Outcomes of younger patients with mantle cell lymphoma experiencing late relapse (>24 months): the LATE-POD study.

ABSTRACT: Patients with mantle cell lymphoma (MCL) who experience first relapse/refractoriness can be categorized into early or late progression-of-disease (POD) groups, with a threshold of 24 months from MCL diagnosis. Bruton tyrosine kinase inhibitors (BTKi) are the established standard treatment at first relapse, but their effectiveness compared with chemoimmunotherapy (CIT) in late-POD patients remains unknown. In this international, observational cohort study, we evaluated outcomes among patients at first, late POD beyond 24 months. The primary objective was progression-free survival from the time of second-line therapy (PFS-2) of BTKi vs CIT. Overall, 385 late-POD patients were included from 10 countries. Their median age was 59 years (range, 19-70), and 77% were male. Median follow-up from the time of second-line therapy was 53 months (range, 12-144). Overall, 114 patients had second-line BTKi, whereas 271 had CIT, consisting of rituximab-bendamustine (R-B; n = 101), R-B and cytarabine (R-BAC; n = 70), or other regimens (mostly cyclophosphamide-hydroxydaunorubicin-vincristine-prednisone]- or platinum-based; n = 100). The 2 groups were balanced in clinicopathological features and median time to first relapse. Overall, BTKi was associated with significantly prolonged median PFS-2 than CIT (not reached [NR] vs 26 months, respectively; P = .0003) and overall survival (NR and 56 months, respectively; P = .03). Multivariate analyses showed that BTKi was associated with lower risk of death than R-B and other regimens (hazard ratio, 0.41 for R-B and 0.46 for others), but similar to R-BAC. These results may establish BTKi as the preferable second-line approach in patients with BTKi-naïve MCL.

Candidate germline biomarkers of lenalidomide efficacy in mantle cell lymphoma: the Fondazione Italiana Linfomi MCL0208 trial.

In the Fondazione Italiana Linfomi MCL0208 phase 3 trial, lenalidomide maintenance (LEN) after autologous stem cell transplantation (ASCT) in mantle cell lymphoma (MCL) improved progression-free survival (PFS) vs observation (OBS). The host pharmacogenetic background was analyzed to decipher whether single-nucleotide polymorphisms (SNPs) of genes encoding transmembrane transporters, metabolic enzymes, or cell-surface receptors might predict drug efficacy. Genotypes were obtained via real-time polymerase chain reaction of the peripheral blood germ line DNA. Polymorphisms of ABCB1 and VEGF were found in 69% and 79% of 278 patients, respectively, and predicted favorable PFS vs homozygous wild-type (WT) in the LEN arm was 3-year PFS of 85% vs 70% (P < .05) and 85% vs 60% (P < .01), respectively. Patients carrying both ABCB1 and VEGF WT had the poorest 3-year PFS (46%) and overall survival (76%); in fact, in these patients, LEN did not improve PFS vs OBS (3-year PFS, 44% vs 60%; P = .62). Moreover, the CRBN polymorphism (n = 28) was associated with lenalidomide dose reduction or discontinuation. Finally, ABCB1, NCF4, and GSTP1 polymorphisms predicted lower hematological toxicity during induction, whereas ABCB1 and CRBN polymorphisms predicted lower risk of grade ≥3 infections. This study demonstrates that specific SNPs represent candidate predictive biomarkers of immunochemotherapy toxicity and LEN efficacy after ASCT in MCL.

Breast Implant-Associated Anaplastic Large Cell Lymphoma: Two Distinct Clinical Presentations.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare CD30 positive T cell lymphoma whose incidence has recently increased. Until 2020, 733 cases of BIA-ALCL and 36 deaths have been reported around the world, with only one confirmed case in Portugal. The authors describe two clinical cases of BIA-ALCL after breast cancer reconstruction using macrotextured implants. Case 1: A 45-year-old patient, who presented with a typical late-onset seroma five years after breast reconstruction and underwent capsulectomy, confirming localized disease to the capsule. Case 2: A 43-year-old patient presented with an atypical presentation of pleural effusion and tumor mass, 14 years after reconstruction. She underwent implant removal and chemotherapy, due to metastatic disease. These clinical cases illustrate two very distinct clinical presentations of BIA-ALCL. Early diagnosis of this entity allows for effective treatment of the disease, which should be approached in a multidisciplinary setting.

O linfoma anaplásico de grandes células associado aos implantes mamários é um linfoma T CD30 positivo raro, cuja incidência tem aumentado recentemente. Até 2020, estavam registados 733 casos de BIA-ALCL e 36 mortes, em todo o mundo e apenas um caso confirmado em Portugal. Os autores descrevem dois casos de BIA-ALCL, após reconstrução mamária por cancro de mama, com próteses macrotexturadas. Caso 1: Doente com 45 anos, que se apresentou com a manifestação típica de seroma tardio, cinco anos após a colocação da prótese, tendo sido submetida a capsulectomia, que confirmou doença localizada à cápsula. Caso 2: Doente de 43 anos, que se manifestou de forma atípica com derrame pleural e massa tumoral, 14 anos após a colocação da prótese. A doente foi submetida a remoção de prótese e quimioterapia, tendo em conta a doença metastática. Os casos clínicos descritos ilustram duas formas distintas de apresentação clínica de BIA-ALCL. O diagnóstico precoce desta patologia possibilita o seu tratamento de forma eficaz e deve ser abordado em equipa multidisciplinar.

Mantle Cell Lymphoma of Mucosa-Associated Lymphoid Tissue: A European Mantle Cell Lymphoma Network Study.

While classical nodal mantle cell lymphoma (cMCL) is often associated with involvement of multiple extranodal sites, isolated extranodal disease (ED) at the time of diagnosis is a rare event; data on the outcome of these forms are lacking. On behalf of the European MCL Network, we conducted a retrospective analysis on the clinical characteristics and outcomes of MCL presenting with isolated or predominant ED (MALT MCL). We collected data on 127 patients with MALT MCL diagnosed from 1998 to 2015: 78 patients (61%) were male with a median age of 65 years. The involved sites include: upper airways + Waldeyer ring (40; 32%), gastrointestinal tract (32; 25%), ocular adnexa (17; 13%), oral cavity and salivary glands (17; 13%) and others (13; 1%); 7 patients showed multiple extranodal sites. The median follow-up was 80 months (range: 6-182), 5-year progression-free survival (PFS) was 45% (95% CI: 35-54) and 5-year overall survival (OS) was 71% (95% CI: 62-79). In an explorative setting, we compared MALT MCL with a group of 128 cMCL patients: MALT MCL patients showed a significantly longer PFS and OS compared with nodal cMCL; with a median PFS of 4.5 years vs 2.8 years (p = 0.001) and median OS of 9.8 years vs 6.9 years (p = 0.018), respectively. Patients with MALT MCL at diagnosis showed a more favorable prognosis and indolent course than classical nodal type. This clinical variant of MCL should be acknowledged to avoid possible over-treatment.

How Allogeneic Hematopoietic Stem Cell Transplantation has Evolved Over Time: 30-Years' Experience at a Single Institution.

INTRODUCTION: Allogeneic stem cell transplantation is an established procedure for a variety of diseases of the hematopoietic system. Our transplant program started in 1987 and since then advances have been made in the care of patients undergoing transplantation. We conducted a study to evaluate whether the changes implemented over time have improved the outcomes of transplantation. MATERIAL AND METHODS: We analyzed changes in patients, cell source, transplantation and outcome among 682 consecutive patients receiving their first transplant between 1987 and 2016. We compared overall survival, progression-free survival, the incidence of nonrelapse mortality and relapse in 10-year cohorts over the three decades of the study. RESULTS: The median age of transplanted patients, the use of peripheral blood and unrelated donors all increased very significantly. There was an increase in the number of high-risk patients when comparing the first decade with the two subsequent ones. The 3-year non-relapse mortality decreased significantly from 29% to 20% (p = 0.045), while the overall survival, progression free survival and cumulative incidence of relapse remained stable. DISCUSSION: Allogeneic hematopoietic stem cell transplantation has evolved considerably since its introduction in clinical practice. In the present study, we evaluated how these changes affected our practice along 30 years of activity and compared the results with those published in the literature. CONCLUSION: Despite increasing age, higher risk patients and the increasing use of unrelated donors our results show a continuous significantly reduced non-relapse mortality, with stable overall survival, progression free survival and relapse rate.

Introdução: A transplantação alogénica de células hematopoiéticas é utilizada regularmente no tratamento de uma grande variedade de doenças hematológicas. O nosso programa de transplantação teve início em 1987 e desde então têm sido numerosos os avanços nesta área. Este estudo foi conduzido para avaliar se as alterações introduzidas ao longo de 30 anos melhoraram os resultados obtidos. Material e Métodos: Analisámos os resultados numa população de 682 doentes submetidos consecutivamente a um primeiro transplante alogénico entre 1987 e 2016. Para tal, os doentes foram divididos em intervalos de 10 anos e comparámos a sobrevida global, a sobrevida livre de progressão, a mortalidade não associada a recaída e as recaídas em cada década do estudo. Resultados: A mediana de idades dos doentes transplantados, a utilização de células progenitoras provenientes do sangue periférico e a transplantação com dadores não familiares aumentaram muito significativamente ao longo do estudo. Verificou-se, comparativamente com a primeira década, um aumento do número de doentes de alto risco nas duas décadas subsequentes. A mortalidade não relacionada com recidiva, avaliada aos três anos pós-transplante, diminuiu significativamente de 29% para 20% (p = 0,045), mantendo-se estáveis a sobrevida global e a sobrevida livre de progressão, assim como a incidência cumulativa de recaídas. Discussão: A transplantação alogénica hematopoiética tem evoluído consideravelmente desde a sua introdução na prática clínica. No presente trabalho são avaliados os reflexos dessa evolução ao longo de 30 anos sendo analisados os resultados obtidos e comparados com os referidos na literatura. Conclusão: Apesar das características mais desfavoráveis verificadas ao longo das três décadas (doentes mais idosos, doenças de risco mais elevado, aumento do número de dadores não familiares) foi possível reduzir significativamente a mortalidade associada ao procedimento, mantendo-se estáveis a sobrevida global e livre de progressão, assim como a incidência de recaídas.

What determines therapeutic choices for elderly patients with DLBCL? Clinical findings of a multicenter study in Portugal.

BACKGROUND: Age is a negative prognostic factor in lymphomas, and elderly patients are often undertreated because of toxicity concerns. The pattern of treatment in elderly patients with diffuse large B-cell lymphoma (DLBCL) in Portugal has not been previously described. PATIENTS AND METHODS: We conducted a multicenter retrospective study including 378 elderly patients with DLBCL receiving alkylating agent-containing regimens between 2003 and 2010. We compared the outcome of patients aged 60 to 79 years with patients > 79 years and analyzed the second group according to treatment. RESULTS: R-CHOP (rituximab, cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine [Oncovin], prednisolone) was prescribed in only 60% of patients and was prescribed significantly less in patients > 79 years, despite no significant differences being found in comorbidities between the 2 age groups. Similarly, dose reductions frequently were instituted because of chronologic age and not always because of toxicity. When different regimens were compared, multivariate analysis showed an independent beneficial effect of R-CHOP in treatment outcomes. Additionally, treatment with anthracyclines and rituximab predicted a better progression-free survival (PFS) and time to progression (TTP) in patients > 79 years. CONCLUSION: This was the first characterization of the clinical care of elderly Portuguese patients with DLBCL. We showed that R-CHOP is effective even in patients > 79 years, emphasizing that treatment decisions based on age alone can compromise treatment efficacy and outcome in fit patients.

Clonal Hypereosinophilia with ETV6 Rearrangement Evolving to T-Cell Lymphoblastic Lymphoma: A Case Report and Review of the Literature.

Hypereosinophilia, either clonal or reactive, has been described in association with multiple hematological malignancies. We describe a case of a patient presenting with hypereosinophilia that evolved into T-cell lymphoblastic lymphoma. Complete remission was achieved with chemotherapy; however, hypereosinophilia recurred 5 months later in association with myeloblastic bone marrow infiltration and without evidence of lymphoblastic lymphoma relapse. Cytogenetic analysis of the bone marrow showed a complex translocation involving chromosomes 7, 12, and 16. A rearrangement of ETV6 gene (12p13) was demonstrated by FISH studies, thus confirming the clonality of this population. The association of lymphoblastic lymphoma, eosinophilia, and myeloid hyperplasia has been described in disorders with FGFR1 rearrangements. We hypothesize that other clonal eosinophilic disorders lacking this rearrangement could behave in a similar fashion through different pathogenic mechanisms.

Transient neonatal cyanosis associated with a new Hb F variant: Hb F viseu.

Neonatal cyanosis in healthy newborns can be associated either with methemoglobin due to cytochrome b5 reductase deficiency or to M-hemoglobin, a group of hemoglobin variants resulting from mutations in the globin chain genes. We report the clinical case of a neonate with cyanosis and normal cardiac and respiratory function. At birth the hematological parameters were normal; however, the methemoglobinemia was 16%. Spontaneously, the cyanosis gradually decreased and by the fifth month of age the methemoglobin level was normal. A heterozygous Gγ-globin gene (HBG2) missense mutation 87 C-A (Leu28Met) was identified. His father, with a history of transfusion in the neonatal period, is heterozygous for the same mutation. This hemoglobin variant, not previously described, was called Hb F Viseu and is the sixth Gγ-chain variant reported in association with neonatal cyanosis.

Treatment of chronic myelomonocytic leukemia with 5-Azacitidine: a case series and literature review.

Chronic myelomonocytic leukemia (CMML) is a clinically heterogeneous disease, with no standard treatment. We present the outcome of ten patients diagnosed with CMML and treated with AZA in our institutions between 2005 and 2010. All patients were transfusion dependent at the time of initiation of therapy. The overall response rate was 60%. Responses were obtained in 2/3 of the patients with proliferative CMML. The median survival from start of therapy was 20 months. AZA treatment was well-tolerated and associated with a significant response rate in all forms of the disease.