Significant differences in access to tests and treatments for multiple myeloma between public and private systems in Latin America. Results of a Latin American survey. GELAMM (Grupo de Estudio Latino Americano de Mieloma Múltiple).

The incidence of multiple myeloma (MM) has increased in the last 20 years, particularly in middle and low-middle income countries. Access to diagnostic and prognostic tests and the availability of effective care is highly variable globally. Latin America represents 10% of the world population, distributed in countries of varied size, population, and socio-economic development. In the last decade, great improvements have been made in the diagnosis and treatment of MM. Applying these advances in real life is a challenge in our region. Local data regarding MM standards of care and outcomes are limited. A survey was carried out among hematologists from 15 Latin American countries to describe access to MM diagnostic and prognostic tests and the availability of effective care options. This study provides real-world data for MM in our region, highlighting striking differences between public and private access to essential analyses and therapeutic options.

Self-reported changes in the expanded disability status scale score in patients with multiple sclerosis after autologous stem cell transplants: real-world data from a single center.

In order to reset the immune system to baseline function, autologous hematopoietic stem cell transplantation (HSCT) has been performed in patients with multiple sclerosis (MS). After June 2015, 617 new consecutive patients with MS were autografted in our center with non-frozen peripheral blood stem cells. The autografts were performed on an out-patient basis, after conditioning with cyclophosphamide and rituximab. The aim of the study was the assessment of both safety and efficacy of the method. The study's primary co-end-points were recovery of granulocyte and platelet counts and transplant-related mortality. Secondary end-points were overall survival and clinical response (improvement or stabilization of the self-reported expanded disability status scale score). The protocol was registered in ClinicalTrials.gov identifier NCT02674217.0. We included 401 females and 216 males, with a median age of 46 years. A total of 259 patients had relapsing-remitting MS (RRMS), 228 had secondary progressive (SPMS) and 130 had primary progressive (PPMS) multiple sclerosis. All procedures were initially performed on an out-patient basis and only 32 individuals (5%) required hospitalization. One to three aphereses (median 1) were required to harvest at least 1 × 106 /kg viable CD34+ cells. The total number of viable CD34+ infused cells ranged between 1 and 37·83 × 106 /kg (median 5·68). Patients recovered more than 0·5 × 109 /l absolute granulocytes by day 8 (median, range = 2-14), and platelet values were above 20 × 109 /l by day 4 (median, range = 0-11). Eleven individuals required red blood cells and six needed platelet transfusions. To date, there have been no deaths attributable to the transplant, yielding a 30-month overall survival of 100%. Patients have been followed for 3-42 months (median = 12). The overall response rate (decrease or stabilization of the self-reported EDSS score) at 12 months was 78% for all patients (83% in RRMS, 78% in PPMS and 73% in SPMS), while the disability progression-free survival was 82% for all patients (86% in RRMS, 78·5% in SPMS and 78% in SPMS). Changes in the self-reported EDSS score in parallel with neurological improvement were observed in people with all types of MS after HSCT, employing the 'Mexican method'.

Therapeutic choices in patients with Ph-positive CML living in Mexico in the tyrosine kinase inhibitor era: SCT or TKIs?

A total of 72 patients with Ph-positive CML in first chronic phase were followed during a 6-year period in two different institutions in México. Among them, 22 were given a reduced-intensity allogeneic SCT, whereas 50 were given a tyrosine kinase inhibitor (TKI), mainly imatinib mesylate. The 6-year overall survival (OS) after the therapeutic intervention for patients allografted or given a TKI was 77 and 84%, respectively (P, NS); the median OS for both groups has not been reached, being above 90 and 71 months, respectively (P, NS). The freedom from progression to blast or accelerated phases was also similar for both groups, as well as the overall OS after diagnosis. Most patients allografted (91%) chose this treatment because they were unable to afford continuing treatment with the TKI, whereas most treated with the TKI (84%) were given the treatment without charge, through institutions able to pay for their treatment. The median cost of each nonmyeloablative allograft was US$18,000, an amount that is enough to cover 180 days of treatment with imatinib (400 mg per day) in México. Cost considerations favor allogeneic SCT as a 'once only' procedure whereas lifelong treatment with an expensive drug represents an excessive burden on resources.

Non-myeloablative stem cell transplantation in patients with relapsed acute lymphoblastic leukemia: results of a multicenter study.

Using non-myeloablative conditioning, allogeneic hematopoietic stem cell transplantation (HSCT) was conducted in 43 ALL patients in a CR2. The median age of the patients was 19 years. Patients received oral busulfan 4 mg/kg/day for 2 days; i.v. cyclophosphamide 350 mg/m(2)/day for 3 days; and i.v. fludarabine 30 mg/m(2)/day for 3 days. Oral cyclosporin A 4 mg/kg was started and methotrexate 5 mg/m(2) was delivered on days 1, 3, 5 and 11. The median CD34+ cell dose received was 5.0 x 10(6)/kg. The medium time to achieve a granulocyte count above 0.5 x 10(9)/l was 14 days. Thirteen patients were alive 30-1050 days after the HSCT. The 3-year overall survival rate was 30%. Ten patients (23%) developed acute GVHD, whereas eight patients (18.6%) developed chronic GVHD. Thirty patients died between days 47 and 1050 after the HSCT, most of them (70%) because of an ALL relapse. One hundred-day mortality was 15%, whereas transplant-related mortality was 21%. These results are inferior to those obtained using the same allografting method in other leukemias, probably as a consequence of poor susceptibility to the graft-versus-leukemia effect of the ALL cells beyond first remission as compared with other hematological malignancies.

Outpatient allografting using non-myeloablative conditioning: the Mexican experience.

A group of 132 patients with both malignant and nonmalignant conditions was allografted using the 'Mexican' method of non-ablative conditioning. The conditioning was delivered on an outpatient basis and the procedure was planned to be conducted on outpatients in all cases. While 103 patients (78%) were able to complete the procedure totally as outpatients, 29 (22%) were hospitalized because of fever, mucositis or acute graft-versus-host disease. In a multivariate analysis, although differences were not statistically significant, it was found that the patients who were allografted as outpatients had higher levels of hemoglobin (12 versus 11.8 g/dl), higher platelet counts (248 versus 191 x 10(9)/l), lower white blood cell counts (11.7 versus 12.4 x 10(9)/l), higher Karnofsky scale scores (100 versus 90%) and lower creatinine levels (0.9 versus 0.93 mg/dl). A total of 86% of the patients with normal values for these variables could be allografted as outpatients, whereas only 67% of those with abnormal values completed the entire procedure as outpatients. It is concluded that allografting can be accomplished totally on an outpatient basis using the 'Mexican' reduced intensity-conditioning regimen.

Autologous peripheral blood stem cell transplantation in multiple myeloma using oral versus I.V. melphalan.

Autologous peripheral blood stem cell transplantation is the therapy of choice for the treatment of multiple myeloma (MM) patients younger than 70 years old. Between August 1993 and November 2004, 54 patients with MM were autografted after conditioning with high-dose oral melphalan 140 mg/m(2) in combination with etoposide and carmustine (28 patients) or with high-dose melphalan 200 mg/m(2) I.V. (26 patients). The oral and IV melphalan groups were comparable. There were no significant differences in disease-free survival (DFS) and overall survival (OS) between the groups; however, in patients transplanted in remission, OS and DFS were better in the I.V. melphalan group. Four good-prognostic factors were identified: interval between diagnosis and transplant <18 months, number of prior chemotherapy lines < or =2, remission status (complete or partial), and the use of I.V. melphalan. In conclusion, I.V. melphalan is the therapy of choice for conditioning patients with MM who are in remission.

Latin America: the next region for haematopoietic transplant progress.

Haematopoietic cell transplant activity in the 28 countries comprising Latin America is poorly defined. We conducted a voluntary survey of members of the Latin American Bone Marrow Transplantation Group regarding transplant activity 2009-2012. Collated responses were compared with data of transplant rates from the Worldwide Network for Blood and Marrow Transplantation for other geographic regions. Several socio-economic variables were analysed to determine correlations with transplant rates. In total, 94 teams from 12 countries reported 11 519 transplants including 7033 autotransplants and 4486 allotransplants. Annual activity increased from 2517 transplants in 2009 to 3263 in 2012, a 30% increase. Median transplants rate (transplant per million inhabitants) in 2012 was 64 (autotransplants, median 40; allotransplants, median 24). This rate is substantially lower than that in North America and European regions (482 and 378) but higher than that in the Eastern Mediterranean and Asia Pacific regions (30 and 45). However, the Latin America transplant rate is 5-8-fold lower than that in America and Europe, suggesting a need to increase transplant availability. Transplant team density in Latin America (teams per million population; 1.8) is 3-4-fold lower than that in North America (6.2) or Europe (7.6). Within Latin America, there is substantial diversity in transplant rates by country partially explained by diverse socio-economic variables including per capita gross national income, health expenditure and physician density. These data should help inform future health-care policy in Latin America.

The Latin American experience of allografting patients with severe aplastic anaemia: real-world data on the impact of stem cell source and ATG administration in HLA-identical sibling transplants.

We studied 298 patients with severe aplastic anaemia (SAA) allografted in four Latin American countries. The source of cells was bone marrow (BM) in 94 patients and PBSCs in 204 patients. Engraftment failed in 8.1% of recipients with no difference between BM and PBSCs (P=0.08). Incidence of acute GvHD (aGvHD) for BM and PBSCs was 30% vs 32% (P=0.18), and for grades III-IV was 2.6% vs 11.6% (P=0.01). Chronic GvHD (cGvHD) between BM and PBSCs was 37% vs 59% (P=0.002) and extensive 5% vs 23.6% (P=0.01). OS was 74% vs 76% for BM vs PBSCs (P=0.95). Event-free survival was superior in patients conditioned with anti-thymocyte globulin (ATG)-based regimens compared with other regimens (79% vs 61%, P=0.001) as excessive secondary graft failure was seen with other regimens (10% vs 26%, P=0.005) respectively. In multivariate analysis, aGvHD II-IV (hazard ratio (HR) 2.50, confidence interval (CI) 1.1-5.6, P=0.02) and aGvHD III-IV (HR 8.3 CI 3.4-20.2, P<0.001) proved to be independent negative predictors of survival. In conclusion, BM as a source of cells and ATG-based regimens should be standard because of higher GvHD incidence with PBSCs, although the latter combining with ATG in the conditioning regimen could be an option in selected high-risk patients.

Significance of one human leukocyte antigen mismatch on outcome of nonmyeloablative allogeneic stem cell transplantation from related donors using the Mexican schedule.

Using the Mexican approach to conduct nonablative stem cell transplantation (NST), we have prospectively performed 58 allografts in individuals with various malignant and nonmalignant hematological diseases using sibling donors, either HLA identical (6/6) or compatible, with one mismatch (5/6). When comparing allografts obtained from HLA identical (n=40) or compatible (n=18) siblings, respectively, the overall median survival was found to be 33 vs 8 months (P<0.01), the 52-month survival was 47 vs 38% (P>0.2), the prevalence of acute graft-versus-host disease (GVHD) 57 vs 38%, that of chronic GVHD 25 vs 11% and the relapse rate 45 vs 55%. The two patients who failed to engraft were both 5/6 matches. Probably stemming from the low number of patients, and despite a trend toward worse results in patients allografted from HLA compatible (5/6) siblings, most differences in outcome were not significant. It seems that NST can be offered to individuals with either an HLA identical or a compatible sibling donor.

Bloodless (transfusion-free) hematopoietic stem cell transplants: the Mexican experience.

We have analyzed the transfusion requirements of a group of 132 peripheral blood stem cell transplants from a single institution (73 allografts and 59 autografts) over a 10-year period. The allografts were conducted using the 'Mexican' nonmyeloablative conditioning regimen, while the autografts were given single-day high-dose melphalan. For the allografts, the median number of transfused packed red blood (PRBC) cell units was 1 (range 0-22), while the median number of platelet transfusion (PLT) sessions was 1 (range 0-9); 45% of allografted individuals did not require PRBC transfusions and 35% did not require PLT. For autografts, the median number of PRBC units was 2 (range 0-21), while the median number of PLT was 2 (range 0-21); 33% of autografted individuals did not require PRBC and 25% did not require PLT. We conclude that, by using certain preparative regimens, both allo and auto hematopoietic stem cell grafts can be conducted without the transfusion of blood products.

The early referral for reduced-intensity stem cell transplantation in patients with Ph1 (+) chronic myelogenous leukemia in chronic phase in the imatinib era: results of the Latin American Cooperative Oncohematology Group (LACOHG) prospective, multicenter study.

Using a reduced-intensity stem cell transplantation (RIST) schedule, 24 patients with Philadelphia (Ph1) (+) chronic myelogenous leukemia (CML) in first chronic phase (CP) were prospectively allografted in four Latin American countries: México, Brazil, Colombia and Venezuela, using HLA-identical siblings as donors. The median age of the patients was 41 years (range 10-71 years); there were eight females. Patients received a median of 4.4 x 10(6)/kg CD34 cells. The median time to achieve above 0.5 x 10(9)/l granulocytes was 12 days, range 0-41 days, and the median time to achieve above 20 x 10(9)/l platelets was also 12 days, range 0-45 days. In all, 22 patients are alive 81-830 (median 497) days after RIST. The 830-day probability of survival is 92%, and the median survival has not been reached, being beyond 830 days. A total of 11 patients (46%) developed acute graft-versus-host disease (GVHD), and seven of 23 (30%) developed chronic GVHD. Two patients died 43 and 210 days after RIST, one as a result of sepsis and the other of chronic GVHD. The 100-day mortality was 4.4%, and transplant-related mortality was 8%. RIST for patients with CML in CP appears to be an adequate therapeutic option.

Infectious mononucleosis mimicking a B cell immunoblastic lymphoma associated with an abnormality in regulatory T cells.

An elderly woman is described with infectious mononucleosis in whom cervical node biopsy was interpreted as showing immunoblastic lymphoma. Concomitant reactive lymphocytosis, Epstein-Barr virus serologic results consistent with an acute infection, and demonstration of polyclonal B cell infiltration of other tissues argued against intervention. Defective in vitro T cell responses were demonstrated during the acute phase of Epstein-Barr virus infection. Infectious mononucleosis has rarely been reported as mimicking a non-Hodgkin's lymphoma. At 18 months, our patient's course has been typical for infectious mononucleosis with no evidence of disseminated malignancy.

Cell surface markers in multiple myeloma.

OBJECTIVE: To describe the immunophenotype of normal and myelomatous plasma cells (PCs) and the changes in immunoregulatory nonmyelomatous cells in multiple myeloma (MM). DESIGN: The cell surface markers (antigens) associated with this common cancer were reviewed. MATERIAL AND METHODS: Immunophenotypic characterization of both normal PCs and their counterpart malignant hematopoietic cells can be achieved by using monoclonal antibodies and either flow cytometry or immunocytochemical techniques. RESULTS: Normal PCs are heterogeneous and express, in addition to cytoplasmic immunoglobulins, the antigens CD9, CD10, CD13, CD19, CD20, CD33, CD38, and D-related human leukocyte antigen (HLA-DR). This heterogeneity also occurs in malignant PCs. Myelomatous PCs may express, in addition to CD38 (the most typical PC marker), the antigens CD9, CD10, HLA-DR, and CD20. Other non-B-cell lineage markers such as myeloid (CD13, CD14, CD15, CD33, CD41, and glycophorin A), T-cell (CD2 and CD4), and natural killer-associated (CD56) antigens, as well as CD23, CD24, CD25, CD37, CD39, CDw40, CD45R, CD71, and certain unclustered antigens (R1-3, PCA-1, PCA-2, PC1, 62B1, 8A, 8F6, and MM4), have been noted in myelomatous PCs. The presence of these antigens in the myeloma cells may have a prognostic value--for example, the expression of CD20 and of myelomonocytic antigens (CD11b, CD13, CD14, CD15, and CD33) may be related to a poor prognosis. The adverse prognostic implication of the expression of CD10 initially described in MM has not been subsequently confirmed. Patients with MM may have mononuclear cells in their peripheral blood that express the same antigens as those expressed by the myeloma cells in their bone marrow. The presence of such cells or their therapy-associated decrease or disappearance may be related to the prognosis of patients with MM. CONCLUSION: The presence of cell surface markers on PCs and their prognostic significance in patients with MM warrant further investigation.

The incidence of hybrid acute leukaemias.

During a 4-yr period, 292 patients with acute leukaemia were studied using morphology, cytochemistry and immunologic reagents to determine the cell lineage of the leukaemia. One hundred and sixty-three cases were shown to be acute lymphoblastic leukaemia (ALL), 127 acute myeloblastic leukaemia (AML) and two cases (0.6%) were classified as hybrid acute leukaemias. One was biphenotypic in which the blast cells displayed both T-lymphoid (60% E-rosettes) and megakaryocytic markers (47% CDw41/glycoprotein IIb/IIIa antigen, 50% myeloperoxidase). The second was a bilineal acute leukaemia in which some blast cells displayed B-lymphoid (47% CD10/CALLA, 40% acid phosphatase) features and other megakaryocytic (33% coagulation factor VIII:WVf antigen)/myeloid (30% Sudan Black) features. This study suggests that hybrid acute leukaemia are rare.

Leukaemia and nutrition. I: Malnutrition is an adverse prognostic factor in the outcome of treatment of patients with standard-risk acute lymphoblastic leukaemia.

A group of 43 pediatric patients with standard-risk ALL were studied. Thirty-seven per cent of them presented with malnutrition at diagnosis. Malnourished children had a significantly worse outcome than well-nourished children. Five-year DFS was 83% for well-nourished children (WNC) and 26% for under-nourished children (UNC) (p less than 0.001). Relapses presented more frequently in the bone marrow in UNC than in WNC (56% vs 7%, p less than 0.0001). The doses of maintenance chemotherapy had to be reduced in 68% of UNC and 11% of WNC (p less than 0.005); the doses of maintenance myelosuppressive chemotherapy (6-MP, oral MTX and hydroxyldaunorubicin) received by UNC were approximately 50% of those received by WNC (p less than 0.01). The correlation between malnutrition and compromised treatment was 0.92. Malnutrition might be included as an adverse prognostic factor in acute lymphoblastic leukaemia (ALL).

Hematopoietic stem cell allografts using a non-myeloablative conditioning regimen can be safely performed on an outpatient basis: report of four cases.

Using a non-myeloablative, immunosuppressive, fludarabine-based conditioning regimen, we performed allogeneic peripheral blood stem cell transplants totally on an outpatient basis in four patients (two with chronic myelogenous leukemia, one with acute myelogenous leukemia and one with thalassemia major). The median granulocyte recovery time to 0.5 x 109/l was 10 days and the lowest absolute neutrophil count was 0.064 x 109/l; only one patient developed thrombocytopenia below 20 x 109/l. No patient required red blood cell transfusions and one was given a single prophylactic platelet transfusion. All patients are alive at 210-390 (median 285) days and have definite evidence of chimerism; one developed biopsy-proven GVHD on day 50, with a limited cutaneous rash. The procedure is less costly than its counterpart using myeloablative conditioning regimens and may represent another approach in the management of patients requiring an allogeneic stem cell transplant. Bone Marrow Transplantation (2000) 25, 131-133.

Chronic lymphocytic leukemia is infrequent in Mexican mestizos.

Chronic lymphocytic leukemia (CLL) is the most frequent leukemia in adults living in Western countries, and accounts for approximately 30% of adult leukemias. In a 15-year period in a single institution, we identified 19 patients with CLL in a group of 211 adults with leukemia (9% of adult leukemias). Of these 19 CLL patients, 8 had a Caucasian phenotype, 4 were born outside the country, and only 11 were Mexican mestizos. On the other hand, in a multicenter experience involving 1968 Mexican adults with leukemia, CLL represented 6.6% of the cases, a figure significantly lower than that reported in Caucasians (P < 0.01). CLL is the least frequent type of leukemia in Mexican mestizos, and this low prevalence may stem from the genetic origin of this racial group. The data also suggest a genetic predisposition of Caucasians to suffer from this disease.

Chemotherapy alone may be an efficient alternative in the treatment of early stage Hodgkin's disease if optimal radiotherapy is not available.

Because radiotherapy (RT) equipment technology in some developing countries is outdated, its side effects are more frequent and severe and its efficacy suboptimal, whereas chemotherapy (CT) meeting international standards is generally more consistent. With this in mind, we treated 29 patients with stages I and II Hodgkin's disease with the MOPP or the MOPP/ABV hybrid schedule without prior staging laparotomy. The complete remission rate was 96%: five patients relapsed and of these, two died and three were rescued with CT, in one case followed by an autologous stem cell autograft. The median follow-up is 54 months (range 9 to 126), the overall survival of the group 88% at 126 months, and the relapse-free survival 72% at 110 months. Conventional CT alone has been shown to be useful in achieving acceptable long-term results. This observation could be important in circumstances where RT is unavailable or of suboptimal quality.

Tuberculosis-associated fatal hemophagocytic syndrome in a patient with lymphoma treated with fludarabine.

A patient with a stage IV high-grade non-Hodgkin's lymphoma who developed a fatal hemophagocytic syndrome is presented: When the patient had achieved complete remission and receiving fludarabine and chlorambucil/prednisone, she developed miliary tuberculosis, the CD4+ T-cell count then being 50/microL; the hemophagocytic syndrome ensuing at this point was fatal. Speculations about the predisposing factors that could have led to this complication are discussed focusing on the severe cellular immunosuppression which developed probably related to the use of fludafabine: it could be useful in the future to use anti-tuberculous prophylaxis in selected patients treated with this purine nucleoside analog.

Congenital Acute Megakaryoblastic Leukaemia in Down's Syndrome.

The case of a newborn with Down's syndrome and congenital leukaemia is reported. The malignant white blood cells displayed the CD41 antigen (glycoprotein Ilb/IIIa) identified by monoclonal antibodies HP1-ld and FMC24 and the CD9/p24 antigen identified by monoclonal antibody FMC27. The number of cells in S-phase was 14%, as assessed by the incorporation of 5-bromo 2-deoxyuridine. No other chromosomal abnormalities were identified in addition to 47 XY + 21. The patient died 15 days after the diagnosis, due to Pneumocystis Carinii pneumonia. Post-mortem examination showed heavy leukaemic infiltration and cardiac abnormalities including inter-atrial septal defect and a patent Ductus arteriosus. This patient appears to be the first identified case of congenital leukaemia with megakaryocytic differentiation, although previous instances of transient abnormal myelopoiesis with megakaryocytic differentiation have been recorded in Down's syndrome.