Fanconi anemia medical therapy
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shyam Patel [2]
Overview
Treatments for Fanconi anemia include red blood cell transfusions, and marrow stem cell transplants, and medicines.
Medical therapy
Active surveillance
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 is the only accepted curative therapy for fanconi anaemia with severe bone marrow failue, MDS or AML, transfusion dependent anaemia or thrombocytopenia,
We immediately refer these patients for HCT. The recommended approach is to use bone marrow (rather than peripheral blood stem cells) from an eligible sibling who is HLA matched at 8 of 8 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.
This testing is very important because family donors those are apparently asymptomatic and healthy may have FA 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:
- 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 its 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.[1] 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.
●Unrelated cord blood transplantation (CBT) 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.[2] 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 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. [3] [4]
Based on the above conclusion, CBT or haploidentical HCT should only be performed for patients with FA in the context of active clinical trials.
Patients with FA are at risk for significant toxicity from standard chemotherapy doses which used for HCT conditioning. Strategies revised at the Minnesota university and other centre that incorporate reduced dose of cyclophosphamide (20-60mg/kg) representing 50-90% reduction compared with conventional cyclophosphamide doses, also combination with immunosuppressive but low toxicity agents such as fludarabine and anti thymocyte globulin, have been extremely effective in matched sibling donor HCT for FA.
Rates of engraftment associated with these approaches are >90 percent, and overall post-HCT survival is >95 percent in most series reported since 2005.[5]
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 essential to delaying HCT while attempting to use non-curative supportive care approaches to increasing 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.[6]
Androgens — Androgen therapy is not curative but it may be a good 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 eligible.[7] 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.
Only half of patents with FA will respond to androgen therapy.[8] 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. Thus, the recommended time to initiate a trial of androgen therapy when a patient has developed moderate to severe bone marrow failure but is not consistently transfusion dependent. 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.
Oxymetholone is the most commonly used androgen in FA (starting dose 2 to 5 mg/kg/day); danazol and oxandrolone have also been used.[9] If the blood counts stabilize or improve, the daily dose may be tapered to the minimum effective dose to avoid non-hematologic toxicity. If no response is seen after three months, oxymetholone should be discontinued.
Androgen therapy can be associated with a number of side effects, including 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.
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.[10] More experience with this agent is needed.
Transfusions and growth factors — 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.
● 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. An approach to assessing and treating transfusional iron overload (eg, with phlebotomy or chelation therapy) is presented separately
● Platelets – Platelet transfusion is indicated in patients with platelet counts <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.
- G-CSF – Granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) raises the neutrophil count in most neutropenic patients.[11] However, we reserve the use of G-CSF for patients with FA to those with an ANC <200/microL, or those with known active invasive bacterial or fungal infections and an ANC <1000/microL, due to concerns that G-CSF or GM-CSF may increase the risk of MDS and AML in patients with bone marrow failure syndromes.
- For those who require growth factor support, experience is greater with G-CSF than with GM-CSF. The starting dose of G-CSF is 5 mcg/kg daily, and the dose is adjusted towards a target goal of ANC 1500 to 2000/microL. If possible, the administration of G-CSF is adjusted to every other day to minimize the frequency of administration. If GM-CSF is used, the starting dose is 250 mcg/m2/day. There are no clinical trials comparing G-CSF with GM-CSF. If there is no improvement in the neutrophil count after eight weeks, treatment should be discontinued.
- Importantly, patients with neutropenia and fever should be evaluated urgently, cultures obtained, and broad spectrum antibiotics administered until the fever resolves or cultures are negative, to reduce the risk of life-threatening infections. However, we do not give routine prophylactic antibiotics to patients with FA, as there are no studies to indicate clinical benefit from this practice, and it may potentially increase the risk of fungal infections and antibiotic resistance.
HEMATOLOGIC NEOPLASMS— Clonal hematopoiesis is very common in patients with FA. For newly diagnosed patients who have not had a bone marrow evaluation, we obtain a unilateral bone marrow aspirate and biopsy (>1 cm) for morphologic review. Flow cytometry analysis should be performed if dysplasia or increased myeloblasts are seen. Cytogenetic analysis should also should be performed, and at minimum should include G-banding analysis of at least 20 metaphases to assess for acquired chromosomal aberrations. Fluorescence in situ hybridization (FISH) analysis for specific aberrations associated with transformation to myelodysplastic syndrome (MDS) (eg, +1q, +3q, -7, -7q) and whole genome single nucleotide polymorphism (SNP) array with copy number analysis may increase sensitivity and the ability to detect subtle chromosome aberrations. If adequate cytogenetic analysis was not done on a bone marrow performed prior to the diagnosis of FA, we repeat the bone marrow to obtain cytogenetics.
Greater intensity monitoring and other interventions are generally based on the presence of dysplasia, blast count, and specific cytogenetic findings. Our approach is as follows:
●As noted above, an initial bone marrow aspirate and biopsy with cytogenetics is done in all patients diagnosed with FA. This is usually repeated annually as long as no concerning features are noted.
●Patients with morphologic features concerning for hematologic neoplasm, including multilineage dysplasia and/or excess blasts, or those with poor-risk cytogenetic features (eg, -7, +3q) even in the absence of dysmorphology, should be referred for urgent hematopoietic cell transplantation (HCT) with the best available donor. Pre-HCT chemotherapy cycles are not advised in these patients, because of the risk of prolonged aplasia and the lack of evidence for a survival benefit, even in young patients without FA who develop MDS.[12] Regardless of the pre-HCT cytoreduction approach, it is critical to identify the HCT donor prior to initiating chemotherapy for MDS or AML in patients with FA because of the risk of chemotherapy-induced aplasia.
●Patients with advanced MDS (eg, bone marrow blast count >10 to 15 percent) or acute myeloid leukemia (AML) may be treated with a course of chemotherapy followed by HCT. One piloted strategy used a single cycle of reduced intensity FLAG (fludarabine, cytarabine, and G-CSF) three weeks prior to the initiation of HCT conditioning (without waiting for hematologic recovery from the FLAG regimen); this may be an effective approach, as all six patients in a study using this approach were alive and disease free at a follow-up of 28 months.[13] However, the use of pre-transplant cytoreduction remains highly controversial and is best discussed with experts in FA prior to initiation.
●Certain cytogenetic abnormalities such as +1q, del(20q), and del(5q) are not associated with poor-risk MDS for patients with FA. For patients with these findings who do not have another indication for HCT such as severe bone marrow failure, dysplasia, or acute leukemia, we monitor the complete blood count (CBC) closely (eg, once per month) and repeat the bone marrow every one to six months until the stability (or instability) of the clone is established.
●Patients with biallelic BRCA2 (FANCD1) mutations (and perhaps also those with FANCN mutations) present a special challenge, as these patients have a very high risk of presenting early in childhood with MDS or AML in the absence of bone marrow failure. A 2015 study using a theoretical survival analysis approach suggested that some patients with biallelic BRCA2 mutations might benefit from pre-emptive HCT because of the nearly 80 percent actuarial risk of leukemia by 10 years of age.[14]
SOLID TUMORS — As noted above, individuals with FA are at increased risk for a number of types of solid tumors, and this risk is likely to be increased in those who have undergone hematopoietic cell transplantation (HCT).
Screening and prevention — We screen for the following, with referrals as appropriate:
●Skin cancer – A full skin examination should be performed, and all concerning skin lesions should be evaluated by a dermatologist.
●Head and neck squamous cell carcinoma (HNSCC) – We advise patients with FA to avoid tobacco and alcohol, since these are known risk factors for HNSCC. We also advise good oral hygiene and regular dental care including thorough examination of the oral cavity every six months, since poor oral hygiene is also a risk factor for HNSCC in patients with FA. In addition, all patients older than 10 years of age and patients under 10 years who have undergone HCT and have a history of graft-versus-host disease (GVHD) should have laryngoscopic examination of the nasopharynx and oropharynx by an otolaryngologist at least annually.
Any lesions suspicious for oral leukoplakia should be evaluated by an oral surgeon. Patients with difficulty swallowing or similar complaints should undergo esophagoscopy.
●Liver tumors – Patients who are receiving androgen therapy or have received androgens in the past should be screened for liver tumors as outlined above.
●Gynecological and anogenital cancer – Human papilloma virus (HPV) vaccination should be given to all patients prior to the onset of puberty. Information on HPV vaccine administration is presented in detail separately.
Adolescent girls should have a visual examination of the external genitalia beginning at menarche and a comprehensive gynecologic evaluation including PAP test once they become sexually active or by the age of 18 years, whichever comes first.
Routine anoscopy is indicated for patients with prior anogenital dysplasia due to increased risk of anal squamous cell carcinoma.
●Breast cancer – Breast self-examination should be performed monthly beginning in the early 20s, and routine physical examinations should include evaluation for breast masses. Screening mammography may be initiated as early as age 25, particularly if self-examination or physician examination identifies any concerning lesions.
●Gastrointestinal cancer – Stomach and colon cancers are not common in FA; however, any patient with FA who has abnormal upper or lower gastrointestinal bleeding, discomfort, pain, or other attributable symptom that is not explained by other evaluations should undergo upper and/or lower endoscopic evaluation.
Management with chemotherapy dose reductions -- For patients with FA who requires chemotherapy and/or radiation therapy, treatment is complicated by the extreme sensitivity to genotoxic agents, especially radiation and alkylating agents such as cyclophosphamide. Dose reduction of these agents or switching to alternative regimens may be necessary depending on the type of tumor and stage of disease. Chemotherapy regimens to treat solid tumors should be discussed with experts in the management of patients with FA prior to their initiation. Additionally, patients who have not undergone HCT who are treated with intensive chemotherapy or radiation therapy for solid tumors are at high risk for developing therapy-related bone marrow failure, and discussion with a center with both FA and HCT expertise is indicated before chemotherapy is initiated.
TESTING OF SIBLINGS AND MANAGEMENT OF HETEROZYGOTES — Once a patient is diagnosed with FA, all first degree siblings should be tested, as the phenotype is variable within families and it is common to see more than one child with FA in a family. Additionally, since siblings are potential donors for hematopoietic cell transplantation (HCT), it is important to exclude siblings with FA as potential HCT donors. Testing for known familial mutations can also be pursued for other interested family members in addition to siblings.
Testing family members of an affected individual can be done by assessing for chromosomal breakage using peripheral blood lymphocytes, or by genetic testing if the familial mutation(s) have been characterized. Testing should be accompanied by counseling with a genetic counselor or clinician with expertise in FA and the management of heterozygotes. Counseling and testing of siblings should be done as soon as possible after proband diagnosis, so that alternative donor strategies can be pursued if there are no unaffected siblings who are an HLA match.
Prenatal testing is possible using cells obtained by chorionic villus sampling, amniocentesis, or cordocentesis. In vitro fertilization with PGD as discussed above is another method utilized to detect disease or carrier status prior to implantation of sibling embryos.Carrier status for an FA mutation may have implications for reproductive decision-making. For most individuals who are heterozygous for an FA mutation, there may be a slight increased risk of cancer, but the absolute risk appears to be relatively small, and there are no specific recommended screenings for individuals who are heterozygous carriers. Exceptions include the following:
●Individuals who are heterozygous for a mutation in FANCD1/BRCA2 or FANCS/BRCA1 have a high risk of developing breast and ovarian cancers. As a consequence, mothers of patients with either of these mutations should be referred to adult oncologists for discussions of high-risk screening and prevention strategies. Heterozygous siblings and fathers should also be offered genetic counseling and cancer screening as appropriate.
●Males with a mutation in FANCB (which is X-linked recessive), and any patient with a mutation in FANCR (RAD51), which is autosomal dominant, are treated as affected individuals rather than carriers.
PROGNOSIS — Prior to the year 2000, the median survival of individuals with FA was 21 years of age. Since that time, there has been a dramatic improvement in survival for patients with FA who live in the developed world. In large part this is due to a reduction in deaths due to bleeding or infectious complications that arise in the setting of pancytopenia. Bone marrow failure can often be cured, and myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) can often be cured or prevented with hematopoietic cell transplantation in most patients [27-29]. However, as many more individuals are living well into adulthood, the cumulative incidence of solid tumors continues to rise, a phenomenon that may limit life expectancy until new approaches to treatment for these tumors are developed.
Medical Therapy[edit | edit source]
Androgen therapy is helpful in moderate bone marrow failure cases if no donor is available for HCT, or whom do not meet eligibility criteria for HCT due to pre existing organ dysfunction or ongoing infection, and those who decline HCT.
References
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ Hasle H, Niemeyer CM (2011). "Advances in the prognostication and management of advanced MDS in children". Br J Haematol. 154 (2): 185–95. doi:10.1111/j.1365-2141.2011.08724.x. PMID 21554264.
- ↑ 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.