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Co-provided by The Medical College of Wisconsin.

Physicians' Education Resource®, LLC, is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Physicians' Education Resource®, LLC, designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Acknowledgment of Commercial Support

This activity is supported by an educational grant from Sanofi Genzyme.

Community Practice Connections™: Optimizing Outcomes Through Stem Cell Mobilization: Applying Evidence to Patients With Multiple Myeloma and Non-Hodgkin Lymphoma


Release Date: April 30, 2019
Expiration Date: April 30, 2020
Media: Internet - based

Activity Overview

The treatment landscape for hematologic malignancies such as multiple myeloma and non-Hodgkin lymphoma is evolving at a rapid pace. Hematopoietic stem cell transplantation (HSCT) has remained a cornerstone approach for the management of many patients with these conditions, but questions remain concerning the timing of HSCT use and how newer frontline treatment regimens may influence transplantation decisions. Furthermore, techniques for optimal stem cell mobilization are continuing to be investigated, with the goals of minimizing the burden on the patient and maximizing the likelihood of successful stem cell collection for anticipated procedures.

This continuing medical education activity will help you address these and other challenges that you may be facing with your patients. Featuring commentary from clinical experts in the field of hematopoietic stem cell transplantation, this educational initiative will help you apply the data effectively to the management of your patients who may be candidates for HSCT. Key decision points pertaining to transplantation and stem cell mobilization will be reviewed in depth.

CME Activity Table of Contents

  • Preactivity Questions
  • Considerations for Successful Stem Cell Mobilization
  • Updates on Stem Cell Mobilization and Transplant for Multiple Myeloma
  • Updates in Mobilization of Lymphoid Malignancies
  • Postactivity Questions

Acknowledgement of Commercial Support

This activity is supported by an educational grant from Sanofi Genzyme.

Instructions for This Activity and Receiving Credit

  • You will need to log in to participate in the activity.
  • Each presentation may contain an interactive question(s). You may move forward through the presentation; however, you may not go back to change answers or review audio files/content until you finish the presentation.
  • At the end of the activity, educational content/audio files will be available for your reference.
  • In order to receive a CME certificate, you must complete the activity.
  • Complete the Posttest and pass with a score of 70% or higher, complete the Evaluation, and then click on “Request for Credit.” You may immediately download a CME certificate upon completion of these steps.


Target Audience

This educational program is directed toward hematologists, medical oncologists, and researchers/investigators who treat or are interested in the treatment of hematologic malignancies. Other allied healthcare professionals, including nurse practitioners, physician assistants, and nurses involved in the treatment and management of patients with hematologic malignancies, are also invited to participate.

Learning Objectives

Upon successful completion of this educational program, you should be better prepared to:

  • Describe current strategies for mobilizing CD34-positive cells in patients with MM and NHL prior to transplantation
  • Personalize decision making to optimize outcomes for cell mobilization in the context of mitigating treatment-related toxicities
  • Evaluate recent clinical data regarding emerging strategies to improve outcomes in the mobilization of CD34-positive cells
  • Integrate recent evidence to optimize individualized approaches for autologous stem cell transplantation mobilization among patients with hematologic malignancies

Faculty, Staff, and Planners’ Disclosures

Shaji K. KumarShaji K. Kumar, MD
Professor of Medicine
Consultant, Division of Hematology, Department of Internal Medicine
Mayo Clinic
Rochester, MN
 

Disclosures: Grant Research/Support: AbbVie, Amgen (to institution), Bristol-Myers Squibb, Celgene, Genentech, Kite, MedImmune, Merck, Novartis, Roche-Genentech, Sanofi, Takeda; Consultant: AbbVie, Celgene (with no personal payments), Genentech, Janssen, Kite, MedImmune, Merck, Takeda.


Sergio A. GiraltSergio A. Giralt, MD
Professor of Medicine
Weill Cornell Medical College
Chief Attending Physician, Adult Bone Marrow Transplant Service
Melvin Berlin Family Chair in Myeloma Research
Memorial Sloan Kettering Cancer Center
New York, NY


Paul ShaughnessyPaul Shaughnessy, MD
Program Medical Director
Blood and Marrow Transplant
Texas Transplant Institute
San Antonio, TX
 

Disclosures: Consultant: Advisory Board: Amgen, Sanofi, Takeda; Speakers’ Bureau: Kite, Sanofi, Takeda.


Sergio A. Giralt; the staff of Physicians’ Education Resource®, LLC; and The Medical College of Wisconsin have no relevant financial relationships with commercial interests to disclose.

Disclosure Policy and Resolution of Conflicts of Interest (COI)

As a sponsor accredited by the ACCME, it is the policy of PER® to ensure fair balance, independence, objectivity, and scientific rigor in all of its CME activities. In compliance with ACCME guidelines, PER® requires everyone who is in a position to control the content of a CME activity to disclose all relevant financial relationships with commercial interests. The ACCME defines “relevant financial relationships” as financial relationships in any amount occurring within the past 12 months that creates a COI.

Additionally, PER® is required by ACCME to resolve all COI. PER® has identified and resolved all COI prior to the start of this activity by using a multistep process

Off-Label Disclosure and Disclaimer

This CME activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CME activity is for continuing medical education purposes only, and is not meant to substitute for the independent clinical judgment of a physician relative to diagnostic or treatment options for a specific patient’s medical condition.

The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of The Medical College of Wisconsin; Physicians’ Education Resource®, LLC; or the company that provided commercial support for this activity.

PER Pulse™ Recaps

1 of 3
Considerations for Successful Stem Cell Mobilization

There are several criteria for a successful stem cell collection. It should mobilize a sufficient number of cells capable of prompt and durable hematopoietic reconstitution, and achieve adequate neutrophil and platelet engraftment, with rapid recovery of hematopoietic function.1-3 Based on retrospective data, patients who receive <1 x 106 CD34+ cells/kg have a high incidence of poor platelet recovery, whereas those who receive ≥2 x 106 CD34+ cells/kg have adequate hematopoietic engraftment. The American Society for Blood and Marrow Transplantation and other guideline-issuing organizations have established the latter value as the minimum threshold for transplantation.4,5 The majority of patients receiving >2.5 x 106 CD34+ cells/kg experience durable neutrophil engraftment by day 18, and a level of 5 x 106 CD34+ cells/kg has been associated with rapid platelet engraftment.6,7

Some factors associated with poor mobilization outcomes are an elevated number of cycles/duration of prior chemotherapy, female gender, age ˃60 years, low platelet count, and exposure to such medications as fludarabine, platinum-based chemotherapy, bendamustine, or lenalidomide. Insufficient collection of stem cells may result in several poor outcomes, such as more days of apheresis, bone marrow harvesting, and ineligibility for transplantation. Use of a suboptimal apheresis product may lead to delayed, partial, or failed stem cell engraftment,8 as well as increased need for transfusions.9

Collection of an adequate number of CD34+ cells has been associated with more-rapid recovery of platelet function.10 A retrospective analysis of patients with multiple myeloma or non-Hodgkin lymphoma showed that platelet recovery was robust when the CD34+ cell dose transplant was ≥4 x 106/kg. No significant difference in benefit was shown between groups receiving 4 to 6 x 106 CD34+ cells/kg and those receiving ≥6 x 106 CD34+ cells/kg.11 Successful stem cell mobilization has also been associated with lower transplant-related costs. Patients who undergo transplantation with a quality stem cell mobilization spend less time in the hospital for their transplantations.12

Key Points:

  • New stem cell mobilization strategies for patients with hematologic malignancies may have the potential to lead to not only rapid neutrophil recovery, but also to rapid immune recovery, resulting in a lower risk of relapse.
  • Prior treatment regimens may influence the likelihood of success with subsequent mobilization approaches.
  • Mobilization cellular content has the potential to improve patient outcomes.

References

  1. Champlin RE, Schmitz N, Horowitz MM, et al. Blood stem cells compared with bone marrow as a source of hematopoietic cells for allogeneic transplantation. IBMTR Histocompatibility and Stem Cell Sources Working Committee and the European Group for Blood and Marrow Transplantation (EBMT). Blood. 2000;95(12):3702-3709.
  2. Akkӧk CA, Liseth K, Nesthus I, et al. Autologous peripheral blood progenitor cells cryopreserved with 5 and 10 percent dimethyl sulfoxide alone give comparable hematopoietic reconstitution after transplantation. Transfusion. 2008;48(5):877-883. doi: 10.1111/j.1537-2995.2008.01648.x.
  3. Ali MY, Oyama Y, Monreal J, et al. Reassessing the definition of myeloid engraftment after autotransplantation: it is not necessary to see 0.5 x 10(9)/l neutrophils on 3 consecutive days to define myeloid recovery. Bone Marrow Transplant. 2002;30(11):749-752. DOI: 10.1038/sj.bmt.1703741.
  4. To LB, Haylock DN, Simmons PJ, Juttner CA. The biology and clinical uses of blood stem cells. Blood. 1997;89(7):2233-2258.
  5. Schiller G, Vescio R, Freytes C, et al. Transplantation of CD34+ peripheral blood progenitor cells after high-dose chemotherapy for patients with advanced multiple myeloma. Blood. 1995;86(1):390-397.
  6. Kiss JE, Rybka WB, Winkelstein A, et al. Relationship of CD34+ cell dose to early and late hematopoiesis following autologous peripheral blood stem cell transplantation. Bone Marrow Transplant. 1997;19(4):303-310. DOI: 10.1038/sj.bmt.1700671.
  7. Weaver CH, Hazelton B, Birch R, et al. An analysis of engraftment kinetics as a function of the CD34 content of peripheral blood progenitor cell collections in 692 patients after the administration of myeloablative chemotherapy. Blood. 1995;86(10):3961-3969.
  8. Haas R, Mӧhle R, Frühauf S, et al. Patient characteristics associated with successful mobilizing and autografting of peripheral blood progenitor cells in malignant lymphoma. Blood. 1994;83(12):3787-3794.
  9. Schiller G, Vescio R, Freytes C, et al. Transplantation of CD34+ peripheral blood progenitor cells after high-dose chemotherapy for patients with advanced multiple myeloma. Blood. 1995;86(1):390-397.
  10. Glaspy JA, Shpall EJ, LeMaistre CF, et al. Peripheral blood progenitor cell mobilization using stem cell factor in combination with filgrastim in breast cancer patients. Blood. 1997;90(8):2939-2951.
  11. Stiff PJ, Micallef I, Nademanee AP, et al. Transplanted CD34+ cell dose is associated with long-term platelet count recovery following autologous peripheral blood cell transplant in patients with non-Hodgkin lymphoma or multiple myeloma. Biol Blood Marrow Transplant. 2011;17(8):1146-1153. doi: 10.1016/j.bbmt.2010.11.021.
  12. Stockerl-Goldstein KE, Reddy SA, Horning SF, et al. Favorable treatment outcome in non-Hodgkin's lymphoma patients with "poor" mobilization of peripheral blood progenitor cells. Biol Blood Marrow Transplant. 2000;6(5):506-512. DOI: https://doi.org/10.1016/S1083-8791(00)70021-8.

2 of 3
Updates on Stem Cell Mobilization and Transplant for Multiple Myeloma

The number of patients undergoing stem cell transplantation (SCT) for multiple myeloma (MM) in the United States is increasing. One recent estimation reported more than 8000 transplants for MM/plasma cell disorders, with the majority of these being autologous stem cell transplants (ASCTs).1 The role of upfront ASCT continues to evolve. New medications, such as proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies, have the potential to generate deep responses with initial therapy. Data from the IFM 2009 trial continue to support the role of transplantation. In this study, patients with MM were randomized to receive induction with 3 cycles of RVD (lenalidomide, bortezomib, dexamethasone) consolidation therapy, with either 5 more cycles of RVD or ASCT plus high-dose melphalan followed by 2 more cycles of RVD.2 Patients who underwent transplantation had a significantly greater median progression-free survival than those who did not (50 vs 36 months; HR, 0.65; P <.001). Patients receiving a transplant also had a significantly greater rate of complete response (59% vs 48%; P =.03), as well as a greater percentage of cases where minimal residual disease was not seen (79% vs 65%; P <.001).2 There was no difference in overall survival (OS).2

The introduction of plerixafor was supported by findings from initial studies that demonstrated an increased likelihood of collecting a designated target of 6 x 106 CD34+ cells/kg with a combination of plerixafor and granulocyte colony-stimulating factor (G-CSF) compared with placebo and G-CSF. This advantage was demonstrated on each day of stem cell collection.3,4 When chemotherapy was compared with the combination of growth factor and plerixafor in a retrospective analysis, patients who received cyclophosphamide had lower rates of successful mobilization and collection (78% vs 98%; P <.01); a greater incidence of complications requiring hospitalization (30% vs 2%; P <.01); and greater average cost per patient successfully completing mobilization.5 Studies have also assessed the role of salvage transplantation for patients with MM. In one randomized study of patients with relapsed/refractory MM, patients who received salvage ASCT compared with a chemotherapy-based approach had improved OS at first relapse; delay of ASCT to treatment in the third line or later may not provide the same degree of benefit.6 Repeat mobilization is possible for patients with MM. Multiple aphereses may be required, with regimens involving a combination of G-CSF and plerixafor frequently yielding a successful stem cell collection.7

Guidelines for approaches to stem cell mobilization have been established. Among the key goals are reduction of overall failure rates to below 5%, minimization of mobilization-associated complications, and optimization of resource utilization.8 Pre-apheresis peripheral blood CD34+ cell count monitoring may help to identify poor mobilizers and to trigger additional measures for mobilization enhancement. Upfront steady-state mobilization with plerixafor plus G-CSF may help to reduce the need for remobilization.8 The combination of chemomobilization plus plerixafor plus G-CSF has been studied and is the subject of ongoing clinical investigation.8 With respect to remobilization, the use of cytokine therapy alone has a high likelihood of failure, and incorporation of other options, such as plerixafor and chemomobilization, should be considered.

Key Points:

  • The role of ASCT continues to evolve for patients with MM.
  • Cytokine and chemomobilization regimens have been studied for patients with MM, as well as regimens incorporating plerixafor.
  • Guidelines for approaches to stem cell mobilization have been established that address key goals to optimize outcomes for patients.

References

  1. D'Souza A, Fretham C. Current uses and outcomes of hematopoietic cell transplantation (HCT): CIBMTR summary slides, 2018. Center for International Blood & Marrow Transplant Research website. cibmtr.org. Accessed April 1, 2019.
  2. Attal M, Lauwers-Cances V, Hulin C, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017;376(14):1311-1320. doi: 10.1056/NEJMoa1611750.
  3. DiPersio JK, Stadtmauer EA, Nademanee A, et al. Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma. Blood. 2009;113(23):5720-5726. bloodjournal.org/content/113/23/5720.
  4. Calandra G, McCarty J, McGuirk J, et al. AMD3100 plus G-CSF can successfully mobilize CD34+ cells from non-Hodgkin's lymphoma, Hodgkin's disease and multiple myeloma patients previously failing mobilization with chemotherapy and/or cytokine treatment: compassionate use data. Bone Marrow Transplant. 2008;41(4):331-338. DOI: 10.1038/sj.bmt.1705908.
  5. Costa LJ, Miller AN, Alexander ET, et al. Growth factor and patient-adapted use of plerixafor is superior to CY and growth factor for autologous hematopoietic stem cells mobilization. Bone Marrow Transplant. 2011;46(4):523-528. doi: 10.1038/bmt.2010.170.
  6. Cook G, Ashcroft AJ, Cairns DA, et al; National Cancer Research Institute Haemato-oncology Clinical Studies Group. The effect of salvage autologous stem-cell transplantation on overall survival in patients with relapsed multiple myeloma (final results from BSBMT/UKMF Myeloma X Relapse [Intensive]): a randomised, open-label, phase 3 trial. Lancet Haematol. 2016;3(7):e340-e351. doi: 10.1016/S2352-3026(16)30049-7.
  7. Parrish C, Morris CTCM, Williams CD, et al; National Cancer Research Institute Haemato-Oncology Clinical Studies Group. Stem Cell Harvesting after Bortezomib-Based Reinduction for Myeloma Relapsing after Autologous Transplantation: Results from the British Society of Blood and Marrow Transplantation/United Kingdom Myeloma Forum Myeloma X (Intensive) Trial. Biol Blood Marrow Transplant. 2016;22(6):1009-1016. doi: 10.1016/j.bbmt.2016.01.016.
  8. Giralt S, Costa L, Schriber J, et al. Optimizing autologous stem cell mobilization strategies to improve patient outcomes: consensus guidelines and recommendations. Biol Blood Marrow Transplant. 2014;20(3):295-308. doi: 10.1016/j.bbmt.2013.10.013.

3 of 3
Updates in Mobilization of Lymphoid Malignancies

Stem cell transplantation (SCT) may be used for a wide variety of lymphoid malignancies, including aggressive B-cell non-Hodgkin lymphoma (NHL), follicular NHL, mantle cell lymphoma (MCL) in first complete remission, peripheral T-cell lymphoma in first complete remission, and Hodgkin lymphoma (HL). Patients with these malignancies may have different treatment histories and salvage therapies that may impact timing and ability to mobilize autologous hematopoietic stem cells. Patients with recurrent diffuse large B-cell lymphoma (DLBCL) may have a poor prognosis, even with aggressive salvage and autologous stem cell transplantation (ASCT). If patients are chemosensitive to salvage therapy, survival outcomes are better than those for patients who are chemoresistant.1,2 Chimeric antigen receptor (CAR) T-cell therapy is being evaluated in the management of patients with DLBCL as an alternative to ASCT.

Currently, chemotherapy stem cell mobilization approaches for patients with NHL do not differ significantly from cytokine stem cell mobilization approaches with respect to disease-free survival (DFS) or overall survival (OS) outcomes.3-5 The choice of mobilization approaches, as with multiple myeloma (MM), often depends on patient-related and logistical factors. Center-specific capabilities are also factors, including the ability to obtain flow cytometry results of peripheral blood CD34+ cell counts, weekend staffing after chemomobilization, and familiarity of staff with tracking and planning different mobilization regimens.

Several retrospective studies have compared chemotherapy versus cytokine-based mobilization strategies. A recent study from the University of Wisconsin and the University of West Virginia retrospectively evaluated standard RICE (rituximab, ifosfamide, carboplatin, etoposide) chemotherapy mobilization versus a scheduled granulocyte colony-stimulating factor (G-CSF)/plerixafor mobilization versus an algorithm-based plerixafor mobilization for patients with HL and NHL. In this study, more stem cells were collected in the group receiving chemotherapy mobilization; however, this group was younger and less heavily treated than the other groups of patients.6 Ultimately, no differences in DFS or OS were seen in this study.6

There is concern that some chemotherapy agents may have a negative impact on stem cell mobilization for patients with lymphoid malignancies. Bendamustine has been shown to adversely affect stem cell mobilization in patients with MCL.7,8 Other agents, such as bortezomib, may actually facilitate stem cell mobilization for patients with MCL.9 Paclitaxel may be an option to consider, as well.10

Key Points:

  • The method of mobilization may not ultimately influence survival outcomes.
  • Chemomobilization may be best for patients with lymphoid malignancies when the chemotherapy is incorporated into the treatment regimen.

References

  1. Crump M, Neelapu S, Farooq U, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood. 2017;130(16):1800-1808. doi: 10.1182/blood-2017-03-769620.
  2. Van Den Neste E, Schmitz N, Mounier N, et al. Outcome of patients with relapsed diffuse large B-cell lymphoma who fail second-line salvage regimens in the International CORAL study. Bone Marrow Transplant. 2016;51(1):51-57. doi: 10.1038/bmt.2015.213.
  3. Dazzi C, Cariello A, Rosti G, et al. Is there any difference in PBPC mobilization between cyclophosphamide plus G-CSF and G-CSF alone in patients with non-Hodgkin's lymphoma? Leuk Lymphoma. 2000;39(3-4):301-310.
  4. Narayanasami U, Kanteti R, Morelli J, et al. Randomized trial of filgrastim versus chemotherapy and filgrastim mobilization of hematopoietic progenitor cells for rescue in autologous transplantation. Blood. 2001;98(7):2059-2064. https://doi.org/10.1182/blood.V98.7.2059.
  5. Pusic I, Jiang SY, Landua S, et al. Impact of mobilization and remobilization strategies on achieving sufficient stem cell yields for autologous transplantation. Biol Blood Marrow Transplant. 2008;14(9):1045-1056. doi: 10.1016/j.bbmt.2008.07.004.
  6. Dhakal B, Veltri LW, Fenske TS, et al. Hematopoietic progenitor cell mobilization with ifosfamide, carboplatin, and etoposide chemotherapy versus plerixafor-based strategies in patients with Hodgkin and non-Hodgkin lymphoma. Biol Blood Marrow Transplant. 2016;22(10):1773-1780. doi: 10.1016/j.bbmt.2016.06.016.
  7. Alahwal H, Chapani P, Villa D, et al. Bendamustine adversely affects stem cell mobilization among patients with mantle cell lymphoma (MCL): a comparison of the BR Vs RCHOP eras in British Columbia (BC), Canada. Blood. 2018;132(suppl 1):4556. bloodjournal.org/content/132/Suppl_1/4556.
  8. Greenbaum AM, Geen DJ, Holmberg LA, et al. Bendamustine, etoposide, and dexamethasone to mobilize peripheral blood hematopoietic stem cells for autologous transplantation in non-Hodgkin lymphoma. Blood Res. 2018;53(3):223-226. doi: 10.5045/br.2018.53.3.223.
  9. Abhynakar S, Lubanski P, DeJarnette S, et al. A novel hematopoietic progenitor cell mobilization regimen, utilizing bortezomib and filgrastim, for patients undergoing autologous transplant. J Clin Apher. 2016;31(6):559-563. doi: 10.1002/jca.21449.
  10. McKibbin T, Burzynski J, Greene R, et al. Paclitaxel and filgrastim for hematopoietic progenitor cell mobilization in patients with hematologic malignancies after failure of a prior mobilization regimen. Leuk Lymphoma. 2007;48(12):2360-2366. https://doi.org/10.1080/10428190701665970.

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