Bone Marrow Transplantation, (1997) 20, 369–374  1997 Stockton Press All rights reserved 0268–3369/97 $12.00

Allogeneic bone marrow transplantation for relapsed and refractory Hodgkin’s disease and non-Hodgkin’s lymphoma EJ Dann, CK Daugherty and RA Larson Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL, USA

Summary: The relative benefit of allogeneic bone marrow transplantation (alloBMT) vs autologous BMT (autoBMT) for patients with relapsed or refractory Hodgkin’s disease (HD) or non-Hodgkin’s lymphoma (NHL) remains uncertain. Toxicity from graft-versus-host disease (GVHD) may diminish the potential benefits both of graft-versus-tumor activity and of receiving uncontaminated donor marrow stem cells. From 1987 to 1995, 27 adults (ages 18–60 years; median 36) underwent alloBMT for lymphoma after failure of standard chemotherapy. Twenty-one had NHL and six had HD (nodular sclerosis). Thirteen patients had primary refractory disease or chemotherapy-resistant relapses; two of these had relapsed after autoBMT. Three patients had untested relapses (one of them had relapsed after autoBMT), and 11 had chemotherapy-sensitive relapses. Twenty-four received HLA-matched bone marrow from a sibling (one twin); three received haploidentical marrow cells. Nine (33%) died from lymphoma. Eleven (41%) died of treatment-related causes. Opportunistic infections were a substantial problem leading to eight of these deaths (30%). Six patients (22%) survive free of lymphoma 17–70 months post-BMT (median, 56 months); four had had sensitive relapses, one had had a resistant relapse, and one had had nontested relapse. Three have chronic GVHD (limited in one; extensive in two). One HD patient who had relapsed after autoBMT remains in remission 19 months after alloBMT. No therapy-related myelodysplasia has been observed. We conclude that alloBMT has substantial morbidity in heavily pretreated lymphoma patients due to acute toxicity, infections and GVHD. However, 22% of our HD/NHL patients have had long-term disease-free survival. Keywords: allogeneic marrow transplantation; Hodgkin’s; lymphoma

Hodgkin’s disease (HD) and non-Hodgkin’s lymphoma (NHL) are hematologic malignancies characterized by differences in their clinical, morphological, and biological Correspondence: Dr EJ Dann, Section of Hematology/Oncology, The University of Chicago Medical Center, 5841 S Maryland Ave, MC2115, Chicago, IL 60637-1470, USA Received 12 February 1997; accepted 11 May 1997

characteristics. Non-Hodgkin’s lymphomas are typically divided into low, intermediate and high-grade categories. In general, intermediate and high-grade lymphomas are sensitive to a variety of anti-neoplastic agents and about half of patients are cured with conventional dose multiagent chemotherapy regimens. However, patients relapsing after an initial complete remission or those who have primary refractory disease rarely obtain long-term survival with conventional salvage chemotherapy.1 For intermediate and high-grade lymphomas, high-dose chemotherapy (HDC) with autologous stem cell rescue (SCR) provides long-term disease-free survival in 40–60% of patients who relapse with chemotherapy-sensitive disease, and has been shown to be superior to conventional salvage chemotherapy alone.2 Long-term survival for patients with primary refractory or chemotherapy-resistant disease treated with HDC and autologous SCR, however, is only about 10%.3 Low-grade lymphomas are indolent disorders with a high rate of response to initial treatment and a median survival duration of 7–9 years.3 Although aggressive chemotherapy regimens including HDC and autologous SCR in this group of patients have shown progression-free survival rates of 50%, follow-up has been relatively short.4,5 Again, patients with advanced, recurrent or refractory disease have had a very poor prognosis. Several groups have begun examining the role of allogeneic bone marrow transplantation (alloBMT) for those HD/NHL patients who are younger than 60 years of age and have a suitable HLA (human leukocyte antigen) compatible donor. Advantages of alloBMT include hematopoietic rescue with tumor-free marrow, the potential for a graft-versus-lymphoma effect leading to a lower incidence of relapse post-transplantation, and lower rates of therapyrelated leukemia. The few studies that have been performed using alloBMT have reported a 25–35% early mortality rate, with deaths secondary to graft-versus-host disease (GVHD), as well as regimen-related toxicities and infection.6 However, lower than expected relapse rates have been observed in surviving patients, thus suggesting the possibility of an immune-mediated graft-versus-lymphoma effect.7–9 Here, we report our results from a single institution in a group of 27 adult patients who underwent alloBMT for relapsed and refractory HD and NHL. Patients and methods Twenty-seven consecutive patients with relapsed or refractory HD or NHL after standard chemotherapy were

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370

included in this study. Patients were transplanted between October 1987 and September 1995. There were 19 males and eight females with a median age of 36 years (range 18– 60). Twenty-one patients had NHL. Diagnoses according to the Working Formulation included nine patients with highgrade lymphoma, six with intermediate-grade disease, one with mantle cell lymphoma, two with low-grade lymphoma transformed to intermediate grade, and three with lowgrade lymphoma (Table 1). Six patients had nodular sclerosing Hodgkin’s disease. With regard to the source of allogeneic marrow cells, three patients received marrow from a haplo-identical family member, one patient received marrow from an identical-twin donor, and 23 patients received marrow from a 5/6 or 6/6 HLA-matched sibling donor. All patients gave written informed consent and were treated on protocols approved by the University of Chicago Institutional Review Board.

tained an anthracycline or cis-platinum, or a combination of these agents. Chemotherapy-sensitive relapse was defined as a 50% or greater reduction in disease following salvage chemotherapy for relapsed disease. Resistant relapse was defined as less than a 50% response to salvage chemotherapy. Thirteen patients had primary refractory disease or a resistant relapse; three of these had relapsed after autologous HDC and SCR. Three patients had untested relapses. Of these three, one had undergone autoBMT for a prior relapse and had relapsed again 13 months later. This patient did not receive further chemotherapy prior to undergoing alloBMT and was included in the untested relapse group. Eleven patients had a relapse with chemosensitive disease. Transplant regimens Three different preparative regimens were used sequentially during the 8-year period. Eight patients received busulfan and cyclophosphamide: busulfan 4 mg/kg/day on days −8 to −5 and cyclophosphamide 60 mg/kg/day on days −4 and −3. Fourteen patients received busulfan/cyclophosphamide/cytarabine: busulfan 4 mg/kg/day on days −10 to −7, cyclophosphamide 60 mg/kg/day on days −6 and

Definitions Primary refractory disease was defined as less than 50% reduction in the sum of the product of the two greatest perpendicular diameters of measurable lesions despite treatment with a combination chemotherapy regimen that conTable 1

Patient characteristics prior to allogeneic bone marrow transplantation

REAL classification

IWF

No. of patients

Median age (range)

Male/ female

Primary refractory/ refractory relapse

Chemosensitive relapse

Untested relapse

1

Hodgkin’s disease (nodular sclerosis)

Hodgkin’s disease (nodular sclerosis)

6

31 (26–41)

5/1

1

4

Follicle center,

Low-grade NHL

3

38 (36–40)

2/1

2

1

39, 42

2/0

2

57 34 (22–46)

1/0 3/3

3

1 2

1

36 (18–60)

6/3

5

3

1

37 (18–60)

19/8

13

11

3

Follicular grade I grade II

Follicle center, Follicular – grade I B small lymphocytic, transformed to diffuse large B cell Mantle cell

Diffuse large B cell Follicle center, diffuse

Precursor T lymphoblastic Peripheral T cell High-grade B cell, Burkittlike Total

Follicular, small cleaved Follicular, mixed small and large cell Transformed to intermediate-grade

2 1 2

Follicular, small cleaved

1

Small lymphocytic lymphoma transformed to diffuse large cell

1

Mantle cell Intermediate-grade NHL

1 6

Diffuse, large cell Diffuse, mixed small and large cell Diffuse, small cleaved High-grade NHL

3 2 9

Lymphoblastic Diffuse, large cell Small noncleaved cell, non-Burkitt

4 1 4

1

27

NHL = non-Hodgkin’s lymphoma; REAL = revised European–American lymphoma classification; IWF = International Working Formulation. Primary refractory or refractory relapse were defined as ,50% reduction of tumor mass to last salvage therapy. Chemosensitive relapse was defined as .50% reduction in tumor mass, assessed by computerized tomography and physical examination.

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371

1.00

Survival probability

−5, followed by cytarabine 1000–1500 mg/m2 continuously over 48 h on days −3 and −2. Five patients received total body irradiation (TBI) and etoposide: TBI twice daily on days −7 to −3 with 1350 cGy (nine fractions of 150 cGy) plus etoposide 60 mg/kg on day −3. All patients received intrathecal methotrexate 15 mg plus hydrocortisone 50 mg at the beginning of the preparative regimen. Busulfan levels were not performed. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine at 5 mg/kg/day i.v. from day −2 until day +3. Thereafter, the daily 4-h i.v. dose was adjusted to maintain trough blood levels of 200–400 ng/ml. After day 30, patients were usually switched to an equivalent oral dose. Cyclosporine was continued until day 180. Methylprednisolone 0.5 mg/kg/day i.v. was started on day +7 and then increased to 1 mg/kg/day on day +14. After day 30, steroids were tapered over 2 months.

0.75

0.50

0.25

0.00 0

1

2

3

4

5

Time in years Figure 1 Overall survival following allogeneic bone marrow transplantation for 27 adults with relapsed and refractory Hodgkin’s disease or nonHodgkin’s lymphoma.

Statistical methods We estimated survival and progression-free survival (PFS) using the Kaplan–Meier method.10 The log-rank test was employed to test for differences in survival and PFS between patient groups. Progression-free survival was measured from the day of BMT until first documented disease relapse or progression, or death; patients were censored at last contact. Patients who appeared to have recurrent lymphoma in the immediate post-transplant period (within the first 3 months) were documented on the day of death since a precise day of relapse was difficult to determine, and all these patients died within 84 days post-transplant. Overall survival was defined from the day of BMT until death, or censored at last patient contact. Disease-free survival (DFS) was calculated for patients who obtained a clinically documented complete remission after transplantation to first evidence of relapse (an event) or until death from toxicity or any other cause. The statistical significance of the association between sensitive or refractory disease status and death within 100 days following BMT was assessed using Fisher’s exact test. All P values reported are two sided. Data were updated and analyzed as of September 1996. Results Six of 27 patients (22%) survive free of lymphoma between 17–70 months post-allogeneic BMT with a median followup of 4.7 years. The median overall survival was 83 days (Figure 1). Of the six surviving patients, four had had sensitive relapses and one had had resistant relapse. One additional surviving patient who had relapsed after autologous HDC and SCR was considered to have an untested (second) relapse. Four patients had NHL and two patients had HD (Tables 2 and 3). All surviving patients remain in complete remission. The median survival of patients with chemoresistant disease prior to transplant was 67 days vs 539 days in the chemosensitive group (P = 0.035 for logrank test comparing both survival curves; see Figure 2). Eleven patients died from multiple treatment-related causes, with infection in eight, pulmonary toxicity in four, hepatic veno-occlusive disease in two, and GVHD in four. Nine of these patients underwent post-mortem examination

Table 2 tation

Disease-free survival after allogeneic bone marrow transplan-

Diagnosis

Hodgkin’s disease Non-Hodgkin’s lymphoma Low-grade Transformed low-grade Mantle cell Intermediate-grade High-grade Total

No. treated

No. alive and well

Follow-up time (months)

6

2

17, 20

3 2 1 6 9

1 1 0 1 1

68 70

27

6

56 61 range 17–70

and no evidence of lymphoma was found in seven. Six patients died as a result of progressive lymphoma within 100 days of alloBMT, and two more patients died from relapse 712 and 721 days after transplantation. One of these patients had lymphoblastic lymphoma and the other had Hodgkin’s disease. One other patient died of disseminated Herpes zoster infection 14 months after allogeneic transplantation and did not have any evidence of Hodgkin’s disease at autopsy. None of the three patients who had haploidentical donors survived the immediate post-transplant period due to acute GVHD and infections. The single patient who had a twin transplant died on day 24 from progressive high-grade lymphoma. Of the 23 patients transplanted from sibling donors who were serologically matched for HLA class I and II antigens, five patients (22%) had a relapse of lymphoma, and six patients (26%) have had long-term disease-free survival. Of those patients who have died, 12 had had chemoresistant disease, seven had chemosensitive disease, and two had untested relapses prior to alloBMT. There were notable differences between the two subsets of patients in mortality within the first 100 days: death occurred in the first 100 days in 11 of the 13 patients with chemoresistant disease but in only two of the 11 patients in the chemosensitive group (P = 0.003, Fisher’s exact test). The causes of death

BMT for HD and NHL EJ Dann et al

Table 3

Long-term survival after allogeneic BMT

IWF diagnosis

Age at transplant/sex

Therapy prior to BMT

Chemosensitivity status

GVHD a

Follow-up (months)

Small lymphocytic lymphoma transformed to diffuse, large cell

39 M

CLB/PRED; CHOP

refractory relapse

Extensive cGVHD (skin)

70

Follicular, small cleaved cell lymphoma

36 M

CHOP; CVP

sensitive relapse

None

68

Small noncleaved cell, non-Burkitt

31 M

PROMACE; CYTABOM

sensitive relapse

None

61

Diffuse, small cleaved cell

30 F

PROMACE/ CYTABOM; MINE

sensitive relapse

Limited cGVHD (skin)

56

Hodgkin’s, NS

29 M

MOPP/ABV; Auto-BMT

untested second relapse

None

20

Hodgkin’s, NS

26 F

ABVD; MOPP

sensitive relapse

Extensive cGVHD (skin)

17

a

All six patients had HLA-identical sibling donors.

P = 0.035

Discussion

1.00

Survival probability

372

0.75

0.50

S 0.25

R 0.00 0

1

2

3

4

5

Time in years Figure 2 Survival following allogeneic bone marrow transplantation for 11 lymphoma patients with chemosensitive relapses (S) and 13 lymphoma patients with chemoresistant relapses (R).

in the chemoresistant group were equally divided between disease progression and regimen-related toxicity, while in the chemosensitive group, toxicity was the sole cause of early death. Fungal infections were a major cause of morbidity and mortality in our patients. Four patients died from aspergillus infections, and one patient died with disseminated fusarium within the first 100 days. There were seven deaths altogether in the chemosensitive group. Two died in the early post-BMT period (,100 days), two died from GVHD, and one died a sudden death 6 months post-BMT. Two died from late complications: one from Varicella zoster 393 days after transplantation and one from progressive multifocal leukoencephalopathy 540 days after transplantation. Neither had any residual lymphoma. There have been two late relapses. One patient died from recurrent Hodgkin’s disease 712 days after transplantation. One late death in a patient with chemotherapy-resistant disease occurred from relapsed lymphoblastic lymphoma 721 days post-transplantation.

Many factors pose significant obstacles to the use of autologous stem cells as a source for hematopoietic rescue following HDC for patients with NHL. As many as 38% of autologous peripheral blood stem cell products may contain contaminating lymphoma cells and thus place patients at greater risk for relapse following reinfusion.11 For patients with low-grade lymphomas, 50–80% of patients have marrow involvement at presentation, and nearly all patients have marrow involvement at relapse.12,13 In addition, some patients have circulating monoclonal B lymphocytes in their peripheral blood which may contribute to relapse postautologous SCR.14,15 Such concerns have proven to be real obstacles in other diseases, as evidenced by gene marking studies of autologous bone marrow transplants in neuroblastoma and acute myeloid leukemia patients.16,17 Purging methods may reduce the risk of relapse, but their effectiveness has yet to be proven. With regard to HD, about 75% of patients can expect long-term disease-free survival. Chemotherapy failures share a poor prognosis and a median survival of only 1.5– 2.5 years.18 In one study of 186 HD patients treated with HDC and SCR, 94 patients achieved CR following transplantation.19 The 3-year progression-free survival was 40% among those obtaining a CR and 28% among these obtaining a partial response. The outcome following autologous HDC and SCR is poor due to early mortality secondary to infection and early and late regimen-related toxicities.5,6 A growing concern is therapy-related leukemia, reported in 5–15% of surviving patients after autologous bone marrow transplantation.20–22 This secondary malignancy is relatively refractory to treatment and, in most cases, fatal. Thus, the optimal treatment for patients with primary refractory or relapsing lymphoma has yet to be defined. While HDC and autologous SCR carries lower morbidity and mortality rates compared to alloBMT, the risk of relapse remains high, especially for patients with chemotherapy-resistant disease. Several series suggest a lower

BMT for HD and NHL EJ Dann et al

probability of disease progression for lymphoma patients undergoing alloBMT as compared to autologous SCR, although no randomized studies have been conducted.7–9 One explanation for these results is a graft-versuslymphoma effect. Laboratory experiments support this hypothesis. Two murine models have identified a role for a T lymphocyte mediated graft-versus-lymphoma effect, both in B-cell lymphoma and in Hodgkin’s disease.23,24 Anderson et al,25 summarizing more than two decades of experience at the University of Washington, compared all patients with HD undergoing alloBMT with those undergoing autologous HDC and SCR. There was no statistically significant difference in event-free survival among these patients (22% in the allogeneic group vs 13% in the autologous and syngeneic group, P = 0.9). There was a trend toward decreased relapse rates in the patients undergoing alloBMT (48 vs 77%, P = 0.06). There was a statistically significant increase in non-relapse mortality among the alloBMT patients (58 vs 41%, P = 0.047). Gajewski et al26 reviewed the outcomes among 100 patients with Hodgkin’s disease who received HLA-identical allogeneic bone marrow transplants that were reported to the International Bone Marrow Transplant Registry (IBMTR). The 3-year DFS for this group of patients was 21%. Thirtytwo percent of patients who were in remission after transplantation relapsed within 3 years. This rate is lower than the relapse rates reported following HDC and autologous SCR. However, regimen-related toxicity was very high and contributed to the majority of deaths reported (61%). Chopra et al27 reported on the European Bone Marrow Transplant (EBMT) group experience comparing 101 NHL allogeneic graft recipients with a series of matched autologous SCR recipients. The probability of disease progression was higher in patients with high-grade lymphoma who had undergone autologous SCR. Jones et al7 compared the outcomes of 38 patients undergoing allogeneic BMT at Johns Hopkins with 80 patients who received autologous SCR. The probability of relapse was significantly lower among the allogeneic transplant patients. However, the difference in progression-free survival was not statistically significant between the two groups. Ratanatharathorn et al8 found a lower probability of disease progression in 31 patients undergoing alloBMT compared to 35 patients who received autologous SCR (20 vs 69%). However, overall survivals were not significantly different. Van Besien et al9 reported a 65% 2-year survival for patients with low-grade lymphoma after allogeneic BMT, but only one of 14 patients with intermediate-grade lymphoma was alive and only three of 25 patients with high-grade lymphoma were free of disease after transplantation. Among our patients, there were no significant differences in survival among the different disease classifications, but there were only small numbers in each subgroup. In our series of heavily pretreated patients, transplantrelated mortality was 40%. During the period of this trial, autologous transplantation was the preferred therapy at our institution, and in general alloBMT was only offered when the marrow or blood were heavily involved with lymphoma. Thus, allogeneic BMT was generally performed only following the failure of HDC and autologous SCR or multiple prior salvage therapies. Nevertheless, survival was

better among those patients who had had .50% response following their most recent treatment (ie chemosensitive relapse) than among the patients with primary refractory disease or those who had chemoresistant relapses. In spite of the toxicity of alloBMT procedures in this group of heavily pretreated patients, these results can be viewed as encouraging. Reduced toxicity and possibly better survival rates might be achieved if alloBMT were to be performed earlier in the disease course for patients with relapsed lymphoma who have an HLA-compatible donor. Allogeneic BMT remains a reasonable option for many patients with relapsed malignant lymphoma.

Acknowledgements This work was supported in part by a grant from American Physicians Fellowship for Medicine in Israel (EJD). We thank the many physicians, nurses and data managers who were involved in the care of these patients. We are indebted to Ken Kobayashi, MD, and Phil Schumm, MS for their help in the statistical analyses, and to Brenda Brown for her secretarial assistance.

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