Reduction in the Frequency of Transplant-Related Complications In

Reduction in the frequency of transplant-related complications in patients with chronic myeloid leukemia undergoing BMT preconditioned with a new, non-myeloablative drug combination

´ ´ ´ E Kelemen1, T Masszi2, P Remenyi2, A Barta1 and K Paloczi1 ´ ´ 1National Institute of Hematology and Immunology, Budapest; and 2Saint Laszlo Hospital, Budapest, Hungary

Summary: new conditioning protocol may be superior to other proto- cols with regard to post-BMT complications. A radiation-free, non-myeloablative, myelosuppressive On the basis of our favorable experience with the non- protocol, containing dibromomannitol and cytosine ara- myeloablative DBM-protocol which is myelosuppressive binoside, that remarkably reduced the frequency of rather than supralethal, we considered that the eradication transplant-related complications, such as veno-occlusive of the leukaemic clone may not be mandatory for clinical liver disease (VOLD), severe mucositis, bacterial sepsis, cure.1 hemorrhagic cystitis, interstitial pneumonitis, has been applied in 19 CML patients, allotransplanted from identical siblings. Five patients were in accelerated Patients and methods phase. Acute GVHD developed in two patients and chronic GVHD occurred in 66% of patients. Follow-up The observation period was from July 1990 until December was 3 to 7. years. Although only eight patients were 1997, and includes all HLA-identical sibling transplants under 30 years of age, and only two patients had a his- from July 1990 to December 1994, preconditioned with the tory of less than 1 year, the leukemia-free survival was DBM-containing protocol, described below. The follow-up 82%. There were four hematological relapses. The period ranged between 3 years, set as a minimum, and 7. reduction in post-BMT complications has greatly years. Five patients were in accelerated phase of the disease enhanced quality of life. The nurses reported significant with poor outlook, and seven patients were younger than reduction of work-load. Savings in eliminating the need 30 years at the time of BMT. Only two patients had a his- for irradiation, parenteral nutrition, and several anti- tory of less than 1 year. Against these odds, 17 of 19 biotics are also remarkable. The remarkable reduction patients (89.47%) are alive and 14/17 (82.35%) are free of of certain transplant-related complications shows some leukaemia at the time of this report. Successful trilineage advantage against busulphan-preconditioning. engraftment was documented in 17/19 cases. Keywords: chronic myeloid leukemia; identical; allo- The conditioning protocol consisted of DBM p.o., geneic BMT; dibromomannitol-containing non-myelo- 120 mg/kg (all doses in total) on days −9, −8, −7; cytosine ablative preconditioning; transplant-related complications arabinoside i.v., 60 mg/kg on days −7, −6 and −5; and cyclophosphamide i.v., 150 mg/kg on days −4, −3 and −2. All doses were evenly distributed over the 3 days. The number of bone marrow cells infused ranged from 1.6 to We previously proposed that the use of a radiation-free 5.6 × 108/kg, average: 3 × 108/kg. Short-term methotrexate preconditioning protocol containing mitobronitol and cyclosporine were used for prevention of graft-versus- (dibromomannitol, DBM) as a myelosuppressive agent host disease (GVHD). We investigated chimerism, in the could improve the therapeutic efficacy of bone marrow sixth month, in 16 patients: full chimerism was present in transplantation (BMT) in chronic myeloid leukemia (CML) 12, mixed chimerism in three, and no chimerism in one by reducing the frequency and severity of several post- patient. BMT complications.1 Although the effect was unambigu- ous, the relatively small number of patients in the study (eight) afforded only a rough estimate of the benefit in Results quantitative terms. In the present communication, we would like to report our observations on 19 additional CML Table 1 shows the incidence of various post-BMT compli- patients who underwent BMT with DBM preconditioning, cations. Reduction in the frequency of most complications, and whose results appear to strengthen our claim that this with an apparent absence of severe mucositis, veno-occlusive liver disease (VOLD) and bacterial sepsis, indicates highly significant improvement of the therapeutic efficacy Correspondence: E Kelemen, National Institute of Hematology and Immu- of BMT. These changes, on the other hand, were not asso- nology, 1519 Budapest, POB 424, Hungary ciated with a reduction of chronic GVHD, which is con- Received 16 June 1997; accepted 20 November 1997 sidered beneficial for the patient because of a simultaneous Reduction in transplant-related complication in CML E Kelemen et al 748 Table 1 Transplant-related complications of HLA-identical sibling transplants in CML patients observed for more than 3 years and using a relatively mild dibromomannitol-containing conditioning protocol

19 CML: stabil 14/18 (19) accelerated 4/18 (5/19), (1 accelerated died before engraftment) Age (year): 21–30 = 8; 31–45 = 4, 46–51 = 6. History: Ͻ1 years: 2/18, Ͻ1. years: 7/18, Ͼ1. years: 9/18 Follow-up: more than 3 years (3–7.). Months: 89, 83, 74, 71, (63a), 61, 56, 53, 50, 44, 41, 41, 40, 39, 38, 37, 37 (1 accelerated died at month 6) Living: 17/19, (89.47%) Leukemia-free: 14/17 (82.35%) Acute GVHD (II–IV) 2/18 11.1%b (3.1–32.8) Chronic GVHDc 12/18 66.6% (43.7–83.7) VOLD 0/18 0 (0–17.5) Permanent alopecia 1/17 6 (1.1–27.1) Severe mucositis 0/18 0 (0–17.5) Herpes zoster 1/17 6 (1.1–27.1) Bacterial sepsis 0/18 0 (0–17.5) Cataract 1/17 6 (1.1–27.1) Invasive fungal infection 1/18 5.5 (1.0–25.7) Second malignancy 0/17 0 (0–18.4) Interstit pneumonitis 1/18 5.5 (1.0–25.7) Relapses (total) 6/18 33 (16.3–56.2) CMV 1/18 5.5 (1.0–25.7) cytogenetic Other viral complication 0/18 0 (0–17.5) and molecular 2/18 11.1 Hemorrh cystitis 0/18 0 (0–17.5) hematological 4/18 22.2 (9.0–45.2)

Hematological relapse occurred in patients infused with less than 2.9 × 108/kg cells. Donor lymphocyte infusion in ﬁve patients. aSecond transplant with TBI in the 17th month. b95% conﬁdence intervals in parentheses c9 limited, 3 extended.

antileukemic effect. Another observation is the post-BMT ried out between 1980 and 1988, for first chronic phase of return of fertility in four of 12 eligible cases. CML, using unmanipulated marrow cells from HLA-ident- DBM-plasma levels in 18 patients were investigated by ical sibling donors, merits special attention and can serve ´ ´ Erdelyi-Toth et al (manuscript in preparation). We did not as a comparison with other results.5 Patients conditioned find low DBM-plasma levels among relapsed patients. with a non-TBI conditioning regimen, as well as T cell- For comparison, the reported long-term survival and fre- depleted transplants, and patients receiving methotrexate quency of complications following HLA-identical BMT in only as GVHD prophylaxis were excluded from the analy- CML patients at the Seattle BMT center, using busulphan- sis. The median follow-up was 7 years. Acute GVHD containing chemotherapy for conditioning (45 patients: 36 developed in 47% of patients. Absence of chronic GVHD in chronic and nine in accelerated phase) are as follows: was a risk factor for both early and late relapses, whilst leukemic relapse 15.5% (12.8% in CP), Ͼgrade II acute male donor sex only increased the risk of late relapse. The GVHD 57% among patients with busulphan plasma levels probability of relapse occurring more than 2 years after above the median, extensive chronic GVHD 74%, muco- transplant (‘late relapse’) was increased more than five-fold sitis 95%, VOLD 34%. No relapse occurred among patients in patients transplanted from a male donor. Patients with who achieved busulphan levels above the median. The 3- no chronic GVHD and a male donor had an overall prob- year survival estimate was 82% for patients above the ability of relapse of 34.9% compared to only 5.1% for those median busulphan levels.2 Comparing busulphan with total without chronic GVHD and a female donor. Recipient sex body irradiation as conditioning in 167 allogeneic marrow and acute GVHD proved to be significant determinants of transplant recipients, Ringden et al3 found that patients leukemia-free survival (LFS). Female recipients who did treated with busulphan had an increased incidence of VOD not develop acute GVHD (II–IV) post-marrow transplant, of the liver (12%) and 24% had hemorrhagic cystitis, 26% achieved a LFS of nearly 70%. Conversely, a LFS of only grade II–IV acute GVHD, and 14% interstitial pneumonitis. 38% was observed in male recipients of male donor mar- There was a 22% relapse rate at 3 years, and the relapse- row. While 42% of patients transplanted in advanced phase free survival at 3 years for CML was 67% (30 patients). developed severe acute GVHD,6 only one patient developed The median observation time for our cases is 4 years. If a severe form of this syndrome among our eight accelerated we consider the 4-year results of the International Bone (advanced) cases (applying the IBMTR criteria). Marrow Center (Milwaukee, USA, 1996) we observe a Although the number of observations is small, our 6 57% leukemia-free survival in chronic (2753 patients), and months survival (17/19) merits mentioning. According to 36% in accelerated (490 patients) CML, while 65% of the 1997 edition of a well-known textbook of oncology, in patients in chronic, and 42% in accelerated phase are alive. allogeneic bone marrow transplantation for chronic mye- Probability of relapse after HLA-identical sibling BMT for logenous leukemia ‘in all, 20% to 30% of patients have CML was 19% among chronic, and 40% among acceler- died from treatment-related complications within 6 months ated cases.4 of the procedure’.7 Apart from the patients described here, we have infor- mation on 18 additional cases with a follow-up period of Discussion less than 2. years. Except for acute GVHD, the pooled data show no substantial changes in the occurrence of compli- The latest comprehensive report from the Chronic Leu- cations: acute GVHD 8/36; VOLD 0/36; severe mucositis kaemia Working Party of the European Group for Blood 0/36; bacterial sepsis 2/36; invasive fungal infection 2/36; and Marrow Transplantation based on 373 transplants car- interstitial pneumonitis 2/36; CMV reactivation 3/36; other Reduction in transplant-related complication in CML E Kelemen et al 749 viral infections 0/36; chronic GVHD 24/36 (19 limited, five 2 Slattery JT, Clift RA, Buckner CD et al. Marrow transplan- extended). The actuarial leukemia-free survival is 75%.8 tation for chronic myeloid leukaemia: the influence of plasma Our mild preconditioning, which may also permit consider- busulphan levels on the outcome of transplantation. Blood 9 1997; 89: 3056–3060. able lymphoid restoration could explain the relatively rare ´ occurrence of infectious complications. Although the num- 3 Ringden O, Ruutu T, Remberger M et al. A randomized trial comparing busulphan with total body irradiation as condition- ber of our ‘eligible’ observations is very small, if the pre- ing in allogeneic marrow transplant recipients with leukemia: 1990 patients are included, we have six cases surviving a report from the Nordic Bone Marrow Transplantation Group. 10 more than 5 years. Quite recently, Apperley et al collected Blood 1994; 83: 2723–2730. nearly 4000 transplants and formed a score that has prog- 4 Rowlings PA. 1996 summary slides show current use and out- nostic value. Accordingly a patient with a score of 2 (1506 come of blood and marrow transplantation. ABMTR News- patients) has a 36% probability of leukemia-free survival letter 1996; 3: 6–12. at 5 years. Six CML patients over 5 years post-transplant 5 van Rhee F, Szydlo RM, Hermans J et al. Long-term results with a score of 2 are leukemia-free 61 to 89 months after allogeneic bone marrow transplantation for chronic mye- (average 75.5) after BMT. We could consider that DBM- logenous leukaemia in chronic phase. Bone Marrow Trans- conditioning may represent a special subgroup. plant 1997; 20: 553–560. Last, but not least, the higher frequency of relapses 6 Savage DG, Szydlo RM, Chase A et al. Bone marrow trans- among our patients is disturbing. Altogether, there were six plantation for chronic myeloid leukaemia: the effects of dif- fering criteria for defining chronic phase on probabilities of relapses between 7 and 29 weeks post-transplant, and hem- survival and relapse. Br J Haematol 1997; 99: 30–35. atological relapse occurred in four cases. Hitherto no late 7 Deisseroth AB, Kantarjian H, Andreeff M et al. Chronic leu- hematological relapse (2 years or more post-transplant) kemias. In De Vita V Jr, Hellman S, Rosenberg SA (eds). emerged. Interestingly, there was no relapse among the four Cancer: Principles and Practice of Oncology, 5th edn. Lippin- patients transplanted in accelerated phase. Although elimin- cott-Raven, Philadelphia, USA, 1997, pp 2334. ´ ´ ation of cytogenetic and/or molecular relapse was achieved 8 Barta A, Batai A, Sipos A et al. Low frequency of transplant- in only two of our five cases, administration of donor buffy related complications using a radiation-free conditioning regi- coat offers significant help to relapsed CML patients.11 men in BMT of CML patients. Bone Marrow Transplant The reductions in post-BMT complications has greatly 1997; 19 (Suppl. 1): 128 (Abstr.). enhanced quality of life in our patients. The nurses report 9 Szebeni J, Barna K, Uher F et al. Comparison of the lymphoid significant reduction of work load, and savings in eliminat- toxicities of mitobronitol and busulphan in mice: reduced B ing the need for irradiation, parenteral nutrition and anti- cell toxicity and improved thymic recovery as possible con- biotics are also remarkable. tributors to the reduced risk for complications following BMT with mitobronitol preconditioning. Leukemia 1997; 11: 1769–1774. References 10 Apperley JF, Hermans J, van Biezen A, Gratwohl A. Risk assessment for allogeneic transplantation in chronic myeloid ´ 1 Kelemen E, Jakab K, Varadi G et al. Non-supralethal leukaemia. Bone Marrow Transplant 1997; 19 (Suppl. 1): mitobronitol/cytarabine/cyclophosphamide conditioning with- 578 (Abstr.). out irradiation before bone marrow transplantation for acceler- 11 Kolb HJ, Schattenberg A, Goldman JA et al. Graft-versus- ated chronic granulocytic leukemia: apparent absence of acute leukemia effect of donor lymphocyte transfusion in marrow- graft-versus-host disease. Leukemia 1993; 7: 939–945. grafted patients. Blood 1995; 86: 2041–2045.