ALL & Lymphoblastic Lymphoma

Acute Lymphoblastic Leukemia (ALL) & Lymphoblastic Lymphoma

Disclaimer

The chemotherapy protocol-specific suggestions herein are for patients who are not on a clinical trial (see Patients on a Clinical Trial section     ). The aim is to provide a forum for the exchange of information concerning interactions between the evolving COVID-19 pandemic and ALL/LBL therapy and supportive care.  They are dependent on the local epidemiology of the COVID-19 infection. We have tried to conduct a substantive review of each item recommended, but we also know that the state of the science during the pandemic is dynamic. It remains the responsibility of the patient’s medical professional to decide on the appropriate medical advice, diagnosis, and treatment for patients. For patients on clinical trials, the Study Chair must be consulted before deviation from the protocol.

 

During the COVID-19 pandemic, the suggestions will be updated every few days, with the version dated for reference. Check the suggestions frequently in case they have changed.

 

Also, assist us by identifying information that has been particularly helpful so that we might more prominently feature it, as well as any information that is inaccurate, outdated or inappropriate so that we can remove it.  The FAQs pull-down menu on the homepage has a field at the bottom to submit questions and comments.

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Background & Rationale

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Frontline Therapy

    -Pediatric Regimen

    -Hyper-CVAD

Relapse / Refractory

    -Stem Cell Trans.

    -Immunotherapy

    -Phase I & II       

 

    -Chemotherapy

    -Off Therapy

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Background & Rationale

The global COVID-19 pandemic has required unprecedented changes in healthcare delivery. The evolution is so dynamic that this background description, as of April 21, 2020, must be updated with new information when reviewed.

Rationale 

A report from a hematology ward in Wuhan (1) describes 4 patients with ALL of ages 14,27, 31, and 35 who developed COVID-19 infection the week after chemotherapy-induced neutropenia. The 14 year-old (T-ALL) and 31 year-old (B-ALL) died with respiratory failure and DIC. In addition, 1 physician and 5 nurses 22-37 years of age (all AYAs) on the ward developed and were documented to have COVID-19. With one exception of bacterial super-infection, all of the healthcare providers recovered completely. The authors concluded that “extreme measures to protect hematological patients from COVID-19 are required, and postponing of chemotherapy for stable blood cancer patient(s) should be considered in endemic areas.”

 

A report from Memorial Sloan Kettering Cancer Center describes children with cancer in general who were of mean [SD] age 11.1 [8.5] years as not having a worse outcome, with only 5% of symptomatic patients having been hospitalized (2). The authors concluded that pediatric patients with cancer may not be more vulnerable than other children to infection or morbidity resulting from Covid-19. Andrew Kung, MD, Chair of the Department of Pediatrics, provided additional information about 42 of their patients on active treatment for ALL, of which 7 tested positive for Covid-19. Of those, 5 were >14 years of age, and none required hospitalization for Covid-19 symptoms.  He added that the numbers were too small to allow any conclusions either about infectivity or symptomatology.

 

Thus, AYAs (age 15-39) treated with chemo- and/or immunotherapy are at greater risk both for acquiring COVID-19 and may more likely die of it than their malignancy.  Their risk is greater than in children since they are:

  1. Diagnosed to have "high risk" ALL/lymphoblastic lymphoma and receive more intensive therapy;

  2. Hospitalized more often and have more clinic visits

  3. Older, and therefore at higher risk of severe COVID-19 infection and death and, by virtue of age alone, of severe COVID-19 infection and death;

  4. Older, more mobile (even with shelter-in-place), more exposed to COVID-19 sources, and therefore at higher risk of infection.

Information Sources and Contributors (Figs. 3-5    )

These suggestions for AYAs 15 to 39 years of age are recommended by AYA leukemologists (3) and reviewed by pediatric oncologists (4). They are also based on recommendations provided for adults with ALL by the American Society of Hematology (ASH) (5) and other oncology organizations (6,7). The primary protocols on which they are based are those of the Alliance (A041501 and its precursor, C10403, Children’s Oncology Group (COG) AALL1732 (high risk), AALL1631 (Ph+), and their precursors, hyper-CVAD and mini-hyper-CVD.

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Number of Patients Potentially Affected 

As shown in Figure 4      , as many as 850 patients with ALL who are not on clinical trials may be affected by the pandemic, of whom ~650 are on Maintenance phase of treatment (Fig. 5      ). If AYA patients being treated for refractory or relapsed ALL who are not on a clinical trial are included, the estimate is >1,000.

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Summary 

For each of the phases of treatment, consideration was given to which therapy can be delayed, withheld, modified or incorporate new elements to reduce vulnerability to virus acquisition or severity of infection.  The overall intent is to:

  • Apply the suggestion to the type of ALL/LBL therapy (pediatric, hyper-CVAD, immunotherapy regimen, relapse regimen) and the phase or treatment, include off-treatment and in follow-up.

  • Enable as much indicated and planned primary therapy as possible

  • Reduce/eliminate as many clinic and hospital visits as possible

  • Enable blood tests and chemotherapy at home, whenever feasible

  • Reduce the likelihood of fever and neutropenia (F&N) and need for rapid evaluation and institution of intravenous antibiotics, episodes of which frequently occur in ALL/LBL patients on chemotherapy.

  • Reduce/delay the most immunosuppressive components of therapy (e.g., type and duration of corticosteroid)

 

Reminder - Application of these suggestions is dependent on the:

  • Prevalence of COVID-19 in the patient’s community and associated risk of COVID-19 infection.

  • Duration of COVID-19 endemically, since the treatment suggestions are for temporary consideration.

  • Age of the patient being AYA, since children with ALL/LBL have not been reported to have died of COVID-19 and AYAs have.

  • Non-clinical trial status of the patient (cf. Clinical Trials).

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Frontline Therapy

 

Pediatric Regimen

Induction: (as posted by ASH, v1.0, April 6) (Figure 6)

  • Testing for SARS-CoV-2 is recommended before initiating intensive chemotherapy, irrespective of symptoms. If patient is SARS-CoV-2 positive, delay systemic treatment although IT therapy may be given if CNS symptoms are present. If SARS-CoV-2 testing is not available, careful symptom screening and a chest CT scan may indicate need to delay induction.

  • Ph- patients: Most centers are proceeding with standard curative induction therapy because delay is associated with very poor outcomes.

  • Steroids: Most agree their use should be minimized (e.g. anti-emetic therapy), albeit they are a crucial element of initial therapy.

  • Patients at high risk for complications: Dose reducing daunorubicin  (50%) or pegaspargase (e.g. 1000 Iu/m2).

  • Once all induction chemotherapy has been administered, one could consider use of G-CSF to facilitate count recovery.

  • Consider keeping patient hospitalized until count recovery if the inpatient environment is safer than frequent clinic visits.

  • Ph+ Patients: a TKI with minimal steroid exposure is favored over aggressive multi-agent chemotherapy for initial treatment, thereby avoiding prolonged hospitalization during the pandemic.

 

Consolidation: (as posted by ASH, v1.0, April 6) (Figure 6)

  • Intensive post-remission therapy is critical for cure and should be initiated without delay, with some modifications.

  • Cytarabine (araC): Subcutaneous or IV cytarabine may be prepared by pharmacy for home administration on Days 2-4, 9-11, 30-32,37-39 (Fig. 6).

  • Rituximab:  Some feel that it should be given with monitoring of IgG levels and replacement.

  • Consider G-CSF at the end of consolidation and delayed intensification courses to minimize periods of neutropenia.

Interim Maintenance: (Figure 6)

  • 2nd dose of pegASNase on day 22 may be omitted since nearly all patients still have asparagine depletion from the 1st dose on day 3, 4 or 5.

  • Since asparagine depletion inhibits MTX effect, MTX dose #2 can be omitted, as well as dose 3 but IV vincristine is due that day.

Delayed Intensification: (Figure 6)

  • Since this phase is re-induction and re-consolidation, see Induction and Consolidation

Second Interim Maintenance: (in some protocols)

  • Interim Maintenance II may be delayed until the local COVID-19 surge subsides.

  • Meanwhile, apply standard Maintenance.

  • Cf. suggestions for Interim Maintenance I.

Maintenance: (Figure 7)

  • Defer vincristine pulses and IT MTX until local COVID-19 surge subsides [also eliminates clinic visits].

  • Missed vincristine pulses can be replaced in patients on q12 week pulses by administering them q4 weeks; In patients on q 4 week vincristine pulses, add them to end of Maintenance.

  • Missed IT MTX doses can be replaced when delayed vincristine pulses are administered.

  • If starting 6MP, begin at 50% dose for 1 month and increase by 25% according to ANC etc. thereafter until COVID-19 risk abates.

  • Continue 6MP po qD and MTX po qwk but use higher ANC (e.g. ~1.0) for dose adjustment

  • Some preliminary laboratory evidence suggests that 6MP can inhibit SARS-CoV (8); continuing 6MP at full dose and on schedule; preference for decreasing antimetabolite when ANC warrants should be given to MTX.

  • Send oral medications (6MP, MTX, corticosteroid) to patient’s home.

Hematopoietic Transplantation: (as posted by ASH, v1.0, April 6)

  • For patients with high-risk ALL, individualized decision-making regarding transplantation is necessary, balancing the risks of the transplant/COVID-19 against the risk of death from ALL.

 

Hyper-CVAD / Mini-hyper-CVD

  • For all phases administer GCSF if patient is severely neutropenic (ANC <0.5) and expected to be severely neutropenic for several days.

  • Consider prophylactic oral antibiotics during severe neutropenia to decrease risk of bacteremia

  • If F&N, test for SARS-CoV-2

Induction/Cycles A-B:

Switch to pediatric regimen, to reduce/avoid:

  • Hospitalizations for every course of therapy during 1st 8 months,

  • in contrast to the pediatric regimen for which there is no inpatient therapy (9).

  • High  rate of readmission for F&N, which is uncommon with the pediatric regimen (10).

  Otherwise:

  • Use mini-hyper-CVD for Induction (Fig. 8     )

  • If most regularl hyper-CVAD A-B cycles are completed, consider starting Maintenance

  • Transfer to mini-hyper-CVD (Fig. 8     ) if MRD negativity achieved.

  • Rituximab: monitor IgG levels prior to each cycle and administer as indicated, albeit the exposure in clinic increases for nurses and other patients during the infusion.

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Consolidation (CNS):

  • If CrRT scheduled, delay [5 days/week hospital visits x2 weeks] until COVID-19 subsides.

Maintenance:  (Fig. 9    )

  • Use mini-hyper-CVD intensification

  • Continue 6MP po qD and MTX po qWk but reduce CBC/LFT monitoring

  • D/C after 18 months of Maintenance, with blinatumomab or inotuzumab supplementation before earlier termination.

  • Some preliminary laboratory evidence suggests that 6MP can inhibit SAR-CoV (8).  Continuing 6MP at full dose and on schedule.

  • Preference for decreasing antimetabolite when ANC warrants should be given to MTX.

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Second Line Relapse / Refractory Therapy

Stem Cell Transplantation: 

  • Individualized decision-making regarding HSCT is necessary, balancing the risks of the transplant/COVID-19 against the risk of death from ALL/LBL. 

  • If HSCT is conducted, the patients should:

    • Have donor onsite before starting HSCT (NMDP recommendation).

    • A backup donor should be available.

    • Be confined to a laminar air floor room and discharge delayed until clinic visits can be minimized.

Immunotherapy: (anti-PD-1/PDL-1, CAR-T [including CAR-NK], CDK4/6 checkpoint inhibitors)

  • For B-ALL: Avoid hospitalization by using inotuzumab or transitioning blinatumomab to outpatient if possible; blinatumomab is better tolerated.

  • For T-ALL: Nelarabine/nelarabine-based regimens may be given as usual, with minimization of clinic visits and blood specimens for monitoring obtained at home.

  • Patients who achieve CR2 should be considered for allogeneic transplant expeditiously despite the pandemic.

  • CAR-T therapy: Proceed for patients who are likely to respond better to than chemotherapy.

Phase I or II Chemotherapy: 

  • CAR-T is preferred over chemotherapy, if feasible.

  • Select protocol with fewer clinic visits and hospitalizations.

Chemotherapy Interactions with Potential COVID-19 Prophylactic or Therapeutic Agents (11): 

  • Hydroxychloroquine: Does not interact with MTX or 6MP

  • Hydroxychloroquine may interact with other QTc-prolonging agents such as levofloxacin.

  • If levofloxaxin is used as prophylactic oral antibiotic during periods of severe neutropenia ,the decision to use hydroxychloroquine should include this risk

  • Remdesivir: Its hepatoxicity could increase antimetabolite hepatotoxicity.

  • Lopinavir/ritonavir (Kaletra)

  • Can increase vincristine levels (Grade D interaction); vincristine reduction apropos.

  • Can increase MTX concentration and increased need to monitor CBC/LFTs.

  • Not known to interact with 6MP, daunorubicin, or pegASNase.

Off Therapy: 

  • If <3 months off therapy, proceed with MRD monitoring for relapse.

  • If >3 months off therapy, delay/cancel routine scheduled follow-up clinic visits until local COVID-19 risk abates.

  • For MRD monitoring, use blood Clonoseq, preferable at home, instead of bone marrow aspiration in clinic.

  • Call attending oncologist or survivorship clinic if any concerns; can arrange video-conferencing with health care professionals.

 
 
 

  1. Wu Y, Liu F, Fang Y, Lu X, Wu Y, Xia L, Hong M.  A report of clustered COVID-19 in a hematology ward. Blood Advances. In Press.

  2. Boulad F, Kamboj M, Bouvier N, Mauguen A, Kung AL. COVID-19 in Children With Cancer in New York City [Research Letter]. JAMA Oncol. 2020 (May 13); doi: 10.1001/jamaoncol.2020.2028

  3. Dan DeAngelo, Wendy Stock, Bijal Shah, Anjali Advani, Martha Arellano, Nicola Gὃkbuget, Hagop Kantarjian, Caitlan Rausch, Archie Bleyer,Stuart Siegel

  4. Jennifer McNeer, Stacy Cooper, Archie Bleyer, Linda Stork, Paul Gaynon, Mignon Loh, Vincent Giusti, Scott Howard, Stuart Siegel,2. Kjeld Schmiegelow, Ron Louie

  5. COVID-19 and ALL: Frequently Asked Questions, with Input from Wendy Stock, Anand Patel, Kristen O’Dwyer, Renato Bassan, Xianfeng Zhou, Xiao-jun Huang, Mark Litzow, Elias Jabbour, Dan DeAngelo, Selina Luger, Nicola Gokbuget, Richard Larson, and Jacob Rowe. www.hematology.org/covid-19/covid-19-and-all

  6. Ueda M, Martins R, Hendrie PC, et al. Managing cancer care during the COVID-19 pandemic: Agility and collaboration toward a common goal. J Natl Compr Canc Netw. 2020 Mar 20:1-4 https://jnccn.org/view/journals/jnccn/aop/article-10.6004-jnccn.2020.7560/article-10.6004-jnccn.2020.7560.xml

  7. Benoit You B, Ravaud A, Canivet A. et al.  The official French guidelines to protect patients with cancer against SARS-CoV-2 infection.Lancet Oncology   Published March 25, 2020 https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(20)30204-7/fulltext

  8. Chen X, Chou CY, Chang GG. Thiopurine analogue inhibitors of severe acute respiratory syndrome-coronavirus papain-like protease, a deubiquinating and deISGylating enzyme. Antiviral Chem Chemother.  2009;19:151-6.

  9. The exception is HDMTX if used during Interim Maintenance I and which can be switched to the outpatient MTX/ASNase regimen, as per A01450 and C10403 and recommended.

  10. Douer D, DeAngelo DJ, Advani A, et al. Applying pediatric therapeutic strategies to adults with  acute lymphoblastic leukemia and lymphoma. II. Comparison with adult treatment regimens, including hyper-CVAD. Amer Oncol & Hemat Rev 2014:47-53.

  11. COVID-19 and ALL: Frequently Asked Questions. Reference #9   www.hematology.org/covid-19/covid-19-and-all