A Retrospective Chart Review of Treatment Patterns and Overall Survival among a Cohort of Patients with Relapsed/Refractory Mycosis Fungoides in France, Germany, Italy, Spain and the United Kingdom.

(1) Background: Most patients with mycosis fungoides (MF), a form of cutaneous T-cell lymphoma (CTCL), develop relapsed/refractory (R/R) disease following front-line systemic therapy. This report describes treatment patterns and outcomes from the subpopulation with R/R MF. (2) Methods: This observational, retrospective, cohort study analyzed patient records (1984-2016) from 27 clinical sites in Europe. Outcomes included treatments received, response to first-, second- and third-line treatment, overall survival (OS) and progression-free survival (PFS). (3) Results: Of 104 patients with MF, 100 received second-line and 61 received third-line therapy. The median (range) times from the start of first-line therapy to the first R/R MF and from the first to the second R/R MF were 11.2 (0.3-166.5) and 13.5 (0.0-174.6) months, respectively. Second-and third-line treatment options varied and comprised systemic therapies (85% and 79% of patients, respectively), radiotherapy (32% and 34%, respectively) and topical therapies (48% and 36%, respectively). The median (95% confidence interval [CI]) OS from the diagnosis of the first R/R MF was 11.5 (6.5-not reached [NR]) years and was higher with non-chemotherapy (NR) versus chemotherapy (6.5 years); the estimated median PFS (95% CI) from the time of the first R/R MF was 1.3 (1.0-2.1) years. (4) Conclusions: High rates of R/R disease were observed after second- and third-line treatments in this real-world cohort, with longer median OS in patients receiving non-chemotherapy treatment versus chemotherapy. Following the standard management of MF and using recently approved targeted therapies can help improve patient outcomes in advanced-stage MF.

First-line treatment of stage IIB to stage IV classical Hodgkin lymphoma in Italy, Israel, and Spain: Patient characteristics, treatment patterns, and clinical outcomes.

Classical Hodgkin lymphoma (cHL) is curable in 90% of cases, but advanced stage patients who do not respond well to first-line (1L) therapy have poorer outcomes. This retrospective study examines patient characteristics, treatment patterns, clinical outcomes, and safety management of 1L cHL therapies in common clinical practice in Italy (IT), Israel (IL), and Spain (SP). The overall sample (n = 256) included patients with stage IIb to IV cHL, of which 86.3% received ABVD as 1L therapy (n = 221). Clinical outcomes were similar for the overall population and ABVD subsample: complete response (CR) in 75% and 76.5%; 30-month (30-mo) survival (OS) of 92.5% and 93.6%; and 30-mo progression-free survival (PFS) of 70.7% and 72.6%. Thirty-month PFS was significantly lower for patients ≥ 60 years and/or with high (4-7) IPS. Treatment-induced pulmonary and cardiac toxicities, and febrile neutropenia occurred, respectively, in 10%, 2.3%, and 6.8% of ABVD-treated patients. Interim PET or PET-CT scans were performed after two cycles of 1L therapy (PET2) for 70.3% and 66.6% of the overall and ABVD cohorts, respectively. PET2 positive rates were nearly 30% (49/173), yet PET-adapted strategy of dose modification only occurred in a small fraction of patients.

Effectiveness of brentuximab vedotin monotherapy in relapsed or refractory Hodgkin lymphoma: a systematic review and meta-analysis.

This systematic review and meta-analysis aimed to determine the effectiveness of brentuximab vedotin (BV) in relapsed/refractory classical Hodgkin lymphoma (R/R cHL) in the clinical practice setting using most recent results. A total of 32 observational studies reporting on treatment patterns, overall response rate (ORR), complete response (CR) rate, progression-free survival (PFS), overall survival (OS), and adverse events were found. After four cycles, a random-effect model yielded pooled ORR and CR rates of 62.6% (95% confidence interval (CI): 56.0-68.9; I2 = 9.7%) and 32.9% (95% CI, 20.8-46.3, I2 = 64.8%), respectively. Regarding survival, 1-year, 2-year, and 5-year PFS ranged from 52.1% to 63.2%, 45.2% to 56.2%, and 31.9% to 33.0%, respectively. OS rates were 68.2-82.7%, 58.0-81.9%, and 58.0-62.0%, respectively. Most common adverse events were hematological toxicities (neutropenia: 13.3-23%, anemia: 8.8-39.0%, and thrombocytopenia: 4-4.6%), and grade ≥3 peripheral neuropathy (3.3-7.3%). This study supports the effectiveness and safety of BV in R/R cHL patients in the real-world setting.

Contemporary Treatment Patterns and Response in Relapsed/Refractory Cutaneous T-Cell Lymphoma (CTCL) across Five European Countries.

The treatment pattern of cutaneous T-cell lymphoma (CTCL) remains diverse and patient-tailored. The objective of this study was to describe the treatment patterns and outcomes in CTCL patients who were refractory or had relapsed (R/R) after a systemic therapy. A retrospective chart review study was conducted at 27 sites in France, Germany, Italy, Spain and the United Kingdom (UK) of patients who received a first course of systemic therapy and relapsed or were refractory. Data were collected longitudinally from diagnosis to first-, second- and third-line therapy. The study included 157 patients, with a median follow-up of 3.2 years. In total, 151 proceeded to second-line and 90 to third-line therapy. In the first line (n = 147), patients were treated with diverse therapies, including single- and multi-agent chemotherapy in 67 (46%), retinoids in 39 (27%), interferon in 31 (21%), ECP in 4 (3%), corticosteroids in 3 (2%) and new biological agents in 3 (2%). In the second line, the use of chemotherapy and retinoids remained similar to the first line, while the use of new biologics increased slightly. In sharp contrast to the first line, combination chemotherapy was extremely diverse. In the third line, the use of chemotherapy remained high and diverse as in the second line. From the time of first R/R, the median PFS was 1.2 years and the median OS was 11.5 years. The presented real-world data on the current treatments used in the management of R/R CTCL in Europe demonstrate the significant heterogeneity of systemic therapies and combination therapies, as expected from the European guidelines.

Efficacy and safety of front-line treatments for advanced Hodgkin lymphoma: a systematic literature review.

OBJECTIVE: To assess evidence on the safety and efficacy of ABVD (doxorubicin [Adriamycin®], bleomycin, vinblastine, and dacarbazine), BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone), and A+AVD (brentuximab vedotin, with doxorubicin, vinblastine, and dacarbazine) for advanced-stage Hodgkin lymphoma (HL). METHODS: A systematic literature review (SLR) was conducted on 29 July 2016 (updated 26 July 2018) to identify randomized controlled trials (RCTs) and non-RCTs assessing the treatment of newly-diagnosed advanced-stage HL with ABVD and BEACOPP (and their variants), and A+AVD. RESULTS: The SLR identified 62 RCTs and 42 non-RCTs. Five-year overall survival rates for ABVD and BEACOPP were 60-97% and 84-99%, and 5-year progression-free survival rates were 58-81% and 83-96%, respectively. Both regimens were associated with tolerability issues and side effects. Discontinuation or dose reduction of bleomycin resulted in fewer adverse events, without significantly affecting efficacy. A head-to-head trial demonstrated improved efficacy for A+AVD vs ABVD, with an acceptable tolerability profile. No data from head-to-head trials comparing A+AVD with BEACOPP were available, and an indirect treatment comparison was not feasible. CONCLUSION: New therapies, such as A+AVD, maintain the efficacy observed with current treatments, and may provide a more tolerable treatment option for patients with advanced-stage HL.

Real-world effectiveness and safety of ixazomib-lenalidomide-dexamethasone in relapsed/refractory multiple myeloma.

Real-world data on regimens for relapsed/refractory multiple myeloma (RRMM) represent an important component of therapeutic decision-making. This multi-centric, retrospective, observational study conducted by the treating physicians evaluated the effectiveness and safety of ixazomib-lenalidomide-dexamethasone (IRd) in 155 patients who received ixazomib via early access programs in Greece, the UK, and the Czech Republic. Median age was 68 years; 17% had an Eastern Cooperative Oncology Group performance status ≥ 2; median number of prior therapies was 1 (range 1-7); 91%, 47%, and 17% had received prior bortezomib, thalidomide, and lenalidomide, respectively. Median duration of exposure to ixazomib was 9.6 months. Overall response rate was 74%, including 35% very good partial response or better (16% complete response). Median progression-free survival (PFS) was 27.6 months (27.6 and 19.9 months in patients with 1 or > 1 prior lines, respectively). IRd treatment for ≥ 6 months was associated with longer PFS (hazard ratio 0.06). Fourteen patients (9%) discontinued IRd due to adverse events/toxicity in the absence of disease progression. Peripheral neuropathy was reported in 35% of patients (3% grades 3-4). These findings support the results of the phase III TOURMALINE-MM1 trial in a broader real-world RRMM population.

Brentuximab vedotin for the treatment of patients with relapsed or refractory Hodgkin lymphoma after autologous stem cell transplantation.

Brentuximab vedotin (BV) is the first approved novel agent for salvage treatment of relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL) after autologous stem cell transplantation (ASCT). In this study, a literature-based analysis was undertaken to assess, via an indirect treatment comparison, the comparative efficacy of BV to salvage chemotherapy as treatment for R/R cHL patients following ASCT. This comparative effectiveness research was undertaken to support a reimbursement submission for BV to the Australian Pharmaceutical Benefits Advisory Committee. Retrospective analysis of individual patient data from four data sources demonstrated that the use of BV as first salvage treatment in cHL patients relapsing or progressing post-ASCT achieved improvements in both clinical response and overall survival. More specifically, BV was associated with an incremental improvement of 22% in overall response rate compared to salvage chemotherapy. Five-year overall survival and progression-free survival rates were 92·2% [95% confidence interval (CI): 85·5-99·3%] and 32·2% (95% CI: 19·1-54·6%) respectively for BV, compared to 30·5% (95% CI: 22·2-42·0%) and 3·2% (95% CI: 1·1-8·9%) respectively for salvage chemotherapy. The encouraging results from this conservative analysis have the potential to support informed clinical management and funding decisions for the first salvage of cHL patients demonstrating recurrence after ASCT.

Hypercalcemia remains an adverse prognostic factor for newly diagnosed multiple myeloma patients in the era of novel antimyeloma therapies.

OBJECTIVES: To evaluate the prognostic impact of hypercalcemia in newly diagnosed patients with symptomatic multiple myeloma (MM), especially after the incorporation of new agents. METHODS: we analyzed the outcomes of newly diagnosed patients with symptomatic myeloma included in the database of the Greek Myeloma Study Group for the prognostic effect of the presence of hypercalcemia (defined as corrected serum calcium ≥11 mg/dL) at diagnosis. RESULTS: Among 2129 consecutive patients with symptomatic MM, 19.5% presented with hypercalcemia at the time of diagnosis. The presence of hypercalcemia was associated with anemia, thrombocytopenia, lower estimated glomerular filtration rate (eGFR), advanced ISS stage, and presence of lytic lesions. Hypercalcemia was more common in patients with high-risk cytogenetics and was associated with inferior survival across different time periods, age groups, and primary treatments. Hypercalcemia was also associated with a twofold increase in the risk of early death. In patients without available FISH, hypercalcemia could substitute for the presence of high-risk cytogenetics and identify patients with worse prognosis along with ISS stage and elevated serum LDH. CONCLUSION: Hypercalcemia remains a poor prognostic feature in the era of novel agents despite the improvement in the outcomes of patients who present with elevated calcium.

Evaluation of the Revised International Staging System in an independent cohort of unselected patients with multiple myeloma.

The Revised International Staging System (R-ISS) was recently introduced in order to improve risk stratification over that provided by the widely used standard International Staging System. In addition to the parameters of the standard system, the R-ISS incorporates the presence of chromosomal abnormalities detected by interphase fluorescence in situ hybridization [t(4;14), t(14;16) and del17p] and elevated serum lactate dehydrogenase. The R-ISS was formulated on the basis of a large dataset of selected patients who had participated in clinical trials and has not been validated in an independent cohort of unselected patients. Thus, we evaluated the R-ISS in 475 consecutive, unselected patients, treated in a single center. Our patients were older and more often had severe renal dysfunction than those in the original publication on the R-ISS. As regards distribution by group, 18% had R-ISS-1, 64.5% R-ISS-2 and 18% R-ISS-3. According to R-ISS group, the 5-year survival rate was 77%, 53% and 19% for R-ISS-1, -2 and -3, respectively (P<0.001). The R-ISS could identify three groups with distinct outcomes among patients treated with or without autologous stem cell transplantation, among those treated with either bortezomib-based or immunomodulatory drug-based primary therapy and in patients ≤65, 66-75 or >75 years. However, in patients with severe renal dysfunction the distinction between groups was less clear. In conclusion, our data in consecutive, unselected patients, with differences in the characteristics and treatment approaches compared to the original International Myeloma Working Group cohort, verified that R-ISS is a robust tool for risk stratification of newly diagnosed patients with symptomatic myeloma.

Direct evidence for normalization of platelet function resulting from platelet count reduction in essential thrombocythemia.

Essential thrombocythemia is characterized by persistent elevation and functional disturbances of platelets. Both the platelet function analyzer-100 (PFA-100) collagen-epinephrine (CEPI) cartridge and aggregometry with epinephrine are considered sensitive and valid methods in detecting abnormal platelet function in essential thrombocythemia. We attempted to confirm that restoration of abnormal platelet function results from platelet count reduction in essential thrombocythemia, by using these two methods. Thirty-nine essential thrombocythemia patients were divided into two groups on the basis of their platelet count. Group A participants (n = 20) exhibited platelet counts greater than 500 × 10/l, whereas group B participants (n = 19) had platelet counts below this limit. Hematological parameters, plasma von Willebrand factor (vWF) antigen and activity levels were assessed. Platelet function was analyzed by the PFA-100 and light transmission aggregometry with epinephrine, collagen, and ADP. The point mutation JAK2 V617F was identified and its effect on platelet function tests was also investigated. By using logistic regression analysis, white blood cell count, vWF activity level, and the measurements of aggregation in response to epinephrine were significantly different between the two groups. Epinephrine-induced aggregation retained the statistical significance in the multivariable procedure (P : 0.002). PFA-100 CEPI closure times were lower - but not statistically significant - in group B. Neither the JAK2 V617F positivity nor different cytoreductive treatments had any influence on ex-vivo platelet function tests. Our findings demonstrate normalization of platelet function resulting from platelet count reduction in essential thrombocythemia and reinforce the concept of lowering platelet counts in these patients.

Prognostication of the high-risk WM patient.

Waldenström's macroglobulinemia is characterized by a protracted course in most patients and the median survival may be long. However, a subset of patients may present with more aggressive disease that is associated with short survival. In order to better characterize these "poor-risk" patients, we identified patients who died within 2 years from the initiation of front-line treatment. These patients were older and had more often features of aggressive disease, such as elevated LDH and low serum albumin than the standard-risk population. Furthermore, only a minority of poor-risk patient had a response to initial therapy. However, conventional clinical factors or even the lack on response could not adequately identify poor-risk patients, indicating the need for novel molecular or other markers that would be able to effectively recognize patients at greatest need for aggressive therapies.

No significant improvement in the outcome of patients with Waldenström's macroglobulinemia treated over the last 25 years.

The treatment of Waldenström's macroglobulinemia (WM) has changed over the last decades, mainly because of the introduction of nucleoside analogues and of rituximab while novel agents such as bortezomib have been recently introduced. We performed an analysis to investigate whether the outcome of patients with WM has improved over the last years, compared to that of patients who started treatment before new drugs became widely available, especially as part of the frontline treatment. We analyzed 345 symptomatic patients with WM: 130 who initiated treatment before and 215 who started treatment after January 1, 2000. Patients who started treatment in the latter group were older and had more often elevated beta2-microglobulin but the other characteristics were similar between the two groups. Most patients who started treatment before January 1, 2000 were treated upfront with alkylating agent-based regimens and most patients who started treatment after January 1, 2000 received rituximab-based regimens as initial treatment. Objective response (63 and 59%, respectively) and median overall survival, OS, (106.5 months for Group A and is estimated at 94 months for Group B, P = 0.327) were similar. There was also no difference regarding OS or cause specific survival (CSS) in each risk group according to IPSSWM. Our observation may be explained by the indolent course of WM in several patients and by the lack of profound cytoreduction in patients with high-risk disease. Possible differences in the 15- or 20-year survival rate between the two groups may be detected with further follow-up of these patients.

High serum lactate dehydrogenase adds prognostic value to the international myeloma staging system even in the era of novel agents.

OBJECTIVES: High serum lactate dehydrogenase (LDH) is associated with features of advanced disease and inferior survival in multiple myeloma. It is however unclear whether LDH adds to the prognostic value of International Staging System (ISS) and whether it retains its prognostic significance in patients who are exposed to novel agent-based therapies. PATIENTS/METHODS: To address these issues we analyzed 996 consecutive symptomatic patients who were included in the database of the Greek Myeloma Study Group and received frontline treatment between January 1, 1995 and December 31, 2008. RESULTS: The median overall survival (OS) of all patients was 40 months with a clear improvement in those who started treatment after January 1, 2000 (49 vs. 31 months; P < 0.01). A multivariate model showed that LDH, ISS, performance status, age and platelet counts had an independent prognostic value for OS (P < 0.001 for all parameters). The median OS of patients with high (11% of patients) and normal LDH was 15 vs. 44 months (P < 0.001). High LDH was associated with inferior OS within all ISS groups: 22 vs. 76 months for high and normal LDH groups, respectively, in ISS-1 (P < 0.01); 11 vs. 40 months in ISS-2 (P < 0.001) and 17 vs. 27 months in ISS-3 (P < 0.01). The median OS of high and normal LDH groups among patients who received novel agents was 21 vs. 51 months, respectively (P < 0.001). CONCLUSIONS: Lactate dehydrogenase is a readily available and inexpensive variable, which has a major impact on the survival of myeloma patients even when they belong to a low or intermediate ISS subgroup and even when they receive novel agent-based therapies.

Validation of the International Prognostic Scoring System (IPSS) for Waldenstrom's macroglobulinemia (WM) and the importance of serum lactate dehydrogenase (LDH).

The recently proposed, ISSWM staging system for symptomatic patients with WM was based on patients treated with alkylating agents and nucleoside analogs and has not been externally validated nor has been validated for cause-specific survival (CSS). We independently validated ISSWM both for overall survival (OS) and for CSS and assessed whether addition of elevated serum LDH may add to the strength of ISSWM in 335 patients treated upfront mainly with alkylating agents (43%), and rituximab-based therapies (47%). ISSWM could discriminate three groups with significantly different OS and CSS (p<0.01 for both). High serum LDH was predictive of shorter OS and CSS (p<0.01). The combination of high risk according to ISSWM and elevated serum LDH identified a subset of patients for whom innovative treatment approaches are needed.

Prognostication in young and old patients with Waldenström's macroglobulinemia: importance of the International Prognostic Scoring System and of serum lactate dehydrogenase.

We analyzed 232 patients with previously untreated, symptomatic WM, of whom 10% were < or = 50 years of age and 21% were > 75 years of age. Disease features and response to treatment were similar among age groups. Patients > 75 years of age had significantly shorter survival (OS; 53 months vs. 113 months for those > 50-75 years vs. not reached for patients < or = 50 years of age; P < .001). Despite the fact that 33% of elderly patients died of causes unrelated to WM, disease-specific survival (DSS) was 72 months for patients > 75 years, 120 months for those > 50-75 years and not reached for patients < or = 50 years (P = .001). International Prognostic Scoring System for WM (IPSSWM) could discriminate 3 risk groups with significantly different OS or DSS. The addition of elevated serum lactate dehydrogenase in the IPSS improved the ability of IPSS to identify a group of patients with a significantly worse outcome (median survival, 55 months).

Scintigraphy with technetium-99m methoxyisobutylisonitrile in multiple myeloma patients: correlation with the International Staging System.

(99m)Tc-2-methoxyisobutylisonitrile ((99m)Tc-MIBI) scintigraphy has been suggested in multiple myeloma (MM) patients. According to the International Staging System (ISS), serum b2-microglobulin (Sbeta(2)M) and serum albumin (SA) are dominant predictive factors and different cut-off values of these factors can separate patients into various stages of the disease. The purpose of this study was to assess the relationship between ISS staging, by Sbeta(2)M and SA, and the (99m)Tc-MIBI scan findings. Twenty-five MM patients have been studied. Eighteen patients were at stage I, three at stage II and four at stage III of MM. (99m)Tc-MIBI scans were obtained and scored according to intensity (I) and extent (E) of the radiotracer uptake. A summed score (S) for the (99m)Tc-MIBI scan was calculated for each patient. A statistically significant negative correlation between E, I and S uptake scores versus the SA levels (P=0.004, 0.049 and 0.018 respectively), as well as a statistically significant positive correlation between E and S scores and the Sbeta(2)M levels (P=0.012 and 0.032) were detected. A statistically significant difference between the E and S uptake scores among the MM patients examined for every stage separately was also found (P=0.007 and 0.024 respectively). The gradual increase of the E and S scores across the three stages of MM was also significant (P=0.003 and 0.021 respectively), despite the relatively small number of patients in stages II and III. In seven patients who died at the end of the follow-up period all three scores were significantly increased as compared to the scores of the patients who remained alive at that time. In conclusion, this study provides additional evidence that (99m)Tc-MIBI scan not only reflects myeloma disease activity in bone marrow but it is also well correlated with the Sbeta(2)M and SA levels according to ISS.

Primary treatment with pulsed melphalan, dexamethasone and thalidomide for elderly symptomatic patients with multiple myeloma.

Fifty patients with multiple myeloma >or=75 years of age received primary treatment with melphalan (M) 8 mg/m(2) on days 1-4, dexamethasone (D) 12 mg/m2 on days 1-4 and 17-20 and thalidomide (T) 300 mg at bedtime on days 1-4 and 17-20. This regimen was repeated every 5 weeks for three courses. Patients without evidence of disease progression received nine additional courses of MDT, but without DT on days 17-20, every 5 weeks. Sixty-two percent of patients achieved a partial response and 10% a complete response. The median time to response was 2 months. The median time to progression for all patients was 21.2 months. Deep venous thrombosis and peripheral neuropathy each occurred in 9% of patients.

Prognostic value of serum beta2-microglobulin in patients with Waldenstrom's macroglobulinemia requiring treatment.

PURPOSE: Waldenstrom's macroglobulinemia (WM) is a lymphoplasmacytoid lymphoma characterized by a relatively indolent course with median survival ranging from 5 years to 10 years in different series. Several clinical and laboratory variables have been associated with inferior survival, such as advanced age, hyperviscosity, presence of cytopenia, and hypoalbuminemia. Recent data indicate that serum 2-microglobulin (2M) might also be significant. The purpose of our study was to assess possible correlations of 2M with clinical and laboratory variables and to further evaluate its association with cause-specific and overall survival (OS) of patients with WM requiring treatment. PATIENTS AND METHODS: We analyzed 124 patients with WM with an available pretreatment value of 2M. Median age was 70 years (range, 28-89 years), and median survival was 105 months. Multiple clinical and laboratory parameters were evaluated for their possible correlation with OS. RESULTS: Patients with older age, anemia, thrombocytopenia, hypoalbuminemia, and higher creatinine levels had significantly greater serum 2M levels. This variable was associated with impaired cause-specific survival and OS in the whole group of patients and in patients aged 4 mg/dL versus