Chapter 12: Autologous Hematopoietic Progenitor Cell Transplantation

High-dose chemotherapy (HDC) with autologous hematopoietic progenitor cell (HPC) transplant is an effective treatment modality for several hematologic malignancies and selected solid tumors. This chapter reviews its current role in the treatment of cancer and outlines promising future directions of progress.

High-dose radiation and chemotherapy are limited by toxicity to normal tissues, particularly the bone marrow. The doses of certain chemotherapeutic agents and radiation can be substantially escalated, with the goal of exploiting their dose-response effect, when followed by autologous or allogeneic transplantation of HPCs to restore hematopoiesis. Pluripotent HPC progenitors present in the graft proliferate and differentiate into the mature blood and immune cells. Autologous transplantation involves collection, cryopreservation, and infusion of the patient’s own HPCs.

Preceding Conventional Dose Chemotherapy

Standard chemotherapy is usually given to reduce the tumor burden prior to proceeding with HPC transplantation (Fig. 12-1). In general, the best outcomes are noted in patients with chemosensitive disease, in complete remission (CR), or with minimal tumor burden at time of transplantation.

Stem Cell Collection

Bone marrow is collected via multiple aspirations from the posterior-superior iliac crest in a sterile environment (usually a surgical operating room) while the patient is under anesthesia. Ideally, HPCs should be collected while the patient’s marrow is normocellular and uninvolved by the malignancy. Currently, bone marrow HPC collection is rarely, if ever, done for the purpose of autologous transplantation because HPCs can be collected from peripheral blood and engraft more rapidly when collected this way. Hematopoietic progenitor cells are normally infrequent in the blood but are mobilized into the blood during the recovery after chemotherapy and following treatment with granulocyte colony-stimulating factor (G-CSF). Peripheral blood progenitor cells (PBPCs) are collected using apheresis with continuous-flow cell separation. One to four daily apheresis sessions are usually required to achieve the minimal target CD34⁺ cell dose (at least 2 × 10⁶/kg). The collected PBPCs are subsequently cryopreserved and stored.

Multiple factors have been shown to predict poor success in mobilization and collection, including advanced age; amount of preceding chemotherapy; presence of marrow-infiltrating disease; history of pelvic radiation; prior exposure to certain drugs (melphalan, carmustine, bendamustine); low premobilization platelet counts; short intervals from last chemotherapy cycle to mobilization; inadequate chemotherapy-mobilizing regimens or low-dose G-CSF (¹); and previous treatment with four or more cycles of lenalidomide (²). Peripheral blood CD34⁺ cells more than 10/μL are usually necessary for an adequate collection. Plerixafor has become available as a second PBPC-mobilizing agent, effective for “poor mobilizers,” acting synergistically with G-CSF (³).

High-Dose Therapy

Autologous transplants are most effective in diseases where up to a three- to fivefold dose escalation of myelosuppressive drugs or radiation leads to a markedly increased cytotoxic effect against the malignancy. The most commonly used drugs are alkylating agents.

The most common cause of failure after autologous HPC transplantation is relapse of the underlying malignancy. This usually occurs because of inadequate systemic cytoreduction, although it may also be caused by reinfusion of malignant cells contaminating the transplant infusion. The optimal HDC regimen is disease specific. Various approaches are being studied to improve the final outcomes, including novel chemotherapy agents (^4,5), monoclonal antibodies (⁶), chemoradiotherapy (^7,8), and targeted radiation treatments. “Tandem” autologous HPC transplants have been studied in myeloma and germ-cell tumors (⁹). In chemosensitive malignancies, increasing the total dose of therapy may markedly improve the tumor response, but this increases the severity of side effects. Thus, novel HDC regimens must be developed in carefully designed clinical trials to provide the optimal therapeutic index.

Reinfusion of Collected Stem Cells

Stem cells are infused intravenously after HDC is eliminated from the patient’s bloodstream, usually 1 to 3 days after completion of the treatment. The cells circulate transiently and home to the bone marrow. Hematopoiesis is restored within a few weeks. Hematopoietic recovery is most rapid with infusion of high doses of CD34⁺ cells. Most centers require a minimum 2 × 10⁶/kg CD34⁺ cells per kilogram from peripheral blood (¹⁰). Neutrophils recover typically in 7 to 10 days and platelets recover in 10 to 14 days after infusion.

Supportive Care

Patients usually receive G-CSF or other hematopoietic growth factors to accelerate neutrophil recovery. Patients are routinely prescribed prophylactic antibiotics and antiviral and antifungal therapy for prevention of infection during the initial phase of marrow engraftment and hematologic recovery.

Autologous Versus Allogeneic Hematopoietic Progenitor Cell Transplants

The relative role of allogeneic versus autologous transplants has been long debated for specific hematologic malignancies. Autologous HPC transplantation is a process that carries less overall morbidity and mortality because the reinfused cells are not subject to immunologic rejection and do not produce graft-versus-host disease (GVHD). On the other hand, there is a risk of tumor contamination of the autologous HPCs. Some clinical studies have shown that autograft contamination is correlated with shortened disease-free survival (DFS) (¹¹) and that the presence of tumor cells or their inadequate purging in autologous samples may correlate with the extent of the disease. Gene-marking studies in neuroblastoma showed that persistent cancer cells in the autograft can contribute to systemic relapse. The risk of contamination of the graft is higher in patients with uncontrolled tumors and known marrow involvement. Perhaps more important, there is no evidence that immune-mediated graft-versus-tumor effect associated with allogeneic HPC transplantation occurs with autologous transplants.

High-dose chemotherapy produces profound pancytopenia that usually lasts from 7 to 10 days. Infectious complications can occur in the neutropenic period (ranging from febrile neutropenia to life-threatening septic episodes) and up to 6 months or more posttransplant in the case of Pneumocystis jirovecii, fungal infections, or zoster reactivation. Antibacterial prophylaxis with a fluoroquinolone, antiviral prophylaxis with acyclovir/valacyclovir, and antifungal prophylaxis with fluconazole are generally started at the time of stem cell infusion and continued until recovery from neutropenia. Pneumocystis prophylaxis (eg, trimethoprim/sulfamethoxazole) is usually started day 30 posttransplant for at least 6 months. Antiviral prophylaxis (acyclovir, valacyclovir) are given for 6 to 12 months (¹²).

High doses of chemotherapy may produce major toxicities in nonhematopoietic tissues. The oral mucosa and the gastrointestinal tract are generally the most sensitive tissues. The lungs, heart, liver, brain, and kidneys are less commonly affected and are generally affected in heavily pretreated patients or those with comorbid conditions. Overall, up to 4% of patients die from regimen-related toxicities or infections. This rate of treatment-related mortality makes autologous transplantation substantially safer than allogeneic transplantation.

Toxic interstitial pneumonitis occurs in up to 40% of patients undergoing high-dose therapy. It has been described with several different chemotherapy agents, such as carmustine (^13,14) and total-body irradiation (TBI) (¹⁵). It is particularly common in patients previously treated with mediastinal radiotherapy (^16,17). Steroids constitute the mainstay of treatment of interstitial pneumonitis.

Cardiac toxicity is uncommon. It can be seen after high doses of cyclophosphamide or melphalan. Prior radiation therapy to the mediastinum or left chest wall and advanced age are also predictors of an increased risk of cardiac complications (¹⁸).

Central nervous system complications are rare, but dementia and leukoencephalopathy have been described as complications of HDC. Hypothyroidism frequently occurs 6 months to 2 years after therapy.

Hemorrhagic cystitis, after high-dose cyclophosphamide or ifosfamide, is uncommon and can be effectively prevented with MESNA (2-mercaptoethanesulfonate) (^19,20).

Sinusoidal obstruction syndrome (SOS) (formerly known as veno-occlusive disease or VOD) of the liver is one of the most feared complications associated with HDC. Its clinical syndrome is characterized by fluid retention, hyperbilirubinemia, and hepatomegaly, which can be painful (²¹). Its severity depends on the presence of multiorgan failure and the rapidity of bilirubin rise. Mild cases are often self-limited; severe cases are fatal in more than 80% of patients. Several factors predispose to the development of SOS, including prior liver impairment, older age, and iron overload. The use of oral busulfan and TBI have been most commonly associated with SOS, particularly if used along with cyclophosphamide (²²). Andersson et al pioneered the use of intravenous busulfan, which decreases the risk of SOS compared with the oral drug formulation (²³). Pharmacokinetic-guided dosing of busulfan has further decreased the incidence of SOS. Systemic anticoagulant and thrombolytic therapies to treat SOB are ineffective and are associated with major bleeding complications. Defibrotide has emerged as a promising therapy for severe cases of SOS but has not received approval by the Food and Drug Administration yet. Supportive care plays a crucial role, using diuretics and sodium restriction, avoidance of hepatotoxins, oxygen support, and renal replacement therapy if needed.

Non-Hodgkin Lymphoma

Autologous transplantation has been extensively studied in refractory-relapsed non-Hodgkin lymphoma (NHL).

Aggressive Lymphoma

High-dose chemotherapy and autologous stem cell transplant comprise a standard of care for patients with chemosensitive, relapsed, diffuse large B-cell lymphoma (DLBCL) (²⁴) (Fig. 12-2). Resistance to salvage chemotherapy, increased lactic dehydrogenase at the time of relapse or progression, prior complete remission (CR) of less than 12 months, and secondary International Prognostic Index (IPI) (ie, at the time of relapse or progression) greater than 1 have been described as adverse predictors of survival (²⁵). In the modern era of exposure to rituximab as part of first-line therapy (R-CHOP), the CORAL study has shown 3-year EFS rates of 25% in chemosensitive relapsed patients undergoing autologous stem cell transplantation (²⁶).

High-dose chemotherapy in the first CR has also been evaluated for patients with DLBCL and a high IPI (^27,28,29,30). While some randomized studies have demonstrated an improvement in EFS, none has shown a benefit in overall survival (OS). Thus, autologous transplantation is not routinely used as consolidation in a first remission for DLCL.

Follicular Lymphoma

The role of autologous HPC transplantation remains unclear in the management of patients with chemosensitive, relapsed low-grade lymphoma (eg, follicular lymphoma, FL). The use of high-dose cyclophosphamide (³¹) and TBI (³²) has resulted in a 5-year EFS of 60% but has been largely abandoned due to the risk of secondary malignancies.

Historically, a major challenge has been the contamination of the autologous graft by malignant cells (³³). Recently, systemic treatment with rituximab has reduced the numbers of circulating lymphoma cells, thus yielding effective in vivo purging with high likelihood polymerase chain reaction–negative tumor-free PBPC grafts (^34,35).

Several randomized trials have shown improved outcomes after HDC for chemosensitive relapsed FL (^36,37). However, these studies were largely conducted in the prerituxumab era. The role of HDC in this setting in the current era remains unsettled.

Hodgkin Lymphoma

The majority of patients with Hodgkin lymphoma (HL) are curable with first-line therapy (Fig. 12-3). However, up to 20% of patients will not respond to first-line chemotherapy, and 30% will relapse after an initial response (^38,39). The use of HDC has been proven to be beneficial in the two settings, with expected long-term EFS of 30% to 40% for patients with primary refractory tumors sensitive to subsequent salvage therapy and of 30% to 65% for patients with chemosensitive relapsed HL (^40,41).

Unfavorable prognostic features for autologous transplant include a first CR shorter than 1 year, extranodal relapse, B symptoms at the time of relapse or progression, bulky (>5-cm) lesions at relapse, and relapse within a prior radiation field. Patients without unfavorable prognostic features have 4-year EFS rates of 70%, compared with less than 20% in patients with adverse features (⁴²). Positron emission tomographic scan uptake at the time of HD has recently emerged as the main prognostic factor (^43,44).

Multiple Myeloma

High-dose therapy with autologous HPC transplantation is an established treatment for multiple myeloma, where the use of high-dose melphalan provides OS benefit as consolidation of a response to first-line therapy (^45,46,47,48) (Fig. 12-4). To date, no other preparative regimen has been shown to be superior to single-agent melphalan (200 mg/m²) (⁴⁹). The use of a second course of high-dose melphalan (“tandem” autologous transplants) has been shown to be superior to a single transplant in some (^49,50,51), but not all, studies (⁵²), particularly in patients who do not achieve at least a very good partial remission after the first procedure. The timing of transplant has been prospectively investigated in randomized studies. Early (after a brief course of first-line therapy) and late autotransplant (at a time of relapse after prolonged first-line therapy) trials (⁵³) resulted in similar OS, with early autotransplantation offering improved quality of life, shorter duration of chemotherapy, and a longer median EFS. Induction therapy, including novel agents such as bortezomib or lenalidomide, appears to be the most effective induction treatment before HDC. Ongoing randomized trials in the United States and Europe are addressing the question of optimal timing of autologous transplant in the present era of novel agents.

Several retrospective analyses have demonstrated durable responses of a second salvage course of HDC with autologous SCT for patients with relapsed disease (⁵⁴). In general, the outcomes appear more favorable for patients who relapse more than 12 months after a first autologous transplant and who respond to subsequent salvage treatment (⁵⁵). More recently, the first randomized controlled trial has been completed comparing salvage HDC and autologous transplant to salvage conventional chemotherapy (⁵⁶). In this study, there was a benefit for the transplant arm, with a significant improvement in time to progression.

Maintenance therapy posttransplant with lenalidomide prolongs EFS and perhaps OS, as shown in several randomized studies (^57,58). There is uncertainty about the optimal duration of lenalidomide treatment. Its use after allogeneic stem cell transplantation has been associated with a small risk of secondary malignancies in the French, but not in the US, study.

Solid Tumors

The use of HDC for breast cancer or ovarian cancer has been abandoned. In contrast, tandem courses of carboplatin-containing HDC have been successful in curing patients with relapsed or refractory germ-cell tumors. Long-term EFS rates range from 10% for patients with cisplatin refractoriness and other poor-prognostic features to 70% for those with good-risk chemosensitive tumors in first relapse (⁵⁹).

Patients with rapid recovery of lymphocyte counts have had the best progression-free survival after autologous stem cell transplantation (⁶⁰). Following myeloablative therapy and autologous transplantation, there is homeostatic expansion of lymphocytes. This provides an opportunity for active vaccination or infusion of antigen-specific, tumor-reactive lymphocytes or to infuse genetically modified lymphocytes to enhance antitumor effects. One recent approach utilizes redirecting the specificity of T cells using a chimeric antigen receptor T cell (CAR-T) toward tumor-related antigens such as CD19 or CD20 in lymphomas (⁶¹).

High-dose chemotherapy with autologous HPC transplantation is an effective modality to achieve major antitumor cytoreduction. Autologous transplants need to be integrated into the multimodality management of hematologic malignancies and GCTs. Many current studies focus on posttransplant strategies to prevent regrowth of minimal residual disease, including molecularly targeted approaches and angiogenesis inhibition. Further clinical trials are needed to optimize the use of autologous HPC transplantation in the overall treatment of cancer.