EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: Fanconi anemia is a congenital bone marrow failure syndrome that is associated with congenital anomalies and increased risk of cancer. Hematopoietic stem cell transplant is a potentially curative modality for bone marrow failure in Fanconi anemia patients. Here, we report our center’s experience regarding adolescent and young adult patients with Fanconi anemia and hematopoietic stem cell transplant.

Materials and Methods: We conducted a retrospective patient record analyses of patients who presented at our center from 1988 to 2014. We included patients greater than 14 years old with confirmed Fanconi anemia based on positive chromosome breakage study and who underwent hematopoietic stem cell transplant at our institution.

Results: Our study group comprised 12 patients with Fanconi anemia who underwent hematopoietic stem cell transplant at our institution. The median age was 20 years (range, 14-31 y) with a female predominance of 83%. Low-dose cyclophosphamide (20-80 mg/kg)-based conditioning regimens were used with different combinations that included fludarabine, antithymocyte globulin, or total body irradiation. All patients had HLA-matched sibling grafts. In all patients, stem cell source was the bone marrow. All patients showed engraftment. Four patients (33%) developed acute graft-versus-host disease. Three patients (25%) died early before day 100 after hematopoietic stem cell transplant due to infectious complications, with 1 patient having steroid refractory acute graft-versus-host disease. Overall survival was 75% at a median follow-up of 43 months. All patients who survived are well and remained transfusion independent without evidence of secondary malignancy.

Conclusions: Our findings support the feasibility of reduced intensity conditioning allogeneic hematopoietic stem cell transplant in older and more heavily pretreated patients with Fanconi anemia, especially for those who are engrafted.

Key words : Anemia, Bone marrow failure, Adult, Transplant

Fanconi anemia (FA) is an autosomal recessive disorder, characterized by multiple congenital malformations, progressive bone marrow failure, and increased risk of malignancies.¹ Fanconi anemia patients have hypersensitivity to DNA cross-linking agents and higher rate of acute myeloid leukemia progression.² Although with the characterization of 16 complementation group genes, including 5 familial breast cancer genes, a better sense of the biology of FA has emerged,³ how mutations in the FA proteins contribute to the pathophysiology of birth defects, bone marrow failure, and cancer remains unclear.⁴ The biologic diagnosis of FA is primarily based on the sensitivity of peripheral blood lymphocytes to DNA interstrand cross-linking chemicals such as diepoxybutane or mitomycin C.⁵ Presently, the only cure for the hematologic complications of FA remains hematopoietic stem cell transplant (HSCT).⁶

Most reports of HSCT in FA are in younger or pediatric patients. Adult FA patients are usually more heavily pretreated and transfused and are therefore at higher risk of HSCT complications and mortality. There are scarce data in the literature to describe the outcomes of HSCT in adult FA, with the largest included number of adults reported by the European Bone Marrow Transplant (EBMT) registry.² We sought to analyze the outcomes in our cohort of adolescent and young adult patients with FA who underwent HSCT at our institution.

Materials and Methods

We retrospectively reviewed patients aged 14 years and older with a diagnosis of FA identified from our HSCT database who presented from 1988 to 2014 at our center. Electronic and paper medical records were studied, and laboratory reports were checked to confirm that patients had a positive chromosomal breakage test. Data on cytogenetic studies, bone marrow biopsy results, previous treatment options, conditioning regimens, stem cell source and dose, donor biographic data, treatment-related toxicities, engraftment and graft-versus-host disease (GVHD), and long-term follow-up were collected. The study was conducted according to the guidelines of the Declaration of Helsinki, and the study protocol was approved prior to the beginning of the study by our Ethics Committee.

The primary outcome studied was survival. Patients were considered to have an event at time of death from any cause; survivors were censored at last contact. Time to engraftment was calculated as the interval from transplant to the first of 3 consecutive days with an absolute neutrophil count of ≥ 500/mm³. Primary graft failure was defined as failure to achieve an absolute neutrophil count of ≥ 500/mm³ after HSCT, and secondary graft failure was defined as sustained loss of absolute neutrophil count (< 500/mm³) after initial recovery. Acute GVHD was graded using the consensus conference severity index.⁷ Chronic GVHD was diagnosed and graded according to published criteria.⁸ Death without an event was considered a competing event for engraftment and GVHD.

Overall survival probability was estimated using the Kaplan-Meier method. Survival curves were drawn using Kaplan-Meier methodology. The statistical analyses were performed with SPSS 13.0 (SPSS Inc. Chicago, IL, USA) and R (R Development Core Team 2009, Vienna, Austria) software packages.

Our patient group comprised 12 patients who met inclusion criteria and were seen from October 1988 to October 2013. Detailed baseline characteristics are shown in Table 1 and Table 2. All patients underwent chromosomal breakage test to confirm a diagnosis of FA. All patients underwent bone marrow morphologic evaluation, and 11 patients (92%) had cytogenetic evaluation. Three patients (25%) had evidence of myelodysplastic features either by morphology or cytogenetic analyses, as shown in Table 2. All patients were on supportive therapy either in the form of blood products, steroids, and/or androgens with a median ferritin level for 10 patients (before transplant) of 2151 μg/L (range, 134-5067 μg/L).

Conditioning regimen
Low-dose (20-80 mg/kg) cyclophosphamide was used in all patients as part of the conditioning regimen; antithymocyte globulin (ATG) was administered in 10 patients (84%). Six patients (50%) received total body irradiation (TBI) of 200 to 600 cGy. Six patients (50%) received fludarabine as part of their conditioning regimen.

Donor characteristics
Median donor age was 19.5 years (range, 5-31 y). All patients received an HLA-matched sibling stem cell transplant. Ten patients (84%) had ABO-compatible stem cell transplant, 1 patient received a major ABO-incompatible HSCT, and 1 received a minor ABO-incompatible HSCT. Median CD34-positive dose was 4.35 × 106/kg in 10 patients. Two patients received a total nucleated cell dose of 1.6 × 108/kg and 1.19 × 108/kg. Bone marrow was the primary source for stem cells in all patients. Six of the transplants (50%) were sex matched.

Engraftment
There were no reported primary or secondary graft failures in our cohort. Of note, 1 patient died 6 days after HSCT due to septic shock and multiorgan failure. Median time to engraftment was 14 days (range, 12-60 d).

Graft-versus-host disease
Graft-versus-host disease prophylaxis consisted of cyclosporine alone in 7 patients (58%) or in combination with methotrexate in 4 patients (33%) and steroids in 1 patient. Incidence of grade ≥ 2 acute GVHD was 33% (4 patients), involving mainly gut and skin; it was managed with systemic steroid. One patient had grade 3 steroid refractory acute gut GVHD despite being on steroids for 7 days. Chronic GVHD occurred in 4 patients, mainly involving the skin.

Treatment-related toxicities
Febrile neutropenia occurred in 4 patients (33%). Cytomegalovirus reactivation occurred in 6 patients (50%), which was treated preemptively with intravenous ganciclovir. Hemorrhagic cystitis occurred in 2 patients (16%). Veno-occlusive disease occurred in 1 patient (8%). Mucositis (grade ≥ 2) occurred in 6 patients (50%), but this was successfully treated with analgesics.

Survival
Overall survival was 75% at a median follow-up of 43 months (Figure 1). All deaths occurred before day 100 post-HSCT. The cause of death was mainly sepsis, including fungal pneumonia (1 patient), pulmonary hemorrhage (1 patient), and septic shock with multiorgan failure (1 patient). No secondary malignancy was observed during follow-up in our cohort.

Allogeneic stem cell transplant is a potentially curative treatment modality for bone marrow failure in FA patients; however, this does not prevent the future risk of hematologic and nonhematologic malignancies. Patients with bone marrow failure who happen to have underlying undiagnosed FA will not respond to immunosuppression therapy, which is usually given to treat patients with idiopathic aplastic anemia.⁹

Hematopoietic stem cell transplant for FA from a matched sibling donor is currently associated with better overall survival than matched unrelated donor. The EBMT experience reported their outcomes of HSCT in FA, with a 5-year overall survival for HLA-matched sibling donors of 76% and matched unrelated donors of 64% (P = .01). There was a significantly higher rate of acute GVHD at day 100 after transplant with matched unrelated donor versus matched sibling donor of 36% versus 19%.

Patients with FA have a higher susceptibility to chemotherapy and therefore are at a higher risk of regimen-related toxicity. The EBMT reported an almost 15% nonrelapse mortality with matched sibling donors that might double with unrelated donors.²

Conditioning regimens for FA have evolved over the past 3 decades. As reported by the EBMT, fludarabine has been used more frequently between 2000 and 2007, whereas irradiation was more frequently used between 1972 and 1999. Use of fludarabine was associated with a better 1-year overall survival, whereas use of TBI was associated with an inferior outcome.² Low-dose cyclophosphamide (20-80 mg/kg) has been used as a backbone for most FA-conditioning regimens.^10-12 In our cohort, we used different conditioning regimens, reflecting an evolution in the conditioning protocols over the years, as well as the practice of using TBI in patients with myelodysplasia based on local experience. At our center, the TBI-based conditioning regimen was used between 1988 and 2006, whereas fludarabine-based conditioning was used from 2007 to 2013. In our cohort, there were 2 deaths among patients receiving TBI, and 1 death in the group that did not receive TBI.

Peripheral blood stem cell source is reported to be associated with an inferior outcome (hazard ratio = 1.48; P = .039) compared with bone marrow source.2 In our cohort, all patients received bone marrow stem cells, which leads to better outcomes in older FA patients.

Patients with FA and myelodysplastic or clonal abnormalities on presentation are a distinct group, requiring more intensive conditioning before stem cell transplant, as the presence of either may herald the development of acute myeloid leukemia and hence is a marker for an adverse outcome.^13,14 Mitchell and associates reported 5-year overall survival of HSCT for acute leukemia and advanced myelodysplastic syndrome in FA patients of 33% with a relapse rate of 24%.¹⁵ Myeloablative conditioning was used by the Seattle group for 5 patients with FA and evidence of leukemia using cyclophosphamide (140-200 mg/kg) plus TBI of 12 Gy in 4 patients and busulfan (14 mg/kg) and cyclophosphamide (100 mg/kg); 4 patients died from treatment toxicity, and only 1 patient survived without evidence of disease at 8 years after stem cell transplant.¹⁶ In our cohort of adolescent and young adult FA patients, 3 patients had myelodysplastic features either by morphology or cytogenetic analyses without evidence of increased blast count. Two of three patients did poorly during the course of the disease; 1 died at day 6 after HSCT and 1 died at day 65 after HSCT. No pre-HSCT chemotherapy was given to myelodysplastic syndrome patients.

King Faisal Specialist Hospital and Research Centre reported the results of 11 pediatric FA patients with leukemia or myelodysplasia who were given cyclophosphamide (total of 20 mg/kg), ATG (total dose of 160 mg/kg of the equine product or 52 mg/kg of the rabbit product), and TBI of 450 cGy and found 90% overall survival rate at median follow-up of 46 months.¹⁷

In our experience, adolescent and young adult patients with FA who receive HSCT have higher treatment-related toxicities, which were limited to the early posttransplant period. Patients who survived beyond day 100 after transplant had good outcomes, and late mortality did not occur in our cohort. Therefore, optimization of peritransplant care with good chelating therapies could lead to better outcomes. A factor contributing to the relatively good outcome was the presence of a 10/10 matched sibling donor. Age (20-50 years) at time of transplant has been shown to play an important prognostic factor (hazard ratio = 2.88; P ≤ .0001).² We report a seemingly better survival rate compared with that reported by EBMT (75% at our center [median age of 19.5 y] vs 68% reported by EBMT for age 10-20 y vs 50% reported by EBMT for age 20-50 y) and with a longer follow-up.

Death occurred in 4 patients (25%). Two patients died from early fungal pneumonia and acute respiratory distress syndrome (1 patient at day 6 after HSCT with bone marrow myelodysplastic syndrome findings by morphology and cytogenetic analyses, and 1 patient at day 32). The third patient died at day 60 from fungal pneumonia, pulmonary hemorrhage, and steroid refractory acute GVHD of the gut (grade 3). Given the small cohort size, definitive conclusions cannot be drawn as to the best conditioning regimen, although the fludarabine-cyclophosphamide-ATG combination seems to be a reasonable option based on better outcome.

A limitation of our study is the small sample size, which is not unexpected given the rarity of the disease especially in older patients.¹⁸ Focus should be on reducing peritransplant conditioning-related mortality. Because it is rare, FA patients need registry studies and collaborative multicenter studies to further study optimal strategies. These patients need to be followed in a comprehensive multidisciplinary late-effects program.

Volume: 14 Issue: 6 December 2016

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