Bendamustine-Based Regimens as Salvage Therapy in Refractory/Relapsed Multiple Myeloma Patients: A Retrospective Real-Life Analysis by the Polish Myeloma Group.

Multiple myeloma (MM) is an incurable disease and patients become refractory to the treatment in the course of the disease. Bendamustine-based regimens containing steroids and other agents are among the therapeutic options offered to MM patients. Here, we investigated the safety and the efficacy of bendamustine used in patients with refractory/relapsed MM (RRMM). The patients were treated with bendamustine and steroids (n = 52) or bendamustine, steroids and immunomodulatory agents or proteasome inhibitors (n = 53). Response rates, progression-free survival (PFS), overall survival (OS) and frequency of adverse events were compared between both study groups. Most efficacy measurements were better in patients treated with three-drug regimens: overall response rate (55% versus 37%, p = 0.062), median PFS (9 months versus 4 months, p < 0.001), median OS survival (18 months versus 12 months, p = 0.679). The benefit from combining bendamustine and steroids with an additional agent was found in subgroups previously treated with both lenalidmide and bortezomib, with stem cell transplant and with more than two previous therapy lines. Toxicity was similar in both study groups and bendamustine-based therapies were generally well-tolerated. Our study suggests that bendamustine may be an effective treatment for patients with RRMM. Three-drug regimens containing bendamustine, steroids and novel agents produced better outcomes and had acceptable toxicity. The efficacy of bendamustine combined with steroids was limited.

Low serum albumin level deteriorates prognosis in azacitidine-treated myelodysplastic syndromes patients - results of the PALG study 'PolAZA'.

BACKGROUND: Azacitidine (AZA) is the standard of care for higher-risk myelodysplastic syndrome (HR-MDS) patients ineligible for intensive therapy. Clinical outcome discrepancies reported in clinical trials and real-life settings stimulate the search for new prognostic factors. METHODS: We retrospectively evaluated 315 MDS, 20-30% blast acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML) patients treated with azacitidine in 12 centers cooperating within the Polish Adult Leukemia Group (PALG). RESULTS: The median number of AZA cycles was 7 (1-69) and 24% patients received fewer than 4 cycles (early failure, EF). Serum albumin level was an independent predictor of EF occurrence. Complete remission (CR) was obtained in 20% and partial remission (PR) in 12% of patients. Hematologic improvement - erythroid (HI-E), neutrophil (HI-N), or platelet (HI-P) was achieved in 51%, 36%, and 48% of patients, respectively. No factors significantly predicted CR or PR in the multivariate analysis. For HI-E and HI-P, lower LDH level predicted response. Median survival was 15 (13-19) months. Lower serum albumin level, serious infection and receiving <4 AZA cycles independently predicted a worse overall survival (OS) (p < 0.05). CONCLUSION: Serum albumin assessment before azacitidine treatment can help to identify patients with higher risk of early failure and worse clinical outcome.

Long-term Efficacy of Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia: Results of the Polish Adult Leukemia Study Group Observational Study.

BACKGROUND/AIM: To study the long-term clinical efficacy and tolerability of ibrutinib monotherapy in real-world relapsed and refractory chronic lymphocytic leukemia (RR-CLL) patients outside clinical trials. PATIENTS AND METHODS: Clinical data of 171 RR-CLL patients treated with ibrutinib were collected within the observational study of the Polish Adult Leukemia Study Group. RESULTS: Median patient age was 64 years. Patients were pretreated with 3 (1-10) median lines of therapy, while 42 (24.6%) had 17p deletion. The median observation time was 40 months (range=1-59 months), while median ibrutinib monotherapy reached 37.5 months (range=0.4-59.2 months). Response was noted in 132 (77.2%) patients. The estimated 5-year progression-free survival (PFS) and overall survival (OS) rates were 61.1% (95%CI=49.3-70.9%) and 56.8% (95%CI=45.6-66.6%), respectively. At the time of analysis 97 (56.7%) remained under ibrutinib monotherapy. CONCLUSION: Ibrutinib is clinically effective and tolerable as a monotherapy in real-world RR-CLL patients.

Outcome of a Real-Life Population of Patients With Acute Promyelocytic Leukemia Treated According to the PETHEMA Guidelines: The Polish Adult Leukemia Group (PALG) Experience.

BACKGROUND: Acute promyelocytic leukemia (APL) has a favorable prognosis. However, results of randomized studies do not necessarily reflect the outcomes of a real-life population. PATIENTS AND METHODS: We analyzed 283 unselected APL patients treated in 20 Polish hospitals between 2005 and 2017. All patients were intended to be treated with PETHEMA (Programa Español para el Tratamiento de las Hemopatías Malignas) protocols based on all-trans retinoic acid plus chemotherapy. RESULTS: The probability of overall survival at 4 years was 67%, while event-free survival was 64%. The early death (ED) rate was 20.1% (n = 57), while 3.5% (n = 10) patients died before induction therapy was started. The main causes of ED included hemorrhage (45.6%), infections (17.5%), and differentiation syndrome (14.5%). Of 273 treated patients, 214 (78.4%) experienced hematologic morphologic remission, 2 (0.7%) were found to have resistant disease, 47 (17.2%) could not be evaluated for response because of ED, and in 6 (3.7%) no data concerning the response were available. Multivariate analyses showed that predictors of ED and overall survival were Eastern Cooperative Oncology Group performance status > 2, age > 60 years, and all types of bleeding episodes that occurred before starting therapy, while an additional predictor of event-free survival was high white blood cell count (> 10 109/L). CONCLUSION: ED remains a major problem in APL patients, especially in a real-life population. Shortening of the time between the initial contact with a health care professional, and all-trans retinoic acid administration and the use of appropriate supportive care could improve the outcome of unselected APL population, mainly by reducing the ED rate.

Ibrutinib discontinuation in patients with relapsed or refractory chronic lymphocytic leukemia treated in a compassionate use program: A report from the Polish Adult Leukemia Study Group (PALG).

BACKGROUND: Development of a novel class of drugs, the B-cell receptor-signaling inhibitors, including ibrutinib, has been a major achievement in the therapy of refractory or relapsed chronic lymphocytic leukemia (CLL). However, the CLL patients who have discontinued the ibrutinib treatment in clinical trials have been reported to have poor prognosis. OBJECTIVES: In this retrospective study by the Polish Adult Leukemia Group (PALG), we analyzed the reasons for ibrutinib cessation and outcomes after discontinuing ibrutinib in refractory or relapsed CLL patients treated in a compassionate use program in Poland. MATERIAL AND METHODS: Polish CLL patients were included if they discontinued ibrutinib for any reason. The clinical data on the course of ibrutinib treatment was collected anonymously using electronic Case Report Forms (CRFs). The causes of discontinuation of ibrutinib as reported by the treating physicians were analyzed. RESULTS: Thirty-seven patients who discontinued ibrutinib were identified. The median duration of ibrutinib treatment in this group was 4.4 months (range: 0.2-25.2). The main reason for discontinuing ibrutinib was adverse events (n = 20, 54%), while 14 (38%) patients discontinued therapy due to disease progression and 3 (8%) due to other causes. The most common treatment complications that led to ibrutinib cessation were severe respiratory tract infections (9 patients, 24%). In the group discontinuing ibrutinib for progressive disease, 11 patients progressed with untransformed CLL, while in 3 patients, a rare type of Richter transformation to Hodgkin's lymphoma was diagnosed. Twenty-nine patients (78%) died during the follow-up period, and median overall survival (OS) reached 2.0 months (95% CI = 0.8-5.5 months). Importantly, no significant survival difference was detected between patients who discontinued ibrutinib due to disease progression and due to adverse events. CONCLUSIONS: The results of this analysis indicate that ibrutinib discontinuation in relapsed or refractory CLL is associated with poor prognosis regardless of the reason for ibrutinib cessation.

Efficacy of daratumumab monotherapy in real-world heavily pretreated patients with relapsed or refractory multiple myeloma.

PURPOSE: Daratumumab is a promising new agent for relapsed/refractory multiple myeloma (RRMM). However, there are limited data on its clinical activity and tolerability in the real-world patients. The purpose of this study is to determine the efficacy and toxicity profile of daratumumab monotherapy in the real-life setting. PATIENTS AND METHODS: Thirty RRMM patients treated with daratumumab who had previously received at least three treatment lines including a proteasome inhibitor and an immunomodulatory drug or had been double refractory (DRMM) were included to the Polish Myeloma Group observational study. RESULTS: The objective response rate to daratumumab was 42.8%. Median progression-free survival (PFS) and overall survival reached 9.5 and 13.8 months, respectively. Importantly, patients with DR-MM had a significantly shorter PFS than other patients (median PFS of 4.1 vs. 12.1 months). Daratumumab was generally well tolerated, however two patients had their therapy interrupted due to adverse events. CONCLUSION: Daratumumab monotherapy has significant activity and good tolerance in heavily pretreated RRMM patients.

Hodgkin lymphoma transformation of chronic lymphocytic leukemia-A real life data from the Polish Lymphoma Research Group.

Richter transformation (RT) of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) to Hodgkin lymphoma (HL) is a rare and unexpected event in the course of the disease and data on this phenomenon is still limited. To better understand the clinical and histological characteristics and the outcomes of HL variant of RT (HvRS) the Polish Lymphoma Research Group performed a nationwide survey which identified 22 patients with histologically proven HvRS diagnosed between 2002 and 2016. There were 16 (73%) males. The median age at CLL/SLL and HvRS diagnosis was 59 (39-77) and 64 (40-77) years, respectively. The median interval between CLL/SLL and HvRS diagnosis was 38 months (range: 0-187). All patients had an advanced stage HL, and majority, 17 (77%), presented with B symptoms. The predominant subtypes of HL were nodular sclerosis (12; 55%) and mixed cellularity (9; 41%). Eighteen patients received non-palliative treatment, including 13 who received driamycin, bleomycin, vinblastine, and dacarbazine (ABVD) regimen first line. Objective response was: 50%, with 33% complete remissions (61% and 46% for ABVD, respectively). Median overall survival reached 13.3 months (95% CI, 3.7-NA). The only adverse prognostic factor for survival was a higher number (≤1 versus ≥2) of prior lines of treatment given for CLL/SLL with HR 3.57 (95% CI, 1.16-10.92). We conclude, HvRS harbors a poor prognosis, especially in patients heavily pretreated for CLL/SLL. Response to standard first-line anti-HL chemotherapy is unsatisfactory, and new agents should be tested to improve the outcome.

Hodgkin lymphoma of the elderly patients: a retrospective multicenter analysis from the Polish Lymphoma Research Group.

We retrospectively analyzed long-term disease outcome of 350 elderly Hodgkin Lymphoma (eHL) patients treated with ABVD/ABVD-like regimen enrolled in the PLRG-R9 study between 2001 and 2013 in Poland. Complete remission was reported for 73% of early (ES) and 61% advanced stage (AS) patients. Nine (10%) ES and 56 (20%) AS patients have died. With the median follow-up of 36 (1-190) months, 3-year EFS and OS was 0.74 (95%CI: 0.63-0.85) and 0.90 (95%CI: 0.82-0.98) for ES; 0.51 (95%CI: 0.44-0.57), and 0.81 (95%CI: 0.75-0.86) for AS patients, respectively. For ES patients, Cox regression revealed ECOG <2 and age >70 as predictive for inferior OS and EFS. For AS patients, the most predictive for OS was the presence of cardiovascular disorders (CVD) (p = .00044), while for EFS four factors were significantly associated with a poor outcome: ECOG< 2, age >70 years, CVD and extranodal disease. In conclusion, CVD significantly impacts outcomes of ABVD-treated advanced eHL patients.

Concomitance of monosomal karyotype with at least 5 chromosomal abnormalities is associated with dismal treatment outcome of AML patients with complex karyotype - retrospective analysis of Polish Adult Leukemia Group (PALG).

Monosomal karyotype (MK) and complex karyotype (CK) are poor prognostic factors in acute myeloid leukemia (AML). A comprehensive analysis of cytogenetic and clinical factors influencing an outcome of AML-CK+ was performed. The impact of cladribine containing induction on treatment results was also evaluated. We analyzed 125 patients with AML-CK+ treated within PALG protocols. MK was found in 75 (60%) individuals. The overall complete remission (CR) rate of 66 intensively treated patients was 62% vs. 28% in CK+ MK- and CK+ MK+ group (p = .01). No difference in CR rate was observed between DA and DAC arms. The overall survival (OS) in intensively treated patients was negatively influenced by MK, karyotype complexity (≥5 abnormalities), and WBC >20 G/L in multivariate analysis. The addition of cladribine to DA regimen improved OS only in MK- but not in MK+ group. In conclusion, concomitance of MK with ≥5 chromosomal abnormalities is associated with dismal treatment outcome in AMK-CK+.

Are myelodysplastic syndromes underdiagnosed in Poland? A report by the Polish Adult Leukaemia Group.

OBJECTIVES: The epidemiology of myelodysplastic syndromes (MDS) differs among countries. Here, we present the first epidemiological indices determined for Poland. METHODS: Twenty-one haematological centres participated in the study. Patients diagnosed with MDS and acute myeloid leukaemia (AML) with 20-29% blasts were enrolled. Data collection was conducted for strictly predefined period. RESULTS: The overall crude incidence rate for all MDS subtypes was 1.95 (95% CI, 1.81-2.09) per 100 000 person-years: 2.46 (95% CI, 2.24-2.69) for males and 1.47 (95% CI, 1.31-1.65) for females; after excluding AML cases, the indices were as follows: 2.35 (95% CI, 2.08-2.66) for males and 1.27 (95% CI, 1.08-1.5) for females. Prevalence rate was 6.2 per 100 000 persons (95% CI, 5.96-6.45), that is 6.86 (95% CI, 6.49-7.24) for males and 5.58 (95% CI, 5.26-5.92) for females. Both incidence and prevalence increased with increasing age. The most frequently diagnosed MDS subtype was refractory cytopenia with multilineage dysplasia (RCMD), responsible for 30.3% of all newly diagnosed MDSs. CONCLUSIONS: RCMD is the most frequent MDS subtype in Poland. Incidence and prevalence indices are lower than those reported for other populations, which probably results from inadequate diagnosis of potential cases of this disease.

Analysis of free serum light chains in patients suffering from multiple myeloma complicated by light-chain amyloidosis.

BACKGROUND: AL amyloidosis is an acquired systemic disease in which a pathologic amorphous substance produced as a result of abnormal protein metabolism is deposited in the extracellular space of various tissues. OBJECTIVES: The aim of the study was to investigate the relationship between the kappa and lambda serum free light chains (sFLCs) and the development of AL amyloidosis in patients suffering from multiple myeloma (MM). MATERIAL AND METHODS: The investigations included 70 MM patients, 40 females and 30 males, aged 28-83 years. In 37 persons, MM was had been diagnosed recently; 33 patients had been undergoing treatment. Amyloidosis was diagnosed in 18 patients (25.7%), including nine females, nine males; six had newly diagnosed disease. Fifteen patients developed kidney failure. The control group consisted of 10 healthy donors. The concentration of sFLC ls were determined using the immunonephelometric method and expressed in mg/L. RESULTS: In 18 MM patients with amyloidosis the concentration of κ sFLCs ranged from 0.3 to 4780 (x = 854.5, SD = 1289), and was significantly higher (p = 0.039) than in the group without amyloidosis, where the range was from 0.3 to 426.0 (x = 68.9, SD = 98.1). The highest concentration of κ sFLCs was observed in the group of five patients with amyloidosis and renal failure. The concentration of λ sFLCs in patients with amyloidosis ranged from 0.5 to 41600 (x = 3035.7, SD = 9735) and was higher than in MM patients without amyloidosis, where it ranged from 0.5 to 834.0 (x = 79.3, SD = 193). In amyloidosis patients, the concentration of λ sFLCs was significantly higher (p = 0.05) in cases of renal failure as compared with the patients with normal renal function. CONCLUSIONS: The concentration of sFLCs is a strong indicator of amyloidosis development in MM patients.

The occurrence of Al amyloidosis (light-chain amyloidosis) in patients with multiple myeloma in Lower Silesia Region, Poland.

BACKGROUND: The incidence of amyloidosis is difficult to determine because the disease is often undiagnosed or diagnosed incorrectly. In Polish studies, there are no statistics and analyses of the factors that may influence the development of amyloidosis in patients with multiple myeloma. OBJECTIVES: The goal of this study was to estimate the incidence of AL amyloidosis in MM patients in Lower Silesia region. MATERIAL AND METHODS: 70 patients treated at the Department of Hematology, Provincial Hospital in Legnica and the Department of Hematology, Blood Neoplasm and Bone Marrow Transplantation, Medical University in Wroclaw were enrolled in the survey. 37 patients were newly diagnosed, 33 had been treated for 2-34 months. The basis for the diagnosis of amyloidosis was the presence of green colored amyloid deposits in the polarized light microscope in the adipose tissue (received from abdominal fold and stained with Congo red). RESULTS: Amyloidosis was diagnosed in 18 (25.7%) patients with MM, 9/9 F /M, aged 47-83 years. 6 (33%) pts with amyloidosis had newly diagnosed MM, in 12 (67%) progression of the disease was diagnosed. Amyloidosis occurred significantly more often (p = 0.048) in already treated patients. The odds ratio (OR) was 2.95. Amyloidosis occurred most frequently in patients with IgG myeloma (67%), (OR = 1.98), was more often found in patients with kappa light chain versus lambda, respectively 67% and 33%. The probability of amyloidosis in patients with clinical stage III was 1.5 times higher (p = 0.05) than in other stages (OR = 1.5), in persons with renal dysfunction was twice as high (OR = 2.4) compared to the renal competence group (p = 0.05). CONCLUSIONS: AL amyloidosis in the course of MM occurs in Lower Silesia region with a comparable rate to other regions of the world. It is significantly more often diagnosed in patients with relapsed or refractory disease, in persons with clinical stage III and with renal failure.

Case-adjusted bortezomib-based strategy in routine therapy of relapsed/refractory multiple myeloma shown to be highly effective--a report by Polish Myeloma Study Group.

The observational study was aimed at evaluating response, survival and toxicity of bortezomib-based, case-adjusted regimens in real-life therapy of 708 relapsed/refractory MM patients. Bortezomib was combined with anthracyclines, steroids, thalidomide, alkylators or given in monotherapy. The ORR was 67.9% for refractory and 69.9% for relapsed MM. The median PFS was 14 months and OS 57 months. Patients responding to the therapy had the probability of a 4-year OS at 67.0%. No toxicity was noted in 33.1% of patients. Severe events (grade 3/4) were reported in 35.9% of patients: neurotoxicity (16.7%), neutropenia (9.2%), thrombocytopenia (8.5%), and infections (6.5%). Bortezomib-based, case-adjusted regimens are in real-life practice effective in salvage therapy offering reliable survival with acceptable toxicity for relapsed/refractory MM patients.