Low-dose continuous chemotherapy (LBCMVD-56) for refractory and relapsing lymphoma

Annals of Oncology 11: 857-860, 2000. © 2000 Kluwer Academic Publishers. Printed in the Netherlands.

Original article Low-dose continuous chemotherapy (LBCMVD-56) for refractory and relapsing lymphoma J. Shamash,1 J.Walewski,2 J. Apostolidis,1 A. M.Wilson,1 I M. Foran,1 R. K. Gupta,1 A. Z. S. Rohatiner,1 S. M. Kelsey3 & T. A. Lister1 1

ICRFDepartment of Medical Oncology, St. Bartholomew's and Royal London Hospitals, London; 2The Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland; 3Department ofHaematology, St. Bartholomew's and Royal London Hospitals, London, UK

Results: The overall response rate at 12 weeks was 67% (21% complete remission (CR)) with a median overall survival Background: Although lymphoid malignancies are generally of 13 months. A symptomatic response was seen in 72%. chemosensitive, relapse is common. The use of high-dose Previous high-dose therapy did not compromise the response therapy can make subsequent cytotoxic therapy intolerable. rate. Toxicity was acceptable with grade 3-4 haematological There is a need to develop regimens with low acute toxicity toxicity seen in 27% of cycles, gastrointestinal toxicity seen in which are suitable for use in patients post-high dose therapy 11% and pulmonary toxicity seen in 8%. Thirty-one percent of and following the failure of standard protocols. patients required hospitalisation at some point during this Patients and methods: Twenty-six patients with lymphomas, treatment most commonly for neutropenic sepsis. fifteen of whom had received high-dose therapy, were treated Conclusions: LBCMVD-56 is an inexpensive, outpatientwith a novel regimen consisting of low-dose lomustine, based regimen with low acute toxicity and a high response rate chlorambucil, daily subcutaneous bleomycin, vincristine and in this heavily pre-treated group of patients. methotrexate with dexamethasone on an eight-week cycle (LBCMVD-56). A median of three cycles was given. Key words: low-dose continuous chemotherapy, lymphoma Summary

Introduction

The treatment of lymphoma following the introduction of cyclical combination chemotherapy has been one of the success stories of modern medicine, with perhaps half the younger patients being cured with initial therapy [1] and 25% 'salvaged' at recurrence [2, 3]. The latter results have probably improved with use of high-dose therapy and autologous transplantation [4]. Sadly, however, there is still a significant proportion in whom conventional strategies fail but for whom a palliative approach with cytotoxic therapy may be the best option [5]. Initial observations suggested that low doses of bleomycin [7] might be effective in lymphomas and that small, daily subcutaneous doses had the advantage of low pulmonary toxicity by avoiding high peak levels. This is important , as many patients may have received either mantle irradiation or a nitrosourea as part of a high-dose preparative regimen. Methotrexate is a well tolerated drug which is less frequently used in lymphoma and, with folinic acid rescue, myelosuppression can be minimised. It has been used as an adjunct to radiation for early stage HL in the regimen VBM [8]. A combination of chlorambucil and lomustine or lomustine and bleomycin in the pre-high-dose era produced responses in refractory Hodgkin's lymphoma

(HL) [9]. Vinblastine therapy remains a useful single agent in HL following failure of high-dose therapy (HDT) [10]. These observations led to the design of a low-dose continuous chemotherapy regimen that avoided the acute side effects of nausea, vomiting and alopecia. The daily continuous administration of bleomycin allowed treatment to continue even when patients were myelosuppressed.

Patients and methods Patients Patients who had a lymphoid malignancy and who had relapsed following either HDT or conventional anthracycline based chemotherapy regimen but were not considered fit enough for HDT, were eligible. Patient characteristics and lymphoma sub-type are shown in Table 1. A therapy episode was defined as being the intended therapy at a certain time. In some cases radiation was intentionally given following chemotherapy (e.g., mantle field irradiation as consolidation for bulky HL); this counted as one therapy. If, however, radiotherapy was given for progressive disease, this was counted separately. Fifty-eight percent of these patients had previous high-dose therapy, twenty-seven percent had primary refractory disease and a further nineteen percent had absolute refractory disease prior to this episode of low-dose

858 Vinblastine 6 mg/m!

Table 1. Patient characteristics.

|

i

+ folinic acid 24 hr later

|

I

Lomustine 1 mg/kg

I

Methotrexate 100 mg/m 2

Number of patients Sex Male Female Age at start of LBCMVD-56 (years) Median Range Hodgkin's lymphoma Diffuse large B-cell lymphoma Follicular lymphoma Transformed follicular lymphoma Peripheral T-cell lymphoma Lymphoplasmacytoid lymphoma Time between first therapy and LBCMVD-56 (years) Range Number of therapy episodes prior to LBCMVD-56 Median Range High-dose therapy prior to LBCMVD-56 Extranodal disease at time of LBCMVD-56 Primary refractory disease ( < PR to first-line therapy) Absolute refractory disease (never achieved PR with conventional therapy)

26 19 7 34 18-85 15 4 3 2 1 1 2.4 0.3-21.4 4 3-9 15 18 7 5

Table 2. Dose reductions based on haematological toxicity in LBCMVD-56.

Day 1 Day 22 Day 22 Day 22

Platelets (x 109/l)

Neutrophils (x 1O9/1)

Vinblastine dose (%)

Methotrexate dose (%)

3=80 >40 3=40 <40

3=1.5 3=1.5 1.0-1.4 <1.0

100 100 50 0

100 100 100 0

If treatment omitted on day 22, repeat blood count on day 29 and give treatment as for day 22, otherwise omit completely. If platelet nadir <40, reduce lomustine on subsequent cycles by 25%. If day 56 platelets < 100, reduce lomustine and chlorambucil by 25% on subsequent cycles. If delay in restarting full cycle, bleomycin should continue to be given.

continuous chemotherapy. Sixty-nine percent had developed extranodal disease by the time they received this therapy. Chemotherapy protocol The protocol and dose adjustments for LBCMVD-56 are shown in Figure 1 and Table 2, respectively. Patients who had received either prior mantle irradiation or a nitrosourea as part of high-dose therapy were given prophylactic inhaled steroids (budesonide) in the form of a dry powder inhaler (Pulmicort Turbohaler 800 ug twice a day). Bleomycin was administered using prefilled, disposable syringes prepared by the pharmacy (1000 units/ml H2O) kept at room temperature. Patients were taught how to self-administer this as a subcutaneous injection and advised to rotate the injection sites. Full blood counts (FBC) were repeated on days 1, 22 and 35. If the platelet count fell to <50 x io 9 /l, a weekly FBC was measured. The next cycle commenced 56 days after the first.

Staging and evaluation of response A full clinical examination, full blood count and chemical pathology profile, as well as a CTscan of the chest, abdomen and pelvis, and bone

Chlorambucil 5 mg/day

<

>

Dexamethasone 4 mg/day

<

>

Bleomycin 1 unit sc daily

<

FBC

• Day1

«

> —

OayS

• Day 15 Day 22

• Day 29 Day 35 Day 42 Day 49

>

Day 56

Figure 1. diagram of LBCMVD-56 chemotherapy programme. Give inhaled budesonide 800 ug/2 x day if prior nitrosourea or mantle radiotherapy. marrow trephine were carried out prior to chemotherapy. Restaging was carried out after one and a half cycles (12 weeks) and after three cycles (24 weeks). The outcome at 12 weeks was taken as being the documented response to therapy. A complete response was defined as disappearance of all symptoms with no clinical or radiological evidence of disease. A partial response (PR) was denned as being at least a 50% reduction in the summed products of the disease site diameters. Stable disease was defined as < 25% reduction or < 25% increase in the summed products of the dimensions of the disease site and the absence of new disease sites or new symptoms. Progressive disease was defined as the appearance of new disease sites or > 25% increase in the summed products of the dimensions of the disease sites. The combined PR and CR rate was taken to be the objective response rate.

Results (see Table 3) Twenty-six patients received LBCMVD-56. Two died of infection during the first three weeks of treatment, twenty-four were evaluable for response. A median of 3 cycles was given (24 weeks) with a range of 1-6 cycles. At 12 weeks an objective response rate to therapy of 67% was seen, of which 21% were complete responses. Patients who were chemosensitive to prior therapy were more likely to respond and had enhanced survival (56 vs. 37 weeks, P =0 .001). Prior high dose therapy did not have a negative effect on survival (55 vs. 40 weeks, P = 0.3). Twelve out of fourteen, who had received prior highdose therapy, responded, as opposed to four out of eleven who had not. A symptomatic response - defined as disappearance of symptoms presumed due to lymphoma (i.e., malaise, cough, pain, itch) - for more than eight weeks was seen in 72% of patients. Five patients progressed between weeks 12 and 24; their maximum response was CR in one, PR in three and SD in one. One patient who had a PR at twelve weeks was in CR at twenty-four weeks. Two patients with HL went on to receive a second transplant procedure - one received HLA marrow from a sibling and died of infection in remission on day 115. The other received a second autograft and engrafted poorly despite re-infusion of an adequate number of stem cells. Patients who achieved a CR to LBCMVD-56 had an enhanced median survival compared to those who did not (74 vs. 49 weeks, P = 0.04). Those who had previously sensitive disease had prolonged median survival over those with absolute refractory disease (63 vs. 38 weeks, P = 0.001). Seven patients (a quarter of this

859 Table 3. Results: (a) by disease histology, (b) by prior disease chemosensitivity and (c) survival by absence or presence of absolute refractory disease. (A) Response by disease. Disease

No. of pts

CR

Hodgkin's lymphoma Diffuse large B-cell Follicular lymphoma Transformed follicular lymphoma T-cell lymphoma Lymphoplasmacytoid lymphoma Evaluable for response (%)

15 4 3

3 1 0

2 1 1 24

SD

PD

Nonevaluable

8 1 1

3 0 1

1 2 1

0 0 0

1 0

1 0

0 0

0 0

0 1

0

0

0

0

1

5(21)

PR

11 (46) 4(17) 4(17) -

(B) response by prior disease chemosensitivity.

Sensitive to first-line therapy and assessable for response Previous CR at any time and assessable Primary refractory disease Absolute refractory disease

No. of pts

CR (%)

PR (%)

SD (%)

PD (%)

17

5(29)

9(53)

2(12)

1(6)

10 7 5

4(40) 0(0) 0(0)

6(60) 2(29) 0(0)

0 2(29) 3(60)

0 3(45) 2(40)

(C) Survival by previous disease sensitivity (weeks). Median Range Absolute refractory range to prior therapy Yes 38 No 63 CRonLBCMVD-56 Yes 74 No 49

/"-value

4-48 0.001 1-108

Table 4. Treatment toxicity. Number of cycles administered Median per patient Range WHO grade 3 ^ (%) Haematological toxicity Gastrointestinal toxicity Pulmonary toxicity Alopecia (grade 1) Number of patients hospitalised Number of patients required blood transfusion Number of patients required platelets

66 3 1-6 17(27) 7(11) 5(8) 5(8) 8 3 1

of prophylactic antibiotics in this setting may be considered. The reasons for hospitalisation varied: one patient required antibiotics with the first cycle because of heavy bone marrow infiltration. As this was reduced as the result of therapy, it was not a problem with subsequent cycles. One patient was admitted with a vinblastine ileus and one with clostridium difficile diarrhoea on two occasions. The other admissions were for neutropenic sepsis. Local skin irritation from bleomycin was seen in five patients. This usually resolved with the administration of topical clobetasone. Although significant pulmonary toxicity was seen in five patients, the presence of progressive disease made the contribution of bleomycin difficult to quantify. Two patients appeared to develop pulmonary toxicity for which no other cause could be found, one had received prior mantle irradiation and high dose carmustine as well as previous bleomycin, the other had received multiple courses of chemotherapy some of which had included bleomycin as well as irradiation.

26-108 0.04 1-72

Conclusions LBCMVD-56 is an active regimen in relapsed and refractory lymphoma. The observation that a regimen with relatively little acute toxicity and low intensity can result in response in heavily pre-treated patients is encouraging. The use of daily subcutaneous bleomycin in this group of patients with poor marrow reserve appears to have avoided the development of pulmonary problems. Self-administration by patients was feasible, did not appear to be problematic and local skin reactions were rarely of significance. Only three patients developed cough which could be attributed to bleomycin, although no CT evidence of pulmonary toxicity was found. It is Toxicity (see Table 4) possible that a fixed dose of 1000 units/day may not Two patients died during thefirstcycle of therapy, one of have led to ideal pharmacokinetics in some patients and, listeria meningitis and the other of infection due to in view of the variability in plasma levels seen, underneutropenia in the presence of rapidly progressive dis- dosing may have contributed to therapy failure. ease. 66 cycles were evaluable for toxicity. Although The ability to treat patients post high dose therapy pronounced neutropenia and thrombocytopenia were without undue symptomatic myelosuppression is also seen, they were not usually symptomatic, however, as a reassuring. The assessment of patients at 12 weeks could total of nine did develop intercurrent infection, the use be criticised for leading to unduly optimistic response group) had absolute refractory disease and although none achieved a formal PR, stabilisation of disease was achieved, with a median survival of 38 weeks, suggesting it be worth giving even in this group. There was no suggestion that patients with extra-nodal disease were any less likely to respond to treatment than those who had predominantly nodal disease. Histological subtype did not appear to have any bearing on outcome. Most patients had HL, patients with transformed follicular lymphoma also had responses to this treatment, which was encouraging.

860 rates. The number of options for therapy in refractory lymphoma continues to increase; monoclonal antibody therapy (rituximab) may be suitable for B-cell lymphomas although response rate and duration do not appear better than described here [11]. In HL, responses to anti-CD25 [12] or anti-CD30 have been seen [13] although none has been long-lasting. Other palliative regimens designed for use in elderly patients may include combinations of oral agents, such as chlorambucil and etoposide [14], and may be considered in this setting although they are myelosuppressive. Intensive regimens, e.g., MIME [15] or EPIC [16] have been used in relapsing lymphoma - durable remissions have been obtained although such regimens do not appear suitable for patients who have had high-dose therapy. As might be expected, the patients who had responded to chemotherapy before were most likely to respond again. Most patients who achieved CR, had achieved it with prior therapy. Such patients who achieved a CR to LBCMVD-56 had a longer survival than those who did not and might be suitable for further therapy as consolidation. Few protocols have been formally tested in the posthigh dose environment where the tendency has been either to try an anthracycline-based therapy again or perhaps use palliative irradiation. This protocol appeared suitable for use in this setting where toxicity and response were both acceptable. In summary, LBCMVD-56 is a novel chemotherapy protocol suitable for patients who have received previous therapy including high dose therapy. Its lack of acute toxicity is an advantage and it may well be worth investigating earlier in the management of lymphoma, eg in the elderly population where current therapy proves unduly toxic for many.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

Acknowledgements

We would like to thank the staff on the oncology day ward for their help in running this study particularly in teaching the patients to self-administer bleomycin.

16.

University results and prognostic indices. Blood 1997; 89 (3): 801-13. Chopra R, McMillan AK, Linch DC et al.The place of high-dose BEAM therapy and autologous bone marrow transplantation in poor-risk Hodgkin's disease. A single-center eight-year study of 155 patients. Blood 1993; 81 (5): 1137-45. Philip T, Guglielmi C, Hagenbeek A et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma (see comments). N Engl J Med 1995; 333 (23): 1540-5. Johnson PW, Rohatiner AZ, Whelan JS et al. Patterns of survival in patients with recurrent follicular lymphoma: A 20-year study from a single center. J Clin Oncol 1995; 13 (1): 140-7. Vose JM, Bierman PJ, Anderson JR et al. Progressive disease after high-dose therapy and autologous transplantation for lymphoid malignancy: Clinical course and patient follow-up. Blood 1992; 80 (8): 2142-8. Yagoda A, Mukherji B, Young C et al. Bleomycin, an antitumor antibiotic. Clinical experience in 274 patients. Ann Intern Med 1972; 77 (6): 861-70. Horning SJ, Hoppe RT, Hancock SL, Rosenberg SA. Vinblastine, bleomycin, and methotrexate: An effective adjuvant in favorable Hodgkin's disease. J Clin Oncol 1988; 6 (12): 1822-31. Sutcliffe SB, Economopoulos T, Wrigley PF et al. Prognosis of Hodgkin's disease: Patients who fail to remit or who relapse after combination chemotherapy. Clin Oncol 1980; 6 (4): 329-36. Little R, Wittes RE, Longo DL, Wilson WH. Vinblastine for recurrent Hodgkin's disease following autologous bone marrow transplant. J Clin Oncol 1998; 16 (2): 584-8. McLaughlin P, Grillo-Lopez AJ, Link BK et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: Half of patients respond to a four-dose treatment program. J Clin Oncol 1998; 16 (8): 2825-33. Schnell R, Vitetta E, Schindler J et al. Clinical trials with an anti-CD25 ricin A-chain experimental and immunotoxin (RFT5SMPT-dgA) in Hodgkin's lymphoma. Leuk Lymph 1998; 30 (5-6): 525-37. Renner C, Hartmann F, Pfreundschuh M. Treatment of refractory Hodgkin's disease with an anti-CD16/CD30 bispecific antibody. Cancer Immunol Immunother 1997; 45 (3-4): 184-6. Levis A, Depaoli L, Bertini M et al. Results of a low aggressivity chemotherapy regimen (CVP/CEB) in elderly Hodgkin's disease patients. Haematologica 1996; 81 (5): 450-6. Enblad G, Hagberg H, Gustavsson A, Glimelius B. Methyl-GAG, ifosfamide, methotrexate and etoposide (MIME) as salvage therapy for Hodgkin's disease: A prospective study. Eur J Haematol 1998; 60 (3): 166-71. Hickish T, Roldan A, Cunningham D et al. EPIC: An effective low toxicity regimen for relapsing lymphoma. Br J Cancer 1993; 68 (3): 599-604.

Received 7 February 2000; accepted 17 April 2000.

References 1. Canellos GP, Anderson JR, Propert KJ et al. Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD (see comments). N Engl J Med 1992; 327 (21): 1478-84. 2. Horning SJ, Chao NJ, Negrin RS et al. High-dose therapy and autologous hematopoietic progenitor cell transplantation for recurrent or refractory Hodgkin's disease: Analysis of the Stanford

Correspondence to: J. Shamash, MD Department of Medical Oncology Barts and The London NHS Trust 1st Floor King George V Building St. Bartholomew's Hospital West Smithfield London EC1A 7BE UK