Interferon-α 2b Added to Melphalan-Prednisone for Initial and Maintenance Therapy in Multiple Myeloma

Methods

Participating Centers

One hundred seven hospitals in Sweden, Norway, Denmark, Finland, and Iceland, representing a combined population of 12 million persons, cooperated in this study. Fifteen were university hospitals, and 92 were county hospitals. The participating centers were asked to report all newly diagnosed cases of myeloma. Our study was approved by the ethics committees and health authorities of the Nordic countries.

Diagnostic Criteria

The following criteria were established: A) serum monoclonal immunoglobulin [M protein] concentration of IgG greater than 30 g/L, M protein concentration of IgA greater than 20 g/L, the presence of M protein of IgD or IgE regardless of concentration, or Bence Jones proteinuria greater than 1 g/24 h; B) M protein in serum or urine at a lower concentration than that described in criterion A; C) at least 10% plasma cells in a bone marrow aspirate or biopsy-verified plasmacytoma of bone or in soft tissue; and D) osteolytic bone lesions. A diagnosis of multiple myeloma was accepted if criteria A + C, A + D, or B + C + D were fulfilled.

Eligibility Criteria

Only patients with symptomatic disease were accepted for randomization. Patients were considered ineligible if they were elderly (usually more than 80 years of age), if they were young (usually less than 55 years of age) and were being considered for intensive chemotherapy protocols, if they had psychiatric disease, if they had other active malignant disease, if they had severe heart disease or other severe coincident illness, or if they were terminally ill.

Statistical Considerations

Assuming a median survival in the control arm of 30 months, a prolongation of median survival by 12 months in the experimental arm, a follow-up period of 2 years after the last included patient, and a survival analysis with a statistical power of 80% and a significance level of 5%, we estimated that 580 patients would be needed for the trial. Given an expected accrual rate of 50% of all patients with newly diagnosed myeloma in a population of 10 million persons in which the crude incidence of myeloma is 6.3 per 100 000 inhabitants per year [20], we anticipated entering the 580 patients within 24 months. This goal was nearly reached, but the inclusion period had to be prolonged by 5 months before the accrual was completed.

Patients

From 1 June 1990 to 3 November 1992, a total of 1083 patients with myeloma were reported. This corresponds to 67% of the estimated total number of patients with newly diagnosed myeloma [20] during the inclusion period. The reasons for non-entry into the trial are shown in Table 1. Of 1083 reported patients, 592 (55%) were randomly assigned to receive melphalan-prednisone or melphalan-prednisone and interferon. All patients were given both verbal and written information and were asked to give verbal consent before being entered into the study. All patients were followed until death or until November 1994.

Study Design

Randomization

The study was stratified according to coordinating center. Patients were randomly assigned to treatment in blocks of four. This was done at the coordinating center by means of sealed envelopes at a telephone call from the responsible clinician.

Treatment Protocol

Patients randomly assigned to receive melphalan-prednisone were given oral melphalan, 0.25 mg/kg of body weight, and prednisone, 100 mg/d, on days 1 to 4. This course was repeated every 6 weeks. If tolerated, the three initial courses could be given at 4-week intervals; this was optional.

We checked the degree of myelosuppression by measuring neutrophil and platelet counts 2 to 3 weeks after the first courses were given and before each additional course; standard guidelines were provided for escalation and reduction of melphalan dose to guarantee that all patients received adequate doses without undue hematologic toxicity.

Patients randomly assigned to receive melphalan-prednisone and interferon were given the same doses of melphalan and prednisone that were given to those patients receiving melphalan-prednisone alone. In addition, they were given interferon-α 2b (Introna, Schering-Plough, Stockholm, Sweden) from the start of therapy at a dose of 5 MU, subcutaneously, three times weekly. Melphalan doses were adjusted according to the same rules in both treatment groups. To avoid undue reductions of melphalan dose caused by combined melphalan-interferon bone marrow suppression, interferon therapy was temporarily suspended if the interval between two courses of melphalan-prednisone had to be prolonged by more than 2 weeks or if the melphalan dose had to be reduced to less than 50% of the initial dose. For patients with other symptoms that suggested substantial interferon toxicity, interferon therapy was reduced or interrupted and later, if feasible, reinstituted at a dose of 3 or 1 MU, three times weekly.

Duration of Initial Therapy

In both treatment groups, at least eight courses of melphalan-prednisone were given if progression was not seen. In patients who achieved at least a minor response and a plateau phase, melphalan-prednisone therapy was discontinued and was reinstituted after relapse. Interferon therapy was continued throughout the plateau phase and relapse, until definitive failure of melphalan-prednisone therapy occurred. For patients who did not respond to melphalan-prednisone therapy, the responsible physician was free to choose any therapy, but combination chemotherapy, including that with doxorubicin or mitoxantrone, was generally recommended as second-line therapy. All patients, including those who stopped receiving interferon therapy because of toxicity, were considered to be on study until the time of definitive melphalan-prednisone failure.

Follow-up Evaluation

All patients were seen at intervals of no more than 6 weeks for clinical and laboratory evaluation. Partial response was considered to have occurred if the initial serum M protein concentration was reduced by at least 50%, if the Bence Jones protein level was reduced to less than 0.2 g/24 h, and if the patient's clinical status was improved without persistent anemia (hemoglobin concentration more than equals to 90 g/L without transfusions), hypercalcemia, or signs of progressive renal or skeletal disease. Complete response was considered to have occurred in patients who fulfilled the criteria for partial response if the M protein in serum and urine was no longer detectable with agarose gel electrophoresis and if the proportion of plasma cells in a bone marrow aspirate was less than 5%. Minor response was considered to have occurred if the initial serum M protein concentration was reduced by 25% to 50% and the Bence Jones protein level was reduced by at least 50% but to no less than 0.2 g/24 h in patients fulfilling the criteria for partial response. Failure was defined as a confirmed increase of the M protein concentration in serum or urine of more than 25%, persistent hypercalcemia or progression of renal failure, skeletal lesions, or soft-tissue plasmacytomas. The term “definitive failure” on melphalan-prednisone therapy (or melphalan-prednisone and interferon therapy) included patients with primary failure and patients with secondary failure after reinstitution of melphalan-prednisone therapy. Time to response was calculated from the start of treatment until the first time the patient fulfilled the criteria for response. A plateau phase was considered to be present in responding patients if three consecutive measurements of the M protein concentration, 6 weeks apart, varied by less than 20%. Time to plateau phase was calculated from the start of therapy until the time of the first of the three M protein concentration measurements done to identify plateau phase. Relapse was defined as a confirmed increase of more than 25%, in responding patients, of the serum M protein concentration; by an increase of the Bence Jones protein level to more than 1 g/24 h; or by other unequivocal signs of disease progression, such as hypercalcemia or the progression of skeletal lesions or soft-tissue plasmacytomas. Response duration was calculated from the first time the patient fulfilled the criteria for response until the time the patient fulfilled the first criterion for relapse or until death. Plateau phase duration was calculated from the start of the plateau phase. Both time to definitive failure on initial therapy and survival were calculated from the start of treatment.

Dose Intensity

The dose intensity for melphalan was calculated for each patient by dividing the cumulative received dose of melphalan during the first year on study by the cumulative projected dose according to the study protocol. The dose intensity for interferon was determined by calculating the proportion of patients who—according to the study protocol—should have been receiving interferon and were still receiving it 6, 12, 18, and 24 months after randomization.

Statistical Methods

Comparisons between the treatment arms for response rate and for the proportion of patients reaching response and plateau phase were done using the Fisher exact test for 2 × 2 tables with two-tailed P values. The curves describing remission duration and survival were constructed using the Kaplan-Meier method and compared using the log-rank test. Median survival time and median response and plateau phase duration were estimated from the survival curves. An unpaired t-test was used to compare the mean dose intensity of melphalan in the treatment groups. A Wilcoxon-type test for trend was used to compare performance status and toxicity. The Cox proportional-hazards model was used to estimate β-coefficients and relative risks and to estimate the risk ratio for death after adjustment for differences in prognostic factors between the treatment groups.

Results

Evaluable Patients

Two hundred ninety-nine patients were randomly assigned to receive melphalan-prednisone, and 293 were assigned to receive melphalan-prednisone and interferon. Two patients in each group were excluded after randomization because they did not fulfill the diagnostic criteria. Five more patients in the melphalan-prednisone and interferon group were excluded after randomization: Three were excluded because they refused interferon therapy immediately after randomization, and 2 were excluded because they had mistakenly been entered in another, simultaneous trial. The remaining patients in the melphalan-prednisone group (n = 297) and the melphalan-prednisone and interferon group (n = 286) were all included in the analyses of response and survival according to the principle of intention-to-treat. All patients were evaluable for survival, and no patients were lost to follow-up. One patient in the melphalan-prednisone group and 7 patients in the melphalan-prednisone and interferon group were not evaluable for response because of other, coincident illnesses or protocol violations. In the analysis of response, these patients were considered nonresponders.

Patient Characteristics

Clinical and laboratory characteristics of the patients at the time of randomization are shown in Table 2. In the melphalan-prednisone and interferon group, a higher proportion of patients had a low performance status (3 to 4 according to World Health Organization [WHO] criteria), and a higher proportion had light-chain disease. For all other patient characteristics presumed to have prognostic importance, the treatment groups were well balanced.

Response Evaluation

Response Rate

Forty-five percent of patients in the melphalan-prednisone group and 44% of patients in the melphalan-prednisone and interferon group achieved at least a partial response (Table 3). The median time from randomization to response was 4 months in both groups.

Response Duration

For patients achieving minimum partial response, the response duration (relapse-free survival) was longer in the melphalan-prednisone and interferon group (median duration, 21 months) than in the melphalan-prednisone group (median duration, 15 months; P = 0.005) Figure 1 A. For patients achieving only minor response, no difference between the treatment groups was seen Figure 1 B.

Plateau Phase

Fifty-four percent of patients in the melphalan-prednisone group and 56% of patients in the melphalan-prednisone and interferon group reached a plateau phase. The time to plateau phase was similar for both groups (median time to plateau phase, 7 months).

Plateau Phase Duration

For patients who reached a plateau phase after a partial or complete response, the duration of the plateau phase was longer in the melphalan-prednisone and interferon group (median duration, 19 months) than in the melphalan-prednisone group (median duration, 14 months; P = 0.03) Figure 1 C.

Secondary Response Rate

Melphalan-prednisone therapy was reinstituted at the time of relapse in 89 patients in the melphalan-prednisone group and 74 patients in the melphalan-prednisone and interferon group. Fifty-six percent of patients in the melphalan-prednisone group and 51% of patients in the melphalan-prednisone and interferon group responded by achieving at least a stabilization of disease.

Time to Definitive Failure of Melphalan-Prednisone Therapy

The time to definitive failure of initial therapy (melphalan-prednisone or melphalan-prednisone and interferon) or death was similar in both treatment groups. The risk ratio for the melphalan-prednisone group compared with the melphalan-prednisone and interferon group was 1.09 (95% CI, 0.88 to 1.34; P = 0.43). The median time to failure or death was 20 months in the melphalan-prednisone group and 25 months in the melphalan-prednisone and interferon group.

Survival

At the time of our analysis, 169 patients in the melphalan-prednisone group and 164 patients in the melphalan-prednisone and interferon group had died. No difference in crude survival was seen between the treatment groups (Figure 2). The median survival time was 29 months in the melphalan-prednisone group and 32 months in the melphalan-prednisone and interferon group. The risk ratio for death in the melphalan-prednisone group compared with the melphalan-prednisone and interferon group was 1.02 (CI, 0.83 to 1.23; P = 0.84).

A multivariate Cox analysis of patient characteristics at time of diagnosis showed independent prognostic importance for the following factors: age (relative risk for death, 1.02 per year [CI, 1.01 to 1.04]); WHO performance status (relative risk for death, 0.54 [CI, 0.43 to 0.70] for status 0 to 2 compared with status 3 to 4); and serum β₂-µglobulin level (relative risk for death, 1.08 per 1 mg/L [CI, 1.05 to 1.11]). No prognostic importance was seen for sex, Durie/Salmon stage, blood hemoglobin concentration, serum albumin level, M protein class, or serum creatinine concentration. After adjusting for the differences between the treatment groups with respect to prognostic factors, the risk ratio for death in the melphalan-prednisone group compared with the melphalan-prednisone and interferon group was 1.12 (CI, 0.89 to 1.40; P = 0.33).

Subgroup Analyses of Survival

A retrospective analysis of survival was done separately for patients with IgG myeloma, patients with IgA myeloma, and patients with light-chain disease. Among patients in these subgroups, no statistically significant differences in survival were seen between the treatment groups.

A retrospective analysis of survival was also done for those patients in the melphalan-prednisone and interferon group who stopped receiving interferon prematurely (see below) compared with those who did not. No statistically significant difference was seen in survival between these patient groups.

Toxicity and Adverse Events

The proportion of patients having toxicity grades I to IV according to WHO criteria is shown in Figure 3. Hematologic toxicity grades III-IV (mainly neutropenia) were noted more frequently in the melphalan-prednisone and interferon group than in the melphalan-prednisone group (71% compared with 52%; P < 0.001). However, the number of serious infections was similar in both treatment groups. In 13 patients in each group, infection was the primary cause of death.

Severe cardiovascular events were seen in 30 patients in the melphalan-prednisone and interferon group and 20 patients in the melphalan-prednisone group; fatal outcome was seen in 17 patients in the melphalan-prednisone and interferon group and 11 patients in the melphalan-prednisone group. Cardiac failure or myocardial infarction with fatal outcome or sudden death was seen in 12 patients in the melphalan-prednisone and interferon group and 7 patients in the melphalan-prednisone group. Cardiac failure, unstable angina, or myocardial infarction without fatal outcome was seen in 11 patients in the melphalan-prednisone and interferon group and 7 patients in the melphalan-prednisone group. Other vascular events (including stroke, pulmonary embolism, and renal artery thrombosis) with fatal outcome were seen in 5 patients in the melphalan-prednisone and interferon group and 4 patients in the melphalan-prednisone group. Such events without fatal outcome were seen in 1 patient in each treatment group.

The combined number of treatment-related and cardiovascular deaths occurring during treatment on study was 31 in the melphalan-prednisone and interferon group and 25 in the melphalan-prednisone group. The difference is not statistically significant for the combined number of deaths or for cardiovascular deaths separately.

Dose Intensity

Melphalan

The melphalan-prednisone and interferon group had a higher prevalence of melphalan dose reductions and a higher occurrence of delayed melphalan-prednisone courses than did the melphalan-prednisone group. The mean dose intensity for melphalan was 88% in the melphalan-prednisone group and 76% in the melphalan-prednisone and interferon group; the difference was statistically significant (P < 0.001).

Interferon

The proportion of those patients remaining on study who continued to receive full-dose interferon diminished steadily during the follow-up period (Figure 4). Among only those patients who achieved a plateau phase, 66% were receiving interferon at the start of the plateau phase and 42% were receiving it at full dose. After 6 months in plateau phase, 63% were still receiving interferon and 27% were receiving it at full dose.

Among patients still on study, interferon therapy was prematurely discontinued in 129 patients. The total duration of these periods was 139 patient years, corresponding to 29% of the total observation time on study in the melphalan-prednisone and interferon group. The reasons for cessation of interferon therapy were central nervous system toxicity in 26% of patients, hematologic toxicity in 26%, infections in 7%, fever and muscle pains in 9%, gastrointestinal toxicity in 10%, skin reactions in 5%, other side effects in 7%, cardiac disease in 4%, protocol violations in 5%, and “other” in 3%.

Discussion

The principal idea determining the design of our study was our desire to maximize the potential benefits of interferon therapy by 1) using it in the experimental group from the start of therapy in combination with melphalan-prednisone and 2) continuing it after the achievement of response and plateau phase as well as during relapse, until the time of definitive failure on melphalan-prednisone. The chosen scheduled dose of interferon was assumed to be tolerable for most patients during long-term treatment.

The trial was done in a multicenter setting that involved all types of hospitals, including both county and university hospitals, providing care for myeloma patients. The patients studied constituted 55% of all reported patients diagnosed in a defined population of 12 million persons, corresponding to 37% of the estimated total number of newly diagnosed patients in this population during the inclusion time of the study. Patients not entered into the study were either ineligible according to the study protocol or had never been reported to the study secretariat. On the basis of previous experience [20], patients not reported to the study secretariat were assumed to be primarily elderly patients and persons otherwise ineligible for trials. Consequently, our patient sample is highly representative of the total population of patients with myeloma, and our results have a high degree of generalizability.

Our primary hypothesis was that interferon therapy—during induction, maintenance, and relapse—could prolong survival better than standard melphalan-prednisone therapy. Unfortunately, our results show that this is not the case. We were unable to find any statistically significant survival advantage for either the total sample or for any subgroup. Furthermore, the addition of interferon to melphalan-prednisone for initial therapy was associated with an enhancement of toxicity, causing a premature discontinuation of interferon therapy in about one third of patients.

Our results agree with those of Cooper and colleagues [13], although the dose of interferon used by these investigators was lower (2 MU/m² body surface area three times weekly for 2 weeks during each 4-week cycle) than the one we used and was given concomitantly with melphalan-prednisone during both induction and maintenance. Both studies indicate that adding low-dose interferon to standard melphalan-prednisone therapy does not improve response rate or survival in patients with myeloma.

We cannot rule out the possibility, however, that other doses and schedules of interferon may prove more effective. Osterborg and coworkers [14] used natural leukocyte interferon-α intermittently at higher doses in combination with melphalan-prednisone for initial therapy, and they followed this with low-dose interferon combined with melphalan-prednisone as maintenance therapy. The response rate in their study was higher for patients receiving combined therapy than for patients receiving melphalan-prednisone, but, other than a survival advantage for patients with IgA myeloma and light-chain disease, no differences in response duration or survival were seen. An alternative concept—the sequential use of interferon alternating with the five-drug combination VBCP—is currently being explored in a randomized trial by the Eastern Cooperative Oncology Group, after a preliminary report on the promising results of an uncontrolled pilot study [21]. The results of this and of other trials still in progress must be awaited before a final consensus can be reached about the role of interferon in the initial treatment of myeloma.

The role of interferon as maintenance therapy has already been the subject of several studies; our trial was not primarily designed to explore this question. Thus, no randomization was done between interferon and no maintenance therapy at the time of response or at the time of achievement of plateau phase. Nevertheless, a comparison between the treatment groups with regard to response and plateau phase duration is worthwhile, bearing in mind that the comparison is influenced by the fact that approximately one third of the patients had stopped receiving interferon therapy because of side effects before entering a plateau phase.

In our study, response duration and plateau phase duration for patients who achieved at least a partial response were prolonged by interferon therapy compared with no maintenance therapy. The difference in median response duration between the treatment groups was 6 months. No effect was seen for patients with minor response. These results agree with those of Mandelli and coworkers [15], who found a statistically significantly longer response duration (as estimated by a difference in median response duration of 12 months), and those of Westin and colleagues [16], who found an 8-month prolongation of the median plateau phase duration when they compared interferon therapy with no maintenance therapy. In neither study could a statistically significant prolongation of survival be shown [22]. These results are contradicted by those of a study by the Southwest Oncology Group [17], in which maintenance therapy with interferon did not prolong either response duration or survival. On the other hand, the preliminary results of other ongoing studies [23, 24] favor interferon as an efficacious way to postpone relapse in responding patients. Preliminary reports show that maintenance therapy with interferon prolonged survival and response duration in complete responders after high-dose chemotherapy with stem cell support [25]. These results may indicate a more important role for interferon in patients with a good (“complete”) response to chemotherapy.

Thus, it seems likely that interferon exerts a biological effect on myeloma in patients who have responded to initial chemotherapy. The magnitude of this effect can be gauged by the 6- to 12-month prolongation of response or median plateau phase duration associated with interferon maintenance therapy in these trials. Maintenance chemotherapy similarly prolongs response duration [26] but has been rejected because of the lack of a concomitant survival advantage and because of the side effects associated with prolonged chemotherapy, including increased risk for the secondary myelodysplastic syndrome and acute myelogenous leukemia [1, 27]. Similarly, with interferon, the advantage of a prolonged response duration has to be weighed against the inconvenience and side effects of interferon administration. Reliable data on this will require quality-of-life and cost–utility analyses that compare responders receiving interferon with responders not receiving therapy. Such data are forthcoming from a quality-of-life study linked to our study.

The toxicity profile of interferon is well known. In our study, hematologic toxicity was higher for the melphalan-prednisone and interferon group than for the melphalan-prednisone group, but it was not associated with an increased incidence of severe infections. Hematologic toxicity was the main reason for reductions in melphalan dose and was therefore responsible for a statistically significant difference in melphalan dose intensity. Despite this, the response rate with melphalan-prednisone and interferon therapy was not inferior to that with melphalan-prednisone therapy.

Central nervous system toxicity, gastrointestinal side effects, skin reactions, and the flu-like syndrome are also well known. The possibility of a relation between interferon therapy and cardiovascular events is less well recognized. Sonnenblick and Rosin [28] reviewed 44 reported cases of interferon-associated cardiac events, including arrhythmias, manifestations of ischemic heart disease, and cardiomyopathy. Six of the cases had fatal outcomes. In our study, the rate of severe cardiac events was higher in the melphalan-prednisone and interferon group than in the melphalan-prednisone group. Although the difference was not statistically significant, it suggests the possibility of a causal relation between melphalan-prednisone and interferon therapy and cardiac events. This concern should be taken into account when interferon therapy is considered for elderly patients and patients with heart disease.

In summary, this management trial did not show any advantage in response rate or survival from the concomitant use of continuous low-dose interferon and melphalan-prednisone for initial and maintenance therapy in patients with myeloma. However, our results do support those of earlier studies; they show a prolongation of relapse-free survival after the achievement of response or plateau phase. The value of this effect needs to be assessed in quality-of-life studies and cost–utility analyses before definitive treatment recommendations can be made. Until this is done, interferon can be used as maintenance therapy for selected patients who have responded favorably to initial chemotherapy and who are expected to tolerate interferon during long-term therapy.

Appendix

Authors

Martin Hjorth, MD, PhD, Lidkoping Hospital, Lidkoping, Sweden, and Sahlgrenska University Hospital, Goteborg, Sweden; Jan Westin, MD, PhD, Lund University Hospital, Lund, Sweden; Inger Marie S. Dahl, MD, PhD, Tromso University Hospital, Tromso, Norway; Peter Gimsing, MD, PhD, Rigshospitalet, Kobenhavn, Denmark; Erik Hippe, MD, PhD, Kobenhavn University Hospital, Herlev, Denmark; Erik Holmberg, MSc, Sahlgrenska University Hospital, Goteborg, Sweden; Jon Lamvik, MD, PhD, Trondheim University Hospital, Trondheim, Norway; Johan Lanng Nielsen, MD, PhD, Arhus University Hospital, Arhus, Denmark; Eva Lofvenberg, MD, PhD, Norrland University Hospital, Umea, Sweden; Ilmari P. Palva, MD, PhD, Tampere University Hospital, Pirkkala, Finland; Stig Rodjer, MD, PhD, Ostra University Hospital, Goteborg, Sweden; Ingebrigt Talstad, MD, PhD, Haukeland Hospital, Bergen, Norway; Ingemar Turesson, MD, PhD, Malmo University Hospital, Malmo, Sweden; Finn Wisloff, MD, PhD, Ulleval Hospital, Oslo, Norway; and Goran Zador, MD, PhD, Schering-Plough, Stockholm, Sweden.

The Nordic Myeloma Study Group

Steering Committee: Jan Westin (Chairman); Martin Hjorth (Coordinator); Eva Lofvenberg; Stig Rodjer; Ingemar Turesson; Goran Zador, Schering-Plough AB, Stockholm, Sweden; Finn Wisloff; Ingebrigt Talstad; Jon Lamvik; Inger Marie S. Dahl; Erik Hippe; Peter Gimsing; Johan Lanng Nielsen; Ilmari Palva; and Sigmundur Magnusson, Reykjavik, Iceland.

Secretariat and Data Management: Susanne Amsler-Nordin, Martin Hjorth, Erik Holmberg, MajLis Polgary, and Stig Rodjer, Goteborg, Sweden.

Statistics: Anders Oden, Kungalv, Sweden.

Safety Committee: Arne Wallgren and Lars Wilhelmsen, Goteborg, Sweden.

Local Collaborators and Centers: Sweden: Louise Hellqvist, Halmstad; Sverker Hasselblom, Varberg; Jan Carneskog and Stig Rodjer, Goteborg; Sigvard Olsson, Molndal; Olof Lindqvist, Uddevalla; Peter Hoffman, Lysekil; Kurt Olsson, Stromstad; Anders Tholen, Alingsas; Carl-Magnus Stolt, Boras; Arne Rindner, Skene; Rolf Svensson, Falkoping; Martin Hjorth, Lidkoping; Jan Vaart, Skovde; Soren Hansen, Eksjo; Leif Engqvist, Varnamo; Owe Lannemyr, Saffle; Ingemar Turesson, Malmo; Per-Gunnar Nilsson, Lund; Inger Linne, Trelleborg; Goran Lilja, Angelholm; Gustav Tallroth, Ystad; John Hallgren, Simrishamn; Birgitta Andersson, Hassleholm; Rolf Billstrom, Helsingborg; Sigvard Persson, Kristianstad; Torgny Samuelsson, Vaxjo; Hakan Odeberg, Karlskrona; Magnus Adriansson, Kalmar; Hans Tove, Oskarshamn; Nils Stobeus, Motala; Jan Habberstad, Vastervik; Tiina End, Norrkoping; Magnus Dahlen, Visby; Leif Engqvist, Varnamo; Eva Lofvenberg and Mikael Eriksson, Umea; Nils Anagrius, Falun; Dic Aronson, Mora; Lubor Nezadal, Hudiksvall; Karin Eriksson, Ostersund; Michael Hedenus, Sundsvall; Jan Ryde, Harnosand; Lennart Westin, Solleftea; Lars-Olof Andersson, Ornskoldsvik; Anita Bjurman, Lycksele; Karin Forsberg, Skelleftea; Dan Fors, Pitea; Staffan Wikstrom, Lulea; Bernt Thule, Kalix; Ulf Bolsoy, Gallivare; Klas Lennermo, Kiruna; and Tomas Strand, Sandviken.

Finland: Ilmari Palva, Tampere; Anders Almqvist, Vasa; Bo Isomaa, Jakobstad; and Kalevi Oksanen, Hameenlinna.

Norway: Finn Wisloff, Clas Eika, and Bernt Ly, Oslo; Eystein Brandt, Lillehammer; Kjetil Weyde and Christian Fossum, Gjovik; Kare Lovasen and Jon Arne Sparby, Kongsvinger; Eva Marie Jacobsen and Marit Rinde, Elverum; Sverre Nyhus, Larvik; Johannes Kahrs, Fredrikstad; Tore Steen and Hege Gravdahl, Akershus; Lars Borge, Drammen; Kjell A Grottum, Kristiansand; Oystein Flotterod, Porsgrunn; Bjarne Riis Strom, Honefoss; Havar Knutsen, Gjettum; Audun Drivenes, Moss; Jorn Paulsen, Rjukan; Svein Riis and Petra Weber Hauge, Sarpsborg; Ingebrigt Talstad and Ingerid Nesthus, Bergen; Peter Coll, Voss; Knut Hakon Hole, Odda; Trygve Saeter, Stord; Terje Sindre, Floro; Sigbjorn Berentsen and Harald Nes, Haugesund; Geirfinn Vagstad, Forde; Reino Heikkela and Victor Shammas, Stavanger; Jon Lamvik, Trondheim; Bottolf Lodemel, Volda; Odd R. Skogen, Alesund; Yngve Sorum, Molde; Vidar Kvambe, Kristiansund; Otto Bull, Levanger; Inger Marie S. Dahl, Tromso; Steinar Jaeger, Bodo; Per Gunnar Ingvaldsen, Hammerfest; Kjell Pedersen, Harstad; Berit Dahl, Kirkenes; Arne Fossli, Narvik; Gjermund Liljedal, Gravdal; Leif Tormod Hansen, Stokmarknes; Martha Onkiehong, Mo i Rana; Tor Haugnes, Mosjoen; and Dag Stefansen, Sandnessjoen.

Denmark: Erik Hippe, Peter Gimsing, and Ole Gadeberg, Kobenhavn; Johan Lanng Nielsen and Niels Abildgaard, Arhus; Henning Jans, Holstebro; Torben Mourits-Andersen, Esbjerg; Bent Neubauer, Vejle; and Nielsaage Toffner Clausen, Haderslev.

Iceland: Sigmundur Magnusson and Gudmundur Eyjolfsson, Reykjavik; and Sigurdur Bjornsson, Tungotu.

Dr. Westin: Department of Medicine, Lund University Hospital, S-22185 Lund, Sweden.

Dr. Dahl: Medisinsk Avdelning IA, Regionsykehuset, N-9012 Tromso, Norway.

Dr. Gimsing: Medicinsk Haematologisk afd L, Rigshospitalet, DK-2100 Kobenhavn O, Denmark.

Dr. Hippe: Medicinsk-Haematologisk afd L, Kobenhavn University Hospital, DK-2730 Herlev, Denmark.

Mr. Holmberg: Oncology Center, Sahlgrenska University Hospital, S-41345 Goteborg, Sweden.

Dr. Lamvik: Med avd, Hematologisk, Regionsykehuset, N-7006 Trondheim, Norway.

Dr. Lanng Nielsen: Medicinsk-Haematologisk afd., Arhus University Hospital, DK-8000 Arhus C, Denmark.

Dr. Lofvenberg: Department of Medicine, Norrland University Hospital, S-90185 Umea, Sweden.

Dr. Palva: Oikotie 8A, FIN-33950 Pirkkala, Finland.

Dr. Rodjer: Department of Medicine, Ostra University Hospital, S-41685 Goteborg, Sweden.

Dr. Turesson: Department of Medicine, Malmo University Hospital, S-21401 Malmo, Sweden.

Dr. Talstad: Torjusbk, 19-2, N-0378 Oslo, Norway.

Dr. Wisloff: Med. avd., Ulleval Sykehus, N-0407 Oslo 4, Norway.

Dr. Zador: Schering-Plough AB, Box 27190, S-10252 Stockholm, Sweden.