Leukemia & Lymphoma

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Autologous Blood Stem Cell Transplantation in Malignant Lymphomas: An Italian Cooperative Study Ignazio Majolino, Anna Maria Quaglietta, Antonio Iacone, Rosanna Scime, Giuseppe Fioritoni, Luca De Rosa, Luca Pierelli, Alessandro Indovina, Antonio Spadano, Antonio De Laurenzi & Giacomo Menichella To cite this article: Ignazio Majolino, Anna Maria Quaglietta, Antonio Iacone, Rosanna Scime, Giuseppe Fioritoni, Luca De Rosa, Luca Pierelli, Alessandro Indovina, Antonio Spadano, Antonio De Laurenzi & Giacomo Menichella (1992) Autologous Blood Stem Cell Transplantation in Malignant Lymphomas: An Italian Cooperative Study, Leukemia & Lymphoma, 7:sup1, 11-16, DOI: 10.3109/10428199209061557 To link to this article: http://dx.doi.org/10.3109/10428199209061557

Published online: 01 Jul 2009.

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Leukemia and Lymphoma, Vol. 7, Supplement, pp. 11-16

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Autologous Blood Stem Cell Transplantation in Malignant Lymphomas: An Italian Cooperative Study IGNAZIO MAJOLINO’, ANNA MARIA QUAGLIETTA’, ANTONIO IACONE’, ROSANNA SCIME’, GIUSEPPE FIORITONI’, LUCA DE ROSA3, LUCA PIERELL14, ALESSANDRO INDOVINA’, ANTONIO SPADANO’, ANTONIO DE LAURENZ13 and GIACOMO MENICHELLA4 ‘Divisionedi Ematologia, Unita Trapianti, Ospedale V. Cervello, Palermo, ’Divisione di Ematologia e Centro Trasfusionale, Ospedale Civile, Pescara, 3Divisionedi Ematologia, Ospedale S. Camillo, Roma, 4Servizio di Ematologia, Universita Cattolica del Sacro Cuore, Roma. Twenty-three patients with malignant lymphoma, (7 Hodgkin’s, and 16 non-Hodgkin’s) in different phases of disease were autografted in 4 Italian Haematology institutions using only chemotherapy-mobilized blood stem cells (BSC) collected by apheresis. Clinical and laboratory data were analysed centrally and showed mean collection yields of 8.1 x 10’ kg mononuclear cells (MNC) (SE 0.5; range 2.613.8) and 24.1 x lo4 kg CFU-GM (SE 7.4; range 1.4162.9). The mean times required to attain 0.5 x 109/1 neutrophils and 50 x 109/1 platelets after marrow-ablative high-dose chemo + radiotherapy and BSC reinfusion were 14.9 days (SE 1.5; range 7-38) and 18.6 days (SE 2.6; range U 9 ) respectively. The incidence of early deaths was < 5 % and the requirement for support with blood product transfusion was moderate. The progression free survival (PFS) is >50% at 3 years with a median follow-up of 17.3 months. Results were significantly better for patients autografted in remission. These results suggest that autologous blood stem cell transplantation (ABSCT) may be proposed for the primary treatment of poor prognosis malignant lymphomas. However, ABSCT needs to be compared with autologous bone marrow transplantation (ABMT) followed by infusion of growth factors to accelerate recovery. KEY WORDS:

Circulating stem cell autograft lymphoma high-dose chemotherapy apheresis

Hodgkin’s disease

now become apparent’**. ABSCT and the use of growth factors, may then represent a means of improving clinical results by reducing the incidence of early deaths. We report a retrospective analysis of 23 patients, 7 with Hodgkin’s disease (HD) and 16 with nonHodgkin’s lymphoma (NHL), autografted with BSC in 4 haematological institutions in Italy. In all cases BSC were collected after one or multiple courses of intense chemotherapy, without growth factors. The study was addressed principally at determining: the efficiency of BSC mobilizing modalities; the time required for haematological reconstitution after autografting; the incidence of infectious complica-

INTRODUCTION Autologous blood stem cell transplantation was first used to treat patients with bone marrow involvement and patients who had previously received pelvic irradiation treatment. However the major advantage associated with this approach of a reduced period of post-graft cytopenia, with (presumably) reduced risk of infectious and haemorrhagic complications, has Address for correspondence: Dr lgnazio Majolino, Divisione di Ematologia, Unita Trapianti, Ospedale V. Cervello, Via Trabucco 180, 90146 Palermo, Italy. This work was in part supported by a grant of the “Associazione ltaliana per la Ricerca sul Cancro”.

I1

I . MAJOLINO, et al.

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tions; and the blood product transfusion support requirement.

to first-line chemotherapy and 9 (39%) had bone marrow involvement.

Blood stem cell mobilization, collection and cryopreservation In all cases, intensive chemotherapy was used to mobilize stem cells into the circulation. BSC were collected after each course of mobilizing chemoPatients therapy using continuous-flow cell separators (CSPatient characteristics are shown in Table 1. Mean 3000 (Baxterk19 patients and Vivacell (Didecok-3 age at autograft was 36.9 years for the whole group patients). In one case both the CS-3000 and the of patients with no statistical significant difference discontinuous-flow V50S (Haemonetics Corp) were between the HD and NHL groups. At diagnosis, over used. The collections were started at the time of rapid 90% were stage 111-IV, 60% had marrow involve- leucocyte and platelet increase after treatmentment (mainly NHL) patients and more than 50% had induced cytopenia. Timing of subsequent apheresis B symptoms. According to the data reported by procedures varied from centre to centre and is not individual centres, histological pattern for patients analysed here. After collection, cells were processed with HD was of mixed cellularity in 4, nodular with different methods, but invariably frozen in 10% sclerosing in 2 and lymphocyte predominant in 1. Of DMSO with a programmed device and stocked in the NHL group, 8 had high-grade malignancy, 5 liquid nitrogen in DF-700 Gambro bags. intermediate-grade, 2 low-grade and 1 unclassified Eleven different mobilizing regimens were emhistology. The status of patients at the time of BSC ployed, alone (22 patients) or in succession (1 patient). collection is shown in Table 1. At that time, 15 (65%) They were roughly classified into: (a) regimens patients had active disease and were either in relapse, containing only one drug at high dose (7g/m2 had progressive disease or shown a partial response Cyclophosphamide, HD-CY-7 patients; 2 g/m2 VP,

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MATERIAL AND METHODS

Table 1 Clinical characteristics of patients ( H D = Hodgkin's disease; NHL = non-Hodgkin's lymphoma) at diagnosis, at time of blood stem cell collection and at time of autograft. The age reported is that at time of autograft. Months Dia-ABSCT = time (in months) from diagnosis to autologous blood stem cell transplantation. CRI = 1st complete remission; CR > I = 2nd or subsequent complete remission; PR = partial remission (50% or more reduction of initial tumor burden); SR = sensitive relapse; P D = progressive disease. HD

NHL

All patients

No. patients Age, mean ( f SE) and (range) Sex (M/F) Months Dia-ABSCT, mean ( f SE) and (range)

7 38.4 & 4.1 (2C52) 413 40.5 f 14.3 (10.9-113.6)

16 36.2 f 3.1 ( 1 3-54) 1313 17.5 f 4.2 ( 7-17.2)

23 36.9 f 2.5 ( 1 3-54) 1716 24.5 f 5.5 (7- I 16.6)

At diagnosis

Stage 111-IV Marrow involvement B symptoms

6 1 5

12 13 8

21 14 13

collection

CR 1 CR > I PR Relapse PD Marrow involvement

-

5 2 1

CR 1 CR > I PR SR PD

-

Disease

At

At

autografi

I ~

3 3 1

2 ~

1

4

1

5 3 1 4 4

8

9

1 1 5 1 2

7 3 5 2 6

1

13

ABSCT IN MALIGNANT LYMPHOMAS

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HD-VP---I patient; 4 x 2 g/m2 ARA-C-1 patient) and (b) multiple-drug standard regimens (L-VAMP-2 patients ; CHOP-2 patients ; CY-AR A-C- 1 patient ; PROMACE, DHAP-3 patients; MINE-1 patient; BACHOMP-3 patients; LNH-86-1 patient; ACVP-1 patient). A mean of 2 (SE 0.2; range 1 4 ) courses of mobilizing chemotherapy and a mean of 8.6 (SE 0.6; range 4-15) apheresis collection procedures were used. In most cases, the chemotherapy administered for stem cell mobilization was also employed with the intention of reducing tumour burden. Autologous transplantation Mean time from diagnosis of ABSCT was 24.5 months (SE 5.5; range 7-1 16.6)for the entire population, with no statistically significant difference between H D and NHL patients (Table 1). A t the time of transplantation, 10 patients were in complete remission (CR), 5 in partial remission (PR), 2 in sensitive relapse (SR) and 6 had progressive disease (PD). NHL patients were predominantly autografted in remission, while over 50% of H D patients were autografted with PD. Transplant preparative regimens differed. The cyclophosphamide -TBI (CY-TBI) regimen was employed in 6 patients and in the remaining 17, only chemotherapy was used. The cyclophosphamideetoposide-BCNU (CVB) combination was used in 15 patients and the BCNU-etoposide-ARA-C-melphalan (BEAM) combination in 2. In all patients, only BSC were reinfused as autograft and in no cases were bone marrow cells added or growth factors employed to accelerate recovery.

RESULTS Blood stem cell mobilization and collection The wide variation in the numbers of collection procedures was at least in part dependent on the type of drug regimen used for BSC mobilization. The patients who received a high-dose, single drug mobilization protocol, such as HD-CY, had a high number of MNC and CFU-GM collected after a single course (Table 2). A mean of 8.1 x 10'kg MNC (SE 0.5; range 2.6-13.1) and 24.1 x lo4 kg CFU-GM (SE 7.4; range 1.4-162.9) were collected in the whole population. There was no statistical difference between HD (mean 8.3 x 10*kg MNC, SE 1.2 and mean 9.1 x 104kg CFU-GM, SE 3.2) and NHL patients (mean 8.0 x lo8 kg MNC, SE 0.6 and 30.7 x 104kg CFU-GM, SE 10.3). A weak correlation (r = 0.26) was found between number of MNC/kg and CFU-GM collected. However, when this analysis was carried after grouping patients according to the number of mobilization courses, a positive correlation between the numbers of MNC/kg and CFU-GM/kg collected was found for the group with < 2 mobilizing courses (r = O S O ) , while an inverse correlation (r = 0.71) was found for the group with >2 mobilizing courses. The efficiency of individual apheresis was analysed comparing the mean number MNC/kg AND CFU-GM/kg collected per single apheretic procedure according to the number of mobilizing courses given. As shown in Figure 1, the best yields were those aphereses conducted after a single drug mobilization protocol.

Table 2 Patients and relative collections were subgrouped according to the number of blood stem cell mobilization courses. Best CFU-GM yields, in contrast with apparently equal MNC yields, were obtained in patients submitted to 1 or 2 courses. These patients were also those who underwent a lower number of collection procedures. In most cases, the one-drug mobilization course was a high-dose cyclophosphamide regimen. No. Collection courses

No. patients No. drugs used:

1 >1

I

2 9 7 2

4

3 7 1

5 ~

2 ~

2

5.6 f 0.2 ( W

6 9.1 f 0.7 (7-12)

5

No. procedures, mean ( fSE) and (range)

12.8 f 0.8 (1&15)

10 f 2.0 (8-12)

Total MNC x 108/Kg collected, mean ( fSE) and (range) Total CFU-GM x 104/Kg collected, mean (kSE) and (range)

8.1 f 1.0 (3.8-13.8)

6.4 1.0 ( 2 . 6 1 1.3)

9.6 f 0.5 (7.8-1 1.3)

9.9 f 1.7 (8.2-1 1.6)

42.4 f 17.3 (8-1 62.9)

19.8 f 4.6 (2.942.9)

5.4 & 2.2 (1.4-13.7)

4.1 0.8 (3.3-4.9)

I. MAJOLINO, et al.

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1

I

1.56-11.6) and 21.7 x lo4 kg CFU-GM (SE 6.0; range 1.4-132.9) (Table 3). The number of CFU-GM infused was calculated on the basis of pre-freezing assays, due 10 , 1 60 to the lack of reliability of post-thawing data. There a 40 was no statistically significant difference in the number of infused MNC and CFU-GM between the C I 3O F NHL patients. H D and M U N Haematological reconstitution was evaluable in all c 4 20 0 M but one of the patients. This patient with H D died with tumour progression and bronchopneumonia on 2 (0 day +38 before engraftment had occurred. The time 0 0 required to attain 0.5 and 1.0 x 109/L PMN and 1 2 3 4 50.0 x 109/L platelets are shown in Table 3. NHL NUMBER OF MOBILIZING COURSES patients showed earlier recovery of PMN and platelet Figure 1 Mean yields of individual aphereses compared on the counts but these differences were not statistically basis of the number of mobilizing chemotherapy courses given t o patients. Best M N C and CFU-GM yields were those after a single significant. course of mobilizing chemotherapy. Significative differences for The probability of achieving 0.5 x 109/L PMN M N C were those between the groups with 1 and 2 courses within 14 and 21 days was respectively 44% and 79% (p < 0.05), as well as between the groups with 1 and 3 (p < O.Ol), while for CFU-GM a significative difference was found between 2 for the whole population. In the HD group these and 3 (p < 0.01) as well as between 2 and 4 (p < 0.01). percentages were respectively 30% and 6470, while in the NHL group they were 51% and 85%. The probability of achieving 50.0 x 109/L platelets within 14 and 21 days from ABSCT was respectively 35% Blood stem cell reinfusion and haematological and 57% for the whole population, 24% and 39% for reconstitution the H D group and 41 YOand 69% for the NHL group. After the completion of the preparative regimen, the No correlation was found between the number of patients received an autologous transfusion with a CFU-GM or MNC infused and haematological mean of 6.7 x lo8 kg viable MNC (SE 0.6; range recovery. MNC X l O E l l K 0

CFU-ON X lOE4IKO

Table 3 Number of mononuclear cells (MNC, x 108/Kg) and of CFU-GM ( x 104/Kg) infused, days to reach 0.5/1.0 P M N x 109/L and 50.0 Plt x 109/L, days of fever (>38"C) and of systematic antibiotics, number of packed red cell (PRC, units) and single donor platelet (Plt) units transfused. ~

Disease group

MNC infused ( x 108/Kg) CFU-GM infused ( x 104/Kg) Days to: PMN 0.5" PMN 1.0" Plt 50.0" Fever > 38°C. days Systemic antibodies, days PRC, units Platelets, units (single donor) a

x 1091~.

HD mean f SE (range)

6.6 k 1.2 (2.5-1 1.3) 9 k 3.2 (1.423.6) 18 f 3.2 (1 3-34) 28.8 f 8.1 ( 14-64 25.3 6.6 ( 1 ~ 9 ) 5.8 k 1.6 (@ 12) 18.7 f 6.0 (1-53) 5.7 f 1.6 (1-12) 8.5 f 3.7 (@30)

NHL mean f S E (range)

AN paiienis mean k SE (range)

6.8 f 0.7 (1.5-1 1.6) 27.3 f 8.3 (3.3-1 32.9) 13.8 & 1.7 (7-38) 17.6 f 2.3 ( I 1-50) 16.1 f 2.4 (639) 2.8 0.7 1) 10.6 1.6 ~ 7 2.8 f 0.6 (0-7) 3.6 f 0.6

6.7 f 0.6 ( 1 . 5 6 1 1.6) 21.7 k 6.0 (1.4-132.9) 14.9 f 1.5 (7-38) 20.7 f 2.8 (1 1-64) 18.6 k 2.6

(1-10)

(U9)

)

3.7 f 0.7 (0-12) 13.6 f 2.5 @53) 3.6 f 0.6 (1-30) 5.1 1.2 (0-30

+

15

ABSCT I N MALIGNANT LYMPHOMAS

Progression-free surv i u a l (years1 b y r e m l s s l o n a t ABSCT

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Post-graft course During the post-graft cytopenia 17 patients (77%) developed fever, with a bacterial or fungal isolation in only 8 patients (36%). Days of fever, systemic antibiotic therapy and quantitation of transfusional support are shown in Table 3. Seven out of the 13 patients not in CR prior to autograft achieved remission after ABSCT. We have used progression-free survival from time of ABSCT, rather than disease-free survival, in the follow-up of these patients. This takes into account the fact that complete resolution of lymphoma, as evaluated by imaging techniques, after transplantation may take months. The Kaplan-Meier product limit estimate was used. Of the 23 patients, 8 underwent progression of disease or relapse after 1.2-12.0 months (median 4 3 , 2 died with non-progressive disease at 5 and 13 months and 13 are currently alive and progression free at 5.6-36.9 (median 17.3) months from ABSCT. Progression free survival is > 50% at 3 years from ABSCT (Figure 2). No patient has undergone progression of disease beyond a year from ABSCT. A significant difference (Log Rank Test) in progressionfree survival was found between patients autografted in complete remission and the rest of patients (p = 0.02) (Figure 3). Progression-free survival was slightly better for HD than for NHL patients and for patients without bone marrow involvement. However, these differences were not statistically significant. Progression-free surv i u a i (years)

0

I

2

3

4

S u r v i v a l Time Figure 2 Kaplan-Meier product limit estimate of progression-free survival. More than 50% patients are projected to survive free of progression at 3 years from ABSCT. No patient has undergone progression of disease beyond a year from ABSCT.

1=CR Z=CR

-

4

Y

cr) Q d

I u)

L 0 3 d

z. L

3

cn

o.d 0

I

2

3

Suru i v a l Time Figure 3 Kaplan-Meier product limit estimate of progression-free survival by status at autograft. A significative (Log Rank Test) difference was found between patients autografted in complete remission and the rest of patients (p = 0.02). Progression-free survival did not differ significantly when analysed for disease type ( H D vs NHL) and for marrow involvement or remission at BSC collection.

DISCUSSION Intensive chemotherapy, growth factors or both may be used to mobilize stem cells into the circulation, resulting in a many fold increase of BSC yield on apheresis collection, the magnitude of which being related to intensity of the preceding myelosuppression'. Any of these mobilization methods enable re-infusion of a high number of committed progenitor cells, thus shortening the period of post-graft cytopenia. The haemopoietic reconstitutive capacity of BSC seems to be related to the number of committed progenitors3. In this multi-centre retrospective study, we have shown that a high number of MNC and CFU-GM may be collected in the majority of patients. The assignment to any of the mobilizing regimens was made by individual centres and as this was not randomised, comparison is of limited value. Moreover, the methods for assay of CFU-GM differed among contributing centres, a problem that will be overcome using the more reliable determination of CD34 + ve cells by flow cytometry4. We have shown that patients receiving single high-dose regimens, such as HD-CY, yield greater numbers of stem cells on apheresis as compared to other multiple-drug conventional regimens. This is in agreement with data

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1. MAJOLINO, et a/.

reported by other investigators. It is worth noting that together with evaluation of advantages offered by in our hands, HD-CY has also proved to effectively growth factors is needed. reduce tumour burden in a considerable fraction of advanced lymphoma patients’, another argument in favour of its use prior to ABSCT. We still don’t know exactly what factors influence REFERENCES the BSC collection in lymphoma patients and the present study does not clarify this point. In fact, after 1. Majolino, I., Scime, R. and Indovina, A. (1990). Autoloyous Blood Haematologica, 75, 555-66. statistical analysis, factors such as lymphoma type 2. Kessinger, A. and Armitage, J. 0.(1991). The evolving role of (HD vs NHL), marrow involvement by tumour or autologous peripheral stem cell transplantation following remission status at time of BSC collection do not high-dose therapy for malignancies. (Editorial) Blood, 77, 21 1-13, appear to be significant. We have not analysed the 3. To, L. B., Dyson, P. G. and Juttner, C. A. (1986). Cell-dose amount of chemotherapy prior to BSC collection, a effect in circulating stem cell autografting. Lancet, 1I, 404-5. factor, along with degree of marrow involvement by 4. Siena, S., Bregni, P. G., Brando, B., etal. (1991).Flow cytometry for clinical estimation of circulating hematopoietic progenitors tumour, found to be related to CFU-GM collection6. for autologous transplantation in cancer patients. Blood, 77, In the context of ABSCT, bone marrow contamina4w9. tion at the time of BSC harvest is hardly analysable 5 . Gianni, A. M., Bregni, M., Siena, S., Orazi, A,, Stern, A. C., Gandola, L. and Bonadonna, G. (1990). Recombinant human as an independent variable. In fact, it may influence granulocyte-macrophage colony-stimulating factor reduces the final outcome at least in two different ways, hematologic toxicity and widens clinical applicability of namely by contamination of the graft and as a high-dose cyclophosphamide treatment in breast cancer and non-Hodgkin’s lymphoma. J. Clin. Oncol., 8, 768-78. separate prognostic factor per se. 6. To, L. B., Shepperd, K. M., Haylock, D. N., et a/. (1990). Single We have shown that the use of chemotherapy high doses of cyclophosphamide enable the collection of high mobilized BSC leads to a recovery of 0.5 x 109/L numbers of haemopoietic stem cells from the peripheral blood. Exp. Hematol., IS, 442-7. PMN in approximately 50% of patients by day 14 7. Indovina, A., Majolino, I., Scime, R., et al. (1991). High-dose and 80% by day 21 post graft. As a comparison, the cyclophosphamide: assessment of anti-tumour effect, toxicity median time to recover these counts were much longer and stem cell mobilizing activity in haematological malignancies. 2nd International Symposium on Peripheral Blood (30 days) in the study of Kessinger’, who reinfused Stem Cell Autograft. Mulhouse, September 3&0ctober 2, 1991 only steady-phase collected cells. In our study, (abstract). duration of fever and incidence of microbiological 8. Kessinger, A,, Bierman, P. J., Vose, J. M. and Armitage, J. 0. (1990). High-dose cyclophosphamide, carmustine, and etopoisolations were encouraging. This however should be side followed relapsed Hodgkin’s disease. Blood, 77, 2322 - 5 . judged with caution, since progress in antibiotic 9. Carella, A. M., Carlier, P., Congiu, A., et a/. (1990). Nine years prophylaxis and treatment may be more relevant than experience with ABMT in 128 patients with Hodgkin’s disease: an Italian study group report. Proceedings of the fifth duration of cytopenia. International Symposium on Autologous Bone Marrow In malignant lymphomas, conventional salvage Transplantation. Dicke, K. A,, Armitage, J. 0. and Dicke regimens offer largely disappointing results with Evinger, M. J., Eds. pp. 509-18. The University of Nebraska Centre. 25-30% of patients achieving CR, ABMT has a 10. McMillan, A. K. and Goldstone, A. H. (1991).Autologous bone mortality rate ranging from 2 to as high as 50°h9*’0. marrow transplantation for non-Hodgkin’s lymphoma. Eur. J . In the present study, the < 5 % early mortality rate Haematology, 46, 129-35. compares favourably with most ABMT studies in 11. Rabinowe, S . N., Nemunatis, J., Armitage, J. and Nadler, L. M. (1991). The impact of myeloid growth factors on engraftment lymphomas. A larger retrospective study possibly in following autologous bone marrow transplantation for malignant lymphoma. Sem. Haematol., 28, 6-16. the context of EBMT, comparing ABSCT and ABMT

Autologous blood stem cell transplantation in malignant lymphomas: an Italian Cooperative Study.

Twenty-three patients with malignant lymphoma, (7 Hodgkin's, and 16 non-Hodgkin's) in different phases of disease were autografted in 4 Italian Haemat...
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