key: cord-0005605-6xn8ccri
authors: Kumar, M; Saleh, A; Rao, PV; Ochoa, S; Meyers, L; Miller, A; Graham-Pole, J
title: Toxicity associated with high-dose cytosine arabinoside and total body irradiation as conditioning for allogeneic bone marrow transplantation
date: 1997-12-18
journal: Bone Marrow Transplant
DOI: 10.1038/sj.bmt.1700797
sha: 3acaad158867a7ddaf26b24bc6c6ba51477b10cd
doc_id: 5605
cord_uid: 6xn8ccri

Seventy-three patients with hematological cancers undergoing allogeneic bone marrow transplantation (BMT) were evaluated for event-free survival (EFS) and toxicity. All received 36 g/m(2) cytosine arabinoside (HDA) and 1200 cGy fractionated total body irradiation (TBI). We assessed the association of EFS and toxicities with the following risk factors: age, gender, diagnosis, initial relapse risk and patient–donor histocompatibility. The EFS probability is 33% at 800 days post-BMT. Twenty-six patients (36%) died of toxicity within 100 days and 14 (19%) have relapsed. EFS was inversely associated with age (P < 0.0001) and initial relapse risk (P = 0.007). The risk of pulmonary (P = 0.023) and hepatic toxicity (P = 0.011) increased with age. Diagnosis other than acute lymphoblastic leukemia (ALL) was a risk factor (P = 0.015) for graft-versus-host disease (GVHD); and fewer ALL patients died from toxicity (P = 0.014). The probability of sepsis within 100 days post-BMT correlated (P = 0.007) with initial relapse risk. We conclude: (1) the lower EFS and greater pulmonary and hepatic toxicity associated with increasing age indicate a need for less toxic regimens that maintain high antileukemic efficacy for older patients; (2) the high GVHD and sepsis rates seen in certain categories of patients indicate a need for careful definition of eligibility criteria for this still highly toxic treatment.

1062 Table 1 Demographic details of the 73 patients rank test. 8 The Cox proportional hazards model 8 was used to assess the association of the covariates with post-BMT year were from toxic deaths within 100 days (38 (86%) vs MUD = matched unrelated donor.

6 (14%) due to relapse). Table 2 shows the risk factors for EFS, toxic death, organ toxicity, sepsis, and GVHD. The probability of EFS mia one and myelofibrosis two. Fifty patients were fully decreased significantly (P = Ͻ0.0001) with age. The rela-HLA-matched including five syngeneic BMT, 21 tive risk (RR) of failure was estimated as 1.07 (CI: 1.04, mismatched, and two had unrelated donors phenotypically 1.09) per year of age. That is, for every 1 year increase in matched. Mismatched donors included those mismatched age, the risk of an event (relapse or death) increased by a for up to three histocompatibility loci (7, 10 and 4 factor of 1.07. Figure 2 shows a plot of the RR as a function respectively). The latter 23 patients were grouped together of age, using the risk for an 11-year-old as baseline (ie RR for this analysis. Twenty-nine patients were considered to = 1 for age = 11). be at higher initial relapse risk, namely those with ALL in Probability of EFS was also significantly (P = 0.007) later than second remission, ANLL in later than first lower for patients with a high initial relapse risk (RR = remission, or CML in blast crisis or relapse at the time of 2.23, CI: 1.22, 4.04). Of the 29 high-risk patients, 12 (41%) BMT. One of these 29 patients had HD but was considered died of toxicity and seven (24%) have relapsed, compared at high risk because it was his second malignancy.

with 13 (30%) toxic deaths and seven (16%) relapses among the 43 standard-risk patients.

Increasing age was also associated with higher risks of Toxicity criteria pulmonary (P = 0.023, RR = 1.06 per year, CI: 1.01, 1.11) Organ toxicity was graded per standard NCI common toxand hepatic (P = 0.011, RR = 1.07 per year, CI: 1.01, 1.12) icity scoring criteria from 0 to IV for lung, liver, kidney and gastrointestinal (GI) tract. Also, Herzig et al 7 have described organ toxicity for the liver and GI tract in patients on similar doses of Ara-C. Toxicity of grade III or higher was analyzed for possible associations with patient age, gender, diagnosis, initial relapse risk and matching status. Toxic death was defined as death within 100 days of BMT irrespective of cause. For this analysis patients were considered to have graft-versus-host disease (GVHD) if they required treatment for it. Patients with positive blood cultures for bacteria, viruses or fungi and/or histopathological proof of infection were considered to have sepsis.

Patients were grouped according to age, gender, diagnosis, initial relapse risk, and HLA matching status. These covariates were analyzed for their association with EFS probability, organ toxicity, sepsis and GVHD. EFS was defined EFS curves were developed and compared using the log- PT is the probability of developing toxicity. c CI is the 95% confidence interval. NS = P Ͼ 0.05.

Causes The overall EFS probability of approximately 33% is com-11 years); (-----) 95% CI. RR for age 11 is 1. parable to that reported in other studies of similar patients. 11,15,16 We found increasing age to be a significant risk factor for low EFS probability. Data from other studies of similar patients conditioned with HDA-TBI or cytoxan-toxicities, while GU and GI toxicities were not associated with any of the covariates tested in this study. . Also a high initial relapse risk age effects in larger cohorts of patients treated with cytoxan-TBI. In a large multicenter analysis of 14 insti-was a significant risk factor for sepsis (RR = 4.40, CI: 1.50, 12.98) (P = 0.007). We identified no specific organ toxicity tutions that used HDA-TBI and included the patients reported here, Weyman et al 16 did find age to be a signifi-associated with the use of HDA as a conditioning agent. Major pulmonary complications included interstitial pneu-cant risk factor for EFS. We also found age to be a significant risk factor for lung monitis (11%), pulmonary hemorrhage (4%) and adult respiratory distress syndrome (19%), all occurring at the and liver toxicity. Patients 20 years old and older had at least a 38% risk of severe lung toxicity and at least a 55% expected rate. 11-13 Veno-occlusive disease (8%) and hemorrhagic cystitis (10%) also occurred in the frequencies risk of severe hepatic toxicity, higher than the 10-20% toxicity reported in other series. Initial relapse risk was also seen in other series. 11,14 The minor side-effects of acral erythema and conjunctivitis were observed in similar positively associated with sepsis and negatively associated with EFS probability. frequencies to that described following HDA in other series. 4, 14, 15 Causes of toxic death are depicted in Table 3 .

This high-risk group was comprised of multiply relapsed the need to define closely selection criteria for allogeneic

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and therefore such a conclusion may be skewed. Also, other