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.

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.

High dose melphalan is an adequate preparative regimen for autologous hematopoietic stem cell transplantation in relapsed/refractory lymphoma.

INTRODUCTION: High-dose melphalan (HD-Mel) has been successfully employed in autografting patients with multiple myeloma. An advantage of this regimen is that the total dose of Mel can be delivered in a single day, being particularly useful when non-frozen hematopoietic stem cells are employed in the autograft. MATERIAL AND METHODS: All consecutive patients with R/R lymphomas, both HL and NHL studied and treated at two different centers were prospectively included in a study of ASCT employing a single dose of HD-Mel (200 mg/m2). A group of R/R HL or NHL autografted employing BEAM-like preparative regimens was constructed matched by diagnosis and age. The primary endpoint of the study was overall survival (OS), the secondary endpoint was event-free survival (EFS). RESULTS: Twenty-five R/R HL/NHL patients were prospectively accrued in the study. There were 8 (32%) females, 13 (52%) patients had at least 1 adverse effect: 7 (28%) developed mucositis, 5 (20%) neutropenic fever, and 6 (24%) grade IV nausea. In the HD-Mel group, median overall survival (OS) was not achieved and OS at 36 months was 71%, the transplant-related mortality being 0%. In the control group, median OS was not achieved and the 36-month OS was 76%, results not statistically significant (p 0.5). The EFS was also similar in both groups (p 0.5). CONCLUSION: HD-Mel alone is non-inferior to a BEAM-like regimen as a preparative regimen for autografting patients with R/R HL and NHL. The regimen is adequate to graft persons with non-frozen stem cells.

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.

PERSPECTIVES IN DIAGNOSIS AND THERAPEUTICS IN HEMATOLOGY.

In this article, the perspectives on both the diagnosis and treatment of acute leukemias, chronic leukemias, multiple myeloma, anemia, platelet, and coagulation disorders are briefly discussed. We emphasize the limitations facing the practice of hematology in low- and middle-income countries.

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.

Determine safety of outpatient chemotherapy and autotransplants using refrigerated, non-frozen grafts in persons with multiple sclerosis.

BACKGROUND: Persons with multiple sclerosis are increasingly treated with intermediate- or high-dose chemotherapy and a hematopoietic cell autotransplant. This is often done in an inpatient setting using frozen blood cell grafts. OBJECTIVE: Determine if chemotherapy and a hematopoietic cell autotransplant can be safely done in an outpatient setting using refrigerated, non-frozen grafts. METHODS: We developed an autotransplant protocol actionable in an outpatient setting using a refrigerated, non-frozen blood graft collected after giving cyclophosphamide, 50 mg/kg/d × 2 days and filgrastim, 10 µg/kg/d. A second identical course was given 9 days later followed by infusion of blood cells stored at 4°C for 1-4 days. The co-primary outcomes were rates of granulocyte and platelet recovery and therapy-related mortality. RESULTS: We treated 426 consecutive subjects. Median age was 47 years (range, 21-68 years). A total of 145 (34%) were male. Median graft refrigeration time was 1 day (range, 1-4 days). Median interval to granulocytes >0.5 × 10E + 9/L was 8 days (range, 2-12) and to platelets >20 × 10E + 9/L, 8 days (range, 1-12). Only 15 subjects (4%) were hospitalized, predominately for iatrogenic pneumothorax (N = 5) and neutropenic fever (N = 4). There was only 1 early death from infection. CONCLUSION: Intermediate-dose chemotherapy and a hematopoietic cell autotransplant can be safely done in an outpatient setting using, refrigerated, non-frozen grafts.

IKAROS Gene Deleted B-Cell Acute Lymphoblastic Leukemia in Mexican Mestizos: Observations in Seven Patients and a Short Review of the Literature.

BACKGROUND: In B-cell acute lymphoblastic leukemia, one of the most frequent cytogenetic alterations is the presence of the Philadelphia chromosome. Recently, newly identified genetic alterations have been studied, among them the IKZF1 deletion. IKZF1 encodes IKAROS, a zinc finger protein that plays an important role in hematopoiesis involving the regulation process of adhesion, cellular migration, and as a tumor suppressor. OBJECTIVE: We aimed to study the impact of IKAROS deletion in the evolution and prognosis of B-cell acute lymphoblastic leukemia. MATERIALS AND METHODS: At a single center we prospectively studied patients diagnosed with B-cell acute lymphoblastic leukemia and screened for IKZF1 deletion using the multiplex ligation-dependent probe amplification method. We did a descriptive analysis of patients positive for the IKZF1 deletion to determine its impact on the evolution of the disease and survival rate. RESULTS: Between 2010 and 2015, 16 Mexican mestizo patients with B-cell acute lymphoblastic leukemia were prospectively screened for IKZF1 deletion; seven (43%) were positive and were included for further analysis. The age range of patients was 13-60 years; six were males and one female. All cases had type B acute lymphoblastic leukemia. Of the seven patients, two died, three were lost to follow-up, and two continue in complete remission with treatment. Results are worse than those in a group of patients with non-mutated IKAROS B-cell acute lymphoblastic leukemia previously studied in our center. CONCLUSIONS: Although this is a small sample, the presence of IKAROS deletion in acute lymphoblastic leukemia patients could represent a poor-prognosis marker and was probably related to therapy failure. It is also possible that this variant of leukemia may be more prevalent in Mexico. More studies are needed to define the role of IKZF1 deletion in acute lymphoblastic leukemia and the real prevalence of the disease in different populations.

Advances in the diagnosis and treatment of acute and chronic leukemia in Mexico.

In the last 60 years, there have been substantial advances regarding the diagnosis and treatment of patients with acute and chronic leukemia in Mexico. Immunologic and molecular classifications of these diseases have improved both diagnosis and therapeutic capabilities. Although the pace of diagnostic and therapeutic advances has been slower compared with developed countries, Mexico is at the forefront among developing countries. Supporting research in these fields is expected to enhance the generation of new knowledge and improve the care of patients suffering from these diseases.

Haploidentical peripheral blood stem cell transplantation with posttransplant cyclophosphamide in children and adolescents with hematological malignancies.

BACKGROUND: Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) using posttransplant cyclophosphamide (Cy) for graft versus host disease (GVHD) prophylaxis has emerged as an alternative transplant strategy for patients without related donors, especially in the setting of limited resources in which T-cell ex vivo depletion is not affordable. Experience with this transplant modality in children and adolescents is limited. PROCEDURE: We report a retrospective analysis of 25 consecutive outpatients under 21 years of age with high-risk hematological malignancies, who received a haplo-HSCT using posttransplant Cy as GVHD prophylaxis. RESULTS: Twenty-three (92%) of the 25 patients engrafted, and 20 (95%) of 21 evaluable subjects achieved full donor chimerism by day +30. One-year estimated overall survival and event-free survival were 50% and 33%, respectively. The cumulative incidence rate of severe acute GVHD was 19%, and 15% of patients developed chronic GVHD. CONCLUSIONS: Haplo-HSCT with posttransplant Cy is a feasible therapeutic option for children and adolescents with high-risk hematological malignancies in a limited resource setting.

Advances in the diagnosis and treatment of acute and chronic leukemia in Mexico / Avances en el diagnóstico y tratamiento de las leucemias agudas y crónicas en México

Abstract In the last 60 years, there have been substantial advances regarding the diagnosis and treatment of patients with acute and chronic leukemia in Mexico. Immunologic and molecular classifications of these diseases have improved both diagnosis and therapeutic capabilities. Although the pace of diagnostic and therapeutic advances has been slower compared with developed countries, Mexico is at the forefront among developing countries. Supporting research in these fields is expected to enhance the generation of new knowledge and improve the care of patients suffering from these diseases.

Resumen En los últimos 60 años ha habido avances notables en el diagnóstico y tratamiento de los pacientes con leucemia aguda y crónica en México. Las clasificaciones inmunológicas y moleculares de esta enfermedad han mejorado tanto la capacidad diagnóstica como las derivaciones terapéuticas. Si bien el ritmo de los avances diagnósticos y terapéuticos en México se ha visto retrasado cuando se compara con el de países desarrollados, se encuentra a la vanguardia entre los países en vías de desarrollo. El apoyo a las labores de investigación en estas áreas del conocimiento seguramente redundará en beneficio de la generación de nuevos conocimientos y de la atención de los pacientes que sufren estas enfermedades.

Reduced-intensity stem cell allografting for PNH patients in the eculizumab era: The Mexican experience.

Background Paroxysmal nocturnal haemoglobinuria (PNH) presents as two major entities: the classical form, predominantly haemolytic and a secondary type with marrow failure and resultant aplastic anaemia (AA-PNH). Currently, the treatment of choice of the haemolytic variant is eculizumab; however, the most frequent form of PNH in México is AA-PNH. Patients and methods Six consecutive AA-PNH patients with HLA-identical siblings were allografted in two institutions in México, employing a reduced-intensity conditioning regimen for stem cell transplantation (RIST) conducted on an outpatient basis. Results Median age of the patients was 37 years (range 25-48). The patients were given a median of 5.4 × 10(6)/kg allogeneic CD34(+) cells, using 1-3 apheresis procedures. Median time to achieve above 0.5 × 10(9)/l granulocytes was 21 days, whereas median time to achieve above 20 × 10(9)/l platelets was 17 days. Five patients are alive for 330-3150 days (median 1437) after the allograft. The 3150-day overall survival is 83.3%, whereas median survival has not been reached, being above 3150 days. Conclusion We have shown that hypoplastic PNH patients can be allografted safely using RIST and that the long-term results are adequate, the cost-benefit ratio of this treatment being reasonable. Additional studies are needed to confirm the usefulness of RIST in the treatment of AA-PNH.

Secondary malignancies after allogeneic hematopoietic stem cell transplantation using reduced-intensity conditioning and outpatient conduction.

BACKGROUND: Patients given allogeneic hematopoietic stem cell transplants (HSCT) may develop secondary malignant neoplasms (SMN). Several variables have been identified but there are no data about the incidence of this complication in individuals given HSCT using reduced-intensity conditioning (RIC) methods. OBJECTIVE: Define the incidence of SMN in patients given HSCT using a RIC preparative regimen conducted on an outpatient basis. MATERIALS AND METHODS: Patients given HSCT in two institutions between October 1998 and 2012 were analyzed. To appraise the SMN appearance, those patients dead were also regarded as censored at that moment, as well as those lost to follow up and those alive at the closing of the study. 95% Confidence intervals (CI) for the survival or failure estimate were calculated with the Greenwood's method. RESULTS: A total of 416 allografted patients with a Karnofsky performance index of 100% were included in the study. All patients received peripheral blood stem cells allografts. The conditioning regimen was delivered as an outpatient procedure in all individuals. No patient was given radiotherapy nor antithymocyte globulin during the conditioning. Three hundred and sixty five patients (88%) were never admitted to the hospital, whereas 12% were admitted because of grade III-IV acute graft versus host disease (aGVHD), fever, or mucositis. Median survival time was 15.7 months. Survival at 6 months (95% CI): 66.4% (61.5-70.8%), at 12 months: 53.3% (48.1-58.1%), at 60 months: 30.6% (30.5-41.5%). Eight patients with a SMN were identified in the group of 416 allografted patients, SMN rates (95% CI) were: one year post graft: 1.9% (0.7-4.9%), 5 years: 3.8% (1.6-9.2%), 10 years: 6.8% (2.6-17.7%) and 13 years post-graft: 20.2% (5.5-59.2%), the cumulative probability of SMN being 6.8 at 10 years. Since the number of expected cases in the general population is 0.62, the ratio of observed to expected cases is 12.9 (P < 0.001). This figure means that the risk of developing a malignant neoplasm in allografted individuals using our method is 12.9 times higher than that in the general population. There were three non-Hodgkin's lymphomas, two M2 acute myelogenous leukemias, one hairy cell leukemia, one tongue epidermoid carcinoma, and one breast carcinoma. CONCLUSIONS: We have found a low incidence of SMN in this group of Mexican patients allografted with the Mexican RIC method. Possible explanations for this difference are discussed, focusing on the RIC preparative regimen.

In pursuit of the graft-versus-myeloma effect: a single institution experience.

Partly because of a potential graft-versus-myeloma effect, allogeneic stem cell transplantation is a potentially curative treatment modality in patients with multiple myeloma (MM). Initial attempts have been hampered by the high transplant-related mortality in this setting. With a reduction of toxicity, allogeneic transplant approaches with reduced-intensity conditioning (RIC) have been utilized, although they are subjected to continued disease progression and relapse following transplantation. We analyze here the experience of allografting four patients with MM in a single institution, along a 16-year period in which a total of 152 individuals were allografted, using an RIC regimen; three of the patients have had previous autografts. All patients engrafted successfully and a graft-versus-myeloma effect was shown in all of them. One patient relapsed in the face of graft-versus-host disease (GVHD). Three patients have died (two as a result of GVHD) and one is alive with a limited form of chronic GVHD. The graft-versus-myeloma effect can be induced by means of allogeneic transplantation but the morbidity and mortality associated with the procedure leads into a relatively small proportion of MM patients being cured.

Simultaneous romiplostin, eltrombopag, and prednisone were successful in severe thrombocytopenia of Evans syndrome refractory to hydrocortisone, splenectomy, intravenous IgG, and rituximab.

A 58-year-old woman presented with rheumatoid arthritis-associated Evans syndrome (simultaneous autoimmune hemolytic anemia and autoimmune thrombocytopenic purpura); she was treated unsuccessfully with steroids, romiplostin, rituximab, immunoglobulin G, and splenectomy. The platelet count responded to the combined use of prednisone, eltrombopag, and romiplostin. It may be more reasonable to use combined treatments than sequential monotherapies.