Granulocyte Colony-Stimulating Factor-Based Stem Cell Mobilization ...

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ABSTRACT. Granulocyte colony-stimulating factor (G-CSF) has been reported to exacerbate vaso-occlusive crises in sickle cell disease. It has been ...
Biology of Blood and Marrow Transplantation 14:719-723 (2008) Q 2008 American Society for Blood and Marrow Transplantation 1083-8791/08/1406-0001$32.00/0 doi:10.1016/j.bbmt.2008.03.001

Granulocyte Colony-Stimulating Factor-Based Stem Cell Mobilization in Patients with Sickle Cell Disease Cara Rosenbaum,1 David Peace,2 Elizabeth Rich,1 Koen Van Besien1 1

Section of Hematology/Oncology, Department of Medicine and Cancer Research Center, 2 Division of Hematology/Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois Correspondence and reprint requests: Koen Van Besien, MD, The University of Chicago, Section of Hematology/Oncology, 5841 S. Maryland Avenue, MC-2115, Chicago, IL 60637 (e-mail: [email protected]. uchicago.edu). Received November 17, 2007; accepted March 3, 2008

ABSTRACT Granulocyte colony-stimulating factor (G-CSF) has been reported to exacerbate vaso-occlusive crises in sickle cell disease. It has been recommended to avoid its use for stem cell mobilization in this population, yet autologous transplant is the standard of care and at times a life-saving treatment for patients with various hematologic malignancies such as relapsed aggressive lymphoma or multiple myeloma. We report 5 cases of patients with sickle cell disease and related hemoglobinopathies who underwent granulocyte-colony stimulating factor (G-CSF)-mobilization of peripheral blood stem cells (PBSC). Three of them developed manageable vasoocclusive pain symptoms requiring parenteral narcotics alone. The 2 others had no complications. These cases demonstrate that stem cell mobilization using G-CSF, although complicated and not without risk, is feasible in patients with sickle cell syndromes.

Ó 2008 American Society for Blood and Marrow Transplantation

KEY WORDS Stem cell mobilization  Granulocyte colony stimulating factor  Sickle cell disease

INTRODUCTION The feasibility of stem cell mobilization in sickle cell disease (SCD) has been questioned, as granulocyte colony-stimulating factor (G-CSF) can exacerbate vaso-occlusive crises (VOC) [1-3]. We report our experience of 5 adults in total: 4 with hemoglobin SS (HbSS), and 1 with hemoglobin SC (HbSC) disease who underwent G-CSF mobilization followed by peripheral blood stem cell (PBSC) collection either prior to receiving an autologous stem cell transplant (autoSCT) for relapsed lymphoma or as back-up for a planned allogeneic stem cell transplant (allo-SCT) for severe SCD. Patients

The clinical features of the 5 patients at presentation and during mobilization are shown in Table 1. All patients participated in institutional review board-approved studies, and consents to collect mobilized PBSCs were obtained that explained the risks of the procedure. Apheresis was performed ac-

cording to standards for autologous [4] or normal donor [5] collection. A brief description of each patient follows. Patient 1

A 40-year-old woman with HbSS disease complicated by frequent VOC and severe end-organ damage including end-stage renal disease underwent back-up autologous PBSC collection prior to planned alloSCT. She received G-CSF 5 mg/kg twice daily for 3 consecutive days. On day 3 (d3), outpatient leukapheresis was performed with a peak WBC count of 41  109/L and peripheral blood (PB) CD341 count of 25.3/mL. During the procedure, she became hypertensive and developed generalized bone pain requiring a 24-hour hospitalization. The following day, her hypertension and symptoms resolved and leukapheresis was successful with WBC and PB CD341 counts of 34  109/L and 22.8/mL, respectively, resulting in a combined 2-day yield of 3.29  106/kg CD341 cells. 719

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Table 1. Clinical Characteristics of Patients with Hemoglobinopathies at Presentation and during PBSC Mobilization with G-CSF Patient no. 1

Patient no. 2

Patient no. 3

Patient no. 4

Patient no. 5

Indication for mobilization

Back-up autologous stem cell collection for allo-SCT

Back-up autologous stem cell collection for allo-SCT

Back-up autologous stem cell collection for allo-SCT

Back-up autologous stem cell collection for allo-SCT

Auto-SCT for Hodgkin lymphoma

Type of SCD

HbSS

HbSC

HbSS

HbSS

HbSS

Significant comorbidities

1. End-stage renal disease (peritoneal dialysis) 2. Pulmonary hypertension 3. Transfusion-related red blood cell antibodies

1. Pulmonary emboli 2. Pulmonary/cerebral infarctions 3. Avascular necrosis hips, shoulders 4. Proliferative retinitis 46

1. 2. 3. 4. 5.

1. 2. 3. 4. 5.

1. Hodgkin’s lymphoma 2. Peripartum cardiomyopathy 3. HIT 4. Pulmonary embolism

Hemoglobin S level (%), NA pre-apheresis Peak WBC on G-CSF, x109/L 40.9 Peak CD341 cells/mL 25.3 peripheral blood CD341 cells, x106/kg apheresis 3.29 product No. days of collection 2 Complications of G-CSF 1. Generalized bone pain, mild mobilization 2. Hypertension Hospitalization Yes

ACS Decreased DLCO Multiple transfusions Iron overload Splenomegaly/splenic infarcts 75

ACS/TIAs Narcotic dependence Iron overload Degenerative hip disease Transfusion-related red blood cell antibodies 25

14.4

53 16.38

44.1 23.54

105 68.25

10 307

1.63

2.29

7.01

28.6

2 None

2 None

No

No

2 Headaches, moderate Yes

1 Bone pain, moderate Yes

PBSC indicates peripheral blood stem cell; SCD, sickle cell disease; alloSCT, allogeneic stem cell transplant; NA, not available; ACS, acute chest syndrome; TIA, transient ischemic attack; autoSCT, autologous stem cell transplant; HIT, heparin-induced thrombocytopenia.

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Patient 2

A 56-year-old woman with HbSC disease complicated by frequent VOC, recurrent pulmonary emboli, cerebral infarcts, avascular necrosis of bilateral hips and shoulders, and proliferative retinitis underwent back-up autologous PBSC collection prior to planned allo-SCT. HbS and HbC levels were 46% and 47%, respectively. She received G-CSF 5 mg/kg twice daily for 3 consecutive days. The WBC count was 53  109/L and PB CD341 count 16.38/mL on the first day of collection, with 1.63  106/kg CD341 cells in total collected over 2 days. No complications related to mobilization occurred. Patient 3

An 18-year-old woman with HbSS disease complicated by numerous VOC, recurrent episodes of pneumonia, acute chest syndrome (ACS), and frequent transfusions underwent back-up autologous PBSC collection prior to planned allo-SCT. HbS level was approximately 75% prior to receiving G-CSF 5 mg/kg twice daily for 3 days followed by 2 days of outpatient leukapheresis. On collection day 1, the WBC count was 44.1  109/L and PB CD341 count 21.52/mL, which peaked at 23.54/mL on d2. A 2-day collection yielded 2.29  106/kg CD341 cells. No complications related to mobilization occurred. She subsequently underwent allo-SCT but rejected the graft. On d30, the previously collected autologous stem cells were infused because of persistent pancytopenia and graft failure. Autologous recovery occurred 10 days after infusion of back-up stem cells. Patient 4

A 23-year-old woman with HbSS disease and frequent VOC complicated by episodes of ACS and transient ischemic attacks underwent back-up autologous PBSC collection prior to planned allo-SCT. G-CSF 5 mg/kg twice daily was started although mild vaso-occlusive pain developed requiring hospitalization. HbS level was 25%. Subsequently, G-CSF was briefly held for bifrontal headaches attributed to leukocytosis with a WBC count of 60  109/L. Harvest was unsuccessful as the PB CD341 count was negligible. Her headaches resolved and G-CSF was restarted at 5 mg/kg daily. Six days later, leukapheresis was performed with a peak WBC count of 105  109/L and PB CD341 count of 68.25/mL. Two days of collection yielded a total of 7.01  106/kg CD341 cells. Patient 5

A 30-year-old woman with HbSS disease and recurrent Hodgkin lymphoma (HL) underwent chemo-

therapy-based stem cell mobilization prior to planned auto-SCT. She had mild vaso-occlusive pain responsive to narcotics prior to beginning chemotherapy. She received ifosfamide 3330 mg/m2 by continuous infusion for 3 days, etoposide 150 mg/m2 every 12 hours for 3 days, and 5 mg/kg of G-CSF daily starting d5, increased to twice daily on d11 and d12. Baseline hemoglobin ranged between 9 g/dL and 10 g/dL. Transfusions were given to maintain HbS \30% prior to leukapheresis, and reduced the percentage to 14.4%. On d8, 3 days after initiating G-CSF, she developed back and extremity pain, which improved with narcotics. On d13, PBSCs were collected when the WBC count recovered to 10  109/L and a peak PB CD341 count was 307/mL. A 1-day collection yielded 28.6  106/kg CD341 cells. She subsequently underwent auto-SCT, and remains in complete remission 1 year posttransplant. Results and Discussion

Leukocytosis, and in particular granulocytosis with neutrophil activation, has been postulated to play a key role in both steady-state and acute complications of SCD [6]. In 1 case report, an asymptomatic donor with HbSC disease developed a fatal VOC during G-CSF-mobilization with a peak WBC count of 71  109/L [1]. Another case report highlights a breast cancer patient with asymptomatic sickle cell disease/ b1thalassaemia and HbS component of 57% who received daily G-CSF during adjuvant chemotherapy and developed acute multiorgan failure syndrome after 4 doses [2]. No leukocytosis was observed because of recent chemotherapy administration. The authors postulate that a threshold HbS level may predispose to VOC and severe complications, acknowledging the report by Kang et al. [7], which shows the safety of administering G-CSF in sickle cell trait patients with HbS levels of 35%-40%. Abboud et al. [3] conclude that G-CSF-mobilization is unsafe in this population based on a report of a SCD patient who developed ACS with marked leukocytosis on the fourth day of G-CSF administration, which resolved with hydroxyurea and G-CSF withdrawal. By contrast, in our experience complications of PBSC mobilization were transient, and occurred in only 3 of 5 patients but without correlation to percentage of HbS. Two patients developing mild VOC with pain alone had low HbS levels of 14% and 25%, whereas patients with higher HbS levels had no complications. The patient with the HbS level of 14% was the only one who had received packed red blood cell transfusions to lower the HbS percentage prior to leukapheresis, while the remainder of the cohort received no transfusions. Nevertheless, we caution against performing G-CSF-based mobilization with

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hemoglobin S levels .30% based on literature that specifies a therapeutic goal of decreasing hemoglobin S levels to \30% with red cell exchange transfusion in the setting of VOC [8]. The peak WBC count during mobilization should also be monitored closely and values .80,000/mL should be avoided by early discontinuation of G-CSF [1,9,10]. All patients had a marked rise in their WBC counts at the time of collection except for the patient with HL who was recovering from mobilizing chemotherapy. Of the 3 patients developing symptoms, 1 had bone pain prior to receiving G-CSF, and worsening pain during mobilization was manageable with parenteral narcotics. Two others developed mild bone pain and headaches, respectively, which did not interfere with collection of adequate stem cell yields. Others have reported similar results with G-CSF mobilization in SCD patients with relapsed lymphoma requiring auto-SCT. A recent report demonstrates the safety and efficacy of G-CSF-mobilization in a HbSC patient undergoing auto-SCT for diffuse large B-cell lymphoma [11]. GCSF was administered twice daily in a split-dose schedule to minimize leukocytosis, and hypophosphatemia was avoided during mobilization. In another report, an SCD patient undergoing autologous bone marrow transplantation for diffuse large B-cell lymphoma received G-CSF following initial chemotherapy administration and posttransplantation, similar to our patient [12]. In both reports, a low HbS percentage was maintained throughout the transplant with strategies of exchange transfusion and hypertransfusion, respectively, which effectively lowered HbS levels to 6% and 0%. The authors in the latter report comment that hypertransfusion may prevent G-CSFinduced complications in SCD. As the average life expectancy of patients with SCD increases, patients with concomitant hematologic malignancies are encountered more frequently, and some need an auto-SCT. The recommendation to avoid stem cell mobilization takes into account only the risks but not the benefits of auto-SCT, nor the risks of alternative treatment options. Although complications were frequent after G-CSF-mobilization, they were transient and manageable. Methods such as hydroxyurea withdrawal have not proved to be effective for stem cell mobilization [13]. The novel mobilizing agent, AMD3100, is investigational and associated with its own side effect profile, has not yet been studied in this patient population, and has demonstrated highest efficacy when used in combination with G-CSF [14]. Phase II studies of AMD3100 in normal participants to date report higher stem cell yields with the addition of AMD3100 to G-CSF compared to AMD3100 given as a single agent [15-17]. An alternative option to procure stem cells would be to harvest bone marrow, but this usually requires general anesthesia, which entails considerable risks in patients

C. Rosenbaum et al.

with SCD [18]. Allo-SCT is curative for both SCD and hematologic malignancies, but has a high rate of fatal complications such as graft rejection and graft failure [19,21]. Furthermore, the likelihood of identifying a related or matched unrelated donor is low [22,23]. Our case series demonstrates that G-CSF mobilization can be performed with a tolerable risk profile and manageable VOC symptoms, and that adequate stem cell yields are achievable in patients with sickle cell syndromes in need of a hematopoietic SCT. A better understanding of the complex relationship between HbS levels, leukocytosis, and the rate of WBC count rise in provoking VOC is necessary for further improving the tolerability of G-CSF mobilization in this patient population. ACKNOWLEDGMENTS We would like to thank Ellen Jessop, RN, for her contribution in retrieving records. REFERENCES 1. Adler BK, Salzman DE, Carabasi MH, Vaughan WP, Reddy VV, Prchal JT. Fatal sickle cell crisis after granulocyte colony-stimulating factor administration. Blood. 2001;97: 3313-3314. 2. Grigg AP. Granulocyte colony-stimulating factor-induced sickle cell crisis and multiorgan dysfunction in a patient with compound heterozygous sickle cell/beta1 thalassemia. Blood. 2001;97:3998-3999. 3. Abboud M, Laver J, Blau CA. Granulocytosis causing sickle-cell crisis. Lancet. 1998;351:959. 4. Donato ML, Champlin RE, Van Besien KW, et al. Intensive dose ifosfamide and etoposide with G-CSF for stem cell mobilization in patients with non-Hodgkin’s lymphoma. Leuk Lymphoma. 1999;35:317-324. 5. Ko¨rbling M, Przepiorka D, Huh YO, et al. Allogeneic blood stem cell transplantation for refractory leukemia and lymphoma: potential advantage of blood over marrow allografts. Blood. 1995; 85:1659-1665. 6. Assis A, Conran N, Canalli AA, Lorand-Metze I, Saad ST, Costa FF. Effect of cytokines and chemokines on sickle neutrophil adhesion to fibronectin. Acta Haematol. 2005;113:130-136. 7. Kang EM, Areman EM, David-Ocampo V, et al. Mobilization, collection, and processing of peripheral blood stem cells in individuals with sickle cell trait. Blood. 2002;99:850-855. 8. Swerdlow PS. Red cell exchange in sickle cell disease. Hematology Am Soc Hematol Educ Program. 2006;48-53. 9. Fadlon E, Vordermeier S, Pearson TC, et al. Blood polymorphonuclear leukocytes from the majority of sickle cell patients in the crisis phase of the disease show enhanced adhesion to vascular endothelium and increased expression of CD64. Blood. 1998;91:266-274. 10. Wun T. The role of inflammation and leukocytes in the pathogenesis of sickle cell disease; haemoglobinopathy. Hematology. 2001;5:403-412. 11. Kamble RT, Tin-U CK, Carrum G. Successful mobilization and transplantation of filgrastim mobilized hematopoietic stem

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G-CSF Mobilization in Sickle Cell Disease

12.

13.

14.

15. 16.

17.

cells in sickle cell-hemoglobin C disease. Bone Marrow Transplant. 2006;37:1065-1066. Onitilo AA, Lazarchick J, Brunson CY, Frei-Lahr D, Stuart RK. Autologous bone marrow transplant in a patient with sickle cell disease and diffuse large B-cell lymphoma. Transplant Proc. 2003; 35:3089-3092. Richard RE, Siritanaratkul N, Jonlin E, Skarpidi E, Heimfeld S, Blau CA. Collection of blood stem cells from patients with sickle cell anemia. Blood Cells Mol Dis. 2005;35:384-388. Larochelle A, Krouse A, Metzger M, et al. AMD3100 mobilizes hematopoietic stem cells with long-term repopulating capacity in nonhuman primates. Blood. 2006;107:3772-3778. Cashen AF, Nervi B, DiPersio J. AMD3100:CXCR4 antagonist and rapid stem cell-mobilizing agent. Future Oncol. 2007;3:19-27. Gazitt Y, Freytes CO, Akay C, et al. Improved mobilization of peripheral blood CD341 cells and dendritic cells by AMD3100 plus granulocyte-colony-stimulating factor in nonHodgkin’s lymphoma patients. Stem Cells Dev. 2007;16: 657-666. Calandra G, McCarty J, McGuirk J, et al. AMD3100 plus GCSF can successfully mobilize CD34+ cells from non-Hodgkin’s lymphoma, Hodgkin’s disease and multiple myeloma patients

18. 19.

20.

21. 22.

23.

previously failing mobilization with chemotherapy and/or cytokine treatment: compassionate use data. Bone Marrow Transplant. 2008;41:331-338. Firth PG. Anaesthesia for peculiar cells—a century of sickle cell disease. Br J Anaesth. 2005;95:287-299. Van Besien K, Bartholomew A, Stock W, et al. Fludarabinebased conditioning for allogeneic transplantation in adults with sickle cell disease. Bone Marrow Transplant. 2000;26: 445-449. Bhatia M, Walters MC. Hematopoietic cell transplantation for thalassemia and sickle cell disease: past, present and future. Bone Marrow Transplant. 2008;41:109-117. Vermylen C. Hematopoietic stem cell transplantation in sickle cell disease. Blood Rev. 2003;17:163-166. Walters MC, Patience M, Leisenring W, et al. Barriers to bone marrow transplantation for sickle cell anemia. Biol Blood Marrow Transplant. 1996;2:100-104. Dew A, Collins-Jones D, Artz A, et al. Section of Hematology/ Oncology, Department of Medicine, University of Chicago, Chicago, IL unrelated donor searches for African-Americans with hematologic malignancies: paucity of HLA identical donors. Blood. 2007;110(Suppl 1): abstract 5064.