Q39-85: Pre-HCT Preparative Regimen (Conditioning)

Question 39: Was a pre-HCT preparative regimen given?

Recipients are generally transplanted using a specific protocol that defines the radiation and / or systemic therapy the recipient is intended to receive in preparation for transplant. This protocol, which may be either a research protocol or standard of care protocol, should be referred to when completing this section.

However, there are instances when a preparative regimen may not be given. Examples may include, but are not limited to:

• Primary diagnosis of an immune deficiency.
• Subsequent allogeneic HCT due to loss of, or poor, neutrophil engraftment.
  

If a preparative regimen was given, select “yes” and continue with question 40. If a preparative regimen was not given, select “no” and continue with question 86.

Question 40: Specify protocol intent: (check only one)

Indicate whether “all agents given as outpatient,” “some, but not all, agents given as inpatient,” or “all agents given as inpatient.” Agents are defined as systemic therapy drugs or radiation therapy.

Question 41: Was irradiation performed as part of the pre-HCT preparative regimen?

If irradiation was performed as part of the preparative regimen, check “yes” and continue with question 42. If irradiation was not performed, check “no” and continue with question 58. Irradiation performed as previous treatment should not be reported in this section, but as previous treatment on the appropriate Disease Specific Form or in question 58, if applicable (radiation given within 21 days of the transplant).

Question 42: What was the radiation field?

Indicate if the recipient received irradiation to “total body,” “total body by intensity modulated radiation therapy (IMRT),” “total lymphoid or nodal regions,” or “thoracoabdominal region.” This information is often available on the radiation oncology summary.

If “total body by intensity modulated radiation therapy (IMRT)” is selected, continue with question 43. If not, continue with question 54.

Question 43: Average organ doses (completed only if organ has been contoured and planned as an avoidance organ)

Total marrow irradiation (TMI) is a more targeted form of TBI that became feasible with the introduction of IMRT (intensity modulated radiation therapy) technologies that allow for the delivery conformal dose distributions to the entire body. This method allows for reduction in radiation doses to organs and the potential to escalate doses to target regions such as bone marrow better than standard TBI [1].

¹ Stein A, Palmer J, Tsai N-C, Al Malki MM, Aldoss I, Ali H, et al, Phase I trial of total marrow and lymphoid irradiation transplantation conditioning in patients with relapsed/refractory acute leukemia. Biology of Blood & Marrow Transplantation 2017;23:618-24.

Indicate if the average organ doses administered via IMRT are “known” or “unkown.” If “known” continue with questions 44-53, if “unknown” continue with question 54.

Questions 44-53: Average Organ Doses

Report the known average organ doses of IMRT for the organs listed in questions 44-53.

Question 54: Total dose: (dose per fraction X total number of fractions)

Enter the total dose of radiation given. If radiation was given as a single dose, the amount of radiation delivered in the single dose constitutes the total dose. If the radiation was given in fractionated doses, multiply the total number of fractions by the dose per fraction to determine the total dose. Enter the total dose of radiation in either grays (Gy) or centigrays (cGy).

Example:
Radiation Order: TBI, 200 cGy/day for three days (3 doses)
Total dose: 200 cGy x 3 doses = 600 cGy
Report “Total Dose” as: 600 cGy

Question 55: Date started:

Enter the date the single dose or first fraction of radiation was administered.

Question 56: Was the radiation fractionated?

Radiation is either delivered as a single dose or in several treatments (fractions). Radiation is fractionated to increase the destruction of diseased cells as they do not recover as quickly as disease-free cells.

If the radiation was fractionated, check “yes” and continue with question 57. If the radiation was not fractionated, check “no” and continue with question 58.

Question 57: Total number of fractions:

Enter the total number of fractions (treatments) of radiation that were administered. The recipient may receive more than one fraction per day (hyperfractionation).

The total number of fractions multiplied by the dose per fraction must be equal to the total dose reported in question 54.

Question 58: Was additional radiation given to other sites within 21 days of the HCT?

*Additional Radiation
Additional radiation start dates may be prior to the HCT event. If additional radiation began more than 21 days prior to the HCT event, but at least one dose was received within 21 days prior to the HCT event, report the actual start date of the additional radiation in this section, even if the start date is more than 21 days prior to the start of the HCT event. Radiation treatments completed more than 21 days prior to the HCT event should be reported on the appropriate Disease Specific Form in the treatment section.

In this section, report any sites that received a “radiation boost.” Boosts are often given to smaller sites that may have residual malignant cells or to areas that were shielded (ex. chest wall or lung). Include any radiation boosts that were administered within 21 days prior to the HCT event.

Questions 59-75: Specify radiation field:

Indicate if the recipient received radiation to each site listed. For each site that received additional radiation, indicate the dose, units, and start date.

*Questions 76-85, Reporting Multiple Drugs for Preparative Regimen
FormsNet3^SM application: Complete questions 76-85 for each drug given for the preparative regimen by adding an additional instance in the FormsNet3^SM application.
Paper form submission: Copy questions 76-85 and complete for each drug given for the preparative regimen.

Questions 76-78: Drugs (choose from list)

!Preparative Regimen: Drugs
The following questions refer to the drug therapy that was actually given as part of the preparative regimen versus the prescribed drug therapy that was reported on the Pre-TED. In this section, include any intrathecal drugs the recipient received for prophylaxis or treatment of CNS disease within 21 days prior to the start date of the preparative regimen. Do not include drugs that are intended to offset the side effects of the systemic therapy (e.g., corticosteroids for nausea, MESNA for hemorrhagic cystitis, etc.).

*Occasionally, protocols list drugs that may be given before and after day 0. If the drugs are given before and after day 0, only the doses given before day 0 should be quantified in the preparative regimen section. The doses given after day 0 should be reported on the Post-HCT Disease Specific form (if applicable on that form) or GVHD Prophylaxis section of the 100 Day Post-HCT Data Form (Form 2100). For example, if bortezomib or rituximab is given on Days -2, +1, +4, and +7, report the day -2 dose in the preparative regimen section, and the post-transplant doses as planned post-HCT therapy on the disease insert.

*Drugs during the Peri-Transplant Period
ATG, alemtuzumab (Campath), defibrotide, KGF, and ursodiol may be given during the peri-transplant period. Previously, if these drugs were administered prior to Day 0, they were reported in the preparative regimen section of the Baseline (2000) Form. However, the Baseline (2000) Form has been updated – if these drugs were administered prior to Day 0, report them in questions 86-103, not in questions 76-78.

Select the drugs given as part of the preparative regimen. Report the total dose of each drug that was actually given. Do not report the prescribed dose or the daily dose. The pharmacy record or Medication Administration Record (MAR) should be used for determining the exact total dose given.

Some drugs used as part of the preparative regimen are administered with guidance of serum pharmacokinetic testing to determine the recipient’s metabolism of the drug. This allows for individual “customization” of the drug dosing to optimize the desired effect and minimize the toxicity. Depending upon when the drug used to monitor drug levels is administered, it can be reported in one of two different ways on the CIBMTR Pre-TED (2400) and Baseline (2000) forms.

A common example of this situation occurs in the use of busulfan. In some cases, a “test dose” of the drug is given before the actual preparative regimen is started, and this dose is used for acquiring drug levels that are used to adjust the dose that will be used in the preparative regimen. In other situations, the first dose of the drug is given in the usual fashion as part of the preparative regimen. After this first dose, serum drug levels are drawn and sent to a reference lab. The drug is continued at the starting dose until the lab results are reported and adjustment is made to later doses.

When a drug is used for the preparative regimen where pharmacokinetics will be tested, it is important to distinguish whether the testing will be done with a “test dose” before beginning the preparative regimen or using the first dose of the preparative regimen. The reporting of the dosing for the CIBMTR forms depends upon this distinction. This helps distinguish whether the dose is part of the therapeutic regimen, or not.

A test dose was given > 24 hours prior to the intended therapeutic dosing.
Example: A patient with AML underwent allogeneic HCT from a sibling; busulfan and cyclophosphamide were used as the preparative regimen. The patient presented to clinic 9 days before the HCT, where a dose of busulfan at 0.5 mg/kg was given intravenously. Blood samples were drawn for the next 6 hours, after which the patient left the clinic. His samples were sent to a lab, results were returned the next day, and an adjusted dose of busulfan was calculated. He returned to the hospital 6 days before HCT, and began to receive busulfan at the adjusted dose intravenously for 4 days, followed by cyclophosphamide, and proceeded to receive his cells. Since he received 0.5 mg/kg as a “test dose,” this would not be reported in his total preparative regimen dose.

If a test dose was given, where the dose was distinct from the therapeutic dosing preparative regimen (often 1-2 or more days prior to the initiation of regular dosing), the following should be reported:

• On the Pre-TED (2400) form, the total prescribed dose per protocol would NOT include the test dose.
• On the Baseline (2000) form, the start date of the chemotherapy agent should be reported as the date the first therapeutic dose was administered. The actual dose received would NOT include the test dose.

The first dose of therapeutic dosing is used for monitoring.
Example: A patient with MDS received an allogeneic HCT from an unrelated donor; busulfan and fludarabine were used as the preparative regimen. She was admitted to the hospital 7 days before her HCT, and received a dose of busulfan at 0.8 mg/kg IV at 6:00 AM. Serum samples were drawn every 30 minutes until the next dose of Busulfan at 0.8 mg/kg IV was given at 12:00 noon. Her blood was sent to a reference lab, and she continued to receive busulfan every 6 hours. On day -6, the lab called with her drug levels, and it was determined that the current dose was correct. No adjustment was made, and she completed all 16 doses of busulfan. Since the dose of busulfan (0.8 mg/kg) that was used for drug testing was ALSO her first dose of the preparative regimen, it should be included in the amount of drug that was given for preparative regimen.

If the first dose of the preparative regimen was used to determine pharmacokinetics, the following should be reported:

• On the Pre-TED (2400) form, the total prescribed dose per protocol would include the dose used for monitoring.
• On the Baseline (2000) form, the start date of the chemotherapy agent should be reported as the date the first dose was administered. The actual dose received would include the dose used for monitoring.

Test doses must be reported consistently at your center. Since most centers follow a consistent approach to pharmacokinetic testing, it should be straightforward for the center to adopt a consistent approach to the reporting of test doses.

Drug doses may be reported to the tenth decimal place. For paper submission, do not modify the number of boxes or include decimal values.

The “other drug” category should only be used if the drug is not one of the listed options. If more than one “other” drug is prescribed, list the generic name of the drugs in question 78 and attach a copy of the source document to the form in FormsNet3^SM.

Drugs given for prophylaxis of infection, GVHD, or organ toxicity should not be reported in this section. Report these drugs on the Post-HCT Follow-Up (2100) Form.

If the Baseline is completed for a subsequent HCT, do not report therapy that was given to treat the recipient’s disease (between the previous and current planned HCTs) in the preparative regimen section. Report this therapy on the appropriate Disease Specific Form.

Question 79: Date started

Enter the date when the first dose of the preparative regimen drug was administered. The pharmacy record or Medication Administration Record (MAR) should be used for determining the date the drug was started.

Question 80: Dosing weight

Report the recipient’s dosing (adjusted) body weight calculated by the pharmacy / physician to determine the total dose of the drug given as part of the preparative regimen and specify the units of measurement. The dosing body weight is usually documented on the transplant preparative regimen chemotherapy orders.

Questions 81-82: Was the exposure of busulfan measured?

Indicate if the exposure of busulfan was measured. If “yes” report the overall exposure (with the appropriate unit of measure) in question 82. See below for an example on how to report the overall exposure. If “no” continue to question 83.

Example: A recipient received busulfan daily for four doses as part of the preparative regimen – the busulfan exposure was measured. The target AUC was 1000 – 1400 umol x min/L per dose. Pharmacokinetics were obtained after the first dose; the AUC was 900 umol x min/L. The busulfan dose was increased in order to meet a target AUC of 1200 umol x min/L. Pharmacokinetics were obtained again after the second dose; the AUC was 1200 umol x min/L. No additional adjustments were made to doses three and four. The overall busulfan exposure would be 900 + 1200 + 1200 + 1200 = 4500 AUC. The overall busulfan exposure should be reported as “4500 AUC (umol x min/L).”

Question 83-84: Was the busulfan dose adjusted based on pharmacokinetics?

Pharmacokinetic testing can be used to determine whether the drug concentration in the bloodstream is appropriate to the dose given. This reflects the speed of absorption and elimination of the drug. These tests are usually performed with a test dose prior to the preparative regimen, or performed after the first dose of systemic therapy, where multiple samples are drawn at specific time points following the first dose. The samples are sent to a laboratory that performs the testing to determine the drug concentration. Pharmacokinetic evaluation of busulfan dosing, as in the examples shown above, is common. If it is not known whether or not this testing was performed, consult with a transplant physician.

Indicate if the busulfan dose was adjusted based on pharmacokinetics. If “yes,” specify how the dose was modified in question 84. If “no,” continue with question 85.

Question 85: Specify administration (busulfan only)

Report the busulfan administration route as either “oral,” “IV,” or “both.”

Section Updates:

Question Number	Date of Change	Add/Remove/Modify	Description	Reasoning (If applicable)
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