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Table of Contents

Original ArticlesOptimal Management of Acute Lymphoblastic Leukemia (ALL) in Adult Patients During the Novel Coronavirus Disease 2019 (COVID-19) Pandemic ...........................................................................................................................07Ahmad Alhuraiji, Saleem Eldadah, Feras Alfraih, Ramesh Pandita, Ahmad Absi, Amr Hanbali, Mahmoud Aljurf, Riad El Fakih

Combined Intraoperative Radiotherapy (IORT) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) with Cytoreduction Surgery (CRS) as a Novel Approach in the Management of Resectable Pancreatic Cancer ....................................19Ayman Zaki Azzam, Tarek Mahmoud Amin

Peritoneal Carcinomatosis of Colorectal origin in Cyclosporine Immunosuppressed Rats .....................................................................27Elie Rassy, George Hilal, Viviane Track-Smayra, Joseph Kattan, Riad Sarkis, Aline Khazzaka

A Comparative Study of Uninterrupted Treatment by Radiotherapy versus Standard Gap Correction after Interruptions in Oropharyngeal Cancer .............................................................................................................................................31Satya Narayan, Neeti Sharma, Sweta Soni, Rajkumar Niwan

The Frequency and Specific Features of Rare Epidermal Growth Factor Receptor Mutations in Moroccan Patients with Lung Adenocarcinoma whose Tumors harbor positive EGFR mutations ..........................................................40Hind El Yacoubi, Mohamed Lemine Sow, Meryem El Ghouti, Fouad Kettani, Lamia Gamra, Amina Mestari, Lamia Jabri, Ibrahim Elghissassi, Hassan Errihani

Dosimetric Evaluation and Comparison Between Volumetric Modulated Arc Therapy (VMAT) and Intensity Modulated Radiation Therapy (IMRT) Plan in Head and Neck Cancers ..............................................................................45Murugaiyan Nagarajan, Ramesh Banu, Balraj Sathya, Thangavel Sundaram, Thirumalai Palanichamy Chellapandian

Mode of Presentation of Laryngeal Cancer: A Single Radiotherapy Institute Experience in Iraq ............................................................51Shkar Othman Arif, Yousif Ibrahem Al Chalabi, Hiwa Asaad Abdul Kareem, Karzan Marif Murad, Jalil Salih Ali, Sazgar Star Majeed, Shwan Ali Mohammed, Nyan Othman Saeed, Bamo Mohammed Muhsin, Ayah Said, Layth Mula-Hussain

Factors Affecting Survival in Glioblastoma: A 10-year Single-Center Experience from Saudi Arabia ...................................................58Abdullah Azab, Nasser Alsayegh, Omar Kashkari, Suliman Hanbazazah, Yazid Maghrabi, Fahad Alghamdi, Rolina Al-Wassia, Saleh S. Baeesa

Prognostic Impact of Alpha Fetoprotein at Diagnosis on Overall Survival of Single Small Hepatocellular Carcinomas ........................64N. Lahmidani, FZ. Hamdoun, M. Lahlali, H. Abid, M El Yousfi, DA .Benajah, M. El Abkari, SA. Ibrahimi

Clinical Outcomes of Head and Neck Cancer Patients Treated with Palliative Oral Metronomic Chemotherapy at a Tertiary Cancer Center in Kerala, India .......................................................................................................................68Vinin NV, Geetha Muttath, Joneetha Jones, Kalpita Shringarpure, Karthickeyan Duraisamy, Vanitha Priya Deenathayalan, Priya Rathi

Case ReportPrimary Squamous Cell Carcinoma of the Trachea: Two Cases Report ....................................................................................................75Amany Hussein, Khaled Al-Saleh, Mustafa El-Sherify, Hamdy Sakr, Jitendra Shete, Marwa Nazeeh

Bilateral Vocal Cord Immobility After Chemoradiotherapy For Nasopharyngeal Carcinoma ...................................................................80Selvamalar Vengathajalam, Thevagi Maruthamuthu, Nik Fariza Husna Nik Hassan, Irfan Mohamad

Toxic Leukoencephalopathy: An unusual Presentation by 5-Fluorouracil Infusion .................................................................................84Virendra Kumar Meena, Punnet Pareek, Satya Narayan, Sweta Soni

Transformation of Grade I Follicular Lymphoma to Anaplastic Large Cell Lymphoma CD30+ ALK1 - with Complete Response to Brentuximab Vedotin and High-Dose Methotrexate ................................................................................87Mubarak Al-Mansour, Hatim Al-Maghraby, Bader Shirah

Conference Highlights/Scientific Contributions• News Notes .............................................................................................................................................................................................91

• Scientific events in the GCC and the Arab World for 2020 ...................................................................................................................95

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Abstract

The outbreak of coronavirus disease 2019 (COVID-19) has become a public health emergency of major international concern. In December 2019, an outbreak of atypical pneumonia known as COVID-19 was identified in Wuhan, China. The newly identified zoonotic coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is characterized by rapid human-to-human transmission. Acute lymphoblastic leukemia (ALL) patients are often in need for intensive chemotherapy to induce remission that will be complicated with prolonged period of cytopenias. They are often recalled to the hospital for treatment and disease surveillance. These patients may be immunocompromised due to the underlying malignancy or anti-cancer therapy. ALL patients are at higher risk of developing life-threatening infections. Several factors increase the risk of infection and the presence of multiple risk factors in the same patient is common.

Cancer patients had an estimated 2-fold increased risk of contracting SARS-CoV-2 than the general population. With the World Health Organization declaring the novel coronavirus outbreak a pandemic, there is an urgent need to address the impact of such pandemic on ALL patients. This include changes to resource allocation, clinical care, and the consent process during a pandemic. Currently and due to limited data, there are no international guidelines to address the optimal management of ALL patients in any infectious pandemic. In this review, we will address the potential challenges associated with managing ALL patients during the COVID-19 infection pandemic with suggestions of some practical approaches, focusing on screening asymptomatic ALL patients, diagnostic and response evaluation and choice of chemotherapy in different scenarios and setting and use of hematopoietic stem cell transplantation (HSCT).

Keywords: Coronavirus, COVID-19; Influenza, acute lymphoblastic leukemia; Pandemic, SARS-CoV-2

Original Article

Optimal Management of Acute Lymphoblastic Leukemia (ALL) in Adult Patients During the Novel Coronavirus

Disease 2019 (COVID-19) PandemicAhmad Alhuraiji1, Saleem Eldadah2, Feras Alfraih3, Ramesh Pandita1, Ahmad Absi2, Amr Hanbali3,

Mahmoud Aljurf3, Riad El Fakih3

1Department of hematology, Kuwait Cancer Control Center, Shuwaikh, Kuwait 2Adult Hematology/BMT, Princess Noorah Oncology Center, Ministry of the National Guard -

Health Affairs, Jeddah, Saudi Arabia. 3Adult Hematology and HSCT, Oncology Center, King Faisal Specialist Hospital and

Research Center, Riyadh, Saudi Arabia

Corresponding author: Ahmad Alhuraiji, MD, MRCP (UK), Department of Hematology, Kuwait

Cancer Control Center. Tel No.: +965 97594447. [email protected]

Introduction In December 2019, severe acute respiratory syndrome

(SARS) caused by corona virus (SARS-CoV-2) has been reported in Wuhan, China with a very high transmission rate that affected more than 200 countries in the world 1. The World Health Organization (WHO) has declared this novel virus to be a pandemic outbreak on March 12th, 2020 and it became an international public concern 2. The disease caused by SARS-CoV-2 called corona virus disease -2019 (COVID-19). Currently, there are more than 3 million people affected worldwide. To date, there are neither available vaccines nor treatments for COVID-19.

Patients with cancer especially those with hematological malignancies are at higher risk for infections due to their immunocompromised state, diseased- or chemotherapy-induced neutropenia and lymphopenia. In a nationwide report by Liang et al, COVID-19 has been reported to be associated with higher severe events and mortality in cancer patients than those without cancer, although the

Management of ALL patients during the novel coronavirus disease 2019 (COVID-19) pandemic, Ahmad Alhuraiji, et. al.

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sample size was small in this study 3. In hematological malignancies in particular, 64 cases reported at American society of hematology (ASH) Hub website infected with COVID-19 were likely to have a more severe disease (~30%) and higher mortality (~30%)4.

The optimal approach to patients with acute lymphoblastic leukemia (ALL) during COVID-19 is challenging and we will try to address the challenges in the treatment of ALL during COVID-19 pandemic focusing on optimal induction remission management in different scenarios, role of hematopoietic stem cell transplantation (HSCT), outpatient management during maintenance period and supportive care.

Screening for COVID-19 in asymptomatic ALL patients:

It is probably indicated to screen all newly diagnosed patients with ALL who are planned for intensive chemotherapy for COVID19 infection during COVID-19 pandemic 3. That is true especially for areas with high incidence of this novel viral infection. Screening is usually done through quantitative real-time polymerase chain reaction (qRT-PCR) testing of nasopharyngeal swap. If RT-PCR testing is not available one may consider baseline computerized tomography (CT) of the chest looking for signs of COVID-19 pneumonia which include ground glass infiltrates and consolidation or both 5-7. Some retrospective studies suggest higher incidence of severe complication and subsequent mortality in cancer patients infected with COVID-19 3, hence earlier identification of this infection is of paramount importance.

Given the above and under the current COVID-19 pandemic, we recommend the following:

• Screen all patients with ALL before intensive chemotherapy.

• Screening using RT-PCR of the nasopharyngeal swab.

Diagnostic workup of newly diagnosed ALL patients during COVID-19:

Patient with suspected diagnosis of ALL should have a full work up to confirm the diagnosis and to distinguish certain subtypes which would alter the treatment strategy8.

Bone marrow (BM) aspirate and biopsy should be done within 1-2 working days for full diagnostic work up with cytogenetics and molecular testing. The diagnosis of ALL is confirmed by the presence of >20% blasts in the peripheral blood and/or the bone marrow aspirate sample 9. Differentiation of T from B cell ALL depends on flow cytometric markers (CD19 in addition to other

B cell markers CD10, CD79a, CD22 in B cell ALL and cCD3 + with other T cell markers CD1a, CD4, CD5, CD7, CD8 in T cell ALL). During extreme situations and to save consumables, BM assessment might be omitted especially in patients with highly proliferative disease (high white blood cell (WBC) count with circulating blast) where we can do almost all acute leukemia workup from peripheral blood (PB).

Cytogenetics studies including conventional karyotype and fluorescent in-situ hybridization (FISH) help to distinguish Philadelphia (Ph) positive from Ph negative Precursor B ALL, which has important therapeutic implications. Additionally, cytogenetic studies help in baseline risk stratifications 10. Further work up includes molecular testing for Ph ALL and Ph like ALL and evaluation for NOTCH1/FBW7 /RAS/PTEN alterations in T-ALL. CT imaging is indicated in the work up for suspected extramedullary leukemic involvement. Central nervous system (CNS) evaluation by lumbar puncture is usually done early in induction course.

Cardiac evaluation using echocardiography or cardiac nuclear scan is recommended for all patients with ALL, since anthracycline is an important backbone of therapy11. During COVID-19 pandemic this can be omitted in young otherwise fit patients to minimize the exposure to other health-care professionals (HCP).

Pneumonia per se could present in ALL patients at diagnosis. Therefore, it would be rational to have a baseline CT chest before starting induction chemotherapy in ALL patients who are having respiratory symptoms. Additionally, in those patients with respiratory symptoms and fever, COVID-19 infection should be clearly ruled out before commencing subsequent intensive chemotherapy.

Under the current COVID-19 pandemic, we recommend the following:

• Follow the usual ALL diagnostic workup .

• Bone marrow examination might be omitted if the patient has a high white cell count (WBC) with circulating blasts.

• Cardiac evaluation might be omitted especially for young fit patients without co-morbidities.

• A baseline CT chest and nasopharyngeal swab for SARS-CoV-2 by RT-PCR for patients with respiratory symptom.

Frontline induction therapy:

The treatment landscape for adult ALL patients changed significantly in the last decade with the adoption of pediatric-inspired chemotherapy protocols to treat adult patients, embracing new prognostic tools,

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introducing new immunotherapies and identifying new ALL-subtypes 12-14.

ALL is a chemosensitive disease and complete remission (CR) rates above 90%, both with pediatric and adult-type therapy protocols, are universally achieved 12,14-17. Multiagent chemoimmunotherapy and CNS directed therapies are the backbone of therapy. During the intensive phase of therapy (induction, consolidation and intensification) the pediatric-inspired protocols use less myelosuppressive agents and rely more on corticosteroids, vinca-alkaloids and asparaginase with short treatment-free periods, as compared to the use of more myelosuppressive agents and longer treatment-free periods to allow recovery in the adult type protocols. The intensive phase is usually followed by a long maintenance period in both types of protocols 12-14,16,17. Additionally, the adult type therapy protocols rely heavily on HSCT for consolidation 18. These protocols were never compared to each other in appropriately designed trials. Nevertheless, in adult patients with ALL, a 3-year disease free survival (DFS) is expected to be between 60 and 70% with pediatric regimen compared to 45 and 55% with an adult regimen 12,14,19-21. The outcomes of older patients (>55-year-old) however remain poor as compared to the young adults due to difference in disease biology, presence of comorbidities, poor tolerance to chemotherapy among other reasons. These patients account for around 30% of ALL cases and for 50% of deaths from ALL. They suffer from a higher induction death rate and higher morbidity and intensive care admission during the intensive phase of therapy. As a result, the expected 5-yr overall survival (OS) in this population is 10-20% 22-27. Studies also showed worse outcome with the use of intensive therapy in older but fit ALL patients 23,27. However, patients who were able to tolerate intensive therapy derived some benefit, although less than half of them were able to receive it 23,27. The expected CR rate is between 41% and 80% for patients older than 50 to 60 years, as compared to above 90% consistently for younger patients 26. Enrolling old patients on ALL clinical trials is rare with few exceptions. As a result, there are no established guidelines to make treatment decisions for older patients. When caring for these patients, the treating team should focus on minimizing the risk for early death while avoiding unnecessary attenuation of the treatment intensity.

Immune therapies, in the form antibodies, are a major breakthrough for the treatment of ALL patients. Using these therapies, researchers may decrease the intensity of therapy while preserving efficacy. The immunophenotype of the ALL blasts is different according to the age groups, 89% of older patients are expected to have a B cell phenotype as compared to 66% for young patients 28.

Currently three antibodies are commonly used in the treatment of ALL. Rituximab is a chimeric murine/human monoclonal IgG1 kappa antibody directed against the CD20 antigen, blinatumomab is a bispecific T-cell engager (BiTE) antibody that engages the CD19 on the surface of B-cell to the CD-3 on the surface of T-cell 29, and inotuzumab which is an antibody-drug conjugate against CD22 on the surface of B-cells. There are no antibodies approved for the treatment of T-cell ALL.

In patients younger than 60-years, rituximab showed significant improvement in the CR rate, EFS and OS in CD20+ ALL patients 30,31 and as a result rituximab is routinely added to the frontline treatment regimens of CD20+ ALL patients. The other 2 antibodies (blinatumomab and inotuzumab) are currently approved for relapsed/refractory ALL based on phase III randomized trials proving the benefit of these antibodies compared to standard of care 32,33. Compared to young patients, older patients (>65 years) receiving blinatumomab are expected to have similar response rate but higher neurotoxicity 34. Inotuzumab-treated older patients had similar CR duration as compared to younger patients, but risk of myelosuppression is higher 35. In the frontline setting, inotuzumab combined with low dose hyperCVD (cyclophosphamide, vincristine and corticosteroids) for older adults (median age 68 years) showed an overall response rate (ORR) of 98% with 100% minimal residual disease (MRD) negativity among responding patients. The 3-year PFS and OS rates were 87% and 70%, respectively, and these were better than the historical PFS and OS with the full dose hyperCVAD (cyclophosphamide, vincristine, adriamycin and corticosteroids). Grade 3 and higher adverse events were thrombocytopenia (79%), infections during consolidation (74%), transaminitis (19%), and hyperbilirubinemia (17%). Four patients developed veno-occlusive disease, and 2 died as a result 35. Blinatumomab is currently being investigated in the frontline setting in combination with shorter hyperCVAD course or as a single agent for induction followed by POMP (prednisone, vincristine, methotrexate and mercaptopurine) maintenance (SWOG S1318, NCT02143414).

The current pandemic of coronavirus has claimed many lives, with data emerging from China and other countries showing that cancer patients probably have an increased risk of complications and ICU admission. The number of cancer patients is small, and patients had different cancers and were in different phases of their therapy, however a significant number of the reported cases were ALL patients during intensive phase of therapy 36-38. Obviously, we cannot draw robust conclusions based on these reports, but it is reasonable to assume that patients with hematologic cancers are at a high risk of


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complications, as in many other types of infections. Firm conclusions will come from randomized, controlled trials but these are impractical to run in the setting of coronavirus pandemic. In these circumstances, the treating team has to make complex decisions based on reasoning and taking into account several factors. These include, but not limited to, curability of the disease, risk of the patient or caregiver to contract coronavirus infection, comorbidities, drug interactions, alternative therapies, availability of ICU beds, the functional capacity of the healthcare system, and the patient age. Philadelphia negative ALL is a curable disease. We recommend proceeding with standard induction with granulocyte colony-stimulating factor (G-CSF) and antimicrobial support in all young and fit patients. For older patients a strategy based on light-chemotherapy combined with antibodies is a reasonable approach. When using immunotherapies, we recommend checking immunoglobulin levels and to replace as needed. The use of corticosteroids is controversial as these were used to treat the coronavirus infection complications in several uncontrolled studies, however a recent meta-analysis reported them ineffective with prolonged virus clearing (role of corticosteroids in SARS-CoV-2, SARS-CoV and MERS-CoV infections. Huan et al., Leukemia, in press).

Finally, there is no one size fits all approach and induction therapy needs to be individualized based on local and patient’s condition. In the absence of solid data, we strongly recommend preventive measures to minimize the risk of infection.

During COVID-19 Pandemic, we recommend the following:

• Young (< 60 yrs) fit patients should receive standard induction regimens as induction mortality remains low.

• Old (≥ 60 yrs) unfit patients should receive low intensity chemotherapy with immunotherapy (+/- Rituximab +/- Inotuzumab ozogamicin)

• Use G-CSF routinely during induction therapy.

• Immunoglobulins levels should be monitored when using immunotherapy.

Special consideration for Philadelphia positive B-cell ALL

Ph-positive disease is rare in childhood ALL and increases gradually with advancing age constituting almost 50% of Pre-B ALL in adults 39. Historically, and prior to introduction of Tyrosine Kinase inhibitors (TKI), patients with Ph-positive ALL had a grim prognosis if treated with chemotherapy alone. Patients eligible for

allogenic stem cell transplant (allo-SCT) were offered this modality as a way to intensify therapy and, hopefully, achieve improved long-term survival and cure. This was shown in the LALA-94 study, which was conducted in the Pre-TKI era 40. In this study, patients who had donors and went on to receive allo-SCT had better OS outcomes than those who did not pursue transplant due to lack of a donor. Based on this study; allo-SCT continued to be considered as standard of care for allo-SCT -eligible patients even in the post-TKI era. Imatinib was the first TKI to be combined with traditional ALL type chemotherapy and it was clear that it induced better remission rates but with frequent relapses thereafter if patients were not consolidated with allo-SCT 41. The introduction of second-generation TKI’s improved the outcomes even further. One of the most used regimens to treat Ph-positive ALL is HyperCVAD-Dasatinib. A single-arm phase II study examined this regimen in 94 patients with newly diagnosed Ph-positive ALL 42. Patients received dasatinib at 100 mg or 70 mg daily in combination with chemotherapy for 8 cycles during an intensive phase, followed by dasatinib plus chemotherapy as maintenance therapy, or alloSCT for patients with an available donor. The OS rate at 3 years was 69% across the whole cohort, and the 3-year EFS rate was 55%, suggesting that patients who received dasatinib had a reasonably good outcome. The 12-month relapse-free survival rate in 41 patients who received a transplant was 83% 42.

Nilotinib was also combined with chemotherapy and had results to similar dasatinib but with different side effects profile 43.

The best results so far were reported with Ponatinib, which was evaluated in combination with hyper-CVAD in 76 adults with Ph-positive ALL in a single-center phase II trial 44. Ponatinib was dosed at 45 mg daily, subsequently reduced to 30 mg daily after a protocol amendment. Almost all patients achieved MRD negativity by flow cytometry, suggesting a very deep molecular response to this combination therapy. Of more importance, an impressive proportion of patients were alive at 3 and 5 years (76% and 71%, respectively), bringing into question the role of allo-SCT as a consolidation in this setting.

Another aspect of induction therapy for Ph-positive ALL has been the intensity of chemotherapy needed. It is always a matter of balancing the TKI side effects with those of chemotherapy and assuring continuous delivery of therapy. Only one clinical trial addressed this question directly. The GRAAPH-2005 trial evaluated the use of imatinib plus a lower intensity chemotherapy regimen versus imatinib plus a more traditional intensive induction regimen (Hyper-CVAD) 45. The lower intensity therapy was associated with less early mortality (0.7 versus 6.7

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percent) and a higher hematologic complete remission rate (98.5 versus 91.0 percent). Similar percentages of patients achieving major molecular response (MMolR) (66 versus 65 percent) and molecular complete remission (ie, absence of detectable BCR-ABL1) after cycle 2 (29 versus 23 percent. Finally; both arms had similar 5 years overall survival (48 versus 43 percent) and event-free survival (42 versus 32 percent) 45. This lower-dose chemotherapy approach will need to be followed by allo-SCT in eligible patients. Also, substituting imatinib by dasatinib may improve the results even further 46. It is worth to mention that Ph+ ALL patients who achieve early major molecular response (MMR) at 3 months will have good outcomes regardless if allo-SCT is performed or not 47.

Given the above and under the current COVID-19 pandemic, we recommend the following for treating patients with Ph+ ALL:

• The local center experience and familiarity factor is of utmost importance; therefore, it is advised to transfer ALL patients to centers with higher experience.

• Given the need to better allocate hospital resources and decrease the patients’ hospital stays; it is advised to use a second generation TKI with low dose chemotherapy and planning for an Allo-SCT in the future for eligible patients.

• Another approach for hospitals who have no issues with bed availabilities and who have good supply for blood products is to treat those patients with ponatinib-HyperCVAD in order to achieve the deepest response possible and for responding patients deferring the Allo-SCT in case they relapse.

Special consideration for response evaluation during COVID-19

End of induction assessment by bone marrow evaluation is essential in ALL management. Patients who don’t achieve CR at the end of induction have a grave prognosis 15. The aim of the initial ALL therapy is to complete remission with no detectable residual disease. MRD evaluation can be done by means of flow cytometry and/or molecular testing. It is well known that MRD is the most important prognostic marker in adult and pediatric ALL 48,49 and the earlier a deeper response is achieved, the better the outcome 50. There are different time points of MRD assessment depending on the protocol used at 4 weeks, 3 months and 6 months 51-54. During COVID-19 pandemic, from a cost effectiveness point view; it is recommended to limit MRD assessment to 3 months. Follow up CT imaging is indicated in patients with pneumonia to document radiological response before commencing subsequent courses of intensive chemotherapy.

During the COVID-19 pandemic, we recommend the following:

• Bone marrow assessment to document complete remission at day 21-28 post treatment.

• To limit the MRD assessment to 3 months’ time point during the course of therapy.

Special consideration for relapsed / refractory ALL (R/R ALL) during COVID-19

Despite high CR rate in ALL, relapse remains high (40-60%) which is associated with poor overall survival rate (<10%)55. The induction mortality rate during salvage or reinduction in the relapse setting is high reaching approximately 20% 32,56. Furthermore, elderly patients have poor tolerance to chemotherapy with higher early mortality 55. Novel immunotherapeutic approaches have revolutionized the treatment of R/R ALL 57. Without stem cell transplantation, the outcome of R/R ALL remains poor55.

The primary goal of therapy in the R/R ALL setting is to control the disease and achieve MRD negativity followed by stem cell transplantation. Use of novel immunotherapy has led to better CR rates with lower induction mortality rate.

Inotuzumab Ozogamicin has been tested as a single agent in 109 patients with R/R ALL in a phase 3 trial 56 resulted in 81% remission rate with 74% MRD negativity. Inotuzumab Ozogamicin with reduced intensity chemoimmunotherapy (miniCVD) 58 with reduced doses of cyclophosphamide, cytarabine, methotrexate and no anthracycline has been evaluated in phase 2 single center of 59 patients, 35 of them (59%) achieving complete response. The overall MRD negativity rate among responders was 82%. The early mortality was 12%. Veno-occlusive disease (VOD) has been observed (15%) in inotuzumab treated patients. Risk factors for VOD included older age and the use of dual alkylators during conditioning for HSCT.

A phase 3 randomized trial compared blinatumomab (n=271) to the chemotherapy (n=134) regimen of the investigator’s choice in patients with R/R ALL 32, the overall response rates were 45% and 30% (P = .007), respectively with higher MRD negativity rate in blinatumomab treated patients.

During COVID-19 pandemic, it would be reasonable to treat patients with novel immunotherapeutic approach incorporating inotuzumab ozogamicin or blinatumomab with minimal chemoimmunotherapy to minimize the rate of myelosuppression and induction-related mortality. All patients achieving complete remission (CR2) should proceed with allogenic HSCT without delay.


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During COVID-19 pandemic, we recommend the following:

• Given the high induction-related mortality in R/R ALL with standard chemotherapy to incorporate novel agents with reduced intensity chemotherapy.

• Patients achieving CR2, it is recommended to proceed with allogenic HSCT

Special consideration for hematopoietic stem cell transplantation (HSCT)

Despite the improvement in outcomes of ALL using pediatric inspired chemotherapy protocols, HSCT is still considered a standard of care in the management of a selected group of adult patients. The role of HSCT in ALL is directly related to both myeloablative chemoradiotherapy and graft versus leukemia effects. 8,59 Delaying necessary HSCT due to the COVID-19 pandemic might lead to harm for such patients. Hence, additional efforts are needed before proceeding for HSCT during such global crisis, including focused communications with patients and their caregiver to alleviate any anxiety about COVD-19 and ensuring the availability of stem cell product prior to start of the conditioning. American Society for Transplantation and Cellular Therapy (ASTCT) recommends cryopreservation of all related and unrelated stem cell donor products.60

HSCT centers should closely monitor and regularly assess their existing resources including, available inpatient and intensive care beds, essential medications stock and inventory of blood products upon each transplantation planning. Furthermore, COVID-19 has led to temporary reductions of the HSCT workforce as certain groups of healthcare professionals for example, above 60 years of age, pregnant or on immunosuppressive agents, were given a medical exemption from providing direct care for patients. 61 Implementation of robust infection and environmental control and staffs’ education are indispensable to avoid further reduction of workforce or disruption of services.

Currently, patients who will undergo HSCT should be screened for SARS-COV-2 using qRT-PCR specifically in areas with a high prevalence of COVID-19 before starting the conditioning regimen. 62 If the test is positive or the patient was in close contact with COVID-19 confirmed case, HSCT should be deferred for at least 14 days. HSCT donor also has to be screened for SARS-COV-2. If the test is positive, he/she is considered ineligible to donate for at least 28 days 60 . See HSCT algorithm for donor and recipient evaluation (Figure 1 & 2). Any patient who has a high-risk disease or in CR2 should proceed to allogenic HSCT. According to European Bone Marrow Transplant (EBMT) guidelines, if HSCT is considered standard of care (S) should be evaluated for HSCT if possible 63 (Table 1).

Post HSCT: patients, caregivers and health care providers shall take extra precautions and exceptional approaches to reduce the risk of COVID-19, like using telemedicine or home health care services to minimize patient visits to the hospital. HSCT patients who developed COVID-19 had dismal outcomes. 64

With all of the above, we recommend the following:

• Screen all donors and recipients for SARS-CoV-2 by qRT-PCR.

• Evaluate the HSCT urgency. If highly indicated especially in those with positive MRD, it is recommended to proceed with HSCT

• All eligible patients in remission should proceed to HSCT in CR2 if suitable.

Special consideration for supportive care during COVID-19

Expanding the use of G-CSF is recommended during COVID-19 pandemic to minimize risk of infections and shorten days of hospitalization. National Comprehensive Cancer (NCCN) recommended changing the threshold for the use of prophylactic G-CSF from only with high-

Disease Disease status MSD Allo

MUD Allo

MMAD Allo

Auto

ALL Ph (—), CR1 (standard risk and MRD—)a GNR/II GNR/II GNR/III C0/III

Ph (—), CR1 (standard risk and MRD+)a CO/II CO/II CO/Il GNR/Il

Ph (—), CR1 (high risk)a S/II S/II CO/Il GNR/III

Ph (+), CR1 (MRD—) S/II S/ll CO/Il CO/Ill

Ph (+), CR1 (MRD+) S/II S/II S/II GNR/II

CR2 S/II S/II S/II GNR/II

Relapse or refractory CO/II CO/II CO/Il GNR/III

GNR: Generally not recommended, CO: Clinical Options, S: Standard (Duarte et. al. EBMT 63).

Table 1. EBMT Recommendation 2019

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risk febrile neutropenia regimens (≥20%) to include also intermediate-risk regimens (≥=10%). Therapeutic use of G-CSF is recommended for all those who develop febrile neutropenia, not only for patients at a risk for complication. 65 Caution is required in using G-CSF in patients with suspected or confirmed COVID-19 to avoid the theoretical risk of increasing cytokines release syndrome. 66,67

In line with expected blood product shortages due to current health recommendations for social distancing, curfew and lockdowns, it is recommended to restrict red blood cells (RBC) transfusion to patients with hemoglobin levels below 7 g/dL 68 and platelet (PLT) transfusion to patients with platelet count of < 10 x109/L 69. Broadening the use of erythropoietin stimulating agents (ESA), thrombopoietin mimetics (e.g. romiplostim and eltrombopag)) and tranexamic acid at the lowest dose should be recommended during COVID-19 pandemic.

Caution is needed for the risk of thrombosis using these agents. Moreover, unnecessary platelet transfusion outside recommended practices should be avoided. 70

For antimicrobial prophylaxis, it is recommended to follow the protocol policy regarding antibiotic, anti-viral and antifungal. The use of standard approaches in the management of febrile neutropenic patient should be practiced. 65,71

With all of the above, we recommend the following:

• Use of G-CSF is recommended during intensive courses of therapy

• Restrict the RBC and PLT transfusion to patients with hemoglobin level of below 7 g/dL and PLT count below 10 x 109 /L respectively.

• Use of standard prophylactic antimicrobial during ALL therapy.

Figure 1. HSCT During COVID-19 Evaluation – Recipient

Figure 2. HSCT During COVID-19 Evaluation – Donor


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Special consideration for the outpatient setting during maintenance therapy

Maintenance therapy is given to all subtypes of ALL (with the exception of mature B-cell/Burkitt subtype) in order to reduce the chances of relapse. It has to be noted that no randomized clinical trials support the use of maintenance therapy in Adult ALL and that all data and practices referring to that component is extrapolated from pediatrics literature and from the fact that patients receiving shorter maintenance have a higher risk of relapse.

Typical maintenance in Adult ALL protocols consists mainly of mercaptopurine (6MP) and methotrexate (MTX) backbone with other medications being added to this depending on the protocol chosen, with the most commonly used being the POMP protocol (MP, MTX, Prednisolone, Vincristine and variable number of intrathecal therapies given for 2 years. Some groups prolong the maintenance duration beyond conventional 2 years of total treatment duration. In children, a meta-analysis of 42 trials showed that both prolonged maintenance therapy (3 years versus 2 years), as well as the use of pulses with vincristine and steroids, result in increased rates of death in remission but also in lower relapse rates 72,73. Also, the use of dexamethasone instead of prednisolone in maintenance therapy may lead to an increased incidence of infection deaths 74. On the other hand, the intensity of 6MP is also relevant since individuals with either homozygous or heterozygous thiopurine methyltransferase (TPMT) – deficient genotype does not tolerate typical 6MP doses and may suffer from severe myelosuppression. Many groups currently perform TPMT genetic testing looking for polymorphisms and adjust the dose appropriately given that 5% - 10% of the general population have intermediate enzyme activity 75,76.

Another practice that is extrapolated from pediatrics protocols is dose escalation targeting an intermediate level of myelosuppression since data has shown better outcomes for patients achieving myelosuppression compared to other with higher absolute neutrophils count (ANC) and typically 6MP dose is escalated in small increments to achieve ANC levels between 1.0 to 1.5 77.

With all the above we recommend the following:

• All AYA and adult patients with ALL should receive maintenance as part of the protocol.

• If the protocol calls for DEXA to be part of maintenance, we recommend replacing it with prednisolone and considering discontinuation of the steroids completely in patients with high risk for infections.

• For patients starting maintenance therapy and if no TPMT testing is performed to start with a dose that is

25% - 50% of the recommend dose and to increase it gradually with ANC monitoring with target ANC ~ 1.0 x 109 /L.

• Limit the maintenance to a maximum 2.5 years.

Special consideration for the optimal approach for neutropenic fever in ALL patients during COVID-19

Acute leukemia patients are at a higher risk of pneumonia during remission induction with estimated risk of 20%, mostly bacterial but viral causes accounts for 2-3% 78. Therefore, respiratory viruses including SARS-CoV-2 should routinely be included in the differential diagnosis of febrile neutropenia in leukemia patients. The rate of febrile neutropenia during salvage therapy for refractory ALL or re-induction for relapsed ALL is considerably high (40-50%) using standard chemotherapy while it is reduced by 50% using novel agents (blinatumumab or inotuzumab ozogamicin) 32,56.

Diagnostic algorithms for COVID-19 continues to evolve as emerging data is published. It is wise to avoid testing for SARS-CoV-2 using enzyme-linked immunosorbent assay (ELISA) serology for immunoglobulin (Ig) M and G as leukemia patients might not mount immune response owing to their underling disease or chemoimmunotherapy. qRT-PCR-based diagnostic nasopharyngeal swab for SARS-CoV-2 should routinely be performed. In the setting of negative initial test and persistent fever or respiratory symptoms, it is recommended to repeat the test 79. In patients with respiratory symptoms, routine chest x-ray (CXR) is recommended as part of initial evaluation according to the infectious disease society of America (IDSA) 71. High-resolution chest CT demonstrated pneumonia in more than one-half of persistently febrile neutropenic patients who had normal findings on routine CXR 80 and CT scan of chest may further supplement the diagnosis of COVID-19 79.

Use of GCSF in patients on intensive chemotherapy courses of therapy should be considered to minimize the duration of neutropenia 81. Empiric outpatient treatment for low risk stable cancer patient should be considered to maintain home isolation, minimize exposure via tele-medicine and by phone 82. However, patients with ALL are considered to be high risk patients and therefore, careful evaluation and admission to the hospital is needed. Empiric therapy with broad spectrum antibiotic is required as per IDSA and NCCN guidelines 65,71

With all the above we recommend the following:

• Serological testing should be avoided in ALL patients

• qRT-PCR of the nasopharyngeal swab for SARS-CoV-2 should be done routinely in ALL patients with febrile neutropenia.

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• In case of persistent fever or ongoing respiratory symptoms, it is wise to repeat the test if initial one was negative

• CT scan of the chest may complement the diagnosis of COVID-19 in ALL patients with febrile neutropenia.

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Figure 3. Optimal Approach to ALL Patients during COVID-19 Pandemic


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