95 protocol.

Kocak et al. (ALL-BFM 95 treatment in Turkish children with acute lymphoblastic leukemia-experience of a single center, Pediatr Hematol Oncol. 2012 Mar;29(2):130-40) reported that their 13 years’ experience treating 140 Turkish  children with ALL with original ALL-BFM (Berlin-Franfurt-Münster) 95 protocol.

  • Complete remission rate was 97.7% with a relapse rate of 12.9% and death rate 17.9% during a median follow-up of 69 months.
  • The event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) in these patients at 12 years were 75.0%, 87.1%, and 80.6%, respectively.

In the article, Hope for children with leukemia (http://sg.theasianparent.com/hope-for-children-with-leukemia/#), Eeleen Lee reported on the experiences of childhood leukemia treatment in Singapore.

  • It is a highly curable disease with intensive chemotherapy. The current cure rates in the developed world surpass 80%.
  • Associate Professor Allen Yeoh, Principal Investigator of the study and Senior Consultant, Division of Paediatrics Haematology-Oncology, National University of Singapore Hospital said: Leukemia treatment creates a conundrum. On one hand, leukaemia is a rapidly fatal cancer if not treated correctly. On the other hand, chemotherapy drugs cause significant side effects that worry both doctors and parents
  • One of the significant side effects of the treatment is damage to organs like the heart, skin and brain, which may lead to long-term complications, including secondary cancers. In fact, the costs related to treating the side effects of chemotherapy often exceed those of treating leukemia.
  • The increased complications put the young patients at a high risk of long-term side effects, which can be life threatening and significantly reduce quality of life.

G. Gustafsson and S. O. Lie (Acute leukaemias in Cancer in children – clinical management) wrote:

  • One hope for the future is that the therapy of the acute leukaemias in children should be more globally available to children. Probably not more than 20 percent of the children on this planet with leukaemias are offered a therapy that gives any chance of cure.
  • Modern, high-intensity protocols are expensive and carry a high risk of morbidity and even mortality.  Therapy-related death or complications are of great concern, between 3 and 5 percent die from therapy-related complications.
  • Long-term late effects are also of increasing concern, especially when it comes to the commonly used anthracyclines and the development of heart failure. Clearly, the risk of heart failure is very significant in children. (Note; Examples of anthracyclines are Andriamycin, Doxorubicin, Epirubicin, Indarubicin, Mitoxoanthrone).

Points to Ponder

  • Treatment of childhood leukemia represents the most outstanding achievement of oncology. In spite of such success story, still 30 percent of patients die – either of the disease or from the treatment itself.
  • Other cancers such as sarcomas, ovarian cancer, breast cancer, small cell lung cancer, myeloma, follicular lymphoma are described low cure rate cancers. What do you think of the chance of success then?
  • Do you ever wonder why, Allen Rose, worldwide vice-president of Glaxo-SmithKline said (Daily Express, 8 Dec. 2003): Drugs for cancer are only effective in 25 percent of the patients?  Perhaps that is the most and the best that chemo-drugs can do for most of our common cancers!
  • Treatment of Leukemia is not cheap and comes with drastic side effects. And according to Professor Yeoh (above), the costs related to treating the side effects of chemotherapy often exceed those of treating leukemia.
  • Do you wonder if that is all scientific medical science can offer this world?
  • Has anyone ever attempted to find a better and effective alternative? No, that cannot happen because that will threaten the status quo.

Materials for this article are taken from:

http://emedicine.medscape.com/article/990113-treatment

http://www.cancer.org/cancer/leukemiainchildren/overviewguide/childhood-leukemia-overview-treating-children-with-all

http://www.cancer.umn.edu/cancerinfo/NCI/CDR258001.html

http://www.cancer.gov/cancertopics/factsheet/Therapy/bone-marrow-transplant

Acute Lymphoblatic Leukemia: https://www.orpha.net/data/patho/Pro/en/AcuteLymphoblasticLeukemia-FRenPro3732.pdf

Multifaceted Approach to the Diagnosis and Classification of Acute Leukemias http://www.clinchem.org/content/46/8/1252.full.pdf+html

An excellent article on Childhood Leukemia was written by Theodore Zipt et al (in Chapter 81: Clinical Oncology, 2nd Ed. Harcout Publishers, 2000).