Treatment-free Response Research Articles

Real-world use of thrombopoietin receptor agonists for the management of immune thrombocytopenia in adult patients in the United Kingdom: Results from the TRAIT study.

Few studies have reported the real-world use of both romiplostim and eltrombopag in immune thrombocytopenia (ITP). TRAIT was a retrospective observational study aimed to evaluate the platelet responses and adverse effects associated with the use of these thrombopoietin receptor agonists (TPO-RAs) in adult patients with ITP in the United Kingdom. Of 267 patients (median age at diagnosis, 48 years) with ITP (primary ITP [n = 218], secondary ITP [n = 49]) included in the study, 112 (42%) received eltrombopag and 155 (58%) received romiplostim as the first prescribed TPO-RA. A platelet count ≥30 × 109/L was achieved in 89% of patients with the first TPO-RA treatments, while 68% achieved a platelet count ≥100 × 109/L. Treatment-free response (TFR; platelet count ≥30 × 109/L, 3 months after discontinuing treatment) was achieved by 18% of the total patients. Overall, 61 patients (23%) switched TPO-RAs, most of whom achieved platelet counts ≥30 × 109/L with the second TPO-RA (23/25 who switched from eltrombopag to romiplostim [92%]; 28/36 who switched from romiplostim to eltrombopag [78%]). TFR was associated with secondary ITP, early TPO-RA initiation after diagnosis, the presence of comorbidity and no prior splenectomy or treatment with steroids or mycophenolate mofetil. Both TPO-RAs had similar efficacy and safety profiles to those reported in clinical studies.

Real-world Management of CML: Outcomes and Treatment Patterns.

Chronic myeloid leukemia (CML) is a disease that previously signified a poor prognosis, but treatment options and outcomes have improved over the last several decades. Despite this, challenges remain in optimal management in clinical practice, as the characteristics in trial populations differ from patients who are treated in a real-world setting. This review describes recent updates in real-world treatment patterns and outcomes in patients with CML. Several analyses describing real-world practice patterns show that tyrosine kinase inhibitors (TKIs) are the most commonly prescribed agents in multiple lines of therapy. First-generation (1G) and second-generation (2G) TKIs are the most commonly prescribed, even in the third line and beyond. Third-generation (3G) TKIs are typically utilized in patients with resistant disease who are younger with fewer comorbidities. Hematopoietic stem cell transplant (HSCT) is utilized significantly less, given other treatment options available. The goals of treatment with CML have shifted to quality of life, cost savings, and treatment-free response (TFR). Despite clear guidelines for attempting TFR, discontinuation practice patterns remain inconsistent. TKIs are the mainstay of CML treatment, including those in later lines of therapy. In real-world practice, several challenges still remain with regard to optimal management. Specifically, ideal sequencing of treatments, side effect profiles of tyrosine kinase inhibitors (TKIs), current role and timing of transplant, and adherence to recommendations for attempting to achieve a treatment-free response (TFR). A national registry could characterize these practice patterns in order to find ways to optimize care for CML patients.

Response to Tyrosine Kinase Inhibitors in Patients with BCR-ABL1 Positive Chronic Myeloid Leukemia; 13.5 Years’ Experience at Patan Hospital, Nepal

Background: Since the advent of Tyrosine Kinase Inhibitor (TKI), well controlled studies in developed world have shown that the life expectancy of patients with CML is comparable to normal people without the disease. But long-term follow up studies are lacking in resource poor setting.
 Methods: This is a retrospective follow up study looking at the molecular response and resistance to Tyrosine Kinase Inhibitors (TKI) in patients enrolled in the Max Access Program since February 2003 till March 2017. Patients with two or more BCR-ABL1 levels by Karyotyping/ fluorescent in situ hybridization (FISH) / reverse transcriptase polymerase chain reaction (RT-PCR) were included. At baseline, complete blood count (CBC), renal function test (RFT), and liver function test (LFT) were evaluated. Bone marrow aspiration and biopsy for morphology, cytogenetic analysis by Karyotyping/FISH and/or molecular analysis by RT-PCR were also done if these tests were not performed earlier. FISH or RT-PCR was done on peripheral blood every 3–12 months as necessary if the patient could afford. Patients with warning response/failure underwent BCR-ABL1 Resistance Mutation Analysis (IRMA).
 Results: Three hundred and forty six (346) patients had two or more BCR-ABL1 monitoring tests done. Optimal response was seen in 49.42%. Similarly, suboptimal response and failure were seen in 16.5% and 34% respectively. Overall Survival is 89.6% (at 1.8 -165 months, mean 62 months) . If only CML related events is considered survival is 95.9%. Seventy seven (77) patients with a total of 80 BCR-ABL1 domain Imatinib Resistance Mutation Analyses (IRMA) showed 19 different types of mutations with the most common being T315I mutation (8 and 19.5%). About 22.25% of the total patients showed resistance to Glivec out of which 10.98% showed mutations. Nine patients underwent trial for treatment free response (TFR) and 5 of them relapsed between 2-8 months.
 Conclusions: Despite all the odds of having financial problem, accessibility problem due to distances, transportation, etc. and difficulty monitoring with routine BCR-ABL1 and IRMA, our findings show that the outcome of TKI therapy in our CML patients is comparable to well controlled studies done elsewhere. Overall survival, molecular and cytogenetic responses and mutations in our patients who developed resistance as well as TFR are also similar to other studies. The resistance rate of 22.25% is slightly higher compared to other studies in developed world. This is mainly because of poor monitoring due to unavailability of the test including IRMA in our country and affordability until 2012. It proves that TKI is very effective in CML even in a resource-poor, developing country.

Maintenance of efficacy and its predictors after discontinuation of eltrombopag in adults with primary immune thrombocytopenia

Objective: To determine the efficacy of eltrombopag for primary immune thrombocytopenia (ITP) in adults and the predictive factors for treatment-free response (TFR) . Methods: Clinical data of adults with ITP who received eltrombopag from June 14, 2013 to May 31, 2021 in the Hematology Department of Ruijin Hospital affiliated with Shanghai Jiao Tong University Medical College were retrospectively analyzed. The initial dose of eltrombopag was 25 mg/d, and the maximum dose was 75 mg/d; the dose was adjusted to maintain the platelet count to within 50-150×10(9)/L. Treatment was discontinued according either to the protocol, on the patient's wishes or doctor's judgment (prescription medication), or based on clinical trials. The efficacy of eltrombopag and factors for TFR among patients who achieved complete response and those who discontinued treatment were analyzed. Results: Overall, 106 patients with ITP (33 men and 73 women) were included in the study. The median age of patients was 50 (18-89) years. There were 2, 10, and 94 cases of newly diagnosed, persistent, and chronic ITP, respectively. The complete response rate was 44.3% (47/106), the response rate was 34.0% (36/106), and the overall response rate was 78.3% (83/106). Meanwhile, 83 patients who responded to treatment discontinued eltrombopag; of these, 81 patients were evaluated. Additionally, 17 patients (21.0%) achieved TFR. The median follow-up duration of patients who achieved TFR was 126 (30-170) weeks. The recurrence rate was 17.6% (3/17), and the relapse-free survival rate was 76.5%. The results of univariate analysis revealed that non-recurrence after discontinuation of other treatments for ITP (P=0.001), and platelet count and eltrombopag dose of ≥100×10(9)/L (P=0.007) and ≤25 mg/d (P=0.031), respectively, upon discontinuation of eltrombopag were predictors of TFR; these effects were attributed to prolonged effective duration of eltrombopag. Multivariate analysis showed that there was a correlation between non-recurrence and prolonged effective duration after discontinuation of other treatments for ITP (P=0.002) . Conclusion: Eltrombopag is effective for patients with ITP as it can result in TFR. Predictors for TFR include non-recurrence after discontinuation of concomitant ITP treatment, and platelet count and eltrombopag dose of ≥100 × 10(9)/L and ≤25 mg/d upon discontinuation of treatment, respectively.

Treatment- Free Remission in Chronic Myeloid Leukemia -Experience of a Single Brazilian Private Institution Using Imatinib Copies

Introduction: In addition to the best possible overall survival, discontinuation of the tyrosine kinase -inhibitor (TKI) treatment [treatment free response (TFR)] without observing a recurrence of the disease has become a standard part of chronic myeloid leukemia (CML) care. Evidence of several studies suggest that patients who have achieved a sustained stable deep molecular response (DMR) as MR4 and MR4.5 can be safely discontinued with close monitoring without relapse, despite BCR/ABL1 DNA remaining detectable. In Brazil, CML patients have received almost exclusively Imatinib as first-line treatment and since 2013, only generics and copies of imatinib mesylate have been used in first-line throughout the whole Public Health System and in several institutions within the private system. However, in both scenarios there is a limit coverage of PCR exams/ year which allows for adequate monitoring but it is not sufficient for the implementation of TFR safely in eligible patients Aims: To report a Brazilian single institution Imatinib discontinuation trial and to evaluate factors impacting treatment -free response (TFR) and treatment free survival (TFS) Methods: From 2020 -2021 , 26 eligible patients were invited to participate in a single arm trial of Imatinib discontinuation (DIP). Inclusion criteria: age > 18 years, chronic phase, minimum of 04 years of Imatinib therapy, deep molecular response sustained > or = 02 years (confirmed by 04 tests in the last two years, defined MR4.0 or MR 4.5 and a confirmatory exam at the moment of the screening). Atypical transcripts were excluded. After discontinuation, patients were monitored by RT- PCR monthly in the first year, every two months in the second year and every three months since the third year. Criteria for Imatinib re-initiation: loss of MMR confirmed by two exams, loss of cytogenetic response, loss of hematologic response, disease progression. TFR was calculated from the date of discontinuation until first event: loss of MMR, Imatinib reintroduction, death any cause or last follow up. TFS was calculated from the date of imatinib discontinuation until reintroduction or last follow- up (censoring deaths not related to CML). The costs of exams were provided by own founds of our institution. Results: From 26 patients, 20 patients agreed to consent inform to discontinuation of imatinib. 06 patients declined despite information because their insecurity about TFR. Twelve patients (60%) presented MR4 . Median age was 52.3 years old and 13 (65%) were female. Median time diagnosis to discontinuation of imatinib 8.04(4.6-15.5) years. Twelve (60%) patients sustained TFR. Seven patients of twelve had presented MR 4 and five had MR 4.5 in the screening, respectively . (p=0,85) .It means 58,3% of the total of patients with MR 4 and 62,5% with MR 4.5 . In this interim analysis the median time of follow up was 14.5 (2.7-18.8) months. One patient died due to COVID19 with major molecular response (MMR). Eight (40%) lost MMR and imatinib was restarted. In this group the median time until MMR loss was 7.24 (2.1-13.8) months. At this moment, 07 patients (87,5 %) recovered MMR . In addition , in this group 06 patients (75%) achieved the same level of MR with reintroduction of imatinib with median 5.2 (3.7-6.3) months. Regarding adherence, 4 (20%) had some absences in monthly medical consultations and 1(5%) missed follow-up. Fifteen tests (6.14%) were performed to confirm MR loss, however only in 8 tests (53.3%) were confirmed. In fact, 04 patients (33,33%) still in TFR because of the double confirmatory test. There was no transformation to advanced phases. Gender, age at de diagnosis , age at discontinuation, Sokal , BCR-ABL trasncripts type , duration of Imatinib therapy , duration of MR 4.0 or MR4.5 did not affect TFR. Withdrawal syndrome occurred in 05 patients (25%) ; 04 patients with grade 1 and 01 patient with grade 2, had been used corticosteroid for few days. Conclusions: Despite the small number of patients included and short time of follow-up, the preliminary results of this trial demonstrated the feasibility and safety of Imatinib discontinuation , even using Brazilian copies, and the results were similar of that presented in another trials . The confirmatory exam to establish the loss of TFR was useful and safe. Adhesion of a discontinuation is one of the most important keys of the success of TFR.

Treatment-Free Response in Chronic Myeloid Leukemia Using Brazilian Imatinib Copies As First Line - Results from Two Prospective Clinical Trials

Introduction: Several trials have demonstrated the feasibility of tyrosine kinase inhibitors (TKI) treatment in chronic myeloid leukemia (CML) patients with a deep molecular response, but little data is available about the results using imatinib copies. Brazil has been using imatinib copies as a first-line treatment since 2013. Aim: To report the results of two Brazilian imatinib copies trials and to evaluate factors impacting treatment-free remission (TFR) and treatment-free survival (TFS) after imatinib discontinuation. Methods: From Dec-2016 until Oct-2018 (USP trial, NCT03239886) and from Oct-2020 until Apr-2021(Hemomed Trial- DIP), 51 eligible patients were included to participate in two trials of imatinib discontinuation. Inclusion criteria: age > 18 years, chronic phase, minimum of three years (USP trial) and four years (DIP) of imatinib copies therapy, a deep molecular response, defined as MR4.0 or MR4.5 sustained for more than 2 years, and a confirmatory test at the moment of the screening. Atypical transcripts were excluded. After discontinuation, patients on the USP trial were monitored by Q-PCR monthly for the first 6 months and bimonthly after 6 months for the first year and quarterly afterwards. Patients in DIP monitoring were monthly for the first year and every 2 months in the second year. Minimal criteria for IM re-initiation was loss of major molecular response (MMR) confirmed by two exams. Results: Median age was 53 years at the time of discontinuation. 58% male (USP) and 65% female (DIP). Imatinib´s therapy was 9.9 years (3-15.5 y). 52.9% had MR4.5 at the screening. TFS at 6 months was 78% (95 Cl 67-90), 12 months 66% (95 Cl 54-80) and at 24 months 54% (95 Cl 42-71). TFS by center at 12 months were 64.5 % (USP) and 67% (DIP). TFS according to previous molecular response after 24 months of follow-up (MR4 vs. MR4.5) (p =0,086). MMR recovery was present in 100% with a median time of 3.5 months. Four patients are still on TFR because the double testing of MMR loss was not confirmed. Conclusion: These two trials demonstrated the feasibility and safety of imatinib discontinuation, even using Brazilian copies, and the results were similar to that presented in another trial. The confirmatory exam to establish the loss of TFR was useful and safe. However, the results no suggest a benefit on monthly Q-PCR after six months of follow-up. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

TREATMENT- FREE REMISSION IN CHRONIC MYELOID LEUKEMIA -EXPERIENCE OF A SINGLE BRAZILIAN PRIVATE INSTITUTION USING IMATINIB COPIE

Evidence of several studies suggest that patients who have achieved a sustained stable deep molecular response (DMR) as MR4 and MR4.5 can be safely discontinued with close monitoring without relapse, despite BCR/ABL1 DNA remaining detectable. In Brazil, CML patients have received almost exclusively Imatinib as first-line treatment. However, in both scenarios there is a limit coverage of PCR exams/ year which allows for adequate monitoring but it is not sufficient for the implementation of TFR safely in eligible patients. To report a Brazilian single institution Imatinib discontinuation trial and to evaluate factors impacting treatment -free response (TFR) and treatment free survival (TFS) provided by own founds. From 2020 -2021, 26 eligible patients were invited to participate in a single arm trial of Imatinib discontinuation (DIP). Inclusion criteria: age > 18 years, chronic phase, minimum of 04 years of Imatinib therapy, deep molecular response sustained > or = 02 years (confirmed by 04 tests in the last two years, defined MR4.0 or MR 4.5 and a confirmatory exam at the moment of the screening). Atypical transcripts were excluded. After discontinuation, patients were monitored by RT- PCR monthly in the first year, every two months in the second year and every three months since the third year. Criteria for Imatinib re-initiation: loss of MMR confirmed by two exams, loss of cytogenetic response, loss of hematologic response, disease progression. TFR was calculated from the date of discontinuation until first event: loss of MMR, Imatinib reintroduction, death any cause or last follow up. TFS was calculated from the date of imatinib discontinuation until reintroduction or last follow- up (censoring deaths not related to CML). The costs of exams were provided by own founds of our institution. From 26 patients, 20 patients agreed to consent inform to discontinuation of imatinib. 06 patients declined despite information because their insecurity about TFR. Twelve patients (60%) presented MR4. Median age was 52.3 years old and 13 (65%) were female. Median time diagnosis to discontinuation of imatinib 8.04(4.6-15.5) years. Twelve (60%) patients sustained TFR. Seven patients of twelve had presented MR 4 and five had MR 4.5 in the screening, respectively. (p = 0,85). It means 58,3% of the total of patients with MR 4 and 62,5% with MR 4.5. In this interim analysis the median time of follow up was 14.5 (2.7-18.8) months. One patient died due to COVID19 with major molecular response (MMR). Eight (40%) lost MMR and imatinib was restarted. In this group the median time until MMR loss was 7.24 (2.1-13.8) months. At this moment, 07 patients (87,5 %) recovered MMR. In addition, in this group 06 patients (75%) achieved the same level of MR with reintroduction of imatinib with median 5.2 (3.7-6.3) months. Regarding adherence, 4 (20%) had some absences in monthly medical consultations and 1(5%) missed follow-up. Fifteen tests (6.14%) were performed to confirm MR loss, however only in 8 tests (53.3%) were confirmed. In fact, 04 patients (33,33%) still in TFR because of the double confirmatory test. There was no transformation to advanced phases. Gender, age at de diagnosis, age at discontinuation, Sokal, BCR-ABL trasncripts type, duration of Imatinib therapy, duration of MR 4.0 or MR4.5 did not affect TFR. Withdrawal syndrome occurred in 05 patients (25%); 04 patients with grade 1 and 01 patient with grade 2, had been used corticosteroid for few days. The preliminary results of this trial demonstrated the feasibility and safety of Imatinib discontinuation, even using Brazilian copies, and the results were similar of that presented in another trials.

Long Term Discontinuation of Eltrombopag after Remission in Primary Immune Thrombocytopenia: 8-Year Follow-up Data from 15 Spanish Centers

Background: Successful discontinuation of eltrombopag in certain immune thrombocytopenia (ITP) patients after complete response has already been demonstrated. However, the frequency of this phenomenon and type of candidate patients are still matter of discussion. Moreover, possibility of long term discontinuation responses is not clearly established. Methods: Here we retrospectively evaluated our whole cohort of 508 adult patients (aged 18 years or more) with primary ITP treated with eltrombopag included in the Spanish Eltrombopag Registry with a focus on the patients who achieved a durable (at least six months) platelet response after stopping eltrombopag. Successful discontinuation of eltrombopag (SDOE) was defined as those patients who reached remission and maintained platelet counts ≥ 50x109/l for at least 6 months in absence of eltrombopag or any rescue therapies administered. Long term discontinuation of eltrombopag (LTDOE) was defined as those patients who reached remission and maintained platelet counts ≥ 50x109/l for at least 36 months in the absence of eltrombopag or any rescue therapies administered. The study was approved by the Hospital Universitario de Burgos Ethics Committee and fulfilled Helsinki declaration standards. Results: While 37.4% of our patients relapsed of ITP with subsequent platelet count drop sometime during first six months of discontinuation of eltrombopag, a total of 74 patients (14.6%) were able to achieve SDOE. The median age of SDOE patients was 62 [range, 47-79] years. There were 47 women and 27 men. According to the standard definition, patients were allocated to newly diagnosed (n=17), persistent (n=15) and chronic (n=42) ITP groups. The median time from diagnosis to eltrombopag initiation was 31 [range, 4-104] months. The median number of previous therapies was 2 [range, 1-2], including splenectomy (14%), rituximab (18%) and romiplostim (12%). As expected, all patients but 1 achieved a complete response (platelet count ≥100 x 109/L) prior to eltrombopag discontinuation The median duration of eltrombopag treatment was 7 [range, 2-19] months. Reasons for eltrombopag discontinuation were: persistent response despite a reduction in dose over time (n=43), platelet count >400x109/L (n=16), aspartate aminotransferase elevation (n=5), diarrhea (n=4), thrombosis (n=3), patient's request (n=2) and other reasons (n=1). Analysis of these SDOE discontinued patients show that with a median follow-up of 55 [range, 29-79] months, 38 patients (51.3%) maintained treatment-free response 36 months after stopping eltrombopag with no need of additional ITP therapies (median time of eltrombopag discontinuation was 70 [range, 50-77] months).This condition is what we define now as LTDOE. Nevertheless, 36 patients relapsed beyond 6 months but before 36 months of eltrombopag discontinuation (median time of eltrombopag discontinuation was 10 [range,7 -22] months). Characteristics of LTDOE population were a median time since ITP diagnosis of 32 [range, 5-88] months with 15/38 patients having ITP <1 year. 9 patients (24%) were male and their median age was 50 [range, 37-64] years. They had received a median of only two previous treatment lines [range: 1-2 lines]. The median platelet count before starting eltrombopag was 19 x 109/L [range, 8-40]. Meanwhile, platelet count before eltrombopag stop was 218 x 109/L [range, 123-356]. The main characteristics (age, gender, duration of ITP, prior ITP lines, platelet count before starting eltrombopag, duration of eltrombopag treatment, and platelet count before eltrombopag withdrawal) of the 38 patients with LTDOE were compared with those of the SDOE cohort who did not achieve a LTDOE. Unfortunately, no predictive factors of LTDOE could be identified. Conclusion: Durable platelet response following eltrombopag cessation may be observed in only 15% of primary ITP patients treated with this drug. On the contrary, half of patients who achieve a sustained response after eltrombopag withdrawal will get a long term discontinuation. However, we are lacking predictor factors for successful and long-term discontinuation of eltrombopag in primary ITP. Disclosures Gonzalez-Lopez: Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Pascual Izquierdo:Novartis: Consultancy; Sanofi: Consultancy. Sánchez-González:Amgen: Consultancy, Speakers Bureau; Gilead: Speakers Bureau; Navartis: Consultancy, Speakers Bureau; Shire: Speakers Bureau; Takeda: Consultancy, Speakers Bureau. Jarque:Takeda: Consultancy, Speakers Bureau; Shire: Consultancy, Speakers Bureau; Shionogi: Consultancy, Speakers Bureau; Servier: Speakers Bureau; Roche: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Grifols: Consultancy; Gilead: Consultancy, Speakers Bureau; CellTrion: Consultancy; Celgene: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Abbie: Consultancy, Speakers Bureau; Alexion: Consultancy, Speakers Bureau.

Long-term treatment with romiplostim and treatment-free platelet responses in children with chronic immune thrombocytopenia.

Children with immune thrombocytopenia for ≥6 months completing a romiplostim study received weekly subcutaneous romiplostim (1-10 μg/kg targeting platelet counts of 50-200×109/L) in this extension to examine romiplostim’s long-term safety and efficacy. Sixty-five children received romiplostim for a median of 2.6 years (range: 0.1-7.0 years). Median baseline age was 11 years (range: 3-18 years) and platelet count was 28×109/L (range: 2-458×109/L). No patient discontinued treatment for an adverse event. Median average weekly dose was 4.8 mg/kg (range: 0.1-10 mg/kg); median platelet counts remained >50×109/L, starting at week 2. Nearly all patients (94%) had ≥1 platelet response (≥50×109/L, no rescue medication in the previous 4 weeks), 72% had responded at ≥75% of visits, and 58% had responded at ≥90% of visits. Treatment-free response (platelets ≥50×109/L ≥24 weeks without immune thrombocytopenia treatment) was seen in 15 of 65 patients while withholding romiplostim doses. At onset of treatment-free response, the nine girls and six boys had a median immune thrombocytopenia duration of four years (range: 1-12 years) and had received romiplostim for two years (range: 1-6 years). At last observation, treatment-free responses lasted for a median of one year (range: 0.4-2.1 years), with 14 of 15 patients still in treatment-free response. Younger age at first dose and platelet count >200×109/L in the first four weeks were associated with treatment-free responses. In this 7-year open-label extension, three-quarters of the patients responded ≥75% of the time, and romiplostim was well tolerated, with no substantial treatment-related adverse events. Importantly, 23% of children maintained treatment-free platelet responses while withholding romiplostim and all other immune thrombocytopenia medications for ≥6 months. (Registered at clinicaltrials.gov identifier: 01071954)

A 60-Year-Old Female With Metastatic Malignant Melanoma of the Scalp Responding to Ipilimumab

Melanoma is an aggressive disease that accounts for approximately 75% of skin cancer-related deaths. In the past, treatment options for patients with advanced stage melanoma have been limited with poor response rate and failure to improve overall survival (OS). Immunotherapy is a promising treatment that has been shown to improve OS and in cases produce durable remissions—a novel concept in the treatment of advanced melanoma. We report a case of advanced stage metastatic malignant melanoma of the scalp with a durable (31 months) response to ipilimumab immunotherapy. This is the first case study reporting long-term, progression-free response to ipilimumab in metastatic melanoma without side effects of therapy. This case adds to the evidence supporting early referral and initiation of ipilimumab in patients who can tolerate it, with the goal of producing a sustained treatment-free response and preserved quality of life.

Standard Dose Rituximab and 3 4-Day Cycles of Dexamethasone (R+3D) Appears Curative in Females with ITP < 12 Months Duration

▪Background: Therapies in ITP primarily increase the platelet count while treatment continues: IVIG, steroids, IV RhIg, romiplostim, eltrombopag and others. Curative effects of treatments other than splenectomy are uncertain; 2 recent studies with rituximab provided disappointing results. ITP in children often spontaneously improves but in children with chronic ITP and adults, this is much less common and management may be difficult. The aim of this study is to explore the efficacy and safety of R+3D.Methods: ITP patients were managed with R+3D if appropriate. Forty-nine adults and 33 children with ITP (newly diagnosed, persistent, and chronic) were treated at Weill Cornell Medical College with the previously described R+3D treatment plan: weekly rituximab infusion 375mg/m2 x 4 weeks + three 4-day cycles of 28mg/m2 (max. 40mg) dexamethasone at 2-week intervals. Patients who came to the platelet disorders center were included even if they received all or part of their treatment elsewhere. Counts were obtained weekly, monthly, and 2-3x monthly thereafter for responders. Response was either partial (PR, plt count > 50,000-100,000) or complete (CR > 100,000). Analysis was descriptive and by Kaplan-Meier. Children and adults are presented separately.Results: The overall estimated response (initial and long-term) in the 49 adults (22 men, 27 women) was associated with greater initial platelet response, female gender, and duration of ITP < 1 year. There was a significant difference in the projected 78% lasting response rate at 5 years in women with ITP of < 1 yr duration. All other groups (men < or > 1 yr duration of ITP and women > 1 yr duration of ITP) had highly inferior results (<25%).Ninety % of the 49 adults (44/49; 11 PRs and 33 CRs) initially responded to R+3Dex at 8 weeks. Children had lower initial responses at 45% (15/33; 2 PRs and 13 CRs). Four adults further improved from PR to CR and 2 children, 1 NR, 1 PR, to CR. Kaplan Meier projected long-term treatment-free response for all adults treated with R+3Dex is 33.5%. Only 1 PR but 22/37 (59.5%) of CRs continue to maintain adequate platelet counts. Parallel projection of long-term response for children is 23.9%. In children, 10/16 (62.5%) responders continue to maintain their response at last follow-up., Female patients maintained a 44% long-term response at 5 years whereas male patients projected a rate of only 19% (p value = 0.009). In children, girls projected a 37% long-term response and boys projected 11% at 5 years.Further divided by the duration of ITP, both adult and pediatric female patients with duration of ITP less than 12 months fared better than females with longer duration of disease (and males of any duration).Conclusions: ITP does not typically display a large gender disparity compared to other autoimmune diseases such as systemic lupus erythematosus), (1.5F:1Mcompared to 9F:1M ). No gender differences were found in responses to first- and second-line treatments in a previous report (Andres et al., 2012). However, gender bias in especially long term response is dramatic and is shown separately in both children and adults; when combined with earlier treatment initiation, the difference in projected long-term, treatment-free remission is remarkable (Table 1). Studies in lymphoma and 2 other indications have also suggested a gender effect in response to rituximab, but attributed it to Pk in elderly women. The influence of gender on autoimmune diseases, ITP in particular, is complicated and warrants further study as to the mechanism of effect. Table 1Adults (n=49) Female: n=27 // Male: n=22Children (n=33) Female: n=18 // Male: n=15Initial ResponseNR = 5 (10.2%)NR = 18 (54.5%)PR = 11 (22.4%)PR = 2 (6.1%)CR = 33 (67.4%)CR = 13 (39.4%)Female: 26/27 (96.3%) Male: 18/22 (81.8%)Female: 8/18 (44.4%) Male: 7/15 (46.7%)Best ResponseNR = 5 (10.2%)NR = 17 (51.5%)PR = 7 (14.3%)PR = 1 (3.0%)CR = 37 (75.5%)CR = 15 (45.5%)Female: 26/27 (96.3%) Male: 18/22 (81.8%)Female: 9/18 (50%) Male: 7/15 (46.7%)Relapsed21/44 (47.7%)6/16 (37.5%)Female: 10/26 (38.5%) Male: 10/18 (55.5%)Female: 2/9 (22.2%) Male: 4/7 (57.1%)Ongoing23/44 (52.3%)10/16 (62.5%)Female: 16/26 (61.5%) Male: 8/18 (44.4%)Female: 7/9 (77.7%) Male: 3/7 (42.9%) DisclosuresBussel:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; protalex: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; rigel: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

One-quarter of ITP patients achieve 5-year treatment-free response

One-quarter of ITP patients achieve 5-year treatment-free response

Outcomes 5 years after response to rituximab therapy in children and adults with immune thrombocytopenia

AbstractTreatments for immune thrombocytopenic purpura (ITP) providing durable platelet responses without continued dosing are limited. Whereas complete responses (CRs) to B-cell depletion in ITP usually last for 1 year in adults, partial responses (PRs) are less durable. Comparable data do not exist for children and 5-year outcomes are unavailable. Patients with ITP treated with rituximab who achieved CRs and PRs (platelets > 150 × 109/L or 50-150 × 109/L, respectively) were selected to be assessed for duration of their response; 72 adults whose response lasted at least 1 year and 66 children with response of any duration were included. Patients had baseline platelet counts < 30 × 109/L; 95% had ITP of > 6 months in duration. Adults and children each had initial overall response rates of 57% and similar 5-year estimates of persisting response (21% and 26%, respectively). Children did not relapse after 2 years from initial treatment whereas adults did. Initial CR and prolonged B-cell depletion predicted sustained responses whereas prior splenectomy, age, sex, and duration of ITP did not. No novel or substantial long-term clinical toxicity was observed. In summary, 21% to 26% of adults and children with chronic ITP treated with standard-dose rituximab maintained a treatment-free response for at least 5 years without major toxicity. These results can inform clinical decision-making.

Structural Mean Effects of Noncompliance

A randomized, placebo-controlled blood pressure (BP) reduction trial has recorded compliance measures by electronic monitoring. Causal questions regarding dose effects are of interest, but one often wants to avoid the assumption that compliance quantiles on both randomized arms are comparable. Structural mean models (SMMs) do avoid this assumption; however, they do not allow for interaction effects between variables observed on different randomized arms. Such an interaction between observed exposure on the treatment arm and latent treatmentfree response (i. e., placebo response) was suggested by the data. Building on structural models, we propose an approach that makes this possible. To allow for a structural interaction effect with potential placebo response, we invoke a compliance selection model. It turns out that SMMs imply identifiable selection models; hence the secondary model is testable. Next, to assess the amount of variation explained by the structural model, we identify separate variance components for different error types. This yields a measure of the variation in treatment effects over individuals. In addition, it allows us to compare the fit of different plausible structural models. On the BP data, we find a significant interaction effect: Higher exposure levels are estimated to have more effect in subgroups with poorer placebo response. Finite-sample properties of the proposed estimators are verified through simulation.