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, 1 to 3 × 108 mononucleated cells/kg of the recipient’s body weight are procured. The procedure has no long-term adverse 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 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 GCSF (filgrastim) to prime the patient before one to three apheresis procedures. In particular, in patients for whom this is not successful, the use of plerixafor has been 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 before cryopreservation.
Indications for Transplant
The expanded methods of HCT have complicated transplant 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 whether the benefit of HCT (reduction in relapse) significantly outweighs its toxicity and upfront mortality risks.
Acute Myelogenous Leukemia
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 (induction failure or relapse with second or subsequent complete remission). In general, if the possibility of cure for a given patient in first remission is estimated to be 30% to 40% or less, one could justify the use of allogeneic HCT despite its non-relapse mortality rate of 20% to 30%. Thus, high-risk patients (ie, high-risk chromosome abnormalities [ie, −7, −5, complex abnormalities], therapy-related acute myelogenous leukemia (AML), transformed AML from prior myelodysplastic syndrome (MDS), high white blood cell counts at presentation) should be considered for allogeneic HCT. Autologous HCT has not been very successful in these patients. Low-risk patients in first complete remission (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). Patients with 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). It is increasingly important that these molecular markers be tested at presentation of AML. Autologous HCT can be considered for select cases of intermediate- to low-risk AML in first complete remission, although the role of autologous HCT in the intermediate-risk group is diminishing due to improvements in allogeneic HCTs, which are expanding the pool of potential donors outside the family setting. Autologous HCT is also indicated for patients with acute promyelocytic leukemia in second complete remission if they are in a molecular remission. Otherwise, these patients should be considered for allogeneic transplant.
Acute Lymphoblastic Leukemia
Like for patients with AML, allogeneic HCT is considered as potential curative therapy for patients with acute lymphoblastic leukemia in second complete remission. Patients with acute lymphoblastic leukemia with high-risk features need to be considered for allogeneic HCT in first complete remission. These include Philadelphia chromosome, white blood cell counts greater than 30,000/μL (B lineage) or greater than 50,000/μL (T lineage), hypodiploidy, or mixed lineage leukemia gene rearrangement. Autologous HCT is not considered effective for this disease.
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 Classification-Based Prognostic Scoring System 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. Patients with therapy-related MDS or severe cytopenia should also be considered for allogeneic HCT even if their risk category is in intermediate-1.
Chronic Myelogenous Leukemia
Over the past decade, the indications for HCT in chronic myelogenous leukemia (CML) have dramatically changed as a result of the development of tyrosine kinase inhibitors (TKIs). Three TKIs (imatinib, dasatinib, 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
Chronic lymphocytic leukemia is associated with a wide range of prognoses and disease courses and many therapeutic agents. Allogeneic HCT can be considered for select patients in whom one or more standard courses of treatment, including fludarabine/rituximab-containing regimens with high-risk features (ie, short duration of response, ZAP70+, CD38+, chromosome 17p deletion), have failed. Autologous HCT is generally not considered for chronic lymphocytic leukemia because the results from earlier studies have been disappointing.
Allogeneic HCT is the only potentially curative therapy for myelofibrosis/myeloproliferative disorders. But because of 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 have increased blasts in bone marrow/peripheral blood are considered eligible for allogeneic HCT.
Autologous HCT is the treatment of choice for patients with relapsed/refractory diffuse large B-cell non-Hodgkin lymphoma (NHL) that responded to salvage therapy, including those patients with lymphoma in the setting of human immunodeficiency virus (HIV) infection. With the improved outcomes with first-line regimens incorporating rituximab, autologous HCT as consolidation for first complete remission patients with diffuse large B-cell NHL has not been clearly proved beneficial by randomized trials. Autologous HCT is not recommended for patients who have had multiple relapses.
Autologous HCT is considered for patients with mantle cell lymphoma who are in first complete remission. Patients who fail to achieve remission or who have relapsed disease can be cured by an allogeneic approach because the graft-vs-lymphoma effect is strong against mantle cell lymphoma. Autologous HCT has been 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 patients with relapsed/induction failure intermediate- or high-grade NHL who could not proceed with auto-HCT because of bone marrow involvement of lymphoma or failure to collect a 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 in whom secondary MDS developed are clearly candidates for allogeneic HCT. Select patients with relapsed low-grade NHL can also be considered for allogeneic HCT (ie, multiple relapse, first relapse with high-risk features, and relapse after autologous HCT).
Studies by the British National Lymphoma Investigation and the German Hodgkin Study)/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.
Autologous HCT is associated with high response rates and remains the standard of care for patients with multiple myeloma 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 younger than 65 years, 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 complete remission or very good partial response. A delayed second autologous HCT can be beneficial for select myeloma patients who relapsed after the first HCT.
It should also be noted that these randomized studies were designed before the availability of thalidomide, revlimid, and bortezomib. Therefore, the role of autologous HCT may evolve and be refined in the future. Autologous HCT is not considered curative for multiple myeloma, 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.
In general, only autologous transplant is used for some solid tumors, such as germ cell tumors, 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.
The worldwide study of nonmyeloablative or reduced-intensity transplantation approaches has facilitated transplant for many patients who otherwise would not have been candidates because of 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 transplant, whereas those with advanced disease (eg, leukemia in relapse, high-grade lymphoma) benefit less, because 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 transplant is performed. For young patients with severe aplastic anemia (SAA) who have a matched sibling donor, an allogeneic BMT is the standard therapy. Those who are considered at 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; 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 transplant after gene modification (adenosinedeaminase deficiency, chronic granulomatous disease).
HIV infection and HIV-associated malignancies
NHL is an acquired immune deficiency syndrome (AIDS)-defining malignancy and Hodgkin lymphoma is among the most common non–AIDS-defining malignancies. The incidence of NHL and Hodgkin lymphoma is markedly increased in patients with HIV infection compared with the general population. HIV-associated lymphomas frequently show poor prognostic features, such as an advanced stage, extranodal disease, “B” symptoms, and intermediate or high International Prognostic Index. The advent of highly active antiretroviral therapy (HAART) dramatically changed the natural history of HIV infection and related malignancies by reducing the incidence of opportunistic infections and improving the underlying immune deficiency. Autologous HCT has been successfully used for the treatment of patients with relapsed or refractory HIV-associated lymphoma receiving HAART in both prospective and retrospective studies. Consideration of HCT for treatment of malignancy is only appropriate in patients for whom it is anticipated that the HIV-1 itself can be controlled.
Small numbers of allogeneic HCTs have been performed, and in the era of effective HAART, they have yielded encouraging results. Outcomes for a very small number of patients appear similar to what might be expected in the general population. Among the recipients of allotransplant was a patient in Berlin with AML who received a graft from a donor who was homozygous for a polymorphism that confers resistance to HIV-1 infection; HAART was discontinued, and 3.5 years later it appears that the patient was cured of AML and of HIV-1 infection. This polymorphism involves CCR5, an HIV co-receptor. Homozygosity for CCR5Δ32 confers profound resistance against HIV infection, and heterozygous mutation that induces a decrease in CCR5 surface expression is associated with lower plasma viral load and delayed progression to AIDS. Basic and clinical studies are under way in evaluating various approaches of genetic engineering of mature T cells or hematopoietic stem cells with autologous HCT used to treat the underlying HIV-associated malignancy.
Timing of Transplant
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 a marrow transplant is performed early in the natural history of an inherently chemosensitive tumor. Studies to date indicate that patients who undergo transplant late in their disease course have inferior disease-free survival compared with those who undergo transplant early.