Traditional chinese herbal medicine in the supportive management of patients with chronic cytopaenic marrow diseases - a phase i/ii clinical study

Complementary Therapies in Clinical Practice Traditional Chinese herbal medicine in the supportive management of patientswith chronic cytopaenic marrow diseases e A phase I/II clinical study Yeh-ching Linn ,Jiahui Lu Lay-cheng Lim , Huili Sun , Jue Sun , Yongming Zhou a Department of Haematology, Blk 6 Level 5, Singapore General Hospital, Outram Road, Singapore 169608, Singaporeb Department of Haematology, Yueyang Hospital, No. 110, Ganhe Road, Shanghai 200437, Chinac Bao Zhong Tang TCM Center, Blk 5 Level 1, Singapore General Hospital, Outram Road, Singapore 169608, Singapore We report on a phase I/II, single arm clinical trial studying the safety and efficacy of Traditional Chinese Medicine (TCM) in patients with various chronic cytopaenic marrow diseases including myelodysplastic syndrome (MDS), myelofibrosis (MF), aplastic anaemia (AA) and thalassemia intermedia, who either have failed, are unfit for or refused currently available Western medical treatment. Patients took oral herbal concoctions according to their TCM syndromes for 24 weeks while continuing with western medicalmanagement. The median age of this group of 31 patients was 61 (26e84) years old and median diseaseduration was 5 years (0.3e40 years). TCM herbs were well tolerated in these patients with multiplecomorbidities and previous disease-related complications. Twenty-three patients completed the studywith 5 (2 with MDS, 2 with MF and 1 with SAA) achieving some degree of haematological improvement.
EORTC quality of life indicators improved in more than half of patients. This small study offers positiveresults and provides the basis for future larger studies which should randomize patients with MDS, MFand AA managed with standard Western medical treatment to without and with upfront combinationswith TCM herbs. This will conclusively define the role of TCM in the supportive management of thesediseases. This study was registered with as NCT01224496.
Ó 2011 Elsevier Ltd. All rights reserved.
modern medical practice the best supportive care for such patientsincludes transfusion support, growth factors, myelosuppressants, Chronic cytopaenia is a common and problematic manifestation iron chelation therapy and treatment directed towards ameliorating of a broad range of haematological diseases, especially in non- malignant conditions such as myelodysplastic syndrome (MDS), Traditional Chinese Medicine (TCM) is a comprehensive system myelofibrosis (MF), aplastic anaemia (AA) and thalassemia (thal), of medical practice with a long history of over 2000 years. While it where the disease may run a protracted course. Over the past 2 is regarded as a form of “Complementary and Alternative Medicine” decades, significant advances have been made in the management by the orthodox medical community, it enjoys equal status as of these diseases. This has included immnosuppressive therapy, Western Medicine (WM) in the healthcare system in China and is haemopoietic stem cell transplant and targeted therapies that are often integrated with WM to a variable degree in the management still in various stages of clinical trial. There is however, a large of many diseases, including haematological diseases. In the Chinese proportion of patients who will not benefit from these modalities literature, there is an abundance of basic science studies on the due to significant comorbidities that preclude them from high risk activity of single herbs or herbal concoctions on haemopoiesis in treatment or other factors such as high cost or unavailability of normal or diseased marrow.Clinical reports of varying level of medical expertise. Thus for most of these patients, their manage- evidence range from single case reports, case series to comparative ment is largely supportive with an emphasis on ameliorating cyto- trials.In the use of TCM for the management of various chronic paenia, preventing complications and improving quality of life. In haematological diseases, TCM herbs are used either alone or oftenin combination with WM. These clinical reports generally demon-strate encouraging improvements in the cytopaenia and well being * Corresponding author. Tel.: þ65 6321 4855; fax: þ65 6225 0210.
In Singapore, a unique scenario exists whereby although WM is (J. Lu), (L.-c. Lim), (H. Sun),(J. Sun), (Y. Zhou).
the mainstream healthcare system, TCM is commonly used alongside 1744-3881/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi: Please cite this article in press as: Linn Yeh-ching, et al., Traditional Chinese herbal medicine in the supportive management of patients withchronic cytopaenic marrow diseases e A phase I/II clinical study, Complementary Therapies in Clinical Practice (2011), doi:10.1016/j.ctcp.2011.01.004 Y.-c. Linn et al. / Complementary Therapies in Clinical Practice xxx (2011) 1e5 WM and is widely consumed by patients on their own often without changes in the patients’ symptoms. Details of the criteria for their physicians’ knowledgThis often raises concerns on the syndrome classification, composition of each standard formulation part of the treating WM physician when attempting to consider and herbs allowed for addition are shown in possible adverse reactions which may include a deterioration of The TCM herbs were imported in bulk from a regular source in cytopaenia, organ toxicity or drugeherb interaction. As haematolo- Shanghai and were brewed and vacuum-packed by the TCM gists in a tertiary care WM hospital, we were interested in exploring pharmacy serving the TCM center. Each preparation provided 3e4 additional treatment modalities that may improve the outcome of weeks medication. The vacuum packets of 160 mL per dose were patients with chronic cytopaenic marrow diseases in whom we do refrigerated at home and consumed on an outpatient basis twice not have much to offer beyond supportive care. Studying the use of TCM for this group of patients in the context of a clinical trialtherefore is meaningful and of great relevance.
Patients were screened at baseline for blood counts, urea, electrolytes, creatinine, liver panel, viral markers and G-6PD status.
This is a phase I/II, single arm interventional study to explore the A pre-recruitment marrow study was requested if this had not been safety and efficacy of TCM in a defined group of patients, conducted done within the last one year or if there was a suspicion of disease in the Singapore General Hospital (SGH). It involved collaboration progression since the last marrow study. Each visit involved a joint between WM haematologists from SGH and TCM haematologists consultation with both WM and TCM haematologists who evalu- from the Shanghai Yueyang Hospital of Integrated Chinese and ated the patient together and conducted the appropriate patient Western Medicine, together with residential TCM oncologists from management. This included prescriptions of ongoing WM drugs the Bao Zhong Tang TCM Center situated in SGH. Suitable patients and transfusion support by the WM haematologist, assessment and from SGH or other public hospitals were recruited into this study prescription of TCM formulation by the TCM haematologist.
during the 6-month period between July 2009 and Dec 2009. The Patients were reviewed at one week after commencement of the study was approved by the Central Institutional Review Board and TCM herbal concoction and then every 3e4 weekly depending on done in accordance to the Helsinki declaration. It was registered the frequency of transfusion of each patient. FBC was done at every visit; biochemistry was done at one week into the study and every8e9 weeks thereafter. The duration of the study was 24 weeks for each patient. For the quality of life evaluation, patients filled in theEORTC-QLQC30 at the first and last visits with the study coordi- Inclusion criteria included patients between ages of 15e85 years nator. The QOL was analyzed and interpreted according to pub- with a diagnosis of MDS, AA, MF or thal based on published criteThe patients must have been assessed to be unfit, orhave declined or failed established therapies such as haemopoietic stem cell transplant, immunosuppressive therapy, chemotherapy,growth factors, thalidomide, hypomethylating agent or androgens.
A total of 31 patients were recruited into the study. This was Each patient must have undergone a preceding follow up period a generally elderly cohort with a long duration of disease. Twenty- with or without treatment for at least 3 months as a baseline before two out of the 31 patients had failed previous treatments. Twenty- being enrolled into this study. They must understand the trial four patients had significant comorbidities and 11 had a history of nature of this treatment, agree to be compliant to medication, not serious complications. Twenty-three were transfusion dependent to self medicate and have signed informed consent.
and 6 patients had severe thrombocytopaenia. summarizes Exclusion criteria: all patients entered into the study must not the pre-treatment characteristics of the whole group.
have a life expectancy of shorter than one year. Significant organfailure defined as (a) renal impairment with serum creatinine above 200 mmol/L (b) liver impairment with serum bilirubin > 2Âupper limits or transaminase >3Â upper limits were excluded.
The most common side effect reported was mild gastrointestinal Women who were pregnant or lactating were excluded.
symptoms such as bloating (n ¼ 4), loose stools (n ¼ 6) and con- During the study period, continuation of ongoing therapy for the stipation (n ¼ 2). Polyuria was reported by 2 patients. All symptoms haematological disease at same dose was allowed but escalation of resolved after minor adjustment to the composition of the herbal treatment or the introduction of any new agents was not allowed.
concoctions. There were no changes observed in renal or liver All other ongoing medications for other comorbidities continued function when compared to their baseline levels. Three patients with thalassemia intermedia had an increase in serum bilirubinfrom their already elevated baseline but without an increase in transfusion requirements. Two patients with diabetic nephropathyon angiotensin receptor blocker developed hyperkalaemia in rela- Each patient was classified into one of the following 4 TCM tion to TCM ingestion. This resolved after stopping the TCM syndromes based on the principles of TCM theory and published ingestion, detailed discussion of these 2 cases will be reported in diagnostic criteria: (1) Yin deficiency of liver and kidney, (2) Yang deficiency of spleen and kidney, (3) Deficiency of both Yin and Yang,and (4) Stagnation of dampness and poison in the blood. The “liver”, “kidney” and “spleen” are TCM concepts of function rather than thespecific organs in the WM anatomical sense, similarly “dampness” Eight patients dropped out at a median of 7 weeks (range 1.7e9 and “poison” are TCM descriptions of various pathogenic factors weeks) after joining the study. One patient with secondary MF and and not their literal meaning. A corresponding standard formula- one patient with MDS developed leukemic transformation at 4 tion consisting of 12 herbs was used for each of the syndromes, but weeks and 9 weeks after joining the study respectively. One patient allowing for modification in the herbal composition according to who had occult gastrointestinal bleeding likely present before Please cite this article in press as: Linn Yeh-ching, et al., Traditional Chinese herbal medicine in the supportive management of patients withchronic cytopaenic marrow diseases e A phase I/II clinical study, Complementary Therapies in Clinical Practice (2011), doi:10.1016/j.ctcp.2011.01.004 Y.-c. Linn et al. / Complementary Therapies in Clinical Practice xxx (2011) 1e5 Summary of patients’ characteristics.
Improvement in quality of life indicators.
Myelodysplastic syndrome ¼ 16 (IPSS 0 ¼ Myelofibrosis ¼ 6 (Lilles 1 ¼ 3;2 ¼ 3);MPN-U Changes in the QOL indicators for the subset of 15 MDS and MF patients are presented in bold and for all 23 patients who completed the study are presented in italics.
Total ¼ 11 (DKA ¼ 1; HHNK ¼ 1; DAH ¼ 1; liver abscess ¼ 2; neutropenic sepsis ¼ 2; This included 2 patients with MDS, 2 with MF and 1 with SAA. Their pneumonia ¼ 2; melioidosis ¼ 1; Sweet’s As the EORTC-QLQC30 is designed for patients with malignancy, Failed erythropoietin ¼ 12; Failed androgen Æ fined to the subset of 15 patients with MF and MDS only. Assessment of QOL indicator for these 15 patients thymocyte globulin) ¼ 7; Failed transplant ¼ 1; showed an improvement in half to two-thirds of patients in the functional scale, symptom scale and global health status, as shown in When analysis was extended to include the whole group (1) Yin deficiency of liver and kidney ¼ 15(2) Yang de of 23 patients who completed the study, a similar outcome was (3) Deficiency of both Yin and Yang ¼ 8 observed. An additional question at the completion of study was included to ask whether patients wished to continue on TCM if it were continued to be provided free of charge. This yielded a posi- IPSS ¼ International Prognostic Scoring System; MPN-U ¼ myeloproliferative tive response in 16 of the 23 (70%) patients.
neoplasm-unclassifiable; DKA ¼ diabetic ketoacidosis; HHNK ¼ hyperglycemichyperosmolar nonketotic coma; DAH ¼ diffuse alveolar haemorrhage.
recruitment, where the source could not be identified, was dis- As far as we know, this is the first report on a prospective clinical qualified from the study. One patient with MF developed acute study conducted in a tertiary care WM Haematology unit outside cholecystitis and Escherichia coli bacteraemia at 12 days into the China on the use of TCM herbal preparation for patients with study and succumbed to complications. Others included severe various advanced chronic haematological diseases. Our patient drug allergy to allopurinol (n ¼ 1), recurrent hyperkalaemia cohort had the common feature of significant cytopaenia for whom, thought to be related to TCM herbs (n ¼ 1) and loss of interest currently available WM treatment was not viable options, due (n ¼ 2). Therefore 23 patients completed 24 weeks of TCM herbs.
to either previous treatment failure, significant comorbidities orrefusal. To offer an alternative treatment modality to this group of patients in the context of a clinical study is therefore ethicallyacceptable in our healthcare setting.
Out of the 23 patients who completed the study, 5 had an Use of TCM in combination with WM is common practice in improvement in their blood counts based on published criteri China and therefore routinely adopted in first line management of Table 2Characteristics of responders.
CsA/Pred/androgen Hb 4.3e6.3 g% (6.3 g%), PRV ¼ Polycythemia rubra vera, PR ¼ partial response, HI-E ¼ haematological improvement in erythrocyte, HI-N ¼ haematological improvement in neutrophil, Hypo-MDS ¼ hypoplastic MDS, ATG ¼ anti-thymocyte globulin, CsA ¼ cyclosporine A, MDS-U ¼ MDS-unclassifiable.
Please cite this article in press as: Linn Yeh-ching, et al., Traditional Chinese herbal medicine in the supportive management of patients withchronic cytopaenic marrow diseases e A phase I/II clinical study, Complementary Therapies in Clinical Practice (2011), doi:10.1016/j.ctcp.2011.01.004 Y.-c. Linn et al. / Complementary Therapies in Clinical Practice xxx (2011) 1e5 these diseases. Its early introduction could explain the much higher different from that of WM. Traditionally TCM formulations include response rate reported in the TCM literature. In the treatment of a customized combination of herbs according to the patient’s MDS patients, an overall response rate of 70% is generally reported syndrome, which is classified based on a range of subjective symp- for patients treated with various TCM concoctions prescribed based toms including pulse and tongue signs. While there is inevitable on TCM syndromes without or with concurrent WM treatment, and inter-observer variation, subjectivity is minimized by adherence to is often superior to the group treated with WM alone in compar- a set of diagnostic criteria, as listed in . The pros ative Similar results were obtained for treatment of and cons of a fixed versus a flexible combination have been exten- and MFwith TCM concoctions. Even in patients with sively discussed in the context of TCM study methodology.The thalassemia intermedia a response to TCM treatment was also former approach enables analysis in the manner like any drug study, repattributed to the increase in expression of gamma allowing for reproducibility and widespread use, therefore more chain gene resulting in an increase in haemoglobin F,a mecha- readily acceptable from the perspectives of Evidence-based medicine nism similar to that induced by hydroxyurea. However, in this study (EBM) standards. On the other hand, prescribing based on each done in the setting of our healthcare system, TCM was not offered patient’s unique constitution is a practice inherent in the TCM upfront in the inclusion criteria. Twenty-two out of the 31 patients principles of individualized treatment. While it poses a difficulty in had failed multiple lines of treatment, therefore in terms of disease making definitive conclusions on the efficacy of specific treatment biology, these patients are more likely to have diseases refractory to formulations, it is upheld as the optimal treatment approach by TCM treatment. TCM added onto their ongoing supportive management physicians. For the purpose of exploring whether TCM can be of resulted in a modest response in 2 out of 16 MDS, 2 out of 6 MF and benefit to this particular group of patients, we attempted to reconcile 1 out of 2 SAA patients. There did not seem to be any pre-treatment the two approaches by standardizing formulations corresponding to factors that could predict likelihood of response to treatment. None 4 TCM syndromes, while allowing some modifications based on of the 6 patients with thalassemia intermedia had a response.
patients’ symptoms. With this strategy we aimed to reflect the actual Many of the herbs used for the TCM syndromes in this clinical TCM usage in a non-study context, while not too severely compro- study fall into the categories of “nourishing spleen and kidney” and mising the quality from an EBM perspective. At the least, this “nourishing blood and Qi” according to TCM theory. Modern approach provides the basis for future studies which should then biomedical science has found that many of these herbs have focus on refining the treatment regimen.
properties that potentiate the immune system and haemopoiesis.
In conclusion, this study shows that TCM can improve blood Astragalus root and Rehmannia root are the most common herbs counts in some patients with MDS, AA and MF who do not have used in the standard formulation for 3 out of the 4 TCM syndromes other treatment options. It was also notable that QOL can improve defined in this clinical study. They promote haemopoiesis by independently of an objective haematological response, therefore various mechanisms including proliferation of colony forming unit making this as an invaluable option for the supportive care for this of haemopoietic progenitand stromal suppression of group of patients. Further randomized controlled studies in a larger inflammatory cytokines,inhibition of apoptosis,and inhibi- group of homogenous patients treated as first or second line tion of aberrant signaling pathwayOther component herbs in the treatment in combination with standard WM management should formulations are also reported to have immune-regulatory activi- be carried out. This will provide high level evidence on the efficacy ties (Wolfberry Fruit, Glossy Privet Fruit, Fresh Turtle Shell, of TCM and define its role as a treatment option for this group of Heterophylly false starwort Root, Moutan Bark, Codonopsis Root, chronic cytopaenic haematological diseases.
Epimedium, Psoralea Fruit, Morinda Root, Eclipta, etc) or haemo-poiesis-promoting activities (Angelica Root, Chinese Yam, Wolf- berry Fruit, Glossy Privet Fruit, Notoginseng, Codonopsis Root,Epimedium, Psoralea Fruit, The authors acknowledge Ms. Li Xiaomei and Mr. Darius Seow of Our study involved a cohort of patients with multiple comor- Singapore General Hospital in coordinating this clinical study, and bidities and therefore with increased susceptibility to adverse all the staff of Bao Zhong Tang TCM Center for providing their reactions and drugeherb interactions which were major concerns assistance in this clinical study. This work was supported by the of their WM doctors. We have shown in this study that the use of SingHealth Research Foundation SHF/TCM002/2008.
TCM even in this group of patients with multiple comorbidities islargely safe and well tolerated. In patients with impaired renal function especially with concomitant usage of potassium con- The authors declare that there is no conflict of interest.
serving drugs, regular monitoring of serum potassium is warrantedas the potassium content in a formulation of largely plant origin can add a further potassium load which may overwhelm the potassiumexcretion capacity of kidneys with impaired function. While some Supplementary data associated with this article can be found in herbs are known to have myelosuppressive properties, we did not observe any deterioration in blood counts in the non-responders asour formulations did not contain any of these herbs.
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Please cite this article in press as: Linn Yeh-ching, et al., Traditional Chinese herbal medicine in the supportive management of patients withchronic cytopaenic marrow diseases e A phase I/II clinical study, Complementary Therapies in Clinical Practice (2011), doi:10.1016/j.ctcp.2011.01.004


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