Why, When and Where to Report Conditioning Regimens Marcelo C

Why, When and Where to Report Conditioning Regimens Marcelo C. Pasquini, MD, MS

Training and Development Disclosures

I have no relevant financial conflicts of interest to disclose.

Acknowledgement: Janet Brunner, Swati Kulkarni and Sharon Meiers

Training and Development 2 Objectives • Rationale of conditioning or preparative regimen • Does the type of conditioning regimen matter? • Types of regimens and different intensities • Tips and overview of data collection (TED & CRF)

Training and Development 3 Q#1 What are conditioning regimens A. A combination of different hair styling products B. Chemotherapy or irradiation prior to transplant used to allow engraftment of donor cells and/or control a malignant disease C. Behavioral modification approaches D. A new diet

Training and Development 4 Q#1 What are conditioning regimens A. A combination of different hair styling products B. Chemotherapy or irradiation prior to transplant used to allow engraftment of donor cells and/or control a malignant disease C. Behavioral modification approaches D. A new diet

Training and Development 5 Allogeneic Hematopoietic Stem Cell Transplantation

Conditioning Regimen  Anticancer  Myeloablative Allogeneic

 Immunosuppressive HLA-identical Other Unrelated sibling relative

Hematopoietic stem cells Graft sources

Bone Peripheral Umbilical Post-transplant marrow Blood cord blood supportive care

BAS05_9.ppt Hematopoietic Stem Cell Transplantation - Classification -

Allogeneic Syngeneic Autologous Donor HLA-identical Other Unrelated sibling relative

Umbilical Graft Bone marrow Peripheral Blood cord blood Source

Reduced Non- Conditioning Myeloablative Intensity meyloablative Regimen Intensity

Other important considerations: • Degree of HLA matching •CMV serology, patient and donor •ABO compatibility •Graft manipulation BAS05_14.ppt Graft vs Host Disease/Graft Rejection

HLA differences stimulate detrimental immune responses

GvHD

Rejection

Donor Stem Cells

Patient

BAS05_41.ppt Q#2 Conditioning Regimen is an absolute requirement for transplantation. • A. True • B. False

Training and Development 9 Q#2 Conditioning Regimen is an absolute requirement for transplantation. • A. True* • B. False

*Exception is in case of stem cell boost….however the patient has received a transplant already.

Training and Development 10 Collection of Conditioning Data • Weight • Was a preparative regimen given • Classification of regimen intensity • Date of regimen • Irradiation/Total Doses • Drugs • Pharmacokinetics (CRF only)

Training and Development 11 Collection of Conditioning Regimen Information: TED vs. CRF (rev4.0)

Prescribed Given

mg/kg Total Targeted mg Dose AUC mg/m2

Pre-TED Baseline Form 2400 2000 CRID Form HCT 60d 100d 2804

Actual Dosing Weight Weight Weight

Training and Development 12 Calculation of Dosing Body Weight (DBW)

DBW = IBW + 0.4(ABW-IBW) DBW = 150 lbs + 0.4(250-150) DBW = 150 lbs + 40 lbs DBW = 190 lbs (or 86.4 kg)

IBW = Ideal Body Weight

Training and Development 13 Patient Scenario #1

Jane’s prep regimen consists of: • Busulfan 130 mg/m2 daily x 4 doses • Fludarabine 40 mg/m2 daily x 4 doses

Height = 62 inches ABW = 65 Kg DBW = 54 Kg BSA = 1.53

Training and Development 14 Determining Chemotherapy Dose

How is the Busulfan dose calculated? 130 mg/m2 x 4 doses = 520 mg/m2 520 mg/m2 x 1.53 m2 = 796 mg (or 800 mg)

How is the Fludarabine dose calculated? 40 mg/m2 x 4 doses = 160 mg/m2 160 mg/m2 x 1.53 m2 = 245 mg (or 240 mg)

Training and Development 15 Chemotherapy Reporting Form 2400

• The total prescribed dose to report on F2400 for Busulfan should be 520 mg/m2 & for Fludarabine 160 mg/m2

• However, this is what was reported for Jane……..

Training and Development 16 Chemotherapy Reporting • On F2400, the following was reported- Bu 130 mg/m2 Flu 40 mg/m2

• On F2000, the following was reported- Bu 800 mg Flu 240 mg

Training and Development 17 Chemotherapy Reporting

If Bu 130 mg/m2 was the total prescribed dose, then the total dose reported on Form 2000 for Bu should have been 200 mg instead of 800 mg based on the patient’s BSA.

Training and Development 18 Pre-TED dose reporting affects Baseline reporting

If the correct total prescribed Bu dose of 520 mg/m2 had been reported on the Pre-TED, then 800 mg reported on the Baseline form is correct.

Training and Development 19 Conditioning Regimen Intensity

- Increase immediate anti-tumor effect - Increase toxicity Low High Intensity Intensity conditioning regimen spectrum

Number of - Rely on later graft versus candidates disease effect for HCT -Decreased regimen related toxicity Champlin Criteria for Non-myeloablative Regimens

• Prompt hematopoietic recovery (<28 days) without stem cell support. • Mixed chimersim can be detected upon engraftment following hematopoietic transplantation. A Continuum of Conditioning Regimen Intensity

Immunosuppression

Haplo / l T-cell Dep Cy + ATG + Thymic XRT l TBI+Cy F+TBI TBI+F+TT 2Gy l MUD l l l FluMel l Flu/Bu4 l F+Cy Bu8+F+ATG Bu16+Cy

Matched l sibling l l BEAM GENETIC DISPARITY GENETIC TBI 2Gy Flag-Ida

Myelosuppression CLL / CML LCL AML LGL MM AGGRESSIVENESS OF MALIGNANCY

HVD05_13.ppt

CLASSIFICATION OF PREPARATIVE REGIMENS FOR ANALYSIS PURPOSES

CIBMTR OPERATIONAL GUIDELINES

Training and Development 23 Jargons

• High Intensity: ablative, myeloablative, traditional myeloablative • Low Intensity: NST, nonmyeloablative, reduced intensity, minimally ablative • Other less desirable: mini, transplant lite. • Papa bear, mama bear and baby bear…. Myeloablative (MA) Regimens: 1) TBI >500 cGy (single) or >800 cGy (fractionated) 2) Cyclophosphamide (Cy) + TBI (TBI >500 cGy (single) or TBI >800 cGy fractionated) 3) Cy + VP16 + TBI (TBI >500 cGy (single) or TBI >800 cGy fractionated)

Training and Development 25 MA Regimens (continued) 4) Busulfan (Bu) >7.2 mg/kg IV (or >9.0 mg/kg po) 5) Bu >300 mg/m2 IV (or 375 mg/m2 po) 6) Bu >7.2 mg/kg IV (or >9.0 mg/kg po) + Cy 7) Bu >7.2 mg/kg IV (or >9.0 mg/kg po) + Melphalan >150 mg/m2

Training and Development 26 MA Regimens (continued)

8) Melphalan > 150 mg/m2 9) Thiotepa > 10 mg/kg 10) Treosulfan > 30,000 mg/m2 (or > 30 g/m2) 11) Addition of clofarabine

Training and Development 27 Reduced Intensity Conditioning & Non-myeloablative Regimens

1) TBI <500 cGy (single) or TBI <800 cGy (fractionated) 2) ATG + Cy 3) BEAM 4) Bu <7.2 mg/kg IV or <9.0 mg/kg po 5) Bu <300 mg/m2 IV or <375 mg/m2 po 6) Melphalan <150 mg/m2

Training and Development 28 RIC/NMA Regimens (continued)

7) Fludarabine + ARA-C 8) Fludarabine + Cy 9) Fludarabine + TBI (TBI <500 cGy (single) or TBI <800 cGy (fractionated) 10) Thiotepa <10 mg/kg 11) Treosulfan <30,000 mg/m2 (or <30 g/m2) 12) VP16 + Cy

Training and Development 29 Regimen Definitions and Abbreviations

Bacigalupo et al; BBMT 2009; 15: 1628

Operationally Defined Basis : expected duration of cytopenia & need for HSC support for recovery MA: irreversible cytopenia & manadatory HSC support

NMA: minimal cytopenia & do not need HSC support

RIC : a regimen that does not fulfill MA or NMA criteria Myeloablative Conditioning Regimen • Younger patients • Busulfan based are the currently most commonly done in the country • TBI >800cGY – mainly in ALL • Does it matter?

Training and Development 31 Overall Survival of Recipients of IV-BU Compared to TBI- based Myeloablative Conditioning for Malignant Diseases

100 100

90 90

80 80 IV- Bu: 56% (95% CI 53-60%) @ 2y

70 70

60 60

50 50 TBI: 48% (95%CI 43-54%) @2y

40 40 Probability, % Probability, 30 30

20 20

10 P=0.019* 10

0 0 0 6 12 18 24 Months *pointwise p-value at 2 years Bredeson C et al, Blood 2013

Xz13_9.ppt How about timing of transplant? • The order of how drugs are given may altered its side effect profile…..

Training and Development 33 Transplant Outcomes by Cy and TBI Sequence 100 100 90 90 Treatment-related Mortality Progression/Relapse 80 80 70 70 60 60 50 CY->TBI (n=939) 50 40 TBI->CY (n=817) 40 30 30

20 20

Cumulative Incidence, % Incidence, Cumulative CY->TBI (n=939) 10 TBI->CY (n=817) 10 0 0 0 1 2 3 4 5 6 0 1 2 3 4 5 6 Years Years 100 100 90 Progression-free Survival Overall Survival 90 80 80

70 70 CY->TBI (n=939) CY->TBI (n=948) 60 60 50 50 40 40

Probability, % Probability, 30 30 TBI->CY (n=817) 20 TBI->CY (n=821) 20 10 10 0 0 0 1 2 3 4 5 6 0 1 2 3 4 5 6 Years Holter-Chakrabarty J et al Tandem 2014 Years Conditioning Regimens: Paradigm Change

NEW OLD • Host immune suppression & • Engraftment requires marrow ablation survival advantage for donor HSC are key

• Conditioning regimen is the • Graft versus Tumor Effect is mainstay for tumor eradication significant in many diseases

• Linear dose-response relationship • Traditional conditioning --- between cytotoxicity and tumor kill prohibitive toxicity in older patients & those with co • Narrow Therapeutic window morbidities

• Wider Therapeutic Index with lower intensity conditioning Low intensity conditioning TRANSPLANT-RELATED MORTALITY BY AGE Standard vs. Reduced Intensity Conditioning

Myeloablative

Reduced Intensity NRM and REL cumulative incidence estimates (36-month) from a competing risk model, estimated separately for both conditioning regimens for MDS

Martino, R. et al. Blood 2006;108:836-846

100 100

90 90

80 80

70 70

60 60

50 50 55-59 yrs 40 40 40-54 yrs

Probability, % 30 30 60-64 yrs 20 65+ yrs 20

10 10 p=0.71 0 0 0 12 24 36 48 60 Months Luger S. et al Blood 2010

Tp08_4.ppt Overall Survival after HCT for Acute Leukemia with RIC vs. Myeloablative conditioning regimens Caveats of Comparing Populations According to Regimen Intensity

Age +/- Comorbidities +++ no Previous HCT yes

Myeloablative RIC

Eligibility Within low intensity regimens • Not all regimens are created equal • Concepts – Disease specific vs. general immunoablative regimens (FCR vs. low dose TBI in lymphoma) • Difficult to discern regimen from regimen/GVHD prophylaxis packages

Training and Development 42 Comparison of TBI vs. non TBI-based nonmyeloablative conditioning regimens for lymphoma

100

80 No-TBI (n=515, 3-yr prob=58%)

40 TBI (n=382, 3-yr prob=53%)

20 Adjusted Probability, %

p=0.35 0 0 1 2 3 4 5 Years Hong S. et al, BBMT 2014 Reduced Toxicity Concept • Newer Regimens with lower extra-medullary toxicity: • IV Busulfan/Fludarabine, treosulfan • Allows for extending the number of eligible patients. • The degree of toxicity is also dependent on the patient-related characteristics (end organ function, age, number of prior treatments) How about ATG? • Is it part of the conditioning or GVHD prophylaxis? • ATG is considered in-vivo T-cell depletion • Tip: – Report as conditioning: if the intent is to allow engraftment, usually given at lower dose at the start of the conditioning. – Report as GVHD prophylaxis: if the intent is such, usually given at high doses close to stem cell infusion.

Training and Development 45 Autologous HCT Conditioning Regimen

• High dose therapy with stem cell rescue – This is true for malignant diseases – Intent is to escalate the intensity to maximize disease control • Does the concept of reduced intensity exist in autologous HCT? Yes, mainly in autoimmune diseases, where immunoablation is the main focus. Comparison of Conditioning Regimens prior to AutoHCT for Follicular Lymphoma

100 CBV High BuCy

TBI CBV High BEAM

40 Probability, % Probability,

0 0 1 2 3 4 5 Years Chen Y. et al BBMT 2015 47 Comparison of Conditioning Regimens prior to AutoHCT for Diffuse Large Cell Lymphoma

100 Beam CBV Low

CBV High BuCy TBI Probability, % Probability,

0 0 1 2 3 4 5 Years Chen Y. et al BBMT 2015 48 Comparison of Conditioning Regimens prior to AutoHCT for Mantle Cell Lymphoma

100 CBV High Beam 80

TBI 60 BuCy

40 CBV Low Probability, % Probability,

0 0 1 2 3 4 5 Years Chen Y. et al BBMT 2015 49 Comparison of Conditioning Regimens prior to AutoHCT for Hodgkin Disease

100 Beam CBV Low

60 CBV High

40 TBI Probability, % Probability, BuCy 20

0 0 1 2 3 4 5 Years Chen Y. et al BBMT 2015 50 Probability, % conditioning compared with BEAMwith compared conditioning HL with patients PFSamong Shorter BuCyE after 100 20 40 60 80 0

1 p=0.40

p<0.001

NHL NHL NHL Years HD HD - –

Pasquini Pasquini MC etal, BMT Tandem 2014 BEAM (n=466); 55% 55% @ 2y (n=466);BEAM BuCyE - -

BuCyE

BEAM (n=253); 59% 59% @ 2y (n=253); BEAM

(n=119); 60% 60% @2y (n=119);

(n=64); 33% 33% @ (n=64);2y 2

Patient Scenario #2

A 65 yo female with IgG kappa myeloma is being admitted for an autologous HCT. The written chemotherapy orders state Melphalan 70 mg/m2 IV daily x 2 days. • The height of the patient is 159 cm • Actual body weight (ABW) = 72 kg • Dosing body weight (DBW) = 59 kg • BSA = 1.6 m2

Training and Development 52

Chemotherapy Reporting Form 2400

What is the total prescribed cumulative Melphalan dose to report on Form 2400 Q252 for the preparative regimen?

A) 70 mg/kg B) 70 mg/m2 C) 140 mg/kg D) 140 mg/m2

Training and Development 53

Chemotherapy Reporting Form 2000 • The actual Melphalan dose the patient received would be found in the chemotherapy administration records. • Form 2000 – The dose would have been calculated using the patient’s BSA.

Training and Development Chemotherapy Reporting Form 2000

70 mg/m2 x 1.6 m2 = 112 mg daily Daily dose x BSA

What is the total dose given? 112 mg x 2 days = 224 mg Total Melphalan dose given

Training and Development 55 Chemotherapy Reporting Form 2000 - Patient Scenario # 2

What is the total Melphalan dose actually given that would be reported on Form 2000 Q192?

A) 70 mg B) 112 mg C) 140 mg D) 224 mg

Training and Development 56 Conditioning Regimens • Vital component of HCT • Many varieties of combination and intensities • Data collection attempts to capture the exact intent, dose planned and given. • Updated classification on conditioning regimen types, incorporating current practices such as PK are needed.

Training and Development 57 Questions

Training and Development 58 ESTIMATED NUMBERS OF POTENTIAL TRANSPLANT CANDIDATES vs. TRANSPLANT RECIPIENTS IN U.S.

60k

55,000 Allografts 50k Autografts

40k

30k 65y

20k 15,000 11,000 10k 8,000 7,500

4,500 4,000 NUMBERS IN THOUSANDS IN NUMBERS 0 NHL MM AML HD CLL CML ALL

JUO04_34.ppt