Fludarabine‐based stem cell transplantation protocol for Fanconi's anaemia in myelodysplastic transformation

Summary:A fludarabine-based protocol (fludarabine (25 mg/m 2 / day Â 6 days), cyclophosphamide (10 mg/kg/day Â 2 days) and ATG (ATGAM 10 mg/kg/day Â 4 days)) was used in four multiply transfused Fanconi's anemia (FA) patients aged 5-15 years to reduce rejection during allogeneic bone marrow transplantation (BMT). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and mini methotrexate. The graft source was G-CSF-stimulated bone marrow or peripheral blood stem cells (PBSC) in two patients each. All patients engrafted with median time to ANC4500/mm 3 being 14 days (range: 12-17) and unsupported platelet count 420 ,000/mm 3 being 13 days (range: 11-18). One patient had secondary graft rejection on day 56 and expired on day 69 due to fungal pneumonia. One patient who developed acute myeloid leukemia on day 56 underwent successful induction with cytosine and daunorubicin followed by peripheral blood stem cell (PBSC) rescue on day 70 and is presently in remission with complete donor chimerism and grade I GVHD. At a median follow-up of 13 months (range: 4-21), three patients (75%) are well with complete donor chimerism. Addition of fludarabine to the conditioning regimen for BMT in FA can provide additional immunosuppression for engraftment without increasing toxicity. Allogeneic bone marrow transplantation (BMT) has produced excellent survival rates in patients with Fanconi's anemia (FA) using low-dose cyclophosphamide with or without radiation therapy. 1 Graft rejection rates of 30-60% occur in multiply transfused patients with aplastic anemia requiring intensification of immunosuppression. 2 Few case reports exist on the use of fludarabine-based protocols as conditioning regimens for patients with FA with encouraging results 3-8 and we describe our experience in multiply transfused FA patients. Patients and methodsBetween 1999 and 2003, four male patients with FA underwent six antigen-matched sibling or family donor BMT at our center. The diagnosis of FA was confirmed by stress cytogenetics using mitomycin C and all had a bone marrow aspirate suggestive of aplastic anemia done 3-6 months prior to BMT. Standard karyotyping was not performed. Conditioning regimen consisted of fludarabine 25 mg/m 2 /day (day À11 to À6); cyclophosphamide 10 mg/ kg/day for 2 days (days À7 and À6), antithymocyte globulin (ATGAM, Pharmacia Upjohn, USA) 10 mg/kg/ day for 4 days (days À5 to À2). Graft source was either G-CSF-stimulated bone marrow or G-CSF-stimulated peripheral blood stem cells (PBSC) in two patients each. Supportive carePatients were nursed in HEPA-filtered rooms with adequate sterile precautions and barrier nursing. G-CSF (5 mg/ kg/day) was started on day þ 7 following the infusion of bone marrow or PBSC. Broad-spectrum antibiotics and antifungals were administered as per existing protocols for febrile neutropenia. Acyclovir and Septran were administered as CMV and Pneumocystis carinii prophylaxis, respectively. Ganciclovir was administered started as preemptive prophylaxis if the CMV polymerase chain r...

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Fludarabine-based conditioning for allogeneic stem cell transplantation for multiply transfused patients with Fanconi's anemia

George

Shaji

Srivastava

et al. 2005

“…16,17 There are some reports in the literature of the use of this modality in patients with FA. 11,[18][19][20][21] However, as far as we are aware, there are no published reports of successful unrelated transplants performed without the use of irradiation. Also, there appears to be no single protocol suitable for both related and unrelated allografts and applicable to the different stages (AA/MDS) of this heterogeneous disease.…”

Section: Discussionmentioning

confidence: 99%

“…A report of this transplant and early follow-up has been published previously. 11 P2-SIB2 was diagnosed to have FA at age 5 years and was subsequently shown to belong to the FA complementation group A. He had short stature, several cafe au lait spots, thumb abnormalities, characteristic 'Fanconi facies' and developmental delay.…”

Section: Patients and Sct Conditioningmentioning

confidence: 99%

Non-TBI stem cell transplantation protocol for Fanconi anaemia using HLA-compatible sibling and unrelated donors

Fuente

Reiss

McCloy

et al. 2003

Summary:Allogeneic haemopoietic stem cell transplantation (SCT) is the only curative option for severe bone marrow (BM) failure in patients with Fanconi anaemia (FA). We have developed a non total body irradiation (TBI) conditioning protocol consisting of fludarabine (120-150 mg/m 2 ), low dose of cyclophosphamide (40 mg/kg) and antilymphocyte globulin (45 mg/kg). Graft-versus-host disease (GVHD) prophylaxis was with cyclosporin alone for sibling allografts but also included Campath-1 H (days 1-5 post SCT) for the unrelated allografts. We have performed two sibling and two unrelated BM transplants with a follow-up of 11-51 months. All patients experienced minimal toxicity and were discharged from hospital 28-32 days post SCT. Neutrophil and platelet engraftment occurred from days 11 to 19 and 15 to 34, respectively. All patients achieved stable full donor haemopoiesis with normalisation of the peripheral blood count despite one of them having myelodysplasia (MDS) with 8% blasts prior to the SCT. The only site of acute GVHD was in the skin (grade I-II) and only one patient progressed to limited chronic GVHD. This protocol is associated with reduced toxicity and prompt engraftment in FA patients with AA and/or MDS undergoing SCT using sibling or unrelated donors.

“…The addition of other agents such as fludarabine has also allowed further reduction of the CY doses with still favorable outcomes. [15][16][17][18] The role and the optimal dose of ATG in preparing FA patients for SCT are equally unclear; however, the addition of ATG after graft infusion as an in vivo T-cell depletion method has been shown to dramatically reduce the incidence of acute GvHD, and subsequently chronic GvHD. [19][20][21] A major concern associated with the use of ATG (pre-and post-SCT) has been the profound immune suppression, which may increase the susceptibility to EBVrelated post transplant lymphoproliferative disorders (PTLD); in our series, no such cases were observed, nor were there other secondary malignancies noted thus far.…”

Section: Discussionmentioning

confidence: 99%

Stem cell transplantation for patients with Fanconi anemia with low-dose cyclophosphamide and antithymocyte globulins without the use of radiation therapy

Ayas

Al‐Jefri

Al-Mahr

et al. 2005

Summary:In all, 22 patients with confirmed Fanconi anemia (FA) underwent stem cell transplantation (SCT) from HLAmatched, related donors at KFSHRC. Median age at SCT was 7.6 years (range, 2.5-14.6 years). Conditioning regimen consisted of cyclophosphamide (CY) 15 mg/kg/ day intravenously (i.v.) for 4 consecutive days, in addition to equine antithymocyte globulins (ATG) given i.v. at 40 mg/kg/day for four doses pre-SCT. No radiation therapy was given. For graft-versus-host disease prophylaxis, we used cyclosporin at the standard doses; ATG was added at 20 mg/kg/dose i.v. on days 2, 4, 6, 8, 10, and 12 post-SCT (total of six doses). All patients engrafted and are alive and transfusion independent with a median follow-up time of 20.2 months (range, 3.3-59 months). One patient however developed a decrease in her WBC and platelet count. Her work-up revealed slightly hypocellular bone marrow, and a series of chimerism studies over 1 year confirmed that she has stable mixed chimerism; she remains transfusion independent. We conclude that low-dose CY without radiation therapy can be used satisfactorily in the conditioning of patients with FA undergoing related SCT.