Division of HematologyOncology, European Institute of Oncology, Milan, Italy (E-mail: francesco.bertolini@ieo.it)
High-dose chemotherapy (HDCT) followed by reinfusion of autologous peripheral blood progenitor cells (PBPC) is widely used in the treatment of cancer patients. However, controversy still remains around the issue of the adequate number of PBPC to be reinfused in order to obtain a prompt and stable hematopoietic rescue. According to recent studies and reviews [13], the recommended dose for autologous transplantation is 58 x 106 CD34+ cells/kg. This recommendation is mostly based upon faster platelet (rather than neutrophil) recovery with increasing CD34+ cell dose, and the fact that reconstitution of durable hematopoiesis capable of coping with further chemotherapy and/or radiation therapy, infections or surgery occurred in one single 1994 study on 34 cancer patients who received 8 x 106 CD34+ cells/kg after HDCT [4]. Here, we report our experiences of 433 patients who underwent a total of 1019 HDCT courses followed by reinfusion of PBPC collections containing a median of 2.4 x 106/CD34+ cells/kg. Median patient follow-up was 34 months.
Of the 433 patients evaluated, 281 had high-risk, stage IIIII breast cancer (BC), 14 had ovarian cancer (OC), 22 had other solid tumors (ST), 93 had non-Hodgkins lymphoma (NHL), 18 had multiple myeloma (MM) and five had Hodgkins disease (HD). PBPC were mobilized by granulocyte colony-stimulating factor (G-CSF) alone in BC patients. ST, NHL, MM and HD patients were mobilized by cyclophosphamide 47 g/m2 plus G-CSF. OC patients were mobilized by epirubicin and docetaxel plus G-CSF. CD34+ cells were enumerated by flow cytometry using an FDA-approved, single plat-form kit (Procount; Becton Dickinson, Mountain View, CA). Results of intra- and interlaboratory controls (provided by Becton Dickinson and the European Working Group on Clinical Cell Analysis) [5] always fell within appropriate limits.
In all patients, the collection target was at least 2 x 106/CD34+ cells/kg for every planned HDCT course. BC patients underwent three courses of EC (cyclophosphamide and epirubicin; 49% of patients), T-EC (EC plus docetaxel; 21% of patients), ICE (ifosfamide, carboplatin and etoposide; 15% of patients) or T-ICE (ICE plus docetaxel; 15% of patients). OC and ST patients received three courses of ICE. NHL and HD patients received high-dose sequential therapy [4], and MM patients received a first course of melphalan and a second course of melphalan plus idarubicin. After HDCT, all patients received 5 µg/kg/day G-CSF until their neutrophil count exceeded 1000/µl.
Table 1 shows PBPC collection data and hematopoietic recoveries. A statistical comparison of G-CSF alone compared with chemotherapy plus G-CSF (Ch-G) data would be misleading for two reasons. First, CD34+ cell collection targets were different. Secondly, 39% of patients mobilized by G-CSF alone were previously treated with neo-adjuvant chemotherapy, whereas 87% of patients mobilized with Ch-G received multiple previous chemotherapy courses (P <0.01 by chi-square test). The 2 x 106/CD34+ cells/kg per planned HDCT course target was not reached in 52 out of 281 (18%) and 12 out of 204 (5%) patients mobilized by G-CSF alone and Ch-G, respectively (P <0.01). Among 204 patients mobilized by Ch-G, 52 were at the second mobilization attempt after mobilization with G-CSF alone. The frequency of patients mobilized by G-CSF alone who failed to collect 2 x 106/CD34+ cells/kg per planned HDCT course was not significantly increased among previously treated patients (19% compared with 17% in untreated patients). Following a crossover approach, patients who failed mobilization with G-CSF alone were mobilized by Ch-G, and 43 out of 52 (82%) collected >2 x 106/CD34+ cells/kg per planned HDCT course. On the other hand, 10 patients who failed Ch-G mobilization were mobilized by G-CSF alone, and 4 out of 10 collected >2 x 106/CD34+ cells/kg (P = 0.013).
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Regarding the durability of long-term hematopoiesis, after a median follow-up of 34 months (range 957), irreversible grade 24 cytopenia was not observed despite further radiotherapy administered to 67 and 21% of BC and NHL patients, respectively, and further chemotherapy administered to 33 and 48% of BC and NHL patients, respectively. No myelodysplastic syndromes (MDS) were observed. Two BC patients developed secondary acute leukemia (one AML FAB M4 and one pro-B ALL).
To the best of our knowledge, this is the largest series of data about autologous PBPC mobilization, single platform CD34+ cell enumeration, and HDCT and PBPC reinfusion reported from a single institution. Our data indicate that in a HDCT program, a PBPC collection policy based upon standardized, single platform CD34+ cell evaluation and a 2 x 106/CD34+ cells/kg threshold is associated with prompt hematopoietic recovery in >99% of patients mobilized with G-CSF. In more intensively pretreated patients mobilized with Ch-G, a prompt recovery was observed in 14 out of 179 patients (92%), whereas hematopoietic recovery was delayed for 1 or 2 and 3 or 4 weeks in the remaining 6 and 1%, respectively. Regarding PBPC mobilization failures, in the present study, 18% of patients mobilized by G-CSF alone failed to collect at least 6 x 106/CD34+ cells/kg in order to receive three HDCT courses. In 82% of these patients, a crossover Ch-G mobilization was effective. In previously treated patients who failed to mobilize after Ch-G, the crossover to mobilization with G-CSF alone was significantly less effective. Finally, it should be noted that all patients had a sustained long-term engraftment despite frequent boost radiotherapy and/or secondary chemotherapy, and the incidence of MDS and/or secondary hematopoietic malignancies was better or similar when compared with results reported in other studies where the PBPC collection threshold was two- to four-fold higher [14].
C. Corsini, F. Bertolini, P. Mancuso, S. Cinieri, F. Peccatori & G. Martinelli
Division of HematologyOncology, European Institute of Oncology, Milan, Italy (E-mail: francesco.bertolini@ieo.it)
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