Dose-Adjusted EPOCH Plus Inotuzumab Ozogamicin in Adults With Relapsed or Refractory B-Cell ALL: A Phase 1 Dose-Escalation Trial.

Importance: Options for adults with relapsed or refractory B-cell acute lymphoblastic leukemia or lymphoma (B-ALL) are limited, and new approaches are needed. Inotuzumab ozogamicin (InO) has been combined with low-intensity chemotherapy, with modest improvements over historical controls, and dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH) treatment is safe and active for newly diagnosed ALL. Objective: To assess the safety and clinical activity of DA-EPOCH and InO in adults with relapsed or refractory B-ALL. Design, Setting, and Participants: This single-center, single-arm, nonrandomized, phase 1 dose-escalation trial included adults with relapsed or refractory CD22+ B-ALL and was conducted between September 2019 and November 2022. At least 5% blood or marrow blasts or measurable extramedullary disease (EMD) was required for enrollment. Interventions: DA-EPOCH was given on days 1 to 5, while InO was given on day 8 and day 15 of a 28-day cycle. Three dose levels were studied using a bayesian optimal interval design. Main Outcomes and Measures: The primary outcome was the maximum tolerated dose of InO when combined with DA-EPOCH, defined as the highest dose level that produced a rate of dose-limiting toxicity below 33%. Secondary objectives included response rates, survival estimates, and descriptions of toxic effects. Results: A total of 24 participants were screened and enrolled (median age, 46 [range, 28-76] years; 15 [62%] male). The median number of lines of prior therapy was 3 (range, 1-12). Three of 11 participants (27%) treated at the highest dose level (InO, 0.6 mg/m2, on day 8 and day 15) experienced dose-limiting toxicity, making this the maximum tolerated dose. No deaths occurred during the study, and only 1 patient (4%; 95% CI, 0.1%-21%) developed sinusoidal obstructive syndrome after poststudy allograft. The morphologic complete response rate was 84% (95% CI, 60%-97%), 88% (95% CI, 62%-98%) of which was measurable residual disease negative by flow cytometry. Five of 6 participants with EMD experienced treatment response. The overall response rate was 83% (95% CI, 63%-95%). Median overall survival, duration of response, and event-free survival were 17.0 (95% CI, 8.4-not reached), 15.0 (95% CI, 6.7-not reached), and 9.6 (95% CI, 4.5-not reached) months, respectively. Conclusions: In this study, adding InO to DA-EPOCH in adults with relapsed or refractory B-ALL was feasible, with high response rates and sinusoidal obstructive syndrome occurring rarely in a heavily pretreated population. Many patients were able to proceed to poststudy consolidative allogeneic hematopoietic cell transplant and/or chimeric antigen receptor T-cell therapy. Further investigation of this combination is warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT03991884.

Hyper-CVAD versus dose-adjusted EPOCH as initial treatment for adults with acute lymphoblastic leukemia.

OBJECTIVES: We recently performed a single-arm phase II trial of DA-EPOCH in adults with acute lymphoblastic leukemia (ALL). We sought to compare these results to those with standard Hyper-CVAD. METHODS: We created a retrospective matched cohort of patients who received Hyper-CVAD (n = 69) at our center and otherwise met eligibility criteria for the DA-EPOCH trial (n = 53). RESULTS: Our outcomes support the use of Hyper-CVAD over DA-EPOCH in Ph- disease for both overall survival (OS; HR 0.18, p = .004) and event-free survival (EFS; HR 0.51, p = .06). In contrast, outcomes were similar in Ph+ disease (OS HR 0.97, p = .96; EFS HR 0.65, p = .21). Rates of morphologic remission and measurable residual-disease negativity were similar between the regimens. Hyper-CVAD was associated with significantly more febrile neutropenia (OR 1.9, p = .03) and a greater incidence of Grade 4 or 5 adverse events (20% vs. 6%). Average transfusions per cycle of both red blood cells (p < .001) and platelets (p < .001) were five-fold higher with Hyper-CVAD. CONCLUSIONS: Our findings support continued use of Hyper-CVAD for Ph- ALL but suggest that DA-EPOCH may be a reasonable alternative for Ph+ ALL. These data also highlight a potential role for DA-EPOCH in resource-limited settings or when more intense therapy is not feasible.

Successful Treatment of Persistent Symptomatic Coronavirus Disease 19 Infection With Extended-Duration Nirmatrelvir-Ritonavir Among Outpatients With Hematologic Cancer.

Persistent symptomatic coronavirus disease 2019 (COVID-19) is a distinct clinical entity among patients with hematologic cancer and/or profound immunosuppression. The optimal medical management is unknown. We describe 2 patients who had symptomatic COVID-19 for almost 6 months and were successfully treated in the ambulatory setting with extended courses of nirmatrelvir-ritonavir.

Successful Treatment of Prolonged, Severe Coronavirus Disease 2019 Lower Respiratory Tract Disease in a B cell Acute Lymphoblastic Leukemia Patient With an Extended Course of Remdesivir and Nirmatrelvir/Ritonavir.

A patient with B-cell acute lymphoblastic leukemia (ALL) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had persistent, progressive pneumonia with viremia after 5 months of infection despite monoclonal antibodies, intravenous (IV) remdesivir and prolonged oral steroids. Twenty days of nirmatrelvir/ritonavir and 10 days of IV remdesivir led to full recovery.

CSF3R T618I mutant myelodysplastic/myeloproliferative neoplasm in the elderly: An age-related disease with unfavorable prognosis.

We reported two MDS/MPN-U and one CMML patients with CSF3R T618I mutation. There were two males and one female, with a median age of 84 years. Three patients presented with leukocytosis and anemia, two with thrombocytopenia, and one with monocytosis. In all the patients, bone marrow showed hypercellularity with myeloid or erythroid predominant trilineage hematopoiesis and dysplasia. Two cases carried -7/-7q abnormalities. In addition to CSF3R T618/I mutation, each case carried 3-5 additional somatic mutations. The median survival was only 2 months. These rare patients were characterized by old age, high mutation rates, clonal hematopoiesis-associated mutations, clonal evolution, and unfavorable prognosis.

The pharmacokinetics of therapeutic arsenic trioxide in acute promyelocytic leukemia patients.

Arsenic trioxide (ATO) treats Acute Promyelocytic Leukemia (APL). ATO is converted from inorganic arsenic (iAs) to methylated (MAs) and dimethylated (DMAs) metabolites, which are excreted in the urine. Methylation of iAs is important in detoxification, as iAs exposure is deleterious to health. We examined ATO metabolism in 25 APL patients, measuring iAs, MAs, and DMAs. Plasma total iAs increased after ATO administration, followed by a rapid decline, reaching trough levels by 4-6 h. We identified two patterns of iAs metabolism between 6 and 24 h after infusion: in Group 1, iAs increased and were slowly converted to MAs and DMAs, whereas in Group 2, iAs was rapidly metabolized. These patterns were associated with smoking and different treatments: ATO with all-trans retinoic acid (ATRA) alone vs. ATO preceded by ATRA and chemotherapy. Our data suggest that smoking and prior chemotherapy exposure may be associated with ATO metabolism stimulation, thus lowering the effective blood ATO dose.

Evaluation of the efficacy and safety of arsenic trioxide dosing in obese patients with acute promyelocytic leukemia.

Arsenic trioxide (ATO) is the backbone of acute promyelocytic leukemia (APL) treatment and is dosed based on weight with no upper limit, therefore obese patients receive large doses and may be vulnerable to adverse effects and dose holdings. Twenty-seven patients receiving ATO during induction were categorized as obese (N = 16) or non-obese (N = 11) based on body mass index (BMI) ≥30 kg/m2 in this retrospective study. Doses were held or modified due to composite adverse effects in 9 (56%) obese patients and 7 (64%) non-obese patients (p = 1.00). There were higher rates of dose holdings (13% versus 0%; p = .5) and dose modifications (13% versus 0%; p = .5) due to hepatotoxicity in obese versus non-obese patients. There were no differences in efficacy parameters. These data suggest that obese patients have similar overall incidence of adverse effects to ATO as non-obese patients; any difference in risk of hepatotoxicity will require clarification in a larger study.

A pilot study treatment of malignant tumors using low-dose 18F-fluorodeoxyglucose (18F-FDG).

Photons, electrons and protons have therapeutic use however positrons have only been used for diagnostic imaging purposes. The energies of positrons (ß+) from F-18 (0.633 MeV) and electrons (ß-) from I-131 (0.606 MeV) are very close and have similar equilibrium dose constants. Since [18F]-fluorodeoxyglucose (18F-FDG) clears rapidly from circulation, administration of 37-74 GBq (1-2 Ci) of 18F-FDG is relatively safe from an internal radiation dosimetry point of view. We initiated a phase I dose escalation study to assess the safety, toxicity, and potential therapeutic utility of administering 100-200 mCi/m2 18F-FDG delivered over a 1 to 5 day period in patients with advanced lymphomas and solid tumors refractory to standard of care treatment (SCT). Here we report the results of the first four patients treated. Four patients with advanced cancers received a single dose of 3.7-7.4 GBq/m2 (100-200 mCi/m2) 18F-FDG. We monitored the patients for adverse effects and for response. No treatment-related toxicities were observed. There was no increased radiation exposure to personnel. Two patients showed decrease in the index lesions' SUVs by 17-33% (Day 1) and 25-31% (Day 30) post treatment. The two other patients showed stable disease on 18F-PET-CT. Interestingly, responses were seen at low radiotherapy doses (below 1 Gy). This exploratory study demonstrated the safety of therapeutic administration of up to 14.2 GBq (385 mCi) 18F-FDG. In patients with 18F-FDG-avid cancers, targeted radionuclide 18F-FDG therapy appears safe and may offer clinical benefit.

Vemurafenib-induced pancreatitis in a patient with recurrent hairy cell leukaemia.

Recent studies have shown that BRAF inhibitors, such as vemurafenib, are effective in inducing long periods of remission in relapsed hairy cell leukaemia. Acute pancreatitis is one of the rare complications that is reported with vemurafenib use. As severe pancreatitis can be life threatening, physicians should be vigilant of this side effect and promptly treat patients that develop clinical signs and symptoms while receiving vemurafenib. We present an interesting case of vemurafenib-induced pancreatitis that not only resolved but also did not recur after reintroduction of the drug at a reduced dose.

Unusual case of dasatinib-associated acute bilateral hyphemas leading to blindness in a patient with chronic myeloid leukaemia.

Chronic myeloid leukaemia (CML) is a myeloproliferative disorder with an incidence of 1-2 cases per 100 000 adults per year.1 Since the International Randomized Study of Interferon and STI571 trial (IRIS trial) in 2003, treatment with tyrosine kinase inhibitors (TKIs) has become the standard of care for patients with newly diagnosed CML in the chronic phase.2 Dasatinib is a second-generation TKI and is generally well tolerated, with cytopenias, gastrointestinal (GI) symptoms and fluid retention being the most commonly observed side effects.3-5 Bleeding complications, although unusual, have been reported with dasatinib, with an incidence ranging from 8% to 24%.3-6 The most commonly reported site of bleeding is the GI tract.3 5 We report an unusual case of dasatinib-associated bleeding presenting with acute bilateral hyphemas, which, to our knowledge, is the first report of its kind.

Bilateral Angle Closure Following the Infusion of a Monoclonal Antibody to Treat Relapsing Multiple Myeloma.

PURPOSE: We describe a case of bilateral angle closure glaucoma following the infusion of daratumumab, a monoclonal antibody used to treat relapsing multiple myeloma. METHODS: This is an interventional case report. RESULTS: A 59-year-old woman presented with bilateral angle closure glaucoma one day following her first infusion of daratumumab. B-scan echography showed ciliochoroidal effusions in both eyes. Cycloplegia was implemented given the suspicion for drug-induced angle closure, which resulted in prompt deepening of the anterior chambers and normalization of intraocular pressures. The ciliochoroidal effusions resolved 16 days following the cessation of daratumumab. CONCLUSIONS: Daratumumab may be associated with drug-induced secondary angle closure glaucoma.

Light chain Fanconi syndrome in a patient with acute myeloid leukemia and monoclonal gammopathy of undetermined significance.

Proximal tubules are a target for paraproteinemic diseases. Cast nephropathy, light chain deposition diseases, and amyloidosis are frequently encountered in patients with multiple myeloma. Rarely, a subset of patients develop light chain Fanconi syndrome (LCFS). LCFS has been reported with multiple myeloma, monoclonal gammopathy of renal significance (MGRS), chronic lymphocytic leukemia, Waldenstrom's macroglobulinemia and diffuse large B-cell lymphoma. No cases have been described with other hematologic malignancies. We report the first case of lambda LCFS in a patient with both acute myeloid leukemia (AML) and monoclonal gammopathy of undetermined significance (MGUS).