A nationwide phase II study of delayed local treatment for children with high-risk neuroblastoma: The Japan Children's Cancer Group Neuroblastoma Committee Trial JN-H-11.

PURPOSE: Survival rates of patients with high-risk neuroblastoma are unacceptable. A time-intensified treatment strategy with delayed local treatment to control systemic diseases has been developed in Japan. We conducted a nationwide, prospective, single-arm clinical trial with delayed local treatment. This study evaluated the safety and efficacy of delayed surgery to increase treatment intensity. PATIENTS AND METHODS: Seventy-five patients with high-risk neuroblastoma were enrolled in this study between May 2011 and September 2015. Delayed local treatment consisted of five courses of induction chemotherapy (cisplatin, pirarubicin, vincristine, and cyclophosphamide) and myeloablative high-dose chemotherapy (melphalan, etoposide, and carboplatin), followed by local tumor extirpation with surgery and irradiation. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), response rate, adverse events, and surgical complications. RESULTS: Seventy-five patients were enrolled, and 64 were evaluable (stage 3, n = 8; stage 4, n = 56). The estimated 3-year PFS and OS rates (95% confidence interval [CI]) were 44.4% [31.8%-56.3%] and 80.7% [68.5%-88.5%], resspectively. The response rate of INRC after completion of the treatment protocol was 66% (42/64; 95% CI: 53%-77%; 23 CR [complete response], 10 VGPR [very good partial response], and nine PR [partial response]). None of the patients died during the protocol treatment or within 30 days of completion. Grade 4 adverse effects, excluding hematological adverse effects, occurred in 48% of patients [31/64; 95% CI: 36%-61%]. Major Surgical complications were observed in 25% of patients [13/51; 95% CI: 14%-40%]. CONCLUSION: This study indicates that delayed local treatment is feasible and shows promising efficacy, suggesting that this treatment should be considered further in a comparative study of high-risk neuroblastoma.

Indisulam synergizes with melphalan to inhibit Multiple Myeloma malignancy via targeting TOP2A.

Multiple myeloma (MM) is the second most prevalent hematologic malignancy which remains uncurable. Numerous drugs have been discovered to inhibit MM cells. Indisulam, an aryl sulfonamide, has a potent anti-myeloma activity in vitro and in vivo. This study aims to explore the new mechanism of indisulam and investigate its potential use in combination with melphalan. We examined DNA damage in MM cells through various methods such as western blotting (WB), immunofluorescence, and comet assay. We also identified the role of topoisomerase IIα (TOP2A) using bioinformatic analyses. The impact of indisulam on the RNA and protein levels of TOP2A was investigated through qPCR and WB. Cell proliferation and apoptosis were assessed using CCK-8 assays, Annexin V/PI assays and WB. We predicted the synergistic effect of the combination treatment based on calculations performed on a website, and further explored the effect of indisulam in combination with melphalan on MM cell lines and xenografts. RNA sequencing data and basic experiments indicated that indisulam caused DNA damage and inhibited TOP2A expression by decreasing transcription and promoting degradation via the proteasome pathway. Functional experiments revealed that silencing TOP2A inhibited cell proliferation and induced apoptosis and DNA damage. Finally, Indisulam/melphalan combination treatment demonstrated a strong synergistic anti-tumor effect compared to single-agent treatments in vitro and in vivo. These findings suggest that combination therapies incorporating indisulam and melphalan have the potential to enhance treatment outcomes for MM.

Advanced Interventional Treatments in Retinoblastoma Management: A Comprehensive Review.

Retinoblastoma is the most common eye malignancy in children that if left untreated can invade intraocular structures, metastasize, and rarely lead to death. Traditionally treated with systemic chemotherapy, Intra-arterial chemotherapy is gaining popularity as it allows for the direct administration of chemotherapy through the ophthalmic artery, thus reducing systemic side effects. Intra-arterial chemotherapy procedures have evolved, with refinements to reduce risks and radiation exposure. Intra-arterial chemotherapy boasts an impressive technical success rate and one year ocular survival even amongst advanced cases. This review offers a thorough examination of the technique, indications, contraindications, outcomes, and alternative options for Intra-arterial chemotherapy.

A case of peripheral T-cell lymphoma in which therapy-related myelodysplastic syndrome developed and a second autologous transplantation was performed.

We report a case of therapy-related myelodysplastic syndrome (MDS), which developed 9 years after autologous peripheral blood stem cell transplantation (PBSCT) for peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). A 65-year-old male was diagnosed with PTCL-NOS. After 6 cycles of the CHOP (cyclophosphamide [CPA], doxorubicin, vincristine, and prednisone) regimen, he achieved a first complete response (CR). He relapsed 33 months later and received salvage chemotherapy, which consisted of the CHASE regimen (CPA, high-dose cytarabine, dexamethasone, and etoposide). During the recovery phase of the first cycle of CHASE, his peripheral blood stem cells (PBSCs) were harvested and frozen in 2 bags. After 2 courses of CHASE, he underwent autologous PBSCT, which involved the use of the LEED preconditioning regimen (melphalan, CPA, etoposide, and dexamethasone) and one of the frozen bags. This resulted in a second CR. At 39 months after PBSCT, he relapsed with a tumor in his right arm. After it was resected, he received eight cycles of brentuximab vedotin and 45 Gy of involved-field irradiation concurrently and achieved a third CR. Nine years after autologous PBSCT, he was diagnosed with MDS with excess blasts 2 (MDS-EB-2). His disease progressed to acute myeloid leukemia after 2 courses of azacitidine therapy. He successfully underwent a second autologous PBSCT involving the busulfan and melphalan preconditioning regimen and the other frozen bag, which had been stored for 9 years. He has been in complete cytogenetic remission for 1 year since the second autologous PBSCT.

In the era of Bortezomib-based Induction, intensification of Melphalan-based conditioning with Bortezomib does not improve Survival Outcomes in newly diagnosed Multiple Myeloma: a study from the Chronic Malignancies Working Party of the EBMT.

Bortezomib (Vel)- Melphalan 200 mg/m2 (Mel200) (Vel-Mel) has been utilised to intensify conditioning in autologous hematopoietic stem cell transplantation (AHCT) for multiple myeloma (MM). This EBMT registry-based study compared Vel-Mel with Mel200 during upfront AHCT. Between 2010 and 2017, MM patients who received Vel-Mel (n = 292) conditioning were compared with 4,096 Mel200 patients in the same 58 centres. Pre-AHCT, compared to Mel200 patients, Vel-Mel patients had similar International Staging System (ISS) scores and cytogenetic risk profiles; a similar proportion had received bortezomib-based induction (85% and 87.3%, respectively) though they were younger with a better performance status. Vel-Mel patients were more likely to achieve CR post-induction (40.6% vs 20.3%, p < 0.001) and by day 100 of AHCT (CR/VGPR: 70.2 % vs. 57.2%, p < 0.001). There was no difference in 3-year PFS (49% vs 46%, p = 0.06) or early post-AHCT mortality. In multivariable analysis, Vel-Mel associated with inferior PFS (HR: 1.69 (1.27-2.25, p < 0.001) and OS (HR:1.46 (1.14-1.86,p = 0.002), similar to negative effects on PFS of advanced ISS (HR:1.56 (1.33-1.83, p < 0.001), high-risk cytogenetics (HR:1.43(1.18-1.74, p < 0.001) and poor post-induction response(<=PR)(HR: 1.43(1.25-1.62, p < 0.001) Overall, despite superior pre- and post-AHCT responses, there was no improvement in PFS or OS following Vel-Mel. This data supports the findings of the smaller prospective IFM study.

Retrospective Evaluation of Melphalan, Vincristine, and Cytarabine Chemotherapy for the Treatment of Relapsed Canine Lymphoma.

Dogs diagnosed with multicentric lymphoma often relapse following induction therapy within the first year of treatment. The primary aim of this study was to evaluate the tolerability of a novel drug combination using melphalan, vincristine, and cytarabine (MOC) for the treatment of relapsed lymphoma. On day 1, dogs were treated with vincristine (0.5-0.6 mg/m2 IV) and cytarabine (300 mg/m2 IV over 4-6 hr or subcutaneously over 2 days). On day 7, dogs were treated with melphalan (20 mg/m2per os). This 2 wk protocol was repeated for at least three cycles or until treatment failure. Twenty-six dogs were treated with MOC and met the inclusion criteria. Twenty-three dogs had toxicity data, and all experienced adverse events with the majority graded as mild. The overall response rate was 38%, which included 19% of dogs who achieved a complete response. The median progression-free survival was 29 days (range 1-280 days). The overall clinical benefit was 65% for a median of 37 days (range 33-280 days). MOC is a safe treatment option for relapsed lymphoma in dogs.

Comparison of fludarabine-based conditioning regimens in adult cord blood transplantation for myeloid malignancy: A retrospective, registry-based study.

Fludarabine/busulfan and fludarabine/melphalan are viable options as conditioning regimens. However, the optimal fludarabine-based conditioning in cord blood transplantation (CBT) remains unclear. Therefore, this retrospective, registry-based study aimed to analyze the impact of five fludarabine-containing conditioning regimens on 1395 adult patients (median age, 61 years) with acute myeloid leukemia, myelodysplastic syndrome, and chronic myeloid leukemia who underwent their first CBT. Treatment outcomes of fludarabine combined with melphalan (100-140 mg/m2 ) and low-dose total body irradiation (TBI; FM140T); melphalan (80-99 mg/m2 ) and TBI (FM80T); busulfan (12.8 mg/kg) and melphalan (FB4M); busulfan (12.8 mg/kg) and TBI (FB4T); and busulfan (6.4 mg/kg) and TBI (FB2T) were compared. The 3-year survival rate was 67%, 53%, 44%, 36%, and 39%, respectively (p < .0001). The FM140T survival rate was the most favorable after adjusting for confounders, and the hazard ratios (vs. FM140T) for overall mortality were as follows: FM80T, 1.6 (95% confidence interval [CI], 1.2-2.2); FB4M, 2.1 (95% CI, 1.6-2.8); FB4T, 2.7 (95% CI, 2.0-3.7); and FB2T, 2.2 (95% CI, 1.6-3.1). The better survival observed with FM140T, regardless of the disease, disease risk, age, or transplant year, was attributed to the lower relapse rate and lower non-relapse mortality (NRM) associated with fewer infectious deaths. Conversely, FB4T was associated with a higher relapse rate and higher NRM. The findings indicate that the outcomes of CBT in myeloid malignancies were highly dependent on both the alkylating agent and its dose in combination with fludarabine. Therefore, compared with fludarabine/busulfan-based conditioning, FM140T may be the preferred regimen.

Investigating the effect of pre-transplant thrombocytopenia and anemia on the engraftment and long-term survival in multiple myeloma patients.

BACKGROUND: Autologous stem cell transplantation (ASCT) following high-dose melphalan is the standard treatment for Multiple Myeloma (MM). Despite new treatments, further investigation is needed to identify prognostic factors of ASCT. This study evaluated the impact of thrombocytopenia and anemia on the engraftment of MM patients after ASCT. MATERIALS AND METHODS: This retrospective study involved 123 MM patients who underwent ASCT with high-dose Melphalan. Successful engraftment is achieved when both platelets (Plt) and white blood cells (WBC) engraft successfully. We examined the statistically significant cut-offs for the prognostic factors on the admission day. Ultimately, the association of risk factors with the Plt and WBC engraftment and long-term survival were analyzed as the outcomes of interest. RESULTS: Spearman's correlation coefficient between Plt and WBC engraftment was 0.396 (p < 0.001). The engraftment in the patients with Plt < 140,000/µL was 17.4% slower (p = 0.036) and the odds of long-term survival was 72% lower (p = 0.016) than in patients with higher Plt. Patients with Hb < 11 g/dL were 12.7% slower in engraftment. Age over 47 was a significant factor in slower engraftment (p = 0.036) which decelerated the engraftment by 15.2%. CONCLUSION: Thrombocytopenia and anemia before transplantation are related to slower Plt/WBC engraftment and as prognostic factors might predict the long-term survival of MM patients following ASCT.

Efficacy of intravitreal injections of melphalan in the treatment of retinoblastoma vitreous seeding.

BACKGROUND: The introduction of intravitreal injections of melphalan (IVIM) has significantly improved the efficacy of retinoblastoma treatment and the prognosis for eye preservation. OBJECTIVES: To evaluate the results of using IVIM to treat retinoblastoma vitreous seeding. MATERIAL AND METHODS: This was a clinical, retrospective, single-center study. Twenty-six children (27 eyes) who met all of the following inclusion criteria qualified for the study: 1) active vitreous seeding at the time of retinoblastoma diagnosis; 2) IVIM performed between 1 January 2017 and 30 September 2020; and 3) a minimum follow-up period of 12 months since the last IVIM. Doses of 20-40 µg melphalan per injection were used. RESULTS: The eye observation period from the last IVIM to the last ophthalmic examination averaged 32.41 months (median 30.00; range 13.00-56.00). Success (no active tumors in the vitreous body) was achieved in 24 eyes (88.9%), and a doubtful result (recurrence in the retina with a difficult-to-determine etiology) in 2 eyes (7.4%). In 1 eye (3.7%), despite treatment, active tumors were still present in the vitreous body. Out of all 27 eyes, 4 eyeballs were removed, but the direct cause of enucleation was not vitreous seeding. There were no complications in the form of intraocular inflammation, extraocular retinoblastoma or distant metastases. There was 1 case of anterior uveitis and 1 case of cataract. CONCLUSIONS: The IVIM is a highly effective and safe form of treatment for retinoblastoma vitreous seeding.

Comparison of fludarabine/melphalan (FluMel) with fludarabine/melphalan/BCNU or thiotepa (FBM/FTM) in patients with AML in first complete remission undergoing allogeneic hematopoietic stem cell transplantation - a registry study on behalf of the EBMT Acute Leukemia Working Party.

Conditioning protocols for patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) are being developed continuously to improve their anti-leukemic efficacy and reduce their toxicity. In this study, we compared the conditioning protocol of fludarabine with melphalan 140 mg/m2 (FluMel) with conditioning protocols based on this same backbone but with an additional alkylating agent i.e., either fludarabine/BCNU (also known as carmustine)/melphalan (FBM), or fludarabine/thiotepa/melphalan (FTM) 110 mg/m2. We included 1272 adult patients (FluMel, n = 1002; FBM/FTM, n = 270) with acute myeloid leukemia (AML) with intermediate/poor cytogenetic risk in first complete remission (CR) from the registry of the EBMT Acute Leukemia Working Party. Despite patients in the FBM/FTM group were older (64.1 years vs. 59.8 years, p < 0.001) and had a worse Karnofsky performance score (KPS < 90, 33% vs. 24%, p = 0.003), they showed a better overall survival (OS) (2 y OS: 68.3% vs. 58.1%, p = 0.02) and less non-relapse mortality (NRM) (2 y NRM: 15.8% vs. 22.2%, p = 0.009) compared to patients treated with FluMel. No significant differences were observed in relapse incidence (RI) (2 y RI: 24.9% vs. 23.7%, p = 0.62). In conclusion, the addition of a second alkylating agent (BCNU/carmustine or thiotepa) to FluMel as FBM/FTM conditioning, improves OS in AML patients in first CR with intermediate/poor risk cytogenetics after allo-HCT.

Quality of life after melphalan percutaneous hepatic perfusion for patients with metastatic uveal melanoma.

BACKGROUND: Recent studies indicate that melphalan percutaneous hepatic perfusion (M-PHP) for liver metastases from ocular melanoma (mUM) improves survival. Importantly, this benefit must be carefully balanced with changes in a patient's quality of life (QoL). This study examines the QoL changes post-M-PHP. METHODS: Retrospective analysis of the change in QoL using the Functional Assessment of Cancer Therapy-General (FACT-G) with mUM patients receiving M-PHP ( n  = 20). The FACT-G scores, which comprise physical (PWB), social (SWB), emotional (EWB) and functional (FWB) wellbeing were measured pre-procedure and at day 1, day of discharge (mean = 2.4 days), 7, 14 and 28 days after M-PHP therapy. Wilcoxon signed-rank test gauged QoL domain changes. RESULTS: Baseline FACT-G median (IQR) scores were 101.8 (21.8). QoL scoring significantly decreased immediately after the procedure [day 1; 85 (27.5); P  = 0.002] and gradually improved over time. By day 28, QoL almost returned to pre-procedure levels [100.3 (13.8); P  = 0.31]. Subscore analysis revealed that the initial drop in QoL at day 1 post-procedure was attributable to the PWB (28 vs. 24; P  = 0.001) and FWB domains (26 vs. 18.5; P  < 0.001). By day 28 there was a statistically significant improvement in EWB ( P  = 0.01). CONCLUSION: QoL following M-PHP decreases immediately after therapy and is not significantly different from baseline by the day of discharge. By day 28 there is improved emotional well-being. This study could help to optimize the time between treatment cycles when combined with toxicity data and blood count recovery.

Melflufen in relapsed/refractory multiple myeloma refractory to prior alkylators: A subgroup analysis from the OCEAN study.

Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone demonstrated superior progression-free survival (PFS), but not overall survival (OS), versus pomalidomide plus dexamethasone in relapsed/refractory multiple myeloma in the OCEAN study. Time to progression (TTP) <36 months after a prior autologous stem cell transplantation (ASCT) was a negative prognostic factor for OS with melflufen. This post hoc exploratory analysis evaluated patients refractory to prior alkylators (e.g., cyclophosphamide and melphalan) in OCEAN. In 153 patients refractory to prior alkylators (melflufen, n = 78; pomalidomide, n = 75), the melflufen and pomalidomide arms had similar median PFS (5.6 months [95% CI, 4.2-8.3] vs. 4.7 months [95% CI, 3.1-7.3]; hazard ratio [HR], 0.92 [95% CI, 0.63-1.33]) and OS (23.4 months [95% CI, 14.4-31.7] vs. 20.0 months [95% CI, 12.0-28.7]; HR, 0.92 [95% CI, 0.62-1.38]). Among alkylator-refractory patients with a TTP ≥ 36 months after a prior ASCT or no prior ASCT (melflufen, n = 54; pomalidomide, n = 53), the observed median PFS and OS were longer in the melflufen arm than the pomalidomide arm. The safety profile of melflufen was consistent with previous reports. These results suggest that melflufen is safe and effective in patients with alkylator-refractory disease, suggesting differentiated activity from other alkylators.

Clinical factors associated with autologous stem cell transplantation outcomes in multiple myeloma: upfront transplant with MEL200 remains the standard of care.

Autologous stem cell transplantation (ASCT) remains the mainstay of the treatment in newly diagnosed transplant-eligible multiple myeloma (MM) patients. This retrospective study was performed to investigate the potential prognostic markers which may modify transplant course in a total of 256 ASCT recipients [median age: 58 (30-74) years; male/female: 138/118], including pretransplant (PET0) and day + 60 (PET2) PET/CT assessments and comparative analysis of melphalan (Mel) dose. Better responses with significantly higher complete response/very good partial response rates were achieved in patients who proceeded to transplant within 301 days from diagnosis (p < 0.001). Patients who had received < 1.5 lines of treatment prior to transplant had significantly higher probability of overall survival (OS) (p = 0.004) and progression-free survival (PFS) (p < 0.001). The probability of OS was significantly higher in patients with low Eastern Cooperative Oncology Group (ECOG) performance score (PS = 0-1) (p = 0.003) and HCT-Comorbidity Index (HCT-CI = 0) (p = 0.011). The number of involved areas (p = 0.028) and maximum standardized uptake value (SUVmax) (p = 0.021) in PET0 represented significant impact on OS. The probabilities of OS (p < 0.001) and PFS (p = 0.01) were significantly better with Mel200 mg/m2 conditioning compared to Mel140 mg/m2. Conditioning with Mel200 mg/m2, early and upfront ASCT and low pretransplant treatment burden were found to be significantly associated with ASCT outcome in MM patients. Despite its predictor impact on survival and prognosis, further studies are warranted to standardize PET/CT-based response assessments before being used as a guide for treatment decisions in clinical practice.

Pharmacokinetics and Metabolism of Melflufen, an Alkylating Peptide-Drug Conjugate, in Patients with Relapsed Refractory Multiple Myeloma.

Melphalan flufenamide (melflufen) is a novel lipophilic peptide-drug conjugate recently approved in the European Union and the United Kingdom for the treatment of relapsed refractory multiple myeloma. Melflufen rapidly crosses the cell membrane, and inside tumor cells, melflufen utilizes peptidases and esterases to release entrapped hydrophilic metabolites with alkylating activity. In vitro, in whole blood, melflufen was rapidly distributed into blood cells and quickly converted to its main metabolite melphalan, with maximum cellular concentrations of noncovalently bound melflufen and melphalan after 1 and 6 minutes, respectively. Melphalan outflow from blood cells was slow, with peak concentrations in plasma after 25 minutes. The pharmacokinetics of melflufen was best described by a 2-compartment model. Following a 30-minutes intravenous infusion of 40 mg in 27 patients with relapsed refactory multiple myeloma, mean half-life in the α phase of the curve was 1.24 minutes, half-life in the ß phase of the curve 26.7 minutes, and clearance 13.4 L/min. Desethyl-melflufen exposure was below 20% compared to melflufen. Based on population analysis (298 patients with relapsed refactory multiple myeloma), the melphalan pharmacokinetics were well characterized by a 3-compartment model with melflufen dosing into a peripheral compartment, assuming instantaneous distribution of melflufen into cells and subsequent rapid metabolism to melphalan. Mean clearance and central and deep peripheral volumes of distribution were 22.4 L/h, 2.70 L, and 51.3 L, respectively. Clearance increased and maximum concentration decreased with increasing body weight and estimated glomerular filtration rate. In conclusion, melflufen administration differs from melphalan administration by a more rapid distribution into cells, which, in conjunction with a rapid intracellular metabolism, allows for higher maximum concentrations of alkylating agents, and by a more extensive distribution of melphalan to peripheral tissues.

Allogeneic Hematopoietic Cell Transplantation for Juvenile Myelomonocytic Leukemia with a Busulfan, Fludarabine, and Melphalan Regimen: JPLSG JMML-11.

Juvenile myelomonocytic leukemia (JMML), which is classified as a myelodysplastic/myeloproliferative neoplasm, is a rare hematologic malignancy of childhood. Most patients with JMML require allogeneic hematopoietic cell transplantation (HCT) as a curative therapy. A Japanese retrospective analysis demonstrated favorable outcomes for a busulfan (BU) + fludarabine (FLU) + melphalan (MEL) regimen, with an overall survival (OS) of 72% and an event-free survival (EFS) of 53%. To further validate the efficacy and safety of this regimen, the Japan Pediatric Leukemia/Lymphoma Study Group (JPLSG) conducted a nationwide prospective study, JMML-11. Between July 2011 and June 2017, 28 patients with newly diagnosed JMML were enrolled in JMML11. Low-dose chemotherapy for tumor control before HCT was recommended, and patients treated with AML-type chemotherapy and azacitidine were excluded. The conditioning regimen comprised i.v. BU, 16 doses administered every 6 h, with dose adjustment based on pharmacokinetic (PK) studies on days -11 to -8; FLU, 30 mg/m2/day or 1 mg/kg/day for patients <10 kg or age <1 year on days -7 to -4; and MEL, 90 mg/m2/day or 3 mg/kg/day for patients <10 kg or <1 year on days -3 to -2. The donor was selected by the physician in charge. A family donor was available for 7 patients (3 HLA-matched siblings, 3 HLA-1-antigen mismatched parents, and 1 haploidentical father). Overall, 21 patients received grafts from unrelated donors, including 8 HLA-matched donors and 13 HLA-mismatched donors. The graft source was related bone marrow (BM) for 7 patients, unrelated BM for 14 patients, and unrelated cord blood for 7 patients. Neutrophil engraftment was achieved in 21 of 28 patients (75%), with a median of 20.5 days (range, 11 to 39 days) after transplantation. The 3-year OS, 3-year EFS, 3-year relapse rate, and 3-year transplantation-related mortality were 63% (95% confidence interval [CI], 42% to 78%), 52% (95% CI, 32% to 69%), 18% (95% CI, 6% to 34%), and 21% (95% CI, 9% to 38%), respectively. WBC count before the conditioning regimen (≥7.0 × 109/L) was significantly associated with inferior EFS and OS. Body surface area ≥.5 m2, spleen size <4 cm before conditioning, and HLA-matched unrelated BM donors were significantly associated with better OS. Adverse effects related to the conditioning regimen included febrile neutropenia (86%), diarrhea (39%), hypoxemia (21%), and mucositis (18%). BU-associated toxicity, including sinusoidal obstruction syndrome (SOS) and thrombotic microangiopathy (TMA), occurred in 7 patients (25%; SOS, n = 6; TMA, n = 2). Retrospective analysis of PK data after the first BU dose in 23 patients, including 6 with SOS and 17 without SOS, did not show significant differences between groups. The JMML-11 study confirms the positive results of previous retrospective analyses. BU+FLU+MEL might become a standard conditioning regimen for patients with JMML.

Age Impacts Risk of Mixed Chimerism Following Reduced-Intensity Conditioning Hematopoietic Cell Transplantation for Non-Severe Combined Immune Deficiency Inborn Errors of Immunity.

Alemtuzumab, fludarabine, and melphalan containing-reduced intensity conditioning (RIC) is commonly used in patients undergoing allogeneic hematopoietic cell transplantation (HCT) for definitive treatment of high-risk inborn errors of immunity (IEI). Although survival is favorable, there is an increased risk of mixed chimerism leading to secondary graft failure. This study evaluated factors associated with the risk of developing mixed chimerism, particularly the influence of age in patients undergoing allogeneic HCT for non-severe combined immune deficiency (SCID) IEI who received a uniform RIC regimen that included intermediate schedule alemtuzumab, fludarabine, and melphalan. We hypothesized that age would impact the incidence of mixed chimerism. We retrospectively reviewed records of patients who underwent HCT for non-SCID IEI with a uniform RIC regimen that included intermediate schedule alemtuzumab (1 mg/kg divided over days -14 to -10), fludarabine (150 mg/m2 or 5 mg/kg if weight <10 kg divided over days -9 to -4), and melphalan (140 mg/m2 or 4.7 mg/kg if weight <10 kg on day -3) between 2010 and 2020 at our institution. Mixed chimerism was defined as <95% donor chimerism on 2 or more consecutive occasions in whole blood. Ninety-three patients who underwent RIC-HCT for non-SCID IEI using intermediate schedule alemtuzumab, fludarabine, and melphalan were categorized into 3 groups: age <1 year, age 1 to 5 years, and age >5 years. Forty-nine patients (52.7%) developed mixed chimerism, at a median of 34 days post-HCT (range, 10 to 1396 days). Mixed chimerism developed in 88.9% (n = 16/18) of the age <1 year group, in 57.1% (n = 20/35) of the age 1 to 5 years group, and in 35% (n =14/40) of the age >5 years group. Patients age <5 years were significantly more likely to develop mixed chimerism (χ2 (3, N = 93) = 14.8; P = .001). We observed a significantly increased cumulative incidence of developing mixed chimerism associated with age <1 year (P = .0002). Competing risk regression analysis showed a 3-fold higher risk of developing mixed chimerism for age <1 year (subdistribution hazard ratio (HR), 3.05; 95% confidence interval [CI], 1.11 to 8.38; P = .031,) compared to age >5 years and a significantly decreased risk of mixed chimerism in patients who developed acute GVHD prior to any intervention (OR, .24; 95% CI, .09 to .65; P = .005) There were no significant associations between mixed chimerism and graft source, graft type, CD34+ or CD3+ cell dose, HLA match, or underlying disease (hemophagocytic lymphohistiocytosis [HLH] versus non-HLH). Additionally, the need for secondary intervention was evaluated; 27 patients (29.0%) required 1 or more secondary interventions (donor lymphocyte infusion, CD34 boost, or second HCT). Patients age <1 year with mixed chimerism were significantly more likely than patients age >5 years to require secondary intervention for mixed chimerism (P = .004). Our study demonstrates that age <5 years, especially age <1 year, is associated with an increased risk of developing mixed chimerism in patients undergoing RIC-HCT for non-SCID IEI using intermediate-schedule alemtuzumab, fludarabine, and melphalan. Our data suggest tailoring regimen intensity based on age to reduce the incidence of mixed chimerism. Children age <5 years, particularly those age <1 year, require a higher-intensity regimen. Possible strategies include adding thiotepa or using a busulfan-based reduced toxicity regimen.

Is There Still a Role for Stem Cell Transplantation in Multiple Myeloma?

No therapy in multiple myeloma has been as extensively investigated as stem cell transplantation following high-dose chemotherapy. A search of the national library of medicine in February 2023 revealed over 27,000 publications covering stem cell transplantation. No other treatment for multiple myeloma has been so vigorously investigated. However, given the rapid advances seen in the treatment of multiple myeloma, it is legitimate to ask whether the technique first introduced in 1983 by Thomas McIlwain still has relevance. In 1984,Barlogie introduced infusional vincristine, doxorubicin, and dexamethasone and in 1986 published a first series on high-dose therapy with autologous marrow-derived stem cells. At this point, the only available therapies were melphalan, prednisone, other intensive steroids such as methylprednisolone, and interferon. Cyclophosphamide was used both orally and parenterally. VBMCP was introduced as a combination therapy at Memorial Hospital subsequently shown not to be superior to melphalan and prednisone.

[Updated treatment strategy for transplant-eligible multiple myeloma: current status and future perspectives].

Treatment outcomes of multiple myeloma (MM) have dramatically improved in the past 20 years. The IFM/DFCI group reported that triplet induction (bortezomib, lenalidomide, and dexamethasone), followed by up-front high-dose melphalan and autologous stem cell transplantation (HDM/ASCT) and maintenance therapy, demonstrated a median progression-free survival (PFS) of 50 months. Therefore, up-front HDM/ASCT is considered standard care even in the era of novel agents. Daratumumab, lenalidomide, and dexamethasone have also been reported to prolong PFS for newly diagnosed transplant-ineligible MM. Quadruplet induction, including anti-CD38 antibody, will be approved even for transplant-eligible MM soon. Conversely, the success of chimeric antigen receptor T-cell therapy revealed that cellular immunotherapy may play an important role in treating MM. This review discussed the current standard of care and future perspectives for transplant-eligible MM.