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ORIGINAL ARTICLE Combined Use of Chinese Medicine with Allogeneic Hematopoietic Stem Cell Transplantation for Severe Aplastic Anemia Patients YE Bao-dong (叶宝东), ZHANG Xiang (张 翔), SHAO Ke-ding (邵科钉), CHEN Dan (陈 ZHANG Yu (张 宇), WU Di-jiong (吴迪炯), YU Qing-hong (俞庆宏), SHEN Jian-ping (沈建平), SHEN Yi-ping (沈一平), and ZHOU Yu-hong (周郁鸿)

丹),

Objective:: To determine the effect of combined treatment with Chinese medicine (CM) and allogeneic ABSTRACT Objective Methods:: Eleven hematopoietic stem cell transplantation (allo-HSCT) on patients with severe aplastic anemia (SAA). Methods patients were treated with CM plus allo-HSCT. Nine patients received a conditioning regimen consisting of fludarabine (Flu), anti-thymocyte globulin (pig ALG), or anti-lymphocyte globulin (Rabbit ATG) and cyclophosphamide (CY), and two patients received pig ALG and CY. All patients were treated with Kidney (Shen)-reinforcing, blood-activating, and stasis-removing (KBS) herbal preparation beginning at 1 week before transplantation and ending at 8 weeks after Results:: transplantation. Chimerism status was assessed by analyzing short tandem repeat (STR) polymorphisms. Results All patients recovered hematopoietic function and none had graft failure. The median number of days required for the absolute neutrophil count (ANC) increased to >0.5×109/L was 15 days (12–22 days) and for spontaneous platelet recovery to >20×109/L without post-transplantation transfusion was 17 days (15–27 days). Nine patients were longterm survivors and achieved full donor chimerism. The overall cumulative incidence of acute graft versus host disease (GVHD) grades Ⅰ–Ⅱ and Ⅲ–Ⅳ was 18.2% (2/11) and 9.1% (1/11), respectively. The overall accumulated incidence of chronic GVHD was 27.3% and all patients had limited chronic GVHD. At a median follow-up time of 32 months (range: 12–97 months), 9 patients were still alive. The estimated 5-year overall survival (OS) rate was 81.8%. The incidence of treatment-related mortality, 2-year post-transplantation, was 18.2%. Two patients died from GVHD after Conclusion:: Treatment with the KBS formulation may reduce the rate of graft failure and treatmenttransplantation. Conclusion related mortality and improve the rate of OS in SAA patients with allo-HSCT. KEYWORDS severe aplastic anemia, allogeneic, hematopoietic stem cell, transplantation, Chinese medicine

A life-threatening bone marrow failure disorder, severe aplastic anemia (SAA), is characterized by pancytopenia and a hypocellular bone marrow. (1) According to the British Committee for Standards in Haematology (BCSH) guidelines, (2) allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the first choice and the best treatment for young patients with SAA, contributing to their long-term survival in about 30%–85% of cases. (3-6) However, the incidence of Ⅱ–Ⅳ acute and chronic graft versus host disease (GVHD) is still high (i.e., 18%–77% and 27%–57%, respectively). (5,7) The rate of graft failure has not changed significantly, and that of graft rejection is about 5%–33%. (5,7-9) The problematic incidence of Ⅱ–Ⅳ acute and chronic GVHD and graft rejection raises the question of whether Chinese medicine (CM) can be used to reduce complications of allo-HSCT, and improve the rate of graft implantation? We previously reported our early results on the use of CM combined with HSCT to

treat patients with leukemia and refractory severe autoimmune disease.(10,11) In the present study, we investigated the effect of CM on treatment with AlloHSCT in 11 cases of SAA.

METHODS Patients and Donor Selection SAA was diagnosed based on criteria described by Camitta(12) and Zhang.(13) Eleven patients with SAA

© The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag Berlin Heidelberg 2014 Supported by State Administration of Traditional Chinese Medicine (No. JDZX2012178), 2011 Special Research Funds for the Traditional Chinese Medicine Industry (No. 201107001) and Zhejiang Provincial Traditional Chinese Medicine Administration Bureau Program (No. 2007CA025) Hematology Department, The First Affiliated Hospital, Zhejiang University of Traditional Chinese Medicine, Hangzhou (310006), China Correspondence to: Dr. YE Bao-dong, Tel: 86-571-86620325, E-mail: [email protected] DOI: 10.1007/s11655-014-2026-9

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[7 males and 4 females; median age 23 years (range 6–46)] received CM combined with allo-HSCT at the Hematology Department, The First Affiliated Hospital of Zhejiang University of Traditional Chinese Medicine from Jan. 2005 to Dec. 2011. The interval between diagnosis and transplantation was more than 2 years in 7 of the patients (63.6%). All patients relied on blood transfusion and 6 of the patients (54.5%) whose ferritin levels were maintained above 1,000 ng/mL were heavily transfused prior to HSCT. Seven of the patients (63.6%) had failed previous antithymocyte globulin (ATG) therapy and/or cyclosporine A (CsA)based immunosuppressive treatment. Six patients were treatment naïve prior to allogeneic HSCT.

Table 1. Characteristics of the Patients Receiving Allo-HSCT [Case (%)] Characteristics of patients

Result

Number of patients

11

Median age in years (Range)

23 (6–46)

Sex (Male/Female)

7/6

Interval between diagnosis and transplantation [Months (%)] 24

7 (63.6%)

Median (Months, range)

16 (2–216)

Karnofsky performance status [Case (%)] Good (80–100)

6 (54.5%)

Poor (0–70)

5 (45.5%)

Prior therapy [Case (%)]

Donors were selected on the basis of best available human leucocyte antigen (HLA) match at the time of transplantation. HLA-A, B, C, DRB1, and DQB1 loci were again confirmed by a high-resolution molecular method for all patients and donors in Dec. 2011. Grafts from a matched sibling donor, a HLA-mismatched related donor, and a HLA-matched unrelated volunteer from the China Marrow Donor Program (CMDP) were transplanted in 9, 1, and 1 patient, respectively, and the unmanipulated peripheral blood stem cells were harvested according to the policies of the National Marrow Donor Program and brought to the transplantation center by courier. The clinical characteristics of the patients and donors are outlined in Table 1.

Androgen+CM

4 (36.4%)

CsA + androgen+CM

6 (54.5%)

CsA + ATG+CM

1 (9.1%)

Ferritin level [Case (%)] 2000 ng/mL

5 (45.5%)

Donor HLA match [Case (%)] Related matched

9 (81.8%)

Related mismatched

1 (9.1%)

Unrelated matched

1 (9.1%)

Donor age Median [Year (range)]

25 (15–39)

Notes: HSCT: hematopoietic stem cell transplantation; CsA: cyclosporine; ATG: anti-thymocyte globulin

Stem Cell Source The stem cell source was only unmanipulated bone marrow (n =2), only unmanipulated peripheral b l o o d (n = 1 ) , o r u n m a n i p u l a t e d b o n e m a r r o w combined with peripheral blood (n =8). The median nucleated cell count was 5.98×108 cells/kg [range (4.21–8.45)×10 8 /kg] and CD34 + cell count was 3.78×10 6 /kg [range (1.79–5.89)×10 6 /kg]. The therapeutic schedules are outlined in Table 2.

Conditioning Regimen Nine patients received the same conditioning regimen [i.e., fludarabine (Flu): 30 mg/m2×5 days, antithymocyte globulin or anti-lymphocyte globulin (pig ALG, Wuhan Institute of Biologicals, Wuhan, China): (25–30) mg/kg×5 day; rabbit ATG (Genzyme Polyclonals S.A.S, Lyon, France): (2.5–3) mg/kg×5 days and cyclophosphamide (CY): (40–50) mg/kg×2 days]. Two patients received anti-lymphocyte globulin (Pig ALG: 25 mg/kg×5 days and CY: 40 mg/kg×4 days).

GVHD Prophylaxis GVHD prophylaxis consisted of mycophenolate mofetil [MMF: (1200–1500) mg/m2 per day], CsA (levels between 200 and 300 ng/mL) and methotrexate (MTX: 15 mg/m2 per day on day +1 and 10 mg/m2 per day on days +3 and +6). Patients were evaluated for GVHD daily during initial hospitalization, and at least once weekly after initial discharge during the first 100 days. Acute GVHD was graded based on findings in skin, liver, and intestinal tract according to the modified Glucksberg criteria as described by Martin, et al.(14,15) Chronic GVHD was characterized as being limited (mild skin involvement only) or extensive.(16) Patients with stage Ⅱ or later GVHD were treated initially with methylprednisolone [(1–2) mg/kg per day, intravenously or oral equivalent] daily for a minimum of 2 weeks prior to tapering.

Treatment CM treatment with a Kidney (Shen)-reinforcing,

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Therapeutic Schedules of the SAA Patients

Item

Result

Number of patients

11

Conditioning regimen [Case (%)] CY+ALG

2 (18.2%)

CY+ALG/ATG+Flu

9 (81.8%)

GVHD prophylaxis [Case (%)] CsA +MTX

2 (18.2%)

CsA+MMF+MTX

9 (81.8%)

Stem cell source [Case (%) ] Bone marrow

2 (18.2%)

Peripheral blood

1 (9.1%)

Bone marrow and peripheral blood

8 (72.7%)

Median number of infused cells (range) Nucleated cells (108/kg)

5.98 (4.21–8.45)

CD34+ cells (106/kg)

3.78 (1.79–5.89)

CM treatment course (Weeks) 8

8 (72.7%)

Notes: CY: cyclophosphamide; ALG: anti-lymphocyte globulin, ATG: anti-thymocyte globulin; Flu: fludarabine; CsA: cyclosporine A; MTX: methotrexate; MMF: mycophenolate mofetil

blood-activating, and stasis-removing herbal formulation started from 1 week before transplantation lasting to 8 weeks after transplantation. The CM syndrome of all patients was re-assessed every week. The Chinese herbal drugs included Radix Rehmanniae Praeparata , Radix Polygoni Multiflori , Semen Cuscutae , Fructus Psoraleae , Herba Epimedii , Radix et Rhizoma Salviae Miltiorrhizae , Radix Angelicae Sinensis , Radix Paeoniae Rubra , Cortex Moutan , and Flos Carthami were formulated as granules by Tianjiang Pharmaceutical Co. Ltd, Jiangsu, China. Written informed consents were obtained from all participants or their representatives prior to study admission.

Engraftment The time to hematopoietic recovery was the interval between the date when transplantation was performed and the date when absolute neutrophil count was >0.5×109/L for 3 consecutive days and platelet count was >20×109/L without transfusion.

Graft Failure Graft failure was classified as: (1) primary non-

engraftment (failure to reach a neutrophil count of 0.5×10 9 /L after transplantation); (2) rejection (decrease in neutrophil count to less than 0.5×109/L after having reached 0.5×109/L); (3) late graft failure, (decrease in blood count beyond day +100, to less than 1×10 9/L neutrophils and less than 30×10 9/L platelets).

Assessment of Chimerism Chimerism status was assessed by analyzing short tandem repeat (STR) polymorphisms. Peripheral blood samples were collected on the day of engraftment and on days 30, 60, and 180 after transplantation for donor chimerism studies. Serial STR polymerase chain reaction analysis was used to confirm the conversion from mixed chimerism to a predominantly donor type.

Supportive Care All patients were isolated and treated in single laminar air flow rooms. Ofloxacin, fluconazole, and acyclovir were used as prophylaxis for infection. Sulfamethoxazole was given for Pneumocystis carinii prophylaxis. Intravenous immune globulin (0.5 g/kg) was infused weekly until day 100, and then monthly until day 180. When fever exceeded 38 ℃, broadspectrum antibiotics were administered. Transfusions were given to maintain the hemoglobin level above 80 g/L and the platelet count above 20×10 9 /L. All blood products were irradiated with 20 Gy or leukofiltered to avoid the risk of acute GVHD induction. Granulocyte colony stimulating (G-CSF) 300 mg/m2 was administered on day 6 after transplantation and then discontinued when the absolute neutrophil count (ANC) increased to more than 1.0×109/L for 3 consecutive days. Prophylactic lipo-PGE1 was given for veno-occlusive disease (VOD).

Statistical Analysis Statistical analysis was performed by using SPSS for Windows (version 15; Chicago, IL, USA). Survival curves for overall survival (OS) and treatment-related mortality (TRM) were estimated by the Kaplan-Meier method. Statistically significant differences existed when P 0.5×10 /L

15 (12–22)

9

17 (15–27)

platelet >20×10 /L Graft failure At 100 days

0

At 1 year

0

Chimerism data On days 30 post transplantation (n =11)

8 (72.73%)

On days 60 post transplantation (n =11)

11 (100%)

On days 180 post transplantation (n =10)

10 (100%)

Acute GVHD at 100 days Grades (Ⅰ–Ⅱ) Grades (Ⅲ–Ⅳ)

2 (18.2%) 3 (27.3%)

Serious infection

1 (9.1%)

Veno-occlusive disease

0

Hemorrhagic cystitis

1 (9.1%)

Overall survival

CM Syndrome Type Analysis Before transplantation, "Kidney yin deficiency syndrome" was diagnosed in 2 patients, "Kidney yin and yang deficiency syndrome" in 6, "Spleen (Pi)Kidney yang deficiency syndrome" in 2, and "severe heat toxin" in 1. All patients received the Kidneyreinforcing, blood-activating, and stasis-removing formulation beginning at 1 week before transplantation. Although the conditioning regimen was mild, treatment was interrupted because of nausea and vomiting on day 10 after transplantation in 1 patient and because of diarrhea within 6 weeks after transplantation in 2 patients. The tolerance of the formulation was good in 8 patients treated for 8 weeks.

1 (9.1%)

Accumulated chronic GVHD

Days of follow-up (Month)

all 9 patients who survived on day 120.

32(12–97) 9 (81.8%)

Notes: ANC: absolute neutrophil count; graft versus host disease: GVHD

Engraftment and Graft Failure All patients achieved neutrophil and platelet engraftment. The median number of days required to reach an absolute neutrophil count (ANC) of >0.5×109/L was 15 (range 12–22) and platelet count of >20×109/L without transfusion post-transplantation was 17 (range 15–27). All patients became transfusion independent. Among the nine long-term survivors who achieved complete donor hematopoiesis on bone marrow examination, seven showed complete hematologic recovery and two failed to show complete platelet count recovery to (70–80)×109/L. No graft failures occurred and no late graft failure has yet occurred, except in one patient (who died on day 45 post-transplantation).

Chimerism Data On day 30 after transplantation, STR-PCR analysis confirmed the establishment of full donor chimerism in 8 of the 11 patients (72.7%) and almost full donor chimerism (82.0% and 85.0%, respectively) in two patients (27.3%). Full donor chimerism was established in 10 patients who survived on day 60 and

All patients after transplantation had a pale complexion, palpitation and shortness of breath, dizziness and fatigue, macular rash on the skin, redness on the tip and edge of the tongue, thin lingual fur with little fluid, and rapid pulse. "Severe heat toxicity" due to high fever was diagnosed in 1 patient, and "Kidney deficiency and blood stasis" was diagnosed in 10 (90.9%). Eight patients recovered who received the Kidney-reinforcing, blood-activating and stasis-removing formulation for more than 8 weeks and was regarded as long-term survivors. Among 3 patients who received the treatment less than 6 weeks, 1 who died from acute intestinal GVHD on day 45 had an interruption of the treatment because of nausea and vomiting, and 1 died from chronic intestinal GVHD on day 167.

GVHD and Other Complications The overall cumulative incidence of acute GVHD grades Ⅰ–Ⅱ and Ⅲ–Ⅳ was 18.2% (2/11) and 9.1% (1/11), respectively. Two patients developed grades Ⅰ–Ⅱ acute skin GVHD, which resolved instantly with administration of low-dose methylprednisolone on day +25 and +42, respectively. One patient developed grade Ⅳ acute intestinal GVHD on day +22 and died on day +45 despite treatment with CD25 and FK 506. The overall accumulated incidence of chronic GVHD was 27.3%, and in all cases, it was limited. One patient developed hemorrhagic cystitis on day +32, which resolved instantly with hyperhydration, urinary alkalinization, and diuresis. A child patient who developed disseminated fungal infection due to

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Rhizopus microspores 1 year after transplantation was successfully treated with hepatic drainage and amphotericin B.

Overall Survival Two patients died from after transplantation: one from early GVHD (within 100 days after transplantation: early mortality 9.1%) and the other from chronic intestinal GVHD on day 167. The estimated 5-year overall survival (OS) rate was 81.8%. The incidence of TRM 2 years after transplantation was 18.2% (Figure 1). With a median follow-up time of 32 months (range: 12–97), 9 patients remained alive. A

1.0

Proportion surviving

0.8

with ATG and/or CsA and remain reliant on blood transfusion, the allo-HSCT is perhaps the only available curative therapy. However, the procedure is associated with problems like graft failure, GVHD, and infections, which are major causes of death.(5,6) Over the past decade, changes in the conditioning regimen, more stringent criteria of HLA compatibility for donor selection, and improved supportive care have greatly reduced transplant-related mortality in patients with SAA. But the optimal conditioning regimen has not yet been established. One study showed a better outcome in patients who receive a combination of Flu, CY, ATG, and low dose (2 Gy) total body irradiation than in those who only receive a combination of Flu, CY, and ATG (FCA). (5) In the FCA group, the actuarial 5-year survival was 73% and the incidence of acute GVHD grade Ⅲ–Ⅳ was 18%. In both groups combined, the overall cumulative incidence of graft failure was 17.0% (17 of 100 patients).

0.6

Since radiation has a negative effect on growth, development, endocrine function, fertility, and so on,(17) the non-radiation fludarabine-based conditioning regimen has been studied further. Although the results have been promising,(18) TRM remains high.

0.4

0.2

0 0

40.0 60.0 80.0 20.0 Months after allo-HSCT

100.0

0

40.0 60.0 80.0 20.0 Months after allo-HSCT

100.0

DISCUSSION

Can we use CM to reduce the severity of alloHSCT-related complications in patients with SAA, and improve the rate of graft implantation? In the present study, we assessed the effectiveness of CM combined with HSCT in patients with leukemia and refractory severe autoimmune disease. We preliminarily found Kidney deficiency and blood stasis presented in nearly all of the patients who received HSCT within 2 months after transplantation, so we prescribed treatment with a Kidney-reinforcing, blood-activating, and stasis-removing herbal formulation. Allo-BMT combined with CM was previously shown to effectively reduce the incidence of acute severe GVHD and raise the disease-free survival rate in treated leukemia patients.(11) We also found that combined use of CM with auto-hematopoietic stem cell transplantation could accelerate hematopoiesis, restore hematologic function, and significantly reduce the severity of complications, clinical symptoms, and signs.(10,12)

Allo-HSCT, the only curative therapy to date, and immunosuppressive therapy (IST) are the predominant treatments for SAA. For patients who have failed a previous immunosuppressive treatment

"Aplastic anemia (AA)" does not appear in the Incunabula of CM, and may be considered (based on clinical manifestations) to be "Consumptive

B Treatment-related mortatity

1.0

0.8

0.6

0.4

0.2

0

Figure 1. Kaplan-Meier Analysis of Data from 11 Patients Undergoing Allo-HSCT Note: (A) Five-year overall survival and (B) Two-year treatment-related mortality

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Diseases"(虚劳) or "Hemorrhagic syndrome"(血证). Our department, with 50 years' experience in the treatment of AA with CM, defines "four patterns and three stages" of acute AA.(19) In our study, 11 SAA patients received AlloHSCT combined with our Kidney-reinforcing, bloodactivating, and stasis-removing formulation beginning 1 week before transplantation and ending 8 weeks after transplantation. A combination of Flu, CY, and ATG (FCA) was the conditioning regimen in most cases. The outcome of the treatment was inspirational. All patients recovered hematopoietic function and no patients experienced graft failure. Donor chimerism was complete in all 9 patients who were long-term survivors. This suggests that Kidney-reinforcing, blood-activating, and stasis-removing treatment can improve engraftment of hematopoietic stem cells and reduce the risk of graft failure. One study found that infusion of mesenchymal stem cells (MSCs) can enhance engraftment of hematopoietic stem cells and reduce the risk of graft failure in children with SAA. (20) Our previous study indicated a deficiency in the number and proliferative ability of bone marrow MSCs in AA patients and improvement in the effectiveness of bone marrow MSCs by treatment with the Kidney-reinforcing, blood-activating, and stasis-removing formulation, probably through increasing expression of MSC adhesion molecules and quality of the bone marrow hematopoietic microenvironment. Therefore, we consider that the Kidney-reinforcing, blood-activating, and stasis-removing formulation could improve implantation rate in SAA patients.

with SAA and pre-transplant serum ferritin level over 1,000 ng/mL were long-term survivors. Therefore, treatment with the Kidney-reinforcing, blood-activating, and stasis-removing formulation may also improve the OS rate of SAA patients with high serum ferritin level. Our study has its limitations due to its retrospective nature and cases are partial less, but these results suggest that treatment with the Kidney-reinforcing, bloodactivating, and stasis-removing formula may reduce the rate of graft failure, reduce the rate of treatment-related mortality, and increase the rate of OS in SAA patients with allo-HSCT. Prospective studies to evaluate the role of Kidney-reinforcing, blood-activating, and stasisremoving therapy with larger samples are needed.

Conflicts of Interest All the authors do not have any possible conflicts of interest.

Author Contributions Ye BD designed the subject and revised the article. Shao KD, Chen D, Zhang Y, Yu QH and Shen JP collected cases. Zhang X and Wu DJ performed the statistical analysis. Shen YP and Zhou YH provided their advice. All authors approved the final version of the article.

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Combined use of Chinese medicine with allogeneic hematopoietic stem cell transplantation for severe aplastic anemia patients.

To determine the effect of combined treatment with Chinese medicine (CM) and allogeneic hematopoietic stem cell transplantation (allo-HSCT) on patient...
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