Booster of plerixafor can be successfully used in addition to ...

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eral blood after chemotherapy plus G-CSF-based mobilization regimen, despite raise in leukocytosis. In this situation, we decided to administer a booster of pler-.
© Ann Transplant, 2010; 15(4): 61-67

Received: 2010.07.06 Accepted: 2010.09.07 Published: 2010.12.22

Case Report

Booster of plerixafor can be successfully used in addition to chemotherapy-based regimen to rescue stem cell mobilization failure Grzegorz Wladyslaw Basak, Elzbieta Urbanowska, Piotr Boguradzki, Tigran Torosian, Kazimierz Halaburda, Wieslaw Wiktor-Jedrzejczak Department of Hematology, Oncology and Internal Diseases, The Medical University of Warsaw, Warsaw, Poland

Summary

Background:

Autologous stem cell transplantation (autoSCT) is currently considered one of the standard approaches in the treatment of patients suffering from multiple myeloma and recurrent or relapsed lymphomas. Unfortunately, a significant proportion of those patients fail to mobilize minimum CD34+ cell dose to undergo this procedure. Here we present the strategy that allows to rescue the outcome of ongoing unsuccessful chemotherapy based mobilizations.



Case Report:

All five patients failed to release satisfactory number of CD34+ cells to peripheral blood after chemotherapy plus G-CSF-based mobilization regimen, despite raise in leukocytosis. In this situation, we decided to administer a booster of plerixafor, a specific CXCR4 receptor inhibitor. We observed rapid 2.6 to 16-fold increase of peripheral blood CD34+ cells number that allowed to start aphereses in all cases. Consequently, all five patients who would not otherwise collect required number of CD34+ cells, collected above 2.0×106 CD34+ cells/kg that allowed for hematopoietic stem cell transplantation.



Conclusions:

We would like to suggest that poor mobilizers could be rescued with the timely addition of plerixafor, thus they can avoid another procedure of stem cell mobilization.



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Author’s address:

AMD3100 • plerixafor • stem cell mobilization • lymphoma http://www.annalsoftransplantation.com/fulltxt.php?ICID=881353 2951 — 1 17

Grzegorz Wladyslaw Basak, Department of Hematology, Oncology and Internal Diseases, The Medical University of Warsaw, Banacha 1A Str., 02-097 Warsaw, Poland, e-mail: [email protected]

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Background The strategy of autologous stem cell transplantation (autoSCT) in hematologic malignancies is based on administration of myeloablative chemotherapy followed by re-infusion of patient’s own hematopoietic stem cells (HSCs) required for recovery of hematopoiesis. Nowadays, HSCs used in this setting are usually isolated from peripheral blood (PB) of patients [1]. In order to ensure the harvest of optimum number of those cells from PB (minimum of 2.0×106 CD34+ cells/kg body weight), the procedure known as mobilization is required. The commonest mobilization regimens are based on administration of granulocyte-colony stimulating factor (G-CSF) alone or in combination with chemotherapy. G-CSF induces functional changes in BM microenvironment, as enzymes released from myeloid cells cleave adhesion molecules and disrupt the interactions between chemokines, their receptors and extracellular matrix [2]. Vascular cell adhesion molecule-1 (VCAM-1), c-kit, CXCR4 and its ligand stromal-derived factor-1 (SDF-1) have been identified among the most important factors that protect HSCs from leaving the BM niche, and are being disrupted during mobilization. Chemotherapy was also observed to increase the number of circulating HSCs during the phase of hematopoietic recovery [3,4]. The regeneration after injury may increase the total number of stem cells and additional ones are shed to the circulation. Moreover, the cellular injury to various types of cells may lead to release of endogenous cytokines with stem cell mobilizing activity. Although the stem cell mobilization with chemotherapy alone is no longer used in current clinical practice because of low efficiency, the mobilizing effect of chemotherapy has been frequently combined with administration of G-CSF. This combination was shown to decrease the mobilization failure rate and increase the total CD34+ cell yield [5]. Moreover, some chemotherapy regimens used for mobilization, play also important role as therapy of patient’s primary disorder. Unfortunately, the currently used procedures of stem cell mobilization fail in significant number of patients. The failure rate of mobilization was reported to be as high as 5% in MM and up to 35% in lymphomas [2,5,6]. Plerixafor (AMD3100, Mozobil) is a selective and reversible inhibitor of CXCR4 receptor which disrupts its interactions with SDF-1. SDF-1 is a chemokine which strongly affects the retention

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of HSCs in bone marrow (BM) milieu and therefore blockade of CXCR4 leads to release of HSCs to the circulation. Plerixafor was recently shown to significantly improve the outcomes of granulocyte-colony stimulating factor (G-CSF)-based mobilization regimens [7–9]. A number of prospective [10] and retrospective [11] studies documented the overall success rate of mobilization with plerixafor and G-CSF of 66-100%, even in patients, who failed previous mobilizations. The currently recommended schedule of administration includes G-CSF (10 µg/kg) as a daily injection for 4 consecutive days, and then injection of plerixafor (240 µg/kg) 10–12 hours before the first planned apheresis. This schedule may be then repeated in similar fashion on the consecutive days. Recently Dugan et al. [12] presented results of the prospective study in which patients had received plerixafor in addition to a conventional stem cell mobilization regimen of chemotherapy and G-CSF. The presented data suggested that plerixafor can be safely added to chemotherapy-based mobilization regimens and may accelerate the rate of increase in CD34+ cells on the second day of apheresis. We would like to report that plerixafor can be also used as a salvage intervention in the first-line mobilization with chemotherapy-based regimen in patients who fail to mobilize satisfactory number of CD34+ cells. All the patients included in the study suffered from hematologic disorders and had standard indications for hematopoietic stem cell mobilization and transplantation. They have been treated in a single centre. Patients UPN#1, 3 and 4 have been mobilized after rescue chemotherapy ICE (ifosfamide 5000 mg/m2, day 1; carboplatin 800 mg, – day 2; etoposide 100 mg/m2, days 1–3) used for relapsed or refractory lymphoma [13], while patients UPN#2 and 5 received highdose cyclophosphamide especially for the purpose of stem cell mobilization [14]. All of them were treated with G-CSF, while the optimal time and dosing of G-CSF was at discretion of treating physician and differed between patients. The PB CD34+ cell concentration was assessed by flow cytometry and the absolute number of CD34+ cells/µL was calculated according to the formula: WBC count/µL × proportion of CD34+ cells in nucleated cell fraction. The institutional custom was to start measurement of PB CD34+ cells on day 9 following chemotherapy in case when PB leukocytosis exceeded 3.5 G/L. In patients UPN#1 and 2, first CD34+ cell measurements were done later due to slower recovery of white blood cells (WBC). In patient UPN#4 the optimal time

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for CD34+ cell enumeration and collection was missed due to state holidays. When the PB CD34+ cell number exceeded absolute minimum of 10 CD34+ cells/µL, aphereses were performed on the same day, just after CD34+ cell enumeration (about 2 hours after blood puncture). Plerixafor (Mozobil) was generously provided by the manufacturer (Genzyme) within the Compassionate Use Protocol. The decision about administration of plerixafor was made individually by treating physicians, based on their conviction that certain patient is on high risk of mobilization failure. In such situation, plerixafor was administered subcutaneously, 10–11 hours prior to planned stem cell collection. For the purpose of cell collections COBE Spectra cell separator was used, equipped with version 6.1 software. Manual MNC procedure was applied with the aim of processing of 2 times the Total Blood Volume.

Case Reports UPN#1 28-year old male patient diagnosed with diffuse large B-cell lymphoma (DLBCL) received 8 courses of R-CHOP chemotherapy (rituximab 375 mg/m2, day 1; cyclophosphamide 750 mg/m2, day 1; vincristine 1.4 mg/m2, day 1; doxorubicin 50 mg/m2, day 1; prednisone 100 mg, day 1–5) after which he achieved complete remission. Unfortunately, he relapsed after 8 months and decision about further treatment with rescue ICE chemotherapy followed by autoSCT was made. The 3rd course of chemotherapy was followed by administration of G-CSF at a dose of 5 µg/kg b.w. since day 2 after chemotherapy which was further escalated to 10 µg/kg b.w. since day 8 (Figure 1A). Monitoring of PB CD34+ cells started on day 10, however despite increase in leukocytosis to 10 G/L, the number of circulating CD34+ cells was low (0.2 and 1 on days 10 and 11, respectively). This number was not sufficient to start apheresis and therefore, we decided to administer plerixafor in the evening of day 11 in order to boost the CD34+ cell release. Next day, while the leukocytosis doubled, the number of PB CD34+ cells increased 16-fold and reached 16 CD34+ cells/kg b.w. This allowed us to start first apheresis in which 1.8×106 CD34+ cells/kg b.w. were collected. After second application of plerixafor on day 12, the number of PB CD34+ cells reached 40/µL and further 3.5×106 CD34+ cells/kg b.w. were obtained from consecutive apheresis. Thus, the patient collected 5.3×106 CD34+ cells/kg b.w. in total.

Basak GW et al – Plerixafor rescues chemotherapy-based mobilizations

UPN#2 19-year old female patient was diagnosed with Hodgkin’s lymphoma. She received 6 courses of ABVD chemotherapy (doxorubicin 25 mg/ m2, day 1 and 15; bleomycin 10 mg/m2, day 1 and 15; vinblastine 6 mg/m2 day 1 and 15; dacarbazine 375 mg/m2, day 1 and 15) without satisfactory response. Therefore, she has been further treated with 4 courses of dose-escalated BEACOPP chemotherapy (bleomycin 10 mg/m2, day 8; etoposide 200 mg/m2, days 1–3; doxorubicin 35 mg/m2 day 1; cyclophosphamide 1250 mg/m2, day 1; vincristine 1.4 mg/m2, day 8; procarbazine 100 mg/m2, days 1–7; prednisone 40 mg/m2, days 1–14) followed by 3 courses of BEACOPP chemotherapy (bleomycin 10 mg/m2, day 8; etoposide 100 mg/m2, days 1–3; doxorubicin 25 mg/m2 day 1; cyclophosphamide 650 mg/m2, day 1; vincristine 1.4 mg/m2, day 8; procarbazine 100 mg/m2, days 1–7; prednisone 40 mg/m2, days 1–14) after which she achieved complete remission. In order to consolidate the remission, autoSCT was planned. After 2 months following last chemotherapy course, she was admitted for stem cell mobilization with chemotherapy and G-CSF. She received infusion of high dose cyclophosphamide (HD-Cy, cyclophosphamide 4 g/m2, day 1) and G-CSF at a dose of 10 µg/kg b.w. since day 6 following chemotherapy (Figure 1B). The PB CD34+ cells were enumerated since day 10 following chemotherapy, when the PB WBC count reached 3.5 G/L. On day 10, only 8 CD34+ cells/µL were observed in PB, that increased to 14 CD34+ cells/µL on day 11. On that day (Thursday) the first apheresis was performed, but only 0.7×106 CD34+ cells/kg b.w. were collected. The day 12 (Friday) was the last day when stem cell collection was possible, because the apheresis center does not work on weekends. Therefore, in order to prevent mobilization failure, we decided to administer plerixafor in the evening of day 11. Next morning, we observed about 4-fold increase in the number of circulating CD34+ cells, which allowed us to collect further 2.2×106 CD34+ cells/kg b.w. UPN#3 57-year old male patient diagnosed with diffuse large B cell lymphoma (DLBCL) has been first treated with 8 courses of R-CHOP chemotherapy, however he achieved only partial remission. In this situation, the decision about autoSCT was made with stem cell collection after rescue chemotherapy. He received first course of

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Figure 1. The kinetics of white blood cell (WBC) recovery and CD34+ cell mobilization following chemotherapy, G-CSF and plerixafor. Black arrows indicate plerixafor injections. Lines represent WBC count and bars represent peripheral blood CD34+ cell count/µL. N.D. – not done.

ICE chemotherapy, followed by G-CSF at a dose of 10 µg/kg since day 2 following chemotherapy (Figure 1C). The PB CD34+ cells have been monitored since day 9, when the PB leukocytosis reached 5 G/L. On that day, the number of PB CD34+ cells was only 9 cells/µL and increased to 11 CD34+ cells/µL on day 10, while the leukocytosis exceeded 10 G/L. The apheresis performed on day 10 allowed to collect only 0.7×106 CD34+ cells/kg b.w. The low kinetics of CD34+ increase despite raise in leukocytosis stimulated us to administer a booster of plerixafor on day 10 following chemotherapy. The next morning CD34+ cell count increased to 39 CD34+ cells/µL (3.5-fold). On that day, 2.0×106 CD34+ cells/kg b.w. were collected in single apheresis. The injection of plerixafor was repeated and next day apheresis provided 1.4×106 CD34+ cells/kg b.w. UPN#4 30-year old male patient was diagnosed with Hodgkin’s disease. He achieved complete remission after 6 cycles of BEACOPP chemotherapy, however he relapsed after 3 months that suggested primary refractory disease. Therefore, the decision was made about autoSCT preceded by cytoreductive treatment with ICE chemotherapy. In

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order to mobilize HSCs, he has received G-CSF at a dose of 10 µg/kg b.w. since day 5 following second course of ICE chemotherapy (Figure 1D). The first PB CD34 measurement was made on day 11 following chemotherapy, when the leukocytosis exceeded 6 G/L. It revealed only 0.5 CD34+ cells/µL. Unfortunately, during next three days, due to state holidays, the CD34+ measurements were not made. On day 15 following chemotherapy, the PB leukocytosis reached already 37 G/L with only 6 CD34+ cells/µL, which was not sufficient to start apheresis. As the optimum time for stem cell collection has already passed (when leukocytosis was lower), we did not expect further increase in CD34+ cell number and therefore, we decided to administer plerixafor. Next morning, increase in PB leukocytosis to 49 G/L accompanied by 2.6-fold increase in CD34+ cell number was observed, which exceeded 16 CD34+ cells/µL. This allowed to start first apheresis in which 0.7×106 CD34+ cells/kg b.w. were collected. After second plerixafor administration, the PB CD34+ cell number increased to 32 CD34+ cells/µL and in following apheresis 1.5×106 CD34+ cells/kg b.w. were obtained. The third injection of plerixafor allowed to collect another 1.5×106 CD34+ cells/kg b.w. on day 18 following chemotherapy treatment.

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UPN#5 19-year old female patient was diagnosed with POEMS syndrome (polyneuropathy, organomegaly, endocrynopathy, monoclonal gammapathy and skin lesions) with solitary plasmocytoma localized in a hip bone. Decision about upfront stem cell mobilization was made after reduced dose cyclophosphamide treatment (2.0 g/m2) followed by G-CSF (10 µg/kg b.w.) administered since day 5 following chemotherapy [15]. The monitoring of PB CD34+ cells was made since day 9 (Figure 1E). On days 9 and 10, only 3.2 and 6.5 CD34+ cells were observed in PB respectively, that did not allow for stem cell collection. In this situation, we decided to administer plerixafor in the evening of day 11. Next morning, we observed increase in leukocytosis with 16-fold increase in circulating CD34+ cell number, up to 108 CD34+ cells/µL. In the single apheresis performed on day 11 following chemotherapy, 5.8×106 CD34+ cells/kg b.w. were collected.

Discussion Stem cell mobilization failure constitutes a serious problem in the treatment of patients with hematologic malignancies who are candidates for autoSCT. Failure may lead to increased number of apheresis days, increased resources use, repeated mobilization procedures, need for invasive bone marrow collection and even to abandonment of transplantation. In turn, transplantation of stem cell product that contains low number of CD34+ cells (15 CD34+ cells/µL) despite increase in WBC count to minimum of 5 G/L. After first administration of plerixafor, the PB CD34+ count increased 2.6 to 16-fold which allowed to perform stem cell collections in all patients. Importantly, in patients UPN#2, 3, and 5 only single dose of plerixafor was needed to achieve a minimum target of 2.0×106 CD34+ cells/kg b.w., while patients UPN#1 and 4 required two doses to achieve this goal. Consequently, all the patients who would most likely fail first line mobilization, collected required number of CD34+ cells due to our protocol. Independently of us D’Addio at al. [17] published recently similar study regarding addition of plerixafor to chemotherapy-based mobilization regimen in a group of 13 patients. They also managed to collect a minimum of 2.0×106 CD34+ cells/kg b.w. in all the treated patients, that confirms the high efficiency of this strategy. From these studies a new important clinical question aroused, regarding what is the optimal time point for plerixafor injection. In our patients, the decision about plerixafor administration was made individually by the treating physician. It was based on PB CD34+ cell count and leukocytosis combined with clinical experience. Moreover, the G-CSF dosing regimen also differed between patients and therefore the number of days on G-CSF could not guide the treatment. Looking at our data, the most pronounced increase in PB CD34+ cell number was observed in patients with moderate PB leukocytosis not exceeding 15 G/L on the day of plerixafor injection. In patient UPN#4, in whom booster of plerixafor was administered late after chemotherapy when the PB leukocytosis was already about 35 G/L, we observed low (only 2.6-fold) increase in PB CD34+ cell number. On the other hand, even in this particular patient, the required number

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of CD34+ cells was finally collected. In patient UPN#2, the PB CD34+ cell number before plerixafor administration almost exceeded the satisfactory level of 15 CD34+ cells/µL, so it was still possible that the patient could collect required cell dose after several apheresis procedures, without plerixafor. However, this measurement was made on Thursday, while our apheresis center does not work on weekends. Thus the patient had just one chance of stem cell collection on Friday, before weekend. Plerixafor was administered because the successful collection in one apheresis was unlikely without increasing PB CD34+ cell number. Application of plerixafor as rescue procedure for failing chemotherapy-based mobilizations has several advantages over mobilization with plerixafor and G-CSF as first line treatment. Before all, this strategy seems to be associated with lower cost of mobilization, as plerixafor is administered only in selected patients. Moreover, the mobilizing regimen including chemotherapy may be superior in some patients, especially in those suffering from lymphoma. In those patients, autoSCT is usually performed in case of disease relapse or progression, so the procedure of stem cell mobilization is usually incorporated into chemotherapy courses used for treatment of relapsed disease. Mobilization without chemotherapy could potentially prolong the distance between chemotherapy courses and thus lead to progression of the disease. In this group of patients, efficient mobilization is especially important as autoSCT may lead to cure of the disease.

Conclusions The described cases suggest that plerixafor may be successfully used in addition to chemotherapy-based regimen to rescue stem cell mobilization failure. This approach seems to be especially useful for young lymphoma patients, who are mobilized after chemotherapy administered for treatment of primary disease. This strategy allows both to administer chemotherapy at regular intervals and proceed to autoSCT as soon as possible. However, the optimal timing of plerixafor administration needs to be further explored.

References: 1. Gratwohl A, Baldomero H, Schmid O et al: Change in stem cell source for hematopoietic stem cell transplantation (HSCT) in Europe: a report of the EBMT activity survey 2003. Bone Marrow Transplant, 2005; 36(7): 575–90

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2. Bensinger W, DiPersio JF, McCarty JM: Improving stem cell mobilization strategies: future directions. Bone Marrow Transplant, 2009; 43(3): 181–95 3. Richman CM, Weiner RS, Yankee RA: Increase in circulating stem cells following chemotherapy in man. Blood, 1976; 47(6): 1031–39 4. Fu S, Liesveld J: Mobilization of hematopoietic stem cells. Blood Rev, 2000; 14(4): 205–18 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): 1045–56 6. Villalon L, Odriozola J, Larana JG et al: Autologous peripheral blood progenitor cell transplantation with