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Sequential peripheral blood progenitor cell transplantation after mobilization with salvage chemotherapy and G-CSF in patients with resistant lymphoma

Sequential peripheral blood progenitor cell transplantation after mobilization with salvage chemotherapy and G-CSF in patients with resistant lymphoma
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  American Journal of Hematology zy 6:18-23 (1994) Sequential Peripheral Blood Progenitor Cell Transplantation After Mobilization With Salvage Chemotherapy and G-CSF in Patients With Resistant Lymphoma Simona Sica, Antonella Di Mario, Prassede Salutari, Benedict Etuk, Michela S. Jovino, Luca Pierelli, Roberto Marra, Luciana Teofili, Giacomo Menichella, Giuseppe D’Onofrio, and Giuseppe Leone lstituto di Semeiotica Medica Divisione di Ematologia Universita Cattolica Sacro Cuore Rome Italy We enrolled 18 patients affected by refractory or relapsed lymphoma (HD, NHL) in a two-step protocol that included salvage chemotherapy with mitoxantrone, carboplatinum, methylprednisolone, and cytosine arabinoside (MiCMA) plus G-CSF (5 pglkglday), periph- eral blood progenitor cell (PBPC) collection, and subsequent transplantation after BUCY2 regimen. After MiCMA chemotherapy, four patients (22 ) achieved complete response, eight patients (44 ) obtained a partial response, and six showed progression of disease (PD). Fourteen out of 18 patients (78Y0) were considered eligible for PBPC transplantation. Three patients with complete response refused PBPCT; they are currently in continuous complete remission (CCR) at 15, 13, and 15 months, respectively. One patient has been recently transplanted but is too early to be evaluated. Ten patients so far completed the study, eight of whom are currently alive in CR, with a median follow-up of 7.5 months (range 2-13). Hematologic reconstitution was very rapid with a median time to achieve WBC > 1 x 109/L, PMN > 0.5 x 109/L, platelets > 50 x 109/L and > 100 x 10Q/L of 13 (range 9-15), 12 (range 9-14), 10 (range 0-22), and 14 (range zyxw -49 days, respectively. Our protocol is highly effective as a salvage treatment, while permitting PBPC collection after G-CSF administration. Hemopoietic reconstitution after transplantation of PBPCs col- lected with this procedure s complete, rapid, and sustained. Key words: lymphoma, salvage chemotherapy, peripheral blood progenitor cells, G-CSF zy   994 Wiley-Liss, Inc. INTRODUCTION zyxwvutsr utologous hemopoietic stem cells collected from the peripheral blood after high-dose chemotherapy [ 1-31 have been successfully used to restore marrow function after myeloablative chemotherapy and their use has been recommended in patients with marrow involvement or fibrosis. This procedure is therefore a viable alternative to autologous bone marrow transplantation (ABMT) and offers a number of advantages, which include collection of progenitor cells without general anaesthesia, more rapid engraftment with a reduction of supportive care, and reduction of length of hospitalization [4]. Although initially used in leukemias zyxwvutsr 5,6], hese transplants are now performed in lymphomas, myelomas and solid tu- mors [7-91. PBPCs represent less than 1 per 1,000hucleated cells circulating in steady-state condition. Several strategies 994 Wiley-Liss, Inc. for mobilization of PBPCs into the bloodstream have been reported [8,10,11]. Chemotherapy-induced mobili- zation occurs during the recovery phase after hypoplasia. Hemopoietic growth factors (G-CSF, GM-CSF, and IL3) also expand the pool of circulating progenitors. This ef- fect is amplified by combining chemotherapy with growth factors [ 11-15]. Thus far, supralethal chemother- apy followed by bone marrow transplantation is a world- wide accepted approach only in patients with resistant or relapsed lymphoproliferative malignancies. Received zyxwv or publication March 26, 1993; accepted September 22, 1993. Address reprint requests to Dr. Simona Sica, Istituto di Semeiotica Medica, Divisione di Ematologia, Universita Cattolica del Sacro Cuore, Largo A Gemelli 8-00168, Roma, Italia.  PBPCT After Mobilization With Salvage Chemotherapy and G-CSF 19 TABLE 1 Characteristics zyxwvutsr f Patients* zyxwvuts t Sexlage Previous PCT zyxwvut   Disease Status Response to Rx 1 CA MI57 F-MACHOP NHL PD PD 2 PM Fl45 CHOP NHL Re1 PR 3 LS MI57 CHOP NHL PR PR 4 CM MI38 MOPP/ABVD HD Res PD zyx   MF MI2 1 Promace-Cyt NHL Res PD 6 MV MI28 ABVDIMOPP HD Res PR 8 PG MI49 Promace-Cyt NHL Res PR 9 MI Fl17 LSA-L2 (mod) NHL PR PR 11 FM Fl27 Promace-Cyt NHL PD PD 13 BA M/58 Promace-Cyt NHL PR CR 14 CT MI38 Promace-Cyt NHL PR CR 15 DA F/33 Promace-Cyt NHL PD PD 16 MF MI20 F-MACHOP NHL PD PD 17 CM MI6 Promace-Cyt NHL Re1 PR 18 CA MI57 F-MACHOP NHL Re1 CR *NHL, Non-Hodgkin’s lymphoma; HD, Hodgkin’s lymphoma; PR, partial remission; PD, progressive disease; Res, resistant disease; Rel, relapse; Rx, treatment of patients 2-10 and 17, 18, were submitted to PBPCT. 7 CG M/47 Promace-Cyt NHL Res PR 10 GA Fl58 Promace-C yt NHL Re1 PR 12 AE MI43 Promace-Cyt NHL PR CR The aim of our study was to assess the feasibility of a two-step protocol including salvage chemotherapy with non-cross-resistant cytotoxic drugs (mitoxantrone, carbo- platinum, and cytosine arabinoside), followed by G-CSF, PBPC collection, and subsequent supralethal chemotherapy with PBPC reinfusion in patients affected by lymphoma, resistant to conventional chemotherapy. MATERIALS AND METHODS Eligibility Patients with hematoiogical malignancies (Hodgkin’s disease and non-Hodgkin’s lymphoma), aged 14-65 years, and performance status 0-1 WHO grading, were eligible. Patients resistant to standard chemotherapy or in partial remission (PR) or in untested relapse within 1 year were enrolled. The renal and hepatic parameters had to be normal and the left ventricular ejection fraction greater than 50 . Eighteen consecutive patients fulfilling the eligibility criteria entered the study. Ten patients (three females, seven males) completed so far the protocol; the median age was 46 years (range 18-61). The characteris- tics of patients and previous therapy are listed in Table I. Informed consent was obtained from each patient prior to the transplantation. Salvage-Recruitment Therapy The salvage chemotherapy used to recruit PBPCs con- sisted of mitoxantrone 10 mg/sm/day on day 1, carboplat- inum 100 mg/m2/day on days 1-4, methylprednisolone 500 mg/sm/day on days 1-5, and cytosine arabinoside 2,000 rngismiday on day 5 (MiCMA). G-CSF (Amgen Roche) was started the day after completion of chemo- therapy at a dose of 5 pg/kg/day subcutaneously for 10 days or more when leukapheresis was performed. Leukapheresis and Cryopreservation PBPCs were collected by leukapheresis during G-CSF administration when WBC was greater than 5 X 109L and PLTs were greater than 30 X 109/L. Leukaphereses were performed using the Fresenius AS 104 continuous- flow blood cell separator, using a previously described automated collection protocol. [ 161. PBPCs were cryopreserved using 20 dimethylsulfox- ide (DMSO) in 4% human albumin solution mixed with an equal volume of cell suspension. After freezing, PBPCs were stored in liquid nitrogen at 96°C. Clonogenic Assay for Hemopoietic Progenitor Cells Isolated mononuclear cells from each apheresis were plated at a concentration of 2 X lo5 per ml in IMDM containing 30% FCS, 1 L-glutamine, 10 PHA-LCM, 1 Pen-Strep, and 0.9% methylcellulose. Aliquots of 1 ml were plated in duplicate in 35-mm Petri dishes for 14 days in an atmosphere of 5 CO,, at 37°C. CFU-GM were scored as colonies of more than 40 cells. Pretransplant Conditioning Regimen (PBPCT) were treated with high-dose chemotherapy con- sisting of Bulsulfan 4 mg/kg/day on days -7 through -4 and of cyclophosphamide 60 mg/kg/day on days -3 and -2. Prophylactic phenytoin was given to all patients. To prevent cyclophosphamide-induced hemorrhagic cystitis, All patients submitted to PBPC transplantation  20 Sica et al. zyxwvutsrq e used hyperhydration, urine alkalinization with i.v. bicarbonate, and MESNA administration. PBPC Reinfusion On day 0, the PBPC bags (100 ml vol/bag) were thawed in a 37°C water-bath bedside, divided into two administrations, and then reinfused rapidly through a central venous catheter (Groshong, Salt Lake, UT). Asymptomatic transient hemoglobinuria was observed in all patients, together with transient serum lactate dehy- drogenase (LDH) elevation. Supportive Measures All transplanted patients were maintained in a positive- pressure room and given irradiated blood products zyxwv   1,500 cGy). They received prophylactically cyprofloxacine, acyclovir, cotrimoxazole (until day , and oral ampho- tericin B. When fever exceeded 38 C, broad-spectrum antibiotics were administered; and when fever persisted for more than zyxwvutsrq   days, despite appropriate antibacterial treatment, amphotericin B was added empirically. The patients also received i. v. immunoglobulin (400 mg/kg/ week). Definitions of Hematologic Recovery Time to reconstitution of hematologic function was defined as the number of days from reinfusion of PBPC to recovery of WBC greater than I X 109/L, PMN greater than 0.5 X 109/L, PLTs greater than 50 X 109/L and 100 X 109/L. Hemopoietic recovery was also evaluated on bone marrow examination on days +7, + 14, and +21 after PBPC reinfusion. RESULTS Eighteen patients entered the protocol. A minimum of two courses of MiCMA was scheduled for each patient in order to obtain an adequate number of PBPCs. Actually, two patients were given only one course, since they died early from progressive disease, whereas most patients were given additional courses of MiCMA in order to reduce tumour burden in responsive patients and/or to obtain an adequate number of PBPCs. In resistant cases, PBPC collection was started shortly after the first course of MiCMA, whereas in relapsed patients the leukaphereses were postponed after the sec- ond course of MiCMA. G-CSF was always given after each course of MiCMA. No severe toxicity related to the treatment was observed. All patients experienced short (less than 1 week) but profound neutropenia (60 grade 3 and 40% grade 4 WHO) and thrombocytopenia (grade zyxwv   WHO). Moreover no life-threatening infections were ob- served and no platelets transfusions were required. No adverse events caused by G-CSF were observed during the administration. Response to treatment was defined TABLE II. Treatment and Outcome of Patients No. of Disease status MiCMA Response Tx survival Pt courses to Rx YIN mo) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 zyxwvut 3 3 3 3 3 4 3 2 3 2 2 4 3 2 1 3 3 PD PR PR PD PD PR PR PR PR PR PD CR CR CR PD PD PR CR N Y Y zy   Y Y Y Y Y Y N N N N N N Y Y PDD 3+ CRA 12+ CR A 13+ PDD 7- PDD 9- CRA z   CRA 8+ CRA 7+ CRA 2+ CRA 5 CR A IS CR A 13+ CR A z S PDD 4- PDD 1- PDD 1- CRA 3+ NE *Rx, treatment; Tx, transplant; NE, not evaluable. according to the following criteria: partial response (PR) was considered a reduction of more than 75% of srcinal disease, resistant disease (RD) as a reduction of less than 75% of srcinal disease, and progressive disease (PD) as no response (less than 25%) or progression. Complete response was observed in four patients (22%), eight pa- tients achieved PR (44%), and six patients showed PD, three of whom died from disease before transplantation and one of whom was considered uneligible because of extensive deep venous thrombosis with recurrent pulmo- nary embolism. Fourteen patients were eligible for PBPCT; three patients with complete response refused to proceed to transplantation and are currently alive and in CCR with a follow-up of 15, 13, and 15 months, respec- tively. One patient has been transplanted too recently to be evaluated (Table 11). At the time of this writing, 10 patients completed the protocol, and the following results are from the above- mentioned patients. A median number of eight leuka- phereses (range 5-10) was performed and a median num- ber of 11.75 mononuclear cells (MNC) X 10S/kg bw was achieved (range 4.08-17.9). The median number of CFU-GM X 104/kg bw was 90.55 (range 20-257.5). The patients started PBPC collection at a median of 13 days (range 9-17) after completion of chemotherapy. The me- dian time to achieve WBC > 1 x 109/L, PMN > 0.5 X 109/L, platelets > 50 X 109/L and > 100 X 109/L was, respectively, 13 (range 9-15), 12 (range 9-14), 10 (range 0-22), and 14 (range 5-49) days. Starting from day +7 the morphological examination showed the pres- ence of trilineage engraftment in all patients.  PBPCT After Mobilization With Salvage Chemotherapy and G-CSF 21 TABLE 111 Hemopoietic Reconstitution After PBPCT zyxwv NC zyxwvutsr FU-GM PMN PLTs Pt No. LKP zyxwvutsrq   IOs/kg X 104/kg X 10 zyxwvut 0.5 >1 X 10 >50 >I00 2 3 4 5 6 7 8 9 10 17 18 10 8 9 8 9 8 8 zyxwvutsrqp   5 8 zyxwvutsr   12.6 13.2 11.8 17.9 11.7 13.9 9.3 3.58 9.96 7 8.6 122.3 94.8 86.52 257.3 69.8 83.02 129.3 68 1 I6 77,7 131.65 14-15 12-13 12-14 14-15 11-13 10-11 9-9 12-14 10-12 13-15 10-1 1 10-19 1 2-30h 20-4Oh 9- 1 2h 1 1-12b 8-14 8-1 10-49b 10-1 1 -8 *LKP, leukaphereses. aPatient No. 5 showed PLTS >50,000/mm3 for the entire post-transplant period hPatients who experienced late zyxwvut nd ransient thrombocytopenia. Six out of 10 patients showed a transient thrombocy- topenia about 30-50 days after transplantation. They did not required platelets transfusion and a normal platelet count was restored in all patients within 2 weeks (Table 111). The median number of days with Tc > 38°C was 3.5 (range 0-6). We observed only five microbiologically documented infections (four Staphylococcus epidermidis and one Staphylococcus simulans septicemia). Only five patients required RBC transfusion. The pa- tients required a mean of 8 platelets units. The median time of hospitalization was 25 days (range 22-27). Of these patients, eight are currently alive, all of them in CR with a median follow-up of 7.5 months (range 2-13); the two patients transplanted in PD died from disease pro- gression after 7 and 9 months, respectively. DISCUSSION Encouraging data are currently available on the use of salvage chemotherapy with or without autologous bone marrow transplant in lymphoproliferative disease. The experience of MD Anderson has already showed the effi- cacy of a high-dose salvage chemotherapy, including dexamethasone, ara-C, and cisplatin, and a large multi- center trial is currently ongoing comparing this regimen alone or in combination with autologous bone marrow transplant in relapsed non Hodgkin's lymphoma 17,181. The combination of mitoxantrone, carboplatinum, cy- tosine arabinoside, and methylprednisolone in our expe- rience had several advantages: the drugs that have been used are not generally included in the first-line chemo- therapy regimen in lymphoma patients, they still retain a high antitumor efficacy with minimal adverse effect (i.e., cardiotoxicity and nefrotoxicity), and finally they can influence the mobilization of PBPC and their collection, particularly in combination with G-CSF 12-19]. These considerations probably account for the low toxicity and high efficacy obtained with our protocol. The capability of PBPCs, collected after chemotherapy or in steady-state condition, to restore hemopoietic func- tion after myeloablative regimen is already well estab- lished [1,2,4,6]. The recent introduction of growth fac- tors (GM-CSF, G-CSF, and IL-3) to clinical practice has renovated the interest in the field of PBPCT. In fact, these molecules determine an increase of hemopoietic progenitors and their mobilization in the peripheral blood [ll-14,20-221. In our study, G-CSF was employed successfully in order to collect PBPCs after chemotherapy. A high num- ber of CFU-GM and MNC were collected in patients treated with MiCMA chemotherapy + G-CSF adminis- tration; in our previous experience, the yield of CFU-GM from the same median number of eight leukaphereses in patients given only MiCMA (unpublished data) or other chemotherapy without G-CSF [23] was markedly inferior (median 20.7 vs. 110). The high efficiency of our protocol made it possible to proceed to PBPC reinfusion without bone marrow sup- port. Furthermore our salvage chemotherapy was able to obtain a high percentage of response in heavily pretreated patients (CR 22%, PR 44%). In our patients submitted to PBPCT, we observed a very short period of neutropenia; this has been reported by us and others who were also using PBPC not primed with growth factors [5-231. No major infectious episodes were observed, with a median of 3.5 days with fever >38 C (range 1-10). Our data confirm the emergency of gram-positive bacterial infections after BMT, probably related to central venous access [24]. Unexpectedly we observed a striking reduction in the length of thrombocytopenia, this finding confirming data reported by other authors and by us in a previous report  22 zyxwvutsrq ica et al. zyxwvuts 4-251. Duhrsen et al. described the sudden appearance of circulating megakaryocyte precursors, as shown by the presence of a high number of CFU-Meg after G-CSF exposure zyxwvutsrq 26] Thus, the above-mentioned observation can partially account for the difference in the length and severity of thrombocytopenia after infusion of PBPCs recruited with G-CSF zyxwvut 4] oth the shortening of neutro- penia and thrombocytopenia justify the low toxicity of our schedule, thus permitting admittance of elderly pa- tients to an aggressive protocol. Considering the median age of our series, no differences in terms of toxicity were observed in patients over the age of zyxwvuts 0. Comparing our results, in terms of engraftment, with other series using PBPCT followed by G-CSF [4], we agree that the use of the G-CSF also after transplantation does not further reduce the time requested t achieve a sustained engraftment [27]. Due to the kinetic of engraft- ment, the requirement of platelets and of red blood cell transfusion was particularly low, with some patients re- quiring no transfusion. This observation indirectly con- firms the capability of G-CSF to mobilize precursors of erythroid and megakaryocytic lineage [26]. On the other hand, in vitro studies, conducted in our laboratory, on purified CD 34+ PBPCs obtained from some of above mentioned patients, showed the presence of a high num- ber of BFU-E and CFU-Meg (unpublished data). Almost all patients experienced a transient fall in platelets counts about 3 days after PBPCT, but they did not show hem- orrhagic symptoms and they did not require platelets transfusions. In all patients a normal platelet count was restored within 2 weeks. This phenomenon is already well known [25-271 and is probably related to the gap generated by the exhaustion of committed megakaryo- cytic precursors and the delay in the differentiation from more primitive progenitor cells. We failed to demonstrate any correlation between the number of CFU-GM or MNC and the time requested for hemopoietic recovery, as reported by others [3], yet the high number of MNC infused in all patients could ob- scure this correlation. The number of leukaphereses per- formed in our study is undoubtedly high but is related to a prudential approach favouring a collection of a high num- ber of PBPCs. The scarce yield of some collection could be related to the previous exposure to several courses of chemotherapy and to the age of patients in which mobili- zation was attempted. Long-term follow-up of these pa- tients shows complete self-sustaining of hemopoiesis, with the longest observation being 13 months after PBPCT. In conclusion, the sequential administration of a sal- vage chemotherapy such as MiCMA plus G-CSF, fol- lowed by transplantation of mobiiized PBPCs, is feasi- ble, with an almost negligible toxicity, as testified by the high number of patients completing the protocol, includ- ing many elderly patients. Furthermore, the pretransplant regimen BuCy2 differs from conventional salvage proto- col offering the possibility to rescue partial responders. Nonetheless, a longer observation is necessary to confirm these data. However, some conclusion can be drawn on patients with progressive disease who are probably not susceptible to response neither to our chemotherapy nor to the transplantation procedure. ACKNOWLEDGMENTS This work is supported in part by a grant from ARC (Associazione Italiana per la Ricerca sul Cancro). REFERENCES zyx . 2. 3. 4. zyxwv 5 6. 7. 8. 9. 10. 11. 12 Kessinger A, Armitage JO, Landmark JD, Weisemberger DD: Autol- ogous peripheral hemopoietic stem cell transplantation restores he- mopoietic function following marrow ablative therapy. Blood 71 :723- 727, 1988. Kessinger A, Armitage JO, Smith DM, Landmark SD, Bierman BJ, Weisemberger DD: High-dose therapy and autologous peripheral blood stem cell transplantation for patients with lymphoma. Blood 74: 1260-1265, 1989. Brice P, Marokau JP, Dombret H, Lepage E, Baruchel A, Adam M, Miclea JM, Sitthy X, Gisselbrecht C Autologous peripheral blood stem cell transplantation after high-dose therapy in patients with ad- vanced lymphomas. Bone Marrow Transplant 9:337-342, 1992. Sheridan WP, Begley CG, Juttner CA, Szer J, To LB, Maher D, McGrathic K, Morstyn G, Fox RM: Effect of peripheral blood progen- itor cells mobilized by Filgrastim (G-CSF) on platelet recovery after high-dose chemotherapy. Lancet 339:64&644, 1992. 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Abrams RA, Johnston-Early A, Kramer C: Amplification of circulat- ing granulocyte-monocyte stem cell numbers following chemotherapy in patients with extensive small cell carcinoma of the lung. Cancer Res 413-39, 1981. Elias AD, Ayash L, Anderson KC, Hunt M, Wheeler C, Schwartz G, Tepler 1, Mazanet R,Lynch C, Pap S, Pelaez S, Reich E, Critchlow J, Demetri G Bibbo J, Schnipper L, Griffin JD, Frein E 111, Antman KM: Mobilization of peripheral blood progenitor cells by chemother- apy and GM-CSF for hematologic support after high-dose intensifica- tion for breast cancer. Blood 7930363044, 1992. Shea TC, Mason JR, Stomiolo AM, Newton B, Breslin M, Muller M, Miller M: Beneficial effect from sequencial harvesting and reifusion of PBSC in conjunction with recombinant GM-CSF and high dose Carbo- platinum (CBDCA). Blood 76(suppl 1):165a, 1990.
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