Nirav N. Shah

Plasmacytic post‐transplant lymphoproliferative disorder: a case series of nine patients

Post‐transplant lymphoproliferative disorder (PTLD) is a serious complication of organ transplantation. Although PTLD typically has a B‐cell histology, an uncommon variant, plasmacytic PTLD can present as a monoclonal plasma cell proliferation similar to plasmacytomas seen in multiple myeloma. A retrospective analysis was performed on nine patients at our center with plasmacytic PTLD as characterized by plasmacytic histology with the presence of CD138 and lack of CD20. Of the 210 adult solid organ transplant PTLD patients diagnosed between 1988 and 2012, 9 (4%) had a histological appearance consistent with plasmacytic PTLD. The median time from transplant to diagnosis was 3.7 years (range 8 months–24 years). All patients presented with extranodal and often subcutaneous solid tumors. Laboratory features included elevated LDH and beta‐2 microglobulin levels, monoclonal gammopathy, and EBV positivity of the tumor. Unlike conventional multiple myeloma, patients had normal calcium levels and only mild anemia. Six patients who have completed treatment achieved complete responses with radiation therapy and/or reduction in immunosuppression with two patients now greater than 5 years in continuous complete response. Plasmacytic PTLD, despite its plasmacytic histology, is responsive to conventional therapies used for B‐cell PTLD including reduction in immunosuppression and radiation therapy.

The role of FDG‐PET imaging as a prognostic marker of outcome in primary mediastinal B‐cell lymphoma

Primary mediastinal B‐cell lymphoma (PMBL) is a subtype of diffuse large B‐cell lymphoma (DLBCL) that arises in the mediastinum from B‐cells of thymic origin. Optimal management of patients with PMBL remains controversial. The present study evaluates outcomes of 27 PMBL patients treated with R‐CHOP with or without radiation therapy (RT). It investigates the role of both interim and posttreatment fluorodeoxyglucose‐positron emission tomography (FDG‐PET) as prognostic markers of outcome. Additionally, it assesses postprogression therapies in the six patients who had progressive disease. At a median follow‐up of 41.5 months (range: 6.1–147.2 months), OS was 95.5% (95% CI = 71.9–99.4) and progression‐free survival (PFS) was 70.4% (95% CI = 49.4–83.9) for the entire cohort. The negative predictive values of interim and posttreatment FDG‐PET scans were both 100%. Patients who failed initial therapy and were treated with salvage regimens and autologous stem cell transplantation (ASCT) all achieved and maintained CR. PMBL patients can achieve excellent outcomes with minimal toxicities when treated with R‐CHOP with or without RT. Negative interim and negative posttreatment FDG‐PET results identified PMBL patients who achieve long‐term remission. However, the significance of both positive interim and positive posttreatment FDG‐PET results needs to be better defined. Those who failed initial therapy were successfully treated with salvage regimens and ASCT.

R‐CHOP versus dose‐adjusted R‐EPOCH in frontline management of primary mediastinal B‐cell lymphoma: a multi‐centre analysis

Primary mediastinal (thymic) large B‐cell lymphoma (PMBCL) is an uncommon subtype of non‐Hodgkin lymphoma (NHL) that presents with a mediastinal mass and has unique clinicopathological features. Historically, patients with PMBCL were treated with R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy ± involved field radiation. Since a phase II trial, published in April 2013, demonstrated excellent results using dose‐adjusted (DA) R‐EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin), this treatment has gained popularity. We performed a retrospective, multicentre analysis of patients aged ≥18 years with PMBCL since January 2011. Patients were stratified by frontline regimen, R‐CHOP versus DA‐R‐EPOCH. 132 patients were identified from 11 contributing centres (56 R‐CHOP and 76 DA‐R‐EPOCH). The primary outcome was overall survival. Secondary outcomes included progression‐free survival, complete response (CR) rate, and rates of treatment‐related complications. Demographic characteristics were similar in both groups. DA‐R‐EPOCH use increased after April 2013 (79% vs. 45%, P < 0·001), and there was less radiation use after DA‐R‐EPOCH (13% vs. 59%, P < 0·001). While CR rates were higher with DA‐R‐EPOCH (84% vs. 70%, P = 0·046), these patients were more likely to experience treatment‐related toxicities. At 2 years, 89% of R‐CHOP patients and 91% of DA‐R‐EPOCH patients were alive. To our knowledge, this represents the largest series comparing outcomes of R‐CHOP to DA‐R‐EPOCH for PMBCL.

Improving the Safety of Oral Chemotherapy at an Academic Medical Center

PURPOSE Over the last decade, the use of oral chemotherapy (OC) for the treatment of cancer has dramatically increased. Despite their route of administration, OCs pose many of the same risks as intravenous agents. In this quality improvement project, we sought to examine our current process for the prescription of OC at the Abramson Cancer Center of the University of Pennsylvania and to improve on its safety. METHODS A multidisciplinary team that included oncologists, advanced-practice providers, and pharmacists was formed to analyze the current state of our OC practice. Using Lean Six Sigma quality improvement tools, we identified a lack of pharmacist review of the OC prescription as an area for improvement. To address these deficiencies, we used our electronic medical system to route OC orders placed by treating providers to an oncology-specific outpatient pharmacist at the Abramson Cancer Center for review. RESULTS Over 7 months, 63 orders for OC were placed for 45 individual patients. Of the 63 orders, all were reviewed by pharmacists, and, as a result, 22 interventions were made (35%). Types of interventions included dosage adjustment (one of 22), identification of an interacting drug (nine of 22), and recommendations for additional drug monitoring (12 of 22). CONCLUSION OC poses many of the same risks as intravenous chemotherapy and should be prescribed and reviewed with the same oversight. At our institution, involvement of an oncology-trained pharmacist in the review of OC led to meaningful interventions in one third of the orders.

Autologous transplantation versus allogeneic transplantation in patients with follicular lymphoma experiencing early treatment failure

Early treatment failure (ETF) in follicular lymphoma (FL), defined as relapse or progression within 2 years of frontline chemoimmunotherapy, is a newly recognized marker of poor survival and identifies a high‐risk group of patients with an expected 5‐year overall survival (OS) rate of approximately 50%. Transplantation is an established option for relapsed FL, but its efficacy in this specific ETF FL population has not been previously evaluated.

Tocilizumab, tacrolimus and methotrexate for the prevention of acute graft-versus-host disease: low incidence of lower gastrointestinal tract disease

We conducted a phase 2 study in which patients undergoing allogeneic hematopoietic stem cell transplantation received tocilizumab in addition to standard immune suppression with tacrolimus and methotrexate for graft-versus-host disease prophylaxis. Thirty-five patients were enrolled between January 2015 and June 2016. The median age of the cohort was 66 (range: 22-76). All patients received busulfan-based conditioning, and were transplanted with human leukocyte antigen-matched related or matched unrelated bone marrow or peripheral stem cell grafts. The cumulative incidences of grades II-IV and III-IV acute graft-versus-host disease were 14% (95% CI 5-30) and 3% (95% CI 0-11) at day 100, and 17% (95% CI 7-31) and 6% (95% CI 1-16) at day 180, respectively. Notably, there were no cases of graft-versus-host disease of the lower gastrointestinal tract within the first 100 days. A comparison to 130 matched controls who only received tacrolimus and methotrexate demonstrated a lower cumulative incidence of grades II-IV acute graft-versus-host disease (17% versus 45%, P=0.003) and a significant increase in grades II-IV acute graft-versus-host disease-free survival at six months (69% versus 42%, P=0.001) with tocilizumab, tacrolimus and methotrexate, which was the primary endpoint of the study. Immune reconstitution was preserved in patients treated with tocilizumab, tacrolimus and methotrexate, as T-cell and B-cell subsets recovered to near normal levels by 6-12 months post-transplantation. We conclude that tocilizumab has promising activity in preventing acute graft-versus-host disease, particularly in the lower gastrointestinal tract, and warrants examination in a randomized setting.

Use of propylene glycol-free melphalan conditioning in light-chain amyloidosis patients undergoing autologous hematopoietic cell transplantation is well tolerated and effective

To the Editor: Light-chain amyloidosis (AL) is a malignant plasma cell disorder, characterized by misfolded fibrillar protein deposition in vitals organs of the body, leading to organ failure and eventually death [1]. Treatment is directed at eradicating the underlying plasma cell clone using systemic chemotherapy [2]. Autologous hematopoietic cell transplantation (auto-HCT) has been a preferred approach in transplant-eligible patients to improve long-term outcomes [3]. High-dose melphalan conditioning is the standard of care for auto-HCT in patients with plasma cell disorders [4]. The lyophilized melphalan formulation has inadequate solubility and stability after reconstitution, and propylene glycol (PG), which is used as a co-solvent to improve solubility and chemical stability of lyophilized melphalan, is associated with cardiac, neurologic, metabolic, and renal toxicities [5, 6]. A novel PG-free melphalan preparation, Evomela (PG-free melphalan), uses captisol as a solubilizing agent and thus may be less toxic than PG melphalan formulations. In a phase IIb study of multiple myeloma (MM) patients undergoing auto-HCT, PG-free melphalan showed an acceptable safety profile and comparable efficacy [7]. Consequently, PG-free melphalan was granted FDA approval for use as a conditioning regimen in patients undergoing auto-HCT. Since AL patients have increased peri-transplant complications, we sought to determine the safety and efficacy of PG-free melphalan conditioning in AL patients undergoing auto-HCT compared to PG melphalan. We switched to PG-free melphalan for auto-HCT conditioning on 15 November 2016. Herein, we compare early post-transplant outcomes of AL patients in the year before and after the change. We retrospectively analyzed AL patients who underwent auto-HCT from 31 October 2015 to 31 October 2017 at our institution (N= 18), nine each in PG melphalan and PG-free melphalan group. AL staging was determined using the 2012 revised staging system [8]. Hematologic response was defined according to the 2012updated AL response criteria [9]. Chart review was conducted to identify events in the first 100 days following auto-HCT, including arrhythmias, cardiac and/or renal failure, mucositis, engraftment syndrome, days in hospital, rehospitalization, and transfer to intensive care unit (ICU). We also reviewed charts for need of platelet and pack red blood cell (PRBC) transfusion post auto-HCT in PG melphalan and PG-free melphalan group. The threshold for PRBC transfusion was hemoglobin <7 g/dl and for platelet transfusion was <10,000/mm during this entire period. Incidence and severity of chemotherapy-induced mucositis was determined based on documentation of oral mucositis in the charts and use of opioid medications for oral, throat, or abdominal pain. We also took into account the use of intravenous dexamethasone, intubation to protect airway, and ICU transfer due to suspected oropharyngeal mucositis. Categorical variables between groups were compared using χ test. Continuous variables were compared by nonparametric t test using analysis of variance. Baseline characteristics are summarized in Table 1 and the two groups were comparable. One patient in the PG melphalan arm received BEAM (carmustine, etoposide, cytarabine and melphalan) conditioning before auto-HCT due to concurrent diagnosis of Waldenstrom macroglobulinemia with IgM AL. The median time to neutrophil and platelet engrafment was similar in both groups as well as the incidence of post-transplant cardiac or renal failure. * Anita D’Souza anitadsouza@mcw.edu

Outcomes of Medicare-age eligible NHL patients receiving RIC allogeneic transplantation: a CIBMTR analysis

The application of allogeneic hematopoietic cell transplantation (allo-HCT) in non-Hodgkin lymphoma (NHL) patients ≥65 years in the United States is limited by lack of Medicare coverage for this indication. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we report allo-HCT outcomes of NHL patients aged ≥65 years (older cohort; n = 446) compared with a cohort of younger NHL patients aged 55-64 years (n = 1183). We identified 1629 NHL patients undergoing a first reduced-intensity conditioning (RIC) or nonmyeloablative conditioning allo-HCT from 2008 to 2015 in the United States. Cord blood or haploidentical transplants were excluded. The median age was 68 years (range 65-77) for the older cohort vs 60 years (range 55-64) in the younger cohort. The 4-year adjusted probabilities of nonrelapse mortality (NRM), relapse/progression (R/P), progression-free survival (PFS), and overall survival (OS) of the younger and older groups were 24% vs 30% (P = .03), 41% vs 42% (P = .82), 37% vs 31% (P = .03), and 51% vs 46% (P = .07), respectively. Using multivariate analysis, compared with the younger group, the older cohort was associated with increased NRM, but there was no difference between the 2 cohorts in terms of R/P, PFS, or OS. The most common cause of death was disease relapse in both groups. In NHL patients eligible for allo-HCT, there was no difference in OS between the 2 cohorts. Age alone should not determine allo-HCT eligibility in NHL, and Medicare should expand allo-HCT coverage to older adults.

Fludarabine and Busulfan versus Fludarabine, Cyclophosphamide, and Rituximab as Reduced-Intensity Conditioning for Allogeneic Transplantation in Follicular Lymphoma

Large, multicenter studies comparing commonly used reduced-intensity conditioning (RIC) approaches in follicular lymphoma (FL) have not been performed. Using the Center for International Blood and Marrow Transplant Research database, we report the outcomes of the 2 most commonly used RIC approaches, fludarabine and busulfan (Flu/Bu) versus fludarabine, cyclophosphamide, and rituximab (FCR) in FL patients. We evaluated 200 FL patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) who received RIC with either Flu/Bu (n = 98) or FCR (n = 102) during 2008 to 2014. All patients received peripheral blood grafts, and graft-versus-host disease (GVHD) prophylaxis was limited to calcineurin inhibitor-based approaches. Median follow-up of survivors in the Flu/Bu and FCR groups was 48 months and 46 months, respectively. On univariate analysis in the Flu/Bu and FCR groups, the 3-year rates of nonrelapse mortality (11% versus 11%, P = .94), relapse/progression (18% versus 15%, P = .54), progression-free survival (PFS) (71% versus 74%, P = .65), and overall survival (OS) (73% versus 81%, P = .18) were not significantly different. On multivariate analysis no difference was seen between the FCR and Flu/Bu cohorts in terms of grades II to IV (relative risk [RR], 1.06; 95% confidence interval [CI], .59 to 1.93; P = .84) or grades III to IV (RR, 1.18; 95% CI, .47 to 2.99; P = .72) acute GVHD, nonrelapse mortality (RR, .83; 95% CI, .38 to 1.82; P = .64), relapse/progression (RR, .99; 95% CI, .49 to 1.98; P = .97), PFS (RR, .92; 95% CI, .55 to 1.54; P = .76), or OS (RR, .70; 95% CI, .40 to 1.23; P = .21) risk. However, RIC with FCR was associated with a significantly reduced chronic GVHD risk (RR, .52; 95% CI, .36 to .77; P = .001). RIC with either Flu/Bu or FCR in patients with FL undergoing allo-HCT provides excellent 3-year OS, with acceptable rates of nonrelapse mortality. FCR-based conditioning was associated with a lower risk of chronic GVHD.

Pharmacokinetics of High-Dose Propylene Glycol Free Melphalan in Multiple Myeloma Patients Undergoing Autologous Hematopoietic Cell Transplantation

High-dose melphalan followed by autologous stem cell transplant (ASCT) is standard of care for eligible patients with multiple myeloma (MM). Evomela (propylene glycol-free melphalan HCl [PG-Free Mel]; Spectrum Pharmaceuticals, Irvine, CA) was approved by the US Food and Drug Administration as conditioning therapy for ASCT in MM in 2 daily 100-mg/m2 doses for a total dose of 200 mg/m2. In this phase II, open-label study PG-Free Mel (Evomela) conditioning was given at single dose of 200 mg/m2 on day -2 pre-ASCT to establish pharmacokinetic (PK) parameters and safety. Twenty-four patients (median age, 64 years) were enrolled between August 2016 and February 2017. Myeloablation followed by successful neutrophil engraftment occurred at a median of 10 days in all patients. Peak melphalan concentration was observed at 10 minutes after infusion, whereas there was considerable variation in the maximum plasma concentration (Cmax) and area under concentration time curve (AUC). Median Cmax was 7380 ng/mL (interquartile range [IQR], 6522 to 8027). Similarly, median AUC was 533,552 ng/mL∙min (IQR, 450,850 to 662,936). PG-Free Mel had an acceptable safety profile regardless of the exposure, with no mortality and an overall response rate of 96% and a very good partial response rate of 75%. In conclusion, although PG-Free Mel at a single dose of 200 mg/m2 was safe, considerable PK variability was observed with the highest quartile having an ~3-fold higher AUC than the first quartile, suggesting that strategies for higher targeted exposure could be explored in future trials to optimize clinical benefit.