Klinische

Klin Wochenschr (1990) 68:539-544

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9 Springer-Verlag 1990

Review

Refractory and Relapsing Hodgkin's Disease: Role of High-Dose Chemotherapy with Bone Marrow Transplantation M. Thomas, N. Gattermann, and W. Schneider Abteilung ffir H/imatologie, Onkologie und Klinische Immunologie, Medizinische Klinik und Poliklinik der Heinrich-Heine-Universitfit, Dfisseldorf

Summary. Thirty percent of adult patients with Hodgkin's disease fail primary treatment or relapse after treatment. Whereas overall mortality for Hodgkin's disease is about 20%, half the patients who relapse will die. Among patients with refractory or relapsing disease, about a third can be rescued by conventional salvage treatment. Unfortunately, except for patients with late relapse, remission after conventional salvage treatment is generally not of long duration. However, durable complete remissions can now be achieved in nearly a third of patients with refractory or relapsing disease by means of very aggressive (myeloablative) chemotherapy with consecutive autologous bone marrow transplantation (aBMT). The rate of durable complete remissions seems to be even higher if previous exposure to chemotherapeutic agents is not in excess of two different treatment protocols (optimal timing of aBMT) and if responsiveness to cytotoxic drugs is preserved (low degree of drug resistance). Bone marrow transplantation should be restricted to patients whose resulting long-term prognosis justifies such radical treatment. Reflecting List of Abbreviations: aBMT= autologous bone marrow transplantation; pS = pathological staging; C[M]OPP/ABVD = Cyclophosphamide [Mustargen], Vincristine (Oncovin), Procarbazine, Prednisone/Doxorubicin (Adriamycin), Bleomycin, Vinblastine, Dacarbazine; CEVD=Lomustine (CCNU), Etoposide, Vindesine, Dexamethasone; Dexa-BEAM=Dexamethasone, Carmustine (BCNU), Etoposide, Cytarabin (Ara-C), Melphalan; COPP/ABV/IMEP = Cyclophosphamide, Vincrisfine (Oncovin), Procarbazine, Prednisone/Doxorubicin, Bleomycin, Vindesine/Ifosfamide, Methotrexate, Etoposide, Prednisone; CEP = Lomustine (CCNU), Etoposide, Prednimustine; MIME=Mitoguazone, Ifosfamide, Methotrexate, Etoposide; CVB=Cyclophosphamide, Etoposide (Vepeside), Carmustine (BCNU); CR = complete remission; n.r. = not reported

ongoing clinical therapy-studies, in particular in Germany, the role of bone marrow transplantation in a general concept of salvage treatment should be pointed out. Patients should be considered candidates if they fail alternating primary chemotherapy or develop an early relapse after this treatment, but still show responsiveness to chemotherapeutic agents.

Key words: Hodgkin's disease - Salvage-treatment - Radiotherapy - Chemotherapy - Bone marrow transplantation - Hematopoietic stem cells

With current treatment protocols about 70% of patients with Hodgkin's lymphoma achieve longterm complete remissions [4]. Primary treatment for patients requiring chemotherapy usually involves seven or eight drugs, often as alternating regimens [11]; e.g., C[M]OPP/ABVD with Cyclophosphamide [Mustargen], Vincristine, Procarbazine, Prednisone and Doxorubicin, Bleomycin, Vinblastine and Dacarbazine [5]. Nearly a third of patients relapse or show primary resistance to induction chemotherapy. Half the patients with relapse and an even higher proportion of patients failing primary treatment do not survive. Overall mortality for Hodgkin's disease thus amounts to some 20%. However, there are subgroups of patients with unfavorable prognosis, with cure rates of less than 50% [22]. Due to relapse or primary resistance about a third of patients with Hodgkin's lymphoma come to require efficient salvage treatment, which aims at a high rate of stable complete remissions. If therapy-induced mortality remains low, salvage treat-

540

M. Thomas et al. : Salvage Treatment for Hodgkin's Disease

ment may reduce the overall mortality of Hodgkin's disease. Bone marrow transplantation subsequent to high-dose chemotherapy has proved to be efficient in several hematologic neoplasms. In Hodgkin's disease resisting conventional chemotherapy this approach seems to be successful as well. We should like to summarize the results of conventional salvage treatment after failure of induction therapy. Reflecting ongoing clinical therapystudies, in particular in Germany, the (limited) role of myeloablative chemotherapy with subsequent reconstitution of hemopoietic stem cells by bone marrow transplantation in a general concept of salvage-treatment should be pointed out. Concerning the situation in Germany, in particular for generalists interested in oncology, an overview to practicable management of Hodgkin's disease resisting induction therapy will be given.

Salvage Treatment after Primary Radiation Therapy

Hodgkin Study Group. All other patients should be treated with alternating chemotherapy regimens or an equally effective cytostatic drug protocol [11]. Patients failing primary radiation therapy or relapsing after primary radiation therapy still have a favorable prognosis, because the possibility of cure through chemotherapy has not yet been exhausted. They should be treated with conventional (alternating) induction chemotherapy if relapse is multinodal or extranodal. Up to 50% of relapses after primary radiation therapy can be managed with salvage radiotherapy [25], especially if recurrent lymphoma is located at the margin of the primary radiation field or adjacent to it. Conventional salvage treatment (chemo- and/ or radiotherapy) after primary radiation therapy can achieve durable complete remission for about 50% of patients. Some 60% survive for at least 5 years [19, 39].

Salvage Treatment after Chemotherapy

By current standards [5, 16, 19, 35, 39] patients with Ann-Arbor stages p S I and pS II without risk factors (Table 1) should receive primary radiation therapy. This is also the concept of the German Table 1. Risk factors leading to chemotherapy for patients with

Ann-Arbor stage I-II Bulky disease of the mediastinum (1/3 of the maximal thoracic diameter on a frontal plane) Extranodal disease Massive splenic involvement (> 5 nodes; diffuse infiltration) Involvement of > 3 lymph node regions ESR > 50 m m / l h (A-stages) > 30 mm/1 h (B-stages) Modified after [11]

The chance of cure is much lower for patients who require salvage treatment after adequate induction chemotherapy. Of these patients, 10-30% may be rescued by salvage radiotherapy [14] for localized relapses. Once again, success seems to be based on the opportunity to employ a different therapeutic modality. If radiation therapy cannot offer a chance of cure to patients pretreated with alternating chemotherapy, however, rescue must be attempted by yet another trial of chemotherapy. After failure of adequate induction chemotherapy, the hope for renewed response to cytotoxic treatment is based on a different combination chemotherapy with drugs that do not show cross-resistance [28]. However, in light of the cure rate of just about 20% in the comparable situation of patients failing

Table 2. Salvage Chemotherapy: "Third"-line

Protocol

CEP CEP CEVD MIME

Patients

CR

Mean duration of CR

Mean duration of survival

(n)

(%)

(months)

Patients with CR (months)

58 15 32 47

40 26 44 23

15 12 10 + n.r.

24 n.r. 26 n.r.

All patients (months) 17 n.r. 18 12

Reference

Santoro et al. [36] Cervantes et al. [10] Pfreundschuh et al. [24] Hagemeister et al. [17]

CEP: Lomustine, Etoposide, Prednimustine; CEVD: Lomustine, Etoposide, Vindesine, Dexamethasone; M I M E : Mitoguazone, Ifosfamide, Methotrexate, Etoposide; CR = complete remission; n.r. = not reported

M. Thomas et al. : Salvage Treatment for Hodgkin's Disease

primary MOPP-treatment [4, 34], one should not be too expectant. Finding yet another set of different drugs is of course rendered difficult by the fact that patients have already received alternating chemotherapy with non-cross-resistant agents. Current investigation of conventional "third-line" protocols shows that complete remissions are usually achieved in less than 50% (Table 2). The mean duration of complete remission is less than one year, and overall survival does not reach two years. An important prognostic parameter for achieving renewed complete remission is the duration of remission after induction chemotherapy [7, 13, 18]. Late relapses after more than 12 months fare much better than early relapses, as shown for patients requiring salvage chemotherapy after primary MOPP-treatment [13, 18]. According to preliminary data, about 30% of patients with late relapse after alternating induction chemotherapy can achieve a durable complete remission once again through salvage treatment with CEVD (Lomustine, Etoposide, Vindesine, Dexamethasone) (personal communication: Prof. Pfreundschuh, Cologne). Salvage treatment with conventional third-line protocols thus seems to offer a real chance for patients with late relapse, whereas the prospect is very bad indeed for patients who fail primary chemotherapy or develop an early relapse. Role of Bone Marrow Transplantation Considering the steep dose-response curve of chemotherapeutic agents [38] with known tumoricidal effect in Hodgkin's lymphoma, therapy may be improved by the use of maximal drug dosage [37]. Delivering unusually high doses of anticancer agents with still-tolerable organ toxicity, but ablative toxicity to the bone marrow, requires bone marrow transplantation. Apart from syngenic transplants, the optimal source of hemopoietic stem cells for marrow rescue is still a matter of debate.

541

9 Syngenie transplants from identical twins should of course be used if available. Although rare, this situation provides an interesting model for research [12]. 9 Allogenic bone marrow transplantation excludes reinfusion of tumor cells and may contribute the possibility of a graft-versus-Hodgkin effect [4, 26]. Data from the literature on 23 patients treated with allogenic BMT yielded a rate of 30-50% of treatment-related deaths; only 3 patients (13 %) achieved a durable complete remission [2, 3, 23, 31, 32]. Relapses occured in the face of chronic graftversus-host disease, which argues against a strong graft-versus-Hodgkin effect [32]. Allogenic bone marrow transplantation remains a treatment option especially for patients with persisting bone marrow infiltration for w h o m a suitable donor can be found [26]. 9 Autologous bone marrow transplantation (Table 3) lacks the problem of graft-versus-host disease but does pose the risk of reinfusion of tumor cells [4]. This hazard should not be overestimated, however, since bone marrow infiltration occurs in fewer than 10% of patients with Hodgkin's disease [26]. The preparation of autologous hemopoietic stem cells from peripheral blood is less inconvenient to the patient than multiple bone marrow aspirations. Further advantages are an adequate yield of stem cells despite previous radiation to the pelvis and a low risk of contamination with tumor cells even in the case of previous bone marrow infiltration. Marrow rescue with autologous peripheral blood stem cells was performed in 40 patients with lymphoma (24 patients with Hodgkin's disease), of w h o m 25% achieved long-term complete remission [21]. Because similar results were achieved with autologous bone marrow transplantation (Table 3), the two approaches are currently considered of equal value.

Table 3. Autologous bone marrow transplantation for Hodgkin's disease

Protocol

CVB ~ CVB a BEAM b

Patients

Mortality

Complete remission

Diseasefree

Reference

(%)

Duration of follow-up (months)

(n)

(%)

(%)

61 72 44

7 12 5

57 47 50

66 61 95

2~88 4-83 12--49

Jagannath et al. [20] Carella et al. [8] Gribben et al. [15]

a CVB = Cyclophosphamide, Etoposide (Vepeside), Carmustine (BCNU) b B E A M = Carmustine (BCNU), Etoposide, Cytarabine (Ara-C), Melphalan

542

Several methods of "purging" are employed to selectively eliminate malignant cells from bone marrow aspirates, with a minimum of damage to normal stem cells. Monoclonal antibodies are most commonly used [i, 6]. Despite demonstrable efficacy in vitro, clinical results are still unsatisfactory [26]. As far as autologous bone marrow transplantation for Hodgkin's disease is concerned, there is a lack of clinical data on the effect of purging. It must be taken into consideration, however, that purging would benefit only the small fraction of patients whose bone marrow is in fact contaminated with tumor cells. A preparative regimen of ablative chemotherapy and total body irradiation (TBI) generally preceeds autologous marrow transplantation for hematological malignancies. For Hodgkin's disease, however, this approach is associated with intolerable organ toxicity. Patients pretreated with high doses of bleomycin or mediastinal radiotherapy often develop fatal interstitial pneumonitis if subjected to total body irradiaton [30, 32]. Meanwhile, TBI for conditioning in Hodgkin's disease (Table 3) has largely been abandoned [8, 15, 20]. Table 3 summarizes clinical results obtained by high-dose myeloablative chemotherapy and subsequent autologous bone marrow transplantation. About half the patients failing induction chemotherapy or relapsing after treatment with two or even more drug combinations can be rescued. Among patients reaching complete remission, 50-60% show long-term survival without relapse [4, 9]. Early death due to treatment-related toxicity occurs in about 10% of cases [4]. Analysis of unrelated variables predicting longterm survival after myeloablative chemotherapy with subsequent aBMT reveals that a good performance status (Karnofsky index > 80%) is important. A favorable response also depends on optimal timing of aBMT and a low degree of drug resistance. In other words, pretreatment must not be in excess of two different chemotherapeutic regimens, and successful aBMT may be expected for those patients with response to a further conventional drug regimen ("sensitive relapse") [20, 29]. If these criteria are met, the situation looks promising for patients undergoing aBMT for refractory or relapsing Hodgkin's disease.

Conventional Salvage Chemotherapy or Bone Marrow Transplantation? "Third-line" chemotherapy protocols can hardly offer a chance of cure to patients who fail primary chemotherapy or develop an early relapse. Failing primary treatment means not reaching complete

M. Thomas et al. : Salvage Treatment for Hodgkin's Disease

remission after adequate induction chemotherapy or showing progression after the first cycle of cytotoxic drug treatment. Through myeloablative chemotherapy with subsequent aBMT, however, a fourth or a third of these patients may achieve durable complete remissions [4, 20, 33], and the cure rate may be even better for a subgroup of patients responsive to conventional salvage chemotherapy [20]. The latter group of patients meets the entry criteria for bone marrow transplantation within the salvage protocol of the German Hodgkin Study Group. This protocol suggests BMT only for those patients with refractory or relapsing Hodgkin's disease who, according to current knowledge, should profit most of all, i.e., patients still responsive to the "Mini"-Dexa-BEAM protocol (Fig. 1) [27]. Patients with late relapse after successful induction chemotherapy require separate consideration. Preliminary data indicate that about a third of them can be rescued by conventional salvage chemotherapy. A cure rate similar to that of BMT can thus be achieved with less treatment-related toxicity. Along the lines of the German Hodgkin Study Group, patients with late relapse therefore receive salvage chemotherapy according to the Dexa-BEAM protocol (Fig. 1) [26, 27] and are not submitted to BMT. In summary, myeloablative chemotherapy with subsequent marrow rescue may significantly improve survival only for a small group of patients with refractory or relapsing Hodgkin's disease. Responsible use of bone marrow transplantation implies the identification of prognostic subgroups related to primary treatment protocols. Therefore

After COPP / ABVD or COPP / ABV / IMEP (without curative chance of radiotherapy)

4=

Dexa B E A M ~/

primary failure relapse

4=

- early

4=

- late

a B M T 2/

aBMT only if responsiveness to Dexa-BEAM can be demonstrated

Fig. 1. Salvage protocol of the German Hodgkin Study Group [26, 27]. 1) Dexa-BEAM: Dexamethasone, Carmustine (BCNU), Etoposide, Cytarabine (Ara-C), Melphalan. 2) aBMT: autologous bone marrow transplantation; bone marrow conditioning with CVB [Cyclophosphamide, Etoposide (Vepeside), Carmustine (BCNU)]

M. Thomas et al. : Salvage Treatment for Hodgkin's Disease

this drastic measure should be performed only in controlled clinical studies, in particular to identify prognostic subgroups that will clearly benefit. If a patient's chance to reach long-term survival through conventional salvage treatment falls short of 33% but responsiveness to chemotherapy can still be demonstrated, bone marrow transplantation should be attempted [26]. References 1. Anderson KC, Ritz J, Takvorian T, Coral F, Daley H, Gorgone BC, Freedman AS, Canellos GP, Schlossman SF, Nadler LM (1987) Hematologic engraftment and immune reconstitution post-transplantation with anti-B1 purged autologous bone marrow. Blood 69 : 597-604 2. Appelbaum FR, Sullivan KM, Thomas ED, Buckner CD, Clift RA, Deeg H J, Neimann PJ, Sanders JE, Stewart P, Storb R (1985) Allogenic marrow transplantation in the treatment of MOPP-resistant Hodgkin's disease. J clin Oncol 3 : 1490-1494 3. Appelbaum FR, Sullivan KM, Buckner CD, Clift RA, Deeg HJ, Fefer A, Hill R, Mortimer J, Neimann PE, Sanders JE, Singer J, Stewart P, Storb R, Thomas ED (1987) Treatment of malignant lymphoma in 100 patients with chemotherapy, total body irridation, and marrow transplantation. J clin Oncol 5:1340-1347 4. Armitage JO (1989) Bone marrow transplantation in the treatment of patients with lymphoma. Blood 73 : 1749-1758 5. Bonadonna G, Valagussa P, Santoro A (1986) Alternating non-cross-resistantcombination chemotherapy or MOPP in stage IV Hodgkin's disease. Ann intern Med 104:739-746 6. Bregni M, Lappi DA, Siena S, Formosa A, Villa S, Soria M, Bonadonna G, Gianni AM (1988) Activity of monoclonal antibody-saporin-6 conjugate against B-lymphoma cells. J Natl Cancer Inst 80 (7):511-517 7. Buzaid AC, Lippman SM, Miller TP (1987) Salvage therapy of advanced Hodgkin's disease. Am J Med 83 : 523-532 8. Carella M, Congiu A, Mazza P, Gaozza E, Ricci P, Visani G, Meloni G, Cimino G, Mangoni L, Coser P, Cetto GL, Cimino R, Alessandrino EP, Brusaliamo E, Santini G, Tura S, Mandelli F, Rizzoli V, Bernasconi C, Marmont AM (1988a) High-dose chemotherapy with autologous BMT "rescue" in advanced resistant Hodgkin's disease. An Italian retrospective study group. J clin Oncol 6:1411-1416 9. Carella M, Marmont AM (1988b) Salvage treatment for advanced resistant Hodkin's lymphoma: the role of bone marrow transplantation. Haematologica 73 : 93-99 10. Cervantes F, Reverter JC, Montserrat E, Rozman C (1986) Treatment of advanced resistant Hodgkin's disease with lomustine etoposide and prednimustine. Cancer Treatm Rep 70: 665-667 11. Diehl V, Diihmke E, Georgii, Fischer, Hfibner, Schwarze (1989) BMFT-Studie zum Morbus Hodgkin des Erwachsenen. Studienprotokolle HD 4, HD 5 und HD 6. Kurzfassung ffir Chemo- und Strahlentherapeuten. Studienprotokoll der Deutschefi Hodgkinstudiengruppe (3. korrigierte Fassung 8/89) K61n, S 13 12. Fefer A (1986) Current status of syngenic marrow transplantation and its relevance to autografting. Clin Hemat 15 :49-65 13. Fisher RI, De Vita VT, Hubbard SP, Simon R, Young RC (1979) Prolonged disease-free survival in Hodgkin's disease with MOPP reinduction after first relapse. Ann intern Med 90 : 761-763

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Received: January 9, 1990 Returned for revision: February 21, 1990 Accepted: March 12, 1990

Prof. Dr. W. Schneider Abteilung fiir Hfimatologie, Onkologie und Klinische Immunologie Medizinische Klinik und Poliklinik der Heinrich-Heine-Universit/it Moorenstr. 5 D-4000 D/isseldorf