Minimal antileukaemic treatment followed by reduced-intensity conditioning in three consecutive children with Fanconi anaemia and AML

Patients with Fanconi anaemia (FA) who have progressed to AML and are therefore referred for haematopoietic SCT (HSCT) represent a major therapeutic challenge. An important question in this unfortunate situation is whether a CR status of the leukaemia is necessary prior to HSCT. Indeed, CR status before transplant has been shown to result in superior relapse-free survival after HSCT in non-FA patients.1

A total of 15 patients with FA and AML could be retrieved from the German AML-BFM database. Six out of 15 patients underwent HSCT and three out of the six became long term survivors. Here we report on these three consecutive children who underwent HSCT at our institution. For these three patients only, more detailed information was available. Presenting features are shown in Table 1. Two of the three children received low dose pre-transplant chemotherapy only in order to delay leukaemia progression before transplant (Table 2), the third was taken directly to HSCT without cytoreductive therapy. Transplant specifics are summarised in Table 2. All patients are alive, independent of transfusions and remain in CR.

Table 1 Details of FA patients with AML before undergoing HSCT
Table 2 Patients with Fanconi anaemia and AML treated by Allo-SCT

Information regarding mangement of this high-risk FA population is lacking. A recent analysis of transplant data from the Center of International Blood and Marrow Transplantation Research (CIBMTR) identified 12 patients with AML from 113 FA patients with clonal evolution, myelodysplastic syndrome (MDS) or AML. The authors state that at the time of HSCT, 3 of 12 patients were in first CR, one was in second CR and 4 patients failed to achieve remission (1 patient never received chemotherapy before HSCT). Furthermore, they point out that data on the remission status of the remaining four patients were absent. Altogether, pre-HSCT chemotherapy data were available in 5 of 12 patients but was not specified. Outcome of these patients was not separately analyzed, but pooled for all patients with acute leukaemia (including 2 patients with ALL). The 5 year OS was 36%.2 A second large report from the European Group for Blood and Marrow Transplantation (EBMT), which was published in the same year, examined HSCT outcomes in 795 patients with FA. The authors of this analysis argued that a detailed analysis of this subgroup of FA patients with clonal disease, MDS and/or AML was not performed because the CIBMTR had already published on this topic.3

None of our three patients had an HLA-matched family donor and thus received alternative donor allografts for their HSCT. Two of the children were given HLA-matched (10/10 as determined by high-resolution molecular typing at the HLA A, B, C, DRB1 and DQ loci) unrelated donors (matched unrelated donor (MUD)) grafts and the third child received a CD34-positive selected graft from an haploidentical (5/10 HLA matched) father. The two MUD patients received non-manipulated BM stem cells while the patient with the haploidentical graft received T-cell depleted PBSC. All three children were treated with a reduced-intensity conditioning (RIC) regimen consisting of fludarabine, with either BU and/or CY. GVHD prophylaxis was heterogenous. MTX was avoided in all patients. Antithymocyte globulin (ATG, Fresenius, Neovii Biotech GmbH, Munich, Germany) or alemtuzumab plus CsA/rapamycin with or without MMF were used. For the T-cell depleted graft muromonab-CD3 (OKT3) was added. Acute GVHD (aGVHD) was graded according to the criteria of Glucksberg et al.,4 chronic GVHD (cGVHD) according to the criteria by Shulman et al.5 No patient had prior androgen therapy.

Neutrophil engraftment was achieved by days +10, +20 and +22. Platelet recovery occurred between day +21 and +69. All three patients had 100% donor chimerism on last follow up (14, 75 and 174 months), are independent of red cell and platelet transfusions, and remain in remission. There was no severe therapy-related toxicity; however, cGVHD developed in all three patients. In two patients, the cGVHD was extensive (lung involvement), the remaining patient had limited cGVHD. In all patients cGVHD appeared in the background of aGVHD (grade I, n=2; grade II, n=1).

The increased sensitivity to DNA cross-linking agents makes FA patients ineligible for conventional conditioning regimens. Treating FA-AML appears even more challenging considering the fact that intensive induction therapy with anthracyclines and cytarabine is the key to cure non-FA patients with AML.6 Published data on pre-transplant treatment concepts for AML associated with FA are rare. The Cincinnati-group piloted in four children a mini FLAG regimen consisting of fludarabine (30 mg/m2), cytarabine (300 mg/m2) for three days followed by G-CSF. This cytoreductive course was well tolerated. Response to treatment could not be fully evaluated because the children proceeded to HSCT without the recovery of normal hematopoiesis, but one child in the study was a long term survivor.7 A similar concept with more encouraging results using a sequential treatment approach, chemotherapy followed by RIC, was recently presented by a French group. Here, the chemotherapy regimen consisted of similar doses of fludarabine combined with cytarabine at 1000 mg/m2 for 2/5 days.8 Conversely, experiences at the University of Minnesota do not clearly support the use of cytoreduction prior to transplant. Their current concept favors transplantation using CY, fludarabine, ATG and TBI 300 cGy in MUD FA transplants irrespective of whether AML/MDS is present or not.9

The three FA patients reported here, either received oral thioguanin (40 mg/m2/day) and very low dose cytarabine (40 mg/m2/day; n=2) or no cytoreductive therapy (n=1) before transplantation. Nevertheless, the low intensity chemotherapy administered to these two patients had a significant impact on their leukaemic burden as both were found to have marrow aplasia at the time of transplant. Hence, on the basis of this small case series, one might cautiously conclude that administering intensive pre-transplant ‘AML-like’ therapy may not be necessary for patients with FA and AML. On the other hand, a recent report demonstrated that the risk of relapse remains high in FA AML,10 suggesting that there may be value in administering some cytoreductive pre-transplant chemotherapy in this setting.

In summary, three patients were successfully treated using minimal antileukaemic therapy followed by RIC HSCT. All patients are alive and in CR. cGVHD (two extensive, one limited) was the predominant treatment-associated adverse effect. This reflects the experience that children with AML and FA can be rescued with tolerable acute toxicity, but the development of cGVHD still remains a major problem.


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This work was in part supported by the Deutsche Forschungsgemeinschaft and the BMBF (SFB 738, TPA3 and IFB-TX, CBT_6, both to MGS). MC is supported by the Deutsche Kinderkrebsstiftung (A 2013/14 DKS 2013.16 Fanconi-Anämie-Register).

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Correspondence to M G Sauer.

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Beier, R., Maecker-Kolhoff, B., Sykora, K. et al. Minimal antileukaemic treatment followed by reduced-intensity conditioning in three consecutive children with Fanconi anaemia and AML. Bone Marrow Transplant 50, 463–464 (2015).

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