Interferon Failure Research Articles

Hematopoietic cell transplantation for chronic myeloid leukemia in developing countries: perspectives from Latin America in the post-tyrosine kinase inhibitor era

Tyrosine kinase inhibitors (TKIs) are currently the first line treatment for chronic myelogenous leukemia (CML) in countries with high and intermediate-high gross national income. Hematopoietic cell transplantation (HCT) in these countries is considered salvage therapy for eligible patients who failed TKI or progress to advanced disease stages. In Latin America, treatment for CML also changed with availability of TKI in the region. However, many challenges remain, as the cost of this class of medication and recommended monitoring is high. CML treatment practices in Latin America demonstrate that the majority of patients are treated with TKI at some point after diagnosis, most commonly imatinib mesylate, but still TKI can only be used after interferon failure in some countries. Other treatment practices are different from established international guidelines, outlying the importance of continuing medical education. Allogeneic HCT is a treatment option for CML in this region and could be considered a cost-effective approach in a small subset of young patients with available donors, as the overall cost of long-term non-transplant treatment may surpass the cost of transplantation. However, there are many challenges with HCT in Latin America such as access to experienced transplant centers, donor availability, and cost of essential drugs used after transplant, which further impacts expansion of this treatment approach in patients in need. In conclusion, Latin American patients with CML have access to state of the art CML treatment. Yet, drug costs have a tremendous impact on developing health systems. Optimization of CML treatment in the region with appropriate monitoring, recognizing patients who would be transplant candidates, and expanding access to transplantation for eligible patients may curtail these costs and further improve patient care.

Plasma IL-6 and IL-9 predict the failure of interferon- plus ribavirin therapy in HIV/HCV-coinfected patients

The cytokine profile plays an important role in treatment outcome of hepatitis C virus (HCV) infection, and probably modulates the immune response against HCV. The aim of this study was to evaluate which cytokines affect the response to interferon-α (IFN-α) and ribavirin therapy and how these cytokines change 72 weeks after starting anti-HCV therapy in HIV/HCV-coinfected patients. We carried out a retrospective follow-up study of 65 patients on anti-HCV therapy. A sustained virological response (SVR) was defined as an undetectable HCV viral load up to 24 weeks after the end of treatment. Cytokines were measured using a multiplex immunoassay kit. On starting anti-HCV therapy, non-responder (NR) patients had higher levels of interleukin (IL)-6, IL-9, IL-10 and tumour necrosis factor (TNF)-α (P < 0.05), while IL-17A levels were increased in SVR patients (P = 0.058). However, only patients with high levels of IL-6 and IL-9 had decreased odds to achieve SVR (P < 0.05). Plasma levels of IL-6 and IL-9 had a high predictive value for SVR failure [area under the ROC curve (AUC) 0.839 (95% CI 0.733-0.945) and AUC 0.769 (95% CI 0.653-0.884)]. In addition, during anti-HCV therapy, IL-1β showed an increase in NR patients (P = 0.015) and IL-10 decreased in SVR patients (P = 0.049). After clearing HCV infection, low levels of TNF-α, IL-6, IL-9, IL-10, IL-13 and IL-22 were found in SVR patients (P < 0.05), as well as IL-1β, but only near statistical significance (P = 0.073). High plasma levels of IL-6 and IL-9 had a high predictive value for SVR failure. Furthermore, clearing of HCV infection was associated with low inflammatory and T helper (Th)2/Th9/Th22 cytokine levels.

Imatinib in chronic myeloid leukemia elderly patients

The median age at diagnosis of Chronic Myeloid Leukemia (CML) reported in clinical trials is generally of 50-55 years; it is higher (more than 60 years) in epidemiologic registries and in observational studies [1]. Therefore, a significant proportion of CML patients are “elderly”, according to the most widely accepted definition of “old person” (age > 65 years). Prior to imatinib (IM) introduction, an orally taken tyrosine kinase inhibitor, older age was associated to a worse outcome (lower response rates and lower long-term survival), regardless of the treatment used (busulfan, hydroxyurea, interferon alpha), basically, for unknown reasons. It can be speculated that, with interferon, the reason of an inferior outcome of elderly patients lied in a poorer compliance; however, this worsen prognosis of elderly CML patients have been described even employing well tolerated drugs (like hydroxyurea). Age was included in the 2 most used risk scores for CML: Sokal score (1984), referring to patients treated with conventional chemotherapy, and EURO score (1998), for patients treated with interferon [2, 3]. The introduction of IM has revolutionized the therapy of CML patients, significantly improving survival [4]. However, in the early days of IM, many physicians felt that the prognosis of an old CML patient, particularly those older than 75-80 yrs, could not be positively influenced by IM and a not negligible part of elderly patients are still not allocated to IM (or enrolled in clinical trials) for different reasons (co-morbidities, toxicity, long term outcome, socio-economic factors) [5]. The importance of age in the IM era has been investigated in different studies, leading to a re-evaluation of its prognostic significance. A large study in late chronic phase patients treated with IM after interferon failure, conducted by GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) CML Working-Party (WP), showed lower hematologic and cytogenetic response rates in older patients (> 65 years old), but similar overall survival with a 36 months median follow-up [6]. In another large but heterogeneous (early chronic phase, late chronic phase, and advanced phases) series of patients treated with IM at the MDACC, older age appeared to be not associated with a worse outcome; however, the cut-off to define older patients was 60 years, elderly early chronic phase patients were few (49) and no long term data were available [7]. The first study to evaluate the effect of age in large series of front-line IM treated patients and with a long follow-up was recently published by the GIMEMA CML WP [8]. Five hundred and fifty nine patients, of whom 115 ≥ 65 years old, were enrolled in 3 prospective, multicenter, trials. After a median follow-up of 60 months, hematologic, cytogenetic and molecular response rates were identical in older and younger patients while survival was significantly inferior in older patients. This lower survival was due to a higher number of deaths occurred in chronic phase, reasonably unrelated to IM therapy or toxicity, and not to a higher progression rate in older patients. Recently a new prognostic score was elaborated based on 2060 patients enrolled in studies of first-line IM-based regimes and collected by the European Leukemia Net / EUTOS Registry [9]. Of the all variables analyzed, only spleen size and basophils percentage, best discriminated between high-risk and low-risk patients; age had no more a prognostic impact, a further confirmation that IM has cancelled the differences in prognosis between younger and older patients. No doubt, the overall toxicity and the need for dose optimization are higher for IM with respect to conservative and palliative treatments, like hydroxyurea, particularly when older patients are treated; however, in the hands of expert physicians IM is generally manageable. Moreover, as the lower survival of elderly patients is mainly determined by age-related factors and co-morbidities, rather than by the progression of CML, a geriatric assessment (frailty status) may be helpful in the decision to allocate selected patients to IM therapy [10]. In conclusion, age had relevance when therapeutic strategies, like IM, were not available. However, today, older age per se must not be a limitation for treating patients with IM and the enrollment of these patients in clinical trials should be encouraged. Second generation tyrosine kinase inhibitors (dasatinib and nilotinib) as front-line therapy showed higher response rates and lower toxicities compared to IM [11, 12]; probably these results will be confirmed also in elderly patients. Importantly, extra-hematologic toxicities are distinct between IM, dasatinib and nilotinib, allowing the selection of the more appropriate drug in relation to the presence of co-morbidities. Although data on dasatinib and nilotinib in elderly patients are still few and the follow-up is still short, these second generation tyrosine kinase inhibitors will probably further improve the outcome of CML elderly patients.

Dasatinib As a Late Second Line Therapy in Chronic Myeloid Leukemia Patients: A Retrospective Study From a Tertiary Care Centre in India

Abstract 4438 Introduction-Chronic myeloid leukemia in Indian patients manifests a decade earlier than reported in the West. However, patients present later to the hospital, with advanced disease as evinced by large spleen size, fever and other symptoms and a high Sokal score. The cost of medicines and lack of health insurance means that most will receive Imatinib mesylate (Glivec) from the GIPAP program only, or locally produced Imatinib. The usual option for imatinib failure is to increase the dose to 600 or 800mg. Switching patients to second line therapy is difficult due to financial constraints; patients who fail Imatinib are offered allogeneic stem cell transplantation. Methods-We present a single-institution retrospective data of Dasatinib as second line therapy in CML patients resistant to imatinib. In a total of 1200 CML patients followed in our clinic, 24 patients were treated with dasatinib over a period of 4 years. 17 of whom were in chronic phase (switched after failure of Interferon and Imatinib -2, not in CHR at time of switch- 4), accelerated phase-5 and blast crisis-2 patients, at the time of starting dasatinib. They either refused transplant, did not have donor or had co-morbid factors (3-diabetes mellitus and CVD, 1- chronic renal disease along with diabetes) which made transplant difficult. Results-The median age of patients was 45 years (26–65 years) with 12 males and 12 females. They had received imatinib for a median of 50 months (20–98 months) before starting dasatinib. After a median follow up of 12 months (6.6 – 39.6 months), there was 2 deaths (CML-BC-1, CML-AP-1). Non-hematologic toxicity was generally mild to moderate (grades 1 or 2); dyspnea, gastrointestinal disorders (diarrhea, nausea) and fluid retention were seen. Pleural effusion occurred in two patients. Conclusions-Toxicities with Dasatinib were generally reversible and could be managed effectively with dose adjustments. Our limited experience showed this to be effective and well tolerated even in late failure patients with high disease burden. Disclosures:No relevant conflicts of interest to declare.

Prediction of Molecular Response of Chronic Phase CML Patients by the EUTOS Score: Results of the Randomized CML-Study IV,

Abstract 3762 Introduction:The EUTOS Score was developed and validated as a prognostic tool for the achievement of complete cytogenetic response (CCR) at 18 months for chronic phase (CP) CML patients under imatinib therapy. The score identifies high-risk patients not reaching CCR at 18 months with a positive predictive value of 34% and a specificity of 92% using only two variables, peripheral blood basophils and spleen size at diagnosis (Hasford et al. Blood 2011). We sought to evaluate the clinical impact of the EUTOS score to predict molecular response. Therefore, we analyzed the EUTOS score with patients from the German CML-Study IV, a randomized 5-arm trial (imatinib 400 mg vs. imatinib 800 mg vs. imatinib in combination with interferon alpha vs. imatinib in combination with araC vs. imatinib after interferon failure). Results:From July 2002 to December 2010, 1,502 patients with BCR-ABL positive CML in CP were randomized. 129 patients with imatinib after interferon alpha and 36 other patients had to be excluded (14 due to incorrect randomization or withdrawal of consent, 22 with missing baseline information). 1,337 patients were evaluable for overall and progression-free survival (OS and PFS), 1,252 for molecular responses. 749 of these patients were part of the score development sample. Therefore cytogenetic analyses are not described here.By EURO score, 36% of patients (n=475) were low risk, 51% (n=681) intermediate risk, and 12% (n=167) high risk. The EUTOS score was low risk in 88% (n=1163) and high risk in 12% (n=160). The high-risk patients differed between the two scores: EUTOS high-risk patients were classified according to EURO score in 12% as low (n=19), in 45% as intermediate (n=68) and in 43% as high risk (n=73).Patients with high, intermediate, and low risk EURO score achieved MMR in 22, 16, and 13 months and CMR4 (BCR-ABL <=0.01%) in 59, 41, and 34 months. P-values for low vs. intermediate risk groups were borderline only (0.03 for MMR and 0.04 for CMR4), whereas p-values for high vs. low/intermediate risk groups were for both molecular response levels <0.001. At 12 months the proportion of patients in MMR was 38%, 46%, 54% for high, intermediate, and low risk patients, respectively. Similar results were observed with the Sokal score.Patients with high risk EUTOS score achieved deep molecular responses (MMR and CMR4) significantly later than patients with low risk EUTOS score (MMR: median 21.0 vs. 14.8 months, p<0.001, Fig. 1a; CMR4: median 60.6 vs. 37.2 months, p<0.001, Fig. 1b). [Display omitted] The proportions of patients achieving MMR at 12 months were significantly lower in the EUTOS high-risk group than in the EUTOS low-risk group (30.8% vs. 50.6%, p<0.001).OS after 5 years was 85% for high and 91% for low risk patients (p=n.s.), PFS was 85% and 90%, respectively. Conclusions:The EUTOS score clearly separates CML patients also according to MMR and CMR4 (MR4). The new EUTOS score should be used in future trials with tyrosine kinase inhibitors in CML. Disclosures:Neubauer:Novartis: Honoraria, Research Funding; Roche: Research Funding. Kneba:Hoffmann La Roche: Honoraria. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Hochhaus:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. German CML Study Group:Deutsche Krebshilfe: Research Funding; Novartis: Research Funding; BMBF: Research Funding; EU: Research Funding; Roche: Research Funding; Essex: Research Funding.

Very Long-Term Follow-up Results of Imatinib Mesylate Therapy in Chronic Phase Chronic Myeloid Leukemia After Failure of Interferon Alpha Therapy

Abstract 2749 Background:The long-term outcome of patients with chronic phase chronic myeloid leukemia treated with imatinib after failure of interferon alpha therapy has not been detailed. Patients and Methods: 368 patients were analyzed. Univariate and multivariate analyses for survival were conducted using standard statistical methods. Results: Overall, 247 patients (67%) achieved complete cytogenetic response (CCyR). Of 327 patients studied, 207(63%) achieved major molecular response (MMR), and 99 (30%) had undetectable BCR-ABL levels at some time on therapy. The estimated 10-year survival rate was 68%, progression-free survival rate 67%, and event-free survival rate 51%. By multivariate analysis, age ≥ 60 years, hemoglobin < 10g/dl, marrow basophils ≥ 5%, any peripheral blasts, and clonal evolution were independent adverse factors for survival. The estimated 7-year survival by the presence of none (n=154), 1–2 (n=190), or ≥ 3 factors (n=24) were 93%, 70%, and 25% respectively (p <0.01). Achievement of MMR, CCyR, or partial cytogenetic response at 12 months were associated with significantly better 10-year survival rate by landmark analysis (10-year survival 80–90%) vs. achieving minor cytogenetic response or complete hematologic response (10-year survival 55–65%) vs. other response (10-year survival 10%). Using landmark analysis to include imatinib response at 12 months, achievement of major cytogenetic response or better (hazard ratio 0.12; p< 0.001) and complete hematologic response or minor cytogenetic response (hazard ratio 0.36; p=0.003) were significant favorable prognostic factors. Conclusions: The estimated 10-year survival rate of 68% in patients with chronic myeloid leukemia receiving imatinib after interferon failure has improved. Disclosures:Cortes:Novartis: Consultancy; Novartis: Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Kantarjian:Novartis: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; BMS: Research Funding.

LOW INCIDENCE RATE OF OPPORTUNISTIC AND VIRAL INFECTIONS DURING IMATINIB TREATMENT IN CHRONIC MYELOID LEUKEMIA PATIENTS IN EARLY AND LATE CHRONIC PHASE

Background:Imatinib has become first line therapy in chronic myeloid leukemia patients. Little is known about the infective consequences during the treatment with this drug in large series of chronic phase patients.Material and methods:From January 2001 to September 2006 we treated with imatinib 250 patients in first line (early CP) or after interferon failure (late CP), out of clinical trials and recorded all the bacterial and viral infections occurred.Results:We recorded a similar incidence of bacterial and viral infections both in first line and late CP patients (respectively, 16% and 13%) during 3.5 years of follow-up. Analysis of presenting features predisposing to infections revealed differences only in late CP patients, with elevated percentage of high Sokal risk patients and a more longer median time from diagnosis to start of imatinib.Conclusions:Opportunistic infections and reactivation of Herpes Zoster are observed during imatinib therapy at very low incidence.

Prognostic Significance of the Lost of a Major Molecular Response In Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia (Ph+CML).

AbstractAbstract 3435 Background:Albeit of well-known, dramatic improvements, there remain some questions to be solved around Ph+CML in treatment with tyrosine kinase inhibitors (TKI). Among these, the significance of the amount of minimal residual disease (MRD) measured by RT-PCR. For instance, loss of a so-called major molecular response (MMR) is claimed to be a Òsuboptimal responseÓ and following the ELN recommendations, a change in treatment should be considered in these patients. Aims:To evaluate the relevance of a loss of MMR in patients with complete cytogenetic response (CCR). Study Group and Methods:We have analized 81 patients treated with imatinib for CML in chronic phase with a median follow up of 66 months. 36 patients started imatinib after interferon failure and 45 as front line therapy. Major Molecular Response (MMR; BCR-ABL/ABL ratio<0.1% IS) at any time was achieved by 63 patients. Results:22 patients (34%) lost MMR (documented al least twice). The risk of losing MMR was higher in late MMR (>18 months) compared with those cases whose MMR came much earlier (<18 months): 70% vs 18% (p=. 000). We have found no correlation among the lost of MMR and classical prognostic factors (Sokal-Index, mutations at the TK domain or imatinib plasma levels). Of these 22 patients, 7 (32 %) recovered MMR later with no therapy changes, 8 (36%) experienced fluctuations in the BCR-ABL transcript-levels without losing CCR, 4 (19%) did not attain a MMR but remained in stable CRR, and 3 (13%) lost CCR. These regained MMR after being treated on second generation TKI. The results show how the stability of the early MMR is greater than late MMR (table1). Conclusions:In our experience, one third of the patients who lost MMR recovered it later on the same treatment. And only 13% went on to treatment failure. Perhaps some similar cases (after first losing MMR) should be closely monitored before a change in treatment. Also of note is, of course regarding only our experience, that the risk of a loss of MMR seems to be maximal in patients who achieve a late MMR.Table 1Evolution of patients after lossing MMREarly MMR (n= 9)Late MMR (n=13)Recover MMR45% (4)23% (3)Fluctuations33% (3)38% (5)Remained in Suboptimal Response11% (1)23% (3)Lost CCR11% (1)15% (2) Disclosures:No relevant conflicts of interest to declare.

Failure of Interferon γ to Induce the Anti-Inflammatory Interleukin 18 Binding Protein in Familial Hemophagocytosis

BackgroundFamilial hemophagocytosis (FHL) is a rare disease associated with defects in proteins involved in CD8+ T-cell cytotoxicity. Hyperactivation of immune cells results in a perilous, Th1-driven cytokine storm. We set out to explore the regulation of cytokines in an FHL patient who was clinically stable on low-dose immunosuppressive therapy after bone marrow transplantation over a six-month period. During this period, chimerism analyses showed that the fraction of host cells was between 1 and 10%. Both parents of the patient as well as healthy volunteers were studied for comparison.Methods/Principal FindingsUsing ELISA, quantitative real-time PCR, and clinical laboratory methods, we investigated constitutive and inducible cytokines, polymorphisms, and clinical parameters in whole blood and whole blood cultures. Although routine laboratory tests were within the normal range, the chemokines IP-10 and IL-8 as well as the cytokine IL-27p28 were increased up to 10-fold under constitutive and stimulated conditions compared to healthy controls. Moreover, high levels of IFNγ and TNFα were produced upon stimulation. Unexpectedly, IFNγ induction of IL-18 binding protein (IL-18BP) was markedly reduced (1.6-fold vs 5-fold in controls). The patient's mother featured intermediately increased cytokine levels, whereas levels in the father were similar to those in the controls.Conclusions/SignificanceSince IL-18 plays a major role in perpetuating hemophagocytosis, the failure of IFNγ to induce IL-18BP may constitute a fundamental pathogenetic mechanism. Furthermore, increased production of IL-8 and IL-27 appears to be associated with this disease. Such dysregulation of cytokines was also found in the heterozygous parents, providing a novel insight into genotype-phenotype correlation of FHL which may encourage future research of this rare disease.

Failure of Interferon to Prevent Disease Progression and Liver Cancer in Hepatitis C Virus Infection: Proof of Absence or Absence of Proof?

Failure of Interferon to Prevent Disease Progression and Liver Cancer in Hepatitis C Virus Infection: Proof of Absence or Absence of Proof?

Chronic myeloid leukemia (CML) with e1a2 BCR-ABL fusion transcript type: Analysis of characteristics, outcomes, and prognostic significance

7030 Background: The most common BCR-ABL fusion transcripts in CML are e13a2 (b2a2) and e14a2 (b3a2). Rarely, other transcripts like e1a2 are seen. Currently, there is no published series of data on efficacy of imatinib or other tyrosine kinase inhibitors (TKIs) in CML with e1a2. Methods: We analyzed records of 1,292 CML patients treated with TKI at our institution between January 2000 and November 2008. Results: 14 CML patients with e1a2 transcripts were identified, 9 in chronic phase (CP), 1 in accelerated phase (AP), and 4 in blast phase (BP). Median age at diagnosis was 60 (range 28–86) years, median follow-up 39.5 (range 2–109) months. Of the 9 in CP, 3 received interferon and then imatinib after interferon failure, 6 received TKI as first-line therapy (5 imatinib, 1 nilotinib): 5 achieved CHR only, 1 CCyR, 1 MCyR, 1 PCyR, and 1 did not respond to imatinib. 5 patients (2 post-interferon failure - 1 in CHR, 1 in PCyR; 3 frontline imatinib - 1 in CHR, 1 in CCyR, 1 non-responder) progressed to advanced phases (3 myeloid BP, 1 lymphoid BP, 1 AP) at a median 48 (range 4–92) months after CML diagnosis; with only 1 alive and in CMR after allogeneic SCT. AP patient received various TKIs sequentially and achieved only CHR with disappearance of clonal evolution. BP patients received Hyper-CVAD+imatinib/dasatinib or idarubicin+Ara-C; 2 did not respond, 1 had CCyR lasting 12 months with Hyper-CVAD+Imatinib and 1 had CMR after allogeneic SCT lasting 2 months. In all 14 patients, cytogenetic responses lasted 1–9 months before being lost and none (except 2) achieved MMR or CMR on imatinib or other TKI therapy. Six patients (5 CP, 1 AP) were alive at a median 39 (range 2–85) months after initial diagnosis: 4 with CHR (2 on imatinib, 1 nilotinib, 1 bosutinib), 1 with MCyR on imatinib, and 1 with CMR after allogeneic SCT. Conclusions: CML with e1a2 BCR-ABL fusion transcripts is rare and is associated with an inferior outcome to therapy with TKI, with responses being usually short-lived. These patients need to be identified as high-risk patients and monitored closely for efficacy during therapy with TKI. No significant financial relationships to disclose.

Efficacy of Pre-S-containing HBV Vaccine Combined with Lamivudine in the Treatment of Chronic HBV Infection

Treatment of chronic hepatitis B (CHB) is difficult. The response rate to interferon (IFN) as well as nucleoside analogs is not more than 30% in general. While interferon has many side effects, development of resistance in most of the nucleoside analogs precludes long-term use. Both groups of drugs are most efficacious in patients who already had or develop strong cellular immunity with treatment. A pre-S2-containing vaccine was shown to enhance cellular immunity and suppress hepatitis B virus (HBV)-DNA in subjects with chronic hepatitis B. We aimed to test the efficacy of short-term use of a nucleoside analog in combination with a pre-S2-containing vaccine in patients with CHB. In this open study, 48 consecutive patients (32 males and 16 females, mean age +/- SD: 33 +/- 12 years) with CHB without cirrhosis were treated with 100 mg/day lamivudine and four weekly intramuscular injections of Genhevac B 20 mcg (six doses) for 24 weeks. While 19 patients were hepatitis B e antigen (HBeAg) positive (+ve), 29 patients were Anti-HBe/HBV-DNA +ve at the outset. Response was defined as seroconversion to anti-HBe in HBeAg +ve subjects and normalization of alanine aminotransferase (ALT) with loss of HBV-DNA in anti-HBe/HBV-DNA +ve subjects. HBeAg seroconversion occurred in 5/19 subjects (26%). Eighteen of 29 anti-HBe/HBV-DNA +ves responded. In the follow-up, while relapse was not observed in any of the patients who seroconverted, 11/18 from the anti-HBe/HBV-DNA +ve group relapsed, resulting in a sustained response (SR) rate of 24% in this group. All the relapses happened in the first 48 weeks of follow-up, with no relapse thereafter. Pretreatment high serum HBV-DNA was a strong negative predictor of sustained response (SR) in HBeAg +ve group. Pretreatment serum ALT over 2 x upper limit of normal and HBV-DNA less than 200 pg/ml appeared positive predictors. None of HBeAg +ve previous interferon failures responded. Twenty-four weeks of lamivudine and hepatitis B vaccine treatment induces SR in around 1/4 of the patients with CHB. Most of the responders had high ALT and relatively low DNA.

Malignancies Occurring during Therapy with Tyrosine Kinase Inhibitors (TKI) for Chronic Myeloid Leukemia (CML) and Other Hematologic Malignancies.

Background: Success of tyrosine kinase inhibitors (TKIs) (imatinib, dasatinib, nilotinib, bosutinib) in chronic myeloid leukemia (CML) has given patients (pts) hope for a long disease free survival, and with increased survival, may be some late effects of TKI treatment in the form of development of another malignancy. One prior report suggested an unexpected increased incidence of cancers among pts treated with imatinib after failure to interferon (Roy et al, Leukemia 2005).Aims: To investigate the frequency and characteristics of 2nd malignancies (other than AML, ALL or MDS) among pts with CML or other hematologic malignancies treated with TKI.Methods: We analyzed the records of 1647 pts treated with TKIs at our institution: 384 in chronic phase treated with imatinib after interferon failure, 338 treated with imatinib in advanced phases, 312 treated with imatinib as initial therapy, 422 treated with 2nd generation TKI after imatinib failure, and 109 treated with 2nd generation TKI as frontline therapy.Results: A total of 67 (4.07%) pts (47 male, 20 female) developed a 2nd cancer. Their median age was 67 (range 31–85) years; the median follow-up after CML diagnosis was 94 (range 13–480) months (mo), and median time from start of TKI to development of another cancer was 38 (range 2–95) mo. These included 31/67(46%) pts who received imatinib as 1st line therapy for median 39.5 (range 16–88) mo, 5 pts who received 2nd generation TKI after imatinib failure (4 dasatinib, 1 bosutinib) for a median 10 (range 3–22) mo, and 1 pt received nilotinib as frontline therapy for 3 mo before diagnosis of 2nd cancer. The accompanying table summarizes the findings. The most common cancer was non-melanoma skin cancer representing 31% of all cancers. Excluding these, the 2nd cancers were seen in 2.8% of all pts treated. The skin cancers and melanomas were scattered and not localized to any particular anatomical site. Prostate cancer patients had median age 69 (range 43–83) years and imatinib treatment of median 38 (range 18–74) mo, for a cumulative incidence of 1.18% among male pts. Two patients with CLL were diagnosed on flow cytometry after loosing their hematologic response while still maintaining complete cytogenetic response (CCyR) on imatinib. After median follow up of 22 (range 1–95) mo from diagnosis of 2nd cancer, 12 (18%) pts have died (none from 2nd cancer). 49 pts continue on therapy with TKI after the diagnosis of 2nd cancer with 15 in complete molecular response (CMR), 25 with complete cytogenetic response (CCyR), 4 with partial cytogenetic response (PCyR), 5 having only complete hematologic response (CHR). All the frontline imatinib patients who are alive with a second cancer are in CCyR except one who is having CHR onlyType of second cancerNo. of patients (n=67)Skin Cancer (BCC+SCC)21 (11+10)Melanoma7Prostate cancer11GU cancer (Ovarian+Uterine)2 (1+1)GU cancer (Urinary bladder+Kidney)4 (1+3)GI cancer (Colon+Gastric+Esophageal)6 (3+2+1)GI cancer (Hepatobiliary)1Lung cancer1Thyroid cancer (Papillary+Follicular)2 (1+1)Thymoma1Lymphoma (large B-cell)1CLL2MPD1Breast cancer (relapse+new)4 (2+2)Head & neck cancer2Cancer of Unknown Primary1BCC: basal cell carcinoma, SCC: squamous cell carcinoma, GU: genito-urinary, GI: gastro-intestinal, CLL: chronic lymphocytic leukemia, MPD: myeloproliferative disorderConclusion: Second cancers occur in a small percentage of pts receiving therapy with TKI for hematologic malignancies, mostly CML. These results need to be analyzed in the context of the underlying lifetime risk of developing cancer in the general population and in cancer survivors. There is no evidence at the moment to suggest that exposure to TKI is carcinogenic.

Long-Term Efficacy of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) in Patients (pts) with Advanced Chronic Myeloid Leukemia (CML) Post Imatinib Failure.

Allogeneic HSCT is a potentially curative treatment for pts with CML, and is effective after imatinib failure. We assessed the long-term results of HSCT in 92 consecutive pts with CML that had failed imatinib. Herein are the results of this review. Preparative regimens were reduced-intensity intravenous (IV) busulfan (Bu)-fludarabine (Flu) in 40 pts, IV Bu-cyclophosphamide in 39, Flu-melphalan in 6, and total body irradiation (TBI) based regimens in 7. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and mini-methotrexate 5 mg/m2. Donors were matched related in 49 (53%) and matched unrelated in 43 (47%). Prior to HSCT, 43 (47%) pts received imatinib therapy after interferon failure and 49 (53%) as frontline therapy. At the start of imatinib therapy, 48 (52%) pts were in chronic phase (CP), 23 (25%) in accelerated phase (AP), and 21 (23%) in blastic phase (BP). Median time on imatinib before HSCT was 15 months (range, 2–50). Best response to standard-dose imatinib was complete cytogenetic response (CCyR) in 32 (35%), partial (PCyR) in 10 (11%), minor (mCyR) in 10(11%), and complete hematologic response (CHR) in 25 (27%). Median age at HSCT was 43 years (range, 14–69). At HSCT, 30 pts were in CP (33%), 27 in AP (29%), 17 in BP (18%), and 18 in second CP (20%). Pts were followed for a median of 48 months (range 4–93) from HSCT. All but 2 pts engrafted within a median of 12 days (range, 5–20). Acute GVHD was observed in 42 (46%) pts (Grade I in 15, Grade II/III in 19, Grade IV in 8). Chronic GVHD was observed in 35 pts (extensive in 20). Chimerism studies at day 30 post HSCT were available in 81 pts and were 100% of donor type in 61 (75%) and mixed in 20 (25%). Seventy-nine pts (86%) responded (100% for pts in CP, 93% for pts in AP, 94% for pts in 2nd CP, 41% for pts in BP). Sixty-three pts achieved a major molecular response (MMR), complete (CMR) in 60; 16 achieved a CCyR only. Of the 30 pts in CP that responded, 2 (7%; both achieved a CMR) relapsed, 9 and 24 months post HSCT. Of the 25 pts in AP who responded, 8 (32%: 6 CMR, 2 CCyR) relapsed after a median of 13 months (range, 2–51) post HSCT. Of the 17 pts in 2nd CP who responded, 6 (35%; 2 CMR, 4 CCyR) relapsed. Of the 7 pts in BP who responded, 4 (57%; 4 CMR) relapsed after a median of 16 months (range, 3–45) post HSCT. At the last follow-up, 49 (53%) pts were alive and 43 (47%) died. Causes of death included progressive disease in 29, GVHD in 6, infections in 5, diffuse alveolar hemorrhage in 2, and unknown cause in 1. One and 2-year survival rates were 65% and 54%. The median survival for pts in BP, 2nd CP, and AP were, 4, 14, and 72 months, respectively. The median survival for pts in CP has not been reached. The estimated 1- and 4-year survival by disease stage is as follows : BP, 24% and 12%; 2nd CP, 67% and 49%; AP, 67% and 62%; CP 87% and 74%, respectively.In conclusion, HSCT remains an effective salvage strategy post imatinib failure, and disease stage at HSCT remains the stronger prognostic factor.Response to allogeneic HSCT (MMR, major molecular response; CMR, complete molecular response; CCyR, complete cytogenetic response)CPAP2nd CPBPN30271817MMR (%)83706741CMR (%)77676741CCyR (%)100939541Relapse rate (%)7323557Median survival (mos)NR721441- and 4-year survival (%)87 & 7467 & 6267 & 4924 & 12

Better Molecular Response to Imatinib for Patients (pts) with Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) Carrying the b3a2 Transcript Compared to b2a2.

Background. Different types of BCR-ABL fusion mRNAs can be found in pts with CML due to different genomic breakpoints and alternative splicing. The two major forms join ABL exon 2 with exons 13 or 14 of BCR, resulting in two main transcripts, b2a2 and b3a2, respectively, that codify for a p210 protein present in the majority of CML patients. b3a2 is more frequent in newly diagnosed patients than the b2a2 transcript, and occasionally both transcripts may be present. The clinical significance of the specific transcript among CML pts treated with imatinib has not been clearly established, and some have suggested that b2a2 may be associated with better outcome. (Blood 2006 108: Abstract 4780) Genet.Mol. Res. 4(4): 803–811 ( 2005)Journal of Clinical Oncology , 2007 Vol 25, No 18S (June 20 Supplement), 2007: 7043.Purpose: To determine if there is a difference in outcome after imatinib therapy in CML pts according to their BCR-ABL transcript.Methods: We analyzed 480 pts with CP CML treated with imatinib, 251 receiving imatinib as frontline therapy and 229 after interferon (IFN) failure. Molecular response was evaluated using RT PCR every 3 months (mo).Results: The median follow-up was 62 mo (range 1–92 mo) Median age was 51 years (range 15–84). Overall, 187 of 480 (39%) pts expressed b2a2, 234 (49%) b3a2, 55 (11%) expressed both, and 4 (1%) expressed e1a2. The rates of major and complete cytogenetic response were similar for pts with b3a2 and b2a2, both in the newly diagnosed and the post-IFN failure: CCyR 91% for b3a2 and 89% for b2a2 in frontline, and 72% and 78%, respectively in the post-IFN failure group. However, among 433 pts evaluable for molecular response, transcript levels were significantly lower at 3, 6 and 12 months from start of therapy for pts with b3a2 compared to those with b2a2 (Table 1).Table 1Median BCR-ABL transcript levels over time by transcript type3 months6 months9 monthsoverallb2a21.82840.3180.1860.0464b3a20.51750.05530.03520.0033p-value0.001<0.001<0.001<0.001This resulted in a significantly higher probability of achieving a major molecular remission (MMR) and complete molecular remission (CMR; ie, undetectable transcript levels) for pts with the b3a2 transcript (Table 2).Table 2Molecular Response in patients Post IFN failure and patients newly treatedTranscriptNo.*MMR**(%)P valueCMR***(%)P valueNew Dx b2a210663592625New Dx b3a211588770.00854470.002Post IFN b2a26221341016Post IFN b3a29761630.00141420.001*Number of evaluable patients. Dx=DiagnosisThere was a trend for an improved transformation-free survival for pts with b3a2 compared to those with b2a2 (4-yr rates 98% vs 93%, respectively, p=0.08) and event-free survival (94% vs 87%, p=0.37). Although fewer pts co-expressed both transcript types, they behaved like the pts with b3a2.Conclusion: Pts with the b3a2 transcript have a better molecular response to imatinib that those with b2a2. This prognostic factor should be considered when evaluating response to therapy.

Impact of Imatinib Mesylate Dose Escalation on Resistance and Sub-Optimal Responses to Standard-Dose Therapy in Patients (pts) with Chronic Myeloid Leukemia (CML).

Background: Dose escalation has been reported to be of benefit in some pts after standard-dose imatinib failure. This benefit is based on small series of pts with short follow-up. Although dose escalation is also recommended for pts with suboptimal response to imatinib (as defined by the European LeukemiaNet recommendations), the efficacy of this approach has not been reported. Methods: We assessed the long-term efficacy of dose escalation in 102 pts with CML in chronic phase who met the criteria of failure (n=85) or suboptimal (n=9) response to imatinib, or had their dose escalated by physician’s choice for responses better than suboptimal (n=8). Results: Median age was 52 years (range, 18–79). 89 pts were receiving imatinib after interferon failure and 13 as frontline therapy. Median time on imatinib before dose escalation was 19 mos (range, 3–87). Best response to standard-dose imatinib was complete cytogenetic response (CCyR) in 33 (32%), partial (PCyR) in 10 (10%), minor (mCyR) in 14 (14%), complete hematologic response (CHR) in 30 (29%), and partial hematologic response (PHR) in 1 (1%). 86 pts had their dose escalated from 400 to 800 mg/day and 24 from 300 to 600 mg[JC1]. Pts were followed for a median of 50 mos (range 3–83) from dose escalation. Among pts with criteria for failure, 45/61 (74%) treated for cytogenetic resistance (n=31) or relapse (n=30) responded, including complete molecular response (CMR) (n=2), major molecular response (MMR) (n=4), CCyR (n=24), PCyR (n=9), and minor CyR (n=6). Another 24 pts were treated for hematologic resistance (n=5) or relapse (n=19), and 13 (54%) responded: 1 MMR, 2 CCyR, 2 PCyR, 7 CHR, and 1 PHR. Median time to cytogenetic response was 9 mos (range, 2–54). 31/58 (53%) failure pts who responded to dose escalation relapsed after a median of 68 mos (range, 6–79), with relapses in 6/33 pts (18%) who achieved a CCyR. CCyR occurred in 31/77 (40%) pts who escalated to 800mg and 2/9 (22%) of those who escalated to 600mg (p=0.29). Among 9 pts with suboptimal response (8 no MMR at 18 mo, 1 no PCyR at 6 mos), 2 (22%) responded: 1 MMR and 1 PCyR. The later lost his response to minor CyR 2 years after escalation. Among 8 pts with response better than suboptimal, 6 (75%) improved their response to CMR (n=1) and MMR (n=3) from CCyR, and to CCyR (n=2) from PCyR at 3 and 9 mos,respectively. Table 1 summarizes responses and outcome for the 3 categories. Conclusion: Imatinib dose escalation can induce sustained molecular and cytogenetic responses in patients with failure or suboptimal response to standard-dose imatinib. Many of these responses can be durable. Table 1. Outcome after dose escalation (%) 2-year (%) from dose escalation CCyR MMR Transformation Event Loss CCyR EFS TFS EFS=Event-free survival; TFS=Transformation-free survival. * One evaluable pt not in CCyR at dose escalation. **4 evaluable pts not in CCyR at dose escalation Failure 33/85 (39) 7/85 (8) 9/58 (15) 31/58 (53) 6/33 (18) 85 86 Cytogenetic 30/61 (49) 6/61 (10) 4/40 (10) 15/40 (37) 5/30 (17) Hematologic 3/24 (12) 1/24 (4) 5/18 (28) 16/18 (89) 1/3 (33) Suboptimal 0/1* (0) 1/9 (11) 0 (0) 1 (11) 0 (0) 88 100 Other 4/4** (100) 4/8 (50) 0 (0) 0 (0) 0 (0) 100 100

Evaluation of the Cepheid GeneXpert BCR-ABL Assay

Patients with chronic myeloid leukemia harbor the chromosomal translocation t(9;22), which corresponds to fusion of the BCR and ABL genes at the DNA level. The translated fusion product is an oncogenic protein with increased ABL tyrosine kinase activity causing cell transformation. To date, reverse transcriptase-polymerase chain reaction is considered the most sensitive method available for detecting low copy numbers of the BCR-ABL gene fusion. Recently, Cepheid introduced its GeneXpert-based assay for the identification of the BCR-ABL gene fusion in cells from blood samples. This system comprises a walk-away self-contained instrument that combines cartridge-based microfluidic sample preparation with reverse transcriptase-polymerase chain reaction-based fluorescent signal detection and BCR-ABL and ABL Ct (threshold cycle) determination. The difference between the BCR-ABL Ct and ABL Ct (DeltaCt) is expected to represent the ratio of the two populations of mRNAs and ultimately the percentage of neoplastic cells present. We tested whether this BCR-ABL fusion detection system could be used as a clinical diagnostic tool for monitoring patients with minimal residual disease of chronic myelogenous leukemia. We report similar performance characteristics, including limit of detection, specificity, sensitivity, and precision, of this automated BCR-ABL fusion detection system to those of a manual TaqMan reverse transcriptase-polymerase chain reaction-based test.

Antioxidant therapy for chronic hepatitis C after failure of interferon: Results of phase II randomized, double-blind placebo controlled clinical trial

To assess the safety and efficacy of antioxidant therapy for patients with chronic hepatitis C virus (HCV) infection. One hundred chronic HCV infection patients failed in interferon treatment were enrolled and randomly assigned to receive combined intravenous and oral antioxidants or placebo, or oral treatment alone. Primary end points were liver enzymes, HCV-RNA levels and histology. Combined oral and intravenous antioxidant therapy was associated with a significant decline in ALT levels in 52% of patients who received antioxidant therapy vs 20% of patients who received placebo (P = 0.05). Histology activity index (HAI) score at the end of treatment was reduced in 48% of patients who received antioxidant therapy vs 26% of patients who received placebo (P = 0.21). HCV-RNA levels decreased by 1-log or more in 28% of patients who received antioxidant therapy vs 12% who received placebo (P = NS). In part II of the trial, oral administration of antioxidants was not associated with significant alterations in any of the end points. Antioxidant therapy has a mild beneficial effect on the inflammatory response of chronic HCV infection patients who are non-responders to interferon. Combined antiviral and antioxidant therapy may be beneficial for these patients.

Sokal and Hasford Scores Are Able To Predict Cytogenetic Response and Survival in CML Patients Who Failed Prior Therapy and Are Receiving Salvage Therapy with Imatinib or Other Tyrosine Kinase Inhibitors.

Sokal and Hasford scores have been used to estimate the survival of CML patients following alkylator-based or interferon-based therapy, and may also predict the outcome of patients receiving first-line imatinib. These scores were designed for patient characteristics at the time of diagnosis and they have been assumed to have no clinical value at other times during the course of the disease (eg. second-line or subsequent therapy). We seek to determine the applicability of the Sokal and Hasford scores in predicting outcomes in patients receiving second or subsequent-line therapy with imatinib and other novel tyrosine kinase inhibitors (TKI). This analysis is based on 379 CML patients in chronic phase (90%) or accelerated phase as defined by cytogenetic clonal evolution (10%), who were enrolled on clinical trials of imatinib following interferon failure (n=294), or nilotinib or dasatinib following imatinib failure (n=85). Significance of relationship between Sokal and Hasford risk categories and response were tested using the Chi-Square test, and differences in survival assessed using the log-rank method. P-values are summarised below:Imatinib following Interferon FailureNilotinib/Dasatinib Following Imatinib FailureSokalHasfordSokalHasfordLow Risk219 (74%)176 (60%)39 (46%)45 (53%)Intermediate Risk65 (22%)111 (38%)34 (40%)38 (45%)High Risk10 (3%)6 (2%)12 (14%)2 (2%)Any Cytogenetic Responsep<0.001p<0.001p=0.01p=NSMajor Cytogenetic Responsep<0.001p<0.001p=0.002p=0.04*Complete Cytogenetic Responsep<0.001p<0.001p=0.005p=0.07*Survivalp<0.0001p<0.0001Insuff EventsInsuff Events*comparison between low and intermediate risk groups onlyAmong patients receiving imatinib following failure of interferon therapy, both Sokal and Hasford scores were highly predictive of cytogenetic response and overall survival. Due to the low number of deaths (n=5) on the nilotinib and dasatinib trials, the effect of Sokal and Hasford scores on predicting survival could not be assessed but they remain predictive of cytogenetic response. We conclude that the Sokal and Hasford scores calculated at the time of therapy failure are useful predictors of subsequent response to salvage therapy with imatinib and other TKIs.

Rapid and simple detection of IFN‐neutralizing antibodies in chronic hepatitis C non‐responsive to IFN‐α

Different mechanisms have been proposed for the failure of interferon (IFN) therapy in patients with chronic hepatitis C and multiple sclerosis, for example, the presence of IFN-neutralizing antibodies. In this study, a novel assay system based on the IFN-inducible Mx-promoter was used to detect IFN-neutralizing antibodies in sera of patients with chronic hepatitis C. To monitor IFN bioactivity in IFN-treated patients, a real-time RT-PCR for MxA gene expression in PBMCs was established. Using these two methods, patients with chronic hepatitis C virus (HCV) infection receiving IFN therapy and patients with treatment induced HCV clearance were monitored. Importantly, neutralizing anti-IFN antibodies were detected in the sera of 3 of 38 chronically HCV-infected patients who failed to respond to therapy but none in sera of patients who cleared HCV after IFN therapy. Interestingly, the presence of these antibodies correlated with the lack of MxA induction in PBMCs after initiation of IFN-alpha therapy. Retrospective analysis of one patient's sera revealed that the anti-IFN-alpha antibodies had already developed after the first of four unsuccessful IFN therapies, suggesting that neutralizing antibodies may have contributed to the failure of previous IFN treatments. In summary, a novel screening assay was established that may be helpful for testing IFN non-responders for the presence of clinically relevant anti-IFN-alpha antibodies and for selecting alternative IFN preparations not neutralized by these antibodies.