In-depth characterization of NK cell markers from CML patients who discontinued tyrosine kinase inhibitor therapy.

Introduction: Treatment-free remission (TFR) in patients with chronic myeloid leukemia in chronic phase is considered a safe option if suitable molecular monitoring is available. However, the question arises as to which factors can contribute to the maintenance of TFR, and immunologic surveillance of the remaining leukemic cells is believed to be one of them. Argentina Stop Trial is an open-label, single-arm, multicenter trial assessing TFR after tyrosine kinase inhibitors interruption, that after more than 4 years showed a successful TFR rate of 63%. Methods: In this context, we set up an immunological study by flow cytometry in order to analyze specific NK cell subsets from peripheral blood patient samples both at the time of discontinuation as well as during the subsequent months. Results: At the time of discontinuation, patients show a mature NK cell phenotype, probably associated to TKI treatment. However, 3 months after discontinuation, significant changes in several NK cell receptors occurred. Patients with a higher proportion of CD56dim NK and PD-1+ NK cells showed better chances of survival. More interestingly, non-relapsing patients also presented a subpopulation of NK cells with features associated with the expansion after cytomegalovirus infection (expression of CD57+NKG2C+), and higher proportion of NKp30 and NKp46 natural cytotoxicity receptors, which resulted in greater degranulation and associated with better survival (p<0.0001). Discussion: This NK cell subset could have a protective role in patients who do not relapse, thus further characterization could be useful for patients in sustained deep molecular response.

Inequalities in access to treatment in Argentina: Differences in management of CLL and multiple myeloma?

Health equity is today an important objective to evenly reach the population among different health care systems. This article will focus on diagnosis and treatment access inequalities in Argentina. Although different aspects must be optimized to overcome access barriers worldwide, access inequalities in some regions of Argentina may depend basically on the type of health coverage or insurance. Health care in Argentina is divided into Public, Social security and Private care systems. Access to diagnosis and disease monitoring will vary according whether the patient is under each of these systems. Reducing inequalities may help target some important aspects not covered today and that may directly impact patients' outcome. Disparities in health cancer care were analyzed according to Public, Social security and Private sectors. A disadvantage in resource access, inadequate funding and limited medical infrastructures are common characteristics of the public health care systems. In our country the disparity between the public and private sectors in terms of timely diagnosis, stage of disease at diagnosis, accuracy of diagnosis, access to novel agents and transplantation is notorious, with the public sector lagging behind in access to diagnostic and treatment resources. While the Private sector has treatment outcomes comparable to those of high-income countries, challenges remain in the Public sector for patients who rely on early and accurate diagnosis and timely access to treatment. There is an urgent need to provide equitable care for multiple myeloma and CLL patients and reduce the emotional and financial consequences of the disease for the patient. A survey about diagnosis and therapeutic resources was conducted between April and May 2023 among large centers in the Public, Social security and Private systems. A total of 49 hematologists from 31 institutions from five provinces of Argentina participated in the survey. We observed differences between the different systems with more access for the Private system on genetic diagnosis (FISH-IGVH access). More CLL patients in the public and social security systems were treated with CIT reflecting the inaccessibility in these sectors of more expensive targeted therapies rather than a gap in information since the Public centers surveyed were large hospitals with knowledgeable physicians. Access to different treatments both in first-line and relapsed settings was more equitable in the treatment of multiple myeloma for the different systems with the exception of access to daratumumab in first-line that was extremely infrequent in the public coverage. With increasing cost and treatment complexity as the introduction of CARTs and BITEs for CLL and MM, the gap will probably deepen more if the problem is not treated comprehensively by all the actors of the health sector: government, physicians, patients' organizations and pharmaceutical companies.

Gammapatía monoclonal de significado incierto: factores de pronóstico, evolución y riesgo / Monoclonal gammopathy of undeterminaded significance: prognostic factor and risk of progression

La Gammapatía Monoclonal de Significado Incierto (GMSI) tiene una prevalencia que varía entre 1 y 3%, su frecuencia tiende a aumentar con la edad y aunque presentan evolución indolente y una sobrevida prolongada, un porcentaje de ellas desarrollará una enfermedad maligna. Con el objetivo de evaluar el valor pronóstico de diversos parámetros proteicos y hematológicos al momento del diagnóstico, se estudiaron mediante estudios proteicos completos en sangre y en orina, 407 pacientes con diagnóstico de GMSI que ingresaron a la institución en el período comprendido entre 1982 y 2008. La concentración del componente monoclonal (CM) (>1,5 g/dL) y el tipo inmunológico (No IgG), la disminución de las inmunoglobulinas no comprometidas (INC), el porcentaje de infiltración de células plasmáticas en médula ósea (>5%) y la mediana de las relaciones anormales de las cadenas livianas monoclonales libres, fueron los parámetros que marcaron riesgo de progresión a una enfermedad maligna. El estudio proteico completo de orina demostró una asociación entre el aumento en la concentración de proteínas de bajo peso molecular con valores de estimado de filtración glomerular menor de 60 mL/min/1,73 m2 y presencia de proteinuria de Bence Jones, independientemente del tipo de cadena liviana y de los niveles de proteínas totales. Debido a ello, la adición de dichos marcadores de daño tubular podría ofrecer una visión más profunda, siendo su aumento un posible indicador, en la profilaxis renal, de una severa lesión tubular futura. Finalmente, en pacientes con GMSI, los controles de laboratorio deberán ser ajustados en su periodicidad pero no en su contenido. La mayor información así obtenida será lo que permitirá una decisión médica más segura al momento de recomendar la frecuencia del seguimiento del paciente y la consiguiente detección temprana de una evolución maligna de la enfermedad.(AU)

Gammapatía monoclonal de significado incierto: factores de pronóstico, evolución y riesgo / Monoclonal gammopathy of undetermined significance: prognostic factor and risk of progression / Gamopatia monoclonal de significado indeterminado: fatores prognósticos: risco da evoluþÒo

La Gammapatía Monoclonal de Significado Incierto (GMSI) tiene una prevalencia que varía entre 1 y 3%, su frecuencia tiende a aumentar con la edad y aunque presentan evolución indolente y una sobrevida prolongada, un porcentaje de ellas desarrollará una enfermedad maligna. Con el objetivo de evaluar el valor pronóstico de diversos parámetros proteicos y hematológicos al momento del diagnóstico, se estudiaron mediante estudios proteicos completos en sangre y en orina, 407 pacientes con diagnóstico de GMSI que ingresaron a la institución en el período comprendido entre 1982 y 2008. La concentración del componente monoclonal (CM) (>1,5 g/dL) y el tipo inmunológico (No IgG), la disminución de las inmunoglobulinas no comprometidas (INC), el porcentaje de infiltración de células plasmáticas en médula ósea (>5%) y la mediana de las relaciones anormales de las cadenas livianas monoclonales libres, fueron los parámetros que marcaron riesgo de progresión a una enfermedad maligna. El estudio proteico completo de orina demostró una asociación entre el aumento en la concentración de proteínas de bajo peso molecular con valores de estimado de filtración glomerular menor de 60 mL/min/1,73 m2 y presencia de proteinuria de Bence Jones, independientemente del tipo de cadena liviana y de los niveles de proteínas totales. Debido a ello, la adición de dichos marcadores de daño tubular podría ofrecer una visión más profunda, siendo su aumento un posible indicador, en la profilaxis renal, de una severa lesión tubular futura. Finalmente, en pacientes con GMSI, los controles de laboratorio deberán ser ajustados en su periodicidad pero no en su contenido. La mayor información así obtenida será lo que permitirá una decisión médica más segura al momento de recomendar la frecuencia del seguimiento del paciente y la consiguiente detección temprana de una evolución maligna de la enfermedad.(AU)

Monoclonal gammopathy of undetermined significance (MGUS) is considered a premalignant state with a stable clinical course, and increased prevalence/risk of developing multiple myeloma (MM) or related malignancy according to age. To evaluate some hematologycal and protein parameters of prognostic value, 407 patients diagnosed as MGUS had been analyzed between 1982 to 2008 by means of complete urine and serum profile. A densitometry spike value (>1.5 g/dL), the monoclonal immunoglobulin class (No-IgG), the reduced concentration of non related immunoglobulin’s, the percentage of plasma cells in bone marrow (>5%) and an abnormal serum kappa/lambda free ratio; marked the increased risk of malignant progression. In urine, the presence of low molecular weight proteins has been associated with eGFR < 60 mL/min/1.73 m2 and the confirmation of Bence Jones proteinuria, independently of light chain type and the proteinuria level, reflecting a tubular damage. With an in deep view, a urine protein profile should detect an early renal compromise. We concluded that laboratory controls in patients with MGUS should be adjusted by periodicity but not in its content. A clear medical decision for the controls frequency or for establishing a worse outcome should be based on a complete protein profile evaluation.(AU)

A gamopatia monoclonal de significado indeterminado (GMSI) tem uma prevalÛncia variando de 1 a 3%, a sua frequÛncia tende a aumentar com a idade, apesar de apresentarem sobrevivÛncia indolentes e prolongada, uma percentagem de los a desenvolver uma doenþa maligna. A fim de avaliar o valor prognóstico da proteína vários parÔmetros hematológicos e no momento do diagnóstico, foram estudados 407 pacientes com diagnóstico de MGUS que foram internados em nossa instituiþÒo entre 1982 a 2008, com estudos de proteínas completas em sangue e urina. A concentraþÒo do componente monoclonal (CM) (>1,5 g/dL e imunológica (no IgG), diminuiþÒo da imunoglobulina nÒo confirmada (INC), a percentagem de infiltraþÒo de células de plasma na medula óssea (>5%) e mediana de relaþ§es anormais de cadeias leves livres monoclonais, foram os parÔmetros que marcaram risco de progressÒo para malignidade.O estudo de proteína total de urina mostraram que o aumento da concentraþÒo de proteínas de baixo peso molecular associados com valores estimados de filtraþÒo glomerular de menos de 60 mL/min/1.73 m2 e proteinúria Bence Jones, independentemente da cadeia leves e total níveis de proteína. Como resultado, a adiþÒo destes marcadores de dano tubular, pode oferecer um conhecimento mais profundo, e seu aumento um indicador possível para a profilaxia lesÒo tubular renal de futuro grave. Finalmente, em pacientes com GMSI, controles laboratoriais devem ser ajustados em frequÛncia, mas nÒo no conteúdo. A maioria da informaþÒo obtida será permitindo uma decisÒo médica mais segura quando recomendando a frequÛncia da monitorizaþÒo do paciente e, por conseguinte, a detecþÒo precoce de progressÒo maligna da doenþa.(AU)

Gammapatía monoclonal de significado incierto: factores de pronóstico, evolución y riesgo / Monoclonal gammopathy of undeterminaded significance: prognostic factor and risk of progression / Gamopatia monoclonal de significado indeterminado: fatores prognósticos: risco da evolução

La Gammapatía Monoclonal de Significado Incierto (GMSI) tiene una prevalencia que varía entre 1 y 3%, su frecuencia tiende a aumentar con la edad y aunque presentan evolución indolente y una sobrevida prolongada, un porcentaje de ellas desarrollará una enfermedad maligna. Con el objetivo de evaluar el valor pronóstico de diversos parámetros proteicos y hematológicos al momento del diagnóstico, se estudiaron mediante estudios proteicos completos en sangre y en orina, 407 pacientes con diagnóstico de GMSI que ingresaron a la institución en el período comprendido entre 1982 y 2008. La concentración del componente monoclonal (CM) (>1,5 g/dL) y el tipo inmunológico (No IgG), la disminución de las inmunoglobulinas no comprometidas (INC), el porcentaje de infiltración de células plasmáticas en médula ósea (>5%) y la mediana de las relaciones anormales de las cadenas livianas monoclonales libres, fueron los parámetros que marcaron riesgo de progresión a una enfermedad maligna. El estudio proteico completo de orina demostró una asociación entre el aumento en la concentración de proteínas de bajo peso molecular con valores de estimado de filtración glomerular menor de 60 mL/min/1,73 m2 y presencia de proteinuria de Bence Jones, independientemente del tipo de cadena liviana y de los niveles de proteínas totales. Debido a ello, la adición de dichos marcadores de daño tubular podría ofrecer una visión más profunda, siendo su aumento un posible indicador, en la profilaxis renal, de una severa lesión tubular futura. Finalmente, en pacientes con GMSI, los controles de laboratorio deberán ser ajustados en su periodicidad pero no en su contenido. La mayor información así obtenida será lo que permitirá una decisión médica más segura al momento de recomendar la frecuencia del seguimiento del paciente y la consiguiente detección temprana de una evolución maligna de la enfermedad.

Serum free light chains and oligoclonal bands in patients with multiple myeloma and autologous stem cell transplantation.

BACKGROUND: To establish stringent complete remission (SCR) in patients with multiple myeloma (MM), it is currently recommended to obtain a normal serum free light chains (sFLC) ratio. The appearance of serum oligoclonal bands (OB) after autologous stem cell transplantation (ASCT) is considered a favorable prognostic factor. The objective of this study was to examine sFLC for assessing SCR in patients with MM, and ASCT with OB. We also examined how capillary electrophoresis (CE) compares with agarose gel electrophoresis (Aga) in identifying oligoclonal bands. METHODS: Out of 238 patients studied in our institution between April 1992 and December 2008 a serum protein electrophoresis (SPE) was performed by means of CE and sFLC determination on 37 patients with MM in complete remission (CR), ASCT and OB presence were assigned by conventional Aga electrophoresis and IF. RESULTS: Statistically significant differences (SSD) were found when comparing CE vs. Aga, regarding BO visualization in SPE, favoring the latter. In connection with sFLC, the group of patients with an abnormal ratio presented elevated values in the γ-globulin zone of the SPE, whereas the group of patients with a normal ratio of sFLC presented with normal values resulting in SSD between the groups. CONCLUSIONS: It is essential to perform immunofixation to certify the presence of OB, especially if CE is used as it is difficult to distinguish them using this method. A normal sFLC was observed in most of the patients with OB and normal values of the SPE γ-globulin zone. The above-mentioned information might demonstrate a limitation of sFLC test in SCR evaluation for patients with MM, ASCT and CR if OB has been detected.

Oligoclonal bands and immunoglobulin isotype switch during monitoring of patients with multiple myeloma and autologous hematopoietic cell transplantation: a 16-year experience.

BACKGROUND: Over the last 20 years, high dose therapy followed by hemopoietic stem cell transplantation has been employed in patients with multiple myeloma (MM). During 16 years of follow-up, the degree of tumor response and survival in 238 patients with autologous stem cell transplantation (ASCT) and changes in the serum protein electrophoretic pattern were analyzed. METHODS: Agarose gel electrophoresis with densitometric analysis and immunofixation were performed to evaluate serum monoclonal protein. IgM, IgA, IgG and beta(2)-microglobulin (beta2M) were quantitated. Urine protein electrophoresis with IF was performed on cellulose acetate gel using colloidal silver staining without concentrating. RESULTS: After 34 months of follow-up (range 1-160 months), eight patients (3.4%) showed a distinct monoclonal protein band that was different from their original isotype switch. This was observed to be a transient phenomenon (22.2 months). Thirty-seven patients (15.5%) developed oligoclonal bands (OB) between the first and the twentieth month after ASCT (mean 4.4 months), which persisted for 7.9 months (1-36 months). The mean overall survival time was statistically different (p<0.05) between the group with OB and the group without them. Mean values of serum albumin, beta2M, and non-involved immunoglobulins did not show statistical differences. CONCLUSIONS: The occurrence of OB could be a potential favorable prognostic marker after transplantation due to the prolonged survival observed. Close follow-up of anomalous protein bands, either in serum or urine, is essential due to the additional difficulty in interpretation when the therapeutic response and evolution are evaluated.

Prognostic factors in monoclonal gammopathy of undetermined significance.

A retrospective evaluation of 285 patients with monoclonal gammopathy of undetermined significance was performed to identify variables associated with progression, actuarial progression free survival (PFS) and overall survival (OS). Three variables, level of uninvolved immunoglobulins (HR 4.98, CI95% 2 -12.4, p=0.0006), monoclonal protein concentration (HR 4.04, CI95% 1.6-10.34, p=0.004), and erythrosedimentation rate (HR 3.94, CI95% 1.33-11.6, p=0.01), showed independent prognostic significance. With a median follow-up of 66 months (range 6-378), PFS and OS at 10 years were 89% and 91% respectively.