Seminars in Hematology
Volume 40, Issue 1 , Pages 22-33, January 2003

Interferon-alfa for chronic myeloid leukemia☆☆☆

Institute of Hematology and Medical Oncology “L. and A. Seràgnoli,” University of Bologna and S.Orsola Hospital, Bologna; and the Department of Hematology, University of Brescia, Brescia, Italy

Article Outline

Abstract 

Interferon-alfa (IFNα) became the first-line agent for the treatment of chronic myeloid leukemia (CML) because it prolongs survival significantly compared to conventional chemotherapy (CHT). Responses to IFNα and the benefits from achieving a response are greater in low-risk than in high-risk patients. The best therapeutic results are obtained in low-risk patients who achieve a complete hematologic response (CHR) within 3 to 6 months, a major cytogenetic response (MCgR) within 1 year, and a complete cytogenetic response (CCgR) thereafter. Cytogenetic responses (CgRs) to IFNα are stable and durable, so that about 50% of complete responders become long-term survivors. Combining IFNα with other drugs, like arabinosyl cytosine (AC), and with other treatments, like autologous stem cell transplantation (autoSCT), may provide additional benefit, although this has not been proven. The biologic and molecular bases of the action of IFNα are still poorly understood, but are worth investigating further to determine whether it will still have a therapeutic role when used in combination with the protein tyrosine kinase inhibitors and other new agents. Semin Hematol 40:22-33. Copyright 2003, Elsevier Science (USA). All rights reserved.

 

For too many years the treatment of chronic myeloid leukemia (CML) was based on busulfan (BUS) and hydroxyurea (HU), treatments that were not able to modify the progression of disease from chronic phase (CP) to accelerated and blastic phases (ABP).14, 28, 73, 78 Allogeneic stem cell transplantation (alloSCT) provided a powerful tool to cure CML, but in spite of the progress that has made it possible to raise the upper age limits and to employ unrelated donors, alloSCT can be applied in less than 50% of cases and carries a substantial risk of mortality and chronic morbidity.14, 28, 73, 78 For these reasons, when interferon-alfa (IFNα) was found to induce true and stable cytogenetic responses (CgRs) without necessitating a phase of marrow aplasia,84, 85 many simultaneous studies of IFNα in CML led rapidly to the conclusion that IFNα was the first-line agent for the treatment of CML, apart from alloSCT.52, 73, 78, 86

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IFNα versus conventional chemotherapy—The randomized studies 

Five major prospective randomized studies of IFNα versus conventional chemotherapy (CHT) were activated in 1986 (in Italy, Germany, and the United Kingdom), in 1987 (Benelux), and in 1988 (Japan), and the results were published between 1992 and 19981, 8, 35, 43, 44, 46, 67 (Table 1).

Table 1. Summary of the randomized studies of IFNα versus conventional CHT
Cytogenetic Response
StudyTreatment ArmNo. of CasesCompleteMajorMedian Survival (mo)P Value
Italy5, 6IFN21810%21%62.002
CHT104*01%45
Germany35IFN1335%6%58.44 IFN v HU
HU1940.5%1%48.008 IFN v BUS
BUS18600.5%46
United Kingdom1IFN2936%11%61.0009
CHT294†03%41
Japan67IFN858%15%>60.03
BUS852%5%50
Benelux8IFN1009%16%64.84
HU9502%68
* Ninety-four patients received HU and 10 BUS. † One hundred fifty-two patients received HU and 142 BUS.

NOTE. The scheduled dose of IFNα was 5 MIU/m2 daily in all studies but the Benelux one, where it was 3 MIU daily 5 days per week. However, also in the other studies the administered dose of IFNα was less than scheduled, and decreased with time.

All confirmed that the CgR rate was significantly higher with IFNα than with conventional CHT. In four of the five trials, survival also was better than with conventional CHT, either HU alone (the Italian study), or HU and BUS (the UK study), or BUS alone (the German and the Japanese study). The German and the Benelux studies failed to show a survival superiority of IFNα over HU. When the Italian and the German data were carefully reviewed for inclusion/exclusion criteria and for population characteristics, it appeared that the German study also showed a survival superiority of IFNα over HU.25 A similar comparative analysis of the Benelux study could not explain the lack of difference between IFNα and HU (J. Hasford and J.C. Kluin Nelemans, personal communication). Meta-analysis of the data from all five studies showed that IFNα was better than HU, with an absolute difference in 5-year survival of 12% (SD = 4; log-rank P = .001), that IFNα was better than BUS, with an absolute difference in 5-year survival of 20% (SD = 5; log-rank P < .001), and that the benefit from IFNα was significant in all three Sokal risk groups.18

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Predicting the response to IFNα 

Not all patients with Philadelphia chromosome (Ph)-positive CML respond to IFNα, but response can be predicted because it is related to the phase and duration of the disease as well as some clinical characteristics. Thus patients who have already progressed to ABP do not respond to IFNα and should not be treated with this agent.72, 73, 86 Patients in late CP respond to IFNα less well than those who are in early CP; although this issue has not been investigated in depth, IFNα is not likely to provide substantial benefit to patients with a long history of CML.72 Patients in early CP are the best candidates for IFNα treatment; in them, achievement of a complete hematologic response (CHR) or a significant CgR, which can be either complete (100% Ph-negative metaphases, CCgR) or major (Ph-negative metaphases > 65%, MCgR), is significantly related to the relative risk (RR) of the disease. The RR can be calculated either using the classic Sokal formulation developed 20 years ago and based on patients treated with conventional chemotherapy81 or the new European formulation, proposed more recently and based on patients treated with IFNα.34 Both formulations are illustrated and discussed elsewhere in this issue by Hasford et al. All of the main studies of IFNα have used the Sokal risk score, and we have shown that both risk definitions, Sokal and European, apply equally well to IFNα-treated patients.49 Table 2 shows the relationship between Sokal risk score and CgR.

Table 2. Pooled data of 1,028 cases of early CP, Ph+ CML enrolled in the Italian studies of IFNα44, 47 and IFNα plus LDAC6
Cytogenetic Response
Complete + PartialMinor + MinimalNone
Ph-negative metaphases (%)66-1001-650
Low risk (RR < 0.8)46%30%24%
Intermediate risk (RR 0.8-1.2)24%35%41%
High risk (RR > 1.2)10%23%67%
RR, median0.670.800.88
RR, mean (SD)0.76 (0.25)0.91 (1.18)1.44 (1.43)

NOTE. The relationship between cytogenetic response and risk is very significant. The relative risk (RR) is calculated according to Sokal et al.81

The relationship is very significant, although it should be noted that some high-risk patients can respond as well and that many low-risk patients do not reach a MCgR.

Outcomes in high-risk patients who are responsive to IFNα will be discussed below. The fate of low-risk patients who do not respond to IFNα is not dramatic. They remain at low risk and can have a long survival, but they do not benefit substantially from continuing IFNα treatment and it is not advisable to continue treatment under these circumstances. The question of the time required to evaluate the response has never been investigated systematically and prospectively. The first evaluation of treatment must be HR, which should be complete (CHR). The time to achieve a CHR can vary, partly because many patients are pretreated or “cotreated” with HU, but any patient receiving an IFNα-based regimen who has not achieved a CHR within 6 months and who is not able to maintain the response with IFNα alone should be considered a treatment failure and alternative therapies considered. The second check must be CgR. Achieving MCgR can take more than a year, and transforming an incomplete response to complete can take many years.1, 44, 46, 48, 52 To assess the time necessary to define achievement of a CHR and also a major or a complete CgR, we have analyzed retrospectively 1,028 cases of early CP CML who were enrolled in three consecutive studies of the Italian Cooperative Study Group (ICSG) on CML.6, 44, 47 Ninety-two percent of the patients who achieved a MCgR had achieved at least a minimal response (1% to 33% Ph-negative) at 6 months and 87% of them had achieved at least a minor CgR (34% to 65% Ph-negative) after 12 to 15 months of treatment. Therefore, a patient who is still 100% Ph-positive after 6 months or who is still more than 34% Ph-positive after 1 year is not likely to improve or benefit from continuing IFNα. However, the opposite is not true because almost 50% of patients who are in minimal CgR at 6 months and 35% of patients who are in minor CgR at 1 year will not improve and will not become major or complete cytogenetic responders. The risk score34, 81 will contribute to the treatment choice, since low-risk patients are less likely to progress and more likely to benefit, while high-risk patients should be moved to other treatments more rapidly.

The mechanism of action of IFNα is probably different from that of conventional cytotoxic agents, so other factors might also be expected to predict the response to IFNα. Reports on the relationship between transcript type (b3a2 v b2a2) and treatment results have not provided any convincing evidence in favor of either transcript.45, 63 The relationship between the response to IFNα and the human leukocyte antigen (HLA) phenotype19 suggested that IFNα may enhance an HLA-restricted immune response,68 but this has not been confirmed.

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Cytogenetic response and survival 

In CML, as in many other conditions, achieving a response is always better than not achieving a response. This is a truism. However, the level of benefit and the effect on survival, especially long-term, are problematic. With IFNα the relationship between CgR and survival can vary to some extent but there is little doubt that achieving a CgR, either complete (100% Ph-negative metaphases) or major (Ph-negative metaphases > 65%), is associated with a substantial prolongation of survival. The results of 12 studies of IFNα alone and four studies of IFNα and low-dose arabinosyl cytosine (LDAC) are summarized in Table 3 and Fig 1.

Overall, the relationship between MCgR and survival is significant, considering either 5-year survival, which was reported in all studies, or long-term survival (7, 9, or 10 years), which could sometimes be calculated from the original reports and sometimes was updated in subsequent meeting presentations. Figure 2 shows a landmark analysis of survival in two studies of the ICSG on CML,44, 47 according to the degree of the CgR.
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  • Fig. 2. 

    Overall survival of 427 patients less than 56 years of age who were enrolled in 2 consecutive ICSG studies of IFNα in CML.44, 47 The median follow-up of living patients is 104 months. The graph shows a landmark analysis at 2 years, the calculation including only the patients who were alive and in CP after 2 years. The patients are divided into 3 groups according to the CgR obtained during the first 2 years: major (66%-100% Ph-negative), any other (1%-65% Ph-negative), and none. The difference is very significant (P < .0001, log-rank test).

To account for the time to response bias, the calculation was made on patients who were alive and in CP at 2 years, according to the CgR that they had achieved during that period. The median survival was not yet reached for MCgRs, was 88 months for all the other responders, and was 56 months for nonresponders (log-rank P < .0001). Ten-year survival rates were 70%, 28%, and 16%, respectively. Thus, there is evidence that a substantial survival prolongation with IFNα is associated with CgR, so that achieving a MCgR predicts for a long survival and can be used as a surrogate marker of survival.

Table 3. Summary of cytogenetic response and survival in the major studies of IFNα alone or in combination with LDAC, in early CP, Ph+ CML
Cytogenetic Response (%)Survival (%)
ReferenceTreatment DescriptionNo. of CasesMajorComplete5-YearLong-Term
Kantarjian et al, 199953IFNα + LDAC, single center18645276855 at 7 yr
Montastruc et al, 1995,55 and Mahon et al, 199859IFNα, single center11344337053 at 9 yr
Talpaz et al, 1991,86 and Kantarjian, et al, 1995,52 199953IFNα, single center27438266240 at 9 yr
Guilhot et al, 199733IFNα + LDAC, multicentric, randomized36035137040 at 9 yr
Kloke et al, 200054IFNα, single center7130136040 at 10 yr
Baccarani et al, 20026IFNα + LDAC, multicentric, randomized27528146858 at 7 yr
Ozer et al, 199369IFNα, multicentric11228135435 at 7 yr
ICSG on CML, 199947IFNα, multicentric27224126335 at 10 yr
ICSG on CML, 1992,43 1994,44 199846IFNα, multicentric, randomized21821106230 at 10 yr
Guilhot et al, 199733IFNα, multicentric, randomized3612196227 at 10 yr
Baccarani et al, 20026IFNα, multicentric, randomized2631886555 at 7 yr
Benelux CML Study Group, 19988IFNα, multicentric, randomized10016954NA
Ohnishi et al, 199567IFNα, multicentric, randomized8515863NA
Allan et al, 19951IFNα, multicentric, randomized29311650NA
Lindauer et al, 200257IFNα + LDAC, multicentric6511556NA
Hehlmann et al, 199435IFNα, multicentric, randomized133655830 at 7 yr

NOTE. The studies are ordered according to the percentage of major cytogenetic responses (Ph-negative metaphases > 65%), from highest to lowest. “Long-term” survival was estimated either from the original or a subsequent report, or from subsequent meeting presentations.

Abbreviations: LDAC, low-dose arabinosyl cytosine; NA, not available.

Cytogenetic response, survival, and risk 

The relationship between CgR and survival is important but is complex and depends on another independent variable—the risk score.13, 36, 48 Figures 3 and 4 show the survival of low-risk patients and non–low-risk patients, by Sokal and by European risk scores, according to the CgR during the first 2 years of IFNα treatment.

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  • Fig. 3. 

    Survival according to cytogenetic response and risk score. The patients and the calculations are the same as in Fig 2, but the patients are divided according to Sokal risk score,81 into low risk (A) and non–low risk (B). The cytogenetic response being equal, 10-year survival is better for low-risk patients than for the others.

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  • Fig. 4. 

    As in Fig 3, but the patients are divided into low risk (A) and non–low risk (B) according to the European risk score.35 Low-risk patients survived longer than non–low risk ones, the cytogenetic response being equal.

It is evident that all of the responders achieved some benefit, irrespective of risk, clearly long-term benefit was much greater for low-risk patients than for non–low-risk ones, responses being equal. The great majority (76% to 78%) of low-risk patients who had achieved a MCgR were alive after 10 years, while for non–low-risk MCgR group the 10-year survival was only 45% (Sokal) or 48% (European). The importance of the risk score is even greater for patients who achieved a CCgR (Fig 5): almost all low-risk patients in CCgR were alive after 10 years, versus less than 50% of the non–low-risk patients in CCgR.
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  • Fig. 5. 

    Selecting the complete cytogenetic responders stresses even more the importance of the risk as an independent indicator of a long survival. All of the patients had achieved the best possible cytogenetic response to IFNα (complete), but 10-year survival was close to 100% for low-risk patients v less than 50% for the others, either using the risk definition according to Sokal (A) or the European risk score (B).

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Treatment dose and duration 

It was known in the 1980s that daily IFNα at 5 MIU/m2 was effective and tolerated, so this dose was selected and used for most of the multicentric prospective studies of IFNα alone or in combination. Today, in retrospect, this dose may appear excessive. Twenty years ago CML was perceived as a rapidly fatal disease and the main concern was to improve the response. The issue of the dose-response relationship, with obvious implications for compliance, quality of life, and cost, was raised by the results of some monocentric and multicentric studies1, 8, 75 where the scheduled dose of IFNα was substantially lower, as little as 3 MIU three times per week. Outcomes did not appear to be inferior to those obtained with higher doses. A retrospective analysis of the studies of standard- or high-dose IFNα (5 MIU/m2 daily) was not helpful because of the great variability of the administered dose. Patients who are more sensitive to IFNα often have their dose decreased because of leukopenia and thrombocytopenia, while those who are less sensitive to treatment can tolerate higher doses and receive, paradoxically, more therapy. However, two national study groups, one from the United Kingdom and the other from the Netherlands, designed a prospective study of “high-dose” (5 MIU/m2 daily) versus “low-dose” (3 MIU daily, 5 days a week),77 which has provided evidence that the lower dose does not negatively affect the response rate but influences positively compliance, quality of life, and cost. At this point one cannot predict whether the low dose will have any effect on long-term survival.

The optimal duration of IFNα treatment has never been investigated prospectively and has not been the subject of specific retrospective analysis. Obviously treatment continuation is not likely to be helpful and should not be recommended in case of no or minimal CgR. Treatment continuation could be useful in case of a minor or a partial CgR. IFNα should be compared to other treatments like imatinib and alloSCT. However, in patients who achieve and maintain a stable CCgR it is not known if and when the treatment should be discontinued, and the decision regarding treatment continuation must be based on the molecular monitoring of minimal residual disease22 and on patient compliance and agreement.

There is no evidence that administration of IFNα for many years increases the frequency or the severity of associated events.13, 46, 48, 52 However, patients should be monitored for the development of autoimmune complications, especially thyroiditis, of behavioral or psychiatric manifestations, and of cardiovascular disease. Secondary cancers are not likely to develop.13, 47

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IFNα sensitivity and resistance 

A response to IFNα requires that a sufficient number of normal hematopoietic cells survive and that Ph-positive cells are preferentially inhibited. The longer the time from diagnosis, the fewer residual normal hematopoietic cells24 and the lower the sensitivity of Ph-positive cells to IFNα—a possible explanation for the clinical observation that IFNα is more effective in early CP than in late CP and largely inactive after progression to ABP. The reasons why normal hematopoietic cells are “consumed” during the course of the disease, even in the absence of treatment, are obscure, as are the mechanisms by which Ph-positive cells escape IFNα-induced growth inhibition. Some molecular findings have been associated with a better response: an increased expression of IFN regulatory factor 1,35 of a member of the family of the signal transducers and activators of transcription (STAT 1),55 of a member of the IFN regulatory factors family,74 and of the IFNα receptor 2c.7 However, these data are not conclusive and the molecular bases of the sensitivity and the resistance of Ph-positive cells to IFNα are still poorly understood. The peculiar activity of IFNα in Ph-positive CML suggests that the mechanism of action of IFNα may be relatively specific and related to bcr/abl expression and to the function of the bcr/abl oncoprotein. One study refuted the possibility that IFNα might downregulate bcr/abl transcription,2 while another more recent report has renewed interest in this very specific mechanism.70 Moreover, exposure to IFNα restores the adhesion of Ph-positive progenitors to marrow stromal cells so that these leukemic cells regain, at least in part, normal microenvironment control.9, 21, 88 IFNα possibly enhances the immune response against leukemia, either through overexpression of HLA antigens on leukemic cells,66 or by promoting the recovery of the immune system31 and eliciting a specific immune response against bcr/abl peptides.20 Furthermore, the development of resistance to IFNα can be related to large deletions on the derivative chromosome 9,17, 41, 79 to the methylation of the ABL1 promoter,5, 12, 42 and to other genomic abnormalities that mark the progression from CP to ABP.

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IFNα in combination with other treatments 

IFNα is frequently used in combination with HU, which can be given prior to IFNα for a quick cytoreduction, or together with IFNα to facilitate hematologic control, or when IFNα is discontinued due to toxicity. Prescribing HU prior to IFNα has become common practice allowing easy and inexpensive control of the disease during the screening period before a patient is enrolled in a study and because the antileukemic effect of HU is more rapid than that of IFNα. There are no formal assessments of the utility of this practice. It may be beneficial, or at least convenient, in case of a very high leukocyte count or of a huge symptomatic splenomegaly, but in many patients HU is not necessary and has the disadvantage of obscuring the response to IFNα. However, allowing a patient to take HU when it is felt to be useful, probably results in better compliance, as suggested by a comparison of the Italian and the German studies.25 In the Italian study, where HU was used without restriction, there were more CgRs and survival was longer than in the German study, where use of HU was limited and in which many more patients abandoned IFNα treatment.35, 44

IFNα has been used in combination with other treatments, particularly SCT. IFNα has been administered before autologous SCT (autoSCT) to allow harvesting of Ph-negative stem cells4, 47 and has been given almost always after autoSCT, to improve and to maintain the CgR.15, 47, 62, 71 IFNα has also been given after alloSCT, particularly in case of early cytogenetic relapse.3, 38, 83 Whether IFNα is useful under these conditions and improves treatment outcome and overall survival has never been investigated prospectively. The issue of the combination of IFNα with AC, particularly LDAC, has been approached systematically. The studies of IFNα and LDAC were triggered by a finding of Sokal et al,80 who reported that exposing human granulocye/macrophage colony-forming cells (CFU-GM) to a concentration of AC lower than 5 ng/mL inhibited Ph-positive CFU-GM more than normal CFU-GM. This low AC concentration is similar to the peak plasma concentration that is reached by a low intravenous infusion or subcutaneously at a dose of 20 mg/m2/d (for some time popular, for the treatment of the myelodysplastic syndrome and of acute nonlymphocytic leukemia of the elderly).82 Based on these observations, LDAC was also used alone and especially in combination with IFNα for treating CML in late CP and ABP with promising results.32, 53, 57 Thereafter, the French and Italian groups ran two multicentric prospective studies of IFNα alone versus IFNα and LDAC in early CP CML.6, 33 The design of the two studies was similar, with a scheduled IFNα dose of 5 MIU/m2 daily and a scheduled AC dose of 20 mg/m2 in the French study and 40 mg, fixed dose, in the Italian study, daily, 10 days per month. Seven hundred twenty-one patients were enrolled in the French study and 538 in the Italian study. The results are summarized and compared in Table 4.

Table 4. Comparison of the main results of the two prospective controlled studies of IFNα + LDAC versus IFNα alone6, 33
French StudyItalian Study
IFNα + LDACP ValueIFNαIFNα + LDACP ValueIFNα
CHR, 6 mo66%.00355%62%.1155%
MCgR, 12 mo35%.00121%21%.01213%
MCgR, 24 moNA—NA28%.00318%
Median survival89 mo.0177 mo86 mo.9086 mo
8-yr survival56% 45%50% 50%

NOTE. The French study33 enrolled 721 patients and the Italian study,6 538 patients. Survival figures are updated with respect to original publications.

In both, the CHR rate was superior with IFNα + LDAC, but the difference was significant only in the French study (P = .003). In both trials, the MCgR rate was significantly higher with IFNα + LDAC. Overall survival (median and long-term) of the patients who had been assigned to IFNα + LDAC was longer in the French study (P = .01), but not in the Italian study where survival was identical with either treatment. Although the two study protocols were very similar, there were some differences in recruitment and eligibility criteria and in dose and treatment amendments (the administered IFNα dose was identical in the two studies, but French patients received more AC than Italian patients) so that a careful meta-analysis or a critical comparison is required to settle the issue of the superiority of the combination over IFNα alone.

Since an oral formulation of AC became available (YNK01, Starasid, Nippon Kayaku, Tokyo, Japan) the French and Italian groups continued their studies of the combination to determine whether conventional AC could be replaced by YNK01.50, 60 Study protocols were identical, with the same inclusion/exclusion criteria, the same response criteria, and the same treatment, human recombinant IFNα-2b (Intron-A, Schering Plough, Kenilworth, NJ) at 5 MIU/m2 daily and YNK01 at 600 mg daily for 14 days per month. The results are shown in Table 5, where they are also compared with the results obtained in prior studies with IFNα and conventional LDAC, and with IFNα alone.

Table 5. Short-term results (CHR at 6 months; MCgR at 12 months) of two studies of IFNα and oral AC (YNK01)51, 60 and of two studies of IFNα and conventional LDAC versus IFNα Alone6, 33
No. of CasesCHRMCgR
IFNα + oral AC (YNK01)
Italian study518678%28%
French study609277%16%
IFNα + conventional LDAC
Italian study627562%22%
French study3336066%35%
IFNα alone
Italian study626355%13%
French study3336155%21%

NOTE. All of the studies were performed by the same 2 groups, with very similar treatment protocols. The scheduled dose of IFNα was always 5 MIU/m2 daily. The scheduled dose of conventional AC was 20 mg/m2 daily in the French study and 40 mg (total dose) in the Italian study, 10 days per month. The scheduled dose of YNK01 was 600 mg daily, 14 days per month in both studies.

The response rate to IFNα and YNK01 was higher in the Italian study than in the French one, with MCgR rates at 12 months of 28% and 16%, respectively. Overall, the results of IFNα and YNK01 are in the range of the results of IFNα and conventional LDAC and are in the upper range of results of IFNα alone. A randomized study would be necessary to establish the value of YNK01, unlikely to be done after the introduction of the tyrosine kinase inhibitors. Moreover, both studies of IFNα and YNK01 have shown that the combined toxicity of high-dose IFNα and 600 mg YNK01 affects significantly quality of life, so that 25% to 36% of patients did not comply with the treatment.50, 60 If this approach is worth pursuing, the drugs should be tested at lower doses (IFNα at 3 MIU daily and YNK01 at 200 mg daily).

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Long-term survival 

The long-term survival (9 or 10 years) of patients assigned to an IFNα-based regimen who are not submitted to allo-SCT ranges between 40% and 50% in single-center reports and between 30% and 40% in multicenter prospective studies (Table 3). Many long-term survivors have achieved a CCgR and form a particularly interesting and important group because they represent true candidates for a possible cure. A multicentric European review of 317 cases induced to CCgR with IFNα alone13 has confirmed that many were in the low- or intermediate-risk category (88% by Sokal, 94% by European risk score). Ten years after achieving the first CCgR, 50% of them were in continuous CCgR and 72% were alive. This study has confirmed that, even after CCgR, the risk score remains an important determinant of survival, since the 10-year survival is approximately 90% for low-risk patients versus less than 50% for the few high-risk patients; it was impossible to detect any relationship between the administered dose of IFNα and the duration of CCgR. Treatment duration could not be analyzed because at the time of data collection many patients were still receiving IFNα, at a low dose of 3 MIU three to five times per week. IFNα had been discontinued during CCgR in only 36 cases. In 28 of these, IFNα was discontinued because of non-compliance; eight were alive in continuous CCgR, 16 had lost the CCgR, and four had progressed to ABP. In only eight cases was IFNα discontinued because it was felt that treatment was no longer required; seven patients were alive and in continuous unmaintained CCgR for 2 to 5 years, and one died of an alloSCT done in CCgR. In this multicenter retrospective study of CCgRs, the data on molecular response were not reported because they were technically heterogeneous, coming from several laboratories using different nonstandardized techniques. However, only a few cases were reported to be molecularly negative, in confirmation of earlier data.16, 41, 61 Molecular remission and possible cure of CML with IFNα has been discussed in detail elsewhere22, 23, 29, 58 and the conclusions remain unchanged. Very long survival, something approaching clinical cure, is achieved in about 50% of the patients who achieve and maintain a complete and a stable CgR, but in the great majority of these cases molecular evidence of Bcr-Abl transcripts can be detected at very low level almost indefinitely, so that the criteria of a true molecular remission or biologic cure are not satisfied.

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IFNα and SCT 

The possible interactions between IFNα and the outcome of alloSCT have been the subject of several retrospective studies (Table 6).

Table 6. Summary of the reports of the outcome of alloSCT in CP CML, according to prior treatment (IFNα or conventional CHT)
No. of CasesStem Cell Donor
ReferenceIFN+IFN−TotalHLA-Identical SiblingOther
Giralt et al, 19932623184141—No difference
Beelen et al, 199510508313310330TRM and graft failure increased; DFS and OS decreased
Shepherd et al, 19957653561097039No difference
Zuffa et al, 199889161632275No difference
Tomas et al, 19988730215151—No difference
Morton et al, 1998659534129—129AGVHD increased; OS decreased
Beelen et al, 19991163*90†1538370TRM increased; OS decreased
Hehlmann et al, 1999378666152104485-yr survival better for the 36 pts who discontinued IFNα > 3 mo prior to alloSCT
Giralt et al, 200027209664873873—Graft failure increased; relapse decreased
Lee et al, 200156489251740—740No difference
* Including only the patients who had received IFNα for more than 6 months. † Including also the patients who had received IFNα for less than 6 months.

NOTE. Hehlmann et al38 reported for the German National Study Group. Giralt et al27 and Lee et al56 reported from the International Bone Marrow Transplant Registry.

Abbreviations: TRM, transplant-related mortality; DFS, disease-free survival; OS, overall survival; AGVHD, acute graft-versus-host disease.

Giralt et al26 reported no difference in a series of 41 patients who were grafted in CP from an HLA-identical sibling, but 2 years later a report from Beelen et al10 on 133 patients, mostly grafted from HLA-identical siblings, called attention to the possibility that prior administration of IFNα may negatively affect the outcome of alloSCT. In the latter trial, transplant-related mortality (TRM) was significantly higher, mainly due to infectious complications; the risk of graft failure was also significantly increased and overall survival and disease-free survival were decreased. Three subsequent reports from United Kingdom,76 Italy,89 and Spain87 failed to confirm these data and did not show any difference between IFNα-treated patients and others, but the issue recurred in a report from Seattle65 suggesting that in the unrelated donor setting, pretreatment with IFNα was associated with a worse outcome, mainly due to an increased risk of acute graft-versus-host disease. Beelen et al updated their study and confirmed an adverse effect of prior IFNα on alloSCT, either from an HLA-identical sibling or other donors.11 Overall survival was significantly poorer in patients who had been pretreated with IFNα for more than 6 months and even more for pretreatment for more than 12 months; TRM was significantly increased in the patients who had not discontinued IFNα for more than 3 months before SCT.11 A subsequent report from Germany did not find any adverse effect, but confirmed that overall survival was better if IFNα was discontinued at least 3 months before alloSCT.37 The International Bone Marrow Transplant Registry published a retrospective analysis of 873 patients who received a SCT from an HLA-identical sibling27 and of 740 patients who received marrow from unrelated donors.56 Neither study showed any effect attributable to prior IFNα, with the exception of an increase in the risk of graft failure from 0.2% to 2.0%, balanced by a decrease in the risk of relapse, from 8% to 1%.27 In conclusion, there is no evidence that prior IFNα treatment will affect adversely the outcome of alloSCT, but it is wise to discontinue IFNα treatment as soon as a decision for alloSCT is made, or at least 3 months before.

IFNα has been widely used to treat relapses after alloSCT and was effective in about 50% of cases, especially in very early, cytogenetic relapse.3, 38, 83 The introduction and the success of donor lymphocyte infusion has greatly reduced the use of IFNα in this setting.

IFNα has also been employed in combination with autoSCT, either before or after the transplant. Stem cells can be collected from the bone marrow and peripheral blood after a successful or an unsuccessful treatment with IFNα, and can be used for hematopoietic reconstitution after high-dose CHT.4, 47 A prospective Italian study found that the patients who had achieved a MCgR after 1 year of IFNα treatment and were submitted to a procedure of autoSCT with high-dose BUS and melphalan had an excellent (80%) 10-year survival rate.47 However, many were low risk, and many received low-dose IFNα also after the autoSCT. Because similar conditions were present in several other nonprospective studies of autoSCT,15, 62, 71 it is impossible to conclude whether IFNα and autoSCT prolong survival compared to IFNα alone, or which contributes more to survival prolongation.

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Conclusion 

IFNα is revolutionary drug that has substantially improved the treatment of leukemia and other tumors, as well as of some infectious diseases. In CML, IFNα has improved the prognosis for many patients, especially those in the low-risk category, and has become the reference agent for first-line treatment. The original reports from the Houston group that IFNα could induce hematologic and cytogenetic remissions84, 85 were confirmed by multi-institution studies in the United States and in Europe,54, 59, 64, 69, 86 which triggered a number of randomized prospective studies of IFNα versus conventional CHT in the late 1980s.1, 8, 35, 43, 44, 46, 67 At the same time, it was quickly understood that the efficacy of IFNα decreased with the duration of CP and was almost of no value in ABP, with a few exceptions, so that it was almost universally agreed that the place of IFNα was in early CP. The randomized prospective studies of IFNα versus conventional CHT demonstrated the superiority of IFNα, which was confirmed by a meta-analysis.18 The prognostic features were refined, with emphasis on the relationship between risk, response, and survival. The value of CgR as a surrogate of survival duration was established.1, 35, 43, 48, 52, 86 Long-term survivors with IFNα were identified.13 Several attempts were made to combine IFNα with other treatments, mainly LDAC,6, 32, 50, 53, 60 but also intensive CHT34 and autoSCT.15, 47, 62, 71 The relationship between response and dose has been investigated prospectively.77 Debate about the possible adverse effects of pretreatment with IFNα on the outcome of alloSCT was initiated and subsequently concluded.10, 11, 26, 27, 37, 56, 65, 76, 87, 89 Some conclusions are evidence-based. Other suggestions have been consolidated by practice. Many issues are still a matter of discussion or are poorly known, and would require more time and investigation to be settled. In particular, it would be important to investigate more thoroughly the biologic bases of the effects of IFNα to determine whether there is a rationale for combining IFNα with the new generation of molecularly targeted agents such as the protein tyrosine kinase inhibitors.30

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☆ Supported in part by a grant from the Italian Ministry of University and the University of Bologna (COFIN 1999 and 2001).

☆☆ Address reprint requests to Michele Baccarani, MD, Institute of Hematology and Medical Oncology “L. and A. Seràgnoli,” S.Orsola Hospital, Via Massarenti 9, 40138 Bologna, Italy.

PII: S0037-1963(03)70040-7

Seminars in Hematology
Volume 40, Issue 1 , Pages 22-33, January 2003

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