Stem Cell Mobilization and Collection in Autologous Stem Cell Transplantation

Activity Faculty Luciano J. Costa, MD, PhD Associate Professor of Medicine Department of Medicine and UAB-CCC Bone Marrow Transplantation and Cell Therapy Program School of Medicine University of Alabama at Birmingham Birmingham, AL

Learning Objectives Upon completion, participants should be able to: Identify factors that place patients at risk of poor AHSC mobilization, thereby requiring guideline-recommended mobilization protocols Apply guideline-based strategies that optimize first-attempt stem cell mobilization and collection in patients undergoing AHSC transplantation

Key Considerations in Mobilization for AHSC Transplant Three key overarching concepts are presented in this activity. First, the rate of success of autologous hematopoietic stem cell (AHSC) transplants in patients with hematologic malignancies such as multiple myeloma (MM) and non-Hodgkin’s lymphoma (NHL) has increased over the last several years with the advent of AHSC mobilization regimens such as chemotherapeutic agents, growth factors, and novel agents such as plerixafor. Second, not all patients with hematologic malignancies have success with current mobilization regimens because of risk factors such as prior high-dose chemotherapy, prior radiotherapy, or comorbidities such as diabetes. Third, it is important to become familiar with current guidelines and recommendations for AHSC mobilization so that these recommendations can be applied to practice to help optimize the success of AHSC mobilization and transplant and to improve patient outcomes. We have highlighted practice pearls related to these points on various slides in this activity. Mobilization of AHSCs using chemotherapy, growth factors, and novel agents has increased the success rates of AHSC transplants Risk factors for poor AHSC mobilization include prior chemotherapy, radiotherapy, age, low platelet count before mobilization, and diabetes New guidelines exist to help optimize mobilization regimens and increase the success of AHSC transplant

Mobilization Regimens for AHSC Transplant Several regimens are used in the mobilization of hematopoietic stem cells (HSCs) for autologous transplant. These agents are known to disrupt adhesive properties and induce the proliferation of HSCs, leading to an increase in circulating HSCs.1 High-dose chemotherapy has also been shown to prolong progression-free survival and overall survival when administered to patients with MM prior to AHSC transplant.2,3 Several of the most common regimens for chemomobilization of AHSCs are shown here. Common side effects of these regimens include general malaise and fatigue, gastrointestinal issues, myelosuppression, and skin and mucosal effects.4 REFERENCES Morrison SJ, et al. Proc Natl Acad Sci U S A. 1997;94:1908-13. Attal M, et al. N Engl J Med. 1996;335:91-7. Child JA, et al. N Engl J Med. 2003;348:1875-83. Hopman RK, et al. Blood Rev. 2014;28:31-40. Chemomobilization ICE (ifosfamide, carboplatin, etoposide) ± rituximab DHAP (dexamethasone, cytarabine, cisplatin) ± rituximab ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin) ± rituximab Single-agent chemotherapy: cyclophosphamide, etoposide Child JA, et al. N Engl J Med. 2003;348:1875-83; Hopman RK, et al. Blood Rev. 2014;28:31-40.

Mobilization Regimens for AHSC Transplant Myeloid growth factors such as granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are also used for AHSC mobilization.1 G-CSF is the most commonly used agent for AHSC mobilization and has been shown to lead to greater yields of AHSCs, shorter time to platelet/neutrophil recovery, and shorter hospital stays. The most common dose of G-CSF is a subcutaneous injection of 10 µg/kg/day, with apheresis being initiated on day 5.1 Common adverse events associated with cytokine mobilization include bone pain, headache, thrombocytopenia, increased liver enzymes, and elevated lactate dehydrogenase.1,2 Plerixafor, a CXCR4 antagonist, is approved for HSC mobilization in combination with G-CSF.1,2 In early studies, a single injection of plerixafor was shown to increase the number of circulating CD34+ cells by 6 fold.2 Common adverse events associated with plerixafor include gastrointestinal issues and injection-site reactions.2 REFERENCES 1. Motabi IH, et al. Blood Rev. 2012;26:267-78. 2. Hopman RK, et al. Blood Rev. 2014;28:31-40. Plerixafor Approved by the FDA in 2008 in combination with G-CSF for AHSC mobilization in MM and NHL Reversible CXCR4 antagonist Cytokines G-CSF GM-CSF Motabi IH, et al. Blood Rev. 2012;26:267-78.

Mobilization Guidelines—Algorithm Recently released guidelines for the mobilization of HSCs detail the recommended collection targets and dosages for AHSC transplant.1 The ultimate goal of mobilization should be to collect enough HSCs for a successful transplant. As depicted in this algorithm, G-CSF is a first-line mobilization option because its kinetics are well understood. If mobilization with a G-CSF alone yields a sufficient number of CD34+ cells, apheresis should be started after 4 days of G-CSF treatment. Of note, mobilization with standard doses of G-CSF (5-16 µg/kg/day) has been associated with higher rates of mobilization failure (up to 38%), whereas mobilization with higher doses (up to 40 µg/kg/day) shows improved HSC yields, but with increased cost and toxicity.1 If patients have mobilized poorly with a G-CSF (as indicated by a pre-apheresis peripheral blood (PB) CD34+ cell count of < 10 to 20 cells/µL), plerixafor may be given preemptively, “just in time”; this approach has been shown to decrease the rate of mobilization failure from about 22% (with chemomobilization and G-CSF) to 2%.2 REFERENCES Giralt S, et al. Biol Blood Marrow Transplant. 2014;20:295-308. Costa LJ, et al. Bone Marrow Transplant. 2011;46:523-8. Giralt S, et al. Biol Blood Marrow Transplant. 2014;20:295-308; Costa LJ, et al. Bone Marrow Transplant. 2011;46:523-8.

First-Line Mobilization Strategies: What Do the Guidelines Say? Guidelines released in 2014 by the American Society for Blood and Marrow Transplantation (ASBMT) suggest that patients with MM or NHL who have a low risk of mobilization failure be mobilized with steady-state G-CSF, although this regimen may have a higher failure rate in patients with NHL than in those with MM.1 In either case, plerixafor should be added preemptively if the patient has a low PB CD34+ cell count.1 Chemomobilization is an appropriate strategy, either as initial planned therapy or as salvage therapy.1 REFERENCE Giralt S, et al. Biol Blood Marrow Transplant. 2014;20:295-308. “For patients with MM: Steady-state mobilization with G-CSF alone in doses of 10-16 μg/kg/day is an option, but should be limited to patients with no more than 1 previous line of therapy, not previously treated with melphalan or > 4 cycles of lenalidomide; in such patients, PB CD34+ cell count monitoring with preemptive plerixafor will allow for successful collection in the vast majority of patients For patients with NHL: Steady-state mobilization with G-CSF alone in doses of 10-16 μg/kg/day, although associated with higher failure rates in some patient populations, may be an option owing to low toxicity and ease of scheduling; it should be limited to those at low risk for mobilization failure; again, PB CD34+ count monitoring with preemptive plerixafor will allow successful collection in the vast majority of patients CM, either incorporated into the initial 3 to 6 cycles of planned chemotherapy or as part of a salvage regimen, is appropriate” Giralt S, et al. Biol Blood Marrow Transplant. 2014;20:295-308.

Target vs. Ideal The recommended target for stem cell collection is 3-5 x 106 cells/kg, and the lowest recommended dose of stem cells for AHSC transplant is 2 x 106 cells/kg.1 However, when the benefit of an AHSC transplant for certain patients is “sufficiently compelling,” AHSC transplant may be attempted with 1-2 x 106 cells/kg, based on individual patient circumstances and clinical parameters.1 Although guidelines do exist for minimum yields and doses of HSCs (as depicted in the algorithm on the previous slide), ideal target numbers are not as clear, and there is some variation in the number of cells that each center feels is ideal to proceed to AHSC transplant.1.2 When interviewed, a small set of transplant specialists stated that the ideal number of cells for an AHSC transplant is anywhere from 2.5 to 5 million cells.3 Higher numbers of cells may lead to faster engraftment times, but a balance must be maintained between target numbers and the number and length of apheresis sessions.1 Of course, higher targets must be met if more than one AHSC transplant is to be attempted. In these cases, the target number of cells for collection should be twice that of a single transplant.1 REFERENCES 1. Giralt S, et al. Biol Blood Marrow Transplant. 2014;20:295-308. 2. Costa LJ, et al. Bone Marrow Transplant. 2011;46:523-8. 3. Med-IQ In-Practice Research, 2014. Recommended target for stem cell collection is 3-5 x 106 cells/kg Minimum recommended dose of AHSCs for transplant is 2 x 106 cells/kg Ideal target numbers for AHSC transplant are less clear Practice Pearl: the ideal number of AHSCs varies among transplant centers Giralt S, et al. Biol Blood Marrow Transplant. 2014;20:295-308; Med-IQ In-Practice Research, 2014.

Risk Factors for Poor Mobilization Many risk factors may result in poor mobilization of AHSCs, several of which are listed here, and the most common of which is previous exposure to myelotoxic chemotherapeutic agents.1 Radiation therapy administered before AHSC mobilization is also a risk factor.2 Some patients may have a low bone marrow reserve as a result of prior chemotherapy, radiation therapy, or other factors, which can be indicated by a low platelet count, low bone marrow cell count, or low PB CD34+ cell count.1-3 Increased age is also a consistent risk factor for poor mobilization.1-3 Patients with diabetes or impaired glucose tolerance may also have a risk of poor AHSC mobilization.1,2,4 Although the mechanism is not completely understood, baseline CD34+ cell counts are thought to be diminished in these patients. Although risk factors such as these are clues that patients may have a risk of poor mobilization, it is often difficult in practice to predict whether a patient will mobilize poorly.3 Therefore, alternative strategies for minimizing mobilization failure are needed. REFERENCES Motabi IF, et al. Blood Rev. 2012;26:267-78. Hopman RK, et al. Blood Rev. 2014;28:31-40. Giralt S, et al. Biol Blood Marrow Transplant. 2014;20:295-308. Fadini GP, et al. Diabetologia. 2007;50:2156-63. Prior chemotherapy with lenalidomide, melphalan, platinum-containing agents, alkylating agents, fludarabine, etc. Previous radiotherapy Age Low bone marrow reserve Low cellularity Low platelet count Low PB CD34+ count Comorbidities such as diabetes Motabi IF, et al. Blood Rev. 2012;26:267-78; Hopman RK, et al. Blood Rev. 2014;28:31-40; Fadini GP, et al. Diabetologia. 2007;50:2156-63; Giralt S, et al. Biol Blood Marrow Transplant. 2014;20:295-308.

Frontline Perspectives One strategy to decrease the risk of poor HSC mobilization is the “preemptive” or “just-in-time” administration of plerixafor. Using this approach, patients are initially mobilized with chemotherapy or G-CSF, and pre-apheresis PB CD34+ cell counts (which are predictive of collection yield) are monitored. If cell counts after initial mobilization are not sufficient, plerixafor is administered.1 This strategy has been shown to reduce the failure rates that are seen with chemomobilization or growth factor alone.1 In a recent survey of HSC transplant specialists, two-thirds of physicians interviewed said that patients with risk factors for poor mobilization such as prior chemotherapy or diabetes are given growth factor plus planned plerixafor.2 The remaining one-third said that they do not treat patients with risk factors any differently than those without risk factors. However, these physicians stated that they do monitor all patients’ PB CD34+ counts after mobilization with growth factor and administer plerixafor “just-in-time” if needed, thereby minimizing rates of mobilization failure. REFERENCES Costa LJ, et al. Bone Marrow Transplant. 2011;46:64-9. Med-IQ In-Practice Research, 2014. “So if someone had prior—especially pelvic—radiation, then I would consider that a risk factor. Multiple lines of prior chemotherapy, especially purine analogs like fludarabine. If they’ve had a lot of the alkylators over time. Our group found that diabetes seems to cause poor mobilization, too... [In] some of those, we might just do [plerixafor] from the get-go, plan on it, and not do the just-in-time where you add it in when you need to.” “[We] will add plerixafor if they have been heavily pretreated with chemo.” Med-IQ In-Practice Research, 2014.

Mobilization Failure Traditionally, mobilization failure occurs in as many as 38% of patients with MM who are mobilized with standard doses of growth factor alone.1 Higher doses of growth factor can increase the chance of mobilization success, but are associated with higher costs and increased toxicity.1 With the advent of plerixafor, however, rates of HSC mobilization failure have decreased.1 In a recent survey, nearly all AHSC transplant specialists interviewed reported that their rates of mobilization failure in patients with MM were “negligible.”2 Of note, rates of mobilization failure were reported to be slightly higher (between 10% and 15%) in patients with NHL, even with the addition of plerixafor.2 This may be because poor mobilization is more common in patients with NHL that in patients with other hematologic malignancies; in a univariate analysis, patients with NHL who were mobilized with G-CSF alone failed to mobilize adequately 62% of the time.3 REFERENCES Giralt S, et al. Biol Blood Marrow Transplant. 2014;20:295-308. Med-IQ In-Practice Research, 2014. Hosing C, et al. Am J Hematol. 2009;84:335-7. Practice Pearl: since the advent of plerixafor, mobilization failure is almost nonexistent in MM patients and has decreased greatly in NHL patients “Plerixafor has contributed almost 100% to increased success [of AHSC mobilization].” Giralt S, et al. Biol Blood Marrow Transplant. 2014;20:295-308; Med-IQ In-Practice Research, 2014.

Remobilization Cytokines alone are insufficient When initial mobilization fails and an insufficient number of cells are collected for an AHSC transplant, attempts to remobilize HSCs must be made. If a patient has mobilized poorly on a cytokine regimen, that same regimen will usually be insufficient to mobilize enough cells during subsequent attempts.1 Even combinations of growth factors, although less expensive than high-dose G-CSF, have a failure rate of about 82% when used to remobilize HSCs.1 Historically, chemomobilization has been recommended for remobilization attempts, but the failure rate is still approximately 74%. Attempts to harvest HSCs from bone marrow, which are sometimes used as a last resort, are expensive, difficult for patients, and rarely successful.1 ASBMT guidelines state that cytokines alone should not be used for remobilization, but that plerixafor should be added to G-CSF or G-CSF/chemotherapy regimens in patients who have already failed a non-plerixafor–containing regimen.1 The addition of plerixafor may be helpful even when patients have failed plerixafor-containing regimens in the past. REFERENCE Giralt S, et al. Biol Blood Marrow Transplant. 2014;20:295-308. Cytokines alone are insufficient Remobilization with chemotherapy has historically been used Obtaining cells from bone marrow is a rarely used option Guidelines recommend using plerixafor (with either G-CSF or G-CSF + chemo) to remobilize Remobilization with chemotherapy is an acceptable strategy Giralt S, et al. Biol Blood Marrow Transplant. 2014;20:295-308.

Frontline Perspectives on Remobilization In a 2014 survey, specialists cited several different methods for remobilizing their patients. Interestingly, approximately one-half of those interviewed said that they approach remobilization the same way that they approach initial mobilization, whereas approximately 17% move on to use chemotherapeutic agents. Only about one-third of those interviewed indicated that they use a higher dose of G-CSF plus planned plerixafor for remobilization. These differences in remobilization methods suggest that it may be particularly useful to disseminate new recommendations made in recently published treatment guidelines on patients who are poor mobilizers.1 REFERENCE Med-IQ In-Practice Research, 2014. One-half of specialists said that they use the same protocol that is used for initial mobilization One-third use high-dose G-CSF plus planned plerixafor Approximately 17% use chemomobilization Med-IQ In-Practice Research, 2014.

Frontline Perspectives Although specific guidelines regarding HSC target numbers, doses of HSCs and mobilization agents, initial mobilization strategies, prevention of mobilization failure, and remobilization strategies do exist, ASBMT guidelines state that it is important that each transplant center “develop and implement its own algorithms for applying various mobilization strategies, with the goal of optimizing collection yields.”1 In a 2014 study, all specialists interviewed stated that they do not follow one specific set of guidelines, but noted that their respective centers have their own protocols and internal standard operating procedures.2 REFERENCES Giralt S, et al. Biol Blood Marrow Transplant. 2014;20:295-308. Med-IQ In-Practice Research, 2014. Practice Pearl: to optimize the yield of HSCs, each transplant center should use a mobilization regimen based on algorithms developed at their own centers “We follow the spirit of the guidelines.” Giralt S, et al. Biol Blood Marrow Transplant. 2014;20:295-308; Med-IQ In-Practice Research, 2014.

Key Considerations in Mobilization for AHSC Transplant Several options are available for the mobilization of AHSCs. It is important to recognize risk factors for poor mobilization so that efforts can be optimized to ensure greater success with AHSC transplants. The recommendations and guidelines described in this activity may be helpful in determining which strategies might work best for your center and for your patients. Mobilization of AHSCs using chemotherapy, growth factors, and novel agents has increased the success rate of AHSC transplants Risk factors for poor AHSC mobilization include prior chemotherapy, radiotherapy, age, low platelet count before mobilization, and diabetes New guidelines exist to help optimize mobilization regimens and increase the success of AHSC transplant

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