Regimen For Stem Cell Transplantation Research Articles

Safety and efficacy of bendamustine in the conditioning regimen for autologous stem cell transplantation in patients with relapsed/refractory lymphoma.

BackgroundBendamustine is an attractive option for the management of both de novo and relapsed lymphomas. It is being increasingly used in the conditioning regimen for autologous stem cell transplantation (SCT) and can be an alternative to the traditionally-used carmustine. In this study, we aimed to determine the safety and efficacy of bendamustine in the conditioning regimen for autologous SCT in refractory/relapsed lymphomas.MethodsWe designed a descriptive study to evaluate bendamustine in combination with etoposide, cytarabine, and melphalan (BeEAM) in the conditioning regimen for autologous SCT.ResultsFourteen patients (median age, 28 yr) with Hodgkin's lymphoma (HL) (N=8), non-Hodgkin's lymphomas (NHL) (N=5), or peripheral T-cell lymphoma, not otherwise specified (PTCL NOS) (N=1) were included in the study. A median number of 5.95×106 CD34+ cells/kg were transfused. Median times to absolute neutrophil count and platelet engraftment were 17 days and 24 days, respectively. The 100-day transplantation mortality rate was 28% (4 patients). Eight patients (57.14%) had GII-III acute kidney injury, four patients (28.5%) had GIII-IV hyperbilirubinemia, and twelve patients (85%) had GII-III diarrhea. After 3 months, 37% (5 patients) and 21.4% (3 patients) demonstrated complete response and partial response, respectively. The median follow-up was 5.5 months (15 days–19 mo). At the final follow-up, 7 patients (50%) were alive and in CR.ConclusionOur study showed that bendamustine is a potentially toxic agent in the conditioning regimen for autologous SCT, resulting in significant liver, kidney, and gastrointestinal toxicity. Further studies are required to assess its safety and efficacy at reduced doses.

PS1559 EFFICACY AND TOXICITY OF SEAM (SEMUSTINE, ETOPOSIDE, CYTARABINE, AND MELPHALAN) CONDITIONING REGIMEN FOLLOWED BY AUTOLOGOUS STEM CELL TRANSPLANTATION IN LYMPHOMA

Background:BEAM (carmustine, etoposide, cytarabine, and melphalan) is considered the gold standard conditioning regimen for autologous stem cell transplantation (auto‐SCT) in lymphoma. However, a shortage of old drugs is a worldwide problem, and carmustine (BCNU) is on this list. Alternative regimens are therefore being developed and used by many institutions. Semustine (Me‐CCNU), an alternative oral nitrosourea agent, has been chosen as a potential substitute. In China, we substituted BCNU by Me‐CCNU to provide the modified conditioning regimen SEAM (semustine, etoposide, cytarabine, and melphalan).Aims:The aim of this study was to evaluate the safety and efficacy of the SEAM regimen followed by auto‐SCT for malignant lymphoma patients.Methods:We retrospectively reviewed the records of patients with lymphoma who underwent auto‐SCT with SEAM regimen (n = 97) from January 2010 to June 2018 in our center. We evaluated the safety and efficacy of the SEAM regimen by comparing with previous studies using BEAM as conditioning regimen.Results:The median age of patients (n = 97) was 42 years (range, 15–65). The median time to neutrophil engraftment was 9.5 days (range, 7–15 days), and the median time to platelet engraftment was 12 days (range, 7–25 days). Grade 3–4 nausea/vomiting, mucositis and diarrhea were observed in 21.6%, 36.1%, and 11.3% of patients, respectively. Veno‐occlusive disease (VOD) and idiopathic pulmonary syndrome (IPS) were not observed. Treatment‐related mortality (TRM) at 100 days occurred in 2 patients (2.1%). After a median follow‐up time of 53.9 months, 31 patients (32.0%) showed progression over a median duration of 4.87 months (range, 1.1–40.53) after transplantation. In addition, the 3‐year incidence of disease relapse or progression (CIR) was 34%. The estimated progression‐free survival (PFS) and overall survival (OS) at 3 years were 62% and 75%, respectively. Compared with previous studies using BEAM as the conditioning regimen, this study shows that the SEAM conditioning regimen has a comparable efficacy and safety profile.Summary/Conclusion:The incidence and severity of non‐hematological regimen‐related toxicities of the SEAM conditioning regimen in this study were almost identical to that of BEAM conditioning regimen as reported in the previous studies. The SEAM conditioning regimen followed by auto‐SCT was well tolerated and had an efficacy and safety profile comparable to BEAM. Therefore, SEAM conditioning regimen is feasible whether in efficacy, safety or sources of drugs and might be an ideal alternative to BEAM conditioning regimen for auto‐SCT in lymphoma.image

Acute lymphoblastic leukemia in routine practice: A Turkish multicenter study

Objective:Significant developments occurred in the clinical management of acute lymphoblastic leukemia (ALL) in adults in recent decades. However, treatment results are still not satisfactory, especially in routine practice. The objective of this study was to evaluate the general clinical features, treatment details, and outcomes of a large group of patients followed in multiple centers in Turkey with a diagnosis of ALL.Materials and Methods:A retrospective analysis of the data of patients with ALL was made, the patients having been diagnosed and treated between January 2003 and June 2017 by different protocols in the hematology clinics of ten different centers. A total of 288 patients, aged between 17 and 76 years old, were included in the study. In this retrospective multicenter analysis of patients with ALL, classification of patients was performed based on treatment period, Philadelphia chromosome positivity, treatment regimen, and administration of allogeneic hematopoietic stem cell transplantation (allo-HSCT).Results:The majority of cases were B-cell in origin, while 224 patients had B-ALL and 64 of the patients had T-ALL. Median follow-up duration for all patients was 18.2 months (range: 0.03-161 months). Philadelphia chromosome positivity was determined in 49 patients (21.9%), and 54 patients (18.8%) were receiving allo-HSCT. After induction chemotherapy, 219 patients (76.0%) achieved complete remission, 32 patients (11.2%) were evaluated as treatment refractory, and 37 patients (12.8%) were deceased. Median overall survival was 47.7 months (95% confidence interval: 36.1-59.2) and median disease-free survival was 23.4 months (95% confidence interval: 6.7-40.0) for all patients.Conclusion:Multicenter studies are extremely important for defining the specific clinical features of a particular disease. The results of this study will make a significant contribution to the literature as they reflect real-life data providing valuable information about the Turkish ALL patient profile.

Adolescent male fertility following reduced-intensity conditioning regimen for hematopoietic stem cell transplantation in non-malignant disorders.

The effects of RIC for HSCT on male fertility remain unknown. We investigated spermatogenesis and gonadal hormonal status among adolescent male patients who received RIC HSCT for non-malignant diseases. Patients with non-malignant disease who had undergone a RIC HSCT were recruited and evaluated for spermatogenesis via semen analysis and gonadal hormonal function via serum hormone levels. Those who had received prior chemotherapy or radiation were excluded from the study. We reviewed the charts to record demographic factors, conditioning regimen and complications during and after transplant. Five patients were enrolled. The median age at the time of transplant was 15years (range, 11-19years), and the median time between bone marrow transplant and semen analysis was 5years (range, 3-11years). Median age of patients was 20years (range, 18-25years) at the time of the study. Serum FSH and LH levels were elevated in four patients, and inhibin B levels were low for age in three patients. Semen analysis showed two patients had azoospermia, and the remaining three patients showed severe oligozoospermia. Normal morphology and motility were seen in only one patient. This case series suggests that RIC transplants may be associated with impaired spermatogenesis and sequential follow-up is necessary given the potential for either permanent impairment or delayed recovery. Further larger studies are needed to confirm these findings.

Napabucasin (BBI608) eliminate AML cells in vitro and in vivo via inhibition of Stat3 pathway and induction of DNA damage

Acute myeloid leukemia (AML) is a heterogeneous malignancy of hematopoietic stem cells with poor clinical outcome despite recent improvements in chemotherapy and stem cell transplantation regimens. Thus, new therapeutic agents are urgently needed in order to prolong the disease-free survival of AML patients in clinic. Here, we report that BBI608 is highly active against diverse AML cell lines in vitro and primary samples obtained from patients with AML ex vivo, as well as effective in vivo in AML xenograft models. Meanwhile, the anti-AML property of BBI608 is closely associated with the inhibition of Stat3 pathway and induction of DNA damage. Of note, BBI608 combined with Bcl-2 inhibitor (i.e., ABT-199) exerts a significantly enhanced anti-leukemia effect in BBI608-resistant cell line Kasumi-1. Together, the present findings suggest that BBI608 might represent a potential candidate agent for AML treatment.

Comparison of Myeloablative Versus Reduced-Intensity Conditioning Regimens for Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia: A Cohort Study

Objective:Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective treatment modality for a variety of malignant and non-malignant hematologic disorders. Myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC) regimens could have different clinical outcomes. This purpose of this study was to assess the long-term outcome of MAC versus RIC regimens in patients with acute myeloid leukemia (AML) undergoing allogeneic HSCT.Materials and Methods:We retrospectively compared long-term outcomes with MAC and RIC regimens in patients with AML who underwent allo-HSCT at our tertiary transplantation center.Results:We analyzed survival outcomes after MAC-HSCT versus RICHSCT among 107 adult patients with AML diagnosed from 2001 through 2017. Of those, 44 patients underwent a MAC regimen, whereas 63 patients received a RIC regimen. The median follow-up time was 37 months (range: 6-210) for the entire group. The 3-year overall survival (OS) for RIC and MAC patients was 67% and 60%, respectively (p>0.05). The 3-year progression-free survival (PFS) for RIC and MAC patients was 88% and 77%. In multivariate analysis, the type of conditioning regimen (RIC vs. MAC) did not influence PFS (p=0.24). Acute graft-versus-host disease (GVHD) was seen in five of the RIC patients and 9 of the MAC patients. Chronic GVHD was seen in 16 of the RIC patients and 6 of the MAC patients. There was no significant difference between the two groups in terms of acute GVHD (p=0.089), but there was a significant difference between the two groups in terms of chronic GVHD (p=0.03).Conclusion:This retrospective analysis confirmed that MAC and RIC regimens had a consistently equivalent rate of OS and PFS in AML patients who underwent allo-HSCT. The choice of MAC versus RIC conditioning regimen might be decided on the basis of patient and disease characteristics.

Perspectives on the Use of a Medium-Dose Etoposide, Cyclophosphamide, and Total Body Irradiation Conditioning Regimen in Allogeneic Hematopoietic Stem Cell Transplantation: The Japanese Experience from 1993 to Present.

The outcome for adults with acute lymphoblastic leukemia (ALL) treated with chemotherapy or autologous hematopoietic stem cell transplantation (HSCT) is poor. Therefore, allogeneic HSCT (allo HSCT) for adults aged less than 50 years with ALL is performed with myeloablative conditioning (MAC) regimens. Among the several MAC regimens, a conditioning regimen of 120 mg/kg (60mg/kg for two days) cyclophosphamide (CY) and 12 gray fractionated (12 gray in six fractions for three days) total body irradiation (TBI) is commonly used, resulting in a long term survival rate of approximately 50% when transplanted at the first complete remission. The addition of 30 mg/kg (15 mg/kg for two days) etoposide (ETP) to the CY/TBI regimen revealed an excellent outcome (a long-term survival rate of approximately 80%) in adults with ALL, showing lower relapse and non-relapse mortality rates. It is preferable to perform allo HSCT with a medium-dose ETP/CY/TBI conditioning regimen at the first complete remission in high-risk ALL patients and at the second complete remission (in addition to the first complete remission) in standard-risk ALL patients. The ETP dose and administration schedule are important factors for reducing the relapse and non-relapse mortality rates, preserving a better outcome. The pharmacological study suggests that the prolonged administration of ETP at a reduced dose is a promising treatment.

Side Effects of CXC-Chemokine Receptor 4-Directed Endoradiotherapy with Pentixather Before Hematopoietic Stem Cell Transplantation.

The chemokine receptor CXC-chemokine receptor 4 (CXCR4) is a transmembrane receptor involved in survival, proliferation, and dissemination of different cancers, including hematopoietic malignancies. Relapsed or refractory hematopoietic cancers are frequently resistant to conventional therapy, and novel highly active strategies are urgently needed. CXCR4-directed endoradiotherapy constitutes a highly promising targeted therapeutic concept. Here, we investigated the adverse effects of this novel treatment approach. Methods: Twenty-two patients with heavily pretreated lymphoproliferative or myeloid malignancies were treated with 177Lu- or 90Y-pentixather-a CXCR4-directed therapeutic radioligand-before conventional conditioning therapy followed by autologous or allogeneic hematopoietic stem cell transplantation. Twenty-five CXCR4-directed endoradiotherapies were administered to those patients. Adverse events occurring between endoradiotherapy and the start of conventional conditioning therapy were retrospectively analyzed and graded for the estimation of the safety profile. Results: CXCR4-directed endoradiotherapy with pentixather showed a favorable toxicity profile. As expected, the hematopoietic system was most affected, with all subjects developing cytopenias. Except for 1 acute kidney failure, grade 3, due to tumor lysis syndrome, overall nephro- and hepatotoxicity was low. Other higher-grade adverse events were either transient and resolved or easily manageable. Conclusion: Therapy with radiolabeled pentixather appears to be well tolerated and easily applicable when preceding conventional conditioning regimens for hematopoietic stem cell transplantation.

A Comparison between BEAM and BEM Conditioning Regimens for Autologous Hematopoietic Stem Cell Transplantation in Relapsed Lymphoma: A Retrospective Analysis

High dose chemotherapy (HDT) followed by autologous hematopoietic cell transplantation (auto-HCT) is an effective treatment for relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). Historically, carmustine, etoposide, cytarabine, and melphalan (BEAM) has been shown to improve progression free survival (PFS) and overall survival (OS) with relatively low toxicity. However, high doses of carmustine and etoposide with melphalan (BEM) has also demonstrated efficacy as a more intensive regimen tolerated in younger patients. We performed a single institution retrospective study to compare outcomes of lymphoma patients treated with either BEAM or BEM and auto-HSCT. We identified 65 patients treated at USC Norris Comprehensive Cancer Center for R/R NHL or HL with HDT and auto-HCT between 2013 and 2018. 14 patients were excluded from statistical analysis due to insufficient data. The primary outcome was 1-year OS and the secondary outcomes were 100-day mortality and 1-year relapse rate (RR). BEAM consisted of carmustine 150 mg/m2, etoposide 200 mg/m2, cytarabine 200 mg/m2, and melphalan 140 mg/m2, while BEM was carmustine 12 mg/kg, etoposide 60 mg/kg, and melphalan 140 mg/m2. The T-test and Fisher's exact test were used to describe groups with continuous and categorical outcomes respectively. A p-value of 22 BEM patients and 29 BEAM patients were included for statistical analysis. Baseline characteristics are shown in Table 1. There was an insignificant trend towards increased 1-year OS (100% vs. 93.10%; p = 0.4996) but a higher 1-year RR (35.29% vs. 33.33%; p = 0.77) in BEM than BEAM. No difference in 100-day mortality was observed between BEAM and BEM. Notable differences in demographics between BEAM and BEM patients were in age and diagnosis. Compared to BEAM, BEM was utilized more in younger patients (mean age at transplant 41.7 vs. 58.6 years old; p BEAM and BEM HDT resulted in similar outcomes with no difference in 100-day mortality and minor differences in 1-year OS and 1-year RR. However, significant differences in age and diagnoses of patients treated with these regimens challenge more direct and applicable comparisons. Further analyses including tighter-matched patient cohorts, prior induction/salvage therapy and treatment-related toxicities would better differentiate these two regimens to provide additional clinical utility. Despite the wider usage of BEAM for auto-HSCT in patients with R/R lymphomas, BEM appears to be an efficacious alternative, and, therefore, warrants further consideration for future studies.

Pharmacokinetic-Guided Therapeutic Dose Monitoring (TDM) of Busulfan Reduces Relapse of Non-Hodgkin Lymphoma (NHL) Patients Undergoing Autologous Stem Cell Transplantation (ASCT)

Introduction Busulfan (Bu) is integral to many preparative regimens for hematopoietic stem cell transplantation but its metabolism is variable and unpredictable. At our institution, Bu was administered with fixed weight-based dosing (WBD) for NHL patients (pts) undergoing ASCT until 2014 when we initiated a prospective clinical trial (NCT01959477) with pharmacokinetic (PK)-guided therapeutic dose monitoring (TDM) of Bu with cyclophosphamide (Cy) and etoposide (VP16). We subsequently adopted this practice as a standard for all NHL pts. Here, we compare outcomes of NHL pts who received ASCT with WBD vs. PK-directed TDM. Methods We collected clinical features and outcomes of 336 adult NHL pts who underwent ASCT with Bu/Cy/VP16 using WBD (n=258) from 1/2007-12/2013 or TDM from 5/2014-12/2017 (n=78) excluding mantle cell lymphoma. For WBD, Bu was given at 2.8 mg/kg q24 hours on day -9 to -6. For TDM, plasma Bu concentration was serially determined via an in-house liquid chromatography–tandem mass spectrometry (LC–MS/MS) assay as previously described and externally validated. Bu area under the curve (AUC) after first dose was calculated for each pt and used to adjust subsequent doses to target a daily AUC of 4500 μM-minute. Results Baseline features of WBD and TDM pts were similar, although more TDM pts received plerixafor for stem cell mobilization and TDM pts were more often categorized as having a complete remission (CR) prior to ASCT (Table), likely due to more use of PET scan. To adjust for differences, propensity-matched cohorts of WBD and TDM pts were also studied (Table). 36% of TDM pts had increases and 41% had decreases in Bu dose. As shown in the Figure, 24 months after ASCT, relapse was significantly lower with TDM vs. WBD (19% vs. 38%, P = 0.004) and relapse-free survival (RFS) was also improved (69% vs. 55%, P = 0.038). Overall survival (OS) did not differ between WBD and TDM cohorts, likely due to subsequent therapy at the time of relapse. Propensity matched cohorts displayed similar patterns of outcomes. For pts in CR at time of ASCT, RFS did not differ between WBD and TDM (P = 0.79) whereas RFS was improved for pts in Conclusion Compared to WBD, PK-directed TDM of Bu safely reduces relapse when used in combination with Cy + VP16 for NHL pts undergoing ASCT, particularly for pts in

Pharmacokinetics and Efficacy of Generic Melphalan Is Comparable to Innovator Formulation in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplantation

High-dose Melphalan (MEL) is the standard conditioning regimen for Autologous Haematopoietic Stem Cell Transplantation (ASCT) in Multiple Myeloma (MM). Generic MEL is in routine use in our centre and others due to the reduced cost and ease of availability. However, the pharmacokinetics (PK) and the clinical efficacy of generic MEL in comparison with innovator MEL has not been tested before. We aimed to compare the PK of generic Melphalan (Megval, Emcure & Alphalan, Natco) with that of the innovator formulation (Alkeran, Aspen) in MM patients undergoing ASCT. Fifty-five patients diagnosed with MM at Christian Medial College (CMC), Vellore receiving high dose MEL (200mg/m2 or renal adjusted to 140 mg/m2) [generic (Megval, Emcure & Alphalan, Natco n=32], and innovator [Alkeran, Aspen, n=23] between March 2016 and August 2018 were included in this study. Peripheral blood samples were collected at different time points during and after MEL infusion, plasma was separated immediately and stored at -800 until analysis. MEL levels were analysed using LC-MS/MS as per previously published protocol (Guitton et al, 2009). The AUC and clearance of MEL was determined using trapezoidal rule assuming linear PK. The PK estimates as well as available clinical outcomes were compared between generic and innovator MEL. The Inter-individual variability (IIV) in Mel AUC and clearance were 4.39 and 5.88 fold for generic and 4.34 & 6.85 fold for innovator formulation respectively. The median MEL AUC and clearance were comparable between the two formulations [AUC: 12.71 (6.56-35.36) vs. 12.89 (4.16-22.22) mg*L/h and clearance 24.53 (8.69-57.9) vs. 25.06 (11.91-93.61) L/hr/m2 respectively for the generic and innovator formulations]. These parameters were also comparable to previous reports on Mel PK in patients with MM (Kuhne et al, 2008, Nath et al, 2010, Phelps et al, 2017). There were no significant differences in terms of onset and severity of mucositis, day to neutrophil and platelet engraftment, as well as response status on day 100 post ASCT between patients receiving generic or innovator formulations of MEL. Also, neither MEL AUC nor clearance was significantly associated with response, relapse or toxicity. Our study suggests that the PK and efficacy of the generic MEL is comparable to the innovator formulation.

Phase II Clinical Trial of NEPA (Netupitant/Palonosetron) for Prevention of Chemotherapy Induced Nausea and Vomiting (CINV) in Patient Receiving the BEAM Conditioning Regimen

The management of chemotherapy-induced nausea and vomiting (CINV) during preparative regimens for Hematopoietic Stem Cell Transplant (HSCT) continues to be a poorly studied area and an unmet patient need. The primary aim of this study was to assess the efficacy of NEPA to prevent N/V both during and after HSCT conditioning. NEPA is a recently approved combination antiemetic, containing fixed doses of netupitant and palonosetron. Nausea, emesis, and nutritional intake, were evaluated from the start of conditioning through day 4 post-transplant. NEPA was administered Days 1, 3 and 6 of conditioning, dexamethasone (Days 1-6) and BEAM (Carmustine (300 mg/m2 D1), Etoposide/Cytarabine (200/400 mg/m2 D2-5), Melphalan (140 mg/m2 D 6)) preparative regimen (Days 1-6) in 17 patients. Patient nausea and emesis was self-reported using daily assessments and rescue therapy was determined using chart review. Two out of 17 patients experienced emesis (11.7%) after all chemotherapy was completed with no emesis in any patient during chemotherapy. During the observation period, 6 patients did not receive rescue medications (35%) and time to first rescue in other patients was a mean of 188.9 hours from the start of chemotherapy (median 172.4, SD 89 hrs). Responses were classified as either complete (CR) or major (MR), with CR defined as: no emesis, mild-moderate nausea for hours 0-264 (6 days of chemotherapy and 5 days post-chemotherapy), and (MR) defined as: 1-2 emesis on only 1 day with any level nausea or no emesis with severe nausea. Five out of 16 patients reported CR (31%) and 11 reported a major response (69%) at their end of treatment (EOT) visit. One patient did not participate in the EOT visit. The patient population in this study was 47% female, 100% Caucasian, the average age was 62 years old and the following diagnoses were included: Peripheral T-cell Lymphoma (24%), Hodgkin lymphoma (23%), mantle cell lymphoma (29%), and Diffuse large B-cell lymphoma (24%). The following expected adverse events were reported amongst 17 treated patients: anemia (82%); neutropenia (65%); lymphocyte decrease (94%); decreased neutrophils (94%); white blood cell decrease (88%); abdominal pain (59%); constipation (53%); diarrhea (59%); abdominal cramping (35%); nausea (82% all grades); bacteremia (29%); hypophosphatemia (24%); and hypokalemia (29%). Constipation was deemed possibly related to NEPA; additional reported adverse events were not related to study drug. In this interim analysis, NEPA plus dexamethasone was effective in preventing emesis with BEAM conditioning with no increase in adverse events prior to HSCT.

Prevention of chemotherapy-induced nausea and vomiting after high-dose melphalan and stem cell transplantation: review of the evidence and suggestions.

High-dose melphalan (HDMel) is the most common conditioning chemotherapy regimen for autologous stem cell transplantation (SCT) in patients affected by multiple myeloma (MM). No consensus exists for the emetogenicity or prophylaxis of chemotherapy-induced nausea and vomiting (CINV) in this regimen. Data on the incidence and efficacy/safety of CINV prophylaxis among patients affected by MM undergoing autologous SCT with the HDMel regimen was extracted from electronic databases and analyzed. Eleven studies involving multiple CINV prophylaxis regimens were identified and included. No consensus on HDMel emetogenicity was reached, but most studies summarized the emetogenicity as moderate-high risk. An aprepitant-based three-drug regimen (aprepitant + serotonin receptor antagonist (5HT3RA) + dexamethasone) showed better efficacy than a two-drug regimen (5HT3RA + dexamethasone) for CINV prevention without increasing the frequency in adverse events. The aprepitant-based three-drug regimen should be the regimen of choice for CINV prophylaxis for MM patients undergoing autologous SCT with HDMel conditioning.

Phase I/II Study of Escalating Doses of Thalidomide in Conjunction with Bortezomib and High Dose Melphalan As a Conditioning Regimen for Autologous Stem Cell Transplantation in Patients with Multiple Myeloma

Phase I/II Study of Escalating Doses of Thalidomide in Conjunction with Bortezomib and High Dose Melphalan As a Conditioning Regimen for Autologous Stem Cell Transplantation in Patients with Multiple Myeloma

Treosulfan, Fludarabine and Cytarabine As Conditioning before Allogeneic Hematopoietic Stem Cell Transplantation

Background: The combination of treosulfan witth fludarabine was successfully introduced into toxicity-reduced conditioning regimens for hematopoietic stem cell transplantation (HCT). However, the risk of post-HCT relapse remains of concern. Here we report for the first time on the results of an individual treatment approach with treosulfan, fludarabin and cytarabine as conditioning for allogeneic HCT in patients with AML, MPN or MDS.Methods: 22 patients were treated with fludarabine 30 mg/m² given on day -6 to day -2, treosulfan 14 g/m² administered on days -4 to day -2 and cytarabin 2g/m² given on days -6 and -5. GvHD-prophylaxis consisted of cyclosporine A and methotrexate or MMF. In addition, antithymocyte globulin was applied in case of an unrelated donor. One patient received bone marrow and the remaining patients received peripheral blood stem cells from matched related donors (9%), matched unrelated donors (73%) or mismatched unrelated donors (18%). All patients were considered to have high risk of relapse because of unfavourable cytogenetic features and/or insufficient or missing response to previous treatment. Three patients (14 %) with CML after blast crisis received the combination because of the reported high relapse rate (46%) after three-day scheduled conditioning with treosulfan [1]. In addition, patients were considered to be ineligible for myeloablative standard conditioning because of multi-morbidity (n = 4; 18% with HCT-CI >2) and/or age >55 years (n = 14; 64%).Results: The median age of patients was 59 (35-68) years. Patients suffered from acute myeloid leukemia (n = 14, 64%), myeloproliferative neoplasia (n = 6, 27%) or myelodysplasic syndrome (n = 2, 9%). The conditioning regime was well tolerated and nearly all patients engrafted and achieved complete donor-type chimerism, except for one who died very early from sepsis. Another patient with underlying myelofibrosis suffered from secondary graft failure on day 100. Two patients developed aGVHD °III/ IV. None of the patients suffered from veno-occlusive disease or severe chronic GVHD. Overall survival and event-free survival at one year reached 60.2% and 59.6%, respectively. Six patients died from infectious disease, two from relapse and one patient from acute GVHD °IV.Conclusion: The combination of cytarabine with the established conditioning of treosulfan and fludarabine is feasible in patients with high risk of relapse and ineligible for myeloablative standard conditioning.Holowiecki J, Giebel S, Wojnar J et al. Treosulfan and fludarabine low-toxicity conditioning for allogeneic 334 haematopoietic stem cell transplantation in chronic myeloid leukaemia. Br J Haematol 335 2008; 142(2): 284-92. DisclosuresHilgendorf:Novartis: Other: Travel support, Research Funding; Medac: Other: Travel support, Research Funding. Frietsch:Deutsche Krebshilfe: Research Funding. Scholl:Abbivie: Other: Travel support; MDS: Other: Travel support; Novartis: Other: Travel support; Carreras Foundation: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Deutsche Krebshilfe: Research Funding; Alexion: Other: Travel support. Hochhaus:Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Incyte: Research Funding; Takeda: Research Funding; Pfizer: Research Funding. Casper:Medac: Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding.

Establishment and Evaluation of Gvhd Mouse Model for Allogeneic Hematopoietic Stem Cell Transplantation

Objective:To study the feasibility of using cyclophosphamide alone without total body irradiation (TBI) as conditioning regimen for allogeneic hematopoietic stem cell transplantation (allo-HSCT) and establish a graft-versus-host disease (GVHD) mouse model.Methods:Single cell suspension of spleen and bone marrow were prepared from donor C57/BL/6 mice (B6 mice) . The recipient B6D2F1 mice (F1 mice) were signed into 4 groups with 12 mice per each group. Groups I~III mice were conditioned with peritoneal injection of cyclophosphamide (300 mg/m2/d) on day -5, -4 and -3 of allo-HSCT, and group IV mice were used as control with saline injection. On day 0, group I mice were injected through tail vein with a mixture of 2×107 spleen cells, 5×106 bone marrow cells and 1×104 P815 cells; group II with 5×106 bone marrow cells and 1×104 P815 cells; group III with 1×104 P815 cells and group IV with RPMI1640 culture medium. The blood leukocyte counts were analyzed, GVHD score and the pathological leukemia infiltration of skin, liver and colon were evaluated and compared on day 30 after allo-HSCT.Results:(1) The GVHD scores of group I mice were 2 to 4 on day 14 post allo-HSCT, and mice started to die on day 15, eight (8) mice survived and the GVHD scores of them were 1 to 6 with a survival rate of 66.7% on day 30. Group II mice began to die on day 6 and only one survived on day 30 with a survival rate of 8.3%. All of group III mice died on day 18. Group IV mice survived (Figure 1).(2) The leukocyte counts in group I and group II were significantly increased on day 7 post allo-HSCT(p<0.05). There was also a significant difference in total leukocyte counts between groups I/II and group IV (p<0.05). The leukocyte counts in mice of groups I~III were significantly decreased, and there were a significant difference between group I and groups II/III/IV respectively (p<0.05) on day 14 post allo-HSCT. On day 21 after allo-HSCT, the leukocyte count of Group I and II mice were ≥1×109/L, which means that allo-HSCT were successful. The leukocyte counts in group I mice were again increased on day 28 post allo-HSCT. There was no significant difference between Group I and Group IV (p>0.05).(3) Pathological observation: The cell atrophy and necrosis in the hepatic portal area and slight infiltration of the leukemia cells in central vein were observed in group I recipient mice. The number of hepatocytes of the mice decreased, and the infiltration of the leukemia cells in the liver sinus were observed in group II. The liver was heavily infiltrated by leukemic cells in group III mice. The mouse livers were normal in group IV mice.Conclusion:It is feasible to establish GVHD model of the leukemia mice with cyclophosphamide conditioning regimen of allo-HSCT, and simple to operate. This is less harmful to people, animals and the environment.Discussion:The traditional animal model of GVHD is based on TBI conditioning regimen prior to allo-HSCT. However, the process can lead to systemic adverse reactions such as myelosuppression, radiation gastroenteritis, endocrine disorders and systemic function disorders, etc. in both the operators and animals. Therefore, the radiotherapy doses have to be low. At the same time, it is difficult to establish animal models of GVHD due to the uneven distribution of the doses. Cyclophosphamide was selected for the conditioning regimen of allo-HSCT in the study. Cyclophosphamide had the effect direct on killing tumor cells, induced recipients to tolerate the immune of donors, enabled to implant donor cells into recipients smoothly. The stable chimeras were obtained. There are a large number of T and B lymphocytes in donor's spleen cells. By injecting donor spleen cells and active immune cells derived from proliferation and differentiation of hematopoietic stem cells, the effects of graft-anti-leukemia are availably activated in recipients.AcknowledgmentsWe thank Dr Zhifu Xiang very much for his great helpful revisions. DisclosuresNo relevant conflicts of interest to declare.

A Comparison between BEAM and BEM Conditioning Regimens for Autologous Hematopoietic Stem Cell Transplantation in Relapsed Lymphoma: A Descriptive Analysis

Background:High dose chemotherapy (HDT) followed by autologous hematopoietic stem cell transplantation (auto-HSCT) is an effective choice of treatment for relapsed/refractory non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). Historically, carmustine, etoposide, cytarabine, and melphalan (BEAM) has been the most widely used conditioning regimen, shown to significantly improve progression free survival (PFS) and overall survival (OS) with relatively low toxicity. However, high doses of carmustine and etoposide combined with melphalan (BEM), despite increased risks of pulmonary toxicity and severe mucositis, has also demonstrated efficacy as a more intensive preparative regimen with acceptable tolerability in younger populations. We performed a single institution descriptive study in order to compare the outcomes of patients with both NHL and HL treated with either consolidative BEAM or BEM preparative regimens and auto-HSCT.Methods:We identified 65 patients who were treated at USC Norris Comprehensive Cancer Center for relapsed/refractory NHL or HL with HDT and auto-HSCT between 2013 and 2018. 14 patients were excluded from statistical analysis due to insufficient data. The primary outcome was 1-year OS and the secondary outcomes were 100-day mortality and 1-year relapse rate (RR). BEAM consisted of carmustine 150mg/m2, etoposide 200mg/m2, cytarabine 200mg/m2, and melphalan 140mg/m2, while BEM was carmustine 12mg/kg, etoposide 60mg/kg, and melphalan 140mg/m2. Patient baseline characteristics, including age, sex, and diagnosis, were identified to describe the population. The T-test was used to describe groups with continuous outcomes and the Fisher's exact test was used to describe groups with categorical outcomes. A p-value of < 0.05 was considered statistically significant.Results:22 patients who received BEM and 29 patients who received BEAM were included for statistical analysis. The patient's baseline characteristics are shown in Table 1. There was an insignificant trend towards increased 1-year OS (100% vs. 93.10%; p = 0.4996) but a higher 1-year RR (35.29% vs. 33.33%; p = 0.77) in BEM than BEAM. All patients were alive at 100 days; so, no difference was observed between BEAM and BEM with regards to 100-day mortality.Notable differences in demographics between the patients treated with BEAM versus BEM were observed primarily in age and diagnosis. Compared to BEAM, BEM was utilized significantly more in younger patients (mean age at transplant 41.7 vs. 58.6 years old; p < 0.0001) with a significantly larger percentage of HL diagnosis (48.28% vs. 5.56%; p = 0.0001). There was no significant difference in the 1-year OS, 100-day mortality or 1-year RR between HL and NHL (p = 0.5333, p = 1, and p = 0.7287, respectively) or between age < 50 and age ≥ 50 (p = 0.5271, p = 1, and p = 1, respectively).Conclusions:Both BEAM and BEM HDT for auto-HSCT to treat relapsed/refractory NHL or HL resulted in similar outcomes with no difference observed in 100-day mortality and only minor differences in 1-year OS and 1-year RR. However, significant differences in age and diagnoses of patients treated with these conditioning regimens serve as obstacles for more direct and applicable comparisons. Further analyses including tighter-matched patient cohorts, induction and salvage therapy prior to auto-HSCT, maintenance therapy, as well as treatment-related toxicities are necessary to better differentiate these two preparative regimens and provide additional utility in the clinical setting. Nonetheless, despite the much wider usage of BEAM as a preparative regimen for auto-HSCT in patients with relapsed/refractory lymphomas, BEM appears to be an efficacious alternative, and, therefore, warrants further consideration for future studies. DisclosuresNo relevant conflicts of interest to declare.

Health Care Utilization in Transplanted Versus Non-Transplanted Sickle Cell Disease Patients

Sickle cell disease (SCD) is an inherited red blood cell disorder that leads to substantial morbidity and a heavy burden on the health care system. Nonmyeloablative allogeneic hematopoietic stem cell transplantation (HSCT) regimens using HLA-matched related donors have recently demonstrated high rates of engraftment and a favorable safety profile in adults with SCD. The long term effects of these HSCT regimens on health care utilization, particularly in SCD adults who have had a high burden of SCD-related acute and chronic complications, has not been previously reported.Between 8/2011 and 4/2016, 86 SCD patients who received their routine care at our institution were referred to the Blood & Marrow Transplant Clinic. Sixteen patients received a HSCT from an HLA-match related donor during this time period. Reasons for not proceeding to transplantation in the 70 patients included lack of an HLA-matched related donor in 36 (51%), patient/family declining in 21 (30%), insurance denial in 11 (16%), and the presence of RBC antibodies to potential donors in 2 (3%) patients. We compared health care utilization patterns between 1) 1-year pre-HSCT vs. 1- and 2-years post-HSCT in 16 transplanted SCD adults and 2) 16 transplanted vs. 70 non-transplanted SCD patients at 1- and 2-years from the time of HSCT or referral. Comparisons of linear variables and categorical variables were performed using the Kruskal-Wallis and Chi-square test, respectively.In the 16 SCD patients who met standard transplant eligibility criteria and underwent HSCT, the median age at the time of HSCT was 33 years (interquartile range [IQR], 24 - 34 years), 56% were male, and 94% were HbSS genotype. Treatment prior to HSCT was hydroxyurea in 10 (63%), chronic red blood cell (RBC) transfusion therapy in 5 (31%), and no disease modifying therapy in 1 (6%) patient. Thirteen of 16 (81%) transplanted SCD patients maintained a stable graft. Emergency room (ER) visits were lower 1-year and 2-year post-HSCT compared to 1-year pre-HSCT (P=0.03) (Table 1). In the 2nd year post-HSCT, ER visits, hospital length of stay, RBC transfusion requirements, and rates of documented infections were all lower compared to 1-year pre-HSCT (P<0.03).We then compared health care utilization patterns between the 16 SCD patients that underwent HSCT vs. the 70 SCD patients that were not transplanted. The HSCT and non-HSCT patients were similar with respect to median age (33 vs. 31 years old; P=0.2), gender (35% vs. 56% male, P=0.1), number of eligibility criteria met for HSCT (PMID: 24319206) (2 for each group; P=0.4) and SCD genotype (80% vs. 94% HbSS genotype, P=0.4), respectively. During the first year after transplant or of observation, we observed lower rates of emergency room visits but a greater number of inpatient hospital days in the HSCT vs. no HSCT groups (Figure 1). During the second year, both the number of emergency room visits and the number of inpatient hospital days were lower in the HSCT vs. the no HSCT patients (Figure 1).In conclusion, we demonstrate that allogeneic HSCT leads to lower health care utilization by the second year post-HSCT in adults with SCD. These results support the role for HSCT to lower the morbidity, health care burden and costs associated with SCD and should encourage universal insurance coverage for HSCT in adults with SCD. [Display omitted] DisclosuresPatel:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Honoraria. Khan:Teva: Speakers Bureau.

Treatment Regimens for Patients with Newly Diagnosed Multiple Myeloma Who Are Ineligible for Stem Cell Transplantation: A Systematic Literature Review and Network Meta-Analysis

Background: In patients with newly diagnosed multiple myeloma (ndMM) who are ineligible for autologous stem cell transplantation (ASCT), bortezomib, melphalan, and prednisone regimen (VMP) is standard of care as a first-line treatment in most regions of the world. Daratumumab is a new monoclonal antibody aimed to improve outcomes in ndMM. The ongoing ALCYONE study demonstrated significant improvement in progression-free survival (PFS) and overall response rate (ORR) for the combination of daratumumab plus VMP (D-VMP) compared to VMP in transplant-ineligible ndMM patients (Mateos, 2018). While direct head-to-head randomized controlled trials (RCTs) are lacking, it is important to assess how D-VMP compares with other treatment regimens used in clinical practice for ndMM patients who are ineligible for ASCT.Aims: The aim of this study is to investigate the comparative effectiveness (PFS, ORR) of D-VMP with other relevant treatment regimens used in patients with ndMM who are ineligible for ASCT.Methods: We conducted a Bayesian network meta-analysis (NMA) based on RCTs identified through a systematic literature review (SLR). Both fixed effects and random effects models were tested. The results are depicted in a network of evidence, forest plots, ranking histograms and probabilities of D-VMP being better than the comparator treatment regimens.Results: The SLR revealed 25 RCTs conducted in patients with ndMM who are ineligible for ASCT. For PFS, the NMA included 20 RCTs covering 20 treatments and for ORR, the NMA included 20 RCTs covering 21 treatments. Random-effects model is preferred for PFS as well as for ORR as this model showed lower deviance information criterion (DIC), and as the homogeneity assumption was violated for PFS. The results for both PFS and ORR are summarized in Table 1. For PFS and ORR, D-VMP ranked first in the evidence of network. For PFS, D-VMP was statistically significantly more effective compared to 10 out of the 19 treatment regimens. For ORR, D-VMP was significantly more effective as compared to 12 out of the 20 treatment regimens.Conclusion: In the absence of head-to-head RCTs, NMAs allow delineation of the comparative effectiveness of different treatments. This NMA suggests that D-VMP has a higher potential of being effective in improving ORR and PFS in patients with ndMM who are ineligible for transplant compared to other available treatment options. Updated results based on a 1-year update of ALCYONE will be presented at the meeting.

Safety and Efficacy of Yttrium-90-Labeled Anti-CD45 Antibody (90Y-DOTA-BC8) Followed By a Standard Reduced-Intensity Hematopoietic Stem Cell Transplant (HCT) Regimen for Patients with Refractory/Relapsed Leukemia or High-Risk Myelodysplastic Syndrome (MDS)

▪Although HCT offers the best potential for cure for patients with high risk leukemia and MDS, the procedure may not be an option for all patients due to the toxicity of the conditioning regimen. Reduced-intensity conditioning (RIC) allo-HCT regimens are associated with lower non-relapse mortality (NRM), but patients receiving these regimens have a higher risk of relapse. Radioimmunotherapy (RIT) can potentially deliver high doses of targeted radiation while minimizing toxicity to normal tissue. When combined with RIC allo-HCT, RIT may improve responses without increasing toxicity associated with myeloablative conditioning.We evaluated the safety and efficacy of yttrium 90 (90Y)-anti-CD45 antibody (MAb; BC8) followed by a standard RIC regimen with fludarabine (Flu) and 2 Gy total body irradiation (TBI) as a means of developing an improved HCT strategy for high-risk acute leukemia or MDS patients. We used CD45 as a target due to its ubiquitous expression on hematopoietic stem cells including the leukemic blasts. We used the high-energy (2.2 MeVmax) beta-emitter 90Y, which has a relatively short half-life (2.7 days) to eliminate targeted malignant cells.This phase I dose-escalation trial (NCT01300572) was designed to estimate the safety, feasibility and maximum tolerated dose (MTD) of 90Y-BC8-DOTA MAb when combined with Flu and 2 Gy TBI followed by HLA‐matched, related or unrelated allo-HCT for patients with high-risk leukemia or MDS. The MTD was defined as the radiation absorbed dose delivered by 90Y-BC8-DOTA MAb associated with a true dose-limiting toxicity (DLT) rate of 25%, where a DLT is defined as Bearman grade III/IV regimen-related toxicity. Doses of 90Y were escalated in increments of 2 Gy depending on the occurrence of DLT. Inclusion required patients to have advanced leukemia or high-risk MDS (defined as primary refractory or relapsed AML/ALL, secondary AML, MDS expressed as RAEB or CMML). To determine the dose of 90Y-BC8-DOTA, patients first underwent a biodistribution step using a trace-labeled infusion of 111Indium (111In)-BC8-DOTA followed by gamma-camera imaging. On pre-HCT day -12, patients received 90Y-BC8-DOTA at a prescribed radiation dose calculated from the trace-labeled 111In-BC8-DOTA biodistribution, followed by Flu (30 mg/m2/day) on days -4 to -2. TBI (2 Gy) was administered on day 0, prior to G-CSF mobilized donor PBSC infusion. GVHD prophylaxis consisted of mycophenolate mofetil and cyclosporine.Fifteen patients, median age of 62 (range 37-76), were treated (10 with advanced AML, 5 with high-risk MDS). At time of HCT, 9 patients had refractory active disease while 6 were in remission with minimal residual disease (Table 1). The patients received 22.8 to 151.2 mCi of 90Y, delivering an average of 10.5 Gy to marrow, 70 Gy to spleen, and 17 Gy to liver. Although a maximum dose of 28 Gy was delivered to the liver, no DLT was observed. Therefore, the MTD could not be estimated.Treatment led to complete remission in 13 patients (87%), 2 patients had persistent disease after HCT. All patients engrafted with a median donor-derived CD3 and CD33 chimerism both 100% by day 28 after HCT. Ten patients (67%) developed grade II-IV acute GVHD (grade II: n=7; III: n=2; IV: n=1). Five patients (33%) developed chronic GVHD. Six patients relapsed, 5 of whom subsequently died due to progression of disease. The median time to relapse among these 6 patients was 59 days (range, 6- 351 days). One patient died from stage IV steroid-refractory GVHD. One patient died in remission from acute renal failure at 7 months after HCT. Eight patients (53%) are surviving with a median follow-up of 1.8 (range, 0.9-5.9) years. Estimated overall survival at one and two years were 66% and 46%, respectively, with progression-free survival estimated to be 46% at each of these time points. The 1-year estimate of relapse was 41% (Fig. 1).The inclusion of 90Y-BC8-DOTA into a RIC allo-HCT regimen is feasible, tolerable and no DLTs were observed. The efficacy of this approach is promising considering the high-risk leukemia/MDS patients with active disease enrolled. Current studies are evaluating the use of an alpha emitter, astatine-211, which is short-lived (t ½ = 7.2 hours) and provides high-energy radiation, conjugated to anti-CD45 MAb BC8 as part of an HCT conditioning regimen for patients with advanced AML, ALL, or high-risk MDS, in place of 90Y with the goal of continuing to improve outcomes using RIT for allo-HCT (NCT03128034). [Display omitted] DisclosuresOrozco:Actinium Pharmaceuticals: Research Funding. Green:Juno Therapeutics: Patents & Royalties, Research Funding. Gopal:Incyte: Consultancy; Pfizer: Research Funding; Gilead: Consultancy, Research Funding; Teva: Research Funding; Aptevo: Consultancy; Merck: Research Funding; Janssen: Consultancy, Research Funding; Spectrum: Research Funding; Takeda: Research Funding; BMS: Research Funding; Seattle Genetics: Consultancy, Research Funding; Brim: Consultancy; Asana: Consultancy. Pagel:Pharmacyclics, an AbbVie Company: Consultancy; Gilead: Consultancy.