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·Chemotherapy
• Leukemia mo
Leukosarcoma
WILLIAM DAMESHEK,MD
MARVIN L BLOOM, MD
LOUIS WEISFUSE,MD
MILTON H FREEDMAN, MD
MIGUEL LAYRISSE, MD
NEW ENGLAND CENTER HOSPITAL TUFTS COLLEGE MEDICAL SCHOOL
BOSTON, MASSACHUSETTS
A reprint of an exhibit presented at the
American Medical Association Convention
Atlantic City June 1949
Ces
PUBLISHED BY GRUNE & STRATTON NEW YORK

·Copyright 1950
by Grune & Stratton
New York
PRINTED IN USA

·PREFACE We know little about the fundamental mechanisms controlling cell growth We know less as to why certain body cells began to proliferate wildly The white cells of the blood forming tissues are also sub ject to neoplastic proliferation which is likely to be generalized even from the start Surgical extirpation is hardly ever possible, as in lo cal cancer Radium xray therapy and radio active materials have often proved disappointing The introduction of nitrogen mustard during the wor years resulted in a revival of interest in chemother apeutic methods, coinciding with an awakened interest in the finer histology and histochemistry of individual cells The past few years have witnessed some rather startling developments in the field striking remissions induced by nitrogen mustard in Hodgkin's disease and in some cases of generalized lymphosarcoma, sustained remissions induced by urethane in chronic myelocytic leukemia, modification by urethane of the abnormal marrow and serum protein picture in multiple myeloma and even temporary reversal, thru use of the folic acid antagonists, of the relentless trend towards death in acute leukemia If these accomplishments have occurred within a few years and with our relatively meager knowledge, is it too much to hope that as we know more, there will ultimately come control of our biggest problem in hematology, namely, that of leukemia? This little book, the outgrowth of an American Medical Association exhibit, expresses briefly some of our present-day knowledge in this field, in which much remains to be done

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·CHEMOTHERAPY OF LEUKEMIA & LEUKOSARCOMA
THE PREMISE Specific Chemicals kill Specific Cells
HN2
URETHANE
R-E
System
FOLIC ACID ANTAGONISTS
Bone
Marrow
re
Lymphoid
Tissue
THE HOPE Ultimate Control of Leukocytic Proliferations
Lies in Chemotherapy

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·LEUKEMIA AND LEUKOSARCOMA NEOPLASTIC PROLIFERATIVE DISEASES OF WHITE CELL TISSUES A CLASSIFICATION The Leukemias The Leukosarcomas (Leukoses) (Lymphomas) Generalized -- Localized Myelocytic (Myelogenous) Muelosarcoma Acute . Subacute (Chloroma) Chronic Very rare (Eosinophilic-Basophilic types very rare ) Lymphocytic (Lymphatic) Lymphosarcoma Acute Lymphoblast Sarcoma Subacute Lymphocyte Sarcoma Chronic Leukemia Cutis Giant Follicle Lymphosaroma Monocytic Reticulosarcoma Acute Reticulum Cell Sarcoma Subacute Hodgkin's Disease (rapid, "Sarcoma") Chronic Reticulo-endothelioma Hodgkin's Disease (slow,"Granuloma) Mycosis fungoides Plasmacytic (Multiple Myeloma) Plasmacytoma (Solitary Myeloma) The Leukemias (Leukoses) are either Leukemic or Aleukemic The Leukosarcomas, generally Aleukemic, may become Leukemic

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·LEUKEMIA AND LEUKOSARCOMA A SCHEMA Correlating Cell Growth Rate with Clinical Activity LEUKEMIAS LEUKOSARCOMAS GENERALIZED LOCALIZED CELL GROWTH RATE EXTREMELY RAPID "Acute "Blast" Sarcoma All cells primitive Nucleoli very prominent No differentiation Many Mitoses Fulminating course (1-8 wks) Highly Invasive hapid Marrow Involvement Widely Metastatic Anemia, Granulocytopenia Bone, Lungs, etc. Thrombocytopenia Bleeding CELL GROWTH RAPID "Subacute" "Blast-Cyte" Sarcoma Most Cells primitive Nucleoli fewer Some differentiation Fewer Mitoses Less Rapid Course Invasive (8 wks. - 1 yr. ) Metastatic Marked Marrow Involvement CELL GROWTH RATE RELATIVELY SLOW "Chronic" is "cyte" Sarcoma Most cells mature Few nucleoli Marked differentiation Few Mitoses Slow course (1-10 yrs.) Relatively benign Slow marrow involvement Slowly invasive

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·LEUKEMIA AND LEUKOSARCOMA ETIOLOGIC FACTORS Death rate for Leukemia shows sharp Increase. Is this better diagnosis? Actual increase? Both ? If actual increase, why ? Maybe it's Civilization. 5 GRUDE DEATH RATE 4 -FROM LEUKEMIA 1900-1944 Deon Rote Per 100,000 Population 0 1900 1910 1930 1920 Years 1940 SACKS POSSIBLE HAZARDS TO BLOOD FORMING TISSUES IN "CIVILIZED" LIVING SOME SPECULATIONS CHEMICAL EXPOSURE RADIATION EXPOSURE Medications: Sulfa Drugs, other Benzene Drugs Occupational: Radiologists Skin Lotions & Ointments X-ray technicians Phenol Tars Atomic energy personnel Unsupervised use of potent Growth Cyclotron workers Factors (vitamins, hormones) Too many Xray examinations Industry: Benzo! Xylol, Solvents X-ray Therapy: Thymus in infancy Farming: Insecticides, (Arsenic) :Skin Disease Roads. Tors, Gases Radio-Active Isotopes The Home: Lotions, Cosmetics, Atomic bombs Paint removers. Foods. Chemical Preservatives OTHER FACTORS: HEREDITY, INFECTION (VIRUSES ?) MAY BE IMPORTANT

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·LEUKOSARCOMA . LEUKEMIA AND LEUKOSARCOMA DIAGNOSTIC TRIAD 1. History: Fatigue, Fever, Night Sweats, Itching, Bleeding II. Examination •Neck: Lymph Nodes Head: Other masses Pallor, icterus Chest: Conjunctivac, Retinge Supra-Cardiac Duliness Mouth: Tongue Sternal-tenderness Gums: Hyperplasia •Lymphadenopathy : Bleeding Cervical Buccal mucosae Supraclavicular Throat: Tonsillar ++ Axillary Glands: Epitrochlear Mickulicz' Syndrome Inguinal Parotid, Lachrymal, Extremities: Submaxillary Petechiae, Ecchymoses . Abdomen: Bone Tenderness Hepatomegaly Skin: Rash Splenomegaly Hemorrhages Masses Edema . III. Laboratory Data • Blood Counts. Smcars All-Important Recognize Primitive cells And Diminished Platelets Scdimentation Rate.Serum Proteins Xrays: Mediastinum Bones Spleen Size Sone Marrow Puncture: Sternum, lliac Crest Spinous Process Trephine Biopsy: occasionally • Tissue Biopsy: Lymph Nodes Biopsy, Aspiration, imprints Skin Liver, Spleen

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·<
LEUKEMIA & LEUKOSARCOMA
CYTOLOGIC STUDIES
Minute Study of the cell has become All-Important
To reveal secrets of Cell Growth and Death
To aid in selecting specific drugs
A diagnosis of “Acute Leukemia” is not enough
Is it Myeloblastic, Lymphoblastic, Monocytic?
METHODS NOW IN GENERAL USE
I. Correlation with Clinical Features
Splenomegaly : Myeloblastic
Lymphadenopathy: Lymphoblastic
Gingival Hyperplasia: Monocytic
II Romanowsky
Stains
(e.g. Wrights )
Myeloblast Lymphoblast Monocyte
III Peroxidase
Stains
(e.g Sato-Sekiya
Myeloblast Lymphoblast Monocyte
IV Supravital
Stains
(e.g. Janus Green,
Pinacyanol )
Myeloblast Lymphoblast Monocyte
• Sometimes, these methods fail to make a definitive diagnosis
· Newer Cytologic techniques reveal Fundamental Structures.

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·NEWER AIDS IN CYTOLOGIC STUDIES PHASE MICROSCOPY Manipulation of light waves achieves contrast LEGEND Glan Disco Plane Condensers Phare retarding stenal CA Abrorbing mytenal ZBIR Annuler Diaphragma These Oil immersion objectives These + + Diffraction Plates Phase Microscopy •Can Adjust contrast by different diffraction plates 1. Bright Contrast object brighter than background 2. Dark Contrast object darker than background Great Clarity and Contrast achieved in the study of: Unstained living cells Unstained fixed cells Supravital preparations Histochemical reactions (counterstains not necessary) Unstained Cell in Smear Ordinary Microscope Unstained Cell in Smear Phase Microscope Myeloblast Lymphoblast Monocyte Myeloblast Lymphoblast Sudan Black Supravital-Pinacyanol (Phase Photomicrographs ) Phase Microscopy_often discloses materials previously invisible

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·NEWER AIDS IN CYTOLOGIC STUDIES HISTOCHEMISTRY - Study of the Chemistry of individual Cells • Histochemical studies may open up new vistas for attacking Proliferating Cells THE WHITE CELL AND SOME OF ITS CONSTITUENTS (1949) Vitamin A & Cytochrome- Nucleoprotein Oxidase Systems Ribonucleoprotein Mitochondria Cytoplasm & Nucleolus Desoxyribonucleoprotein -Alkaline Phosphatase Nucleus Cytoplasm - Nucleus Myeloid Cells and .Glycogen Lymphocyte Granulocyte Cytoplasm Acid Phosphatase Megakarjocyte Cytoplasm Platelets Mainly Nuclear Lipids - Phospholipids • Metachromasia Specific Granules (Megakarocyte Cytoplasm Mitochondria Mast Cell Granulis), Golgi Element (? Acid Mucopolysaccharide Auer Body ? Ribonucleoprotein) SUDAN BLACK 6 An Important Histochemical Tool. Defines Lipids. In dry smears defines patterns previously seen only in Supravital Preparations Reacts with specific Granules, Auer Bodies, Mitochondria, Golgi Element . 1 Leukemic Myeloblast Leukemic Lymphoblast Leukemic Monocyte

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·THE THERAPY OF LEUKEMIA & LEUKOSARCOMA
HISTORICAL
ARSENIC
First Chemotherapeutic Agent used (1865)
BENZOL
Used in early 1900's; found too toxic
X-RAYS
Became prominent after 1910; in wide use since
RADIO-ACTIVE ISOTOPES
Continued experience indicates very limited value
X RAYS AND CHEMOTHERAPY: A COMPARISON
X-rays
Chemicals
piffuse
May have specific
Non Selective
actions on specific
cell mechanisms
NITROGEN MUSTARDS
Shown to have tissue effects like X-rays (1942)
Special value in Hodgkin's Disease and Lymphosarcoma
URETHANE (1946) AND FOLIC ACID ANTAGONISTS (1948)
Show distinct promise in Leukemia
Although X-ray still the Standard R
Chemotherapy offers more for the future

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·THE "MUSTARDS" POISON GASES TO USEFUL DRUGS SULFUR MUSTARD SULFUR MUSTARD -CH2 - CH2 - CL -CH2 - CH2 - CL Sulfur Mustard Gas killed many in World War 1. The more deadly Nitrogen Mustards ready in World War II Bis (B Chloroethyl) Sulfide NITROGEN MUSTARDS NITROGEN MUSTARDS . CH2-CH2-CL CH3-N N CH2 - CH2-CL -CH2 - CH2 -CL CH2 - CH2-CL CH2-CH2-CL Methyl Bus (B Chloroethyl) Amine (HN2) Tris (B Chloroethyl) Amine (HN3) Pharmacologic studies revealed marked Leukopenic effect • Possible value in W.B.C. proliferations was suggested . Thus, a Poison "Gas." properly controlled, became a CH2-N CH2-CH2-CL -CH2-CH2-CL CH CH2-N -CH2-CH2-CL CH2-CH2-CL Llseful Drug 1,3 Propane Diamine NNNN Tetrakis 2 Chloroethyl (SK 136)

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·NITROGEN MUSTARDS PHARMACOLOGY • Nitrogen Mustards are readily soluble. Dissolved in water, rapid transformations occur, producing cytotoxic effects within few minutes TRANSFORMATIONS CH2-CH CI CH2 CH3-N + CI" CH3 CH2 CH2 CH2 C1 CH2 CH2 CI "Intramolecular Cyclization (Gilman and Philips ) Highly reactive Onium Cation and Liberation of CI CH2 CH2 OH CH3-N CH3 N CH2-CH2 OH CHE CHE GI H2O HY GHz CH2 CL CH2 CH2 OH CHEN it CH2-CH2 OH Numerous Cellular Enzyme Systems inactivated: Hexokinase, Pyrophosphatase, Diaminase, Cholinesterase, Choline Oxidase, Pyruvate, Phosphokinase, Phosphatase, Peptidase, Pyridoxine, etc. LEADING TO DEATH OF PROLIFERATING CELLS Nuclear, Mitotic, Chromosomal activities sharply affected Involution of normal Lymphoid tissue Desquamation of Intestinal Epithelium Hypoplasia of Marrow Regression of Lymphosarcoma and Leukemia in experimental animals The Mustards, altho chemicals, act much like X-rays

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·NITROGEN MUSTARDS
ADMINISTRATION
Dosage:
About 0.07-0.08 mg./kg. body weight
Course: 4-6 injections-given once daily
First Dose - 3-5 mgs.: Increase by 1 mg. daily
Course may be repeated in 8-10 weeks
Mode of Administration:
wand
1
Immediate Reactions: Nausea and vomiting in 1-2 hours
lasting 1-3 hours
Occasional chills and fever

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·NITROGEN MUSTARDS THERAPEUTIC ACTIVITY Clinical trials with HN2 and HN3 in: • Acute Leukemia: No definite effects . Chronic Leukemia: Equivocal effects Lymphosarcoma: Good effects in some • Hodgkin's Disease: Good effects frequently In Hodgkin's Disease: Most striking effects seen in advanced, generalized, X-ray refractory cases RESULTS IN 50 CONSECUTIVE SEVERE CASES SYMPTOMATIC RESPONSE OBJECTIVE RESPONSE % % % % % COMPLETE PARTIAL NO COMPLETE PARTIAL RELIEF RELIEF RELIEF RELIEF RELIEF RELIEF • Fatigue 45 42 13 Fever 47 15 38 * Anorexia 67 22 11 Weight Loss 65 32 3 Sweats 83 17 Lymphadenopathy 48 33 19 .Itching 44 44 12 Mediastinum 29 39 32 Pain 79 11 10 Splenomegaly 38 35 27 Cough 30 30 40 Hepatomegaly 32 16 Dyspnea 20 53 27 Edema 13 46 41 Hoarseness 13 87 Paralysis 44 56 Chills 83 17 . Constitutional symptoms and pain most strikingly affected About 80% of the cases showed Responses % NO * * 52 *

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·HN2 THERAPY IN HODGKIN'S DISEASE
EFFECTS ON FEVER AND LYMPHADENOPATHY
FEBRLE RESPONSE TO MNE THERAPY
KD
293 TEMPERATURE
THERAN
4.3
APRIL 194
MH
Fever usually subsides 1-4 days
after HNz completed.
Fever response may be used
as a diagnostic measure
104
TEMPERATURE
wim
NE
THERAPY
PW
TEMPERATURE
THERAPY
HING
%0
BEFORE Rx
3 WEEKS AFTER R
Mediastinal Lymphadenopathy subsides most quickly
in least fibrotic cases

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·HN2 THERAPY OF HODGKIN'S DISEASE
t
X-ray Refractory Left Supraclavicular Mass
Before and After one course of HN2 R
Terminal Xray Refractory Case with Right Thoracic Mass
Before and After one course of HN2 R
HN2 is often successful in X-ray Refractory Cases.

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·16
HN2 THERAPY IN HODGKIN'S DISEASE
Tissue Reactions: Bone Marrow Hypoplasia develops quickly
Blood shows reduction in white cells, mostly Granulocytes
o
Hemoglobin
Erythrocytes
(59% of Costs)
Percentage Decreose in Blood Count
Leucotyles
(98% of Coses)
HN2
Plotalets
(20% of Coses)
16
20
40
3
Time (Days)
Lymphoid Tissue Affected:
Liver Occasionally Involved:
Miliary Necrosis in Lymphnode Toxic Necrosis in Liver
Beware excessive dosage of HN2
Jaundice contraindicates use of HN2
*Scc Translites

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·17 HODGKIN'S DISEASE A NEOPLASM OF RETICULUM CELL ORIGIN Growth rate and course highly variable Most malignant: Many Giant Cells, little Fibrosis (Sarcoma" type) Most benign: Few Giant Cells, much Fibrosis Most cases: Giant Cells, Fibrosis, Eosinophilia These are not separate diseases, but represent variations in growth rate We do not consider Hodgkin's an Infection or a "Granuloma STAGE 1 COURSE SYMPTOMS TREATMENT Begins in one Lymph Node. a painless, non-tender lump (1) Extirpate Lymph Node Mass if possible. (2) X-ray Bc (3) HNER STAGE 2 Spreads to group of Nodes Fatigue, Fever (1) Drastic X-ray R (2) HN2 R STAGE 3 (1) HNZ R best (2) X-ray R as adjuvant Involves Central Organs: Spleen, Liver, Bones Mesentery, Spinal Cord Many Constitutional Symptoms STAGE 4 Becomes Universal Extreme Debility, Relapsing Fever, Bone Pains, Cachexia, Death (1) Try HN2 R (2) Symptomatic R Transfusions

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·18 HN2 THERAPY IN HODGKIN'S DISEASE Case Report: P.D.C. Generalized Hodgkin's (STAGE III) PDC Apr 56 -- F. E- . 08 mann TEMP N ITA AXILL MAY ADENOPAT MY MEDLASTHAL ADENOPATHY 2 -RM PERNY MEPATO- SPLENOMEGALI WEIGHT 140 MZ HO 10 ME 150 190 RBC Hgb 496.sw.com HN2 122) 9 N000 Leucocytes Granulocytes ороо epoo OC 8000 Lpoo 1,000 Lymphocytes Monocytes OCTODER 1 NOVEMBER 1 DECEMBER JANUARY FEBRUARY - DECEMBER 146 1947 Persistent fatigue, fever, weight loss, splenomegaly, despite X-ray treatment. NOTE: Striking effect of HN2 on constitutional symptoms. Gain in appetite, vitality, and weight (60 LBS.) Striking effect on Lymphadenopathy, Splenomegaly. Remission persisted 18 months HN2 most useful in generalized and refractory cases.

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·19
HN2 THERAPY IN HODGKIN'S DISEASE
Case Report: Katherine D. Severe mediastinal disease 5 years.
Progressive X-ray refractoriness.
Kommen
Ty
wo
1-42
MEDLASTIMAL
ADENOPATHY
.
M
gu vi
ANULOCYTES
LETTO
MOWOCYTES
UN
TURUARY
UUMALA
NOTE: Enhancement of X-ray effect by previous HN2 R
: Improvement lasting 4 months with combined R
HN2 enhances X-ray sensitivity; HN2 plus X-ray
prolongs remission.
HN2 (generalized effect) plus X-ray (local effect)
may be valuable in early cases

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·20 HN2 THERAPY IN HODGKINS DISEASE Case Report: B.D. Hodgkin's since 1944 - X-ray refractory 1946 HN2 induced 6 month remission; Development of back pain, January 1947 BERNARD DAR 38 NI WAS BASDAL ty LRT ORAGE NIL wird ATM NA DAT ADA Lent MOUNT wa 9WUM CERVICAL Nun ME PATO SPLENO- MEGALY TO bo LA TOTAL C 000 1 GRANULOCYTES 4000 4000 7000 YMPHOCYTES MONOCYTIS 0 JAN PEU MAA JUNE .. NOTE. lack of response of back pain to X-ray treatment Complete dynamic block of spinal fluid & extremely high proteins : Response to HNz almost incredible: Pain relief in 24 hrs. Continues (JUNE 1949) free of pain & still responsive to HNz treatment Pain due to intra-or extraspinal lesions of Hodgkin's often quickly and completely arrested. Paralysis of intraspinal involvement responds poorly unless treated carly

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·TRIS MUSTARD (HNB) THERAPY IN HODGKIN'S DISEASE Case Report: Mary S. Hodgkin's “Sarcoma" Rx with HN3. Aplastic Anemia AMAL tous OROWE * WERE ADOWY le 10 PLATELET 71 PANDUO 1900 & mottaste! E MENOMAA PETLONA, LETOSCS LEEDING ONL, METHAL MENORGE. Els Motoru Monde sroostet wees old Tues MALAYO NO Arstimazat nt mm NOTE: Marrow Aplasia: Pancytopenia Active Symptomatic Therapy: Recovery : Patient continues well: Rclapscs respond to HN2 and X-ray Tris Mustard more toxic than Bis form Hodgkin's “Sarcoma" often very sensitive to Mustard R Marrow reactions usually improve spontaneously * Sec Trosslites

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·THE EFFECT OF TRIS MUSTARD (HN3) THERAPY
ON BONE MARROW
Before Re
Eight days after Ry
Hypocellularity
20 days after R:
Marked Hypocellularity
38 days after R
Beginning Marrow Recovery
Although Nitrogen Mustards cause Marrow Hypoplasia,
no permanent Aplasia has followed our low dosage.

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·HN2 RX IN LYMPHOSARCOMA HN2 R in Lymphosarcoma may produce remarkable Remissions 21 consecutive cases of Generalized Lymphosarcoma 7 showed complete Remissions of 6 to 24 months Case Report: "Termina!"Gencralized Lymphosarcoma, X-ray Refractory Remarkable response with one course of HN2 Ferne B. Age: 49 April, 1947 History: P.E. 1945: Lumps in Axillac Weight 122 lbs. : Biopsy: Giant Follicle Lymphoma Extreme Dyspnea, Cachexia :X-ray Res almost constantly Masses of Lijmph Nodes: Neck, Feb.'47:Xray Rs of spleen, neck, ax supraclavicular, axillac, groins. illac, left cye (cxophthalmos) Splenomegaly, 3-4 f.b. Apr 47: Extremc Dyspnea Fluid Both Chests Extreme weakness 501b, weight loss Swollen Legs Lab. Data: Hab. 11.7 gms. R. 6.C. 3.95 M. Retics. 0.8% Matelets 337,000 W.B.C. 2800; P.59, L.17, M.22 Lymph Node Biopsy: Lymphoblast Sarcoma, highly malignant. Ximais chest: Fluid bilaterally; Mediastinum +++ Coursc HNZ Ry, 22 mgs. (4 injs.) Apr. 13-17, 47) Apr. 25: No Lymphadenopathy Spleen 17.6. Scpt. 16: No symptoms; weight 1281b5 Spleen not felt P.E.ncgative Nov. 17: Weight 134 ibs. Jan.14: Goes to gym; plays badminton Apr. 6: Weight 143 lbs. Looks 20 yrs. younger Jan 49: Continued cxccllent health .

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·SK-136': ANOTHER MUSTARD SK 136 is one of a large group of Mustards tried clinically No particular value in Hodgkin's disease Slight value in Chronic Myelocytic Leukemia Some value in Acute Monocytic Leukemia MILDRED BY AGE 61- ACUTE MONOCYTIC LEUKEMIA 10 TOLEN MUSTARD-113 lo 62 tit 77 000 52 000 - 10000 1800 .67,000 Metylen) BO000 WBC S. Monocytes 40,000 39000 20,000 Acute Monocytic Leukemia Definite Remissions Induced 10000 PLATELETS 300,000 400 000 300000 200,000 UN 100,000 0 DAYS OF OBSERVATION O 50 100 150 PA Blood Smear Before SK 136 Blood Smear During Kemission Other types of Acute Leukemia (10 CASES) not affected by SK-136 Other Mustards may prove of specific valuc for specific cells

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·THE NITROGEN MUSTARDS
CONCLUSIONS
In Hodgkin's Disease HN2 is indispensable:
In generalized, X-ray Refractory cases
To relieve pain and constitutional symptoms
In conjunction with X-ray, may prove valuable in carly cases
Many "Terminal" cases salvaged for 6-36 months
In Lymphosarcoma and Reticulum Cell Sarcoma
HNz worth a trial, especially in generalized cases
A few injections may cause a startling Remission
In Acute Leukemia
"SK -136" may be of temporary benefit in monocytic type
Used with Care and Discretion
the Mustards are Useful Drugs

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·THE NITROGEN MUSTARDS
CONCLUSIONS
In Hodgkin's Disease HN2 is indispensable:
In generalized, X-ray Refractory cases
To relieve pain and constitutional symptoms
In conjunction with X-ray, may prove valuable in early cases
Many "Terminal" cases salvaged for 6-36 months
In Lymphosarcoma and Reticulum Cell Sarcoma
HN2 worth a trial, especially in generalized cases
A few injections may cause a startling Remission
In Acute Leukemia
"SK-136” may be of temporary benefit in monocytic type
Used with Care and Discretion
the Mustards are useful Drugs

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·FOLIC ACID PTEROYL GLUTAMIC ACID PGA A POTENT GROWTH FACTOR CH2 COOH OM CH2 CH-NH NH CH NH COOH N PTERIDINE RING P-AMINOBENZOIC ACID GLUTAMIC ACID Originally found in liver Extract Residucs: A fraction of B complex Folic Acid Synthesized 1945 Conjugates (E.G. TRIGLUTAMIDE ) formed by adding extra Glutamic Acids • Necessary for Bacterial Growth (L. Casei Factor Strep. Fecalis R Factor). Important in Animal Nutrition • Important in White Cell • Enhance Growth of Growth Certain Neoplasms CONJUGATES • Inhibit Growth of Certain Neoplasms (Triglutamide -Teropterin ) Deficiency Leukopenia PGA or . High Content in Primitive White Cells Red Cell Growth Factor (Bethell) Deficiency.Megaloblastic Marrow (cf. P.A., Sprue, etc.) Knowledge of these cffects led to Synthesis of PGA Antagonists

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·LU
FOLIC ACID ANTAGONISTS
POTENT GROWTH INHIBITORS
Certain alterations of PGA Molecule create powerful Antagonists to PGA
OH
NH)
PGA (Folic Acid )
GROWTH FACTOR
PGA Antagonist (Aminopterin)
GROWTH INHIBITOR
NUMEROUS ANTAGONISTS HAVE BEEN SYNTHESIZED
| TMI
FITI WYS MWEMA
CO
XVII 121
• Inhibit growth of bacteria
• Prevent normal growth in animals
Chick Pig Rat
Dog Mouse
• Inhibit normal Marrow growth:
Leukopenia, Anemia, Thrombopenia
. Inhibit growth of Rous Chick Sarcoma
Act on other Tumors
Carcinolytic activity
Act on Animal Leukemia
and Loukosarcoma
LISTWY.

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·-
FOLIC ACID ANTAGONISTS
Exact Mode of Action Uncertain
ONE POSSIBILITY
Anti-PGA resembles PGA so closely that it is readily accepted by cell,
but cannot be utilized
Result: Cell Death
NH2
ENZYMES
+
Anti PGA
In the human body the Folic Acid Antagonists affect numcrous tissues
HAIR
Alopecia
BONE MARROW
Hypoplasia
MUCOUS MEMBRANES
Glossitis
FOLIC
Stomatitis
ACID
Gastro-enteritis
ANTAGONIST
CAPILLARIES
Vascular Purpura
Hemorrhages
LEUKOCYTES OF
LEUKEMIA-LEUKOSARCOMA
-Cell Death
Clinical Trials indicated its use in Acute Leukemia

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·30 FOLIC ACID ANTAGONISTS PATTERN OF THERAPY IN ACUTE LEUKEMIA I. Give Drug $ methy 45 caz. $ SUITITOR NIZ y fut weinte VIVO # 1 we Ney RAMSA W 1. rhin wow how > WORTIF SE LA ws . K... er Neve RUV ra RS www. Cow w AMINOPTERIN A-NINOPTERIN A METHOPTERIN AMINO-AN-FOL 1-4 MGS 5-15 MGS 2-5 MGS 25-75 MGS Dose varies with Drug, Age, W.B.C. Oral Medication as effective as Parenteral IL Watch for reactions and marked drop in W.B.C. Anorexia, Sorc Mouth, Nausca, Diarrhea, Abdominal Discomfort, Mucous Membrane Lesions, Hemorrhagic Rash IL Stop Drug at first sign of reaction V as indicated V. Watch for Remission Rise in Platelets particularly, fall in W.B.C. and 'blasts VI. Give Maintenance Therapy, usually oral Aminopterin 1/4 to 1 mg. daily; A-ninopterin 5mgs.daily Adjust dosage according to further reactions or relapses

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·31 FOLIC ACID ANTAGONISTS CLINICAL EFFECTS IN ACUTE LEUKEMIA 1. Reaction [L. Remission (Occurs in one-third of the cases ) Subjective Objective Appetite Fever Weight 1 Activity Lymph Nodes Splenomegaly I Well Being 1 General Appearance 1 Irritability! Hemorrhagic Phenomenat WEEKS 2 3 4 WBC 250,000 90% BLASTS PLTS 600,000 MARROW HYPOPLASIA MARROW MEGAS PANCYTOPENJA APPEAR BLASTS STILL PRESENT PLATELETS INCREASE RETICULOCYTES INCREASE R.B C. 4.0M WHITE COUNT NORMAL BLASTS DISAPPEAR RBC. 15 m NOW WBC. 6000 NO BLASTS PLTS 20,000 DRUG MAINTENANCE REACTION REMISSION TRANSFUSIONS & PENICILLIN WEEKS 1 2 3 Remission continucs with maintenance thompy 1 to 12 mos. III. Rclapses occur. More Drug: More hcmission IV. Finally: Relapses + Incrcasing Toxicity - Death

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·FOLIC ACID ANTAGONISTS CLINICAL EFFECTS IN ACUTE LEUKEMIA 1. Reaction II. Remission (Occurs in one-third of the cases) Subjective Objective Appetite Fever 1 Weight Activity t Lymph Nodes I Splenomegaly Well Being 1 General Appearance 1 Irritability! Hemorrhagic Phenomena! 1 WEEKS 2 3 WBC 250,000 90 % BLASTS PLTS 600,000 MARROW HYPOPLASIA MARROW MEGAS PANCYTOPENIA APPEAR BLASTS STILL PRESENT PLATELETS INCREASE RETICULOCYTES INCREASE hE.C 401 WHITE COUNT NORMAL BLASTS DISAPPEAR RBC 15 M PLTS 20,000 DRUG REACTION REMISSION TRANSFUSIONS & PENICILLIN WEEKS 1 2 3 Remission continues with maintenance therapy 1:20 III. Rclapses occur. Morc Drug: More Remission IV. Finally: Relapses + Incrcasing Toxicity - Deco

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·FOLIC ACID ANTAGONISTS
R OF ACUTE LEUKEMIA
REACTIONS
*
Redness and ulceration of Buccal Mucosae
Palatal Lesions
· Lesions also occur in lower gastro-intestinal tract

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·FOLIC ACID ANTAGONISTS
R OF ACUTE LEUKEMIA
REACTIONS
Vascular Purpura: Aggravated by Thrombocytopenia
Alopecia develops slowly
Brown Pigmentation of Skin also occurs

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·FOLIC ACID ANTAGONISTS: R OF ACUTE LEUKEMIA Case Report: Joseph C. 3/2 yrs. Subacute (Aleukemic) Lymphocytic Leukemia . HD HA 10 10 30 101 . 30 000 D- 20.000 10 000 PUTELITI 600 000 soopoo 400,000 300, pod 200 DOO 109,000 DAYS OF OLUTION 100 150 too DO 200 DID Red Note: 2 separate Remissions induced Remission heralded by: Platelet increase :Megas. in marrow Patient lived 8/2 months Death due to: Increasing Leukemia Increasing Toxicity . At end of first Remission

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·FOLIC ACID ANTAGONISTS:
R OF ACUTE LELIKEMIA
• RESPONSE ON PART OF MARROW:
Case J.C. (CONTINUED )
Before Aminoptcrin:
All Lymphoblasts
Beginning Remission:
Megakaryocytes
Beginning Remission:
Normal Marrow
Cells;
Lymphoblasts
Full remission but few
Lymphoblasts persist

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·FOLIC ACID ANTAGONISTS: R OF ACUTE LEUKEMIA Case Report: Katherine B. Age 29. Subacute Lymphocytic Leukemia . PAMA IA 11 10 .. AIC 40 10 ID tapoor 15.000 10,000 ADOO PLATTUN Voopoo poopoo soooo soopoo 400poa ht zoboo OF DONATION O 100 ba DO UNO Note: Severe reaction before remission Platelet increase beginning remission Complete Marrow & Blood remission Development of Torula Meningitis Death in 6 months Death due to Meningitis +Leukemia At end of first remission

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·FOLIC ACID ANTAGONISTS: R OF ACUTE LEUKEMIA Case Report: Edgar W. Age 42. Subacute Lymphocytic leukemia . 10 Complete Remission for several months KO poo F Mpoo pool spoo Nacios LATTLLTS hoopoor ogpool popoo C00000 Ons Montematon 140 log Note: Disabling bonc pain completely relieved Drug itactions: Right lower quadrant abdominal pain. Marked Alopccia. Macrocytosis of Red Cells. Death in 9/2 months Death duc to: Increasing Leukemia : Incrcasing Toxicity During Remission

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·FOLIC ACID ANTAGONISTS R OF "MYELOBLAST CRISIS" Case Rcport: Julia S. Chronic Myelocytic Leukemia: Rx for 5 years with X-rays and Urethane. Sudden onset of acute symptoms. Reversion of Blood Picture from "Chronic" to "Acute" type. OPTE APTER TWW ht 1 room YTLARLAST +700(MILAN . Remission induced with Folic Acid Antagonist Rx 39000 WC Myeloblants 40poo 30.000 20,000 10,000 0 . Patient lived 4 months (Usual life span in crisis: 1-2 wecks) PLATELETS 300.poo 400000 300000 Roopoo A 1oQ000 O DAYS OF OO SCAVATION SO 50 10 LIO DIEO 3/13A! Chronic Myclocytic Leukemia Acute 'Blast Crisis (Nov. 22,1948) kcmission after Aminopterin (January 13, 1949)

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·ACUTE AND SUBACUTE LEUKEMIA Occur at any age: Most common form of Cancer in Children Generalized, rapidly progressivc, highly invasive processes Like Weeds in a garden, destroy Normal Marrow Cells Rapidly Progressive Anemia, Granulocytopenia and Thrombocytopenia Symptoms those of Anemia, Infection, Bleeding and Invasion of Bonc Course 2 wks. to 6 mos; Spontaneous Remissions rare TREATMENT Xrays, Radio-active Phosphorous, Arsenic, Benzol of no value, in fact often harmful. Transfusions add Red Cells and a few Platelets, help temporarily. Exsanguino-Transfusions (BESSIS,(PARIS)) may induce Remissions. Folic Acid Antagonists the first substances producing Remissions consistently · Acute Leukemia offers a readily available source of Primitive Neoplastic Cells for various experimental and Therapeutic Studies.

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·FOLIC ACID ANTAGONIST THERAPY
OF ACUTE LEUKEMIA
SUMMARY AND CONCLUSIONS
1.) 40 cases treated, 34 adults, 6 children
2) 8 cases died within 1 wk., excluded from evaluation
3.) Remissions in ten (31%) of 32 evaluated cases:
a. Subjective improvement
b. Objective improvement
C. Rise in Platelets to Normal or Ncar Normal
d Fall in White Count to Normal or Near Normal
e Disappearance of 'blasts from blood
Maintenance for at least 2 months
4.) Results: Best in Lymphoblastic type, worst in Monocytic
CASES REMISSIONS
Lymphoblastic 14
6
Myeloblastic 11
3
Monocytic 4
0
Unclassified 3
Remissions occur in adults as well as in children
5.) 4, Amino - PGA (Aminopterin) the "Standard "drug
A-ninopterin less toxic, almost as effective
6) These drugs do not cure
That they even produce Remissions is remarkable
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·URETHANE
A Llrea product: Ethyl Ester of Carbamic Acid
NH2-CO-OC2H5
Originally used in Anesthesia and Surgery
Mild Anti-Carcinogenic effect noted
Diminished Mitotic Activity of Lcukocytes
Development of Leukopenia
Use in Leukemia suggested
Striking cffccts noted in Chronic Myclocytic Leukemia
Given orally: 1-3 gms, daily
Coated tablets, in syrup
Rectal and Intravenous routes used at times
Chicf Toxic effects: Anorexia and Indigestion
Chief Lises: in Chronic Myclocytic Leukemia
In Multiplc Mycloma

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·4. URETHANE R OF CHRONIC MYELOCYTIC LEUKEMIA Casc Reports: JANE W AGE 57 --CHRONIC MYELOCYTIC LEUKEMIA SPLEEN TA M V3 sh WBC 60,000 40,000 20,000 Early Mild Case Urethane the sole Rusco Almost completc Remissio Splenomegaly persists DETTANTUL COUNT TUT MEUYNOU 100% BO 60 40 20 WETMtott WELCTIUS URETHANE 1947 1948 MURRAY L AGE 22 - CHRONIC MYELOCYTIC LEUKEMIA SPLEEN M Vw yo 10000 000 WAC 60,000 40,000 W Urethanc: Slight response X-ray By: Partial Acmission Urethanc then produced almost total Remission, now 20 months 20.000 DAETL 100% COURT GO MATURE 60 hu 40 wowy LOCT 20 13 1 48

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·43 URETHANE Rx OF CHRONIC MYELOCYTIC LEUKEMIA Casc hcports: JANE W AGE 57 - CHRONIC MYELOGYTIG LEUKEMIA - SPLEEN W IM VIA 30 os WBG 60 000 40,000 Early Mild Case Urethane the sole Rc uscd Almost complete Remission Splcnomcgaly persists 20,000 OTTIMEWTWE COUNT NUTOS 100% 80 60 40 20 WDCYTES MULOCYTUS URETHAN 2 1947 1948 MURRAY L AGE 22 - CHRONIC MYELOCYTIC LEUKEMIA SPLEEN M W VO WAT 0000 JOCKOO 60.000 40,000 Urethanc: Slight response Xray B: Partial Remission Urethanc then produced almost total Remission, 110w 20 months 29,000 DITET OOX LOVAT DO MTU 60 MUS 30 wher WAST 20 witang Jun 2 1- 1947 1940 2 f

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·46
URETHANE
R IN CHRONIC MYELOCYTIC LEUKEMIA
20 Consecutive Cases treated 6-24 months
Dosage: 1-3 gms daily, given regularly
: "Enscal" coated tablets (0.3 gm.cach) T.I.D. P.C.
: Usually given at end of X-ray induced Remission
when W.B.C. beginning to risc
Rcactions: Gastro-intestinal: 12 cases
Anorexia, Nausea, vomiting, Epigastric distress, "Gas"
General: Weakness, 5 cascs
Neurological: 3 cases
(1) Symptoms of increased Intracranial Pressure, Papilledemo
(2) Blurring of vision, Secondary Optic Atrophy
(3) Paralyses, involvement of Pons
Blood: Thrombocytopenia: 4 cases
Purpura - case
Bleeding from Peptic Ulcer - I case
Results:
Remissions well maintained for 3-18 months, if drug tolerated
General health good: Patients ambulatory
Splenomcgaly: Slight to moderate reduction
blood: W.B.C. 5000 - 20,000
Myclocytos greatly reduced
Basophiles clevated
R.B.C. unchanged
Comments: Drug acts as a “brakc" to Granulocytic Hyperplasia
Valuable in maintaining & prolonging Xray induced Remission
Dosage adjusted casily

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·URETHANE R OF MULTIPLE MYELOMA Case Report: Edith P. Severe bone pains. Numcrous Spontaneous Fractures Urethane R. 2-3 gms daily P.O. begun Nov. 27, 1948 BLOOD - ROULEAUX MARROW. PLASMA CELLS +++ ALOOD NO ROULEAUX ALARROW. ALMOST NOLA LAL 0 9.5 gms 7.5 gms TNov. 25,1948) Sedimentation Rate 135 mms/hr Total protein Alb. 4.3 Glob, 5.2 •Blood Counts: HGB. 10.5 gms R.B C. 4.15 M W.B.C. 5200 (Apr. 7,1949) Sedimentation Rate 55 mms/hr Total protein Alb. 4.0 Glob. 3.5 Blood Counts: HGB. 11.O.gms. R.BC. 3.50 M W.BC. 3900 X-ray Claviclc (Jan 5,1949) X-ray Clavicic (Apr. 7, 1949)

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·49 URETHANE THERAPY OF MULTIPLE MYELOMA BEFORER 6 Blood - Morrow Rouleaux Formation Extensive Replacement by Plasmocytic Myeloma Cells AFTER R . Blood - Marrow- No Rouleaux Formation Rclativc Hypocellularity, great reduction in Plasmocytes Urcthane rcduccs Plasmocytic Proliferation in Marrow, may slow progression of discase.

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·URETHANE THERAPY OF MULTIPLE MYELOMA BEFORE R Blood - Marrow houleaux Formation Extensive Replacement by Plasmocytic Mycloma Cells AFTER R wap Blood - Marrow- No Rouleaux Formation hclative Hypoccllularity, great reduction in Plasmocytes Urethane reduces Plasmocytic Proliferation in Marrow, may slow progression of discase.

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·URETHANE THERAPY
CONCLUSIONS
1.) No value in Acute Lcukemia and Lcukosarcoma
2) Far inferior to X-ray R in Chronic Lymphocytic lcukemia
3.) Great value in Chronic Myelocytic Leukemia
In mild cases may be used as sole Re
In severe cases, often prolongs X-ray induced
remission 3-18 months
Remission may be complete
W.B.C. levels at 5000 - 10,000
Early Granulocytes diminish or disappear
4) Easy to Administer
Control by Internist. No special apparatus
Discontinuance of drug stops reactions
5) Definite value in Multiplc Myeloma
Relief of Bone Pain; Bone Healing
Changc in Marrow Picture
Reduction in Abnormal Plasma Proteins
6) Disadvantages:
Somc patients develop marked Anorexia & Indigestion
Drug discontinued, W.6.C. rises quickly
Splenomegaly only slightly affected
Not a cure

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·URETHANE THERAPY
CONCLUSIONS
1.) No value in Acute Leukemia and Lcukosarcoma
2) Far inferior to X-ray Re in Chronic Lymphocytic leukemia
3.) Great value in Chronic Myelocytic Leukemia
In mild cases may be used as sole Re
In scvere cases, often prolongs X-ray induced
remission 3-18 months
Remission may be complete
W.B.C. levels at 5000 - 10,000
Early Granulocytes diminish or disappear
Easy to Administer
Control by Internist. No special apparatus
Discontinuance of drug stops reactions
5) Definite value in Multiple Mycloma
Relief of Bone Pain; Bone Healing
Changc in Marrow Picture
Reduction in Abnormal Plasma Proteins
6) Disadvantages:
Some patients develop marked Anorexia 4 Indigestion
Drug discontinued, W.6.C. rises quickly
Splenomegaly only slightly affected
Not a cure

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·51
THE R OF LEUKEMIA AND LEUKOSARCOMA
BEST AVAILABLE THERAPY (1949)
LEUKEMIA
• Acute Myelocytic Folic Acid Antagonists
Lymphocytic Folic Acid Antagonists
Monocytic A Nitrogen Mustard (SK 136)
plus Transfusions; Antibiotics
Chronic Myclocytic X-rays; Rap; Llrethane
Lymphocytic X-rays
Monocytic HN2; X-ray
Plasmacytic Urethane; Stilbamidine
(Multiple Myeloma) Rap may be tricd
•
LEUKOSARCOMA
Lymphosarcoma Extirpation, if possible
X-rays; HN2, especially if gencralized
Aminopterin, in special cascs, with
high degree of cell primitivity
Rcticulum Cell Sarcoma X-rays; HN2
Hodgkin's Discasc Extirpation, if possiblc
X-rays and HN2, carly cases
HN2, cspccially if generalized
Plasmacytoma X-rays; Urethanc
(Local Mycloma)
These "Irreversible" Proliferations demand use of all
known methods. Each casc must be Individualized.

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·52 X-RAY THERAPY VS. CHEMOTHERAPY X-RAY THERAPY ADVANTAGES DISADVANTAGES Tricd and Truc Non-specific Induccs Full Rcmissions Affects all cells alike in carly cascs of Requires Special Expensive Chronic Leukemia Apparatus Hodgkin's Discase Rcquires Additional Specialist Lymphosarcoma (Radiologist) Leads to Divided Responsibility (Internist Loses Control) No Valuc in Acute Leukemia Little Valuc in Generalized Hodgkins & Lymphosarcomatosis ADVANTAGES CHEMOTHERAPY DISADVANTAGES Affects all parts of body at once Little valuc in: (HN2 intravenously) Chronic Lymphocytic leukemia Rcquircs no special apparatus Solitary Masses of Leukemic May attack Calls not affected by Xrays or Sarcomatous Nodes Farticularly Valuable in Marked Splenomegaly of Gencralized Discasc Chronic Myclocytic leukemia Hodgkin's Lymphosarcoma Acute Leukemia Has many possibilities i.c. Specific Chemicals for Specific Cells CONCLUSIONS X-rays and Chemotherapy cach have a job to do. Both are disappointing sincc ncither curcs. Chemotherapy holds most promise for the future

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·53
CHEMOTHERAPY OF
LEUKEMIA AND LEUKOSARCOMA
GENERAL SUMMARY
Chemotherapy prolongs life:
In Hodgkin's disease (HN2)
in Lymphosarcoma (HN2)
In Acute Leukemia (Aminoptcrin)
This is a start in the fe of these "Irreversible" Proliferations
Certain degrec of specificity is observed
HN2: Hodgkin's discase, Lymphosarcoma
Urethanc: Chronic Myclocytic Lcukemia, Mycloma
Aminopterin: Acute Lymphocytic leukemia
Studies of cell reactions in Leukemia-Leukosarcoma
contribuite to Cancer studies in gc11cm!
Chemothcrapy: Morc a future hope than a present-day cure
Ultimate control of Leukemia-Leukosarcoma will come
through integrated cfforts of thc purc Chemist, thc Enzymologist,
thc Morphologist and the Clinician.
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·BIBLIOGRAPHY 1. INTRODUCTORY Sacks, M.S. & Seeman, I.: (Incidence of Leukemia) BLOOD 2:1, 1947 Rheingold, J.J. & Wislocki, G.: (Histochemical Methods) BLOOD 3:641, 1948 Jones, O.P. (Phase Microscopy) J. Lab. and Clin. Mcd. 32:700, 1947 Forkner, C.E.: Leukemia & Allied Disorders, MacMillan 1938 (Early Chemotherapy) Dameshck, W.: Chemotherapy of "Lymphoma" and Leukemia. Bull. N.E.M. Center 11:49, 1949 II. NITROGEN MUSTARD Gilman, A. & Philips, E.S. (Pharmacology) Science, 103:409, 1946 Goodman, L.S, Wintrobc, M M., Dameshek,w., Goodman, M.J., Gilman, A., & McLennan, M.T. (Clinical) J.A.M.A.132:126, 1946 Damcshek, W., Weisfusc, L., & Stein, T. (Clinical) Blood 4:339, 1949 IIT. FOLIC ACID ANTAGONISTS Angier, R.B., Subbarow, Y. ct al (Chemistry) Science 103:667,1946 Smith, J.M.,Jr. ct al (Chemistry) Tr. N.Y. Acad. Sci. 10:82, 1948 Farber, S. ct al (Clinical) N.E.J. Med. 238:787, 1948 Farber, S. (Clinical) blood 4:160, 1949 Damcshck, W. (Clinical) Blood 4:169, 1949 IV. URETHANE Haddow, A., Scxton, W.A.(Pharmacology) Naturc 157:500,1946 Paterson, ct al (Climcal, Leukemia) Lancet 1:677,682,1946 Haddow, A. & Paterson, E. (Clinical, Leukemia) JA.M.A. 136:643, 1948 Creskoff, A.J ct al (Clinical, Leukemia ) blood 3:896, 1948 Snappcr, l.: (Stılbanidinc) J.A.M.A. 133:263, 1946 Loge, & fundics, Waync: (Multiplc Myeloma) Blood:4:201,1949

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