Improving Unrelated Donor Equity: Assessing Mismatched Donor Opportunities with Real-World Data in a Minority-Predominant Cohort.

Recent advances in graft-versus-host disease (GVHD) prophylaxis including post-transplant cyclophosphamide (PTCy) and abatacept have significantly improved outcomes following HLA-mismatched allogenic hematopoietic stem cell transplantation (allo-HSCT) and have tremendous potential for reducing racial disparities in donor availability. A recent small study employing bone marrow as the source of stem cells showed similar outcomes after 5/8 versus 7/8 matches and is currently being tested in a larger study using peripheral blood stem cells. In this study, we examine real-world alternative donor HSCT options for a minority-predominant cohort in the Bronx, NY, focusing on the availability of lesser-matched (5/8 to 7/8) donors. Records of patients who underwent HLA typing at Montefiore Medical Center (2019 to 2022) were reviewed. The National Marrow Donor Program registry was queried to evaluate the availability of donors with at least 99% likelihood of HLA match at various levels (5/8, 6/8, 7/8, 8/8). Two hundred forty-one patients were included, 70% were non-White. Although the availability of ≥7/8 donors was less common in non-White patients, 100% of patients from each group had at least one or more 5/8 and 6/8 HLA-matched donors and more than 80% of these patients had >100 potential 5/8 and 6/8 HLA-matched donors. There was no statistical difference by race or ethnicity in the mean number of donors at 5/8 and 6/8 HLA-match levels. We demonstrate through real-world data that patients from diverse ethnic and racial backgrounds have access to 5/8 and 6/8 HLA-matched donors for allo-HSCT, potentially eliminating disparities in donor availability and allowing prioritization of other donor selection characteristics such as donor age, sex, ABO, and B leader matching. Further work is needed to study whether the use of mismatched donors offers a more potent graft-versus malignancy effect and optimal GVHD prophylaxis.

A Metabolically Optimized, Noncytotoxic Low-Dose Weekly Decitabine/Venetoclax in MDS and AML.

PURPOSE: Venetoclax (VEN) added to the hypomethylating agents (HMA) decitabine or azacitidine is the new standard of care for elderly patients with acute myeloid leukemia (AML) and is being evaluated in myelodysplastic syndrome (MDS). Current dosing of HMA/VEN relies on leukemia suppression through cytotoxicity which also impacts normal hematopoiesis. A regimen using once-weekly low-dose decitabine (LDDec) has demonstrated activity in myeloid malignancies. To overcome the severe myelosuppression often seen with HMA/VEN, we evaluated a once-weekly dosing regimen of VEN and LDDec in elderly and/or frail patients who were felt less likely to tolerate severe myelosuppression. PATIENTS AND METHODS: This is a retrospective, single-center analysis of patients with AML, MDS, or chronic myelomonocytic leukemia treated with a once-weekly LDDec/VEN regimen. We also compare this regimen with a cohort treated with standard dosing HMA/VEN. RESULTS: In a retrospective cohort of 39 patients, the overall response rate for patients receiving LDDec/VEN for first-line AML and MDS was 88% and 64%, respectively. In patients with TP53 mutations, the composite complete response rate was 71% and the median overall survival was 10.7 months. When compared with 36 patients receiving standard dose HMA/VEN, the LDDec/VEN patients had a longer time on therapy (175 vs. 78 days; P = 0.014) and a trend toward a higher rate of transfusion independence (47% vs. 26%; P = 0.33). Neutropenic fever occurred in 31% of patients, with a median of one hospitalization at any point during treatment. CONCLUSIONS: This preliminary clinical experience, although retrospective, provides proof-of-activity of noncytotoxic DNA methyltransferase 1-targeting by allowing frequent, sustained drug exposure often not possible with standard HMA/VEN regimens.

Chimeric Antigen Receptor T-Cell Therapy for Patients With Multiple Myeloma-A Call for Equal Opportunity.

This Viewpoint examines the equity of US Food and Drug Administration approval and the clinical distribution of chimeric antigen receptor T-cell therapy for patients with multiple myeloma.

Universal posttransplant cyclophosphamide after allogeneic transplant, a retrospective single institution study.

BACKGROUND: The excellent results of posttransplant cyclophosphamide in decreasing graft-versus-host disease (GVHD) after haploidentical (HI) allogeneic transplant have challenged current donor selection algorithms. PATIENTS AND METHODS: We compared outcomes after matched sibling (MSD) versus alternative donor transplant using identical graft-versus-host disease (GVHD) prophylaxis including posttransplant cyclophosphamide (PTCy. Endpoints included engraftment, time outside of the hospital in the first 100 days after transplant, overall survival (OS), non-relapse mortality (NRM) and percentage of patients disease-free and off immunosuppression (DFOI) at one year and at the last follow-up. RESULTS: There were significant differences at baseline between matched donor versus HI donor transplants with higher disease-risk index (DRI), more female-to-male donor recipient pairs and a higher percentage of Black patients in the HI group. Engraftment and time out of the hospital favored MSD and matched unrelated donor transplants. Multivariate analysis showed that high DRI and Black race were associated with decreased survival and Black race was associated with a higher NRM. CONCLUSIONS: With the use of PTCy, our results support current donor selection algorithms. The finding of decreased survival and increased NRM in Black patients requires confirmation in a larger number of patients as well as the development of mitigation strategies.

Successful administration of chimeric antigen receptor (CAR) T-cell therapy in patients requiring hemodialysis.

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of relapsed/refractory B-cell malignancies. However, there is no data on the safety and efficacy of CAR T-cell therapy in patients with end stage renal disease (ESRD) requiring dialysis. In this report, we present two patients with DLBCL and ESRD who were successfully treated with different CAR T-cell products. Patient #1 is a 66 year-old woman with a history of HIV who was treated to complete response with axicabtagene ciloleucel with treatment complicated by grade 1 cytokine release syndrome (CRS) and grade 2 immune effector cell-associated neurolotoxicity syndrome (ICANS). Patient #2 is 52 year old woman whose ESRD was caused by ifosphamide toxicity and was treated to complete response with lisocabtagene maraleucel and did not experience either CRS or ICANS. Both patients received lymphodepletion chemotherapy with fludarabine and cyclophosphamide, which was dose-adjusted for ESRD with scheduled dialysis 12 h after each dose of lymphodepletion chemotherapy. Patients with DLBCL and ESRD can be safely administered both lymphodepletion chemotherapy and CAR T-cell therapy. Additionally, the fact that both patients achieved complete response to therapy suggests that CAR T-cell therapy should be strongly considered in patients with ESRD. Long-term follow up is needed to determine if therapy in this setting is of curative intent.

Persistent opioid use in patients with multiple myeloma post-ASCT.

PURPOSE: Bone pain is a common presenting symptom of multiple myeloma (MM) and is frequently treated with opioids in addition to myeloma directed therapy. With improved response and survival with modern myeloma therapy, it is important to re-examine the role of opioids in managing symptomatic myeloma. PATIENTS AND METHODS: We performed a retrospective analysis of patients with myeloma at Rutgers Cancer Institute of New Jersey (RCINJ) who received an ASCT between January 1, 2012, and December 30, 2017, and who had subsequent follow-up (a total of 138 patients). We sought information specifically from the visits after induction therapy but prior to ASCT, at 100 days and 1-year post-ASCT follow-up visits. We compared opioid users and non-users in relation to treatment response, co-morbid conditions, and symptoms. We also examined amounts, duration, and odds of continued opioid use. RESULTS: At the time of the first analysis (before transplant), 34.8% of patients were using opioids and opioid use was more frequent in younger patients and, as expected, in patients with bone lesions. At 1 year, 31.9% of patients were still using opioids and continued opioid use was not correlated with disease response. Of the patients using opioids at the time of transplant, 58% either maintained their opioid dose or increased it at 1-year post-transplant. CONCLUSIONS: This retrospective analysis shows that despite a small decrease in opioid use over time, opioid use remains frequent in MM patients and is correlated with younger age and bone involvement but not with response to therapy. Over half the patients using opioids at the time of transplant continued or increased opioid use over the following year. With increasing survival in myeloma patients, further attention is required to distinguish cancer pain from chronic pain in cancer patients.

COVID-19 Vaccine Responses in Patients With Plasma Cell Dyscrasias After Complete Vaccination.

INTRODUCTION: Due to functional hypogammaglobulinemia, patients with multiple myeloma are at increased risk for infection and generally have poorer responses to vaccines. In this study, we examined antibody responses after complete COVID-19 vaccination in patients with plasma cell dyscrasias, most of whom were receiving treatment. PATIENTS AND METHODS: Real world study of consecutive patients with multiple myeloma and other plasma cell dyscrasias (PCD) were evaluated after complete vaccination with either the 2-shot mRNA vaccines from BioNTech and Moderna or the 1-shot adenoviral vector vaccine from Johnson & Johnson (J&J). Patients received vaccines 1-4 months before antibody testing without controlling for the type of vaccine or the timing of drug therapy. Patients with a clinical history or antibody evidence of prior infection were excluded. Antinucleocapsid and quantitative anti-spike antibody levels were measured with the Roche Elecys assay. RESULTS: Ninety-five percent of patients had detectable antibody responses. Multivariate analysis showed that higher age, ongoing anti-CD38 monoclonal antibody therapy and the J&J vaccine negatively affected quantitative response. A small number of ineffectively vaccinated patients receiving IVIG subsequently had detectable nucleocapsid and spike antibodies confirming the presence of the latter in currently administered IVIG. CONCLUSIONS: Nearly all PCD had detectable anti-spike antibodies after vaccination but age, anti-CD38 monoclonal antibody therapy, and the single-shot J&J vaccine negatively affected responses. In patients who received the J&J vaccine, second doses or heterologous mRNA vaccines should be tested. Quantitative antibody testing might make future management more rational, particularly in patients with poor responses.

Refractory DLBCL: Challenges and Treatment.

Despite a greater understanding of pathologic factors that increase the chance for treatment failure, initial therapy of diffuse large B cell lymphoma (DLBCL) has not evolved from R/CHOP. Although it was anticipated that the genetic underpinnings of the cell or origin would dramatically change treatment, thus far, this has not been realized. Similarly, contrary to the situation with Hodgkin lymphoma, meaningful early treatment response assessment with PET-CT has yet to be established in DLBCL. Nevertheless, there is tremendous enthusiasm that circulating tumor DNA, possibly in combination with PET- T may facilitate earlier recognition of treatment failure or relapse. And, in contrast to the situation with front-line treatment, therapy for recurrent disease appears to be on the cusp of dramatically improving. Thus, in addition to high dose therapy with autologous transplant, a treatment that is not feasible for many older patients, CAR-T cells, bispecific T-cell engagers (BiTEs), antibody-drug conjugates and new monoclonal antibodies are all offering the possibility of long-term disease control and possible cure. The success of the cell and immunotherapies even offer hope for a chemotherapy-free strategy, initially for recurrent disease. Herein, we review the landscape of the novel agents in resistant DLBCL and speculate about their appropriate sequencing and possible migration to earlier use.

Lenalidomide in DLBCL: are we past the cell of origin?

Single-agent lenalidomide has modest activity in diffuse large B-cell lymphoma (DLBCL) and is thought to be more potent in activated B-cell (ABC) lymphomas, which are more treatment-resistant. However, the addition of lenalidomide to rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in randomized clinical trials has shown equivocal benefit, despite phase 2 studies that suggested otherwise. These equivocal results suggest that either the cell of origin (COO) has limited importance for prescribing lenalidomide, or that lenalidomide is not the optimal agent for exploiting the vulnerability of ABC lymphomas. As more recent analyses have shown that the genetic landscape of DLBCL is considerably more complex than the binary COO paradigm, the disappointing impact of lenalidomide is less surprising. In contrast to the marginal benefit from the addition of lenalidomide to R-CHOP, recent studies suggest that lenalidomide in combination with novel agents has potent activity. Lenalidomide was recently approved in combination with the anti-monoclonal B-cell antibody tafasitamab for patients with relapsed DLBCL after 1 to 3 previous treatments. This combination has led to surprisingly prolonged progression-free survival rates, along with possible cure in a subset of patients. In addition, early-phase single-arm trials are also showing deep and durable responses in relapsed patients when lenalidomide is combined with the novel agents ibrutinib and venetoclax. Although these drugs have limited single-agent activity in DLBCL, their pronounced activity in combination suggests a possible unique synergistic effect. Overall, recent studies suggest that lenalidomide will continue to be an active player in the treatment for DLBCL but likely in combination with other novel agents rather than in combination with chemotherapy.

Tandem high-dose influenza vaccination is associated with more durable serologic immunity in patients with plasma cell dyscrasias.

Patients with plasma cell dyscrasias (PCDs) experience an increased burden of influenza, and current practice of single-dose annual influenza vaccination yields suboptimal protective immunity in these patients. Strategies to improve immunity to influenza in these patients are clearly needed. We performed a randomized, double-blind, placebo-controlled clinical trial comparing tandem Fluzone High-Dose influenza vaccination with standard-of-care influenza vaccination. Standard-of-care vaccination was single-dose age-based vaccination (standard dose, <65 years; high dose, ≥65 years), and patients in this arm received a saline placebo injection at 30 days. A total of 122 PCD patients were enrolled; 47 received single-dose standard-of-care vaccination, and 75 received 2 doses of Fluzone High-Dose vaccine. Rates of hemagglutinin inhibition (HAI) titer seroprotection against all 3 strains (H1N1, H3N2, and influenza B) were significantly higher for patients after tandem high-dose vaccination vs control (87.3% vs 63.2%; P = .003) and led to higher seroprotection at the end of flu season (60.0% vs 31.6%; P = .04). These data demonstrate that tandem high-dose influenza vaccination separated by 30 days leads to higher serologic HAI titer responses and more durable influenza-specific immunity in PCD patients. Similar vaccine strategies may also be essential to achieve protective immunity against other emerging pathogens such as novel coronavirus in these patients. This trial was registered at www.clinicaltrials.gov as #NCT02566265.

Incorporation of posttransplant cyclophosphamide as part of standard immunoprophylaxis for all allogeneic transplants: a retrospective, single institution study.

The addition of posttransplant cyclophosphamide (PTCy) to standard graft-versus-host disease (GVHD) prophylaxis following haploidentical blood stem transplants has resulted in relatively low rates of GVHD. As GVHD remains a major cause of morbidity and mortality in patients receiving transplants from matched donors, we began to use PTCy in all blood stem cell transplants in 2016 and compared our recent experience with PTCy after matched sibling and unrelated donor transplants (N = 49) to the earlier 2-year period (N = 41) when PTCy was not used. Endpoints included graft-versus-host, relapse-free-survival (GRFS), overall survival, non-relapse mortality, and percentage of patients disease-free and off immunosuppression (DFOI) at 1 year and at the last follow-up. The difference in GRFS between the standard and the PTCy cohort was not statistically significant. There was a statistically improved relapse-free and overall survival in the PTCY cohort that was due to a significant decrease in non-relapse mortality secondary to GVHD. There was also a borderline statistically improved DFOI at 1 year and at last follow-up in the PTCY group. These results suggest that PTCy after HLA-matched transplants provides at least comparable efficacy to other GVHD strategies and may allow more frequent discontinuation of immunosuppression.

Pomalidomide desensitization for hypersensitivity: A case report.

INTRODUCTION: Pomalidomide is an immunomodulating agent that is used to treat relapsed and/or refractory multiple myeloma. Although the incidence of hypersensitivity with pomalidomide is not well documented, the most common type of hypersensitivity involves a cutaneous reaction. Previous reports have successfully utilized a desensitization protocol in patients who developed hypersensitivity to pomalidomide. Here we describe a case of a patient who developed urticaria on pomalidomide and successfully underwent a desensitization using the previously reported method in a case report. CASE REPORT: A 68-year-old woman with relapsed multiple myeloma and no known drug allergies developed urticaria a day after taking the first dose of pomalidomide. MANAGEMENT AND OUTCOME: The patient underwent a 10-step desensitization process in the medical intensive care unit without any reported adverse events. The following day in the medical intensive care unit, the patient was able to tolerate a full dose of pomalidomide with no further reactions and was discharged with instructions to take a full dose of pomalidomide daily for 21 days out of a 28-day cycle. The patient was followed up in the outpatient clinic and noted no further reactions from pomalidomide at the three-month visit. DISCUSSION: The 10-step desensitization protocol with pomalidomide was well tolerated in the patient with hypersensitivity to pomalidomide. Whether this approach would work in patients with more severe reactions such as anaphylaxis and angioedema is still unknown.

Checking in on Lenalidomide in Diffuse Large B Cell Lymphoma.

Lenalidomide has modest single-agent activity comparable with other newer drugs in recurrent diffuse large B cell lymphoma with response rates between 19% and 28%. Retrospective series and 1 prospective study suggest that clinically significant responses were predominantly limited to patients with activated B cell (ABC) lymphoma, a finding in agreement with lenalidomide's potent inhibition of nuclear factor κB, the key driver of ABC lymphomas. Recently completed trials will determine whether the additional use of lenalidomide with R/CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) enhances survival compared with R/CHOP alone and whether this activity is limited to ABC lymphomas. Lenalidomide also appears to have activity in the maintenance setting regardless of cell of origin and might play an important role in patients with recurrent disease who are not transplantation candidates. Similarly, because of the ability of lenalidomide to cross the blood-brain barrier, it needs to be further explored in patients with high risk for central nervous system spread. The results of lenalidomide combination studies with chemotherapy and with checkpoint inhibitors are eagerly awaited.

Clinical and Serologic Responses After a Two-dose Series of High-dose Influenza Vaccine in Plasma Cell Disorders: A Prospective, Single-arm Trial.

BACKGROUND: Patients with multiple myeloma (MM) and other plasma cell disorders are highly susceptible to influenza infections, which are major causes of morbidity in this population, despite the routine administration of a seasonal influenza vaccination. Existing data are limited by small and retrospective studies, which suggest poor seroprotection rates of < 20% after standard influenza vaccination in patients with MM. PATIENTS AND METHODS: Patients with plasma cell dyscrasia (n = 51) were treated with a 2-dose series of high-dose inactivated trivalent influenza vaccine during the 2014 to 2015 influenza season. Laboratory-confirmed influenza infections were identified through seasonal surveillance, sera were collected for influenza hemagglutination antibody inhibition (HAI) titer assays, and logistic regression models were used to identify the clinical correlates to the HAI serologic responses. RESULTS: Influenza vaccine was well tolerated, without any vaccine-related grade ≥ 2 adverse events. Only 3 patients (6%) experienced laboratory-confirmed influenza. The rates of HAI seroprotection against all 3 vaccine strains (A/California/7/2009 [H1N1] pdm09-like virus; A/Texas/50/2012 [H3N2]-like virus; and a B/Massachusetts/2/2012-like virus) increased from 4% at baseline to 49% and 65% after 1 and 2 doses, respectively. The risk factors associated with a lower likelihood of HAI serologic response included plasma cell disorder requiring therapy, less than a partial response found on disease response assessment, and active conventional chemotherapy. Alternatively, active therapy with an immunomodulatory drug alone or with a proteasome inhibitor was associated with a greater likelihood of an HAI serologic response. CONCLUSION: These data have demonstrated that, in contrast to the historically poor results with standard influenza vaccination, this novel high-dose booster vaccination strategy leads to high rates of seroprotection. Randomized controlled studies are needed to compare this novel strategy to the standard vaccination strategy.

Infusion reactions are common after high-dose carmustine in BEAM chemotherapy and are not reduced by lengthening the time of administration.

PURPOSE: Carmustine (BCNU) is used in the conditioning regimens BEAM and CBV for autologous stem cell transplantation. Carmustine-related infusion reactions, while not described in the BEAM literature, occurred in 95 % of patients who received CBV. The most common symptoms include flushing, facial pain, headache, and hypotension. These reactions have been attributed to the absolute ethanol that is used in the reconstitution process or alternatively by a direct effect of carmustine. It is currently recommended that carmustine 300 mg/m2 be infused over at least 100 min (3-5 mg/m2/min). Prior to October 2014, carmustine infusions were given over 90 min but were changed to 120 min based on the above recommendation. We compared the two infusion rates in patients receiving BEAM to see if lengthening the infusion decreased the frequency of reactions. METHODS: Overall, 100 patients received BCNU as part of BEAM or Zevalin BEAM and were equally divided between 90 and 120 min infusion times. The primary outcome was the incidence of infusion-related reactions which were graded based on CTCAE 4.03 descriptions of flushing and infusion-related reactions. We also evaluated the impact of premedication as well as the efficacy of medications used to treat infusion reactions. RESULTS: Between the years 2013-2016, there were 50 patients who received BCNU over 90 min and 50 patients over 120 min. There were no significant differences observed for diagnosis, age and gender between the two groups. Twenty-eight (56 %) in the 90-min and 26 (52 %) in the 120-min infusion intervals developed a reaction (p = 0.6882). Of the patients that developed a reaction, 19 patients (67 %) in the 90-min and all 26 patients (100 %) in the 120-min infusion were given premedications predominately acetaminophen, in addition to dexamethasone. Among reacting patients, 57 % of the 90-min and 65 % of the 120-min groups received additional intervention (p = 0.53). CONCLUSION: Infusion reactions during high-dose BCNU are common and are not clearly reduced by modestly extending the duration of infusion or giving premedications.

Autologous Stem Cell Mobilization in the Age of Plerixafor.

BACKGROUND: Autologous stem cell transplantation remains important in the treatment of myeloma and relapsed lymphoma. Plerixafor has been shown to significantly enhance stem cell mobilization but is very expensive. PATIENTS AND METHODS: We evaluated plerixafor use in the 3-year period after its approval in December 2008. RESULTS: A total of 277 patients with myeloma and lymphoma had stem cell mobilization; 97.5% were successfully mobilized, including 41.5% who received plerixafor. Plerixafor was generally used for rescue after suboptimal granulocyte-colony stimulating factor (G-CSF) mobilization ("just in time") or for remobilization after an unsuccessful attempt with chemotherapy plus G-CSF. In addition, 10% of patients received planned G-CSF plus plerixafor because of high risk factors for inadequate collection. Rescue plerixafor was more effective in patients with myeloma than lymphoma as after 1 dose of plerixafor; 85% versus 55% collected a minimum number of stem cells (2 × 10E6 CD34 cells/kg) for 1 transplant and 51% versus 15% collected > 5 × 10E6 CD34 cells/kg. After transplantation, there were no significant differences in engraftment as a consequence of plerixafor use. Among all patients, there were less platelet transfusions in patients provided ≥ 3.5 × 10E6 CD34(+) cells/kg. CONCLUSION: With the judicious use of plerixafor, nearly all patients can collect enough stem cells to proceed to transplantation. Further studies, including hematologic tolerance to posttransplantation therapy, are required to determine the cost-effectiveness of using plerixafor to convert adequate to more optimal mobilizers.

Chemoimmunotherapy and withdrawal of immunosuppression for monomorphic posttransplant lymphoproliferative disorders.

BACKGROUND: Monomorphic PTLDs are the most aggressive type of PTLD occurring after SOT. Current guidelines for treatment suggest a stepwise approach that includes a reduction of immunosuppression (RIS) with or without rituximab, followed by chemotherapy if there is no response. Nevertheless, recommendations regarding the extent and duration of RIS are nonstandardized and RIS as an initial strategy might be associated with an unacceptably high frequency of graft loss and disease progression. PATIENTS AND METHODS: We reviewed the outcome of a combination program of aggressive chemoimmunotherapy and complete withdrawal of immunosuppression in treating 22 patients with monomorphic PTLD between January 1995 and August 2012. RESULTS: Twelve of 22 patients (55%) received CHOP-R (cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab) every 2 weeks (dose-dense CHOP-R) and 10 patients received other doxorubicin-based regimens. There was no treatment-related mortality. Complete response was seen in 91% of patients. Median OS was 9.61 years (95% confidence interval (CI), 5.21-10.74). Median progression-free survival was 5.39 years (95% CI, 2.10-10.74). The graft rejection rate was 18% (95% CI, 0.03-0.34). CONCLUSION: The use of aggressive chemoimmunotherapy in combination with the withdrawal of immunosuppression approach yields excellent results and should be prospectively studied in a multi-institutional setting.