Prognostic factors for progression in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia in complete molecular response within 3 months of therapy with tyrosine kinase inhibitors.

BACKGROUND: The achievement of a 3-month complete molecular response (CMR) is a major prognostic factor for survival in patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). However, 25% of patients relapse during therapy with tyrosine kinase inhibitors (TKIs). METHODS: The authors reviewed 204 patients with Ph-positive ALL who were treated between January 2001 and December 2018 using the combination of hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) plus a TKI (imatinib, 44 patients [22%]; dasatinib, 88 patients [43%]; or ponatinib, 72 patients [35%]). Progression-free survival (PFS) was defined as the time from the start date of therapy to the date of relapse, death, or last follow-up. Overall survival (OS) was defined as the time from the start date of therapy to the date of death or last follow-up. RESULTS: Overall, a 3-month CMR was observed in 57% of patients, including 32% of those who received imatinib, 52% of those who received dasatinib, and 74% of those who received ponatinib. The median follow-up was 74 months (imatinib, 180 months; dasatinib, 106 months; ponatinib, 43 months). Among 84 patients in 3-month CMR, 17 (20%) proceeded to undergo allogeneic stem cell transplantation (ASCT). The 5-year PFS and OS rates were 68% and 72%, respectively. By multivariate analysis, ponatinib therapy was the only significant favorable independent factor predicting for progression (P = .028; hazard ratio, 0.388; 95% CI, 0.166-0.904) and death (P = .042; hazard ratio, 0.379; 95% CI, 0.149-0.966). ASCT was not a prognostic factor for PFS and OS by univariate analysis. CONCLUSIONS: In patients with Ph-positive ALL, ponatinib is superior to other types of TKIs in inducing and maintaining a CMR, thus preventing disease progression. ASCT does not improve outcome once a 3-month CMR is achieved.

Clinical characteristics and outcomes in patients with acute myeloid leukemia with concurrent FLT3-ITD and IDH mutations.

BACKGROUND: Isocitrate dehydrogenase (IDH1 and IDH2) mutations commonly co-occur with FMS-like tyrosine kinase 3 (FLT3) mutations in patients with acute myeloid leukemia (AML). METHODS: The authors reviewed cases of patients with FLT3-internal tandem duplication (FLT3-ITD)-mutated AML with concurrent IDH mutations diagnosed between January 2011 and December 2018. RESULTS: A total of 91 patients with FLT3-ITD and IDH1 or IDH2 "double-mutated" AML were identified; 36 patients had concurrent FLT3-ITD/IDH1 mutations (18 in the frontline and 18 in the recurrent and/or refractory [R/R] setting) and 55 patients had concurrent FLT3-ITD/IDH2 mutations (37 in the frontline and 18 in the R/R setting). FLT3 and/or IDH inhibitors (FLT3Is and/or IDHIs) were given as a single agent or in combination with cytotoxic chemotherapy (CCT) or low-intensity therapy (LIT). Rates of complete remission (CR) plus CR with incomplete count recovery (CRi) with the use of CCT and FLT3Is were 100% and 64%, respectively, in patients in the frontline and R/R settings. CCT with IDHIs was given in 2 frontline patients and both achieved a CR. LIT with FLT3Is in the frontline and R/R settings demonstrated CR and CRi rates of 67% and 28%, respectively. Single-agent FLT3Is and IDHIs demonstrated limited activity with a CR and/or CRi rate of 14% in patients with disease in the R/R setting. CONCLUSIONS: The combination of FLT3I-based therapy with CCT or LIT appeared to be effective in both the frontline and R/R settings among patients with FLT3-ITD/IDH co-mutated disease. Fewer patients with double-mutated disease received CCT or LIT with IDH1/2 inhibitor in the frontline setting; however, high response rates also were noted with this approach. LAY SUMMARY: The prognostic influence of FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) and isocitrate dehydrogenase (IDH) co-mutation status on outcomes in patients with acute myeloid leukemia receiving an FLT3 inhibitor, non-FLT3/IDH inhibitor-based regimens, or an IDH inhibitor is unclear. This is an important clinical question because multiple targeted therapies for FLT3 and IDH1/2 mutations have become available. The results of the current study demonstrated that a combination of a FLT3 inhibitor with cytotoxic chemotherapy or low-intensity therapy appears to be an effective approach in patients with FLT3-ITD/IDH co-mutated disease in both the frontline and recurrent and/or refractory settings. Fewer dual-mutated patients received cytotoxic chemotherapy or low-intensity therapy with an IDH1/2 inhibitor in the frontline setting; however, excellent responses also were observed with this approach.

Discontinuation of Maintenance Tyrosine Kinase Inhibitors in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia outside of Transplant.

BACKGROUND: The addition of tyrosine kinase inhibitors (TKIs) to chemotherapy has dramatically improved outcomes of patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). When allogeneic hematopoietic stem cell transplant (HSCT) is performed, maintenance TKI is generally given for a fixed duration. However, the optimal duration of TKI outside of HSCT remains unknown, and the common practice is to continue indefinitely. Here, we report characteristics and outcomes of 9 patients treated with chemotherapy + TKI without HSCT and later discontinued TKI. METHODS: Among 188 patients with Ph-positive ALL who did not undergo HSCT, 9 of them discontinued maintenance TKI mainly due to side effects. Patients were closely monitored with serial PCR testing for the BCR-ABL1 transcript. Major molecular response (MMR) was defined as BCR-ABL1 transcript ≤0.1% on the international scale for p210 transcripts and a 3-log reduction from baseline for p190 transcripts. Deep molecular remission (DMR) was defined as the absence of quantifiable BCR-ABL1 transcripts with a sensitivity of 0.01%. Molecular relapse was defined as loss of MMR. Treatment-free remission (TFR) was defined from time of TKI discontinuation to molecular relapse, last follow-up, or death from any cause. RESULTS: At the time of TKI discontinuation, transcript level was undetected in 6 patients, <0.01% in 2 patients, and 0.01% in another patient. Prior to discontinuation, the median duration of TKI therapy and of DMR was 70 and 47 months, respectively. No morphological relapse occurred. Three patients (33%) had molecular relapse at a median of 6 months. All 3 resumed TKI therapy, and 2 of them regained DMR after a median of 13 months. After a median follow-up of 49 months, the median TFR was not reached, and the 4-year TFR rate was 65%. The median duration of DMR in patients with and without molecular relapse was 22 and 58 months, respectively (p = 0.096). CONCLUSION: TKI discontinuation outside of HSCT in Ph-positive ALL in the setting of compelling toxicity may be safe only among a highly selected group of patients with deep and prolonged DMR undergoing close and frequent monitoring. Validation of these findings in prospective clinical trials is highly needed.

Should we screen patients with hematologic malignancies for COVID-19?

The coronavirus disease (COVID-19) pandemic has posed several challenges to the hematology community to re-organize the medical care of patients with hematologic malignancies. Whereas the oncology societies favored a more or less conservative approach which considered the possibility of delaying treatment administration on a case-by-case basis, the hematology community guidelines were less stringent and recommended adequate individualized regimens. As countries are de-escalating the lockdown and the medical community is unable to foresee the end of the current outbreak will and whether the pandemic would eventually come back as a seasonal infection, there is interest in screening of patients with hematology malignancies with COVID-19 instead of limiting access to curative treatments. The rapidly accumulating knowledge about COVID-19 allows a better understanding of the diagnostic tools that may be potentially used in screening. Herein, we briefly review the pathophysiology of COVID-19, the rationale of screening of patients with hematologic malignancies, tools for screening, and available guidelines.

Targeting the VEGF Pathway in Osteosarcoma.

Osteosarcoma is the most common primary tumor of the bones affecting mainly young adults. Despite the advances in the field of systemic anticancer therapy, the prognosis of relapsed of metastatic osteosarcoma patients remain dismal with very short survival. However, the better understanding of the pathophysiology of this subtype of sarcoma has led to the identification of new targeted agents with significant activity. In fact, increased angiogenesis plays a major role in the tumor growth and survival of osteosarcoma patients. Several targeted agents have demonstrated a significant anti-tumor activity including multi-kinase inhibitors. In this review, we will discuss the pathophysiology, rationale, and role of targeting angiogenesis via the VEGF pathway in patients with osteosarcoma with emphasis on the published clinical trials and future directions.

Long-term outcome of hyper-CVAD-R for Burkitt leukemia/lymphoma and high-grade B-cell lymphoma: focus on CNS relapse.

Burkitt leukemia/lymphoma (BL) and high-grade B-cell lymphoma (HGBL) have a high incidence of central nervous system (CNS) involvement, which is associated with poor prognosis. The hyper-cyclophosphamide, vincristine, Adriamycin, and dexamethasone plus rituximab (CVAD-R) regimen includes systemic and intrathecal CNS-directed therapy to treat and prevent CNS disease. We report here the long-term safety and efficacy of the hyper-CVAD-R regimen in adults with BL and HGBL, focusing on its efficacy to prevent CNS relapse. Among 79 adults (54 BL, 25 HGBL), the median age was 44 years (25% ≥60 years old), 73% had bone marrow (BM) involvement, and 28% had CNS involvement. The complete response rate was 91% (BL 96%; HGBCL 79%; P = .16). The 5-year relapse-free survival (RFS) and overall survival (OS) rates were 58% and 52%, respectively. The cumulative incidence of relapse (CIR) was 21% (BL 14%; HGBCL 37%, P = .06) and was associated with baseline BM (27% vs 0%; P = .02) and CNS (42% vs 12%; P < .01) involvement. In multivariate analyses, age and CNS involvement were independent predictors for OS and RFS. The 5-year CNS CIR was 6% (BL 4%; HGBL 11%; P = .31); 16% with baseline CNS involvement (P = .03). Our data support the use of hyper-CVAD-R in preventing CNS relapse, especially among high-risk patients with BM or CNS involvement.

Patterns of Resistance Differ in Patients with Acute Myeloid Leukemia Treated with Type I versus Type II FLT3 inhibitors.

Despite promising results with FLT3 inhibitors (FLT3i), response durations remain short. We studied pretreatment and relapse bone marrow samples from patients with FLT3-mutated AML treated with FLT3i-based therapies (secondary resistance cohort), and pretreatment bone marrow samples from patients with no response to FLT3i-based therapies (primary resistance cohort). Targeted next generation sequencing at relapse identified emergent mutations involving on-target FLT3, epigenetic modifiers, RAS/MAPK pathway, and less frequently WT1, and TP53. RAS/MAPK and FLT3-D835 mutations emerged most commonly following type I and type II FLT3i-based therapies, respectively. Patients with emergent mutations at relapse had inferior overall survival compared with those without emergent mutations. Among pretreatment RAS mutated patients, pretreatment cohort level variant allelic frequencies for RAS were higher in non-responders, particularly with type I FLT3i-based therapies, suggesting a potential role in primary resistance as well. These data demonstrate distinct pathways of resistance in FLT3-mutated AML treated with type I versus II FLT3i.

Venetoclax-Based Combinations in Acute Myeloid Leukemia: Current Evidence and Future Directions.

The past decade has witnessed major advances in our understanding of molecular biology, which led to breakthrough novel therapies, importantly including the B-cell lymphoma-2 (BCL-2) inhibitor venetoclax. Notably, venetoclax-based combinations have improved outcomes, including both remission rates and overall survival, of older patients with acute myeloid leukemia (AML) deemed "unfit" for intensive chemotherapy due to age or comorbidities. This has translated into a rapid and widespread use of venetoclax-based combinations in both academic and community-based settings. Other venetoclax-based combinations are being investigated in AML with the ultimate goal of improving cure rates across many subgroups; frontline and relapsed/refractory, in combination with intensive chemotherapy, in the post-transplant setting, or as maintenance strategy. In this article, we summarize the current available data on venetoclax-based combinations. We also highlight areas of unmet medical need, and we offer practical clinical pearls for management of patients receiving such therapy.

Evolving therapy of adult acute lymphoblastic leukemia: state-of-the-art treatment and future directions.

Recent years have witnessed major advances that have improved outcome of adults with acute lymphoblastic leukemia (ALL). The emergence of the concept of measurable residual disease has fine-tuned our prognostic models and guided our treatment decisions. The treatment paradigms of ALL have been revolutionized with the advent of tyrosine kinase inhibitors targeting BCR-ABL1, monoclonal antibodies targeting CD20 (rituximab), antibody-drug conjugates targeting CD22 (inotuzumab ozogamicin), bispecific antibodies (blinatumomab), and CD19 chimeric antigen receptor T cell therapy (tisagenlecleucel). These highly effective new agents are allowing for novel approaches that reduce reliance on intensive cytotoxic chemotherapy and hematopoietic stem cell transplantation in first remission. This comprehensive review will focus on the recent advances and future directions in novel therapeutic strategies in adult ALL.

Screening Strategies for COVID-19 in Patients With Hematologic Malignancies.

COVID-19 has been declared a pandemic by the world health organization. Patients with cancer, and particularly hematologic malignancies may be at higher risk for severe complications due to their malignancy, immune dysregulation, therapy, and associated comorbidities. The oncology community has been proactive in issuing practice guidelines to help optimize management, and limit infection risk and complications from SARS-COV-2. Although hematologic malignancies account for only 10% of all cancers, their management is particularly complex, especially in the time of COVID-19. Screening or early detection of COVID-19 are central for preventative/mitigation strategy, which is the best current strategy in our battle against COVID-19. Herein, we provide an overview of COVID-19 screening strategies and highlight the unique aspects of treating patients with hematologic malignancies.

Clinical Characteristics and Outcomes of Caribbean Patients With Adult T-Cell Lymphoma/Leukemia at Two Affiliated New York City Hospitals.

PURPOSE: Adult T-cell lymphoma/leukemia (ATL) is a rare and aggressive peripheral T-cell malignancy caused by human T-cell lymphotropic virus-1 infection, which occurs in areas of high prevalence, predominantly in Japan and the Caribbean basin. Most ATL literature is derived from Japan and little is published about Caribbean patients. We describe the clinicopathologic characteristics and treatment outcomes of our Caribbean patients who have ATL at the State University of New York Downstate Medical Center and Kings County Hospital. PATIENTS AND METHODS: We conducted a retrospective analysis of our patients with ATL who were diagnosed between 2005 and 2017. Medical records were reviewed for clinicopathologic data and treatment outcomes. The final analysis included acute and lymphomatous subtypes only. For the univariable analysis, outcomes were calculated by using a log-rank test, and survival curves were estimated by the Kaplan-Meier method. RESULTS: We identified 63 patients with acute (55%) and lymphomatous (45%) subtypes, 95% of whom had Ann Arbor stage III to IV disease. The median age was 54 years, and the study population was predominantly female (65%). Most patients (82%) received first-line etoposide, cyclophosphamide, vincristine, doxorubicin, and prednisone (EPOCH) or cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) chemotherapy (10%) with an overall response rate of 46%. The median overall survival was 5.5 months, and the median progression-free survival was 4 months. Incidence of atypical immunophenotype (32%) was higher than previously reported in the Japanese literature and was associated with worse survival (P = .04). Abnormal cytogenetics correlated with shorter progression-free survival (P < .05). CONCLUSION: We describe here the clinicopathologic characteristics and treatment outcomes of our Caribbean patients with aggressive ATL, which is largely chemotherapy resistant, and the challenges of treating a population with unmet medical needs.

Characteristics and outcomes of patients with therapy-related acute myeloid leukemia with normal karyotype.

Normal karyotype in therapy-related acute myeloid leukemia (t-AML) is rare and the relative contribution of prior exposure to chemotherapy or radiotherapy to outcomes in these patients remains uncertain. We performed a retrospective study of 742 patients with newly diagnosed AML and normal karyotype (t-AML, n = 61, and non-t-AML, n = 681). Patients with t-AML were older but had a similar mutational profile compared to those with non-t-AML. Overall survival (OS) and relapse-free survival (RFS) were significantly worse for patients with t-AML (P < 0.01 and P = 0.02, respectively). Patients with t-AML had a higher cumulative incidence of death in remission (51% versus 16%, P < 0.01), but not higher cumulative incidence of relapse (42% versus 56%, respectively, P = 0.21). Both intensive induction and allogeneic hematopoietic stem cell transplantation in first remission were associated with improved OS and RFS in non-t-AML but not in t-AML. Overall, although disease biology appears similar between t-AML and non-t-AML with normal karyotype as indicated by similar risks of relapse, death in remission is the main driver of inferior outcome in t-AML. Careful therapeutic decisions are required to mitigate potential treatment-related toxicity in this rare subgroup of patients with t-AML and normal karyotype.

An Exceptional Responder to Nivolumab in Metastatic Non-Small-Cell Lung Cancer: A Case Report and Literature Review of Long-Term Survivors.

BACKGROUND: Exceptional responders to immune checkpoint inhibitors in metastatic non-small-cell lung cancer (NSCLC) are rare. Furthermore, the optimal duration of immunotherapy in patients who achieve complete remission and the benefit of rechallenge after recurrence remain unknown. Studying the clinical course of exceptional responders can help identify potential predictors of response to immunotherapy and further fine-tune our management algorithms in the absence of standard of care in challenging scenarios. CASE PRESENTATION: We highlight the case of a 73-year-old Vietnam War Veteran with active tobacco dependence who achieved complete response with nivolumab for metastatic NSCLC after four prior lines of chemotherapy. Nivolumab was discontinued after 10 cycles due to immune-mediated hepatitis that resolved with steroids. He remained in complete remission for 14 months while off therapy. Then, his tumor recurred twice locally in the mediastinum and he again achieved complete and durable responses after each recurrence with radiotherapy. Due to recurrence in both lungs one year later, he was rechallenged with nivolumab and achieved partial response after two months of therapy. He continues to do well five and a half years since his initial diagnosis of de novo metastatic NSCLC. CONCLUSION: Optimal management of exceptional responders to immune checkpoint inhibitors in metastatic NSCLC is largely unknown. Our case report adds to the limited data supporting the use of localized therapy for oligometastatic recurrences and rechallenge with immunotherapy for widespread disease in achieving disease control and long-term survival.

Screening Colonoscopy Unmasking Colonic Metastasis from an Occult Breast Ductal Carcinoma: A Case Report and Review of the Literature.

Metastatic spread from breast cancer to the gastrointestinal tract is rare. Such cases are predominantly lobular carcinomas and they usually occur later on during the course of disease progression with the stomach being the most common site involved. Furthermore, occult breast primary tumor is extremely uncommon. To the best of our knowledge, we describe here the first case of incidental colonic metastasis as first presentation of an occult breast ductal carcinoma. We also provide a review of the literature on gastrointestinal-and specifically colonic-involvement from breast ductal carcinoma.

Doxorubicin-associated takotsubo cardiomyopathy in a patient with adult T-cell leukemia/lymphoma.

This case highlights the first reported association of doxorubicin with takotsubo cardiomyopathy (TC) presenting as cardiogenic shock during the first continuous infusion in a patient with adult T-cell leukemia/lymphoma. We aim to raise awareness to recognize and distinguish between irreversible doxorubicin-associated cardiomyopathy and reversible doxorubicin-associated TC in patients with cancer.

Checkpoint inhibitors in head and neck cancer: current knowledge and perspectives.

The emergence of immunotherapy has provided significant clinical improvements in the treatment of metastatic solid tumors. Recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) has dismal prognosis with median survival ranging between 6and12 months. Our aim is to review the current knowledge on the role of the immune system and immune checkpoint inhibitors in HNSCC. We will focus on the landmark trials that led to the regulatory approvals of pembrolizumab and nivolumab, and discuss a few promising contenders in clinical development and highlight the need to identify better biomarkers other than programmed death-ligand 1 to improve patient selection and help predict response.

Primary Pulmonary Hodgkin's Lymphoma: A Rare Etiology of a Cavitary Lung Mass.

Primary pulmonary Hodgkin's lymphoma (PPHL) is an uncommon disease. This entity is different from Hodgkin's lymphoma with parenchymal or nodal lung involvement. In this report, we highlight the case of a young female presenting with a six-month history of a productive cough and constitutional B symptoms. Imaging showed cavitary lesions in the right-upper and right-middle lobes. The initial comprehensive infectious workup was negative. Histopathology and immunochemistry confirmed the diagnosis of PPHL. PPHL is an uncommon etiology of cavitary lung lesions. Despite its diagnostic difficulties, awareness of such a disease is crucial, given its high rate of response to treatment, especially in the young population.

Anti-PD-1/PD-L1 antibodies in non-small cell lung cancer: the era of immunotherapy.

INTRODUCTION: Advanced non-small cell lung cancer (NSCLC) has been conventionally treated with cytotoxic chemotherapy with short-lived responses and significant toxicities. Monoclonal antibodies to programmed death-1 receptor (PD-1) and programmed death ligand 1 (PD-L1) have shown tremendous promise in the treatment of advanced NSCLC in various clinical trials. Areas covered: In this article, we will review the outcomes of various trials of anti-PD-1/anti-PD-L1 antibodies in the treatment of NSCLC. We will also discuss their mechanism of action and toxicities. Expert commentary: Anti-PD-1/PD-L1 antibodies offer several advantages including significant antitumor activity, induction of long lasting responses, and favorable safety profile. Several trials are now being conducted to evaluate their efficacy as first line agents as well as in combination with other agents. More research is also needed to identify other biomarkers, in addition to PD-L1 expression, that could more reliably predict response to these drugs, and aid in better patient selection.

Idiopathic Hemophagocytic Lymphohistiocytosis During Pregnancy Treated with Steroids.

Hemophagocytic lymphohistiocytosis (HLH) is a rare and severe clinical syndrome characterized by a dysregulated hyperinflammatory immune response. The diagnosis of HLH during pregnancy is especially challenging due to the rarity of this condition. The highly variable clinical presentation, laboratory findings, and associated diagnoses accompanying this syndrome further complicate the problem. A pronounced hyperferritinemia in the setting of systemic signs and symptoms along with a negative infectious and rheumatological workup should raise suspicions for HLH. While treatment ideally consists of immunosuppressive chemotherapy and hematopoietic stem cell transplant, the potential toxicity to both the pregnant woman and the fetus poses a challenging decision. We report the first case of idiopathic HLH presenting as fever of unknown origin in a pregnant woman successfully treated with steroids.