Safety of AFM11 in the treatment of patients with B-cell malignancies: findings from two phase 1 studies.

BACKGROUND: The prognosis for patients with relapsed and/or refractory (R/R) non-Hodgkin's lymphoma (NHL) or acute lymphoblastic leukaemia (ALL) remains poor, with existing treatments having significant side effects. Developed for the treatment of these cancers, AFM11 is a tetravalent, bispecific humanised recombinant antibody construct (TandAb®) designed to bind to human CD19 and CD3 and lead to the activation of T cells inducing apoptosis and killing of malignant B cells. METHODS: Two open-label, multicentre, dose-escalation phase 1 studies evaluated the safety, pharmacokinetics and activity of AFM11 in patients with R/R CD19-positive B cell NHL (AFM11-101) and in patients with CD19 + B-precursor Philadelphia-chromosome negative ALL (AFM11-102). Adverse events (AEs) were assessed and recorded; imaging (NHL) or bone marrow assessment (ALL) were used to evaluate response. Additional pharmacodynamic assays undertaken included cytokine release analysis and B-cell and T-cell depletion. RESULTS: In AFM11-101, 16 patients with R/R NHL received AFM11 in five different dose cohorts. Of which, 14 experienced drug-related treatment-emergent AEs (TEAEs) [including five serious AEs (SAEs)], five patients experienced dose-limiting toxicity (DLT) and ten patients discontinued the study. The high number of neurological events led to a decrease in infusion frequency during the study. No objective response to treatment was observed. In AFM11-102, 17 patients with R/R ALL received AFM11 in six different dose cohorts. Thirteen patients experienced drug-related TEAEs (including four SAEs), DLTs occurred in two patients and five patients discontinued the study. An objective response was recorded in three patients. The maximum tolerated dose could not be determined in either study due to early termination. CONCLUSIONS: AFM11 treatment was associated with frequent neurological adverse reactions that were severe in some patients. In ALL, some signs of activity, albeit short-lived, were observed whereas no activity was observed in patients with NHL; therefore, further clinical development was terminated. TRIAL REGISTRATION: NCT02106091 . Safety Study to Assess AFM11 in Patients With Relapsed and/or Refractory CD19 Positive B-cell NHL. Registered April 2014. NCT02848911 . Safety Study to Assess AFM11 in Patients With Relapsed or Refractory Adult B-precursor ALL. Registered July 2016.

The average relative dose intensity of R-CHOP is an independent factor determining favorable overall survival in diffuse large B-cell lymphoma patients.

The prognosis of diffuse large B-cell lymphoma (DLBCL) patients depends on lymphoma- and patient-related risk factors and is best estimated by the international prognostic index (IPI). The aim of the study was to determine whether the average relative dose intensity (ARDI) of an anthracycline-containing regimen could predict DLBCL outcome independently from the IPI. We analyzed 223 white Caucasian DLBCL patients who completed at least four cycles of first-line immunochemotherapy with rituximab, doxorubicin, cyclophosphamide, vincristine, and prednisone (R-CHOP). The ARDI was calculated by specially developed software in each individual patient, simultaneously with the chemotherapy prescription, which instantly revealed all causes of its decrease. The relevance of the ARDI for progression-free/overall survival (PFS/OS) was evaluated. Prolonged intervals between cycles of immunochemotherapy-the most common cause of decreased ARDI (49.3%, 110/223)-were due to neutropenia (absolute neutrophil count <1.0 × 109 /L) and infections. Reductions in cytostatic doses were observed in 19.7% (44/223) of patients, mainly as the consequence of cardiotoxicity (23/223, 10.3%). The OS varied significantly when the ARDI was >90% (P < 0.00001). Multivariate analysis confirmed that an ARDI>90% was an IPI-independent predictor of prolonged PFS (HR = 0.31; 95%CI: 0.20-0.47; P < 0.00001) and OS (HR = 0.32; 95%CI: 0.21-0.48; P < 0.00001). With an analytic tool allowing real-time ARDI assessment, it was possible to maintain an ARDI above 90% in 161 of 223 patients (72%). DLBCL patients with an ARDI >90% have significantly better outcome regardless of the IPI; therefore, our official recommendation is an adequate dose density through efficient neutropenia prophylaxis and cardiac protection.

Primary Cardioprotection Reduces Mortality in Lymphoma Patients with Increased Risk of Anthracycline Cardiotoxicity, Treated by R-CHOP Regimen.

BACKGROUND: Advances in anti-lymphoma therapy prolong overall survival, making late adverse effects, like doxorubicin-related cardiotoxicity, an even more important clinical issue. The effectiveness of cardioprotective strategies with close monitoring, angiotensin-converting enzyme inhibitors and/or ß-blockers as well as liposomal doxorubicin are still unconfirmed in clinical practice. METHODS: This study evaluated the role of a primary cardioprotection strategy in preventing cardiovascular mortality and heart failure occurrence in non-Hodgkin lymphoma (NHL) patients with a high risk of anthracycline cardiotoxicity. Thirty-five NHL patients were subjected prospectively to ramipril and/or bisoprolol at NHL diagnosis, before implementing doxorubicin-containing regimens. Additionally, patients with a diagnosis of asymptomatic/mild heart failure received the liposomal form of doxorubicin. The clinical outcome and frequency of all serious cardiac events were compared with the results in a historical cohort of 62 high-risk cases treated without primary cardioprotection. RESULTS: NHL patients with a primary cardioprotection strategy did not experience cardiovascular deaths in contrast to the retrospective control group where cardiovascular mortality was 14.5% at 3 years (p < 0.05). Primary cardioprotection also decreased the frequency of new cardiotoxicity-related clinical symptoms (2.8 vs. 24.1%; p < 0.05) and prevented the occurrence of cardiac systolic dysfunction (0 vs. 8.5%, respectively; p < 0.05). Although the study was not planned to detect any survival benefit, it demonstrated a trend towards increased response rates (complete response 82 vs. 67%; p not significant) and prolonged survival (projected 5-year overall survival 74 vs. 60%; p < 0.05) for patients treated with primary cardioprotection. CONCLUSIONS: A primary personalized cardioprotection strategy decreases the number of cardiac deaths and may potentially prolong overall survival in NHL patients with increased risk of anthracycline cardiotoxicity.

Ferritinemia and serum inflammatory cytokines in Swedish adults with Gaucher disease type 1.

BACKGROUND: The storage of glucosylceramide in macrophages produces an inflammatory response in Gaucher disease type 1 (GD1) resulting in iron metabolism dysregulation and cytokine release. PATIENTS AND METHODS: The study included 16 adults with GD1 aged 20-86years. All but one patient carried at least one allele with the c.1226A>G (N370S) mutation in the GBA1 gene. Ferritinemia, iron metabolism profiles including hepcidin, and inflammatory cytokine concentrations were assessed in GD1 patients in Sweden. RESULTS: Hyperferritinemia was present in 81% of patients. There was no correlation between hyperferritinemia and patient's gender, spleen status, or clinical status. Hepcidin was discrepantly low in relation to ferritin levels. TNF-α was moderately increased in 5 of 11 patients; 2 patients with the highest TNF-α concentrations showed mildly elevated IL-6 levels. The concentrations of IL-1ß, IL-8, and IL-10 were normal in all patients. Upon treatment, ferritinemia ameliorated but S-ferritin levels did not normalize. The increased TNF-α level however, normalized in all treated patients, reaching the lowest values after 2years of therapy and continued to be stable during the remaining 2years of follow-up. CONCLUSIONS: Hyperferritinemia is a frequent finding in GD1 in Sweden. The relatively low hepcidin levels reveal a distorted relationship between hepcidin and ferritin in GD1. Therapy has the potential to not only ameliorate hyperferritinemia but to also normalize the serum TNF-α concentration in GD1.

Single-agent MOR208 salvage and maintenance therapy in a patient with refractory/relapsing diffuse large B-cell lymphoma: a case report.

BACKGROUND: Diffuse large B-cell lymphoma is the most common subtype of non-Hodgkin's lymphoma. Standard first-line treatment for this aggressive subtype comprises the anti-CD20 antibody rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone. If patients receiving such treatment have an early relapse, or their disease is initially refractory to such treatment, standard salvage regimens may not be effective. There is therefore a high unmet clinical need for new targeted agents that might improve the outcome for such patients. CD19 is a B-lymphocyte lineage-specific cell surface antigen that is expressed by most B-cell non-Hodgkin's lymphomas. MOR208 is an fragment-crystallizable engineered humanized monoclonal antibody with enhanced antitumor activity that targets CD19 and that may consequently have clinical utility in this setting. CASE PRESENTATION: We describe the case of a 33-year-old Caucasian man who presented with a 3-month history of general symptoms and who was admitted to our pulmonology ward with dyspnea due to pneumonia and severe anemia. A histopathological examination of an enlarged right suprasternal lymph node confirmed a diagnosis of T-cell/histiocyte-rich large B-cell lymphoma, an uncommon morphological variant of diffuse large B-cell lymphoma. Our patient had a complete response to first-line rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone, but had an early relapse 5 months after the end of treatment. After intensive salvage therapy consolidated with an autologous stem-cell transplant, our patient again had an early relapse and was subsequently enrolled in a phase IIa trial of single-agent MOR208. Following a scheduled 3 months of weekly treatment, a partial response was confirmed and MOR208 was continued as maintenance therapy, with administration every second week. Positron emission tomography-computed tomography confirmed a complete response 9 months later. This response is ongoing, with a duration of 24 months. MOR208 was well-tolerated by our patient and his quality of life and performance status remain high. No hospitalizations were required and our patient engaged in full-time work and physical activities. CONCLUSION: Third-line single-agent therapy with the CD19 antibody MOR208 was highly effective in this patient, despite a history of early relapse after standard first-line and second-line treatment regimens. These data provide support for future randomized studies of MOR208.

Multiple Myeloma in Pregnancy--A Review of the Literature and a Case Series.

Multiple myeloma (MM) typically affects older patients with a median age at diagnosis of 67 to 70 years and only 3% of cases are diagnosed before the age of 40. Moreover, MM is more common in men. Therefore, pregnancy rarely occurs in patients with MM and only 37 cases of MM in pregnancy have been reported in the literature. Herein we report an additional 5 cases. The diagnosis of MM might be problematic in this context because some of the symptoms and signs, such as back pain and anemia, can be attributed to pregnancy. Furthermore, if the patient wishes to continue her pregnancy, therapeutic options are currently limited. The list of agents that can be safely administered in pregnant women includes glucocorticoids. Moreover, any continuation of pregnancy has obvious long-term psychosocial repercussions for the patient and her family because of the currently incurable nature of MM. The reported cases of MM in pregnancy represent a spectrum of clinical manifestations. The selection of efficacious and safe treatments is challenging, especially if continuation of pregnancy is desired. Although some authors postulate that pregnancy might lead to progression of MM, data are limited and no consensus on this point has been reached.

Cutaneous involvement in multiple myeloma: a multi-institutional retrospective study of 53 patients.

Skin infiltration in multiple myeloma (skin MM) is a rare clinical problem. Only a few cases of skin involvement have been reported, primarily in single case reports. We analyzed and present the clinical outcomes, immunohistochemistry and cytogenetic features, and relevant laboratory data on 53 biopsy-proven skin MM cases. The median time from MM diagnosis to skin involvement was 2 years. There appears to be an overrepresentation of immunoglobulin class A (IgA) and light chain disease in skin MM. We found no correlation between CD56 negative MM and skin infiltration. We found that skin MM patients presented in all MM stages (i.e. ISS stages I to III), and there was no preferential cytogenetic abnormality. Patients with skin MM carry a very poor prognosis with a median overall survival (OS) of 8.5 months as time from skin involvement. Moreover, patients with IgA disease and plasmablastic morphology appear to have a worse OS.

[Psychological health's predictors of patients after bone marrow transplantation (BMT) 40 years of psychological researches of patients with blood cancers].

A study on the psychological health`s predictors of patents after BMT is presented. The theoretical base of researches is Helena Wrona- Polanska's Functional Model of Health (FMH Wrona-Polanska 2003), in which health is a function of creative coping with stress. 110 patients after BMT - 64 males and 46 females ­ at the Hematology Clinic of Jagiellonian University of Collegium Medicum, were studied clinically. Examined methods were the questionnaires: Spielberger`s STAI, Endler`s, Parker`s CISS and CHIP, Antonovsky`s SOC-29, Rosenberg`s self-esteem scale, 10-point rating scales: of sense of health, sense of calm and sense of anxiety. Objective health was examined by physician on the 10-point rating scale. Cluster analysis to show psychological health`s predictors of patients after BMT: level of stress, styles and effective coping strategies with stress, personal resources, temporal factor since transplantation and gender. The psychological predictors of health are the base of health promotion of patients after BMT.

Percutaneous Vertebroplasty for Pathological Vertebral Compression Fractures Secondary to Multiple Myeloma--Medium-Term and Long-Term Assessment of Pain Relief and Quality of Life.

BACKGROUND: In patients with multiple myeloma (MM) there is a high risk of compression fractures of the spine. In the majority of cases, the method of treatment is percutaneous vertebroplasty (PV) or kyphoplasty (PK). The number of studies verifying their efficacy in MM is still relatively small. OBJECTIVES: The aim of this study has been to assess medium- and long-term pain relief as well as improvement in the quality of life (QL) after PV in MM cases. MATERIAL AND METHODS: There was a prospective group of 34 MM cases in which a total of 131 vertebral bodies were augmented by means of PV. It was possible to follow up 22 patients who agreed to take part in the assessment. Their level of daily activity and the level of pain were assessed using the Oswestry Back Pain scale and a visual analogue scale (VAS) before PV and at a later date (medium-term follow up was a mean of 10 months after the last operation). Five out of eight cases in which 4.5-5 years had elapsed since the first PV were tested again (long-term follow-up). RESULTS: Relief of pain and improvement of QL, assessed a mean of 10 months after PV, proved to be statistically significant. On the average, pain decreased by 4.7 points as measured on the VAS scale and the average improvement in the QL measured on the Oswestry scale was 27.7%. There were no neurological or general complications. After 4.5-5 years, there has not been any significant change in the level of pain relief or the improvement in the QL in the 5 cases in which long-term assessment was possible. CONCLUSIONS: In MM cases, PV is a simple, effective and safe method for the treatment of vertebral infiltration and compression fractures, giving permanent long-term pain relief and concomitant improvement in the QL.

[The role of the bone marrow microenvironment in the pathogenesis of multiple myeloma]. / Rola mikrosrodowiska szpiku kostnego w patogenezie szpiczaka plazmocytowego.

Multiple myeloma (MM) is one of the most common hematologic malignancies. It remains an incurable disease, so far. The mainstay of treatment for decades was pointless therapy with cytostatic agents and immunosuppressant's. Because myeloma is most common in the elderly population, vulnerable to aggressive therapy, non-specific treatment approaches led to poor patient survival. Intensive study of MM, allowed identification of the molecular interactions between myeloma cells and bone marrow tumour microenvironment, responsible for the development of the disease and associated complications, such as osteolytic bone lesions. Understanding the molecular mechanisms of action of adhesion molecules, cytokines and signalling pathways involved in the development of myeloma, has led to develop of novel, targeted therapies to improve the quality of patients life and significantly prolong the median survival time. This paper discusses the current state of knowledge of signalling pathways involved in the progression of cancer and the destruction of bone tissue, with particular emphasis on interactions with the bone marrow microenvironment of the tumour.

Plasma fatty acid profile in multiple myeloma patients.

New membrane formation in the proliferating tumor cells consequently results in hypermetabolism of fatty acids (FA), as seen in many cancer patients, including multiple myeloma (MM). The FA composition of plasma reflects both endogenous synthesis as well as the dietary supply of these compounds. Additionally, obesity is a risk factor for the development of MM. The aim of this study was to compare the FA composition of plasma in 60 MM patients and 60 healthy controls. We noted significant differences in the FA profile of plasma from patients with MM when compared to the control group. Increased levels of saturated and n-6 polyunsaturated fatty acids in MM patients suggest that there may be increased endogenous synthesis of these fatty acids, likely due to increased expression of desaturase and elongase. Furthermore, cluster analysis showed differences in the distribution of FA in plasma from MM patients compared to controls. Dietary fat and a deranged endogenous FA metabolism may contribute to cancer-associated inflammation through an abnormal arachidonic acid metabolism, caused by pro-inflammatory derivatives. Our study supports further research on the biochemistry of lipids in patients with MM.

Liposomal cytarabine in the prophylaxis and treatment of CNS lymphoma: toxicity analysis in a retrospective case series study conducted at Polish Lymphoma Research Group Centers.

Lymphomas with primary or secondary involvement of central nervous system (CNS) have poor prognosis despite specific treatment protocols which include whole brain radiotherapy and high-dose systemic and/or intrathecal chemotherapy. Toxicity of intrathecal liposomal cytarabine-based regimens collected between November 2006 and January 2012 was assessed retrospectively. Data from 120 adult lymphoma patients with, or at high risk of CNS involvement who received intrathecal liposomal cytarabine-based regimens at six Polish Lymphoma Research Group centres between November 2006 and January 2012 were assessed retrospectively. Patients were divided into three cohorts: A (high risk of CNS disease, n = 88), B (cerebrospinal fluid pleocytosis without neurological symptoms or pathological imaging findings, n = 7), and C (CNS disease/neurological involvement; n = 25). In all examined groups, toxicity of treatment was found to be acceptable (including the prophylactic setting). None of the patients in cohorts A or B who took intrathecal liposomal cytarabine 50 mg, repeated every 2-4 weeks (mean 3.8 doses) had experienced a CNS relapse at a median follow-up time of 3 years. Patients in cohort C had a 76 % overall neurological response rate (including a 40 % complete response rate) and median overall survival of 4.8 years. Regimens incorporating liposomal cytarabine seem to be safe and effective treatments for lymphomas with CNS involvement.

The Analysis of the Relationship between Multiple Myeloma Cells and Their Microenvironment.

The bone marrow microenvironment plays a key role in the stimulation of growth and survival of multiple myeloma (MM) cells. We investigated whether membrane microfragments (MFBs) exert a stimulatory effect on mesenchymal stem cell (MSC) gene expression or differentiation. MSCs from patients with multiple myeloma (MMBM-MSCs) proliferated at a slower rate than MSCs from healthy volunteers (BM-MSCs), and fewer MMBM-MSCs adhered to the substrate as compared to BM-MSCs. Phenotypic analysis revealed that MMBM-MSCs and BM-MSCs differed significantly in terms of their CD166 and CXCR4 expressions. In conclusion, our comparative analysis of mesenchymal cells from MM patients and healthy volunteers revealed differences in the genetic and phenotypic profiles of these two populations, their potential for osteodifferentiation, and expression of surface antigens. Moreover, we showed that membrane MFBs may alter the genetic profile of MSCs, leading to disorders of their osteodifferentiation, and interact with the WNT pathway via presentation of the DKK-1 protein.

Efficacy and safety of stem cell mobilization with cyclophosphamide plus etoposide versus cyclophosphamide alone.

The use of the combination of two cytostatics cyclophosphamide (CTX) and etoposide (VEP) and G-CSF is a reasonable alternative, especially for stem mobilization in multiple myeloma (MM) patients from countries in which newer treatments are limited due to financial constraints. The aim of this study was to compare the efficacy and safety of CTX-VEP versus CTX alone for mobilization of hematopoietic stem cells in MM patients. The analysis included 48 consecutive MM patients mobilized with CTX-VEP compared to 43 consecutive historical controls mobilized with CTX alone. The two groups of MM patients did not differ in terms of the median number of apheresis procedures, median yield the first day, median numbers of harvested CD34+ cells, proportion of patients with at least 5 x 106/kg yield and incidence of non-hematological complications. The median cumulative dose of G-CSF given to individuals in the CTX-VEP group was significantly lower than in the CTX group (p < 0.001). The incidence of post-mobilization thrombocytopenia was higher in the CTX group (p<0.001). The median time to platelet count > 20 x 109/l (10 vs. 11 days, p = 0.004) and the median time to neutrophil count > 50 x 109/l (11 vs. 13 days, p < 0.001) were significantly shorter among the patients mobilized with CTX-VEP than in those treated with CTX alone. These findings suggest that CTX-VEP is as efficacious and possibly safer than CTX alone.

[Significant changes in diagnostic and therapeutic procedures in smoldering multiple myeloma]. / Znaczace zmiany w postepowaniu diagnostyczno-terapeutycznym w tlacej postaci szpiczaka plazmocytowego.

Smoldering multiple myeloma (SMM) is a precursor disease of multiple myeloma (MM) with an average annual risk of progression to MM of 10%. Several prognostic factors have been identified and combined in models to discriminate patient groups with different outcomes. These factors include size of the M-protein, plasma cell (PC) infiltration in the bone marrow (BM), serum free light-chain ratio, immunoparesis and percentage of aberrant BMPCs on flow cytometry or the presence of focal lesions on magnetic resonance imaging. The current standard of care has been to initiate treatment with progression to symptomatic MM. Current approaches aim at identifying patients with an ultra-high risk of progression (≥ 80% within the first 2 years) who are considered as 'early myeloma' patients requiring therapy. A recent trial on high-risk SMM patients, comparing early treatment with lenalidomide plus dexamethasone (Rd) versus observation, reported a benefit with respect to time to progression and survival for Rd-treated patients. Therefore, in 2014, the International Myeloma Working Group (IMWG) revised the diagnostic criteria and proposed to treat patients with ultra-high risk SMM as symptomatic MM. Promising markers for further studies may be high levels of circulating and high proliferative rate of PCs, abnormal PC phenotype with > 95% plus immunoparesis, evolving SMM, specific cytogenetic subtypes, genomic and additional biomarkers; all being acknowledged by the IMWG be added to the diagnostic criteria in the future, if any proves to be associated with a risk of progression of SMM to MM of at least 80% within 2 years.

The roles of consolidation and maintenance therapy with novel agents after autologous stem cell transplantation in patients with multiple myeloma.

Novel agents including immunomodulatory drugs and proteasome inhibitors incorporated into induction regimens and subsequently followed by autologous stem cell transplantation in cases of multiple myeloma have resulted in enhancement of response rate and its depth. Maintaining or even improving the response is an important treatment goal. Most clinical trials have revealed increased progression-free survival after consolidation and maintenance therapy. Some of them have also shown prolongation of overall survival. However, continuous therapy may be associated with significant side effects and costs, and therefore remains controversial. Treatment decisions should be individualized and based upon projected benefits and risks.

[Cutaneous involvement in multiple myeloma--case report and literature review]. / Zajecie skóry w przebiegu szpiczaka plazmocytowego--opis przypadku i przeglad literatury.

Cutaneous involvement in multiple myeloma is a very rare clinical problem. It occurs in less than 1% myeloma patients. Skin manifestation may be primary or secondary to MM. Primary involvement (PCP) according to the current WHO classification is one of the marginal zone lymphomas of the skin. PCP are characterized by significantly better prognosis than infiltrations secondary to MM. Skin manifestations require a thorough diagnosis to differentiate between myeloma-specific changes, MM-associated and non-specific skin disorders. Isolated primary infiltration can usually be successfully treated with radiation therapy or surgery. So far treatment of multiple and secondary to MM involvement are not satisfactory.

[Daratumumab--breakthrough drug in multiple myeloma therapy]. / Daratumumab--przelomowy lek w terapii szpiczaka plazmocytowego.

Multiple myeloma (MM) remains incurable despite important recent advances in treatment. Over the last 2 years, an anti-CD38 monoclonal antibody daratumumab (DARA) has emerged as a breakthrough targeted therapy for patients with MM. Early-stage clinical trials have found DARA to be safe and to have encouraging clinical activity as a single agent and in combination with lenalidomide in heavily pretreated, relapsed patients in whom other novel agents (such as bortezomib, thalidomide and lenalidomide) as well as stem cell transplant has already failed. This review discusses the preclinical and clinical development of DARA, its pathophysiological basis, and its prospects for future use in MM.

Lenalidomide in heavily pretreated refractory diffuse large B-cell lymphoma: a case report.

INTRODUCTION: In diffuse large B-cell lymphoma, first-line treatment with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone; salvage with cisplatin-based regimens for relapsing patients; and autologous stem cell therapy are standards of care. Treatment approaches are less clear for patients who are refractory or who are not candidates for autologous stem cell therapy. Options may include palliative regimens or clinical trial enrollment. One therapy under investigation in diffuse large B-cell lymphoma is lenalidomide, an immunomodulatory agent with antiangiogenic activity. CASE PRESENTATION: We present the case of a 55-year-old Caucasian male patient diagnosed with diffuse large B-cell lymphoma who had an early relapse after treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. He then had a subsequent early relapse after cisplatin-based salvage consolidated with autologous stem cell therapy. The efficacy of gemcitabine-cisplatin-rituximab was limited to five months, followed by systemic and central nervous system progression. Fourth-line treatment with lenalidomide plus rituximab and involved-field radiotherapy followed by lenalidomide monotherapy greatly improved this patient's quality of life and performance status, allowing over two years of progression-free survival to date (excluding a brief relapse due to treatment interruption). CONCLUSION: A lenalidomide-based regimen was highly effective in this patient with diffuse large B-cell lymphoma.

[Atypical BCR-ABL transcripts in patients with chronic myeloid leukemia--the scheme for the diagnosis and monitoring of minimal residual disease]. / Nietypowe odmiany transkryptu BCR-ABL u chorych na przewlekla bialaczke szpikowa--schemat postepowania diagnostycznego w monitorowaniu minimalnej choroby resztkowej.

More than 95% of patients with detected translocation t(9;22), is characterized by the fusion between exons e13 or e14 of BCR gene, which are located in major breakpoint cluster region (M-bcr) and exon a2 of ABL gene. These fusions are described as b2a2 (e13a2) and b3a2 (e14a2). Other fusions of exons e1, e6, e8, e12, e19, e20 of BCR gene with exons a2 or a3 of ABL gene occur very rarely and lead to formation of so called unusual fusion BCR-ABL genes. The aim of this study is to describe long-term observations of the occurrence and routine procedure in the diagnosis of atypical variants of the fusion gene BCR-ABL in a population of patients with chronic myeloid leukemia (CML). It was found that the vast majority of patients with detected BCR-ABL transcripts were b3a2 and b2a2. Other detected variants, which are described as rare were: e1a2, b2a3, b3a3, c3a2, e6a2, e6a3. At the stage of diagnosis as well as during monitoring of the effects of treatment, molecular methods which are based on polymerase chain reaction were used (multiplex RT-PCR, nested RT-PCR, RQ-PCR). Multiplex RT-PCR reaction gave possibility to detect variants of the fusion BCR-ABL gene in one reaction and was crucial in the selection of appropriate test used for further monitoring of the disease and the effectiveness of treatment. This paper proposes a scheme for dealing with the diagnosis and monitoring of minimal residual disease (MRD) in patients with CML treated with tyrosine kinase inhibitors (TKIs) in the presence of rare fusion of the BCR and ABL genes.