Hematological and cytogenetic response of interferon alpha 2b alone and combined interferon alpha plus cytarabine as a first-line treatment in chronic myeloid leukemia

Treatment with interferon-alpha (IFNalpha) prolongs survival in chronic myeloid leukemia (CML). Additionally, cytarabine (AraC) can reduce the number of Ph + metaphases. Fortythree previously untreated patients with CML in chronic phase were randomly assigned to receive either. IFNalpha 2b (5 MU sqm/daily) or IFNalpha 2b in the same dosages plus monthly courses of low-dose AraC. The aim were complete hematologic remission at 6 months and cytogenetic response at 12 months. A complete hematologic remission occurred in 60.4% patients with single IFNalpha 2b in 76.2% patients with combination therapy. A cytogenetic response was present in 13.9% (major in 2 patients) with IFN therapy and in 38.1% patients with combination therapy. Two of 21 patients treated with IFNalpha/AraC therapy achieved major (9.52%), 4 partial (19.04%) and 2 minor (9.52%) cytogenetic response. Major side effects were cytopenia (20.1%), flu-like syndromes (42.4%) and increase of hepatic transaminases (3.4%). The side effects were more significant in the group receiving combination therapy. Based on published data that show a survival advantage for patients who achieved any cytogenetic response, and high rate of cytogenetic response which we observed in our study we believe that IFN plus AraC regimen could be a front-line therapy for CML.     

Risk and early cytogenetic response to imatinib and interferon in chronic myeloid leukemia

BACKGROUND AND OBJECTIVES: We compared the early cytogenetic response (CgR) to a combination of imatinib mesylate (Glivec, Novartis Pharma, Basel, Switzerland) and a pegylated form of human recombinant interferon-alpha2b (pegIFN-alpha2b, PegIntron, Schering Plough, Kenilworth, New Jersey, USA) with the relative risk, either according to Sokal's or Euro scoring systems. DESIGN AND METHODS: Seventy-seven patients with early chronic phase, previously untreated, Ph-positive chronic myeloid leukemia (CML) received a combination of imatinib mesylate (400 mg/day) and pegIFN-alpha2b (3 consecutive cohorts treated with 50, 100 or 150 mg/weekly). Fifty-seven patients have completed the first 6 months of treatment and are evaluable for CgR. RESULTS: After 6 months of treatment, the overall major CgR rate was 89% and 90% in low risk patients (Sokal's and Euro, respectively), 76 and 59% in intermediate risk and 23% and 17% in high risk patients. These differences were significant (p=0.0001 for Sokal and 0.001 for e). INTERPRETATION AND CONCLUSIONS: For the first time, these data suggest that the early CgR rate to a imatinib mesylate-based regimen is significantly risk-related.     

Interferon alfa-2c in chronic myelogenous leukemia (CML): Hematologic,cytogenetic and molecular-genetic response of patients with chronic phase CML previously resistant to therapy with interferon gamma

Summary Alpha- and gamma-interferons have been shown to actively suppress hematopoiesis in patients in the chronic phase of chronic myelogenous leukemia in vitro and in vivo. Since both interferons act through different receptors on their hematopoietic target cells, they are expected to be capable of independently inhibiting abnormal blood cell development in patients with chronic myelogenous leukemia. We have utilized recombinant human interferon alfa-2c to treate 11 patients with Philadelphia chromosome positive chronic myelogenous leukemia in chronic phase, who were resistant to previous interferon gamma therapy. Ten of the patients were evaluable for hematologic, cytogenetic and molecular-genetic response following interferon alfa-2c therapy for 6 to 30 months. In 5 patients, IFN alfa-2c treatment failed due to lack of hematologic response. A complete hematologic or partial hematologic response was achieved in the remaining 5 patients. Three of these experienced cytogenetic improvement with reappearence of 100% diploid hematopoietic cells and disappearence of c-abl/bcr rearrangement in one patient. In two patients interferon alfa-2c did not prevent transformation of the disease into an accelerated state or blast crisis, respectively. We conclude that recombinant human interferon alfa-2c may also control hematopoiesis in interferon-gamma resistant chronic myelogenous leukemia patients, although the long-term response will need to be elucidated in further studies.     

Autologous transplantation with Philadelphia-negative progenitor cells for patients with chronic myeloid leukaemia (CML) failing to attain a cytogenetic response to alpha interferon

Between October 1993 and March 1999, 29 patients with CML who were ineligible for allogeneic BMT underwent PBSC harvest using idarubicin, cytarabine and G-CSF. In 9/29 (31%) patients all collected stem cells were Ph-negative, and 15/29 patients' (52%) collections were substantially (>95%) Ph-negative. The proportion of patients from whom Ph-negative stem cells were obtained was similar between patients who had, or had not, received prior alphaIFN. Fifteen patients in chronic phase (median age 45) proceeded to PBSCT following busulphan 16 mg/m2 and cyclophosphamide 120 mg/m2. Nine of the 13 patients who had failed to respond to prior alphaIFN proceeded to stem cell transplantation as soon as was feasible and six of the newly diagnosed patients were transplanted after failing to achieve a cytogenetic response after a minimum of 12 months on alphaIFN following progenitor cell harvest. The median number of days to neutrophils >0.5 and platelet >50 was 18 (range 13-69) and 28 (range 13-234), respectively. There was no procedure-related mortality. At median follow-up of 2.3 years post autograft 10 of 15 patients remain alive and in chronic phase. Overall survival for all 27 patients at 5 years after initial diagnosis is 70% and median survival from diagnosis 7.3 years. Survival for alphaIFN non-responders who were transplanted is 74% at 5 years from diagnosis and 75% at 3 years from transplant. Cytogenetic analysis performed 3 months post transplant demonstrated one patient with a complete cytogenetic response, seven with a partial response and three with no response. Six patients remain partially Ph-negative, with one major CR. Survival for all patients in the protocol is favourable compared with conventional therapy and is particularly encouraging following PBSCT for alphaIFN non-responsive patients. Patients not responding to alphaIFN can be induced into Ph-negativity with PBSCT but this may not always be sustainable. There seems to be no obvious disadvantage in harvesting stem cells after prior exposure to alphaIFN, providing an adequate alphaIFN-free rest period is used.     

Interferon versus ribavirin plus interferon in chronic hepatitis C previously resistant to interferon: a randomized trial.

BACKGROUND: More than 70% of patients with chronic hepatitis C are resistant to interferon therapy. Ribavirin, in association with interferon, has been demonstrated as effective, at a dose of 800-1200 mg/day, but the efficacy of a lower dose has not been established. METHODS: We assessed the effectiveness of the combination of 600 mg/day of ribavirin plus 3 MU of interferon over a period of 6 months, in a group of patients previously resistant to interferon. Sixty-two patients with chronic hepatitis C with serum and hepatic HCV RNA relapsers or non-responders to interferon, were randomly divided into two groups: group A received 3 MU of interferon alpha-2b, three times a week for 6 months; group B was given the same dose plus 600 mg per day of ribavirin for 6 months. Two patients from each group dropped from therapy. One patient from group A and two from group B withdrew from treatment because of adverse effects. RESULTS: Mean alanine aminotransferase levels were similar in both groups throughout the study. A sustained response was observed in 7% and 7.4% of groups A and B with short-term response in 39% and 59%, and no response in 54% and 34% from both groups respectively (non-significant). At 12 months, 4 and 7 patients from groups A and B respectively, cleared serum HCV RNA however, only one sustained responder from each group cleared HCV RNA from peripheral blood mononuclear cells. At 18 months, 3 patients remained serum HCV RNA negative. Adverse effects were similar. Only haemoglobin values were lower in group B in the first month of therapy (p<0.05). CONCLUSION: In conclusion, the combination of 3 MU of interferon plus 600 mg of ribavirin is not effective in chronic hepatitis C resistant to interferon.     

Clonal cytogenetic abnormalities in patients with chronic myeloid leukemia in complete cytogenetic response to imatinib mesylate

The emergence of clonal chromosomal abnormalities in Philadelphia-negative cells during treatment with imatinib in patients with Philadelphia-positive chronic myeloid leukemia has been reported. We add information to this issue presenting a series of 29 patients in complete cytogenetic response after imatinib treatment, three of whom developed clonal aberrations.     

Interferon versus ribavirin plus interferon in chronic hepatitis C previously resistant to interferon: a randomized trial

Abstract: Background: More than 70% of patients with chronic hepatitis C are resistant to interferon therapy. Ribavirin, in association with interferon, has been demonstrated as effective, at a dose of 800–1200 mg/day, but the efficacy of a lower dose has not been established. Methods: We assessed the effectiveness of the combination of 600mg/day of ribavirin plus 3 MU of interferon over a period of 6 months, in a group of patients previously resistant to interferon. Sixty-two patients with chronic hepatitis C with serum and hepatic HCV RNA relapsers or non-responders to interferon, were randomly divided into two groups: group A received 3 MU of interferon alpha-2b, three times a week for 6 months; group B was given the same dose plus 600 mg per day of ribavirin for 6 months. Two patients from each group dropped from therapy. One patient from group A and two from group B withdrew from treatment because of adverse effects. Results: Mean alanine aminotransferase levels were similar in both groups throughout the study. A sustained response was observed in 7% and 7.4% of groups A and B with short-term response in 39% and 59%, and no response in 54% and 34% from both groups respectively (nonsignificant). At 12 months, 4 and 7 patients from groups A and B respectively, cleared serum HCV RNA however, only one sustained responder from each group cleared HCV RNA from peripheral blood mononuclear cells. At 18 months, 3 patients remained serum HCV RNA negative. Adverse effects were similar. Only haemoglobin values were lower in group B in the first month of therapy (p<0.05). Conclusion: In conclusion, the combination of 3 MU of interferon plus 600 mg of ribavirin is not effective in chronic hepatitis C resistant to interferon.     

Severe autoimmune hepatitis in a chronic myeloid leukemia patient treated with interferon alpha and with complete genetic response

A patient with chronic myeloid leukemia (CML) treated with interferon alpha (IFN alpha) and who developed autoimmune hepatitis (AIH) is described. The patient was treated with IFN alpha 2a, a complete cytogenetic response was achieved 5 months later, and this response has lasted now more than 7 years. Autoimmune hypothyroidism appeared at 18 months of treatment, and 1 year later severe type I autoimmune hepatitis developed. To our knowledge this is the first report of such complication in an IFN alpha-treated CML patient. Am. J. Hematol. 59:95–97, 1998. © 1998 Wiley-Liss, Inc.     

Serial cytogenetic studies in allografted patients with chronic myeloid leukemia.

Serial marrow karyotyping was performed in 31 chronic myeloid leukemia (CML) patients treated with allogeneic bone marrow transplantation (BMT). Of 11 hematological relapses, seven were heralded for up to 20 months by a cytogenetic relapse (characterized by increasing percentages of Philadelphia (Ph)-positive metaphases, seen on serial karyotypes). Chromosomal abnormalities additional to the Ph, seen before BMT, were not found again at relapse. Relapses were characterized by clonal evolutions of the Ph-positive cells, likely corresponding to cytogenetic patterns of treatment-induced leukemia [del(5q), del(7q), complex karyotypes] and were different from those generally found in CML evolution. Involvement of chromosome 1 was also frequent. Sporadic Ph-positive metaphases (not seen in repeated karyotypes) were seen only during the first 8 months after BMT.     

Synergistic cytotoxicity of AZT plus alpha and gamma interferon in chronic myeloid leukemia cell line K562*

Abstract: We have previously reported that the antineoplastic activity of 3′ -azido 3′ deoxythymidine (AZT) can be increased by drugs that inhibit “de novo” thymidylate synthesis, such as 5-fluorouracil, methotrexate and hydroxyurea. In the present study we tested the combinations AZT + alpha interferon (IFN) and AZT + gamma IFN on in vitro growth of the human acute-phase chronic myeloid leukemia (CML) cell line K562. After 72 hours incubation, not only AZT + α-IFN but also AZT + γ-IFN were synergistic in inhibiting K562 growth, as demonstrated by isobologram analysis of the data. This enhanced cytotoxicity was confirmed by the evaluation of [3H]AZT incorporation into cellular DNA, that was increased by 50% and 222% in the presence of α- and γ-IFN, respectively. The addition of 50 μmol/l thymidine to the culture medium was able to reduce the cytotoxicity of the drug combinations to the degree observed with each compound alone; furthermore, the increased incorporation of AZT into DNA was completely reversed. These data indicate the existence of a biochemical interaction between AZT and IFNs that results in an increased cytotoxic effect. While the combination AZT + α-IFN is currently being tested in HIV-related malignancies, AZT + γ-IFN is new and deserves further study in human CML acute and chronic phase models, in view of possible clinical applications.     

Interferon alpha treatment of accelerated-phase chronic myeloid leukemia in relapse after bone marrow transplantation: a case with complete cytogenetic and molecular remission

We describe here a patient with Philadelphia-positive chronic myeloid leukemia who had a hematologic and cytogenetic relapse after bone marrow transplantation. A diagnosis of accelerated phase was made when an additional malignant clone was detected. This clone was probably derived from the primitive Philadelphia clone, with duplication and rearrangement of the Philadelphia chromosome. The patient was treated with interferon alpha 2a and experienced a complete cytogenetic and molecular remission, with full reconstitution of the donor marrow.     

Factors predicting molecular and cytogenetic response in chronic myeloid leukemia patients treated with imatinib

We studied 94 clinically heterogeneous chronic myeloid leukemia (CML) patients and found that the duration of treatment with interferon-alpha (IFN-alpha) prior to imatinib therapy may not improve response to imatinib for patients in chronic phase but a shorter period between CML diagnosis and the initiation of imatinib is predictive for a better molecular response to therapy (p<0.05).     

Improved tolerability by a modified intermittent treatment schedule of dasatinib for patients with chronic myeloid leukemia resistant or intolerant to imatinib

Intermittent dosing of dasatinib with a once daily regimen has been shown to reduce side effects while preserving clinical efficacy in early and advanced phase chronic myeloid leukemia (CML). Yet, hematologic toxicity and fluid retention demand a dose modification or treatment discontinuation in selected patients. Patients resistant or intolerant to imatinib were retrospectively evaluated based on the toxicity-guided administration of a dose-reduced dasatinib regimen. Patients were treated with an on/off regimen (3 to 5 days on, 2 to 4 days off) to allow regression of dasatinib-dependent off-target toxicity. Patients were followed up by routine hematologic and cytogenetic assessment and molecular monitoring to safeguard clinical response to the altered drug schedule. Thirty-three CML patients primarily in chronic phase with imatinib intolerance (n?=?11) or resistance (n?=?22) were investigated. Nonexclusive reasons for dose reduction were hematologic toxicity (17/33, 51 %) and pleural effusions (18/33, 55 %). On/off treatment with a weekend drug holiday significantly reduced pleural effusions and hematologic toxicity. Eighteen of 31 (58 %) patients showed effective disease control despite reduced total weekly dasatinib doses, either demonstrated by achieving an improved response level (12/31) or keeping the response level achieved by conventional continuous dosing (6/31). Of note, 10/12 patients with subsequently improved response have been treated for a minimum of 6 months with continuous dosing dasatinib regimens without having achieved the response level achieved after allowing drug holiday. Weekend treatment interruption of dasatinib allows continuation of dasatinib treatment for patients suffering from side effects. These data mandate prospective investigation of alternative intermittent targeting regimens.     

Long-term response to interferon plus ribavirin in patients with chronic hepatitis C refractory to interferon.

OBJECTIVE: A sustained response (SR) to interferon (IFN) is only observed in 15-20% of patients with chronic hepatitis C (CHC). The aim of this study was to determine the long-term effectiveness and safety of the treatment with IFN plus ribavirin (RIB) over two years in CHC patients without SR to IFN. DESIGN: A prospective and open longitudinal follow-up study was conducted over 3 years. PATIENTS AND METHODS: A total of 77 CHC patients were included: 63 non-responders (NR) and 14 relapsers (R) to IFN. Patients were treated with IFN (3 MU s.c. three times a week) and RIB (1,000-1,200 mg p.o. daily) for 12 months. Treatment tolerance and viral response (HCV-RNA in serum < 1,000 copies/ml) were assessed after 1, 3, 6 and 12 months of treatment. SR and relapsing rates were subsequently evaluated 6, 12 and 24 months after the end of the treatment, together with those variables capable of predicting SR. RESULTS: At the end of the treatment, 19/77 patients responded (24.7%), 9/63 (14.3%) were non-responders and 10/14 (71.4%) relapsers, and these same patients exhibited SR after 6 months. The SR rate two years after treatment was 22.1% [8/63 (12.7%) NR and 9/14 (64.3%) R]. The relapse rate after 6 months and two years was respectively 0 and 10.5% (2/77). Independent variables capable of predicting SR were negative viremia conversion within the first month of treatment, maintenance of such negative viremia after 6 months, and R status to IFN. Side effects were recorded in 90.9% of cases (70/77), the most frequent being pseudoinfluenza syndrome. Treatment had to be discontinued in 33.8% of patients (26/77). CONCLUSIONS: Combined IFN-RIB therapy for 12 months in CHC patients without SR to IFN obtains a long-term SR of 22.1%, this rate being higher in relapsers to prior IFN therapy (64.3% in R versus 12.7% in NR).     

Interferon plus ribavirin in patients with hepatitis C virus positive mixed cryoglobulinemia resistant to interferon

OBJECTIVE: Only a small fraction of patients with hepatitis C virus (HCV) positive mixed cryoglobulinemia achieve longterm recovery after interferon (IFN) therapy; we evaluated the effectiveness and safety of combination therapy (interferon plus ribavirin) in nonresponders or those who relapsed after one or more courses of IFN. METHODS: Twenty-seven patients with HCV positive mixed cryoglobulinemia were studied. All were treated with IFN-a2b (3 MU 3 times weekly) for one year, plus daily oral ribavirin 1000 or 1200 mg. RESULTS: Five patients (18.5%) obtained complete recovery from viral infection and from all signs and symptoms of disease. During treatment, most patients (85%) improved clinically. All 5 responders were "relapsers" to the first treatment(s). CONCLUSION: Combination therapy of IFN plus ribavirin could be useful for patients with mixed cryoglobulinemia resistant to IFN as monotherapy.