Haploidentical Hematopoietic Stem Cell Transplantation in Leukemia's: Experience from a Cancer Center in India.

There has been a surge in haploidentical hematopoietic stem cell transplantation (HSCT) in India recently. However, there is a paucity of data on haploidentical HSCT from India. The report is an analysis of data of haploidentical HSCT performed at our center. Analysis of patients with acute leukemia or chronic myeloid leukemia who underwent haploidentical HSCT during 2014-2019 was performed. The graft versus host disease (GVHD) prophylaxis was post-transplant Cyclophosphamide with Mycophenolate-mofetil and Cyclosporine. All patients were transfused peripheral blood stem cells from donors. Overall survival (OS) was calculated using the Kaplan-Meier method. Twenty-one patients underwent haploidentical HSCT. Fourteen-patients were males. The median age of patients was 15 years. Fludarabine with total body irradiation was the most common conditioning regimen (n = 15, 71.4%). The median duration for neutrophil and platelet engraftment was 14 days. Cumulative incidence of acute and chronic GVHD was 19%, and 38% respectively. The median follow-up was 26 months and the two-year OS was 38%. Twelve (57%) patients died during the study period, 8 patients (38%) died from transplant-related mortality (TRM), and 4 from disease relapse. Sepsis was the cause of death in six of the eight TRM. Nine out of 21 patients (42.8%) are leukemia-free on follow-up. Haploidentical HSCT is a promising modality of treatment in patients who have no suitable matched donors. Though the TRM remains high, good disease control was achieved in 42.8% of patients. Multi-drug resistant bacterial infection remains a challenge in performing haploidentical HSCT in developing countries.

Olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced vomiting in children: An open-label, randomized phase 3 trial.

BACKGROUND: Breakthrough chemotherapy-induced vomiting (CIV) is defined as CIV occurring after adequate antiemetic prophylaxis. Olanzapine and metoclopramide are two drugs recommended for the treatment of breakthrough CIV in children, without adequate evidence. We conducted an open-label, single-center, phase 3 randomized controlled trial comparing the safety and efficacy of olanzapine and metoclopramide for treating breakthrough CIV. PROCEDURE: Children aged 5-18 years who developed breakthrough CIV after receiving highly emetogenic chemotherapy or moderately emetogenic chemotherapy were randomly assigned to the metoclopramide or olanzapine arm. The primary objective of the study was to compare the complete response (CR) rates between patients receiving olanzapine or metoclopramide for treating breakthrough CIV during 72 hours after the administration of the study drug. Secondary objectives were to compare CR rates for nausea and toxicities between the two arms. RESULTS: Eighty patients were analyzed (39 in the olanzapine arm and 41 in the metoclopramide arm). CR rates were significantly higher in the olanzapine arm compared with the metoclopramide arm for vomiting (72% vs 39%, P = 0.003) and nausea (59% vs 34%, P = 0.026). Seven patients in the metoclopramide arm crossed over to the olanzapine arm and none crossed over in the olanzapine arm (P < 0.001). The mean nausea score in the olanzapine arm was significantly lower than the metoclopramide arm after the initiation of the rescue antiemetic (P = 0.01). Hyperglycemia and drowsiness were more commonly seen in the olanzapine arm. CONCLUSION: Olanzapine is superior to metoclopramide for the treatment of breakthrough CIV in children. Drowsiness and hyperglycemia need to be monitored closely in children receiving olanzapine for breakthrough CIV.

Intravenous fosaprepitant for the prevention of chemotherapy-induced vomiting in children: A double-blind, placebo-controlled, phase III randomized trial.

BACKGROUND: Fosaprepitant is a neurokinin-1 receptor antagonist, approved for the prevention of chemotherapy-induced nausea and vomiting. The data on the use of fosaprepitant in children are limited and therefore we conducted a phase III randomized controlled trial. PROCEDURE: Children aged 1-12 years scheduled to receive moderately or highly emetogenic chemotherapy were randomly assigned to arm-A (fosaprepitant) or arm-B (placebo). Children recruited to arm-A received intravenous ondansetron plus dexamethasone followed by fosaprepitant infusion. Children recruited to arm-B received the same drugs as those given to children in arm-A, except that fosaprepitant was substituted with a placebo. Ondansetron and dexamethasone were continued for 48 hours after completion of chemotherapy. The primary end point of the study was to determine the proportion of patients who achieved a complete response (CR), defined as no vomiting, no retching, and no use of rescue medication, during the 24-120 hours (delayed phase) after administration of the last dose of chemotherapy. Secondary end points were the proportion of patients who achieved a CR during the acute phase (0-24 hours) and overall after administration of the last dose of chemotherapy. RESULTS: One-hundred-sixty-three patients were analyzed (81 in the fosaprepitant arm and 82 in the placebo arm). CR rates were significantly higher in the fosaprepitant arm compared to those in the placebo arm during the acute phase (86% vs 60%, P < 0.001), delayed phase (79% vs 51%, P < 0.001), and overall phase (70% vs 41%, P < 0.001). Three (4%) patients in the fosaprepitant arm and sixteen (20%) in the placebo arm required rescue anti-emetics (P = 0.0017). CONCLUSION: Addition of fosaprepitant to ondansetron and dexamethasone improved chemotherapy-induced vomiting control in children treated with moderately or highly emetogenic chemotherapy.

Study of NOTCH1 and FBXW7 Mutations and Its Prognostic Significance in South Indian T-Cell Acute Lymphoblastic Leukemia.

NOTCH1/FBXW7 mutations trigger oncogenic NOTCH1 signaling and its downstream target genes play crucial roles in the molecular pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL). In the present study, NOTCH1 and FBXW7 mutations were studied in 25 primary T-ALL samples. All 34 exons of NOTCH1 and hotspot exons (exon 9 and exon 10) of FBXW7 were polymerase chain reaction amplified and sequenced for mutations. Our results showed that 13/25 (52%) were NOTCH1-mutated, of which 11 patients (44%) showed mutation in the hotspot exons. Four patients (16%) had mutations in non-hotspot exons of NOTCH1. Notably, 2 T-ALL patients (8%) harbored mutations in both hotspot and non-hotspot exons of NOTCH1, whereas 2 patients (8%) had mutations in the hotspot exons of FBXW7. In all, 7 mutations were identified which were not previously reported. The real-time polymerase chain reaction study in 15 patients revealed that increased expression of activated NOTCH1 was found in NOTCH1/FBXW7 hotspot exon-mutated cases. In addition, NOTCH1/FBXW7-mutated patients had showed upregulated HES1, c-MYC, NOTCH3 gene expression. When survival analysis was performed including samples (n=50) from our previous study, an early treatment response and better survival was observed in NOTCH1/FBXW7 hotspot-mutated patients. Our study suggests that NOTCH1/FBXW7 hotspot-mutated T-ALL cases had better response to ALL BFM-95 protocol.

Comprehensive Evaluation of Adherence to Therapy, Its Associations, and Its Implications in Patients With Chronic Myeloid Leukemia Receiving Imatinib.

BACKGROUND: Adherence to oral therapy over a long period is important for optimal outcomes in chronic myeloid leukemia (CML). METHODS: Patients in the chronic phase of CML (taking imatinib for ≥ 6 months) were assessed by the 8-item Morisky Medication Adherence Scale and European Organisation for Research and Treatment of Cancer Quality of Life (QoL) Questionnaire (C30 and CML 24). Patients were classified as adherent (score 8) and nonadherent (score ≤ 7) as per the 8-item Morisky Medication Adherence Scale. RESULTS: Among 221 patients (male to female ratio = 133:88; median age, 39 (18-65) years; median duration of imatinib, 4 years), the nonadherence rate was 55% (N = 122/221). None of the demographic parameters, including occupation, education status, income, and availability of caregiver, were associated with nonadherence. QoL scores, especially the symptom scores associated with side effects of imatinib, significantly differed between adherent and nonadherent patients. Multivariate analysis revealed global health status as the sole predictor of adherent behavior (odds ratio, 0.978; 95% confidence interval, 0.963-0.994; P = .007). A higher proportion of adherent patients achieved deeper molecular responses. Low QoL was associated with nonadherence to imatinib in patients with CML. CONCLUSIONS: It is likely that increased long-term symptom burden due to side effects of imatinib could contribute to nonadherence. Interventions targeting individual components of QoL may improve adherence and outcomes in CML.

Etoposide, cisplatin-etoposide, methotrexate, actinomycin-D as primary treatment for management of very-high-risk gestational trophoblastic neoplasia.

OBJECTIVE: To evaluate the efficacy of etoposide, cisplatin-etoposide, methotrexate, actinomycin-D (EP-EMA) chemotherapy as the frontline treatment for gestational trophoblastic neoplasia (GTN) patients with very high (≥ 12) FIGO prognostic scores. METHODS: Nine patients with very-high-risk GTN were treated with EP-EMA at the Cancer Institute, Adyar, India, between January 1, 2001, and December 31, 2007. Salvage chemotherapy, adjuvant surgery, and radiotherapy were used when indicated. Clinical response, toxicity, and survival were analyzed separately. RESULTS: The median FIGO score was 15. Six (66.7%) patients had a complete clinical response, whereas progressive disease occurred for 3 (33.3%) women. None of the patients relapsed. This translated to an overall survival rate of 66.7% in the primary setting. All patients with liver-only metastases were survivors after treatment with EP-EMA. Grade 3 neutropenia was detected in 3 (33.3%) patients only. No life-threatening toxicity was observed after EP-EMA treatment. CONCLUSION: EP-EMA was highly effective for the primary management of very-high-risk GTN.

Management of high-risk gestational trophoblastic neoplasia with etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine chemotherapy.

OBJECTIVE: To evaluate the efficacy and toxicity of etoposide, methotrexate, actinomycin D, cyclophosphamide and vincristine (EMA-CO) chemotherapy for the treatment of high-risk gestational trophoblastic neoplasia (GTN). STUDY DESIGN: Thirty-five patients with high-risk GTN were treated with 196 cycles of EMA-CO between 1997 and 2006. Twenty-nine patients received EMA-CO in the primary setting and another 6 after failure of single-agent chemotherapy. Salvage chemotherapy was offered to selected patients. RESULTS: Of the 29 patients treated with EMA-CO in the primary setting, 22 (75.8%) had a complete clinical response, 5 (17.1%) progressed, and 2 (7.1%) had early deaths. Three patients relapsed after achieving initial complete response. Five were treated with salvage chemotherapy, of which only 2 survived. This translated to overall survival rate of 71% in the primary setting. Five of the 6 patients treated with EMA-CO as second line are survivors. Life threatening toxicity was not seen after EMA-CO. Nine subsequent normal pregnancies were reported after EMA-CO. CONCLUSION: EMA-CO was highly effective for the management of high-risk GTN, and the toxicities were minimal. Reproductive outcome after treatment with EMA-CO was excellent.