Successful treatment of pulmonary hypertension with beraprost and sildenafil after cord blood transplantation for infantile leukemia.

Int J Hematol. 2013 Jan;97(1):147-50.

Kawashima N, Ikoma M, Sekiya Y, Narita A, Yoshida N, Matsumoto K, Hatano T, Kato K.

Department of Hematology/Oncology, Children’s Medical Center, Japanese Red Cross Nagoya First Hospital, 3-35 Michishita-cho, Nakamura-ku, Nagoya, Japan. kwnozomu@med.nagoya-u.ac.jp

Abstract

Pulmonary hypertension (PH) is an infrequently reported complication after hematopoietic stem cell transplantation, and its etiology and therapeutic strategies, especially in infants, remain unclear. We report a case of severe PH that developed in an infant with acute leukemia following administration of busulfan as a preconditioner for cord blood transplantation; the case was successfully treated with sildenafil and beraprost, which to our knowledge is the first reported successful use of this regimen in PH following transplantation for infantile leukemia. From a review of all previous reports, use of busulfan in infants may raise the risk of developing PH, and unlike definitive pulmonary veno-occlusive disease, PH in this subgroup may be reversible by early detection and treatment.

PMID: 23243005

 

Supplement

Pulmonary veno-occlusive disease (PVOD) is a rare but well-known cause of pulmonary hypertension (PH) after hematopoietic stem cell transplant (HSCT). Unlike histologically proven PVOD, which is often fatal, about half of the patients with PVOD after HSCT were alive at the report and substantial clinical heterogeneity was present. Idiopathic pulmonary arterial hypertension (PAH) with isolated pulmonary arterial vasculopathy is another rare cause of PH after HSCT and is often difficult to be clinically distinguished from PVOD.

PVOD and iPAH may represent two parts of the same disease spectrum, and elucidating characteristics of PH after HSCT is essential to medical management. To clarify the clinical features of PH within 100 days after HSCT, we collected clinical data from all the previously published reports of PH after HSCT (Table 1 ). Although not all patients had biopsy, small vein lesions in histology, i.e. the definitive diagnoses of PVOD, were related to higher mortality. Six out of 17 patients had prior HVOD before the onset of PVOD or iPAH. Patients with malignant infantile osteopetrosis were at higher risks of developing PH after HSCT, as previously reported, but infants with congenital immunodeficiency also developed PH. Interestingly, all the infants received busulfan as preconditioner. In animal models, busulfan combined with cyclophosphamide causes endothelial injury via remodeling of resistance arteries and enhanced expression of endothelial nitric oxide (NO) synthase. Therefore, busulfan could be a risk factor for developing endothelial damages that lead to HVOD or PH especially in infants. Unlike definitive PVOD, PH in this subgroup may be reversed by sildenafil and beraprost under careful titration.

 

Table 1

Clinical and pathological characteristics of pulmonary hypertension (PH) developed within 100 days after hematopoietic stem cell transplantation (HSCT)

Age/sex

Dx

Preconditioner

Stem cell

HVOD

Onset of PH post-HSCT

Clinical Dx

Affected vessels confirmed by histology

Therapy

Outcome

12 yr/M

ALL

CY, TBI

MSD-BM

+44 d

IP

Venules

None

Dead

4 yr/M

ALL

CY, VP, BCNU

Allo-sib

+60 d

PVOD

n/a

Steroid

Alive +230 d

39 yr/M

NHL

CY, VP, BCNU, DTIC

Auto-BM

+52 d

PVOD

Venules

Steroid

Dead

36 yr/F

ALL

CY, VP, Mel, TBI, TLI

Allo-BM

+

+6 d

PVOD

Venules

None

Alive +27 d

20 yr/M

NHL

CA, CY, TBI

MSD-BM

+

+73 d

PVOD

Venules and arterioles

Steroid

Dead from NHL +230 d

2 yr/M

NB

CBDCA, VP, Mel

Auto-PBSC

+17 d

PVOD

Venules and arterioles

Steroid, heparin, milrinone, NO

Dead +49 d

48 yr/M

MM

Mel

Auto-PBSC

+11 d

PVOD

n/a

None

Alive +49 d

8 mo/M

OS

BU, CY, VP

MSD-BM

+70 d

PAH

Arterioles

CCB

Alive +840 d

4 mo/M

IM

BU, CY

MSD-BM

+

+21 d

PAH

Arterioles

CCB

Dead +32 d

8 mo/F

SCID

BU, CY

URD-BM

+

+70 d

PAH

n/a

NO, sildenafil

Alive +140 d

2 mo/F

OS

BU, CY

Haplo-BM

+

+57 d

PAH

n/a

NO

Dead +58 d

1 mo/M

MIOP

BU, CY

Haplo-BM

+

+20 d

IP, PAH

n/a

NO, PGI2, CCB

Dead +34 d

2 mo/F

MIOP

BU, CY

PMRD-BM

+48 d

PAH

n/a

NO, PGI2, DF

Alive +750 d

2 mo/F

MIOP

BU, CY

PMRD-BM

+49 d

PAH

Venules

NO, PGI2, surfactant

Dead +84 d

3 mo/F

MIOP

BU, CY

MSD-BM

+53 d

IP, PAH

n/a

NO, PGI2

Alive +930 d

1 mo/F

MIOP

BU, CY

Haplo-BM

+65 d

PAH

n/a

NO

Dead +111 d

21 yr/M

AML

GO, Flu, Mel, TBI

PMRD-BM

+35 d

PVOD

n/a

Steroid

Dead +260 d

7 mo/M

ALL

BU, CY, VP

CB

+

+53 d

PVOD

n/a

Beraprost, sildenafil

Alive +350 d

yr year, mo month, d day, Dx diagnosis, PAH pulmonary arterial hypertension, PVOD pulmonary veno-occlusive disease, HVOD hepatic veno-occlusive disease, IPinterstitial pneumonitis, NHL non-Hodgkin lymphoma, NB neuroblastoma, MM multiple myeloma, OS Omenn syndrome, IM idiopathic myelofibrosis, SCID severe combined immunodeficiency, MIOP malignant infantile osteopetrosis, CY cyclophosphamide, BU busulfan, BCNU carmustine, VP etoposide, DTIC dacarbazine, CAcytarabine, Mel melphalan, CBDCA carboplatin, GO gemtuzumab ozogamicin, DF defibrotide, CCB calcium channel blocker, NO nitrogen monoxide, PGI2prostacyclin, MSD matched sibling donor, PMRD partially mismatched related donor, URD unrelated donor, CB cord blood, n/a not applicable or available

Published reports regarding PH after HSCT were collected from PubMed, using the search terms pulmonary hypertension, pulmonary arterial hypertension, pulmonary veno-occlusive disease and stem cell transplantation. Cases of PH developed until post-transplant day +100 were included, and cases after second HSCT were excluded.

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