0c-interferon in hematological malignancies Frank J. Giles and Howard Ozer University of North Carolina at Chapel Hill, North Carolina, USA Recent studies have generated data demonstrating significant clinical activity of a-interferon therapy in each of six hematological malignancies, chronic myeloid leukaemia, essential thrombocythemia, polycythemia rubra vera, non-Hodgkin's lymphomas, multiple myelomatosis and hairy cell leukaemia. Current Opinion in Biotechnology 1991, 2:1M7-850
Introduction Research into the therapeutic efficacy and mode of action of cx-interferon in the hematological malignancies continues to expand and, in the former, to generate increasingly encouraging data. A detailed knowledge of the mode(s) of action of a-interferon (IFN) continue to elude us. This brief review concentrates on a few recent data which we feel, are most representative of current significant research endeavors although obviously much important work is necessarily excluded.
Chronic myeloid leukemia In patients with chronic myeloid leukaemia (CML) and in normal controls, IFN has an in vitro dose-dependent anti-proliferative effect on bone marrow progenitor cells. As a single agent, it achieves hematological response rates that are at least equivalent to conventional busulfan or hydroxyurea therapy. Unlike busulfan or hydroxyurea, aIFN has been consistently shown to induce a reduction in the percentage of marrow metaphases that are positive for the Philadelphia chromosome (Ph') in a subset of CML patients receiving single-agent therapy. This reduction is considered to represent a partially selective suppression of the malignant clone by a-IFN. Achievement of a hematological response seems to be a necessary, but insufficient, condition for achieving a cytogenetic response. The optimum rates of cytogenetic response are seen when patients with CML who are in a good prognostic group, begin single-agent a-IFN treatment within one year of initial diagnosis, at a minimum dose of 5 Mu/ma/day subcutaneously and who maintain a peripheral total white-cell count of less than 3 x 109 cells/1 during IFN therapy. The rate and degree of cytogenetic response in CML patients receiving recombinant a-IFN is
dose-dependent. With the common methods of administration currently in use, i.e. by bolus, subcutaneously or intramuscularly, the adverse side-effect profile of IFN is such that doses of greater than 15-35MU per week, which are considered optimal in CML therapy, are rarely tolerated for prolonged periods of time, although moderate dose reductions can be employed after clinical and/or cytogenetic response has been achieved. The durability of sustained complete cytogenetic responses to IFN alone in early-stage chronic-phase CML patients has recently been documented [1o*]. A mean length of survival of 62 months was described in a cohort of 96 patients treated with a-IFN alone compared with 39 months in historical controls. Seventy (73%) of a series of 96 chronic phase CML patients, treated within one year of the time of diagnosis, achieved hematologic remission (95% confidence intervals, 63-81%) and 18 (19%) showed complete suppression of the Ph' in at least one cytogenetic test. A complete cytogenetic response was induced in 7 (95% CI, 6-26%) of 51 patients treated with non-recombinant 0t-IFN and in 11 (95% CI, 13--40%) of 45 patients treated with recombinant a.IFN. There was no significant difference between agents in terms of induction of cytogenetic reductions. Eleven patients still had complete cytogenetic responses after at least 6 to more than 40 months (median over 30 months). The mode of action of a-IFN in CML is undefined. The bone marrow micro-environment is a possible alternative or additional site of 0t-IFN action. In CML patients, primitive blast colony-forming cells (BL-CFC) are deficient in their attachment to bone marrow-derived stromal ceils (BMSC) compared with normal BL-CFC. Dowding et at [2oo] have investigated the effect of recombinant a2a-IFN on the interaction between hematopoietic progenitor cells and BMSC by culturing normal stromal ceils with a-IFN (at concentrations of 50--5000 U/ml). At the 50 U/ml level they documented an increased capacity of BMSC to bind BL-CFC from CML and long-term
Abbreviations BL-CFC~Iast colony forming cells; BMSC--bone marrow derived stromal cells; CML--chronic myeloid leukaemia; ET---essential thrombocythemia; OAG---glycosaminoglycan;HCL--hairy cell leukaemia; IFN--~nterferon; MP--mephalon-prednisone; MPO~myeloproliferative disorder; NHL--non-Hodgkin's lymphoma; Pit'--Philadelphia chromosome; PRV~olycythemia rubra vera. © Current Biology Ltd ISSN 0958-1669
847
848 Pharmaceuticalapplications culture-initiating cells. An increase in the stromal layer sulphated glycosaminoglycans (GAGs) was also demonstrated. Sulphated GAGs were not directly involved in binding CML BL-CFC, as they are in binding normal BLCFC. Neuraminidase-treated control BMSC bound an increased number of CML BL-CFC, reproducing the effect of tx-IFN in this model, whereas the binding of ot-IFN treated normal BMSC was unaffected by neuraminidase treatment. Dowding et aL suggest that et-IFN can override the deficient adhesion of CML primitive progenitor cells to BMSC and thus modify their aberrant proliferation.
Essential thrombocythemia and polycythemia rubra vera The promising clinical data on the use of tz-IFN in CML has stimulated study of its effects in other myeloproliferative disorders (MPD) including essential thrombocythemia (ET) and polycythemia rubra vera (PRV). Recombinant cx-IFN has been shown to be an effective induction agent both in ET and in thrombocythemia associated with other MPD. Current cytotoxic therapy is leukaemogenic in the MPD, whereas the therapeutic role of anti-pLatelet aggregation agents remains unclear. A number of pilot studies have demonstrated in which recombinant c~-IFN rapidly and selectively reduces the platelet counts in previously untreated patients and those who have failed other therapeutic modalities. A recent report on the efficacy and tolerability of long-term 0t2a-IFN treatment in ET in a cohort of 22 patients showed that it is an effective, well tolerated maintenance agent at doses of 3-5 Mu thrice weekly, subcutaneously (tiw sc) I3"]. Suppression of megakaryopoiesis, a reduction in platelet halflife and significant impairment of the in vivo Fc-dependent phagocytic ability of the reticuloendothelial system has been reported where cx-IFN has shown a therapeutic effect in the thrombocytosis associated with the MPD [4"',5]. Induction of the immune destruction of platelets may be part of the effect of ct-IFN in ET, as levels of platelet-associated immunoproteins are raised in the initial thrombocytopenia seen in 0t-IFN therapy of, patients with neoplasia. The mechanism of action of cx-IF may not be identical in all MPD-associated thrombocytosis patients. Differential effects of ~x-2c-IFN on megakaryocyte morphology in CML and other MPDs have been documented. A reduction in the inherent risk of leukaemia may result from the anti-proliferative and immuno-modulatory effects of et-IFN. Such an anti-proliferative effect in ET is presumably necessary to cause clonal reduction in the malignant megakaryocyte population and may also decrease the 'base-line' incidence of the acute leukaemialike illness that occurs in this disorder. Although experience using ct-IFN in patients with PRV is more limited, initial data would indicate that further study in this disorder is indicated [6"].
Non-Hodgkin's lymphoma The follicular non-Hodgkin's lymphomas (NHL) accounts for 30-40 % of all cases of lymphoma diagnosed annually, being slightly more common in the USA than Hodgkin's disease with some 12000-15000 new cases being diagnosed each year. Most of the available data on the use of tz-IFN in follicular NHL, are based on relatively low dose regimens of 3 or 5 Mu/m x daily or thrice weekly, respectively. This largely reflects the toxicity of higher doses and the increasing perception that IFN therapy needs to be long-term to be of maximal benefit in this patient population. All data are currently too premature to make definitive comments on the effect, ff any, of IFN in terms of a survival benefit. Early data on three of the more important prospective studies indicate a combination of an alkytating agent and recombinant et-IFN if used as the first line of therapy is at least as effective as single-agent therapy alone. In the CALGB 8553 study ( H Ozer personal communication), involving 73 previously untreated and 103 previously treated patients, the former had a significandy higher objective (86% versus 62%) and complete (58% versus 25%) response rate (53% versus 23%) when treated with a cyclophosphamide/0t2b-IFN combination regimen. The higher complete response was associated with patient freedom from B symptoms and a better performance status. The chance of survival for five years after treatment is estimated to be 63% for previously untreated patients and 39% for those treated prior to study entry. Long-term follow up of this cohort is necessary to make any comment on any ultimate significant differences in failure-free or overall survival between the groups. Early data from a UK [7"] prospective study of treatment with chlommbucilAFN versus chlorambucil alone indicate a significant advantage in terms of remission duration in those patients who, following a response to first-line therapy, were re-randomized to receive an ~x2b-IFN maintenance regimen. In the 68 patients who were re-randomized, those receiving ~x-IFN as part of the induction and of the maintenance regimen have shown fewer relapses. The ECOG 6484 [8.] study, which randomized 249 analyzable patients with low grade or intermediate grade NHL to receive a COPA (cyclophosphamide, vincristine, prednisone, adriamycin) regimen with or without 0t2aIFN therapy, demonstrated that the addition of et2a-IFN increased the mean time before treatment failure from 19.2 months to 28.7 months. Further tests will determine whether a remission duration advantage translated into prolonged survival.
Multiple myelomatosis Clinical studies of c~-IFN in patients with multiple myeloma are currently concentrating on its potential role as part of combined chemotherapy/IFN induction regimens and as a single-agent maintenance therapy in patients who have responded to front-line therapy. Attempts
ac-interteron in hematological malignancies Giles and Ozer to add at-IFNto induction regimens consist of either concurrent or sequential administration of these modalities. The CA/~G MM (RV Smaller',JW Andersen, MJ Hawkins, V Bhide, MM Oken, EC Borden, tx-intefferon improves the effectiveness of induction chemotherapy in patients with prognostically unfavourable moderately aggressive Non-Hodgekin's lyrnphomas (NHL). Est 6484 an ECOG study (abstract) Proc A m So Clin Oncol 1991, 945:272) study randomized 272 evaluable previously untreated patients to receive a Melphalan/Prednisone (MP) regimen with or without u2.b-IFN at a dose of 2 Mu/mv- tiw sc for the first two weeks of each 28-day cycle. Responding patients were treated for two years. At a median followup of 23 months, the overall complete and partial remission rates were 44% in the patients treated with MP alone and 37% in those receiving both MP and IFN. A 1% complete response rate was seen with each type of treatment. There was no significant difference between the treatments in terms of median survival (MP 3.17 years; MP/IFN 3.05 years), time to response or duration of response. An ECOG MM [9"] pilot study used an alternating VBMCP-o.2b-IFN induction regimen on 54 previously untreated patients with myelomatosis: an overall objective response was observed in 43 patients (80%) including 16 patients (30%) who had a complete response and 8 patients (15%) who had a near-complete remission. The average duration of response was 35 months for all patients treated and this extended to 44 months in those patients who had shown a complete or near-complete response. A prolonged response duration and overall survival advantage was seen when a low dose maintenance regimen of ct-IFN, followed either MP or VMCP/VBAP induction therapy was applied to a subset of objective responders, in a retrospective analysis [10]. Initial data from a combined Swedish/Italian group on a cohort of 308 patients, with previously untreated Stage II or llI disease, appears to confirm the evidence that maintenance IFN therapy prolongs remission duration in patients who have responded to a MP induction. In this study, 120 patients (median age 71 years) who had already responded to MP and were in the plateau phase were randomized to receive either ct-IFN and MP (53 patients) or MP alone (56 patients) at the time of relapse. After a median observation time of 20 months from time of randomization, a highly significant difference in duration of plateau phase is evident, such that when ct-IFN is used, the duration of the plateau extends from 26 weeks to 59 weeks. At that time, 34 patients taking part in the study had died, of which 13 were receiving ct-IFN maintenance therapy (three of whom had minimal interferon exposure) and 21 were control patients. We await definitive proof that tx-IFN prolongs life in some patients with myelomatosis.
Hair), cell leukaemia Numerous studies have shown that over 80% of patients with hairy cell leukaemia (HCL) respond to ct-IFN therapy including patients in whom splenectomy has failed [11..]. Less than 5% of patients respond completely to
~t-IFN alone. Sustained responses are typical, with an average response duration of more than 3 years. Neutralizing antibodies to recombinant ct-IFNmay be responsible for loss of effect in some patients with HCL [12°]. Current clinical studies are mainly concerned with evaluathag tx-IFNversus splenectomy as first-line therapy in HCL patients, the role of recombinant growth factors during induction therapy, and comparisons of efficacy and safety of ~z-IFNwith the halogenated antimetabolites, deoxycoformycin and 2-chlorodeoxyadenosine.
References and recommended reading Papers of special interesL published within the annual period of review, have been highlighted as: • of interest •, of outstanding interest 1. •.
TALPaZM, KANTARJIANH, KURZROCKR, TRUJILLOJM, GLrrrERMAN jU: Interferon-alpha Produces Sustained Cytogenetic Responses in Chronic Myelogenous Leukemia. Ann Intern Med 1991, 114:532-538. Report of first prospective study to show sustained, complete cytogenetic responses in a subset of patients with CML treated with singleagent 0t-IFN therapy. Highlights hematological response as pre-requisite for cTtogenetic response. Suggests that sur~9,~ advantage may result from use of cc-IFN therapy versus traditional cytotoxic agents. 2. ,,
DOWD~G C, GUO A, Os'rERHOIZ J, SICZKOWSKIM, GOLDMANJ, GORDONM: interferon-cz Overrides the Deficient Adhesion o f Chronic Myeloid Leukemia Primitive Progenitor Cells to Bone Marrow Stromal CcUs. B/ood 1991, 78:499--505. First report o f the specific effect o f ct-IFN on the bone marrow microenvironment. The authors postulate this may mediate an indirect norIi~ali:,ation o f the aberrant proliferation o f the CML progenitor cells. 3. ,
Gazs FJ, ANDERSONC, GRAm" IK HO~aRAND AV, MEVIrAAB, M A C H ~SJ, GOLDSTONEAH: Recombinant Alpha 2a interferon An Effective Maintenance Agent in Essential Thrombocythemia. Leukem/a L.vrrqgJon~ 1990, 3:103--107. Reports sustained remissions in a subset of the study cohort of ET patients treated with 0t2a-IFN. Suggests that tx-IFN produces a long-term reduction in tumor load in ET.
4. •e
WADENVlKH, KtrrH J, RIDELL B, REVESZ P, JACOBSSON S, MAGNUSSON B, WEST~ J, VmtN L: The Effect o f ~t-Interferon on Bone Marrow Megakaryocytcs and Platelet Production Rate in Essential Thrombocythcmia. B/ood 1991, 77:2103--2108. Reports reduction in platelet production rates and peripheral platelet counts by 0t-IFN mainly through an anti-proliferative action on
megakaryoc~les. 5-
SCHEITHAUERW, GUISSLINGER H, TE.~CCH EM, ~ H M, ~ H W, Lt~WIG H: Effect o f Recombinant Interferontx2C o n Reticuloendothclial Function in Patients with Thro~osis. J Interferon Res 1990, 10:237-242.
6. SILVERRT: A New Treatment for Polycythemia.Vera: Rccom, binant Interferon-alpha. B/ood 1990, 76:664-665. Initial data on five patients documenting the elimination of the need for phlebotomy in PRV patients treated with Qt.IFN. No changes in serum er/thropoietin levels or marrow reticulin were evident after the first)'ear of IFN therapy. 7. •
GAYNORER, FISHER RI: Clinical Trials of Alpha-interferon in the Treatment of Non-Hodgekin's Lymphoma. Semin Oncol 1991 18(suppl 7):12-17. Cytotoxiointerferon combinations are tolerable and effective as induction therapy in low grade NHL with long term survival benefits yet to be demonstrated.
849
850
Pharmaceutical applications COOPERMR: A Review of the Clinical Studies of Alphatnterf¢on in the Management of Multiple Myeloma. Semin OncoI 1991, 18(suppl 7:18-29 A significant contributing factor in the degree of et~cacy of combination cytotoxic-interferon induction therapy in myelomatosis may be the precise gay in which the combination is administered (e.g sequentially versus concurrently). 8. •
9. •
OKEN MM, KYIE RA: Strategies for combininginterferonwith chemotherapy for the treatment of Multiple Myeloma. Semin Oncol 1991, 18 (suppl 7): 30-32. Documents the remarkable success of a sequential VBMCP/a-2b-interferon inductidn regimen in a cohort of previously untreated myelomatosis patients. 10.
11, o•
MANDELUF, AVVlSATIG, AMADOmS, BOCCADOROM, GERNONEA, LAUTAV) blARMONTF) PETRUCCIMT) TRIBALTOM) VEGNAML, ET aL: Maintenance Treatment with Recombinant Interferon Alpha.2b in Patients with Multiple Myeloma Responding to Conventional Induction Chemotherapy. N Engl J Med 1990, 322:1430-1434. GOLOMBI'-IM, FEFER DW, GOLDE DW, OZER H, PORTLOCK C, SILBER R, RAPPEPORTJ, RATALNMJ, THOMPSONJ, BON,'NEM
E, Er aL: Survival Experience of 195 Patients with Hairy Cell Leukemia Treated in a Multi-institutional Study with Interferon-alpha 2b. Leukemia Lymp~ma 1991, 4:99-102. Documents response and minimum 3 year follow-up data on very large cohort treated with single-agent recombinant tz.IFN. 12. •
VON WUSSOWP, Pl~aLm H, HOCHKEPPELH, JAKSO-Im.SD, SO.VNEN S, SCHMIDT H, MULLER-ROSENAUD, F'RANKEM, HAFERtACH T, ZWINGEILST, ET AL: Effective Natural Interferon-alpha Therapy in Recombinant Interferon-or.resistant Patients with Hairy Cell Leukemia. Eight patients with clinically significant neutralizing antibodies to recombinant ¢x2a-lFN regained control of their disease gahen treated with nat. ural a-IFN
FJ Giles and H Ozer, Di~Ssionof Medical Oncology, School of Medicine, 3009 Old Clinic Building, The Un/vemity of North Carolina, Chapel Hill, North Carolina 27599-7505, USA.
Introduction Research into the therapeutic efficacy and mode of action of cx-interferon in the hematological malignancies continues to expand and, in the former, to generate increasingly encouraging data. A detailed knowledge of the mode(s) of action of a-interferon (IFN) continue to elude us. This brief review concentrates on a few recent data which we feel, are most representative of current significant research endeavors although obviously much important work is necessarily excluded.
Chronic myeloid leukemia In patients with chronic myeloid leukaemia (CML) and in normal controls, IFN has an in vitro dose-dependent anti-proliferative effect on bone marrow progenitor cells. As a single agent, it achieves hematological response rates that are at least equivalent to conventional busulfan or hydroxyurea therapy. Unlike busulfan or hydroxyurea, aIFN has been consistently shown to induce a reduction in the percentage of marrow metaphases that are positive for the Philadelphia chromosome (Ph') in a subset of CML patients receiving single-agent therapy. This reduction is considered to represent a partially selective suppression of the malignant clone by a-IFN. Achievement of a hematological response seems to be a necessary, but insufficient, condition for achieving a cytogenetic response. The optimum rates of cytogenetic response are seen when patients with CML who are in a good prognostic group, begin single-agent a-IFN treatment within one year of initial diagnosis, at a minimum dose of 5 Mu/ma/day subcutaneously and who maintain a peripheral total white-cell count of less than 3 x 109 cells/1 during IFN therapy. The rate and degree of cytogenetic response in CML patients receiving recombinant a-IFN is
dose-dependent. With the common methods of administration currently in use, i.e. by bolus, subcutaneously or intramuscularly, the adverse side-effect profile of IFN is such that doses of greater than 15-35MU per week, which are considered optimal in CML therapy, are rarely tolerated for prolonged periods of time, although moderate dose reductions can be employed after clinical and/or cytogenetic response has been achieved. The durability of sustained complete cytogenetic responses to IFN alone in early-stage chronic-phase CML patients has recently been documented [1o*]. A mean length of survival of 62 months was described in a cohort of 96 patients treated with a-IFN alone compared with 39 months in historical controls. Seventy (73%) of a series of 96 chronic phase CML patients, treated within one year of the time of diagnosis, achieved hematologic remission (95% confidence intervals, 63-81%) and 18 (19%) showed complete suppression of the Ph' in at least one cytogenetic test. A complete cytogenetic response was induced in 7 (95% CI, 6-26%) of 51 patients treated with non-recombinant 0t-IFN and in 11 (95% CI, 13--40%) of 45 patients treated with recombinant a.IFN. There was no significant difference between agents in terms of induction of cytogenetic reductions. Eleven patients still had complete cytogenetic responses after at least 6 to more than 40 months (median over 30 months). The mode of action of a-IFN in CML is undefined. The bone marrow micro-environment is a possible alternative or additional site of 0t-IFN action. In CML patients, primitive blast colony-forming cells (BL-CFC) are deficient in their attachment to bone marrow-derived stromal ceils (BMSC) compared with normal BL-CFC. Dowding et at [2oo] have investigated the effect of recombinant a2a-IFN on the interaction between hematopoietic progenitor cells and BMSC by culturing normal stromal ceils with a-IFN (at concentrations of 50--5000 U/ml). At the 50 U/ml level they documented an increased capacity of BMSC to bind BL-CFC from CML and long-term
Abbreviations BL-CFC~Iast colony forming cells; BMSC--bone marrow derived stromal cells; CML--chronic myeloid leukaemia; ET---essential thrombocythemia; OAG---glycosaminoglycan;HCL--hairy cell leukaemia; IFN--~nterferon; MP--mephalon-prednisone; MPO~myeloproliferative disorder; NHL--non-Hodgkin's lymphoma; Pit'--Philadelphia chromosome; PRV~olycythemia rubra vera. © Current Biology Ltd ISSN 0958-1669
847
848 Pharmaceuticalapplications culture-initiating cells. An increase in the stromal layer sulphated glycosaminoglycans (GAGs) was also demonstrated. Sulphated GAGs were not directly involved in binding CML BL-CFC, as they are in binding normal BLCFC. Neuraminidase-treated control BMSC bound an increased number of CML BL-CFC, reproducing the effect of tx-IFN in this model, whereas the binding of ot-IFN treated normal BMSC was unaffected by neuraminidase treatment. Dowding et aL suggest that et-IFN can override the deficient adhesion of CML primitive progenitor cells to BMSC and thus modify their aberrant proliferation.
Essential thrombocythemia and polycythemia rubra vera The promising clinical data on the use of tz-IFN in CML has stimulated study of its effects in other myeloproliferative disorders (MPD) including essential thrombocythemia (ET) and polycythemia rubra vera (PRV). Recombinant cx-IFN has been shown to be an effective induction agent both in ET and in thrombocythemia associated with other MPD. Current cytotoxic therapy is leukaemogenic in the MPD, whereas the therapeutic role of anti-pLatelet aggregation agents remains unclear. A number of pilot studies have demonstrated in which recombinant c~-IFN rapidly and selectively reduces the platelet counts in previously untreated patients and those who have failed other therapeutic modalities. A recent report on the efficacy and tolerability of long-term 0t2a-IFN treatment in ET in a cohort of 22 patients showed that it is an effective, well tolerated maintenance agent at doses of 3-5 Mu thrice weekly, subcutaneously (tiw sc) I3"]. Suppression of megakaryopoiesis, a reduction in platelet halflife and significant impairment of the in vivo Fc-dependent phagocytic ability of the reticuloendothelial system has been reported where cx-IFN has shown a therapeutic effect in the thrombocytosis associated with the MPD [4"',5]. Induction of the immune destruction of platelets may be part of the effect of ct-IFN in ET, as levels of platelet-associated immunoproteins are raised in the initial thrombocytopenia seen in 0t-IFN therapy of, patients with neoplasia. The mechanism of action of cx-IF may not be identical in all MPD-associated thrombocytosis patients. Differential effects of ~x-2c-IFN on megakaryocyte morphology in CML and other MPDs have been documented. A reduction in the inherent risk of leukaemia may result from the anti-proliferative and immuno-modulatory effects of et-IFN. Such an anti-proliferative effect in ET is presumably necessary to cause clonal reduction in the malignant megakaryocyte population and may also decrease the 'base-line' incidence of the acute leukaemialike illness that occurs in this disorder. Although experience using ct-IFN in patients with PRV is more limited, initial data would indicate that further study in this disorder is indicated [6"].
Non-Hodgkin's lymphoma The follicular non-Hodgkin's lymphomas (NHL) accounts for 30-40 % of all cases of lymphoma diagnosed annually, being slightly more common in the USA than Hodgkin's disease with some 12000-15000 new cases being diagnosed each year. Most of the available data on the use of tz-IFN in follicular NHL, are based on relatively low dose regimens of 3 or 5 Mu/m x daily or thrice weekly, respectively. This largely reflects the toxicity of higher doses and the increasing perception that IFN therapy needs to be long-term to be of maximal benefit in this patient population. All data are currently too premature to make definitive comments on the effect, ff any, of IFN in terms of a survival benefit. Early data on three of the more important prospective studies indicate a combination of an alkytating agent and recombinant et-IFN if used as the first line of therapy is at least as effective as single-agent therapy alone. In the CALGB 8553 study ( H Ozer personal communication), involving 73 previously untreated and 103 previously treated patients, the former had a significandy higher objective (86% versus 62%) and complete (58% versus 25%) response rate (53% versus 23%) when treated with a cyclophosphamide/0t2b-IFN combination regimen. The higher complete response was associated with patient freedom from B symptoms and a better performance status. The chance of survival for five years after treatment is estimated to be 63% for previously untreated patients and 39% for those treated prior to study entry. Long-term follow up of this cohort is necessary to make any comment on any ultimate significant differences in failure-free or overall survival between the groups. Early data from a UK [7"] prospective study of treatment with chlommbucilAFN versus chlorambucil alone indicate a significant advantage in terms of remission duration in those patients who, following a response to first-line therapy, were re-randomized to receive an ~x2b-IFN maintenance regimen. In the 68 patients who were re-randomized, those receiving ~x-IFN as part of the induction and of the maintenance regimen have shown fewer relapses. The ECOG 6484 [8.] study, which randomized 249 analyzable patients with low grade or intermediate grade NHL to receive a COPA (cyclophosphamide, vincristine, prednisone, adriamycin) regimen with or without 0t2aIFN therapy, demonstrated that the addition of et2a-IFN increased the mean time before treatment failure from 19.2 months to 28.7 months. Further tests will determine whether a remission duration advantage translated into prolonged survival.
Multiple myelomatosis Clinical studies of c~-IFN in patients with multiple myeloma are currently concentrating on its potential role as part of combined chemotherapy/IFN induction regimens and as a single-agent maintenance therapy in patients who have responded to front-line therapy. Attempts
ac-interteron in hematological malignancies Giles and Ozer to add at-IFNto induction regimens consist of either concurrent or sequential administration of these modalities. The CA/~G MM (RV Smaller',JW Andersen, MJ Hawkins, V Bhide, MM Oken, EC Borden, tx-intefferon improves the effectiveness of induction chemotherapy in patients with prognostically unfavourable moderately aggressive Non-Hodgekin's lyrnphomas (NHL). Est 6484 an ECOG study (abstract) Proc A m So Clin Oncol 1991, 945:272) study randomized 272 evaluable previously untreated patients to receive a Melphalan/Prednisone (MP) regimen with or without u2.b-IFN at a dose of 2 Mu/mv- tiw sc for the first two weeks of each 28-day cycle. Responding patients were treated for two years. At a median followup of 23 months, the overall complete and partial remission rates were 44% in the patients treated with MP alone and 37% in those receiving both MP and IFN. A 1% complete response rate was seen with each type of treatment. There was no significant difference between the treatments in terms of median survival (MP 3.17 years; MP/IFN 3.05 years), time to response or duration of response. An ECOG MM [9"] pilot study used an alternating VBMCP-o.2b-IFN induction regimen on 54 previously untreated patients with myelomatosis: an overall objective response was observed in 43 patients (80%) including 16 patients (30%) who had a complete response and 8 patients (15%) who had a near-complete remission. The average duration of response was 35 months for all patients treated and this extended to 44 months in those patients who had shown a complete or near-complete response. A prolonged response duration and overall survival advantage was seen when a low dose maintenance regimen of ct-IFN, followed either MP or VMCP/VBAP induction therapy was applied to a subset of objective responders, in a retrospective analysis [10]. Initial data from a combined Swedish/Italian group on a cohort of 308 patients, with previously untreated Stage II or llI disease, appears to confirm the evidence that maintenance IFN therapy prolongs remission duration in patients who have responded to a MP induction. In this study, 120 patients (median age 71 years) who had already responded to MP and were in the plateau phase were randomized to receive either ct-IFN and MP (53 patients) or MP alone (56 patients) at the time of relapse. After a median observation time of 20 months from time of randomization, a highly significant difference in duration of plateau phase is evident, such that when ct-IFN is used, the duration of the plateau extends from 26 weeks to 59 weeks. At that time, 34 patients taking part in the study had died, of which 13 were receiving ct-IFN maintenance therapy (three of whom had minimal interferon exposure) and 21 were control patients. We await definitive proof that tx-IFN prolongs life in some patients with myelomatosis.
Hair), cell leukaemia Numerous studies have shown that over 80% of patients with hairy cell leukaemia (HCL) respond to ct-IFN therapy including patients in whom splenectomy has failed [11..]. Less than 5% of patients respond completely to
~t-IFN alone. Sustained responses are typical, with an average response duration of more than 3 years. Neutralizing antibodies to recombinant ct-IFNmay be responsible for loss of effect in some patients with HCL [12°]. Current clinical studies are mainly concerned with evaluathag tx-IFNversus splenectomy as first-line therapy in HCL patients, the role of recombinant growth factors during induction therapy, and comparisons of efficacy and safety of ~z-IFNwith the halogenated antimetabolites, deoxycoformycin and 2-chlorodeoxyadenosine.
References and recommended reading Papers of special interesL published within the annual period of review, have been highlighted as: • of interest •, of outstanding interest 1. •.
TALPaZM, KANTARJIANH, KURZROCKR, TRUJILLOJM, GLrrrERMAN jU: Interferon-alpha Produces Sustained Cytogenetic Responses in Chronic Myelogenous Leukemia. Ann Intern Med 1991, 114:532-538. Report of first prospective study to show sustained, complete cytogenetic responses in a subset of patients with CML treated with singleagent 0t-IFN therapy. Highlights hematological response as pre-requisite for cTtogenetic response. Suggests that sur~9,~ advantage may result from use of cc-IFN therapy versus traditional cytotoxic agents. 2. ,,
DOWD~G C, GUO A, Os'rERHOIZ J, SICZKOWSKIM, GOLDMANJ, GORDONM: interferon-cz Overrides the Deficient Adhesion o f Chronic Myeloid Leukemia Primitive Progenitor Cells to Bone Marrow Stromal CcUs. B/ood 1991, 78:499--505. First report o f the specific effect o f ct-IFN on the bone marrow microenvironment. The authors postulate this may mediate an indirect norIi~ali:,ation o f the aberrant proliferation o f the CML progenitor cells. 3. ,
Gazs FJ, ANDERSONC, GRAm" IK HO~aRAND AV, MEVIrAAB, M A C H ~SJ, GOLDSTONEAH: Recombinant Alpha 2a interferon An Effective Maintenance Agent in Essential Thrombocythemia. Leukem/a L.vrrqgJon~ 1990, 3:103--107. Reports sustained remissions in a subset of the study cohort of ET patients treated with 0t2a-IFN. Suggests that tx-IFN produces a long-term reduction in tumor load in ET.
4. •e
WADENVlKH, KtrrH J, RIDELL B, REVESZ P, JACOBSSON S, MAGNUSSON B, WEST~ J, VmtN L: The Effect o f ~t-Interferon on Bone Marrow Megakaryocytcs and Platelet Production Rate in Essential Thrombocythcmia. B/ood 1991, 77:2103--2108. Reports reduction in platelet production rates and peripheral platelet counts by 0t-IFN mainly through an anti-proliferative action on
megakaryoc~les. 5-
SCHEITHAUERW, GUISSLINGER H, TE.~CCH EM, ~ H M, ~ H W, Lt~WIG H: Effect o f Recombinant Interferontx2C o n Reticuloendothclial Function in Patients with Thro~osis. J Interferon Res 1990, 10:237-242.
6. SILVERRT: A New Treatment for Polycythemia.Vera: Rccom, binant Interferon-alpha. B/ood 1990, 76:664-665. Initial data on five patients documenting the elimination of the need for phlebotomy in PRV patients treated with Qt.IFN. No changes in serum er/thropoietin levels or marrow reticulin were evident after the first)'ear of IFN therapy. 7. •
GAYNORER, FISHER RI: Clinical Trials of Alpha-interferon in the Treatment of Non-Hodgekin's Lymphoma. Semin Oncol 1991 18(suppl 7):12-17. Cytotoxiointerferon combinations are tolerable and effective as induction therapy in low grade NHL with long term survival benefits yet to be demonstrated.
849
850
Pharmaceutical applications COOPERMR: A Review of the Clinical Studies of Alphatnterf¢on in the Management of Multiple Myeloma. Semin OncoI 1991, 18(suppl 7:18-29 A significant contributing factor in the degree of et~cacy of combination cytotoxic-interferon induction therapy in myelomatosis may be the precise gay in which the combination is administered (e.g sequentially versus concurrently). 8. •
9. •
OKEN MM, KYIE RA: Strategies for combininginterferonwith chemotherapy for the treatment of Multiple Myeloma. Semin Oncol 1991, 18 (suppl 7): 30-32. Documents the remarkable success of a sequential VBMCP/a-2b-interferon inductidn regimen in a cohort of previously untreated myelomatosis patients. 10.
11, o•
MANDELUF, AVVlSATIG, AMADOmS, BOCCADOROM, GERNONEA, LAUTAV) blARMONTF) PETRUCCIMT) TRIBALTOM) VEGNAML, ET aL: Maintenance Treatment with Recombinant Interferon Alpha.2b in Patients with Multiple Myeloma Responding to Conventional Induction Chemotherapy. N Engl J Med 1990, 322:1430-1434. GOLOMBI'-IM, FEFER DW, GOLDE DW, OZER H, PORTLOCK C, SILBER R, RAPPEPORTJ, RATALNMJ, THOMPSONJ, BON,'NEM
E, Er aL: Survival Experience of 195 Patients with Hairy Cell Leukemia Treated in a Multi-institutional Study with Interferon-alpha 2b. Leukemia Lymp~ma 1991, 4:99-102. Documents response and minimum 3 year follow-up data on very large cohort treated with single-agent recombinant tz.IFN. 12. •
VON WUSSOWP, Pl~aLm H, HOCHKEPPELH, JAKSO-Im.SD, SO.VNEN S, SCHMIDT H, MULLER-ROSENAUD, F'RANKEM, HAFERtACH T, ZWINGEILST, ET AL: Effective Natural Interferon-alpha Therapy in Recombinant Interferon-or.resistant Patients with Hairy Cell Leukemia. Eight patients with clinically significant neutralizing antibodies to recombinant ¢x2a-lFN regained control of their disease gahen treated with nat. ural a-IFN
FJ Giles and H Ozer, Di~Ssionof Medical Oncology, School of Medicine, 3009 Old Clinic Building, The Un/vemity of North Carolina, Chapel Hill, North Carolina 27599-7505, USA.
