The International Prognostic Score and HIV status predict red cell concentrate transfusion needs in Hodgkin lymphoma.

Despite the burden of anemia among Hodgkin lymphoma (HL) patients, data evaluating red cell concentrate transfusion are limited. We retrospectively studied 285 newly diagnosed HL patients who received first-line adriamycin, bleomycin sulfate, vinblastine sulfate, and dacarbazine (ABVD) treatment at Groote Schuur Hospital, Cape Town. HIV prevalence in the cohort was 39.5% and 74.2% of patients had advanced stage HL. Patient prognosis was scored using the HL International Prognostic Score (IPS-7) and HL IPS-3. Seventy (24.6%) patients were transfused with a median of 2 (IQR 1-5) units per patient. Compared to HIV-negative patients, more HIV-positive patients were transfused (14.1% vs. 40.4%, p < .001) and received more units, median 2 (IQR 1-3) vs. 3 (IQR 2-5), p = .035. HL IPS-7 (OR 2.1, p < .001) and HL IPS-3 (OR 2.6, p < .001) were independently associated with transfusion. HL IPS-7, HL IPS-3, and HIV positivity remained associated with transfusion after adjusting for covariates. For patients with newly diagnosed HL, HL IPS-7, HL IPS-3, and HIV status predicted transfusion.

Predictors of poor haematopoietic stem cell mobilisation in patients with haematological malignancies at a South African centre.

BACKGROUND: Autologous stem cell transplant (ASCT) is an established consolidation strategy in the treatment of haematological malignancies, however poor mobilisation (PM) can contribute to patient morbidity and high resource utilisation. Identifying the incidence, risk factors for PM and engraftment outcomes are important goals in our resource limited setting. METHODS: We retrospectively analyzed patients with haematological malignancies that consecutively underwent ASCT at Groote Schuur hospital, Cape Town, South Africa from January 2013 to January 2019. RESULTS: 146 patients - majority with multiple myeloma (MM)(41,8%), F:M= 1:2, underwent leukapheresis with median age of 32 years (range, 9 - 66 years). PM occurred in 25/146 (17%), mobilisation failure (MF) in 3/146 (2%) and super mobilisation (SMs) in 99/146 (68%), respectively. Risk factors for PM were: diagnosis of acute leukaemia (RR = 25, 95% CI 3.4 - 183, p = 0.002) and Hodgkin lymphoma (RR = 19, 95% CI 2.6 - 142, p = 0.004); low white cell count (WCC) at harvest (WCC < 9 × 109/L (RR=4.3, 95% CI 2.3 - 8.3, p < 0.0001) and two vs one line of prior therapy (RR = 3.1, 95% CI 1.45 - 6.7, p = 0.0037). Median days to neutrophil and platelet engraftment were 14 days (95% CI 14-15 days) and 16 days (95% CI 15-16 days) respectively. CONCLUSION: PM occurred in 17% of a contemporary South African ASCT cohort, albeit with a low MF rate (2%). There was surprisingly high rate (68%) of SMs, possibly reflective of superfluous mobilisation strategy in MM patients. We identified predictive factors for PM that will lead to enhanced cost-effective use of plerixafor.

Is Haploidentical Hematopoietic Cell Transplantation Using Post-Transplantation Cyclophosphamide Feasible in Sub-Saharan Africa?

Identifying a suitable volunteer unrelated donor (UD) in South Africa is challenging due to the highly diverse ethnic groups and mixed-race populations in this region. Haploidentical hematopoietic cell transplantation (haploHCT) is thus an attractive procedure for patients with high-risk hematologic malignancies. This study was conducted to assess the safety and feasibility of haploHCT in South Africa. We retrospectively analyzed the outcome of 134 patients with hematologic malignancies who received unmanipulated haploHCT with post-transplantation cyclophosphamide at 2 high-volume HCT centers between 2014 and 2019. We assessed overall survival (OS), disease-free survival (DFS), nonrelapse mortality (NRM), relapse incidence (RI), and incidence of acute GVHD. The median recipient age was 44 years (range, 15 to 73 years) and the median donor age was 36 years (range, 9 to 68 years). Acute myelogenous leukemia or myelodysplastic syndrome (AML/MDS) and acute lymphoblastic leukemia (ALL) were the most common indications for haploHCT (61.2%). The European Society for Blood and Marrow Transplantation risk score was ≥5 in 44 patients (32.8%). Seventy-seven patients (57.4%) received a myeloablative conditioning regimen. The majority of patients received a sex-matched transplant (57.4%) and had peripheral blood stem cells (PBSCs) as the stem cell source (70.9%). Sixteen patients (11.9%) had an incongruent cytomegalovirus serostatus at transplantation. The median duration of follow-up was 10.8 months (range, 0.36 to 70.8 months). OS was 56% (95% confidence interval [CI], 47% to 64%) at 1 year and 37% (95% CI, 28% to 47%) at 3 years. DFS was 47% (95% CI, 38% to 55%) at 1 year and 32% (95% CI, 24% to 41%) at 3 years. The 100-day and 3-year cumulative incidence of NRM was 18% (95% CI, 11% to 25%) and 41% (95% CI, 32% to 50%), respectively, and the 1- and 3-year cumulative RI was 16% (95% CI, 11% to 24%) and 21% (95% CI, 14% to 29%), respectively. The 1-year OS was 55% (95% CI, 40% to 67%) for the patients with AML/MDS versus 41% (95% CI, 21% to 60%) for those with ALL. Forty-five patients (41.7%) developed acute GVHD by day +100; of these, 80% had grade I-II disease. Fifty patients (37.5%) developed cytomegalovirus infection that required therapy. On multivariable analysis, older donor age was an independent risk factor for lower DFS. RI was higher for diagnoses other than acute leukemia/MDS (relative risk [RR], 2.62; 95% CI, 1.12 to 6.15; P = .027), decreased for PBSC versus bone marrow (RR, 0.43; 95% CI, 0.19 to 0.95; P = .038) and decreased for offspring donors (RR, 0.25; 95% CI, 0.09 to 0.67; P = .006). These data support the feasibility of haploHCT and suggest that unmanipulated haploHCT using a younger parent or offspring donor is a viable option for adults in sub-Saharan Africa with acute leukemia and MDS who lack a suitable related or unrelated donor.

Outcomes for Patients With Acute Promyelocytic Leukemia in South Africa.

BACKGROUND: The characteristics and outcomes of patients with acute promyelocytic leukemia (APL) from sub-Saharan Africa have not been published. PATIENTS AND METHODS: We report retrospectively on consecutively diagnosed APL patients treated in Cape Town, South Africa, during 1998-2019. A total of 69 patients were treated, of whom 27 (39%) were classified as having high risk APL. RESULTS: Early death rates at 7 and 30 days were 7% and 13%, respectively, including 4 patients who died before any treatment could be administered. Overall survival at 3 years was 76.5% (95% confidence interval, 63.9-85.2) for the entire cohort, and 82.5% (95% confidence interval, 69.7-90.2) if patients who died within 7 days of diagnosis were excluded. For 13 patients (18.8%), there was a delay of 5 or more days from time of initial presentation at a peripheral hospital until arrival at the leukemia center and administration of all-trans retinoic acid; only 1 of these patients died within 30 days. CONCLUSION: Despite the challenges faced in the public healthcare system of a developing country, outcomes of APL patients treated at our center are similar to outcomes from developed countries.

Conditioning with purine analogs leads to good engraftment rates of immunodepleted grafts for aplastic anemia.

Immunodepletion with alemtuzumab is an effective strategy for preventing graft-versus-host disease after allogeneic stem cell transplantation (SCT), but it may be associated with graft failure. We tested the effectiveness of a purine analog-based reduced-intensity conditioning combination in patients undergoing allogeneic SCT for bone marrow aplasia. Patients with severe marrow aplasia who had a tissue-compatible sibling donor were conditioned with fludarabine 30 mg/m(2) for 5 days and cyclophosphamide 120 mg/kg. Stem cells from HLA-identical sibling donors were mobilized with filgrastim, and the harvested blood concentrates were incubated ex vivo with alemtuzumab. After graft infusion, patients received therapeutic doses of cyclosporine up to day 90. The primary objective of this study was to examine the proportion of patients who achieved engraftment and overall survival. Secondary objectives were the rates of graft-versus-host disease, posttransplantation infections, and graft failure. The study group comprised 30 patients who received a total of 31 cytokine-mobilized blood stem cell transplantations. The median CD34(+) cell dose infused was 4.99 × 10(6)/kg. All patients engrafted at a median of 12 days post-SCT. Two patients exhibited delayed graft failure, at 3 months and 7 months post-SCT, and required retransplantation or donor lymphocyte infusion to reestablish full-donor chimerism. At a median of 1,560 days post-SCT, all patients survived and were transfusion-free. We confirm that the combination of purine analog and cyclophosphamide is adequate for engraftment of grafts immunodepleted with alemtuzumab. This strategy is associated with excellent outcomes.

Is there a role for autologous stem cell transplantation for patients with acute myelogenous leukemia? A retrospective analysis.

For patients with acute myelogenous leukemia (AML) who are unable to secure an acceptable HLA donor, the role of autologous stem cell transplantation (auto-SCT) has remained controversial. Its effectiveness remains unclear as, when analyzed on intention-to-treat strategies, a significant number do not undergo the procedure, whereas others seem to fail therapy from pretransplant recurrences. To improve our counseling to our patients on these 2 therapeutic options, we compared the outcome of patients in first remission of AML who actually underwent autologous or allogeneic transplantation. The choice for the type of graft was based on availability of HLA identical siblings. Patients received myeloablative conditioning followed by allogeneic or autologous cytokine mobilized peripheral blood stem cell transplantation. For prophylaxis of graft-versus-host disease (GVHD), grafts were incubated ex vivo with anti-CD52 antibodies and patients were prescribed cyclosporin until day 90. Patients were stratified by clinical and laboratory factors as well as cytogenetic risk. The endpoints were treatment-related mortality (TRM), disease-free survival (DFS), and overall survival (OS). The median presentation age for both transplant groups was 35 (14-60) years. Of the 112 consecutive patients achieving remission, autologous or allogeneic grafts were transplanted to 43 and 32 patients, respectively. There was no significant difference in the presentation clinical features, laboratory parameters, marrow morphology, or proportion of low and intermediate cytogenetic risk for both transplant options. Treatment mortality as well as relapse rate was similar (14% and 15%; 39% and 27%, respectively). At a median of 1609 and 1819 posttransplant days, 56% and 63% in each group survived. In univariate analysis performance status, cytogenetic risk, morphologic features of dysplasia, blast count, and lactate dehydrogenase (LDH) were significant factors for survival. Although for the entire group there was no difference in survival between both modalities, all patients with unfavorable cytogenetics receiving an autologous graft died of disease recurrence (3-year survival 35% versus 0%; P = .05). We conclude that patients with AML who have low or intermediate cytogenetic risk undergoing myeloablative conditioning followed by autologous or allogeneic T cell-depleted stem cell transplantation appeared to have similar outcome. However, those with unfavorable karyotype are unlikely to be cured with autologous grafts and are candidates for experimental modalities.

Combined submyeloablative and myeloablative dose intense melphalan results in satisfactory responses with acceptable toxicity in patients with multiple myeloma.

We studied in patients with multiple myeloma (MM) the efficacy, cost-effectiveness, and toxicity of a strategy of submyeloablative doses of Mel and stem cell support in the ambulatory setting, followed by a standard myeloablative dose transplant. Patients with recently diagnosed symptomatic MM received dexamethazone to induce clinical response. Cytokine mobilized peripheral blood progenitor cells (PBPC) were split into 2 aliquots and cryopreserved. Patients then received Mel 100 mg/m(2) (Mel100) and infusion of the first PBPC aliquot in an ambulatory facility. Individuals received standard neutropenia prophylaxis and no growth factor support, but were seen regularly at the clinic until recovery. The cost of this step was calculated in a cohort of 23 patients where information for the expenditure was available. Six months later patients were conditioned in the hospital with Mel 200 mg/m(2) (Mel 200) followed by nfusion of the second aliquot. This study tested the cost, effectiveness, and the toxicity of out-patient-based transplantation, as well as the rate of response (complete remission [CR], very good partial remission [VGPR], partial remission [PR], and stable disease [SD]) and overall survival (OS) of this strategy. Twenty-six female and 16 male patients, with a median age of 53 years (range: 33-68 years) and median Salmon & Durie clinical disease stage III (range: II-III) were studied. The paraprotein was IgA in 17%, IgG in 52%, and light chains in 26%. The median harvested CD34(+) x 10(6) cells/kg was 12.03 (2.25-55.4). The median interval between the 2 transplant procedures was 239 (105-376) days. The median Karnofsky presentation score was 40%, but improved to 80% after the Mel 100 and was 90% following Mel 200. Subsequent to MEL 100 response was complete (CR) in 7 and it was VGPR in 9. Mel 100 grade 3-4 toxicity was mainly hematologic, but 15 (36%) required hospital admission for a median of 5 days. The median cost of MEL100 and corresponding supportive therapy was U.S. $2,142.35. In addition, the total median cost of those who needed admission to hospital was U.S. $6,042.78. Thus, pooling costs from patients who needed or did not need admissions the average cost of this strategy was U.S. $3,546.50 per patient. Among Mel 200 patients, except for hematologic toxicity, no patient had greater than grade 2 side effects. On completion of the program, 20 (48%) patients achieved CR, a further 14 (33%) had VGPR, whereas 6 had PR. At a median follow-up of 659 days there were 8 deaths, 1 (2%) was related to the treatment procedures and 6 from disease progression; thus, the 1000 days OS was 73%. Significant adverse factors included older age, lower presentation Hb, and lower Karnofsky %. Nonparametric testing confirmed that good performance scores and VGPR or CR were associated with more favorable outcome. Importantly, these satisfactory results were obtained in the absence of the new biologic cell modifiers. Mel 100 was well tolerated in the outpatient setting and the overall strategy seems to be effective in inducing durable responses with acceptable toxicity.

In stem cell transplantation, by limiting the morbidity of graft-versus-host disease tolerance to myeloablative conditioning is improved.

Myeloablative conditioning followed by T-cell depletion of grafts and reduced intensity conditioning (RIC) has both been shown to decrease treatment related mortality (TRM). However in RIC the incidence of graft vs. host disease (GvHD) is high and patients with aggressive diseases tend to relapse. Following myeloablative conditioning, patients with chemotherapy-responsive hematological malignancies underwent transplantation from HLA identical siblings. GvHD prophylaxis was by ex viva T-cell depletion with alemtuzumab. The outcome of these patients was analysed. At transplantation, the median age of 81 consecutive individuals was 45 years (range 15-60). GvHD was seen in 10% and was commonly associated with infections resulting in one and 3 year TRM of 15 and 20.5%. Fifteen patients relapsed, 10 who had myeloproliferative syndromes or lymphoma and two with myeloma responded to DLI. For the whole group, median follow up is 777 (range 7-2702) days and 73% remain disease free. Cox regression analysis for survival showed that only occurrence of GvHD was a significant adverse factor. Age order than median was not associated with worse outcome. By reducing the incidence and severity of GvHD, T-cell depletion of grafts leads to greater tolerance to myeloablative chemotherapy, resulting in acceptable TRM. This strategy should be compared with the RIC approaches.

Thrombotic thrombocytopenic purpura in patients with retroviral infection is highly responsive to plasma infusion therapy.

We prospectively studied presentation biological differences and the response to therapy in patients with thrombotic thrombocytopenic purpura (TTP) associated with, or unrelated to human immunodeficiency virus (HIV) infection. TTP patients underwent standard evaluations and were treated with prednisone 1 mg/kg in addition to infusions of fresh frozen plasma (FFP; 30 ml/kg/d) until normalization of the platelet count. Unresponsive patients were referred for plasma exchange. Compared with HIV- TTP patients (n=23), in HIV+ subjects (n=21) microangiopathy was dominant among Black females, who had lower presentation Hb (median 5.8 g/dl; P=0.03), platelet count (13 x 10(9)/l; P=0.05) and a CD4 count of 0.096 x 10(9)/l. HIV+ individuals responded to FFP faster than HIV- patients and none of them required apheresis. Ten HIV- TTP patients required apheresis (P=0.03) and four died. Responses in the HIV+ and HIV- groups occurred after treatment with a median of 33 and 55 units (one unit=320 ml) of FFP (P=0.004) respectively. Response to this protocol was seen in 84% (95% response in HIV+ patients). Regression analysis showed that survival was associated with younger age (P=0.001), rapid platelet (P=0.001) and Hb (P=0.0009) recovery, and fewer FFP units to normal lactate dehydrogenase levels (P=0.006). We conclude that in HIV+ individuals, microangiopathy is highly responsive to plasma infusions. This observation is important particularly when apheresis is not available.

Thrombotic thrombocytopenic purpura after allogeneic stem cell transplantation: a survey of the European Group for Blood and Marrow Transplantation (EBMT).

A survey was carried out among the European Group for Blood and Marrow Transplantation (EBMT) centres to determine the incidence, risk factors, treatment and outcome of thrombotic thrombocytopenic purpura (TTP) following allogeneic haematopoietic stem cell transplantation. TTP was defined as the simultaneous occurrence of red cell fragmentation, laboratory findings of haemolysis, red cell transfusion requirement and de novo or persistent thrombocytopenia caused by consumption, in the absence of disseminated intravascular coagulation. Forty-five centres reported all patients (n = 406) transplanted between July and December 1996. Twenty-three patients developed TTP; the risk of developing TTP was 6.7% at 2 years (95% CI: 4.1% to 9.3%). The median time of onset was 44 d (range 13-319) post transplantation. Significant risk factors for the development of TTP were female gender (P = 0.005) and an unrelated donor (P = 0.046). To treat TTP, cyclosporin administration was discontinued in 10 cases, plasma exchanges were performed in five cases and 12 patients received plasma infusions without plasma exchange. TTP resolved in 13 of the 23 patients (57%). The only factor predictive of resolution of TTP was the absence of nephropathy. Seven patients (30%) were alive at follow-up of 38-45 months from the onset of TTP. Sixteen patients died; the causes were multiple, only three patients had TTP as a central factor. The median time to death was 41 d (range 1-762 d) from the onset of TTP. TTP is a relatively frequent complication of allogeneic stem cell transplantation and it is associated with high mortality, though death is usually caused by multiple factors.