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Acute Promyelocytic Leukemia (APL)

 by: Joe Hing Kwok Chu

This is a type of leukemia that can be treated successfully. The therapy was developed in Shanghai, China and has been used in the West for many years with good results. The methods were discovered from the observation on the use traditional Chinese herb formulae.

It was noticed that most cancer patients showed a lower level of natural vitamin A in their blood.  It was found that the vitamin A levels of those who were using a classical Chinese herb formula called "xiao chai hu tang" were closer to normal and had higher survivor rate. Thus all-trans-retinoic acid, a vitamin A derivative came to the attention of medical researchers in China.

 

The most serious problems of APL patients are blood clots (disseminated intravascular coagulation  or DIC) [4], bleeding and fungal infection. The risk of thrombosis and bleeding is mainly due to the decline of the total platelets. The risk of fungal infection, especially infection of Aspergillus nigers, is due the lowering of the total functional white cells caused by the disease, chemotherapy and the use of steroids to counter the side effect of ATRA therapy and at the same time of intra venous feeding which is necessary for medication and for the infusion of platelets (when the total platelet count is dangerously low).

The lowering of the total white cells in chemotherapy can be a side effect instead of the goal which many practitioners believe. In the editor's opinion, when the condition has been stabilized Chinese herb to promote platelets and white cells can be used. Use of Chinese herb formulae for fungal infection should also be investigated.

Many medical professionals cannot see the risk of thrombosis because of the high prothrombin time of the APL patients.  Actually these are different issues. The hypercoagulopathy (pervasive blood clot) is caused by the thromboplastin - like substance secreted by the abnormal Auer rods of the bone marrow cells. According one statistical source, 60 % of the patients died of bleeding in the brain before receiving treatment. The hypercoagulopathy in the blood vessels causes the drop of the total platelets, thus causes the bleeding. The editor first learned of risk of hypercoagulopathy through a stressful way. The editor was visiting his son in Stanford hospital near midnight and found that his pulse reading (traditional Chinese pulse reading) indicated an eminent pending massive blood clot. Using qi on certain acupoints relieved his symptoms temporarily. The editor raised the issue with a medical student who were on duty and she was not convinced because of the high prothrombin time shown on the blood test reports. While discussing the issue, a nurse arrived with the heparin medication ordered previously by the patient's main doctor .

Another problem is that antifungal drugs are highly toxic. The survival rate in cases of fungal infection in immune deficient patients is low because of the toxicity of antifungal drugs.

All-trans-retinoic Acid (ATRA)

The use of All-trans Retinoic Acid for promoting the forming of bone marrow cells was first published by Prof. Zhen Yi Wang (王正儀) of Shanghai Medical School during the later part of the 80's.  This brought the ATRA out of the research stage from the laboratories into clinical use.

This therapy modality is definitely different from the traditional Western approach where the therapy has been focusing on eradicating the cancer cells. Although ATRA cannot eliminate the cancer genes and cannot completely cure the patients of APL but it can lower 85% of the hyper coagulation and achieving the remission rate of 80% to 90% and lower the mortality rate of 85% to less than 10%. Using conventional chemotherapy, the resulting of sepsis caused by the lowering of white cells count, can happen.  Compared to using chemotherapy or the highly difficulty of bone marrow transplant, this ATRA therapy is better in many ways, like quality of life of patients are better and without the side effects of chemotherapy. But, the short coming of ATRA therapy is the risk of overproduction of white cells and the rapid development of drug resistance. Thus chemotherapy is still being used in conjunction with ATRA therapy.

 

Arsenic trioxide (As2O3) Therapy

The use of arsenic trioxide has a long history. Some classical formulae are found in writings dated to the Han dynasty (more than two thousand years). The use of arsenic in modern clinical application is much earlier than the use of ATRA.  As early as 1972, in mainland China, arsenic trioxide was being used in myelocytic leukemia. The result was reported in Chinese journals [1] that 22 patients out of 81 were completely in remission, 7 of M2 and 15 of M3. The substance used was extract of arsenic: As2O3 1mg/ml and HgCl 0.01mg/ml. The result was that the Aur rods of promyelocyte gradually disappeared or shrunk. Later it was found that it was especially effective for APL. Subsequently the results were published in various Chinese journals. [2,3]  The common discovery was that the remission rates were 60 ~ 70%, regardless of if they were first time patients or refractory patients, or recurring after ATRA or chemotherapy. Later it was discovered that excluding HgCl or just taking arsenic sulfide could achieve the same result. During the 90's the understanding of the apoptosis of cells, the transformation of bone marrow cells and peripheral blood lead to the understanding of the function of arsenic trioxide that causes the apoptosis of cells leading to the cure of APL. The side effects include nausea, vomiting, lack of appetite, diarrhea, numbness in the extremities of limbs, edema in the lower limbs, settlement of skin pigments, abnormal function of the liver. But, because of the low dosage, cirrhosis of the liver or organ exhaustion has never occurred.  Later, in vitro experiments also proved that arsenic trioxide also can cause apoptosis of cells, especially promyelocytes.

It is deemed that the first scientific report was written by Hong De Sun (孫洪德) et al of Harbin city, China, in 1992. Thirty two patients with acute promyelocytic leukemia were treated with arsenic trioxide in combination with traditional Chinese medical diagnostics and therapy methods. The results: total remission was 65.6% (21 patients out of 32). 50% survived more than 5 years and 18.8% survived more than 10 years.

In 1995, Shi lin Huang (黃世林) [2] of Da Lian city, China reported using a formula of qing dai (indigo) containing xiong huang (realgar) as main Chinese herb treating 60 APL patients and resulted 98.3% with total remission. The main ingredient of xiong huang is As2S2As2S3 and As4S4 and a small amount of As2O3. Before that there were report of using the formula called "niu huang jie du pian" (containing xiong huang) or just using xiong huang (realgar) by itself to treat APL.  The above shows that arsenic compounds are effective in treating APL.

A scientific report on using arsenic trioxide therapy was published by "Chinese Hematology Journal" (中華血液學雜誌) in 1996. It reported using arsenic trioxide therapy on 72 new patients and also on refractory patients. The complete remission rate on the new patients was 73.3% and on on refractory patients was 52.3% .

 

Note: In nature 95% of arsenic exists as As2O3. Its lethal dosage is 1 - 2.5 mg/kg according to the Information Toxic Chemicals Section of the Environmental Protection Agency of Republic of China in Taiwan.  In prescription, it is suggested not to exceed 0.1g.

According to a Chinese medical classics, "Ben Cao Gang Mu" (本草綱目) the antidote  for arsenic is to use mung bean soaked overnight with cold water (for oral consumption) or use goat blood.

Although the modern therapy was discovered through the old Traditional Chinese Medicine (TCM) formulae, in the editor's opinion, modern hospitals are more equipped to handle APL patients because of the rapid development of the sickness.

Two reports from China have suggested that arsenic trioxide can induce complete remissions in  patients with acute promyelocytic leukemia (APL).

Simultaneous Determination of All-trans-and 13-cis-Retinoic Acid in Human Serum by HPLC

A Study of APL Treatment in China

Classical Chinese herb formula: xiao chai hu tang

Effects of ATRA treatment (in Chinese)

Sample report on bone marrow biopsy

Complete blood cell count

Other information site

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Note and Explanation:

About side effect or goal     

When the editor asked Dr. Beth Martin of Stanford University Medical School and Hospital about the lowering of white cell count in chemotherapy, she expressed that it used to be considered as the goal but it seems to be a side effect instead, and there were patients whose white cell count did not drop, also had recovered from the illness.

Beth Martin M.D. is one of the two best medical doctors in the field of Leukemia and Multiple Myeloma in United States,  as told by various oncologists, also by Prof. Richard Dorsay M.D., a retired radiologist  who headed the radiology department of South San Francisco Kaiser Hospital for 15 years and who was a professor in the Stanford Medical School and University of California -S.F. Medical School.

Auer Rod

John Auer: "Some hitherto un-described structures found in the large lymphocytes of a case of acute leukemia."
Rod or crystalline shaped including. cell organelles present in the cytoplasm of myeloblasts, myelocytes, and monoblasts. In enzyme content and structure Auer’s rod resemble lysosomes. They are pathogonomic of leukaemia and chiefly occur in leukaemia cells in acute leukaemia.

Bibliography on Auer rod:
American Journal of the Medical Sciences, Thorofare, N.J., 1906, 131: 1002-1015.

  • [1] 張亭棟,李元善。癌靈1號治療急性粒細胞白血病臨床分析及實驗研究。中西醫結合雜誌1984, 4(1), 19-20.

    [2] 黃世林等。復方青黛片為主治療急性早幼粒細胞白血病的臨床研究。中華血液學雜誌1995, 16(1), 26-8.

  • [3] 張鵬等。三氧化二砷注射液治療72例急性早幼粒細胞白血病。Chin J Hematol 2:58, 1996.
  • [4] Barbui T, Falanga A. Disseminated intravascular coagulation in acute leukemia. Semin Thromb Hemost. 2001;27:593–604.[CrossRef][Medline]
  •  

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    See chronic myelocytic leukemia

    See a bone marrow biopsy report.

    See other leukemia herb formulae.

    See vitamin K

    表一、比較不同引導治療方式的無 病 生 存 率

    Chart 1: Comparison of different induced therapy

    disease free survival rate

     

    一年

    1 year

    兩年

    2 years

    三年

    3 years

    chemotherapy 化學治療

    57%43% 32%

    ATRA

    87%70% 67%

    p

     < 0.001  

     

    表二、比較不同維持治療方式的無 病 生 存 率

    Chart  2: Comparison of different maintenance therapy

    disease free survival rate

     

    一年

    1 year

    兩年

    2 years

    三年

    3 years

    觀察組

    Obervation group

    53%40% 40%

    ATRA

    82%68% 65%

    p

     <0.001  

     

    表三、比較不同引導治療及維持治療方式的疾病復發率

    Chart 3: Comparison of different induced therapy and

    maintenance therapy disease free survival rate

    引導治療/維持治療

    induced therapy/maintenance therapy

    三年疾病復發率

    Rate of relapses after 3 years

    p

    ATRA/ATRA

    21.7%

     

    化學治療/ATRA

    chemotherapy/ATRA

    39.6%

     

    ATRA/觀察

    ATRA/observation

    38.8%

     

    化學治療/觀察

    Chemotherapy/observation

    76.5%

    <0.001

     

    表四、比較不同引導治療方式的 一 般 生 存 率 。

    Chart  4: Comparison of different induced therapy

    disease free survival rate

     

    一年

    1 year

    兩年

    2 years

    三年

    3 years

    化學治療

    Chemotherapy

    75%57% 50%

    ATRA

    82%72% 67%

    p

     0.003  

    Source of the above 4 figures:

    http://www.vghtpe.gov.tw/~tcfund/document/ATRA_APL.HTM   (in Chinese)

     

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