Phase II Study of the PD-1 Inhibitor Pembrolizumab for the Treatment of Relapsed or Refractory Mature T-cell Lymphoma.

BACKGROUND: Programmed cell death-1 (PD-1) and programmed death-ligand 1 (PD-L1) are frequently expressed in T-cell lymphomas. This provides a rationale for exploration of immune checkpoint inhibitors in the management of T-cell lymphomas. PATIENTS AND METHODS: In this phase II single-arm multicenter trial, patients with relapsed or refractory systemic T-cell lymphoma were treated with 200 mg pembrolizumab intravenously every 21 days. The primary endpoint was progression-free survival (PFS). The secondary endpoints were response rate, overall survival, response duration, and safety. We assessed PD-L1, p-AKT expression, and peripheral blood immune cells as potential predictive biomarkers. RESULTS: Of 18 enrolled patients, 13 were evaluable for the primary endpoint. The trial was halted early after a preplanned interim futility analysis. The overall response rate was 33% (95% confidence interval [CI], 9%-55%); 4 patients achieved a complete response (27%; 95% CI, 5%-49%). The median PFS was 3.2 months (95% CI, 1.2-3.7 months), and the median overall survival was 10.6 months (95% CI, 3.2-100 months). The median duration of response was 2.9 months (95% CI, 0-10.1 months). Two of the 4 complete responders remain in remission > 15 months. Rash was the most common adverse event (17%; n = 3). The most common ≥ grade 3 treatment-emergent adverse events were rash and pneumonitis (11%; n = 2 each). Neither PD-L1 nor p-AKT expression were associated with outcomes. However, a higher relative frequency of CD4+ T lymphocytes pre-treatment was associated with improved PFS (hazard ratio, 0.15; 95% CI, 0.03-0.74). CONCLUSION: Pembrolizumab demonstrated modest single-agent activity in relapsed or refractory T-cell lymphoma.

NCCN Guidelines Insights: Multiple Myeloma, Version 3.2018.

The NCCN Guidelines for Multiple Myeloma provide recommendations for diagnosis, evaluation, treatment, including supportive-care, and follow-up for patients with myeloma. These NCCN Guidelines Insights highlight the important updates/changes specific to the myeloma therapy options in the 2018 version of the NCCN Guidelines.

Increasing use of allogeneic hematopoietic cell transplantation in patients aged 70 years and older in the United States.

In this study, we evaluated trends and outcomes of allogeneic hematopoietic cell transplantation (HCT) in adults ≥70 years with hematologic malignancies across the United States. Adults ≥70 years with a hematologic malignancy undergoing first allogeneic HCT in the United States between 2000 and 2013 and reported to the Center for International Blood and Marrow Transplant Research were eligible. Transplant utilization and transplant outcomes, including overall survival (OS), progression-free survival (PFS), and transplant-related mortality (TRM) were studied. One thousand one hundred and six patients ≥70 years underwent HCT across 103 transplant centers. The number and proportion of allografts performed in this population rose markedly over the past decade, accounting for 0.1% of transplants in 2000 to 3.85% (N = 298) in 2013. Acute myeloid leukemia and myelodysplastic syndromes represented the most common disease indications. Two-year OS and PFS significantly improved over time (OS: 26% [95% confidence interval (CI), 21% to 33%] in 2000-2007 to 39% [95% CI, 35% to 42%] in 2008-2013, P < .001; PFS: 22% [16% to 28%] in 2000-2007 to 32% [95% CI, 29% to 36%] in 2008-2013, P = .003). Two-year TRM ranged from 33% to 35% and was unchanged over time (P = .54). Multivariable analysis of OS in the modern era of 2008-2013 revealed higher comorbidity by HCT comorbidity index ≥3 (hazard ratio [HR], 1.27; P = .006), umbilical cord blood graft (HR, 1.97; P = .0002), and myeloablative conditioning (HR, 1.61; P = .0002) as adverse factors. Over the past decade, utilization and survival after allogeneic transplant have increased in patients ≥70 years. Select adults ≥70 years with hematologic malignancies should be considered for transplant.

Multiple Myeloma, Version 3.2017, NCCN Clinical Practice Guidelines in Oncology.

Multiple myeloma (MM) is caused by the neoplastic proliferation of plasma cells. These neoplastic plasma cells proliferate and produce monoclonal immunoglobulin in the bone marrow causing skeletal damage, a hallmark of multiple myeloma. Other MM-related complications include hypercalcemia, renal insufficiency, anemia, and infections. The NCCN Multiple Myeloma Panel members have developed guidelines for the management of patients with various plasma cell dyscrasias, including solitary plasmacytoma, smoldering myeloma, multiple myeloma, systemic light chain amyloidosis, and Waldenström's macroglobulinemia. The recommendations specific to the diagnosis and treatment of patients with newly diagnosed MM are discussed in this article.

NCCN Guidelines Insights: Multiple Myeloma, Version 3.2016.

These NCCN Guidelines Insights highlight the important updates/changes specific to the 2016 version of the NCCN Clinical Practice Guidelines in Oncology for Multiple Myeloma. These changes include updated recommendations to the overall management of multiple myeloma from diagnosis and staging to new treatment options.

Donor Lymphocyte Infusion in Hematologic Malignancies--Good to be Fresh?

BACKGROUND: Donor lymphocyte infusion (DLI) has been used with variable success in a variety of hematologic malignancies. PATIENTS AND METHODS: We conducted a retrospective analysis of all patients who were treated with DLI for persistent or relapsed disease at the Temple University Bone Marrow Transplant Unit from July 1, 1993 to December 31, 2013 to evaluate the effect of the type of DLI (fresh vs. cryopreserved) on event-free survival (EFS) and overall survival (OS). Median follow-up was 64.8 months (range, 0.3-142.6 months). RESULTS: We found that EFS and OS were similar between patients receiving cryopreserved cells and those receiving fresh DLI (median OS for cryopreserved cells, 0.39 years; median OS for fresh cells, 0.32 years; P = .793; median EFS for cryopreserved cells, 0.410 years; median EFS for fresh cells, 0.420 years; P = .4264). In the setting of relapsed disease, treatment with any chemotherapy regimen before receiving DLI did not significantly impact OS (n = 63; P = .2203) or EFS (n = 40; P = .542). A subgroup analysis limited to patients with acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) (32 patients) showed that differences in OS and EFS between cryopreserved and fresh DLI approached significance (median OS for cryopreserved cells, 0.34 years; median OS for fresh cells, 0.17 years; P = .16; median EFS for cryopreserved cells, 0.37 years; median EFS for fresh cells, 0.094 years; P = 0.11). CONCLUSION: We conclude that the use of fresh cells versus cryopreserved cells does not have an impact on outcomes, and selected patients can achieve long-term survival with DLI for treatment of relapse after transplantation, although the overall outcomes remain dismal.

Multiple Myeloma, Version 2.2016: Clinical Practice Guidelines in Oncology.

Multiple myeloma (MM) is a malignant neoplasm of plasma cells that accumulate in bone marrow, leading to bone destruction and marrow failure. Recent statistics from the American Cancer Society indicate that the incidence of MM is increasing. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) included in this issue address management of patients with solitary plasmacytoma and newly diagnosed MM.

The Impact of Graft-versus-Host Disease on the Relapse Rate in Patients with Lymphoma Depends on the Histological Subtype and the Intensity of the Conditioning Regimen.

The purpose of this study was to analyze the impact of graft-versus-host disease (GVHD) on the relapse rate of different lymphoma subtypes after allogeneic hematopoietic cell transplantation (allo-HCT). Adult patients with a diagnosis of Hodgkin lymphoma, diffuse large B cell lymphoma, follicular lymphoma (FL), peripheral T cell lymphoma, or mantle cell lymphoma (MCL) undergoing HLA-identical sibling or unrelated donor hematopoietic cell transplantation between 1997 and 2009 were included. Two thousand six hundred eleven cases were included. A reduced-intensity conditioning (RIC) regimen was used in 62.8% of the transplantations. In a multivariate analysis of myeloablative cases (n = 970), neither acute (aGVHD) nor chronic GVHD (cGVHD) were significantly associated with a lower incidence of relapse/progression in any lymphoma subtype. In contrast, the analysis of RIC cases (n = 1641) showed that cGVHD was associated with a lower incidence of relapse/progression in FL (risk ratio [RR], .51; P = .049) and in MCL (RR, .41; P = .019). Patients with FL or MCL developing both aGVHD and cGVHD had the lowest risk of relapse (RR, .14; P = .007; and RR, .15; P = .0019, respectively). Of interest, the effect of GVHD on decreasing relapse was similar in patients with sensitive disease and chemoresistant disease. Unfortunately, both aGVHD and cGVHD had a deleterious effect on treatment-related mortality and overall survival (OS) in FL cases but did not affect treatment-related mortality, OS or PFS in MCL. This study reinforces the use of RIC allo-HCT as a platform for immunotherapy in FL and MCL patients.

Gastrointestinal side effects and adequacy of enteral intake in hematopoietic stem cell transplant patients.

BACKGROUND: Patients undergoing hematopoietic stem cell transplant (HSCT) can experience gastrointestinal (GI) side effects as a complication of the treatment. Limited research exists describing how the duration and severity of GI side effects influence the consumption of adequate calorie intake in this population. The purpose of this study was to assess differences in GI side effects between patients who consumed adequate calories compared with those who did not. METHODS: The MD Anderson Symptom Inventory-Gastrointestinal (MDASI-GI) tool was used to record daily GI side effects of 72 HSCT patients. Daily calorie intake was determined via calorie counts. Data were collected from day of transplant until engraftment. RESULTS: Median percentage of caloric needs consumed for all patients was 49.2% (interquartile range, 35.1-66.6). Calorie intake decreased from baseline to transplant day 8 as severity of GI symptoms increased. An inverse relationship between percentage of caloric needs met and MDASI-GI component score, MDASI-GI symptom score, and lack of appetite score was observed. The only significant difference in MDASI-GI symptom scores between those who consumed adequate calories and those who consumed inadequate calories was for diarrhea; subjects who consumed >60% of caloric needs had significantly lower median diarrhea scores. CONCLUSION: Most patients consumed <60% of their caloric needs from time of transplant to time of engraftment. More research is needed to provide insight into strategies to increase intake and to describe the implications of prolonged inadequate intake in HSCT patients.

Anger, provider responses, and pain: prospective analysis of stem cell transplant patients.

OBJECTIVE: Patient anger can be challenging for providers, and may hinder the patient-provider relationship. Research on the relationships among patient anger, relationships with health care providers and medical outcomes, however, has been limited to anecdotal accounts and cross-sectional studies. This study examined relationships among patient anger, perceptions of provider positive support and negative interactions, by prospectively studying a sample of stem cell transplant (SCT) patients. METHOD: A prospective design was used to study patient anger, perceived positive support from providers and perceived negative interactions with providers among 88 SCT patients. Data were obtained upon patient's hospitalization before SCT and at 1, 2, and 3 month follow up periods. Repeated-measures mixed models assessed relationships among study variables. RESULTS: Patient anger was associated with a gradual decline in perceived positive support and higher levels of concurrent perceived negative interactions with providers. Further, a significant lagged relationship was found such that patient anger was associated with increased perceived negative interactions with providers 1 month later. Exploratory analyses revealed that perceived negative interactions were also associated with higher levels of physical distress. Perceived positive support buffered the relationship between patient anger and physical distress, such that anger was not associated significantly with physical distress when perceived provider support was high. CONCLUSIONS: Patient anger may contribute to a deterioration of the patient-provider relationship, and contribute to negative medical outcomes including physical distress. The association between patient anger and physical distress may be reduced by supportive providers.

Dosing algorithm for concomitant administration of sirolimus, tacrolimus, and an azole after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Allogeneic hematopoietic stem cell transplant patients are at risk of invasive fungal infections and prophylaxis with azole agents is common practice. The concomitant use of these agents with sirolimus and tacrolimus for the prevention of graft-versus-host disease may result in excessive immunosuppression or toxicity. METHODS: This retrospective study identified hospitalized patients who underwent allogeneic hematopoietic stem cell transplantation between August 2009 and April 2011 at Rush University Medical Center. From this group, patients who underwent concomitant tacrolimus, sirolimus, and azole therapy were included for evaluation. The immunosuppression dosing in conjunction with azole use at discharge was analyzed to develop a dosing algorithm dependent on whether fluconazole, posaconazole, or voriconazole was used. RESULTS: A total of 36 patients were screened for inclusion, of which 8 were excluded due to acute renal failure and/or hemolysis. The remaining patients were stratified by the azole they were concomitantly taking with tacrolimus and sirolimus. The fluconazole arm required the lowest magnitude of dose reductions, while voriconazole required the greatest. CONCLUSION: Dose reductions of 50-75% for both sirolimus and tacrolimus, in combination with standard dosing of azole antifungal agents, were necessary to achieve therapeutic drug concentrations for immunosuppressants and potentially avoid toxicities.

Older patients with myeloma derive similar benefit from autologous transplantation.

Autologous hematopoietic cell transplantation (AHCT) for plasma cell myeloma is performed less often in people >70 years old than in people ≤70 years old. We analyzed 11,430 AHCT recipients for plasma cell myeloma prospectively reported to the Center for International Blood and Marrow Transplant Research between 2008 and 2011, representing the majority of US AHCT activity during this period. Survival (OS) was compared in 3 cohorts: ages 18 to 59 years (n = 5818), 60 to 69 years (n = 4666), and >70 years (n = 946). Median OS was not reached for any cohort. In multivariate analysis, increasing age was associated with mortality (P = .0006). Myeloma-specific mortality was similar among cohorts at 12%, indicating an age-related effect on nonmyeloma mortality. Analyses were performed in a representative subgroup comparing relapse rate, progression-free survival (PFS), and nonrelapse mortality (NRM). One-year NRM was 0% for age >70 years and 2% for other ages (P = not significant). The three-year relapse rate was 56% in age 18 to 59 years, 61% in age 60 to 69 years, and 63% age >70 (P = not significant). Three-year PFS was similar at 42% in age 18 to 59 years, 38% in age 60 to 69 years, and 33% in age >70 years (P = not significant). Postrelapse survival was significantly worse for the older cohort (P = .03). Older subjects selected for AHCT derived similar antimyeloma benefit without worse NRM, relapse rate, or PFS.

Loss of CD26 protease activity in recipient mice during hematopoietic stem cell transplantation results in improved transplant efficiency.

BACKGROUND: A firm understanding of the biology of hematopoietic stem and progenitor cell (HSC/HPC) trafficking is critical to improve transplant efficiency and immune reconstitution during hematopoietic stem cell transplantation (HSCT). Our earlier findings suggested that suppression of CD26 (dipeptidyl peptidase IV) proteolytic activity in the donor cell population can be utilized as a method for increasing transplant efficiency. However, factors in the recipient should not be overlooked, given the potential for the bone marrow (BM) microenvironment to regulate HSCT. STUDY DESIGN AND METHODS: We first evaluated CD26 expression and then investigated the effects of the CD26 inhibitor diprotin A and the absence of CD26 (CD26-/-) in recipient mice on HSC/HPC homing and engraftment using an in vivo congenic mouse model of HSCT. RESULTS: A significant increase in donor cell engraftment into the peripheral blood (PB), and to a lesser extent homing into the BM, was observed in CD26-/- mice or CD26 inhibitor-treated mice. Increased PB engraftment of CD26-/- mice was significant at 3 and 6 months, but not 1 month, after transplant. It was noted that the increased homing was statistically greater with donor cell manipulation (CD26-/- donor cells) than with recipient manipulation (CD26-/- recipient mice). Conversely, donor and recipient manipulation both worked well to increase PB engraftment at 6 months. CONCLUSION: These results provide preclinical evidence of CD26, in the HSCT recipient, as a major regulator of HSC/HPC engraftment with minor effects on HSC/HPC homing and suggest the potential use of CD26 inhibitors in HSCT patients to improve transplant efficiency.

CD26 protease inhibition improves functional response of unfractionated cord blood, bone marrow, and mobilized peripheral blood cells to CXCL12/SDF-1.

Hematopoietic stem cell transplantation (HSCT) is an important treatment option for patients with malignant and nonmalignant hematologic diseases. Methods to improve transplant efficiency are being explored with the intent to improve engraftment and immune reconstitution post-HSCT. A current approach under investigation involves treatment of donor cells with inhibitors that target the protease CD26, a negative regulator of the chemokine CXCL12/stromal cell-derived factor-1. CD26 inhibitor treatment has been shown to improve the functional response of CD34(+) cord blood (CB) cells, but not CD34(+) granulocyte colony-stimulating factor-mobilized peripheral blood stem cells, to CXCL12/stromal cell-derived factor-1. The effect of CD26 inhibitors on unfractionated CB, bone marrow, or granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cells has not been evaluated previously. We observed that although CB had greater CD26 expression than bone marrow or mobilized peripheral blood, treatment with a CD26 inhibitor (Diprotin A) resulted in increased responsiveness to stromal cell-derived factor-1 for all three mononuclear cell sources tested. This suggests that clinical therapeutic benefit might be gained by using CD26 inhibitors as a strategy to improve engraftment of unfractionated mobilized peripheral blood cells as well as CB cells.

A simplified technique for delivering total body irradiation (TBI) with improved dose homogeneity.

PURPOSE: Total body irradiation (TBI) with megavoltage photon beams has been accepted as an important component of management for a number of hematologic malignancies, generally as part of bone marrow conditioning regimens. The purpose of this paper is to present and discuss the authors' TBI technique, which both simplifies the treatment process and improves the treatment quality. METHODS: An AP/PA TBI treatment technique to produce uniform dose distributions using sequential collimator reductions during each fraction was implemented, and a sample calculation worksheet is presented. Using this methodology, the dosimetric characteristics of both 6 and 18 MV photon beams, including lung dose under cerrobend blocks was investigated. A method of estimating midplane lung doses based on measured entrance and exit doses was proposed, and the estimated results were compared with measurements. RESULTS: Whole body midplane dose uniformity of ±10% was achieved with no more than two collimator-based beam modulations. The proposed model predicted midplane lung doses 5% to 10% higher than the measured doses for 6 and 18 MV beams. The estimated total midplane doses were within ±5% of the prescribed midplane dose on average except for the lungs where the doses were 6% to 10% lower than the prescribed dose on average. CONCLUSIONS: The proposed TBI technique can achieve dose uniformity within ±10%. This technique is easy to implement and does not require complicated dosimetry and/or compensators.

Cellular therapies supplement: strategies for improving transplant efficiency in the context of cellular therapeutics.

The field of hematopoietic stem cell transplantation (HSCT) has overcome many obstacles that have led to our current clinical ability to utilize cells collected from marrow, mobilized peripheral blood, or umbilical cord blood for the treatment of malignant and nonmalignant hematologic diseases. It is in this context that it becomes evident that future progress will lie in our development of an understanding of the biology by which the process of HSCT is regulated. By understanding the cellular components and the mechanisms by which HSCT is either enhanced or suppressed it will then be possible to design therapeutic strategies to improve rates of engraftment that will have a positive impact on immune reconstitution post-HSCT. In this review we focus primarily on allogeneic hematopoietic stem cell transplantation (allo-HSCT), the current challenges associated with allo-HSCT, and some developing strategies to improve engraftment in this setting.

Safety and efficacy of combination therapy with fludarabine, mitoxantrone, and rituximab followed by yttrium-90 ibritumomab tiuxetan and maintenance rituximab as front-line therapy for patients with follicular or marginal zone lymphoma.

BACKGROUND: We conducted a single-institution phase II clinical trial evaluating the safety and efficacy of combination chemoimmunotherapy followed by radioimmunotherapy consolidation and rituximab maintenance as front-line treatment in indolent lymphomas. PATIENTS AND METHODS: We enrolled 20 patients with intermediate- to high-risk follicular lymphoma and 2 patients with marginal zone lymphoma. Treatment consisted of 4-6 cycles of FM (fludarabine 25 mg/m(2) on days 1-3, mitoxantrone 12 mg/m(2) on day 1 of each 28-day cycle). The protocol was amended after enrolling the first 4 patients to include rituximab 375 mg/m(2) on day 1. After 6-8 weeks, responders received (90)Y-ibritumomab tiuxetan (Zevalin) followed by maintenance rituximab (375 mg/m(2) weekly × 4 doses, repeated every 6 months for 2 years). RESULTS: After R-FM, the overall response rate was 95% with a complete response rate (CR) of 45% (n = 10), a partial response (PR) rate of 50% (n = 11), and stable disease in 1 patient. Nineteen patients received (90)Y-ibritumomab tiuxetan with a 60% conversion rate of PR to CR, resulting in an improved CR of 79% (n = 15) and a PR of 21% (n = 4). Fifteen patients proceeded to rituximab maintenance resulting in 3 patients with PR converting to CR. At median follow-up of 49.6 months, median progression-free survival (PFS) was 47.2 months and median overall survival (OS) was not reached in an intent-to-treat analysis. The most common adverse effects were hematologic, with 2 patients experiencing treatment-related myelodysplastic syndrome (MDS), evolving to acute myelogenous leukemia (AML) in 1 patient. CONCLUSION: R-FM with (90)Y-ibritumomab tiuxetan consolidation and rituximab maintenance is well tolerated, improving CR rates and maintaining durable responses in patients with untreated indolent lymphomas.

In vivo expansion of the megakaryocyte progenitor cell population in adult CD26-deficient mice.

OBJECTIVE: Megakaryopoiesis involves commitment of hematopoietic stem cells (HSC) toward the myeloid lineage in combination with the proliferation, maturation, and terminal differentiation of progenitors into megakaryocytes. The exact mechanism of megakaryocyte development from HSC is unknown, but growth factors such as thrombopoietin have been identified as critical. Additionally, it has been suggested that the chemokine CXCL12/stromal-cell derived factor-1α has a role in regulating megakaryopoiesis and thrombopoiesis. We recently reported the importance of the extracellular protease CD26 (dipeptidylpeptidase IV) in regulating HSC responses to CXCL12, as well as modulating HSC trafficking into and out of the bone marrow. However, the importance of CD26 for megakaryopoiesis has not been reported. We therefore compared megakaryocyte development between CD26-deficient (CD26(-/-)) mice and C57BL/6 control mice. MATERIALS AND METHODS: Adult CD26(-/-) mice and C57BL/6 control mice were evaluated using blood differentials, histological analysis, flow cytometric analysis, and progenitor colony assays. RESULTS: Bone marrow from CD26(-/-) mice has a significantly expanded megakaryocyte and megakaryocyte progenitor population compared to control C57BL/6 mice bone marrow. CONCLUSIONS: Our results indicate that endogenous CD26 normally suppresses megakaryopoiesis and that loss of CD26 activity results in expansion of the megakaryocyte progenitor population in vivo. This suggests the potential use of CD26 inhibitors to improve megakaryocyte progenitor function and/or reconstitution of the megakaryocyte cell population.