Bone marrow transplantation in chronic lymphocytic leukemia and lymphomas

Biomed & Pharmaeother 1996;50: I 18-124 © Elsevier, Paris

Dossier "Non-Hodgkin's lymphomas"

Bone marrow transplantation in chronic lymphocytic leukemia and lymphomas ZS P a v l e t i c , M R B i s h o p * ,

PJ Bierman,

JO Armitage

Department c~/ Internal Medicine, Section o[" Oncology and Hematology, University of Nebraska Medical Center, Omaha, NE 68198-3332. USA

Summary - Until recently younger patients with B-cell chronic lymphocytic leukemia (CLL) have not been considered for treatment with high dose therapy and bone marrow transplantation (BMT). Current results show that both autologous and allogeneic bone marrow transplantation can induce a high percentage of long lasting remissions in younger patients with poor-risk CLL. Because of the investigational character of BMT for CLL, all eligible patients should be enrolled in clinical trials. Autologous BMT or peripheral blood stem cell transplantation (PSCT) have become standard therapies for relapsed patients with Hodgkin's disease (HD) or intermediate- and high-grade non-Hodgkin's lymphoma (NHL). Data on autologous transplantation for low-grade NHL are not mature enough and more experience is needed in order to assess the long-term value of such approach. Ongoing studies of high-dose therapy in lymphomas are focused on performing BMT earlier in the course of the disease and exploring alternative sources of hematopoietic rescue such as allogeneic stem cell transplantation.

chronic lymphocytic leukemia / lymphoma / bone marrow transplantation

BONE MARROW TRANSPLANTATION IN CHRONIC LYMPHOCYTIC LEUKEMIA B-cell chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the United States and Western Europe [14]. Median age at presentation is 65 years, and 85-90% of patients with CLL are older than 50 years at diagnosis. The prognosis is highly related to the stage of the disease, and presently there is no curative therapy for CLL [45]. It is estimated that in Europe and the USA about 2000 persons younger than age 50 are diagnosed each year [33]. Young patients with unfavourable prognosis have median survival less than three years. Until recently patients with CLL have not been considered for treatment with high-dose therapy and bone marrow transplantation (BMT). Recent improvements in supportive care and availability of new cytoreductive drugs such as fludarabine may allow the use of BMT in CLL.

* Correspondence and reprints.

Allogeneic bone marrow transplantation The European Bone Marrow Transplant Group (EBMTG) reported a multicenter experience on 17 younger patients with refractory CLL who were treated with allogeneic BMT [32]. All patients received a total-body-irradiation (TBI) containing preparative regimen, and most received cyclosporine and methotrexate for graftversus-host-disease (GVHD) prophylaxis. Three patients received T-cell depleted marrow. The complete remission (CR) rate was 88%. Eight patients died from various causes including one graft failure, one refractory CLL and two relapses. All evaluable patients developed acute GVHD. Fifty-nine percent had grade II-IV; there was one case of extensive chronic GVHD. Nine patients remained in CR at 4 to 48 months after transplant (table 1). This experience was updated in a combined report of the E B M T G and International Bone Marrow Transplant Registry [31].

Bonc marrow transplantation in chronic lymphocytic leukemia

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Table I. Results of bone marrow transplants in chronic lymphocytic leukemia.

Transplant type (ref no) Allogeneic EBMTG [32] Dana Farber [37] MD Anderson [29] Autologous Dana Farber [371 MD Anderson [29] Nebraska (peripheral blood)

No patients

Age (years)

No patients (Rai stage II1 or IV at transplant)

Complete remission*

Survival and median jollou' up (months)

Disease-/)'ee survival (months)

17

40 (32-49) 40 (31-54) 42 i25-55)

12

15 (88%)

1

6 (75%)

9

8 (73c7~)

9 (53%) (25.6) 7 (87%) ( I 1.7) 10 (91%) ( l 1)

9 (53%) (4-48) 6 (75%) (6-18) 9 (82%)*** (2-36)

45 !27-54) 59 (37-66) 50 (39 58)

5

10 (83c/i)

3

10 (91%)

0

8 (89%)

8 I1"*

12 11 9

I1 (92%) (5) 6 (54c/c) (10) 8 (89c~) (24)

10 (83%) (2-31) 3 (27%) (4-29) 6 (67%) (2-36)

* Including nodular remissions: ** one syngeneic transplant; *** one patient entered remission after second allogeneic BMT.

A total of 54 patients received allogeneic BMT from a matched sibling donor; 54% were Rai stage III or IV at transplant, 70% achieved hematologic remission and 44% r e m a i n e d alive a median of 27 months (5-80 months) after transplantation. Five patients died of progressive leukemia. Acute (grade II-IV) GVHD developed in 17 patients and extensive chronic GVHD in six. In two recent single-institution reports, all BMT patients were pretreated with multiple chemotherapy regimens including fludarabine [29, 37]. In one study [29] 7/11 patients had already failed fludarabine therapy. In both series preparative regimens included cyclophosphamide and TBI. Graft-versus-host disease prophylaxis consisted of T-cell depletion [37] or cyclosporinemethotrexate [29]. The rate of CR was high, ie, 75 and 73% respectively. Nearly all remissions were both phenotypic and molecular as determined by double-fluorescence and immunoglobulin gene rearrangement studies. There were two therapy-related deaths; only one patient had acute GVHD _> grade II, and one developed extensive chronic GVHD. The authors postulated that the low incidence of GVHD was due to pretransplant exposure to fludarabine and its additive immunosuppressive effects [29].

Autologous bone marrow transplantation The use of autologous bone marrow transplantation (ABMT) for CLL has recently been at-

tempted. The availability of new nucleoside analogues for cytoreductive therapy prior to bone marrow harvest has facilitated this approach. In pilot-studies from Dana Farber Cancer Institute and MD Anderson Cancer Center, a pre-transplant prerequisite was a state of minimal disease at harvest defined as less than 20% CLL cells in the bone marrow biopsy [29, 37]. Although all patients had failed prior therapies, the rate of CR was 83 and 91%, respectively (table I). Most remissions were confirmed both by phenotypic and molecular analysis. Median time to achieving neutrophil count > 0.5 x 109/L was 21 and 20.5 days, and average hospital stay was 31 and 32 days. At Dana Farber, there was only one toxic death and 10/12 (83%) patients remained alive in continuous CR [37], At MD Anderson, three patients relapsed with Richter's syndrome and died soon after transplant, two patients died of non-leukemic causes and only 6/11 (54%) survived, three in continuous CR, two in relapse and one with refractory CLL [29]. It is of interest that the patient with the longest remission received unpurged bone marrow. There were some differences between these two series. In the MD Anderson series, patients were older (median age difference 14 years) and much further from diagnosis (48 months versus 25 months). This may explain the higher mortality and higher relapse rate as compared to the Boston series. Furthermore, doses of TBI were not the same (10.2 cGy12.0 cGy versus 14.0 cGy) [7]. An update of results from Dana Farber [2] shows disease-free

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survival of 74% at 18 months without a difference between autologous and allogeneic groups. Little has been published on CLL and autologous peripheral blood stem cell transplantation (PSCT). Bastion et al [3] reported two patients who received autologous blood stem cells mobilized with cyclophosphamide and recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF). One patient died from graft failure, and the other was in CR at 12 months. At the University of Nebraska Medical Center, nine previously-treated CLL patients received high-dose therapy and GM-CSF mobilized autologous PSCT between 1991-1995 (unpublished results). There was one toxic death and all patients engrafted. Time to absolute neutrophil count > 0.5 x 109/L was 12 days [11-46] (unpublished results), and median length of hospitalization was 24 days [6-52] (unpublished results). All evaluable patients achieved CR, and 5/5 tested were in molecular remission. At median follow-up of two years, eight patients are still alive. Two relapsed at 25 and 30 months and six are in their original CR at 2-36 (median 13.5 months) postransplant (table I).

Infections

Bone marrow transplant patients with CLL are reported to have a higher incidence of unusual infections [2, 46, 53]. Bartlett-Pandite et al described two patients who developed toxoplasmosis infection of the central nervous system which had not been seen in more than 500 previous cases of ABMT for non-Hodgkin's lymphoma (NHL) at the same institution [2]. The group from Royal Marsden reported two patients after allogeneic BMT who had recurrent and unusually severe cytomegalovirus viremia and another patient with Listeria meningitis [53]. The first case of Legionella pneumophilia pericarditis ever reported in a BMT patient was diagnosed in an allogeneic BMT recipient with CLL [46]. One explanation for these infections is the underlying immunodeficiency associated with CLL. Another possibility may be immunosuppression caused by prior treatment with fludarabine. Fludarabine suppresses CD4 cells and is associated with increased number of infections in non-transplant patients [ 1].

Remission and cure

The definition of remission after BMT for CLL is controversial. Blood and bone marrow lymphocytosis, lymphadenopathy and organomegaly are observed to decrease within four weeks after transplant [32]. However, in some cases of allogeneic BMT for CLL, complete responses were delayed up to seven months [27, 44]. It is postulated that this delayed response could be caused by gradual disappearance of irreversibly damaged leukemic cells or by the effect of an immunologic graft-versus-leukemia mechanism. The role of residual lymphocytic hyperplasia in the bone marrow (so-called nodular remission) is not known. In one study, four out of five patients with nodular remissions after BMT had lymphocytes that were polyclonal. In a non-transplant setting, such changes were associated with shorter disease-free survival but did not adversely affect survival [42]. Chronic lymphocytic leukemia patients attain molecular remissions gradually within six months after BMT, and the presence of immunoglobulin rearrangements early posttransplant does not neccessarily represent a treatment failure [37]. However, absence of molecular markers of clonality posttransplant has a powerful negative predictive value for relapse [20]. Relapses observed as late as four years posttransplant warrant caution in defining cure after BMT for CLL [45]. Who should receive BMT for CLL?

Because of the investigational character of BMT for CLL all such patients should be enrolled in clinical trials. Current results show that BMT is a therapeutic option for younger patients with poor-risk CLL. Patients who have an HLAmatched sibling donor are candidates for allogeneic BMT. If autologous transplantation is considered, marrow collection should be performed while in a state of minimal disease and proceed to autologous BMT or PSCT, preferentially before disease progression. BONE M A R R O W T R A N S P L A N T A T I O N IN L Y M P H O M A

A substantial proportion of patients with NHL and Hodgkin's disease (HD) are not cured by their initial therapy. Results of conventional salvage

Bone marrow transplantation in chronic lymphocytic leukemia

chemotherapy for these patients are disappointing. This has led to the use of high-dose therapy regimens followed by ABMT or autologous PSCT for patients with lymphomas. Of 6,000 cases reported to the North American Autologous Bone Marrow Transplant Registry (NAABMTR) in 1994, 26% patients had NHL and 12% HD [25].

Intermediate and high-grade non-Hodgkin's lymphoma The use of ABMT for patients with recurrent and refractory intermediate- and high-grade NHL was evaluated in 100 patients from institutions in the United States and Europe [35]. Responders to conventional salvage chemotherapy (sensitive relapse) had a projected 3-year disease-free survival of 36%, while patients who failed to respond (resistant relapse) had a projected disease-free survival of 14%. A third group of patients who were refractory to primary therapy had a 0% projected disease-free survival. Other nonrandomized trials had demonstrated the prognostic significance of chemotherapy sensitivity for patients undergoing ABMT for NHL [11, 19, 22, 38, 5l]. In the PARMA trial, 109 patients with relapsed intermediate-grade and high-grade NHL were randomized between conventional salvage chemotherapy or ABMT [36]. After a median follow-up of 63 months the 5-year event-free survival and overall survival were significantly different, ie, 46 and 53% respectively in the ABMT group as compared to 12 and 32% in the chemotherapy group. Additional evidence for the utility of high-dose therapy in NHL comes from results of patients transplanted in first partial remission (PR) [11, 19, 22]. This concept has been further validated in two recent trials that show superior diseasefree survival rates of 63 and 72% for patients transplanted in first PR versus 46 and 49% with conventional salvage chemotherapy [18, 23]. A Dutch trial, however, failed to demonstrate improvements in outcome for patients in PR after three cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) who were randomized between ABMT or five additional cycles of CHOP [49]. High-dose therapy may be of greatest benefit if used as consolidation therapy for high-risk patients in first complete remission (CR). Several pilot studies have shown projected disease-free survival of 60-85% [15, 21, 34, 50]. The French-

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Belgian LNH87-2 study randomized 464 first CR NHL patients to receive conventional consolidation therapy or ABMT [24]. After a median follow-up of 53 months, 5-year disease-free survival and overal survival were not different. However, patients with poor-prognostic features had disease-free survival and overal survival rates of 57 and 65%, respectively, in the high-dose therapy arm versus 36 and 52% with conventional chemotherapy (P = 0.01 and 0.06, respectively).

Low-grade non-Hodgkin's l y m p h o m a There is relatively little experience with transplantation for low-grade lymphoma. At the Dana Farber Cancer Institute, a 47% 3-year disease-free survival was projected for 51 patients with lowgrade NHL after transplantation with autologous marrow purged with monoclonal antibodies directed toward B-lymphocytes [15]. Follow-up data from 142 patients shows a 51% projected disease-free survival at four years [17]. At the University of Nebraska Medical Center, failurefree survival at four years is estimated at 44% for 100 patients with follicular low-grade lymphoma undergoing unpurged ABMT or PSCT (unpublished results). These studies show a continued pattern of relapse after ABMT, and it is yet unclear if any patients have been cured [4, 12, 26, 43].

Hodgkin's disease Several large trials have investigated the role of ABMT for HD in relapse [5, 10, 13, 38, 40, 52]. Progression-free survival in these series varies from 25 to 50%. Improved outcome has generally been seen in patients without extensive prior therapy, with good performance status, longer initial remission duration and sensitivity to chemotherapy before transplant. The only reported randomized comparison of ABMT and conventional-salvage chemotherapy for HD was performed by the British National Lymphoma Investigation [30]. The event-free survival was projected to be 53% following ABMT, compared with 10% for patients who received conventional salvage therapy with the same drugs. Overal survival was not significantly different, however. Hodgkin's disease patients who fail to enter remission with initial c h e m o t h e r a p y have an extremely poor prognosis. At the University of

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z s pavletic et al

N e b r a s k a M e d i c a l C e n t e r , the 3 - y e a r p r o g r e s s i o n f r e e s u r v i v a l for s u c h p a t i e n t s a f t e r A B M T is 2 2 % ( u n p u b l i s h e d results). R e s u l t s f r o m o t h e r institutions s u g g e s t that 2 0 - 4 0 % o f p a t i e n t s w h o fail to e n t e r C R w i t h initial c h e m o t h e r a p y can a c h i e v e prolonged remissions following transplantation [10, 13, 41, 52]. As with N H L , t h e r e is p r e l i m i n a r y e v i d e n c e that t r a n s p l a n t a t i o n o f h i g h - r i s k H D p a t i e n t s in first r e m i s s i o n m a y i m p r o v e outc o m e [8].

Other sources of h e m o p o i e t i c rescue A u t o l o g o u s P S C T is m o s t useful for p a t i e n t s w i t h h y p o c e l l u l a r m a r r o w o r m a r r o w i n v o l v e d with tumor. O t h e r p o t e n t i a l a d v a n t a g e s o f P S C T o v e r A B M T i n c l u d e m o r e r a p i d e n g r a f t m e n t , less m a l i g n a n t c o n t a m i n a t i o n and i n c r e a s e d a n t i t u m o r e f f e c t . A r e t r o s p e c t i v e a n a l y s i s at the U n i v e r s i t y of Nebraska showed significantly better eventfree s u r v i v a l for g o o d p r o g n o s i s p a t i e n t s w i t h int e r m e d i a t e - g r a d e N H L w h o r e c e i v e d P S C T in c o m p a r i s o n w i t h A B M T [51]. A l t h o u g h o t h e r studies h a v e f a i l e d to n o t e such d i f f e r e n c e s , results o f a u t o l o g o u s P S C T for N H L and H D a p p e a r at least as g o o d as A B M T [4, 6, 38]. T h e use o f a l l o g e n e i c B M T e l i m i n a t e s the p o s s i b i l i t y o f m a l i g n a n t c o n t a m i n a t i o n and m a y also y i e l d an i m m u n o l o g i c 'graft-versus-lymp h o m a ' e f f e c t . A l t h o u g h studies c o m p a r i n g a l l o g e n e i c B M T w i t h a u t o l o g o u s B M T in h i g h - g r a d e N H L and H D s h o w l o w e r r e l a p s e rate with a l l o g e n e i c t r a n s p l a n t a t i o n , this d o e s not t r a n s l a t e into i m p r o v e d e v e n t - f r e e s u r v i v a l due to h i g h e r proc e d u r e - r e l a t e d m o r t a l i t y w i t h a l l o g e n e i c B M T [9, 28, 39]. R e c e n t results w i t h a l l o g e n e i c B M T for l o w - g r a d e N H L s h o w that this a p p r o a c h can ind u c e d u r a b l e r e m i s s i o n s in a s i g n i f i c a n t p r o p o r tion o f p a t i e n t s w i t h a d v a n c e d and r e f r a c t o r y dise a s e [47, 48].

ACKNOWLEDGMENT This work has been supported in part by American Cancer Society COF award No 95-103-1.

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