Preparative regimens for bone marrow transplant
What every physician needs to know:
What is the conditioning regimen?
The preparative regimen is the combination of chemical and physical agents that is given to the patient prior to stem cell transplantation (SCT) with the purpose of reducing tumor burden and in the case of an allogeneic transplantation, allow engraftment of the donor cells.
How are conditioning regimens classified?
Traditionally, all preparative regimens were considered myeloablative (that is, that if given without stem cell support, they would cause irreversible myelosuppression. More recently with the advent of reduced intensity conditioning regimens, preparative regimens are now divided into myeloablative, reduced intensity, and truly non ablative. The distinction among these is arbitrary, and differentiates ablative from reduced intensity conditioning regimens. In general, regimens that include radiation doses of less than 500cGy, busulfan doses of 8mg/kg or less, or melphalan doses of less than 140mg/m2, are considered reduced intensity conditioning regimens.
What benefits do reduced intensity conditioning regimens have?
Reduced intensity conditioning regimens are associated with less tissue damage and therefore less toxicity. When compared to myeloablative regimens, they result in lower rates of severe lung, heart, kidney, and/or liver toxicity. This allows extending transplant to older patients and patients with co-morbidities. Retrospective analysis suggests that the risk of relapse may be higher.
No randomized trials comparing a reduced intensity conditioning regimen to a myeloablative regimen has been published, although a couple are being planned. The impact of conditioning regimen intensity on long term disease control post transplant, may depend on disease type, remission status as well as donor type, and until prospective trials are done, myeloablative regimens should be considered the standard of care for young patients with hematologic malignancies.
How to decide the type of conditioning a patient should receive
In general, young patients should continue to receive the standard well established myeloablative regimens, combining total body irradiation with cyclophosphamide, or busulfan in combination with fludarabine or cyclophosphamide, or multi-alkylator conditioning regimens.
Recently, a stem cell transplant comorbidity index has been proposed as a way of determining the risk of serious toxicities with a myeloablative regimen. Patients with comorbidity scores of two or greater, have a transplant related mortality rate with myeloablative regimens of almost 40% at two years and therefore should be considered for a reduced intensity conditioning regimen. For patients with myeloid leukemias (acute myelogenous leukemia and myelodysplastic syndromes), retrospective data suggests that intensity of the conditioning regimen may impact long term disease control.
Patients receiving a non ablative conditioning regimen, have an inferior event free survival than patients conditioned with either a reduced intensity conditioning regimen or a myeloablative regimen.
What features of the presentation will guide me toward possible causes and next treatment steps:
What laboratory studies should you order to help make the diagnosis and how should you interpret the results?
What tests can help decide the optimal conditioning regimen to deliver to a patient?
Standard pre-transplant evaluation includes measurements of cardiac function (multi gated acquisition scan [MUGA] scan, echocardiogram, stress tests), pulmonary function (FEV1, FVC, the diffusing capacity [DLCO]), and laboratory tests measuring liver and kidney function. None of these tests individually should determine whether a patient is a candidate for myeloablative conditioning.
In general, the more abnormal the tests, and the more number of abnormal tests an individual patient has, the more likely he/she should receive a reduced intensity, rather than a myeloablative conditioning regimen.
What conditions can underlie preparative regimens for bone marrow transplant?
When do you need to get more aggressive tests:
What imaging studies (if any) will be helpful?
Radiologic evaluation of the sinuses, lung, and liver are useful in individual cases, to determine the presence or absence of organ specific pathology, as well as the extent of potential damage. Table I summarizes different imaging modalities and their utility in the transplant planning process.
|Imaging modality||Potential utility in transplant planning potential decision|
|Computed tomography (CT) sinus||Determine presence or absence of acute or chronic sinusitis. Delay SCT until resolution.|
|Magnetic resonance imaging (MRI) brain||Determine presence or absence of leptomeningeal disease. Delay SCT.Plan central nervous system (CNS) prophylaxis post SCT.|
|Ultrasound or MRI liver||Determine potential risk for veno-occlusive disease (VOD). Delay SCT. Liver complications by documenting fatty liver, reduced intensity versus ablative conditioningiron liver deposits, gallstones, liver abscess, etcetera. Use of “liver protectants” ursodiol, defibrotide, etcetera.|
|CT chest/abdomen/pelvis||Document evidence of previous infections (for example, pneumonia, diverticulitis abscess, etcetera). Delay SCT.|
What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?
What other therapies are helpful for reducing complications?
What should you tell the patient and the family about prognosis?
“What if” scenarios.
What other clinical manifestations may help me to diagnose preparative regimens for bone marrow transplant?
What other laboratory studies may be ordered?
What’s the evidence?
Appelbaum, F. “Hematopoietic stem cell transplantation at 50.”. N Engl J Med. vol. 357. 2007. pp. 1472-5. [Excellent review on the historical evolution of hematopoietic stem cell transplantation.]
Summary Slides – HCT Trends and Survival Data, Current use and outcome of hematopoietic stem cell transplantation. [Best online resource to obtain up to date information regarding stem cell transplant activity in North America and the world.]
Armand, P, Gibson, C, Cutler, C. “A disease risk index for patients undergoing allogeneic stem cell transplantation”. Blood.. vol. 120. 2012. pp. 905-913. [First modern validated model that looks at the impact of diagnosis and stage on stem cell transplant outcomes, applicable for all types of conditioning regimens.]
Sorror, ML, Maris, MB, Storb, R. “Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT”. Blood.. vol. 106. 2005. pp. 2912-2919. [Most commonly used and validated comorbidity index used in SCT. Allows for tailoring intensity of conditioning to transplant recipient. Predictive value in autologous stem cell transplantation less certain. Together with the other assessments allows one to determine the risk benefit ratio of stem cell transplantation in individual patients.]
Bacigalupo, A, Ballen, K, Rizzo, D. ” Defining the intensity of conditioning regimens: working definitions”. Biol Blood Marrow Transplant. vol. 15. 2009. pp. 1628-33. [Current consensus definition of what constitutes a reduced intensity regimen.]
Luger, S, Ringden, O, Zhang, MJ. “Similar outcomes using myeloablative versus reduced intensity regimens for allogeneic transplants for AML or MDS”. Bone Marrow Transplant.. vol. 47. 2012. pp. 203-211. [Large retrospective comparison of transplant outcomes demonstrating that at least in AML (acute myeloid leukemia) and MDS (myelodysplastic syndromes), dose may be important.]
Tuncer, HD, Rana, N, Milani, C, Darko, A, Al-Hasmi, S. “Gastrointestinal and hepatic complications of hematopoietic stem cell transplantation.”. World J Gastro. vol. 18. 2012. pp. 1851-1860. [Excellent up to date review.]
McDonald, GB. “Hepatobiliary complications of hematopoietic cell transplantation, 40 years on”. Hepatology. vol. 51. 2010. pp. 1450-60. [Must read for anybody wanting to learn from one of the foremost experts in hepatobiliary complications of SCT.]
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- Preparative regimens for bone marrow transplant
- What every physician needs to know:
- What features of the presentation will guide me toward possible causes and next treatment steps:
- What laboratory studies should you order to help make the diagnosis and how should you interpret the results?
- What conditions can underlie preparative regimens for bone marrow transplant?
- When do you need to get more aggressive tests:
- What imaging studies (if any) will be helpful?
- What therapies should you initiate immediately and under what circumstances - even if root cause is unidentified?
- What other therapies are helpful for reducing complications?
- What should you tell the patient and the family about prognosis?
- “What if” scenarios.
- What other clinical manifestations may help me to diagnose preparative regimens for bone marrow transplant?
- What other laboratory studies may be ordered?
- What’s the evidence?