Late chimerical status after bone marrow transplantation in severe aplastic anemia according to two different preparatory regimens

Quiroga, Marcia; Pereira, Noemi Farah; Bitencourt, Marco Antonio; Bonfim, Carmem; Monteiro, Marianna Gendre de Mesquita; Pasquini, Ricardo

doi:10.1016/j.htct.2017.11.011

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Hematology, Transfusion and Cell Therapy

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Original articles • Hematol., Transfus. Cell Ther. 40 (2) • Apr-Jun 2018 • https://doi.org/10.1016/j.htct.2017.11.011 copy

Late chimerical status after bone marrow transplantation in severe aplastic anemia according to two different preparatory regimens

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Background:

This study investigated the influence of two conditioning regimens on the chimerical status of 104 patients with acquired severe aplastic anemia.

Methods:

Patients were monitored for at least 18 months after related bone marrow transplantation and reaching partial or complete hematologic recovery. Group I patients (n = 55) received 200 mg/kg cyclophosphamide alone and Group II (n = 49) received 120 mg/kg cyclophosphamide associated with 12 mg/kg busulfan. Patients were classified in three chimerism levels according to the percentage of donor cells in the peripheral blood.

Results:

Chimerism ≤50% occurred in 36.4% of Group I and none of Group II; chimerism 51–90% was found in 20.0% of Group I and 10.2% of Group II; and chimerism >90% was found in 43.6% of Group I versus 89.8% of Group II. A significant association (p-value < 0.001) was found between conditioning type and chimerism levels. A higher number of infused cells was associated with higher levels of chimerism only in Group I (p-value = 0.013). Multivariate analysis showed that chimerism >90% is associated with the cyclophosphamide plus busulfan conditioning (p-value < 0.001) and higher number of infused cells (p-value = 0.009), suggesting that these factors are predictive of graft outcome. Regarding hematological recovery, higher chimerism levels were associated with higher neutrophil (p-value = 0.003) and platelet counts (p-value < 0.001) in Group I only. These results show that myeloablative conditioning favors full donor chimerism and non-myeloablative conditioning predisposes to mixed chimerism or autologous recovery of hematopoiesis.

Conclusion:

These data show that autologous recovery depends on the intensity of immunosuppression and that the immunosuppressive function of cyclophosphamide alone can induce this type of hematopoietic recovery.

Keywords:
Severe aplastic anemia; Bone marrow transplantation; Conditioning regimen; Chimerism

Characteristic	Conditioning CY alone	Conditioning CY + BUS
Number of patients	55	49
Age (years) – median (range)	17 (1–35)	18 (6–45)
Gender (M/F)	40/15	34/15
Transfusions before BMT – median (range)	10 (1–60)	30 (16–238)
<16 – n (%)	44 (80.0)	0 (0)
≥16–50 – n (%)	10 (18.2)	43 (87.8)
>50 – n (%)	1 (1.8)	6 (12.2)

Previous treatment – n (%)
None	42 (76.4)	29 (59.2)
PDR	8 (14.5)	5 (10.2)
Cyclosporin-A + PDR	3 (5.5)	8 (16.3)
Androgens + PDR	1 (1.8)	2 (4.1)
Others	1 (1.8)	5 (10.2)

Time diagnosis-BMT (months) – median (range)	2 (0–36)	3 (0–127)

Characteristic	Conditioning CY alone	Conditioning CY + BUS
Number of patients – n (%)	56/119 (47)	63/119 (53)
Age (years) – median (range)	19 (3–44)	20 (2–46)
Gender (M/F) – n	33/23	32/31
Transfusions before BMT – median (range)	30 (5–229)	41 (12–292)
<16 – n (%)	14 (25.0)	0 (0)
≥16–50 – n (%)	27 (48.2)	34 (54.0)
>50 – n (%)	15 (26.8)	29 (46.0)

Time from diagnosis to BMT (month) – median (range)	4 (1–232)	5 (1–94)
Patients with chimerism testing – n (%)	7/56 (12.5)	20/63 (31.7)
Chimerism ≤50%	4/7 (57.1)	7/20 (35)
Chimerism 51–90%	1/7 (14.3)	6/20 (30)
Chimerism >90%	2/7 (28.6)	7/20 (35)

Day post-BMT at last chimerism testing – median (range)	762 (38–3951)	181 (27–4074)
Causes of death – n (%)
Bacterial infection	6/56 (10.7)	9/63 (14.3)
Fungal infection	4/56 (7.1)	9/63 (14.3)
Viral infection	2/56 (3.6)	4/63 (6.3)
Acute GVHD	1/56 (1.8)	3/63 (4.8)
Chronic GVHD	4/56 (7.1)	6/63 (9.5)
CNS hemorrhage	2/56 (3.6)	4/63 (6.3)
Lung hemorrhage	3/56 (5.3)	1/63 (1.6)
Heart failure	1/56 (1.8)	0 (0)
Hepatic failure	0 (0)	1/63 (1.6)
Kidney failure	0 (0)	1/63 (1.6)
Lung failure	0 (0)	1/63 (1.6)
Multiple organ failure	0 (0)	4/63 (6.3)

Rejection – n (%)	31/56 (55.4)	18/63 (28.6)
Death not related to BMT – n (%)	2/56 (3.6)	2/63 (3.2)

Characteristic	Conditioning CY alone	Conditioning CY + BUS
Number of patients	55	49
Conditioning/dose	CY 200 mg/kg	CY 120 mg/kg + BUS 12 mg/kg
Donor age (years) – median (range)	18 (0–48)	18 (2–48)
Donor gender (M/F)	35/20	28/21
No. of infused nucleated cells (×10⁸ cells/kg) – median (range)	3.3 (1.0–7.7)	3.1 (1.5–9.0)
Immunoprophylaxis – n
Cyclosporin-A only	1	1
Methotrexate + Cyclosporin-A	54	48

Variable	Chimerism			p-Value
Variable	≤50% (n = 20)	51–90% (n = 11)	>90% (n = 24)	p-Value
Neutrophil count (×10³/µL) – median (range)	2.2 (1.0–5.9)	2.3 (1.5–6.4)	3.3 (2.3–8.2)	0.003^b b Kruskal–Wallis non-parametric test.
Hemoglobin (g/dL) – median (range)	15.1 (9.2–17.3)	15.2 (11.7–17.0)	15.1 (13.3–19.2)	0.597^a a ANOVA com um factor.
Platelet count (×10³/µL) – median (range)	143 (12–249)	163 (131–315)	218 (131–315)	<0.001^b b Kruskal–Wallis non-parametric test.

Variable	Chimerism		p-Value^a a Student t-test or Mann–Whitney non-parametric test. (univariate)	p-Value^b b Logistic regression model and Wald test. (multivariate)	OR^b b Logistic regression model and Wald test. CI (95%)
	≤90% (n = 36)	>90% (n = 68)
Patient age (years) – median (range)	16.5 (1–35)	18.5 (5–45)	0.039	0.056	1.11 (1–1.23)
Donor age (years) – median (range)	17 (1–48)	19.5 (0–48)	0.105	0.471	0.97 (0.90–1.05)
Time from diagnosis to BMT (months) – median (range)	2 (1–36)	3 (0–127)	0.125	0.861	1.01 (0.93–1.08)
Conditioning regimen – n (%)
CY	31 (56.4)	24 (43.6)
CY + BUS	5 (10.2)	44 (89.8)	<0.001	<0.001	16.68 (4.75–58.63)

Number of infused cells (×10⁸ cells/kg)	3.17 (1.01–7.75)	3.37 (1.86–8.96)	0.107	0.009	1.9 (1.17–3.1)

GVHD	Chimerism (CY alone) n = 55		n (%)	Chimerism (CY + BUS) n = 49	n (%)
GVHD	≤50% (n = 20)	51–90% (n = 11)	>90% (n = 24)	51–90% (n = 5)	>90% (n = 44)
Acute GVHD grade I	0	1 (9.1)	0	0	1 (2.3)
Acute GVHD grade II	0	0	1 (4.2)	0	3 (6.8)
Acute GVHD grade III	0	0	1 (4.2)	0	2 (4.5)
Acute GVHD grade IV	0	0	0	0	1 (2.3)
Chronic GVHD	0	0	0	0	3 (6.8)

Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular (ABHH) R. Dr. Diogo de Faria, 775 cj 133, 04037-002, São Paulo / SP - Brasil - São Paulo - SP - Brazil
E-mail: htct@abhh.org.br

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[1] *Corresponding author at: Rua: Emilio Cornelsen, 570 ap. 102, Bloco 6, Ahu, Curitiba, PR, Brazil. marciarquiroga@gmail.com