- TABLE OF CONTENTS
- Types of transplantation
- Allogenic transplantation
- Autologous transplantation
- Collections of the graft
- Indications for transplantation
- Timing of transplantation
- Phases of transplantation
- Post-transplantation therapies
- Management of relapse
- Second malignancy after HCT
- Suggested reading
Collection of the graft
Allogeneic bone marrow cells
Current techniques for harvesting bone marrow involve repeated aspirations from the posterior iliac crests that are designed to obtain adequate numbers of cells that can lead to hematopoiesis. While the donor is under general or spinal anesthesia, between 1 × 108 mononucleated cells/kg to 3 × 108 of the recipient's body weight are procured. The procedure has no long-term side effects and poses little risk if care is taken to ensure that the donor has no confounding medical conditions. In most cases of ABO incompatibility, the marrow can be treated to remove red blood cells to prevent lysis after infusion.
Autologous peripheral stem cells
Collection of circulating peripheral blood progenitor cells is performed via an apheresis technique. Although this procedure can be accomplished in an individual with a baseline blood count, the number of cells and the efficiency of collection are increased if the cells are procured during white blood cell (WBC) recovery following chemotherapy or after the administration of hematopoietic growth factors.
The most effective strategy appears to be the collection of cells after the administration of both chemotherapy and growth factors. In most circumstances, adequate numbers of cells can be collected using granulocyte colony-stimulating factor (G-CSF, filgrastim(Drug information on filgrastim) [Neupogen]) to prime the patient prior to one to three apheresis procedures. In particular, in patients for whom this is not successful, the use of plerixafor (Mozobil) may be effective.
Currently, the adequacy of the number of hematopoietic stem cells is assessed by determining the number of cells that have the CD34 antigen (stem cell) marker. Usually, a minimum of 2 × 106 CD34 cells/kg of body weight is required to ensure engraftment.
The use of autologous stem cells continues to undergo refinement. Approaches under study include ex vivo expansion to augment the number of progenitor cells, as well as techniques that separate hematopoietic cells from any potential contaminating tumor cells. In addition, hematopoietic stem cells are the usual targets of marrow-based gene therapy using viral vectors for transduction of cells prior to cryopreservation.
Indications for transplantation
The expanded methods of HCT have complicated transplantation choices for patients and their physicians. Therefore, the decision requires evaluation of the patient and the disease involved. The most common use of allogeneic HCT has been for the eradication of hematologic malignancies, such as leukemia and non-Hodgkin lymphoma. HCT is associated with significant toxicity and mortality risks (in particular with allogeneic HCT). Thus, the important principle is to consider the prognosis of the patient if HCT is not performed, and assess if the benefit of HCT (reduction in relapse) significantly outweighs its toxicity and upfront mortality risks.
AML
Patients who are unlikely to be cured with conventional chemotherapy alone should be considered for allogeneic HCT. These include patients who are beyond first complete remission (CR; induction failure or relapse with second or subsequent CR). In general, if the possibility of cure for a given patient in first remission is estimated to be 30%-40% or less, one could justify the use of allogeneic HCT despite its non-relapse mortality rate of 20%-30%. Thus, high-risk patients (ie, high-risk chromosome abnormalities [ie, −7, −5, complex abnormalities], therapy-related AML, transformed AML from prior MDS, high WBC counts at presentation) should be considered for allogeneic HCT. Autologous HCT has not been very successful in these patients. Low-risk patients in first CR (ie, good risk cytogenetic abnormalities) are not generally considered for allogeneic HCT. New molecular markers improved the decision-making process for AML patients with normal cytogenetics (intermediate risk). Normal cytogenetics AML with Flt-3 mutation are considered as allogeneic HCT candidates whereas those without Flt-3 mutation but with NPM-1 mutation are at good risk and not considered for allogeneic HCT. A c-kit mutation also identifies a high-risk group within good risk cytogenetic abnormalities (core-binding factor AML) of t(8;21) and inv(16). These molecular markers are increasingly important to be tested at presentation of AML. Autologous HCT can be considered for selected cases of intermediate to low-risk AML in first CR. It is also indicated for acute promyelocytic leukemia in second CR if in a molecular remission. Otherwise, these patients should be considered for allogeneic transplantation.
ALL
Like AML, allogeneic HCT is considered as potential curative therapy for patients in second CR. ALL with high-risk features needs to be considered for allogeneic HCT in first CR. These include Philadelphia chromosome, WBC counts > 30,000/μL (B lineage) or > 50,000/μL (T lineage), hypodiploidy, or MLL gene rearrangement. Autologous HCT is not considered effective for this disease.
Myelodysplastic syndromes (MDS)
Allogeneic HCT is the only potentially curative option for MDS. However, the natural course and prognosis of MDS varies widely and the optimal timing of HCT is difficult to determine, particularly with recent availability of hypomethylating agents. The decision needs to consider several factors such as patient age, comorbid conditions, International Prognostic Scoring System (IPSS) or World Health Organization (WHO) Classification-Based Prognosic Scoring System (WPSS) score, psychosocial status including the availability of a caregiver, and the availability of a donor. Allogeneic HCT is generally considered for MDS patients with high risk or intermediate-2 risk by IPSS. Therapy-related MDS or severely cytopenic patients should also be considered for allogeneic HCT even if their risk category is in intermediate-1.
CML
Over the past decade, the indications for HCT in CML have dramatically changed due to development of tyrosine kinase inhibitors (TKIs). Three TKIs (imatinib, dasatinib(Drug information on dasatinib), nilotinib(Drug information on nilotinib)) are currently available. Allogeneic HCT is considered for patients with a history of blast crisis (second or subsequent chronic phase) after blast crisis. It is considered as salvage therapy for patients with accelerated phase and chronic phase after failing to achieve hematologic/cytogenetic response to TKIs. Autologous HCT is generally not indicated for CML.
Chronic lymphocytic leukemia (CLL)
CLL is associated with a wide range of prognoses and disease courses and many therapeutic agents. Allogeneic HCT can be considered for selected patients who failed one or more standard regimens including fludarabine/rituximab-containing regimens with high-risk features (ie, short duration of response, zap-70+, CD38+). Autologous HCT is generally not considered for CLL because the results from earlier studies have been disappointing.
Myelofibrosis/myeloproliferative disorders (MF/MPD)
Allogeneic HCT is the only potentially curative therapy for MF/MPD. But due to the heterogeneity in their prognosis and natural course, selection of high-risk patients is important. There have been efforts in developing prognostic scores for these patients. Those who are transfusion-dependent, or having increased blasts in bone marrow/peripheral blood are considered eligible for allogeneic HCT.
Non-Hodgkin lymphoma (NHL)
Autologous HCT is the treatment of choice for relapsed/refractory diffuse large B cell NHL which responded to salvage therapy, including those patients with lymphoma in the setting of HIV infection. With the improved outcomes incorporating rituximab(Drug information on rituximab) in first-line regimens, autologous HCT as consolidation for first CR patients with diffuse large B cell NHL has not been clearly proved beneficial by randomized trials. Autologous HCT is not recommended for multiply relapsed cases.
For mantle cell lymphoma, autologous HCT is considered for patients in first CR. Patients who fail to achieve remission or who have relapsed disease can be cured by an allogeneic approach as the graft-vs-lymphoma (GVL) effect is strong against mantle cell lymphoma. Autologous HCT has shown to prolong overall and progression-free survival for relapsed/refractory follicular NHL, although it is not considered curative.
Allogeneic HCT can be considered for relapsed/induction failure intermediate-high grade NHL patients who could not proceed with auto-HCT due to bone marrow involvement of lymphoma/failure to collect sufficient number of CD34+ hematopoietic progenitor cells. NHL patients who relapsed after prior autologous HCT can be considered for allogeneic HCT using reduced-intensity conditioning. NHL patients who developed secondary MDS are clearly candidates for allogeneic HCT. Selected cases of relapsed low-grade NHL can also be considered for allogeneic HCT (ie, multiple relapse, first relapse with high-risk features, relapse after autologous HCT).
Hodgkin lymphoma
Studies by the British National Lymphoma Investigation and the German Hodgkin Study (GHSD)/European Group for Bone and Marrow Transplantation demonstrated improved progression-free/event-free survival (but not overall survival) with autologous HCT compared with conventional chemotherapy in relapsed or refractory Hodgkin lymphoma. Reduced-intensity allogeneic HCT can be considered for Hodgkin lymphoma patients who relapsed after autologous HCT.
Multiple myeloma (MM)
Autologous HCT is associated with high response rates and remains the standard of care for MM after initial induction therapy. Its benefit over conventional cytotoxic chemotherapy has been clearly demonstrated in multiple randomized studies (ie, IFM 90, MRC VII). While most of these studies enrolled patients < 65 years old, recent studies suggest benefits for older eligible patients. Tandem autologous HCT has been associated with improved event-free survival (and overall survival in IMF 94 study). However, the added benefit was not seen in a subset of patients with a CR or very good partial response (VGPR). A delayed second autologous HCT can be beneficial for selected cases of myeloma patients who relapsed after the first HCT.
It should also be noted that these randomized studies were designed prior to the availability of thalidomide(Drug information on thalidomide), revlimid, or bortezomib(Drug information on bortezomib). Therefore, the role of autologous HCT may evolve and be refined in the future. Autologous HCT is not considered curative for MM and recent efforts include post-HCT maintenance therapy to delay future recurrences. An approach of combined auto-HCT followed by non-myeloablative HCT showed a promising result in phase II studies, yet the results from phase III trials showed mixed data without clear advantage in this approach. Thus, upfront allogeneic HCT is only recommended in the context of clinical trials.
Solid tumors
In general, only autologous transplantation is used for some solid tumors, such as germ cell, soft-tissue sarcomas, and neuroblastoma. Allogeneic transplant studies in patients with renal cell cancer suggest that a graft-vs-tumor effect can be elicited against this tumor, but the results are inconsistent.
Disease sensitivity to a graft-vs-malignancy effect
The worldwide study of nonmyeloablative or reduced-intensity transplantation approaches has facilitated transplantation for many people who otherwise would not have been candidates due to concomitant medical problems or older age. The results indicate that slower-growing malignancies are the most responsive. Thus, patients with low-grade lymphoma, AML, myeloma, myelodysplasia, and CML are probably good candidates for this type of allogeneic transplantation, whereas those with advanced disease (eg, leukemia in relapse, high-grade lymphoma) benefit less, as the allogeneic antitumor effect requires time to develop and achieve remission of the disease. Table 3 shows the relative sensitivity of different hematologic malignancies to a graft-vs-malignancy effect that could be mediated by a nonmyeloablative transplant.
Benign hematologic or congenital disorders
In general, for disorders that require replacement of an abnormally functioning hematopoietic system, such as thalassemia and aplastic anemia, an allogeneic transplantation is performed. For young patients with severe aplastic anemia (SAA) who have a matched sibling donor, an allogeneic BMT is the standard therapy. For those who are considered high risk for BMT (elderly, with comorbidity) are treated with immunosuppressive therapy (IST) using antithymocytoglobulin/cyclosporine. SAA patients with no sibling donors are also initially treated with IST while unrelated donors are searched, and BMT is considered if there is no response to IST.
Congenital immune deficiency can be corrected by allogeneic HCT. As genetic therapy for hematopoietic stem cells becomes more of a reality, patients with these diseases may also be candidates for autologous transplantation after gene modification (adenosinedeaminase deficiency, chronic granulomatous disease).
Timing of transplantation
The Goldie-Coldman model proposes that the probability that a tumor contains treatment-resistant cells is a function of its size and inherent mutation rate. This finding suggests that the likelihood of cure is greatest when marrow transplantation is performed early in the natural history of an inherently chemosensitive tumor. Studies to date indicate that patients undergoing transplantation late in their disease course have inferior disease-free survival when compared with those who undergo transplantation early.
