Interferon Alpha 2a (IFN) Maintenance Therapy After Imatinib Plus IFN Induction Therapy in Chronic Myeloid Leukemia (CML) Induces Stable Long-Term Molecular Remissions and Is Associated with Increased Proteinase 3 (PR3) Expression and the Presence of PR1-Specific T-Cells.

Abstract Abstract 647 Imatinib is a selective and very potent inhibitor of the BCR/ABL kinase. It induces ongoing complete cytogenetic remissions in the vast majority of chronic phase CML patients. However, BCR/ABL persistence is the rule despite ongoing imatinib therapy. This suggests that imatinib will not to cure CML and raises concerns about emerging imatinib resistance, long-term imatinib tolerability and compliance to therapy. We previously suggested that a combination of imatinib and immunotherapy by IFN may additionally control CML via induction of autologous cytotoxic T-cell (CTL) responses, such as those directed against the leukemia-associated antigen proteinase 3 (PR3). For example, induction of PR1-CTL which recognize PR3 on CML blasts was previously shown to be associated with IFN-, but not imatinib response. Indeed, we could recently demonstrate on a cohort of 20 newly diagnosed CML patients that low dose of IFN maintenance therapy alone was able to maintain or improve remissions obtained by a prior imatinib/IFN combination treatment (A. Hochhaus et al. , ASH 2007). After a median time of IFN maintenance therapy of 1.2 years 80% of the patients remained or improved molecular remission. Here we report a significantly longer follow up of these patients and translational studies to examine markers of IFN response. Twenty pts (14 m, 6 f; median age 45, range 23-74 yrs) with low (n=13), intermediate (n=6), and high risk (n=1) according to the Hasford score risk calculation have been investigated. Imatinib therapy had been administered for 2.4 yrs (0.2-4.9), combined with PEG-IFNa2a (Pegasys®, n=17) or IFN a2a (Roferon®, n=3). Maintenance therapy consisted of PEG-IFN (n=16) or IFN (n=4). Dose was adjusted according to response and tolerability and ranged between 135 μg PEG-IFN every 3 weeks to 180 μg PEG-IFN every week, or alternatively 2 to 5 * 3 Mill IU IFN/week. Imatinib was terminated due to side effects (n=5) or upon personal request of the patients after informed consent (n=15). At the time of imatinib withdrawal, two pts were in complete molecular remission (CMR) and 15 pts in major molecular remission (MMR). After a median observation time of 2.8 yrs (range 0.5-4.5), 15 pts were in MMR, 5 of them in CMR. Thus, the number of MMR patients increased from 2 at baseline to 5 after two years. Five patients relapsed within 0.4 years (range, 0.2-0.8) after imatinib discontinuation, but were rescued with imatinib, re-establishing molecular remission. Side effects to maintenance IFN were minor. We also studied putative markers of IFN response. IFN therapy was associated with an increase in the expression of PR3, and in the presence of auto-reactive PR1-CTL. PR1-CTL frequencies were prospectively assessed without prior in vitro amplification. In one of five assessable patients PR1-CTL were detected prior to imatinib withdrawal, but in four of seven assessable patients during IFN maintenance therapy. Longitudinal measurements of PR-1 CTL counts suggested an inhibition of the expansion of PR1-CTL by imatinib, implying that an optimal CTL expansion may occur preferentially in the absence of imatinib. This would explain the conversion to a CMR status in some patients only after imatinib withdrawal. Together, IFN maintenance after a prior imatinib/IFN induction therapy may be an effective alternative to permanent imatinib therapy, because it enables to safely discontinue imatinib even in those patients that have not achieved a CMR at the time of pausing imatinib. Induction of a PR1-specific CTL response by IFN may contribute to the particular efficacy of IFN after CML-debulking by imatinib. Disclosures: Burchert: Roche: Research Funding. Off Label Use: Pegasys(R) therapy in CML. Neubauer:Roche: Research Funding. Hochhaus:Roche, Novartis: Research Funding.

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Analysis of Long-Term Survival in Multiple Myeloma Patients after First-Line Autologous Stem Cell Transplantation: Impact of Clinical Risk Factors and Duration of Response

Blood ◽

10.1182/blood.v128.22.4649.4649 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4649-4649

Author(s):

Nicola Lehners ◽

Natalia Becker ◽

Axel Benner ◽

Maria Pritsch ◽

Elias Karl Mai ◽

...

Keyword(s):

Maintenance Therapy ◽

Board Of Directors ◽

Induction Therapy ◽

Research Funding ◽

Conditional Survival ◽

First Line ◽

Advisory Committees ◽

Term Survival ◽

Long Term Survival

Abstract Background: In the last decade, the introduction of novel agents into multiple myeloma (MM) therapy has significantly improved response rates and enabled long-term survival in a subset of patients. Yet, clinical characteristics of these long-term survivors as well as the exact impact of depth and sustainment of response still remain a matter of debate. Methods: MM patients treated at our center with high-dose melphalan supported by autologous stem cell transplantation (ASCT) as part of their first-line therapy between June 1992 and July 2014 were retrospectively analyzed. Response assessment was performed 100 days after ASCT according to EBMT criteria, since 2008 response according to IMWG criteria was also available. Overall survival (OS) and progression-free survival (PFS) were calculated from day of first ASCT. Additionally, landmark analyses regarding OS were performed at 1, 2, 3, and 5 years after ASCT. Impact of variables on PFS and OS were analyzed using multivariate Cox regression models. Furthermore, in order to assess evolution of prognosis over time, the conditional survival CS(t|s), which expresses the conditional probability of surviving further t years, was calculated as the ratio of two Kaplan-Meier estimates Ŝ(t) with . Results: 865 patients were included in this analysis, median age was 57.0 years (range 24-74), 509 were male. New agents based induction therapy was administered in 358 patients, 258 patients underwent tandem ASCT. Following ASCT, 386 patients received maintenance therapy, mainly with interferon or thalidomide. 75 patients proceeded to allogeneic transplantation and were censored at that time. Median PFS was 2.1 years, median OS was 6.4 years. Analysis of clinical influence factors revealed novel agent based induction therapy (p<0.01), maintenance therapy (p<0.01) and achievement of complete response (CR) (p=0.01) to be significantly associated with prolonged PFS, while older age (p=0.01) and thrombocytes at diagnosis < 150/nl (p=0.02) were identified as risk factors; a negative trend was seen for ISS stage 3 (p=0.067). With regard to OS, novel agent based induction therapy (p<0.01), maintenance therapy (p<0.01) and duration of time to progression (p<0.01) showed a highly significant positive impact, older age (p<0.01) and renal insufficiency at diagnosis (p=0.048) exerted a negative influence. To assess the importance of duration of response, landmark analyses were performed at 1, 2, 3, and 5 years after ASCT evaluating OS of patients with sustained CR, sustained inferior responses (non-CR), lost CR and lost non-CR at these respective time points. Remarkably, sustainment of any response showed a highly significant impact on survival at each of these time points (p<0.01) with no discernable difference between sustained CR and sustained non-CR patients. Landmark analysis at 1 year is shown in Figure 1. Administration of maintenance therapy independently improved outcome (p<0.01). Conditional survival regarding the probability to survive further three years CS(3|s) was calculated starting from the time of first ASCT stratified for the different response cohorts (see Figure 2). No significant differences could be found between patients with complete and partial response. In contrast, patients with progressive disease (PD) at day 100 after ASCT had a much lower probability of surviving the following three years after ASCT compared to patients responding to ASCT. However, those patients with PD that did survive the first year after ASCT, achieved a similar conditional three-year survival to that of patients responding initially. Conclusions: In this large retrospective study, sustainment of response after first-line ASCT was revealed as a major impact factor for OS independent of the depth of response. Administration of maintenance therapy further improved outcome, supporting the hypothesis that interventions prolonging responses achieved after ASCT are essential to reach long-term survival. Figure 1 OS of patients with sustained vs not-sustained responses at 1-year landmark analysis. Figure 1. OS of patients with sustained vs not-sustained responses at 1-year landmark analysis. Figure 2 3-year-conditional survival CS(3|s) after ASCT stratified for responses achieved. Figure 2. 3-year-conditional survival CS(3|s) after ASCT stratified for responses achieved. Figure 3 Figure 3. Disclosures Hillengass: Amgen: Consultancy, Honoraria; Celgene: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Novartis: Research Funding; Sanofi: Research Funding. Goldschmidt:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Raab:Amgen: Consultancy, Research Funding; BMS: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Research Funding.

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Long-Term Sustained Responses Following Ibrutinib Discontinuation after Frontline Therapy with Obinutuzumab Plus Ibrutinib in Patients with Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood-2020-143473 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 33-34

Author(s):

Paula A. Lengerke Diaz ◽

Michael Y. Choi ◽

Eider F. Moreno Cortes ◽

Jose V. Forero ◽

Juliana Velez-Lujan ◽

...

Keyword(s):

Bone Marrow ◽

Side Effects ◽

Chronic Lymphocytic Leukemia ◽

Disease Progression ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Combination Regimen ◽

Grade 3

Single oral targeted therapies have emerged as a standard of care in chronic lymphocytic leukemia (CLL). However, accessibility, side effects, and financial burden associated with long term administration limit their clinical use. Mainly, it is unclear in what clinical situation discontinuation of oral therapy can be recommended. The combination of type II anti-CD20 antibody obinutuzumab-Gazyva® with ibrutinib (GI) has shown a significant progression-free survival benefit in patients (pts) with CLL, including those with high-risk genomic aberrations. We conducted a phase 1b/2, single-arm, open-label trial to evaluate the safety and efficacy of GI as first-line treatment in 32 CLL pts. We report the outcome in pts that discontinued ibrutinib (either after 3 years of sustained complete response (CR) as stipulated in the clinical protocol, or due to other reasons). CLL pts enrolled in this protocol were ≥65 years old, or unfit/unwilling to receive chemotherapy. Pts received GI for six cycles, followed by daily single-agent ibrutinib. The protocol was designed to ensure that pts with a sustained CR after 36 months were allowed to discontinue ibrutinib. The median age was 66 years (IQR 59-73), and 6% of the evaluated pts had 17p deletion. All pts were able to complete the six planned cycles of obinutuzumab. The combination regimen was well-tolerated, and the most common adverse events (>5% CTCAE grade 3-4) were neutropenia, thrombocytopenia, and hyperglycemia. The rate and severity of infusion-related reactions (IRR) were much lower than expected (Grade≥ 3, 3%), and pts without IRR had lower serum levels of cytokines/chemokines CCL3 (P=0.0460), IFN-γ (P=0.0457), and TNF-α (P=0.0032) after infusion. The overall response rate was 100%, with nine pts (28%) achieving a CR, and four pts (12.5%) with undetectable minimal residual disease (uMRD) in the bone marrow, defined as <10-4 CLL cells on multicolor flow cytometry. At a median follow-up of 35.5 months (IQR 24.5-42.7) after starting treatment, 91% of the enrolled pts remain in remission with a 100% overall survival. Sixteen pts have completed a long-term follow-up of 36 months. Six pts showed CR, with three of them achieving uMRD in the bone marrow. Ten of these pts were in PR, and only one had disease progression and started treatment for symptomatic stage I disease with obinutuzumab plus venetoclax. In total, thirteen pts (41%) have stopped ibrutinib, with a median time on treatment prior to discontinuation of 35 months. Five (16%) of these pts had CRs and discontinued after 36 months. Eight additional pts (25%) had PRs and discontinued ibrutinib without being eligible: three pts discontinued prior to 36 months due to toxicities, and five pts discontinued after 36 months (3 due to side effects, and 2 due to financially driven decision). One patient eligible to discontinue ibrutinib, decided to remain on treatment despite sustained CR. After a median follow up time following ibrutinib discontinuation of 8 months (IQR 3.5-17), only two out of 13 pts have progressed (10 and 17 months after Ibrutinib discontinuation). None of the pts that stopped ibrutinib after achieving a CR have shown signs of disease progression. Of note, the pharmaceutical sponsor provided ibrutinib for the first 36 months, after which pts or their insurer became financially responsible. This particular scenario could bias the discontinuation pattern compared to a real world experience. It also provided us with a perspective about diverse factors affecting the treatment choices of pts. In summary, the obinutuzumab plus ibrutinib combination therapy was well-tolerated, with a much lower IRR rate. Efficacy compares favorably with historical controls with all pts responding to therapy, no deaths associated with treatment or disease progression, and a longer than expected time-to-progression after discontinuation of ibrutinib. The rate of ibrutinib discontinuation was higher than reported in the literature, most likely influenced by the protocol design and financial decisions driven by the switch from sponsor-provided ibrutinib to insurance or self-paid medication. Our observations regarding safety, efficacy and lack of disease progression after ibrutinib discontinuation are encouraging, and warrant confirmation in long-term prospective studies. Clinicaltrials.gov Identifier NCT02315768. Funding: Pharmacyclics LLC. Disclosures Choi: AbbVie: Consultancy, Speakers Bureau. Amaya-Chanaga:AbbVie: Ended employment in the past 24 months, Other: Research performed while employed as an investigator of this study at UCSD.. Kipps:Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Castro:Kite Pharma: Research Funding; Pharmacyclics: Research Funding; Fate Therapeutics: Research Funding.

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DOP73 Efficacy and safety of escalation to tofacitinib 10 mg BID for patients with UC following loss of response on 5 mg BID maintenance therapy: Results from OCTAVE open-label, long-term extension study

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.112 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S110-S111 ◽

Cited By ~ 1

Author(s):

B E Sands ◽

A C Moss ◽

A Armuzzi ◽

J K Marshall ◽

J O Lindsay ◽

...

Keyword(s):

Maintenance Therapy ◽

Treatment Failure ◽

Induction Therapy ◽

Dose Escalation ◽

Safety Data ◽

Mucosal Healing ◽

Incidence Rates ◽

Efficacy And Safety ◽

Open Label

Abstract Background Tofacitinib is an oral, small-molecule JAK inhibitor for the treatment of ulcerative colitis (UC). The efficacy and safety of tofacitinib have been demonstrated in patients with moderate to severe UC in three Phase 3 studies (OCTAVE Induction 1 and 2 [NCT01465763; NCT01458951]; OCTAVE Sustain [NCT01458574]) [1]. Here, we present updated efficacy and safety data of tofacitinib dose escalation in patients with UC participating in an ongoing, open-label, long-term extension (OLE) study (OCTAVE Open, NCT01470612) [2]. Methods We present updated data from the dose-escalation subpopulation of the OLE study (as of May 2019; database not locked) comprising patients who achieved clinical response (CR) following 8 weeks of tofacitinib 10 mg twice daily (BID) induction therapy, entered OCTAVE Sustain receiving tofacitinib 5 mg BID, experienced treatment failure between Week 8 and Week 52, and subsequently entered OCTAVE Open with escalation to tofacitinib 10 mg BID. Treatment failure was defined as an increase of ≥3 points from maintenance study baseline total Mayo score, plus an increase of ≥1 point in both rectal bleeding subscore and centrally read endoscopic subscore (ES), and an absolute ES of ≥2 after ≥8 weeks of maintenance therapy. CR, mucosal healing (MH) and remission (R) were evaluated at Months 2, 12, 24 and 36 of OCTAVE Open (non-responder imputation and last observation carried forward [NRI-LOCF] and observed data). Safety was evaluated throughout the study. Results Of 944 patients enrolled in the OLE study, the dose escalation subpopulation comprised 59 patients. In these patients, CR, MH and R rates 36 months after dose escalation were, respectively, 40.7%, 39.0% and 30.5% for NRI-LOCF and 95.2%, 86.4% and 66.7% for observed data (Table). Of these 59 patients, 29 had prior tumour necrosis factor inhibitor (TNFi) failure; in these patients, CR, MH and R rates at Month 36 were, respectively, 51.7%, 51.7% and 41.4% for NRI-LOCF, and 100.0%, 92,3% and 75.0% for observed data. Incidence rates for safety events and pt-years’ exposure are reported in the table. Conclusion For most patients who lost initial CR to tofacitinib 10 mg BID induction therapy while on tofacitinib 5 mg BID maintenance therapy, including those with prior TNFi failure, dose-escalation back to 10 mg BID recaptured CR by Month 2 and was generally maintained over 3 years. The safety profile with tofacitinib 10 mg BID in the dose-escalation subpopulation was generally consistent with that in the overall study population, although there was a numerically higher rate of herpes zoster. These analyses are limited by low pt numbers and the absence of a comparator arm. References

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A Practical Approach to the Use of Acitretin for the Treatment of Psoriasis

Psoriasis Forum ◽

10.1177/247553031016a00209 ◽

2010 ◽

Vol 16a (2) ◽

pp. 62-68

Author(s):

Tina Bhutani ◽

Kristine Busse

Keyword(s):

Side Effects ◽

Adverse Events ◽

Maintenance Therapy ◽

Plaque Psoriasis ◽

Practical Approach ◽

Serious Adverse Events ◽

Oral Retinoid ◽

Systemic Agents ◽

Term Maintenance

This clinical review outlines a practical approach to the use of acitretin in the treatment of psoriasis. Acitretin is approved by the Food and Drug Administration for the treatment of adult patients with chronic moderate to severe plaque psoriasis. It is an oral retinoid and is the only systemic agent that is not clinically immunosuppressive; it works primarily by enhancing differentiation and maturation of cells. Side effects associated with this medication are usually mild and manageable; serious adverse events are rare. Therefore, it can be used for long-term maintenance therapy or in combination with other topical or systemic agents and phototherapy.

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Imatinib and Interferon-Alpha Maintenance Therapy for Patients with Philadelphia-Positive Acute Lymphoblastic Leukemia (Ph+ALL) Ineligible for Allogeneic Stem Cell Transplantation (SCT).

Blood ◽

10.1182/blood.v114.22.2042.2042 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2042-2042

Author(s):

Heike Pfeifer ◽

Barbara Wassmann ◽

Andreas Käbisch ◽

Michael Lübbert ◽

Lothar Leimer ◽

...

Keyword(s):

Side Effects ◽

Elderly Patients ◽

Maintenance Therapy ◽

Low Dose ◽

Front Line ◽

Consolidation Chemotherapy ◽

Mutation Status ◽

Line Therapy ◽

Remission Duration

Abstract Abstract 2042 Poster Board II-19 Introduction: The tyrosine kinase inhibitor imatinib (IM), alone or in combination with chemotherapy, has become the mainstay of front-line treatment for Ph+ ALL. We recently demonstrated that IM in combination with intensive consolidation chemotherapy of approximately one year duration is feasible in elderly patients with de novo Ph+ ALL, but is associated with a high relapse rate. Allogeneic SCT (alloSCT) is potentially curative but may not be feasible in most elderly or comorbid patients. Maintenance therapy (MT) in such patients is conceptually attractive, but data on whether any type of MT facilitates long-term leukemia-free survival of patients with Ph+ALL in first CR is lacking. Based on data suggesting that interferon-alpha (IFN-a) possesses anti-leukemic activity in patients with Ph+ALL, we conducted a phase II study to determine the feasibility and efficacy of MT consisting of imatinib in combination with low-dose (LD) IFN-a in elderly patients with Ph+ALL who were not eligible for SCT. In addition, we examined whether bcr-abl transcript levels and mutation status were predictive of relapse and remission duration. Methods: Nineteen elderly patients (median age 66 yrs; [60-75 yrs.]) who had received IM-based remission induction and consolidation therapy as reported previously (Ottmann et al., Cancer 109:2068-76, 2007) were enrolled in a clinical trial of IM 400 mg daily in combination with LD-IFNa with a target dose of 3 Mio IU/week. At the time of enrollment, the majority of patients (n=12) had received five (n=3) or six (n=9) consolidation cycles, the remaining patients had discontinued intensive front-line therapy after four (n=2), three (n=1), two (n=1), and one (n=1) consolidation cycles, 2 patients were switched to MT after induction. The median number of cycles of consolidation chemotherapy given concurrently with IM was six. Minimal residual disease (MRD) was serially assessed by quantitative RT-PCR, mutational analyses was performed by D-HPLC and direct sequencing. Results: The median overall duration of MT is 26 mos. (range 3-92 mos.). Seven of 19 pts. (37 %) are in ongoing CR, with a median remission duration from start of maintenance of 76.7 mos. (54-91 mos.). Median overall survival of all pts. is 61 mos. (range: 20-99 mos.). Eleven of 18 evaluable pts. experienced side effects which lead to a dose reduction of IFN. 9 pts. suffered from moderate depressions or fatigue. Hematologic toxicity was mild: only 2 pts. developed grade 3 cytopenia during MT. Remission duration was independent of the number of previous cycles of intensive chemotherapy, of the MRD response during the first 6 mos. of intensive front-line therapy (16 mos. vs. 26 mos.) and of achievement of PCR negativity at any time during intial therapy. Surprisingly, the bcr-abl transcript level at the start of MT likewise had no impact on time to disease recurrence. Conclusions: In elderly Ph+ALL pts. ineligible for allogeneic SCT, maintenance with imatinib in combination with low-dose IFN-a results in long-term sustained remissions in a substantial proportion of patients, with acceptable side effects. Surprisingly, the MRD response and mutation status prior to MT were not significantly predictive of remission duration. Likewise, greater intensity of prior chemotherapy as determined by the number of administered consolidation cycles had no significant benefit with respect to remission duration during MT. More extensive evaluation of tyrosine kinase inhibitors in combination with LD IFNa as MT for Ph+ALL is warrented. Disclosures: Ottmann: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria.

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Different Definitions of Progression-Free Survival (PFS) and Event-Free Survival (EFS) May Result In Perceived but Not Real Differences In Long-Term Outcome When Comparing Trials In Chronic Myeloid Leukemia (CML)

Blood ◽

10.1182/blood.v116.21.672.672 ◽

2010 ◽

Vol 116 (21) ◽

pp. 672-672

Author(s):

Hagop Kantarjian ◽

Susan O'Brien ◽

Elias Jabbour ◽

Jianqin Shan ◽

Farhad Ravandi ◽

...

Keyword(s):

Research Funding ◽

Chronic Phase ◽

Patient Choice ◽

Imatinib Therapy ◽

Free Survival ◽

Blastic Phase ◽

Resistance Loss ◽

Frontline Therapy

Abstract Abstract 672 Background The favorable results of second generation tyrosine kinase inhibitors (TKIs; nilotinib, dasatinib) in frontline therapy of Philadelphia chromosome (Ph) positive-CML may establish them as new standards in frontline therapy. This depends on the maturing data with the long-term endpoints of PFS and EFS. Different definitions are used to define “progression” and “event” in different studies. This may result in perceived but not real differences in outcomes with various TKIs when comparing trials. In addition, multi-institutional sponsored trial designs may compound the variable definitions: 1) patients taken off study for occurrences other than the defined “progression” or “event” (eg toxicity, intolerance, other) are censored at the time they are off therapy and not coded for progression/event/death once they are off TKI; and 2) such studies have limited capacities to follow up patients for progression/event after they are off drug therapy for more than 30–60 days. Single institutional studies have a potential advantage of continuing to monitor patients for progression/events after they are off the particular protocol TKI. Study Aim To analyze the impact of differences in the definitions of PFS and EFS used in the IRIS, ENEST-nd, DASISION, and M.D. Anderson (MDACC) trials on outcome, when these definitions are applied to patients with newly diagnosed CML treated with TKIs on MDACC studies. Patients and Methods 435 patients (July 2000-April 2010) with early chronic phase Ph-positive CML treated with imatinib (n=281), nilotinib (n=78), and dasatinib (n=76)were analyzed for outcome using different definitions. Definitions were: 1) PFS- ENEST: progression = accelerated or blastic phase (AP-BP) on nilotinib/imatinib therapy + CML related death on nilotinib/imatinib therapy or within 30 days off therapy; 2) EFS-IRIS: event = progression to AP-BP on imatinib + death of any cause on imatinib + loss of CHR or major CG response; 3) PFS-DASISION: progression = EFS-IRIS definition + WBC increase to more than 20; deaths are coded on dasatinib and within 60 days off dasatinib; 4) EFS MDACC: event = progression to AP-BP + loss of major CG response +resistance/loss of CHR/lack of achievement of response by ELN criteria + off for toxicity + death from any cause on or off therapy (if not counted prior to death as progression/event). Results The median follow-up is 67 months (2-116). Of the 435 patients treated, 312 (72%) remain on TKI therapy; 123 (28%) were taken off for the following reasons: resistance/loss of response n = 33; blastic phase on TKI therapy n=6; intolerance/toxicity n= 29; other causes n = 55. Reasons off for the latter 55 patients are: lost to follow – up (n=14); non-compliance (n=11); financial issues (n=8): intercurrent illness (n=7); patient choice (n=5); referral to SCT in chronic phase (n=2); and death from non-CML cause (n=8: 1 complications of surgery, 2 old age, 1 CHF, 1 pneumonia, 2 car accident/suicide, 1 cardiac infarction). So far, 33 patients (7.6%) have died; 8 while on TKI therapy (none from CML; detailed earlier); 2 within 60 days off TKIs (1 AML, 1 renal cancer); and 23 off TKIs for > 60 days. Deaths in the latter 23 were from: 10 post resistance/relapse/BP (accounted for as event/resistance at time off TKI); 10 taken off for toxicity/intolerance (censored at time off; 8 deaths later from CML, 1 post SCT, 1 unknown); 4 off for other illness/non-compliance/lost to FU/pt choice (3 deaths later from CML; 1 from other). Thus, of the 33 deaths, only 19 (8 deaths on TKI + 2 deaths within 60 days + 9 off for resistance/relapse/BP) would be counted as progression/events on the IRIS/ENEST/DASISION studies while 14 would be censored at time off TKI. Based on these 4 definitions, the number of progression/events were: PFS-ENEST 26 progressions; EFS-IRIS 40 events; PFS-DASISION 43 progression/events; EFS-MDACC 76 events. The corresponding 5-year PFS EFS rates were 93%, 90%, 89%, and 81%. (Figure) Conclusions With the importance of EFS and PFS in determining whether new TKIs are better than imatinib in frontline therapy, precise and common definitions of these endpoints across randomized clinical trials and single institutional trials are needed. Randomized multi-institutional trials may not collect accurately all events after patients are off TKI therapy for 30–60 days. Disclosures: Kantarjian: Novartis Pharmaceuticals: Research Funding; Bristol Myers Squibb: Research Funding. O'Brien:Novartis: Research Funding; BMS: Research Funding. Kadia:Novartis: Membership on an entity's Board of Directors or advisory committees. Cortes:Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Pfizer: Consultancy.

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Attempt to Discontinue Imatinib Following Interferon Alfa Pre-Treatment In Chronic Phase CML Patients Achieving Stable Complete Cytogentic Responses (CCyR)

Blood ◽

10.1182/blood.v116.21.4898.4898 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4898-4898

Author(s):

Izhar Hardan ◽

Yulia Volchek ◽

Tali Tohami ◽

Ninette Amariglio ◽

Luba Trakhtenbrot ◽

...

Keyword(s):

Conflicts Of Interest ◽

Chronic Phase ◽

Interferon Alfa ◽

Cytotoxic T Cell ◽

Molecular Response ◽

Molecular Remission ◽

Line Therapy ◽

Pre Treatment

Abstract Abstract 4898 Imatinib (IM) has been shown to induce sustained clinical responses and stable remissions resulting in improved survival in chronic phase (CP) CML patients (pts.). Currently the state of the art is life long continuation of IM therapy which raises issues like the emergence of drug resistance, long-term safety and tolerability, compliance and costs. Interferon Alfa (IFNα), which has anti-CML activity and may induce major cytogenetic responses (MCyR), has in contrast to IM, immunoregulatory properties including the induction of anti-CML cytotoxic T-cell activity. Moreover, in initial studies of IM discontinuation it seemed that previous IFNα exposure was beneficial for the maintenance of molecular remission after IM cessation. We, therefore, hypothesized that adding IFNα to IM prior to IM discontinuation will increase the proportion of pts. remaining in continuous molecular response. We report on the long term, median follow up of 40 months (range, 33–41), outcome of CP CML pts. who discontinued IM after the addition of IFNα. CP CML pts. in CCyR for ≥2 years on IM were included. Study pts. received a combination of PegIFN (Pegasys, Roche) (180 μg/week, sc) and IM (400 mg) for 9 months followed by 3 months of PegIFN monotherapy, and were followed up thereafter without any anti leukemia therapy. Twelve CP CML pts. were included, 9 males and 3 females. Median age was 50.5 years (range, 33–67). Disease duration was 67 (18-96) months. Eight of the pts. (67%) received IFNα prior to IM as first line therapy. Eight of the patients had a major molecular response (MMR), 2 were in complete molecular response (CMR) (of 48 and 10 months duration) and 2 had less than a MMR. Of the evaluable pts. only 1 had a BCR ABL KD mutation (E373D). IFNα dose had to be reduce to 90–135 μg/week, sc due to intolerance in 10/12 pts. Median duration of CCyR (n=12) and MMR (n=8) at the time of IM discontinuation was 47.5 (21-86) months and 19.5 (9-84) months, respectively. Cytogenetic relapse occurred in 8 pts. 8 (2-38) months after IM discontinuation. Loss of molecular responses could be detected in all 8 pts. during follow up, and prior to the cytogenetic relapse at 8 (1-25) months post IM discontinuation. An additional 1 pt. had a molecular relapse but has maintained his CCyR 20 months post IM discontinuation. IM (400 mg/day) was reintroduced in all 8 pts. with loss of CCyR and they all re-achieved a CCyR 3.5 (3-7) months after IM re initiation. Five of the 8 pts. (62%) achieved also a MMR at 5, 7, 8, 10, and 11 months post IM re- administration, respectively. After a median follow up of 40 (range 33–41) months, 4 of the 12 study pts. (33.3%) are in persistent molecular remission. These 4 pts. achieved a CMR (n=1) (of 10 months duration) or MMR (n=3) (of 8, 14 and 19 months, respectively) prior to IM discontinuation. Notably, 2 of these 4 pts. had IFNα exposure as front line therapy pre-IM initiation. In summary, only a minority of CML pts. with stable MMR or CMR have a long lasting remission and will not relapse following IM discontinuation. Pts. having a cytogenetic relapse after IM discontinuation respond to IM re-administration by re-achieving CCyR and mostly MMR. The role of IFNα pre treatment, as well as the depth of molecular response needed to be achieved pre-IM discontinuation, should be further evaluated in a well designed 2 arms controlled randomized studies. Disclosures: No relevant conflicts of interest to declare.

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Results of Salvage Autologous Stem Cell Transplantation (ASCT) for Relapsed Multiple Myeloma (MM) in the Era of Novel Agents: Outcome of Patients (Pts) Receiving Prior Bortezomib (BTZ)-Based Therapy

Blood ◽

10.1182/blood.v128.22.5821.5821 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5821-5821 ◽

Cited By ~ 2

Author(s):

Sara Farshchi Zarabi ◽

Esther Masih-Khan ◽

Christine Chen ◽

Vishal Kukreti ◽

Anca Prica ◽

...

Keyword(s):

Maintenance Therapy ◽

Induction Therapy ◽

Research Funding ◽

Chemotherapeutic Agents ◽

Novel Agents ◽

Remission Induction ◽

Group A ◽

Group B ◽

Relapsed Disease ◽

The Impact

Abstract Background: A second (salvage) ASCT has frequently been offered to MM patients with relapsed disease who experience benefit from the first procedure. We have previously reported that pts undergoing a salvage ASCT in the era of VAD or thalidomide (thal) have a median progression-free survival (PFS) of 19 months (mos). The best results were observed in pts who experienced ≥ 2 year benefit after their first ASCT (Jimenez-Zepeda VH et al. Biol Blood Marrow Transplant 2012; 18: 773-9). However, the utility of this approach after the introduction of novel chemotherapeutic agents--such as bortezomib (BTZ)--remains unclear. Initially, provincial funding for BTZ in Ontario was provided only for relapsed disease. However, in 2007, the combination of either BTZ + dexamethasone (BTZ-dex) or cyclophosphamide, BTZ + dex (CyBorD) was adopted as the standard induction regimen for newly diagnosed pts before ASCT performed as part of first-line therapy. We now examine the results of salvage ASCT in our centre after the availability of BTZ. Methods: We used the Princess Margaret Myeloma Database to identify and characterize patients with relapsed MM who had received a bortezomib (BTZ)-based regimen for remission induction prior to their first ASCT or for re-induction before salvage ASCT. A retrospective chart review was performed to investigate the PFS and overall survival (OS) outcomes of these pts. Results: Between 01/2005 and 07/2015, 64 pts with MM who had previously received BTZ-based therapies underwent salvage ASCT for relapsed disease at our centre (Table 1). Median age was 56.9 yrs (range 37-67.3); 37 (58%) were male. ISS stage was 1 in 32 (50%), 2 in 16 (25%), 3 in 14 (22%) and NA in 2 (3%). The median interval between first and salvage ASCT for all pts was 48.6 mos (range 26.9-130.3), reflecting our policy of preferentially offering salvage ASCT to pts with at least a 2-yr benefit from the first transplant; the median time between re- induction therapy and salvage ASCT was 6.3 mos (range 0.3-95.9). Group A pts (n=27) had received BTZ-based therapy before their first ASCT; 48% of these also received BTZ-based regimens again prior to salvage ASCT. Pts in Group B (n=37) received BTZ-based regimens before the salvage transplant only, while induction therapy before the first ASCT consisted of VAD (21), dex alone (8), thal + dex or other regimens (5). Twenty-two (34%) of the pts received maintenance therapy between the first and salvage ASCT (most often thal-based), while 35 (55%) of the pts received maintenance therapy following salvage ASCT (most frequently lenalidomide [len]-based). The survival outcomes are summarized in Table 2. Median duration of follow-up (F/U) following salvage ASCT was 19.1 mos (range 0.8-96.4). One patient (1.6%) died several days following salvage ASCT. No other transplant-related mortality occurred. The median PFS following salvage ASCT was 19.1 mos (range 0.8- 87.5) with a median OS of 26.5 mos (range 0.8-101.9) in all pts. The median PFS after salvage ASCT was 15.8 mos for Group A and 25.2 mos for Group B pts. Conclusions: Even in the era of novel agents, salvage ASCT may provide PFS benefit to pts with relapsed MM who were previously treated with a BTZ-based regimen. However, the details of the optimal approach in this setting are not certain, including the impact of maintenance therapy given after the first and/or salvage ASCT. We are performing additional analyses of this population to try to identify factors associated with the best outcomes. Disclosures Kukreti: Celgene: Honoraria; Lundbeck: Honoraria; Amgen: Honoraria. Prica:Janssen: Honoraria. Tiedemann:Novartis: Honoraria; Celgene: Honoraria; Takeda Oncology: Honoraria; BMS Canada: Honoraria; Amgen: Honoraria; Janssen: Honoraria. Trudel:Celgene: Honoraria; Novartis: Honoraria; Glaxo Smith Kline: Honoraria, Research Funding; Oncoethix: Research Funding. Reece:Merck: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding.

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The Effect of Different Rituximab-Containing Chemotherapy Strategies on Hepatitis C Viremia

Blood ◽

10.1182/blood.v124.21.4448.4448 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4448-4448

Author(s):

Parag Mahale ◽

Francesco Turturro ◽

Jorge Romaguera ◽

Nathan Fowler ◽

Harrys A. Torres

Keyword(s):

Hepatitis C ◽

Maintenance Therapy ◽

B Cell ◽

Induction Chemotherapy ◽

Induction Therapy ◽

Research Funding ◽

Hcv Rna ◽

Continuous Variables ◽

Maintenance Chemotherapy ◽

Before And After

Abstract Background: Rituximab (RXB) -containing chemotherapy forms the backbone of treatment for CD20 positive non-Hodgkin's lymphomas (NHL). RXB is combined with other agents as induction chemotherapy or as a single-agent maintenance therapy for indolent NHLs. RXB has been associated with reactivation of chronic hepatitis C virus (HCV) infection – a condition that leads to discontinuation of chemotherapy in 45% of patients who experience it. However, there is no data on the occurrence HCV reactivation according to the different types of RXB treatment strategies administered. We evaluated the effect of various RXB-containing regimens on HCV viremia. Methods: Medical records of all patients with NHL seen at MD Anderson between 01/2008-05/2014 were screened. Records of those who were treated with RXB-containing regimens and had HCV RNA levels available before and after chemotherapy were analyzed. HCV reactivation was defined as an increase of HCV RNA of ≥ log10IU/mL over pre-chemotherapy levels. Acute exacerbation of HCV infection (AcEx) was defined as an increase of alanine aminotransferase (ALT) levels of ≥ 3 times upper normal limit in the absence of liver infiltration of cancer, hepatotoxic drugs, recent transfusion, and coinfections. The groups compared were those who received RXB + chemotherapy (induction), with those who received RXB + chemotherapy followed by RXB maintenance therapy. Categorical variables were compared using χ2 or Fisher's exact test and continuous variables were compared using Wilcoxon rank sum test. Within each group, continuous variables before and after chemotherapy were compared using Wilcoxon signed-rank test. All P values < 0.05 were considered statistically significant. Results: We analyzed 28 HCV-infected patients (14 prospectively; 14 retrospectively) who received RXB-containing chemotherapy. Most patients were males (64%), whites (57%), and had a median age of 54.7 years (interquartile range, 47.8 – 61.4 years). Types of NHL included diffuse large B cell (54%), follicular (21%), marginal zone B cell (11%), mantle cell (4%), lymphoplasmacytic (4%), small lymphocytic (4%), and undetermined low grade B cell (4%) lymphomas; mostly Ann Arbor stage IV (82%). HCV genotype 1 was the most predominant strain (72%). Very few patients (12%) had cirrhosis when RXB chemotherapy was initiated. HCV treatment was administered before RXB chemotherapy in 9 (32%) patients but no one had resolved viremia (sustained virological response) at the time of cancer treatment. Overall, 43 courses of RXB-containing chemotherapy were administered, mostly as induction therapy (n = 39; 91%). Most common RXB-containing regimens administered were R-CHOP (n = 13; 30%), R-ICE (n = 6; 14%), and RXB with bendamustine (n = 5; 12%). In the entire cohort, when compared to pre-chemotherapy baseline levels, there were significant elevations in HCV RNA (median, log10IU/mL; 6.6 vs. 6.9; P = 0.005) and ALT (median, IU/L; 50 vs. 115; P < 0.0001) only after administration of RXB as induction chemotherapy, with no significant changes being found after RXB maintenance chemotherapy [HCV RNA (6.8 vs. 6.7; P = 1.0); ALT (37 vs. 59; P = 0.07)] (See Figure). When compared to maintenance therapy, those who received induction therapy attained peak HCV RNA (median, days; 590 vs. 140; P = 0.006) and peak ALT (median, days; 172 vs. 43; P = 0.02) earlier after RXB administration. HCV reactivation occurred only when induction chemotherapy was administered (n = 7). Doses of RXB-containing chemotherapeutic agents had to be modified (reduced or postponed) in 4 out of the 7 (57%) episodes of HCV reactivation. Median relapse-free survival for those who had dose modifications was lower than those without (14.6 months vs. 20.1 months; P = 0.13). Conclusion: HCV reactivation occurs after administration of RXB as a part of induction, but not maintenance chemotherapy for NHL. This virologic condition is associated with dose modification of RXB-containing chemotherapeutic regimens in over one-half of cases. Figure: Figure 1 Figure 1. Disclosures Torres: Gilead Sciences: Consultancy; Merck & Co., Inc. : Consultancy, Research Funding; Vertex Pharmaceuticals: Consultancy, Research Funding; Genentech,: Consultancy.

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Impact of Early Progression on Long Term Outcomes Among Myeloma Patients Receiving Lenalidomide, Bortezomib, and Dexamethasone (RVD) Induction Therapy

Blood ◽

10.1182/blood-2018-99-120314 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3302-3302

Author(s):

Ajay K Nooka ◽

Jonathan L Kaufman ◽

Charise Gleason ◽

Nisha Joseph ◽

Craig C Hofmeister ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Induction Therapy ◽

Research Funding ◽

Long Term Outcomes ◽

Advisory Committees ◽

Term Survival ◽

Risk Status ◽

Early Progression

Abstract Background: The incorporation of modern day induction regimens, autotransplant and continuous maintenance has resulted in better long-term outcomes for myeloma patients. Experience and trials demonstrated that by prolonging 1st progression-free survival (PFS1) and pushing the relapse farther, we can gain the OS advantage (McCarthy et al NEJM 2012). Unfortunately, a subgroup of patients fail to exploit this advantage, either due to their disease biology or due to inadequate therapy and suffer early progression (inferior PFS1) that impacts their long term outcomes. First, we evaluated the predictors of early progression to highlight the modifiable factors that can prevent progression. Next, we quantified the impact of shorter PFS1 (<36 months) on the long-term survival (OS). Methods: Of the 1000 consecutive newly diagnosed myeloma patients treated with homogenous induction therapy (RVD) induction therapy per Richardson et al (Blood 2010) from July 2005 until August 2016, 230 patients progressed within the first 36 months while 96 patients progressed beyond the 36-month mark, at the time of analysis. Median follow up duration was 38 months. Demographic and outcomes data for the pts were collected from myeloma database and responses were evaluated per IMWG Uniform Response Criteria. Results: Median age of the pts is 60 years (range 29-78). 29% of the patients are above the age of 66. M/F 54%/46%; W/AA 60%/32%; ISS III 27% were other patient characteristics. Cytogenetic abnormalities of significance: t(11;14): 13.5%, t(4;14): 7.8%, t(14;16): 5% del 17p: 16%, complex cytogenetics: 29% and high-risk status was conferred to 44% of the patients. 83% of patients underwent an autotransplant and median time to transplant was 6 (2-50) months. 68% of patients received maintenance therapy. Response rates are summarized in Fig 1. The median PFS for early and non-early progressors were 32 months (95% confidence interval (CI), 30.293-33.707) and 101 months (95% CI, 77.14-124.86) months, respectively (P<0.001). The median overall survival (OS) for early progressors was 94 months, and non-early progressors was not reached. (Fig 2). Among the predictors of early relapse, presence of high-risk status, ISS stage 3, inability to achieve ≥VGPR after transplant, non-receipt of transplant and/or maintenance were independent predictors of early progression on the multivariate analysis as illustrated in Table 1. Conclusions: Even with the effective use of the 3-drug induction regimen, these functionally high-risk patients that are early progressors have truncated long term survival. Our analysis advocates for using transplant, deepening the responses with modern drugs such as monoclonal antibodies to achieve ≥VGPR after transplant and intense maintenance strategies to prevent relapse. Disclosures Nooka: Spectrum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive technologies: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kaufman:Abbvie: Consultancy; Karyopharm: Other: data monitoring committee; Roche: Consultancy; Janssen: Consultancy; BMS: Consultancy. Hofmeister:Adaptive biotechnologies: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Boise:AstraZeneca: Honoraria; Abbvie: Consultancy. Heffner:ADC Therapeutics: Research Funding; Kite Pharma: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding. Lonial:Amgen: Research Funding.

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