This article comes in two parts: Part 2: Understanding Medical Treatment Protocol for Childhood Leukemia

At CA Care we do not get to see many leukemia cases. If we have the option, we would rather ask you to go for medical treatment. This is because, according to medical literature, modern-day chemotherapy achieve good cure rate with leukemia. However, of late, we get to see more leukemia patients – especially children and young adults. One case that triggered me to write this article is that of Matt (not real name),  an eleven-year-old boy who came to our centre on 21 January 2013. Matt had undergone all the necessary medical treatments but his leukemia did not go away. Eventually the doctors told Matt’s parents to just bring him home. There was nothing else that the doctors could do for him. Under such circumstance, Matt’s parents brought him to see us. We could not refuse this case, since this is probably the last hope for Matt and his parents.  However, we cautioned Matt’s parents that they still need the doctor’s help – for blood transfusion or other life-threatening problems that may crop up.

I brought Matt’s file home to study his case in more detail – what he had gone through. Then I decided to do more reading. Let me share with you what we know about leukemia as of today.

What is leukemia?

It is cancer of the blood that develops in the bone marrow. When a patient has leukemia, the bone marrow, for an unknown reason, begins to make white blood cells that do not mature correctly. They continue to reproduce themselves very quickly and do not function as healthy white blood cells. Then the immature white blood cells, called blasts, begin to crowd out other healthy cells in the bone marrow. The patient experiences many symptoms such as infections, anemia, bleeding, etc.

Childhood leukemia

Leukemia is the most common form of cancer in children. It accounts for about 30 percent of children cancers in American children.  According to Conter V.  et al. (Acute lymphoblastic leukemia. Orphanet Encyclopedia, Dec. 2004) about 3,000 children in the United States and 5,000 children in Europe are diagnosed with ALL (acute lymphoblastic leukemia )each year. The peak incidence of ALL occurs between age two and five years.

The 2003 – 2005 report  of Cancer Incidence in Peninsular Malaysia indicated that leukemia was the most frequent type of cancer among male and female Malaysian children from birth up to 14 years old.

Almost all cases of childhood leukemia are acute, meaning they develop rapidly and get worse quickly if not treated properly. ALL  is the most common type of leukemia in children. It   accounts for three out of every four cases of childhood leukemia in the US, making it the most common type of cancer in children.

Acute myelogenous leukemia (AML) is the next most common type of childhood leukemia.

In Malaysia, about 85 per cent of childhood leukemia cases are due to ALL. The remaining cases are mostly acute myeloid leukemia (AML).  In Singapore three out of every 10 youngsters are diagnosed with ALL annually. Note: Chronic lymphoblastic leukemia (CLL) does not occur in children and chronic myeloid leukemia (CML) is very rarely seen in children. AML is the most common type of acute leukemia in adults.

Symptoms of Childhood Leukemia

Common symptoms are: fatigue or weakness, infection and fever, easy bleeding or bruising, shortness of breath and coughing. Other symptoms may include: bone or joint pains, swelling of the abdomen, face, arms, sides of neck or groin, swelling above the collarbone, loss of appetite, headaches, seizures, balance problems, or abnormal vision, vomiting, rashes and gum problems.

According to Conter V. et al. of Italy, the first symptoms of children with ALL are usually non-specific and include anorexia, irritability and lethargy.  Fever is the most common symptom – found in 60 percent of patients. Progressive bone marrow failure leading to pallor (or anemia), bleeding (thrombocytopenia – low platelets) and susceptibility to infections (due to neutropenia  – low white blood cells). Over one third of patients may present with a limp, and pains in the bone and joints.  Less common signs and symptoms include headaches, vomiting, respiratory distress, oliguria (small amount of urine) and anuria (absence of urine).  At initial diagnosis, 60 to 70 percent of children have enlarged liver or spleen. Lymphadenopathy  (enlargement of lymph nodes, usually painless) is also frequent (Acute Lymphoblastic Leukemia:  https://www.orpha.net/data/patho/Pro/en/AcuteLymphoblasticLeukemia-FRenPro3732.pdf )

The Story of Matt

Mat was 10 years old when he had fevers, gum bleeding and both his lower limbs had bruises and petechiae (tiny red spots) rashes for four days. According to his mother, before this he was breathless and lethargic for about a month. They consulted a doctor in a government hospital in their hometown. On further examination, there were bruises at his lower lip and both lower limbs. There were petechiea rashes over the abdomen. The cervical and inguinal nodes were palpable and measured 0.5 to 1 cm in size. His liver and spleen were swollen.

Blood test showed hyperleucocytosis (abnormally excessive numbers of leukocytes in the blood) and thrombocytopenia (lower than normal platelets). Further test showed 89 percent blast cells, suggestive of acute leukemia.

Due to persistent oozing from a wound at the lower lips, Matt received platelet transfusion for three times. He was also given antibiotics, IV Cefuroxime.

Matt was referred to the General Hospital in Penang.  His blast cells were positive for CD2, CD3, CD7, CD8, cyTdT and weak for CD13 which was consistent with T-ALL.

Matt was started on ALL BFM 95 protocol on 27 December 2011.

• IV Dexamethasone
• Oral Prednisolone
• IT methotrexate
• IM Asparaginase

In addition Matt was given: Bactrim, Morphine, Ranitidine, Ceftazidime, Amikacin, Cloxacillin, Neupogen, Pyridoxine and Dexamethasone eyedrops.

After eight days, his blood showed 58 percent blast, 6786 cells – down from 89 percent.

On 21 January 2012 blood test showed 2 percent blast.

On 25 January 2012 PBF (peripheral blood film) showed no blasts.

On 27 February 2012 Matt received:

• Dexamethasone
• IV Vincristine
• IV Methotrexate
• IV Folinic acid
• IV Ifoshpamide
• IV Daunorubicin
• IV Asparaginase
• IV Kytril

However, the chemotherapy protocol was upgraded from moderate risk to HR (high risk) on 30 January 2012 due the day 8 PBF which showed blast more than 1,000.  Matt completed the following chemotherapy:

• 1^st HR1 protocol on 30 Janruary 2012
• 1^st HR 2 protocol on 27 February 2012
• 1^st HR 3 protocol on 19 March 2012
• 2^nd HR 1 protocol on 14 April 2012
• 2^nd HR 2 protocol on 25 May 2012

Among the drugs Matt received were:

• Ara-C, Etoposide
• Triple IT (Methotrexate + Cytarabine + Hydrocortisone)
•  IV Asparaginase

Matt was started on chemotherapy Protocol IIa on 27 June 2012. He received:

• Dexamehtasone
• IV vincristine
• IV Doxorubicin
• Erwinsa Asparginase

In and Out of Hospital

Matt had been in and out of the hospital for quite a while. For examples:

He was admitted on 26 February 2012 and was discharged on 16 March 2012 due to the following problems:

• Neutropenic fever: Despite being treated with IV Vancomycin, Matt developed multiple temperature spike. Despite starting on Cefepime, Matt still had persistent temperature spike.
• Infection over chemoport.
• Raised ALT. Chemotherapy completed on 16 March 2012 but his ALT = 144 on 16 March 2012.
• Persistent abdominal pain.
• Hypokalemia (lower-than-normal amount of potassium in the blood).

Matt was again admitted on 19 March 2012 and was discharged on 5 April 2012. His problems were:

• Anaphylactic shock (sudden, severe allergic reaction characterized by a sharp drop in blood pressure, urticaria, and breathing difficulties).  Matt present with generalized skin itchness, epigastric pain, vomiting, chills and rigors. BP was lowish and pulse weak. This problem according to the medical report was a problem due to Asparginase.
• Neutropenic fever.
• Asymptomatic thrombocytopenia. Platelet count = 7.
• Anemia.
• Hypokalemia.
• Raised ALT.  On 19 March 2012, ALT = 181; 23 March 2012 = 252; 24 March 2012 = 279; 25 March 2012 = 230.

Matt was admitted on 20 July 2012 due to:

• Rhinorrhoea (persistent watery mucus discharge from the nose)
• Neutropenic sepsis

For these he was covered with IV ceftazidime and amikacin. He had persistent temperature spike and had toothache on Day 3 admission and was reviewed by dental with impression of pericoronitis (infection causing swelling or inflammation of gums and surrounding soft tissues ).

Bone Marrow Transplantation (BMT) 

According to Mattt’s mother, they were in Kuala Lumpur for about a month. Matt underwent an allogenic  BMT on 14 August 2012. The donor was his brother.

Post-BMT Matt was on:

• monthly IT Methotrexate (last done on 19 December 2012)
• Cyclosporin
• Bactrim

Relapse

Matt was admitted on 2 January 2013. This is what the doctor wrote (reproduced per report dated 3 January 2013):

• Admission for poor oral intake for two days associated with lethargy and bilateral knee pain. On examination, he was noted to splenomegaly with hepatomegaly. An urgent Full Blood Picture was taken and verbally reported by our hematologist as 75 percent blast cell seen.
• Both mother and father were explained regarding the patient’s condition and progress. Explained that patient’s FBC is such that TW is increasing trend and other parameters are reducing trend. PBF showed blast cells suggestive of relapse.  Also explained that chemotherapy is not an ideal option in view of his condition.
• Parents were advised regarding palliative care.
• The life expectancy is probable for another 6 months. Explained that prognosis is grave. Parents were also counseled regarding HOSPICE (only available in Penang).
• Parents understood.

Following are excerpts of our conversation:

Chris: (After a year of chemotherapy and BMT, he suffered a relapse). After this, what did the doctor say?

Mother: Doctor said: Go home. The doctor could not do anything more for him. He could undergo more intensive chemotherapy   –  following the adult protocol – but he might not be able to take it.

C: So, after that you were left doing nothing?

Father: We went around the village and started taking herbs and some roots of plants.

M: The doctor told us that if there is any bleeding, then we should bring him back. If there is a need for blood transfusion, we need to do that. That is all that they can do for us.

C: Okay, that is good. We need the doctor – if there is not enough blood, go quickly and have a blood transfusion while we are not doing anything, you can try the herbs. But I cannot guarantee that I can help in this case. Anyway, we can try if you like.   Over the years, I did help some patients. But don’t expect that by taking the herbs for one or two months the problem will go away.

C: (To patient) Did you suffer while undergoing chemotherapy?

Patient: Shaking his head.

F:  They put a chemo-port for him.

M: It was very difficult.

F: But he is a person who can endure pain.

M: Oh, when undergoing BMT it was worse. He had pains in the bones – throughout the whole body. He received six times of intensive radiation – twice a day for three days. Then they gave him chemo. I forget how many cycles. But it lasted only about half an hour each time.

C: Let me have a look at his medical records. He had chemo for about a year? Do you see much success while in the hospital?

Father: Many failures.

M: It was just an experiment hoping to help the children.

Comments

In short, after a year of all possible medical treatments, Matt was back to the same condition he was as in early December 2012.  And he was given six months to live. It was at this point that Matt and his parents came to seek our help on 21 January 2013.

We have learned early that chemotherapy is said to be most effective – high complete response and high cure rate – for five types of cancer: Hodgkin’s disease, testicular cancer, choriocarcinoma, lymphoblastic leukemia and childhood cancers.  So, treating ALL is supposed to be one of chemotherapy’s success stories. Unfortunately for Matt, chemotherapy had failed to help him.

Sverre Lie, President of the International Society of Paediatric Oncology (in Cancer in children – clinical management) wrote:

• The progress which has been achieved in the treatment of childhood cancer is in many ways a remarkable success story. From being an almost lethal disease 20 – 30 years ago, more than 70 percent of children with cancer can now be offered treatment with cure as most likely outcome.
• However, this progress has its dark side …. The diagnostic process is complicated, the therapy very demanding or even life-threatening, and the possibility of relapse a constant threat.
• The problems of long-term sequelae are a matter of concern. (Note:  Sequelae is 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).
• Furthermore, it remains a sad fact that in spite of all the progress made, childhood cancer is still the leading cause of death from disease in children. The remaining third that we are still unable to cure with present strategies remains a tremendous challenge.
• We have three important challenges: first we need to find effective therapy for the third whom we cannot cure with current strategies; secondly we want to get rid of long-term sequelae in the patients were are able to cure today; and thirdly we would like to spread the knowledge of effective treatment of childhood cancer to areas and countries where no such service is available.

Let me close by quoting Conter V. et al. of Italy (cited earlier):

• Treatment has thus become increasingly complex and high levels of organization, expertise and knowledge are nowadays required to achieve optimal results.
• For these reasons children with ALL should be treated in centers which can offer specialized personnel and provide up-to-date diagnostic tools and treatment strategies.