Original Article

Bone Marrow Transplantation (2013) 48, 1112–1116; doi:10.1038/bmt.2013.10; published online 11 March 2013

Post-Transplant Events

Long-term follow up of patients proceeding to transplant using plerixafor mobilized stem cells and incidence of secondary myelodysplastic syndrome/AML

A Deol1,2,3, J Abrams2, A Masood1, Z Al-Kadhimi1,2,3, M H Abidi1,2,3, L Ayash1,2,3, L G Lum1,2,3,4, V Ratanatharathorn1,2,3 and J P Uberti1,2,3

  1. 1Blood and Marrow SCT Program, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
  2. 2Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
  3. 3Department of Internal Medicine, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
  4. 4Department of Immunology and Microbiology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA

Correspondence: Dr A Deol, Oncology 4 HWCRC, Karmanos Cancer Center, Wayne State University, 4100 John R, Detroit, MI 48201, USA. E-mail: deola@karmanos.org

Received 19 September 2012; Revised 10 January 2013; Accepted 15 January 2013
Advance online publication 11 March 2013

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Abstract

We report the long-term follow up of 49 patients (pts) enrolled on plerixafor compassionate use protocol. Thirty-seven pts (76%) had failed one previous mobilization attempt, while 12 (24%) had failed two or more previous attempts. Using the combination of plerixafor and granulocyte colony-stimulating factor, we collectedgreater than or equal to2.5 × 106 CD34+cells/kg in 33 pts (67%). Forty-three of the 49 pts proceeded to an auto-SCT (ASCT). The median days to WBC and platelet engraftment were 11 (range, 9–13 days) and 16 (range, 11–77 days) days post ASCT, respectively. The median WBC count, Hb and platelet counts 1 year after ASCT were 4.7 × 109/L, 12.2g/dL and 109 × 109/L, respectively. With median follow up of 42 months (range <1–54 months), 21 pts had evidence of disease progression. Five pts developed myelodysplastic syndrome (MDS)/AML at median of 29 months post ASCT. The cumulative incidence of MDS/AML at 42 months was 17% (95% confidence interval, 6 to 32%). Development of secondary MDS/AML in pts proceeding to ASCT after plerixafor mobilization needs to be studied further in a larger cohort.

Keywords:

plerixafor; stem cell mobilization; secondary MDS/AML; auto-SCT

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Introduction

Auto-SCT (ASCT) followed by high dose chemotherapy has become the standard of care for successful treatment of patients with certain hematological malignancies.1, 2 The number of cells needed for successful engraftment is in the range of 2.0–2.5 × 106 CD34+cells/kg.3, 4, 5 The failure rate of PBSC mobilization has been estimated to be 5–40%.4, 5

Plerixafor, previously known as AMD3100, is a CXCR 4 receptor antagonist, which was developed to block HIV.6 It was found serendipitously to cause leukocytosis in a phase 1 study in normal volunteers.7 This led to further development of the drug, and it was shown to increase circulating CD34+cells in healthy volunteers8 and cancer patients9 when administered alone or in combination with granulocyte colony stimulating factor (G-CSF).

While plerixafor was awaiting approval from the Food and Drug Administration, the drug was made available for patients who had failed a previous mobilization attempt under a compassionate use protocol. Previously, investigators reported on the efficacy of PBSC mobilization with plerixafor, however, little is known about the long-term follow up. Herein, we report the long-term follow up of the patients who underwent ASCT with PBSC collected with the use of Plerixafor.

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Materials and methods

Patients were enrolled on a compassionate use protocol using plerixafor to mobilize PBSC in preparation for ASCT. The protocol was approved by the Institutional Review Board at Wayne State University. The clinical trial was registered at clinicaltrials.gov with identification number NCT00291811. Eligibility criteria included a previous failed mobilization attempt in preparation for ASCT. In addition, patients needed to meet the following eligibility requirements: greater than or equal to18 years of age; eligible to undergo an ASCT per institutional guidelines; ECOG PS 0-1; no active infection; able to provide an informed consent; WBC countgreater than or equal to3 × 109/L, ANC greater than or equal to1.5 × 109/L; platelet count greater than or equal to100 × 109/L; serum creatinine less than or equal to1.5mg/dL; alanine aminotransferase/aspartate aminotransferase/ Total bilirubin<two times upper limit of institutional normal; and use of contraception while on study, and for 3 months after, no evidence of Hepatitis B, Hepatitis C and HIV infections. All patients provided informed consent before proceeding onto the study.

Treatment protocol

G-CSF 10mcg/kg subcutaneously was administered in the morning on days 1 through 4. On day 4 plerixafor 240mcg/kg subcutaneously was administered in the evening, 10 to 11h before the initiation of apheresis. On Day 5, G-CSF was administered in the morning ~1h before apheresis. Study treatment (plerixafor in the evening and G-CSF the following morning before apheresis) could be repeated on contiguous days as needed for up to four additional apheresis procedures, until the optimal number of CD34+cells were collected.

Apheresis

Apheresis was initiated if the peripheral CD34+cell count was greater than or equal to10cells/μL. Flow cytometry was used for detection of CD34+cells. Pooling of multiple apheresis products including those not mobilized by plerixafor was allowed.

Statistical analysis

Successful mobilization was defined in this study as a total collection of greater than or equal to2.5 × 106 CD34+ cells/kg actual body weight with the use of plerixafor. Platelet and WBC engraftments were defined as platelet count greater than or equal to20 × 109/L (first day without transfusion in 7 days) and ANC greater than or equal to0.5 × 109/L (first day of 3 consecutive days at greater than or equal to0.5 × 109/L).

In this descriptive study, medians of continuous variables are reported with the inter-quartile range (IQR). We report the actual range for age. The cumulative incidence of myelodysplastic syndrome (MDS)/AML was calculated using death from any cause as a competing risk. The overall survival curve was calculated using the Kaplan–Meier method.

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Results

Patient characteristics

Between March 2006 and January 2009, 49 patients were enrolled on the compassionate use protocol at the Karmanos Cancer Institute. The patient characteristics are shown in Table 1. The median age of the patients was 64 years (range, 23–74 years) and 57% were male. Non-Hodgkin’s lymphoma (NHL) was the most common diagnosis (55%), followed by multiple myeloma (MM) (35%) and Hodgkin’s disease (10%). Seven patients with MM had previous exposure to lenalidomide with the median number of cycles being five (range, 1–8). Forty patients (80%) previously received more than two prior chemotherapeutic regimens. Three patients with MM had received a previous ASCT. Ten patients (20%) were treated with radiation, two with radioimmunotherapy and one with both radiation and radioimmunotherapy. At the time of collection 17 patients (35%) achieved CR, 15 (31%) achieved PR, 14 (28%) had refractory disease and three (6%) had stable disease. Pre mobilization BM cytogenetics were normal in 36 patients for whom data were available.


Thirty-seven patients (76%) had failed one previous PBSC mobilization attempt, 11 (22%) had failed two attempts and one patient had failed three previous attempts. During the first mobilization attempt, 39 patients had received G-CSF, while nine patients received CY/G-CSF. Data about the previous mobilization regimen were not available for one patient. For a second mobilization attempt, eight patients received G-CSF/GM-CSF and three patients received G-CSF. For the third failed mobilization attempt, one patient received CY/G-CSF after failing G-CSF and the combination of G and GM-CSF.

PBSC mobilization results

Plerixafor was generally well-tolerated in these patients without any adverse events >grade 2. Thirty-three patients (67%) mobilized greater than or equal to2.5 × 106 CD34+cells/kg with a combination of plerixafor and G-CSF. Sixteen of 27 patients with MM, 13 of 17 patients with NHL and four of five patients with Hodgkin’s disease were among this group of 33 patients. Three MM patients who had previously undergone an ASCT were able to mobilizegreater than or equal to2.5 × 106 CD34 cells/kg. The median cell dose collected was 4.2 × 106 CD34+cells/kg (IQR, 2.9–5.3) and the median day for apheresis was one day (IQR, 1–3). Among these 33 patients, the median peripheral CD34+count on the first day of collection with plerixafor was 22.8/μL (IQR, 17.7–34.3), compared with 6.3/μL (IQR, 3.4–9.9) on the first day of failed previous attempt (highest count if more than one attempt). The median increase in the number of peripheral CD34+cells after plerixafor was 14.9/μL (IQR, 8.8–23.2).

Sixteen of 49 patients (33%) failed to mobilizegreater than or equal to2.5 × 106 CD34+cells/kg. The median cell dose collected in this group was 1.3 × 106 CD34+cells/kg (IQR, 0.7–1.7). All patients who received prior radioimmunotherapy failed to mobilizegreater than or equal to2.5 × 106 CD34+cells/kg. The median peripheral CD34+count on the first day of collection with plerixafor in this group was 6.9/μL (IQR, 3.8–10.6) compared with 11.2/μL (IQR, 5.8–12.8) on the first day of previous failed attempt (highest count if more than one previous attempt). The median decrease in the number of peripheral CD34+cells after plerixafor was 1.5/μL (IQR, −7.3 to 9.4).

The change in peripheral CD34+cell counts from previous mobilization attempt and plerixafor attempt on 38 patients in whom peripheral CD34+cell counts from previous mobilization attempt were available are shown in Figure 1.

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

The change in peripheral CD34+cell count after plerixafor for 38 patients in whom data were available.

Full figure and legend (37K)

Transplant results

Forty-three patients (88%) underwent ASCT (4/5 Hodgkin’s disease patients, 16/17MM patients and 23/27 NHL patients), one patient was lost to follow up after collection of stem cells, and five patients (10%) failed to collect sufficient cells (including pooled product) to safely undergo an ASCT. The preparative regimens used before transplant were R-BEAM (rituximab, carmustine, etoposide, cytarabine and melphalan), BEAM (carmustine, etoposide, cytarabine and melphalan) and melphalan for 21, 16 and six patients, respectively.

Thirty-four patients underwent ASCT withgreater than or equal to2.5 × 106 CD34+cells/kg. The median CD34+cell dose for this group of patients was 3.3 × 106 CD34+cells/kg (range, 2.5–8.5). Nine patients underwent ASCT with <2.5 × 106 CD34+cells/kg. The median CD34+cell dose for this group of patients was 2.1 × 106 CD34+cells/kg (range, 1.7–2.3).

The median days to neutrophil and platelet engraftment were 11 (range, 9–13 days) and 16 (range, 11–77days) days post ASCT, respectively. The median WBC count, Hb and platelet counts 1 year after ASCT were 4.7 × 109/L, 12.2g/dL and 109 × 109/L, respectively. There were no significant differences in engraftment or blood counts at 1 year for patients who received more or less than 2.5 × 106 CD34 cells/kg. There was no early or late graft failure.

Long-term results

The median follow up of the 43 patients who underwent ASCT was 42 months (range, <1–54 months). Twenty-nine patients (67%) had either improved or stable disease status while fourteen patients (33%) had evidence of worsened disease status (relapse/refractory) after ASCT at the time of last disease assessment. Twelve of 43 patients were alive and the overall survival was 20% (95% CI, 8–36%) at 48 months (Figure 2).

Figure 2.
Figure 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Overall survival of patients who underwent ASCT.

Full figure and legend (31K)

Five patients developed secondary MDS/AML post ASCT with the cumulative incidence of 17% (95% CI, 6–32%) at 42 months (Figure 3). One patient developed AML (1.5 years post ASCT) and four patients developed MDS (2, 2.5, 3 and 3.5 years post ASCT). All patients were diagnosed when BM biopsies were performed due to low peripheral blood counts. The patient with AML had normal cytogenetics, while the four patients with MDS had complex cytogenetic abnormalities. Pre mobilization BM cytogenetics were normal in four of five patients and not available for one patient. Four patients had NHL while one had MM. Of the four NHL patients, one had mantle cell lymphoma and received six cycles of part A of hyper CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) and four cycles of part B. Two patients had DLBCL (diffuse large B-cell lymphoma); one of them received six cycles of R-CHOP and three cycles of R-ICE and the second had COPBLAM-III (cyclophosphamide, infusional vincristine, prednisone, infusional bleomycin, doxorubicin and procarbazine) followed by six cycles of R-ICE. The final patient had Burkitt’s lymphoma and received four cycles each of part A and B of hyper CVAD. The patient with MM failed the initial ASCT (Melphalan 200mg/m2 as preparative regimen) and was retreated with thalidomide and bortezomib before mobilization for second ASCT. Four patients had failed one previous mobilization attempt, while one patient had failed two previous mobilization attempts. All five patients were in CR/VGPR at the time of collection and had collectedgreater than or equal to2.5 × 106 CD34+cells/kg. Four patients died with a median survival of 10 months after the diagnosis of secondary MDS/AML. One patient is alive 1.5 years after diagnosis of MDS with low, but stable counts. The characteristics of these patients who developed secondary MDS/AML after transplant are compared with the patients who did not develop MDS/AML in Table 2. One patient with MM underwent mobilization after failing an initial ASCT, but the NHL patients did not have extensive chemotherapy before mobilization. The platelet count in this group was lower at day 100 and 1 year post ASCT. This study was limited by the small number of patients, but the cumulative incidence of MDS/AML post ASCT was higher than expected as discussed below.

Figure 3.
Figure 3 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Cumulative incidence of secondary MDS/AML at 42 months after ASCT.

Full figure and legend (41K)


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Discussion

Previously reported results of compassionate use of plerixafor in other countries by Hubel et al.,10 Duarte et al.,11 Calandra et al.,12 and Basak et al.13 reported successful mobilization rates of 75, 75, 66 and 66%, respectively, which is comparable with our experience. However, the incidence of therapy-related MDS/AML in this group of patients has not been reported previously.

Therapy-related MDS/AML is a well-recognized late complication of ASCT, and has been reported by various groups.14, 15, 16, 17, 18, 19, 20, 21, 22 The actuarial incidence of therapy-related MDS/AML after ASCT has been reported to be from as low as 3% at 5 years to as high 19.8% at 10 years based on these reports. The incidence rates of therapy-related MDS/AML post ASCT, which can be reported either as actuarial incidence (without accounting for competing risks) or as cumulative incidence (accounting for competing risk) have been reviewed in detail by Armitage et al.23 The cumulative incidence of secondary MDS/AML after ASCT of 17% at 42 months, observed in this report is higher than expected and follow-up on larger groups of patients will be needed to determine if the higher incidence of secondary MDS/AML is confirmed. The higher incidence of secondary MDS/AML may be explained by the fact that patients who failed mobilization attempts with other regimens may have suffered multifactorial damage (age, previous chemotherapy or radiation therapy etc) to the stem cell pool. However, the mobilization strategies may either influence mobilization of damaged stem cells or cause damage to the stem cell pool thereby leading to increased incidence of therapy related MDS/AML. Li et al.24 have recently published an elegant study looking at differential gene expression in patients who did and did not develop therapy related AML/MDS post ASCT. They identified a 38 gene signature that may accurately predict the patients at risk of developing therapy related MDS/AML post ASCT. The same group previously described accelerated telomere shortening after ASCT as a risk factor for developing therapy related MDS/AML post ASCT.25 Similar strategies should be incorporated in future studies to ascertain if different mobilization strategies lead to mobilization of a variable number of PBSC, which have the markers associated with the development of therapy-related MDS/AML.

Overall, plerixafor offered patients who had previously failed mobilization an opportunity to proceed to potentially curative therapy with ASCT. Use of plerixafor may not be able to overcome the mobilization failure in patients who received radioimmunotherapy. With median follow up of 28 months reported in this study, 67% patients who underwent ASCT had stable/improved disease at last disease assessment and 12 out of 43 patients who underwent ASCT are alive at this time. In our patients it was difficult to identify differences in the extent of treatment, which may have predisposed them to the development of MDS/AML. Surprisingly, none of the patients who developed MDS/AML post ASCT had received radiation or radioimmunotherapy. These observations warrant further studies which examine the development of therapy-related MDS/AML in larger retrospective or prospective cohort of patients who undergo ASCT with plerixafor mobilized PBSC.

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Conflict of interest

MHA is on speaker bureau and received research funding from Millennium Pharmaceuticals and ZA received research funding from Genzyme Corporation. All other authors have no relevant or competing conflict of interest.

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Acknowledgements

The study sponsor initially was AnorMED Inc. Vancouver, BC and subsequently Genzyme Corporation, Cambridge, MA.