Lymphoma

Outcomes after autologous SCT in lymphoma patients grouped by weight

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Abstract

Obesity continues to be an increasing global health issue contributing to the complexity of chemotherapy dosing in the field of SCT. Investigation into the optimal dosing weight used to calculate chemotherapy doses in obese patients undergoing SCT is limited and inconclusive. Our single-center, retrospective study compared safety and efficacy outcomes by body mass index (BMI) for 476 adult lymphoma patients who underwent auto-SCT with a myeloablative chemotherapeutic regimen of BU, CY and etoposide dosed using adjusted body weight. Three weight groups categorized based on BMI were defined: normal/underweight 24.9 kg/m2, overweight 25–29.9 kg/m2 and obese 30 kg/m2. Severity of mucositis, incidence of secondary malignancy, incidence of bacteremia and median hospital length of stay did not differ among the groups. The median times to absolute neutrophil count and platelet recovery were 10 days (P=0.75) and 14 days (P=0.17), respectively. Obese patients had a lower 100-day mortality compared with other weight groups, although this did not translate into an OS benefit. OS and disease relapse were similar among the groups. Our study demonstrates that use of adjusted body weight to calculate chemotherapy doses does not negatively have an impact on outcomes in obese patients undergoing auto-SCT with BU, CY and etoposide.

Introduction

In the United States, over one-third of Americans are classified as obese, having a body mass index (BMI) of 30 kg/m2.1 Medication pharmacokinetics are altered in obese patients, largely due to increased adipose tissue, various comorbidities and altered organ function, leading to differences in volume of distribution, drug clearance and protein binding.2, 3 Cytotoxic chemotherapy is traditionally dosed using body surface area or body weight; however, in this era of increasing obesity, clinicians are hesitant to use actual body weight to calculate chemotherapy doses because of concerns of overdose and the potential for severe toxicity.4 These concerns have led to practices such as dose capping body surface area at a maximum of 2 m2, or using ideal or adjusted body weight in weight-based dosing of obese patients. Given the delicate balance between efficacy and toxicity, numerous studies evaluating dose-capping and dose-adjustment practices have indicated that they may compromise outcomes in obese patients receiving chemotherapy.2, 4, 5

Recognizing the problems that the extremes of body size incur, the American Society of Clinical Oncology published a clinical practice guideline supporting the use of actual body weight when calculating doses for most chemotherapy agents.6 However, these recommendations were based on results from studies conducted in solid tumor malignancies. Studies evaluating leukemia and SCT patients were excluded from analysis and the American Society of Clinical Oncology guidelines do not apply to such patients. Studies investigating outcomes of overweight and obese patients undergoing SCT have reported mixed results, leading to controversy about the optimal dosing strategy in SCT.7, 8, 9 Citing insufficient evidence to draw conclusive recommendations, the American Society of Blood and Marrow Transplant Practice Guideline Committee recently published a literature review in an effort to help guide chemotherapy dosing in obese patients undergoing SCT.10 The purpose of this single-center, retrospective study was to investigate safety and efficacy outcomes among normal/underweight, overweight and obese patients who underwent auto-SCT and received a standardized chemotherapy conditioning regimen of BU, CY and etoposide dosed using adjusted body weight.

Methods

Patients

Patients were identified using the Institutional Review Board approved Unified Transplant Database, a comprehensive database of patients who underwent SCT at the Cleveland Clinic. All patient characteristics and outcome data were obtained from the Unified Transplant Database. This study included adult patients (age 18 years) who underwent auto-SCT from 2001 to 2011 for Hodgkin (HL) or non-Hodgkin lymphoma (NHL) using a conditioning regimen of BU, CY and etoposide. All patients received stem cell mobilization with etoposide 2000 mg/m2 and growth colony-stimulating factor. Before 2006, BU 1 mg/kg was administered orally every 6 h for 14 doses beginning 9 days before stem cell infusion, followed by etoposide 60 mg/kg intravenously (i.v.) given 5 days before stem cell infusion and then CY 60 mg/kg i.v. given daily for 2 consecutive days beginning 3 days before stem cell infusion. In 2006, the conditioning regimen was amended, replacing oral BU with i.v. BU administered at a dose of 0.8 mg/kg i.v. 6 h for 14 doses beginning 9 days before stem cell infusion. Pharmacokinetic-directed dosing of BU was not performed during the study time period. Per institutional policy, BU, CY and etoposide were dosed based on adjusted body weight for patients whose actual body weight was greater than their ideal body weight, calculated using the Devine formula.11 Adjusted body weight was calculated by adding 25% of the difference between actual and ideal body weight to the patient’s ideal body weight. For patients whose ideal body weight was more than their actual body weight, actual body weight was used to calculate chemotherapy doses.

Included patients were divided into four groups based on BMI as defined by the World Health Organization.12 Patients were categorized into the following groups: underweight <18.5 kg/m2, normal weight 18.5–24.9 kg/m2, overweight 25–29.9 kg/m2 and obese 30 kg/m2. Because of the small number of underweight patients (N=10), the underweight patients were combined with the normal weight group.

All included patients were screened for concomitant cytochrome P4503A4 drug interactions, while undergoing conditioning chemotherapy before SCT. Drug interactions were divided into four classes: strong cytochrome P4503A4 inhibitors (itraconazole, voriconazole, posaconazole and clarithromycin), strong cytochrome P4503A4 inducers (carbamazepine and oxcarbazepine), moderate cytochrome P4503A4 inhibitors (amiodarone, cimetidine, diltiazem, erythromycin, fluconazole, haloperidol, metronidazole, sertraline and verapamil) and other drug interactions.

Study endpoints

The primary endpoint studied was the incidence of toxicity. Specific toxicities studied included sinusoidal obstruction syndrome, nephrotoxicity, mucositis, secondary malignancy and bacteremia. Standard criteria were used to identify sinusoidal obstruction syndrome and nephrotoxicity was documented if stated in the physician’s progress notes. Mucositis was graded using the modified oral mucositis assessment scale and a score of 1 was determined to be consistent with severe mucositis.13 Secondary malignancy was documented through physician follow-up. The National Healthcare Safety Network definition was used to identify bacteremia.14

Time to ANC recovery was defined as days from stem cell infusion to the first of 3 consecutive days of an ANC >500 cells/μL. Platelet count recovery was defined as days from stem cell infusion to the first day when the platelet count was >20 000 cells/μL, with no platelet transfusion in the previous 7 days. Hospital length of stay was calculated from the day of transplant admission to the day of discharge. One-hundred-day mortality was defined as death from any cause within 100 days of stem cell infusion.

Secondary endpoints were time to disease relapse, defined as time from stem cell infusion to onset of clinical disease recurrence, disease progression or identification of persistent disease and OS, defined as time from stem cell infusion to death from any cause.

Statistics

Variables were compared using χ2- or Kruskal–Wallis test. Kaplan–Meier survival estimates were compared with the log-rank test and cumulative incidence of non-survival outcomes with Gray test. Risk factors were identified using Cox or Fine and Gray regression, and summarized as a hazard ratio (HR) and 95% confidence interval (CI). Multivariable models included BMI, to assess the effect of obesity after adjusting for significant prognostic factors. All tests were two-sided with 5% significance.

Results

Patient characteristics

A total of 476 patients were included: 139 were normal/underweight, 168 were overweight and 169 were obese. Median follow-up time for all patients was 60.8 months. Overall, normal/underweight patients were younger, more likely to be female and had a lower International Prognostic Index (IPI) score. Owing to the limited number of drug interactions, all classes of drug interactions were combined to determine the incidence of drug interactions for each weight group. There were no significant differences in the incidence of drug interactions among groups. Patient characteristics are listed in Table 1.

Table 1 Patient characteristics

Transplant-related complications

No patient had sinusoidal obstruction syndrome and only five patients had nephrotoxicity post transplantation; therefore, these events were excluded from analysis. There were no differences in worst reported modified oral mucositis assessment scale scores (P=0.27, Table 2) or severe mucositis (P=0.43). Similarly, there was no difference in incidence of secondary malignancy (P=0.35) in univariable or multivariable analyses. Secondary malignancies are summarized in Table 3. There were no differences among groups in documented bacteremia (P=0.13; Gray test). Although not significant, Fine and Gray analysis suggested a higher risk of bacteremia in the overweight (HR=1.62, 95% CI=0.87–3.04; P=0.13) and obese (HR=1.83, 95% CI=0.99–3.36; P=0.06) groups, compared with the normal/underweight group. Median hospital length of stay was 21 days for all groups (P=0.29).

Table 2 Transplant-related outcomes
Table 3 Summary of secondary malignancies

Time to ANC and platelet recovery

There were no significant differences among the weight groups with respect to time to ANC or platelet recovery. Median time to ANC recovery was 10 days for all groups (P=0.75). Median time to platelet recovery was 14 days for all groups (P=0.17).

One-hundred-day mortality

One-hundred-day mortality was significantly lower in the obese group. The incidence of 100-day mortality for the weight groups was: normal/underweight 7.9%, overweight 6% and obese 1.8% (P=0.04). In the normal/underweight group, the causes of death included eight patients who died from disease relapse, two patients who died of infections and one patient who died of engraftment syndrome. The causes of death in the overweight group included six patients who died from disease relapse, two patients who died of multi-organ failure, one patient who died of pulmonary complications and one patient who died of infection. Of the three patients who died in the obese group, two died of disease relapse and one died of cardiac complications.

Relapse

Disease relapse was not significantly different among groups (P=0.29, Figure 1). The incidence of relapse at 1, 3 and 5 years was 32%, 44% and 47%, respectively, for the normal/underweight group; 25%, 34% and 39% for the overweight group; and 19%, 34% and 42% for the obese group. Subgroup analysis of gender revealed no difference among female weight groups (P=0.39; Figure 2); however, normal/underweight men had a significantly higher risk of relapse compared with overweight and obese men (P=0.006, Figure 3). Subgroup analysis of underweight and normal weight patients found no difference in relapse between groups (P=0.23; results not shown). Other subgroup analyses including BU formulation, disease diagnosis and IPI score revealed no difference in relapse rates among the three weight groups. In multivariable analysis, there was no difference in relapse among the groups. Factors associated with higher risks of relapse were male gender and worse disease status at the time of transplant. In multivariable analysis, overweight (HR=0.70, 95% CI=0.48–1.02, P=0.06) and obese (HR=0.73, 95% CI=0.51–1.05, P=0.09) patients had a lower but nonsignificant risk of relapse than normal/underweight patients after adjusting for gender and disease status at transplant.

Figure 1
figure1

Cumulative incidence estimate of disease relapse according to BMI.

Figure 2
figure2

Cumulative incidence estimate of disease relapse in women according to BMI.

Figure 3
figure3

Cumulative incidence estimate of disease relapse in men according to BMI.

Survival

OS did not differ among the three weight groups (P=0.61, Figure 4). Survival estimates at 1, 3 and 5 years were 75%, 63% and 53%, respectively, in the normal/underweight group; 77%, 64% and 57% in the overweight group; and 83%, 69% and 59% in the obese group. Median survival was 88, 80 and 77 months in the normal/underweight, overweight and obese groups, respectively. When all-cause mortality was divided into relapse and non-relapse causes, there were no differences among the three weight groups (P=0.79 relapse mortality, P=0.96 non-relapse mortality; results not shown). Despite the higher risk of relapse in normal/underweight men compared with overweight and obese men, subgroup analyses of females and males showed no difference in OS among groups. Subgroup analysis of survival between underweight and normal weight patients was not significantly different (P=0.48; results not shown). There was also no difference in subgroup analyses of BU formulation, disease diagnosis or IPI score among the three weight groups. In multivariable analysis, there was no difference in survival among the weight groups. Factors associated with a higher risk of mortality were older age, Karnofsky performance status <90, having received more chemotherapy regimens before auto-SCT and increased serum creatinine on admission.

Figure 4
figure4

Kaplan–Meier probability estimate of OS according to BMI.

Discussion

There are limited data to help guide chemotherapy dosing in patients at extremes of body weight undergoing SCT. In addition, heterogeneity in conditioning regimens and malignancies within the published data make drawing conclusions difficult. To our knowledge, this is the largest study to date conducted exclusively in lymphoma patients using a standardized dose adjustment and conditioning regimen before auto-SCT.

Our results indicate similar toxicity outcomes among normal/underweight, overweight and obese lymphoma patients receiving an auto-SCT with BU, CY and etoposide conditioning. Our results are consistent with previously published results in 121 NHL patients who received high-dose sequential or intensified high-dose chemotherapy before auto-SCT.7 The majority of patients in this study were dosed on actual body weight; however, some patients with a BMI 32 kg/m2 did receive unspecified drug-dose reductions. Although the toxicity outcomes among weight groups were similar to those seen in our study, these sequential and intensified high-dose regimens illustrate the many variations among institutions in cytotoxic therapy used for conditioning before auto-SCT, making direct comparisons with our results difficult.

Platelet and ANC recovery results reported in our study are similar to prior studies using a conditioning regimen of BU, CY and etoposide.15, 16, 17 However, these studies varied from ours in terms of dose and dosing weight adjustments used. Weight adjustments can have an impact on the actual amount of drug administered to patients, potentially impacting transplant outcomes. For example, an obese male weighing 100 kg (height 170 cms) dosed using actual body weight would receive a 34% higher dose of chemotherapy over the course of conditioning compared with dosing using our adjusted body weight protocol. A study investigating the efficacy and toxicity of oral BU 16 mg/kg, etoposide 30 or 45 mg/kg and CY 60 mg/kg before auto-SCT in 53 lymphoma patients reported a 10-day median time to ANC >1000 cells/μL and a 13-day median time to platelet >20 000 cells/μL.15 Dose adjustments used to account for body size were not reported by the authors. In another study of 382 NHL patients, the median time to ANC and platelet recovery was 9 and 16 days, respectively.16 In this study, doses of oral BU, etoposide and CY were identical to those in our conditioning regimen; however, all chemotherapy was dosed using a different dosing weight algorithm: chemotherapy was dosed on the lesser of ideal or actual body weight unless the patient’s actual body weight was 20% greater than their ideal body weight, in which case an adjusted body weight was used. A study of 65 NHL patients reported similar results to ours, with a median time to ANC and platelet recovery at 9 and 11 days, respectively.17 In this study, all patients were dosed using actual body weight; however, doses used for the conditioning regimen were considerably lower than the protocol used at our institution. Despite these studies reporting results of similar conditioning regimens, no standard dose adjustment accounting for body size has been established for lymphoma patients requiring auto-SCT.

Our study demonstrated a significant decrease in 100-day mortality in the obese group compared with the normal/underweight and overweight groups. Unfortunately, this did not translate into an OS benefit. Because of the small number of deaths within 100 days, we were unable to conduct a multivariate analysis. The percentage of drug per kilogram delivered was comparatively lower in obese patients and may provide one explanation for the protective benefit that obesity provided in 100-day mortality; however, this benefit did not translate to any other toxicity endpoint. Given the hypermetabolic state patients endure due to stress placed on the body during transplant, nutrition can be an important factor in patient outcomes and a patient’s BMI can help determine nutritional status before transplant.18, 19, 20, 21 The improved 100-day mortality in the obese group could be attributed to nutritional reserves that prevented malnutrition during the transplant process. Pretransplant assessment of performance status and comorbidities is an important aspect in determining a patient’s ability to tolerate SCT. Although the impact of obesity on transplant remains controversial, selection bias for healthier obese patients in an effort to reduce perceived risk cannot be ruled out. Although intriguing, our 100-day mortality findings warrant further investigation.

For our secondary endpoints of time to relapse and OS, our study demonstrated no differences among the three weight groups. Interestingly, despite the obese group having more high-risk and fewer low-risk IPI score patients, this did not result in increased relapse or mortality, which was also supported when isolating IPI score in subgroup analyses. Our relapse and OS results were consistent with other large retrospective studies in AML and lymphoma patients undergoing auto-SCT.8, 9 Although both of these studies included over 4000 patients, the patient populations were from multiple institutions that varied in conditioning regimens, chemotherapy doses and dosing weight calculations. Despite this, these two studies and ours have shown multiple factors that contribute to relapse and OS outcomes, none of which identified obesity as a prognostic factor impacting patient outcomes. In contrast to our results, the study by Tarella et al.7 using high-dose sequential chemotherapy reported significant reductions in OS and EFS in overweight and obese NHL patients who received auto-SCT. An undetermined number of obese patients in their study received chemotherapy dose reductions and 5 of the 28 overweight patients did not undergo auto-SCT. Through regression analysis, the authors identified a BMI 28 kg/m2, a high IPI score and inability to complete auto-SCT as factors impacting EFS and OS, attributing the differences in obese patients to decreased final tissue drug concentrations, ultimately impacting treatment efficacy. Based on these studies and ours, it is unlikely that obesity as a single factor can alter a patient’s outcome; however, it should be considered along with multiple other factors, such as age and Karnofsky performance status to better predict survival in this patient population following transplantation.

Of note, 10 patients in the normal/underweight group were underweight, a population shown to have poorer mortality outcomes after SCT compared with normal weight patients.8, 9 A subgroup analysis was performed comparing the underweight and normal weight patients to assess heterogeneity. Having found no difference in relapse or survival outcomes, and given the limited number of underweight patients, combining underweight and normal weight patients likely did not have an impact on the overall outcomes or conclusions of our study.

Our study is limited by the single-center, retrospective design and inherent biases that accompany such a design. External validity of this study is also impacted, as our institution used a standardized conditioning regimen and results may not be generalizable to centers that use other conditioning regimens. Both oral and intravenous BU were administered during our study. The erratic absorption of oral BU led to institutional protocol changes in 2006 to i.v. BU, a formulation shown to have more predictable pharmacokinetics compared with oral administration; however, subgroup analysis comparing the two drug formulations did not demonstrate differences in relapse or OS among the three weight groups. Ultimately, therapeutic drug monitoring was not performed during this study and therefore we cannot assess the true impact of the different BU formulations.22, 23, 24 Therapeutic drug monitoring and subsequent pharmacokinetic directed dosing of BU, regardless of formulation, has been associated with lower non-relapse mortality and improved OS and PFS.25, 26, 27 Pharmacokinetic directed dosing of BU may optimize therapy further and limit potential toxicities.28

Despite these limitations, our study provides insight into optimal dosing practices in obese patients. This is the largest study to date in lymphoma patients using a standardized weight adjustment and conditioning regimen, to focus on toxicities and efficacy of chemotherapy in various weight groups. Our results demonstrated that with the exception of 100-day mortality, safety and efficacy outcomes were similar among normal/underweight, overweight and obese patients with lymphoma. We conclude that although current clinical guidelines support the use of actual body weight for chemotherapy dosing in solid malignancies, our study demonstrated that using an adjusted body weight to calculate chemotherapy doses does not negatively impact outcomes in obese patients undergoing auto-SCT with BU, CY and etoposide. As future studies investigate anti-neoplastic drug combinations and chemotherapy doses to optimize conditioning regimens, dose adjustments for patients at the extremes of body weight should also be evaluated.

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Acknowledgements

We thank the Taussig Bone Marrow Transplantation program, all those involved with the Unified Transplant Database and the Cleveland Clinic Department of Pharmacy.

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Correspondence to J E Lau.

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The authors declare no conflict of interest.

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Lau, J., Weber, C., Earl, M. et al. Outcomes after autologous SCT in lymphoma patients grouped by weight. Bone Marrow Transplant 50, 652–657 (2015) doi:10.1038/bmt.2014.327

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