NEW YORK CITY—Mobilize stem cells early, but not too often; consider chemomobilization as part of a salvage regimen for lymphoma and myeloma patients; and for poor mobilizers, consider using plerixafor to augment filgastrim. These are some of the key strategies for stem cell mobilization outlined by William Bensinger, MD, Director of the Autologous Marrow Transplant Program of the Seattle Cancer Care Alliance and Professor and Member of the Clinical Research Division of Fred Hutchinson Cancer Research Center, speaking here at the National Comprehensive Cancer Network Hematologic Malignancies Annual Meeting.
“We routinely use rituximab plus ifosfamide, carboplatin, and etoposide (R-ICE) as salvage for lymphoma patients. We collect stem cells from patients on the rebound from a second cycle of R-ICE, and often are able to mobilize stem cells easily. We like to collect stem cells at a fast tempo for better engraftment. Studies show that collecting more than five million CD34+ cells is associated with rapid engraftment, and a high percentage of patients recover platelets independently after transplant.”
Collection of an optimal number of stem cells is important for engraftment. “Two million to 2.5 million cells is the minimum for stem cell transplantation. We try to collect more to ensure more rapid engraftment,” he said. However, about one-third of lymphoma patients do not mobilize an adequate number of stem cells. Ten to 20 percent of patients fail to collect two million CD34+ cells, and nearly 60 percent do not collect four million.
Factors Affecting Mobilization
The multiple factors associated with poor stem cell mobilization include: increasing age; marrow disease or resistant disease; more than six cycles of conventional chemotherapy; prior use of alkylators or lenalidomide; prior radiation, in particular to the pelvic area; and growth factor mobilization without chemotherapy, which lowers the yield of stem cells.
“Certain things you can't change, such as the patient's age, disease, or stage, but there are things you can change,” Bensinger said. “Mobilize and collect early in the disease course and avoid marrow-toxic drugs. Avoid radiation or collect stem cells before irradiation. And more stem cells are collected with chemotherapy plus stimulating factors.”
Higher doses of granulocyte-colony stimulating factor (G-CSF) are better than lower doses, he said. Studies show that higher doses of G-CSF lead to a higher proportion of patients who achieve target levels of stem cell mobilization. One strategy to improve collection is to use growth factor alone, he noted.
Myeloma induction therapy also has an impact on stem cell yield. Collection of a full yield is difficult for patients exposed to lenalidomide-dexamethasone, and these patients often require a higher number of collections to achieve target levels. Chemomobilization may be a way to overcome this, using cyclophosphamide plus G-CSF. In most cases, the yield is superior with chemomobilization compared with use of G-CSF alone.
More intensive regimens tend to lead to somewhat higher yields, and the yield is higher with three-day regimens.
“You don't want to overdo it. If you are using intensive chemotherapy, collect early. You will get lower yields with successive cycles of cyclophosphamide.”
New Drugs for Mobilization
New drugs for mobilization include pegfilgastrim, a polyethylene glycol version of G-CSF; stem cell factor (which is not yet available in the United States); and plerixafor (formerly AMD3100), a chemokine receptor 4 antagonist.
“Pegfilgastrin may be an alternative way to mobilize stem cells,” Bensinger said, noting that studies show that higher doses lead to a very good yield.
Plerixafor was originally developed as a potential AIDS drug. When plerixafor was given to patients in a clinical trial to prevent infections, the patients had an elevated white blood cell count and elevations in CD34+ cells. The mechanism is believed to involve binding CD34+ cells to the bone marrow stromal cell, thus mobilizing stem cells.
Dose-response studies of plerixafor show that a dose of 240 mcg/kg mobilizes the most stem cells. A single dose of the drug seems to mobilize a similar number of CD34+ cells as G-CSF. “When plerixafor is added to G-CSF, there is augmentation of stem cell mobilization,” Bensinger said, adding that the side effects of plerixafor are generally mild, grade 1 or 2, and do not appear to interfere with patients.
Randomized trials show an increase in stem cell collection with a combination of plerixafor and G-CSF compared with use of G-CSF alone, and the majority of patients mobilize considerably more stem cells, although a small group do not benefit. The majority of patients who are transplanted with plerixafor and G-CSF cells demonstrate prompt engraftment.
Two Phase III Trials
He noted that two Phase III trials of plerixafor have been completed—one in non-Hodgkin lymphoma (NHL) and one in myeloma, with each including 300 patients.
Both trials showed significant benefits in collection of CD34+ cells with the combination compared with use of G-CSF plus placebo. In the NHL trial, two-thirds of plerixafor-treated patients achieved the target goal of five million cells compared with only one-quarter of placebo-treated patients. Similarly, in the multiple myeloma trial, 87 percent of patients who received plerixafor achieved the target goal of more than six million cells compared with 56 percent who did not receive the drug.
“Plerixafor is a very good drug that is relatively well-tolerated,” said Bensinger. “Should all multiple myeloma patients receive the drug? No: The drug is not yet widely used due to the cost factor. It's an expensive drug. With pharmacy mark-up, it costs $10,000 to $12,000 per dose.”
Since stem cell dose helps to determine the transplant outcome, plerixafor may be particularly useful for patients who are poor mobilizers, he said.
For poor mobilizers, Bensinger suggests a real-time rescue strategy using plerixafor. Studies show adding in plerixafor at 240 mcg/kg subcutaneously on the evening before a second collection yields a high collection of stem cells with standard apheresis the following day. “The idea is to use a 'just-in-time' dose of plerixafor to avoid the high cost of the drug for all patients,” he said.
Prior chemotherapies, including the number of prior regimens and therapy with alkylators, melphalan, and fludarabine in the prior two months, can affect mobilization. Thrombocytopenia and radiation to the marrow space also lead to an inadequate yield. “Too few stem cells can lead to delayed engraftment and complications, as well as myelodysplastic syndrome and relapse,” he said.
Bensinger's definition of failed collection includes patients for whom a minimal number of CD34+ cells (conventionally two million cells) are not collected, as well as those for whom more than one million CD34+ cells are not collected despite repeated attempts.
Failed mobilizers cannot proceed to apheresis due to low peripheral blood CD34+ cell counts—conventionally less than 10/microliter. “Consistent definitions are important when comparing different mobilization strategies,” he said.
Strategies for Poor Mobilization
Appropriate strategies for patients who are poor mobilizers, he said, are the following:
* Be proactive—avoid radiation, multiple cycles of chemotherapy, and myelotoxic drugs.
* Collect early in treatment.
* Use higher doses of filgastrim or pegfilgastrim.
* Utilize chemomobilization plus CSF, if appropriate.
* Use plerixafor to augment filgastrim.
In summary, Bensinger said “stem cell mobilization is highly variable between patients. Mobilize early in the diagnostic course before extensive exposure to marrow toxic drugs or radiation. Consider chemomobilization as part of a salvage regimen—that is, after R-ICE. And consider higher doses of G-CSF, pegylated G-CSF, or the use of plerixafor, if you are not using chemotherapy.”
In the question-and-answer session, he was asked the appropriate wait time to collect stem cells after induction therapy with lenalidomide, bortezomib, and dexamethasone (RVD). “Collect before three or four cycles of RVD, and mandate the use of cyclophosphamide,” he said. When asked what is the longest time stem cells can be kept frozen, he replied, “There is only a 10 to 15 percent loss of viability over five to 10 years. In the contract we have patients sign, we arrange for storage for five years. We have no data beyond five years.”
In an interview, session moderator Andrew Zelenetz, MD, PhD, Chief of the Lymphoma Service at Memorial Sloan-Kettering Cancer Center, commented: “Novel agents, such as lenalidomide and bendamustine, have become more effective induction therapies, but they set up a challenge for stem cell mobilization. Strategies using plerixafor, which has a novel mechanism to mobilize stem cells, can be helpful. Using chemomobilization when it fits well into the treatment paradigm is the preferred approach.”
Cyclophosphamide is an active drug for chemomobilization, he said, and adding it to another drug is the preferred treatment strategy. He said that because of the expense of plerixafor, he agrees that it's appropriate to utilize a “just-in-time” delivery. “Plerixafor adds to the armamentarium. It is useful in situations where a patient is unable to mobilize by conventional measures,” he said.