Bone Marrow Transplantation (2014) 49, 1233 © 2014 Macmillan Publishers Limited All rights reserved 0268-3369/14 www.nature.com/bmt
LETTER TO THE EDITOR
Plerixafor and G-CSF for autologous stem cell mobilization in AL amyloidosis Bone Marrow Transplantation (2014) 49, 1233; doi:10.1038/ bmt.2014.117; published online 16 June 2014
Risk-adapted melphalan and SCT (RA-SCT) is considered a standard therapy for selected patients with systemic AL amyloidosis (AL), with median OS exceeding 10 years when used as initial therapy.1 With this approach, peri-transplant mortality has been reduced but complications related to stem cell mobilization, particularly with high-dose G-CSF (16 mcg/kg), remain significant concerns. These concerns are amplified with the growing use of RA-SCT as consolidation post induction or as second-line therapy at relapse. Plerixafor is a small molecule that reversibly inhibits chemokine stromal cell-derived factor 1-α binding to its cognate CXC chemokine receptor, and its addition to G-CSF, compared to G-CSF alone, in patients with multiple myeloma was well tolerated and led to significantly increased CD34+ cell yields.2 Based on this experience we evaluated the use of plerixafor and G-CSF (10 mcg/ kg) for stem cell mobilization in 12 consecutive patients with AL (7 men, 5 women) between 4 June 2012 and 9 September 2013. Median age at mobilization was 58 years (range 46–72), time from diagnosis to mobilization 7.5 months (2–123) and number of organs involved 2 (1–4). The kidney (n = 9) and heart (n = 8, all stage 2) were most commonly involved. Nine patients had had prior bortezomib-based induction therapy (median 3 cycles). One had undergone SCT 10 years earlier and had relapsed, and two were untreated, including one who was a year post orthotopic heart transplant. Five patients had creatinine ⩾ 1.5 mg/dL, including two on hemodialysis (HD). G-CSF was started on the morning of day 1 at a dose of 10 mcg/ kg and plerixafor at 2100 hours on day 4; both were continued daily until collection was complete. For patients with a creatinine clearance (CrCl) >50 mL/min, plerixafor was given at 0.24 mg/kg with a maximum of 40 mg/day, while for those with a CrCl o50 mL/min or on dialysis the dose was 0.16 mg/kg with a maximum of 27 mg/day. The target CD34+ cell collection goal was 10 × 106 CD34+ cells/ kg. Leukapheresis was begun on day 4 if the circulating CD34+ cell count was ⩾ 5/μL and on day 5 otherwise. The median number of collections was 2 (range 2–3). With the first collection, a median of 3.6 × 106 CD34+ cells/kg (0.4–13.8 × 106) were procured and with the second 6.4 × 106 (2.7–19 × 106). Median total number of CD34+ cells/kg was 13.8 × 106 (5–18 × 106). Logistical and fluid balance issues slightly altered the schema for patients on HD. On day 4 of mobilization, HD preceded the daily injection of G-CSF. Apheresis followed if the circulating CD34 cell count was ⩾ 5/μL. On day 5, G-CSF was given followed by apheresis. This was done to avoid HD immediately after drug administration and fluid overload after apheresis. No significant toxicities were observed with plerixafor. Two patients had grade 1 bleeding from the catheter site during apheresis and one had dyspnea due to fluid overload that responded to furosemide. All patients went on to receive RA-SCT and there were no treatment-related deaths. Median number of CD34+ cells/kg infused was 7.7 × 106. Median number of days to ANC>500/μL was 11 (10–22), to platelets>20 000/μL untransfused 15 (9–34) and to lymphocytes>500/μL 14.5 (11–25). One patient developed
veno-occlusive disease and persistent thrombocytopenia and was given the remaining stem cells on day +31 with subsequent normalization of the blood counts. Mobilization with G-CSF and plerixafor was well tolerated in this group of patients with significant organ impairment, including eight who had stage 2 cardiac involvement, two on HD, one with a previous SCT and one who was a year post orthotopic heart transplant. Limited leukaphereses were needed to achieve or exceed the target CD34+ cell dose. Plerixafor is excreted renally but is predicted to be easily dialyzable due to its small size and polarity. While the phase 3 study in myeloma excluded patients with creatinine ⩾ 2.2 mg/dL, studies of dose-adjusted use in myeloma and AL patients with severe renal impairment were not associated with additional toxicity.3,4 With an expanding role of SCT in patients with amyloidosis as initial therapy in selected patients, as consolidation after induction and as second-line therapy, the tolerability and efficacy of mobilization have become important issues. The use of plerixafor with G-CSF for mobilization can make the option of SCT available to patients who have been heavily pretreated or have multiple organs involved and might otherwise be bereft of effective treatment options. In this era of more effective initial therapies, an era in which many AL patients are living longer with moderate to severe organ damage and are receiving multiple lines of therapy including SCT, this approach allows not only the collection of sufficient CD34+ cells for optimal immediate use but also the cryopreservation of aliquots for future use, for a second SCT should it become necessary or for novel cell-based immunotherapies should they become available. CONFLICT OF INTEREST RLC: consultant/scientific advisor, Takeda, Prothena; clinical research funding, Takeda, Prothena, Teva. The other authors declare no conflict of interest.
E Kaul, G Shah, C Chaulagain and RL Comenzo Division of Hematology and Oncology, Tufts Medical Center, Boston, MA, USA E-mail: [email protected] REFERENCES 1 Comenzo RL, Fein DE, Hassoun H, Bello C, Chou JF, Devlin S et al. Long-term outcomes of patients with systemic light chain amyloidosis (AL) treated at diagnosis with risk-adapted stem cell transplant and consolidation with novel agents. ASH Annu Meet Abstr 2012; 120: 3150. 2 DiPersio JF, Stadtmauer EA, Nademanee A, Micallef IN, Stiff PJ, Kaufman JL 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: 5720–5726. 3 Douglas KW, Parker AN, Hayden PJ, Rahemtulla A, D'Addio A, Lemoli RM et al. Plerixafor for PBSC mobilisation in myeloma patients with advanced renal failure: safety and efficacy data in a series of 21 patients from Europe and the USA. Bone Marrow Transplant 2012; 47: 18–23. 4 Dunn D, Vikas P, Jagasia M, Savani BN. Plerixafor in AL amyloidosis: improved graft composition and faster lymphocyte recovery after auto-SCT in patient with end-stage renal-disease. Bone Marrow Transplant 2012; 47: 1136–1137.
LETTER TO THE EDITOR
Plerixafor and G-CSF for autologous stem cell mobilization in AL amyloidosis Bone Marrow Transplantation (2014) 49, 1233; doi:10.1038/ bmt.2014.117; published online 16 June 2014
Risk-adapted melphalan and SCT (RA-SCT) is considered a standard therapy for selected patients with systemic AL amyloidosis (AL), with median OS exceeding 10 years when used as initial therapy.1 With this approach, peri-transplant mortality has been reduced but complications related to stem cell mobilization, particularly with high-dose G-CSF (16 mcg/kg), remain significant concerns. These concerns are amplified with the growing use of RA-SCT as consolidation post induction or as second-line therapy at relapse. Plerixafor is a small molecule that reversibly inhibits chemokine stromal cell-derived factor 1-α binding to its cognate CXC chemokine receptor, and its addition to G-CSF, compared to G-CSF alone, in patients with multiple myeloma was well tolerated and led to significantly increased CD34+ cell yields.2 Based on this experience we evaluated the use of plerixafor and G-CSF (10 mcg/ kg) for stem cell mobilization in 12 consecutive patients with AL (7 men, 5 women) between 4 June 2012 and 9 September 2013. Median age at mobilization was 58 years (range 46–72), time from diagnosis to mobilization 7.5 months (2–123) and number of organs involved 2 (1–4). The kidney (n = 9) and heart (n = 8, all stage 2) were most commonly involved. Nine patients had had prior bortezomib-based induction therapy (median 3 cycles). One had undergone SCT 10 years earlier and had relapsed, and two were untreated, including one who was a year post orthotopic heart transplant. Five patients had creatinine ⩾ 1.5 mg/dL, including two on hemodialysis (HD). G-CSF was started on the morning of day 1 at a dose of 10 mcg/ kg and plerixafor at 2100 hours on day 4; both were continued daily until collection was complete. For patients with a creatinine clearance (CrCl) >50 mL/min, plerixafor was given at 0.24 mg/kg with a maximum of 40 mg/day, while for those with a CrCl o50 mL/min or on dialysis the dose was 0.16 mg/kg with a maximum of 27 mg/day. The target CD34+ cell collection goal was 10 × 106 CD34+ cells/ kg. Leukapheresis was begun on day 4 if the circulating CD34+ cell count was ⩾ 5/μL and on day 5 otherwise. The median number of collections was 2 (range 2–3). With the first collection, a median of 3.6 × 106 CD34+ cells/kg (0.4–13.8 × 106) were procured and with the second 6.4 × 106 (2.7–19 × 106). Median total number of CD34+ cells/kg was 13.8 × 106 (5–18 × 106). Logistical and fluid balance issues slightly altered the schema for patients on HD. On day 4 of mobilization, HD preceded the daily injection of G-CSF. Apheresis followed if the circulating CD34 cell count was ⩾ 5/μL. On day 5, G-CSF was given followed by apheresis. This was done to avoid HD immediately after drug administration and fluid overload after apheresis. No significant toxicities were observed with plerixafor. Two patients had grade 1 bleeding from the catheter site during apheresis and one had dyspnea due to fluid overload that responded to furosemide. All patients went on to receive RA-SCT and there were no treatment-related deaths. Median number of CD34+ cells/kg infused was 7.7 × 106. Median number of days to ANC>500/μL was 11 (10–22), to platelets>20 000/μL untransfused 15 (9–34) and to lymphocytes>500/μL 14.5 (11–25). One patient developed
veno-occlusive disease and persistent thrombocytopenia and was given the remaining stem cells on day +31 with subsequent normalization of the blood counts. Mobilization with G-CSF and plerixafor was well tolerated in this group of patients with significant organ impairment, including eight who had stage 2 cardiac involvement, two on HD, one with a previous SCT and one who was a year post orthotopic heart transplant. Limited leukaphereses were needed to achieve or exceed the target CD34+ cell dose. Plerixafor is excreted renally but is predicted to be easily dialyzable due to its small size and polarity. While the phase 3 study in myeloma excluded patients with creatinine ⩾ 2.2 mg/dL, studies of dose-adjusted use in myeloma and AL patients with severe renal impairment were not associated with additional toxicity.3,4 With an expanding role of SCT in patients with amyloidosis as initial therapy in selected patients, as consolidation after induction and as second-line therapy, the tolerability and efficacy of mobilization have become important issues. The use of plerixafor with G-CSF for mobilization can make the option of SCT available to patients who have been heavily pretreated or have multiple organs involved and might otherwise be bereft of effective treatment options. In this era of more effective initial therapies, an era in which many AL patients are living longer with moderate to severe organ damage and are receiving multiple lines of therapy including SCT, this approach allows not only the collection of sufficient CD34+ cells for optimal immediate use but also the cryopreservation of aliquots for future use, for a second SCT should it become necessary or for novel cell-based immunotherapies should they become available. CONFLICT OF INTEREST RLC: consultant/scientific advisor, Takeda, Prothena; clinical research funding, Takeda, Prothena, Teva. The other authors declare no conflict of interest.
E Kaul, G Shah, C Chaulagain and RL Comenzo Division of Hematology and Oncology, Tufts Medical Center, Boston, MA, USA E-mail: [email protected] REFERENCES 1 Comenzo RL, Fein DE, Hassoun H, Bello C, Chou JF, Devlin S et al. Long-term outcomes of patients with systemic light chain amyloidosis (AL) treated at diagnosis with risk-adapted stem cell transplant and consolidation with novel agents. ASH Annu Meet Abstr 2012; 120: 3150. 2 DiPersio JF, Stadtmauer EA, Nademanee A, Micallef IN, Stiff PJ, Kaufman JL 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: 5720–5726. 3 Douglas KW, Parker AN, Hayden PJ, Rahemtulla A, D'Addio A, Lemoli RM et al. Plerixafor for PBSC mobilisation in myeloma patients with advanced renal failure: safety and efficacy data in a series of 21 patients from Europe and the USA. Bone Marrow Transplant 2012; 47: 18–23. 4 Dunn D, Vikas P, Jagasia M, Savani BN. Plerixafor in AL amyloidosis: improved graft composition and faster lymphocyte recovery after auto-SCT in patient with end-stage renal-disease. Bone Marrow Transplant 2012; 47: 1136–1137.
