SEARCH

SEARCH BY CITATION

Keywords:

  • bezafibrate;
  • medroxyprogesterone;
  • toxicity;
  • efficacy;
  • acute myeloid leukaemia

Summary

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Supporting Information

Acute myeloid leukaemia (AML) causes life-threatening deficits of functional blood cells that require management using red cell and platelet transfusion and aggressive treatment of neutropenic infections. Current cytotoxic chemotherapy further worsens the problem of reduced haemopoiesis and two-thirds of patients are too frail to tolerate intensive chemotherapy at all. Median survival amongst these patients remains at <3 months emphasizing the urgent need for anti-AML therapies that do not suppress haemopoiesis. Our laboratory studies showed combined Bezafibrate and Medroxyprogesterone acetate (BaP) had activity against AML without toxicity to normal stem cells. Here we report the safety and efficacy of BaP in 20 patients (19 AML, 1 high-risk myelodysplasia) for whom intensive chemotherapy was not an option. No patient exhibited haematological toxicity from BaP. Eleven patients took BaP alone for >4 weeks. One reverted from high risk myelodysplasia and remains transfusion independent after 201 weeks of therapy. Three AML patients gained major haematological improvements for 22–30 weeks; in one, marrow was available to document a partial AML response. Thus, this trial indicates that BaP therapy has potential for treatment of elderly and relapsed AML.

Acute myeloid leukaemia (AML) is characterized by the uncontrolled proliferation, abnormal survival and maturation arrest of the malignant cells. The concurrent loss of normal haemopoiesis creates life-threatening deficits of erythrocytes, platelets, and neutrophils that are managed by supportive care, involving blood and platelet transfusion and aggressive treatment of infection arising in association with neutropenia. Current anti-AML therapies are based on cytotoxic chemotherapy, which directly and problematically further reduces haemopoiesis. Although these therapies achieve complete remission in 60–80% of patients <60 years of age, most relapse with resistant disease and 5-year survival rates amongst this age group remain around 30% (Tallman et al, 2005; Kohrt & Coutre, 2008). Survival in patients >60 years of age, which accounts for three quarters of AML patients, is worse (Burnett et al, 2009). This is largely because older patients cannot tolerate intensive cytotoxic chemotherapy and its associated ablation of normal haemopoiesis (Estey, 2007; Kuendgen & Germing, 2009). Even when deemed fit to receive intensive chemotherapy the survival of older patients is worse than in younger patients receiving similar treatments (Tallman et al, 2005; Burnett & Mohite, 2006; Estey, 2007; Kohrt & Coutre, 2008; Burnett et al, 2009; Wheatley et al, 2009a). Indeed, although recent studies have identified relatively high and low risk groups amongst elderly patients (Wheatley et al, 2009b) little improvement has been made in this group in the last two decades (Tallman et al, 2005; Burnett & Mohite, 2006; Estey, 2007; Kohrt & Coutre, 2008; Burnett et al, 2009; Wheatley et al, 2009a). It is therefore clear that these patients in particular would benefit from therapies that have anti-AML activity and low systemic and haematological toxicity.

Our laboratory studies, together with those of others, have identified the individual anti-proliferative and pro-differentiative actions of medroxyprogesterone acetate (MPA) and bezafibrate (BEZ) against AML cell lines (Bunce et al, 1996; Fenton et al, 1999; Scatena et al, 1999). We have now shown that BEZ treatment of AML cells increased prostaglandin D2 (PGD2) synthesis via the generation of reactive oxygen species (ROS) and activation of the lipid peroxidation pathway, whilst MPA reduced the metabolism of PGD2 away from 15-deoxy-delta12–14-prostaglandin J2 (15d-PGJ2). Combined treatment (BaP) resulted in marked accumulation of PGD2 and 15d-PGJ2 and was associated with growth arrest, apoptosis and cell differentiation in both AML cell lines and primary AML cells; actions that were recapitulated by treatment with15d-PGJ2. Importantly, the actions of BaP had little effect on the survival of normal adult myeloid progenitors (Khanim et al, 2009). The aims of this study were to assess whether the combination of both drugs is well tolerated, without haematological toxicity and to look for evidence of anti-AML activity in the absence of other anti-AML therapies.

Methods

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Supporting Information

Ethics approval was obtained from The South Birmingham Research Ethics Committee (ref: 5355), University Hospitals Coventry and Warwickshire (ref: NJ02/0304/EU), and Glasgow Royal Infirmary (ref: 03HA010).

Eligibility was de novo, secondary or relapsed AML or high-risk myelodysplasia. Patients were not eligible where intensive chemotherapy was an option or low dose cytotoxic chemotherapy was likely to be required to control a rising blast cell count. All patients gave written informed consent prior to initiation of therapy. Enrolment of patients took place between April 2002 and October 2006 in a 2-step design according to the statistical method of Gehan (1961). According to Gehan’s method and as the second patient in the study exhibited an AML response, a total of 25 evaluable patients would have been required to provide an AML response rate [complete response (CR) or partial response (PR)] with a standard error of c.±10%. However, because of slow recruitment and lack of funding, the trial was terminated at 20 patients. Response could be determined in 15 patients who took BaP for >4 weeks, of whom four (in violation of trial protocol) took trial drugs with concomitant low grade anti AML therapy and 11 who took trial drugs alone.

Patients were managed mainly as out-patients as per normal clinical practice for supportive care (blood and platelet transfusion and management of infection arising in association with neutropenia). The trial intervention (BaP) was oral administration of 400 mg per day BEZ (Bezalip-Mono®; Roche Products Ltd., Welwyn Garden City, UK) and 200 mg twice daily MPA (Provera®; Pharmacia & Upjohn Ltd, Milton Keynes, UK). In light of complementary in vitro interactions between BaP and physiological levels of all trans retinoic acid and D3 (Khanim et al, 2009), we ensured patients were not deficient in vitamins A and D by the addition of vitamin A 4000 units and vitamin D 400 units (non-proprietary) at the recommended daily allowance (Gerster, 1997; Institute of Medicine, Food and Nutrition Board., 1999). Intended treatment was for 18 weeks, but could be continued if benefit had been gained and the patient and physician wished to do so.

Baseline measurements included full blood count (FBC) and bone marrow assessment on aspirate and trephine material by morphology, cytogenetic analysis and immunophenotyping. Transfusion dependence (TD) in the previous 3 months was recorded. Patients were assessed at weekly intervals for 4 weeks and fortnightly thereafter with measurement of FBC and TD. Subsequent bone marrow examinations were not mandatory in this group of frail patients with limited life expectancy and many patients declined.

Adverse events were assessed according to the National Cancer Institute Common Toxicity Criteria (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).

Assessment of haemopoiesis was pivotal to detection of its impairment by trial drug toxicity and its improvement through anti-leukaemic activity of trial drugs. We used the haematological response criteria as published by the International Working Group (Cheson et al, 2006) to standardize response criteria for myelodysplasia in which haematological improvement (HI) is described by the number of individual, positively affected cell lineages that lasts for at least 8 weeks. We assessed anti-AML activity of the trial drugs by the International Response Criteria for AML (Cheson et al, 2003).

Results

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Supporting Information

Patient characteristics at entry to trial are given in Table I. Four patients had de novo AML, one relapsed and one refractory AML, 13 patients had AML transformed from pre-existing myelodysplasia whilst one patient had refractory anaemia with excess blasts (RAEB) type 2 according to the World Health Organization classification (Harris et al, 1999). The median age was 75 years; only one patient was <60 years. Eighteen patients required red blood cell (RBC) transfusions, 10 patients required platelet (PLT) transfusions, 10 patients had neutropenia with a severity of four and five patients with a severity of three. Individual ages, presentation white cell counts, WHO performance status, previous haematological and comorbid conditions are provided in Table S1. All patients were followed up to death except one who was still alive in November 2009.

Table I.   Patient characteristics at entry to the trial.
CharacteristicsNo. of patients
  1. RAEB2, refractory anaemia with excess blasts type 2; AML, acute myeloid leukaemia; BM, bone marrow; TD, transfusion dependence; RBC, red blood cell; WCC, white cell count; NEU, neutrophil count; Hb, haemoglobin; PLT, platelet count.

Median age (years)75·5
Sex
 Male15/20
 Female5/20
Diagnosis
 AML19/20
 RAEB21/20
Prior therapy5/20
Transfusion dependent
 RBC18/20
 PLT10/20
Median counts
 WCC (×109/l) 2
 NEU (×109/l) 0·61
 Hb (g/l)92
 PLT (×109/l)35·5
 % BM blasts41%

Overall results for patient outcomes and responses are provided in Table II. As to be expected in a patient cohort with such poor expected survival, five patients took the trial drugs for <4 weeks precluding the measurement of AML responses. One patient stopped the drugs because of depression, three because of neutropenic infection and one because of progressive disease.

Table II.   Patient outcome and responses to BaP therapy.
Patient NoDuration of therapy (weeks)Reason for stopping BaP therapyConcurrent therapyHaematological Response (duration, weeks)AML activity during BaP therapy
HI-EHI-NHI-PDuration for which no change or reduced activityTime of progressive disease (weeks)
  1. Patients are grouped according to duration of and response to BaP therapy.

  2. BM, bone marrow; Na, insufficient time to assess haematological response; HI, haematological improvement; -E, erythroid; -N, neutrophil; -P, platelet; maj, major; min, minor; NI, neutropenic infection; Nc, no change; PD, progessive disease.

BaP alone <4 weeks
 P06 <4DepressionNoNaNaNa22 daysNone
 P08 <4NINoNaNaNa17 daysNone
 P11 <4NINoNaNaNa27 daysNone
 P16 <4PDNoNaNaNa14 days2–3
 P17 <4NINoNaNaNa8 daysNone
Concomitant therapy
 P01 13NIYesNcNcNc13 weeksNone
 P04  6PDYesNaNaNa2 weeks2–6
 P12 18PDYesMaj (18)Maj (15)Nc15 weeks15–18
 P19 28PDYesNcNcNc25 weeks25–28
BaP alone >4 weeks
 P02 29InfectionNoMin (29)Maj (29)Maj (29)29 weeksNone
 P03  6NcNoNaNaNa6 weeksNone
 P05  4·5NINoNaNaNa4·5 weeksNone
 P07  5NcNoNaNaNa5 weeksNone
 P09 10DepressionNoNcNcNc10 weeksNone
 P10 51NINoNcNcNc51 weeksNone
 P13 30Died of infectionNoMin (30)Maj (30)Min (30)30 weeksNone
 P14 15PDNoNcNcNc9 weeks9–15
 P15 39NcNoNcNcNc39 weeksNone
 P18201Still on therapyNoNcMin (201)Min (201)201 weeksNone
 P20 25PDNoMaj (22)Maj (22)Min (22)22 weeks22–25

The remaining 15 patients took the trial drugs for 4·5->201 weeks (median 18 weeks). In four of these patients additional concurrent therapy was given, perhaps reflecting more aggressive disease than in patients who received the trial drugs alone. Patient P04 required the addition of hydroxycarbamide after 2 weeks to control disease progression. Patient P19 had received hydroxycarbamide prior to trial entry and continued to do so after entry; there was no change in FBC or transfusion requirements until progression after 25 weeks of continuous BaP therapy. Patient P01 entered with secondary AML refractory to intensive chemotherapy, but had 13 weeks controlled disease with BaP and etoposide until he developed neutropenic infection. In patient P12, with secondary AML, the addition of BaP to granulocyte colony-stimulating factor and erythropoietin resulted in major erythroid (HI-E) and major neutrophil haematological improvement (HI-N) for 15 weeks of BaP therapy, before disease progression at 18 weeks.

Eleven patients took BaP alone for >4 weeks without concomitant AML therapy. HI’s were more frequent amongst those patients that did not receive concomitant medication and the durations longer. Whilst this may again reflect more aggressive disease in those patients that received concurrent medication the numbers are too small to permit analysis. For 29 weeks P02 had major HI-N and platelet haematological improvement (HI-P) with a minor HI-E and partial AML response (marrow blasts reduced from 58% to 15%). P18 changed from RAEB2 to myelodysplasia (blasts reduced from 14% to 4%) and has been transfusion independent for >201 weeks on BaP therapy. Patient P13 exhibited major HI-N and HI-P with minor HI-E for 30 weeks and patient P20 exhibited major HI-N and HI-E with minor HI-P for 22 weeks of BaP therapy; their AML responses could not be assessed because both patients declined bone marrow aspiration. In the other 7 of 11 patients who received trial drugs alone for >4 weeks, no disease progression was seen for 4, 5, 6, 9, 10, 39 and 51 weeks.

Observation for adverse events known to occur with BEZ or MPA alone and potentially combined revealed two cases of depression (grade 2 and 3) but no other toxicity. We used standard haematological response criteria (Cheson et al, 2000, 2006) as well as AML response criteria (Cheson et al, 2003) to assess for haematological toxicity that could be attributed to BaP. In two patients these measures demonstrated worse haemopoiesis after 2 weeks of BaP therapy (P04 and P16) but in both cases this could be attributed to progression of AML as evidenced by rising numbers of leukaemia myeloblasts in the blood (Table II). In a further two patients no deterioration in haemopoietic function was seen until disease progression after 9 and 25 weeks of continuous BaP therapy (P14, P19). In 11 patients no change in haemopoietic function was seen whilst on BaP therapy for periods up to 51 weeks. In a further five patients clinically important improvements in haemopoietic function were observed on BaP therapy for periods up to 201 weeks (P02, P12, P13, P18, P20).

Discussion

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Supporting Information

A review of 36 AML studies involving a total of 12 370 patients (median age 70 years) found that for AML patients receiving supportive care alone, or supportive care plus non-intensive chemotherapy, median overall survival was only 7·5 and 12 weeks respectively (Deschler et al, 2006). The median age of our patients (75 years) is representative of these patients who, by age and comorbidity, cannot tolerate intensive chemotherapy. Thirteen of our 20 patients had prior myelodysplasia, which is associated with significantly worse survival than de novo AML (Derolf et al, 2009). Consequently our patients represent a group with very poor prognosis and in none of whom would an improvement in haemopoiesis or reduction in disease activity be expected without effective anti-AML therapy (Trof et al, 2007).

Haematological toxicity precludes the continuous use of cytotoxic chemotherapy and hence the necessity that a course of intensive chemotherapy achieves ablation of leukaemia cells below detectable numbers (CR). If CR is not achieved, the leukaemia rapidly re-grows and there is no survival benefit. The International AML response criteria (Cheson et al, 2003) state that CR is the most important initial response reported in phase III trials, precisely because it is the sole outcome currently associated with improved survival. However, in patients deemed unfit for intensive chemotherapy, non-myeloablative therapies may have clinical benefit without achieving CR. Such anti-AML therapies could be administered continuously without haematological toxicity, allowing clinically significant recovery of haemopoiesis by sustained suppression rather than transient ablation of AML activity.

Thus the importance of this study is that it demonstrates the safety of BaP in elderly patients with AML combined with strong evidence of both anti-AML activity and improved haemopoiesis in a proportion of the patients. In stark contrast to cytotoxic chemotherapy, BaP had no haematological toxicity and can be administered continuously. P18 has sustained a partial response and transfusion independence for >201 weeks of continuous therapy. We therefore propose that complete ablation of the leukaemia cells (CR) by BaP may not be necessary to allow haemopoiesis to recover towards normal, improving both quality and duration of life.

Since the trial was stopped, our ongoing laboratory studies had further elucidated the molecular targets of BaP and indicated that the daily doses were sub-optimal (Khanim et al, 2009). The standard lipid lowering dose of 400 mg BEZ once daily used in this trial achieves a peak serum concentration of 22 μmol/l (Roche Products Limited). By using BEZ at a dose of six 400 mg tablets twice daily we can expect to achieve peak BEZ concentrations of 264 μmol/l without significant toxicity (Abshagen et al, 1980; Dollery, 1999). From our laboratory studies this is the optimum concentration of BEZ for anti-AML activity. Similarly our laboratory studies indicate the need to maximize the number of patients who achieve MPA concentrations >1·25μmol/l; this can be safely achieved by increasing the daily dose from 400 mg to 1000 mg MPA (Ohtsu et al, 1998; Thigpen et al, 1999). We therefore propose to trial BaP at higher doses before proceeding to randomized trials.

Acknowledgements

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Supporting Information

We would like to acknowledge Leukaemia Research (LR), UK.

References

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Supporting Information
  • Abshagen, U., Sporl-Radun, S. & Marinow, J. (1980) Steady-state kinetics of bezafibrate and clofibrate in healthy female volunteers. European Journal of Clinical Pharmacology, 17, 305308.
  • Bunce, C.M., Mountford, J.C., French, P.J., Mole, D.J., Durham, J., Michell, R.H. & Brown, G. (1996) Potentiation of myeloid differentiation by anti-inflammatory agents, by steroids and by retinoic acid involves a single intracellular target, probably an enzyme of the aldoketoreductase family. Biochimica et Biophysica Acta, 1311, 189198.
  • Burnett, A.K. & Mohite, U. (2006) Treatment of older patients with acute myeloid leukemia–new agents. Seminars in Hematology, 43, 96106.
  • Burnett, A.K., Milligan, D., Goldstone, A., Prentice, A., McMullin, M.F., Dennis, M., Sellwood, E., Pallis, M., Russell, N., Hills, R.K. & Wheatley, K. (2009) The impact of dose escalation and resistance modulation in older patients with acute myeloid leukaemia and high risk myelodysplastic syndrome: the results of the LRF AML14 trial. British Journal of Haematology, 145, 318332.
  • Cheson, B.D., Bennett, J.M., Kantarjian, H., Pinto, A., Schiffer, C.A., Nimer, S.D., Lowenberg, B., Beran, M., De Witte, T.M., Stone, R.M., Mittelman, M., Sanz, G.F., Wijermans, P.W., Gore, S. & Greenberg, P.L. (2000) Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood, 96, 36713674.
  • Cheson, B.D., Bennett, J.M., Kopecky, K.J., Buchner, T., Willman, C.L., Estey, E.H., Schiffer, C.A., Doehner, H., Tallman, M.S., Lister, T.A., Lo-Coco, F., Willemze, R., Biondi, A., Hiddemann, W., Larson, R.A., Lowenberg, B., Sanz, M.A., Head, D.R., Ohno, R. & Bloomfield, C.D. (2003) Revised recommendations of the International Working Group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. Journal of Clinical Oncology, 21, 46424649.
  • Cheson, B.D., Greenberg, P.L., Bennett, J.M., Lowenberg, B., Wijermans, P.W., Nimer, S.D., Pinto, A., Beran, M., De Witte, T.M., Stone, R.M., Mittelman, M., Sanz, G.F., Gore, S.D., Schiffer, C.A. & Kantarjian, H. (2006) Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood, 108, 419425.
  • Derolf, A.R., Kristinsson, S.Y., Andersson, T.M., Landgren, O., Dickman, P.W. & Bjorkholm, M. (2009) Improved patient survival for acute myeloid leukemia: a population-based study of 9729 patients diagnosed in Sweden between 1973 and 2005. Blood, 113, 36663672.
  • Deschler, B., De Witte, T., Mertelsmann, R. & Lubbert, M. (2006) Treatment decision-making for older patients with high-risk myelodysplastic syndrome or acute myeloid leukemia: problems and approaches. Haematologica, 91, 15131522.
  • Dollery, C. (1999) Therapeutic Drugs. Churchill Livingstone, Edinburgh (Scotland).
  • Estey, E. (2007) Acute myeloid leukemia and myelodysplastic syndromes in older patients. Journal of Clinical Oncology, 25, 19081915.
  • Fenton, S.L., Drayson, M.T., Hewison, M., Vickers, E., Brown, G. & Bunce, C.M. (1999) Clofibric acid: a potential therapeutic agent in AML and MDS. British Journal of Haematology, 105, 448451.
  • Gehan, E.A. (1961) The determinatio of the number of patients required in a preliminary and a follow-up trial of a new chemotherapeutic agent. Journal of Chronic Diseases, 13, 346353.
  • Gerster, H. (1997) Vitamin A–functions, dietary requirements and safety in humans. International Journal for Vitamin and Nutrition Research, 67, 7190.
  • Harris, N.L., Jaffe, E.S., Diebold, J., Flandrin, G., Muller-Hermelink, H.K., Vardiman, J., Lister, T.A. & Bloomfield, C.D. (1999) World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997. Journal of Clinical Oncology, 17, 38353849.
  • Institute of Medicine, Food and Nutrition Board. (1999) Dietary Reference Intakes: Calcium, Phosphorus, Magnesium, Vitamin D and Fluoride. National Academy Press, Washington, DC.
  • Khanim, F.L., Hayden, R.E., Birtwistle, J., Lodi, A., Tiziani, S., Davies, N.J., Ride, J.P., Viant, M.R., Gunther, U.L., Mountford, J.C., Schrewe, H., Green, R.M., Murray, J.A., Drayson, M.T. & Bunce, C.M. (2009) Combined bezafibrate and medroxyprogesterone acetate: Potential novel therapy for acute myeloid leukaemia. PLoS ONE, 4, e8147.
  • Kohrt, H.E. & Coutre, S.E. (2008) Optimizing therapy for acute myeloid leukemia. Journal of the National Comprehensive Cancer Network, 6, 10031016.
  • Kuendgen, A. & Germing, U. (2009) Emerging treatment strategies for acute myeloid leukemia (AML) in the elderly. Cancer Treatment Reviews, 35, 97120.
  • Ohtsu, T., Fujii, H., Wakita, H., Igarashi, T., Itoh, K., Imoto, S., Kohagura, M. & Sasaki, Y. (1998) Pharmacokinetic study of low- versus high-dose medroxyprogesterone acetate (MPA) in women. Cancer Chemotherapy and Pharmacology, 42, 18.
  • Scatena, R., Nocca, G., Sole, P.D., Rumi, C., Puggioni, P., Remiddi, F., Bottoni, P., Ficarra, S. & Giardina, B. (1999) Bezafibrate as differentiating factor of human myeloid leukemia cells. Cell Death and Differentiation, 6, 781787.
  • Tallman, M.S., Gilliland, D.G. & Rowe, J.M. (2005) Drug therapy for acute myeloid leukemia. Blood, 106, 11541163.
  • Thigpen, J.T., Brady, M.F., Alvarez, R.D., Adelson, M.D., Homesley, H.D., Manetta, A., Soper, J.T. & Given, F.T. (1999) Oral medroxyprogesterone acetate in the treatment of advanced or recurrent endometrial carcinoma: a dose-response study by the Gynecologic Oncology Group. Journal of Clinical Oncology, 17, 17361744.
  • Trof, R.J., Beishuizen, A., Wondergem, M.J. & Strack van Schijndel, R.J. (2007) Spontaneous remission of acute myeloid leukaemia after recovery from sepsis. Netherlands Journal of Medicine, 65, 259262.
  • Wheatley, K., Goldstone, A.H., Littlewood, T., Hunter, A. & Burnett, A.K. (2009a) Randomized placebo-controlled trial of granulocyte colony stimulating factor (G-CSF) as supportive care after induction chemotherapy in adult patients with acute myeloid leukaemia: a study of the United Kingdom Medical Research Council Adult Leukaemia Working Party. British Journal of Haematology, 146, 5463.
  • Wheatley, K., Brookes, C.L., Howman, A.J., Goldstone, A.H., Milligan, D.W., Prentice, A.G., Moorman, A.V. & Burnett, A.K. (2009b) Prognostic factor analysis of the survival of elderly patients with AML in the MRC AML11 and LRF AML14 trials. British Journal of Haematology, 145, 598605.

Supporting Information

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Supporting Information

Table SI. List of patients (P1-20) with age in years (yrs), WHO Performance Status (PS), white cell count (wcc), previous haematological conditions and comorbidities.

Please note: Wiley-Blackwell are not responsible for the content or functionality of any supporting materials supplied by the authors. Any queries (other than missing material) should be directed to the corresponding author for the article.

FilenameFormatSizeDescription
BJH_8055_sm_tableSI.doc36KSupporting info item

Please note: Wiley Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.