Prevalence and Consequences of a Delayed Diagnosis in Multiple Myeloma: A Single Institution Experience.

BACKGROUND: Multiple myeloma (MM) is a disease with unspecific initial symptoms which may lead into a delay in the diagnosis, seemingly increasing the risk of complications and in turn reducing the overall survival (OS). OBJECTIVE: To analyze the consequences of a delayed diagnosis of MM in both the OS and the progression-free survival (PFS) of the patients in a single center in México. METHODS: The study included patients with MM who were diagnosed at Clínica Ruiz, Puebla, México, between 1983 and 2022. According to the time elapsed between the onset of symptoms to the establishment of the definite diagnosis of MM, 4 groups were constructed: 1) Less than 3 months, 2) 3-6 months, 3) 6-12 months, and 4) More than 12 months. RESULTS: About 136 patients had a complete clinical record and at least a 3-month follow up period. A delay in the diagnosis of MM (more than 3 months from the onset of symptoms) was recorded in 92/136 persons (68%). The median follow-up for the whole group was 24.7 months, median OS was 131.4 months, whereas median PFS was 85.4 months. There was a significant trend for being in earlier stages of the disease and being diagnosed within 3 months from the onset of symptoms (P = .049). Both OS and PFS were similar in the patients diagnosed before or after 3 months from the symptoms onset (P = .772). The 6-12 months group was the group with the better median both OS (197.4 months) and DFS (197.4) from the diagnosis. The median OS for the other groups were similar among them. CONCLUSION: A delay in the diagnosis of MM is very frequent in México (68% of cases); despite the fact that there was a significant trend for being in earlier stages of the disease and being diagnosed within 3 months from the onset of symptoms, we did not find a relationship between a delay on the diagnosis of the disease and a higher risk of complications and/or poor prognosis. Possible explanations to these findings are discussed.

Neutrophil to lymphocyte ratio and systemic immune-inflammatory index as markers of response to autologous hematopoietic stem cell transplantation in persons with multiple sclerosis.

INTRODUCTION: Biomarkers that help to evaluate the immune system and could be useful in multiple sclerosis (MS) are the neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and systemic immune-inflammatory index (SII). The objective of this work is to evaluate the significance of the SII index, PLR, and NLR before and after transplantation in individuals with MS who underwent autologous hematopoietic stem cell transplant (aHSCT) at a single institution. METHODS: Patients with MS who received an aHSCT between 2017 and 2022 were included in the study. NLR, PLR, and SII index were calculated prior to the transplant and 100 days after, and evaluation of the expanded disability status scale (EDSS) was done before the transplant and 12 months after. The cohort was divided into two groups: aHSCT responders (R) and nonresponders (NR). RESULTS: Fifty-eight individuals were examined: 37 patients in the responders group R group and 21 in NR group. There was no statistically significant difference in the SII, NLR, and PLR prior to the transplant, however at 100 days post-HSCT, NLR in the R group was 1.8 versus 3.1 in the NR group (p = 0.003), PLR was 194 versus 295, respectively (p = 0.024), meanwhile SII index was 489.5 versus 729.3 (p < 0.001). CONCLUSION: High NLR and SII index values after the aHSCT were associated with a worsening in the EDSS score. However, since this is the first ever study that compared NLR and SII index with the aHSCT response in persons with MS, further studies must be performed to corroborate this information.

More about post-transplant cyclophosphamide in haploidentical grafts: full or reduced doses?

Haploidentical hematopoietic can be conducted on an outpatient basis but the two main reasons to accept into the hospital a patient in this setting are complications of the hematological toxicity and/or the cytokine-release syndrome. With the aim of reducing the post-transplant cyclophosphamide-dependent toxicity without compromising its effectivity, attempts to reduce the dose of post-transplant cyclophosphamide have been made: Decreases from the conventional total dose of post-transplant cyclophosphamide (100 mg/Kg) have been explored worldwide, showing that decreasing the total dose to even 50 mg/Kg significantly decreases the toxicity of the procedure without compromising its efficacy, safety and results. We present here the salient data of the attempts to diminish the doses of post-transplant cyclophosphamide which have been done and published worldwide, information that suggests that the conventional doses of post-transplant cyclophosphamide can be significantly reduced thus decreasing the toxicity, without compromising the effectiveness of the procedure, mainly the development of graft versus host disease.

The consequences of delayed diagnosis and treatment in persons with multiple sclerosis given autologous hematopoietic stem cell transplantation.

OBJECTIVES: We have analyzed the association of delayed both diagnosis and treatment of persons with MS with the long-term results of patients given autologous hematopoietic stem cell transplantation (aHSCT). METHODS: Patients with MS referred to the HSCT-Mexico program were included in the study; in 103, detailed pre- and post-transplant evolution could be recorded. Two groups of patients were analyzed according to the time of evolution between the onset of symptoms and the definite diagnosis of MS: more than 8 months (delayed diagnosis, DD), or less than 8 months (non-delayed diagnosis, NDD). The progression of MS was assessed by changes in the expanded disability status scale (EDSS). RESULTS: The time elapsed between the onset of symptoms and the correct diagnosis was lower for the NDD group (1.55 vs. 35.87 months, p<0.05). Both groups of patients showed a similar EDSS score at diagnosis (1.5 vs. 1.5); however, the EDSS at the time of the transplant was higher in the DD group (4.5 vs. 3.0, p=0.3) and the response of the EDSS score to the transplant was significantly better for the NDD group, the last EDSS scores being 2.5 vs. 4.25 (p=0.03). Both groups of patients responded to aHSCT by diminishing the EDSS, but the response was significantly better in the NDD group. CONCLUSIONS: These data indicate that both the pre-transplant progression of the disease and the response to aHSCT were significantly worse in the DD group. An early diagnosis and an early aHSCT intervention are critical for a good prognosis, in terms of lowering and stabilizing the motor disability in MS patients given autografts.

Second Autologous Hematopoietic Stem Cell Transplantation in Multiple Sclerosis: A Single-Center Prospective Experience.

Immunosuppressive therapy is useful in persons with multiple sclerosis (MS), and autologous hematopoietic stem cell transplantation (aHSCT) is the most effective immunosuppressive treatment in this setting. Information on the usefulness of a second aHSCT in patients with MS is scarce. In a group of 1225 individuals with MS prospectively managed with aHSCT, we analyzed the salient features of 4 patients who received 2 consecutive transplants. After a moderate initial response to the first aHSCT, the patients were transplanted again after deterioration of their neurologic status; the second transplant was well tolerated and, in all instances, was completed on an outpatient basis and with no associated undesired toxicity. The autograft protocol is registered in ClinicalTrials.gov, identifier NCT02674217. After the second graft, the expanded disability status scale score stabilized in 2 patients; in 1, the post-transplant period was too short to assess the response, and in another, the development of associated Parkinson's disease precluded the assessment of the outcome. In conclusion, a second aHSCT in persons with MS is feasible, safe, and may lead to a positive response in some cases.

In persons with CIDP, auto-HSCT can be conducted fully on an outpatient basis and induces significant clinical responses: A prospective study in a single center.

BACKGROUND: Chronic inflammatory demyelinating polyneuropathy (CIDP) is one of the world's most common treatable neuropathy which usually responds to immunosuppressive treatment. Autologous hematopoietic stem cell transplantation (aHSCT) is an intense way of inducing immunosuppression. OBJECTIVE: We analyze the evolution of CIDP patients treated with aHSCT in our center. METHODS: Between 2018 and 2023, persons with CIDP were prospectively autografted employing the "Mexican method" to conduct grafts on an outpatient basis, employing cyclophosphamide 200 mg/Kg and rituximab 1000 mg. The protocol is registered in ClinicalTrials.gov identifier NCT02674217. RESULTS: In our center 21 autologous transplant cases were completed in 2018-2023. Seven patients provided data to assess the efficacy of the procedure. Positive responses (stabilization and/or improvement) were observed in all seven patients: Five reported improvements in the Inflammatory Neuropathy Cause and Treatment (INCAT) score and one reported stabilization. In the Inflammatory Rasch-Built Overall Disability Scale (I-RODS) score. Median INCAT score was 5 (range 1-9), whereas median I-RODS score was 24 (range 11-29). Five patients (71%) reported improvement in the INCAT score, one reported stabilization and one informed worsening; concerning the I-RODS score 5 (71%) informed improvement, whereas two reported stabilization. CONCLUSION: aHSCT conducted fully in an outpatient basis, employing the conditioning regimen of the "Mexican method" appears to be a feasible therapeutic option for persons with CIDP. Additional studies are needed to confirm these observations.

Can doses of post-transplantation cyclophosphamide in haploidentical stem cell allografts be reduced?

Objectives: Allogeneic hematopoietic stem cell transplantation (HSCT) remains the most important curative modality for several hematologic malignancies, but an HLA-matched sibling or unrelated donor is not always available, particularly for ethnic minorities and multiethnic families. We have shown that Haplo-HSCT can be conducted safely on an outpatient basis, using peripheral blood stem cells; this leading into substantial decreases in the costs. Methods: In this study twenty-one patients prospectively received the conventional dose of post-transplantation cyclophosphamide (PTCy): (50 mg/Kg on days 3 and 4), whereas 10 were given reduced doses of the drug (25 mg/Kg on days 3 and 4). Results: According to the statistical analysis, the two comparative groups (PTCy 50 mg/kg vs PTCy 25 mg/kg) had no significant difference in terms of age, sex, hematological recovery, and type of conditioning regimen. The median OS for the group PTCy 50 mg/kg is 5.7 months meanwhile for the group PTCy 25 mg/kg the median is 6.4 months. The median follow up for entire group is 4.5 months (IQR: 1.1-18.9 mo). Conclusion: These results could indicate that the Cy-dependent hematological toxicity can be reduced without compromising its effectivity. This preliminary observation may be considered as an idea to conduct prospective randomized studies to explore the possibility of significantly reducing the doses of PT-Cy in the setting of Haplo-HSCT.Trial registration: ClinicalTrials.gov identifier: NCT05780554.

Therapy of childhood acute lymphoblastic leukemia in resource-poor geospaces.

The therapy of children with acute lymphoblastic leukemia (ALL) in limited resource geospaces is challenging and must balance safety, efficacy, availability, and affordability. We modified the control arm of the St. Jude Total XI protocol for outpatient delivery including once-weekly daunorubicin and vincristine in initial therapy, postponing intrathecal chemotherapy until day 22, prophylactic oral antibiotics/antimycotics, use of generic drugs, and no central nervous system (CNS) radiation. Data were interrogated from 104 consecutive children ≤12 years (median, 6 years [interquartile range (IQR), 3, 9 years]. All therapies were given in an outpatient setting in 72 children. Median follow-up is 56 months (IQR 20, 126 months). A total of 88 children achieved a hematological complete remission. Median event-free survival (EFS) is 87 months [95% confidence interval (CI), 39, 60], 7.6 years in low-risk children (3.4, 8 years) whereas 2.5 years (1, 10 years) in high-risk children. The 5-year cumulative incidence of relapse (CIR) is 28% (18, 35%), 26% (14, 37%) in low-risk children and 35% (14, 52%) in high-risk children. Median survival for all subjects is not reached but must exceed 5 years. A total of 36 children relapsed at a median of 12 months (5, 23 months). Outcomes were comparable to those reported in the control arm of the Total Therapy XI study, but inferior to current treatment protocols in high-income countries. The average cost of the first 2 years of therapy was $28,500 USD compared with an average cost of approximately $150,000 USD in the US, an 80% saving. In conclusion, using an outpatient-based modification of the St. Jude Total XI protocol, we obtained good results with relatively few hospitalizations or adverse events and at a substantial saving. This model can be applied in other resource-poor geospaces.

Long-term results of autografting persons with multiple sclerosis are better in those not exposed to prior disease-modifying therapies.

INTRODUCTION: Multiple sclerosis (MS) is a disabling disease that affects young adults. Treatments for MS have increased exponentially in number, efficacy and risk. Autologous hematopoietic stem cell transplantation (aHSCT) can change the natural history of the disease. To analyze if aHSCT should be done early in the course of the disease or after failing of other therapies, we have studied the long-term results of aHSCT in a cohort of persons with MS who were given, or not, immunosuppressive drugs before the transplant. MATERIALS AND METHODS: Patients with MS referred to our center for aHSCT between June 2015 and January 2023 were prospectively entered in the study. All phenotypes of MS were included (relapsing remitting, primary progressive and secondary progressive). The follow up was assessed with the patient reported EDSS score in an online form; only patients followed by three or more years were included in the analysis. Patients were divided into two groups: Given or not disease modifying treatments (DMT) before the aHSCT. RESULTS: 1132 subjects were prospectively enrolled. 74 patients were followed for more than 36 months, and the subsequent analysis was done in this cohort. The response rate (RR = improvement + stabilization) at 12, 24 and 36 mo was 84%, 84% and 58% respectively for patients not receiving prior DMT and 72%, 90% and 67% for patients receiving DMT. In the whole group, the EDSS score dropped from a mean of 5.5 to 4.5 at 12 mo, to 5.0 at 24 mo and to 5.5 at 36 mo, after the aHSCT. The EDSS score was on average worsening in patients before the aHSCT, but the transplant stabilized the EDSS score at 3 years in patients with prior exposure to DMT, whereas in persons not given DMT, the transplant resulted in a significant decrease (p = .01) of the EDSS score. This indicates a positive response in all patients given aHSCT, but significantly better in those not exposed to DMT before the graft. CONCLUSION: The response to aHSCT was better for persons not exposed to immunosuppressive DMT before the transplant, thus suggesting that aHSCT should be done early in the course of the disease and probably before the treatment with DMT. Additional studies are needed to further analyze the impact of the use of DMT therapies before the aHSCT in MS, as well as the timing of the procedure.

SARS-CoV-2-infection in the setting of autotransplants for multiple sclerosis.

The severe adult respiratory syndrome virus type 2 (SARS-CoV-2) related acute respiratory distress syndrome (ARDS) has a strong immunological and inflammatory component; accordingly investigators are employing monoclonal antibodies to ameliorate the virus-induced cytokine storm such as antibodies against interleukin 6 (IL-6), tumor necrosis factors alpha (TNF-alpha) and CC chemokine receptor 5 (CCR5) (1). Cyclophosphamide (Cy) has proven its role in various settings including autoimmune diseases, and in the post-haploidentical stem cell transplant setting; Cy depletes cytotoxic and effector T cell populations while relatively sparing the regulatory T cells (Tregs) and could tip the balance away from the overtly pro-inflammatory setting (1). We present here the cases of three persons who were infected by the SARS-CoV-2 virus during the Cy-induced pancytopenia of an autologous hematopoietic stem cell transplantation (HSCT), aimed to down-regulate the immune response in multiple sclerosis (MS) (2). The surprisingly benign course of the COVID-19 in the three cases suggest that the Cy could have had a role in abrogating the inflammatory response in these persons.

Non-alcoholic fatty liver disease and thrombocytopenia IV: its association with granulocytopenia

ABSTRACT Introduction: We have previously shown that some patients present thrombocytopenia (less than 100 × 109/L platelets) in non-alcoholic fatty liver disease (NAFLD). To further explore the nature of this association, we have now analyzed the association of thrombocytopenia with neutropenia (less than 0.5 × 109/L granulocytes) in NAFLD. Material and methods: Persons with NAFLD were prospectively accrued in the study after February 2018. The presence of NAFLD was defined by both serologic determinations (Fibromax ®) and liver transient elastography (TE/Fibroscan ®). Results: In 123 consecutive patients with NAFLD without cirrhosis, thrombocytopenia was identified in 20 (16%), whereas neutropenia was identified in 9 (7%). In the subset of 20 patients with NAFLD and thrombocytopenia, granulocytopenia was identified in 5 (25%), whereas in the subset of 9 patients with granulocytopenia, thrombocytopenia was identified in 5 (55%). We found a significant association between thrombocytopenia and both leukopenia and granulocytopenia (OR 8.25, 95% CI 1.9-34.2, p = 0.004). Conclusions: Both thrombocytopenia and neutropenia were identified in persons with NAFLD and, as there is a significant relationship between these two variables, we speculate that this finding may support the possibility of hypersplenism being involved in the cytopenias found in NAFLD without cirrhosis.

Non-alcoholic fatty liver disease and thrombocytopenia IV: its association with granulocytopenia.

INTRODUCTION: We have previously shown that some patients present thrombocytopenia (less than 100 × 109/L platelets) in non-alcoholic fatty liver disease (NAFLD). To further explore the nature of this association, we have now analyzed the association of thrombocytopenia with neutropenia (less than 0.5 × 109/L granulocytes) in NAFLD. MATERIAL AND METHODS: Persons with NAFLD were prospectively accrued in the study after February 2018. The presence of NAFLD was defined by both serologic determinations (Fibromax ®) and liver transient elastography (TE/Fibroscan ®). RESULTS: In 123 consecutive patients with NAFLD without cirrhosis, thrombocytopenia was identified in 20 (16%), whereas neutropenia was identified in 9 (7%). In the subset of 20 patients with NAFLD and thrombocytopenia, granulocytopenia was identified in 5 (25%), whereas in the subset of 9 patients with granulocytopenia, thrombocytopenia was identified in 5 (55%). We found a significant association between thrombocytopenia and both leukopenia and granulocytopenia (OR 8.25, 95% CI 1.9-34.2, p = 0.004). CONCLUSIONS: Both thrombocytopenia and neutropenia were identified in persons with NAFLD and, as there is a significant relationship between these two variables, we speculate that this finding may support the possibility of hypersplenism being involved in the cytopenias found in NAFLD without cirrhosis.

Long-term results of the treatment of Hodgkin's lymphoma in a resource-constrained setting: Real-world data from a single center.

BACKGROUND: The outcomes of Hodgkin´s lymphoma (HL) in México have not been widely reported. Simplified and affordable treatments have been adopted in middle-income countries. AIM: The aim was to evaluate long-used therapies for HL in México in a long-term basis. METHODS: In a 34-year time period, 88 patients with HL were treated at a single institution in México. Patients were treated with adriamycin bleomycin vinblastine and dacarbazine (ABVD) or mechlorethamine, vincristine, procarbazine, and prednisone (MOPP). Relapsed or refractory patients were given ifosfamide, carboplatin, and etoposide (ICE) followed by autologous or allogeneic stem cell transplants. RESULTS: Thirty-seven women and 51 men were included; the median age was 29 years. Patients were followed for a mean of 128 mo. The 310-mo overall survival (OS) was 83% for patients treated with MOPP and 88% for those treated with ABVD. The OS of patients who received autologous stem cell transplantation was 76% (330 mo) vs 93% (402 mo) in those who did not. CONCLUSION: HL may be less aggressive in Mexican population than in Caucasians. Combined chemotherapy renders acceptable results, regardless of clinical stage.

Hematopoietic stem cell transplantation (HSCT) in the COVID-19 pandemic era / Trasplante de células progenitoras hematopoyéticas (TCPH)en la era del COVID-19

Abstract The pandemic of coronavirus infectious disease-2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a threat to global health. This has become an obstacle for the practice of hematology, mostly in low-middle income countries. For those hematologist and oncologists who perform hematopoietic stem cell transplantation HSCT the usual challenges of this kind of medical procedures have increased because of the COVID-19 pandemic. The importance of find the best route for performing HSCT avoiding excessive COVID-19 risk is of great importance. By doing so, we have been able to conduct 170 hematopoieic stem cell transplants during the COVID-19 pandemia.

Resumen La pandemia de COVID-19 ha causado daños graves a la práctica de la medicina y se ha convertido en un obstáculo para la práctica de algunas especialidades. Los trasplantes de células hematopoyéticas han sufrido las consecuencias de la pandemia y muchos centros de trasplante hematopoyético en todo el mundo suspendieron sus labores. Gracias a la implementación de medidas de escrutinio y aislamiento de los pacientes sometidos a trasplante hematopoyético, hemos podido trasplantar a 170 pacientes en la época del COVID-19.

Up to half of patients diagnosed with chronic lymphocytic leukemia in México may not require treatment.

Introduction: Although therapeutic choices for patients with chronic lymphocytic leukemia (CLL) were once limited, treatment of this disease has vastly improved in the last decades.Patients and methods: Consecutive CLL patients diagnosed in a single institution were analyzed. Treatment was withheld in persons with CLL Rai stage 0 or 1, until progression and in persons with stages 2-4, with a negative expression of ZAP-70 until progression. Between 1983 and 1991, patients were give chlorambucil and prednisone (CP); after 1991 fludarabine and cyclophosphamide (FC) and after 1998, rituximab and FC (FCR).Results: 98 patients with CLL were identified; 49 were followed for >3 months. 21 persons (43%) did not require treatment nor progressed; 14 received CP, 6 FC, 7 FCR and one rituximab. Median overall survival (OS) has not been reached, being above 247 months; median OS for patients given CP was 115 months, for FC above 132 months and for FCR above 136 months (p > 0.5).Conclusion: CLL seems to be less aggressive in Mexican mestizos than in Caucasians; 43% of patients do not need treatment at all.

Treatment of Persons with Multiple Myeloma in Underprivileged Circumstances: Real-World Data from a Single Institution.

BACKGROUND: The treatment of patients with multiple myeloma (MM) has evolved in recent years, and the disease-associated prognosis has improved substantially. This improvement has been driven largely by the approval of novel agents, many of which are expensive and not universally available. Less expensive but effective approaches would be of value globally. PATIENTS AND METHODS: All consecutive MM patients diagnosed in the Centro de Hematología y Medicina Interna de Puebla after 1993 were included in this study. Patients were given oral thalidomide (100 mg/day), oral dexamethasone (36-40 mg/week), and aspirin 100 mg/day. Bor-tezomib (1.75 mg s.c. every week) was administered to those who could afford it. After 4-6 weeks of treatment, patients were offered an outpatient-based hematopoietic cell transplant (HCT). After the recovery of granulocytes following HCT, patients continued indefinitely on thalidomide; those who failed to tolerate thalidomide were switched to lenalidomide (25 mg/day). RESULTS: The median overall survival (OS) for all patients has not been reached and is >157 months. Median follow-up of the patients lasted 14 months (range 1.3-157). The median OS of patients with and without HCT was similar. The response rate (complete remission or very good partial remission) was 72% for those given thalidomide plus dexamethasone versus 88% for those given bortezomib, thalidomide, and dexamethasone before HCT, but OS was not different. As post-HCT maintenance, 37 patients received thalidomide; 26 of those (70%) could be maintained indefinitely on thalidomide, whereas 11 were switched to lenalidomide after a median of 7 months; median OS of patients maintained on thalidomide or lenalidomide after HCT was not different. CONCLUSION: In this series, a regimen incorporating low-cost novel agents and outpatient HCT was associated with excellent long-term survival in the treatment of MM patients. This approach may be a model for MM treatment in underprivileged circumstances.

Nonalcoholic Fatty Liver Disease and Thrombocytopenia III: Its Association With Insulin Resistance.

Thrombocytopenia (less than 100 × 109/L platelets) presents in around one quarter of patients with nonalcoholic fatty liver disease (NAFLD), the hepatic component of insulin resistance (IR). It is unknown whether IR, by itself, associates with thrombocytopenia. Persons with NAFLD and/or IR were prospectively accrued in the study after February 2018. Insulin resistance was defined by assessing α hydroxybutyrate, lynoleoyl glycerolphosphocoline, oleic acid, and insulin (Quantose IR), whereas the presence of NAFLD was defined by serologic determinations (Fibromax) and liver transient elastography (Fibroscan). In 78 patients with NAFLD, thrombocytopenia was identified in 22 (28%), whereas in 19 persons with IR, 14 (73%) were found to have NAFLD. In persons with IR + NAFLD, thrombocytopenia presented in 9 (64%). In the subset of patients with IR, the prevalence of thrombocytopenia was 52%. There was only 1 patient with IR/without NAFLD who displayed thrombocytopenia. Significant statistical association between NAFLD and thrombocytopenia was found (odds ratio [OR]: = 13, confidence interval [CI]: 1.5-162, P = .05), whereas there was no association between IR and thrombocytopenia (OR = 0.38, CI: 0.06-2.3, P = .61). Insulin resistance, by itself, was not found to be associated with diminished platelet counts. The presence of NAFLD, one of the consequences of IR, seems to be required to lead into thrombocytopenia.