selecting the dosing weight for conditioning chemotherapy ... · oncology clinical pharmacy...

Selecting the Dosing Weight for Conditioning

Chemotherapy in Obesity

Joseph Bubalo PharmD, BCPS, BCOP

Oncology Clinical Pharmacy Specialist

Oregon Health & Science University Hospital

Disclosure

• I have no relevant disclosures

• Most agents discussed will contain off label information

2

Objectives

• Describe and summarize creation of the 2014 ASTCT guideline for conditioning regimen dosing in obese individuals

• Outline literature published on Hematopoietic Stem Cell Transplant (HCT) conditioning regimen dosing in obesity since 2014

• Summarize current data for conditioning regimen dosing in obesity with the 2014 guideline

3

Pre-Assessment Question

AA, a 67 year old female with multiple myeloma who presents for a melphalan conditioned autologous HCT. Her BMI = 38 kg/m2. Her lab parameters are normal for her age and her Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) score is 2. Per the 2014 ASTCT guideline she should be dosed based upon.

• A. BSA based upon total body weight

• B. Mg/kg based upon ideal body weight

• C. BSA based upon a 25% adjusted body weight

• D. Mg/kg based upon total body weight

4

Obesity and Cancer Therapy

• Prevalence of obesity in the US continues to rise and currently is 37% of the adult US population

• May affect ability to deliver therapy

• Can contribute to associated morbidity

• Risk factor for—Poor wound healing—Increased co-morbid conditions—Post-operative infections

• >50% of non-cancer deaths in cancer survivors are cardiovascular related

• Diabetes related to additional mortality increase

Ligibel JA et al. JCO 2014;32(31):3568-74Brunstein CG, et al. BBMT 2019;25:480-487.

Defining Obesity

• Pediatrics—< 2 years old – weight at or above the 95th percentile for

recumbent length for age and gender

—2-19 years old – BMI at or above 95th percentile for age and gender. Overweight (85-95th percentile)

• Adults—Overweight – BMI 25-29.9 kg/m2

—Obese – BMI > 30 kg/m2

• Grade I obesity - BMI 30-34

• Grade II obesity - BMI 35-39

• Grade III obesity - BMI > 40

Ogden C et al. JAMA 2014;311(8):806-14. BMI = Body Mass Index

Obesity and Hematopoietic Cell Transplantation (HCT)

• Goals of conditioning chemotherapy:—Provide sufficient immune suppression to prevent graft rejection

—Reduce tumor burden

• Similar overall survival between normal weight and obese allogeneic HCT patients

• Higher NRM (33% vs 20%) but lower rates of relapse (30% vs 41%) in the obese

• Potential for increased and decreased peritransplant morbidity

—Increased infections, drug specific toxicity (SOS, cardiac, skin), longer length of stay

—Decreased drug specific toxicity – less mucositis (melphalan), quicker engraftment (multiple agents)

Bubalo J et al BBMT 2014;20:600-16, Gleimer M, et al BMT 2015;50:402-410, Gyurkocza B et al. Blood 2014;124(3):344-353.. NRM = Non-Relapse Mortality, SOS – Sinusoidal Obstruction Syndrome

How Do We Measure the Patient?

• Ideal body weight (IBW)

• Total body weight (TBW)

• Adjusted body weight (ABW)—ABW = IBW + %(TBW-IBW)

—25% (ABW25), 40% (ABW40), 50% (ABW50) or other % adjustment

• BSA based on TBW vs IBW or ABW—No preferred BSA formula

Bubalo J et al BBMT 2014;20:600-16.

Obesity Recommendations for Preparative Regimens in the Obese Individual

9Cy120 – 60 mg/kg x 2 days, Cy200 – 50 mg/kg x 4 days

Drug Dose

Alemtuzumab Flat Dose (Adults)

Busulfan

ABW25 or BSA based on TBW with PK monitoring for > 12 mg/kgPOequivalent(Adults)

TBW with monitoring (Pediatrics)

Carboplatin BSA based on TBW (Adults)

Carmustine BSA based on TBW unless >120% IBW then BSA based on ABW25 (Adults)

Clofarabine BSA based on TBW (Adults)

CyclophosphamideDose on the lessor of TBW or IBW for CY200Cy120 dose on IBW (adults) or TBW until > 120%IBW then ABW25 (pediatrics)

Cytarabine BSA based on TBW(Adults)Bubalo J et al BBMT 2014;20:600-16

Obesity Recommendations for Preparative Regimens in the Obese Individual (2)

10

Drug Dose

Etoposide Adults use ABW25 for mg/kg dosing or TBW for BSA based dosing (Adults)

Fludarabine BSA based on TBW (Adults)

Melphalan BSA based on TBW (Adults)

Pentostatin BSA based on TBW (Adults)

Thiotepa BSA based on TBW unless >120% IBW then BSA based on ABW40 (Adults)

Antithymocyte globulin -

equine

Mg/kg based on TBW (Adults and Pediatrics)

Antithymocyte globulin -

rabbit

Mg/kg based on TBW (Adults and Pediatrics)

Bubalo J et al BBMT 2014;20:600-16

Ideal Body Weight Calculations

11

Comparison of Ideal Body Weight Equations Using Height

Reference Gender Equation

Devine (1974) Men 50 kg + 2.3 kg/each inch over 5 feet

Women 45.5 kg + 2.3 kg/each inch over 5 feet

Robinson et al. Men 52 kg + 1.9 kg/each inch over 5 feet

(1983) Women 49 kg + 1.7 kg/each inch over 5 feet

Miller et al. Men 56.2 kg + 1.41 kg/each inch over 5 feet

(1983) Women 53.1 kg + 1.36 kg/each inch over 5 feet

Pai MP, Paloucek FP. Ann Pharmacother 2000;34:1066-9

History of IBW• Historical data comparing relative mortality of different height-weight combinations• 1970s Devine formula developed

What is New Since the Guideline?

12

Real World Adjustment of Conditioning Regimen Doses

• 56 European centers

• 45 (80.5%) dose adjusted, 11(19.5%) dosed on TBW—TBW 16 centers (33%)

—IBW 10 centers (21%)

—ABW25 16 centers (33%)

—ABW40 4 centers (8%)

—Other 2 centers (4%)

• 44% also capped at 2 m2, (2 TBW centers capped at 2 m2)—12 centers capped at some number > 2m2

• 36 centers used the same adjustment in MA and 12 used a smaller adjustment in RIC

Shem-tov N, et al Oncologist 2015;20:50-5513

MA – myeloablative, RIC – reduced intensity

Effect of Conditioning Regimen Dose Reductions in Obese Patients Undergoing Autologous Hematopoietic Cell Transplantation (aHCT)

• Retrospective review of CIBMTR registry (> 500 centers worldwide), cutoff 2014

• Adults > 18 years old (y/o) with BMI > 30 kg/m2

• Undergoing first aHCT for MM with single agent Melphalan 200 mg/m2 or HD/NHL receiving the BEAM conditioning regimen

• Pre-transplant TBW, dosing weight (DW), and calculated ideal body weight (IBW) were used to determine if the Melphalan dose was adjusted

• If DW was <80% TBW it was considered adjusted

• Two patient groups —1) DW = TBW (UNADJ)—2) DW was adjusted (ADJ)

• Degree of adjustment (g) was determined by DW = IBW + g(TBW-IBW) e.g. DW is the adjusted body weight for those individuals

Brunstein CG, et al. BBMT 2019;25:480-487

MM = Multiple myeloma, HD = Hodgkin disease, NHL = nonHodgkin lymphoma, BEAM = carmustine/etoposide/cytarabine/melphalan

Results

15LOS = Length of stay in Days

MM LymphomaSignificant

difference?

Cohort (N) 1696 781 N/A

ADJ (%) 1324 (78) 609 (78) N/A

Cohorts matched Yes Yes N/A

Median dose adj% 25 26 No

Median LOS

ADJ/UNADJ14/15 14/15 No

Other

More MM UNADJ had

LOS > 15 days

(p=0.04)


Overall Results: Variable Analysis

• Younger age, KPS >90, HCT-CI <3, and chemotherapy sensitive disease were independent predictors for lower mortality

• Similar treatment related mortality (TRM), treatment failure (TF), and causes of death between groups

• Predictors of lower risk for:—TRM were younger age, KPS >90, and MM diagnosis

—TF were female sex, KPS >90, and chemo-sensitive disease

• Time dependent effect in ADJ on relapse risk—UNADJ 43% decreased relapse risk within 5 months post HCT and similar relapse risk > 5

months post HCT

—Relapse hazard similar in both diseases at 8 months post HCT, and > 8 months post HCT, relapse risk was higher for MM

• Transplant center effect predicted for TRM, PFS, and relapse in MM patients but not lymphoma

Brunstein CG, et al. BBMT 2019;25:480-487KPS = Karnofsky performance status, PFS = progression free survival

Overall Analysis


Results

18OS = Overall Survival, PFS = progression free survival, TRM = treatment related mortality

MM LymphomaSignificant

difference?

2 yr. OS ADJ/UNADJ % 88/89 79/82 No

2 yr. PFS ADJ/UNADJ % 45/50 (p=0.08) 59/61 (p=0.51) MM

2 yr. Progression risk

ADJ/UNADJ %54/48 (p=0.002) 34/38 (p=0.35) MM

TRM ADJ/UNADJ % 1/2 (p=0.29) 3/5 (p=0.42) No

Other No difference between groups in any other variable


Discussion

• Overall findings showed the ADJ group did not have different toxicity or different OS from the UNADJ group

• This report builds upon single center reports and an EMBT report in MM showing similar results

• Strengths: Large patient groups, overall and disease specific analysis, ability to assess disease related outcomes, good representation through BMI of 39

• Weaknesses—No overweight or normal BMI comparator group—No power calculation or other statistical intervention to estimate effect size of different BMI

groups, BMI > 40 under-represented and very obese > 50 dosing is not informed by this study

—Groups following ASTCT position paper would be in UNADJ group but would have adjusted carmustine dosing

—Unable to assess specific toxicities, LOS surrogate provides unclear picture of patient experience

EBMT – European Society for Blood and Marrow TransplantationBrunstein CG, et al. BBMT 2019;25:480-487

BMI Based Patient Population

Variable Myeloma ADJ Myeloma UNADJ Lymphoma ADJ Lymphoma UNADJ

LOS Days N=755 (98 centers) N=287 (60 centers) N=339 (68 centers) N=120 (43 centers)

BMI 30-34

7-14 days # (%) 152 (26) 51(21) 84 (29) 34 (30)

> 15 days 188 (32) 103 (42) 81 (28) 34 (30)

BMI 35-39

7-14 Days 63 (11) 26 (10) 34 (12) 16 (14)

>15 days 83 (14) 32 (13) 28 (10) 14 (12)

BMI >40

7-14 Days 42 (7) 11 (4) 28 (10) 5 (4)

>15 days 66 (11) 25 (10) 30 (11) 11 (10)


Summary

• MM data support current guideline of dosing on TBW when dosing per BSA

• Lymphoma data not per guideline but based upon melphalan adjustments full dose is suggested at least for melphalan with no additional insights into carmustine, etoposide, or cytarabine dosing

• Data for BMI >40 remain equivocal and untested by real life or database data

• Retrospective review at database level unable to assess drug specific toxicity


Impact of Dose Adjusted Melphalan in Obese Patients Undergoing aHCT

• Retrospective single center review

• Adults with MM undergoing first autologous HCT, 2009-2012

• N=270, 171 (63%) obese (O, >120% IBW), 99 (37%) nonobese (NO, < 120% IBW)

• Melphalan 200 mg/m2 and 140 mg/m2 included

• Devine calculation of IBW

MM – Multiple myelomaSchultes KC, et al. BBMT 2018;24:687-693

Patient Weight Weight used for BSA calculation

TBW < IBW TBW

TBW > IBW but < 120% IBW IBW

TBW > 120% IBW IBW + 0.2(TBW-IBW)

Results• Well-matched baseline characteristics, including-high risk disease

• 77% Caucasian, 56% male, median age 61 y/o,

• 94% 200 mg/m2 dose, O dosed per table, NO 83% on IBW and 17% on TBW

• CR increased at Day 100 10%22% O, 3% 21% NO

• VGPR 26% 33% O, 35% 33% NO

• No significant differences in time to neutrophil or platelet engraftment or LOS

Schultes KC, et al. BBMT 2018;24:687-693 EFS = event free survival, CR = complete response, VGPR = very good partial response

All O NO

3 year EFS 41% 51% 40% (p = 0.0025) Non inferior

3 year OS 59.1% 63.6% (p = 0.52)

Discussion

• Highest weight 102 kg, highest BMI 34.8 kg/m2

• Why dose NO on IBW? Does this reduce the ability of this cohort to determine a dose related effect in the O cohort? e.g. was it truly a non-inferior EFS finding vs. an anomaly of study design.

—NO larger % of 140 mg/m2 (8.1% vs 4.1%)

—Authors mentioned this in the discussion

• > 120% IBW = obese common in HCT protocols—Correlation with physiologic parameter?

• Median dosing BSA: O 1.78 (1.63-1.93), NO1.72 (1.57-1.86)

• Low rates of high risk cytogenetics in both cohorts, overall results showed a 16 month decrease in EFS for high risk individuals

Schultes KC, et al. BBMT 2018;24:687-693

Unadjusted BEAM Conditioning Regimen in Obese vs NonObese Patients Undergoing aHCT

• Single center, relapsed HD or NHL treated with BEAM conditioned aHCT and followed prospectively.

• Treated 2013-2015, N = 91

• Dosed on TBW based BSA

• Obesity defined as > 125% IBW (Devine formula)

NonObese (NO, n=46) Obese (O, n=45)

Median weight (range) kg 70 (41 - 105 ) 95 ( 66 - 139 )

Median BMI (range) kg/m2 24.5 ( 18 - 29 ) 31.9 ( 26 - 49 )

Median Age (range) years 58 (22-74) 59 (34-75)

Other 2 With BMI 18.3 (< IBW)

Fair C et al. BMT 2017;52:491-493

Results

• No TRM

• Cumulative incidence of relapse at 1 year: 32% NO, 12% O (p = 0.06)

• PFS at 1 year: 68% NO, 86% O (p = 0.11)

• No significant difference in OS, time to WBC and platelet recovery, re-hospitalization.

• T-cell higher risk for progression while follicular no progression in 1 year

• No difference in mucositis, IV analgesics, non-infectious diarrhea, TPN use, or cumulative density of bacteremia through day 100.

• Equivalent short term survival with BEAM dosed on TBW

Fair C et al. BMT 2017;52:491-493

WBC- white blood cell, TPN = total parenteral nutrition

Discussion

• Exploratory study, small N with no power calculation

• O group not truly obese by BMI (individuals as low as 26)

• Median O patient > 30 but unclear how many were < 30 or > 40 BMI

• NO more T-Cell (15% vs 2%), worse Karnofsky (17% vs 7% = 80) similar in other respects

• Short follow up

Fair C et al. BMT 2017;52:491-493

Adjusted Dose Cyclophosphamide in aHCT for Lymphoma

• Retrospective, single center review, N=147

• > 18 y/o with NHL given aHCT between 2003 – 2012

• All received Cy 60mg/kg IV x 2/TBI 1320 cGY conditioning

• Divided into 3 groups: controls (C ) <120% IBW, overweight (OW)120-149% IBW, and Obese (O) > 150% IBW.

• Those <150% IBW were dosed on TBW, > 150% IBW were dosed on ABW50

Bachanova V et al. BBMT 2016;22:571-588Cy = cyclophosphamide, TBI = total body irradiation

Results

• Demographics—Age 19-73 y/o, median 57

—Median 12 months to HCT

—O 55% female vs OW 30%, C 26%

—All other demographics were similar

• Median follow up 3 years

• Outcomes—OS at 3 years: C 61%, OW 68%, O 80%

—Cumulative relapse incidence at 3 years: C 48%, OW 53%, O 38%

—NRM at 1 year C 4%, OW 4%, O 3%%

—Male and NonCR at HCT were associated with increased mortality

• Weight did not affect OS

• No significant difference in chemotherapy related toxicity between groups

Bachanova V et al. BBMT 2016;22:571-588

Discussion

• Dosed above ASTCT Guideline

• Autologous patients only, not reflective of allogeneic regimens

• No difference in regimen related toxicities—Cardiovascular: 5 heart failure (1 C, 2 OW, 2 O)

—Infection densities (# per 1000 patient days): C 2.3, OW 3, O 0.4

—No SOS or mucositis > grade 1

• Unclear effect of weight and age as related variables—Lower % of 60-73 y/o in O cohort: 45% vs C 74%, OW 70%

• O Weight and BMI more representative of these populations—Small N in each group

< 120% IBW n = 72 120% - 149% IBW n = 48 > 150% IBW n = 29

BMI median (range) 25 (19 - 28) 29 (25 - 34) 36 (30-55)

Weight median (range) kg 77 (48 - 97) 90 (58 – 123) 102 (75 – 177)

Bachanova V et al. BBMT 2016;22:571-588

Outcomes in aHCT for Lymphoma Based Upon Weight

• Single center retrospective review

• Adults > 18 y/o, received BuCyE Auto for HD/NHL between 2001-2011—Bu 1mg/kg PO or 0.8 mg/kg IV x 14 doses (no PK), etoposide 60 mg/kg, Cy 60 mg/kg x

2 days.

• Dosed on ABW25 if TBW was > IBW (Devine formula)—TBW used if TBW was < IBW

• 4 groups: Underweight (UW, BMI <18.5, N=10), Normal weight (NO, BMI 18.5-24.9, N=129), Overweight (OW, BMI 25-29.9, N=168), and obese (O, BMI > 30, n=169)

—UW added to NO for evaluation purposes so 3 groups and UW/NO = 139

Bu = busulfan, Cy = cyclophosphamide, E = etoposideLau JE et al. BMT 2015;50:652-657

Results

• UW/NO more likely to be female, younger, and low IPI

• No significant difference between groups in mucositis, secondary malignancy, infections, time to ANC or platelet recovery, or LOS.

• 100 day mortality was lower in the O group 1.8% vs UW/NO 7.9%, OW 6% (p = 0.04)

• No significant difference in OS or relapse incidence at 1, 3, or 5 years between groups

IPI = International prognostic index, ANC = absolute neutrophil countLau JE et al. BMT 2015;50:652-657

Audience Response Question 1

BB, a 57 year old male with a BMI = 40 kg/m2 and relapsed non-Hodgkin lymphoma who presents for a Cyclophosphamide/Total Body Irradiation conditioned autologous HCT. His lab parameters are normal for his age. Based upon the Bachanova et. al. article his cyclophosphamide could be safely dosed at:

• A. 60 mg/kg daily x 2 days based on total body weight

• B. 60 mg/kg daily x 2 days based on 25% adjusted body weight

• C. 60 mg/kg daily x 2 days based on 50% adjusted body weight

• D. 60 mg/kg daily x 2 days based on ideal body weight

33

Discussion

• Unclear how this applies to the O group given no BMI breakdown

• Bu per 2014 guideline dosing but no Bu PK assessment performed.

• E per 2014 guideline

• Cy above 2014 guideline

• Relatively large patient groups and deeper assessment of toxicity

• Adds to the overall data for lymphoma aHCT population

• Given limited patient data would only consider applying the data to BMI < 40

Lau JE et al. BMT 2015;50:652-657

Issues To Consider when Selecting the Conditioning Body Weight in the Setting of Unclear Data

• Curative Intent?

• Level of organ function

• HCT-CI

• Allogeneic vs Autologous

• Dose limiting toxicity (DLT) of agents involved

• Is there a way to make the regimen safer

• Disease/remission status—CR vs PR or progressive disease

—Relapsed/refractory vs first remission

Summary

• Obese individuals can undergo HCT successfully

• Autologous HCT dosing—Melphalan and etoposide dosing per guideline is supported

—Preliminary data supporting Cy dosing in autologous HCT based on TBW up to BMI of 30

—BEAM dose on TBW based BSA for BMI <40 may be appropriate

• Additional study needed—Prospective assessment by BMI

—Allogeneic research…. ASTCT database paper in writing phase

• Consider ASTCT guideline as a starting point—Consider intent of the dose when choosing the dose parameters

—Consider known DLT and maximum tolerated doses

Audience Response Question 2

CC, a 62 year old male with a BMI = 41 kg/m2 and relapsed non-Hodgkin lymphoma who presents for an autologous HCT. Based on the discussion summarized in this presentation which agent would be the safest to dose based upon total body weight?

• A. Melphalan

• B. Etoposide

• C. Cyclophosphamide

• D. Carmustine

37

Recommended readings

• Brunstein CG, Pasquini MC, Kin S, et al. Effect of Conditioning Regimen Dose Reduction in Obese Patients Undergoing Autologous Hematopoietic Transplantation. Biol Blood Marrow Transplant 2019;25:480-487.

• Bubalo J, Carpenter PA, Majhail N, et al. Conditioning Chemotherapy Dose Adjustment in Obese patients: A Review and Position Statement by the American Society for Blood and Marrow Transplantation Practice Guideline Committee. Biol Blood Marrow Transplantation 2014;20:600-616.

• Gyurkocza B, Sandmaier BM. Conditioning regimens for hematopoietic cell transplantation: One size does not fit all Blood 2014;124(3):344-353.

38

Questions?

selecting the dosing weight for conditioning chemotherapy ... · oncology clinical pharmacy...

Documents