NGS-based IgH gene rearrangement monitoring predicts relapse and guides maintenance therapy in DLBCL: A case report from indolent lymphoma to aggressive lymphoma.

This report describes a case of extranodal marginal zone B-cell lymphoma (ENMZL) of the mucosa-associated lymphoid tissue (MALT) lymphoma that transformed to diffuse large B cell lymphoma (DLBCL) in a 39-year-old female patient with Hashimoto's thyroiditis (HT). The patient presented with MALT lymphoma in the thyroid tissue and DLBCL in the multiple site invasions, including the ovary, breast, and lymph nodes. We assessed the Ig gene rearrangement and mutation profile in lymphoma involved tissues and the collected stem cells. V(D)J sequence of the tumor clonotype detected in thyroid, ovary, and breast was identical, revealing a shared origin of the malignant lymphoma. Noticeably, a small percentage of tumor clonotype (the highest-ranking clonotype in tumor tissues) was detected in the stem cell sample, suggesting the malignant cells was residual in the stem cells, likely conferred disease relapse following ASCT. This patient recieved BTK inhibitor combined with radiotherapy to eradicate the residual tumor cells based on the V(D)J sequence monitoring after ASCT. Now the patient remains in complete remission following 12 months of ASCT.

131 I-Meta-iodobenzylguanidine followed by busulfan and melphalan and autologous stem cell rescue in high-risk neuroblastoma.

INTRODUCTION: Despite the progress in current treatments, the event-free survival of high-risk neuroblastoma (HR-NB) patients does not exceed 40%-50%, and the prognosis of refractory or relapsed patients is poor, still representing a challenge for pediatric oncologist. Therapeutic Iodine-131 meta-iodobenzylguanidine (Th-131 I-MIBG) is a recognized safe and potentially effective treatment for NB. MATERIALS: This retrospective study reports the outcomes of 28 MIBG-avid NB patients with advanced disease either refractory or relapsed, which was undertaken from 1996 to 2014. Th-131 I-MIBG was administered shortly before (median: 17 days) high-dose chemotherapy with busulfan and melphalan (HD-BuMel) and autologous stem cell rescue (ASCR) at the Gaslini Institute in Genoa, with the aim of analyzing the feasibility, safety, and efficacy of this approach. RESULTS: Engraftment occurred in all patients after a median of 14 (11-29) and 30 days (13-80) from ASCR for neutrophils and platelets, respectively. No treatment-related deaths were observed. The main high-grade (3-4) toxicity observed was oral and gastrointestinal mucositis in 78.6% and 7.1% of patients, respectively, whereas high-grade hepatic toxicity was observed in 10.7%. Two patients developed veno-occlusive-disease (7.1%), completely responsive to defibrotide. Hypothyroidism was the main late complication that occurred in nine patients (31.1%). After Th-131 MIBG and HD-BuMel, 19 patients (67.8%) showed an improvement in disease status. Over a median follow-up of 15.9 years, the three-year and five-year overall survival (OS) probabilities were 53% (CI 0.33-0.69) and 41% (CI 0.22-0.59), and the three-year and five-year rates of cumulative risk of progression/relapse were 64% (CI 0.47-0.81) and 73% (CI 0.55-0.88), respectively. MYCN amplification emerged as the only risk factor significantly associated with OS (HR, 3.58;P = 0.041). CONCLUSION: Th-131 I-MIBG administered shortly before HD-BuMel is a safe and effective regimen for patients with advanced MIBG-avid NB. These patients should be managed in centers with proven expertise.

Reduced survival after autologous stem cell transplantation in myeloma and lymphoma patients with low vitamin D serum levels.

High-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) is applied for consolidation in myeloma and relapsing lymphoma patients. Vitamin D (VitD) exerts effects during hematopoietic stem cell proliferation, differentiation and interactions with the immune system. VitD deficiency is frequent in patients with hematological malignancies, but its prognostic relevance after ASCT remains unclear. We investigated the effect of VitD serum levels in patients with lymphomas and myeloma at ASCT on progression-free (PFS) and overall survival (OS). The cohort (n = 183) was divided into two groups: 81 (44%) had VitD levels >52 nmol/L and 102 (56%) ≤52 nmol/L at ASCT. VitD levels >52 nmol/L were associated with better PFS (P = 0.0194) and OS (P = 0.011). Similarly, when evaluating myeloma patients alone, patients with lower VitD levels (≤52 nmol/L) had inferior PFS (P = 0.0412) and OS (P = 0.049). Finally, the multivariate analysis was consistent that varying VitD levels were significantly associated with OS (P = 0.0167), also when stratifying patients in groups with VitD levels > versus ≤52 nmol/L (P = 0.0421). Our data suggest that reduced serum VitD levels in myeloma and lymphoma patients undergoing HDCT/ASCT are associated with inferior outcome. Optimizing VitD levels before ASCT may be warranted.

Feasibility and effectiveness of treatment strategy of tandem high-dose chemotherapy and autologous stem cell transplantation in combination with 131 I-MIBG therapy for high-risk neuroblastoma.

This study was performed to evaluate the safety and effectiveness of tandem HDCT/ASCT combined with targeted radiotherapy using 131 I-MIBG for high-risk neuroblastoma. Patients with high-risk neuroblastoma were treated with 8 to 10 cycles of induction chemotherapy before tandem HDCT/ASCT. Patients received 131 I-MIBG treatment before the second HDCT/ASCT. Local radiotherapy and maintenance therapy were performed after tandem HDCT/ASCT. Between 2012 and 2016, 19 patients were diagnosed with high-risk neuroblastoma in our institution and 18 of them received tandem HDCT/ASCT combined with 131 I-MIBG therapy. For the first HDCT/ASCT regimen, 12 patients received busulfan/melphalan and six patients received melphalan/etoposide/carboplatin. The second HDCT included ThioCy. The median dose of 131 I-MIBG was 17.2 mCi/kg for the first eight patients, while 12 patients in the latter period of the study received reduced dose of 10.7 mCi/kg. The 5-year OS and EFS rates were 79% and 61%, respectively, for all 19 patients with high-risk neuroblastoma, and 83% and 64%, respectively, for 18 patients who completed tandem HDCT/ASCT combined with 131 I-MIBG therapy. Six patients experienced disease relapse and five patients died. Treatment-related mortality was not observed. Among 15 evaluable patients, 11 patients (73%) developed hypothyroidism, six patients (40%) had CKD, and six patients (40%) had growth failure. Hypothyroidism and growth failure were less frequent in patients who received reduced doses of 131 I-MIBG therapy. Tandem HDCT/ASCT combined with HD 131 I-MIBG therapy could be feasible for patients with high-risk neuroblastoma with acceptable toxicity profiles and favorable outcomes.

Risk factors and timing of autologous stem cell transplantation for patients with peripheral T-cell lymphoma.

High-dose chemotherapy with autologous stem cell transplantation (HDC-ASCT) is an option for patients with peripheral T-cell lymphoma (PTCL); however, neither prospective nor retrospective studies support proceeding with ASCT upfront, and the timing of HDC-ASCT remains controversial. We retrospectively analyzed the risk factors for outcomes of 570 patients with PTCL, including PTCL not otherwise specified (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL), who received ASCT for frontline consolidation (n = 98 and 75, respectively) or alternative therapies after either relapse (n = 112 and 75) or primary induction failure (PIF; n = 127 and 83) between 2000 and 2015. Significant risk factors for overall survival (OS) after upfront ASCT were a ≥ 2 prognostic index for T-cell lymphoma (P < 0.001) and partial response (PR) at ASCT (P = 0.041) in PTCL-NOS patients, and > 60 years of age (P = 0.0028) and PR at ASCT (P = 0.0013) in AITL patients. Performance status of ≥ 2 at ASCT (P < 0.001), receiving ≥ 3 regimens before ASCT (P = 0.018), and PR at ASCT (P = 0.018) in PTCL-NOS patients and > 60 years of age at ASCT (P = 0.0077) in AITL patients were risk factors for OS after ASCT with a chemosensitive PIF status. Strategies that carefully select PTCL patients may allow identification of individuals suitable for ASCT.

Comparison of Autologous Stem Cell Transplantation versus Haploidentical Donor Stem Cell Transplantation for Favorable- and Intermediate-Risk Acute Myeloid Leukemia Patients in First Complete Remission.

Stem cell transplantation (SCT) is an attractive postremission treatment option for patients with intermediate-risk acute myeloid leukemia (AML) and for some favorable-risk AML patients with additional nongenetic risk factors. Autologous SCT (auto-SCT) and haploidentical donor SCT (haplo-SCT) are the widely used alternatives in cases of a lack of a HLA-matched donor. However, limited data have been published on the direct comparison between these 2 transplant types. Based on the transplant database in our center, we conducted a retrospective study involving patients with favorable- and intermediate-risk AML in first complete remission (CR1), according to the National Comprehensive Cancer Network guideline. Patients with extramedullary disease or those achieving CR by more than 2 cycles were excluded. In total, 195 patients were included in the study, 88 of whom underwent auto-SCT and 107 haplo-SCT. In the entire cohort analyses the impact of high relapse incidence in the auto-SCT group was compensated by low nonrelapse mortality (NRM), which resulted in a comparable overall survival (OS) (79.0% ± 4.6% versus 80.1% ± 5.0%, P = .769) and relapse-free survival (RFS) (66.1% ± 5.2% versus 77.4% ± 4.8%, P = .079) compared with those observed in the haplo-SCT group. However, for patients with intermediate-risk AML, NRM was similar between the groups, and haplo-SCT exhibited superior survival. In case of post-SCT relapse, patients with intermediate-risk AML showed markedly inferior 3-year OS compared with that shown by patients with favorable-risk AML (23.3% ± 9.8% versus 60.8% ± 14.3%, P = .011). In the multivariate analyses, minimal residual disease (MRD) measured by flow cytometry and gene mutation status before transplantation were independent predictors for both OS and RFS. We concluded that both auto-SCT and haplo-SCT were acceptable options for postremission treatment of patients with favorable- and intermediate-risk AML. Haplo-SCT yielded a better outcome in patients with intermediate-risk AML, but the relapse after SCT still led to a poor outcome. Clearance of MRD before SCT could improve the prognosis after transplantation.

Variability of high-dose melphalan exposure on oral mucositis in patients undergoing prophylactic low-level laser therapy.

The present study outlines the clinical impact and risk factors of oral mucositis in 79 patients with multiple myeloma following high-dose melphalan for autologous transplant. All patients underwent daily prophylactic low-level indium gallium aluminum phosphate diode laser therapy (660 nm, 15 mW, 3.75 J/cm2, 10 s per point) from the beginning of the conditioning regimen up to day +2. Oral mucositis assessments were made daily until hospital discharge. For analysis, oral mucositis was divided into two groups according to severity: group 1, patients with oral mucositis grade

Incorporation of high-dose 131I-metaiodobenzylguanidine treatment into tandem high-dose chemotherapy and autologous stem cell transplantation for high-risk neuroblastoma: results of the SMC NB-2009 study.

BACKGROUND: In our previous SMC NB-2004 study of patients with high-risk neuroblastomas, which incorporated total-body irradiation (TBI) with second high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT), the survival rate was encouraging; however, short- and long-term toxicities were significant. In the present SMC NB-2009 study, only TBI was replaced with 131I-meta-iodobenzylguanidine (MIBG) treatment in order to reduce toxicities. METHODS: From January 2009 to December 2013, 54 consecutive patients were assigned to receive tandem HDCT/auto-SCT after nine cycles of induction chemotherapy. The CEC (carboplatin + etoposide + cyclophosphamide) regimen and the TM (thiotepa + melphalan) regimen with (for metastatic MIBG avid tumors) or without (for localized or MIBG non-avid tumors) 131I-MIBG treatment (18 or 12 mCi/kg) were used for tandem HDCT/auto-SCT. Local radiotherapy, differentiation therapy with 13-cis-retinoic acid, and immunotherapy with interleukin-2 were administered after tandem HDCT/auto-SCT. RESULTS: Fifty-two patients underwent the first HDCT/auto-SCT and 47 patients completed tandem HDCT/auto-SCT. There was no significant immediate toxicity during the 131I-MIBG infusion. Acute toxicities during the tandem HDCT/auto-SCT were less severe in the NB-2009 study than in the NB-2004 study. Late effects such as growth hormone deficiency, cataracts, and glomerulopathy evaluated at 3 years after the second HDCT/auto-SCT were also less significant in the NB-2009 study than in NB-2004 study. There was no difference in the 5-year event-free survival (EFS) between the two studies (67.5 ± 6.7% versus 58.3 ± 6.9%, P = 0.340). CONCLUSIONS: Incorporation of high-dose 131I-MIBG treatment into tandem HDCT/auto-SCT could reduce short- and long-term toxicities associated with TBI, without jeopardizing the survival rate. TRIAL REGISTRATION: ClinicalTrials.gov NCT03061656.

The effects of music therapy in patients with high-dose chemotherapy and stem cell support: a randomized pilot study.

OBJECTIVE: Patients with high dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) are highly distressed. Psycho-oncological support might be beneficial but is not routinely provided. Our aim was to investigate whether music therapy (MT) in addition to standard supportive treatment had any effect on quality of life, depression, anxiety, side effects of therapy, medication, and immunological changes during and within three months after HDC plus ASCT. METHODS: Patients (n = 66) with HDC plus ASCT were randomly assigned to either MT (Intervention Group = IG) or standard supportive treatment (Control Group = CG). Quality of life was measured by EORTC QLQ-C30. Depression and anxiety were measured by the HADS-D before transplantation, during and after the inpatient stay. In addition, adverse events (AE), medication, and immunological parameters were observed. RESULTS: There was no improvement of global quality of life for patients receiving additional MT, but their perception of pain significantly changed (p = 0.027). Patients were neither depressed nor anxious on admission, therefore no improvements were found. IG patients had less 3-4° toxicities (e.g., mucositis). Aprepitant for antiemetic therapy was administered significantly more often in the CG (p = 0.040). The IgA decline and T4 count was less in IG, T8, and NK count decreased most in IG. These findings failed significance. CONCLUSIONS: MT may improve pain perception in patients receiving HDC plus ASCT. Additionally positive effects on toxicities, use of antiemetic medication, and immunological changes were observed. As some of these findings failed significance, studies with larger sample sizes are needed. Copyright © 2016 John Wiley & Sons, Ltd.

Hematologic recovery after tandem high-dose chemotherapy and autologous stem cell transplantation in children with high-risk solid tumors.

Although the number of studies using tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/autoSCT) for the treatment of high-risk pediatric solid tumors has been increasing, documentation of hematologic recovery after tandem HDCT/autoSCT is very limited. For this reason, we retrospectively analyzed the hematologic recovery of 236 children with high-risk solid tumors who underwent tandem HDCT/autoSCT. The median numbers of CD34(+) cells transplanted during the first and second HDCT/autoSCT were 4.3 × 10(6)/kg (range 0.6-220.2) and 4.1 × 10(6)/kg (range 0.9-157.6), respectively (P = 0.664). While there was no difference in neutrophil recovery between the first and second HDCT/autoSCT, platelet and RBC recoveries were significantly delayed in the second HDCT/autoSCT (P < 0.001 and P < 0.001, respectively). Delayed recovery in the second HDCT/autoSCT was more prominent when the number of transplanted CD34(+) cells was lower, especially if it was < 2 × 10(6)/kg. A lower CD34(+) cell count was also associated with increased RBC transfusion requirements and a higher serum ferritin level after tandem HDCT/autoSCT. More CD34(+) cells need to be transplanted during the second HDCT/autoSCT in order to achieve the same hematologic recovery as the first HDCT/autoSCT.

The impact of novel therapeutic agents before and after frontline autologous stem cell transplantation in patients with multiple myeloma

BACKGROUND: Novel agents (NAs) such as thalidomide and bortezomib have been administered in combination with autologous stem-cell transplantation (ASCT) to effectively treat multiple myeloma (MM). However, whether NAs perform better as induction treatments prior to transplantation, or as post-transplant maintenance therapies remains unclear. METHODS: We retrospectively analyzed 106 consecutive patients with MM who underwent ASCT within 1 year of diagnosis as first-line therapy. RESULTS: Eighty-seven (82.1%) patients received NAs before ASCT, whereas 68 (64.2%) received NAs after ASCT. NAs were administered to each patient as follows: before ASCT alone (N=29, 27.4%), after ASCT alone (N=10, 9.4%) or both before and after ASCT (N=58, 54.7%). High-quality rates before and after ASCT were significantly higher for patients who received NAs as induction treatment compared to those who did not receive pre-transplant NAs. At a median follow-up of 37.9 months, the 3-year progression-free survival (PFS) and overall survival (OS) rates were 42.8% and 70.2%, respectively. The PFS and OS were significantly higher in patients with NAs as post-transplant maintenance treatment (P=0.03 and P=0.04, respectively), but not in those with NAs as pre-transplant induction treatment. The PFS of patients with NAs before and after ASCT was higher than that of the patients with NAs as induction therapy alone (P=0.05). Age, serum beta2-microglobulin level, complete response after ASCT, and NA use post-ASCT independently predicted survival outcomes. CONCLUSION: These findings suggest that integration of NAs post-ASCT could benefit patients with MM undergoing ASCT. Induction therapy using NAs also improves high-quality response rates before and after ASCT.

Hematologic Recovery after Tandem High-Dose Chemotherapy and Autologous Stem Cell Transplantation in Children with High-Risk Solid Tumors

Although the number of studies using tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/autoSCT) for the treatment of high-risk pediatric solid tumors has been increasing, documentation of hematologic recovery after tandem HDCT/autoSCT is very limited. For this reason, we retrospectively analyzed the hematologic recovery of 236 children with high-risk solid tumors who underwent tandem HDCT/autoSCT. The median numbers of CD34+ cells transplanted during the first and second HDCT/autoSCT were 4.3 x 10(6)/kg (range 0.6-220.2) and 4.1 x 10(6)/kg (range 0.9-157.6), respectively (P = 0.664). While there was no difference in neutrophil recovery between the first and second HDCT/autoSCT, platelet and RBC recoveries were significantly delayed in the second HDCT/autoSCT (P < 0.001 and P < 0.001, respectively). Delayed recovery in the second HDCT/autoSCT was more prominent when the number of transplanted CD34+ cells was lower, especially if it was < 2 x 10(6)/kg. A lower CD34+ cell count was also associated with increased RBC transfusion requirements and a higher serum ferritin level after tandem HDCT/autoSCT. More CD34+ cells need to be transplanted during the second HDCT/autoSCT in order to achieve the same hematologic recovery as the first HDCT/autoSCT.

Iron overload during follow-up after tandem high-dose chemotherapy and autologous stem cell transplantation in patients with high-risk neuroblastoma.

Multiple RBC transfusions inevitably lead to a state of iron overload before and after high-dose chemotherapy and autologous stem cell transplantation (HDCT/autoSCT). Nonetheless, iron status during post-SCT follow-up remains unknown. Therefore, we investigated post-SCT ferritin levels, factors contributing to its sustained levels, and organ functions affected by iron overload in 49 children with high-risk neuroblastoma who underwent tandem HDCT/autoSCT. Although serum ferritin levels gradually decreased during post-SCT follow-up, 47.7% of the patients maintained ferritin levels above 1,000 ng/mL at 1 yr after the second HDCT/autoSCT. These patients had higher serum creatinine (0.62 vs 0.47 mg/mL, P = 0.007) than their counterparts (< 1,000 ng/mL). Post-SCT transfusion amount corresponded to increased ferritin levels at 1 yr after the second HDCT/autoSCT (P < 0.001). A lower CD34(+) cell count was associated with a greater need of RBC transfusion, which in turn led to a higher serum ferritin level at 1 yr after HDCT/autoSCT. The number of CD34(+) cells transplanted was an independent factor for ferritin levels at 1 yr after the second HDCT/autoSCT (P = 0.019). Consequently, CD34(+) cells should be transplanted as many as possible to prevent the sustained iron overload after tandem HDCT/autoSCT and consequent adverse effects.

Iron Overload during Follow-up after Tandem High-Dose Chemotherapy and Autologous Stem Cell Transplantation in Patients with High-Risk Neuroblastoma

Multiple RBC transfusions inevitably lead to a state of iron overload before and after high-dose chemotherapy and autologous stem cell transplantation (HDCT/autoSCT). Nonetheless, iron status during post-SCT follow-up remains unknown. Therefore, we investigated post-SCT ferritin levels, factors contributing to its sustained levels, and organ functions affected by iron overload in 49 children with high-risk neuroblastoma who underwent tandem HDCT/autoSCT. Although serum ferritin levels gradually decreased during post-SCT follow-up, 47.7% of the patients maintained ferritin levels above 1,000 ng/mL at 1 yr after the second HDCT/autoSCT. These patients had higher serum creatinine (0.62 vs 0.47 mg/mL, P = 0.007) than their counterparts (< 1,000 ng/mL). Post-SCT transfusion amount corresponded to increased ferritin levels at 1 yr after the second HDCT/autoSCT (P < 0.001). A lower CD34+ cell count was associated with a greater need of RBC transfusion, which in turn led to a higher serum ferritin level at 1 yr after HDCT/autoSCT. The number of CD34+ cells transplanted was an independent factor for ferritin levels at 1 yr after the second HDCT/autoSCT (P = 0.019). Consequently, CD34+ cells should be transplanted as many as possible to prevent the sustained iron overload after tandem HDCT/autoSCT and consequent adverse effects.

Iron Overload during Follow-up after Tandem High-Dose Chemotherapy and Autologous Stem Cell Transplantation in Patients with High-Risk Neuroblastoma

Multiple RBC transfusions inevitably lead to a state of iron overload before and after high-dose chemotherapy and autologous stem cell transplantation (HDCT/autoSCT). Nonetheless, iron status during post-SCT follow-up remains unknown. Therefore, we investigated post-SCT ferritin levels, factors contributing to its sustained levels, and organ functions affected by iron overload in 49 children with high-risk neuroblastoma who underwent tandem HDCT/autoSCT. Although serum ferritin levels gradually decreased during post-SCT follow-up, 47.7% of the patients maintained ferritin levels above 1,000 ng/mL at 1 yr after the second HDCT/autoSCT. These patients had higher serum creatinine (0.62 vs 0.47 mg/mL, P = 0.007) than their counterparts (< 1,000 ng/mL). Post-SCT transfusion amount corresponded to increased ferritin levels at 1 yr after the second HDCT/autoSCT (P < 0.001). A lower CD34+ cell count was associated with a greater need of RBC transfusion, which in turn led to a higher serum ferritin level at 1 yr after HDCT/autoSCT. The number of CD34+ cells transplanted was an independent factor for ferritin levels at 1 yr after the second HDCT/autoSCT (P = 0.019). Consequently, CD34+ cells should be transplanted as many as possible to prevent the sustained iron overload after tandem HDCT/autoSCT and consequent adverse effects.