Fanconi anemia medical therapy
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. ; Associate Editor(s)-in-Chief: Shyam Patel  Pervaiz Laghari, MD
There is no single universalized medical therapy for Fanconi anemia. Treatment for Fanconi anemia is diverse and largely depends on severity of disease and the risk assessment for future malignancies. The most conservative management strategy involves active surveillance with routine laboratory monitoring every three months. Allogeneic transplant is a more intense treatment that can be used for curative purposes, though the toxicity is higher. Androgens, transfusions, and growth factor support can help improve anemia. Given the risk of both hematologic malignancies and solid tumors in patients with Fanconi anemia, it is important to understand screening and management strategies for these.
Active surveillance involves monitoring of bone marrow function without pursing specific pharmacologic intervention. The initial approach of monitoring bone marrow function is classified according to the severity of bone marrow failure and the presence or absence of clonal hematopoietic neoplasms. This monitoring T schedule and management approach is consistent with the 2014 Fanconi Anemia Guidelines for Diagnosis and Management from the Fanconi Anemia Research Fund.
- Mild bone marrow failure: This is described as absolute neutrophil count (ANC) between 1000 and 1500/microL, platelet count between 50,000 and 150,000/microL, and hemoglobin ≥10 g/dL. CBC with differential should be monitored every 3-4 months as the blood count remain stable. A bone marrow examination with cytogenetics should be done annually. If there are any changes in blood count without an apparent cause (e.g: infection) we should increase the frequency of CBC monitoring and the bone marrow studies repeated regardless of the date of last study.
- Moderate bone marrow failure: This is described as ANC between 500 and 1000/microL, platelet count between 30,000 and 50,000/microL, hemoglobin between 8 and 10 g/dL. For patients whose counts continue to decrease, stem cell transplant planning should begin with an HLA-matched related donor (first choice) or closely matched unrelated donor. Androgen therapy may be an alternate option to improve blood counts for some patients including those with moderate bone marrow failure for whom no donor is available, those who do not meet medical eligibility criteria for HCT due to pre-existing organ dysfunction or ongoing infection, and those who decline HCT. If a patient is asymptomatic with stable cell counts and no clonal abnormality, it may be reasonable to monitor the CBC every three to four months and perform a bone marrow examination annually as done for mild bone marrow failure. If cytogenetic abnormalities suggest poor risk MDS in the absence of other MDS-defining feature, CBC and bone marrow should be monitored more frequently (eg, CBC every 1-2 months, Bone marrow every 1-6months), and should be proceed with the best available donor.
- Severe bone marrow failure: This is defined as ANC ≤500/microL, platelet count ≤30,000/microL, hemoglobin <8 g/dL), and/or transfusion dependence. Patients should undergo stem cell transplant with the best available donor, an HLA-matched sibling/family member who has been determined not to have FA would be preferable, second choice should be closely matched unrelated donor. If neither of above options available then we should start trial of androgen therapy while pursuing other alternative donor such as cord blood or haploidentical HCT, with attempt to avoid transfusion exposure and opportunistic infection during the androgen trial.
Allogeneic hematopoietic stem cell transplantation
Allogenic HSCT (HCT) is the only accepted curative therapy for Fanconi anaemia with severe bone marrow failue, MDS or AML, transfusion dependent anaemia or thrombocytopenia. Patients with FA are at risk for significant toxicity from standard chemotherapy doses which are used for HCT conditioning. Strategies revised at the Minnesota University and other centres that incorporate reduced dose of cyclophosphamide have been extremely effective in matched sibling donor HCT for FA. Rates of engraftment associated with these approaches are greater than 90%, and overall post-HCT survival is greater than 95% in most series reported since 2005. Additional developments have also improved outcomes from unrelated donors, including matching with high-resolution HLA genotyping, T cell depletion, and conditioning regimens with lower toxicity. Thus, even though unrelated donor HCT may carry a higher risk of long-term toxicity, it is likely to be critical to delaying HCT while attempting to use non-curative supportive care approaches to rising blood counts. Although HCT is curative for bone marrow failure and potentially for hematopoietic neoplasms, it does not cure other manifestations of FA. As noted above, HCT appears to increase the risk of squamous cell cancers, especially in individuals with severe graft-versus-host disease. Additionally, insulin resistance, bone health disorders, and other endocrinopathies may be worsened by HCT, and require close lifelong monitoring.
- Sibling donor transplant: The recommended source of stem cells is the bone marrow (rather than peripheral blood stem cells) from an eligible sibling who is HLA matched at 10 of 10 alleles of the four most commonly tested HLA genes (HLA -A, -B, -C, and DRB1) or a closely matched unrelated donor. It is essential that all sibling or other related donors must go through chromosomal breakage testing or genetic testing to confirm that they do not also have FA. If they also have Fanconi anemia, their cells cannot be used as donor cells. This testing is very important because family donors those are apparently asymptomatic and healthy may have FA genetically but lack classic findings due to mosaicism, incomplete penetrance of FA-associated abnormalities, or young age/late onset of disease manifestations. HCT performed with a family donor who also turns out to have FA, even if mosaic and/or asymptomatic, would possess a very high risk of graft failure. Alternatively, siblings who are only carriers of one heterozygous mutation in an autosomal recessive FA-associated gene are eligible as donors. Options for patients with FA who lack a closely matched related or unrelated donor but still require HCT for bone marrow failure include the following.
- Unrelated cord blood transplant (CBT): This seems to be less effective than matched unrelated donor bone marrow for patients with FA. This was demonstrated in a 2007 series of 93 patients with FA who underwent CBT, in which overall survival was 40 percent. Use of cord blood units with higher stem cell doses and incorporation of fludarabine into CBT conditioning regimens may improve outcomes in the future.
- Haploidentical donor transplant: HCT using a parental or other related donor is still under investigation at several centers. This approach shows promise, although outcomes are not as good as those seen with closely matched unrelated donors.   Based on the above conclusion, CBT or haploidentical HCT should only be performed for patients with FA in the context of active clinical trials.
Those parents who are interested in having additional children, in vitro fertilization (IVF) with pre-implantation genetic diagnosis (PGD) approaches are an established method that not only ensures that future children will not have FA, but also can select for an HLA-matched sibling that can be used as a donor. While not always effective and also associated with challenging ethical and emotional dimensions that must be addressed, this method has facilitated successful matched sibling donor HCT in a number of patients with FA dating back to 2001. This approach is not optimal for somebody with FA who have an urgent need for HCT (eg, those who require transfusions or have severe neutropenia despite optimal supportive care), since it may take one to two years before a healthy sibling donor is available.
Androgen therapy can be a reasonable option for those who lack a closely matched related donor for HCT, or for whom HCT is not pursued due to family preference or medically eligibility. Androgen therapy is used to increase blood count for a period of weeks to month while parents attempt to IVF with PGD and until resulting HLA-matched related donor is available. It is not a curative treatment. Only half of patents with FA will respond to androgen therapy. Patients with severe bone marrow aplasia are less likely to respond than those with residual bone marrow function, and response can take weeks to months. Androgen therapy has the most dramatic effect on the erythroid lineage and can improve hemoglobin within a few weeks of initiation. Responses in the platelet count are generally slower and less complete, and neutropenia may not completely resolve. Androgen therapy can be associated with virilization, growth abnormalities, behavioral changes, and hypertension. The most concerning side effects of androgens in patients with FA involve the liver and include transaminitis, cholestasis, peliosis hepatis, and liver tumors.
- Oxymetholone: This is the most commonly used androgen in FA. If no response is seen after three months, oxymetholone should be discontinued.
- Danazol: This androgen is sometimes also used in anemia related to MDS.
- Oxandrolone: This is rarely used currently but can be tried if other measures are ineffective. If the blood counts stabilize or improve, the daily dose may be tapered to the minimum effective dose to avoid non-hematologic toxicity. A 2014 study was the first to report outcomes of FA patients treated with low-dose oxandrolone, an anabolic steroid with a potentially favorable toxicity profile compared to oxymetholone. Of nine patients with a median follow-up of nearly two years, 78 percent had a hematologic response, none had clinical virilization, and none developed liver tumors. More experience with this agent is needed.
Transfusion and growth factor support
Transfusion and growth factor support may be essential due to progressive bone marrow failure and associated complications in patients with FA. However, increasing evidence supports a judicious approach, as extensive transfusions may be associated with worse outcomes with HCT, and extensive use and high doses of growth factors such as G-CSF and thrombopoietin mimetics in patients with other bone marrow failure syndromes have been associated with increased risks of developing MDS and AML.
- Packed RBCs: Red blood cell (RBC) transfusion is indicated for any patient with symptomatic anemia (eg, decreased activity level, excessive fatigue, shortness of breath, and poor growth) or anemia with hemodynamic instability. Only leukoreduced, irradiated units of RBCs should be used, to minimize the risk of cytomegalovirus transmission, alloimmunization, and transfusion-associated graft-versus host disease (ta-GVHD). Directed donations by family members should be avoided to reduce the risk of graft rejection due to alloimmunization in patients who subsequently undergo HCT. Chronic RBC transfusions can lead to iron overload, which, if not treated, can lead to significant morbidity and mortality.
- Platelets: Platelet transfusion is indicated in patients with platelet counts below 10,000/microL and in any patient with severe bruising, bleeding, or invasive procedures. The use of single donor pheresis platelets minimizes exposure to multiple donors, and all products should be irradiated to prevent ta-GVHD. As with RBCs, directed platelet donations from family members should be avoided.
- Granulocyte colony-stimulating factor (G-CSF): This raises the neutrophil count in most neutropenic patients.
Management of hematologic malignancies
The workup for hematologic malignancies for FA includes bone marrow aspirate and biopsy for morphologic review. Flow cytometry analysis should be performed if dysplasia or increased myeloblasts are seen. Cytogenetic analysis should also should be performed. Fluorescence in situ hybridization (FISH) analysis for specific aberrations associated with transformation to myelodysplastic syndrome. This includes assessment for gain of 1q, gain of 3q, deletion of 7, and deletion of 7q).
- Management of multilineage dysplasia with excess blasts: These patients should be referred for urgent stem cell transplant.
- Management of poor-risk cytogenetics: These patients should be referred for urgent stem cell transplant.
- Management of advanced MDS or AML: These patients can be treated with induction chemotherapy followed by stem cell transplant. For example, FLAG chemotherapy (reduced intensity (fludarabine, araC, and G-CSF) can be used.
- Management of biallelic BRCA2 (FANCD1) mutations: These patients harbor a very high risk of presenting early in childhood with MDS or AML in the absence of bone marrow failure. These patients might benefit from early stem cell transplant.
Management of solid tumors
Since patients with FA are at increased risk for development of certain cancers aside from hematologic malignancies, it is important to perform screening for certain types of these cancers.
- Breast cancer: Monthly breast self-examination should be performed starting in the early 3rd decade of life.
- Skin cancer: A detailed skin examination should be performed annually by a dermatologist.
- Head and neck cancer: These patients should avoid exposure to tobacco and alcohol, since these are known risk factors for HNSCC. Good oral hygiene and regular dental care is especially important.
- Liver tumors: Patients who are receiving androgen therapy may have increased risk for development of liver tumors.
- Gynecological and anogenital cancer: Human papilloma virus (HPV) vaccination is indicated for boys and girls prior to the onset of puberty.
- Stomach and colon cancer: A workup for a gastrointestinal malignancy should be performed in any patient with FA who presents with persistent abdominal discomfort, pain, or other attributable symptom that is not explained by other evaluation. Upper and/or lower endoscopic evaluations should be done.
- ↑ MacMillan ML, Wagner JE (2010). "Haematopoeitic cell transplantation for Fanconi anaemia - when and how?". Br J Haematol. 149 (1): 14–21. doi:10.1111/j.1365-2141.2010.08078.x. PMID 20136826.
- ↑ Barnum JL, Petryk A, Zhang L, DeFor TE, Baker KS, Steinberger J; et al. (2016). "Endocrinopathies, Bone Health, and Insulin Resistance in Patients with Fanconi Anemia after Hematopoietic Cell Transplantation". Biol Blood Marrow Transplant. 22 (8): 1487–1492. doi:10.1016/j.bbmt.2016.05.004. PMC 5545800. PMID 27180116.
- ↑ Gluckman E, Rocha V, Ionescu I, Bierings M, Harris RE, Wagner J; et al. (2007). "Results of unrelated cord blood transplant in fanconi anemia patients: risk factor analysis for engraftment and survival". Biol Blood Marrow Transplant. 13 (9): 1073–82. doi:10.1016/j.bbmt.2007.05.015. PMID 17697970.
- ↑ Zecca M, Strocchio L, Pagliara D, Comoli P, Bertaina A, Giorgiani G; et al. (2014). "HLA-haploidentical T cell-depleted allogeneic hematopoietic stem cell transplantation in children with Fanconi anemia". Biol Blood Marrow Transplant. 20 (4): 571–6. doi:10.1016/j.bbmt.2014.01.015. PMID 24462983.
- ↑ Bertaina A, Merli P, Rutella S, Pagliara D, Bernardo ME, Masetti R; et al. (2014). "HLA-haploidentical stem cell transplantation after removal of αβ+ T and B cells in children with nonmalignant disorders". Blood. 124 (5): 822–6. doi:10.1182/blood-2014-03-563817. PMID 24869942.
- ↑ Zierhut H, MacMillan ML, Wagner JE, Bartels DM (2013). "More than 10 years after the first 'savior siblings': parental experiences surrounding preimplantation genetic diagnosis". J Genet Couns. 22 (5): 594–602. doi:10.1007/s10897-013-9591-5. PMID 23624741.
- ↑ Tischkowitz M, Dokal I (2004). "Fanconi anaemia and leukaemia - clinical and molecular aspects". Br J Haematol. 126 (2): 176–91. doi:10.1111/j.1365-2141.2004.05023.x. PMID 15238138.
- ↑ Dufour C, Svahn J (2008). "Fanconi anaemia: new strategies". Bone Marrow Transplant. 41 Suppl 2: S90–5. doi:10.1038/bmt.2008.63. PMID 18545254.
- ↑ Scheckenbach K, Morgan M, Filger-Brillinger J, Sandmann M, Strimling B, Scheurlen W; et al. (2012). "Treatment of the bone marrow failure in Fanconi anemia patients with danazol". Blood Cells Mol Dis. 48 (2): 128–31. doi:10.1016/j.bcmd.2011.11.006. PMID 22178060.
- ↑ Rose SR, Kim MO, Korbee L, Wilson KA, Ris MD, Eyal O; et al. (2014). "Oxandrolone for the treatment of bone marrow failure in Fanconi anemia". Pediatr Blood Cancer. 61 (1): 11–9. doi:10.1002/pbc.24617. PMID 24019220.
- ↑ Gillio AP, Gabrilove JL (1993). "Cytokine treatment of inherited bone marrow failure syndromes". Blood. 81 (7): 1669–74. PMID 8461458.
- ↑ Talbot A, Peffault de Latour R, Raffoux E, Buchbinder N, Vigouroux S, Milpied N; et al. (2014). "Sequential treatment for allogeneic hematopoietic stem cell transplantation in Fanconi anemia with acute myeloid leukemia". Haematologica. 99 (10): e199–200. doi:10.3324/haematol.2013.098954. PMC 4181270. PMID 25085358.
- ↑ Khan NE, Rosenberg PS, Lehmann HP, Alter BP (2015). "Preemptive Bone Marrow Transplantation for FANCD1/BRCA2". Biol Blood Marrow Transplant. 21 (10): 1796–801. doi:10.1016/j.bbmt.2015.07.006. PMC 4568159. PMID 26183081.