Mobilization in 80% Patients on First-Line Plerixafor

Becky McCall

June 21, 2012

June 21, 2012 (Amsterdam, the Netherlands) — The mobilization of stem cells for transplantation with plerixafor (Mozobil, Genzyme) in patients with lymphoma and myeloma improved the yield of cells with no neutropenia.

"It's clear to us that patients get a better deal when harvested with plerixafor" and G-granulocyte colony-stimulating factor (G-CSF) than with G-CSF and chemotherapy, Richard Clark, MD, consultant hematologist and professor of hematology at the University of Liverpool in the United Kingdom, told Medscape Medical News.

Dr. Clark, who runs the stem cell transplant program for the Merseyside region in the United Kingdom, presented interim results of the PHANTASTIC (Plerixafor Harvesting and No Chemotherapy for Autologous Stem Cell Transplantation in Cancer) trial here at the 17th Congress of the European Hematology Association.

"Ideally, we want at least 4.0 × 106 CD34+ cells/kg; we can achieve that in 1 or 2 harvest collections with plerixafor in 80% of patients, compared with 55% of historic controls," Dr. Clark explained. "If you are prepared to do up to 4 harvests, then 98% of patients deliver the required number of cells."

Plerixafor is already licensed for use in patients who have failed an attempt to mobilize stem cells with chemotherapy and growth factor. "The main concern with conventional chemotherapy is that it causes hair loss, nausea, and white cells to drop to dangerous levels," Dr. Clark said.

"We found that plerixafor has almost no side effects. It worked and the white cell count never dropped in second-line use; this was in the more difficult patients, too. So we decided to investigate its use as a first-line agent."

In Europe, plerixafor is indicated "in combination with G-CSF to enhance mobilization of hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with lymphoma and multiple myeloma whose cells mobilize poorly."

However, Dr. Clark pointed out that if a clinician decides that a certain patient will mobilize poorly, first-line plerixafor use is within the license.

Interim Results

The PHANTASTIC trial involves 100 patients, but the interim results presented cover only the first 60 patients. Recruitment of 100 patients was completed just last week. Participants had myeloma or lymphoma (typical of autograft practice), were older than 18 years, and were eligible for the study if they were undergoing a first-line attempt at autograft.

The primary end point reflected the problem associated with patients receiving conventional chemotherapy plus G-CSF who were hospitalized for neutropenia. The composite primary end point incorporated both an adequate stem cell harvest (at least 4.0 × 106 CD34+ cells/kg in 1 or 2 harvests) and no evidence of clinically important low neutrophils (less than 1.0 × 109 cells/L in the 3 weeks after starting mobilization).

The protocol was similar to that used in the second-line setting — G-CSF 5 µg/kg was given on days 1 to 4 and plerixafor was given on day 4, with a dose reduction in patients with renal impairment. Harvesting was carried out on day 5 and, if necessary, on days 6, 7, and 8, with continuation of G-CSF and plerixafor until the target yield was achieved.

"Plerixafor loosens the attachment of stem cells to the marrow stroma. The number of stem cells mobilized is maximal 10 to 16 hours after the dose, which is when we collect. We repeat this the following day if we don't get enough," Dr. Clark explained.

The comparator group of historic control subjects comprised 152 patients with lymphoma and myeloma harvested for stem cells since 2006. The majority of these patients had received cyclophosphamide (because myeloma patients only receive cyclophosphamide) before commencing mobilization. Lymphoma patients received either salvage chemotherapy or cyclophosphamide.

Results showed that patients on plerixafor experienced no serious adverse events, whereas 16 patients in the control group were hospitalized for neutropenic fever. Plerixafor caused mild gastrointestinal upset in a minority of patients.

The primary end point was achieved by 80% of patients without neutropenia and by 32% of the control group (P < .0001). "A large proportion of the control group failed to reach the primary end point because they did not have enough cells [22% failed to reach the minimum of 2.0 × 106 CD34+ cells/kg]; some of those who did reach a sufficient number of cells became seriously neutropenic," Dr. Clark reported.

"Of the patients who failed chemotherapy mobilization, some yielded no cells and became sick in the process, so we decided not to repeat the attempt," Dr. Clark noted. Some did try again, but failed," he added. He has not yet determined whether those who had successful mobilization in a second round fared differently on actual transplantation.

There was a big difference between the plerixafor and control groups in the ability to yield the required number of cells in 2 harvests (85% vs 60%). The same was true for the ability to yield the required number of cells in 4 harvests (87% vs 68%).

A similar number of patients progressed to transplantation in the plerixafor and control groups (82% vs 81%). However, "45 of the control patients required at least 2 harvests, so there is a subset that really struggled to harvest," said Dr. Clark.

Better Mobilization, Less Neutropenia

Paul Shaughnessy, MD, director of adult BMT at the Texas Transplant Institute in San Antonio, noted that the interim results are important because they demonstrate that plerixafor and G-CSF can mobilize adequate stem cells for autologous transplantation.

"In fact, plerixafor and G-CSF mobilized more stem cells than the chemotherapy-mobilized historic controls. Very importantly, this trial shows that the plerixafor-mobilized patients had less neutropenia, and therefore less risk for complications or serious infection," he emphasized.

"Also, more patients who were chemotherapy-mobilized required subsequent remobilization or bone marrow harvesting," he noted.

Engraftment times were the same for both groups; it took 12 days for neutrophils to reach 0.5 × 109/L and 21 days for platelets to reach 50 × 109/L. "This study and others have demonstrated no difference in engraftment or transplant outcomes, so avoiding excessive toxicity or a delay in proceeding to transplantation are important advantages of plerixafor/G-CSF mobilization," Dr. Shaughnessy said.

He concluded that chemotherapy might always have a role in the salvage therapy of cancer patients, but might not always be warranted just to mobilize stem cells.

Dr. Clark reports receiving research funding from Novartis, Bristol-Myers Squibb, and Sanofi/Genzyme; being on the speakers bureau for Novartis; and been an advisor to Novartis, Bristol-Myers Squibb, Pfizer, and Sanofi/Genzyme. Dr. Shaughnessy reports previously receiving honoraria from Therakos, Genzyme, PDL Biopharma, and Otsuka.

17th Congress of the European Hematology Association (EHA): Abstract 1767, poster 0284. Presented 17 June 17, 2012.

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