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Factors Influencing Platelet Recovery After Blood Cell Transplantation in Multiple Myeloma

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Factors Influencing Platelet Recovery After Blood Cell Transplantation in Multiple Myeloma Bone Marrow Transplantation, (1997) 20, 375–380 1997 Stockton Press All rights reserved 0268–3369/97 $12.00 Factors influencing platelet recovery after blood cell transplantation in multiple myeloma MA Gertz1, MQ Lacy1, DJ Inwards1, AA Pineda2, MG Chen3, DA Gastineau1, A Tefferi1, RA Kyle1 and MR Litzow1 1Division of Hematology and Internal Medicine, 2Division of Transfusion Medicine, and 3Division of Radiation Oncology, Mayo Clinic and Mayo Foundation, Rochester, MN, USA Summary: cells result in durable engraftment after transplantation.2 Hematopoietic recovery can be accelerated by the use of We sought to determine factors that impact on the blood stem cells mobilized with growth factors or chemo- recovery of platelets after blood cell transplantation in therapy (or both). Hematopoietic recovery is more rapid patients with multiple myeloma. We performed retro- after mobilized peripheral blood stem cell transplantation spective analyses in 51 patients undergoing blood cell than after autologous bone marrow transplantation, and transplantation for multiple myeloma. The pro- hematopoietic recovery has been shown to be sustained, portional-hazards model was applied to determine sig- indicating that accessory cells found in the bone marrow nificant risk factors. Of 51 transplants, 14 patients failed are not required for durable engraftment.3 The more rapid to achieve a platelet count of 50 × 109/l. Median time to engraftment with mobilized stem cells is likely due to an a neutrophil count of 0.5 × 109/l was 10.5 days. Median increase in committed progenitors. The addition of bone time to achieve a platelet count of 50 × 109/l was 32 days. marrow to blood stem cells appears to be unnecessary.4–6 Multivariate analysis revealed that cyclophosphamide In myeloma, tumor contamination appears to be less fre- and G-CSF priming before collection of hematopoietic quent in peripheral blood stem cells compared with bone precursors (P , 0.001) was a positive predictor of rapid marrow in the same patient.7 In most but not all cases, engraftment and prior exposure to melphalan given unmanipulated peripheral blood stem cell products are pref- orally (P = 0.02) was a negative predictor of subsequent erable to bone marrow harvests as a method of reducing platelet engraftment. The number of mononuclear cells myeloma autograft tumor contamination.8 For these collected, the patient’s disease status at the time of reasons, mobilized blood stem cell transplants have largely transplant and the presence of circulating plasma cells replaced autologous bone marrow transplants for multiple in the harvested product did not have a significant myeloma. impact on time to platelet engraftment. We conclude The median time to achieve sustained platelet counts that cyclophosphamide and G-CSF priming shortened greater than 50 × 109/l has been reported to be as short as the time to achieve platelet engraftment compared with 15 days after peripheral blood stem cell transplantation.9 G-CSF alone. Prior exposure to melphalan delayed Others have demonstrated a reduced ability to mobilize pro- platelet engraftment and can lead to complete failure of genitors in patients who have myeloma compared with platelet recovery. Stem cells should be collected before those who have lymphoma.10 Moreover, complete failure melphalan administration in patients with multiple of platelet recovery has been reported, and some patients myeloma who are candidates for possible blood cell have taken in excess of 50 days to achieve a platelet count transplantation. of 20 × 109/l.11 Keywords: hematopoietic stem cell; leukapheresis; We also have encountered patients undergoing peripheral melphalan; multiple myeloma; stem cell transplantation blood stem cell transplantation for multiple myeloma who experienced delayed or inadequate platelet engraftment. Failure of platelet recovery is rarely seen in our larger group of patients undergoing peripheral blood stem cell Myeloablative chemotherapy with infusion of hematopo- transplantation for recurrent malignant lymphoma. We ietic precursors, capable of reconstituting marrow function, undertook the current study to determine if there are clinical is applied increasingly in the primary management of predictors for the risk of poor platelet recovery in patients patients with multiple myeloma. Initially, autologous bone who receive transplants for multiple myeloma. marrow was reinfused with up to 30% plasma cells with excellent reconstitution of hematopoietic function.1 It was subsequently demonstrated that there are circulating hema- Materials and methods topoietic progenitor cells that can be collected and these Patient population Correspondence: Dr MA Gertz, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA The patients included in this study all had multiple mye- Received 15 December 1996; accepted 5 May 1997 loma and underwent blood cell transplantation between Platelet recovery in myeloma transplant MA Gertz et al 376 May 1989 and May 1996. All patients gave written infor- cells/kg. In four patients, the goal was 6 × 108 mononuclear med consent. Consent was in accord with the Declaration cells/kg, and this goal was achieved in all four. of Helsinki. The consent form was approved by the Insti- Eleven patients received conditioning with melphalan tutional Review Board of Mayo Foundation. All patients 140 mg/m2, plus total body radiation 12 Gy, and cyclophos- were followed until 1 August 1996, and none were lost to phamide 60 mg/kg daily for 2 days. Thirty-five received follow-up. conditioning with melphalan 140 mg/m2, plus total body radiation 12 Gy. Two received cyclophosphamide 60 mg/kg daily for 2 days and total body radiation of 12 Gy. Two Stem cell procurement and conditioning received standard-dose busulfan and cyclophosphamide, Thirty-one patients received G-CSF priming (Table 1), 5 and one received melphalan 200 mg/m2. Forty-eight of the mg/kg subcutaneously daily, until the completion of periph- 51 received radiation and three received conditioning with eral blood stem cell collection. For patients receiving G- non-radiation-containing regimens. CSF alone, stem cell apheresis was begun on the fifth day following G-CSF initiation. Definition of engraftment Cyclophosphamide priming was added in June 1994.12,13 The 12 patients who received cyclophosphamide priming All patients had the following measurements taken on a were given 1.5 g/m2 over 60 min daily for 2 consecutive daily basis for the first 30 days after stem cell infusion: days. The dose of cyclophosphamide was selected to obvi- white blood cell count, absolute neutrophil count, and plate- ate the need for uroprophylaxis. An attempt was made to let count. From day +30 to day +100, the counts were meas- have the entire collection procedure be performed as an ured at a minimum of once weekly. The definition of gra- outpatient procedure. To minimize the period of severe nulocyte engraftment was the first day of 3 consecutive granulocytopenia, a dose of 1.5 g/m2 × 2 days was selected. days in which the absolute neutrophil count exceeded Following cyclophosphamide, G-CSF was begun on day 3. 0.5 × 109/l. Platelet engraftment was considered the first Stem cell apheresis began when the total white cell count day of 3 consecutive days in which the platelet count recovered to greater than 500/ml. Of the 12 patients, five untransfused exceeded 50 × 109/l. required platelets during collection. Ten liters of blood were processed with each leukapher- Statistical analysis esis collection. The target progenitor cell number was 8 × 108 mononuclear cells/kg in 47 of the patients. This All patients were assessed at day +100 for graft function. goal was achieved in 42 of the 47, with the remaining five At day +100, patients who did not fulfill these criteria were collecting 7.7, 7.4, 6.9, 6.8 and 3.8 × 108 mononuclear censored as graft failures. All patients who died before day Table 1 Patient characteristics Variable Number or range Median Age, years 32–69 (53) Sex 31 M/20 F Myeloma bone disease 48 Creatinine, mmol/l 50–210 (80) b2-Microglobulin, mg/l 0.9–9.5 (3.2) % Marrow plasma cells at transplantation 2–95 (34) Bone marrow labeling index, % 0–7.4 (0.9) No mobilization 8 G-CSF primed collection 31 CTX- and G-CSF-primed collection 12 Disease response to prior chemotherapy 42 Chemotherapy resistant at time of conditioning 34 Post-BMT complete response 18 Pheresis day 1: count, × 109/l Leukocyte 2.0–22.6 (11.5) Lymphocyte 0.04–3.16 (0.86) Monocyte 0.04–1.14 (0.35) Total MNC infused × 108/kg 3.8–18.5 (9.1) Prior exposure Melphalan 37 CTX 22 BCNU 22 Durie–Salmon stage IIA 6 IIB 1 IIIA 36 IIIB 8 CTX = cyclophosphamide; MNC = mononuclear cells. Platelet recovery in myeloma transplant MA Gertz et al 377 +100 who failed to achieve engraftment as defined above above as well as the two patients who had granulocyte were censored on the date of death. No patients were engraftment after day +100. Of the nine remaining patients, excluded from analysis. Graft function analysis was perfor- three represent early deaths before platelet engraftment but med using the Kaplan–Meier method. Multivariate analysis after granulocyte engraftment and six were true failures of was performed using the proportional-hazards model (Cox). platelet recovery in spite of survival beyond day +100. Fig- All P values were calculated by log-rank (Mantel-Cox) test. ure 1 demonstrates the time course of platelet recovery in all 51 patients. There is a steeply sloped portion of the curve from day +7 until day +18 that reflects a subset of Results patients with rapid platelet engraftment. After day +20, the curve levels out, indicating delayed platelet recovery for A total of 51 patients had transplants, and their character- roughly half of the patients. istics are given in Table 1. At the time of pretransplant In vitro measurement of granulocyte–macrophage col- evaluation, the median percentage of bone marrow plasma ony-forming units (GM-CFU) was performed in 35 of the cells was 34%, with 54% of the population having greater 51 patients.
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