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11.2.1. Introduction
Allo-HSCT is a potentially curative treatment modality for otherwise incurable diseases. Unfortunately, after transplantation patients may experience not only the persistence or recurrence of their own disease but also some dramatic clinical complications and toxicities, including death. The clinical indications to transplant have been addressed in the section “indications” of this book, but in general, when the allo-HSCT is advised, the strength of the indication (the likelihood to be cured by transplant), the patient fitness, and his/her personal commitment to transplant must be carefully evaluated for each candidate.
Obviously, a first distinction must be done between patients with a neoplastic versus a non-neoplastic disease, and the transplant option should be progressively discussed with the patient during the course of the disease, particularly in the case of hematologic malignancies. Many professionals should concur to illustrate the patients the curative potential of an allo-HSCT and to help understanding the severe complications that can eventually develop. It is clear that different indications remarkably affect the way a patient is advised. However, there is a time when the transplant option must be formally presented and advised. Therefore, evaluation of each transplant candidate must be based on well-predefined formal standard operating procedures to collect exhaustive clinical, instrumental, and laboratory data that may lead to a robust definition of the risks and benefits related to allo-HSCT. All in all, the counseling is to tailor such evaluation to the individual patients (Shouval et al. 2015), according to both objective data and subjective data such as patient propensity and fear of side effects. At the end of this process, the patient should be aware of the rationale, the benefit and the toxicity associated with each step, and component of the transplant procedure. In this chapter, I will hereby summarize the main topics I cover with my patients when they come to my office to discuss the option of the allo-HSCT.
11.2.2. Understanding the Benefit and Risk of Allogeneic Transplant
Patients must be informed that allo-HSCT is a therapeutic option that is always proposed with the intent to achieve a permanent cure of the underlying disease, but despite this premise, disease progression or relapse may eventually happen. The indication to allo-HSCT depends not only on the disease characteristics but also on patient-related factors such as age and comorbidities (Sorror et al. 2007) so that the transplant proposal is the result of an accurate and wise evaluation of both these factors (Sorror et al. 2013; Wang et al. 2014).
The patient should understand the specific risk/benefit balance associated with a conventional versus a transplant-based proposal, and this may be remarkably different if he has been diagnosed with a non-neoplastic disease such as thalassemia or sickle cell anemia, a bone marrow failure syndrome like aplastic anemia, or a blood cancer, such as an acute leukemia. Even when allo-HSCT may in theory represent the most efficacious treatment modality to get a permanent cure of a specific disease, an accurate description of the available alternatives must be presented. This is particularly important when the non-transplant options, albeit not curative, may have the chance to keep the patient alive for a long time (Samuelson Bannow et al. 2018) or, even more importantly, when the conventional treatment may lead to a definitive cure such as in the case of some patients with acute leukemia with intermediate-risk genetic factors or those achieving a deep molecular remission after conventional chemotherapy (Cornelissen and Blaise 2016).
11.2.3. Understanding the Transplant Procedure: The Donor, the Conditioning Regimen, and the Clinical Complications
Once the indication to transplant has been confirmed, patients and their relatives must be informed on how the transplant is performed. Patients should understand that identifying a stem cell donor is an absolute prerequisite to perform a transplant. Accordingly, patients should be informed about the human leukocyte antigen (HLA) genetic system, its specificity for each individual, how it is inherited by parents according to the Mendelian laws, and what is the probability to find a compatible donor in the family group. Understanding the HLA system is crucial to explain why the use of a HLA family-matched sibling donors is considered standard and when such a sibling is not available; an international search has to be performed to identify a HLA-compatible unrelated donor. It is important to underline that more than 30 million of potentially available donors are registered by the World Marrow Donor Association (WMDA), and the probability to find a compatible donor is between 50 and 80% according to the ethnical origin of each patient.
Once such matched unrelated donor is identified, this type of transplant is considered a standard of care, and its clinical outcome is fully comparable to what was observed when using an HLA-identical sibling. In patients for whom a MSD or a MUD is not available, the patient should be informed that two additional options are available, namely, the use of HSC obtained by a family mismatched donor (commonly defined as haploidentical because sharing only one of the patient’s HLA haplotypes) or a banked cord blood units. Patients should understand how the HLA diversity between patient and donor has been overcome by specific programs of in vitro or in vivo manipulation of the graft.
Patients should be reassured that the incidence and severity of GvHD, the most important side effect of allo-HSCT, seems not to be higher than observed with MUD. In addition, patients should know that many single-arm studies reported that transplants performed with these alternative stem cell sources proved to be effective and safe even when offered to patients of advanced age and/or with existing accompanying illnesses or when the disease was refractory to conventional treatment. All in all, at the present time, the clinical outcome of these alternative types of transplants compares reasonably well with those achieved with MUD. Therefore, the decision to use this type of stem cell source only when an HLA-matched donor is not available is mostly related to the lack of randomized clinical trials that are planned to be performed in the near future.
The goal of an allo-HSCT is to eradicate the patient’s hematopoiesis either neoplastic or normal. This is achieved by the delivery of the conditioning regimen and by the lifelong in vivo effect played by the donor’s immune system. Most often, high doses of chemotherapy and/or radiation are included in the preparations although remarkable differences exist depending on the disease needing transplant and patient tolerance. The patient should understand that the intensity of the conditioning regimen may be particularly important in the case of hematologic malignancies when the aim to remove most of the neoplastic cells present in the patient’s body is the first goal. However, to avoid at least part of the treatment toxicity, the intensity of the preparative regimen can be down-modulated leading to the definition of this preparative regimen as non-myeloablative or reduced intensity. The depletion of the patient bone marrow stem cells induces a prolonged pancytopenia and the need of donor-derived healthy stem cells to grow and establish a new blood cell production system.
The allogeneic HSC, collected from the donor’s BM or PB or a frozen CBU, are infused through the central venous catheter into the bloodstream: HSCT is not a surgical procedure and it is very similar to receiving a blood transfusion. The stem cells find their way into the bone marrow and begin reproducing and growing new, healthy blood cells. It is very important to explain how the donor immune system will develop progressively after transplantation and will either exert a crucial beneficial role against residual neoplastic cells or restore the immune competence against infections, but it could mediate the most harmful GvHD effect against the patient.
After the transplant, supportive care is given to prevent and treat infections, side effects of treatments, and complications. Prolonged anemia, thrombocytopenia, and leukopenia can be dangerous and even life-threatening. A low platelet count can be potentially associated with bleeding in the lungs, GI tract, and brain. Leukopenia, including either a defect of neutrophils and lymphocytes, leads to the development of frequent infections, the most common clinical complications after transplantation. Infections can include not only bacterial, most likely when the patient has a severe bone marrow suppression, but also viral and fungal pathogens. Infections can require an extended hospital stay, prevent or delay engraftment, and/or cause permanent organ damage. On average the time to hematologic engraftment (recovery of the neutrophil and platelet function) is about 2–3 weeks, but a protective recovery of the immune system can take months and sometimes years. High doses of chemotherapy and radiation can cause remarkable toxicities that include but not limited to severe mucositis (inflammation of the mouth and GI tract) that favors bacterial translocation with related infections and GvHD and multi-organ failure mainly the lung, heart, liver, and kidney.
A particular attention should be paid to risk of graft failure that can occur early or late after transplantation. A graft failure is more frequent in some diseases such as myelofibrosis or as the results of infections or when the stem cell content of the graft is insufficient to guarantee a durable engraftment. A graft rejection can also happen after reduced intensity conditioning regimen (when the immune system of the host is not completely eradicated and can actively reject the donor stem cells).
Finally, and most importantly, patients must be aware of what GvHD is, when and how it may develop, and why it represents the most serious complication of a HSCT, being not only life-threatening but also the principal reason of a long-lasting poor quality of life. Transplant candidates should be aware that GvHD is the negative counterpart of the deep interaction of the donor immune system within patient body that at the same time may lead to definitive cure of an otherwise incurable disease. In other words, when transplant is advised, patients must realize that they are accepting the possible onset of a chronic, often invalidating, autoimmune disease. GVHD can appear at any time after transplant. GvHD is conventionally distinguished in an acute form that usually develops within the first 100 days after transplant and the chronic form that occurs later in the transplant course. Patients who develop acute GVHD are more likely to also develop the chronic form of GVHD. Patients must understand the importance of their compliance to all the treatments given post transplant to prevent GvHD and how this is instrumental for a successful transplant. GvHD occurs when the donor’s immune system reacts against the recipient’s tissue. At variance to what happens after a solid organ transplant where the patient’s immune system is driven to reject only the transplanted organ, in GVHD, the donor immune system can react against many different organs of the recipient. This is why the new cells do not recognize the tissues and organs of the recipient’s body as self. Over time, thanks to the effect of immune suppressive drugs, a progressive tolerance can develop. The most common sites for GVHD are the GI tract, liver, skin, and lungs.
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