Bone marrow transplantation for patients with Fanconi anemia - Nature

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http://www.stockton-press.co.uk/bmt. Bone marrow transplantation for patients with Fanconi anemia: reduced doses of cyclophosphamide without irradiation as.
Bone Marrow Transplantation, (1999) 24, 849–852  1999 Stockton Press All rights reserved 0268–3369/99 $15.00 http://www.stockton-press.co.uk/bmt

Bone marrow transplantation for patients with Fanconi anemia: reduced doses of cyclophosphamide without irradiation as conditioning CR de Medeiros, J Zanis-Neto and R Pasquini Bone Marrow Transplantation Service, Hospital de Clinicas, UFPr, Curitiba, Parana, Brazil

Summary: Fanconi anemia (FA), a rare autosomal recessive disease, frequently evolves to bone marrow failure and acute myeloid leukemia, and BMT is the treatment of choice for patients with FA. However, their exquisite hypersensitivity to DNA cross-linking agents is associated with severe complications and several investigators have been looking for the ideal preparatory regimen. We have been involved in a program of progressively decreasing doses of cyclophosphamide (CY) as conditioning therapy, in an attempt to identify the lowest dose of CY capable of maintaining the graft with minimum complications. Here, we describe our experience of allogeneic BMT offered to 16 patients with FA and an HLA-compatible sibling donor, conditioned with 100 mg/kg of CY. The actuarial survival is 88% at approximately 37 months. Mucositis ⭓ grade II was the most common complication (94%), followed by bacteremias (38%). Veno-occlusive disease and hemorrhagic cystitis did not occur. Sustained engraftment was obtained in 94% of patients, and acute and chronic GVHD was diagnosed in 13% and 7%, respectively. The lowest dose of CY for transplant in FA patients is yet to be determined, but further reductions seem possible. Keywords: Fanconi anemia; allogeneic bone marrow transplantation; reduced doses of cyclophosphamide; sustained engraftment

Fanconi anemia (FA) is a rare autosomal recessive disease almost always linked to bone marrow failure, and evolving frequently to acute myeloid leukemia or myelodysplastic syndromes.1 Bone marrow transplantation (BMT) has been considered the best treatment for this disorder.2,3 However, the cellular hypersensitivity of these patients to DNA crosslinking agents used in conditioning regimens, such as cyclophosphamide (CY) and radiotherapy, is associated with a high rate of complications and even mortality.3,4 The combination of radiotherapy and CY, both in low doses, has been utilized in an attempt to provide sustained Correspondence: Dr CR de Medeiros, Servic¸o de Transplante de Medula ´ ssea, Hospital de Clı´nicas, Rua General Carneiro, 181–15° andar–Zip O Code: 80060–900, Curitiba, Parana, Brazil Received 19 February 1999; accepted 20 May 1999

engraftment with acceptable toxicity.3,5 However, longterm effects of radiation, particularly secondary neoplasm, has led some investigators to use CY alone in conditioning.6,7 In an effort to determine the lowest dose capable of maintaining the graft with the minimum complications, we have progressively decreased the dose of CY over the last 15 years with good results,8 even considering that the best preparatory regimen has been difficult to establish, by virtue of the heterogeneity of FA patients probably related to the genetic diversity found in this disease.9 Here, we describe clinical response, engraftment and outcome of 16 FA patients treated by BMT, after a conditioning regimen of reduced dose CY, without radiotherapy.

Patients and methods Patients From October 1995 to March 1998, 16 patients with FA and HLA-matched compatible sibling donors underwent BMT. Diagnosis was based on clinical features of FA and diepoxybutane-induced chromosomal breakage.10 All patients were in the severe or moderately aplastic phase of the illness, with no clinical or hematological evidence of leukemia or myelodysplasia. Characteristics of the 16 patients are given in Table 1. There were 10 males and six females; ages ranged from 4 to 21 years (median 7 years), interval between diagnosis and BMT was from 4 to 156 months (median 14.5 months), number of packed erythrocytes and platelets concentrates given before BMT varied from zero to 50 (median 7.5 units). All donors were tested before transplant and had no evidence of FA. Number of donor nucleated BM cells infused was considered adequate and ranged from 2.24 to 6.2 × 108/kg (median 3.33 × 108/kg). Methods All patients received CY 25 mg/kg once daily i.v. for 4 consecutive days (total dose 100 mg/kg). MESNA (25 mg/kg i.v. per day) was given with the CY. Patients were isolated in single rooms with high efficiency particulate air (HEPA). In the case of ABO incompatibility, red blood cells or plasma were removed by starch sedimentation. Patients seronegative for cytomegalovirus (CMV)

Reduced doses of CY in BMT for FA CR de Medeiros et al

Table 1

1.0

Pre-transplant features of 16 patients

0.9

UPN

603 625 640 653 668 676 678 684 701 703 719 736 746 773 796 817

Age Sex (years)

7 13 4 14 7 21 6 10 17 9 6 7 6 6 7 8

M M M F M F M M M F M F M F M F

Disease features

B,K,S,ST B,E,K,S,ST B,E,RA,ST E,MIG,S,ST B,E,S,ST E,S,ST CT,S,ST B,E,K,S,ST CD,K,S B,S,ST None C,F,S,ST B,C,S,ST B,F,S,ST F,S,ST C,S,ST

WBC ANC Platelets (109/l) (109/l) (109/l)

4.2 2.9 5.3 3.3 4.9 4.3 2.1 2.0 2.5 1.8 5.1 1.0 3.5 4.5 3.3 3.6

1.0 1.1 2.1 1.3 1.7 1.6 0.9 0.25 0.35 0.35 0.87 0.45 0.5 0.56 2.5 1.7

23 45 61 53 18 39 15 18 24 22 21 61 14 23 31 62

Hb g%

7.9 11 7 7 5.9 11 6.2 5 8.5 5.2 8.3 6.8 9.6 10 8.5 12

Transf pre BMT 4 8 5 None 50 23 7 3 None 30 10 31 31 5 2 18

UNP = unique patient number; WBC = white blood cells; ANC = absolute neutrophil count; Hb = hemoglobin; Transf pre BMT = number of transfusions before BMT; B = thumb abnormality; C = consanguinity; CD = cutaneous dyskeratosis; CT = cryptorchidism; E = microphthalmia; F = typical Fanconi’s face; K = urinary tract abnormality; MIG = micrognathia; RA = radius abnormality; S = skin pigmentation; ST = short stature.

were transfused with CMV-negative blood or blood which had been leukadepleted. Acyclovir prophylaxis for herpes virus and trimethropim-sulfamethoxazole for Pneumocystis carinii were used in all patients along with fluconazole for fungus. Graft-versus-host disease (GVHD) prophylaxis was with cyclosporin A (CsA) and methotrexate (MTX) according to the Seattle protocol.11 Based on our previous experience with BMT in FA, MTX was not given to patients when ⭓ grade III mucositis was observed. Acute (a)GVHD grade II to IV was defined using published criteria, and patients surviving ⬎21 days post transplantation with engraftment were considered at risk,12 and patients engrafted and surviving ⬎90 days were considered at risk to chronic (c)GVHD.13 Engraftment was defined as an ANC ⬎0.5 × 109/l for at least 2 consecutive days without growth factor and marrow cellularity ⬎15% by day 21 after transplant with all three cell lines present. Documented donor engraftment was confirmed by ABO typing in patients with major red blood cell group differences, chromosomal analysis for sex-mismatched patient/donors pairs and PCR targeting variable number of tandem repeats (VNTR) loci.14

Results Survival As of March 1998, 14 patients were alive. The Kaplan– Meier15 survival is 88%, with a median follow-up of 599 days (range 15–1071 days) (Figure 1).

Probability of survival

850

16 patients

0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0

250

500

750

1000

1250

Days post transplant Figure 1 Actuarial survival after allogeneic BMT.

Engraftment Sustained marrow engraftment was observed in 15 assessable patients. One patient died of bronchopneumonia on day +15 with no evidence of engraftment. Donor-type hematopoiesis was proven in 14 patients who survived ⬎100 days. In six patients, ABO blood group differences from donor were present before transplantation (UPN 603, 625, 653, 668, 678, 746). All these patients showed red blood cells of donor origin after transplant. One patient (UPN 736) was sex-mismatched with his donor and T lymphocytes analyzed after transplant showed donor karyotype. Seven patients (UPN 640, 684, 701, 719, 773, 796, 817) had VNTR polymorphism studies distinguishing donor from host cells. Four patients (UPN 640, 684, 719 and 796) had 100%, two patients (UPN 773 and 817) had 80% and one patient (UPN 701) had 60% peripheral blood cells of donor origin. Conditioning-related toxicity Among the 16 patients, the most frequent toxicity was mucositis ⭓ grade II in 15 patients (94%). Positive blood cultures were detected in six patients (38%), viral infection in two patients (13%), bronchopneumonia in two patients (13%) and necrotizing enterocolitis in one patient (6%). No patient had veno-occlusive disease or hemorrhagic cystitis. Graft-versus-host disease Six patients received full doses of MTX, nine received three doses and one patient received only two. Two patients had aGVHD, both grade II. One patient received full dose MTX, progressed to extensive cGVHD and is presently alive and well (UPN 746). The second patient (UPN 703) received only two doses of MTX and died on day +55 from bacterial infection. Causes of death Two patients died of infection followed by multiorgan failure. One patient (UPN 676) developed extensive gramnegative bronchopneumonia before engraftment, followed by acute respiratory and multiorgan failures, and death

Reduced doses of CY in BMT for FA CR de Medeiros et al

occurred at day +15. This was a 21-year-old patient, who had had established pancytopenia for 8 years, requiring multiple transfusions and androgen therapy prior to BMT. The second patient (UPN 703) developed aGVHD grade II, and had pseudomembranous colitis caused by Clostridium difficile also followed by multiorgan failure, and expired at day +55. Current status All 14 surviving patients have documented donor engraftment and good hematopoietic recovery. Karnofsky performance score is 100% in 13 patients and 80% in one patient (UPN 746). Discussion The preparatory regimen used in our study was very effective, allowing engraftment even in transfused patients, and was associated with low toxicity. The well-described toxic effects of a CY metabolite in Fanconi patients, including severe mucositis, extensive gastrointestinal lesions and hemorrhages, fluid retention, cardiac failure and hemorrhagic cystitis16 were partially avoided with the reduced CY dose used in the present study. Mucositis was still the most frequent complication, followed by bacteremias secondary to microorganisms that are usual inhabitants of the gastrointestinal tract, and which probably reached the blood stream through mucosal barrier breakage. Sustained engraftment occurred in all but one of our patients, who survived less than 15 days. Gluckman,17 and Kohli-Kumar and colleagues,18 utilizing low doses of CY combined with radiotherapy, with or without antithymocyte globulin (ATG), also experienced good engraftment. Recently, a report from the IBMTR19 analyzed the outcome of 151 patients with FA, all of whom received HLAcompatible sibling donor BMTs. Low rates of graft failure were found with three different conditioning regimens utilizing low doses of CY plus limited field radiotherapy, with or without ATG, low doses of CY plus total body irradiation and CY (⭓100 mg/kg) with or without ATG with no radiotherapy. So, engraftment is not usually a problem in FA patients undergoing BMT from an HLA-matched compatible sibling donor. The major complication after allogeneic BMT is GVHD. Toxicity from conditioning may play an important role in the pathogenesis of aGVHD, and is supposedly related to release of cytokines secondary to damage and activation of host tissue, including the intestinal mucosa and liver.20 The incidence of GVHD in FA patients is variable, and aGVHD and cGVHD among our patients were 13% and 7%, respectively. These results are significantly better than those previously seen in our own patients treated with higher doses of CY,8 where aGVHD and cGVHD varied from 17% to 40% and 17% to 83%, respectively. ZanisNeto et al4 and Flowers et al7 also reported higher rates of acute and chronic GVHD in their series, where patients received CY in doses ranging from 120 to 200 mg/kg. It is possible that less aggressive conditioning regimens resulted in less tissue damage, consequently allowing the use of

more doses of MTX, as shown by the fact that 15 patients received at least three doses of this drug. Kohli-Kumar and colleagues18 reported absence of aGVHD and 16% of cGVHD in patients receiving lowdose CY, limited field radiotherapy and ATG as conditioning and CsA and ATG plus prednisone as immunoprophylaxis. On the other hand, Gluckman21 reported 47% of aGVHD grade II to IV and 46% of cGVHD in patients surviving more than 120 days, with immunoprophylaxis based on CsA alone after usual conditioning with radiotherapy. ATG in conditioning reduces the probabilities of aGVHD and cGVHD19 according to an IBMTR report. Unfortunately, however, it has been related to secondary malignancies, especially EBV-related lymphomas and solid tumors.18 The Kaplan–Meier survival of our group is 88%, with no ATG or radiotherapy, which is similar to several published series.4,6,7,18,19 The follow-up of these patients is not sufficiently long for a conclusive analysis. However, looking at the FA transplants performed at our Center since November 1983, late graft failure was not observed8 and only one patient developed a secondary malignancy (carcinoma of tongue), 6 years after BMT. Recently, Deeg et al22 concluded that a diagnosis of FA and radiotherapy as part of conditioning were risk factors for solid tumors, developing 30 to 221 months (median 99 months) post transplant.22 Genetically, FA is a very heterogeneous disease, and it is possible that different genetic defects determine distinct sensitivity to clastogenic agents. We are some distance from an ideal conditioning regimen for all patients with FA. Nevertheless, the progressively decreasing doses of CY without radiotherapy associated with GVHD prophylaxis with CsA and MTX, have improved our results. Sustained engraftment has been achieved, the incidences of aGVHD and cGVHD have been low, but mucositis remains moderate to severe. The lowest dose of CY for conditioning in FA patients is yet to be determined, and further dose reductions seems possible. Dokal and Roberts23 reported one case of a FA patient conditioned with a total CY dose of 80 mg/kg and two cases conditioned with 20 mg/kg, all of whom received only CsA as prophylaxis for GVHD. Three to 5 years after transplant, they were all well and with normal blood counts. We anticipate that with CY dose reduction, toxicity will be more tolerable, permitting more effective GVHD prophylaxis, which may result in less morbidity and mortality. References 1 Butturini A, Gale RP, Verlander PC et al. Hematological abnormalities in Fanconi anemia: an International Fanconi Anemia Registry study. Blood 1994; 84: 1650–1655. 2 Dooren LJ. Bone marrow transplantation in children. Semin Hematol 1974; 11: 369–382. 3 Gluckman E, Devergie A, Dutreix J. Bone marrow transplantation in Fanconi anemia. A modified conditioning regimen. Exp Hematol 1982; 10: 26–27. 4 Zanis-Neto J, Ribeiro RC, de Medeiros CR et al. Bone marrow transplantation for patients with Fanconi anemia: a study of 24 cases from a single institution. Bone Marrow Transplant 1995; 15: 293–298.

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5 Gluckman E. Radiosensitivity in Fanconi anemia: application to the conditioning for bone marrow transplantation. Radiother Oncol 1990; 1: 88–93. 6 Flowers ME, Doney KC, Storb R et al. Marrow transplantation for Fanconi anemia with or without leukemia transformation: update of Seattle experience. Bone Marrow Transplant 1992; 9: 167–173. 7 Flowers MED, Zanis-Neto J, Pasquini R et al. Marrow transplantation for Fanconi anemia; conditioning with reduced doses of cyclophosphamide without irradiation. Br J Haematol 1996; 92: 699–706. 8 Zanis-Neto J, Pereira NF, de Medeiros CR et al. Bone marrow transplantation for Fanconi anemia, decreasing the cyclophosphamide dose without irradiation. Blood 1998; 92 (Suppl. 1): 136a (Abstr. 546). 9 Strathdee CA, Duncan AMV, Buchwald M. Evidence for at least four Fanconi anemia genes including FACC on chromosome 9. Nat Genet 1992; 1: 196–198. 10 Auerbach AD, Rogatko A, Schroeder-Kurt TM. International Fanconi Anemia registry. Relation of clinical symptoms to diepoxybutane sensitivity. Blood 1989; 73: 391–396. 11 Storb R, Deeg HJ, Farewell V et al. Marrow transplantation for severe aplastic anemia. Methotrexate and cyclosporin for prevention of acute graft versus host disease. Blood 1986; 68: 119–125. 12 Gluckesberg H, Storb R, Fefer A et al. Clinical manifestations of graft versus host disease in human recipients of marrow HLA-matched sibling donors. Transplantation 1974; 18: 295–301. 13 Atkinson K, Horowitz MM, Gale RP et al. Risk factors for chronic graft versus host disease after HLA identical sibling bone marrow transplantation. Blood 1990; 75: 2459–2465.

14 Leclair B, Fre´geau CJ, Aye MT et al. DNA typing for bone marrow engraftment follow-up after allogeneic transplant: a comparative study of current technologies. Bone Marrow Transplant 1995; 16: 43–55. 15 Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–481. 16 Berger R, Bernheim A, Gluckman E et al. In vitro effect of cyclophosphamide metabolites on chromosomes of Fanconi anemia patients. Br J Haematol 1980; 45: 565–571. 17 Gluckman E. Bone marrow transplantation for Fanconi anemia. In: Shahidi NT (ed). Aplastic Anemia and Other Bone Marrow Failure Syndromes. Springer-Verlag: New York, 1990, pp 134–144. 18 Kohli-Kumar M, Morris C, De Laat C et al. Bone marrow transplantation in Fanconi anemia using matched sibling donors. Blood 1994; 84: 2050–2054. 19 Gluckman E, Auerbach AD, Horowitz MM et al. Bone marrow transplantation for Fanconi anemia. Blood 1995; 86; 2856–2862. 20 Ferrara JLM, Cooke KR, Pan L et al. The immunopathology of acute graft versus host disease. Stem Cells 1996; 14: 473–489. 21 Gluckman E. Bone marrow transplantation in Fanconi’s anemia. Stem Cells 1993; 11: 180–186. 22 Deeg HJ, Socie G, Schoch G et al. Malignancies after marrow transplantation for aplastic anemia: a joint Seattle and Paris analysis of results in 700 patients. Blood 1996; 87: 386–392. 23 Dokal IS, Roberts IAG. Bone marrow transplantation for Fanconi’s anemia: conditioning with reduced doses of cyclophosphamide without radiation. Br J Haematol 1996; 94: 423 (letter).