Bone marrow transplantation after failure of autologous ... - Nature

Bone Marrow Transplantation, (1997) 19, 121–127  1997 Stockton Press All rights reserved 0268–3369/97 $12.00

Bone marrow transplantation after failure of autologous transplant for non-Hodgkin’s lymphoma M de Lima, KW van Besien, SA Giralt, IF Khouri, R Mehra, BS Andersson, D Przepiorka, JL Gajewski, M Korbling and RE Champlin Section of Bone Marrow Transplantation, Department of Hematology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Summary: We evaluated the response to and toxicity of allogeneic or autologous bone marrow transplantation (BMT) for patients with non-Hodgkin’s lymphoma (NHL) who relapsed after autologous BMT. Since 1990, 172 patients have received autologous BMTs for NHL at the MD Anderson Cancer Center and 75 have relapsed. Twelve patients (median age, 42 years), with disease recurrence underwent either allogeneic BMT (eight patients) or a second autologous BMT (four patients). Ten patients received thiotepa, busulfan and cyclophosphamide as conditioning, one patient received cyclophosphamide and total body irradiation and one received BCNU, etoposide, Ara-c and melphalan. The median interval between the first and second transplants was 23.5 months (range 5–80 months). Three patients who underwent allogeneic BMT had refractory relapses, three had a responsive relapse and two were in complete response (CR) at the time of BMT. Five patients received peripheral blood stem cells and three patients, allogeneic bone marrow. Three patients are alive and disease-free at 25, 22 and 7 months after allogeneic BMT. Four patients died of treatment-related causes and one from disease recurrence. All four patients undergoing autologous BMT had responsive relapses. Three patients received peripheral blood stem cells and one patient bone marrow. Two patients are alive and disease-free at 12 and 30 months after autologous transplants. There were no treatment-related deaths; two patients died of disease recurrence. This retrospective study shows that in selected patients, allogeneic or autologous BMT is an effective salvage therapy for NHL which recurs after autologous BMT. Keywords: lymphoma; relapse; BMT

Autologous BMT is an effective treatment for patients with chemotherapy sensitive recurrences of intermediate-grade lymphomas,1 and is increasingly used for the initial treatment of poor prognosis non-Hodgkin’s lymphoma

(NHL).2,3 When recurrences occur after autologous BMT, treatment options are limited, and the prognosis is poor.4 Allogeneic BMT is also an effective treatment for selected categories of patients. Allogeneic transplantation is associated with a lower risk of relapse than autologous transplantation,5,6 presumably because of graft-versuslymphoma (GVL) effects, or the lack of occult bone marrow involvement.7 For patients with recurrent NHL after autologous BMT, who had bone marrow involvement or inadequate marrow function, we offered allogeneic BMT. Patients with chemotherapy-sensitive relapse, no bone marrow involvement and good marrow function were offered a second autologous BMT. We report our results with these procedures in 12 patients.

Materials and methods Patients Since 1990, 172 patients have received autologous BMTs for NHL at our institution. It is our practice to offer allogeneic BMT mainly to patients who do not qualify for autologous BMT due to refractory disease or extensive bone marrow involvement.8 Seventy-five patients had disease progression or recurrence after autologous BMT; 12 were treated with a second autologous (four patients) or allogeneic (eight patients) marrow or blood stem cell transplant. Allogeneic BMT was offered to patients who had an HLA-compatible donor (HLA-identical sibling or 1 antigen mismatched relative), regardless of disease responsiveness. Patients who had chemosensitive recurrences, normocellular marrows without involvement and who lacked an HLA compatible donor, were offered an autologous transplant. Additional eligibility criteria included a left ventricular ejection fraction >50%, adequate pulmonary function as measured by a diffusing capacity of carbon monoxide and a forced expiratory volume in 1 second >50% of the predicted capacity, bilirubin 20 × 109/l for the three patients who continue to be in CR was 79 days (13, 79 and 95 days). Grade II or III acute GVHD developed in seven patients. Five patients survived beyond 100 days after BMT and could be evaluated for chronic GVHD; fatal chronic GVHD developed in one; one currently has extensive GVHD of the gut, two are alive without GVHD and one patient died at day +123 without evidence of chronic GVHD.

Autologous transplants Patient characteristics: The four patients who underwent autologous BMT had chemotherapy-sensitive disease at the time of second BMT. Three patients were in CR at the time of transplantation. For the three patients who underwent stem cell transplantation, 9, 8 and 5 days of apheresis were needed to collect the required number of progenitor cells. Response, disease-free survival and toxicity: Two patients continue in CR 13+ months and 31+ months after second autologous BMT, two have relapsed 20 and 11 months after second BMT and both have died. Grade 2 liver toxicity was observed in one patient and grade 2 stomatitis in two patients. No episodes of bacteremia were documented and no other severe toxicities occurred (Table 5). Engraftment: Neutrophil engraftment occurred in all patients. The median time to reach an ANC >0.5 × 109/l was 20 days (range 10–31). Graft failure occurred in one patient (ANC , 0.5 × x109/l and platelet count ,20 × 109/l at day +30 post-transplant) and was treated successfully with GM-CSF and interleukin 3. Median time to achieve a platelet count >20 × 109/l was 46 days (range 25–60). One patient required infusion of bone marrow because of failure of PBSC to engraft. Discussion The use of autologous BMT for lymphoma is increasing, and disease recurrence is the major cause of treatment fail-

Repeat BMT for recurrent NHL M de Lima et al

Table 5 deaths

Regimen-related toxicity, infections and treatment-related

Allo (n = 8)

Autoc (n = 4)

Renal Grade I/II Grade III Grade IV

5 2 1

2 0

Cardiac Grade I

4

0

CNS Grade I/II Grade III

2 1

0 0

Mucositis Grade II

8

2

Hepatic Grade I/II

7

2

Bladder Grade I/II

4

1

Pulmonary Grade I Grade III

1 1

1 0

8.1 (range, 4–11)

3.5b (range, 3–5)

4c 1 2

0 0 1

Toxicity – grade

Mean cumulative toxicitya

Infections Bacterial sepsis Fungal sepsis C. difficile in the stool Treatment-related deaths Allo BMT Pt 2 VOD and respiratory infection Pt 3 Chronic GVHD and CMV pneumonia Pt 4 Disseminated aspergillus infection Pt 7 Renal failure and sepsis. Auto BMT None

Allo = allogeneic transplant as salvage; Auto = autologous transplant as salvage; Pt = patient. a First 28 days post-transplant. b P = 0.01, Student’s t-test. c Four episodes in three patients.

ure. There is no effective long-term therapy for these patients. The response rate to conventional chemotherapy is low, and the majority of patients die of disease progression.4 Such patients are also often ineligible for studies of investigational new agents, mainly because they have limited hematopoietic reserve and have received extensive prior treatment. We have explored the use of second transplantation utilizing alternative, non-crossresistant conditioning regimens. High-dose chemotherapy regimens generally involve alkylating agents, among which crossresistance is unlikely.18 It is therefore conceivable that for patients in whom one high-dose regimen fails, an alternative regimen will be beneficial, especially if the patient’s disease has maintained some degree of chemotherapy sensitivity. Allogeneic marrow may offer additional advantages, such as the lack of tumor contamination, and a graft-versus-lymphoma

effect.19,20 It was therefore usually preferred if a compatible related donor was available. The majority of patients in our series received conditioning with thiotepa, busulfan and cyclophosphamide, a regimen that has been previously demonstrated to have efficacy in end-stage NHL.12 One patient received Cy/TBI, and one patient previously treated with busulfan/cyclophosphamide received BEAM conditioning.13 Five of the 12 patients are alive without disease progression, and four of these have been followed for more than 1 year since their second BMT. Actuarial PFS for the entire group is 40% 6 29% (Figure 1). Allogeneic BMT resulted in prompt engraftment, but the treatment-related mortality due to toxicity, GVHD and infections was high. Mean regimen-related cumulative toxicity was 3.5 after autologous transplantation, while it was 8.1 for those undergoing allogeneic BMT (P = 0.01, Student’s t-test). The additive toxicities of the GVHD prophylaxis and the conditioning regimen, as well as the profound immunosuppression caused by allogeneic transplantation, were poorly tolerated in these heavily pretreated patients. Autologous BMT was better tolerated, and no treatmentrelated deaths occurred. A large number of aphereses was required and hematopoietic recovery, especially platelet recovery, was slow, resulting in increased transfusion requirements and increased morbidity. These findings are in keeping with the delayed megakaryocytic recovery previously reported in heavily pretreated patients.21 Vose et al,4 reported on patients with lymphoid malignancies, in whom disease recurred after autologous BMT between 1983 and 1990. Four underwent allogeneic BMT, one repeat syngeneic BMT, and two repeat autologous BMT. Five patients died of toxicity, one relapsed, and one remained free of disease after an allogeneic BMT. Two other series addressing the issue of repeat BMT for lymphoid malignancies have recently been reported in abstract form. Tsai et al22 described 15 patients (four with NHL, seven with Hodgkin’s disease and four with AML) who underwent allogeneic BMT after failure of autologous BMT. Despite a faster recovery of hematopoietic function, only two patients are alive. Vanderberghe et al23 reported 34 patients reported to the EBMTR who had double autologous transplants for NHL (22 patients) and Hodgkin’s disease (12 patients). In 20 cases the indication for second BMT was disease relapse. The 2-year survival rate was 48% and the treatment-related death rate was 18%. In our study, the patients to whom repeat BMT was offered represented a selected group, who had prolonged remissions after their initial BMT. All received salvage chemotherapy, being referred for the second transplant when good performance status and clinical stability were achieved. These factors, allied to psychological and financial aspects of such prolonged treatment reflected on the median interval of 23.5 months between the first and second BMT. The experience with second BMT in leukemia suggests that a longer interval between first and second BMT has a significant influence on survival. Among 90 patients who underwent a second BMT for leukemia recurrence, the survival rate for patients with an interval between BMTs that was greater than 566 days was 36%, whereas it was 9%

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Progression-free survival after second transplantation

Proportion without disease progression

1.1 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0

200

400

600

800

1000

Days after second transplantation Figure 1

Actuarial progression-free survival after second transplantation for NHL (n = 12).

for patients who had a shorter interval.24 Such observations may apply to heavily pretreated patients with early recurrences of NHL who would be unlikely to tolerate intensive conditioning. In conclusion, this retrospective analysis indicates that second BMT is feasible in selected patients with NHL. Both autologous and allogeneic BMT can lead to durable remissions. Patients relapsing after an autologous BMT should be considered for another transplant, especially if they are young, have a good performance status and a prolonged disease-free survival after the first transplant. Allogeneic transplants are associated with a higher risk of complications but have the potential to promote durable remissions, even in drug-resistant lymphomas. The majority of recurrences of aggressive lymphoma unfortunately occur within the first months after transplantation.4,10 For such patients, less toxic approaches require development.

6 7

8

9

10

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