Historical Perspective of High-Dose Therapy Followed by Autologous Stem Cell Transplantation in Multiple Myeloma.

BACKGROUND: High-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) has become part of standard of care (SOC) in newly diagnosed multiple myeloma. In this review, we provide a historical perspective on ASCT since its introduction in the 1990s. SUMMARY: Overall survival (OS) benefit for HDT followed by ASCT was demonstrated in studies comparing HDT with ASCT to standard-dose therapy (SDT) before the era of novel agents. Conditioning is done with melphalan 200 mg/m2. Lower doses (MEL140, MEL150) for older patients with comorbidities are safe and have comparable results. The addition of busulfan to melphalan improves progression-free survival (PFS) but not OS. HDT with ASCT after induction with novel agents prolongs PFS but not OS compared to SDT alone. The benefit is more evident in patients with high-risk cytogenetics. Mobilization can be achieved with granulocyte colony-stimulating factor alone, but is improved with the addition of chemotherapy. Plerixafor reduces mobilization failure and enables sufficient stem cell collection after induction with novel agents. ASCT is safe with a low rate of mortality (1%), and selected patients can be managed as outpatients. KEY MESSAGES: HDT followed by ASCT remains part of SOC due to its PFS benefit and relatively low toxicity.

Canadian cancer trials group LY.17: A randomized phase II study evaluating novel salvage therapy pre-autologous stem cell transplant in relapsed/refractory diffuse large B-cell lymphoma-outcome of rituximab-dose-intensive cyclophosphamide, etoposide, cisplatin (R-DICEP) versus R-GDP.

The Canadian Cancer Trials Group (CCTG) LY.17 is an ongoing multi-arm randomized phase II trial evaluating novel salvage therapies compared with R-GDP (rituximab, gemcitabine, dexamethasone and cisplatin) in autologous stem cell transplantation (ASCT)-eligible patients with relapsed/refractory diffuse large B-cell lymphoma (RR-DLBCL). This component of the LY.17 trial evaluated a dose-intensive chemotherapy approach using a single cycle of inpatient R-DICEP (rituximab, dose-intensive cyclophosphamide, etoposide and cisplatin) to achieve both lymphoma response and stem cell mobilization, shortening time to ASCT. This report is the result of the protocol-specified second interim analysis of the 67 patients who were randomized to either 1 cycle of R-DICEP or to 3 cycles of R-GDP. The overall response rate (ORR) was 65.6% for R-DICEP and 48.6% for R-GDP. The ASCT rate was 71.9% versus 54.3%, and 1-year progression-free survival rate was 42% versus 32%, respectively, for R-DICEP versus R-GDP. Although the improvement in ORR for R-DICEP versus R-GDP exceeded the pre-specified 10% threshold to proceed to full accrual of 64 patients/arm, higher rates of grade 3-5 toxicities, and the need for hospitalization led to the decision to stop this arm of the study. CCTG LY.17 will continue to evaluate different salvage regimens that incorporate novel agents.

Busulfan, melphalan and carfilzomib high-dose chemotherapy and autologous haematopoietic stem cell transplantation in multiple myeloma.

The standard of care for fit, newly diagnosed multiple myeloma patients includes induction therapy followed by consolidative high-dose chemotherapy with melphalan and autologous stem cell transplant (AHSCT). Intensified preparative regimens, such as busulfan and melphalan (BuMel), have shown promise to lengthen progression-free survival (PFS). We previously reported that the addition of bortezomib to BuMel improved PFS compared to melphalan alone in CIBMTR-matched controls. We now integrate the second-generation protease inhibitor, carfilzomib, before and after BuMel (BuMelCar) in a phase I/II trial with carfilzomib. Patients with NDMM, relapsed/refractory MM (RRMM) and those failing prior AHSCT were eligible. Primary end-points were safety and tolerability. Secondary end-points included minimal residual disease negativity rates, PFS and OS. The study enrolled 19 patients. 73% were high risk either due to R-ISS III status, adverse genetics or relapsed after prior AHSCT. The maximum tolerated dose (MTD) of carfilzomib was determined to be 36 mg/m2. Noted grade 3 toxicities were febrile neutropenia (79%), mucositis (21%) and diarrhoea (16%). The 2-year PFS for the whole cohort and MTD was 89% and 100% respectively. 80% of all patients and 82% of patients in the MTD cohort achieved MRD negativity. Further studies regarding this regimen are planned.

Testing Adaptive Therapy Protocols Using Gemcitabine and Capecitabine in a Preclinical Model of Endocrine-Resistant Breast Cancer.

Adaptive therapy, an ecologically inspired approach to cancer treatment, aims to overcome resistance and reduce toxicity by leveraging competitive interactions between drug-sensitive and drug-resistant subclones, prioritizing patient survival and quality of life instead of killing the maximum number of cancer cells. In preparation for a clinical trial, we used endocrine-resistant MCF7 breast cancer to stimulate second-line therapy and tested adaptive therapy using capecitabine, gemcitabine, or their combination in a mouse xenograft model. Dose modulation adaptive therapy with capecitabine alone increased survival time relative to MTD but not statistically significantly (HR = 0.22, 95% CI = 0.043-1.1, p = 0.065). However, when we alternated the drugs in both dose modulation (HR = 0.11, 95% CI = 0.024-0.55, p = 0.007) and intermittent adaptive therapies, the survival time was significantly increased compared to high-dose combination therapy (HR = 0.07, 95% CI = 0.013-0.42, p = 0.003). Overall, the survival time increased with reduced dose for both single drugs (p < 0.01) and combined drugs (p < 0.001), resulting in tumors with fewer proliferation cells (p = 0.0026) and more apoptotic cells (p = 0.045) compared to high-dose therapy. Adaptive therapy favors slower-growing tumors and shows promise in two-drug alternating regimens instead of being combined.

Optimizing high dose melphalan.

Melphalan, has been a major component of myeloma therapy since the 1950s. In the context of hematopoietic cell transplantation (HCT), high dose melphalan (HDM) is the most common conditioning regimen used due to its potent anti-myeloma effects and manageable toxicities. Common toxicities associated with HDM include myelosuppression, gastrointestinal issues, and mucositis. Established approaches to reduce these toxicities encompass dose modification, nausea prophylaxis with 5HT3 receptor antagonists, cryotherapy, amifostine use, and growth factors. Optimization of melphalan exposure through personalized dosing and its combination with other agents like busulfan, or bendamustine show promise. Propylene glycol-free melphalan (Evomela) represents a novel formulation aiming to enhance drug stability and reduce adverse effects. This review explores strategies to enhance the efficacy and mitigate the toxicity of HDM in multiple myeloma. Future directions involve exploring these strategies in clinical trials to improve the safety and efficacy of HDM, thereby enhancing outcomes for multiple myeloma patients undergoing autologous HCT.

Cardiovascular diseases after high-dose chemotherapy and autologous stem cell transplant for lymphoma: A Danish population-based study.

Cardiovascular diseases, especially congestive heart failure (CHF), are known complications of anthracyclines, but the risk for patients undergoing high-dose chemotherapy and autologous stem cell transplant (HDT-ASCT) is not well established. With T-cell therapies emerging as alternatives, studies of long-term complications after HDT-ASCT are warranted. Danish patients treated with HDT-ASCT for aggressive lymphoma between 2001 and 2017 were matched 1:5 on sex, birth year and Charlson comorbidity score to the general population. Events were captured using nationwide registers. A total of 787 patients treated with HDT-ASCT were identified. Median follow-up was 7.6 years. The risk of CHF was significantly increased in the HDT-ASCT population compared to matched comparators with an adjusted hazard ratio (HR) of 5.5 (3.8-8.1). The 10-year cumulative incidence of CHF was 8.0% versus 2.0% (p < 0.001). Male sex, ≥2 lines of therapy, hypertension and cumulative anthracycline dose (≥300 mg/m2 ) were risk factors for CHF. In a separate cohort of 4089 lymphoma patients, HDT-ASCT was also significantly associated with increased risk of CHF (adjusted HR of 2.6 [1.8-3.8]) when analysed as a time-dependent exposure. HDT-ASCT also increased the risk of other cardiac diseases. These findings are applicable for the benefit/risk assessment of HDT-ASCT versus novel therapies.

High-Dose Paclitaxel and its Combination with CSF1R Inhibitor in Polymeric Micelles for Chemoimmunotherapy of Triple Negative Breast Cancer.

The presence of immunosuppressive immune cells in tumors is a significant barrier to the generation of therapeutic immune responses. Similarly, in vivo triple-negative breast cancer (TNBC) models often contain prevalent, immunosuppressive tumor-associated macrophages in the tumor microenvironment (TME), resulting in breast cancer initiation, invasion, and metastasis. Here, we test systemic chemoimmunotherapy using small-molecule agents, paclitaxel (PTX), and colony-stimulating factor 1 receptor (CSF1R) inhibitor, PLX3397, to enhance the adaptive T cell immunity against TNBCs in immunocompetent mouse TNBC models. We use high-capacity poly(2-oxazoline) (POx)-based polymeric micelles to greatly improve the solubility of insoluble PTX and PLX3397 and widen the therapeutic index of such drugs. The results demonstrate that high-dose PTX in POx, even as a single agent, exerts strong effects on TME and induces long-term immune memory. In addition, we demonstrate that the PTX and PLX3397 combination provides consistent therapeutic improvement across several TNBC models, resulting from the repolarization of the immunosuppressive TME and enhanced T cell immune response that suppress both the primary tumor growth and metastasis. Overall, the work emphasizes the benefit of drug reformulation and outlines potential translational path for both PTX and PTX with PLX3397 combination therapy using POx polymeric micelles for the treatment of TNBC.

Immune responses to COVID-19 booster vaccinations in intensively anti-CD38 antibody treated patients with ultra-high-risk multiple myeloma: results from the Myeloma UK (MUK) nine OPTIMUM trial.

Multiple myeloma (MM) and anti-MM therapy cause profound immunosuppression, leaving patients vulnerable to coronavirus disease 2019 (COVID-19) and other infections. We investigated anti-severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) antibodies longitudinally in ultra-high-risk patients with MM receiving risk-adapted, intensive anti-CD38 combined therapy in the Myeloma UK (MUK) nine trial. Despite continuous intensive therapy, seroconversion was achieved in all patients, but required a greater number of vaccinations compared to healthy individuals, highlighting the importance of booster vaccinations in this population. Reassuringly, high antibody cross-reactivity was found with current variants of concern, prior to Omicron subvariant adapted boostering. Multiple booster vaccine doses can provide effective protection from COVID-19, even with intensive anti-CD38 therapy for high-risk MM.

Impact of Cytogenetic Abnormalities, Induction and Maintenance Regimens on Outcomes After High-Dose Chemotherapy and Autologous Stem Cell Transplantation in Patients With Newly Diagnosed Multiple Myeloma: A Decade-Long Real-World Experience.

Background: High-dose chemotherapy and autologous stem cell transplant (HDT-ASCT) has become a standard of care for transplant eligible newly diagnosed multiple myeloma (NDMM) patients. While cytogenetic abnormalities have been shown to affect outcomes after HDT-ASCT in clinical trials, these trials often exclude or underrepresent elderly patients with comorbidities and those belonging to ethnic minorities. We describe our institutional experience highlighting the impact of high-risk cytogenetic abnormalities (HRCAs) on outcomes after HDT-ASCT for NDMM patients. Methods: A total of 449 patients with NDMM who underwent HDT-ASCT between February 2012 and August 2022 were included in this retrospective analysis. HRCAs included the presence of one or more of: deletion 17p, t(14;16), t(4;14), and amplification 1q. Survival analyses, including progression-free survival (PFS) and overall survival (OS), were performed using Kaplan-Meier estimator. Results: With a median follow-up of 29 (1 - 128) months for the entire patient population, the best overall response rate for the patients with HRCAs was lower compared to those with standard risk cytogenetics (90% vs. 96%; P = 0.01). Patients with HRCAs had an inferior PFS compared to patients with standard-risk cytogenetics (29 vs. 58 months; P < 0.001) without a difference in OS (70 months vs. not reached; P = 0.13). Conclusions: In a multivariable analysis adjusting for factors including age, race, and comorbidities, HRCAs, non-lenalidomide-based maintenance, non-proteasome inhibitor-based maintenance, and age greater than 65 were associated with inferior PFS. Amongst these factors, only non-lenalidomide-based maintenance was associated with inferior OS.

Peri-treatment adverse events of primary mediastinal non-seminomatous germ cell tumors.

Primary mediastinal non-seminomatous germ cell tumors (PMNSGCT) are rare but life-threatening thoracic cancers. We report our experience from eight patients with peri-treatment adverse events. By analyzing changes in tumor extent, serum tumor markers, and pathologies between diagnosis and transfer, those events could be attributed to postbiopsy respiratory insufficiency, growing teratoma syndrome, secondary histiocytic malignancy, and PMNSGCT progression. Subjecting patients to respiratory therapy, conventional or high-dose chemotherapy, and surgery controlled the disease, with five of the eight patients surviving disease free. These outcomes indicate that integrated appropriate and timely approaches are important in tackling peri-treatment adverse events.

Safety Data in Patients with Autoimmune Diseases during Treatment with High Doses of Vitamin D3 According to the "Coimbra Protocol".

BACKGROUND: In 2013, the group of Cicero Coimbra, Brazil, reported the clinical efficacy of high doses of vitamin D3 in patients suffering from autoimmune skin disorders ("Coimbra protocol", CP). However, hypercalcemia and the subsequent impaired renal function may be major concerns raised against this protocol. METHODS: We report for the first time for a broad spectrum of autoimmune diseases in 319 patients (mean age (±SD) 43.3 ± 14.6 years, 65.5% female, 34.5% male) safety data for high doses of orally applied vitamin D3 (treatment period: up to 3.5 years) accompanied by a strict low-calcium diet and regular daily fluid intake of at least 2.5 L. RESULTS: Mean vitamin D3 dose was 35,291 ± 21,791 IU per day. The measurement of more than 6100 single relevant laboratory parameters showed all mean values (±SD) within the normal range for total serum calcium (2.4 ± 0.1 mmol/L), serum creatinine (0.8 ± 0.2 mg/dL), serum creatinine associated estimated GFR (92.5 ± 17.3 mL/min), serum cystatin C (0.88 ± 0.19 mg/L), serum TSH (1.8 ± 1 mIU/L), and for 24 h urinary calcium secretion (6.9 ± 3.3 mmol/24 h). We found a very weak relationship between the dosage of oral vitamin D3 and the subsequent calcium levels, both in serum and in urinary excretion over 24 h, respectively. CONCLUSIONS: Our data show the reliable safety of the CP in autoimmune patients under appropriate supervision by experienced physicians.

Current Management of Refractory Germ Cell Tumors.

PURPOSE OF REVIEW: Germ cell tumors (GCTs) are the most common solid tumors affecting men between ages of 20 and 34 years. Most of the cases, even in advanced disease, will have good prognosis. However, around 20-30% of advanced disease will be refractory or develop relapse after treatment. Herein, we review the current management of refractory/relapsed GCTs. RECENT FINDINGS: Salvage treatment of GCTs has been a controversial topic for the last few decades. Conventional dose chemotherapy (CDCT), high-dose chemotherapy (HDCT) with stem cell infusion, and surgical salvage were proven to be effective and curative options in some cases. The international randomized trial (TIGER) will ultimately answer which chemotherapy approach may be optimal. Furthermore, the usage of immunotherapy is still under investigation with limited data so far in the setting of relapsed/refractory GCTs. Curative paradigms including with CDCT and HDCT are possible, although novel approaches beyond HDCT are still needed to eliminate mortality from this disease.

Noninvasive Monitoring of Mantle Cell Lymphoma by Immunoglobulin Gene Next-Generation Sequencing in a Phase 2 Study of Sequential Chemoradioimmunotherapy Followed by Autologous Stem-Cell Rescue.

BACKGROUND: Minimal residual disease (MRD) monitoring has been used to identify early molecular relapse and predict clinical relapse in mantle cell lymphoma (MCL). Few published data exist in MCL on the performance of next-generation sequencing-based assay of immunoglobulin gene rearrangements for MRD assessment. PATIENTS AND METHODS: In a prospective clinical trial (NCT01484093) with intensive induction chemotherapy and autologous stem-cell transplantation, posttreatment peripheral blood samples were collected from 16 MCL patients and analyzed with an earlier version of the Adaptive Biotechnologies MRD assay. RESULTS: Of the 7 patients whose disease remained in remission, the MRD test remained negative in 5 (71%). Of the 9 patients who experienced relapse, the MRD test was positive at least 3 months before relapse in 6 patients (67%) and positive at the time of relapse in 1 patient (11%). All patients with at least 2 positive MRD tests experienced relapse. CONCLUSION: The next-generation sequencing-based MRD assay identified early molecular relapse, and we observed more sensitivity in the cellular (circulating leukocytes) versus acellular (plasma cell-free DNA) compartment. This observation may be due to availability of tumor target or a limitation of the assay.

The important role of intensive induction chemotherapy in the treatment of acute myeloid leukemia.

Introduction: Intensive induction chemotherapy followed by post-remission consolidation and/or allogeneic hematopoietic transplantation has been a standard-of-care therapy for acute myeloid leukemia (AML) for decades. In recent years, a plethora of new agents have been approved for AML treatment, dramatically changing the AML treatment landscape.Areas covered: This review provides an overview of the current role of intensive chemotherapy in the changing AML treatment landscape. PubMed-indexed publications (through 2020) and abstracts presented at major national and international conferences were reviewed for inclusion.Expert opinion: While intensive chemotherapy is standard-of-care therapy for younger patients with AML, older patients were historically viewed as universally ineligible for intensive chemotherapy; however, several studies suggest many older patients benefit from intensive chemotherapy with a curative intent, and a more holistic approach to determining eligibility for intensive treatment is recommended. Intensive strategies have also been expanded to include novel chemotherapy designs and chemotherapy in combination with targeted agents for patients with certain disease characteristics, which may permit more personalized treatment decisions. Intensive chemotherapy continues to play a pivotal role for the management of many AML patients and can offer the best chance of long-term remission, especially when followed by transplantation.

Relapsed and refractory primary CNS lymphoma: treatment approaches in routine practice.

Despite recent therapeutic progress and improved survival for many patients with primary central nervous system lymphoma (PCNSL), up to 50% of patients will experience refractory or relapsed disease following first-line treatment with high dose methotrexate (HD-MTX) based regimens. The majority of such events occur within 2 years of diagnosis although, unlike their systemic counterpart, the risk of PCNSL relapse remains, even for patients in radiologic complete response at 10 years following diagnosis. Currently, there are no approved therapies, and no widely accepted 'standard-of-care' approaches for the treatment of refractory or recurrent primary central nervous system lymphoma (rrPCNSL). Re-treatment with HD-MTX based regimens, use of non-cross resistant chemotherapy regimens, high-dose chemotherapy and autologous stem cell transplantation (HDT-ASCT), and brain irradiation all remain important therapeutic approaches for rrPCNSL. However, the survival outcomes for patients with rrPCNSL remain extremely poor and the vast majority of patients will die of their disease. Increasingly, novel treatment approaches are being investigated in early phase clinical studies. Importantly, such therapies need to be evaluated in the context of both refractory and relapsed disease; in older patients and those with co-morbid conditions; and those with neurocognitive dysfunction. A deeper understanding of the molecular genetic mechanisms underpinning rrPCNSL and its unique tumor microenvironment is urgently needed to inform biologically rational and effective therapies. rrPCNSL remains a clear unmet clinical need and a high priority area for clinical research that will require national and international collaborative studies with embedded translational science in order to improve outcomes for patients.

Outcomes of older patients with primary central nervous system lymphoma treated in routine clinical practice in the UK: methotrexate dose intensity correlates with response and survival.

Data on older patients with primary central nervous system lymphoma (PCNSL) are scarce. Comorbidities and performance status frequently compromise outcomes in this group. Medical records for consecutive patients ≥65 years (n = 244) with PCNSL diagnosed 2012-2017 from 14 UK centres were retrospectively reviewed. Of these 192 patients received methotrexate (MTX)-based treatment. Patients were categorised based on clinician's treatment choice into 'palliative' (n = 52), 'less intensive: MTX ± rituximab ± alkylators' (n = 74) and 'intensive: MTX/cytarabine combinations' (n = 118) groups. Complete remission (CR) rate, two-year progression-free survival (PFS) and overall survival (OS) rates were 49%, 11% and 24% for the less intensive and 69%, 40% and 50% for the intensive groups. Treatment-related mortality (TRM) was 6·8% for MTX-treated patients. Median MTX cumulative dose was 8·8 g/m2 (range 1·5-21) over a median of three cycles. Higher relative dose intensity of MTX (MTX-RDI) was associated with improved PFS and OS in both groups adjusting for age, Eastern cooperative oncology group (ECOG) score and baseline parameters. Two-year PFS and OS for patients receiving four or more induction cycles followed by consolidation (n = 36) were 65% and 70% respectively. Older patients completing MTX-based induction and consolidation had clinical outcomes similar to those in younger cohorts. These retrospective data suggest that maximising MTX-RDI and delivering consolidation in a subgroup of older patients may improve clinical outcomes.

Clinical characteristics and outcomes of relapsed follicular lymphoma after autologous stem cell transplantation in the rituximab era.

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a therapeutic option for patients with relapsed follicular lymphoma (FL). The clinical characteristics and outcomes of FL relapse after ASCT in the rituximab era have not yet been fully elucidated. We retrospectively reviewed 414 FL patients treated with ASCT between 2000 and 2014 in four hematology departments. All patients received rituximab as a first-line treatment. We specifically analyzed the clinical characteristics, treatment strategies at relapse, and outcomes of 95 patients (23%) who relapsed after ASCT. The patients (median age, 57 y) received a median of two lines of therapy (range, 2-6) prior to ASCT, with 92% in complete response (CR) or partial response (PR) before ASCT. Histological transformation at relapse after ASCT was observed in 20% of the patients. Treatment at relapse after ASCT consisted of chemotherapy with or without rituximab (n = 45/90, 50%), targeted agents (18%), rituximab monotherapy (14%), or consolidation allogeneic transplantation after induction chemotherapy (12%) and radiotherapy (6%). After relapse, the median progression-free survival (PFS) and overall survival (OS) were 1 year (95% CI, 0.541-1.579) and 5.5 years (95% CI, 1.910-9.099), respectively. In the multivariate analysis, histological transformation (HT) was associated with OS (P = .044; HR 2.439; 95% CI, 1.025-5.806), and a high FLIPI score at relapse was associated with PFS (P = .028; HR 2.469; 95% CI, 1.104-5.521). This retrospective study showed that the period of PFS of patients who relapsed after ASCT is short. A biopsy should be performed for these patients to document the HT. Our results indicate that new treatment strategies will need to be developed for these patients.

High-dose therapy and autologous stem cell transplantation for relapsed or high-risk diffuse large B-cell lymphoma: a nationwide survey.

To investigate the use of high-dose therapy and autologous stem cell transplantation (ASCT) for relapsed or high-risk diffuse large B-cell lymphoma (DLBCL) between 1990 and 2007, we conducted a nationwide survey using the registry database of the Japan Society for Hematopoietic Cell Transplantation. Of the 1222 patients in the database, 576 (47%) received ASCT in first complete remission (CR1), 140 (12%) in first partial remission, 281 (23%) in sensitive relapse, 150 (12%) in resistant or sensitivity-unknown relapse, and 75 (6%) in primary refractory status. With a median follow-up of 22 months, the 2-year overall survival (OS) and progression-free survival rates were 71% and 68%, respectively. The cumulative incidences of 2-year non-relapse mortality and relapse/progression were 6% and 26%, respectively. Relapse/progression after ASCT in the rituximab era (2002-2007) was significantly lower than that in the pre-rituximab era (1990-2001; P < 0.001). Older age, male gender, poor performance status at ASCT, non-CR1 at ASCT, ASCT performed in 1990-2001, and LEED or MCEC regimen were adverse predictors of OS. Because ASCT for newly diagnosed high-risk DLBCL has not been performed recently, a registry database study to assess the impact of ASCT for relapsed or refractory DLBCL in the rituximab era is warranted.